Bolile neurodegenerative

Degenerare

?
declin inexplicabil de la un nivel
anterior considerat a fi normal la
un nivel inferior din punct de
vedere al functiei

Neuron normal Neuroni in una din bolile

degenerative
Proces degenerativ
Termen clinic si patologic care se refera la:
Pierdere/ Distrugere progresiva de neuroni, mielina si tesut nervos
Produsii astfel rezultati provoaca o reactie de fagocitoza si astroglioza

O caracteristica a multor bolilor degenerative este afectarea anumitor celule

si sisteme inrudite din punct de vedere functional:
Cortex cerebral
Sistem motor
Sistem extrapiramidal
Cerebel
 Boli cronice cu debut insidios si evolutie progresiva
( fata de tulburarile de dezvoltare ale SN)
( rar, debut clinic aparent brusc, precipitat de un episod patologic acut inflamator, vascular)
Pierderea progresiva a functiei si structurii sistemelor neuronale din SNC si/ sau
SNP (alterare functionala, urmata de moartea neuronala ) care anterior au atins un nivel
normal de dezvoltare (!)
( fata de bolile neurochimice / tulburarile de dezvoltare ale SN/ bolile metabolice ereditare
Conditii ereditare cunoscute ( transmitere mendeliana ) sau sporadice
Cele mai multe b. neurodegenerative: heterogene etiologic
(determinismul genetic nesuperpozabil expresiei fenotipice clinice )

Nu exista o clasificare ideala: manifestari clinice superpozabile
- spectru larg si continuu de manifestari clinice >> entitati bine delimitate

Afectarea sistemelor neuronale:
concomitent sau succesiv
Mecanisme generale ale neurodegenerarii
1. MECANISME GENETICE
mutatii localizate pe o gena, fara o relatie evidenta patogenica cu fenotipul clinic
o ex. repetitii de triplete nucleotidice: CAG ( poliQ 9 boli diferite ), GAA, s.a.
o mutatii ale unor proteine necesare functiei mitocondriale
o mutatii ale unui singur codon ( alt aa. in structura polipeptidica )
o mutatii ale unor proteine necesare functiei ARN ( ex. TDP-43, FUS )
o mutatii ale unor enzime necesare in procesarea proteinelor normale
unele forme familiale de b. Alzheimer ( -secretaza, -secretaza )
enzime din sistemul proteazomilor
o mutatii in introni dereglarea expresiei cantitative sau lungimii polipeptidice a unor
proteine ( ex. frataxine, SMA, s.a. )

mutatii genice insuficiente pentru a genera boala + factori de risc

( de obicei formele sporadice de boli neurodegenerative )
o mecanisme intracelulare intricate
Mecanisme generale ale neurodegenerarii
2. MECANISME INTRACELULARE
De regula consecinta anomaliilor induse de modificarile genetice
Modificari ale cailor de degradare a proteinelor
sistemul proteazomilor ( UPS = "ubiquitin proteasome system" )

agregare de proteine care perturba functiile celulare

Moartea celulara programata

APOPTOZA NECROZA

indusa intrinsec sau extrinsic

(Apoptoza induce un fenomen de imunosupresie locala;
Necroza induce fenomen inflamator local)

AUTOFAGIA
situatie particulara: MITOFAGIA ( AUTOFAGIA MITOCONDRIALA )
Mechanisms of neurodegeneration
Genetic mechanisms
Thousands of gene mutations

Intracellular mechanisms
Usually are the consequence of the abnormalities induced by gene mutations
Specific for each disease, not completely elucidated
Common finding for many ND disorders: accumulation of insoluble protein aggregates
major histopathologic hallmark
protein aggregates contribute to neuronal death or they are merely secondary
bystanders ?
the inability to degrade protein aggregates could lead to cellular dysfunction, impaired
axonal transport and cell death by apoptotic mechanisms

Final pathway mechanism through which neurodegeneration occurs: apoptosis, necrosis,

excitotoxicity
Taylor JP, Hardy J, Fischbeck KH. (2002) Science
Aggregation of misfolded proteins in microscopically visible inclusions or plaques in various
neurodegenerative diseases
(A) Alzheimer's disease. Arrowhead, intracellular neurofibrillary tangles; arrow, extracellular amyloid plaque. (B) Fibrillar tau
inclusions in Pick's disease. (C) PrPSc amyloid deposition in prion disease. (D) Multiple Lewy bodies in a nigral neuron in
Parkinson's disease. (E) Neuronal intranuclear inclusions of mutant ataxin-3 in Machado-Joseph's disease. (F) Higher power
micrograph of nuclear inclusion of mutant ataxin-3, demonstrating that it is distinct from the nucleolus. Magnification, 40.

Toxic Proteins in Neurodegenerative Disease, JP Taylor et al., Science, 296, 1991-1995, 2002
MECANISMELE INTRACELULARE
DE TRAFIC AL PROTEINELOR

Macario AJL et al NEJM 2005; 353 (14):1489-1501

 Mecanismele mortii
celulare

Hotchkiss RS et al NEJM 2009; 361(16):1570-1583

 Mecanismele mortii celulare prin apoptoza

Hotchkiss RS et al NEJM 2009; 361(16):1570-1583

Mecanismele mortii celulare prin apoptoza

Hotchkiss RS et al NEJM 2009; 361(16):1570-1583

Friedlander RM NEJM 2003; 348 (14 ):1365-1375
Diferente:
1.Apoptoza afectea in general celule individuale in timp ce necroza afecteaza
grupuri de celule sau tesuturi.
2.In timpul necrozei nu exista activitate genica si majoritatea sistemelor
enzimatice intracelulare sunt inactivate.
3.In timpul apoptozei exista activitate secventiala, controlata genic, a diferitelor
sisteme enzimatice.
4.In timpul necrozei celule se balonizeaza (oncosis)
5.In timpul apopotozei citoplasma si nulcul formeaza corpi apoptotici
6.Necroza presupune un raspuns inflamator si fagocitarea mediata de granulocite.
7.Corpii apoptotici sunt fagocitati de fagocite neprofesionale: celule vecine +
macrofage.
Clasificarea clinica a bolilor neurodegenerative
( modificata dupa Adams and Victor's Principles of Neurology, 10-th ed., 2014 )

1. Boli cu sd. demential progresiv, fara alte semne neurologice evidente

2. Boli cu sd. demential progresiv asociat cu alte anomalii neurologice

3. Boli cu tulburari de postura si de miscare

4. Boli cu ataxie progresiva

5. Boli cu deficit motor si atrofii musculare progresive

6. Boli cu neuropatii senzitive si senzitivo-motorii

7. Boli cu cecitate progresiva sau oftalmoplegie, cu sau fara alte anomalii neurologice

8. Boli degenerative cu surditate neurosenzoriala

 Boli cu sd. demential progresiv, fara alte semne. 1
neurologice evidente

A. Cu atrofie cerebrala difuza

Boala Alzheimer
Atrofii cerebrale difuze non-Alzheimer
Boala difuza cu corpi Lewy

B. Atrofie cerebrala circumscrisa

Degenerescente fronto-temporale ( DFT )
Afaziile primare progresive
DFT comportamentala ( "b. Pick" )
2. Boli cu sd. demential progresiv asociat cu alte anomalii
neurologice
A. Boala Huntington
B. Boala difuza cu corpi Lewy
C. Boala Parkinson in stadii tardive ( unele cazuri )
D. Degenerescenta cortico-bazala
E. Degenerescenta cortico-strio-spinala
F. Complexul Guam ( Parkinson-SLA-dementa )
G. Degenerescenta cerebelo-cerebeloasa
H. Dementa familiala cu parapareza spastica, amiotrofie sau mioclonus
I. Boala cu corpi de poliglucosan
J. Dementele fronto - temporale cu parkinsonism sau SLA
forme de degenerescenta cortico-bazala
forme de paralizie supranucleara progresiva
 3. Boli cu tulburari de postura si de miscare
A. Boala Parkinson
B. Atrofia multi-sistem
C. Paralizia supranucleara progresiva ( PSP )
D. Boala Huntington
E. Achantocitoza cu miscari involuntare ( coree, distonie )
F. Degenerescenta cortico-bazala
G. Boala difuza cu corpi Lewy
H. Tremorul esential
I. Boala Gilles de la Tourette
 4. Boli cu ataxie progresiva

A. Ataxiile spino-cerebeloase ( cu debut precoce )

Boala Friedreich
Ataxia cu debut precoce non-Friedreich

B. Ataxiile cerebeloase corticale

Atrofia olivo-cerebeloasa pura familiala ( Holmes )
Ataxiile cerebeloase cu debut tardiv

C. Boli ereditare complexe cu ataxie cerebeloasa sporadica (ataxie cu debut

tardiv cu anomalii de trunchi cerebral si alte anomalii neurologice)
5. Boli cu deficit motor si atrofii musculare progresive
A. Tulburari motorii cu amiotrofie
Scleroza laterala amiotrofica ( Boala neuronului motor, Boala Charcot,
Boala Lou-Gehring )
Boala neuronului motor si DFT
Atrofiile musculare spinale progresive
Paralizia bulbara progresiva
Sd. Kennedy & alte forme ereditare de atrofie musculara progresiva si paraplegie
spastica

B. Paraplegie spastica fara amiotrofie

Scleroza laterala primara
Paraplegia spastica familiala ( Strmpell-Lorrain )
6. Boli cu neuropatii senzitive si senzitivo-motorii
A. Neuropatiile senzitivo-motorii ereditare ( HSMN )
B. Neuropatii pur/ predominant senzitive sau motorii
C. Degenerescenta vegetativa Riley-Day

7. Boli cu cecitate progresiva sau oftalmoplegie, cu sau fara alte anomalii neurologice
A. Degenerescenta retiniana pigmentara ( retinitis pigmentosa )
B. Boala Stargardt
C. Boli mitocondriale
Oftalmoplegia externa progresiva cu/ fara surditatesau alte atrofii de sisteme ( sd.
Kearns-Sayre )
Neuropatia optica ereditara Leber
Encefalopatia necrozanta Leigh

8. Boli cu surditate neurosenzoriala degenerativa progresiva

A. Surditatea neurosenzitiva pura
B. Hipoacuzia ereditara asociata cu boli ale retinei
C. Hipoacuzia ereditara cu atrofii de sisteme ale sistemului nervos
 ATAXIILE PROGRESIVE
sindroame cronice progresive: de obicei boli neurodegenerative
izolate
asociate cu alte sindroame / semne neurologice

genetica moleculara clasificari neoperationale clinic !

ataxiile mostenite cu debut precoce ( < 20 ani ) recesive ( nu toate ! )
ataxiile mostenite cu debut tardiv ( > 20 ani ) dominante ( nu toate ! )
NU toate ataxiile progresive
sunt familiale
au un defect genetic cunoscut

ATAXIILE
SPINOCEREBELOASE
CLASIFICARE CLINICA: ATAXIILE CEREBELOASE PURE

ATAXIILE CEREBELOASE COMPLICATE

 ATAXIILE PROGRESIVE

ATAXIILE SPINOCEREBELOASE ( SCA ) EREDITARE

- peste 30 de variante genetice cunoscute
- frecvent: ataxii complicate cu alte sd. neurologice

BOALA (ATAXIA) FRIEDREICH

- predominent spinala
- cca. 50% dintre toate ataxiile ereditare
- diferentiata initial de ataxia luetica ( tabesul dorsal )
- gena mutanta: pe chr. 9q13-2
 SYNDROME OF PROGRESSIVE ATAXIA

Which lesion localizations in the nervous system can lead to ataxia?

Parietal lobe, thalamus (very rarely)

Cerebellum
Brain stem
Spinal cord
Peripheral nerves
 BOALA (ATAXIA) FRIEDREICH
- Boala autosomal recesiva; gena mutanta este localizata pe cromozomul 9 (9q13-2)
* expansiune a trinucleotidului GAA / mutatie non-sense intr-un intron
al genei pt. FRATAXINA ( proteina din matricea mitocondriala: pare sa previna
supraincarcarea cu Fe )
* expansiunea GAA altereaza expresia acestei gene pierderea totala/ partiala a functiei biologice
normale a frataxinei
* Cu cat este mai mare numarul de repetitii CAG cu atat mai severa va fi alterarea fctiei frataxinei
* nr mai mare de repetitii CAG varsta mai mica de debut al bolii, t pana la pierderea ambulatiei
- Descrisa prima data de Nikolaus Friedreich in anul 1863 si prima forma de ataxie diferentiata de ataxia
luetica (tabesul dorsal)
- Cea mai frecventa dintre ataxiile autozomal recesive; cca. 50% dintre toate ataxiile ereditare
 BOALA (ATAXIA) FRIEDREICH

Cells and tissues of the body are differentially sensitive to frataxin

deficiency. Cells normally requiring and producing greater
amounts of frataxin tend to be most affected by FA.
For example, sensory neurons in the dorsal root ganglion responsible for
position sense highly express the frataxin gene and are affected greatly in
FrdA.
Myocardial muscle fiber also requires comparably larger amounts of
frataxin than other tissues and is affected markedly in FrdA.
 BOALA (ATAXIA) FRIEDREICH
The major pathophysiologic finding in Friedreich ataxia is a "dying back
phenomena" of axons, beginning in the periphery with ultimate loss of
neurons and a secondary gliosis.
The primary sites of these changes are the spinal cord and spinal roots.
this results in loss of large myelinated axons in peripheral nerves, which increases
with age and disease duration. Unmyelinated fibers in sensory roots and
peripheral sensory nerves are spared.
The posterior columns and corticospinal, ventral and lateral spinocerebellar
tracts all show demyelination and depletion of large myelinated nerve fibers
to differing extents. This is accompanied by a fibrous gliosis that does not
replace the bulk of the lost fibers.
Overall, the spinal cord becomes thin and the anteroposterior (AP) and
transverse diameters of the thoracic cord are reduced.
 BOALA (ATAXIA) FRIEDREICH
The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons
associated with proliferation of capsular cells.
The posterior column degeneration accounts for the loss of position and vibration
senses and the sensory ataxia.
The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes.
The dentate nuclei exhibit mild to moderate neuronal loss and the middle and
superior cerebellar peduncles are reduced in size.
The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar
tracts, dentate nucleus, superior vermis, and dentatorubral pathways.
The corticospinal tracts are relatively spared down to the level of the
cervicomedullary junction. Beyond this point, the corticospinal tracts are severely
degenerated, which becomes progressively more severe moving down the spinal
cord. This explains the common finding of bilateral extensor plantar responses and
weakness late in the disease.
 BOALA (ATAXIA) FRIEDREICH

Myocardial muscle fibers also show degeneration and are replaced by macrophages
and fibroblasts. Essentially, chronic interstitial myocarditis occurs with hypertrophy
of cardiac muscle fibers; fibers become hypertrophied and lose their striations. This
is followed by swelling and vacuolation and finally interstitial fibrosis. The nuclei
appear hyperchromatic and occasionally vacuolated. The cytoplasm appears
granular with frequent lipofuscin depositions.
Kyphoscoliosis is likely; it is secondary to spinal muscular imbalance.
 BOALA (ATAXIA) FRIEDREICH

Spinal cord - thin

Posterior columns and spinocerebellar tracts few fibers/gliosis
Reduced neuronal number in sensory ganglions
Degeneration of dentate nuclei + and reduced Purkinje cells number
Degeneration of myocardiocites
Minor degeneration of cortico-spinal tract
 ATAXIA FRIEDREICH Manifestari clinice
Varsta de debut de obicei adolescent, dar boala poate debuta oricand intre 2-
70 ani
Manifestarile clinice majore ale Ataxiei Friedreich sunt:
Manifestarile neurologice
Cardiomiopatie
Diabet zaharat
Data fiind natura progresiva a bolii, tabloul clinic devine de obicei complet numai
dupa cativa ani de la debut
BOALA (ATAXIA) FRIEDREICH
MANIFESTARI CLINICE ( ataxie cerebeloasa + spinala)
- ataxia mersului, astazo-abazie, alergatul dificil
- inabilitatea mainilor: dupa luni / ani de la aparitia tulburarilor de mers
- dizartrie cerebeloasa: dupa ataxia mb. superioare
- RAR: debut brusc, asimetric, dupa o boala febrila
- ROT abolite precoce, r. Babinski prezent
- pierderea precoce a sensibilitatii proprioceptive
- Proba Romberg (+) nesistematizat
- uneori nistagmus predominent orizontal
- amiotrofii, de regula moderate in stadiile tardive ( asociaza neuropatie )
- uneori: tulb. de vedere, de auz
- TRASATURI CLINICE ASOCIATE
* cifoscolioza
* pes cavus de obicei inaintea manifestarilor neurologice
* degete "in ciocan"
* CARDIOMIOPATIE asociata in >50% cazuri

deces prin aritmie cardiaca sau insuficienta cardiaca
- agravare prin insuficienta respiratorie ( cifoscolioza )
* cca. 10% dezvolta DIABET ZAHARAT
* cca. 10% au doar TOLERANTA ALTERATA LA GLUCOZA
PES CAVUS DEGETE "IN CIOCAN"
 FRIEDREICH ATAXIA Ancillary investigations
The diagnosis of Friedreich ataxia is based upon clinical findings but should be confirmed by
genetic testing.
Neuroimaging of the brain and spinal cord with MRI is recommended for all patients
presenting with ataxia to exclude other causes (eg, tumor, infarction, hemorrhage) and to evaluate for
cerebellar atrophy.
MRI of the brain and spinal cord in patients with FA consistently shows atrophy of the cervical spinal cord with
minimal evidence of cerebellar atrophy
The absence of cerebellar atrophy on brain MRI is supportive of the diagnosis of Friedreich ataxia. The presence
of significant cerebellar atrophy suggests alternative forms of hereditary ataxia other than Friedreich ataxia
Genetic testing for GAA repeat expansions in the frataxin gene should be performed in all patients
with progressive cerebellar ataxia and autosomal recessive inheritance.
Electrocardiographic and echocardiographic abnormalities indicative of cardiac involvement
are supportive features.
Evidence of a sensory axonal neuropathy on electrodiagnostic testing is a supportive feature
A report of 115 patients from 90 families established the main clinical criteria for Friedreich ataxia,
which were autosomal recessive inheritance, onset before age 25 years, ataxia of all four
limbs, absence of lower limb reflexes, and presence of pyramidal signs!
FA
 FRIEDREICH ATAXIA Management
There is no specific disease-modifying therapy for Friedreich ataxia
The management often requires a team of special services that includes neurology,
physical medicine, cardiology, orthopedics, endocrinology, and speech therapy.
A physical therapy program should be initiated early and modified over time to
address the progressive loss of balance and fine motor control; adaptive devices to
assist in ambulation and activities of daily living eventually will be needed.
Yearly cardiac evaluation for evidence of arrhythmia and cardiomyopathy is
required. Although there is no specific treatment for Friedreich ataxia-related
cardiomyopathy, conventional drugs and device implantation can be used to
manage heart failure and arrhythmia
Swallowing should be evaluated at baseline and as needed thereafter depending
upon symptoms, with speech and swallowing therapy for patients with dysphagia
Scoliosis screening is recommended annually, followed by orthopedic referral for
those with musculoskeletal abnormalities
Patients should be screened annually for the development of diabetes
 FRIEDREICH ATAXIA Prognosis
Severity of disease and rate of progression are variable, with more severe
disease being associated with a higher number of GAA repeats
The mean time from symptom onset to use of a wheelchair ranges from 11 to 25
years
Most patients die between the ages of 30 and 40, with a mean age of 37 years in
some studies, though some patients survive until the eight decade
With late-onset Friedreich ataxia, disease progression is generally slower
The major cause of death is cardiac dysfunction, typically congestive heart
failure or arrhythmia. Less often, death occurs from noncardiac causes, such
as pneumonia due to bulbar dysfunction with inability to protect the airway
 BOALA NEURONULUI MOTOR
(SCLEROZA LATERALA AMIOTROFICA SLA;
Boala Charcot; Boala Lou Gehring)
Grup de boli neurodegenerative
leziuni ale neuronilor motori centrali ( cortexul motor )
+
leziuni ale neuronilor motori periferici ( spinali, bulbo-pontini )

Manifestari clinice cardinale:

amiotrofii ( de regula distale ) + faciculatii musculare
deficit motor progresiv
semne piramidale

Varsta medie de debut: 40-60 de ani

Speranta medie de viata: 2 5 ani de la debut
 BOALA NEURONULUI MOTOR

SUBTIPURI (FORME CLINICE):

-Scleroza laterala amiotrofica (SLA):

amiotrofii+deficit motor progresiv+semne piramidale
-Atrofia musculara progresiva:
amiotrofii+deficit motor progresiv, fara semne piramidale
-Paralizia bulbara progresiva
afectarea musculaturii bulbare
-Scleroza laterala primitiva
deficit motor progresiv, spasticitate, hiperreflexie, r. Babinski, tardive semne de NMP
 Scleroza laterala amiotrofica (SLA)
PATOGENIE

cca. 10%- forme familiale

~ 20% mutatii gena SOD1-chr.21q ("misfolding" SOD1 )
cel putin alte 14 defecte genetice cunoscute ( autosomal dominante sau recesive ) mutatii f.
numeroase in fiecare gena
gena pt. TDP43 ( chr. 9q ) in formele asociate cu FTD
gena pt. FUS ( chr. 16 )

90% - forme sporadice

cel putin 10 locusuri genice semnificativ asociate cu SLA
cel putin alte 41 locusuri genice posibil asociate cu SLA

Zinman L, Cudkowicz M - Lancet Neurology 2011; 10 (5): 481 490

Ticozzi N et al - Archives Italiennes de Biologie, 149: 65-82, 2011
Dunckley T et al NEJM 2007; 357 (8):775-788
Kwiatkowski Jr TJ et al Science 2009; 1205 1208
Events leading to motoneuron death in ALS
 Scleroza laterala amiotrofica (SLA)
ALS = the most common neurodegenerative disease of the motor neuron system.
In its classic form, it affects motor neurons at 2 or more levels supplying multiple regions of
the body. It affects:
lower motor neurons that reside in the anterior horn of the spinal cord and in the brain
stem leads to progressive muscle weakness and wasting (atrophy).
corticospinal upper motor neurons that reside in the precentral gyrus stiffness
(spasticity), abnormally active reflexes, and pathological reflexes
prefrontal motor neurons that are involved in planning or orchestrating the work of the
upper and lower motor neurons sometimes special forms of cognitive impairment
The loss of motor neurons results in the primary clinical symptoms and signs ALS. These
may produce impairment affecting limb, bulbar, axial and respiratory function.
Differences in site of onset, pattern and speed of spread and the degree of upper motor
neuron (UMN) and/or lower motor neuron (LMN) dysfunction produce a disorder that is
remarkably variable between individuals.
 SLA manifestari clinice
SLA forma (cea mai) tipica

debut cu deficit motor distal asimetric la un membru ( initial ca pierderea abilitatii ) cu extensie
spre proximal ( ms. centurilor afectata tardiv );
ulterior: afectarea ms. gatului, limbii, faringelui, laringelui, trunchiului (insuficienta respiratorie
progresiva, tulb. de deglutitie cu reflexele de fund de gat mult timp pastrate )
+ atrofii ms. progresive in teritoriul deficitar
caz particular: sd. Aran-Duchenne mana "scheletica", "cadaverica"
fasciculatii musculare ( f. caracteristic: pe limba ) niciodata izolate !
crampe musculare ( frecvent, adesea f. precoce, legate de actiune, sugestiv dar nespecific ! )
evolutie extensiva insidioasa ( luni ani ), in timp semnele apar bilateral si la toate membrele
ex. clinic:
asociere semne SD. PIRAMIDAL ( vivacitate ROT, r. patologice ) + SD. NMP
 ALS- Clinical features of limb weakness
Lower extremity onset of ALS most often begins with distal leg weakness (foot
drop).
Patients with proximal leg weakness often complain of difficulty climbing stairs
and difficulty arising from chairs.
Upper extremity onset is most often heralded by hand weakness but may begin
in the shoulder girdle muscles.
Patients with hand weakness may complain that they drop things and have
difficulty with tasks such as pinching, writing, typing, managing buttons or
zippers, and picking up small objects.
Patients with shoulder girdle weakness may report difficulty using their arms in
activities such as washing or combing their hair as well as lifting things above
their head.
 Clinical features of bulbar weakness
Patients with dysarthria complain of slurring of speech that is often worse at the end of
the day or with more vigorous use of their voice.
Patients with dysphagia initially complain of difficulty swallowing thin liquids, and may
report the need to swallow multiple times in order to manage a single liquid bolus.
With progression, patients may choke or cough when drinking thin liquids and
eventually develop difficulty managing thicker liquids, their own secretions, and solids.

Clinical features of respiratory muscles weakness

Initially complain of fatigue/shortness of breath triggered by decreasing levels of
activity or by lying flat.
Often develop disturbed nocturnal sleep with frequent awakenings and excessive
daytime sleepiness.
Clinical features of axial muscles weakness

Patients with axial neck weakness complain of posterior neck pain

or strain with a gradually worsening tendency for head drop.
Patients with axial truncal weakness complain of difficulty
maintaining an erect posture when standing or walking. Some will
support their trunk by placing their hands in their front pants
pockets or on their upper thighs.
 ALS- Typical form

The triad:
1)atrophic weakness of the hands, arms or legs
2)generalized hyperreflexia
3)Coarse fasciculation evident in weakened muscles.

Absence of sensory changes

Normal sphincteric control

The muscle of the upper limb and shoulder girdles are typically involved later
Later the atrophic weakness spreads to the neck, tongue, pharyngeal and
laryngeal muscles.
 ALS- Uncommon forms

* ALS + Fronto-temporal dementia

Frontotemporal executive dysfunction may precede or follow the onset
of UMN and LMN dysfunction.
Symptoms include changes in personality, impairment of judgment,
and development of obsessional behaviors.

* ALS + Parkinson syndrome

 SLA investigatii paraclinice
1. EMG
2. Potentiale evocate motorii (prelungite)
3. IRM cerebral si spinal ( atrofie corticala in ariile motorii,
degenerescenta walleriana pe caile piramidale )
4. Analize de laborator
VSH,Hh tiroidinei, electroforeza protein, Vit B12, folate,VDRL, etc.
5. Testare genetica pentru mutatiile SOD (f rar)
 ALS- Diagnosis
El Escorial diagnosis criteria

ALS is primarily a clinical diagnosis

Sensory and motor nerve conduction studies and electromyography (EMG)
are a standard part of the evaluation of motor neuron disease.
 Tabloul clinic SINDROM SLA
DIAGNOSTIC DIFERENTIAL
compresie cronica de maduva cervicala
* hernie de disc cervicala
* stenoza de canal cervical ( probabil prin ischemie cronica )
* pahimeningita cervicala ( sifilis )
* alte cauze ( mai rare )
sd. SLA paraneoplazic ( in limfoame, carcinoame )
sd. SLA post-poliomielitic ( debut tardiv; benign ! )
scleroza multipla ( rar ! )
neuropatia Charcot-Marie-Tooth (istoric familial )
cu amiotrofia spinala progresiva
miopatie inflamatorie
distrofie musculara a centurilo pt. SLA cu debut proximal
miastenia gravis
atrofia bulbo-spinala ereditar pt. paralizia bulbara progresiva
sd. pseudobulbar
polineuropatia motorie cronica cu bloc de conducere
intoxicatia cronica cu plumb
miozita cu incluzii ( debut distal asimetric )
 Criteriile WFN - El ESCORIAL revizuite pentru
diagnosticul sclerozei laterale amiotrofice

Diagnosticul SLA necesita:

A. PREZENTA:
(A:1) dovezilor de degenerescenta a neuronului motor periferic (NMP) prin examinare clinica,
electrofiziologica sau neuropatologica
(A:2) dovezilor de degenerescenta a neuronului motor central (NMC) prin examinare clinica, si
(A:3) evolutiei progresive a semnelor si simptomelor intr-una sau mai multe regiuni, determinata prin
istoricul bolii sau examinare medicala

impreuna cu
B. ABSENTA:
(B:1) dovezilor electrofiziologice si patologice pentru alte procese patologice care pot explica semnele
de degenerescenta ale NMP si/ sau NMC
si
(B:2) dovezilor neuroimagistice in favoarea altor procese patologice care pot explica semnele clinice si
electrofiziologice observate.
 Criteriile WFN - El ESCORIAL revizuite pentru
diagnosticul sclerozei laterale amiotrofice
SLA CLINIC DEFINITA:
doar dovezi clinice pentru semne de NMC si NMP in cel putin 3 regiuni diferite
SLA CLINIC PROBABILA:
doar dovezi clinice pentru semne de NMC si NMP in cel putin 2 regiuni diferite, cu necesitatea ca unele
semne de NMC sa fie localizate rostral de semnele de NMP
SLA CLINIC PROBABILA SUSTINUTA DE PROBE DE LABORATOR:
semne clinice de NMC si NMP doar intr-o singura regiune, sau doar semne de NMC prezente intr-o
singura regiune iar semnele de NMP definite prin criterii EMG sunt prezente la cel putin 2 membre, plus
utilizarea adecvata a neuroimagisticii si protocoalelor de laborator clinic pentru a exclude alte cauze.
SLA CLINIC POSIBILA:
semne clinice de NMC si NMP impreuna intr-o singura regiune / sau doar semne de NMC in 2 sau mai
multe regiuni;
sau,
semnele de NMP se gasesc rostral de semnele de NMC si diagnosticul de "SLA clinic probabila sustinuta
de probe de laborator" nu poate fi sustinut pe baze clinice asociate cu semne electrodiagnostice,
neurofiziologice, neuroimagistice sau studii de laborator clinic. Trebuie excluse alte diagnostice
pentru a accepta dg. de SLA clinic posibila.
SLA SUSPECTATA CLINIC:
sd. de NMP pur, in cadrul caruia dg. de SLA nu poate fi considerat suficient de sigur, pentru a include
pacientul intr-un studiu de cercetare ( dg. exclus din Criteriile revizuite El Escorial pt. SLA)
FORME CLINICE PARTICULARE
ATROFIA MUSCULARA PROGRESIVA
forma limitata: doar afectarea NM periferic
barbati: x4 mai frecvent decat femei
progresie mai lenta, supravietuire mai lunga ( > 15 ani )
cu neuropatii motorii cronice autoimune +/- bloc de conducere

PARALIZIA BULBARA PROGRESIVA

dizartrie, disfonie vorbire neinteligibila
disfagie, tulburari de masticatie ( nmc + nmp ) + r.f.g. prezente ( timp indelungat; se abolesc in stadiile
finale ! )
atrofii ms. & fasciculatii + spasticitate la nivelul fetei, limbii, mm. masticatori, faringelui, laringelui
semne de spasticitate in teritoriul bulbar ( r. maseterin +++ )

SCLEROZA LATERALA PRIMARA (PRIMITIVA)

debut in a 5-a 6-a decada de varsta
debut de obicei cu parapareza spastica progresiva, asimetrica
t afectarea mb. superioare & mm. orofaciali
semne clinice de sd. nmc ( uneori semne subclinice de nmp in < 1 an )
 SLA evolutie si prognostic

ALS is a relentlessly progressive disorder with a clinical course that is nearly

always linear, with a relatively constant slope (ie no remissions or
exacerbations)
Rate of progression varies between individuals.
Symptoms initially spread within the segment of onset and then to other
regions in a relatively predictable pattern.
For patients with unilateral limb onset the pattern of spread is to the
contralateral limb, then to the ipsilateral U/LE, then to the contralateral
remaining U/LE, and then to the bulbar muscles.
In patients with bulbar onset the most common pattern of spread is to one
arm and then to the contralateral arm.
 SLA evolutie si prognostic

The median survival from the time of diagnosis is three to five years; 10% of ALS
patients can live 10 years or more.
The life-threatening aspects of ALS are neuromuscular respiratory failure and
dysphagia.
Dysphagia poses a risk for aspiration of food, liquids, or secretions with resultant
aspiration pneumonia and may also lead to malnutrition and dehydration.
Symptoms can be minimized in patients who choose gastrostomy tube insertion with
aggressive management of secretions.
Complications from being wheelchair-bound or bedridden, including decubitus ulcers
and skin infections (While rare in patients with ALS, these complications can emerge
if appropriate padding is not used.)
Deep vein thromboses and pulmonary emboli (These complications are rare in
patients with ALS, but have been encountered with greater frequency in the active
treatment arm of some clinical trials.)
TERAPIE
Patogenic: RILUZOLUM - alungeste supravituirea in medie cu 3 6 luni
studii de faza III: DESPRAMIPEXOL rezultate nesemnificative
Simptomatic
terapia spasticitatii ( mai ales in scleroza laterala primitiva ): BACLOFEN ( oral / pompa intratecal ),
TIZANIDINE, DANTROLENUM
terapia fizica ( mai ales in prima parte a bolii ), dar neexcesiva
Preventia si terapia complicatiilor
monitorizarea functiei respiratorii: retentia de CO2
asistenta respiratorie in somn ( BiPAP = bilevel positive airway pressure )
traheostomie ( in stadii tardive )
alimentatia: nevoia de hidratare, aport caloric si proteic
initial: alimente in bucati mici, evitarea alimentelor uscate
alimentatie in forma fluida
educarea evitarii deglutitiei in timpul vorbirii
sonda nazo-gastrica sonda pe gastrostoma percutanata ( PEG )
reeducarea mersului, cu sprijin cu diverse dispozitive
Institutionalizarea: cat mai tarziu posibil !