Cursurinp Final

DEZVOLTAREA PSIHOMOTORIE
ȘI
EXAMINAREA NEUROLOGICĂ
LA SUGAR ŞI COPILUL MIC
Catrinel Iliescu
Clinica Neurologie Pediatrică

Spitalul Clinic “Prof. Dr. Alex. Obregia”
UMFCD
Bucureşti
1
OBIECTIVELE CURSULUI
ÎNSUŞIREA NOŢIUNILOR NECESARE:
 evaluării NN la ieşirea din maternitate
 urmăririi periodice a dezvoltării neuro-motorii şi

psihice a sugarului şi copilului mic,
 depistarea sugarilor sau copiilor cu posibile tulburări

neurologice
 îndrumare către serviciile de specialitate, pentru

diagnostic precis şi tratament
2
EXAMENUL NEUROLOGIC
 Aceleași obiective cu examenul neurologic al adultului
 Metodele pot fi diferite – depind de vârstă și de

nivelul dezvoltării (nou-născut, sugar, copil mic)
 >= 3 ani vârstă a dezvoltării – “clasic”:
3
4
5
6
 Structura cursului
 Dezvoltarea motorie (DM)

 Motricitatea generală
 Motricitatea fină - prehensiunea voluntară
 Dezvoltarea psihică (DP)

A. Percepţiile
B. Înţelegerea generală, jocul
C. Limbaj
D. Abilităţi de autoservire
7
 Probleme care pot influenţa evaluarea

corectă:
1. Cabinetul, instrumente
2. Copilul
3. Medicul
4. Relaţia medic-mamă
8
DEZVOLTAREA PSIHO-MOTORIE


A. Percepţiile
C. Limbaj
9
DEZVOLTAREA MOTORIE (DM)
 DM – evoluţie cefalo-caudală şi proximo-

distală
- Controlul capului: 0 - 4 luni
- Controlul mâinilor: 4 - 10 luni
- Controlul poziţiei şezânde: 6 - 10 luni
- Controlul mersului: 12 - 16 luni
SE ACHIZIŢIONEAZĂ PIERZÂND REFLEXELE

ARHAICE ANTERIOARE!
10
 REFLEXELE ARHAICE
developmental reflexes - YouTube [360p].mp4
https://youtu.be/JQQ4RnP_X4E
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1. Reflexul Moro (<L6)
2. Reflexul de supt (<L12)/fixare pentru supt (<L3)/punctelor cardinale (<L3)
3. Reflexul mersului automat (<L2)
4. Reflexele tonice ale gâtului (<L6, intensitate maximă la 2 luni)
5. Reflexul de sprijin şi de depăşire a obstacolului (<L4)
6. Grasping palmar (<L4)
7. Grasping plantar (<L9)
8. Reflexul Galant (< L9)
9. Reflexul Landau (L6 – L24)
10. Reflexul paraşutei (>L7- L8)
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REFLEXUL MORO
 Răspuns normal
14
REFLEXUL MERSULUI AUTOMAT
PREMATUR
15
RĂSPUNSUL TONIC ASIMETRIC AL
GÂTULUI
 Răspuns normal (<L3)

 Membrele de partea feţei în extensie
 Membrele de partea occiputului în flexie
16
DEZVOLTAREA MOTRICITĂȚII
GENERALE
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MOTRICITATEA GENERALĂ (MG)
Evaluare
 Decubitul dorsal
 Reacţia la tracţiune (DD  şezut)
 Suspendarea verticală
 Suspendarea ventrală
 Decubitul ventral
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NOU - NĂSCUTUL
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MG _ nou-născut la termen – sinteză
I. Decubit dorsal:
 Tripla flexie a membrelor, pumnii strânşi, policele în opoziţie, capul pe o parte
 Mişcări involuntare globale, arhaice, accentuate de plâns
 R. Moro, grasping plantar, r. punctelor cardinale, r. de supt
II. Reacţia la tracţiune

 Capul în urma trunchiului, la verticală cade spre anterior, apoi poate exista o
redresare a poziţiei
 Grasping-ul palmar
III. Suspendarea verticală

 Tripla flexie
 R. mersului automat, r. de sprijin
şi de depăşire a obstacolului
IV. Suspendarea ventrală

 Hipotonie axială (capul sub axul trunchiului)
 R. Galant
V. Decubit ventral
 Tripla flexie, pelvisul ridicat, capul pe o parte
20
SUGARUL MIC
21
MOTRICITATEA GENERALĂ
sugar
I. Decubit dorsal
 Hipertonia scade, membrele se extind
 Deschiderea pumnului
 Capul pe linie mediană (3L), ridicarea acestuia de la

nivelul patului (6L)
 Mâinile pe linia mediană (4L)
 Se întoarce de pe burtă pe spate sau de pe spate pe

burtă (până la 6L una dintre mişcări)
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sugar
II. Reacţia la tracţiune (DD  şezut)
- 1L -3L capul este balant,
- 3L-6L capul este în acelaşi plan cu corpul,

după 6 luni poziţia este activă, cu capul
înaintea corpului şi flectarea mb. sup.
- 6L - stă singur în şezut cu sprijin pe

coapse
- 7L-8L - stă în şezut fără sprijin
- 9L-10L – (se ridică din DD în şezut), se

răsuceşte după jucării
23
sugar
III. Suspendarea verticală
-3L – sugarul poate să preia o parte
din greutate
- 6L – încearcă să păşească
- 7L-8L – îşi susţine greutatea dacă

este ţinut de mâini
- 9L – se ridică la marginea patului
- 10L– 11L– merge pe lângă mobilă sau

cu sprijin bilateral
- 11L– 12L – merge cu sprijin unilateral
- 12L– 13L– merge singur

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sugar
IV. Suspendarea ventrală

- 6 săptămâni – capul în acelaşi plan
cu corpul
- 2L – capul deasupra planului

corpului
- 7L-9L – reflexul paraşutei
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sugar
V. Decubitul ventral
1L – îşi ridică capul de la planul

patului
3L – capul ridicat, sprijin pe

antebraţe
5L-6L – capul şi trunchiul

ridicate, sprijin pe mâini
5L-7L – se răsuceşte de pe burtă

pe spate şi invers
8L-9L – merge de-a buşilea

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A. Percepţiile
C. Limbaj
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DEZVOLTAREA MOTORIE FINĂ
prehensiunea
 Depinde de dispariţia grasping-ului
palmar
 Pensa cubito-palmară (L4-L5) /

BILATERAL
 Pensa digito-palmară (pensa

palmară simplă) şi transferul
jucăriilor (L6)
 Pensa radio-palmară (L7-L8)
 Pensa digito-digitală (bidigitală)

(L9)
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MOTRICITATEA FINĂ
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A. Percepţiile
C. Limbaj
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DEZVOLTAREA PSIHICĂ (DP)
sugar
A. PERCEPŢII
 vederea
 de la naştere
 L1- fixează
 L2 – urmăreşte obiectele orizontal şi vertical
 L3 – urmăreşte obiectele circular
 auzul
 > 2 săptămâni
 olfactiv
 de la naştere, foarte intens
5L 7L 91/2 L
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sugar
B. ÎNŢELEGEREA GENERALĂ, JOCUL
- 1L – zâmbeşte fără încărcătură emoţională
- 2L ( > 6 săptămâni) – zâmbetul social
- 3L-4L – râde în hohote
- 7L – recunoaşte mimică veselă / tristă
- 8L – angoasa de a nu fi lăsat singur
- 8L-10L – aruncă jucăria şi se uită după ea, înţelege nu, se

joacă cucu-bau, bravo
- 9L - întoarce capul când e strigat pe nume 32

sugar
C. LIMBAJUL
- 3L – gângureşte
- 4L-5L – imită vocalele interlocutorului, tace când

interlocutorul vocalizează
- 6L-8L – lalalizează
- 11L-12L – poate arăta becul la cerere, de exemplu
- 12L – primele cuvinte cu sens

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sugar
D. ABILITĂŢILE DE AUTOSERVIRE
- L6 – poate bea din cană, poate mânca din biscuit
- L10-L11 - ajută la îmbrăcat
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DEZVOLTAREA – sugarul mare
35
36
37
COPILUL MIC
1 – 3 ani
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Copilul mic (1 – 3 ani)
A. MOTRICITATEA
 2a - aleargă
- 3a - merge pe vârfuri/cu tricicleta, urcă scările

alternând picioarele
B. MANUALITATEA
 18L - introduce şi scoate bile dintr-un borcan
- 16-18L - mâzgăleşte cu creionul
- 2a6l - desenează spirale şi linii
- 3a - desenează cercul şi crucea după model

39
A. ÎNŢELEGEREA GENERALĂ, JOCUL, LIMBAJUL RECEPTIV
 12L- 13 L – face pa, execută o comandă simplă (dă-mi)
 16L-24L – ştie părţile corpului, imită şi recunoaşte

animalele, ştie cine e mama, cine e tata
 18L-20L – pune formele
 24L – poate începe să recunoască culorile, înţelege comenzi

mai complexe, construieşte turnuri din cuburi
 3 ani – ştie sexul / numele / mare-mic / zi-noapte / număr

(unu sau mai mult)
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B. LIMBAJUL EXPRESIV – de știut orientativ!
 fonetic: dislalie fiziologică
 vocabular: 1 an (3-5 cuv), 1a6l (15-20 cuv), 2a (300 cuv), 3a

(1000 cuv)
 morfologic: 1a (subst, interjectii, onomatopee), 2a (verbe,

pronume personal pers a III-a), 3a (pers I a)
 sintactic: 1a-1a6l (cuvânt propozitie); 1a6l-2a (2

substantive); >2a apare predicatul (intâi pers a II-a, apoi a
III-a, apoi a I-a);
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C. ABILITĂŢILE DE AUTOSERVIRE
 1an3luni - scoate pantofii, şosetele
 2ani - scoate şi pune pantofii, şosetele, pantalonii
 3ani - se descurcă cu cei mai mulţi dintre nasturi
 controlul voluntar sfincterian > 15-18 luni
 2ani-2ani6luni – se descurcă la toaletă, mici accidente
 2ani – 50% dintre copii au control pe parcursul nopţii dacă

merg la toaletă înainte de culcare
42
COEFICIENTUL DE DEZVOLTARE
= v. dezvoltării (motorie, psihică) / v. cronologică

X 100
- QD > 85 – normal
- QD < 70 – anormal
- QD între 70 – 85 – de limită
- La prematuri: v corectată (în fc de DPN)

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COMPORTAMENTE PATOLOGICE
MOTORII
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MOTORII
45
Sugar sex F, 9 luni – evaluarea dezvoltarii
46
47
MOTORII
- asimetrice
- absente la nou-născut / sugar mic
- exagerate la nou-născut
- persistente la sugarul mare

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MOTORII
 Hipotonia capului la tracţiune >= 4L
 Lateralizare precoce (< 1 an); apucă

jucăriile cu o singură mână sau nu apucă
deloc la 6L, r paraşutei asimetrică la
7-9L
 Posturi particulare la suspendarea

verticală
 Lipsa mersului independent la 16 – 18

49
luni
PSIHICE, INCLUSIV DE PERCEPŢIE
 Nu fixează, nu urmăreşte la 2L,
 Nu zîmbeşte la 2L, nu râde în hohote la 4L,
 Nu întoarce capul la strigarea numelui la 9 – 10 luni,
 Nu are schema obiectului permanent la 12L,
 Nu imită activităţile, nu potriveşte formele la 18-24L,
 Nu înţelege comenzile, nu recunoaşte animalele în poze,

nu arată părţile corpului până la 18 – 24L
 Nu spune cuvinte bisilabice (până la 18 luni), şi nu le

asociază (până la 2 ani) 50
POSIBILITĂŢI DE DEZVOLTARE
PARTICULARĂ
 Tulburare a dezvoltării legată de anomalii de percepţie (văz,
auz)
 Dezvoltare în limitele mai largi ale normalului (tulb de

învăţare viitoare?)
 Tulburare globală a dezvoltării (motor + psihic)
 Tulburare doar a dezvoltării motorii, sau motor > psihic

 Copii cu boli neuromusculare
 Copii cu hiperlaxitate ligamentară
 Copii cu paralizie cerebrală
 Tulburare doar a dezvoltării psihice

 Inatenţie
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 Autism / Tulburare din spectrul autist
CE SE POATE FACE?
 … până trimitem copilul la specialist?
 Când este treaz - să fie pus frecvent pe

burtă, sub supravegherea părinţilor
 Să spunem “nu” premergătoarelor
 Să spunem “nu” televizorului
 Referinţe pentru părinţi: Copilul de la o zi la 6

ani – Anne BACUS, ed Teora
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Epilepsiile 1
Prof. Dr. DANA CRAIU
As. Univ. Dr. Diana Barca
As. Univ. Dr. Oana Tarta-Arsene
Clinica Neurologie Pediatrica
Spital “Al Obregia”, Bucuresti
Ce discutam?
➢ I. Definiții
➢ II. Clasificarea crizelor epileptice si a epilepsiilor
➢ III. Diagnosticul pozitiv
➢ IV. Sindroame la vârsta de sugar

?
◼ Copil 1 an
◼ Dezvoltare normala
◼ Febra 39 grade C
◼ 1 eveniment – PC, hipertonie, miscari
ritmice cu ambele brate, 40 sec
◼ Criza epileptica?
?
◼ Copil 1 an
◼ Ce este o criza epileptica?
◼ Ce este epilepsia?
http://www.ilae-epilepsy.org/Visitors/Centre/ctf/ctfoverview.cfm
http://www.ilae-epilepsy.org/Visitors/Centre/ctf/seizure_types.cfm
Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League
Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470–472.
Fisher RS1, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer
DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S.ILAE official report: a practical
clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14.
Criza epileptica
◼ Eveniment clinic tranzitor
◼ CAUZA: activitate neuronala cerebrala anormala

excesiva, sau sincrona
◼ ASPECT CLINIC – legat de ariile cerebrale

implicate (motorie, senzitiva, senzoriala, etc.)
◼ TIPURI:
◼ Crize neprovocate – apartin epilepsiei
◼ Crize provocate = acute simptomatice (droguri, alcool,
febra, hipoglicemia, infectii cerebrale, trauma cerebrala,
etc.)
EPILEPSIA?
◼ BOALA CRONICA
crize recurente, neprovocate
> 2 crize spontane (1989 )

Caz, baiat, 18 ani
◼ Traumatism cerebral sever, chist

porencefalic
◼ Dupa 4 luni – 1 criza focala
◼ EEG – interictal – descarcari epileptiforme
focale
◼ Intrebare – este epilepsie?

2015/2016
Ce este nou in intelegerea epilepsiei?
◼ 1989 (ILAE)
◼ 2005 (ILAE)
EPILEPSIE?
◼ BOALA CRONICA

SAU
1 criza + EEG epileptiform (2005)
Caz, baiat, 18 ani

porencefalic
◼ EEG – interictal – fara descarcari
epileptiforme

2017
◼ 2014
Intrebari de rezolvat
◼ Care este definitia operationala a epilepsiei?
◼ Conceptul de risc de recurenta
◼ Crizele reflexe (provocate) sunt epilepsie?
◼ Diagnosticul de EPILEPSIE =
TRATAMENT?
◼ “odata epilepsie – intotdeauna epilepsie”?
(Poate epilepsia sa fie considerata
vindecata?)
Ce inseamna predispozitia
durabila de a genera crize
epileptice?
◼ Dupa 1 criza – exista risc de recurenta
◼ Q – ce risc este necesar pentru definirea epilepsiei?
60%
◼ Raspuns – cercetare (epidemiologie)
◼ 1 criza – 40-52% risc de recurenta (rr)(1)
◼ 2 crize >24h interval – 73% rr (60-90%) pt 95CI (2)
◼ 2 crize <24 h interval – similar cu al unei crize (se considera 1 episod)
◼ 1 criza + leziune distructiva – rr similar cu 2 crize >24h interval (3)
1. Berg AT1, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology. 1991 Jul;41(7):965-72.
2. Hauser WA1, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998 Feb 12;338(7):429-34.
3. Hesdorffer DC1, Benn EK, Cascino GD, Hauser WA. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia. 2009 May;50(5):1102-8. doi:
10.1111/j.1528-1167.2008.01945.x. Epub 2009 Jan 26.
Caz, baiat, 18 ani
◼ Traumatism cerebral sever, chist porencefalic

◼ EEG – interictal – fara descarcari epileptiforme

◼ DA: 1 criza + leziune distructiva – rr similar cu 2
crize >24h interval
Epilepsie = crize recurente
neprovocate
◼ Pacient – 10 ani
◼ 2 crize la calculator – jocuri video cu SLI
◼ Fara alte crize
◼ EEG – raspuns fotoparoxistic
◼ Este epilepsie?
Crizele reflexe sunt epilepsie
Concept nou
◼ Crizele = provocate
◼ Creierul are tendinta de a raspunde
repetat prin crize la acelasi stimul =
intruneste criteriul pt definitia conceptuala
a epilepsiei =
◼ Epilepsiile reflexe se asociaza cu
predispozitia durabila pt asemenea crize
Sindrom epileptic = epilepsie
◼ Natural
◼ Caz particular SLK
◼ EEG epileptiform
◼ Fara crize
Caz baiat, 12 ani
◼ 3 episoade – din somn – se ridica, merge,
nelinistit, pare PC, miscari repetitive
(automatisme), lungi(durata - neclara)
◼ Nu avem EEG
◼ Fara home video
◼ Q – este epilepsie?
◼ Q – trebuie tratat?
Situatie neclara – NU punem dg
de epilepsie!
◼ Semiologie neclara
◼ Fara video
◼ Fara inregistrare video-EEG
◼ Posibil/probabil ?
◼ Termeni inca nerezolvati

Diagnosticul de EPILEPSIE = TRATAMENT?
◼ Barbat tanar, 23 ani – 3 crize TCG – la 2 ani

distanta una de alta
◼ Diagnostic = epilepsie
◼ Tratament?
◼ Discuta rolul tratamentului
◼ Atitudine individualizata
◼ Decizie echilibrata
◼ Risc de recurenta
◼ Raport risc/beneficiu
◼ Dorinta pacientului
◼ Medicamente disponibile, cost

“Odata epilepsie– intotdeauna epilepsie”?
(Epilepsia poate fi vindecata?)
◼ Persoana cu epilepsie la varsta de 5 ani
◼ Tratat 3 ani; medicatia - eliminata
◼ 15 ani fara crize
◼ Are inca epilepsie?

◼ Vindecat = riscul de repetare crize – similar

populatiei generale
◼ Dupa epilepsie – acest risc scazut - imposibil
◼ Termen propus - rezolvata
◼ CAND? Ce limita de timp?

Raspuns = studii epidemiologice
◼ National General Practice Study UK (1) – riscul de recurenta la 3

ani fara MAE:
◼ 44% dupa 6 luni fara crize
◼ rr dupa 5 ani – exista (5%) (2)
◼ rr dupa 10 ani – nu sunt studii – considerat f scazut(3)
= epilepsia = rezolvata dupa 10 ani fara crizecu 5 ani fara
medicatie
1. Hart YM, Sander JW, Johnson AL, Shorvon SD. National General Practice Study of Epilepsy: recurrence after a first seizure. Lancet. 1990 Nov 24;336(8726):1271-4.
2. Lossius MI1, Hessen E, Mowinckel P, Stavem K, Erikssen J, Gulbrandsen P, Gjerstad L. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia. 2008 Mar;49(3):455-63. Epub 2007 Sep 19.
3. Chadwick D, Taylor J, Johnson T. Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group. Epilepsia. 1996 Nov;37(11):1043-50.
CAZ, sex masculin, 21 ani
◼ 3 crize – la varstele 6, 9, 14 ani – clonii obraz
drept + salivare, fara PC
◼ Varfuri C-T dreapta
◼ Tratat 2 ani cu LEV – de la 14 la 16 ani
◼ Fara crize de la 14, fara tratament de la 16
◼ Q – are inca dg de epilepsie?

Epilepsie rezolvata
◼ Epilepsie Rolandica (BECTS)
◼ Sindrom dependent de varsta (auto-

limitat)
◼ Desi nu are 10 ani fara crize, poate fi

considerate epilepsie rezolvata
Take home message
CRIZA EPILEPTICA≠ EPILEPSIE

➢ EPILEPSIE = boala cronica
➢ CRIZA EPILEPTICA = eveniment clinic
CONCLUZIE - Epilepsie
◼ Epilepsie
◼ 2 crize neprovocate la > 24 h distanta
◼ 1 criza neprovocata + rr >60% in urmatorii 10 ani
◼ Sindrom epileptic
◼ Crize reflexe recurente
◼ Epilepsie rezolvata
◼ Sindrom dependent de varsta care au trecut de
varsta rezolvarii sindromului
◼ Pacient fara crize de >10 ani si fara MAE > 5 ani
2017
◼ 2014
Alexandru cel Mare, Iulius Cesar, Napoleon,
Handel, Van Gogh, Dante, Socrate, Tchaikovsky,
Alfred Nobel, Agatha Christie
CLASIFICAREA CRIZELOR SI
SINDROAMELOR EPILEPTICE
De ce clasificare?
◼ Comunicare
◼ Predictia evolutiei
◼ Investigatii – ce si cand?
◼ Tratament: cand? ce? cat timp?
◼ Cercetare – etiologia genetica
◼ Comorbiditati asociate
Mari progrese – cercetare
◼ Neuroimagistica
◼ Neurofiziologie SEEG
◼ Neuropatologie
◼ Genetica epilepsiilor
Dreifuss et al. Proposal for revised clinical and electroencephalographic classification of epileptic
seizures. From the Commission on Classification and Terminology of the International League Against
Epilepsy. Epilepsia. 1981;22:489-501.
Loss (or Impairment) of Consciousness
Elements of consciousness
• Awareness of ongoing activities
• Memory for time during the event
• Responsiveness to verbal or nonverbal stimuli
• Sense of self as being distinct from others
Which would be the best surrogate marker ?

• The 2017 Classification chooses awareness
• Consciousness remains in the classification
but “awareness” is in the seizure name
• In several languages, these words are the same
• Awareness is not used to classify generalized onset seizures
Wording Changes
OLD TE RM NEW TERM
Unconscious (still used, not in name) Impaired awareness (surrogate)

Partial Focal
Simple partial Focal aware
Complex partial Focal impaired awareness
Dyscognitive (word discontinued) Focal impaired awareness
Psychic Cognitive
Secondarily generalized tonic-clonic Focal to bilateral tonic-clonic
Arrest, freeze, pause, interruption Behavior arrest
Informatii suport
◼ Clasificarea crizelor = clinica

◼ Folositoare:
◼ Video adus de familie
◼ EEG
◼ IRM – detectare leziune
◼ Genetica – identificare mutatie
◼ Incadrare in sindrom electroclinic
CRIZELE FOCALE
• Au originea in
retele limitate la o
emisfera
• Descarcarile pot fi
localizate sau mai
larg distribuite
CRIZELE FOCALE
◼ DEBUT MOTOR ◼ DEBUT NON-
◼ Tonic MOTOR
◼ Clonic ◼ Vegetativ
◼ Mioclonic ◼ Oprire din activitate
◼ Aton ◼ Cognitiv
◼ Hiperkinetic ◼ Emotional
◼ Spasm epileptic ◼ senzorial
◼ Automatism
◼ FOCAL EVOLUAND IN BILATERAL

TONIC-CLONIC
◼ Activare initiala unui sistem de neuroni
limitat la o parte a unei emisfere cerebrale
◼ Activare initiala a unui sistem de neuroni limitat la
o parte a unei emisfere cerebrale
◼ Aspect clinic – depinde de zona de debut si de

propagare
Semne clinice – in functie de ariile cerebrale implicate
FOCAL SEIZURES
Netter
◼ Activare initiala a unui system de neuroni limitat la

propagare
◼ EEG focal +/- generalizare secundara

Modificari epileptiforme EEG FOCALE (interictal)
Criza cu debut focal – Temporal stg
Criza evoluand bilateral

Crize focale in functie de topografie
Crizele de lob frontal
◼Caractere generale:
◼Frecventa: mare: mm zi/zilnic, hipnice, salve

◼Durata: scurta, <1 min
◼Aura: rara, nespecifica
◼Evolutie: brusca
◼Fen motorii: precoce, predominante, tonice/clonice
◼Automatisme: majore, hiperkinetice, orientate ‘sexual’
◼Confuzie post: absenta/minora
◼Bilateralizare t-cl:frecventa
◼SE: frecvent
Crize epileptice de lob temporal
◼Frecventa: mica: niciuna-cateva crize/luna

◼Durata: 2-3 min
◼Aura: frecventa (80%)=senzatie epigastrica ascendenta
◼Evolutie: treptata
◼Fen motorii: discrete, tardive (distonie!!)
◼Automatisme: minore
◼Confuzie postictala: marcata, prelungita
◼Bilateralizare T-CL: ocazional
◼SE: rar
Crize de lob parietal
Aura:
◼ Simptome somato-
senzitive controlaterale
(parestezii, disestezii..);
◼ Dureri abdominale;
◼ Halucinatii
gustative/vizuale;
◼ Vertij;
!! migreaza in LF/LT!!
Crize de lob occipital:
◼ Clipit fortat, devierea tonica si
clonica a GO, de obicei controlat;
◼ Frecvent elemente vizuale
negative (cecitate, scotoame,
hemianopsie);
◼ Halucinatii vizuale elementare;
◼ Migrare:
◼ sub fisura calcarina – LT
◼ deasupra fisurii calcarine –
LF/LP;
CRIZE EPILEPTICE
GENERALIZATE
CRIZE
GENERALIZATE
• Origine localizata
(incerta)
• Angajeaza rapid retele
neuronale distribuite
bilateral
• Poate include structuri
corticale si subcorticale
dar nu neaparat tot
cortexul
CLASIFICAREA SEMIOLOGICA A
CRIZELOR GENERALIZATE
▪ Tonice
▪ Clonice
▪ Tonico-clonice
▪ Mioclonice (contractii musculare aritmice, neregulate;

mioclonus negativ – pierdere brusca tonus)
▪ Atone (pierdere tonus muscular)
▪ Absente (privire fixa, neresponsivitate)

Crizele tonice
◼ Clinic - hipertonie musculara – contractie
simultana agonisti + antagonisti
◼ EMG – contractie continua
◼ EEG – activitate rapida de voltaj redus

Crizele tonice
Crizele clonice
◼ Clinic - contractii musculare ritmice cu
amplitudine regulata
◼ EMG: contractii, relaxari repetitive sau
felxii-extensii repetitive
◼ EEG – frecvent asociat cu frecvente

repetitive CVU
Crizele tonico-clonice
◼ Clinic – Clonii ritmice pe fond tonic
◼ EMG
◼ EEG – PVU
Crizele mioclonice
◼ Clinic – contractii musculare aritmice, amplitudini
diferite
◼ EMG – contractie scurta urmata de relaxare
◼ EEG – polivarf unda – simultam cu mioclonia

Crizele atone
◼ Clinic – atonie musculara
◼ EMG – pierdere completa a tonusului
◼ EEG – unda lenta bifazica
- sau CVU
Crizele absenta
◼ Clinic – oprire brusca a activitatii
◼ EMG – variabil
◼ EEG – CVU – 2-4 – clasic 3 Hz – absentele

tipice si absentele juvenile
◼ Discutie – alte opriri din activitate

Crizele absenta tipica
DIAGNOSTIC
Seizure types
Generalized Unknown
Etiology
Focal
onset onset onset Structural
Co-morbidities
Genetic
Epilepsy types Infectious

Combined
Focal Generalized Generalized Unknown
Metabolic
& Focal
Immune
Unknown
Epilepsy Syndromes
DIAGNOSTICUL + AL EPILEPSIEI
1. ANAMNEZA
◼ Martori vizuali/pacient;
◼ AHC!!
2. DESCRIEREA CRIZEI
◼ Debut - brutal, neasteptat
◼ Episod scurt, stereotip
◼ Prezența stertorului
◼ Obnubilare postcritică, astenie, curbatură
musculară
◼ Circumstanțele de producere (veghe/somn)
3. EEG:
◼ ajută dg + / dg de criză epileptică

◼ tipul crizei
◼ sdr electro-clinic
◼ uneori oferă inf-cheie pt etiologie
◼ supraveghere
◼ !! EEG normal NU exclude epilepsia
◼ 5-8% copiii normali – descărcări epileptiforme

4. IMAGISTICA : CT/IRM/SPECT/PET
• IRM – modalitate de electie!
• anomalii structurale
• NU pt toate cazurile!
5. Testarea genetică –>sute de gene descrise SCN1A!
6. Testare metabolică – pt dg etiologic - !! Epilepsii

vitamino-dependente
7. Alte evaluari: psihiatrica, oftamologica, ORL, etc

SINDROAMELE EPILEPTICE
CARACTERISTICI SINDROM EPILEPTIC
◼ Varsta de debut
◼ Preponderenta de sex
◼ Tip/uri de crize
◼ Afectare neuropsihica
◼ Factori declansatori
◼ Ritm circadian
◼ Etiologie
◼ Aspect EEG
◼ Raspunsul la tratament
◼ Evolutie si prognostic
SINDROAME EPILEPTICE (2005) - modificat
1. AXA SIMPTOMATICA:
◼ GENERALIZATE
◼ FOCALE
2. AXA ETIOPATOGENICA:
◼ Epilepsii idiopatice (20%)
◼ Epilepsii simptomatice (40%)
◼ Epilepsii criptogenice (40%)

Seizure types
Generalized Unknown
Etiology
Focal
Co-morbidities
Genetic

Combined
Metabolic
& Focal
Immune
Unknown
Epilepsy Syndromes
SINDROAME EPILEPTICE
ALE SUGARULUI
SD WEST
◼ Spasme epileptice
◼ Intarziere in dezv. pe etape triada clasica
◼ EEG – hipsaritmie
SINDROMUL WEST
◼ Debut 3-12 luni (media – 5-7 luni)

◼ Aspect clinic: SPASME EPILEPTICE
◼ flexie/ extensie
◼ Legate de somn (trezire sau inainte de somn)
◼ In salve, cateva salve pe zi
◼ Dezvoltarea pe etape:
◼ Normal/ intarziat inainte de debut
◼ Oprire din activitate/regres dupa rebutul spasmelor
◼ EEG: hipsaritmia – characteristic (fragmentat in somn)

EEG intercritica – HIPSARITMIE ( gr Hypsos= inalt)
Activitate electrica non-ritmica, haotica, de
amplitudine foarte mare
Sleep fragmentation
Investigatia Imagistica?
◼ DA – important!
◼ Etiologia SW – structurala, metabolica,
genetica
SINDROMUL WEST
◼ Debut: sugar (max 3-12 luni) – vârf 5 luni
◼ Clinic: crize în salve în flexie/extensie, legate de somn

(trezire>>adormire) – SPASME EPILEPTICE;
◼ Dezvoltare psihomotorie: anterior crizelor normală/lentă – după

debutul crizelor regres/retard al dezvoltării;
◼ EEG: intercritic aspect caract - hipsaritmie;
◼ Tratament: corticoterapie (ACTH-Synachten), VGB (linia I in SW din

scleroza tuberoasă!), TPM, VPA, BZD;
◼ Prognostic: rezervat (deficite cognitive, autism, sindrom hiperkinetic,

sindrom Lennox-Gastaut);
?
Epilepsiile 1
Prof. Dr. DANA CRAIU
As. Univ. Dr. Diana Barca
As. Univ. Dr. Oana Tarta-Arsene
Spital “Al Obregia”, Bucuresti
Ce discutam?
➢ I. Definiții
➢ II. Clasificarea crizelor epileptice si a epilepsiilor
➢ III. Diagnosticul pozitiv
➢ IV. Sindroame la vârsta de sugar

?
◼ Copil 1 an
?
◼ Copil 1 an
◼ Ce este o criza epileptica?
◼ Ce este epilepsia?
http://www.ilae-epilepsy.org/Visitors/Centre/ctf/ctfoverview.cfm
http://www.ilae-epilepsy.org/Visitors/Centre/ctf/seizure_types.cfm
Fisher RS1, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer
DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S.ILAE official report: a practical
clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14.
Criza epileptica
◼ Eveniment clinic tranzitor
◼ CAUZA: activitate neuronala cerebrala anormala

excesiva, sau sincrona
◼ ASPECT CLINIC – legat de ariile cerebrale

implicate (motorie, senzitiva, senzoriala, etc.)
◼ TIPURI:
◼ Crize neprovocate – apartin epilepsiei
◼ Crize provocate = acute simptomatice (droguri, alcool,
febra, hipoglicemia, infectii cerebrale, trauma cerebrala,
etc.)
EPILEPSIA?
◼ BOALA CRONICA

Caz, baiat, 18 ani

porencefalic
◼ EEG – interictal – descarcari epileptiforme
focale

2015/2016
◼ 1989 (ILAE)
◼ 2005 (ILAE)
EPILEPSIE?
◼ BOALA CRONICA

SAU
1 criza + EEG epileptiform (2005)
Caz, baiat, 18 ani

porencefalic
◼ EEG – interictal – fara descarcari
epileptiforme

2017
◼ 2014
Intrebari de rezolvat
◼ Care este definitia operationala a epilepsiei?
◼ Conceptul de risc de recurenta
◼ Crizele reflexe (provocate) sunt epilepsie?
◼ Diagnosticul de EPILEPSIE =
TRATAMENT?
◼ “odata epilepsie – intotdeauna epilepsie”?
(Poate epilepsia sa fie considerata
vindecata?)
Ce inseamna predispozitia
durabila de a genera crize
epileptice?
◼ Dupa 1 criza – exista risc de recurenta
◼ Q – ce risc este necesar pentru definirea epilepsiei?
60%
◼ Raspuns – cercetare (epidemiologie)
◼ 1 criza – 40-52% risc de recurenta (rr)(1)
◼ 2 crize >24h interval – 73% rr (60-90%) pt 95CI (2)
◼ 2 crize <24 h interval – similar cu al unei crize (se considera 1 episod)
◼ 1 criza + leziune distructiva – rr similar cu 2 crize >24h interval (3)
1. Berg AT1, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology. 1991 Jul;41(7):965-72.
2. Hauser WA1, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998 Feb 12;338(7):429-34.
3. Hesdorffer DC1, Benn EK, Cascino GD, Hauser WA. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia. 2009 May;50(5):1102-8. doi:
10.1111/j.1528-1167.2008.01945.x. Epub 2009 Jan 26.
Caz, baiat, 18 ani
◼ Traumatism cerebral sever, chist porencefalic

◼ EEG – interictal – fara descarcari epileptiforme

◼ DA: 1 criza + leziune distructiva – rr similar cu 2
crize >24h interval
Epilepsie = crize recurente
neprovocate
◼ Pacient – 10 ani
◼ 2 crize la calculator – jocuri video cu SLI
◼ Fara alte crize
◼ EEG – raspuns fotoparoxistic
◼ Este epilepsie?
Crizele reflexe sunt epilepsie
Concept nou
◼ Crizele = provocate
◼ Creierul are tendinta de a raspunde
repetat prin crize la acelasi stimul =
intruneste criteriul pt definitia conceptuala
a epilepsiei =
◼ Epilepsiile reflexe se asociaza cu
predispozitia durabila pt asemenea crize
Sindrom epileptic = epilepsie
◼ Natural
◼ Caz particular SLK
◼ EEG epileptiform
◼ Fara crize
Caz baiat, 12 ani
◼ 3 episoade – din somn – se ridica, merge,
nelinistit, pare PC, miscari repetitive
(automatisme), lungi(durata - neclara)
◼ Nu avem EEG
◼ Fara home video
◼ Q – este epilepsie?
◼ Q – trebuie tratat?
Situatie neclara – NU punem dg
de epilepsie!
◼ Semiologie neclara
◼ Fara video
◼ Fara inregistrare video-EEG
◼ Posibil/probabil ?
◼ Termeni inca nerezolvati

◼ Barbat tanar, 23 ani – 3 crize TCG – la 2 ani

distanta una de alta
◼ Diagnostic = epilepsie
◼ Tratament?
◼ Discuta rolul tratamentului
◼ Atitudine individualizata
◼ Decizie echilibrata
◼ Risc de recurenta
◼ Raport risc/beneficiu
◼ Dorinta pacientului
◼ Medicamente disponibile, cost

◼ Persoana cu epilepsie la varsta de 5 ani
◼ Tratat 3 ani; medicatia - eliminata
◼ 15 ani fara crize
◼ Are inca epilepsie?

◼ Vindecat = riscul de repetare crize – similar

populatiei generale
◼ Dupa epilepsie – acest risc scazut - imposibil
◼ Termen propus - rezolvata
◼ CAND? Ce limita de timp?

Raspuns = studii epidemiologice
◼ National General Practice Study UK (1) – riscul de recurenta la 3

ani fara MAE:
◼ rr dupa 5 ani – exista (5%) (2)
◼ rr dupa 10 ani – nu sunt studii – considerat f scazut(3)
= epilepsia = rezolvata dupa 10 ani fara crizecu 5 ani fara
medicatie
1. Hart YM, Sander JW, Johnson AL, Shorvon SD. National General Practice Study of Epilepsy: recurrence after a first seizure. Lancet. 1990 Nov 24;336(8726):1271-4.
2. Lossius MI1, Hessen E, Mowinckel P, Stavem K, Erikssen J, Gulbrandsen P, Gjerstad L. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia. 2008 Mar;49(3):455-63. Epub 2007 Sep 19.
3. Chadwick D, Taylor J, Johnson T. Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group. Epilepsia. 1996 Nov;37(11):1043-50.
CAZ, sex masculin, 21 ani
◼ 3 crize – la varstele 6, 9, 14 ani – clonii obraz
drept + salivare, fara PC
◼ Varfuri C-T dreapta
◼ Tratat 2 ani cu LEV – de la 14 la 16 ani
◼ Fara crize de la 14, fara tratament de la 16
◼ Q – are inca dg de epilepsie?

Epilepsie rezolvata
◼ Epilepsie Rolandica (BECTS)
◼ Sindrom dependent de varsta (auto-

limitat)
◼ Desi nu are 10 ani fara crize, poate fi

considerate epilepsie rezolvata
Take home message
CRIZA EPILEPTICA≠ EPILEPSIE

➢ EPILEPSIE = boala cronica
➢ CRIZA EPILEPTICA = eveniment clinic
CONCLUZIE - Epilepsie
◼ Epilepsie
◼ 2 crize neprovocate la > 24 h distanta
◼ 1 criza neprovocata + rr >60% in urmatorii 10 ani
◼ Sindrom epileptic
◼ Crize reflexe recurente
◼ Epilepsie rezolvata
◼ Sindrom dependent de varsta care au trecut de
varsta rezolvarii sindromului
◼ Pacient fara crize de >10 ani si fara MAE > 5 ani
2017
◼ 2014
Alexandru cel Mare, Iulius Cesar, Napoleon,
Handel, Van Gogh, Dante, Socrate, Tchaikovsky,
Alfred Nobel, Agatha Christie
CLASIFICAREA CRIZELOR SI
SINDROAMELOR EPILEPTICE
De ce clasificare?
◼ Comunicare
◼ Predictia evolutiei
◼ Investigatii – ce si cand?
◼ Tratament: cand? ce? cat timp?
◼ Cercetare – etiologia genetica
◼ Comorbiditati asociate
Mari progrese – cercetare
◼ Neuroimagistica
◼ Neurofiziologie SEEG
◼ Neuropatologie
◼ Genetica epilepsiilor
Dreifuss et al. Proposal for revised clinical and electroencephalographic classification of epileptic
seizures. From the Commission on Classification and Terminology of the International League Against
Epilepsy. Epilepsia. 1981;22:489-501.
Loss (or Impairment) of Consciousness
Elements of consciousness
• Awareness of ongoing activities
• Memory for time during the event
• Responsiveness to verbal or nonverbal stimuli
• Sense of self as being distinct from others
Which would be the best surrogate marker ?

• The 2017 Classification chooses awareness
• Consciousness remains in the classification
but “awareness” is in the seizure name
• In several languages, these words are the same
• Awareness is not used to classify generalized onset seizures
Wording Changes
OLD TE RM NEW TERM
Unconscious (still used, not in name) Impaired awareness (surrogate)

Partial Focal
Simple partial Focal aware
Complex partial Focal impaired awareness
Dyscognitive (word discontinued) Focal impaired awareness
Psychic Cognitive
Secondarily generalized tonic-clonic Focal to bilateral tonic-clonic
Arrest, freeze, pause, interruption Behavior arrest
Informatii suport
◼ Clasificarea crizelor = clinica

◼ Folositoare:
◼ Video adus de familie
◼ EEG
◼ IRM – detectare leziune
◼ Genetica – identificare mutatie
◼ Incadrare in sindrom electroclinic
CRIZELE FOCALE
• Au originea in
retele limitate la o
emisfera
• Descarcarile pot fi
localizate sau mai
larg distribuite
CRIZELE FOCALE
◼ DEBUT MOTOR ◼ DEBUT NON-
◼ Tonic MOTOR
◼ Clonic ◼ Vegetativ
◼ Mioclonic ◼ Oprire din activitate
◼ Aton ◼ Cognitiv
◼ Hiperkinetic ◼ Emotional
◼ Spasm epileptic ◼ senzorial
◼ Automatism
◼ FOCAL EVOLUAND IN BILATERAL

TONIC-CLONIC
◼ Activare initiala unui sistem de neuroni
limitat la o parte a unei emisfere cerebrale
◼ Activare initiala a unui sistem de neuroni limitat la

propagare
Semne clinice – in functie de ariile cerebrale implicate
FOCAL SEIZURES
Netter
◼ Activare initiala a unui system de neuroni limitat la

propagare
◼ EEG focal +/- generalizare secundara

Modificari epileptiforme EEG FOCALE (interictal)
Criza cu debut focal – Temporal stg
Criza evoluand bilateral

Crize focale in functie de topografie
Crizele de lob frontal
◼Frecventa: mare: mm zi/zilnic, hipnice, salve

◼Durata: scurta, <1 min
◼Aura: rara, nespecifica
◼Evolutie: brusca
◼Fen motorii: precoce, predominante, tonice/clonice
◼Automatisme: majore, hiperkinetice, orientate ‘sexual’
◼Confuzie post: absenta/minora
◼Bilateralizare t-cl:frecventa
◼SE: frecvent
Crize epileptice de lob temporal
◼Frecventa: mica: niciuna-cateva crize/luna

◼Durata: 2-3 min
◼Aura: frecventa (80%)=senzatie epigastrica ascendenta
◼Evolutie: treptata
◼Fen motorii: discrete, tardive (distonie!!)
◼Automatisme: minore
◼Confuzie postictala: marcata, prelungita
◼Bilateralizare T-CL: ocazional
◼SE: rar
Crize de lob parietal
Aura:
◼ Simptome somato-
senzitive controlaterale
(parestezii, disestezii..);
◼ Dureri abdominale;
◼ Halucinatii
gustative/vizuale;
◼ Vertij;
!! migreaza in LF/LT!!
Crize de lob occipital:
◼ Clipit fortat, devierea tonica si
clonica a GO, de obicei controlat;
◼ Frecvent elemente vizuale
negative (cecitate, scotoame,
hemianopsie);
◼ Halucinatii vizuale elementare;
◼ Migrare:
◼ sub fisura calcarina – LT
◼ deasupra fisurii calcarine –
LF/LP;
CRIZE EPILEPTICE
GENERALIZATE
CRIZE
GENERALIZATE
• Origine localizata
(incerta)
• Angajeaza rapid retele
neuronale distribuite
bilateral
• Poate include structuri
corticale si subcorticale
dar nu neaparat tot
cortexul
CLASIFICAREA SEMIOLOGICA A
CRIZELOR GENERALIZATE
▪ Tonice
▪ Clonice
▪ Tonico-clonice
▪ Mioclonice (contractii musculare aritmice, neregulate;

mioclonus negativ – pierdere brusca tonus)
▪ Atone (pierdere tonus muscular)
▪ Absente (privire fixa, neresponsivitate)

Crizele tonice
◼ Clinic - hipertonie musculara – contractie
simultana agonisti + antagonisti
◼ EMG – contractie continua
◼ EEG – activitate rapida de voltaj redus

Crizele tonice
Crizele clonice
◼ Clinic - contractii musculare ritmice cu
amplitudine regulata
◼ EMG: contractii, relaxari repetitive sau
felxii-extensii repetitive
◼ EEG – frecvent asociat cu frecvente

repetitive CVU
Crizele tonico-clonice
◼ Clinic – Clonii ritmice pe fond tonic
◼ EMG
◼ EEG – PVU
Crizele mioclonice
◼ Clinic – contractii musculare aritmice, amplitudini
diferite
◼ EMG – contractie scurta urmata de relaxare
◼ EEG – polivarf unda – simultam cu mioclonia

Crizele atone
◼ Clinic – atonie musculara
◼ EMG – pierdere completa a tonusului
◼ EEG – unda lenta bifazica
- sau CVU
Crizele absenta
◼ Clinic – oprire brusca a activitatii
◼ EMG – variabil
◼ EEG – CVU – 2-4 – clasic 3 Hz – absentele

tipice si absentele juvenile
◼ Discutie – alte opriri din activitate

Crizele absenta tipica
DIAGNOSTIC
Seizure types
Generalized Unknown
Etiology
Focal
Co-morbidities
Genetic

Combined
Metabolic
& Focal
Immune
Unknown
Epilepsy Syndromes
1. ANAMNEZA
◼ Martori vizuali/pacient;
◼ AHC!!
2. DESCRIEREA CRIZEI
◼ Debut - brutal, neasteptat
◼ Episod scurt, stereotip
◼ Prezența stertorului
◼ Obnubilare postcritică, astenie, curbatură
musculară
◼ Circumstanțele de producere (veghe/somn)
3. EEG:
◼ ajută dg + / dg de criză epileptică

◼ tipul crizei
◼ sdr electro-clinic
◼ uneori oferă inf-cheie pt etiologie
◼ supraveghere
◼ !! EEG normal NU exclude epilepsia
◼ 5-8% copiii normali – descărcări epileptiforme

4. IMAGISTICA : CT/IRM/SPECT/PET
• IRM – modalitate de electie!
• anomalii structurale
• NU pt toate cazurile!
5. Testarea genetică –>sute de gene descrise SCN1A!
6. Testare metabolică – pt dg etiologic - !! Epilepsii

vitamino-dependente
7. Alte evaluari: psihiatrica, oftamologica, ORL, etc

SINDROAMELE EPILEPTICE
◼ Varsta de debut
◼ Ritm circadian
◼ Etiologie
◼ Aspect EEG
SINDROAME EPILEPTICE (2005) - modificat
1. AXA SIMPTOMATICA:
◼ GENERALIZATE
◼ FOCALE
2. AXA ETIOPATOGENICA:
◼ Epilepsii idiopatice (20%)
◼ Epilepsii simptomatice (40%)
◼ Epilepsii criptogenice (40%)

Seizure types
Generalized Unknown
Etiology
Focal
Co-morbidities
Genetic

Combined
Metabolic
& Focal
Immune
Unknown
Epilepsy Syndromes
SINDROAME EPILEPTICE
ALE SUGARULUI
SD WEST
◼ Spasme epileptice
◼ Intarziere in dezv. pe etape triada clasica
◼ EEG – hipsaritmie
SINDROMUL WEST
◼ Debut 3-12 luni (media – 5-7 luni)

◼ Aspect clinic: SPASME EPILEPTICE
◼ flexie/ extensie
◼ Legate de somn (trezire sau inainte de somn)
◼ In salve, cateva salve pe zi
◼ Dezvoltarea pe etape:
◼ Normal/ intarziat inainte de debut
◼ Oprire din activitate/regres dupa rebutul spasmelor
◼ EEG: hipsaritmia – characteristic (fragmentat in somn)

EEG intercritica – HIPSARITMIE ( gr Hypsos= inalt)
Activitate electrica non-ritmica, haotica, de
amplitudine foarte mare
Sleep fragmentation
Investigatia Imagistica?
◼ DA – important!
◼ Etiologia SW – structurala, metabolica,
genetica
SINDROMUL WEST
◼ Debut: sugar (max 3-12 luni) – vârf 5 luni
◼ Clinic: crize în salve în flexie/extensie, legate de somn

(trezire>>adormire) – SPASME EPILEPTICE;
◼ Dezvoltare psihomotorie: anterior crizelor normală/lentă – după

debutul crizelor regres/retard al dezvoltării;
◼ EEG: intercritic aspect caract - hipsaritmie;
◼ Tratament: corticoterapie (ACTH-Synachten), VGB (linia I in SW din

scleroza tuberoasă!), TPM, VPA, BZD;
◼ Prognostic: rezervat (deficite cognitive, autism, sindrom hiperkinetic,

sindrom Lennox-Gastaut);
?
EPILEPSIILE 2
SINDROAMELE EPILEPTICE cont
Prof. Dr. Dana Craiu

◼ Varsta de debut
◼ Ritm circadian
◼ Etiologie
◼ Aspect EEG
SINDROMUL LENNOX-GASTAUT
◼ Debut: 1-8 ani, baietii>fetele
◼ Clinic:
◼ crize epileptice multiple tipuri (tonice axiale hipnice,
atone, absente atipice, tonico-clonice generalizate)
◼ Dezvoltare psihomotorie:
◼ anterior debutului crizelor normala/incetinita
◼ dupa debutul crizelor regres/retard psihomotor
3
SINDROM LENNOX-GASTAUT
◼ EEG
◼ Traseude veghe: activitate de fond

anormala, cu CVU < 3 c/sec, anomalii
multifocale
◼ Somn: ritmuri rapide in somn 10 c/sec

EEG veghe
activitate de fond anormala, cu CVU < 3 c/sec, anomalii multifocale
SCHIMBA POZA
Somn: ritmuri rapide in somn 10 c/sec
6
IRM/CT
◼ Anormala
◼ Normala
7
SINDROM LENNOX-GASTAUT
◼ Tratament:
◼ politerapie, farmacorezistent
◼ eventual dieta cetogenica, VNS, chirurgical
(calosotomia)
◼ Prognostic:
◼ rezervat
(intarziere mintala, tulburari psihice, epilepsie)
Sindromul Lennox-Gastaut
1. Varsta:
◼ 1-8 ani;
2. Tip de crize:
◼ crize generalizate de multiple tipuri
3. Investigatii paraclinice:
◼ EEG: veghe (CVU<3Hz); somn-ritmuri rapide
◼ Imagistic cerebral (este indicat): N/aN
4. Etiologie:
◼ structural/genetic/metabolic
5. Tratament:
◼ Combinatie antiepileptice/trat – este o epilepsie rezistentă
6. Prognostic:
◼ rezervat…. 
9
EPILEPSIA PARTIALA BENIGNA (Epilepsia
Rolandica (centro-temporala) autolimitata
◼ Predispozitie genetica:
◼ AHC + pt convulsii febrile / epilepsie;
◼ Debut 3-12 ani, predominant la sexul masculin

◼ Clinic:
◼ crize focale motorii/senzitive fara PC (debut cu
parestezii facio-brahiale, convulsii tonico-clonice
unilaterale ale fetei +/- membrului superior, anartrie,
sialoree) mai ales in timpul somnului;
◼ DPM + ex neurologic: normal

EEG: focar de virfuri lente CT, activate de somn;
Doua focare diferite in veghe
Exacerbare somn
EPILEPSIA ROLANDICA
AUTOLIMITATA
◼ Imagistica cerebrala:
◼ CT/IRM cerebral – normal – NU se face
◼ Tratament:
◼ Mentinerea in observatie;
◼ eventual VPA, LEV. CBZ, rezerva
◼ Prognostic: excelent al crizelor, cognitiv

Epilepsia Rolandica
(cu varfuri centro-temporale)
1. Varsta: 3-13 ani (max 6-7 ani)
2. Tip de crize: crize focale (zona Rolandica)
◼ EEG: desc focale uni -/bilat C-T, activate de somn
◼ Imagistic cerebral: N – nu se face!!!
4. Etiologie:
◼ genetica
5. Tratament:
◼ VPA, LEV (atentie la CBZ)
6. Prognostic: Excelent… ☺
Este un sindrom autolimitat in jur de 14-16 ani
16
EPILEPSIA ABSENTA A
COPILULUI
◼ Mare predispozitie genetica
◼ AHC + pt convulsii febrile / epilepsie
◼ Debut: 3-12 ani (max 6-7 ani), mai frecventa
la sexul feminin
◼ Clinic:
◼ Crize tip absente de toate tipurile
◼ frecventa zeci-sute/zi
◼ DPM + ex neurologic: normal

HV – factor trigger pt absente
EEG: CVU 3 c/sec, sensibilitate la HV
EPILEPSIA ABSENTA A
COPILULUI
◼ Imagistica cerebrala:
◼ CT / IRM cerebral – normal – NU se face!
◼ Tratament:
◼ Indicate - VPA, ESM (LTG, BZD)
◼ CONTRAINDICATE: CBZ, PHT, VGB
◼ Prognostic: favorabil (crize, cognitiv)

Epilepsia absenta a copilului
1. Varsta: 3-12 ani
2. Tip de crize:
◼ absente
◼ EEG: desc generalizate CVU 3Hz la HV!!
◼ Imagistic cerebral: N
4. Etiologie:
◼ genetica
5. Tratament:
◼ VPA, ETS, LTG (nu CBZ, PHT)
6. Prognostic:
◼ Excelent… ☺
21
EPILEPSIA GENERALIZATA
IDIOPATICA DE ADOLESCENTA
GENETICA
◼ ABSENTE JUVENILE
◼ Predominant crize absente
◼ EPILEPSIA MIOCLONICA JUVENILA
◼ Predominant crize mioclonice
◼ EPILEPSIA CU CRIZE TCG
◼ Crize tonico-clonice generalizate
POT EXISTA COMBINATII INTRE ACESTEA!

EPILEPSIA GENERALIZATA GENETICA DE
ADOLESCENTA (CARACTERISTICI COMUNE)
◼ ETIOLOGIE - Transmitere genetica (poligenica)

◼ CLINIC:
◼ Frecventa crescuta la fete
◼ Debut la adolescenta (cel mai frecvent 13-16 ani)
◼ Crizele apar la trezire si in veghe
◼ Declansare: privare de somn, fotostimulare, exces
alcool
◼ Aspect de crize bilaterale
◼ Examen neurologic, intelect: normal
◼ Neuroimagistica: normal – NU SE INDICA!!!
◼ Tratament: raspuns bun, dar farmacodependente:
VPA, LEV, LTG
EPILEPSIA ABSENTA JUVENILA
◼ Debut: 10-17 ani;
◼ Clinic:
◼ absente mai scurte, mai rare, mai usoare - fata de absentele
copilului
◼ Se pot asocial crize t-cl bilaterale
◼ Ex neuro-psihic: normal
https://www.youtube.com/watch?v=M3ulV9eJKQQ
◼ EEG: CVU > 3 c/sec;
◼ Trat:
◼ VPA, VPA + ESM, farmacodependente
EPILEPSIA MIOCLONICA
JUVENILA (SDR JANZ)
◼ Debut: 12-16 ani (gena – cromozom 6);
◼ Clinic:
◼ crize mioclonice bilaterale, izolate sau repetitive,
simetrice/asimetrice, fara PC, la trezirea din somn
◼ Localizare: membrele superioare (umeri), rar membrele
inferioare
◼ Precipitate de privare de somn, SLI, menstra
◼ Ex neurologic & psihic: normal
◼ EEG: CVU sau PVU > 3c/sec, fotosensibilitate

◼ Trat: VPA, LEV, LTG, farmacodependente
◼ EMJ
TRASEU EEG
EMJ – SLI – factor trigger la pacientii
fotosenzitivi; fotosensibilitatea = frecventa
◼ mioclonii-sli.exe
EPILEPSIA CU CRIZE TONICO-
CLONICE GENERALIZATE LA TREZIRE
◼ Debut: 6-20 ani, mai frecventa la fete

◼ Clinic: tonico-clonice gen. la trezire /relaxare
◼ Factori precipitanti: privare de somn, SLI, alcool
◼ EEG: CVU generalizate > 3 c/sec,
fotosensibilitate
◼ Tratament: VPA, LEV, LTG, farmacodependente
Sindroame epileptice
0-1 AN 1-7 ANI 3-13 ANI 13-16 ANI
1. SDR 2. SDR 3. EPILEPSIA 5. EPILEPSIA

WEST LENNOX-ROLANDICA AUTOLIMITATA4. EPILEPSIA GENERALIZATA
GASTAUT (CU VARFURI ABSENTA A GENETICA DE
CENTRO-TEMPORALE) COPILULUI ADOLESCENTA
(absenta/mioclonica juvenila
Blat t-cl trezire)
Mm crize
(tonice axiale Absente Absente
Mioclonii Spasme
Hipnice) Crize focale infantile
Crize TCG Fara PC
Diagnosticul semiologic!!
31
Sindroame epileptice
0-1 AN 1-7 ANI 3-13 ANI 13-16 ANI
1. SDR 2. SDR 3. EPILEPSIA 5. EPILEPSIA

LENNOX- CU VARFURI 4. EPILEPSIA GENERALIZATA
WEST
GASTAUT CENTRO-TEMPORALE ABSENTA A GENETICA DE
AUTOLIMITATA COPILULUI ADOLESCENTA
(absenta/mioclonica juvenila
Epi cu cr t-cl. Bilat de trezire)
Ex neurologic
HV PRIVARE SOMN Deficienta
+ SLI normal
intelectuala
32
TRATAMENT
Tratamentul antiepileptic:
 Crizei epileptice
 Epilepsiei – medicamentos vs non-

medicamentos
33
TRATAMENT
1. SFATURI ASUPRA CONDITIILOR DE VIATA

2. MEDICAMENTE ANTIEPILEPTICE
3. TRATAMENT CHIRURGICAL
4. DIETA CETOGENICA
5. STIMULARE VAGALA
34
1. CONDITII DE VIATA
◼ Somn
◼ Alimentatie
◼ Tv, computer, discoteca
◼ Sport
◼ Vaccinari
◼ Scolarizare
35
2. Medicamente antiepileptice:
◼ Tratamentul crizei epileptice:

4. Ce faci intr-o criza.mp4
◼ Pozitie de siguranta;
◼ Benzodiazepine:
◼ Diazepam
◼ intrarectal 0,5 mg/kgc/doza;
◼ Intravenos 0,2 mg/kgc/doza;
36
◼ Principii de tratament:
◼ Diagnostic cert de epilepsie
◼ Individualizare tratament
◼ Monoterapie versus politerapie
◼ Mod administrare
◼ Mentinere
37
◼ In functie de semiologia crizelor:

◼ Crize epileptice focale:
◼ I-a linie - CARBAMAZEPINA /OXCARBAZEPINA;
◼ 20-40 mg/kgc/zi;
◼ Crize epileptice generalizate:

◼ I-a linie – VALPROAT DE SODIU;
◼ 20-40 mg/kg/zi;
38
◼ Alte MAE:
◼ Vechi – fenobarbital, fenitoina, etosuccinimida;
◼ Noi – lamotrigina, topiramat, vigabatrin;
39
◼ Indicate in:
◼ Absente – etosuccinimida
◼ Contraindicate:
◼ Absente – carbamazepina;
◼ Mioclonii – carbamazepina,
40
◼ Reguli de administrare:
◼ 1-ul MAE (doza mica – progresiv doza terapeutica)
↓
NERESPONSIV
↓
◼ Al 2-lea MAE (doza mica – progresiv doza terapeutica)
↓
NERESPONSIV
↓
◼ Combinatii de MAE
TIMP DE 2-5 ANI / TOATA VIATA!! (personalizat)
41
3. Tratamentul chirurgical
◼ Chirurgia epilepsiei
◼ CURATIVA = Excizia zonelor epileptogene;
◼ supresia focarului epileptogenic printr-o procedura
resectiva;
◼ PALEATIVA;
◼ Functionala (reducerea intensitatii si frecventei
crizelor – ex. calosotomia / sectiuni subpiale
multiple)
◼ Evaluare prechirurgicala!!;
42
Chirurgia epilepsiei curativa
◼ Maria, 5 ani..
◼ Crize epileptice de la vs de 4 ani, rezistente la
tratament..
◼ EEG (interictal)…
43
EEG ictal
◼ Aspectul clinic&EEG e concordant cu
leziunea..
44
Chirurgia epilepsiei
PALEATIVA
◼ Calosotomia;
◼ Crizele atone / crize focale cu generalizare secundara!!
45
4. Dieta cetogena
◼ Epilepsiile refractare la MAE
◼ Dieta cu continut crescut de lipide + scazut de glucide si
proteine (2 / 3 / 4:1)
◼ Corpi cetonici cantitate crescuta – creste energia
cerebrala= stabilitate neuronala (?)
46
5. Stimularea vagala
◼ Epilepsiile rezistente la tratament
◼ Elibereaza un stimul la o perioada fixa:
◼ moduleaza influxul nervos la nivelul subst reticulate ascendente &
talamus…:
47
Diagnostic diferential
◼ tulburari de somn
◼ atacuri de panica
◼ migrena
◼ sincopa
◼ tulburari de miscare
◼ AIT
◼ crize conversive
MANIFESTARI PAROXISTICE NEEPILEPTICE!!
48
Catrinel Iliescu

Sp Pr Dr Al Obregia
Bucureşti
DE CE O DISCUŢIE DESPRE CEFALEE?
 Cefaleea reprezintă un motiv frecvent de consultaţie

neurologică şi pediatrică în general
 Când se repetă ea poate afecta QoL (calitatea vieţii) –

dependent şi de etiologie
CE DOARE ?
 Structuri sensibile la durere intracraniene
 Arterele cerebrale şi durale

 Sinusurile venoase intracerebrale şi vv tributare
 Nervii cranieni (II, III, V, IX, X)
 Dura mater de la baza craniului
 Structuri sensibile la durere extracraniene
 Arterele extracraniene
 Rădăcinile cervicale
 Structurile delicate ale ochilor, urechilor, cavităţilor nazale,
sinusurilor
 Pielea, ţesutul subcutanat, muşchii, periostul cranian
DE CE DOARE ?
 Vasodilataţia
 Inflamaţia
 Tracţiunea
 Contracţia musculară prelungită
Structurile supratentoriale durere resimţită în cele 2/3

anterioare ale craniului (NC V)
Structurile infratentoriale durere resimţită la nivel

cervical şi occipital (rr cervicale superioare)
CE NU DOARE ?
 Parechimul cerebral
 Ependimul şi plexurile coroide
 Cea mai mare parte a leptomeningelui de la nivelul

convexităţii cerebrale
CLASIFICARE
 Criteriul etiologic
 Criteriul temporal
CRITERIUL ETIOLOGIC
 CEFALEE PRIMARĂ  CEFALEE SECUNDARĂ
Migrena Infecţiile SNC
Cefalee paroxistică unilaterală Hemoragiile intracraniene
Cefaleea în ciorchine HIC – variate etiologii
Cefaleea de tip tensional

CRITERIUL TEMPORAL
 CEFALEE ACUTĂ
 CEFALEE ACUTĂ RECURENTĂ
 CEFALEE CRONICĂ NEPROGRESIVĂ
 CEFALEE CRONICĂ PROGRESIVĂ
 CEFALEE MIXTĂ
ABORDAREA COPILULUI CU CEFALEE
 ISTORICUL
 EXAMINAREA CLINICĂ
 EVALUĂRILE COMPLEMENTARE
DIAGNOSTIC
TRATAMENT
ABORDAREA COPILULUI CU CEFALEE –
ISTORICUL
 Cheia unui diagnostic corect
 Întrebări pentru copil + părinte
 Debutul (abrupt, lent sau mai rapid progresiv..)

 Localizarea
 Tipul
 Intensitatea
 Durata
 Frecvenţa
 Factorii care ameliorează
 Factorii precipitanţi / agravanţi
 Semne asociate (vegetative, neurologice, altele ...)
 ISTORICUL FAMILIAL
EXAMENUL CLINIC
 Foarte important
 Starea generală, febră da/nu, semne meningeale !
 TA!
 Palparea sinusurilor feţei
 Neurologic
 Starea de conştienţă, funcţiile cerebrale cpxe
 NC – edemul papilar
 Mersul, mişcările fine / Coordonarea
 Reflexele (ROT, r patologice)
 Testarea senzitivă
EVALUĂRILE COMPLEMENTARE
Întotdeauna ghidate de istoric şi ex clinic!
 Imagistica
 EEG
 PL – inclusiv cu testarea presiunii LCR
 HLG, biochimie
 Alte evaluări – oftalmologie, ORL, psihiatrie...

SEMNE DE ALARMĂ
 “Thunder-clap headache” (cefalee extrem de severă, debut brusc)
 Cefalee cu următoarele particularităţi:
 cu examen neurologic anormal (inclusiv FO)
 cu febră şi semne meningeale!
 fără febră, cu semne meningeale
 cu crize nou debutate
 Istoric scurt de cefalee
 Cefalee lateralizată persistentă

 Evoluţie progresivă a cefaleei
 Cefalee occipitală la un copil <10a

 Cefalee care trezeşte copilul noaptea din somn
 Creştere anormală a perimetrului cranian

 Vârstă mică
 Scăderea performanţelor şcolare, modificări ale comportamentului
CLASIFICARE - CRITERIUL TEMPORAL
 CEFALEE ACUTĂ
 CEFALEE MIXTĂ
CEFALEE ACUTĂ = debut recent al
cefaleei, fără istoric anterior durere
POSIBILITĂŢI ETIOLOGICE
 Boală febrilă
 Infecţii ale SNC
 Traumatism cranian
 Hemoragie intracraniană
 Cefalee post-puncţională
 Cefalee de efort
 Cefalee după o primă criză epileptică
 Primul atac de migrenă
 Localizată
 CEFALEE ACUTĂ
 CEFALEE MIXTĂ
CEFALEE ACUTĂ RECURENTĂ= atacuri repetate de
cefalee, fără semne/simptome între atacuri
 Migrena – cea mai frecventă cauză de cefalee acută recurentă
 Afecțiune ereditară
 Cefalee recurentă
 Frecvent unilaterală şi pulsatilă
 Asociată cu semne vegetative
 Uneori cu semne neurologice
 La copil în mod tipic ameliorată de somn

CLASIFICAREA MIGRENEI
 Migrena fără aură (migrena comună)
 Migrena cu aură (migrena clasică)
 Variantele de migrenă
EPIDEMIOLOGIA MIGRENEI
 Migrena este una dintre afecțiunile neurologice cele mai
frecvente
 Aproximativ 7% dintre copiii 5-15 ani au migrenă
 Cei mai mulţi adulţi cu migrenă vor avea primul atac
migrenos < v de 20 ani (20% înainte de 5 ani!)
 Istoricul familial este + in aproximativ 60-80% din cazuri

PATOGENIA MIGRENEI
 Mecanisme propuse:
 Neurovascular
 Vascular
 Neuronal
 Neurotransmiţători
 Canalopatie
 Disfuncţie mitocondrială
MIGRENA FĂRĂ AURĂ LA COPIL
(60-85% din cazuri)
 5 sau mai multe atacuri de cefalee
 Durată de 2 (copii) -48 h

 Cefaleea (cel puţin 2 din caracteristicile următoare):
 Localizare unilaterală / bilateral ă (frontal sau temporal) - copii
 Caracter pulsatil – poate lipsi la copii
 Intensitate moderată sau severă
 Agravată de activitatea fizică de rutină
 Fenomene vegetative asociate (cel puţin 1 din următoarele):

 Greaţă sau vărsături
 Hiperestezie (fotofobie, fonofobie)

CARACTERISTICILE MIGRENEI ÎN
COPILĂRIE
 Cefaleea - bilateral (frontal, temporal) > unilateral
 Poate să NU fie pulsatilă
 Severitate moderată, semnele vegetative pot fi

importante / severe, comportament și activitate
modificate
 Somnul apare frecvent, la trezire durerea a dispărut
 Răul de mișcare – mai frecvent la acești copii

MIGRENA CU AURĂ
(15% din cazuri)
 Cel puţin 2 atacuri care îndeplinesc următoarele criterii:
 Aura - cel puţin 3 din caracteristicile următoare:

 Unul sau mai multe simptome neurologice complet reversibile (=
aură), legate de o disfuncţie focală corticală sau a trunchiului

cerebral
 Cel puţin o aură se dezvoltă progresiv, > 4 min sau >=2 simptome apar
în succesiune
 Nici o aură nu durează > 60 min
 Cefaleea urmează la cel mult 60 minute după aură
 Cefaleea şi fenomenele vegetative vor avea

caracteristicile descrise anterior
VARIANTELE DE MIGRENĂ -
- copii mici, evenimente episodice,
fără cefalee
 Vertijul paroxistic benign
 Migrena abdominală
 Vărsăturile ciclice
 CEFALEE ACUTĂ
 CEFALEE MIXTĂ
CEFALEEA CRONICĂ NEPROGRESIVĂ=
cefalee de tip tensional
 Cefalee persistentă, fără simptome vegetative asociate,
fără semne neurologice
 Intensitate redusă, difuză, nu interacţionează cu

activităţile de rutină
 Cel mai frecvent legată de factori psihologici (“tensiune”)
 Cu excepţia evaluărilor psihologice,
restul investigaţiilor
nu sunt necesare
(există unele excepţii)

 CEFALEE ACUTĂ
 CEFALEE MIXTĂ
CEFALEEA CRONICĂ PROGRESIVĂ
ATENŢIE! – de obicei simptomatică
 Cefalee iniţial episodică, în scurt timp devine
persistentă şi progresivă
 Poate trezi copilul din somn (spre dimineaţă) / este severă

imediat după trezire
 Asociază frecvent vărsături, care pot ameliora cefaleea
 Agravată de tuse, strănut, întindere ( PIC)
 Mecanime: tracţiune, infiltrare
 Ex clinic: de obicei (?) anormal dacă este riguros efectuat

(inclusiv FO pentru edem papilar); laterocolis; PC
 CEFALEE ACUTĂ
 CEFALEE MIXTĂ
CEFALEEA MIXTĂ
 Cel mai frecvent un model de cefalee episodică

transformată într-o cefalee cronică nepogresivă
 Factorii psihologici pot contribui
 Abuzul de analgezice
 Migrena transformată (migrenă cronică)

TRATAMENT
 Simptomatic – analgezice (Ibuprofen, acetaminofen)
 Etiopatogenic:
 ATB dc este meningită bacteriană, abces cerebral (NCh)
 Antivirale dacă este encefalită virală (herpetică)
 Lichide, sare, cofeină dacă este postpuncţională
 Nch dacă este hematom extradural / subdural acut (TCC)
 Nch dacă este PEIC / hidrocefalie
 Tratamente specifice antimigrenoase
 Antidepresive uneori – în cefaleea de tip tensional

TRATAMENTUL MIGRENEI
 Tratamentul acut:
 Analgezice doze suficiente
 Antiemetice
 Triptani
 Derivaţii de ergot
 Tratamentul cronic – atacuri frecvente sau complicate

 Propranolol
 Acid valproic, topiramat termen lung (luni)
 Amitriptilină, ciproheptadină
TRATAMENTUL MIGRENEI
 Măsuri generale:
 Evitarea abuzului de analgezice
 Somn ordonat (nici prea mult, nici prea puţin)
 Mese regulate, micul dejun fiind foarte important pentru copii
 În cursul episodului cefalalgic
 Evitarea stimulilor excesivi
 Încurajarea somnului – cel mai bun tratament al migrenei copilului

CONCLUZII
 Cefaleea este un simptom frecvent în copilărie
 Cefaleea episodică este frecvent migrenă
 Cefaleea secundară a copilului are caracteristici ale istoricului

care trebuie recunoscute, şi de obicei un examen neurologic
anormal (există însă excepţii!)
 Tratamentul şi prognosticul depind de etiologie şi de mecanismul

de producere (dgn precis) – istoricul şi examenul neurologic
fiind cele mai importante etape necesare unui diagnostic corect
ENCEFALOPATIA HIPOXIC-
ISCHEMICA PERINATALA

DEFINITIE EHIP
▪ Afectiune caracteristica nou-nascutului
▪ CAUZE: hipoxie + ischemie
▪ MOMENTUL AGRESIUNII:
- antepartum (rol major)
- intrapartum
▪ MECANISM: ↓ aportul O2 la nivelul SNC
▪ CONSECINTE EHIP:
1. Mortalitate infantila crescuta
2. Deficite neurologice neprogresive:
- paralizie cerebrala
- retard mental
- epilepsie
? Momentul agresiunii
antepartum vs. intrapartum
▪ Studii epidemiologice:
▪ National Collaborative Perinatal Project
Freeman , Nelson 1988
Nelson, Leviton 1991
▪ Western Australian Cerebral Palsy Register
Stanley 1993
10-15% dintre pacientii cu PC – istoric de agresiune

H-I severa intrapartum!
FIZIOPATOLOGIE
Agresiune hipoxic - ischemica?

Privarea de oxigen a creierului – 2 mecanisme
▪ Hipoxemie
= scaderea concentratiei O2 in sange
▪ Ischemie
= scaderea scaderea cantitatii de sange
cu care este perfuzat creierul.
▪ Reperfuzia – momentul aparitiei leziunilor in majoritatea
cazurilor
FIZIOPATOLOGIE
EHIP – 2 stadii FP
▪ Compensatorie
▪ Disfunctie cerebrala functionala
precoce
▪ Pastrare reserve energetice
▪ glicoliza ⁭
▪ Perfuzie cerebrala⁭
▪ Depasita
▪ Scad reserve energetice
▪ Acidoza
▪ Pierderi neuronale – leziuni cerebrale
NEUROTRANSMITATORII EXCITATORI SI CALCIUL
↓ ATP Hipoxie
Depolarizare
K+ Canal Ca++
ACIDOZA
mitocondrie
NMDA Na+
↑ glutamat RL
Ca ++
rec. glutamat
MOARTE NEURONALA
Florio P, Abella R, Marinoni E, Di Iorio R, Li Volti G, Galvano F, Pongiglione G, Frigiola A, Pinzauti S, Petraglia F, Gazzolo D. Biochemical markers of
perinatal brain damage. Front Biosci (Schol Ed). 2010 Jan 1;2:47-72. Review.
FIZIOPATOLOGIE
ROLUL RADICALILOR LIBERI
Hipoxie -ischemie/reperfuzie
Membrana
Radicali liberi
Ca++ (NO, O2-, ONOO-, OH) Peroxidare L-P
Inhiba functia Nucleu

respiratorie fragmentare/
lezare ADN
mitocondrie
MOARTE
NEURONALA
Florio P, Abella R, Marinoni E, Di Iorio R, Li Volti G, Galvano F, Pongiglione G, Frigiola A, Pinzauti S, Petraglia F, Gazzolo D. Biochemical markers of
perinatal brain damage. Front Biosci (Schol Ed). 2010 Jan 1;2:47-72. Review.
DIAGNOSTIC
ETAPE
▪ Diagnostic pozitiv
▪ Date anamnestice
▪ Monitorizare fetala
▪ Date clinice:
Scorul Apgar
Examinare clinica
▪ Date paraclinice
DIAGNOSTIC POZITIV. Date anamnestice – posibile cauze
▪ Cauze materne
▪ Anemia materna (<10g/dl)
▪ Afectiuni pulmonare cronice
▪ Cardiopatii
▪ HTA materna preexistenta/ de sarcina
▪ Traumatisme abdominale
▪ Infectii materne cronice + TBC
▪ Crize epileptice
▪ Tulburari coagulare
▪ Patologia sarcinii si a nasterii

▪ Patologie placentara
▪ Patologie de cordon ombilical: scurt/ innodat/ spasme vasculare
▪ Prezentatii anormale: transversa/ pelviana;
▪ Hemoragii in timpul expulziei
▪ Distocii de travaliu: lent, laborios/ rapid, contractii ut. prelungite
▪ Cezariana: decompresiune, anestezie generala
▪ Cauze ce tin de copil

▪ Prematuritatea
▪ Modificari ale transportului de oxigen la fat/ n-n: hemoliza
▪ Modificari ale functiei respiratorii la n-n:
Inhibitia centrului respirator (morfina, barbiturice, TCC obst.)
Dezv. insuficienta a tesutului pulmonar la prematur
Tulburari de ventilatie: membrana hialina/ aspiratie/ malformatie

DIAGNOSTIC POZITIV. Monitorizare fetala
▪ Cord fetal (monitorizare clinica, electrica)

▪ Frecventa: <100/min
▪ Accelerari/ decelerari fara legatura cu
contractiile uterine.
▪ Decelerarile precoce (la debutul contractiei) –
semn de hipoxie prezenta
▪ Monitorizarea pH fetal (probe sg. scalp)

▪ pH ↓ – risc ↑ deces/ afectare neurologica
▪ Prezenta meconiului
DIAGNOSTIC POZITIV. Scorul Apgar
▪ Coloratie tegumente
▪ Respiratie
▪ Alura ventriculara
▪ Tonus muscular
▪ Reflectivitate
▪ La 1’, 10’ de la pensarea cordonului ombilical
▪ Scor mic la nastere – nesesitate resuscitare
▪ Scor mic la 20’ – probabilitate ridicata sechele
Valoare diagnostica si prognostica orientativa

DIAGNOSTIC POZITIV. Date clinice (Sarnat, Sarnat 1976)
Clasificare EHIP in functie de severitate (n-n termen)
▪ EHIP usoara (gradul 1) – prognostic bun

▪ Copil hiperalert, jitter, Moro + la stimuli minimali
▪ Iritabilitate
▪ Tonus muscular normal
▪ ROT vii
▪ Diminuarea reflexelor complexe (supt, etc)
▪ EHIP moderata (gradul 2) – sechele 20-40%
▪ Letargie; jitter la incercari de a-l trezi
▪ Hipotonie
▪ ROT vii
▪ Reflexe complexe diminuate/ absente
▪ Convulsii fruste
▪ Mioclonus
▪ EHIP severa (gradul 3) – sechele 100%
▪ Stupor
▪ Flaciditate/ decerebrare
▪ ROT absente, abolire reflexe complexe
▪ convulsii
DIAGNOSTIC POZITIV. Date paraclinice
▪ EEG
- traseu izoelectric
(Volpe 1995)
- suppression burst
DIAGNOSTIC POZITIV.
Date paraclinice – rasunet hipoxie
▪ Potentiale evocate auditive, vizuale,

somatosenzoriale (nu de rutina)
▪ Teste biochimice: glicemie (↓), calcemie (↓),

natremie (↓), amoniemie (↑), echilibru acido-
basic
Metode imagistice
▪ ETF – foarte utila la prematur
▪ Faza acuta- hiperecogenitate
▪ Tardiv – hipoecogenitate – leziuni
chistice
Metode imagistice
▪ IRM cerebral
▪ Hipersemnal T2 la 12-
18 h = edem
tranzitoriu
Case courtesy of Dr Bita Abbasi, <a
href="https://radiopaedia.org/">Radiopae
dia.org</a>. From the case <a
▪ Hiposemnal T1 la 3 href="https://radiopaedia.org/cases/22712
">rID: 22712</a>
zile si hipersemnal T2
la 6 zile – leziune
cerebrala permanenta
Particularitati circulatorii maturationale –
leziuni tipice in functie de varsta gestationala
▪ Nou-nascutul la termen – zone sensibile la hipoxie localizate

parasagital – intre teritoriile de distributie ale ACA, ACM, ACP
(watershed/ border zones)
Particularitati circulatorii maturationale –
leziuni tipice in functie de varsta gestationala
▪ Prematurul – zone
sensibile la hipoxie
localizate periventricular –
intre teritoriile de
distributie ale vaselor
coroidiene ventriculofuge
si ramurile ventriculopete
ale aa mari cerebrale
(border zones, watershed
zones)
- anastomoze intre rr
meningeale ale ACA,
ACM, ACP
Varsta gestationala
▪ Particularitatile de vascularizatie
▪ Diferentele intre zonele de
proliferare si diferentiere activa
Tipuri de leziuni
Tipuri de leziuni
(anatomopatologic)
N-n la termen Prematur

▪ Necroza neuronala ▪ Necroza neuronala
selectiva selectiva
▪ Status marmoratus ▪ Leucomalacia
al ganglionilor bazali periventriculara
si talamusului ▪ Necroza cerebrala
▪ Leziunea cerebrala ischemica focala si
parasagitala multifocala
▪ Leziunea cerebrala ▪ Infarct hemoragic
ischemica focala periventricular
Necroza neuronala selectiva – corelatii clinico-patologice
▪ La distanta:
encefalomalacie multichistica
BIBLIOGRAFIE:
https://radiopaedia.org/articles
/neonatal-hypoxic-ischaemic-
encephalopathy?lang=us
▪ Clinic – in faza acuta:
deprimarea constientei,
crize epileptice,
anomalii tonus mm,
disfunctii ale muschilor
extraoculari, diplegie
faciala, tulburari de
respiratie, supt,
fasciculatii ale limbii
▪ Clinic – sechele:
▪ DM,
▪ epilepsie (10-30%),
▪ PC spastica (tetra)
▪ Tulb deglutitie -
supravietuire↓
▪ ADHD – formele usoare
Leziune cerebrala parasagitala
caracteristica n-n la termen
▪ Clinic: Sechele pe
termen lung:
tetrapareza
spastica, deficite de
limbaj si vizuo-
spatiale
Status marmoratus al gg bazali si talamusului –
corelatii clinico-patologice
Case courtesy of Dr Jenny Hoang, <a href="https://radiopaedia.org/">Radiopaedia.org</a>.

From the case <a href="https://radiopaedia.org/cases/33510">rID: 33510</a>
▪ Afecteaza:
▪ gg. bazali pierderi neuronale
▪ talamus, glioza aspect marmorat
hipermielinizare
▪ Cauza: distributia anatomica a receptorilor pt glutamat (NMDA in special)

si particularitatilor de proliferare diferentiere ale zonelor respective
▪ Etiologia: asfixie “totala acuta”
▪ Clinic - acut – aspect necunoscut

- sechele: DM, coreoatetoza, distonie, tremor
?
Leziune cerebrala ischemica focala
apare in special la n-n la termen, dar si la prematuri
▪ Cauza probabila: ocluzia vasculara, tromboza

venoasa profunda – trombembolism - sursa:
▪ infarct placentar,
▪ vase placentare care involueaza,
▪ anomalii de dezvoltare ale vaselor cerebrale,
▪ tulburari hematologice (policitemia, def ATIII sau proteina C),
▪ trombocitopenie izoimuna,
▪ CID
▪ La n-n la termen – ACM cel mai frecvent
▪ Sechele: atrofie + cavitatie chistica (↑apa,
↓mielina, proliferare astrogliala ↓)
▪ Clinic:
▪ la n-n – asimptomatici
sau crize focale,
hemipareza contralaterala
(Moro asimetric, miscari
asimetrice). MS, fata > MI
▪ Sechele pe termen lung:

hemipareza spastica , RM,
epilepsie
Leucomalacia periventriculara
▪ Leziunea: necroza de
coagulare a substantei
albe periventriculare –
▪ Caracteristic prematurului
Leucomalacia periventriculara
▪ Clinic – sechele:
????
Abordarea pacientului cu EHIP
▪ Preventia asfixiei intrauterine:
▪ Recunoastere factori de risc materni
▪ Monitorizarea fatului cu risc crescut (sarcina, nastere)
▪ Singurul tratament – Cooling – urgent! <6 ore
(https://www.youtube.com/watch?v=rfsnGaflTuU)
▪ Sustinerea functiilor vitale
▪ Combaterea insuficientei multiorganice
▪ Mentinerea ventilatiei adecvate – evitarea hiperoxiei
▪ Mentinerea nivelului adecvat de glucoza – dai glucoza numai in
faza acuta!
▪ Controlul crizelor epileptice – PB – 20 mg/kg – max 40 mg/kg
(monitorizare c-r); PHT – 20mg/kg (monitorizare cord), BZD. Durata
scurta.
▪ Tratament antiedematos – controversat: corticosteroizi, agenti
hiperosmolari, Hv)
▪ Neuroprotectie: antagonisti rec glutamat; antioxidanti vit E, C,
glucocorticoizi, magneziu, inhibitori de RL (indometacin,
allopurinol)
SINDROMUL DE HIPERTENSIUNE
INTRACRANIANA (HIC)

ANATOMY:
- osul cranian
- meninge
- creier
- LCR
- sistemul vascular intracranian

CAUZE FRECVENTE DE HIC
1. MODIFICARI ALE CUTIEI CRANIENE

- Craniosinostoze primare (boala Crouzon, sd. Apert, craniosinostoze
izolate)
2. LEZIUNI PARENCHIMATOASE si spatiu interstitial, meninge
- procese inlocuitoare de spatiu intracraniene
- orice cauza de edem cerebral
- meningite bacteriene / virale
3. AFECTAREA COMPARTIMENTULUI VASCULAR
- hemoragii intraparenchimatoase
- hemoragii extra-/ subdurale
4. AFECTAREA SPATIILOR CE CONTIN LCR
- hidrocefalii
5. AFECTIUNI GENERALE
- encefalopatia hipoxic-ischemica
- sindrom Reye
- boli metabolice congenitale
- cetoacidoza diabetica
- coma hepatica
MANIFESTARILE CLINICE ALE HIC
?
Clasic se descrie triada: cefalee, varsaturi, edem papilar.
Manifestarile clinice ale HIC difera in functie de

- vârsta (difera proprietatile cutiei craniene),
- afectiune,
- rapiditatea progresiunii.
CEFALEEA
- localizare:
- fronto-temporala în tumorile supratentoriale (prin tractiunea
durei, inervate de trigemen)
- occipitala în tumorile subtentoriale
- exacerbata de actiuni care cresc presiunea intracerebrala: tuse, stranut,

Valsalva, sau de ridicarea brusca a capului din pat (dimineata)
- durata: zile, saptamâni
- analgezicele ajuta putin sau deloc;
- la copiii mici, largirea suturilor poate duce la disparitia cefaleei (sau

cefaleea poate sa nu apara deloc, daca cresterea presiunii este
foarte lenta.)
Varsaturile
- sunt “în jet”, fara efort
- amelioreaza cefaleea
Pareza de nerv VI
- semn indirect de HIC
- cauza: compresiunea n.VI (cel mai lung traiect intracranian
- fals semn de localizare
- uni- sau bilateral
- diplopie binoculara ce se agraveaza când pacientul priveste
spre muschiul paretic
Afectarea privirii în sus
- Cauze: - presiune asupra regiunii pretectale

- afectarea functiei mezencefalice produce retractia
usoara a pleoapei superioare prin hiperactivitate
simpatica
- Efect: privirea “în apus de soare”
Cresterea dimensiunilor craniului

- la copiii care au înca dehiscente suturile si fontanelele cerebrale
- sunt necesare masuratori seriate ale perimetrului cranian
Modificari ale personalitatii:
- iritabilitate
- schimbari bruste ale comportamentului
- apatie, letargie.
Edemul papilar
- este cel mai sigur indicator de HIC, atunci când exista
- lipsa sa nu infirma HIC
- cauza: edematierea stratului fibros al nervului optic
- uni- sau bilateral în leziuni supratentoriale
- bilateral în leziuni subtentoriale
INVESTIGATII:
1. FO - este obligatoriu în caz de suspiciune de edem cerebral;

- se pot vizualiza 4 stadii: staza papilara, edem papilar, hemoragii
retiniene, decolare retiniana.
2. PL - se interzice formal în caz de edem papilar
- se poate efectua cu precautii: decubit lateral (scade presiunea
intracraniana), sau dupa administrare de depletive.
3. CT cerebrala:
- hipodensitate difuza sau localizata în jurul cauzei de HIC (tumora,
hemoragie, TCC)
- stergere a diferentelor între substanta alba si cea cenusie
- diminuarea dimensiunilor ventriculilor cerebrali care sunt comprimati
4. RMN: hiposemnal T1 si hipersemnal T2 localizat sau difuz
5. Radiografia craniana
- dehiscenta suturilor
- subtierea lui dorsum sellae si largirea seii turcesti la copiii mari, stergerea
proceselor clinoide
- impresiuni digitate
COMPLICATIILE HIC ACUT
1. Circulatorii - produse prin comprimarea vaselor cerebrale, cu aparitia

fenomenelor de ischemie cerebrala
2. Mecanice (herniile cerebrale)
- prin foramen magnum: amigdalele cerebeloase producând
compresia bulbului, arterelor vertebrale si radacinilor nervilor
spinali.Clinic: cefalee occipitala, torticolis, tulburari,de ritm
cardiac si vasomotorii; prognosticul este sever
- hernii la nivelul incizurii tentoriale – uncusul hipocampului în jos
sau uneori lobul anterior al cerebelului în sus, rezultând
compresia arterelor comunicante cerebrale, cu aparitia de
midriaza pe partea angajarii, tulburari vizuale, rigiditate prin
decerebrare.
- herniile sub coasa creierului ale corpului calos sau girus cinguli, nu
au expresie clinica
c
• c
TRATAMENTUL
- obiective: combaterea agentului cauzal (tratament etiologic) si

tratamentul edemului cerebral acut propriu-zis (tratament simptomatic).
• Tratamentul simptomatic se poate face prin:

1. Mijloace fizice:
- Restrictia de lichide
- Ridicarea capului deasupra planului corpului
- Hiperventilatia
- Administrarea de oxigen hiperbar
2. Tratament medicamentos:
- Corticoterapia: Dexametazona 0,6-1mg/kg/zi, divizat în 4 doze;
- Agenti osmotic activi – Manitol (1-2 g/kg/zi în mai multe doze divizate,
de preferat la 3-4-6 ore).
- Diureticele de ansa (furosemid si acid etacrinic) 0,5-1mg/kg.
3. Tratament chirurgical
- craniotomie decompresiva
- drenajul LCR;
EDEMUL CEREBRAL
DEFINITIE:
edemul cerebral (EC) este definit ca o crestere a volumului

cerebral datorata cresterii volumului sau de apa.
EC vasogenic
• etiologii -infecţii
- traumatisme
- toxine - Pb
- convulsii focale
- HTA malignă
• mecanism :
- creşterea permeablităţii endoteliului capilar
- alterarea BHE
exudarea în substanţa albă a unui lichid

bogat în albumina şi macromolecule
(edem extracelular).
EC citotoxic
• etiologii - agresiune hipoxic-ischemică
- infecţii severe
- toxine – uremia normotensivă
- status epilepticus
- scăderea fluxului sanguin cerebral
• mecanism
- scade energia intracelulară (ATP, PC)
- funcţionarea deficitară a pompelor ionice
membranare
- balonizarea cu apă a celulelor
(edem celular).
EC hipoosmolar
• etiologii – hiponatremia
- administrarea excesivă de fluide
în cetoacidoza diabetică
- sindromul de dezechilibru în dializă
• mecanism
- dezechilibru hipoosmolaritate plasmatică /
hiperosmolaritatea glială
- acumulare de apă în astrocite
(edem celular).
EC intestiţial
• etiologie – hidrocefalie şi hipertensiune

intracraniană consecutivă
• mecanism – resorbţia transependimară a

LCR în spaţiul extracelular (zona lucens).
http://emedicine.medscape.com/article/1135286-overview
http://www.thamburaj.com/hydrocephalus.htm
HIDROCEFALIA
C
CIRCULATIA LCR
Rapel anatomo-fiziologic
LCR
FORMARE: - 70-90% produs de plexurile coroide;
rată: 21-22 ml/h → 500 ml/zi;
se reînnoieşte de 4-5 ori/zi;
VOLUM: - 50ml la n.n.

60-140 ml la copil
90-150ml (120medie) adult (25 ml intraventricular)
PRESIUNE:
40-50 mm H2O la n.n.
100-150 mm H2Ocopil,adolescent
depinde de - p.de secreţie
- p.venoasă
- rezistenţa căilor prin care circulă
- distensibilitatea spaţiilor ce conţin LCR
(parenchim, meninge, creier)
FUNCŢIE:
mecanică
schimburi substanţe
HIDROCEFALIE – DEFINIŢIE:
• Creşterea volumului de LCR
intracranian în toate sau unele părţi ale
spaţiilor ce conţin LCR
• insotit de creşterea presiunii LCR din

diverse cauze (cel puţin iniţial),
• această creştere de volum nefiind

rezultatul atrofiei sau disgeneziei
cerebrale.
HIDROCEFALIA –mecanisme
etiopatogenice
1. Obstrucţia circulaţiei LCR
Bloc intraventricular: - localizari: foramen Monro,V3, Ap.Sy., V4,
- cauze: tumori, malformaţii, inflamaţie (toxoplasmoză,
meningită, ependimită granulară posthemoragică);
Bloc extraventricular: - localizari: bloc bazilar, bloc de convexitate;
- cauze: inflamaţie (infecţioasă sau posthemoragică, tumori
(gliom chiasmatic, craniofaringiom), însămánţări
maligne pe meninge; mucopolizaharidoze;
2. Deficit de absorbţie LCR

Anomalii ale vililor arahnoidieni (absenţa vililor,blocarea vililor prin conţinut bogat
în proteine al LCR)
Hipertensiune venoasă (compresia sinusurilor venoase, foramine bazale anormale ce
dau compresiune venoasă, obstacole venoase extracraniene)
3. Hipersecreţie LCR
Papilom de plex coroid(?)
HIDROCEFALIE – INVESTIGAŢII
Ecografie transfontanelară (ETF)

CT cerebral
RMN cerebral
Măsurarea presiunii LCR
EEG
PEA de trunchi cerebral
HIDROCEFALIA FETALĂ
Diagnostic:
ecografie fetală (13-16 săpt. susp.; 20-22 săpt. cf.)
RMN (nu de rutină)
Diagnostic diferential:
agenezie corp calos
chist plex coroid
holoprozencefalie
ventriculomegalie neevolutivă
Investigatii:
cariotip
alfa-fetoproteină
serologie pt. diverse infecţii
Etiologie:
cauze genetice (sd.hidroletal, sd.Meckel, Gruber, sd.Walker Warburg,etc.)
cauze nongenetice: - infecţii (toxoplasmoza)
hemoragie prenatală
tumoră congenitală
Evolutie:
avort spontan
ajung la termen: deces / DPM întârziată
Întreruperea sarcinii – la cererea părinţilor sau asociere H + sd. genetic / alte
malformaţii
HIDROCEFALIA LA COPIII SUB 2 ANI
CLINIC:
▪ macrocranie simetrică ( PC la
măsurători repetate);
▪ fontanela anterioară mărită,
suturi depărtate;
▪ tegumente scalp subţiri,
transparente;
▪ reliefare desen venos;
▪ privire “în apus de soare”,
retracţia pleoapei superioare;
▪ întârziere în DPM pe etape (+/-);
▪ atrofie optică în cazurile
avansate;
▪ edemul papilar = neobişnuit
(evoluţie f. rapidă);
▪ crize convulsive;
▪ mişcări oscilatorii ale capului 2-
3Hz / tremor.
HIDROCEFALIA LA COPILUL MARE
Suturi închise; creşterea presiunii LCR nu poate fi compensată de

creşterea PC.
CLINIC:
sindom de HIC: - cefalee, vărsături, edem papilar;
regres neuropsihic;
ataxie ( fluxul sanguin în gg. bazali);
semne piramidale;
semne oculare (nistagmus, sd.Parinaud, tulburări de
convergenţă, anomalii pupilare);
tulburări de memorie;
tulburări de comportament;
letargie;
tulb. ale st. de conştienţă → comă;
HIDROCEFALIE – TRATAMENT
1. Tratament etiologic:
→ excizia tumorii compresive / secretante LCR;
→ chist arahnoidian – excizie / shunt.
2. Tratament medicamentos:
→ Acetazolamidă – 100mg/kg/zi;
→ Furosemid – 1mg/kg/zi;
→ Recomandări: - temporizarea intervenţiei
chirurgicale;
- H lent progresivă;
- Prematuri cu H posthemor.
c
HIDROCEFALIE –
tratament chirurgical
HIDROCEFALIE –
tratament chirurgical
Operatia de shunt:
c.i.: - H ac. posthemoragică sau meningită – faci
tratament medicamentos / PL repetate
- copii>3ani cu H staţionară cu intelect normal;
- prematuri cu hemoragie intraventriculară: -
PL / ventriculare repetate;
tipuri: v-cardiac; v-peritoneal; v-pulmonar; v-
amniotic; ext.;
tubulaturi de presiuni: joasă / medie / înaltă (azi –
reglabile);
complicaţii: infecţii, disconexiuni, obstrucţia
tubulaturii, perforarea org. abd., complicaţii
cardiace, nefrită cu complexe imune
?
NEUROFIBROMATOZA
Neurofibromatoza- definitie
Grup de boli genetice cu transmitere
autosomal dominanta cu expresie clinica –
variabila (dar penetranta completa la adult) cu
punct de plecare - celulele SNC si periferic
datorate disgeneziei ectodermului periferic.
NF-clasificare
• NF-1(tipul periferic), 1:4000 persoane, macule hiperpigmentate
multiple (pete café au lait) si neurofibroame periferice; 17q11.2 –
neurofibromina antioncogen)
• NF-2 (tipul central), 1:50 000 cazuri, neurinoame de nerv acustic si

alte tumori intracraniene si / sau intraspinale; 22q11.2 - merlina
(supresor tumoral)
• Schwannomatoza. Produsa de mutatii ale genelor SMARCB1 si

LZTR1, supresoare tumorale (manifestata prin schwannoame
dureroase.
• NF tipul segmental (NF segmentala), manifestari cutanate apartinând

tipului NF-1, cu distributie exclusiv segmentara (orice dermatom)
7 Criterii diagnostice pentru NF-1:
1.  6 macule café au lait > 5 mm la indivizi prepubertari;
>15mm la indivizi postpubertari;
2. pistrui in zona axilari sau inghinali;
https://eyerounds.org/cases/38-
NeurofibromatosisOpticNerveGlioma.htm
3.
 2 neurofibroame de orice tip sau un neurinom
plexiform situate în regiuni diferite ale corpului;
Neurofibromatosis: Chronological history and current issues - Scientific

https://gudhealth.com/neurofibromatosis/ Figure on ResearchGate. Available from:
https://www.researchgate.net/figure/Plexiform-neurofibroma-
Dermatology-Service-FAMERP_fig5_241693442 [accessed 18 May, 2020]
4. gliom optic
https://eyerounds.org/cases/38-
NeurofibromatosisOpticNerveGlioma.htm
5.
 2 noduli Lisch
(hamartoame iriene)
https://emedicine.medscape.com/article/12
19222-overview
Examinare lampa cu fanta
6. Leziune osoasa distinctiva:
displazie sfenoidala
https://doi.org/10.3348/kjr.2006.7.1.70
6. Subtierea cortexului oaselor
lungi cu sau fara pseudoartroza
Consecinta importanta - scolioza
Current Orthopaedic Practice: January/February 2017 - Volume 28 - Issue https://radiopaedia.org/play/13860/en

1 - p 10-14 doi: 10.1097/BCO.0000000000000462 try/216503/case/49513/studies/54698
Tratament chirurgical - ortopedic
http://spinal-deformity-surgeon.com/case-studies/beth-g/
• 7 – criteriul genetic – clinic sau de analiza
moleculara
o ruda de gradul I (parinte,

frate sau copil) cu NF-1
Gene in panelul de Neurofibromatoza
2 Criterii diagnostice pentru NF-2:
• mase bilaterale la nivelul nervului VIII, diagnosticate cu CT sau RMN;
• o ruda de gradul I cu NF-2 fie cu masa unilaterala de nerv VIII, fie cu
doua din urmatoarele: neurofibrom, meningeom, gliom, schwannom si
opacitate subcapsulara posterioara lenticulara juvenila.

Diagnostic cert
• 2 criterii
NA, 7 luni
• La fiecare trezire – tresariri ambe brate,
cap in fata, mai multe la rand.
• Clinic – foto
• DPM: Nu tine capul, nu

sade, nu urmareste cu
privirea, nu lalalizeaza
• Discuta semiologia
• Cel mai probabil dg?
• Ce alte date ati mai cere pt dg ?

EEG ?
CT cerebral
IRM
Diagnostic de etapa
• Sindrom West
• Complexul sclerozei tuberoase
COMPLEXUL SCLEROZEI
TUBEROASE
Cum apare boala?
(determinism)
GENETICA:
clasic - autosomal dominant
TSC1 – 9q34
TSC2 – 16p13.3
studii recente - mutatii de novo(68%);

Petele acrome
• Apar la nastere
• Cresc ca nr. si dimensiuni odata cu varsta
• Dg. diferential cu vitiligo
• Polioza = mesa de par alb
• Piele alba – cum evidentiem?
Scl tub pete acrome.MPG
CE ALTE SEMNE
CUTANATE CUNOASTETI?
Angiofibroame (fost adenoma sebaceum)
• Anatomopatologic: angiofibroame
• Apar dupa 4 ani – pubertate
• Mici papule rosii
• Dispozitie “in fluture” pe nas si umerii
obrajilor (Pringle)
• Dg. Diferential – acneea juvenila
Angiofibroame
Alte leziuni cutanate
piele shagreen
tumorile Koenen (noduli periunghiali)
placi fibroase ale pielii fruntii

pete café au lait

fibroamele sau papiloamele orale;

defecte de smalt dentar
Aspecte clinice ale afectarii cerebrale
1. Epilepsie - spasme infantile/epileptice
- orice tip de criza epileptica
2. Cognitiv – f variabil
- retard mental – 50%
- inteligenta normala - restul
3. Afectare sfera psihiatrica
- hiperkinezie - 59%
- agresivitate - 13%
- tulburare spectru autist – 25-61% din copiii cu
West
4. Semne de HIC
Leziuni cerebrale principale
• Tuberi corticali
• Noduli periventriculari subependimari
• Astrocitom cu celule gigante

subependimar (SEGA)
c
c
Ce recomandati unei femei
insarcinate care are deja un copil
cu ST?
Discutii – investigatii si sfat genetic

Imagistica prenatala
CE ALTE ORGANE SUNT
AFECTATE?
ASPECTE CLINICE: III. Afectarea altor organe
• Ochi
• Cord
• Rinichi
• Pulmon
• Sistem endocrin
• Tiroida, ficatul, suprarenalele
• Sistemul osos
OCHI
Ochi - FO - .20% - facom retinian - precoce (nastere);
CORD
Cord - 50% - rabdomioame cardiace
Fat 21 sapt, VS
RINICHI
Rinichi
• 60-80% - Angiomiolipoame
• 20-30% - chiste renale
• 2% - boala polichistica a.d.
• <1% - carcinom renal

Afectarea altor organe
• Pulmon - 1% - frecvent femei >20 ani; infiltrat reticular fin
si modificari multichistice ; limfangioleiomiomatoza
Afectarea altor organe
• Orice organ poate fi afectat - hamartoame;

Evolutia cu varsta
Diagnostic
• Nu exista semne patognomonice
• Multe semne – apar si la indivizi care nu

au ST (sanatosi)
• Dg = combinatie de semne majore si

minore
A. Criteriul genetic de diagnostic
• Identificare mutaţie patogenica pe TSC1
sau TSC2 în ADN din ţesut normal =
criteriu suficient
(www.lovd.nl/TSC1, www.lovd/TSC2, and Hoogeveen- Westerveld
et al., 2012and 2013).
• 10-25% pacienţi TSC – fara mutaţie

(testare convenţionala)
• rezultat normal - nu exclude TSC
• Nu infirma diagnosticul clinic de TSC
A. Criterii clinice de diagnostic
Criterii minore
Criterii majore
• Pete acrome (≥3, cel puţin 5mm diametru) • Leziuni cutanate

• Angiofibroame (≥3) sau placă fibroasă “Confetii”
cefalică • Defecte de smalţ dentar
• Fibroame unghiale (≥2) (>3)
• Piele shagreen • Fibroame orale (≥2)
• Multiple hamartoame retiniene • Pete acrome retiniene
• Displazii corticale* • Chiste renale multiple
• Noduli subependimari • Hamartoame nonrenale
• SEGA (astrocitom subependimar cu celule
gigante)
• Rabdomiom cardiac
• Limfangioleiomiomatoză (LAM) **
• Angiomiolipoame (AML ≥2) **
Nivelul de certitudine de diagnostic este:
- ST certă (diagnostic cert): ≥2 criterii majore

sau 1 criteriu major şi ≥2 minore
- ST posibilă: 1 criteriu major sau ≥2 criterii
minore
TRATAMENT?
•4
5
Inhibitia mTOR in ST
• Genele TSC1,2 – coreaza H,T
ST
• Complexul hamartina/tuberina =
principalul inhibitor celular al mTOR TSC1 (9q) TSC2 (16p)
• mTOR = reglator Ser/Thr kinase al
cresterii celulare si metabolismului1
• ST - mutatii TSC1, TSC2, care HAMARTINA TUBERINA
codeaza hamartina si tuberina
• mutatii TSC1/2 (loss of function)
complexul hamartina/tuberina nu
inhiba mTOR, care se activeaza mTOR
• Activarea mTOR explica patogeneza INHIBITOR
ST EXOGEN
• Inhibitorii exogeni ai mTOR = patogeneza ST

strategie terapeutica promitatoare 2,3
1. Wullschleger S, et al. Cell. 2006;124(3):471-484 (tumori, displazii)
2. Krueger, et al. N Engl J Med. 2010;363(19):1801-1811
3. Crino, et al. N Engl J Med. 2006;355:1345-1356
Modificarea dimensiunilor SEGA
•Baseline •3 Luni de Everolimus
•Data provided by DN Franz, University of Cincinnati College of Medicine.

Diminuarea volumului SEGA si
rezolvarea hidrocefaliei
•Baseline •3 Months of Everolimus
•
•Krueger DA, et al. N Engl J Med 2010;363:1801-11.
Disparitia afectarii subst albe asociate
SEGA
•Baseline •3 Months of Everolimus
•
•Data provided by DN Franz, University of Cincinnati College of Medicine.
Indicatii EVEROLIMUS
CRITERIU COPII ADULTI

SEGA in crestere + +
AML in crestere - +
Epilepsie focala rezistenta + +
la MAE
CAZ – la CG
• BD – sex feminin – 14 ani
• Adusa de salvare
• Clinic – miscari ritmice ale membrelor, corp
rigid, PC, privire plafonata
• Dupa o noapte petrecuta la discoteca +
alcool
Q
• Semiologic?
• Sindromic?
• Este SE sau NU?

STATUS
EPILEPTICUS
Gastaut H. Clinical and electroencephalographical classification of epileptic
seizures. Epilepsia1970;11:102–113. (Developed starting 1964)
Definitia 1964-1970:
“afectiune caracterizata printr-o criza

epileptica care este suficient de lunga
sau repetata la intervale suficient de
scurte pentru a produce o stare
epileptic durabila, care nu variaza”
Revised – ILAE 1981
O criza care “persista suficient de mult timp sau

se repeta destul de frecvent astfel incat nu mai
apare recuperare intre atacuri.”
Proposal for revised clinical and electroencephalographic classification of epileptic

seizures. From the Commission on Classification and Terminology of the
International League Against Epilepsy. Epilepsia 1981;22:489–501.
DEFINITIE practica – ILAE 1993
• criza epileptica cu durata > 30’

sau
• mai multe crize fara recapatarea completa
a constientei intre ele durand > 30’
•Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status
Epilepticus. JAMA 1993;270:854–859.
•Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy.
Epilepsia 1993;34:592–596.
De ce 30 min?
• Brain damage
Shorvon J Neurol Neurosurg Psychiatry 2001;70:ii22-ii27

ASTEPTAM 30 MIN?
CARE ESTE DURATA UNEI CRIZE
AUTOLIMITATE?
• Cele mai multe crize
dureaza <2 minute
• Evaluare cu video-
EEG
• 579 crize la159

pacienti (adulti,
putini copii)
Probabilitatea sa devina SE bazat pe
cea mai lunga durata a crizei
• SGTCS >660 s (11

min)
• CPS > 600 s (10 min)
• SPS > 240 s (6 min)
• Prospectiv, prima criza neprovocata, 407
copii
≥ 5’ – 50% distributie exponentiala

≥ 10’ – 29% medie 3,6’ – 76%
≥ 20’ – 16% medie 31’ – 24%
≥ 30’ – 12%
Mai lungi decat la adulti!

CAND sa tratam si DE CE?
• 182 copii cu ≥ 2 crize

= duratie corelate
Shinnar et al 2001;49:659-664
CAND sa tratam si DE CE?
• Cu cat criza este mai lunga – cu atat

probabilitatea de a se opri este mai mica
• Este improbabil ca o criza de > 5 min sa se

opreasca singura – TREBUIE tratat dupa 5 min!!
Shinnar et al 2001;49:659-664
Definitia operationala a SE
convulsiv generalizat
• >5 ani (adulti inclusi) = > 5min
• Sugerat copii <5 ani = 10-15 min

dar nu exista date
Lowenstein, et al. Epilepsia 1999; 40:120-22.

CRIZA > 5’
INTERVENTIE TERAPEUTICA
IMEDIATA!!
Lowenstein DH, Cloyd J. Out-of-hospital treatment of status epilepticus and prolonged
seizures. Epilepsia. 2007;48 Suppl 8:96-8. [Medline].
DE CE?
De ce tratam SE? Leziuni cerebrale!
Dravet
• Imagistica la debut – normal
• Imagistica la varsta mare – SH si modificari subst
alba
DAY 27 after SE DAY 101 after SE
• Mortalitate – pana la 20%
• Sechele neurologice si cognitive
• Prognosticul – depinde de durata

debut SE – debut tratament
• T1 = momentul in care criza trebuie
considerate “anormal de lunga” (>5 min)
• T2 = momentul in decursul unei crize in
desfasurare dincolo de care = risc de consecinte
pe termen lung (>30 min)
CLASIFICARE – PATRU AXE
• Semiologie
• Etiologie
• Corelate EEG
• Varsta
AXA 1. SEMIOLOGICA
Semne motorii proeminente, pastrarea constientei
Axa 2: ETIOLOGICA
Axa 3: Corelate EEG
Nu exista criterii EEG bazate pe dovezi pentru SE!
• Localizate: generalizat (inclusive pattern bilateral sincron),
lateralizat, bilateral independent, multifocal.
• Aspect (pattern): descarcari periodice, ritmice, activitate delta sau
CVU.
• Morfologie: aspect ascutit, numer de faze (ex. trifazic), amplitudine
absoluta sau relativa, polaritate.
• Aspecte legate de timp: prevalenta, frecventa, durata, aspecte si
durata zilnice, debut (brusc vs. treptat), si dinamica (care evolueaza,
fluctueaza, sau static).
• Modulare: indus de stimul sau spontan.
• Efectul interventiei (medicatie) asupra EEG
Axa 4: VARSTA
• Neonatal (0 - 30 zile)
• Sugar (1 luna - 2 ani)
• Copil (> 2 - 12 ani)
• Adolescent si adult (> 12 - 59 ani)
• Batran (≥ 60 ani)
EVOLUTIA NATURALA
SE instalat:
- stadiu precoce (compensat), <30’,
t. nervos protejat
- stadiu tardiv (decompensat), >30-60’,

leziuni cerebrale
Meldrum BS, Horton RW. Physiology of status epilepticus in primates. Arch

Neurol. Jan 1973;28(1):1-9. [Medline].
CE FACETI?
SE = URGENTA MEDICALA !
SE - ABORDARE TERAPEUTICA
1. Anamneza
2. Examenul fizic
3. Investigatii
4. Verificare, corectare parametri vitali
5. Tratament medicamentos anticonvulsivant
1. ANAMNEZA
- TCC
- semne/simptome meningita
- expuneri/ingestii toxice
- afectiuni acute/cronice
- epilepsie in antecedente, tratament, complianta
- antecedente
FACTORI PRECIPITANTI
• sevraj brusc al medicatiei antiepileptice

• complianta scazuta
• alcool
• infectii, alte boli intercurente
• evolutivitatea/decompensarea bolii
subiacente epilepsiei (T, MAV, b. metab.)
CE FACETI INTAI?
SE - ABORDARE TERAPEUTICA
1. Verificare, corectare parametri vitali:

- permeabilitate cai respiratorii
- respiratie
- circulatie
2. Pozitie
3. Asigurare linie venoasa/ intraosos/ tub endotr.
4. Recoltare
https://www.google.ge/search?biw=1280&bih=544&tbm=isch&sa=1&ei=-
Q_jW___KMSqsQGcmJOICA&q=ABC+emergency&oq=ABC+emergency&gs_l=img.3..0i19k1l3.13176.15416.0.1
8495.9.9.0.0.0.0.155.965.0j7.7.0....0...1c.1.64.img..2.7.964...0j0i30k1j0i8i30k1j0i30i19k1j0i8i30i19k1.0.L1gO5qstLEk
#imgrc=WQhRtNLQQVyaMM:
CHECK VITALS & MEASURE

DURATION
CRONOMETREAZA
POZITIA DE SIGURANTA
https://www.youtube.com/watch?v=dv3agW-DZ5I
Evalueaza oxigenarea &
administreaza O2!
Evalueaza glicemia &
administreaza glucoza!
Monitorizeaza semnele vitale
Copyrights apply
Stabilizare
• Prioritate – mentinere schimburi gazoase adecvate
• Repeta evaluari ABC
• IMPORTANT: evaluare glicemie rapid - corectare.
• Crize acute – Glicemie crescuta – nu necesita tratament
• Hipeglicemie cetotica sau non-cetotica +/- precipita SE (poate fi manifestare
precoce de diabet zaharat).
• Hipoglicemia – administreaza glicoza, NU in dieta cetogenica.
• Crize continue + hupoxemie, glucoza cerebrala scazute, se agraveaza
acidoza metabolica care poate determina leziuni neuronale.
• Diabet/ prezentare ca hipoglicemie: crize gen/focale – poate mima crize
epi/stare post critica.
• Acidoza metabolica – se rezolva fara trat dupa oprire crize
• FBRA - antipiretice
SE
NU Access i.v.
ETAPE TRATAMENT
DA
Access
intraosos
/traheal I. Benzo: SE>10’
DZP 0,3 mg/kg
LZP 0,05-0,1
NU DA mg/kg
II. Phenytoin/Fos SE>25’

i.m. 15-20 mg/kg/dose
MDZ
i.r. DZP
III. Intubare, SE>25’
ventilare, SE refractor
PB i.v. -anestezice
https://homesecurity.press/quotes/intraoss
eous-access-sites.html
https://en.wikipedia.org/wiki/Tr
acheal_intubation
SE - COMPLICATII
1. Leziuni neurologice ireversibile

2. Pulmonar: aspiratie, obstructie, hipoventiletie,
edem pl. neurogen
3. Cardiac: aritmii, stop
4. Hipertermie
5. Rabdomioliza insuficienta renala acuta
SE - CAUZE DECES
1. Complicatii
2. Cauza subiacenta
3. Iatrogen:
- neatentie la parametrii vitali
- neatentie la complicatii
- prea multa medicatie (hTA, hventil.)
Nu orice angiom e Sturge Weber
DEFINITIE ?
SSW – DEFINIŢIE
Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains
caused by somatic mutation in GNAQ. N Engl J Med 2013; 368:1971.
-afecţiune vasculară congenitală rară

-non-ereditară, sporadica
-mutaţie somatica în gena GNAQ
-angiom facial
- angiom venos leptomeningeal, ochi homolateral
- clinic: crize epileptice, pareza - hemicorp

contralateral angiomului
- imagistica: calcificari - ‘sina de tren’.
Angiomul facial
- congenital - diagnostic la naştere
- afectează faţa – unilateral (frecv.) /
bilateral (rar) – V1, V2
- pe partea afectată pot fi prinse ochiul şi
buza
- plat şi roşu (ca vinul de porto)
- cauză - genetica
- poate lipsi + aspecte tipice radiologice şi
neurologice ale sindromului (“SSW fără
nev”)
c
Angiomul leptomeningeal
 afectare frecventă a lobului occipital
 necroza corticală subiacentă cu

distribuţie laminară
 calcificăricorticale superficiale ce
urmează conturul circumvoluţiilor, ‘în
şină de tren’ (radiografic)
c
Faceti IRM cu substanta de contrast!!!
Fara contrast
Cu contrast
CT la 1 an 3 luni (calcificarile – inexistente la 3 luni)
Aspectele neurologice
 Contralateralnevului
–Hemipareză / hemiplegie
–Hemianopsie
–Epilepsie – debut – nou-născut , greu
tratabile, SE
 Retard dezvoltare, mental - agravare

Aspecte oftalmologice
 Glaucom
 Buftalmie
 hemangiom episcleral – 100% din

cazurile cu glaucom şi SSW
 hemianopsia omonimă
 Hemangiom coroidian
Glaucom+buftalmie
Hemangiom episcleral FO: hemangiom coroidal
IRM hemangiom coroidal

SINDROM STURGE-WEBER
fosta denumire – confuziva

(angiomatoza encefalo-trigeminală)
Proposed Algorithm for Convulsive Status Epilepticus
From “Treatment of Convulsive Status Epilepticus in Children and Adults,” Epilepsy Currents 16.1 - Jan/Feb 2016
Interventions for emergency department, in-patient setting,
Time Line or prehospital setting with trained paramedics
1. Stabilize patient (airway, breathing, circulation, disability - neurologic exam)

2. Time seizure from its onset, monitor vital signs
3. Assess oxygenation, give oxygen via nasal cannula/mask, consider intubation if respiratory assistance
0-5 Minutes needed
Stabilization 4. Initiate ECG monitoring
Phase 5. Collect finger stick blood glucose. If glucose < 60 mg/dl then
Adults: 100 mg thiamine IV then 50 ml D50W IV
Children ≥ 2 years: 2 ml/kg D25W IV Children < 2 years: 4 ml/kg D12.5W IV
6. Attempt IV access and collect electrolytes, hematology, toxicology screen, (if appropriate) anticonvulsant
drug levels
Does Seizure
YES Continue? NO
A benzodiazepine is the initial therapy of choice (Level A): If patient at baseline,

Choose one of the following 3 equivalent first line options with dosing and frequency: then symptomatic
• Intramuscular midazolam (10 mg for > 40 kg, 5 mg for 13-40 kg, single dose, medical care
Level A) OR
5-20 Minutes • Intravenous lorazepam (0.1 mg/kg/dose, max: 4 mg/dose, may repeat dose
Initial Therapy once, Level A) OR
Phase • Intravenous diazepam (0.15-0.2 mg/kg/dose, max: 10 mg/dose, may repeat dose
once, Level A)
If none of the 3 options above are available, choose one of the following:
• Intravenous phenobarbital (15 mg/kg/dose, single dose, Level A) OR
• Rectal diazepam (0.2-0.5 mg/kg, max: 20 mg/dose, single dose, Level B) OR
• Intranasal midazolam (Level B), buccal midazolam (Level B)
Does Seizure
YES Continue? NO
There is no evidence based preferred second therapy of choice (Level U): If patient at baseline,
Choose one of the following second line options and give as a single dose then symptomatic
• Intravenous fosphenytoin (20 mg PE/kg, max: 1500 mg PE/dose, single dose, medical care
20-40 Minutes Level U) OR
Second Therapy • Intravenous valproic acid (40 mg/kg, max: 3000 mg/dose, single dose,
Phase Level B) OR
• Intravenous levetiracetam (60 mg/kg, max: 4500 mg/dose, single dose, Level U)
If none of the options above are available, choose one of the following (if not given
already)
• Intravenous phenobarbital (15 mg/kg, single dose, Level B)
Does Seizure
YES Continue? NO
40-60 Minutes There is no clear evidence to guide therapy in this phase (Level U): If patient at baseline,
Third Therapy Choices include: repeat second line therapy or anesthetic doses of either thiopental, then symptomatic
Phase midazolam, pentobarbital, or propofol (all with continuous EEG monitoring) medical care
Disclaimer: This clinical algorithm/guideline is designed to assist clinicians by providing an analytic framework for evaluating and treating
patients with status epilepticus. It is not intended to establish a community standard of care, replace a clinician’s medical judgment, or
establish a protocol for all patients. The clinical conditions contemplated by this algorithm/guideline will not fit or work with all patients.
Approaches not covered in this algorithm/guideline may be appropriate.
2016 © Epilepsy Currents
RESEARCH ARTICLE
Antenatal magnesium sulphate and adverse

neonatal outcomes: A systematic review and
meta-analysis
Emily Shepherd ID1,2*, Rehana A. Salam ID1,2, Deepak Manhas3, Anne Synnes ID3,
Philippa Middleton1,2, Maria Makrides ID2, Caroline A. Crowther ID1,4
1 Robinson Research Institute, Discipline of Obstetrics and Gynaecology, Adelaide Medical School,
University of Adelaide, Adelaide, South Australia, Australia, 2 South Australian Health and Medical Research
Institute, Adelaide, South Australia, Australia, 3 University of British Columbia, Vancouver, British Columbia,
Canada, 4 Liggins Institute, University of Auckland, Auckland, New Zealand
a1111111111
a1111111111 * emily.shepherd@adelaide.edu.au
a1111111111
a1111111111
a1111111111
Abstract
Background
OPEN ACCESS There is widespread, increasing use of magnesium sulphate in obstetric practice for pre-
Citation: Shepherd E, Salam RA, Manhas D, eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm
Synnes A, Middleton P, Makrides M, et al. (2019)
labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analy-
Antenatal magnesium sulphate and adverse
neonatal outcomes: A systematic review and meta- sis to assess whether antenatal magnesium sulphate is associated with unintended adverse
analysis. PLoS Med 16(12): e1002988. https://doi. neonatal outcomes.
org/10.1371/journal.pmed.1002988
Academic Editor: Jenny E Myers, University of Methods and findings

Manchester, UNITED KINGDOM
CINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science,
Received: May 27, 2019
were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and
Accepted: November 6, 2019 non-randomised trials, cohort and case–control studies, and case reports assessing antena-
Published: December 6, 2019 tal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis,
compared with placebo/no treatment or a different magnesium sulphate regimen, were
Copyright: © 2019 Shepherd et al. This is an open
access article distributed under the terms of the included. The primary outcome was perinatal death. Secondary outcomes included pre-
Creative Commons Attribution License, which specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened
permits unrestricted use, distribution, and
5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and
reproduction in any medium, provided the original
author and source are credited.
RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differ-
ences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
meta-analysis. Non-randomised data were tabulated and narratively summarised. We
Information files. included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case
Funding: This work was carried out with funding
reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were
from the Cerebral Palsy Alliance Research conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23
Foundation, Australia (https://research. trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotec-
cerebralpalsy.org.au/), grant PG2015 (ES, PM,
tion (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/
MM, CC). The funder had no role in study design,
data collection and analysis, decision to publish, or no treatment, and 22 compared different regimens. For perinatal death, no clear difference
preparation of the manuscript. in randomised trials was observed between magnesium sulphate and placebo/no treatment
PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002988 December 6, 2019 1 / 37

Antenatal magnesium sulphate and adverse neonatal outcomes
Competing interests: The authors have declared (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of
that no competing interests exist. 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moder-
Abbreviations: CI, confidence interval; IM, ate to high risk of bias) observed an increased risk of perinatal death with >48 versus �48
intramuscular; IV, intravenous; MD, mean grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal
difference; RR, risk ratio.
outcomes were observed in randomised trials, and a very limited number of possible
adverse outcomes warranting further consideration were identified in non-randomised stud-
ies. Where non-randomised studies observed possible harms, often no or few confounders
were controlled for (moderate to high risk of bias), samples were small (200 babies or
fewer), and/or results were from subgroup analyses. Limitations include missing data for
important outcomes across most studies, heterogeneity of included studies, and inclusion of
published data only.
Conclusions
Our findings do not support clear associations between antenatal magnesium sulphate for
beneficial indications and adverse neonatal outcomes. Further large, high-quality studies
(prospective cohorts or individual participant data meta-analyses) assessing specific out-
comes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes,
would further inform safety recommendations. PROSPERO: CRD42013004451.
Author summary
Why was this study done?

• Magnesium sulphate is widely used in pregnancy, considered effective for maternal neu-
roprotection in pre-eclampsia/eclampsia and for fetal neuroprotection (cerebral palsy
prevention) in women at risk of preterm birth, and ineffective for preventing preterm
birth or labour (tocolysis).
• It is important to understand whether this treatment, when given to women in preg-
nancy, is associated with any unintended adverse outcomes for babies.
What did the researchers do and find?

• This systematic review incorporates the findings of 197 studies (including 40 rando-
mised controlled trials) that reported on adverse outcomes for babies whose mothers
were treated with magnesium sulphate in pregnancy.
• Meta-analysis of randomised controlled trials showed no clear difference in the risk of
perinatal death between babies whose mothers were treated with magnesium sulphate
and those whose mothers received placebo/no treatment, or between different magne-
sium sulphate regimens.
• No clear adverse outcomes for babies were observed in randomised trials, and a very
limited number of possible adverse outcomes warranting further consideration were
identified in non-randomised studies.

What do these findings mean?

• Magnesium sulphate in pregnancy, when given for the beneficial indications of mater-
nal or fetal neuroprotection, is not associated with an increased risk of perinatal death
or other adverse outcomes for babies.
• Further investigation into specific adverse outcomes, and the impact of particular treat-
ment regimen, pregnancy, and/or birth characteristics, would further inform safety
recommendations.
Introduction
Antenatal magnesium sulphate is commonly used in obstetric practice. Systematic reviews and
clinical practice guidelines support its use when given for maternal neuroprotection in pre-
eclampsia or eclampsia [1–3] and for neuroprotection of the fetus in women at risk of preterm
birth (for cerebral palsy prevention) [4–7]. Despite continued use in some countries [8], avail-
able evidence does not support its role in preventing preterm birth in women with, or follow-
ing, threatened preterm labour (for tocolysis) [7,9].
Concerns surrounding possible unintended adverse outcomes for fetuses or neonates fol-
lowing exposure to antenatal magnesium sulphate emerged over 50 years ago [10,11], and
uncertainty persists today. While the clinical consequences of hypermagnesemia, related to
increased serum concentrations, are well known and documented (such as lethargy, drowsi-
ness, flushing, nausea, vomiting, muscle weakness, loss of deep tendon reflexes, hypotension,
apnoea, coma, cardiac arrest, and, ultimately, death [12]), whether neonates are at risk of such
adverse outcomes following exposure to antenatal magnesium sulphate is unclear.
We have systematically reviewed the maternal adverse effects of different antenatal magne-
sium sulphate regimens [13], and a further systematic review has summarised the effects
specifically on fetal heart rate [14]. To our knowledge, a broad evaluation of evidence sur-
rounding potential unintended neonatal adverse outcomes, informed by current guidance
[15–17], has not previously been conducted. Implementation of this treatment may be
strengthened, and its safety improved, if guidelines and recommendations for practice can be
based on such knowledge.
The aim of our study, therefore, was to conduct a comprehensive systematic review to assess
whether antenatal magnesium sulphate is associated with perinatal death and other unin-
tended adverse neonatal outcomes.
Methods
We conducted a systematic review following the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guideline; the relevant checklist is provided in S1
PRISMA Checklist. Prior to conduct, this systematic review was registered with PROSPERO
(International Prospective Register of Systematic Reviews; CRD42013004451) [18]. The Aus-
tralian Cerebral Palsy Alliance Research Foundation–funded review protocol is available in
S1 Text. Ethical approval was not required.

Search strategy
Comprehensive searches of the bibliographic databases CINAHL, Cochrane Library, LILACS,
MEDLINE, Embase, TOXLINE, and Web of Science were undertaken from their respective
inceptions to 3 September 2019, using combinations of MeSH and free text terms. The search
strategies are available in S2 Text. No date or language restrictions were applied; however,
because of logistical constraints, for non-English papers, only those with an available English
abstract or full-text translation were retrieved. The reference lists of eligible articles were
checked for additional reports.
Inclusion criteria
We included randomised and quasi-randomised controlled trials as well as non-randomised
controlled studies (non-randomised trials, cohort studies, and case–control studies), and case
reports. We excluded cross-sectional studies and case series. We included studies available as
abstracts only, along with full-text publications.
We included neonates who were exposed to antenatal magnesium sulphate, regardless of
their gestational age at exposure or birth. We included studies where antenatal magnesium sul-
phate was given for pre-eclampsia or eclampsia, for neuroprotection of the fetus, or for tocoly-
sis. We excluded studies where magnesium sulphate was given as an adjuvant during obstetric
anaesthesia. We included intervention studies in which magnesium sulphate was compared
with no treatment, placebo, or a different magnesium sulphate regimen. We included observa-
tional studies where magnesium sulphate was assessed as an ‘exposure’. We excluded studies
where magnesium sulphate was compared with another therapy (for example, diazepam for
pre-eclampsia or eclampsia, or nifedipine for tocolysis).
We included studies that reported on adverse outcomes for neonates, however defined. The
primary outcome was perinatal death. Secondary outcomes included pre-specified adverse
outcomes (based on non-systematic literature review: stillbirth, neonatal death or death up to
hospital discharge, low Apgar scores at 1 and 5 minutes, need for active resuscitation at birth,
respiratory depression, spontaneous intestinal perforation, patent ductus arteriosus, hypoten-
sion, lethargy, hypotonia or hyporeflexia, osteopenia or bone fractures, neonatal intensive care
unit admission, and duration of neonatal care unit admission), along with other non-pre-spec-
ified adverse neonatal outcomes.
Study selection
After screening all titles and abstracts, we obtained full-text articles for studies that appeared to
meet the inclusion criteria. All full-text articles were assessed for inclusion. Each stage was car-
ried out by 2 reviewers, and we resolved any discrepancies through discussion, or, if required,
we consulted a third reviewer.
Data extraction and management

For included studies, data were extracted using a standardised form, including information
regarding design, participants, the magnesium sulphate regimen(s), the control/comparison if
applicable, neonatal adverse outcomes reported, results relevant to the review, and the risk of
bias. For all randomised trials, all case reports, and 60% of non-randomised studies, extraction
was carried out by 2 reviewers (for 40% of non-randomised studies, extractions were checked
by a second reviewer), and we resolved discrepancies through discussion, or, if required, we
consulted a third reviewer.

Assessment of risk of bias

Quality appraisal of intervention studies was undertaken utilising established guidelines pro-
vided in the Cochrane Handbook for Systematic Reviews of Interventions [19]. The quality
assessment of observational studies was guided by the RTI Item Bank [20].
Data synthesis and analysis

Data analyses were undertaken by study design. Statistical analyses for randomised trials
were performed using Review Manager, version 5.3 [21]. We present quantitative data from
individual studies as risk ratios (RRs) for dichotomous outcomes and mean differences
(MDs) for continuous outcomes, with 95% confidence intervals (CIs). For all outcomes, we
carried out analyses as far as possible on an intention-to-treat basis. Pooled estimates were
calculated using fixed-effects meta-analysis (Mantel-Haenszel method) where there was a
sufficient quantity of data, with clinical homogeneity. Where there was substantial statistical
heterogeneity (where I2 was greater than 30% and either T2 was greater than 0 or there was a
low P value [less than 0.10] in the χ2 test), summary estimates were calculated using ran-
dom-effects meta-analysis. Where there were 10 or more trials in a meta-analysis, we investi-
gated reporting biases (such as publication bias) using funnel plots, which we assessed
visually.
Separate comparisons were performed for those studies assessing magnesium sulphate ver-
sus no treatment/placebo and those comparing different magnesium sulphate regimens. For
our primary review outcome (perinatal death) and other mortality outcomes, we conducted
subgroup analyses based on indication for use and characteristics of the magnesium sulphate
loading and maintenance dose regimens, as these factors were considered likely to influence
outcomes. It was not possible to conduct subgroup analyses based on other pregnancy or birth
characteristics (gestational age at magnesium sulphate administration, birthweight, mode of
birth, and concomitant maternal treatments) due to paucity of data. We assessed subgroup dif-
ferences by interaction tests available within Review Manager, and, where applicable, we have
quoted the χ2 statistic and P value, and the interaction test I2 value.
For observational studies (non-randomised trials, cohort studies, and case–control studies),
we present effect estimates where possible as adjusted RRs or odds ratios if reported with 95%
CIs, unadjusted RRs or odds ratios with 95% CIs, P values only, or percentages (rates), in tabu-
lar format; we used narrative synthesis to summarise the studies. Data from case reports were
grouped according to common adverse outcomes, tabulated, and summarised narratively.
Results
Study selection
The results of the search strategy, including the sources of the studies, their assessment, and
final inclusion are shown in Fig 1. The database searching identified 5,890 records, and other
searching identified a further 11 records. Review of the titles and abstracts and exclusion of
irrelevant and duplicate records yielded 777. Of these, we excluded 572 for the documented
reasons (see S3 Text for list of records excluded due to absence of an English translation). We
included a total of 205 articles, relating to 197 studies. See S4 Text for references for all
included studies. In the case of multiple publications from the same study, we included the
report with the most relevant data as the primary reference, and only included further publica-
tions as secondary references if they provided additional relevant data.

Fig 1. Flow diagram of included studies. Flow diagram showing the flow of records through the different phases of the review, indicating the number
of records identified, included and excluded, and the reasons for exclusions.
https://doi.org/10.1371/journal.pmed.1002988.g001
Evidence from randomised controlled trials

Forty randomised trials were included, the characteristics of which are detailed in S1 Table,
and the risk of bias assessments are summarised in Fig 2, S1 Fig, and S2 Table [22–61]. The tri-
als assessed a range of different magnesium sulphate regimens with varying control groups,
and are therefore assessed under 8 different comparisons:

Fig 2. Risk of bias for randomised controlled trials. Risk of bias graph showing judgements about each risk of bias item presented as percentages
across the 40 included randomised trials.
https://doi.org/10.1371/journal.pmed.1002988.g002
1. Magnesium sulphate versus placebo or no treatment (18 trials)

2. Lower versus higher dose regimens of magnesium sulphate (8 trials)
3. Intramuscular (IM) versus intravenous (IV) maintenance dose of magnesium sulphate (5
trials)
4. Loading versus loading and maintenance dose of magnesium sulphate (5 trials)
5. Serial IV boluses versus continuous IV infusion of magnesium sulphate (1 trial)
6. Short versus standard maintenance of magnesium sulphate (1 trial)
7. Slower versus standard rate of loading dose infusion of magnesium sulphate (1 trial)
8. Weaning versus no weaning of maintenance of magnesium sulphate (1 trial)
The methodological quality of the 40 trials varied considerably. Considering selection bias,
18 trials were at low risk, reporting adequate methods for sequence generation and allocation
concealment. Twelve and 8 trials received an unclear judgement for 1 and 2 of the selection
bias domains, respectively. Two trials appeared to be quasi-randomised and thus were at high
risk of selection bias. Twelve trials were at low risk of performance and detection bias (with
blinding of participants, personnel, and outcome assessors); 21 were at high risk of both per-
formance and detection bias (all trials of different magnesium sulphate regimens, with no
reported blinding), and the remaining 7 trials had an unclear judgement for 1 or 2 of the blind-
ing domains. The majority of trials (31) were at low risk of attrition bias for neonatal outcome
data, though for 9 trials, this was unclear. Only 5 trials were at low risk of reporting bias, 1 was
at high risk of reporting bias, and for the remaining 34 trials, selective reporting was unclear.
Magnesium sulphate versus placebo or no treatment

This comparison included 18 trials. The indication for use of magnesium sulphate in 6 trials
was the prevention of eclampsia [30,32,39,43,48,61]; in 6 trials, fetal neuroprotection
[28,36,45,47,51,54]; and in 6 trials, the prevention of preterm birth (tocolysis) [33–35,38,40,46].

Magnesium sulphate regimens assessed varied considerably: 4-gram IV loading dose only (2
trials), 4-gram IV loading dose and 1-gram-per-hour IV maintenance dose (4 trials), 4-gram
IV loading dose and 2-gram-per-hour IV maintenance (4 trials), 6-gram IV loading dose and
2-gram-per-hour IV maintenance dose (6 trials), and 4-gram IV and 10-gram IM loading dose
and 5-gram IM maintenance dose every 4 hours (2 trials), with duration of treatment generally
ranging from 12 to 24 hours. Fourteen trials compared magnesium sulphate with a placebo,
while 4 trials had a no-treatment comparison (see Table 1 and S1 Appendix for effect estimates,
forest plots, and funnel plots).
No clear difference was seen between magnesium sulphate and placebo/no treatment for
the primary review outcome perinatal death (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654
babies; analysis 1.1), nor for stillbirth, neonatal death (no obvious asymmetry observed on
visual assessment of funnel plot), death later than 28 days but before discharge, early neonatal
death, or late neonatal death (Table 1; S1 Appendix). When considering indication for use, the
tocolysis subgroup showed an increase in perinatal death (RR 7.99; 95% CI 1.00 to 63.49; 2 tri-
als, 257 babies; analysis 1.1.1) that was not observed in the pre-eclampsia or fetal neuroprotec-
tion subgroups. The subgroup interaction test, however, did not indicate a differential effect
according to treatment indication (χ2 = 4.07, P = 0.13, I2 = 50.8%). For the remaining mortality
outcomes, subgroup interaction tests did not indicate differential treatment effects according
to indication for administration (see Tables 2 and 3 for effect estimates for individual sub-
groups and results from subgroup interaction tests).
Babies exposed to antenatal magnesium sulphate had a 67% relative increase in the risk of
having an Apgar score less than 7 at 1 minute (RR 1.67; 95% CI 1.02 to 2.73; 2 trials, 199 babies;
analysis 1.7), and over 2 times the risk of need for volume expansion compared with babies
not exposed (RR 2.03; 95% CI 1.01 to 4.10; 1 trial, 87 babies; analysis 1.28). A subgroup of
babies born less than 32 weeks gestation exposed to antenatal magnesium sulphate had a 62%
relative reduction in the risk of intracerebral echodensity, compared with babies not exposed
(RR 0.38; 95% CI 0.19 to 0.79; 1 trial, 1,613 babies; analysis 1.46). While a difference in intrace-
rebral echolucency was not observed in all babies, a 39% relative reduction was seen for babies
born less than 32 weeks exposed to antenatal magnesium sulphate (RR 0.61; 95% CI 0.38 to
0.97; 1 trial, 1,613 babies; analysis 1.47.2) (Table 1; S1 Appendix).
There were no clear differences between magnesium sulphate and placebo/no treatment for
all remaining secondary outcomes reported (Table 1; S1 Appendix).
Lower versus higher dose regimens

This comparison included 8 trials, with 6 assessing magnesium sulphate for treatment of
eclampsia or severe pre-eclampsia [22,23,44,52,56,59], and 2 for the prevention of preterm
birth (tocolysis) [26,60]. Regimens assessed varied: lower dose regimens included a 4- to
10-gram loading dose with a 0.625- to 2-gram-per-hour maintenance dose; higher dose regi-
mens assessed included a 4- to 14-gram loading dose with a 1.25- to 5-gram-per-hour mainte-
nance dose (see Table 4 and S1 Appendix for effect estimates and forest plots).
No clear differences between the lower and higher dose regimens of magnesium sulphate
were seen for the primary review outcome perinatal death (RR 1.01; 95% CI 0.75 to 1.36; 6 tri-
als, 543 babies; analysis 2.1), nor for stillbirth or neonatal death (Table 4; S1 Appendix). For all
mortality outcomes, subgroup interaction tests did not indicate differential treatment effects
according to indication for administration of antenatal magnesium sulphate (see Table 5 for
effect estimates for individual subgroups and results from subgroup interaction tests).
Babies exposed to the lower dose versus higher dose regimens of magnesium sulphate had
an increased risk of neonatal intensive care unit admission (RR 1.75; 95% CI 1.06 to 2.88; 5

Table 1. Adverse outcome estimates from randomised controlled trials: Comparison 1—Magnesium sulphate versus placebo or no treatment.
Outcome Studies Participants Method (I2) RR (95% CI)
1.1 Perinatal death 8 13,654 F (23%) 1.01 (0.92, 1.10)
1.2 Stillbirth 9 12,340 F (0%) 0.99 (0.87, 1.12)
1.3 Neonatal death 11 12,987 F (21%) 1.00 (0.86, 1.17)
1.4 Death > 28 days, before discharge 5 10,691 F (0%) 0.96 (0.60, 1.53)
1.5 Early neonatal death 1 9,024 F (NA) 1.09 (0.86, 1.37)
1.6 Late neonatal death 1 9,024 F (NA) 1.54 (0.95, 2.49)
1.7 Apgar score < 7 at 1 minute 2 199 F (17%) 1.67 (1.02, 2.73)
1.8 Apgar score < 7 at 5 minutes 5 12,729 F (0%) 1.02 (0.92, 1.14)
1.9 Meconium at birth 1 210 F (NA) 1.55 (0.89, 2.72)
1.10 Intubated at birth 3 11,364 F (30%) 0.95 (0.87, 1.04)
1.11 Resuscitation in the delivery room
1.11.1 Any 1 2,416 F (NA) 0.99 (0.96, 1.03)
1.11.2 Oxygen bag, mask, or both 1 2,416 F (NA) 1.07 (0.98, 1.17)
1.11.3 Chest compressions 1 2,416 F (NA) 1.11 (0.73, 1.71)
1.12 Respiratory distress syndrome 7 3,639 R (46%) 0.95 (0.79, 1.14)
1.13 Transient tachypnoea of the newborn 2 243 F (0%) 0.96 (0.52, 1.77)
1.14 Surfactant 1 87 F (NA) 0.88 (0.62, 1.24)
1.15 Mechanical ventilation 5 12,751 R (63%) 1.01 (0.94, 1.09)
1.16 Non-invasive ventilation 1 688 F (NA) 1.03 (0.93, 1.15)
1.17 Oxygen required 1 153 F (NA) 0.95 (0.67, 1.35)
1.18 Chronic lung disease 5 4,513 F (0%) 1.06 (0.96, 1.17)
1.19 Apnoea and bradycardia 2 841 F (0%) 1.23 (0.98, 1.53)
1.20 Pneumothorax 1 87 F (NA) 2.44 (0.26, 22.52)
1.21 Pulmonary haemorrhage 1 87 F (NA) 2.44 (0.52, 11.41)
1.22 Necrotising enterocolitis 8 4,804 F (0%) 1.21 (0.98, 1.51)
1.23 Sepsis 4 2,694 R (31%) 0.83 (0.54, 1.28)
1.24 Hypoglycaemia on NICU admission 1 34 F (NA) 0.63 (0.06, 6.34)
1.25 Poor feeding 1 90 F (NA) No events
1.26 Patent ductus arteriosus 3 2,536 F (26%) 0.97 (0.80, 1.17)
1.27 Hypotension 2 3,103 F (22%) 1.03 (0.89, 1.19)
1.28 Volume expansion 1 87 F (NA) 2.03 (1.01, 4.10)
1.29 Mean blood pressure < 10th centile in the first 24 hours 1 87 F (NA) 1.30 (0.67, 2.53)
1.30 Superior vena cava flow < 41 ml/kg/min in the first 24 hours 1 87 F (NA) 1.22 (0.62, 2.40)
1.31 Right ventricular output < 120 ml/kg/min in the first 24 hours 1 87 F (NA) 1.08 (0.51, 2.30)
1.32 Dobutamine 1 87 F (NA) 1.73 (0.84, 3.57)
1.33 Dopamine 1 87 F (NA) 2.17 (0.62, 7.62)
1.34 Any inotrope 1 87 F (NA) 1.54 (0.82, 2.92)
1.35 Retinopathy of prematurity 1 2,415 F (NA) 0.99 (0.85, 1.14)
1.36 Generalised hypotonicity 1 2,415 F (NA) 1.03 (0.77, 1.37)
1.37 Seizures 4 11,397 F (0%) 0.78 (0.57, 1.06)
1.38 Hyperbilirubinaemia 1 90 F (NA) 2.00 (0.19, 21.28)
1.39 Intraventricular haemorrhage 10 4,891 F (0%) 0.95 (0.85, 1.06)
1.40 Intraventricular haemorrhage, grade 3 or 4 6 3,769 F (19%) 0.81 (0.60, 1.09)
1.41 Periventricular leucomalacia 4 4,225 F (0%) 0.93 (0.68, 1.28)
1.42 Any white matter injury 1 665 F (NA) 0.87 (0.62, 1.22)
1.43 Severe white matter injury 1 688 F (NA) 0.85 (0.55, 1.32)
1.44 Severe white matter injury or death 1 688 F (NA) 0.92 (0.66, 1.28)
(Continued )

Table 1. (Continued)

1.45 Persistent parenchymal echogenicity 1 8,260 F (NA) 1.09 (0.66, 1.81)
1.46 Echodensity in children born < 32 weeks 1 1,613 F (NA) 0.38 (0.19, 0.79)
1.47 Echolucency
1.47.1 In all children 1 1,776 F (NA) 0.62 (0.37, 1.03)
1.47.2 In children born < 32 weeks 1 1,613 F (NA) 0.61 (0.38, 0.97)
1.48 Ventriculomegaly 2 10,036 F (0%) 0.98 (0.68, 1.42)
1.49 Any of echodensity, echolucency, intraventricular haemorrhage, periventricular haemorrhage, or
ventriculomegaly
1.49.1 In all children 1 1,776 F (NA) 0.85 (0.69, 1.06)
1.49.2 In children born < 32 weeks 1 1,613 F (NA) 0.92 (0.78, 1.09)
1.50 Composite adverse outcome 1 1,776 F (NA) 0.62 (0.37, 1.03)
1.51 NICU admission 3 8,519 F (17%) 1.00 (0.95, 1.06)
1.52 Intensive care unit stay (days) 1 120 MD, F (NA) 0.02 (−0.17, 0.21)
1.53 Hospital stay (days) 2 257 MD, R −2.75 (–8.92,
(99%) 3.43)
1.54 Special care baby unit admission > 7 days or death 1 9,024 F (NA) 1.01 (0.95, 1.08)
1.55 Special care baby unit admission > 7 days 1 8,260 F (NA) 1.02 (0.93, 1.11)
1.56 Still in hospital at 6 weeks 1 9,024 F (NA) 0.99 (0.06, 15.80)
Statistically significant effect estimates in bold. Test for heterogeneity represented by I2 statistic; where I2 > 30%, summary estimates were calculated using random-
effects meta-analysis.
CI, confidence interval; F, fixed-effects; MD, mean difference; NA, not applicable; NICU, neonatal intensive care unit; R, random-effects; RR, risk ratio.
https://doi.org/10.1371/journal.pmed.1002988.t001
Table 2. Subgroup analyses based on indication for use from randomised controlled trials: Comparison 1—Magnesium sulphate versus placebo or no treatment.
Outcome and subgroup Studies Participants Method (I2) RR (95% CI) χ2, P value, I2
1.1 Perinatal death
1.1.1 Tocolysis 2 257 F (NA) 7.99 (1.00, 63.49) 4.07, 0.13, 50.8%
1.1.2 Pre-eclampsia 2 9,259 F (0%) 1.01 (0.91, 1.13)
1.1.3 Fetal neuroprotection 4 4,138 F (0%) 0.96 (0.80, 1.15)
1.2 Stillbirth
1.2.1 Tocolysis 2 257 F (NA) 5.70 (0.28, 116.87) 1.45, 0.49, 0%
1.2.2 Pre-eclampsia 3 9,961 F (8%) 0.99 (0.87, 1.12)
1.2.3 Fetal neuroprotection 4 2,122 F (0%) 0.85 (0.40, 1.80)
1.3 Neonatal death
1.3.1 Tocolysis 4 445 R (61%) 0.78 (0.11, 5.67) 0.48, 0.79, 0%
1.3.2 Pre-eclampsia 2 9,259 R (35%) 1.03 (0.64, 1.65)
1.3.3 Fetal neuroprotection 5 3,283 R (0%) 0.86 (0.68, 1.08)
1.4 Death > 28 days, before discharge
1.4.1 Tocolysis 3 412 F (0%) 0.76 (0.19, 3.09) 0.37, 0.83, 0%
1.4.2 Pre-eclampsia 1 9,024 F (NA) 1.13 (0.55, 2.31)
1.4.3 Fetal neuroprotection 1 1,255 F (NA) 0.88 (0.44, 1.74)
effects meta-analysis. Result of test subgroup differences represented by χ2 statistic, P value, and I2 statistic.
CI, confidence interval; F, fixed-effects; NA, not applicable; R, random-effects; RR, risk ratio.

Table 3. Subgroup analyses based on regimen characteristics from randomised controlled trials: Comparison 1—Magnesium sulphate versus placebo or no
treatment.
Outcome or subgroup Studies Participants Method (I2) RR (95% CI) χ2, P value, I2
Subgroups based on LD
1.1 Perinatal death
1.1.4 4-g IV LD 5 2,259 R (42%) 0.96 (0.62, 1.49) 0.57, 0.75, 0%
1.1.5 6-g IV LD 1 2,136 R (NA) 1.12 (0.85, 1.47)
1.1.6 4-g IV and 10-g IM LD 2 9,259 R (0%) 1.01 (0.91, 1.12)
1.2 Stillbirth
1.2.4 4-g IV LD 6 2,961 F (0%) 1.25 (0.85, 1.84) 1.57, 0.21, 36.1%
1.2.5 6-g IV LD 1 120 F (NA) No events
1.2.6 4-g IV and 10-g IM LD 2 9,259 F (0%) 0.96 (0.84, 1.10)
1.3 Neonatal death
1.3.4 4-g IV LD 6 2,294 R (7%) 0.86 (0.64, 1.16) 0.44, 0.80, 0%
1.3.5 6-g IV LD 3 1,434 R (2%) 0.83 (0.48, 1.44)
1.3.6 4-g IV and 10-g IM LD 2 9,259 R (35%) 1.03 (0.64, 1.65)
1.4.4 4-g IV LD 3 1,514 F (0%) 0.81 (0.43, 1.53) 0.81, 0.67, 0%
1.4.5 6-g IV LD 1 153 F (NA) 2.47 (0.10, 59.70)
1.4.6 4-g IV and 10-g IM LD 1 9,024 F (NA) 1.13 (0.55, 2.31)
Subgroups based on MD
1.1 Perinatal death
1.1.7 LD only 2 747 R (0%) 0.92 (0.59, 1.44) 2.73, 0.44, 0%
1.1.8 1-g/hour IV MD 1 1,255 R (NA) 0.81 (0.60, 1.09)
1.1.9 2–5-g/hour IV MD 3 2,393 R (71%) 2.27 (0.35, 14.55)
1.1.10 5-g/4-hour IM MD 2 9,259 R (0%) 1.01 (0.91, 1.12)
1.2 Stillbirth
1.2.7 LD only 2 747 F (0%) 0.96 (0.22, 4.17) 2.50, 0.48, 0%
1.2.8 1-g/hour IV MD 2 1,957 F (9%) 1.22 (0.81, 1.83)
1.2.9 2–5-g/hour IV MD 3 377 F (0%) 5.70 (0.28, 116.87)
1.2.10 5-g/4-hour IM MD 2 9,259 F (0%) 0.96 (0.84, 1.10)
1.3 Neonatal death
1.3.7 LD only 2 747 R (0%) 0.93 (0.58, 1.47) 0.72, 0.87, 0%
1.3.8 1-g/hour IV MD 1 1,255 R (NA) 0.81 (0.59, 1.11)
1.3.9 2–5-g/hour IV MD 6 1,726 R (41%) 0.84 (0.30, 2.33)
1.3.10 5-g/4-hour IM MD 2 9,259 R (35%) 1.03 (0.64, 1.65)
1.4.7 1-g/hour IV MD 1 1,255 F (NA) 0.88 (0.44, 1.74) 0.37, 0.83, 0%
1.4.8 2–5-g/hour IV MD 3 412 F (0%) 0.76 (0.19, 3.09)
1.4.9 5-g/4-hour IM MD 1 9,024 F (NA) 1.13 (0.55, 2.31)
Test for heterogeneity represented by I2 statistic; where I2 > 30%, summary estimates were calculated using random-effects meta-analysis. Result of test subgroup
differences represented by χ2 statistic, P value, and I2 statistic.
CI, confidence interval; F, fixed-effects; g, gram; IM, intramuscular; IV, intravenous; LD, loading dose; MD, maintenance dose; NA, not applicable; R, random-effects;
RR, risk ratio.
trials, 409 babies; analysis 2.17). On average, babies exposed to the lower dose regimen had a
longer duration of stay in the neonatal intensive care unit compared with those exposed to the
higher dose regimen (MD 3.10 days; 95% CI 0.78 to 5.42; 1 trial, 104 babies; analysis 2.18)
(Table 4; S1 Appendix).

Table 4. Adverse outcome estimates from randomised controlled trials: Comparison 2—Lower versus higher dose regimens of magnesium sulphate.
2.1 Perinatal death 6 543 F (0) 1.01 (0.75, 1.36)
2.2 Stillbirth 5 471 F (0) 0.94 (0.61, 1.45)
2.3 Neonatal death 6 535 F (0) 1.12 (0.57, 2.22)
2.4 Apgar score < 7 at 1 minute 3 302 F (0) 0.96 (0.68, 1.35)
2.5 Apgar score < 7 at 5 minutes 3 302 R (35%) 1.41 (0.54, 3.65)
2.6 Resuscitation 1 64 F (NA) 1.00 (0.22, 4.59)
2.7 Respiratory distress syndrome 2 154 R (53%) 1.97 (0.76, 5.15)
2.8 Respiratory depression 1 50 F (NA) 0.33 (0.04, 2.99)
2.9 Respiratory disorders 1 64 F (NA) 1.08 (0.87, 1.33)
2.10 Mechanical ventilation 1 64 F (NA) 2.00 (0.39, 10.16)
2.11 Bradycardia 1 104 F (NA) 3.85 (0.45, 33.29)
2.12 Jaundice 1 50 F (NA) 1.25 (0.38, 4.12)
2.13 Hypoglycaemia 1 104 F (NA) 0.96 (0.06, 14.98)
2.14 Hypocalcaemia 1 104 F (NA) 2.89 (0.12, 69.32)
2.15 Hypotonia 1 50 F (NA) 0.14 (0.02, 1.08)
2.16 Requirement for calcium gluconate 1 50 F (NA) 0.25 (0.06, 1.06)
2.17 NICU admission 5 409 F (6%) 1.75 (1.06, 2.88)
2.18 NICU stay (days) 1 104 MD, F (NA) 3.10 (0.78, 5.42)
effects meta-analysis.
CI, confidence interval; F, fixed-effects; MD, mean difference; NA, not applicable; NICU, neonatal intensive care unit; R, random-effects; RR, risk ratio.
No clear differences were seen between the lower and higher dose regimens of magnesium
sulphate for the remaining secondary outcomes reported (Table 4; S1 Appendix).
IM versus IV maintenance dose

This comparison included 5 trials, all assessing magnesium sulphate for the prevention or
treatment of eclampsia [27,31,49,55,58]. Regimens assessed included Bhattacharjee’s regimen
Table 5. Subgroup analyses based on indication for use from randomised controlled trials: Comparison 2—Lower versus higher dose regimens of magnesium
sulphate.
Outcome and subgroup Studies Participants Method (I2) RR (95% CI) χ2, P value, I2
2.1 Perinatal death
2.1.1 Tocolysis 1 104 F (NA) 2.25 (0.61, 8.21) 1.63, 0.20, 38.6%
2.1.2 Pre-eclampsia/eclampsia 5 439 F (0%) 0.94 (0.70, 1.28)
2.2 Stillbirth
2.2.1 Tocolysis 1 104 F (NA) 0.96 (0.06, 14.98) 0.00, 0.99, 0%
2.3 Neonatal death
2.3.1 Tocolysis 1 104 F (NA) 2.89 (0.61, 13.65) 1.99, 0.16, 49.6%
2 2
Test for heterogeneity represented by I statistic; where I > 30%, summary estimates were calculated using random-effects meta-analysis. Result of test subgroup
differences represented by χ2 statistic, P value, and I2 statistic.
CI, confidence interval; F, fixed-effects; NA, not applicable; RR, risk ratio.

(4-gram IV loading dose; 6-gram IV maintenance dose every 8 hours), Dhaka regimen
(4-gram IV and 6-gram IM loading dose; 2.5-gram IM maintenance dose every 4 hours),
Pritchard’s regimen (4-gram IV and 10-gram IM loading dose; 5-gram IM maintenance dose
every 4 hours), Zuspan’s regimen (4-gram IV loading dose; 1-gram IV maintenance dose
every hour), and Sibai’s regimen (6-gram IV loading dose; 2-gram IV maintenance dose every
hour) (all maintenance doses were for 24 hours after birth or last seizure) (see Table 6 and S1
Appendix for effect estimates and forest plots).
No clear differences were observed for
• Pritchard’s versus Zuspan’s regimen for the primary review outcome perinatal death (RR
0.94; 95% CI 0.66 to 1.32; 2 trials, 353 babies; analysis 3.1.1), nor for stillbirth or neonatal
death;
• Pritchard’s versus Sibai’s regimen for the primary review outcome perinatal death (RR 0.90;
95% CI 0.53 to 1.53; 1 trial, 115 babies; analysis 3.1.2), nor for stillbirth or neonatal death;
• Pritchard’s versus Bhattacharjee’s regimen for the primary review outcome perinatal death
(RR 1.28; 95% CI 0.61 to 2.65; 1 trial, 107 babies; analysis 3.1.3), nor for stillbirth or neonatal
death;
• Dhaka versus Zuspan’s regimen for the primary review outcome perinatal death (RR 0.57;
95% CI 0.16 to 2.08; 1 trial, 41 babies; analysis 3.1.4), nor for stillbirth or neonatal death
(Table 6; S1 Appendix).
No clear differences were observed for Pritchard’s versus Zuspan’s regimen, Pritchard’s ver-
sus Sibai’s regimen, or Dhaka versus Zuspan’s regimen for the remaining secondary outcomes
reported (Table 6; S1 Appendix).
Loading dose versus loading and maintenance doses

This comparison included 5 trials, all assessing magnesium sulphate for the prevention or
treatment of eclampsia [25,41,50,53,57]. Trials compared a cumulative 8-, 10-, or 14-gram
loading dose (4 grams IV and 4 to 10 grams IM) with Dhaka or Pritchard’s regimen (see
descriptions above; and see Table 6 and S1 Appendix for effect estimates and forest plots).
No clear differences for loading dose only versus loading and maintenance dose regimens
were seen for the primary review outcome perinatal death (average RR 0.94; 95% CI 0.33 to
2.72; 3 trials, 632 babies; analysis 4.1), nor for stillbirth, neonatal death, or neonatal death at
less than 7 days (Table 6; S1 Appendix).
No clear differences for loading dose only versus loading and maintenance dose regimens
were seen for the remaining secondary outcomes reported (Table 6; S1 Appendix).
Serial IV boluses versus continuous IV maintenance dose

This comparison included 1 trial, assessing magnesium sulphate for the treatment of severe
pre-eclampsia, and compared a serial intravenous bolus regimen (6-gram IV loading dose, and
2-gram IV bolus over 10 minutes every 2 hours as maintenance) with a continuous infusion
(4-gram IV loading dose, and 1-gram-per-hour continuous IV maintenance dose) [37] (see
Table 6 and S1 Appendix for effect estimates and forest plots).
No clear differences between the serial bolus and continuous infusion regimens were seen
for the primary review outcome perinatal death (RR 0.44; 95% CI 0.08 to 2.34; 1 trial, 197
babies; analysis 5.1), nor for stillbirth or neonatal death (Table 6; S1 Appendix).
No clear differences between the serial bolus and continuous infusion regimens were seen
for the remaining secondary outcomes reported (Table 6; S1 Appendix).

Table 6. Adverse outcome estimates from randomised controlled trials: Comparisons 3–8.
Outcome and subgroup Studies Participants Method (I2) RR (95% CI)
Comparison 3: IM versus IV maintenance dose of magnesium sulphate (pre-eclampsia/eclampsia)
3.1 Perinatal death
3.1.1 Pritchard’s versus Zuspan’s regimen 2 353 F (0%) 0.94 (0.66, 1.32)
3.1.2 Pritchard’s versus Sibai’s regimen 1 115 F (NA) 0.90 (0.53, 1.53)
3.1.3 Pritchard’s versus Bhattacharjee’s regimen 1 107 F (NA) 1.28 (0.61, 2.65)
3.1.4 Dhaka versus Zuspan’s regimen 1 41 F (NA) 0.57 (0.16, 2.08)
3.2 Stillbirth
3.2.1 Pritchard’s versus Zuspan’s regimen 1 114 F (NA) 0.79 (0.44, 1.40)
3.2.2 Pritchard’s versus Sibai’s regimen 2 133 F (0%) 0.80 (0.46, 1.41)
3.3 Neonatal death
3.4 Apgar score < 7 at 1 minute
3.5 Apgar score < 7 at 5 minutes
3.6 Respiratory distress syndrome
3.7 Jaundice
3.8 Hypotonia
3.9 NICU admission
Comparison 4: Loading dose versus loading and maintenance doses of magnesium sulphate (pre-eclampsia/eclampsia)
4.1 Perinatal death 3 632 R (63%) 0.94 (0.33, 2.72)
4.2 Stillbirth 3 803 F (26%) 1.10 (0.77, 1.58)
4.3 Neonatal death 2 462 F (0%) 0.78 (0.43, 1.41)
4.4 Neonatal death < 7 days 1 402 F (NA) 0.73 (0.30, 1.77)
4.5 Apgar score < 7 at 0 minutes 1 52 F (NA) 1.07 (0.32, 3.54)
4.6 Apgar score < 7 at 1 minute 1 52 F (NA) 0.86 (0.06, 12.98)
4.8 NICU admission for respiratory distress 2 397 F (0%) 1.02 (0.63, 1.65)
4.9 NICU admission for early onset sepsis 1 80 F (NA) 1.00 (0.06, 15.44)
4.10 NICU admission for late onset sepsis 1 80 F (NA) 3.00 (0.13, 71.51)
4.11 NICU admission for meconium aspiration syndrome 1 80 F (NA) 1.00 (0.06, 15.44)
4.12 NICU admission for birth asphyxia 1 80 F (NA) 0.33 (0.01, 7.95)
4.13 NICU admission 3 435 F (0%) 0.94 (0.77, 1.15)
Comparison 5: Serial intravenous boluses versus continuous intravenous maintenance of magnesium sulphate (pre-eclampsia)
5.1 Perinatal death 1 197 F (NA) 0.44 (0.08, 2.34)
5.2 Stillbirth 1 197 F (NA) 0.29 (0.01, 7.09)
(Continued )

Outcome and subgroup Studies Participants Method (I2) RR (95% CI)

5.3 Neonatal death 1 197 F (NA) 0.58 (0.10, 3.42)
5.4 Intubated at birth 1 197 F (NA) 0.88 (0.29, 2.62)
5.5 Mechanical ventilation 1 197 F (NA) 0.44 (0.11, 1.70)
5.6 Bradycardia (<110 bpm) 1 197 F (NA) 0.44 (0.08, 2.34)
5.7 Special care baby unit admission 1 197 F (NA) 0.84 (0.53, 1.35)
Comparison 6: Short versus standard maintenance course of magnesium sulphate (eclampsia)
6.1 Stillbirth 1 98 F (NA) 0.87 (0.41, 1.82)
6.2 Birth asphyxia 1 98 F (NA) 0.83 (0.24, 2.92)
Comparison 7: Slower versus standard rate of loading dose of magnesium sulphate (fetal neuroprotection)
7.1 Stillbirth 1 51 F (NA) 0.35 (0.01, 8.12)
Comparison 8: Weaning versus no weaning of magnesium sulphate (tocolysis)
Test for heterogeneity represented by I2 statistic; where I2 > 30%, summary estimates were calculated using random-effects meta-analysis. Bhattacharjee’s regimen: 4-g
IV LD; 6-g IV/8 hours MD. Dhaka regimen: 4-g IV and 6-g IM LD; 2.5-g IM/4-hour MD. Pritchard’s regimen: 4-g IV and 10-g IM LD; 5-g IM/4-hour MD. Sibai’s
regimen: 6-g IV LD; 2-g IV/hour MD. Zuspan’s regimen: 4-g IV LD; 1-g IV/hour MD. All MDs for 24 hours after birth/last seizure.
bpm, beats per minute; CI, confidence interval; F, fixed-effects; g, gram; IM, intramuscular; IV, intravenous; LD, loading dose; MD, maintenance dose; NA, not
applicable; NICU, neonatal intensive care unit; R, random-effects; RR, risk ratio.
Short versus standard maintenance course

This comparison included 1 trial, assessing magnesium sulphate for the treatment of eclamp-
sia. Both groups received a 4-gram IV and 10-gram IM loading dose, followed by either a short
maintenance course (2 doses of 5 grams IM 4 hours apart after birth or last seizure) or a stan-
dard maintenance course (5 grams IM every 4 hours for 24 hours after birth or last seizure)
[29].
No clear difference between the short and standard maintenance course regimens was seen
for stillbirth. No clear difference between the short and standard maintenance course regimens
was seen for the only other secondary outcome reported, birth asphyxia (see Table 6 and S1
Appendix for effect estimates and forest plots).
Slower versus standard rate of loading dose

This comparison included 1 trial, assessing magnesium sulphate for fetal neuroprotection, and
compared a slower (over 60 minutes) versus standard (over 20 minutes) rate of administering
a 4-gram IV loading dose of magnesium sulphate (all women received a 1-gram-per-hour
maintenance dose for 24 hours or until birth) [24].
No clear difference between a slower and standard rate of loading dose administration was
seen for stillbirth (see Table 6 and S1 Appendix for effect estimate and forest plot).
Weaning versus no weaning

This comparison included 1 trial, assessing magnesium sulphate for the prevention of preterm
birth (tocolysis), and compared weaning (by 1 gram IV per 4 hours) versus not weaning mag-
nesium sulphate (all women received a 6-gram IV loading dose, and 2- to 3.5-gram IV mainte-
nance dose per hour until tocolysis was achieved) [42].
No clear difference between weaning and no weaning was seen for Apgar score less than 7
at 5 minutes (see Table 6 and S1 Appendix for effect estimate and forest plot).

Evidence from non-randomised comparative studies

One hundred thirty-eight non-randomised studies were included: 5 non-randomised trials, 35
prospective cohort studies (7 with nested case–control analyses), 82 retrospective cohort stud-
ies (16 with nested case–control analyses), 8 non-concurrent cohort studies, and 8 case–con-
trol studies [62–199]. The characteristics of the studies and risk of bias assessments are
detailed in S1 and S2 Tables.
There was substantial variation in the characteristics of these studies regarding participants,
indications for use of magnesium sulphate (prevention or treatment of eclampsia: 30 studies;
prevention of preterm birth (tocolysis): 28 studies; fetal neuroprotection: 25 studies; combina-
tion of aforementioned indications: 38 studies; unclear: 17 studies), comparison groups, out-
comes assessed (and their definitions), and analysis methods employed. Methodological
quality (specifically in relation to the risk of bias for reported review outcomes of interest) also
differed across the studies, with overall judgements of unclear (specifically when only abstracts
were available), high, moderate to high, and moderate risk of bias assigned to 43 studies, 49
studies, 35 studies, and 11 studies, respectively. The most common concerns across studies
related to the potential for confounding (with no attempt to balance allocation between groups
or match groups, and/or important confounding variables not taken into account in relevant
outcome analyses), detection bias (with the consistent implementation of valid and reliable
measures being unclear, and/or the absence of blinding of exposure or outcome assessors),
and performance bias (with protocols not available to assess important variations).
The primary review outcome, perinatal death, was reported by 11 of the 138 non-rando-
mised studies, 10 of which showed either a possible reduction (or lower rate) or no clear differ-
ence (or similar rate) in perinatal death among babies exposed to magnesium sulphate
compared with no magnesium sulphate or a different magnesium sulphate regimen. A possible
increase in perinatal death, specifically among babies exposed to >48 versus �48 grams of
magnesium sulphate for tocolysis was shown in in the 11th study (retrospective cohort of 127
babies, moderate to high risk of bias) [183]. See Table 7 and S3 Table for summaries of individ-
ual study results.
For the majority of secondary pre-specified and non-pre-specified adverse neonatal out-
comes reported, the results from non-randomised studies were consistent with those observed
in randomised controlled trials, with no clear differences (and in some cases, possible benefits
of magnesium sulphate) observed. The direction of the findings (no clear difference, possible
benefit, possible harm, or mixed) from the non-randomised studies are summarised in
Table 8, with the detailed individual study results provided in S3 Table.
Seventeen of the 138 non-randomised studies (14 at moderate or moderate to high risk of
bias, and 3 at unclear risk of bias [abstracts only]) observed a possible increase in the risk of
adverse neonatal outcomes with antenatal magnesium sulphate, with some consideration of
important confounding variables in relevant outcome analyses
[68,73,84,90,106,108,109,129,132,134,140,152,153,173,180,184,191]. Potential increased risks
with antenatal magnesium sulphate of 4 outcomes (discussed below) were observed by more
than 1 study. For the remaining outcomes (nosocomial infection [184], enteral feeding intoler-
ance [68], respiratory disease composite [153], pulmonary interstitial emphysema [191], early
germinal matrix/intraventricular haemorrhage [180], thalamostriate or mineralising vasculo-
pathy [152], and a composite neonatal adverse outcome [73]), single studies reported possible
harms.
Potential increased risk of neonatal death before intensive care unit discharge, and of a
composite outcome of neonatal death before intensive care unit discharge and/or necrotising
enterocolitis, was shown among a subgroup of babies born less than 26 weeks gestation with

Table 7. Perinatal death from non-randomised studies.

Study; design Participants Comparisons Results summary
Adama-Hondegla 178 babies born to women with (1) Babies living at seventh day of life, N = 147 babies, MgSO4 exposure: aOR 1.04, P > 0.05
2013; RCS with CCS eclampsia versus (2) stillbirths and neonatal deaths in first 7
(N) days, N = 31 babies
Alexander 2006; 87 babies born to women with (1) No gestational hypertension, no MgSO4, N = 49 Perinatal death: 6.1% (3/49) versus 0% (0/11) versus
PCS eclampsia babies, versus (2) gestational hypertension, MgSO4, 11.1% (3/27)
N = 11 babies, versus (3) gestational hypertension, no
MgSO4, N = 27 babies
Cawyer 2019; RCS 2,468 babies born to women with (1) MgSO4, N = 1,353 babies, versus (2) no MgSO4, Perinatal or neonatal death: 0.1% (2/1,353) versus
pre-eclampsia >32 weeks GA N = 1,115 babies 0.2% (2/1,115), P = 1.00
Chowdhury 2009; 529 babies born to women with (1) MgSO4 Pritchard’s regimen, N = 406 babies, Perinatal death: OR 1.58, 95% CI 0.93–2.61,
PCS eclampsia versus (2) MgSO4 low dose IV regimen, N = 123 P = 0.075
babies
Jung 2018; RCS 184 babies born to women with (1) MgSO4 for tocolysis, N = 143 babies, versus (2) no Perinatal death: Overall: 7.0% (10/143) versus 19.5%
ROM <32 weeks GA MgSO4, N = 41 babies (8/41), P = 0.0375; ROM at 23 to 27+6 weeks GA:
14.3% (9/63) versus 36.8% (7/19), P = 0.0651; ROM
at 28 to 31+6 weeks GA: 1.25% (1/80) versus 4.5%
(1/22), P = 0.9051
Kamilya 2005; CCS 1,205 babies born to women with (1) Birth year 2002–2004 (almost universal MgSO4), Perinatal death: 24.3% (117/481) versus 54.8% (397/
(N) eclampsia N = 481 babies, versus (2) birth year 1995–1997 (no 724)
MgSO4), N = 724 babies
Kamyar 2016a; RCS 396 babies born to women with (1) MgSO4 for fetal neuroprotection, N = 192 babies, Stillbirth or death by 1 year: Overall: aRR 1.68, 95%
(secondary analysis intrapartum clinical versus (2) placebo, N = 204 babies CI 0.85–3.32; �28 weeks GA: aRR 1.34, 95% CI
RCT) chorioamnionitis 0.47–2.73
Mitani 2011; RCS 425 babies born between 22 and (1) MgSO4 for tocolysis, N = 236 babies, versus (2) no Perinatal death: 5.5% (13/236) versus 9.0% (17/189),
31 weeks GA MgSO4, N = 189 babies P = 0.185
Okusanya 2012; 103 babies born to women with Severe pre-eclampsia: (1) 10-g MgSO4 LD, N = 25 Perinatal death, unclear reporting: Severe pre-
NRT severe pre-eclampsia or eclampsia babies, versus (2) 14-g MgSO4 LD, N = 30 babies eclampsia: (1) PMR 240 per 1,000 (6 deaths) versus
(2) PMR 35 per 1,000 (1 death)
Eclampsia: (1) 10-g MgSO4 LD, N = 29 babies, versus Perinatal death, unclear reporting: Eclampsia: (1)
(2) 14-g MgSO4 LD, N = 19 babies PMR 241 per 1,000 (6 deaths, all IUFD) versus (2) 0
deaths
Scudiero 2000; RCS 127 babies born between 700 and (1) Perinatal deaths, N = 18 babies, versus (2) MgSO4 > 48 g: 72.2% (13/18) versus 45.0% (49/
with CCS(N) 1,249 g, to women who received survivors, N = 109 babies 109), P = 0.03; MgSO4 � 48 g versus >48 g
MgSO4 for tocolysis (multivariable model): OR 4.72, 95% CI 1.12 to
19.97, P = 0.035
(1) MgSO4 � 24 g, N = 43 babies, versus (2) MgSO4 Perinatal death (Cochrane–Armitage trend test, 1
> 24 to � 48 g, N = 25 babies, versus (3) MgSO4 > 48 versus 2 versus 3): 7.0% (3/43) versus 8.0% (2/25)
g, N = 59 babies versus 22.0% (13/59), P = 0.03; perinatal death (1
versus 2): 7.0% (3/43) versus 8.0% (2/25), P = 1.0
Young 1977; NRT 144 babies born to women with (1) MgSO4 IV bolus MD (2 g over 10 minutes every Perinatal death: 2.1% (2/97) versus 2.1% (1/47)
pre-eclampsia or eclampsia 1–2 hours), N = 97 babies, versus (2) MgSO4
continuous IV MD (1 g per hour), N = 47 babies
The bold studies were judged to be of higher quality (moderate to high risk of bias) and presented results adjusted for confounders for the relevant outcome; other
studies were judged to be at high or unclear risk of bias and/or did not present adjusted results for the relevant outcome.
aOR, adjusted odds ratio; aRR, adjusted risk ratio; CCS(N), nested case–control study; CI, confidence interval; g, gram; GA, gestational age; IUFD, intrauterine fetal
demise; IV, intravenous; LD, loading dose; MD, maintenance dose; MgSO4, magnesium sulphate; NRT, non-randomised trial; OR, odds ratio; PCS, prospective cohort
study; PMR, perinatal mortality ratio; RCS, retrospective cohort study; RCT, randomised controlled trial; ROM, rupture of the membranes.
the use of antenatal magnesium sulphate for fetal neuroprotection (293 babies, in a retrospec-
tive cohort of 697 babies born less than 28 weeks gestation) [129]. A possible increased risk of
the composite outcome spontaneous intestinal perforation or neonatal death was also shown
among a subgroup of babies born less than 25 weeks gestation with higher cumulative

Table 8. Summary of outcomes from non-randomised studies.

Outcome Direction of effect for magnesium sulphate versus no magnesium sulphate or a different regimen
Studies showing no clear difference Studies showing possible Studies showing possible harm
benefit
Stillbirth Brazy 1982; Chowdhury 2009� ; Jung 2018^ Jung 2018^; Shamsuddin 2005� Das 2015�
Neonatal death or death before Alston 2016; Ambadkar 2019; Basu 2012; Downey 2017; Garcia Alonso Das 2015� ;Kamyar 2016b^; Lipsitz 1971� ; Rattray
discharge Bertello Grecco 2019� ; Brazy 1982; Canterino 2018; Grether 1998; Shalabi 2014; Rauf 2017
1999; Chowdhury 2009� ; De Jesus 2015; del 2017^; Stockley 2018; Weisz
Moral 2007; de Veciana 1995; Drassinower 2015^
2015; Elimian 2002� ; Elliott 2003; Farkouh
2001; Gibbins 2013; Girsen 2015; Gonzalez-
Quintero 2001; Hechtman 2002� ; Hong 2019;
James 2015; Jazayeri 2003; Jung 2018;
Kamyar 2015a; Kamyar 2015b; Kamyar
2016a; Kamyar 2016b^; Kimberlin 1998;
Lee 2013; Lloreda-Garcia 2016; Mikhael
2019� ; Morag 2016; Narasimhulu 2017;
Nassar 2006� ; Özlü 2019; Paneth 1997;
Rantonen 2001; Shalabi 2017^; Shokry 2010;
Suh 2015; Weisz 2015^; Whitsel 2004;
Yokoyama 2010
Apgar score < 7 at 1 minute Chun 2014^; Gibbins 2013; Lloreda-Garcia Chun 2014^; Das 2015� ; Girsen 2015; Lipsitz
(or � 5) 2016; Mitani 2011; Morag 2016; Narasimhulu 1971�
2017
Apgar score < 7 at 5 minutes (or Canterino 1999; Chun 2014^; Cuff 2018� ; de Jeanneteau 2014; Shalabi 2017 Chun 2014^; Das 2015� ; Girsen 2015; Lipsitz
�5 or <6) Veciana 1995; Drassinower 2015; Elimian 1971� ; Morag 2016
2002� ; Gibbins 2013; Jung 2018; Lloreda-
Garcia 2016; McPherson 2014� ; Mitani 2011;
Narasimhulu 2017; Nassar 2006� ; Nelson
1995; Okusanya 2012� ; Rhee 2012; Schanler
1997; Stockley 2018; Weisz 2015�
Birth asphyxia McGuiness 1980 Shamsuddin 2005�
Meconium at birth Greenberg 2013; Jazayeri 2003
Intubation Basu 2012; De Jesus 2015; Derks 2016; Bajaj 2018; Drassinower 2015; Das 2015� ; Rauf 2017; Weisz 2015� ^
Morag 2016; Narasimhulu 2017; Weisz Weisz 2015^
2015� ^
Intubation (duration) de Veciana 1995 O Reilly 2016^ O Reilly 2016� ^
�
Resuscitation Basu 2012; Brookfield 2015 ; De Jesus 2015; Bajaj 2018; De Silva 2018 Lipsitz 1971� ; Weisz 2015^
Garcia Alonso 2018; Gibbins 2013; Lloreda-
Garcia 2016; McPherson 2014� ; Narasimhulu
2017; Özlü 2019; Weisz 2015� ^
Oxygen bag, mask, or both Bajaj 2018; Drassinower 2015; Riaz 1998; Weisz 2015� ^
(resuscitation) Weisz 2015� ^
Chest compressions Drassinower 2015; Stockley 2018; Weisz Bajaj 2018; Weisz 2015^
(resuscitation) 2015� ^
Adrenaline (resuscitation) Stockley 2018; Weisz 2015� ^ Jeanneteau 2014; Weisz 2015^
Score for Neonatal Acute Stockley 2018; Weisz 2015^ Deering 2005; Shalabi 2017;
Physiology > 10 or 20 in first 24 Weisz 2015� ^
hours
Delayed adaptation Lai 2017; Riaz 1998 Brazy 1982
Respiratory distress syndrome Alston 2016; Ambadkar 2019; Bozkurt 2016; de Veciana 1995^; Özlü 2019
Brookfield 2016; Canterino 1999; De Jesus
2015; de Veciana 1995^; Drassinower 2015;
Elimian 2002� ; Girsen 2015; Gonzalez-
Quintero 2001; Gursoy 2015; Imamoglu
2014; Jazayeri 2003; Jung 2018; Kamyar
2015a; Lee 2013; McPherson 2014� ; Mitani
2011; Rantonen 2001; Schanler 1997; Shokry
2010; Suh 2015; Yokoyama 2010
(Continued )

benefit
Respiratory depression Bertello Grecco 2019� Das 2015�
�
Surfactant use delValle 1998; Elimian 2002 ; Garcia Alonso
2018; Lloreda-Garcia 2016; Rantonen 2001;
Shokry 2010; Weisz 2015�
Ventilation Brookfield 2016; De Jesus 2015^; De Jesus 2015^; Lloreda-Garcia Lipsitz 1971� ; Lloreda-Garcia 2016^; Rauf 2017^
Drassinower 2015; Garcia Alonso 2018; 2016^; Rauf 2017^; Shalabi
Girsen 2015; Havranek 2011; James 2015; Lee 2017
2013; Lloreda-Garcia 2016^; McPherson
2014� ; Nunes 2018; Özlü 2019; Rantonen
2001; Schanler 1997; Shokry 2010
Ventilation (duration) Black 2006; De Jesus 2015; Kimberlin 1998;
Özlü 2019; Suh 2015
Methylxanthine use or duration Black 2006; Havranek 2011; Imamoglu 2014;
Schanler 1997
Chronic lung disease or Alston 2016; Basu 2012; Bozkurt 2016; De Narasimhulu 2017; Stetson 2019
bronchopulmonary dysplasia Jesus 2015; Edwards 2018; Garcia Alonso
2018; James 2015; Jung 2018; Kamyar 2015a;
Kamyar 2016a; McPherson 2014� ; Özlü
2019; Shalabi 2017; Stockley 2018; Suh 2015;
Weisz 2015
Oxygen use (at 28 days, 36 Kimberlin 1998; Morag 2016; Schanler 1997
weeks, or discharge)
Oxygen use (duration) De Jesus 2015; Özlü 2019; Suh 2015
Steroid use (dexamethasone or Mikhael 2019� ; Rantonen 2001; Rattray 2014;
hydrocortisone) Shalabi 2017
Apnoea Bozkurt 2016; Riaz 1998; Wutthigate 2017�
Pulmonary haemorrhage De Jesus 2015; James 2015
Necrotising enterocolitis Alston 2016; Bozkurt 2016; Brazy 1982; De Moschos 2001; Wiswell 1996
Jesus 2015; delValle 1998; de Veciana 1995;
Downey 2017; Edwards 2018; Elimian
2002� ; Elliott 2003; Garcia Alonso 2018;
Ghidini 2001; Gursoy 2015; Hong 2019;
James 2015; Jazayeri 2003; Jung 2018;
Kamyar 2015a; Kamyar 2016a; Kamyar
2016b; Kimberlin 1998; Lee 2013; Lloreda-
Garcia 2016; McPherson 2014� ; Mikhael
2019� ; Morag 2016; Narasimhulu 2017; Özlü
2019; Schanler 1997; Shalabi 2017; Stockley
2018; Suh 2015; Weisz 2015; Yokoyama
2010
Spontaneous intestinal Downey 2017; Mikhael 2019� ; Shalabi 2017 Rattray 2014
perforation
Composite of necrotising Kamyar 2016b� ^; Mikhael 2019� ^ Downey 2017; Mikhael 2019� ^ Kamyar 2016b� ^; Rattray 2014�
enterocolitis/spontaneous
intestinal perforation or death
Necrotising enterocolitis/ Hong 2019; Shalabi 2017
spontaneous intestinal
perforation–associated death
Sepsis Alston 2016; Bozkurt 2016; De Jesus 2015; Whitsel 2004
Elimian 2002� ; Girsen 2015; James 2015;
Jazayeri 2003; Jung 2018; Kamyar 2016a;
Lloreda-Garcia 2016; Mikhael 2019� ; Morag
2016; Özlü 2019; Rantonen 2001; Riaz 1998;
Stockley 2018; Teng 2006; Weisz 2015
(Continued )

benefit
Antibiotic use Elimian 2002� ^; Greenberg 2013 Elimian 2002^
Hypoglycaemia Bozkurt 2016; Grimbly 2015
Feeding intolerance Gursoy 2015; Özlü 2019; Riaz 1998 Belden 2017�
Delayed stooling Lloreda-Garcia 2016^ Lloreda-Garcia 2016^ Brazy 1982; Das 2015�
Meconium passage delay Ambadkar 2019; Lloreda-Garcia 2016
Ileus Brazy 1982; Nakamura 1991�
Delayed voiding Sahin 2001 Das 2015�
Patent ductus arteriosus Basu 2012; Bozkurt 2016; delValle 1998; Qasim 2017 Brazy 1982; del Moral 2007; Gonzalez-Quintero
Elimian 2002� ; Garcia Alonso 2018; Gursoy 2001; Katayama 2011^; Lee 2013; Narasimhulu
2015; Imamoglu 2014; James 2015; Katayama 2017; Shokry 2010
2011� ^; Lee 2013� ; Özlü 2019; Schanler 1997;
Yokoyama 2010
Patent ductus arteriosus De Jesus 2015; del Moral 2007; delValle Bonta 2000�
(treated) 1998; Katayama 2011� ; Lee 2013; Lloreda-
Garcia 2016; Mikhael 2019� ; Shalabi 2017;
Suh 2015
Hypotension Brazy 1982; Derks 2016; Drassinower 2015; De Jesus 2015 Narasimhulu 2017
Gursoy 2015; Morag 2016; Teng 2006
Hypertension Gursoy 2015 Brown 2019
Inotrope use Imamoglu 2014; James 2015; Shokry 2010
Intravenous fluids and/or Greenberg 2013; Rasch 1982
nutritional support needed
Phototherapy Greenberg 2013; Havranek 2011; Imamoglu
2014
Retinopathy of prematurity Basu 2012; Bozkurt 2016; Cuff 2018� ; De Shalabi 2017^ Rauf 2017
Jesus 2015; Elliott 2003; Garcia Alonso 2018;
Jung 2018; Kamyar 2015a; Kimberlin 1998;
Lee 2013; McPherson 2014� ; Narasimhulu
2017; Özlü 2019; Shalabi 2017^; Stockley
2018; Suh 2015; Weisz 2015; Yokoyama
2010
Hypotonia Bertello Grecco 2019� ; Drassinower 2015; Ambadkar 2019; Brazy 1982; Das 2015� ; Rauf
Gibbins 2013; Girsen 2015; Nassar 2006� 2017; Riaz 1998
Seizure Drassinower 2015; Girsen 2015; Kimberlin Shokry 2010
1998; McPherson 2014� ; Rauf 2017
Encephalopathy Girsen 2015; Rantonen 2001; Rauf 2017
Intraventricular haemorrhage Alston 2016; Black 2006; De Jesus 2015; Jung 2018^; Kuban 1992; Salafia 1995
delValle 1998; de Veciana 1995; Drassinower Perlman 1995; Petrova 2012;
2015; Edwards 2018; Elliott 2003; Gano Rantonen 2001; Rauf 2017;
2016; Garcia Alonso 2018; Gasparyan 2017; Shokry 2010
Gonzalez-Quintero 2001; Gursoy 2015; Hom
2018; Imamoglu 2014; Jazayeri 2003; Jung
2018^; Kamyar 2015a; Lee 2013; Leviton
1997; Martin 1998; McPherson 2014� ; Mitani
2011� ; Nassar 2006� ; Nelson 1995; Özlü 2019;
Paneth 1997; Schanler 1997; Stetson 2019;
Stockley 2018; Suh 2015; Yokoyama 2010
Intraventricular haemorrhage del Moral 2007; Downey 2017; Gano 2016; Gasparyan 2017; Perlman 1995; Cuff 2018� ; Khodapanahandeh 2008
grade 3 or 4 James 2015; Jung 2018; Kamyar 2016a; Sarkar 2009; Wiswell 1996
Kimberlin 1998; McPherson 2014� ; Mikhael
2019� ; Narasimhulu 2017; Özlü 2019;
Rantonen 2001; Stockley 2018; Weintraub
2001
(Continued )

benefit
Periventricular leucomalacia Bozkurt 2016; De Jesus 2015; del Moral 2007; FineSmith 1997; Jung 2018^;
delValle 1998; Garcia Alonso 2018; Jung Murata 2005
2018^; Kamyar 2015a; Kamyar 2016a; Lee
2013; Mitani 2011� ; Narasimhulu 2017; Rauf
2017; Suh 2015; Wiswell 1996
Intraventricular haemorrhage or Basu 2012; Canterino 1999� ; Elimian 2002�
periventricular leucomalacia
Intraventricular haemorrhage Bozkurt 2016; Canterino 1999� ; Morag 2016; Koksal 2002; Shalabi 2017^;
grade 3 or 4 and/or Shalabi 2017^; Weisz 2015 Wiswell 1996
periventricular leucomalacia
Hypocalcaemia Cho 2014; Lee 2015; McGuiness 1980 Narasimhulu 2017
Bone abnormalities Yokoyama 2010 Holcomb 1991� ; Matsuda 1997�
Hearing impairment or hearing Jung 2018 Leung 2016
test failure
Composite adverse outcomes Drassinower 2015; Duffy 2012; Kamyar Boyle 2018; Sakae 2017� ^
2015a; Kamyar 2015b; Kamyar 2015c;
Kamyar 2016a; Mitani 2011� ; Narasimhulu
2017; Palatnik 2019; Rizzolo 2019; Sakae
2017� ^; Weisz 2015
NICU admission Ambadkar 2019� ^; Bertello Grecco 2019� ; Ambadkar 2019� ^; Chun 2014^; Das 2015� ;
Cawyer 2019; Chun 2014^; Gibbins 2013; Lai Girsen 2015; Greenberg 2011� ; Greenberg 2013� ;
2017; McPherson 2014� ; Rantonen 2001; Rhee 2012
Riaz 1998�
NICU duration Gibbins 2013; Girsen 2015; Greenberg 2013; Narasimhulu 2017
Jazayeri 2003; Jung 2018; Kimberlin 1998;
Rauf 2017
Hospital stay duration Alston 2016; Basu 2012; De Jesus 2015; de Brazy 1982; Girsen 2015
Veciana 1995; Özlü 2019; Riaz 1998; Schanler
1997; Suh 2015
Other (outcomes reported by Black 2006; Blackwell 2002; Brazy 1982; Deering 2005; Derks 2016; Belden 2017� ; Brazy 1982; Das 2015� ; Katayama
single studies) Derks 2016; Gano 2016; Girsen 2015; Gano 2016; Jeanneteau 2014; 2011; Lai 2017; Lipsitz 1971� ; Mittendorf 2009� ;
Greenberg 2013; Havranek 2011; Hong 2019; Kimberlin 1998; Mittendorf Morag 2015; Morag 2016; Rasch 1982; Shalabi
Imamoglu 2014; Jeanneteau 2014; Jones 2005� ; Petrov 2013 2017^; Verma 2006� ; Weisz 2015; Whitten 2015
2018; Jung 2018; Katayama 2011� ; Kelly
1992; Kimberlin 1998; Lai 2017; Leviton
1997; Lloreda-Garcia 2016; Mittendorf
2005� ; Morag 2016; Nassar 2006� ; Nunes
2018; Özlü 2019; Paneth 1997; Petrov 2013;
Rantonen 2001; Riaz 1998; Sahin 2001;
Schanler 1997; Shalabi 2017^
The bold studies were judged to be of higher quality (moderate or moderate to high risk of bias) and presented results adjusted for confounders for the relevant
outcomes; other studies were judged to be at high or unclear risk of bias and/or or did not present adjusted results for the relevant outcomes.
�
Indicates where studies assessed different magnesium sulphate regimens or 1 or more characteristics of the regimen (such as dose, duration, timing, or indication for
use).
Îndicates where studies demonstrated mixed findings (such as in different subgroups of the population).
NICU, neonatal intensive care unit.
antenatal magnesium sulphate doses for fetal neuroprotection (non-concurrent cohort of 155
babies born less than 1,000 grams) [173].
A possible increased risk of patent ductus arteriosus was observed with magnesium sul-
phate given for pre-eclampsia (retrospective cohort of 81 ‘very low birthweight’ babies; abstract

only) [140] or for pre-eclampsia or tocolysis (retrospective cohort of 941 babies born 500 to
1,000 grams) [90]. Further, a possible increased risk of patent ductus arteriosus in babies born
26 weeks gestation or later was shown with cumulative antenatal magnesium sulphate doses
for pre-eclampsia or tocolysis of at least 50 grams (retrospective cohort of 941 babies born 500
to 1,000 grams) [90]. Potential increased risk of symptomatic patent ductus arteriosus, and of
failure of early closure of the ductus arteriosus, was also observed with the use of antenatal
magnesium sulphate for tocolysis (retrospective cohort of 160 babies born less than 28 weeks
gestation, who all received indomethacin prophylaxis) [132].
A potential increased risk of intraventricular haemorrhage grade 3 or 4 was observed with
antenatal magnesium sulphate for tocolysis (case–control study of 121 babies born less than
1,500 grams) [134], and with a higher dose regimen of antenatal magnesium sulphate for fetal
neuroprotection (6-gram IV loading dose and 2-gram-per-hour IV maintenance dose for 12
hours versus 4-gram IV loading dose only) (retrospective cohort, including 54 babies exposed
to magnesium sulphate within 12 hours of birth) [84].
A possible increased risk of neonatal intensive care unit admission with the use of antenatal
magnesium sulphate for pre-eclampsia was observed (retrospective cohorts of 264 babies and
2,166 babies born at 37 weeks gestation or later) [106,109]. Further increased risks of neonatal
intensive care unit and special care unit admission were observed with higher total hours,
higher total doses, more than 12 hours, and more than 30 grams of antenatal magnesium sul-
phate for pre-eclampsia (retrospective cohort of 242 babies born at 35 weeks gestation or later)
[108].
Evidence from case reports

Nineteen reports describing a total of 134 babies exposed to antenatal magnesium sulphate
with adverse outcomes were included [200–218] (see Table 9; the detailed characteristics of
cases are presented in S4 Table).
Clinical features of neonatal hypermagnesemia, magnesium ‘toxicity’, or magnesium ‘intox-
ication’ at birth were the focus of 5 reports (35 neonates), in which antenatal magnesium sul-
phate was given for pre-eclampsia/eclampsia (with exposure durations and doses ranging
from 3.5 to 46 hours and 11 to 60.4 grams prior to birth, respectively) [202,205,206,213,218],
and were variably described throughout the remaining reports. These included low Apgar
scores, apnoea, cyanosis, hypotonia, and/or hyporeflexia, with or without the need for active
resuscitation and calcium gluconate administration.
Table 9. Summary of main adverse outcomes from case reports.

Outcome Indication for use: studies
Neonatal death Tocolysis: Herschel 2001
Pre-eclampsia/eclampsia: Kurtoglu 2000
Cardiopulmonary arrest after gentamicin exposure following Pre-eclampsia: L’Hommedieu 1983; Rasch 1981
hypermagnesemia at birth
Clinical features of magnesium ‘toxicity’ or ‘intoxication’ at birth Pre-eclampsia/eclampsia: Brady 1967; Cruz
(such as apnoea, cyanosis, hypotonia, and/or hyporeflexia) 2009; Lipsitz 1967; Teng 1989
Not clear: Jashi 2014
Microcolon or ‘meconium-plug syndrome’ Pre-eclampsia/eclampsia: Amodio 1986; Krasna
1996; Sokal 1972
Nonoliguric hyperkalaemia Pre-eclampsia: Tanaka 2018
Bone abnormalities with prolonged magnesium sulphate for Tocolysis: Cumming 1989; Kaplan 2006; Kogan
tocolysis 2003; Lamm 1988; Malaeb 2004
Not clear: Ahmad 2013

Two reports described neonatal death following antenatal magnesium sulphate exposure.
In the first report, death was considered to be related to ‘the toxic effects of magnesium on the
myocardium’ when given for tocolysis (4-gram IV loading dose followed by 2.5-gram-per-
hour IV maintenance dose for approximately 1 day: 51.4 grams total) [204], and in the second,
1 death (of 7) was attributed to ‘overdose’ (unclear dose/regimen) of magnesium sulphate
when given for pre-eclampsia/eclampsia [210].
In the context of hypermagnesemia at birth (following exposure to a total of 24 to 28 grams
of magnesium sulphate for pre-eclampsia), neonatal gentamicin administration for suspected
sepsis was associated with respiratory arrest and cardiac arrest in 2 reports [211,215]. Other
specific adverse outcomes attributed to antenatal magnesium sulphate exposure included
• Microcolon or meconium-plug syndrome (3 reports, 14 neonates, when given for pre-
eclampsia/eclampsia: 25 to 41 grams in the day prior to birth in 1 report; regimen not
described in 2 reports) [201,209,216];
• Nonoliguric hyperkalaemia (1 report, 1 neonate, when given for pre-eclampsia: 0.1 gram to
2 grams per hour IV for 12 days) [217];
• Bone abnormalities (commonly metaphyseal osteopenia, in some cases leading to fracture)
(6 reports, 35 neonates, when given for tocolysis: ranging from 1 to 4 grams per hour for
between 8 and 13 weeks) [200,203,207,208,212,214].
Discussion
Overall, no clear difference in our primary review outcome, perinatal death, was shown in the
randomised trials comparing antenatal magnesium sulphate with placebo/no treatment, nor in
regimen comparisons in randomised trials. While 11 of the 138 non-randomised studies
reported on perinatal death, only 1 cohort study (at moderate to high risk of bias) observed a
possible increased risk of perinatal death, with high-dose (more than 48 grams) antenatal mag-
nesium sulphate exposure for tocolysis [183].
Results for secondary adverse neonatal outcomes were reassuring, with very few clear dif-
ferences observed between antenatal magnesium sulphate and placebo/no treatment or
between different magnesium sulphate regimens. Where possible harms of magnesium sul-
phate were seen, commonly no confounders were taken into account (and studies were judged
to be at high risk of bias), study samples were small (less than 200 babies), and/or differences
were observed in (non-formal) subgroup analyses only. Non-randomised studies identified a
limited number of outcomes justifying further evaluation, such as from large, high-quality
studies (prospective cohorts, individual participant data meta-analyses, or randomised trials of
regimen comparisons). These included neonatal death and intestinal morbidity in very pre-
term neonates with exposure for fetal neuroprotection, patent ductus arteriosus in very pre-
term or very low birthweight neonates with exposure for pre-eclampsia or tocolysis, and
intensive care unit admission in term neonates with exposure for pre-eclampsia. Case reports
suggested an association between neonatal bone abnormalities and long-term, high-dose expo-
sure to antenatal magnesium sulphate for tocolysis.
We are not aware of any other published systematic reviews with a focus on potential
adverse outcomes for neonates following antenatal magnesium sulphate exposure, though we
identified 3 review registrations focused specifically on magnesium sulphate for tocolysis and
the outcomes neonatal respiratory depression (CRD42017058912), patent ductus arteriosus
(CRD42017060049), and bone abnormalities (CRD42017062550) [18]. Three previous system-
atic reviews have assessed ‘adverse events’ [13], ‘side effects’ [219], and ‘safety’ [220] for

women, and a further systematic review has assessed the effects of antenatal magnesium sul-
phate specifically on fetal heart rate parameters, finding a small negative effect on rate, variabil-
ity, and accelerative pattern, ‘not sufficient clinically to warrant medical intervention’ [14].
Our review findings are consistent with those from the relevant Cochrane reviews compar-
ing antenatal magnesium sulphate with placebo/no treatment, or different magnesium sul-
phate regimens [1,2,4,9,221], though our review includes a wider range of outcomes. As was
observed in our review’s tocolysis subgroup for perinatal death, the Cochrane review assessing
magnesium sulphate for tocolysis demonstrated a borderline increased risk of fetal, neonatal,
or infant death with antenatal magnesium sulphate [9].
A recent non-systematic narrative review evaluated ‘whether antenatal MgSO4 is beneficial
or harmful’ in extremely and very preterm neonates [222]. Relevant systematic reviews, meta-
analyses, randomised controlled trials, and observational studies were retrieved, with a broad
search strategy focused on neuroprotection and cerebral palsy, necrotising enterocolitis, and
spontaneous intestinal perforation. The narrative review suggested that current evidence sup-
ports the neuroprotective role of antenatal magnesium sulphate for preterm neonates, and
that, while the effects are ‘controversial’ and ‘not well established’, a ‘high index of suspicion of
gastrointestinal complications in extremely preterms, particularly < 26 weeks of gestation’ is
recommended [222]. While our review similarly identified a possibility of harm, the relevant
studies were of questionable methodological quality, and our systematic review included addi-
tional reports (of higher quality, and involving much larger cohorts) that indicated no
increased risk of intestinal morbidity.
The findings of this review are reassuring and can be considered in conjunction with those
from relevant reviews demonstrating a clear benefit of antenatal magnesium sulphate [1,2,4],
and current international clinical practice guideline recommendations [3,7]. Our review find-
ings of possible adverse outcomes with long-term, high-dose use for tocolysis have implica-
tions for settings with continued use for this indication [8] in spite of the absence of benefit
shown in systematic reviews and international guidance [7–9].
Strengths and limitations

The main limitations of our review relate to missing data for important outcomes across most
studies, the inclusion of published data only, and the heterogeneity of included studies.
Of the 40 randomised trials included in this review, our primary outcome (perinatal death)
was reported by 22 (55%); it was reported by only 11 (8%) of the 138 included non-randomised
studies. Aside from related mortality outcomes (stillbirth and neonatal death), all other adverse
outcomes were reported sparsely, by less than a third of trials, with many outcomes reported
by single trials only. While a broader range of adverse neonatal outcomes were reported by the
non-randomised studies, apart from neonatal death (50 studies), intraventricular haemorrhage
(39 studies), and necrotising enterocolitis (36 studies), all other outcomes were reported by
less than a fifth of studies, again, with many reported by single studies only.
In addition to missing data for important outcomes across most studies, a further limitation
includes the number of studies with relatively small sample sizes comparing different antenatal
magnesium sulphate regimens. Moreover, many studies assessing antenatal magnesium sul-
phate for relevant indications were not included due to lack of reporting of adverse neonatal
outcomes.
We searched extensively across multiple databases and reviewed reference lists for addi-
tional reports; however, we did not seek unpublished data. Recent evidence has suggested that
while much adverse event information remains unpublished, inclusion of such data generally
does not change the direction or statistical significance of pooled risk estimates [223]. While

we were not able to fully evaluate non-English publications without available translations for
inclusion, we have provided a list of these for readers to consider (S3 Text).
As the aim of the review was to provide a comprehensive, general view of potential unin-
tended adverse outcomes, we designed this review with broad scope [15,16]. This presented
challenges, including the number of diverse outcomes, inconsistent reporting, and the vast
quantities of heterogeneous data. The study characteristics (including designs, settings, partici-
pating women and neonates, and antenatal magnesium sulphate regimens) varied greatly, and
reporting was commonly incomplete. The ability to conduct subgroup analyses for the rando-
mised trials was limited, and we did not inappropriately pool data from non-randomised stud-
ies. We conducted this review in accordance with recommendations for systematic reviews of
adverse events [15–17], and of randomised and non-randomised studies more generally [224].
Our evaluation thus provides a firm basis for any further, narrowly focused studies of specific
outcomes and characteristics.
Conclusions
In conclusion, our findings do not support any clear associations between perinatal death or
other adverse neonatal outcomes and antenatal magnesium sulphate exposure when given for
the beneficial indications of maternal neuroprotection in pre-eclampsia/eclampsia and fetal
neuroprotection in cerebral palsy prevention. To further inform safety recommendations of
this widely used treatment in pregnancy, future research should be directed towards identified
research gaps surrounding specific adverse neonatal outcomes and the impact of particular
regimen, pregnancy, and/or birth characteristics.
Supporting information
S1 Appendix. Forest plots and funnel plots for comparisons 1–8.
(DOCX)
S1 Fig. Risk of bias for randomised controlled trials. Risk of bias summary showing judge-
ments about each risk of bias item for the 40 included randomised trials. Green represents
‘low risk of bias’; yellow, ‘unclear risk of bias’; red, ‘high risk of bias’.
(TIF)
S1 PRISMA Checklist. Preferred Reporting Items for Systematic Reviews and Meta-Analy-
ses (PRISMA) checklist.
(DOCX)
S1 Table. Characteristics of included studies.
(DOCX)
S2 Table. Risk of bias of included studies.
(DOCX)
S3 Table. Adverse outcomes from non-randomised studies.
(DOCX)
S4 Table. Adverse outcomes from case reports.
(DOCX)
S1 Text. Protocol.
(PDF)

S2 Text. Search strategies.

(DOCX)
S3 Text. Articles excluded at full-text screening due to absence of English translation.
(DOCX)
S4 Text. References for included studies.
(DOCX)
Author Contributions
Conceptualization: Emily Shepherd, Deepak Manhas, Anne Synnes, Philippa Middleton,
Maria Makrides, Caroline A. Crowther.
Data curation: Emily Shepherd, Rehana A. Salam, Deepak Manhas, Anne Synnes.
Formal analysis: Emily Shepherd.
Funding acquisition: Emily Shepherd, Philippa Middleton, Maria Makrides, Caroline A.
Crowther.
Investigation: Emily Shepherd, Rehana A. Salam, Deepak Manhas, Anne Synnes.
Methodology: Emily Shepherd, Deepak Manhas, Anne Synnes, Philippa Middleton, Maria
Makrides, Caroline A. Crowther.
Project administration: Emily Shepherd.
Resources: Emily Shepherd.
Software: Emily Shepherd.
Supervision: Emily Shepherd.
Writing – original draft: Emily Shepherd.
Writing – review & editing: Emily Shepherd, Rehana A. Salam, Deepak Manhas, Anne
Synnes, Philippa Middleton, Maria Makrides, Caroline A. Crowther.
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212. Lamm C, Norton K, Murphy R, Wilkins I, Rabinowitz J. Congenital rickets associated with magnesium
sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078–82. https://doi.org/10.1016/s0022-3476(88)
80586-9 PMID: 3193315

213. Lipsitz P, English I. Hypermagnesemia in the newborn infant. Pediatrics. 1967; 40(5):856–62. PMID:
6075658
214. Malaeb S, Rassi A, Haddad M, Seoud M, Yunis K. Bone mineralization in newborns whose mothers
received magnesium sulphate for tocolysis of preterm labour. Pediatr Radiol. 2004; 34(384–6).
215. Rasch D, Richardson C. Effect of gentamicin on neuromuscular function (NMF) of a hypermagnese-
mic neonate. Pediatr Res. 1981; 15(4):499.
216. Sokal M, Koenigsberger M, Rose J, Berdon W, Santulli T. Neonatal hypermagnesemia and the meco-
nium-plug syndrome. N Engl J Med. 1972; 286(1):823–5.
217. Tanaka K, Mori H, Sakamoto R, Matsumoto S, Mitsubuchi H, Nakamura K, et al. Early-onset neonatal
hyperkalemia associated with maternal hypermagnesemia: a case report. BMC Pediatr. 2018;
15(1):55.
218. Teng R, Liu H, Tsou Yau K. Neonatal hypermagnesemia: report of one case. Acta Paediatr Sin. 1989;
30(5):333–6. PMID: 2637615
219. Smith JM, Lowe RF, Fullerton J, Currie SM, Harris L, Felker-Kantor E. An integrative review of the side
effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management. BMC
Pregnancy Childbirth. 2013; 13:34. https://doi.org/10.1186/1471-2393-13-34 PMID: 23383864
220. Duffy J, Hirsch M, Pealing L, Showell M, Khan KS, Ziebland S, et al. Inadequate safety reporting in
pre-eclampsia trials: a systematic evaluation. Br J Obstet Gynaecol. 2018; 125(7):795–803.
221. McNamara HC, Crowther CA, Brown J. Different treatment regimens of magnesium sulphate for toco-
lysis in women in preterm labour. Cochrane Database Syst Rev. 2015;(12):CD011200. https://doi.org/
10.1002/14651858.CD011200.pub2 PMID: 26662716
222. Garg BD. Antenatal magnesium sulfate is beneficial or harmful in very preterm and extremely preterm
neonates: a new insight. J Matern Fetal Neonatal Med. 2019; 32(12):2084–90. https://doi.org/10.
1080/14767058.2018.1424823 PMID: 29301419
223. Golder S, Loke YK, Wright K, Norman G. Reporting of adverse events in published and unpublished
studies of health care interventions: a systematic review. PLoS Med. 2016; 13(9):e1002127. https://
doi.org/10.1371/journal.pmed.1002127 PMID: 27649528
224. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool
for systematic reviews that include randomised or non-randomised studies of healthcare interventions,
or both. BMJ. 2017; 358:j4008. https://doi.org/10.1136/bmj.j4008 PMID: 28935701

CONVULSIILE FEBRILE
Diana Bârcă
CRIZE EPILEPTICE OCAZIONALE (ACUTE
SIMPTOMATICE) DEFINITIE.
◼ Crize epileptice survenite la orice varsta, dar in special la sugar si

copil mic ca o reactie a sistemului nervos central fata de
modificarea unor constante homeostazice (termica,
glicemica, fosfo-calcica, acido-bazica etc), neavand la baza o
leziune cerebrala epileptogena.
◼ Acest tip de crize se datoreaza unor modificari predominant

extracerebrale si rar si unor leziuni intracerebrale acute.
UMF, mai 2020

CRIZE EPILEPTICE OCAZIONALE (ACUTE
SIMPTOMATICE) CLASIFICARE.
1. CRIZE OCAZIONALE PRIN MODIFICARI

EXTRACEREBRALE:
◼ Convulsii febrile;
◼ Convulsiile hipocalcemice;
◼ Convulsiile hipoglicemice;
◼ Convulsiile din sindromul de deshidratare acuta;
◼ Convulsiile din intoxicatiile acute;
◼ Convulsiile din carenta de piridoxina;
2. CRIZE OCAZIONALE PRIN LEZIUNI CEREBRALE ACUTE:

◼ Infectii cerebrale acute;
◼ Crizele din tumorile cerebrale;
◼ Crizele din traumatismele cerebrale;
◼ Convulsiile din accidentele vasculare;
UMF, mai 2020

◼ Ce sunt CF?
◼ Definitie
UMF, mai 2020

Definitia CF
✓ “Convulsii survenite la copilul:

✓ in varsta de >6 luni,
✓ in asociere cu o boala febrila, care nu este cauzata de infectie a
SNC,
✓ fara crize neonatale sau alte tipuri de crize epileptice neprovocate
in antecedente,
✓ si fara a intruni criteriile pentru alte tipuri de crize acute
simptomatice*
Comission on Epidemiology and Prognosis,

International League Against Epilepsy. Guidelines for epidemiological studies on
epilepsy. Epilepsia. 1993;34:592-6.
UMF, mai 2020

CF - epidemiologie
• Cel mai comun tip de crize in copilarie
• 2 - 5 % copii
• Dependente de varsta- 6 luni – 5-6ani:

• ! 4% <6 luni
• 85-90% in primii 3 ani
• 6% > 3 ani;
• Febra – o conditie prealabila!;
• in absenta unei infectii a sistemului nervos (meningita,

encefalita)
• ♂ = ♀;
UMF, mai 2020

CF - etiopatogenie
- insuficient cunoscuta;
- multifactoriala: factori genetici & de mediu
- in determinarea excitabilitatii corticale sunt
implicati 4 factori:
1. Febra si fact exogeni;

2. Varsta – susceptibilitate individuala;
3. Factori ereditari
4. Modularea raspunsului imun
UMF, mai 2020

CF - etiopatogenie
1. FEBRA
etiologie: infectii de cai respiratorii superioare,

boli eruptive, infectii urinare si gastroenterite;
CF apar la cresterea brusca a temperaturii;
75% la >39,5 C;
UMF, mai 2020

CF - etiopatogenie
2. VARSTA:
- Foarte importanta;
- rar < 6 luni & > 4-5 ani;
- Datorita:
- maturarii cerebrale
- scaderii frecventei bolilor infectioase;
UMF, mai 2020

CF - etiopatogenie
3. FACTORI EREDITARI:
- Transmitere autozomal dominanta cu penetranta incompleta si

expresivitate legata de varsta – modelul exact este insuficient
clarificat;
- AHC + pt epilepsie: 10-50%;
- AHC + pt CF: 33%;
UMF, mai 2020

CF - clasificare
➢ CONVULSII FEBRILE SIMPLE (CFS)
➢ CONVULSII FEBRILE COMPLEXE

(COMPLICATE) (CFC)
UMF, mai 2020

◼ Ce sunt CFS?
UMF, mai 2020

CONVULSIILE FEBRILE SIMPLE (CFS)
◼ Crize primar generalizate ( tonice, hipotone, tonico-clonice );
◼ bilaterale
◼ < 15 min !! febra poate fi detectata in perioada imediat postcritica !!
◼ T>38.5°C
◼ Episod unic in primele 24 h de febra
UMF, mai 2020

CONVULSII FEBRILE SIMPLE (CFS)
◼ In general survin la copiii normali (exam neurol N, intelect

normal)
◼ Dar daca un copil prezinta (anterior):

❑ Afect neurologica /cognitiva
❑ Leziuni cerebrale
◼ NU UN CRITERIU DE DEFINITIE
UMF, mai 2020

◼ Ce sunt CF complexe?
UMF, mai 2020

CONVULSIILE FEBRILE COMPLEXE (CFC)
◼ rare (4-5% dintre CF);
◼ varsta aparitiei - frecvent înainte de 1 an;
◼ multiple;
◼ durată > de 15 minute;
◼ sunt de obicei unilaterale (focale);
◼ apar la copii cu dezvoltare psihomotorie normala/anormală anterior crizei;
◼ Pot fi urmate de deficit postcritic.
UMF, mai 2020

◼ Ce teste ati cere?
UMF, mai 2020

PL
◼ Cui?
◼ Cand?
UMF, mai 2020

Investigatii - PL
• semne meningeale
• 6-12 luni – cu
imunizari deficitare
• pre-tratament cu
antibiotic
UMF, mai 2020

Investigatii – PL
DA
✓CF < 6 luni POATE
✓6-12 luni - +/- semne - CFC prelungite/ repetitive in 24
meningeale/ sepsis/ fontanela ore, fara semne meningeale/
bombata/ anomalii de sepsis/ fontanela bombata/
dispozitie si comportament anomalii de dispozitie si
comportament
-imunizare incompleta fara alte
semne
NU - tratament antibiotic anterior
✓CFS – fara semne mening , - Context/ semne “suspicioase”
fara anomalii de dispozitie si
comportament
✓ > 4 ore monitorizare
UMF, mai 2020

EEG
◼ rol in dg + & diferential

◼ rol in estimarea recurentelor
◼ rol in aprecierea evolutiei spre
epilepsie
UMF, mai 2020
Investigations - EEG
- in CFS: valoarea dg in encefalitele

virale!
UMF, mai 2020

◼ EEG cu modificari epileptiforme
❑ Care este semnificatia
❑ Va schimba optiunile de tratament
✓Pot fi expresia unei predispozitii genetice

(nu indicator al unei epilepsii viitoare)
UMF, mai 2020

Imagistica
cerebrala
◼ CT/ IRM in camera de garda ?
◼ mai tarziu?
UMF, mai 2020

Investigatii – imagistica CT/IRM
◼ CT- riscul de iradiere

◼ MRI – sedare/ costuri
UMF, mai 2020

Imagistica cerebrala in urgenta?
◼ Depinde de evolutia clinica – absenta ameliorarii st

de constienta la 2 evaluari consecutive la interval de
30 minute
◼ deficite neurologice focale persistente
UMF, mai 2020

Investigatii de
laborator
UMF, mai 2020

Investigatii de lab
-Teste de rutina pt etiologia febrei

-glicemia
UMF, mai 2020

Investigatii
◼ Analize de laborator – in functie de istoric/ex. clinic

◼ EEG nu sunt indicate de rutina
◼ CT/IRM
-Asocierea CF cu infectii serioase – rara, supraestimata
◼ PL? -Abordarea diagnostica trebuie individualizata
-Educarea parintilor! (Pediatric Emergency Care, 2012, FEB 29)

UMF, mai 2020
❑Ce semne clinice trebuie cautate ?
❑Ce intrebari trebuie puse?
❑Ce investigatii trebuie facute ?
UMF, mai 2020

◼ Primul episod < 6 luni ◼ Nu orice copil cu febra are CF !!!

◼ Debutul CF> 24 h de febra ❑ hipotonie – sincopa
◼ prezentare atipica: convulsii focale, ❑ “tremor” – anamneza atenta!!
> 15 min, >1 ep in 24 h
◼ + semne meningeale
◼ + HIC anamneza
semne!!!
◼ Afectarea severa a !!
st de constienta
▪ Crize anoxice – sincope/

Infectii SNC ◼ frison/
◼ Spasmul hohotului de plans
meningita/ encefalita/ abces cerebral
* Sugai, K. Current management of Febrile Seizures in Japan: An overview – Brain and

Development 32 (2010) 64-70 UMF, mai 2020
CONVULSIILE FEBRILE
ABORDAREA
TRATAMENTULUI
UMF, mai 2020

TRATAMENTUL ACUT
la I CF
medicatia de urgenta
PROFILAXIA
antipiretice
medicatie de urgenta
profilaxia intermitenta
tratament continuu
UMF, mai 2020

Prima CFS la sosirea la spital
oprita
✓?interventii ant in ambulanta
Evaluarea
starii de const
✓atitudine fata de parinti –
calmarea familiei!
Raspuns slab Raspuns bun
resp, O2 verif & corect

verif & corect semnelor vitale
semnelor vitale Rolul BZD ?
examen clinic examen clinic

Investig lab pt Investig lab pt
intercurenta fb intercurenta fb
✓HLG, Rx pulm, ✓HLG, Rx pulm,
ORL, etc ORL, etc
Internare sau externare persista
UMF, mai 2020

Prima CFS la sosirea la spital, UPU
persista
✓Pozitie de decubit lateral >3min Access IV

✓O2 Access IV dificil
✓verif & corect. semnelor vitale
✓antipiretice DZP iv – stopul
✓Calmarea familiei DA NU respirator – MIT!
iv DZP 0,25mg/kgc DZP 0,5mg/kgc ir
MDL 0,2-0,3 mg/kgc

nasal, bucal
Cat dureaza prima CF?
CRIZA
• >10 min: 13%
• >15 min: 9% s-a oprit persista
• >30 min: 5% examen clinic
Investig de lab pt SE
•<10 min: 73% intercurenta
febrila
Berg AT, Shinnar S ✓HLG, Rx pulm,
UMF, mai 2020
Epilepsia 1996 Feb; 37(2):126-33 ORL etc
Tratament –prevenirea recurentelor
◼ Prima CF a trecut...
◼ Ce va fi in continuare??
❑ Antipiretice
❑ medicatie de “urgenta”
❑ Benzodiazepine (BZD) intermitent
❑ tratament continuu
UMF, mai 2020

Tratament - SCOPURI
✓ prevenirea recurentelor
✓ Diminuarea anxietatii parintilor –

“credeam ca-mi moare copilul!”
CALM, NU PANICA
✓ Prevenirea CF prelungite
UMF, mai 2020
Suferinta si anxietatea parintilor
◼ Riscul de mortalitate
❑ Niciun caz raportat, fara dovezi
❑ teoretic posibil ( aritmii cardiace, aspiratie, traumatisme

secundare crizelor )
◼ Tulburari de comportament & cognitie
◼ anomalii structurale cerebrale
UMF, mai 2020

Antipireticele & recurenta CF
◼ antipireticele amelioreaza confortul

copilului,
antipiretice: acetaminofen, ibuprofen, bai cu apa
calduta – NU !!! folosirii de gheata , impachetari reci. Pot
cauza frison, cu cresterea temperaturii
DAR
◼ Nu previn recurenta CF
UMF, mai 2020

Medicatia de “urgenta”
◼ DA/NU? – Da – 87% crize se opresc spontan –

13% SE!!!
◼ CAND? – crize acute prelungite
◼ CU CE? – Diazepam, Midazolam, Lorazepam,

Clobazam
◼ CALE de administrare? – rectal, bucal,

nazal…
UMF, mai 2020
DOZA – de ce este importanta?
◼ 0,5 mg/kg intrarectal
◼ Pt un pacient 14kg – 7mg = 3,5 ml
◼ pt>15kg si >3ani – 10 mg!
NU DOZE MAI MICI! – INEFICIENTE
UMF, mai 2020

BZD intermitent & recurenta CF
In caz de febra/ boala febrila
◼ DZP 0,33mg/kgc po la fiecare 8 h

max 3
administrari
◼ DZP 0,5mg/kgc ir la 8 h
DE CE?
UMF, mai 2020

Profilaxia cu medicatie antiepileptica
CAND?
▪ copii cu risc crescut (≥ 3CF in 6 luni, ≥4 in 1an),

▪ durata CF>15 min,
▪ CF necesitand interventie farmacologica pt a fi intrerupte
▪ recurente frecvente,
▪ dezvoltare psihomotorie anormala
▪ parinti inspaimantati, anxiosi
UMF, mai 2020

Profilaxia continua cu MAE (medicamente antiepileptice)
❑ Nu previne epilepsia
❑ ! efectele sec ale MAE (iritabilitate, letargie, afectare
cognitiva, insuficienta hepatica/ pancreatica ) – unele pot fi
permanente!
CU CE?
◼ Fenobarbital 3-5 mg/kg/ zi
❑ Tulb de comportament
❑ Tulb de somn
❑ Disfunctii cognitive
◼ Acid Valproic acid 20-30 mg/kg/zi

❑ Insuf hepatica
◼ Carbamazepina, Fenitoina – fara efect
Meta analysis
UMF, mai 2020
Rantala – J Pediatrics 1997
Offringa, Newton Evid Based Child Health 2013
Cand se trimite copilul la neurologul pediatru?
◼ CF prelungite < 1 an
◼ CFC
◼ Tulburare globala de dezvoltare
◼ examen neurologic anormal
UMF, mai 2020

Factori de risc pentru recurenta CF
◼ istoricul familial de CF la rudele de gradul I;

◼ durata scurtă a febrei înainte de CF;
◼ durata crizei;
◼ temperatura moderată;
◼ caracterul focal al crizei;
◼ vârsta primei crize febrile: < 15 luni: 50-65%;
◼ 50-75% din recurenţe apar în primul an;
◼ recurenţele multiple sunt de 3 ori mai frecvente la sugar;
> 3 factori de risc + : UMF,

50-100%
mai 2020 - recurenta
Factori de risc pentru epilepsie
❑ CF > 15 min;
❑ Mai multe CF in 24 h;
❑ Istoric familial + pentru epilepsie
❑ Anomalii neurologice;
UMF, mai 2020

Factori de risc pentru recurenta CF & epilepsiei
◼ CF ◼ EPILEPSIE
❑ Varsta mica la debut ◼ Anomalii ale neurodezvolt
❑ Istoric familial+ pt CF ◼ Nr CF
❑ Temperatura ◼ CFC
❑ Durata scurta a febrei ◼ Durata scurta a febrei
◼ Istoric familial + pt epilepsie
UMF, mai 2020 Shinnar S, 1999, Pediatric Neurology

Aplicații practice...
UMF, mai 2020

1. Andrei
UMF, mai 2020

In camera de garda este adus Andrei, in varsta de 7 luni care a prezentat la
domiciliu o manifestare paroxistica in care a plafonat privirea, prezentand contractura
simetrica a membrelor, cianoza perioronazala, neresponsivitate, cu durata de ~ 2
minute. La sosirea ambulantei copilul prezenta somn profund, iar temperatura era de 39
°C, parintii afirmand ca anterior episodului paroxistic bebelusul “nu parea racit”, doar
usor inapetent
Cum incadrati manif? CFS
Semne vitale, eval constientei,

Primii pasi? examen fizic
Analize de lab pt etiologia
febrei…& calmarea familiei!
Investigatii?
Etiologia febrei
Tratament? Febra/ confortul copilului
Trimitere catre
NU
neurolog?
UMF, mai 2020

2. Matei
UMF, mai 2020

Matei in varsta de 2 ani, se prez la medicul de familie ptr ca in
cursul zilei a inceput sa prezinte tuse, rinoree si febra peste 39 grdC.
In cabinet prezinta o manifestare cu pierderea constientei, hipertonie
generalizata, respiratie stertoroasa, prima din viata lui.
✓Pozitionare in decubit lat

Diazepam Desitin
✓O2
1. 2. 0.5mg/kg i.r
Suna 112? ✓verif & corect semnelor 3. daca durata crizei >3-5
vitale
min
✓antipiretice
✓calmarea familiei
UMF, mai 2020 2. 3. 1.

112? Criza scurta(< 3min) Trimitere catre
Copilul isi revine rapid la normal neurolog?
Ce investigatii imediat
Da
sunt necesare?
✓Nu stim daca mai tarziu

✓Exam fizic
Diazepamul va ✓investig de lab
opri criza. pt etiol febrei
✓Copilul poate ✓HLG, Rx pulm ,
necesita ORL etc
monitorizare
UMF, mai 2020

3. Alessia
UMF, mai 2020

Alessia, 2 ani, este adusa de ambulanta in camera de garda pentru o
manifestare paroxistica survenita din somn, la domiciliu. Astfel, pe fondul
unei gastroenterocolite debutate din seara precedenta, cu febra, copilul
este gasit de catre parinti cu privire plafonata, foarte “moale”, cianotic,
neresponsiv. Mama relateaza ca niciodata nu a mai prezentat manifestari
paroxistice, desi copilul este in evidenta serviciului de neurologie
pediatrica, fiind diagnosticat cu paralizie cerebrala forma spastica bilaterala
(mare prematur, cu adaptare postnatala dificila si achizitii lente pe etape de
varsta). Manifestarea a fost scurta – aprox 1 minut, copilul adormind apoi,
cu trezire la sosirea ambulantei (in ~ 15 min)
Cum incadrati
Tratament?
manif?
Intrebari pt Investigatii?
familie?
Trimitere la
Primii pasi? neurolog?
UMF, mai 2020

Cum incadrati
Intrebari pt familie? Primii pasi?
manif?
Modif ale starii de Verif semnelor

CFS vitale,
const/ dispozitie
(somnolenta/ meningeale, eval
constientei,
Iritabilitate?)
examen fizic
Investig de lab pt
etiologia fb…&
calmarea
NU familiei!
Trimitere la
Tratament? Investigatii ? neurolog?
Investig de lab investig pt

Antipiretice/ DA, mai
intercurenta febrila
etiologia fb tarziu
✓HLG, Rx pulm, ORL etc
UMF, mai 2020

4. Maria
UMF, mai 2020

Maria, 10 luni, cu dezvoltare psihomot normala, este adusa la UPU pt ca
in timpul zilei a prezentat febra si 3 episoade cu pierderea st de constienta, cu
plafonarea privirii, contractura generalizata, cianoza periorala, ldurata 5-15
min, ultimul survenind cu 1 ora anterior prezentarii, mama notand dupa criza
ca Maria nu misca simetric membrele drepte. Copilul este febril de 3-4 zile si
primeste de cateva zile tratament antibiotic.
Cum incadrati Intrebari pt

Primii pasi?
manifestarile? familie?
Semne vitale,
CFC Modif ale starii de semne
constienta/ meningeala,
dispozitie bombeaza FA?
(somnolenta?
Iritabilitate?
Vaccinari?
UMF, mai 2020

Maria – copil normal, cu 3 CFC intr-o zi, febra anterior, antibiotic
Modif ale st de Trimitere la

CT
constienta – DA - cerebral neurolog?
somnolenta
Normal
Cand?
Investigatii ?
PL discutabil,
individualizat
Encefalita/
meningita
UMF, mai 2020

Victor, 8 luni, se prezinta la cabinetul medicului de familie pentru o
manifestare paroxistica din veghe survenita in context febril 38° C, cu miscari
ritmice ale membrelor stangi cu durata de 20 min, care s-a remis spontan la 1
zi dupa vaccinare. Baietelul are in antecedente inca 2 episoade similare, unul
in urma cu 2 saptamani si altul la varsta de 6 luni primul cu miscari ritmice ale
membrelor stangi si celalalt cu implicarea membrelor drepte, de fiecare data
copilul a avut febra ~ 38, 2° C.
Cum incadrati Multiple CFC

manif?
Modif ale starii de
constienta/ dispozitie DPM normala, fara alte
Intrebari pt (somnolenta?
familie? semne/simptome
Iritabilitate?
DPM anterior?
Investigatii ?
MF/ pediatru/ neurolog
UMF, mai 2020

5. Victor
UMF, mai 2020

Victor copil normal, cu 3 episoade CFC, alterne, la febra mica, cu durata
lunga.
Trimitere catre Dg. sindromologic,

DA !
neurolog? tratament antiepileptic
Investigatii ? analize PL CT/RMN EEG
EEG
RMN cerebral?
Testare genetic pentru fenotipul
complex – Sd. Dravet!
UMF, mai 2020

Clinica sindromului Dravet
◼ Crize epileptice:
❑ generalizate/unilaterale – febrile (statusuri febrile)/afb - în I an de

viaţă la sugari cu DPM n
❑ mioclonii: 8luni-4ani
❑ crize focale simple/complexe
❑ absenţe atipice - “obtundation status”
UMF, mai 2020

◼ Factori declanşatori:
❑ Febra- sensibilitatea la febră:

◼ efect provocator al variaţiilor de temperatură
◼ instabilitatea T corporale
◼ accentuată la vârste mici
◼ persistă la adult !
◼ efortul fizic intens, emoţiile intense,
băile calde (cresc T corpului)
❑ Infecţiile (rinofaringite, infc pulm)

◼ nu întotdeauna cu fb
UMF, mai 2020

◼ DPM
❑ initial normala intarziata
❑ sd hiperkinetic
❑ cognitie – afectarea cognitiva corelata cu severitatea epi în
primii 2 ani de viata (Casse-Perrot 2001)
◼ Semne neurologice:
❑ ataxie 60%
❑ semne piramidale 20%
❑ mioclonus interictal 30-40%
UMF, mai 2020

◼ Probleme ortopedice:
❑ cifoscolioză, picior plat
❑ agravare la vârstnici
❑ afectarea mersului
◼ SUDEP
UMF, mai 2020

Genetica
2000 – mutaţii ale genei care codifică subunitatea alfa 1 a

canalului de Na (SCN1A) – descoperite în GEFS+ (generalized
epilepsy with febrile seizures +) (Escayg 2000,Wallace 2001)
2001 – Claes – identificarea mutaţiei la pacienţii cu EMSS
Mutaţia + în 40-100%,
95% de novo (Claes 2001, Nabbout 2003)
UMF, mai 2020

6. Irina
UMF, mai 2020

Irina, 3 ani, cu DPM normala, a prezentat in ultimul an 5 manifestari paroxistice din
veghe, dar si din somn, toate in prima zi, la debutul unor intercurente respiratorii cu
febra inalta, uneori febra fiind depistata abia dupa ce a prezentat episodul
convulsivant (temp intre 39-40.5°C), toate cu aspect similar.
Astfel, de fiecare data fetita are privire fixa, pierderea starii de ocnstienta, contractura
generalizata si tremor fin al extremitatilor fara hipersalivatie, dar mama descrie faptul
ca fetita “pare sa se inece”. Mama extrem de anxioasa – a administrat Diazepam
pentru ultimele 3 episoade.
- Istoric familial pozitiv pentru CF si epilepsie – mama cu 2 CFS in copilarie si cu o
epilepsie de adolescenta controlata terapeutic.
Cum incadrati Trimitere catre

Primii pasi? Tratament?
manifestarile? neurolog?
Verif semnelor vitale, Febra/

meningeale, eval etiologia
CFS constientei, examen fizic infectiei.
Investig de lab pt etiologia Confortul
fb…& calmarea familiei! copilului
UMF, mai 2020

Irina – copil normal, cu 5 CFS in decurs de 1 an, febra inalta, + istoric familial
pozitiv pentru CF si epilepsei & mama anxioasa.
Risc mare de
recurenta a CF
Investigatii
suplimentare?
Analize de
PL CT/RMN EEG
laborator
DA NU Posibil,
non-
urgent
Trimitere la
neurolog
UMF, mai 2020
Se indruma
catre neurolog?
DA
Diagnostic sindromologic
Tratament antiepileptic–
prophilaxie continua
EEG
RMN cerebral?
Testare genetica –
Canalopatii Na (GEFS+)
UMF, mai 2020

Genetica
SCN1A
+10% GEFS+ DRAVET +70-80%
sdr epileptic familial encefalopatie epileptică, debut la sugar

fenotipuri variate: uşoare severe multiple tipuri de crize
≥ 2 membri ai familiei afectaţi prognostic sever
UMF, mai 2020

◼ Din punct de vedere
patogenic, CF este
considerată un răspuns la o
febră mare instalată brusc,
la un copil predispus
genetic, în perioada de
vârstă în care pragul
convulsivant al creierului
imatur este scăzut (Moshe,
1989).
UMF, mai 2020

Bolile neuromusculare la copil
Nina Butoianu
Spitalul Clinic Al. Obregia, Bucureşti
Bolile neuromusculare la copil
✓ Definiţia bolilor neuromusculare
✓ Clasificarea
✓ Aspecte clinice
✓ Aspecte paraclinice
✓ Principalele afectiuni neuromusculare

✓Sistem nervos
central
integru
✓Sistem nervos
periferic integru
Definiţia bolilor neuromusculare
✓Afectiunile la niv
unitatii motorii
Nervi periferici Jonctiune NM
Neuroni
motori
Nervii periferici
muschi
Clasificarea bolilor neuromusculare
▪ Topografic
▪ Debut şi evoluţie
▪ Etiologic
Bolile neuromusculare - Topografic
CORN ANTERIOR NERV JONCTIUNE NM FIBRE

MUSCULARE
ATROFII NEUROPATII Botulism Miopatii virale
MUSCULARE ACUTE Miopatii Congenitale
Sindrom Guillain Distrofii musculare
SPINALE Miasthenia
Barre congenitale
(AMS) gravis Distrofii musculare
CRONICE progresive
Tipuri 1-4
Sindroame Duchenne / Becker
(Werdnig-Hoffman) N.E.S.M Miastenice Distrofii musculare
(Kugelberg-Welander) centuri
Congenitale
(Charcot- Emery-Dreifuss / FSH
Sindroame Distrofia miotonica
Marie-Tooth, miasteniforme
Déjerine-Sotas) Steinert
S. L. A Mitocondriale
Metabolice
Canalopatii
Endocrine
Clasificare bolilor neuromusculare
debut, evoluţie, etiologie
etiologie Dobandite
debut Inflamator
acut
Infectios
Vasculitic
Metabolic
toxic
etiologie
cronic Genetice
AD, AR, X
linkate
Dobandite
Aspecte clinice in bolile neuromusculare
✓ Anamneză
✓ Examen clinic
✓ Motivele prezentării la medic
✓ Istoric de evenimente recente (inf ,eruptie eritemat,

expunere la agenti toxici, muscat capusa, alimente
contaminate)
✓ Vârsta de debut: antenatal, naştere, sugar, copilărie,
juvenilă
✓ Evoluţie : lentă, rapidă, fluctuantă
✓ Istoric familial
✓ Antecedente personale fiziologice si perinatale
✓ Achiziţiile motorii pe etape de vârstă
✓ Achizitiile privind dezv limbaj, dezv mentala,
performantele scolare
✓ Dificultati functionale (fatigabilit, dificult urcat scari,

imbracat, activitati sportive etc)
Alte afectiuni asociate - cardiace, hepatice, etc
Ingrijorarile parintilor
“Nu tine “ Se
pasul cu chinuieste
ceilalti la sa se
alergat, la ridice de “ Copilul meu
orele de jos “ pare mai
sport” lenes, vrea
“ Se plange
“ Pare
neindemanatic
sa fie luat in
brate
adesea frecvent “
, cade usor “
de dureri
la nivelul
picioarelo
r “
“ Copilului
“ Copilul meu nu-i
meu misca plage sa
foarte putin mearga “
“
✓ debut în perioada antenatală, de sugar şi până la 2 ani predomină

hipotonia
✓ copilul peste 2 ani predomină deficitul muscular

Examen clinic copil 0-2 ani
✓ Gradul de hipotonie și localizarea (trunchi, membre)
✓ Evaluarea deficitului muscular
✓ ROT
✓ Prezența contracturilor/retracțiilor
✓ Examinarea pielii și țesut conjunctiv
✓ Afectarea altor organe și sisteme (cord, ficat)

Anomalii cromoz
Prader Willi, Down
Boli metabolice
Encef hipoxic isch
Malform cerebr
Amiotrofii
Miop congenitale
spinale
Distrofii musc cong
Miopatii metabolice
Neurop cong
Hipomielinica
Degenesc infant
neuroaxonala Miast congenitale
Boltulism
Miast neonat tranz
⚫ Hipotonia:
- Rezistenta scazuta la miscarile pasive in articulatii

- Cresterea gradului de miscare in articulatii
⚫ Tipuri de tonus muscular

− Tonusul fazic : rezistenta la miscarile pasive ale membrelor
− Tonusul postural : rezistenta pasiva a miscarilor la nivelul muschilor
axiali (gat, trunchi, spate)
Examinare generala
-postura ”frog-leg”- membrele inferioare în abducție completă și

membrele superioare care stau pe lânga corp ( în flexie, în extensie)
-pectus excavatus – deficit muscular al m cutiei toracice

-occiput plat- sugari care nu se misca si stau multa vreme numai in
DD
Manevra de tractiune Suspendare Suspendare ventrala
verticala
Semnul esarfei
Deficit muscular:
▪ deficitul muscular se poate manifesta prin
scăderea forței și frecvenței mișcărilor spontane
▪ la sugarul hipoton care are și deficit muscular

mișcările antigravitaționale sunt puține sau lipsesc
▪ abilitatea acestora de a arăta obiectele, atinge

(a ajunge jucaria) și a ridica obiecte,
abilități care trebuie comparate cu
normele de dezvoltare adecvate vârstei
▪ evaluarea plânsului, suptului,
expresivității faciale,
oculomotricității și
efortul respirator
▪ plâns slab (stins) poate arăta un

deficit muscular al diafragmei ,
plans fatigabil (care diminuă pe măsură
ce plânge) poate sugera
un sindrom miastenic congenital
▪ prezența respirației paradoxale sugerează

o afecțiune neuromusculară
▪ diminuarea sau absența ROT sugerează afectiuni de neuron motor periferic
▪ Dislocația de șold - trăsătură frecventă a hipotoniei intrauterine (formarea unei

articulații de șold normale necesită contracție puternică a mușchilor pentru a
pune capul femurului în acetabul)
▪ Artrogripoza - contracturi articulare prezente de la naștere- (picior stramb,
deformări în flexie simetrice la nivelul tuturor articulațiilor membrelor)
▪ Examinarea pielii și a țesutului conjunctiv

- hiperlaxitate predominant distală
în afecțiuni musculare determinate de mutații
la nivelul colagenului
▪ Anomalii ale inimii sau ficatului sunt mai probabil asociate cu bolile
metabolice
▪ Cardiomiopatia poate fi un clue de diagnostic important

- boala Pompe
- în unele miopatii congenitale - miopatie miofibrilară
▪ Hepatosplenomegalia sugerează o boală lizozomală

sau o boală de stocaj de glicogen.
Sindrom hipoton
Antecedente ante-, peri,

postnatale Absenţa mişcărilor la reflexele
Mişcări prezente la reflexele posturale
posturale Fasciculaţii
Alte semne de afectare SNC ROT absente↓
(tulburări cognitive, crize, Artrogripoza 
trăsături dismorfice) Reflexe patologice absente
ROT vii Nervi cranieni 
Reflexe patologice prezente (oculomotricitate, deglutiţie)
Tonusul muscular de obicei creşte Atrofii musculare
(spastic) cu timpul Copil vioi, alert
Cauză centrală Cauză periferică

Examen clinic copil ˃2 ani
1. Mersul
2. Determinarea deficitului muscular
3. ROT
4. Răspunsul muşchiului la percuţie
5. Modificări ale masei musculare
6. Mişcări musculare intrinseci
7. Determinarea deficitului senzitiv
8. Tulburări trofice
9. Afectarea altor organe (inima, SNC)
1. Mersul
1. Mersul
Mers leganat

Deficit de centura pelvina

Miopatii
Amiotrofii spinale III
Examenul clinic
1. Mersul
Mers stepat

Deficit muscular distal

Polineuropatii
▪ Manevra Gowers
▪ Determinarea forţei musculare pe grupe de muşchi
▪ Deficit muscular al muşchilor inervaţi de nervii cranieni

Manevra Gowers

Deficit muscular
proximal

Miopatii
Amiotrofii spinale
Tip III
▪ Determinarea forţei musculare pe
grupe de muşchi
→ deficit muscular proximal şi
paravertebral - miopatii, amiotrofii,
miastenie
→ deficit muscular distal -

polineuropatii
→ deficit muscular generalizat -

miozite, paralizii periodice
▪ Deficit muscular al muşchilor inervaţi de nervi cranieni-

oculomotricitate
Sindroame miastenice
Unele miopatii congenitale
Deficit muscular al
muşchilor inervaţi de
nervii cranieni

Miopatii
Miastenia gravis
Miastenii congenitale
Tulburări
de deglutiţie

Sindroame
miastenice
Miopatii
3. ROT
▪ absente precoce în neuropatii
▪ tind să scadă paralel cu

deficitul muscular în miopatii
▪ prezente în miastenia gravis şi

între episoadele de deficit
muscular recurent (miopatiile
metabolice/paraliziile
periodice)
4. Răspunsul muşchiului la percuţie
Răspunsul muşchiului la
percuţie

Miotonie

miotoniile congenitale,
distrofia miotonică
Steinert,
unele paralizii periodice
între atacuri
Hipertrofia muşchilor

Distrofii musculare
progresive
Amiotrofii spinale tip III
Atrofii musculare
în toate bolile
neuromusculare în diferite
stadii de evoluţie

Proximale – amiotrofii,
miopatii
Atrofii musculare
în toate bolile
neuromusculare în diferite
stadii de evoluţie

Proximale – amiotrofii,
miopatii
Atrofii musculare distale


Polineuropatii cronice
senzitivo - motorii
6. Mişcări musculare intrinseci
Fasciculaţiile
- contracţii punctiforme ale
fibrelor musculare ale uneia
sau mai multor unităţi
motorii
- la muşchiul în repaus (MS,
limbă)

boli degenerative sau iritative de
neuron motor periferic
(amiotrofii spinale)
7. Determinarea deficitului senzitiv
▪ pozitive: parestezii, dureri lancinante
▪ negative: hipo- sau anestezie tipuri de sensibilitate (termică, tactilă,
dureroasă, proprioceptivă)
▪ patternuri de deficit senzitiv:
▪ difuze, distale - pattern "mănuşă -ciorap" polineuropatii
▪ tulburare senzitivă focală un dermatom (rădăcină) /nerv periferic →
radiculopatie, mononeuropatie
▪ tulburări senzitive multifocale → mononeuropatia multiplex şi
leziunile de plex
AFECŢIUNI NERVI PERIFERICI

▪ retracţii tendinoase
▪ atitudinile vicioase (picior

în varus equin, picior
scobit, cifoscolioză)
atitudinile vicioase
(picior în varus equin,
picior scobit,
cifoscolioză)
miopatii
polineuropatii
Deformări scheletice
(toracice, membre)

Amiotrofii spinale
Polineuropatii
Miopatii
▪ Deformări scheletice
(toracice, membre)

Amiotrofii spinale
Miopatii
▪ Retracţii tendinoase
maini

Polineuropatii cronice
Picior scobit

Polineuropatii senzitivomotorii
cronice
Ataxia Friedreich
9. Afectarea altor organe
Afectarea cardiacă

DMD, DMB +++
Distrofie miotonică +++
Distrofii musculare
progresive forma centurilor
▪ Pattern de deficit muscular

▪ Proximal versus distal
▪ Selectiv sau neselectiv
▪ Implicarea muşchilor faciali sauşi oculari
▪ Retractii, atrofii musculare
▪ Afectare cardiacă sauşi respiratorie
▪ Ritm de evoluţie
Impresie clinică
Aspecte paraclinice in bolile neuromusculare
▪ Analize biochimice
▪ Examinarea electrofiziologică
▪ Biopsia de muşchi
▪ EKG, Eco cord
▪ Examene imagistice
▪ Studii moleculare – teste genetice

Analize biochimice
▪ Enzime musculare serice – CK, LDH, GOT, GPT
 - distrofii musculare progresive, miozite

 - amiotrofii spinale,
unele miopatii
Examinarea electrofiziologică
▪ EMG
- EMG - neurogen ( neuropatii, corn ant)
- miogen (miopatii)
- decrement la stim repetitiva- miastenie/ increment- sd Lambert-Eaton
- fenomen miotonic – miotonie
▪ Viteza de conducere nervoasa senzitiva si motorie scazuta in neuropatii

▪ Traseu normal
▪ Traseu miogen
▪ Traseu neurogen
Examene imagistice
▪ Tehnici
- Tomografie computerizată (CT-scan)
- Imagistica prin rezonanţă magnetică (IRM)
▪ Utilitate
- au fost descrise patternuri specifice ptr anumite miopatii
- pentru a selecta sediul biopsiei musculare
Biopsia de muschi
▪ Investigaţie de bază
- în distrofiile musculare
- toate miopatiile congenitale
- miopatii metabolice, boli mitocondriale
▪ Imunocitochimie
▪ Studii de microscopie electronică
– Western Blot
– metoda semi-cantitativa
– reducerea nivelului proteinei sau anomalii in marime si greutate pt un nr redus de
proteine
Studii moleculare – teste genetice
▪ Citogenetică moleculară (FISH - Fluorescence In Situ Hybridization) şi
genetică moleculară (evidenţierea mutaţiilor)
▪ Testele moleculare - accesibile pentru multe forme de neuropatii

ereditare senzitivomotorii, distrofii musculare progresive
Duchenne/Becker, distrofii musculare forma centurilor, miopatii
metabolice, amiotrofii spinale
▪ Costurile lor sunt foarte mari
▪ Accesibilitatea limitată
Interventii terapeutice in bolile neuromusculare
▪ Curative :
- farmacologice- imunosupresoare/imunomodulatoare – afectiunile
dobandite
- Corticosteroizi- DMD
- terapie genica- Nusinersen (AMS), Ataluren (DMD mut nonsens)
▪ Suportiv :
- respirator
- cardiac
- reabilitare fizica (kinetoterapie)
- nutritie
- ortopedic
▪ Preventie :
- Sfat genetic
- Testare prenatala
Principalele afectiuni neuromusculare
Boală de corn anterior (amiotrofii spinale)
Deficit muscular bilateral proximal, axial/sindrom de neuron motor

periferic
ROT abolite proximal
±Fasciculaţii
Atrofii proximale
CK – N sau  uşor
EMG – potenţiale de fibrilaţie, traseu neurogen, VCN normale
Teste genetice specifice
Amiotrofia spinala (AMS)
▪ atrofierea musculara secundara unei degnerescente la nivelul

motoneuronilor spinali
▪ Incidența AMS autozomal recesive- 1/6000-10.000 nou născuți vii (până la

1/25.000)
▪ AMS 5 q - a doua cea mai frecventă boală neuromusculară ereditară după

DMP tip Duchenne
▪ Transmitere AR
Parinti
Purtator Purtator
asimpt AMS asimpt AMS
Copii
Indiv neafectat Purtator asimpt AMS
Risc
AMS 25% 50% 25%
Purtator asimpt AMS: individ cu o copie normala SMN1

si o copie afectata /absenta
Aprox 1/40 to 1/60 indiv sunt purtat asimpt AMS
✓ determinata de mutatii in regiunea cromozomială 5q11.2-13.3

✓ principala gena implicata in producerea amiotrofiei spinale este gena SMN1
✓ gena SMN2 este localizată centromeric față de gena SMN1și este foarte
asemănătoare structural cu gena SMN1, rol in severitatea fenotipului
62
Mutatiile
✓ Deletie homozigota ale unuia sau mai multor

exoni (exon 7) ai genei SMN1-95%
✓ Mutatii punctiforme-5%
Pentru aparitia bolii este necesar ca ambele alele sa prezinte

mutatii!
In unele cazuri se pot asocia o deletie pe una dintre alele cu o
mutatie punctiformă pe cealalta
63
✓ Clasificarea este clinica (1992,

1999 International Consortium
SMA) Debut <6l
Achiz control cap
✓ Criteriile : varsta de debut,

achizitia motorie maxima Debut -6-18 l
Achiz poz sezanda
✓ Au aceleasi mutatii genetice Debut >18 l

Achiz mers
Debut >18 ani
64
AMS I (Werdnig-Hoffmann)
Evolutie
✓Debut < 6 luni
✓maxim de performanta motorie -sustinerea
capului ✓insuficienţă respiratorie
✓Sindrom hipoton
✓Deficit motor sever, bilateral, simetric, ✓suport ventilator,
predominant proximal, progresiv- Miscari traheostoma,
reduse ale membrelor gastrostoma
✓Respiratie paradoxala
✓ROT abolite generalizat
✓Fasciculatii ✓pneumonie de aspiratie
✓Dezvoltare psihica normala – cauza frecventa de
deces
AMS II (forma intermediara)
Evolutie
✓Debut: 6-18 luni
✓afectare
✓maximul performantei motorii pozitia sezand respiratorie, tulburari
de vorbire si
✓Sindrom hipoton deglutitie
✓deficit motor simetric, predom proximal ✓rar necesita

gastrostoma
✓ ROT abolite generalizat
✓infectiilor
✓Deformari scheletice respiratorii în
majoritatea cazurilor-
deces
AMS III (Kugelberg-Welander)
Evolutie
✓Debut > 18 luni ✓deformari
✓dobandesc mersul scheletice rare
✓deficit motor bilateral, simetric, ✓pot necesita
predominant proximal ventilatie
noninvaziva pe per
✓ROT abolite bilateral, simetric de inf resp
✓atrofii musculare proximale ✓risc de obezitate
(±hipertrofia gambei
✓poate duce la
pierderea
ambulatiei
Amiotrofia spinala
▪ Diagnostic pozitiv:
I. Manifestari clinice + maximul functie motorie → tipul de amiotrofie spinala
II. Genetică moleculară: deleţia exonului 7 din gena SMN - 5q12.2-13.3
Examenele electrofiziologice: vitezele de conducere normale, EMG neurogen (in

tipul III , ajuta la diferentierea de afect musc)
Biopsie (nu exista modificari patognomonice)-nu se mai foloseste
Deoarece mutațiile apar în aproximativ 93-95 % din pacienții cu AMS,

testarea genetică a înlocuit studiile electrofiziologice și biopsia în
diagnosticul primar al bolii in tipurile I si II
Amiotrofia spinala
Management
✓ nu exista tratament curativ

✓ ian 2005, 2018 - Spinal Muscular Atrophy Standards of Care Committee-International
Coordinating Committee for Spinal Musculare Atrophy clinical trials (obtinerea consens
stand de ingrijire/investig statutul stiintific in practica clinica)- Standarde de ingrijire
✓ Tratamente aprobate – Nusinersen, terapie genica
Amiotrofia spinala
Management
Diagnostic
Diagnostic 2018
2007 Pulmonar
Pulmonar
Ortopedic
AMS Ortopedic/ AMS
reabilitare Reabilitare
GI/nutritie GI/nutritie
Ingrijiri Paliative Medicamente
Acute care
Acute care
Ingrijiri paliative
STANDARDE DE INGRIJIRE IN AMS

7
1
Amiotrofia spinala
Management
Tipul 1 Tipul 2 Type 3 Type 4
Management Management Kinetoterapie Kinetoterapie

pulmonar pulmonar
Sanatate osoasa
Management Management
(Ortopedic)
nutritional nutritional
Vaccinari Vaccinari
Management Management
ortopedic ortopedic
Kinetoterapie Kinetoterapie
Sanatate oase Sanatate oase
Suport Suport
social/psihologic social/psihologic
STANDARDE DE INGRIJIRE IN AMS

Amiotrofia spinala
Management
Tratamente aprobate
Nusinersen (Spinraza)
✓ I tratament modificator de boala!

✓ achizitii neuromusculare semnificative
✓ supravietuire globala semnificativ
statistica
✓ scaderea utilizarii ventilatiei permanente,
supravietuire fara complicatii
✓ profil favorabil de siguranta,
✓ fara RA legate de
substanta active
✓ Incoveniente – adm intratecala, cost ridicat
✓ Disponibil si in Romania
7
3
Amiotrofia spinala
Management
Tratamente aprobate
Terapia genica
- Aprobat in SUA, aprob in Europa f curand
- La copiii cu varste sub 2 ani
Avantaje – o sing adm i.v
Inconveniente- f scump, pare eficient la pac cu varste <6 luni
Amiotrofia spinala
✓ Sfat genetic
- evaluarea riscului de recurență - 25 %
✓ Diagnostic prenatal
- testarea genetica prenatala - teste moleculare pe celule recoltate prin
biopsie de vilozitati coriale (saptamanile 10-12) sau amniocenteza
saptamanile 16-18)
În ţara noastră este posibilă testarea genetică

diagnosticul de certitudine
diagnosticul prenatal !
Polineuropatii
Deficit muscular bilateral, distal

ROT abolite distal
Tulb. de sensibilitate
Atrofii distale
CK – N
EMG – traseu neurogen, VCN  (demielinizante) sau N/ (axonale)
Biopsia de nerv –nu se mai foloseste
Polineuropatii
Maduva
spinarii
M
Nerv Periferic
mielina
axon Nod Ranvier
POLIRADICULONEVRITA ACUTĂ DEMIELINIZANTĂ
INFLAMATORIE
Sindromul Guillian Barre
✓afecțiune inflamatorie acută a sistemului nervos periferic

✓ mediată imun
✓afectare de tip demielinizant a rădăcinilor, trunchiurilor nervoase
motorii şi senzitive
✓cu evoluție ascendentă
✓ Incidența anuală - 1 – 2,4 la 100.000 locuitori

✓ 26% - 85 % - istoric recent de vaccinare sau infecţie
(gastrointestinală/tract respirator superior) cu 1 -6 S anterior
debutului
❑ Boala evoluează în 3 faze:
✓ Faza de extensie - durata 12 h - 4 S - se instalează manifestările

neurologice;
✓ Faza de platou - durată 1 - 3 S - semnele neurologice sunt staţionare;
✓ Faza de recuperare - durata 1 S - 28 luni, de remitere a

simptomatologiei;
❑ Clinic:
✓ Deficitul motor : musculatura membrelor,

muşchii respiratori, inervată de nervii cranieni
✓ Deficitul motor la nivelul membrelor inferioare -

modalitatea de debut
✓ Afectarea este bilaterală, simetrică, proximală

(interesează centura pelvină), ulterior
progresează ascendent, putând interesa și
membrele superioare
✓ nervului VII, nervii bulbari (IX,X)
✓ ROT - diminuate sau abolite relativ devreme
✓ tipuri de sensibilitate : sensibilitatea profundă ,

tactilă –pattern „ mănuşă - ciorap
❑ Criterii necesare de diagnostic
1. Deficit muscular progresiv la mai mult de un membru (variabil până la paralizie totală a
membrelor)
2. Areflexia osteotendinoasă de grade variate
❑ Criterii suportive de diagnostic
✓ Progresia simptomelor în zile până la 4 săptămâni
✓ Deficit motor bilateral, simetric
✓ Semne sau simptome sensitive discrete /excepție durerea (poate fi semnificativă)
✓ LCR- disociatia albumino –citologica (proteinorahie ↑ (din S 2), < 10 mononucl/mmc)
✓ Anomalii electrofiziologice: VCN ↓↓↓, dispersie temporală, bloc de conducere

❑ Tratament
✓ SGB este o urgență medicală!
❑ Tratamentul patogenic
✓ Imunoglobuline (IG) : 2 g /kgc in 2- 5 zile sau
✓ Plasmafereza (PE)
❑ Tratamentul simptomatic și măsurile generale
de urmărire
❑ Evoluție
✓ Majoritatea copiilor au evoluţie bună, cu ameliorare
semnificativă după aproximativ 2 săptămâni
✓ Pot ramane cu deficit motor
Neuropatii genetice
Neuropatii ereditare senzitivo – motorii
❑ Definitie - polineuropatii cronice cu caracteristici comune:

✓ transmiterea genetica
✓ afectarea clinica predominant motorie simetrica (mai putin senzitiva)
✓ evolutie lent progresiva
✓ degenerarea fibrelor nervoase cu predominanta axonala sau /si mielinica (Dyck)
✓ afectiune heterogena din punct de vedere etiologic-gene diferite – acelasi fenotip
❑ Nomenclatura \ Denumiri
✓ neuropatie ereditara senzitivomotorie (NESM)
✓ CMT (Charcot – Marie - Tooth)
✓ prevalență de aproximativ 1: 2500

Clasificarea actuala a bolii CMT
▪ Modul de transmitere
– Autosomal dominant sau recesiv
– X-linkat
▪ Teste electrofiziologice
– CMT demielinizanta: MNCVs  30 m/s
– CMT axonal : MNCVs > 40 m/s
– Forme Intermediare : 30  MNCVs < 40 m/s
▪ Genetica Moleculara
Neuropatii genetice
Clinic
✓ tulburari de mers- mers stepat
✓ amiotrofii distale simetrice, predominant la membrele inferioare
✓ deformari la nivelul picioarelor (picior scobit)
✓ deficit muscular distal, simetric, predominant la membrele inferioare
✓ ROT abolite, predominant distal
✓ tulburari de sensibilitate minore, distale, simetrice, (sensibilitatea proprioceptiva)
Paraclinic
✓ CK – N
✓ VCN – traseu neurogen,  (demielinizante)/ sau N (axonale)
Neuropatii genetice
Neuropatii genetice
❑ Diagnostic pozitiv
istoric familial + tabloul clinic +VCN
❑ Tehnici speciale de diagnostic

✓ genetica moleculara (evidentierea mutatiilor)-nu este accesibila in tara noastra
Evolutie
▪ este lent progresiva pe durata mai multor ani
▪ majoritatea pacientilor raman activi o perioada nedefinita
▪ pacientii raman clinic stationar mari perioade de timp fara o deteriorare vizibila
▪ deformarea piciorului tinde sa se accentueze cu timpul
▪ tipic varsta precoce de recunoastere clinica si evolutia rapid progresiva la un parinte se

asociaza cu exprimare similara la copii
Tratament
✓ Nu exista tratament curativ
✓ tratament farmacologic - durere de tip neuropatic (gabapentin, antidepresive triciclice).

Durerea poate fi de tip musculoscheletal (osteoartropatie /deformări scheletice) sau de tip
neuropatic;
✓ kinetoterapie - menţine forţa musculară /preveni contracții musculare
✓ dispozitivele ortotice- susţin glezna pentru a ajuta mersul dar şi echilibrul
✓ terapie ocupaţională - ajută cu dezvoltarea de strategii pentru activităţile cotidiene mai

ales la pacienţii cu afectare la nivelul mâinilor.
✓ tratamentul chirurgical este rezervat pacientilor care dezvoltă deformări semnificative ale
piciorului care sunt simptomatice, limitează funcționalitatea și nu răspund la tratamentele
conservatoare
Afecţiuni ale joncţiunii neuromusculare
Deficit muscular nervi cranieni oculomotori, deglutiţie, fonaţie cu variabilitate

Deficit muscular axial, proximal, variabil
ROT prezente
Test la miostin pozitiv
CK – N
EMG cu stimulare repetitivă – decrement semnificativ (15%)
Autoanticorpi + - miastenia gravis ( mecanism autoimun)
Mutatii genetice specifice - miastenii congenitale
▪ Sindroamele miastenice
- afecţiuni dobandite sau genetice

- Tulburare in transmiterea neuro-musculară ( bloc neuro-muscular)
▪ Fiziopatologie - disfunctii la nivelul tuturor partilor componente ale sistemului de

transmisie:
- potentialul de actiune a impulsului nervos

- depozitarea si eliberarea de acetilCol
- activitatea acetilcolinesterazei
- reducerea numarului de receptori de acetilCol
- legarea de receptorii placii neuromusculare
- generarea si propagarea potentialului de actiune
la nivel muscular
Clasificare
ETIOLOGIC : FIZIOPATOLOGIC:
AUTOIMUN PRESINAPTIC
Myasthenia Gravis botulism, unele miast cong
Sindrom Lambert-Eaton (ChAT deficiency), sindr
Lambert-Eaton
Miastenia neonatala tranzitorie
SINAPTIC
TOXIC si/sau INDUS MEDICAM
Otravirea cu organofosforice
Botulism, venoms
unele miast cong (Endplate AChE
Penicilamine, curare, quinine, deficiency )
procainamida
POSTSINAPTIC
GENETIC
Miastenia Gravis, intoxicatia
Sindroame miastenice penicilamine, curare, unele
congenitale miast cong (RAPSN.)
Botulism
✓ Este o forma acuta de otravire

✓ Ingestia de alimente conservate stricate
✓ Este o inf intest det de Clostridium
botulinum, care se
multiplica in intestin si elib toxina
botulinica
✓ Toxina este absorbita in intestin si trece
in sange, la niv jonctiunii
neuromusculare unde blocheaza
ireversibil elib de acetilcolina la niv nv
terminal
Botulism
✓ Debut – constipatie, hipotonie, deficit al muschilor gatului

✓ Ulterior ptoza, oftalmopareza, dipareza faciala
✓ Deficit muscular generalizat cu hyperreflexia
✓ Insuficienta respiratorie poate apare in cazurile severe
✓ Evolutia este craniocaudala!
✓ Midriaza hiporeactiva este inalt sugestiva!!
(dar nu este intotd prezenta!)
✓ Dg- izolarea Clostridium botulinum in culturi cel,
si/sau detectarea toxin botulinum in mat fecale , detectarea toxinei in ser
✓ Trat suportiv, antitoxina botulinica
✓ Prognostic bun
Miastenia neonatala tranzitorie
✓ La nou nascutii din mame cu miastenia gravis

✓ Trecerea auto Ac in sangele n.n
CLINIC
➢ Dificultati de alimentare si supt
➢ Plans slab
➢ Miscari reduse ale membrelor
➢ Risc de insuficienta respiratorie (suport ventilator)
TRATMENT
❖ Remitere spontana a simptomelor in cateva saptamani
❖ Neostigmina poate fi eficienta
❖ Plasmafereza – cazuri severe
Miastenia gravis
• Incidenta: 1-9/1.000.000
• Debut: 15-30 ani
• Mec autoimun
- autoAc anti R ACH +
- legarea de aACH este
blocata
• - activarea musc este
inhibata
- Autoa Ac induc degradarea
med de complement a R ACH,
det deficit progresiv al m
scheletici
Miastenia gravis
▪ Clinica
- Deficitul de forta musculara este variabil de la o zi la alta si in cursul

aceleasi zile, se accentueaza la efort si se atenueaza la repaus
- Topografic :
– Muschii oculomotori extrinseci - cu strabism, diplopie, ptoza uni-/bilaterala,

oftalmoplegie
– Muschii inervati de alti nervi cranieni - facies fijat, tulburari de fonatie, deglutitie
– Muschi extensori ai trunchiului si gatului responsabili de tulburari respiratorii cu dispnee

de efort
– Muschii membrelor cu deficit proximal
– ROT prezente
Miastenia gravis
Diagnosticul pozitiv:
✓ fatigabilitatea cu variabilitatea caracteristica
✓ testul la Miostin pozitiv
✓ EMG cu stimulare repetitiva cu decrement

semnificativ (>15%)
✓ Ac antiRAch +, Ac MuSK+, AC LRP4
✓ CT, RMN mediastin (±timom, hipertrofie timus)

Miastenia gravis
Tratament
❑ Tratamentul simptomatic
anticolinesterazice : neostigmina (2mg/kg/zi), piridistigmina(1-7 mg/kg)
❑ Tratamentul patogenic
✓ imunosupresor:
Corticosteroizi - ca primă linie anticolinesterazicele sunt ineficiente ca
monoterapie
Azatioprina (Imuran), Metotrexatul, Ciclofosfamida Ciclosporina, Rituximab,
Micofenolat mofetil, FK506 (tacrolimus
✓ imunomodulator : Plasmafereza , Imunoglobuline i.v - în cazurile severe, în
cazul crizelor miastenice sau pentru pregătirea preoperatorie în vederea
timectomiei
✓ timectomie - 80% anomalii timice/fara anomalii
Prognosticul, Evolutie
Evoluția clinică este variabilă, cel mai frecvent evoluția este lent progresivă, cu
fluctuații în severitatea bolii în perioada de adult dar majoritatea pot avea o
viață normală.
Miopatii
Deficit muscular proximal, simetric, axial,  muschii inerv de nv cranieni

ROT prezente multa vreme, dispar lent in evolutie
± hipertrofie m (moleti)
± Afectare cardiaca
± Afectare cognitiva
CK - /
EMG – miogen
Biopsia muşchi – utila, arata modificari
caracteristice, dozarea proteinelor
Distrofia musculara
progresiva
✓ un grup heterogen de afecţiuni

progresive
✓ determinate genetic
✓ caracterizate prin distrucţia

muşchiului şi înlocuirea lui cu ţesut
conjunctiv şi adipos
✓ Deficit muscular progresiv la niv

centurilor
✓ Valori CK ↑↑↑
Distrofia musculara progresiva
DMP Duchenne/Becker
Distrofia musculara
Duchenne/Becker
sunt afectiuni allelice
X linkate recesive
determinate de mutatii
pe gena distrofinei
DMP Duchenne
▪ DMD - cea mai frecventa si severa forma de distrofie musculara
▪ DMD ~ 1 : 3500 nn sex masculin
▪ Afectiune X linkata care

afecteaza predominant
baietii
▪ 10 % din femeile
heterozigote sunt
simptomatice
DMP Duchenne
✓ Distrofina mentine integritatea fibrelor

musculare
✓ Mutatia „out of frame” in gena distrofinei

duce la absenta unei proteine
(distrofina) functionale
✓ Aceasta det frecv cicluri de degenerare si

regenerare a fb musculare, iar muschiul
afectat este inlocuit de de tesut
conjunctiv si grasime
✓ Pe termen lung apare leziune ireversibila,

cu potential f limitat de a recastiga
functia muschiului
DMP Duchenne
✓ Debutul insidios este precoce in copilarie (2-5 ani ), ± intarzierea achizitiilor motorii
✓ are caracter progresiv, cu:
A. Afectarea musculaturii scheletice
– deficit muscular (proximal > distal) (MI initial, ult si MS)

dificultati de mers (mers leganat),
de ridicare de la podea si de urcat treptele scarilor
– semn Gowers POZITIV
– hiperlordoza (retractia tensorului fasciei lata)
– pseudohipertrofie de moleti (manifesta la 3-4 ani)
– ROT se diminueaza lent
– Scolioza si afectarea musculaturii respiratorii este
urmata de tulburari respiratorii
- Retractii musculare- achiliene (initial), ulterior retractii
- multiple
DMP Duchenne/Becker
DMP Duchenne
B. Afectarea cardiaca, initial prin modificarii EKG, apoi decompensare

clinica (tahicardie, cardiomiopatie dilatativa tardiv)
C. Afectare cognitiva
• Retardul mintal ( QI este in general<70)
• Afecţiuni neurocomportamentale şi neurodevelopmentale- tulburare de
spectru autist, tulburare hiperkinetică cu deficit atenţional, tulburare
obsesiv-compulsivă
• Epilepsie
D. Afectare digestiva - tulburari de peristaltica, dilatatie gastrica acuta,

vezica paralitica, megacolon
E. Afectare vizuala - Hemeralopia (orbul găinilor sau cecitatea
nocturnă)
DMP Duchenne
❑ Diagnostic pozitiv
✓ tabloul clinic specific + niveluri foarte mari ale CPK sangvine(>5000 UI)
✓ testare genetica: mutatii gena distrofinei
Expresia distrofinei prin imunohistochimie in
celulele musculare
Daca testarea genetica nu arata mutatii:

✓ biopsie musculara – aspect de distrofie
dozarea distrofinei (absenta / valori de 3-5%) Normal
- Mutatii intronice (nu se evid la metod test ADN)
❑ Diagnosticul prenatal este posibil

✓ > 10 saptamani gestationale
DMD
❑ Sfat genetic
✓ sfatul genetic este esenţial
✓ mamă purtătoare -50% risc de a avea un băiat cu DMD şi
50% risc ca fata ei să fie purtătoare
DMP Duchenne
Management
Standarde de ingrijire
Medic
recuperare
Pneumolo
kineto
g Nutritioni
terapeut
Cardiolog st
Gastroent
erolog
Genetician Ortoped
Pacientul Psihiatru
Neurolog /
pediatru familia Psiholog/
Logoped
Medic de Asistent
familie/Pediatru social
Distrofia musculara progresiva Duchenne
Standarde de ingrijire - abordare multidisciplinară
Diagnostic Consiliere genetica
Management extensibilitate
musculara/retractii Stretching, atele, orteze, fotolii rulante manuale/motorizate
Management
Chirurgia retractiilor tendinoase, scolioza
ortopedic
Management
Psihoterapie, interventii farmacologice, instruire
psihosocial
Management
Inhibitori ai enzimei de conversie a angiotensinei, beta blocante
cardiac
Management Ventilatie non-invaziva/ventilatie invaziva, clearance bronșic fie
pulmonar manual/ tuse asistată mecanic
Management GI, Controlul dietei, abordarea farmacologica a refluxului gastric si

nutriție constipatiei
Corticosteroizi Monitorizare si profilaxia efectelor secundare
Bushby K et al. Lancet Neurol 2010;9:77‒93

DMP Duchenne
Management
Tratamente aprobate
✓ Ataluren – mutatii nonsens
- Aprobat si in Europa
✓ Exon skipping 51- implica injectarea de oligonucleotide antisens care induc

exon skipping in timpul splicing ARN m, corectand cadrul de citire al genei
DMD si refacerea expresiei distrofinei (aprob SUA)
DMP Duchenne
Evolutie si prognostic
✓ Studiile arată că folosirea glucocorticoizilor prelungesc ambulatia,
încetineste declinul afectarii respiratorii, previne aparitia scoliozei şi a
cardiomiopatiei
✓ imobilizare in scaun rulant dupa varsta de 6 ani (<13 ani)
✓ de la implementarea standardelor de îngrijire pierderea ambulaţiei
este >12 ani
✓ deces- al 2-lea sau al 3-lea deceniu de viata

(dupa implement stand ingrijire) :
- afectiuni respiratorii
- cardiomiopatie
DMP Becker
✓ Incidenta: de 3 x mai rara decat DMD Duchenne (5,4 la 100000 de n.n.)
✓ Genetica: Bolile Becker si Duchenne sunt alelice, afectarea genei pentru distrofina
producand o distrofina diferita calitativ (greutate moleculara mai mica) si/sau cantitativ
Nivelul distrofinei este peste 20%
- mutatii „in frame„- nu afecteaza cadrul de citire
✓ Tablou clinic
– debutul >5 ani, uneori chiar spre adolescenta
A. Afectarea musculara
- mersul este posibil cel putin pana la 16 ani, uneori chiar pana la varsta de adult.
– pseudohipertrofia moletilor este prezenta, dar mai putin exprimata ca in Duchenne si se
poate atenua cu varsta
– durerea in moleti - cel mai precoce simptom provocat de efort si ameliorat prin relaxare
– crampele musculare
B. Afectarea cardiaca
- cardiomiopatie frecventa
C. Intelectul normal
DMP Becker
✓ Diagnostic pozitiv
- tabloul clinic specific +

- niveluri foarte mari ale CPK sangvine
(>5000 UI)
-testare genetica: mutatii gena distrofinei
✓ Biopsie muschi – rar
Dozarea distrofinei este necesara uneori pentru

diferentierea bolii Becker severe de Duchenne si
alte miopatii autosomal recesive
DMP Becker
Evoluție și prognostic
✓ insuficiența respiratorie cronică secundară afectării diafragmului și ineficienței

ventilației nocturne pot determina insuficiență cardiacă
✓ cardiomiopatia a fost descrisă la 90 % din pacienți, cauză de deces la 50 %
✓ pot rămâne ambulatori mult timp (peste 16 ani)
Sfat genetic
✓ sfatul genetic este essential
✓ O mamă purtătoare are 50% risc de a avea un băiat cu DMD şi 50% risc ca fata
ei să fie purtătoare.
Take home messages….
✓ Prima etapă în diagnostic este examenul

clinic
✓ Examenele paraclinice (CK, EMG cu VCN,
biopsie muşchi) completează
diagnosticul
✓ Testele genetice pun diagnosticul de
certitudine in afectiunile determinate
genetic
Dr. Cristina Motoescu
 Observa
 Descrie
 Pune intrebari
 Identifica
 Pune diagnosticul
 Formuleaza o concluzie
CAZ 1 : PA, 17 ANI,
APF: nesemnificative
APP: 2 CF la 6 si 12 luni
AHC: negative
Examen neurologic normal
Intelect – normal,
Psihic – depresie,
DEBUT
12 ani
Durata prelungita- 3-4 min,
Frecventa 1-2/luna
VID_2805.AVI, VID_2806.AVI
CRIZE - ASPECT
Debut: simte teama, fara pierderea constientei
Heminegligence brat drept

Automatisme MS stg
Roteste capul catre stanga
Automatisme oro-linguale
Agitatie
Postcritic: confuzie
CAZ 1
DIAGNOSTIC? EPI/non EPI
Ce analize ati face pentru a sustine diagnosticul?
CAZ 1
CAZ 3
DISCUTII
Ce tratament recomandati?
TRATAMENT
CBZ, OXC, VPA, TPM, LTG, CZP, PHT, LEV
Ultimul tratament – OXC 1800mg/zi + LEV 2500 mg/zi
Tratament chirurgical – in viitor

CONCLUZII
1. Ce tip de crize sunt?
2. Ce etiologie considerati ca este responsabila pentru aceasta patologie?

CAZUL 2 – AB-18ANI
Epi /non epi
Intelect - normal
Examen neurologic – normal
Debut - 17 ani – versia fortata a umarului drept, urmata de contractura paravertebrala dreapta
Manifestarile dureaza aproximativ 2-4 minute .
DIAGNOSTIC? EPI/non EPI
CAZ 1
VIDEO EEG DE LUNGA DURATA
NORMAL
VIDEO EEG CU INREGISTRAREA MANIFESTARII
Traseu Normal-
Artefacte musculare
in timpul manifestarii
IRM CEREBRAL
Normal
DIAGNOSTIC
Manifestari paroxistice involuntare -tulburare conversiva (PNES)

CAZ 3 AP 7 LUNI,
 Istoric familial de epilepsie: nu
 Sarcina:
 cu evolutie normala, nastere spontana, prematura (VG 30sapt), ;
 Istoric perinatal : da
GN-1400g, APGAR-5, evenimente hipoxice, terapie intensiva;
 Dezvoltare pe etape de varsta:

Motor: intarziata
ISTORIC
 Debutul manifestarilor : la varsta de 6 luni;
Frecventa crizelor: zilnice, multiple crize/zi, 7-9 clustere cu 30-35 de crize

Miscare brusca, rapida, contractia tonica a trunchiului si a membrelor
Examen neurologic: intarziere psihomotorie ( varsta 4luni)
DESCRIETI!!! EPI/NON EPI

EEG
EEG
IRM CEREBRAL
IRM CEREBRAL
Axial FLAIR arata:
- Dilatatie usoara bilaterala a ventriculilor laterali (fara alterarea structurilor invecinate  presiune LCR N)
- bilateral mild ex vacuo dilatation of lateral ventricles,
- Pereti ventriculari cu aspect ondulat
- Banda de glioza subependimala
- band of sub ependymal Gliosis
- substanta alba periventriculara redusa
Diagnostic imagistic: Leucomalacie periventriculara

DIAGNOSTIC EPI/NON EPI
Sindrom West de cauza structurala : leucomalacie periventriculara
Encefalopatie hipoxic-inchemica
Tratament?
CAZ 3 AP 8 LUNI,
 Sarcina:
 cu evolutie fiziologica, nastere spontana, la VG 39 sapt;
 Istoric perinatal : nu
GN-3400g, APGAR-9,
 Dezvoltare psihomotorie:
 in limite normale
ISTORIC
 Debutul manifestarilor: 7 luni;
Frecventa manifestarilor: zilnice, multiple /zi, 5-6 clustere a cate 20-30 de manifestari, doar in
veghe
Examen neurologic – normal

ASPECT
Micarile erau: contractia cu arcuirea trunchiului, balansarea si rasucirea corpului cu forfecarea membrelor
inferioare, hiperventilatie, sudoratie
Constienta prezenta, raspunde la cerere in timpul fiecarui episod care dureaza intre 1 si 5 minutw
episoadele au aspect stereotip
Avea mai multe episoade/zi
Miscarile puteau fi oprite ocazional
Ce analize ati face?
DIAGNOSTIC
Autogratificare
CAZ 5 – M.M., 9 ANI
Sex masculin
Intelect normal,
Examen neurologic normal
Debutul manifestarilor a fost la varsta de 8 ani, in timpul somnului, incepe sa hipersaliveze, dizartrie, hemiclonii
faciale unilaterale initial, ulterior clonii MS ipsilateral, constienta pastrata
Manifestarile sunt exclusiv hipnice
Frecventa rara
EPI/NON EPI
Ce analize ati face?
VIDEO EEG
EEG #1
EEG #2
Considerati ca este necesar IRM cerebral?
Diagnostic?
CAZ 6- MP, 4 ANI
 Sarcina:
 evolutie fiziologica , nastere spontana, VG =39sapt;
 Istoric perinatal : nu
 VG-3400g, APGAR-9,
 Dezvoltare psihomotorie pe etape de varsta:

 in limite normale
 Examen neurologic: in limite normale
 In timpul somnului , deschide ochii, apoi se misca in lateral dintr-o parte in alta, apoi adoarme: >>video EEG
ISTORIC
Debut la 3 ani si 6 luni, in timpul somnului , deschide ochii, apoi se misca in lateral dintr-o parte in alta, plange, se
ridica, merge apoi adoarme dupa 5-6 min.
CONCLUZII
Video-EEG – ul este standardul de aur in diferentierea manifestarilor epileptice de cele neepileptice
Este recomandat pentru pacientii cu episoade recurente
Scopul este sa inregistra, evenimentul si sa documentam corelarea EEG-ului cu aspectul clinic
55
SCOPURILE MONITORIZARII VIDEO-EEG
Este intr-adevar o criza epileptica? (Epilepsie vs manifestari non-

epileptice)
Ce tip de criza este ( caracterizarea tipului de epilepsie)
De unde porneste criza ? Este focala? (debuteaza intr-o anumita zona?)
Neurologia pediatrică
O privire…on-line ☺
Diana Bârcă
UMF, mai 2020

Boli
Epilepsie
metabolice
Tulb de Malf cerebrale

dezvoltare
• Neurologia pediatrică Sindroame Boli neuro-

musculare
– ramură specializată a genetice
medicinei, care se
ocupă de afecțiunile Boli cerebro-
Boli neuro
neurologice ale nou- degenera-
vasculare
Inflamatorii
născuților, sugarilor, tive neurocut…
copiilor și adolescenților
UMF, mai 2020
UMF, mai 2020
UMF, mai 2020
UMF, mai 2020
UMF, mai 2020
Caz 1
• sugar – 5 luni, fara istoric perinatal semnificativ

• mama il consideră “normal”
• Internat pt manifestări paroxistice la vs de 4 luni
1. Ce observați?
2. Ce investigații?
UMF, mai 2020

IRM cerebral
UMF, mai 2020

UMF, mai 2020
UMF, mai 2020
IRM cerebral –
lipsește ceva?
UMF, mai 2020
IRM cerebral – secvența T1 + contrast!!!
UMF, mai 2020

UMF, mai 2020
UMF, mai 2020
Caz 1 - SINDROMUL STURGE-WEBER
Mesaj pentru acasă : inspectați tegumentele!!
UMF, mai 2020

UMF, mai 2020
Caz - Neurofibromatoză
UMF, mai 2020

UMF, mai 2020
Caz - Scleroză tuberoasă
UMF, mai 2020

Caz 2, DN 17.10.2012
• fara istoric perinatal semnificativ – rang I, G 3430 g, Apgar 10, adaptare postnatală bună,
externat din maternitate după 3 zile
• La vs de 8 săpt: inapetent, somnolent – internare pediatrie
• Consult NP – sugar somnolent – EEG – lent unilateral
• ETF – hemoragie intracerebrală parenchimatoasă T-P dr
• Ameliorare spontană
• IRM trimis ulterior – dupa 2 saptamani...
UMF, mai 2020

Caz 2
UMF, mai 2020

Caz 2
✓ La vs de 2luni:
• Crize focale motorii de hemicorp stg

• HIC, GCS 10
• anevrism de ramura de a silviană rupt, evacuat

chirurgical, ulterior clipat cu clip tip yasargil, cu
evoluție postoperatorie favorabilă
• Grasping asimetric, discretă tendință la

lateralitate precoce
• Kinetoterapie susținut
• Evoluție favorabilă
UMF, mai 2020
Caz 2
✓La vs de 5 luni:
• Manifestări paroxistice, survenind grupat
• Predominant la trezirea din somn
• Mama descrie cădere anterioara a capului – “îi scapă capul “
• Inițial fără să producă disconfort – ulterior copilul devine agitat
UMF, mai 2020

UMF, mai 2020
Caz 2
• Sunt crize?
• DA
• Semiologic?
• SPASME EPILEPTICE
• Ce investigații ați face?
UMF, mai 2020

EEG
UMF, mai 2020

EEG
UMF, mai 2020

Caz 2
• Tratament – TPM și Synachten – evoluție rapid favorabilă – fără spasme de la
a 2 a administrare de Synachten
• Program susținut de reabilitare

• Kinetoterapie
• Ergoterapie
• Stimulare cognitivă
• Dezvoltare normală pe etape, lateralitate dreaptă precoce, dar fără deficite

motorii evidente
• Hiperkinetic, deficit atențional
UMF, mai 2020

Caz 2
• Al-2 –lea IRM
Encefalomalacie și glioză în
regiunea TP dr – post anevrism de
ramură de a silviană rupt, cu
hematom intraparenchimatos
UMF, mai 2020

Caz 2 – evoluție
La vs de 6 ani si 9 luni:
• se interneaza de urgență în CG în contextul unei manifestări paroxistice
hipnice :
• La ~ o ora de la adormire - hipertonie generalizata, posibile clonii ale MS
bilateral, privire plafonată, durata ~5 minute, revenire spontană la normal,
somnolenta postcritic, frust deficit de hemicorp stg postcritic.
• semiologic?
• Criză epileptică focală inaugurală
• Tratament- DA/NU?
• În prezent: fără alte crize, QI 108, ADHD
UMF, mai 2020
Caz 3
• În evidența clinicii noastre din 2016 – la vs de 10 ani pt evaluarea epilepsiei &
suspiciune boală metabolică
• Debutul crizelor la vs de 4 ani – rezistente la tratament
• Crize: devierea GO, aresponsivitate, ulterior generalizare, scurte +/ - automatisme

de masticație
• Istoric perinatal nesemnificativ, dar TGD microcefalie

hipostaturalitate
• A sezut la 10 luni, mers independent la 7 ani dismorfism
• Deficit cognitiv sever
• Limbaj expresiv absent
• Agresivitate , TSA
• Cardiomiopatie dilatativă dg la vs de 6 l
• La vs de 10 a → SE + aspirare – stop cardio-respirator resuscitat → traheostoma
UMF, mai 2020
• Investigații?
• Alte informații ?
UMF, mai 2020

IRM
UMF, mai 2020

EEG
UMF, mai 2020

Investigații
• Ce investigații?
1. Metabolice?
SAU
2. Genetice?
• Ce teste?
UMF, mai 2020

TGD + epilepsie + anomalii cardiace + dismorfism
• Dismorfism “sindromic” Indicii ?

•Linie joasa de insertie a
parului,
•Occiput plat – brahicefalie;
•Hipoplazie etaj mijlociu fata,
• Sindrom de deleție •Ochi adanciti,
•Hipertelorism,
•Epicantus,
•Sprancene orizontalizate
•Nas cu baza turtita,
•Barbie ascutita.
• Testare genetică țintită

• Deleție 1p36 ( FISH)
UMF, mai 2020

Cum sunt afectați copiii cu sdr de del 1p36?
Sursa:http://www.1p36dsa.org/1p36-dsa-blog/ UMF, mai 2020

Caz 3 – del 1p36
• cea mai intâlnită deleție terminală.
• Debut crize – frecvent precoce, în primul an de viață :

• spasme epileptice (răspund la corticoterapie)
• crize focale/ generalizate, crize mioclonice
• encefalopatie epileptică – Sd Lennox Gastaut.
• Epilepsia e mai frecvent in DI severă >>ID moderată
UMF, mai 2020

Caz 3 – Mesaj de luat acasă:
Epilepsie
+ TGD
+ Facies particular
+ anomalii congenitale
Testare genetica
Fenotip sugestiv Fenotip nespecific

→FISH/ MLPA →arrayCGH
UMF, mai 2020

Caz 4
• Sugar de 6 luni evaluat pentru întârziere în DPM
• Istoric pre/perinatal nesemnificativ
• Hipotonie marcată (fără controlul capului, nu șade)
• Manifestări paroxistice cu aspect hipermotor, apoi episoade cu postură

anormală a MS, unilateral.
UMF, mai 2020

Caz 4 – Investigații
• EEG: fără corespondent electric al manifestărilor paroxistice
• IRM cerebral: normal
• DAR.. aspect particular al EEG
• Alte investigații?
UMF, mai 2020

UMF, mai 2020
UMF, mai 2020
Caz 4 – Diagnostic
Copil blond, vesel , cu

TGD, hipotonie marcata,
model de miscare
particular (ataxic,
hipermotor)
- Clinic & EEG -> suspiciune sindromică…
UMF, mai 2020

Caz 4 – Sd Angelman
• Mutatie in gena UBE3A; 70% deleții 15q11-13
• Test FISH pentru confirmare/ MLPA ( Multiplex Ligation-Dependent

Probe Amplification)
• 90% asociază epilepsie cu debut între 1-3 ani – crizele preced

diagnosticul sindromului genetic
• EEG sugestiv dar nu patognomonic!
• Crizele sunt polimorfe iar la vârsta mica – statusul nonconvulsivant
UMF, mai 2020

UMF, mai 2020
UMF, mai 2020
UMF, mai 2020
Angelman syndrome – sursa youtube
UMF, mai 2020

SINDROAME GENETICE SPECIALE
Brain gYm ☺
UMF, mai 2020
Caz 5
• Copil cu DPM normală pe etape, elev cu rezultate școlare bune, antecedente medicale
nesemnificative
• Debut la 11 ani 11 luni- manifestari paroxistice survenite recent, din veghe.

• cu 2 saptamani anterior internării - in context infectios, febril (cu 3 -4 zile anterior febra 39-40 de
grd C, somnolenta, stare generala modificata, “pleoape cazute” -> o varsatura, privire fixa, cianoza
perioronazala, devierea spre stanga a comisurii bucale, neresponsivitate, tegumente marmorate,
miscari dezordonate ale membrelor, aspect sugestiv pentru criza epileptica focala prelungită – 1 ora –
SE
• PL: LCR clar, incolor, Pandy negativ, albumina 0,33 g%, glucoza 0,5 g%, cloruri 7,3 g%, elemente
3/mmc (efectuata in ziua debutului)
• CT cerebral – normal; EEG veghe – descarcari frecvente de CVU in derivatiile anterioare cu
amplitudine maxima frontal stanga.
• episoade spontane de irascibilitate, anxietate, miscari involuntare faciale – dispar numai in somnul
profund, afirma dificultati la masticatie, dar fara tulburari de deglutitie, Romberg nesistematizat.
• dg de etapă: encefalopatie acută, cu declanșare febrilă – crize epi + tulburări de micare, modif de
conștiență/ dispoziție
UMF, mai 2020
Caz 5
UMF, mai 2020

• …fenomene diskinetice & crize epileptice în contextul
unei encefalite autoimune
UMF, mai 2020

Caz 6
• ușoară suferință perinatală, dar adaptare postnatală bună
• tulburare globală a dezvoltării
• la vs de sugar – hipotonie – în evoluție sdr extrapiramidal
• dg de paralizie cerebrală diskinetică
• > 3 ani – fenotip comportamental particular - automutilare
UMF, mai 2020

UMF, mai 2020
UMF, mai 2020
Caz 6 - investigații
• Fără anomalii notabile la primele evaluări
• Hiperuricemie!!
• Imagistică cerebrală normală!
UMF, mai 2020

Caz 6- dg: Sdr Lesch-Nyhan
• Mutație gena HPRT1 – cromozom X - transmitere legată de cr X
• Deficit al enzimei HPRT (hipoxantin-guanin-fosforibozil transferaza)
• activitate <1,5%
• Afecteaza metabolismul purinelor
• Acumulare acid uric
Tulburări de comportament –
automutilare
Tulburare globală
de dezvoltare + Hiperuricemie + caracteristic – mușcarea buzelor
& degetelor
Suspiciune sdr Lesch-Nyhan

UMF, mai 2020
Sdr Lesch-Nyhan – clinica
Afectarea Tulburari de
motorie comportament
• miscari involuntare • automutilare
anormale ale mb • heteroagresivitate
• distonii fizica/verbala
• disartrii
• disfagie
• spasticitate
• coreoatetoza
• balism
• opistotonus
Tulburari Alte
Hiperuricemia
cognitive caracteristici
• hiperuricemie • variabila de la pacient • anemie hipocroma
• litiaza renala la pacient megaloblastica
• artrita gutoasa • greu de evaluat • atrofie testiculara
• tofi gutosi • pubertate intarziata
• dezvoltare pe etape
intarziata
UMF, mai 2020

Sdr Lesch-Nyhan – imagistica
UMF, mai 2020

Sdr Lesch-Nyhan – management
• Afectarea motorie:
• Miorelaxante – Baclofen
• Pt sdr extrapiramidal – trihexifenidil, levetiracetam
• Tulburările de comportament:
• Benzodiazepine
• Neuroleptice
• Antidepresive
• Afectarea metabolică:
• Hiperuricemie – Allopurinol
• Litiaza renala – alcalinizante urinare si hidratare
• Anemie megaloblastica – acid folic si vitamina B12
• Evaluări periodice: neurologică, nefrologică, etc
UMF, mai 2020

Caz 7
UMF, mai 2020

Caz 7
• APF - Gn = 4800 g, SA= 10, adaptare postnatala buna, DPM normală
• AHC - patologie neuro/psihiatrică ?

- verișoara maternă – copil cu autism?
- mătușa materna – epilepsie?
- mama (38a) – afirmativ sănătoasă
- tatal (40a) – afirmativ sănătos !CONSANGVINITATE
- frate (11a) – afirmativ sănătos veri gr III
• APP - sindrom hiperkinetic (5 ani)

- astigmatism hipermetropic (7 ani)
UMF, mai 2020

Caz 7 - istoric
• Posturi anormale MS drept
Suspiciune tulburare conversivă - psihiatrie
9a • Modificări scris
• Distonie MS drept
• Dizartrie
9a 10l • Lentoare ideo-verbală
• Distonie accentuată
10a • Afectarea MS bilat
• Distonie oro-facială
• Distonie linguală
12a 10l
• Sdr distonic sever: MS bilat, oro-facial
• Imposibilitatea vorbirii, autoservirii, tulburări alimentație
13a 4l • Atrofii musculare importante, generalizate
UMF, mai 2020
Caz 7: IRM cerebral
UMF, mai 2020

PKAN – imagistica
UMF, mai 2020

Caz 7 - evoluție
❑Clinic: distonie ↑↑↑
❑Imagistic: modif în GB
Boală neurodegenerativă asociată pantotenat-kinazei (PKAN) ?
❑11 ani si 2 luni- testare genetică PKAN
CONFIRMARE PKAN
2 mutații patogene ale PANK2 (exonul 6) – cr 20
pank2c. 1583C>T
pank2c. 1561G>A
UMF, mai 2020
Boli neurodegenerative cu acumulare cerebrală de fier (NBIA)
• grup heterogen de afecțiuni genetice rare
• AR (exc: Neuroferitinopatia)
• acumulare Fe la nivel SNC-GB
• tulburări de mișcare progresive *sd. extrapiramidal
• afectare cognitivă + psihică
• Diferențiere dpdv - clinic

- imagistic
- genetic
UMF, mai 2020
NBIA
1. PKAN (pantothenate-kinase associated neurodegeneration) – 50%
2. PLAN ( phospholipase A2- associated neurodegeneration)
3. FAHN (fatty acid hydraxylase- associated neurodegeneration)
4. MPAN (mitochondrial protein-associated neurodegeneration)
5. Kufor-Rakeb
6. Aceruloplasminemia
7. Neuroferitinopatia
8. SENDA ( static encephalopathy of childhood with neurodegeneration in

adulthood) UMF, mai 2020
PKAN – recomandări
• Tratament symptomatic, paliativ
• Somnografie – ↓ duratei totale de somn
• Sfat genetic !
❑ PKAN – AR (25%)
❑apartinătorii solicită testare genetica pentru frate
❑Testare copil asimptomatic ?
IRM cerebral
UMF, mai 2020

Caz 7 – frate
UMF, mai 2020

Caz 7 – frate - IRM
Depuneri ferice putamen bilat., cu modificări gliotice si demielinizări în globus pallidus

(= PKAN paucisimptomatic)
UMF, mai 2020

Cazuri de neurologie pediatrică – exemple:
• Afecțiuni neurocutanate
• Modele de dezvoltare la sugar
• Sindroame genetice – dismorfismul “sindromic”
• Boli metabolice necesitând echipă multidisciplinară
• Boli neurodegenerative
UMF, mai 2020

…neurologia pediatrică este vastă
Va urma…
UMF, mai 2020

Cazuri clinice
o “calatorie” prin neurologia pediatrica
Nina Butoianu
Diana Barca
UMF, Mai 2020

Cazul 1
Annalyn, 5 ani
✓Prima internare la 10 luni – motivele internarii:
- hipotonie de la nastere
- intarziere in achizitiile motorii

- pozitie sezanda fara suport - 9-10 luni
- apuca obiecte- 6 luni
UMF, mai 2020

Annalyn
Antecedente Antecedente
Heredocolaterale personale fiziologice Dezvoltare motorie
neaga consanguinitate, Sarcina cu evolutie fiziol, pozitie sezanda fara
boli musculare, alte nastere la termen, fara suport-9-10 l
alte afectiuni evenim perinatale, GN -
neurologice
3000 g, APGAR-10
Antecedente Personale
Limbaj Achizitii cognitive
Patologice
Urmareste inconstant cu nesemnificative
Lalalizeaza la 6 luni
privirea, nu se joca
cucu-bau, nu intinde
mana dupa obiecte,
prehenisune absenta
UMF, mai 2020

Annalyn
UMF, Mai 2020

Annalyn
✓Ce vedeti?
• Postura membrelor inferioare- hipotonie

• Miscari putine la nivelul membrelor
• Nu este interesata de obiecte sau persoane
• Miscari stereotipe la nivelul mainilor
UMF, Mai 2020

Annalyn
✓Examenul clinic - ce mai doriti sa aflati?
• ROT
- prezente
• Achizitii cognitive
- Intarziata cu elemente de spectru autist
• Alte simptome/semne clinice

- Crize epileptice
- Microcefalie congenitala
UMF, Mai 2020

Annalyn
UMF, Mai 2020

Diagnostic topografic
✓Sindrom hipoton?
-da
✓Ce tip? Periferic sau central?
- Central
UMF, Mai 2020

Annalyn
✓Ce investigatii ati face?
▪ Analize de sange? Care?
- Uzuale – hemograma, fct hepatica, renala

▪ IRM Cerebral ?
- Da
▪ Teste genetice? Care?
UMF, Mai 2020

Diagnostic final
- Crize epileptice
- tulburare globala de Motor pathway
dezvoltare
IRM cerebral - normal

Test Genetic– MECP 2
Sindrom Rett
UMF, Mai 2020

Cazul 2
Ayan , DN: 02/09/2017
✓I internare la 4 luni:
- intarziere in dezvoltarea motorie – nu sustine capul
UMF, Mai 2020

Ayan
neaga consanguinitate, Sarcina cu evolutie fiziol,
boli musculare, alte nastere la 39 S, fara Nu sustine capul
alte afectiuni evenim perinatale, GN =
neurologice
3250 g, APGAR-10
Antecedente Personale
Limbaj Achizitii cognitive Patologice
Fixeaza tinta, urmareste nesemnificative
Gangureste
cu privirea oriz si
vertical,
Zambet social, rade in
hohote
UMF, mai 2020

Ayan
UMF, Mai 2020

Ayan
Din punct de vedere clinic ce va atrage atentia?
✓Hipotonia
✓Miscari absente la nivelul membrelor inferioare
✓Respiratie abdominala
UMF, Mai 2020

Ayan
✓Din punct de vedere al exam clinic ce ati vrea sa stiti?
• ROT
• absente
• Achizitiile cognitive
• Normale ptr varsta

• Fasciculatii linguale
• Fara crize epileptice
• PC - normal
UMF, Mai 2020
Central
Maduva spinarii
Atrofie musculara spinala
Polineuropatie
Jonctiune neuromusculara
Miopatie
UMF, Mai 2020

Ayan
✓Ce investigatii ati face?
• Analize de sange? Care?

• CK – 250 U/l
• IRM Spinal?
• Nu
• EMG?
• Nu
• Teste genetice? Care?
• deletia exon 7 cr 5
UMF, Mai 2020

Ayan
✓Diagnostic?
• AMS- tipul ?
1- nu sustine capul
✓Ce facem mai departe?

- Tratament cu Nusinersen
- Evaluare respiratorie – suport NIV
- Kinetoterapie
UMF, Mai 2020

Ayan - evolutie
• Evolutie
- 10 administratari Nusinersen
- NIV suport din mar 2018
UMF, Mai 2020

Nu uitati!
UMF, Mai 2020

Cazul 3
Alex, 15 a
✓Ptoza bilaterala
✓Dificultati de inghitire
- Debut la 11 ani
UMF, Mai 2020

Alex
neaga consanguinitate, Sarcina cu evolutie fiziol, Mers nesustinut la 1 an
boli musculare, alte alte nastere la termen, fara
afectiuni neurologice evenim perinatale, GN =
3000 g, APGAR10-10
Antecedente personale patologice
Limbaj Cognitiv
nesemnificative
normal normal
UMF, Mai 2020

Alex
✓ Ce vedeti?
- Ptoza palpebrala bilaterala
- Limitarea privirii lateral OD

- Oftalmoplegie verticala
UMF, Mai 2020

Alex – semne clinice
• Deficit muscular la niv membrelor?

• Da , proximal
• Deficit muscular al m gat?
• Da, flexori
• ROT
• prezente
• Particularitati ale deficitului muscular?
• fluctuant, se agraveaza la efort, se amelioreaza in repaus
UMF, Mai 2020

Central
Maduva spinarii
Polineuropatie
Miopatie
UMF, Mai 2020

Alex – investigatii paraclinice
• Analize lab
Care? Jonctiune neuromusculara
• CK – 230 U/L
• Ac anti R acetilcolina (Ac R ACh)
- pozitiv
Alte investigatii
• EMG?
Cu stimulare repetitiva: decrement semnificativ Miopatie
• Imagistica Timus (CT, IRM)
normal
UMF, Mai 2020

Alex - diagnostic
✓Miastenia gravis
✓Tratament
- Anticholinesterazice–neostigmina, piridostigmina
- Imunosupresoare – corticosteroizi, azathioprine....
- Timectomie
✓Evolutie
-favorabila, se poate agrava(criza miastenica)
UMF, Mai 2020

Cazul 4
Luca , 13 ani
✓Internat ptr dificultati de mers debut de 7 zile, progresive

✓ dureri si parestezii la niv plantelor
✓In urma cu 2 S- infectie de cai resp sup
UMF, Mai 2020

Luca
neaga consanguinitate, Sarcina cu evolutie fiziol, Mers nesustinut la 1 an 1l
afectiuni neurologice evenim perinatale, GN
=2850 g, APGAR-10
Limbaj Cognitiv
nesemnificative
normal normal
UMF, Mai 2020

UMF, Mai 2020
Luca
• La prima vedere ce este in neregula?
Deficit muscular ?
-membre inferioare– proximal > distal
ROT
- Absente la membre inferioare
UMF, Mai 2020

Luca
• Din punct de vedere al exam clinic ce ati vrea sa stiti?

- Dificultati de inghitire?
- nu
- Tulburari de sensibilitate?
- nu
UMF, Mai 2020

Central
Maduva spinarii
Polineuropatie
Miopatie
UMF, Mai 2020

Luca
• Analize lab
- Uzuale – HLG, functia renala, hepatica
- Punctia Lombara
- disociatie albumino – citologica
Cel- 3/mmc
Proteine – 120 mg/dl (N: 20-40 mg/dl)
• Altele ?
• EMG?
- NCV -  , blocuri conducere, dispersie temporala
UMF, Mai 2020

Luca
✓Diagnostic?
Polineuropatie inflamatorie
acuta demielinizanta
(Sindromul Guillian Barre)
UMF, Mai 2020

Luca
• Tratment cu ce?
• Imunoglobulina Ig iv 2g/kg- in 5 zile

• Plamafereza
• evolutie favorabila
UMF, Mai 2020

Cazul 5
Nicolas, 8 ani
▪ Motivele internarii
▪ dificultati de ridicat de la podea
▪ dificultati de urcat scarile
▪ dificultati de ridicat din DD in pozitie sezanda
▪ Copil " moale"
▪ debut: primul an de viata
UMF, Mai 2020

Nicolas
boli musculare, alte alte nastere la termen, fara Copil mai "
afectiuni neurologice evenim perinatale, GN moale„, "neandemanatic"
=3320 g, APGAR-10
Limbaj Cognitiv
Polidactilie congenitala
Intarziat (< 3a) Intarziat (~ 3a) bilaterala (corect chirurg)
UMF, Mai 2020

Nicolas
UMF, Mai 2020

UMF, Mai 2020
Nicolas
Mersul?
- leganat
Deficit muscular ?
- m cervico-axiali - ↑↑
- centura pelvina- Gowers pozitiv
Alte semne?
- Facies hipomimic
- Rigiditate spinala
- Hipotrofie musculara
- Hiperlordoza
UMF, Mai 2020
Nicolas
• Deficit muscular al m inerv de n cranieni?

• Dificultati de inghitire ptr alimente solide, vorbire nazala, plans slab
• ROT
- prezente

- retractii – achiliene, coapse, interfalang bilateral
UMF, Mai 2020

Central?
Maduva spinarii

Polineuropatie
Miopatie ?
UMF, Mai 2020

Investigatii paraclinice
• Analize de lab
• Care?
• CK – 349 (N 0-171) u/l
• Altele?
• EMG? – traseu miogen
UMF, Mai 2020

IRM cerebral – atrofie moderata difuza

Lez punctif hypersemnal T2 si FLAIR
tegmentale bilateral hormoni
tiroidieni – N
Polysomnografie : apnee
obstructiva
Eco
Cardiologic- EKG, Eco- N abdominala
–N
UMF, Mai 2020

Diagnostic
Central Biopsie Muschi

modificari
nespecifice
Miopatie
Miopatie congenitala
Distrofie musculara
congenitala
Miopatie metabolica WES
Mutatie in gena
Selenon
test b Pompe –
negativ
UMF, Mai 2020
Diagnostic
▪ Gena SELENON codifica o glicoproteina localizata in reticulul

endoplasmic
▪ rol in protectia cel imp stres oxidativ si in the reglarea homeostaziei
metab redox-related calcium
▪ Mutatiile sunt asociate cu “MULTIMINICORE DISEASE” (MmD)- distrofie
musculara cu spina rigida, miopatie congenitala disproportie de fibre AR
▪ Forma clasica MmD (75%) : debut precoce cu hipotonie neonatala
intarziere in dezvoltarea motorie, deficit m axiali, scolioza, afectare
respiratorie semnificativa (adesea cu afecatre cardiaca secundara);
rigiditate spinala prezenta
▪ Sfat genetic
UMF, Mai 2020

Cazul 6
Varsta Debut
9a 2016 Insidios cu dificultati
de mers
Sex
Masculin
Data nasterii Evolutie
Andrei
02/2011
2019 Dificultati urcat scarile,
de ridicat de la podea
lent progresive
Simptome
- Dificultati de mers Internare in clinica
2020
- Dificultati urcat scarile
UMF, Mai 2020
Andrei
afectiuni neurologice evenim perinatale, GN =
3500 g, APGAR10-10
Limbaj Cognitiv
nesemnificative
normal Dificultati de invatare
UMF, Mai 2020

Andrei
UMF, Mai 2020

Andrei
Mersul?
-leganat
Deficit muscular?
- axial
- Centura pelvina- Gowers pozitiv
Altele?
- Hipertrofie moleti
- Hiperlordoza
UMF, Mai 2020
Andrei
• ROT
- prezente

- retractii - achiliene
UMF, Mai 2020

Central
Maduva spinarii
a
Polineuropatie
Miopatie
UMF, Mai 2020

• Analize lab
• Care?
• CK – 7900 U/L
• Altele?
• EMG?
–nu Miopatie
• Cardiologic- EKG, Eco- N
UMF, Mai 2020

Andrei
Care este diagnosticul?

Distrofie musculara progresiva
Ce ati face mai departe?

- Teste genetice ?
- Biopsie de muschi ?
Care dintre ele intai ?
Ce tip de teste genetice?
- distrofinopatie
(Duchenne/Becker)
UMF, Mai 2020

Diagnostic
✓Teste genetice- distrofinopatie

(Duchenne/Becker) (rezult in lucru)
Ce tip de DMP credeti ca este? Duchenne sau Becker?

- Becker
✓ Dc testele sunt negative – ce faceti mai departe?
- biopsie muschi–mutatii intronice in
DMD gena/alta proteina absenta
✓Teste genetice - panel for distrofii musculare progresive
UMF, Mai 2020
Andrei
✓Kinetoterapie/orteze achiliene
✓Cardiac follow up
✓Teste genetice – sfat genetic
UMF, Mai 2020

Blitz diagnostic!
✓Ce e in neregula?
✓Ce boala credeti ca are?
UMF, Mai 2020

Caz 8
✓Stefan – 10 ani
✓Se interneaza ptr:
- Tulburari de mers
- Debut de aprox 3 ani
UMF, Mai 2020

Stefan
mama cu tulburari de nastere la termen, fara Mers nesustinut la 1 an 2l
mers evenim perinatale, GN
2920 g, APGAR-10
Limbaj Cognitiv
nesemnificative
Normal Normal
UMF, Mai 2020

Stefan
✓ Din punct de vedere al exam clinic ce ati vrea sa stiti?
▪ Are deficit muscular?
- da, la membrele inferioare distal
▪ ROT
- Absente distal
▪ Tulburari de sensibilitate?
- Da, ptr sensibilit proprioceptiva
▪ Alte simptome/semne clinice
- Retractii achiliene
UMF, Mai 2020

Central
Maduva spinarii
Polineuropatie
Miopatie
UMF, Mai 2020

Stefan
▪ Analize lab ?
- CK- 200 u/l
▪ Punctia Lombara?
- nu
▪ Altele ?
-EMG
- NCV -  , traseu neurogen
▪ Anamneza – ati mai vrea sa vedeti/investigati ceva anume?
- Examinarea mamei, EMG- similare cu ale lui Stefan
UMF, Mai 2020

Stefan
✓Diagnostic?
Polineuropatie ereditara
senzitivomotorie – forma demielinizanta,
Familiala, AD
(Boala Charcot Marie Tooth )
UMF, Mai 2020

Caz 8
Crina, 5 ani
✓Se interneaza pentru :

- Tulburari de mers debutate de la 1 an 6 luni
UMF, Mai 2020

Crina
boli musculare, alte alte nastere la termen, fara Mers nesustinut la 1 an 6l
afectiuni neurologice evenim perinatale, GN
=2500 g, APGAR-10
Limbaj Cognitiv
Nesemnificative
Normal Normal
UMF, Mai 2020

Crina
Ce puteti spune din punct de vedere

neurologic?
Are deficit muscular?
Daca da, la ce nivel?
In afara deficitului muscular mai
recunoasteti alte semne
neurologice?
UMF, Mai 2020

Crina
▪ ROT
- Prezente
▪ Alte simptome/semne clinice

• Tremor la proba indice nas
UMF, Mai 2020

Central?
Maduva spinarii

Polineuropatie
Miopatie ?
UMF, Mai 2020

Crina
▪ Analize de lab - Care?

- CK – 1200(N 0-171) u/l Suspiciuni diagnostice
▪ Altele? - Afectare SNC si
- EMG? – traseu miogen, VCN – N periferic
- Boala mitocondriala
▪ IRM cerebral- ?
- Distrofie musculara
- Atrofie cerebel congenitala cu
▪ Biopsie muschi ? afectare cerebrala
- Modificari nespecifice
UMF, Mai 2020

Blitz diagnostic!
✓Ce e in neregula?
✓Ce boala credeti ca are?
UMF, Mai 2020

Multumesc!
UMF, Mai 2020

Malformatiile SNC
Ioana Minciu
Definitie
• Anomaliile morfologice ale SNC legate de
oprirea sau deviere in dezvoltare, care s-au
constituit inainte de nastere.
Date privind formarea diferitelor structuri nervoase si a
malformatiilor acestora
Perioada gestatiei Stuctura formata defect malformatie
S 3-4 Tub neural Defect de disrafii

inchidere/ de
inductie dorsala
S 4-6 Vezicule Defect de holoprosencefali
cerebrale segmentare si e
clivaj/
S 10-14 Structuri Defect inductie Agenezie corp
mediane ventrala calos
L 4-5 cortex Defect de Lisencefalie,
migrare displazie,
neuronala si polimicrogirie,
organiz corticala heterotopii,
schizencefalie
dupa L5 Distructii porencefalie
parenchim
TULBURARI ALE NEURULATIEI SI FORMARII
TUBULUI NEURAL
Tipuri:
• Craniene
– anencefalia
– cefalocelul
Spinale
• spina bifida chistica
• meningocelul
• mielomeningocelul
• spina bifida oculta
• lipom spinal
• sinus dermal
• diplomielia
• diastematomielia
• filum terminal scurt
Encefalocelul
Encefalocelul tulb de inchidere a tubului neural in care exista tesut cerebral,
cu sau fara invelisurile sale, in afara cutiei craniene printr-un orificiu al
acesteia, preexistent, congenital.
• Tipuri:
– meningocelele cefalice (meninge si LCR)
– encefalomeningocelele (tesut cerebral si meninge)
– encefalocelele (doar tesut cerebral).
• 85% sunt posterioare localizate occipital
• 15% anterioare ( nazal, orbitar, sfenoidal)
• Investigatii paraclinice:
– radiografia
– transiluminarea
– CT, RMN.
• Manifestari clinice sunt functie de cantitatea de tesut cerebral herniat, de
gradul de hidrocefalie si localizare.
Encefalocel posterior
Encefalocel anterior naso-orbitar
Anencefalia
• Definitie – malformatie letala caracterizata prin absenta ambelor emisfere

cerebrale si a boltii craniene.
• Patogenie – se produce prin absenta inchiderii anterioare a tubului neural
( neuropor anterior) in ziua 21-26 de gestatie
• Clinic
– nou-nascutul nu are craniu, ochii si fata sunt prezente.
– supravietuiesc cateva zile pana la doua saptamani
– prezinta miscari stereotipe, spontane sau ca reactie la durere sau stimuli
auditivi, posturi de decerebrare, convulsii
– prezinta reflexe arhaice – reflexul de supt, reflexul Moro
• Diagnostic prenatal
– dozare de AFP (alfafetoproteina) in lichidul amniotic si serul matern
– ultrasonografie
• Profilaxie
Disrafiile spinale
• Fuzionarea imperfecta a structurilor liniei mediane mezenchimatoase,

osoase si nervoase.
• Forme anatomice:
1- Spina bifida chistica – se insoteste de hernia meningelor si tesutului nervos
intraspinal. Localiz frecv lombo-sacrata
• Meningocelul: este hernia de meninge fara tesut nervos.
• Mielomeningocelul: herniere de meninge si tesut nervos
– Manifestarile neurologice:
– paraplegie flasca, areflexie osteotendinoasa sau parapareza;
– atrofii musculare;
– tulburari sfincteriene;
– tulburari de sensibilitate corespunzatoare dermatoamelor interesate;
– tulburari trofice;
• Tratament – chirurgical (0-3 luni)
Meningomielocel
Disrafiile spinale
• 2. Spina bifida oculta – defectul mezenhimal nu se insoteste de hernierea
meningelor sau tesutului neural.
• Diagnosticul malformatiei este neuroimagistic: CT sau RMN
• Tipuri:
– Filum terminal scurt
– Spina lipom (lipom intrarahidian) (tumori lipomatoase intrarahidiene
mediane)
– Sinus (fistula) dermic (comunicare intre piele si nevrax)
– Diplomielia
– Diastematomielia
• Anomalii asociate disrafiilor
– Siringomielie, siringobulbie
– Hidromielie
• Clinic:
– simptomele usoare, severe sau progresive/muta clinic (snp+c)
– stigmate cutanate
– tulburari ortopedice
– tulburari neurologice
• Tratament: chirurgical
Diastematomielie
SPINA BIFIDA OCCULTA
(1.dermal sinus + 2.spinal lipoma)
TULBURARI ALE INDUCTIEI VENTRALE/ tulb de segmentare si
clivaj
HOLOPROZENCEFALIA (Arinencefalia)
• anomalii de clivaj al prozencefalului (s 5-6) in telencefal (din care se vor

forma emisferele cerebrale) si diencefal
• absenta proceselor olfactive = arhinencefalie
• anomalii cromozomiale, (trisomie 13, 18, monosomie 13q-, 18p-, cr 18 in
inel) autosomal dominanta/recesiva
holoprozencefalia
• tipuri:
– holoprozencefalia alobara
– holoprozencefalia semilobara
– holoprozencefalia lobara
• diagnostic imagistic
• manifestari clinice:
– sindrom dismorfic (anomalii de linie mediana)
– sindrom neurologic
– sindrom endocrin, visceral si general
• tratamentul este pur simptomatic
• profilaxie: depistare antenatala prin ecografie fetala si studiul cariotipului
fetal
Holoprozencefalie alobara
Holoprozencefalie semilobara
Holoprozencefalie lobara
PSYCOMOTOR
RETARDATION,
MICROCEPHALY,
EPILEPSY
22
TULBURARI ALE DIFERENTIERII STRUCTURII LINIEI MEDIANE
AGENEZIA DE CORP CALOS

• - defect de diferentiere a placii comisurale (S 11-12 gestatie)
• Poate fi:
– totala
– partiala
• Diagnosticul – eco-transfontanelara, CT, RMN
• Manifestari clinice
– tulburari neurologice
– anomalii cranio-faciale si oculare
– anomalii cardiace, urinare
– afectare hipotalamica
• Etiopatogenie:
– caracter familial
– anomalii cromozomiale
– rareori secundara distructiei totale a unui corp calos
• Forme sindromice:
– sindrom oro-facio-digital (Papillon-Leage-Psaume)
– lipomul corpului calos
– sindromul Shapiro
– sindrom Anderman
– sindrom Aicardi
Agenezie de corp calos
Malformatia Arnold-Chiari
• Tulburare de dezvoltare a somitelor cervicale –Sapt 4
• Anomalie de pozitie a jonctiunii bulbomedulare si a cerebelului in raport
cu foramen magnum si canalul cervical superior.
• Tipul I - deplasarea caudala a polilor inferiori ai emisferelor cerebeloase in
canalul spinal cervical pana la C3
– Manifestari clinice tardiv: cefalee, dureri cervicale, tulburari de deglutitie si
fonatie, anestezie termoalgica, sindrom piramidal sau paralizii de instalare
acuta la hiperflexia capului, ataxie.
• Tipul II - deplasarea caudala in canalul rahidian a bulbului si partii
inferioare a puntii cu alungirea cranio-caudala si ingustarea transversala a
ventricolului IV, hernierea amigdalei cerebeloase si partii inferioare a
cerebelului prin gaura occipitala in canalul rahidian inapoia trunchiului
cerebral, cu sau fara deplasarea maduvei, formand cudura caracteristica la
jonctiunea medulo-bulbara. Se insoteste de meningomielocel lombar si
hidrocefalie. Manifestari clinice precoce de la sugar
• RMN este examenul de electie
TULBURARI ALE DEZVOLTARII CORTEXULUI
TULBURARI DE PROLIFERARE NEURONALA
• Microcefalia - o scadere in volumul si greutatea creierului

tradusa printr-un perimetru cranian mai mic cu doua (
trei)deviatii standard decat media corespunzatoare
varstei, sexului, rasei.
– primara
– Secundara
• Diagnosticul diferential se face cu craniostenoza

Microcefalia antenatala– etiologie:
• 1. Factori genetici:
– Transmitere autosomal recesiva
– - sindroame polimalformative
– - malformatii cerebrale:holoprosencefalie, lisencefalie tip I
– - cu retard mintal izolat: microcefalia vera
– - cu anomalii asociate: oculare, sindrom nefrotic.
– Transmitere x lincata, dominanta (incontinentia pigmenti) sau recesiva
– Transmitere autosomal dominanta
• 2 . Anomalii cromozomiale:
– I. autosomale: trisomie 13, 18, trisomii partiale 4p+, 10q+, deletii 4p-, 5p-,
13q-, 18p-, 18q-
– gonozomale: 48 xxxy, 49 xxxxy
– Infectii in utero:
– virale: (T)ORCH, HIV
– parazitare: toxoplasmoza
• 4. Factori neinfectiosi:
– metabolici: fenilcetonuria, alcoolismul, malnutritia materna
– fizici: iradierea, hipertermia
– chimici: intoxicatia CO, Fenitoin, metil-mercur, organomercuriale,
hipervitaminoza A
Curbele perimetrelor craniene
2 MACROENCEFALIA (Megalencefalia)
• Cresterea greutatii si volumului creierului, tradusa

prin cresterea perimetrului cranian cu mai mult de
doua deviatii standard fata de media pentru varsta,
sex, rasa, in absenta hidrocefaliei, a colectiilor ,
tumorilor intracraniene sau a ingrosarii calotei
craniene.
• Cauze de macroencefalie:
– macroencefalia anatomica
• sindrom Sotos, sindroame neurocutanate, sindrom Klinefelter
– macroencefalie metabolica
• boli lizozomale, aminoacidurii, boala Alexander
– macroencefalie hemodinamica
– macroencefalie cu hidrocefalie
Hemimegalencefalia
megalencefalie
Macrocrania este cresterea perimetrului
cranian cu mai mult de doua deviatii
standard fata de valorile medii
normale.
• Cauze de macrocranie:
1. hidrocefalia
2. macroencefalia
3. colectie subdurala
4. edem cerebral
5. craniu ingrosat
Tulburari de migrare neuronala si formare
a cortexului
– Trimestrul II de sarcina!
– LISENCEFALIE ( creier neted)
– POLIMICROGYRIA: neuronii ajung la niv cortex dar se distribuie anormal,

giratii mici si multe
– HETEROTOPII NEURONALE neuroni cu structura normala dar anormal

localizati si conexiuni sinaptice anormale
– DISPLAZIA CORTICALA: anomalii focale ale cortexului cerebral;
34
TULBURARI DE MIGRARE
LISENCEFALIA (AGIRIA) (creier neted)
• Tipul 1 (tipul clasic) (agirie- pahigirie): un cortex gros

format din 4 straturi asociat cu heterotopii in banda
intinse subcorticale. Diagnostic de certitudine CT si
RMN cerebral.
• monosomie 17 p 13.3 (- gena LIS1-sd. Miller-Dieker).
Clinic: retard mintal profund, hipotonie marcata,
convulsii, microcefalie sindrom dismorfic
caracteristic. (forma severa sau pattern post>ant. )
• Lisencefalia izolata cu facies normal sau us
dismorfic,- mutatii sau deletii la nivelul genei DCX
(pattern sever sau A>P), sau LIS 1-( P>A).
• Lisencefalie cu hipoplazie cerebeloasa (F)
• Xlincat, baieti, (gena ARX)(P>A), hipoplazie genitala,
hipotermie, RM
Lisencefalia tip 2
• Tipul 2
• Cortex lis, dezorganizat, lipsa aproape
completa a stratificarii corticale,meninge
ingrosat, substanta alba anormala,neuroni
heterotopici, hidrocefalie asociata.
• 3 sd autosomal recesive: in ordinea
crescatoare a severitatii lisencefaliei : Distrofia
musculara congenitala Fukuiama (gena
FCMD), Boala muschi-ochi- creier , sd Walker-
Warburg
Diagnosticul lisencefaliei
• Imagistic- IRM
• Ecografia fetala 32-36 saptamani
• Analiza genetica, determinarea mutatiei
Tulburari de migrare
• POLIMICROGIRIA
• Rezulta in urma unei injurii suferita de sistemul nervos
inaintea lunii a 5-a de gestatie. Creierul are aspectul miezului
de castana si se caracterizeaza prin giratii prea mici si prea
numeroase. Se asociaza heterotopii de substanta cenusie,
anomalii de stratificare corticala. Anomaliile de arhitectonica
cerebrala o diferentiaza de microgirie care este consecinta
leziunilor distructive perinatale. Diagnosticul este RMN.
Localizare: zona operculara si insulara, lobii parietal si
temporal superior.
• Clin: epilepsie , spasticitate, retard mintal
Tulburari de migrare
• Heterotopiile neuronale rezulta dintr-o
tulburare de migrare neuronala inainte de
luna 5 de gestatie, si constau in neuroni care
raman suspendati in coridorul lor migrator
intr-un loc neadecvat.Sunt evidentiabile prin
RMN cerebral
Heterotopii neuronale
Heterotopii neuronale
Schizencefalia
• SCHIZENCEFALIA –tulburare migrare neuronala si organizare corticala ,ce

survine inainte de L5 de sarcina se caracterizeaza prin prezenta de
despicaturi in emisferele cerebrale de la cortex la cavitatea ventriculara,
de obicei simetrice situate in zona fisurilor silviene. Cortexul cerebral
care inconjoara defectul este anormal prezentand arii de polimicrogirie.
• Cauze: vasculare, genetice
• Clinic schizencefalia si polimicrogiria: hemi/tetrapareza spastica, epilepsie,
retard mintal
Displazie corticala
= anomalii focale ale cortexului cerebral
MALFORMATII TARDIVE-nu sunt
malformatii!
• Porencefalia - prezenta unei cavitati chistice rezultata din

distructia cerebrala focala ce evolueaza spre resorbtie tisulara.
De obicei este localizata in teritoriul silvian.
– Porencefalia suflanta (expansiva)
• Hidranencefalia este forma extrema de porencefalie,
distructie cvasi-totala a emisferelor, cortexul este inlocuit cu
membrana gliala.
Diagnostic:
• -Clinic
– - dismorfie craniofaciala cu anomalii de forma a craniului, prezenta crestelor
proeminente la nivelul suturilor, inchiderea prematura a fontanelelor.
– semne oculare: exoftalmie, hipertelorism,strabism, nistagmus, scaderea
acuitatii vizuale, edem papilar sau atrofie optica .
– semne neuropsihice:cefalee localizata sau difuza, varsaturi, instabilitate, deficit
intelectual.
– Semne endocrine: retard staturo –ponderal, sindrom adiposogenital, diabet
insipid, mixedem, acromegalie.
• - radiologic: sinostoza cu hiperostoza, impresiuni digitate ca semne
hipertensiune intracraniana.
• Diagnostic diferential: cu alte dismorfii craniofaciale fara craniostenoza, cu

microcefalia ( antecedente de nastere distocica, tulburari de reflexe si
tonus, craniu mic dar armonios, masiv facial mare, absenta semnelor de
hipertensiune intracraniana).
• Tratament - chirurgical
Craniostenoza coronara stga
CT craniu
De retinut
• Malformatii- depind de momentul producerii
• Genetica!!!
• Clinca- dependenta de structurile afectate
• Imagistica diagnostic ( ante si postnatal)
• -alfafetoproteina
• Tratament simptomatic ±neurochirurgical-
• Profilaxia recurentelor
MANIFESTARI PAROXISTICE
NEEPILEPTICE!
Neurologie Pediatrica
Spitalul Clinic de Psihiatrie “Al. Obregia”
1
n Motivatia acestui subiect:
q foarte multe fenomene paroxistice neepileptice pot

mima crizele epileptice
epilepsie rezistentă – poate diagnosticul e gresit
q la copii>> la adulti
imaturitatea sistemului nervos
q crizele de epilepsie pot fi gresit interpretate ca

fiind neepileptice;
2 2
n DEFINITIE
Fenomenele paroxistice neepileptice sunt:

n manifestări neurologice / vegetative / psihice
n apariţie bruscă,
n tranzitorie,
n de scurtă durată
n cu tendinţă la repetiţie
Este obligatoriu diagnosticul diferenţial cu epilepsia!!
O greseala poate avea implicaţii neplăcute terapeutice, psihologice, sociale

şi de prognostic.
3
n Fenomene paroxistice neepileptice!
1. SINCOPA / SPASMUL HOHOTULUI DE PLANS;

2. TICURI;
3. VERTIJ PAROXISTIC BENIGN; 1. PAVOR NOCTURN;
4. ATACURI DE INFIORARE; 2. SOMNAMBULISM;
5. AUTOGRATIFICARE; 3. COSMAR;
6. SINDROMUL MUNCHAUSEN;
7. PSEUDOCRIZE;
4
FILM (S)
5
SINCOPA
n Definitie: pierderea tranzitorie a constientei si tonusului muscular, legat de

o hipoperfuzie cerebrala tranzitorie;
q pierderea stării de conştienţă survine la aprox 10 sec de la hipoperfuzia sistemului
reticular activator din mezencefal;
Clasificare:
- sincopa vaso-vagala - se produce prin mecanism cardio-inhibitor, mediat
prin nervul vag sau prin mecanism vasodepresor
- sincopa cardiaca - datorata unor evenimente primar cardiace
Cauzele declanşatoare: emotii, stress, frica, ortostatismul prelungit,

atmosfera închisa, dureri minore, vederea de sânge, febra mare;
6
SINCOPA
Clinic:
- prodrom: senzatie de rau, de cap gol, vertij nerotator, vedere
încetosata, palpitatii, jena epigastrica sau toracica = LIPOTIMIE!!
- atacurile se produc în general în ortostatism / sezut;
- caderea este lenta (are timp sa se aseze)
- in atac pacientul este palid, ochii pot fi deviati vertical, pulsul
devine slab
- lipsesc fenomenele postcritice întâlnite în epilepsie (somnul
postcritic)
- durata este scurta (1-2 minute sau mai putin)
- exista cazuri asemanatoare în familie (frecvent)
- daca hipoxia se prelungeste poate sa urmeze un adevarat atac
epileptic.
Prognosticul este în general bun;
7
CARACTERISTICI CARE DIFERENȚIAZĂ SINCOPA DE EPILEPSIE
(dupa Baldy – Moulinier, 1998)
Sincopa vagală Criza epileptică
Poziția Ortostatică Indiferent

Paloare, transpirații + - sau + / _
Debut Progresiv Brutal
Lovire în timpul crizei Rar Frecvent
Pierderi de urină Rar Obișnuit
Pierderea conștienței Secunde Minute
(durata)
Revenirea Rapidă Lentă
Confuzie postcritică Rar Frecvent
Factori precipitanți Întotdeauna (stress, emoție, prize rar
de sânge, lipsa aportului
alimentar, aglomerație,
ortostatism prelungit)
8 Modificări EEG - + 8
FILM (S)
Lipotimie vs sincopa!!
Mecanism??
9
Film 1
10
SPASMUL HOHOTULUI DE PLÂNS
n Vârsta de debut: < 3-5 ani (5% între 6-18 luni); M:F = 3:1
n dispare după 5-6 ani.
n Definitie:
q reprezintă o formă particulară de sincopă reactivă la mânie,
durere, frustrare, frică, traumatisme uşoare care produc plâns şi
sunt întreţinute de anxietatea exagerată a mediului familial.
q frecvent caracter familial –posibil transmit AD, cu penetranță
incompletă
n apare în general la copiii cu constituţie nevropată: instabilitate,

emotivitate, irascibilitate
11 11
§ Clinic:
§ debut cu plâns sau “dă să plângă”
§ fixarea toracelui în apnee
§ cianoză / paloare
§ pierderea conştienţei
§ uneori hipertonie generalizată, cu postură în
opistotonus sau chiar mişcări clonice
§ secundar hipoxiei
§ durata secunde
§ Tratament:
§ nu necesită
§ linistirea părintilor referitor la caracterul benign,
prognosticul cognitiv bun
§ Piracetam 40mg/kg/zi sau tratamentul anemiei feriprive
12 12
DD cu crizele epileptice
n Spasmul hohotului de plâns Crizele epileptice
• declansate de plâns, • spontane

• veghe; -episoade stereotipe; • veghe & somn
• + pc doar a.c -cianoză; • +/- pc
apneea este -opistotonus+/- clonii;
prelungită;
13 13
Film 1 + 2
14
Film (whistler boy)
15
TICURILE
n Definitie:
q Miscări anormale, motorii sau vocale intempestive,
n bruste si rapide,
n recurente,
n neritmice,
n stereotipe.
n Clinic:
q debutul: înainte de 18 ani, cu perioada maximă între 5-7 ani
q emotia, zgomotul, efortul exacerbează ticurile
q pot fi controlate voluntar pentru scurt timp, dar apare o
dorintă imperioasă de a relua ticul
q variază în timp în aspectul clinic
q sunt frecvent familiale
16 16
TICURILE
n Clasificare:
q Ticuri motorii / vocale;
q Ticuri simple / complexe;
q Ticuri
n Tranzitorii: zilnice / nu în fiecare zi, nu > 12 luni;
n Cronice: >de 1 an; nu au perioade fara ticuri > 3 luni
consecutiv;
q boala Gilles de la Tourette (ticuri motorii cronice + tic vocal +

tulburări de comportament cu tendințe obsesionale, conduite
impulsive, coprolalie, acte automutilatorii, stereotipii complexe)
17 17
TICURILE
nEEG – normal;
nEvolutie:
q este în pusee, cu remisiuni variabile
q variabilă, unele ticuri trecând spontan, altele devenind
cronice
nTratament:
q Haloperidol,
q Pimozide (Orap),
q Flunarizin (Sibelium),
q Clonidina,
q Tiapridal,
q Clonazepam,
q Clomipramina (Anafranil),
q Tioridazin.
18 18
TICURILE
n Ticurile Crizele epileptice
• pot fi controlate sau reproduse; • nu pot fi controlate și

• doar în veghe; -Atacuri nici reproduse
• perioade de exacerbări (oboseală, repetitive, • veghe & somn
• emoții) și de remisiune; -bruște; • cu modif EEG
• fără modif EEG
valoare a EEG concomitentă

19 19
VERTIJUL PAROXISTIC BENIGN
n Clinic:
- atacuri de vertij cu durata de 1 - câteva minute

- apar brusc fara un factor precipitant
- vârsta de aparitie este între 2-4 ani sau 7-8 ani
- copilul apare speriat, palid, cu constienta pastrata
- se clatina sau cade în timpul atacului
- se lungeste pe podea refuzând sa se miste sau fuge
spre mama cu privirea înspaimântata strigând: ”se
învârte!”
n copilul de câtiva ani poate sa-si exprime clar senzatia subiectiva

de rotire sau de miscare a obiectelor înconjuratoare
20
VERTIJUL PAROXISTIC BENIGN
n CLINIC:
- nu exista simptome cohleare (acufene sau surditate)

- se poate asocia cu nistagmus sau varsaturi
- examenul neurologic, probele vestibulare, audiograma
sunt normale.
- episoadele se repeta timp de 1-2 ani dupa care se
opresc spontan, fara simptome reziduale
n AHC / APP – migrena

n Nu exista tratament specific;
21
Film 1 + 2
22
ATACURILE DE ÎNFIORARE
n Vârsta de aparitie: 4-6 luni, mai frecvent spre 1 an;
n frison, asemănator cu miscările unui copil dezbrăcat în frig;
n fără pc
n durata scurtă
n precipitate zi de frustrare, furie, teamă
n se pot repeta de peste 100 ori/zi;
n dispar spre vârsta de 6-7 ani;
Pot fi simptome premonitorii ale unui tremor esential;

! Nu necesită tratament;
23 23
ATACURILE DE ÎNFIORARE
n Atacurile de înfiorare Crizele epileptice
*veghe & somn

*din veghe doar;
*+/- modif const
* fără pierderea const; *repetate,
* fără fact decl
* +/- factor decl: *stereotipe;
* modificări EEG
bucurie, micțiune etc; *scurte; *alte fenomene
* EEG concomit normal motorii, vegetative
24 24
n 1
n 2
n 3
n 4
25
COMPORTAMENT GRATIFIANT
masturbație /ipsație
n Vârsta:
q orice vârstă;
q la copilul mic nu este de loc neobișnuită
q frecventă>>la fetite
n Clinic:
q adductie puternică cu încrucisarea membrelor inferioare,
favorizată de decubitul dorsal
q privirea devine fixă
q se asociază congestie, transpirație
q urmate de somn
q copilul protestează dacă este întrerupt
q uneori precipitate de disconfort perineal!
q sunt benigne
q nu necesită tratament
26 26
COMPORTAMENT GRATIFIANT
DD cu crizele epileptice / tulburările de mișcare
n Ipsația Crizele epileptice
• doar din veghe; • veghe&somn

ü atacuri cu manif
• pot fi oprite - protest; • nu pot fi întrerupte
motorii + veg;
• durată lungă, • +/- afect conșt
ü repetitive;
• fără afect conștienței • + modif EEG
ü urmate de somn;
• fără modif EEG
observația directă este obligatorie – filmarea

episoadelor evită investigații & tratamente inutile!
27 27
SINDROMUL MUNCHAUSEN
n - inducerea sau inventarea de către părinţi a unei patologii grave a

copilului care antrenează spitalizări multiple.
- explorările clinice şi paraclinice sunt negative
- mamele au profil psihopatologic particular (hiperprotectoare, cu
cunoştinţe paramedicale) sau în scop utilitar.
28
Film
29
8.) DIAGNOSTICUL DIFERENTIAL INTRE PSEUDOCRIZE SI CRIZELE
EPILEPTICE
Pseudocrize Crize epileptice

Debut De obicei după un episod De obicei fără cauză,
psihotraumatizant, în mod progresiv brutal
(veghe) (somn/veghe)
Conştienţa Pastrata Modificata
Mişcări tonico-clonice Neregulate Stereotipe
Cianoză - +/-
Muşcarea limbii Rar Frecvent
Rezistenţa la deschiderea Da Nu
ochilor şi la mişcări pasive
Pierderea reflexelor - +
Prevenirea traumatismului Da (cade lent, nu se loveşte) Nu (cade brutal, se
poate lovi)
Somnolenţă sau confuzie - +
postcritică
Modificări EEG - +
Demonstrativ
Beneficiu secundar
30 30
Manifestari paroxistice neepileptice
(somn!!)
31
Film 3 (Alfie)
32
n PAVORUL NOCTURN(PN)
Definitie: episoade recurente de treziri bruste, incomplete, produse în

prima treime a somnului, la trecerea de la stadiul 3 la stadiul 4 al somnului
lent, non REM.
- varsta de debut: 18 luni si 5 ani si dispare spontan spre 12 ani.
Aspectul clinic:
- ridicarea brusca a copilului în sezut cu tipat, plâns, agitatie
- ochii sunt deschisi, ficsi sau îngroziti
- copilul se zbate, vorbeste neinteligibil sau pronunta fraze legate de
evenimente traite în cursul zilei
- nu poate fi trezit/ linistit de catre parinti
- copilul este congestionat / palid, transpirat, tahicardic, pupilele sunt
dilatate, prezinta dispnee, tonus muscular crescut, (activarea sistemului
vegetativ)
- durata episodului: 1-10 min., apoi copilul se linisteste brusc, readoarme
- amnezia episodului la trezire
33
n PAVOR NOCTURN
Factori favorizanti:
- evenimentele traumatizante din timpul zilei, emotii
puternice, privarea de somn, oboseala, verminoza
intestinala, vegetatiile adenoide
- copiii instabili, anxiosi
Tratamentul nu este în general necesar. În caz de episoade

frecvente, se pot administra benzodiazepine, hipnotice sau
imipramina seara la culcare (reduc somnul non-REM).
34
Film 4 (doggy)
35
AUTOMATISMUL AMBULATOR NOCTURN
n - 15% dintre copiii între 5 - 12 ani (Aicardi 1994)
- frecventa maxima: 4 - 8 ani, dispare spre 15 ani /persista în viata adulta
- mai frecvent la baieti
- 80% din cazuri au istoric familial pozitiv (transmitere genetica?)
n Clinic:
- episoade repetate de trezire incompleta (constienta de tip crepuscular)
- în prima treime a noptii, în somnul lent profund
- se ridica/ pleaca din pat / activitati motorii complexe (de exemplu urinatul într-un loc
neadecvat, facut baie îmbracat, iesit din casa în pijama pe usa sau pe fereastra)
- activitatea vegetativa poate fi intensa ca si în PN/ se poate asocia
- responsivitatea la încercarile anturajului de a-l trezi este redusa
- readoarme + amnezia episodului
n Factori agravanti: febra, oboseala, evenimentele traumatizante din timpul zilei, unele
medicamente ca antipsihoticele, antidepresive
n Tratamentul: necesar când AAN este frecvent - hipnotic care regleaza somnul
(Nitrazepam, Clobazam).
36
COSMARUL
n Clinic:
- frecventa maxima este între 5-6 ani
- mai frecvent la fete decât la baieti
- 10-50% din copii au avut cel putin o data un cosmar
- se produce spre dimineata, în somnul REM, în care apar visele
- trezire completa, repetata dintr-un vis urât cu continut terifiant
- trezire însotita de frica si anxietate
- greutate în a readormi
- fenomene vegetative cu intensitate moderata, fata de PN
- exista memoria episodului
Factorii declanşatori: experiente neplacute sau terifiante din timpul zilei
Tratamentul nu este în general necesar. În caz de repetare frecventa se poate

administra un anxiolitic de tip diazepam sau nitrazepam si linistirea pacientului.
37
Tulburari de somn
(DD cu crizele epileptice)
Tulb de somn Crize epi
•Pot fi oprite;
•Doar din somn;
•1 episod/noapte, -Episoade scurte; -nu pot fi oprite;
•Nu in fiecare noapte; -Repetate; -veghe+somn;
•Repeta cuvinte legate de -Stereotipe; -mm episoade
evenimentele din timpul zilei /noapte
•EEG-N; -PC; -EEG-aN;
Video-EEG!!
38
TAKE HOME MESSAGE!
Nu orice fenomen cu pierderea constientei / cadere = epilepsie!
n Fenomene paroxistice neepileptice!
1. SINCOPA / SPASMUL HOHOTULUI DE PLANS;

1. PAVOR NOCTURN; 2. TICURI;
3. VERTIJ PAROXISTIC BENIGN;
2. SOMNAMBULISM; 4. ATACURI DE INFIORARE;
3. COSMAR; 5. AUTOGRATIFICARE;
6. SINDROMUL MUNCHAUSEN;
7. PSEUDOCRIZE;
39
PARALIZIA
CEREBRALĂ
Catrinel Iliescu

Sp Pr Dr Al Obregia
Despre ce vorbim ?
 Unele date istorice ...
– 1843 – William Little – primul care a definit paraliziile cerebrale ca

deficite motorii rezultate în urma injuriilor cerebrale ale sugarului,
secundare naşterii premature sau asfixiei la naştere
– 1889 – Osler – “The Cerebral Palsies of children” – propune un sistem
de clasificare bazat pe date anatomice
– 1893 – Sigmund Freud – etiologia pare legată mai mult de evenimente
pre sau postnatale şi nu neapărat de “suferinţa la naştere””
 Definiţia Paraliziei Cerebrale
– 1956, 1964, 1992

– 2005 – se stabilesc definiţia şi clasificarea actuală a PC (Rosenbaum
et al)
Despre ce vorbim ?
 Paralizia cerebrală
– ţările francofone – IMOC – infirmitate motorie de

origine cerebrală
– alţii – encefalopatie cronică infantilă - termen util

pentru demersul diagnostic, însă nespecific
Despre ce vorbim ?
 Paralizia cerebrală = grup de afecţiuni permanente ale
a. Mişcării şi posturii
b. Care sunt atribuite unor anomalii neprogresive ale unui creier în

dezvoltare (cauze pre, peri, sau postnatale - vârsta de 3 ani fiind
actual acceptată ca limită)
c. Tulburările motorii sunt adesea asociate cu alte disfuncţii ale

sistemului nervos central
d. Determină limitare a activităţii
e. Pot apărea probleme secundare ale sistemului musculo – scheletic

DISFUNCŢII ASOCIATE ALE SNC – acestea
depind de mecanismul patogenic şi de extensia
leziunilor cerebrale
 Dificultăţi cognitive = întârziere mintală / dizabilităţi de
învăţare
 Epilepsie
 Dificultăţi de comunicare
 Anomalii senzoriale şi de percepţie – vedere, auz
 Tulburări de comportament
CLASIFICARE – în fcţie de sindr.
neurologic
 PC spastică s. piramidal
 PC diskinetică s. extrapiramidal
 PC ataxică s. cerebelos
 PC mixtă piramidal + extrapiramidal

Clasificare (2000, SCPE)
PC
=anomalii de mişcare şi
postură
SPASTICĂ DISCHINETICĂ ATAXICĂ

mişcări involuntare
tonus crescut, persistenţa reflexelor primitive, pierderea coordonării,
reflexe patologice, tonus muscular tulburări de echilibru
posturi anormale variabil , hipotonie
Distonică
Coreoatetozică
bilaterală unilaterală posturi anormale,
hiperchinezie şi
hipochinezie
hipotonie
hipertonie
Diplegie Hemiplegie Tetraplegie

mai puţin afectate
afectate predominant
ETIOLOGIE – CAUZELE PC
 Vasculare
 Infecţioase
 Anomalii genetice
 Malformaţii cerebrale
 Traumatisme
 Altele: incompatilibilitate Rh mamă - copil

EPIDEMIOLOGIE
 Incidenţa globală : 2-2.5 per 1000 NN vii
– SUA: aprox 10.000 cazuri /an
– România: aprox 400 – 500 cazuri / an (200.000 NN / an)
 2005 – Suedia:
– Hemiplegia spastică - 38%

– Diplegia spastică - 35%
– Tetraplegia spastică - 6%
– PC diskinetică - 15%
– Ataxic ă - 6%
PC – forma spastică unilaterală
(HEMIPAREZA SPASTICĂ)
 Definiţie:
– afectare motorie unilaterală, de cele mai multe ori de tip
spastic, de cauze pre, peri sau postnatale precoce
 Etiopatogenie:
– exemplul tipic - AVC de ACM pre sau perinatală, la nou
născut la termen
 Clinic:
– Sindrom piramidal unilateral
 Debut:
– interval liber până la 4-6 luni - lateralizare precoce la MS
 Sindrom piramidal unilateral (= hemipareză spastică):
– Deficit motor unilateral

– Spasticitate – creştere a tonusului muscular la membrele
afectate
– Postură tipică datorită deficitului + spasticităţii
– ROT mai vii de partea afectată
– R patologice - RCP în extensie
 Asociază – în funcţie de topografia leziunilor:
– hemihipotrofie
– defecte de câmp vizual – hemianopsie omonimă laterală
– epilepsie – crize focale, eventual cu generalizare secundară
– retard mintal
 Hemipareză spastică
stângă
– postură în flexie şi pronaţie
a membrului superior stg,
flexia pumnului
– extensia membrului inferior
stg
 Postura mâinii unui copil cu

hemipareză spastică dreaptă
 AVC ischemic vechi în

teritoriul a. cerebrale
medii stgi (aspect CT)
 Malformaţie complexă de
emisfer cerebral stg la un
copil cu hemipareză
dreaptă congenitală,
retard psihic, şi
cheilognatopalatoschizis
PC – forma spastică bilaterală
(dipareza spastică)
 Definiţie:
– afectare motorie bilaterală, în special la
membrele inferioare, de cele mai multe ori de
tip spastic, de cauze pre, peri sau postnatale
precoce
 Etiopatogenie:
– exemplul tipic – leucomalacia periventriculară
a prematurului
 Clinic:
– Sindrom piramidal bilateral
Clinic (1):
 3 faze ale evoluţiei
– hipotonă – primele luni
– distonică
– spastică
 În final: – s. piramidal bilateral

– mai accentuat la membrele inferioare
– deficit motor + spasticitate
– postură tipică
– mâinile- întotdeauna afectate, uneori uşor
Clinic (2):
 Asociază:
– hipotrofia membrelor inferioare în raport cu cele

superioare şi trunchiul
– strabism convergent bilateral - prin afectarea

radiaţiilor optice
– dizabilităţi de învăţare
– mai rar - retard mintal şi epilepsie – leziunile sunt

profunde, de substanţă albă
Clinic (3):
 Hipertonia membrelor
inferioare, cu flexia şi adducţia
coapselor, gambelor şi postură
în var equin a picioarelor
 Hipertonia membrelor
superioare, cu uşoară flexie,
pumnii strânşi
Clinic (4):
 Hipotonia axială, cu flexia

anterioară a trunchiului
Aspect IRM - frecvent:
 Leucomalacie
periventriculară
– discretă creştere a
dimensiunilor VL
– contur neregulat al VL,
predominant posterior
PC – forma spastică bilaterală
(tetrapareza spastică)
 Definiţie:
– afectare motorie bilaterală, atât a membrelor
superioare cât şi a celor inferioare, de cele
mai multe ori de tip spastic, de cauze pre,
peri sau postnatale precoce
 Etiopatogenie:
– malformaţii cerebrale, infecţii intrauterine
 Clinic:
– Sindrom piramidal bilateral
Clinic:
 Retard marcat neuromotor şi psihic din primele
luni
 Sindrom piramidal bilateral
 Asociază:
– Afectare nervi cranieni, sialoree
– Tulburări senzoriale: de vedere, de auz
– Microcefalie
– Epilepsie
– Întârziere severă
 Afectare motorie şi psihică severă

Aspect neuroimagistic
(CT în exemplul de mai jos):
 Calcificări periventriculare
sugestive pentru infecţie
intrauterină cu
toxoplasmă sau CMV
 Adolescent cu tetrapareză
spastică, microcefalie,
retard psihic sever
PC – forma diskinetică:
 Definiţie:
– Formă clinică dominată de mişcările
+posturile anormale
– Se datorează defectului de coordonare a
mişcărilor şi de reglare a tonusului
 Etiopatogenie:
– exemplele tipice: hiperbilirubinemia neonatală
severă datorată incompatibilităţii de Rh +
asfixia severă la naştere a NN la termen
 Clinic:
– Sindrom extrapiramidal bilateral
Clinic (1):
 Iniţial:
– domină sindromul hipoton
– tendinţă la postură în opistotonus, deschidere
exagerată a gurii
– persistenţa unor r. arhaice – Moro, r. tonic asimetric
al gâtului
 Sindrom extrapiramidal:
– apare după 1-2 ani
– mişcări involuntare: coree, atetoză
– posturi anormale, grimaserii
– tonus muscular fluctuant
Clinic (2):
 Asociază:
– Sialoree
– Tulburări de vorbire
– Mai rar: retard mintal şi epilepsie (leziunile domină în

nucleii bazali)
Clinic (3):
 Posturi distonice
 Grimaserii faciale
PC – forma ataxică:
 Definiţie:
– Formă clinică dominată de tulburări de
coordonare şi mers datorate unui sindrom
cerebelos
 Etiopatogenie:
– Factorii genetici foarte importanţi, afecţiuni
AR
 Clinic:
– Sindrom cerebelos
Clinic:
 Iniţial:
– domină sindromul hipoton
 Sindromul cerebelos:
– apare după 2-3 ani
– ataxie a mersului
– ataxie a membrelor, cu dismetrie, hipermetrie şi
tremor intenţional
– disartrie
 Asociază:
– În funcţie de sindromul genetic – întârziere mintală
sau nu
Exemplificare
 PC-ataxica - mersul.mp4
 PC - ataxica.mp4
Și neuroimagistica..
(IRM în exemplul de mai jos):
 Unica secțiune pe care se

observă bine anomalia –
în cazul acesta (DWI)
 “Semnul măseluței” –
Molar tooth sign
 Sindrom Joubert
Aspect neuroimagistic
(CT în exemplul de mai jos):
 Hipoplazie / agenezie de
vermis cerebelos
 Atrofie a emisferelor
cerebeloase
 Copil cu PC ataxică şi
retard psihic
DIAGNOSTIC:
 Clinic
– Sindrom  localizare topografică  încadrare
etiologică
 Paraclinic
– Imagistică (CT, IRM, ETF) pentru precizarea
leziunilor şi etiologiei
– Altele, în funcţie de situaţie
DIAGNOSTIC DIFERENŢIAL:
 Întotdeauna vom face diferenţierea între o
leziune neprogresivă şi o leziune progresivă,
care trebuie exclusă
 Forme clinice speciale:

– PC diskinetică – tabloul clinic caracteristic
poate apare şi în unele boli metabolice
DIAGNOSTIC DIFERENŢIAL:
 Întotdeauna vom face diferenţierea între o
leziune neprogresivă şi o leziune progresivă,
care trebuie exclusă
 Forme clinice speciale:

– PC diskinetică – tabloul clinic caracteristic
poate apare şi în unele boli metabolice
– PC ataxică – cauzele genetice - AR
– Copil hipoton - de exclus cauzele periferice

TRATAMENT:
 Obiectiv: tratamentul afectării motorii (deficit +
spasticitate) şi anomaliilor asociate
 Afectarea motorie
– Kinetoterapie, terapie ocupaţională
– Orteze, tratament ortopedic, chirugical
– Substanţe: miorelaxante, toxină botulinică
 Celelalte anomalii:
– Epilepsia –tratament cu anticonvulsivante
– Stimulare cognitivă şi senzorială
TRATAMENT:
 Foarte important:
– consilierea familiei
 Foarte important:
– sfatul genetic în cazul formelor ataxice
Malformatii Cerebrale
prezentari de cazuri
Ioana Minciu
Obiective
• Recapitularea unor notiuni prezentate la curs
• Recunoasterea
– Semnelor clinice
– Investigatiilor necesare diagnosticului
– Unor malformatii cerebrale in examenele
imagistice de rezonanta magnetica
Caz 1 –fata
• Fara antecedente heredocolaterale si perinatale
semnificative
• Debut la 8 luni cu manifestari paroxistice

– bruste cu flexia tonica bilaterala a bratelor si membrelor inferioare
– Durata scurta sec
– Repetate , grupaje de 10-20
– Repetare de mai multe ori/zi
– Majoritatea la trezire sau adormire
– Examenul Clinic la 10 luni-intarziere usoara in

dezvoltarea psihomotorie
Ce investigatii ati recomanda?
• EEG
?
Diagnostic clinic ?
• Crize motorii generalizate=spasme epileptice
• Sindrom epileptic ?
SD West
• Etiologie?
- structurala , genetica, metabolica, infectioasa,imuna,
necunoscuta?
Etiologie? Sd West
• EEG – anomalii marcate , traseu amplu

dezorganizat cu unde si varfunda bilateral f
ample, hipsaritmia →
• Copil cu tulburare globala de dezvoltare +
spasme
• IRM la 11 luni
Tratament?
• Vigabatrin,
• ACTH, Prednison
Caz 1 – in evolutie:
Caz 1- evolutie
• In evolutie – de la 2 ani :
– crize la trezire – din sezut cu hipertonie generalizata
de durata lunga,
→ Ulterior crize focale stangi
– “episode foarte discrete” grupate , repetate, legate de
trezire sau adormire
– Recent la 5 ani crize tonico-clonice generalizate
Caz1 - evolutie
Evolutie: la varsta de 5ani
• Epilepsie Farmacorezistenta
– Cu Multiple tipuri de crize majoritatea raman – SPASME
epileptice
– Multe AED incercate in asociere: VPA, LEV, CNZ, NTZ,
corticoterapie
• 20 cz/zi
• Tulburari de comportament
• Intarziere Cognitiva moderata
• Probleme sociale
Alte investigatii?
Test Genetic – mutatie DCX (proteina doublecortin) -Xq23
CAZ 1
DUBLU CORTEX – HETEROTOPIA IN

BANDA SUBCORTICAL
Aceeasi mutatie DCX poate determina si lisencefalie izolata !
Cu tablou clinic de afectare neurologica mai severa !!
Caz 2 – baiat 5 ani
• copil unic.
• Fara istoric semnificativ familial / perinatal
• → Tulburare globala de dezvoltare severa

• Marcata hipotonie
• Debutul crizelor la 8 luni–spasme epileptice

Caz 2 ex paraclinic
• EEG
• IRM cerebral
IRM cerebral la debutul
crizelor
Caz 2 – 5ani evolutie
Evolutie:
– Hipotonie Severa , TGD severa
– Epilepsie farmaco-rezistenta: spasme epileptice
mioclonii, crize tonice.
– AE incercate: VPA, TPM, ACTH, CNZ, LEV cortico,
dieta cetogena, - fara efect
– EEG : anormal , dezorganizat
– Alte investigatii?
Testare Genetica
deletie in exon 1 - gena PAFAH1B1 ( Lis 1)-
codifica prot Lis 1 rol in migrarea neuronala
Caz 2
LISENCEFALIE
LIS 1 – LI, HSB , MD ( DEL 17P13.3))
Caz 3 - baiat 14ani
• Motive internare : Crize epileptice
• Debut la 7 ani: din somn focal – deviere cap dr , apoi
generalizare tonico-clonica
• Antecedente heredocolaterale :
– frate nascut mort; sora cu retard cognitiv
• Al 2 lea copil, sarcina normala , nastere la 42 s

• Nastere prin cezariana pt prezentatie transversa,
APGAR 2, a necesitat O2 in prima saptamana de viata.
Caz 3 – clinic
• TGD →
– Sta in sezut la 32 luni,
– merge la 42 luni,
– Primele cuvinte bisilabice dupa 5ani
• Examenul Clinic Microcefalie, tetrapareza
Spastica cu elemente extrapiramidale ,
neprogresiva = diagnosticata ca paralizie
cerebrala datorata hipoxiei perinatale
Caz 3 – evolutie
Evolution:
• Intarziere cognitiva Moderata, QI 48
• Epilepsie Farmacorezistenta
– Multiple tipuri de crize : focale stangi si generalizate
predominant
– Multiple-AE : VPA, TPM, LEV, NTZ, CBZ, CNZ, LTG,
Cortico
• Perioade scurte (maxim cateva luni) fara crize

Caz 3 – investigatii
• EEG – varfuri focale stanga si / complexe varf-

unda focale
• IRM cerebral la 12 ani
Caz 3 – investigatii
• testare genetica – din lucru

Caz 3
POLIMICROGIRIA +
Caz 4 - adult
• spasme epileptice de la 3 ½ luni (flexie/ extensie
de la 2 ani, asimetrice – Stg>Dr,
• persistente si in prezent!!
• Crize tonice Nocturne de la 4 ani , controlate in

prezent ( sd Lennox Gastaut )
Fara intervale libere de crize in evolutie ,

• Afectare cognitiva severa
• Total dependent , incapabil de autonomie
Genetic testing - ongoing
Caz4
HETEROTOPII
Caz 5 – fata 6ani
Antecedente eredo-colaterale - nesemnificative
Antecedente personale fizologice si patologice

❖ Sarcina cu probleme - placenta groasa ecografic la 4 1/2 luni gestatie,
amniocenteza la 5 luni – normal
❖ Deficit de crestere intrauterina
❖ nascuta la 37s gestatie, G: 2016g
❖ A necesitat incubator dupa nastere
❖ Microcefalie congenitala
❖ screening neonatal pt surditate = modificat
Caz 5 – clinic
• Importanta hipotonie , copil f “moale”
• Hemipareza dreapta congenitala

• Hipotrofie staturala , microcefalie
• Intarziere Globala de dezvoltare : motor ~ 8-9 luni,

cognitiv ~ 12-14 luni
• Crize epileptice Focale– farmacorezistente in evolutie

Caz 5 – investigations
• Ex Lab: uzuale normal
• EEG: descarcari ritmice de scuta durata epileptice,
varfuri in derivatiile F stangi
• IRM…
Caz 5 – imagistica
• IRM cerebraI ~ la 1an : malformatie cerebrala cu a
asimetrie emisferica , stanga<dreapta, plagiocefalie,
polimicrogirie, leziuni de substanta alba predominant pr
dr, chiste temporale, intarziere in mielinizare
• CT: confirma aspect IRM de leziuni hipodense difuze de

substanta alba si absenta calcificarilor!
Etiologie
ETIOLOGY
• GENETICA?
• METABOLICA?
• INFECTIE CONGENITALA CU CMV?
✓Terapie cognitiva & kinetoterapie cu achizitii lente .

✓Absenta regresului
• PCR pt CMV pe DBS neonatal ( din Maternitate) –
pozitiva!! -> infectie congenitala CMV
Caz 5
MALFORMATIE COMPLEXA CEREBRALA

– PAHIGIRIE, POLIMICROGIRIE
ANOMALII DE SUBST ALBA +
Inca UNUL …
?
Caz 6 – baiat, 12 ani
Antecedente personale fiziologice si patologice :
• Sarcina aparent Normala
• Nastere la 38 saptamani de gestatie G 2479g, L =46 cm , PC =29 cm, Apgar
9,
• –pneumonie de aspiratie dupa nastere cu detresa respiratorie ac
• Externat din Maternitate la varsta de 10 zile
• Achizitiile pe etape de varsta :

– Controlul capului achizitionat f tarziu
– Nu a stat in sezut , nu a mers
– Fara achizitii de limbaj expresiv
– intarziere cognitiva severa
• debutul crizelor – la 10 luni , persistente in prezent , farmaco-rezistente
Caz 6
• Ex clinic
• Copil cu hipotonie axiala marcata si
spasticitate distal la membre, elemente
dischinetice
• Microcefalie
• Intarziere profunda in dezvoltarea
psihomotorie pe etape ( VD ~ 4-5 luni)
Epilepsie farmacorezistenta crize cu aspectul
urmator :
Caz 6 -
Caz 6
IRM
De Retinut !
• Malformatiile corticale si tulb de migrare

neuronala = cauza frecventa de epilepsie
refractara la tratament
• Epilepsia –nu e insa patognomonica pt aceasta

etiologie !
• IRM cerebral este primul instrument de orientare
diagnostica si incadrare fenotipica si Genetica
este de obicei necesara dg !
MULTUMESC
REVIEW
CURRENT
OPINION Magnesium sulfate use for fetal neuroprotection
Kathleen F. Brookfield and Abigail Vinson
Purpose of review
The aim of this review is to describe the proposed mechanisms of action of magnesium sulfate for fetal
neuroprotection, different dosing regimens of the drug that have shown benefit, and to review recent
pharmacokinetic studies of the drug to better inform clinicians regarding expected benefits and remaining
research questions.
Recent findings
Retrospective secondary analysis of the beneficial effects of antenatal magnesium sulfate trial database and
prospective pharmacokinetic/pharmacodynamic modeling indicate magnesium sulfate administration for
duration longer than 18 h, given within 12 h of delivery, and maintaining a maternal serum level of
4.1 mg/dl may maximize the neuroprotective benefits of the drug.
Summary
Magnesium sulfate in some dosage given before very preterm pregnancy delivery is beneficial for fetal
neuroprotection. The exact dose, duration, and timing of administration to maximize this benefit may be
more precisely studied using pharmacokinetic/pharmacodynamic modeling techniques before conducting
larger randomized trials.
Keywords
cerebral palsy, fetal neuroprotection, magnesium sulfate, pharmacodynamics, pharmacokinetics
INTRODUCTION decreasing rates of cerebral palsy [7–14]. These dif-

Magnesium sulfate is one of the most commonly fering results, along with a poorly understood mech-
prescribed intravenous medications in contempo- anism of action, have led to several ongoing
rary obstetric practice [1,2]. Magnesium has long questions surrounding magnesium sulfate adminis-
been considered the drug of choice for preventing tration for fetal neuroprotection. The aim of this
seizures in women with preeclampsia, a leading review is to describe the proposed mechanisms of
cause of maternal morbidity and mortality [3,4]. action of magnesium sulfate for fetal neuroprotec-
Several retrospective studies of magnesium use tion, different dosing regimens of the drug that have
in preeclamptic women and women in preterm shown benefit, and to review recent pharmacoki-
labor also suggest that magnesium has a beneficial netic studies of the drug to better inform clinicians
effect for fetal neuroprotection when very preterm regarding expected benefits and remaining
delivery is imminent [5,6]. research questions.
Among women delivering very low-birthweight
infants, Nelson and Grether [5] demonstrated an
MECHANISM OF ACTION
86% risk reduction in cerebral palsy in children
who had been prenatally exposed to magnesium Although the mechanism of action is not well
sulfate compared with unexposed controls. Schen- understood, several theories have been proposed
del et al. [6] also showed infants born to women who and have biologic plausibility. Magnesium sulfate
received magnesium sulfate during pregnancy for
preeclampsia or tocolysis were almost 90% less likely
Department of Obstetrics and Gynecology, Oregon Health and Science
to be born with cerebral palsy compared with those University, Portland, Oregon, USA
born to unexposed women, even after adjustment Correspondence to Kathleen F. Brookfield, MD, PhD, MPH, Department
for gestational age. In contrast to these studies sug- of Obstetrics and Gynecology, Oregon Health and Science University,
gesting a benefit to maternal magnesium sulfate 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
administration when very preterm delivery is immi- Tel: +1 505 346 1191; e-mail: brookfie@ohsu.edu
nent, there are several observational studies that Curr Opin Obstet Gynecol 2019, 31:110–115
have demonstrated no effect of the drug on DOI:10.1097/GCO.0000000000000529
www.co-obgyn.com Volume 31 Number 2 April 2019
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Magnesium sulfate use Brookfield and Vinson
the control group; P ¼ 0.38). The rate of motor dys-

KEY POINTS function, a secondary outcome, was significantly
Administration of magnesium sulfate before very lower in the magnesium group compared with the
preterm delivery has a neuroprotective effect for control group (3.4 vs. 6.6%; P ¼ 0.02). Authors con-
the fetus. cluded that the observed neuroprotective benefit of
magnesium sulfate was smaller than anticipated,
The exact dose, duration, and timing of magnesium
and the study was relatively underpowered to detect
sulfate administration to provide optimal fetal
neuroprotection is unknown; however, 6 g bolus some clinically important differences between the
followed by 2 g/h maintenance dose, 4 g bolus two groups. Of note, approximately 16% of the
followed by 1 g/h maintenance dose, and 4 g bolus women who received magnesium sulfate were
only, have all demonstrated benefit. also preeclamptic.
Further studies using pharmacokinetic and
pharmacodynamic modeling may be effective in
evaluating the optimal antenatal magnesium sulfate
Magnesium sulphate given before very-
regimen for fetal neuroprotection considering important preterm birth (PREMAG) trial
clinical covariates. About 573 women carrying singleton, twin, or triplet
pregnancies and who experienced preterm labor
before 33 weeks’ gestation between July 1997 and
July 2003 were randomized to either placebo (iso-
is an N-methyl-D-aspartate receptor antagonist tonic saline solution) or a 4 g bolus of magnesium
believed to reduce excitotoxic damage after a hyp- sulfate infused over 30 min prior to delivery [23]. Trial
oxic ischemic insult. It also has vasodilatory prop- enrollment was discontinued before reaching the
erties. It has been noted that infants born with projected sample size because of dwindling interest
hypoxic ischemic encephalopathy have low magne- and ability to recruit. The primary outcomes, rate of
sium levels [15]. Magnesium sulfate also limits cal- white matter injury and mortality, were lower for the
cium influx through voltage-gated channels, magnesium sulfate group, but overall not statistically
potentially reducing the activation of apoptosis different between the two groups (white matter
[16]. Its anti-inflammatory properties reduce oxida- injury 10% in the magnesium group vs. 11.7% in
tive stress and the production of pro-inflammatory the control group; P ¼ 0.35). Similarly, there were no
cytokines [17–21]. differences in the incidence of cerebral palsy between
Following publication of observational data sug- the two groups. The authors concluded that the data
gesting a neuroprotective effect of magnesium sul- suggested a neuroprotective effect of magnesium
fate, three large randomized trials of magnesium sulfate, but were not sufficient to support its wide-
administration for fetal neuroprotection have spread use for this indication. Of note, preeclamptic
been conducted. women were excluded from enrollment.
RANDOMIZED TRIALS Beneficial effects of antenatal magnesium

The three most commonly cited prospective ran- sulfate (BEAM)
domized trials of antenatal magnesium sulfate use About 2241 women carrying singleton or twin preg-
for fetal neuroprotection are reviewed in some detail nancies and who experienced preterm labor before 32
below: weeks’ gestation between December 1997 and
May 2004 were randomized to receive placebo or
magnesium sulfate in a 6 g loading dose, followed
Australasian collaborative trial of magnesium by a 2 g/h infusion for 12 h [24]. The primary out-
sulfate (ACTOMgSO4) come, a composite of stillbirth or death by 1 year or
About 1062 women carrying singleton or higher cerebral palsy at 2 years, was not significantly differ-
order pregnancies who experienced preterm labor ent between the two groups. However, moderate or
before 30 weeks’ gestation between February 1996 severe cerebral palsy was significantly reduced in the
and September 2000 were randomized to either magnesium group compared with the control group
placebo (isotonic saline solution) or magnesium (1.9 vs. 3.5%; P ¼ 0.03). Magnesium sulfate was asso-
sulfate in a dose of 4 g loading, followed by a 1 g/ ciated with a slight but nonsignificant increased risk
h infusion for 24 h or until birth [22]. The primary of fetal or infant death compared with the placebo
outcome, incidence of cerebral palsy at 2 years of group. The authors concluded that the study results
age, was not significantly different between the two support those of the previously described trials
groups (6.8% in the magnesium group vs. 8.2% in suggesting a role for magnesium sulfate in fetal
1040-872X Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com 111

Maternal fetal medicine
neuroprotection. Again, preeclamptic women were cohort study performed by McPherson et al. [34]
excluded from enrollment in the beneficial effects attempted to answer the question of what duration
of antenatal magnesium sulfate (BEAM) trial. of magnesium sulfate administration maximizes
neuroprotection in the extremely preterm fetus.
The authors noted decreased rates of cerebral palsy
META-ANALYSIS or death with longer durations of magnesium infu-
Meta-analysis of the previously discussed random- sion; however, the differences were not statistically
ized control trials, in addition to two other trials significant (<12 h ¼ 11.7%, 12–18 h ¼ 10.3%, and
>18 h ¼ 8.8%). Turitz et al. [35 ] utilized the same
&&
whose primary objective did not examine magne-
sium as a neuroprotective agent, found a signifi- dataset to assess if the proximity of magnesium
cantly reduced risk of cerebral palsy in children sulfate exposure to delivery provided a quantifiable
exposed in utero to magnesium sulfate [relative risk risk reduction in cerebral palsy rates. Rates of cere-
(95% CI) ¼ 0.7 (0.55–0.89)] [25–27]. bral palsy were reduced by approximately 60% in
A recent Cochrane Review also concluded there the group of women who received magnesium
is high-quality evidence of magnesium sulfate effec- within 12 h of delivery compared with those who
tiveness for neuroprotection of the fetus when com- last received magnesium at least 12 h before deliv-
pared with placebo [28]. The culmination of this ery; odds ratio (95% CI) ¼ 0.41 (0.18–0.91); P ¼ 0.03.
evidence has led The American College of Obstetri- Notably, no power calculation was done for the
cians and Gynecologists to recommend each insti- McPherson et al. [34] study, which may limit its
tution should develop specific guidelines regarding ability to draw conclusions regarding dose duration
&&
inclusion criteria and treatment regimens for mag- based on the sample size. The Turitz et al. [35 ]
nesium sulfate administration when delivery is study is limited by differences between the exposure
anticipated before 32 weeks’ gestation [27–29]. duration groups at baseline, including gestational
age, which is an independent risk factor for cerebral
palsy. The decrease in cerebral palsy rates was not
WHY DOES THE DOSE AND DURATION OF seen when time from last magnesium sulfate admin-
ADMINISTRATION MATTER? istration was analyzed as a continuous variable.
More than 77% of expectant mothers experience Recent literature has also suggested that perhaps
side-effects related to antenatal magnesium admin- adopting a more simplified dosing regimen (i.e.,
istration [24]. Magnesium may also negatively the bolus utilized in PREMAG compared with regi-
impact obstetric outcomes and lead to adverse neo- mens that include a maintenance dose) could
natal effects [1,3,30–32]. Current intravenous mag- enhance uptake of the intervention with no signifi-
&
nesium treatment for various indications cant impact on cerebral palsy rates [36 ,37]. These
(preeclampsia, tocolysis, and neuroprotection) fol- factors point to the problems of using retrospective
lows standardized protocols (4–6 g loading dose analysis to answer questions of dose, duration of
followed by an infusion at 1–2 g/h) based on insti- dose, and area under the curve, and we continue to
tution preference. These protocols proposed by be left with unanswered questions of how much
Pritchard [33] in 1979 were derived clinically to magnesium is needed, how long should it be admin-
provide estimated serum magnesium levels neces- istered, and how close to our endpoint of delivery
sary to treat eclamptic seizures. These standardized does it need to be administered.
protocols are administered unaltered to all patients, To further complicate matters, the desired effect
without adjustment for maternal or fetal factors that of all drugs, including magnesium sulfate, may be
may affect serum magnesium levels. Whenever pos- altered by maternal, fetal, or placental character-
sible, magnesium sulfate administration should istics. So far, attempts to assess these factors through
optimize maternal and fetal outcomes, while pre- retrospective means have not yielded findings lead-
venting maternal and neonatal morbidity associ- ing to recommendations for tailored dosing in cer-
ated with current magnesium treatment protocols. tain patients, that is, obese women. The concept has
been tested before in preeclamptic women receiving
magnesium sulfate with the conclusion that to
PHARMACOKINETIC STUDIES reach goal therapeutic serum magnesium levels,
Despite the knowledge that magnesium sulfate pro- higher doses of magnesium must be administered
vides fetal neuroprotective benefits, the optimal in the obese patient [38]. McPherson et al. [39]
dose and duration remain unknown. Much of the found that morbidly obese women (BMI 40)
recent data regarding dosing of magnesium sulfate who participated in the BEAM trial had higher rates
use for neuroprotection are based on retrospective of cerebral palsy or death after 28 weeks’ gestation;
analyses of the BEAM dataset [24]. A retrospective however, case numbers were small, limiting the
112 www.co-obgyn.com Volume 31 Number 2 April 2019

generalizability of the results to make future dosing model for nonpreeclamptic women was applied to
recommendations. In a secondary analysis of the the BEAM database in an effort to predict the mater-
&
BEAM trial, Vilchez et al. [40 ] also demonstrated nal serum level of magnesium at delivery in women
decreased neuroprotective efficacy of magnesium who delivered an infant with or without cerebral
sulfate in obese women (BMI 30). palsy [42]. In addition to determining this serum
There is no known ‘therapeutic’ level of level, total dose, dose duration, and area under the
maternal serum magnesium for neuroprotection curve were also assessed for their ability to predict
that can be easily assessed with such a retrospective cerebral palsy as an outcome. In support of the
study. previous retrospective studies, the application of a
The limitations of these studies and remaining pharmacokinetic model to the BEAM database sug-
research questions lead to a discussion of novel gested relatively high total doses (>60 g) and longer
approaches to study magnesium sulfate dosing. dose duration maximized cerebral palsy risk reduc-
Pharmacokinetic modeling and simulation is a pow- tion. The maternal serum magnesium level at the
erful approach to quantitatively assess whether time of delivery which minimized cerebral palsy was
alternative dosing regimens may achieve clinical 4.1 mg/dl 95% CI, 3.7–4.4. This level is notably
goals. Although not cited frequently in the medical achievable around the time of delivery with very
literature, there are studies utilizing this approach to different loading and maintenance dose combina-
clinically inform dosing of magnesium sulfate in tions, which could conceivably be tailored to fit a
&
pregnancy [41 ,42–44]. given clinical situation (i.e., need for immediate
The largest prospective pharmacokinetic study cesarean delivery vs. laboring patient).
of magnesium sulfate conducted in pregnant The major limitation of the application of this
women included 19 nonpreeclamptic women with model to the BEAM data include a lack of absolute
multiple serum magnesium levels who received the start and stop times for magnesium sulfate and
&
drug [41 ]. The overall model found the indication several assumptions surrounding magnesium sul-
for receiving magnesium (preeclampsia vs. nonpree- fate administration based on the published protocol
clampsia, i.e., neuroprotection group) as well as [24].
maternal body weight at the time of magnesium
administration, impacted the clearance and volume
of distribution of the drug (Fig. 1). After identifying FUTURE RESEARCH
these covariates as important factors in determining In addition to further elucidating the exact mecha-
serum magnesium levels, the pharmacokinetic nism of how magnesium sulfate works to protect the
FIGURE 1. Simulation of 4 g loading dose of magnesium sulfate, followed by 2 g/h infusion among pregnant women with
and without preeclampsia and women of lowest (55 kg), mean (88 kg), and highest (157 kg) body weights in our sample.
Adapted with permission from [41 ]. &

Maternal fetal medicine
brain of the extremely preterm fetus, several ques- Acknowledgements

tions of importance to the clinician remain. None.
(1) What is the optimal dosing regimen, timing of Financial support and sponsorship
administration, and target magnesium level This work was supported by the Department of Obstetrics
needed to maximize fetal neuroprotection and and Gynecology, Oregon Health and Science University,
minimize unwanted side-effects of the drug? Portland, Oregon, USA.
(2) Which maternal, fetal, or placental factors, if
any, alter clinical outcomes for a given Conflicts of interest
dosing regimen?
There are no conflicts of interest.
(3) Can the desired cerebral palsy risk reduction be
achieved through postnatal administration of
magnesium sulfate?
REFERENCES AND RECOMMENDED
READING
Answers to the first two questions can realistically Papers of particular interest, published within the annual period of review, have
be found with additional application of pharmacoki- been highlighted as:
& of special interest
netic modeling to existing databases with dosing/ && of outstanding interest
timing information and maternal baseline character-

1. Pryde PG, Mittendorf R. Contemporary usage of obstetric magnesium sulfate:
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many details of the australasian collaborative trial of 114:669–673.
2. Fox NS, Gelber SE, Kalish RB, Chasen ST. Contemporary practice patterns
magnesium sulfate (ACTOMgSO4), PREMAG, BEAM, and beliefs regarding tocolysis among U.S. Maternal-fetal medicine specia-
Magpie studies [45], so on may not be available lists. Obstet Gynecol 2008; 112:42–47.
3. Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate
publicly, future research collaborations should be and other anticonvulsants for women with preeclampsia. Cochrane Database
encouraged that would allow for pharmacodynamic Syst Rev 2010; CD000025.
4. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus pheny-
modeling of these data. toin for eclampsia. Cochrane Database Syst Rev 2010; CD000128.
Answering the third question may rely on the 5. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral
palsy in very low birthweight infants? Pediatrics 1995; 95:263–269.
construction of a new pharmacokinetic/pharmacody- 6. Schendel DE, Berg CJ, Yeargin-Allsopp M, et al. Prenatal magnesium sulfate
namic model specific to the neonatal period. Several exposure and the risk for cerebral palsy or mental retardation among very low-
birth-weight children aged 3 to 5 years. JAMA 1996; 276:1805–1810.
randomized controlled trials have shown improve- 7. Chollat C, Sentilhes L, Marret S. Fetal neuroprotection by magnesium sulfate:
ment in short-term outcomes for neonates with hyp- from translational research to clinical application. Front Neurol 2018; 9:247.
8. Paneth N, Jetton J, Pinto-Martin J, Susser M. Magnesium sulfate in labor and
oxic–ischemic encephalopathy following treatment risk of neonatal brain lesions and cerebral palsy in low birth weight infants. The
with magnesium; however, this has not been Neonatal Brain Hemorrhage Study Analysis Group. Pediatrics 1997; 99:E1.
9. Leviton A, Paneth N, Susser M, et al. Maternal receipt of magnesium sulfate
extended to very preterm neonates [46]. These data does not seem to reduce the risk of neonatal white matter damage. Pediatrics
could be use to generate neonatal pharmacokinetic/ 1997; 99:E2.
10. O’Shea TM, Klinepeter KL, Meis PJ, Dillard RG. Intrauterine infection and the
pharmacodynamic models predicting neuroprotec- risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epide-
tive benefit from specific magnesium regimens. miol 1998; 12:72–83.
11. Canterino JC, Verma UL, Visintainer PF, et al. Maternal magnesium sulfate and
the development of neonatal periventricular leucomalacia and intraventricular
hemorrhage. Obstet Gynecol 1999; 93:396–402.
CONCLUSION 12. Boyle CA, Yeargin-Allsopp M, Schendel DE, et al. Tocolytic magnesium
sulfate exposure and risk of cerebral palsy among children with birth weights
The administration of magnesium sulfate before very less than 1,750 grams. Am J Epidemiol 2000; 152:120–124.
13. Elimian A, Verma R, Ogburn P, et al. Magnesium sulfate and neonatal outcomes
preterm delivery decreases rates of cerebral palsy. A of preterm neonates. J Matern Fetal Neonatal Med 2002; 12:118–122.
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DEZVOLTAREA PSIHOMOTORIE

Clinica Neurologie Pediatrică

 evaluării NN la ieşirea din maternitate

 urmăririi periodice a dezvoltării neuro-motorii şi

 depistarea sugarilor sau copiilor cu posibile tulburări

 îndrumare către serviciile de specialitate, pentru

 Metodele pot fi diferite – depind de vârstă și de

 >= 3 ani vârstă a dezvoltării – “clasic”:

 Dezvoltarea motorie (DM)

 Dezvoltarea psihică (DP)

 Probleme care pot influenţa evaluarea

 Dezvoltarea motorie (DM)

 Dezvoltarea psihică (DP)

 DM – evoluţie cefalo-caudală şi proximo-

- Controlul mâinilor: 4 - 10 luni

- Controlul poziţiei şezânde: 6 - 10 luni

- Controlul mersului: 12 - 16 luni

SE ACHIZIŢIONEAZĂ PIERZÂND REFLEXELE

developmental reflexes - YouTube [360p].mp4

1. Reflexul Moro (<L6)

2. Reflexul de supt (<L12)/fixare pentru supt (<L3)/punctelor cardinale (<L3)

3. Reflexul mersului automat (<L2)

4. Reflexele tonice ale gâtului (<L6, intensitate maximă la 2 luni)

5. Reflexul de sprijin şi de depăşire a obstacolului (<L4)

6. Grasping palmar (<L4)

7. Grasping plantar (<L9)

8. Reflexul Galant (< L9)

9. Reflexul Landau (L6 – L24)

10. Reflexul paraşutei (>L7- L8)

 Răspuns normal (<L3)

 Reacţia la tracţiune (DD  şezut)

II. Reacţia la tracţiune

III. Suspendarea verticală

IV. Suspendarea ventrală

 Hipertonia scade, membrele se extind

 Capul pe linie mediană (3L), ridicarea acestuia de la

 Mâinile pe linia mediană (4L)

 Se întoarce de pe burtă pe spate sau de pe spate pe

- 1L -3L capul este balant,

- 3L-6L capul este în acelaşi plan cu corpul,

- 6L - stă singur în şezut cu sprijin pe

- 7L-8L - stă în şezut fără sprijin

- 9L-10L – (se ridică din DD în şezut), se

- 7L-8L – îşi susţine greutatea dacă

- 9L – se ridică la marginea patului

- 10L– 11L– merge pe lângă mobilă sau

- 11L– 12L – merge cu sprijin unilateral

- 12L– 13L– merge singur

IV. Suspendarea ventrală

- 2L – capul deasupra planului

- 7L-9L – reflexul paraşutei

1L – îşi ridică capul de la planul

3L – capul ridicat, sprijin pe

5L-6L – capul şi trunchiul

5L-7L – se răsuceşte de pe burtă

8L-9L – merge de-a buşilea

 Dezvoltarea motorie (DM)

 Dezvoltarea psihică (DP)

 Pensa cubito-palmară (L4-L5) /

 Pensa digito-palmară (pensa

 Pensa radio-palmară (L7-L8)

 Pensa digito-digitală (bidigitală)

 Dezvoltarea motorie (DM)

 Dezvoltarea psihică (DP)