23.

Scleroza multipla si alte afectiuni inflamatorii/demielinizante ale snc

Adams 915

-demielinizare⹀distrugerea mielinei

- o trăsătură importantă este prezența unei reacții inflamatorii în proximitatea demielinizarii

Criteriile anatomo-patologice general acceptate pentru o boala demielinizanta sunt:

1. Distructia tecii de mielina a fibrelor nervoase cu relative cruțate a altor elemente ale tesutului
nervos, de ex. axonilor, a celulelor nervoase și a structurilor de suport care sunt mai puțin afectate

2. Infiltrarea celulelor inflamatorii, cu precădere într-o distribuție perivenoasa

3. Leziunile sunt localizate primar in substanata alba, fie in multiple focare mici, disseminate, fie in
focare mai mari, ce se raspandesc de la unul sau mai multe centre

-exista un anumit grad de degenerescenta axonala si neuronala în majoritatea bolilor demielinizante, dar
efectul preferential asupra mielinei este cel care defineste acest grup

-În unele cazuri de leucoencefalita necrotico-hemoragica, scleroza multipla, procesul inflamator poate fi
suficient de intens incat sa determine o distructie tisulara completa, incluzand vasele de sange și axonii
din regiunea respectivă.
-În unele cazuri de encefalopatie anoxica, tecile de mielina ale fibrelor nervoase radiare din straturile
profunde ale cortexului cerebral sau din focare imprecis delimitate, la nivelul circumvolatiilor sau al
substantei albe centrale sunt distruse, în timp ce majoritatea axonilor sunt crutati
-O degenerescenta relativ selectiva a tecii de mielina poate surveni in focare mici ischemice , ca rezultat
al ocluziei vasculare, sau arii mari, confluente ca in boala Binswanger (Cap.34)

1
-In degenerescenta combinata subacuta a MS, asociata anemiei pernicioase si in parapareza spastica
tropicala mielina poate fi afectata mai precoce si mai sever, decat axonii. Acest lucru este valabil si in
leucoencefalopatia multifocala progresiva (LEMP), demielinizare osmotica (mielinoliza pontina) si boala
Marchiafava-Bignani.

Scleroza multipla

Istoric:

-numita și scleroza diseminata (britanici) si sclerose en plaques (franceza)

Remarci introductive:

-Este o afectiune cronica caracterizată clinic prin episoade de deficite focale ale nervilor optici, creierului,
maduvei spinarii, ce se remit într-un grad variabil, prezinta recurente de-a lungul mai multor ani sunt de
obicei progresive

-manifestari neurologice versatile, fiind determinate de variabilitatea localizarii si extinderii focarelor de

demielinizare

-Aspectele tipice includ slăbiciune, parapareza, parestezii, pierderea vederii, diplopie, nystagmus, disatrie,
tremor, ataxia, afectarea sensibilității profunde și disfunctia vezicala.

-Diagnosticul poate fi incert la debut și în primii ani de boala, cand semnele și simptomele indica o
leziune unică în sistemul nervos

-poate exista o perioada de latenta lungă (de 1 pana la 10 ani sau mai mult) între un semn inițial minor și
dezvoltarea ulterioară a unor simptome mai caracteristice.

UpToDate: A clinically isolated syndrome (CIS) is the first clinical episode that is suggestive
of MS, as characterized by the following features :

● Presents as a monophasic clinical episode with symptoms and objective findings that
reflect a focal or multifocal inflammatory demyelinating event in the central nervous
system

● Develops acutely or subacutely, with a duration of at least 24 hours, with or without

recovery

● Occurs in the absence of fever or infection

● Resembles a typical MS relapse (attack and exacerbation) but occurs in a patient

not known to have MS

In CIS there is no evidence of previous episodes of demyelination from the patient's history or
on imaging.

2
Typical presentations include the following :

● Unilateral optic neuritis, manifesting with painful, monocular visual loss consisting of
visual blurring or scotoma

● Painless diplopia due to internuclear ophthalmoplegia (occasionally bilateral) or, less

commonly, a sixth nerve palsy

● Brainstem or cerebellar syndrome, such as diplopia described above, ataxia with gaze-
evoked nystagmus, vertigo, facial numbness, or paroxysmal episodes of dysarthria or
vertigo

● Partial transverse myelitis, usually with predominant sensory symptoms, including a

partial Brown-Sequard syndrome, or Lhermitte sign; other manifestations can include
sphincter symptoms, with bladder involvement (eg, urge incontinence) more common
than bowel, and erectile dysfunction

Symptoms usually develop over the course of hours to days and then gradually remit over the
ensuing weeks to months, though remission may not be complete. Presenting symptoms and
signs may be either monofocal (consistent with a single lesion) or multifocal (consistent with
more than one lesion). CIS is best thought of as a precursor to MS in most patients, and fewer
patients can be diagnosed with CIS as the diagnostic criteria for MS have become less
stringent.

· SM recurrent remisiv:

-Semnele și simptomele se amelioreaza parțial sau total, fiind urmate la un interval variabil de timp de
recurenta acelorași anomalii sau de aparitia altora noi, în alte parti ale sistemului nervos

-Caracterizat prin pusee clinic certe, cu recuperare clinica completa sau incompleta. Intre pusee, deficitele
neurologice se datorează acumulării sechelelor, fara progresie clinica. (Ghid)

Relapsing-remitting MS is the most common type of MS at disease onset, especially in young

people. It is characterized by clearly defined attacks (also known as relapses, flares, or
exacerbations) with full or incomplete recovery. There is minimal disease progression between
disease relapses, at least as traditionally understood, though relapses themselves may leave
residual disability, which can be severe on occasion.

The initial attack is an isolated neurologic problem, similar to clinically isolated syndrome (CIS),
though patients may meet the formal definition of MS with a single clinical episode if their
magnetic resonance imaging (MRI) reveals the simultaneous presence of enhancing and non-
enhancing lesions. Oligoclonal bands that are present in cerebrospinal fluid but absent in the
serum can also be used to make the diagnosis, though a spinal tap is generally not indicated in
patients whose history, exam, and imaging are highly consistent with MS.

3
Symptoms and signs associated with a relapse usually reach a peak in days to weeks, followed
by a remission during which the symptoms and signs resolve to a variable extent. The minimum
duration for a relapse has been arbitrarily established at 24 hours, though most are much
longer. Clinical symptoms of shorter duration are less likely to represent new lesion formation or
extension of previous lesion size.

In the absence of a new demyelinating event, previous clinical deficits may temporarily worsen
in the setting of any elevated physiological temperature, including fever, physical activity, high
environmental temperature, or metabolic upset, and may last for hours to a day or more. Such
worsening, termed "pseudorelapses," is thought to reflect conduction block in previously
demyelinated axons

· SM primar progresiva:

-La mai puțin de jumătate dintre pacienti, boala capata un curs uniform progresiv, în special la cei cu
varsta peste 40 de ani la debut

-Progresie continua de la debut, ocazional cu faza de platou și ameliorari minore, temporare. Are
distributie egala intre sexe, afecteaza mai frecvent si mai sever maduva spinarii (Ghid)

Primary progressive MS is characterized by progressive accumulation of disability from disease

onset with occasional plateaus, temporary minor improvements, or acute relapses still
consistent with the definition. A diagnosis of primary progressive MS is made exclusively on
patient history, and there are no imaging or exam findings that distinguish primary progressive
MS from relapsing-remitting MS. Primary progressive MS represents approximately 10 percent
of adult MS cases at disease onset . The mean age at onset is approximately 40 years, which is
approximately 10 years older than the mean age of patients presenting with relapsing-remitting
MS. Unlike relapsing-remitting MS, primary progressive MS occurs equally in males and
females .

The most common clinical presentation is a spinal cord syndrome that worsens over months or
years with asymmetric spastic paraparesis and no clear sensory level ]. Less often, primary
progressive MS develops as a progressive cerebellar ataxia, and rarely with cognitive,
brainstem, or visual symptoms. Enhancing lesions may be seen on the MRI in patients with
primary progressive MS These patients have a worse prognosis for ultimate disability in
comparison with patients who have relapsing-remitting MS

· SM secundar progresiva:

-un profil initial recurent remisiv, devine uniform progresiv

-recuperare parțială după pusee și progresie continua întreruptă sau nu de pusee, ocazional cu faze de
platou. Reprezinta transformarea tipului recurent remisiv, după in medie 10 ani de evolutie (Ghid)

4
Secondary progressive MS is characterized by an initial relapsing-remitting MS disease course
followed by gradual worsening with or without occasional relapses, minor remissions, and
plateaus.; the diagnosis of secondary progressive MS is made retrospectively [1]. The transition
from relapsing-remitting MS to secondary progressive MS usually occurs 10 to 20 years after
disease onset.

A radiologically isolated syndrome (RIS) is defined by incidental brain or spinal cord MRI
findings that are highly suggestive of MS, based upon location and morphology within the
central nervous system, in an asymptomatic patient. That is, the patient with an RIS has not had
clinical attacks suggestive of MS.

The diagnosis of RIS is based entirely on the interpretation of MRI findings, after a meticulous
history and examination have excluded any history, symptoms, or signs of MS and excluded
other conditions that could account for the MRI findings

Proposed diagnostic criteria for a RIS require demonstration of lesion dissemination in space by
one or more T2-hyperintense lesions in at least two of four MS-typical regions of the central
nervous system (periventricular, cortical or juxtacortical, infratentorial, and spinal cord) . RIS is
excluded if there is clinical evidence of neurologic dysfunction suggestive of MS based on
historical symptoms and/or objective signs. It is also excluded if there are MRI abnormalities
explained by any other disease process, with particular attention to aging or vascular-related
abnormalities, and those due to exposure to toxins or drugs.

Patients with a CIS or RIS should be monitored for possible manifestations of MS disease
activity including acute clinical attacks (relapses), new lesions on MRI, and onset or progression
of sustained disability. Our preferred protocol is to assess the clinical status of patients routinely
(eg, every three to six months or as needed) with a neurologic examination and sometimes with
the full Expanded Disability Status Scale We obtain a repeat brain or spine MRI whenever there
are new clinical symptoms suggestive of MS.

For patients without new symptoms, the following imaging schedule and treatment strategy is
suggested:

● For patients with a CIS and a normal baseline brain MRI (ie, no demyelinating lesions),
a brain MRI should be repeated between three and six months, and, if stable, another
MRI should be obtained one year later. If these serial MRIs are stable, further scanning is
recommended if there are new symptoms. If any of the serial brain MRI scans show the
interval development of hyperintense T2 lesions that are characteristic of MS in at least
two of four MS-typical regions, treatment with a DMT is suggested.

● For patients with a CIS and demyelinating lesions on baseline brain MRI who were not
started on early DMT, follow-up is similar to that for patients who are on DMT with a
repeat brain MRI every 12 months.

5
 ●For patients with an RIS who remain asymptomatic, a repeat brain MRI at 6 to 12
months and then at yearly intervals for up to five years is suggested.

Aspecte morfopatologice

Ø Secționarea creierului si maduvei spinarii evidențiază numeroase zone separate, în care tesutul este
ușor deprimat fata de suprafata de sectiune și se diferențiază față de substanta alba inconjuratoare prin
culoarea roz cenușie (rezultatul pierderii mielinei)

-Leziunile variaza in diametru, de la cativa mm pana la cativa cm, afecteaza in principal substanta alba a
creierului si maduvei spinării și nu extind dincolo de zonele de intrare ale rădăcinilor nervilor cranieni sau
spinali. Datorită delimitării lor nete sunt denumite plăci.

Localizarea periventriculara a leziunilor este caracteristică, dar numai acolo unde venele subependimare
mărginesc ventriculii (în principal adiacent corpului si atriumului ventriculilor laterali). -Alte structuri
favorite nervii optici si chiasma optica (foarte rar tracturile optice) si maduva spinarii, unde venele piale
se găsesc imediat lângă sau in substanta alba.

-Leziunile sunt distribuite aleator în trunchiul cerebral, maduva spinarii si pedunculi cerebelosi, fără o
preferință pentru un anume sistem de fibre, dar întotdeauna limitate predominant la substanta alba. În
cortexul cerebral și structurile nucleare centrale și spinale, leziunile acute distrug teaca de mielina, dar
lasa celulele nervoase aproape intacte. Leziunile severe, cronice pot distruge axonii în regiunile afectate,
dar leziunea dominanta ramane cea demielinizanta.

Aspectul histologic

· Depinde de varsta leziunilor.

· Leziunile relativ recente: distrugerea partiala sau completa, cu pierderea mielinei, într-o întreaga
zona formată din confluența multor focare mici, predominant perivenoase, axonii din aceeași regiune
sunt relativ crutate. Exista un grad variabil (de obicei usor) de degenerescenta a olidendrogliilor, o
reactie astrocitara variabila și infiltrate celulare mononucleare și limfocitare, perivasculare si para-
adventiceale. Un nr mare de fagocite microgliale (macrofage) infiltreaza leziunile, astrocitele din
interiorul și din jurul leziunilor cresc în nr și dimensiuni

· Leziunile persistente sunt compuse dintr-o împletitură compactă de țesut glial, acelular, cu
prezenta ocazionala a limfocitelor perivasculare si a macrofagelor, in astfel de leziuni se mai găsesc
axoni intacti

· În leziunile vechi cu întreruperi ale axonilor, exista degenerescenta walleriana

ascendentă/descendentă a fibrelor lungi din MS. Se considera ca remielenizarea parțială se poate
surveni la nivelul axonilor intacti—aspect de demielinizare incompletă al ariilor în umbra. Cateva
dintre cele mai severe leziuni vechi vor deveni cavitati, indicând ca procesul patologic a afectat nu

6
 doar mielina și axonii, ci și tesutul de suport si vasele sanguine. (sunt si grade intermediare de
modificări histologice)

· Remielinizarea relativ ineficienta a plăcilor SM—lasă in urma axoni denudati, care sunt putin
mielinizati—placile in umbra.

· Unele oligodendrocite sunt distruse în ariile de demielinzare activa, cele rămase au capacitate de
proliferare scăzută. Exista un influx de celule oligodendrogliale precursoare, ce se maturizează în
oligodendrocite si furnizeaza mielina axonilor rămași.

· Hiperplazia astrocitara la nivelul leziunilor si persistența răspunsului inflamator determina

probabil caracterul inadecvat al procesului reparator.

Leziunile sunt împărțite in subgrupuri histologice conform Lucchinetii colegii:

1. Pattern I: leziuni inflamatorii alcatuite doar din celule T si macrofage

2. Pattern II: leziuni determinate de autoanticorpi, mediate de imunoglobuline si complement

3. Pattern III: apoptoza oligodendrocitelor și absența imunoglobulinelor si a complementului cu

remielinizare parțială

4. Pattern IV: evidențiază exclusiv distrofia oligodendrocitelor, fara remielinizare

-Fiecare caz a demonstrat un singur pattern patologic, sugerand faptul ca la fiecare pacient operează
procese fiziopatologice diferite. Se considera ca ultimele doua tipuri histologice reprezinta o
degenerescenta primara a celulelor oligodendrogliale.

-Aspectele patologice caracteristice formei progresive de SM pot sa difere de cele caracteristice formei cu
recaderi

-Anticorpii și fagocitoza mielinei mediată de complement sunt mecanismele dominante ale demielinizarii
din SM.

-SM- proces in principal inflamator-imun, care tinteste mielina centrala

The characteristic neuropathologic feature of MS is the presence of focal demyelinated plaques

within the central nervous system, accompanied by variable degrees of inflammation and
gliosis, with partial preservation of axons. These lesions tend to be located in the optic nerves,
spinal cord, brainstem, cerebellum, and the juxtacortical and periventricular white matter. In
addition, demyelinated lesions can also be found in the corpus callosum and cortical gray
matter. Axonal injury can be a prominent pathologic feature of the MS plaque, though not in the
acute phase.

· Etiologie si epidemiologie

7
-Incidența SM este de doua-trei ori mai mare la femei, decat la barbati. Probabil din cauza
faptului ca femeile sunt mai susceptibile la afectiuni inflamatorii si imunologice

-Incidența la copii este foarte scăzută, 0.3-0.4% din cazurile apar in prima decada

-La cei cu debut la vârsta de 16 ani sau mai precoce, le trebuia un timp mai lung pentru a ajunge
la un stadiu de dizabilitate ireversibilă, dar atingeau acest stadiu la varsta mai tanara, decât cei cu
debutul bolii la varsta adulta

-riscul de a dezvolta primele simptome ale bolii crește abrupt cu varsta, atingand un maxim la 30
de ani, ramanand ridicat in a patra decada, apoi scazand rapid si devenind foarte redus in a sasea
decada

-SM are o curba a debutului de tip unimodal, dependenta de varsta, similară bolilor infecțioase și
de țesut conjunctiv

-In nr mic de cazuri apare mai tarziu in viata adulta (sfarsitul decadei a cincea, decada a sasea).
La acești pacienți este posibil ca simptomele precoce au fost uitate sau sa nu se fi exprimat clinic

-riscul crescut de dezvolta SM cu cresterea latitudinii, sunt implicate și factori de mediu în

dezvoltarea SM

-Rolul vitaminei D și expunere la soare, unele date sugerează ca riscul de SM este parțial datorat
acestor doi factori de mediu.Fluctuațiile sezoniere in activitatea leziunilor de SM pot avea baza
similară.

-Cateva studii arată ca persoanele care migrează dintr-o zona cu risc înalt către o zona cu risc
scăzut, poarta cu ele, cel putin partial, riscul aferent țării de origine și bagajului genetic, deși
boala poate sa nu devină aparentă clinic un interval de pana la 20 de ani după migrare. Varsta
critică de emigrare pare sa fie 15 ani.

Geographic factors — The incidence and prevalence of MS varies High frequency areas of
the world (prevalence of 60 per 100,000 or more) include all of Europe, southern Canada,
northern United States, New Zealand, and southeast Australia

White populations, especially those from Northern Europe, appeared to be most susceptible,
while people of Asian, African, or Native American origin appeared to have the lowest risk.

-studiile recente sugerează ca factorul genetic dintr-o populatie predomina

-O agregare familiala de SM este stabilita. Aproximativ 15% dintre pacientii cu SM au o ruda

afectata, riscul cel mai mare fiind pt frați si surori. Cauza ereditatii este sustinuta si de studiile cu
gemeni.

8
-Dovada suplimentara a unui factori genetic cauzal in SM: unele antigene pentru locusurile de
histocompatibilitate sunt mai frecvente la pacienții cu SM. Cea mai puternica asociere, locusul
DR, de pe cromozomul 6. Alte haplotipuri care sunt suprareprezentate in SM (HLA-DR2, într-o
masura mai mica DR3, B7, A3)-sunt considerate markeri pentru gena de susceptibilitate pt SM-
posibil o genă pt răspunsul imun. Prezenta unuia dintre acești markeri crește riscul de SM de 3-5
ori. Mai sunt identificate câteva alele IL-2Rα si IL7Rα—aceste constatări susțin faptul ca
dereglarea sistemului imun este un factor de risc pentru dezvoltarea SM

-Incidenta conjugala redusa de SM, indica faptul ca orice expunere comuna la o infecție
generatoare sau un agent de mediu, trebuie sa survina precoce în viața (în general înaintea vârstei
de 14 ani, latenta in jur de 21 ani)

-Studiile sugerează ca probabilitatea dezvoltării SM este mai mare printre locuitorii din mediul
rural fata de cei din mediul urban, este mai frecventă in grupurile cu nivel socio-economic
ridicat.

-Au fost propuși și alți factori de mediu (interventii chirurgicale, traumatismele, anestezia,
expunere la animale de casa, deficit/rezistenta la cobalamina, mercurul din amalgamul de argint
folosit plombele dentare) si boala Lyme, dar nu sunt susținuți de dovezi, marea majoritate sunt
false asocieri

MS is caused by dysregulation of the peripheral immune system, leading to injury in the central
nervous system (CNS). Its pathogenesis requires the combination of a genetically susceptible
individual and a particular environmental trigger.

Genetic susceptibility — Evidence supporting genetic susceptibility comes from risk

projections for the development of MS in family members of affected.In general, the lifetime risk
of MS in first-degree relatives of MS patients is five percent. Studies of monozygotic twins have
consistently demonstrated an even higher risk

Certain immunologic human leukocyte antigen (HLA) genes are associated with an increased
risk for the development of MS, including haplotypes HLA DRB1*1501, DQA1*0102, and
DQB1*0602 The HLA-DR15 haplotype has been strongly associated with early disease onset in
the MS population

Environmental triggers — Possible but unproven environmental triggers for MS include

exposure to infectious agents and low serum vitamin D levels.

Because the pathogenesis of MS is thought to involve the immune system, it has been
hypothesized that vaccination may increase the risk of developing MS. However, substantial
analysis has failed to identify an association between vaccines and MS in adults. There is
limited evidence suggesting that childhood head trauma as a risk factor for MS.

9
Epstein-Barr virus — Environmental exposure to a specific infectious agent during a window of
immunologic vulnerability in childhood may predispose some individuals to the development of
MS . Many viral and bacterial pathogens have been putatively linked to demyelination. Of these,
the Epstein-Barr virus (EBV) has attracted much attention.

Exposure to EBV results in persistent B-cell infection, expansion of EBV-transformed B-cell

clones, and the production of antibodies directed against specific EBV viral antigens as well as
lifelong T-cell surveillance of infected B-cells. EBV nuclear antigen (EBNA) has a similar
structure to myelin basic protein, a major component of CNS myelin. T-cells directed against
EBV antigens may be redirected to attack CNS myelin because of similarity between the
antigens, a process termed molecular mimicry.

Evidence of an etiologic role for EBV in MS may be stronger in the pediatric than the adult
population.

Other viruses – there was no increased risk associated with other viruses, including
cytomegalovirus (CMV) [97]. CMV infection was associated with protection from MS . It is not
clear if this association is causal or spurious, nor is it known precisely how such an infection
would be protective.

Varicella zoster virus (VZV) was linked to MS in some studies.These findings suggest that
VZV may participate in, or be activated at the same time as, MS exacerbations. However, they
require confirmation in additional studies.

Vitamin D — There is a higher prevalence of MS at more northern latitudes, which has

prompted other environmental considerations for the disease. Specific interest has arisen with
vitamin D, which requires exposure of the skin to ultraviolet radiation for its normal biosynthesis

Vitamin D is known to have immunoregulatory effects that include enhancing regulatory T-cell
activity, upregulation of anti-inflammatory molecules, and downregulation of pro-inflammatory
cytokines. Benefit of treatment with 1,25 dihydroxy-vitamin D has been demonstrated in the
experimental autoimmune encephalomyelitis animal model .

Patogeneza

-Datele epidemiologice indica atat o susceptibilitate genetică, cat si un factor de mediu, care este intalnit
în copilărie, și după ani de latenta declanșează boala

-exista o alterare a imunității umorale și a celei mediate celular, fata de agentii virali.

-pana la acest moment niciun virus nu a fost izolat din tesuturile cu SM.

-Agenții bacterieni Chlamydia pneumoniae și Borrelia burgdorferi și herpes virus de tip 6 au fost
implicați, s-a găsit materialul lor genomic în plăcile de SM, dar dovada pt pentru participarea lor directă
la boala nu este convingătoare

10
-dacă într-adevăr o infecție obscură este evenimentul initial in geneza SM, atunci un factor secundar
trebuie sa opereze mai tarziu de -a lungul vieții, pentru a reactiva boala si a determina exacerbari.
Conform unui concept acest mecanism secundar este o reactie autoimuna, cu atacarea unor componente
ale mielinei, și în forma sa cea mai intensă cu distrugerea tuturor componentelor tisulare, inclusiv a
axonilor. In sprijinul acestui concept vin si anticorpi impotriva proteinelor specifice mielinei, de ex.
proteina bazica a mielinei (MBP)-atat in ser cat si in LCR. Acești anticorpi împreuna cu celule T care sunt
reactile la MBP si la alte proteolipid din mielina, cresc odată cu creșterea activității bolii. MBP
reactioneaza incruscisat cu ac. anti virusul rujeolei. Argumentele ca o infectie virala se reactivează si
perpetuează boala , sunt mai puțin convingatoare decat acela care propun un rol pt virusuri în inițierea
procesului, la indivizi susceptibili

(ADEM afectiune autoimuna de tip hipersensibilitate intarziata)

-Implicarea sistemului imun umoral este demonstrat prin prezenta in LCR a ac. împotriva proteinelor
imunologice oligoclonale, anticorpi care sunt produsi de limfocitele B în SNC.

-Ac. împotriva oligodendrocitelor sunt prezenți în ser în 90% din cazuri.

-Autoanticorpi directionati impotriva glicoproteinelor oligodendrocitare mielinice (MOG) si a MBP se

gasesc inconstant

-subseturi de celule T (cel. CD41 Th2) sunt activate de MBP si MOG, pentru a activa celulele B, pt
producerea benzilor oligoclonale si a complexelor de atac membranar si pentru eliberarea de citokine
(TNF-α, interleukine, interferon-gamma.

-Procesul inflamator erodează bariera hematoencefalica (reprezentată prin adeziunea limfocitelor la

celulele endoteliale din SNC) și în cele din urma distruge oligodendrogliile si axonii.Exista activitatea
cascadei inflamatorii și afectare axonala.

-SM este mediată de o sensibilizare a celulelor T pt unele componente ale mielinei. Patrunderea celulelor
T in SNC, are ca rezultat o reacție inflamatorie perivasculara.

-Este de presupus ca stimularea intensa a celulelor T este insasi suficienta pt a induce demienilizarea, dar
este posibil ca tinta primara a reactiei imune sa fie teaca de mielina sau o componenta a acestea și
infiltrarea cel T sa fie o reactie la demielinizare.

-este necesara o agresiune aditionala, mielina singura nu este suficient, fiind necesar un stimul imun
adjuvant

-interactiuni citovasculare

-in fundal sta elementul de susceptibilitate genetica, care predispune anumiți indivizi la aceste evenimente
imunologice

Immunopathology — Several lines of evidence support an important and possibly defining role
for the immune system in the development of MS. The cellular immunology of MS involves

11
altered interactions between T cells, B cells, myeloid cells, and additional immune cell
populations .Studies have demonstrated that inflammatory T cells, B cells, and macrophages
are typically seen on histopathologic examination of MS lesions. Magnetic resonance imaging
(MRI) studies have also demonstrated disruption of the blood-brain-barrier, as defined by
leakage of gadolinium-based contrast agents, at early points during the development of MS
lesions in patients with relapsing-remitting disease. This is at a time associated in
neuropathologic studies with infiltration by inflammatory cells. T helper 17-type (Th17) cells that
are involved in inflammatory and tissue destruction in many immune-mediated systemic
diseases are also associated with active MS lesions

The risk of developing MS is associated with certain class I and class II alleles of the major
histocompatibility complex loci that are involved in T cell activation and regulation. In that
regard, myelin-reactive T cells are found in MS plaques, the cerebrospinal fluid (CSF), and the
peripheral circulation of patients with MS . In addition, antibodies against one myelin protein
(myelin oligodendrocyte glycoprotein [MOG]) are associated with an MS-like demyelinating
disease.

It has long been suspected that a foreign antigen, such as a virus or bacteria, provides an
antigenic trigger for MS autoimmunity through molecular mimicry Attention has centered on the
Epstein-Barr virus. Antigen presenting cells, including B cells, may activate CD4+ T cells in
response to foreign and endogenous antigens, leading to inflammatory responses and tissue
damage. Furthermore, the CSF of patients with MS contains immunoglobulin G (IgG) and IgM
oligoclonal bands that are not present in the serum of these patients; this indicates production of
antibodies by plasma cells specific to the neuraxis.

Immunomodulatory drugs that reduce the Th1 immune response (eg, interferon beta), increase
the Th2 and the T regulatory cell Th3 responses (eg, glatiramer acetate), block T cell movement
from the blood into the central nervous system (eg, natalizumab), or deplete B cells (eg,
ocrelizumab) are effective for decreasing MS disease activity

In addition to loss of myelin and oligodendrocytes, axonal injury is a prominent pathologic

feature of the MS plaque. Disease progression involves a degenerative phase of cerebral
atrophy and axonal loss that is not fully attributable to immune mechanisms or inflammation.

Neuropathologic evidence suggests that oligodendrocyte apoptosis, perhaps triggered by viral

or glutamate excitotoxicity, may be the primary event preceding inflammation in at least some
newly forming lesions in patients with relapsing-remitting MS. However, the importance of
oligodendrocyte apoptosis in the pathogenesis of MS remains to be established.

Efectele fiziologice ale demielinizarii

-principalul efect este afectarea conducerii electrice saltatorii a impulsului nervos, de la un nod Ranvier,
unde sunt concentrare canalele de sodiu, la nodul urmator.

-eșecul transmisiei electrice sta la baza majorității anomaliilor funcționale ce rezulta din afectiunile
demielinizante, atat in SNC cat si in nervii periferici de ex. intarzierea conducerii electrice (dovedita prin

12
stimulare vizuala). Cand procesul de demielinizare este acut si reversibil in cateva zile, blocarea
conducerii in fibrele nervoase este evident fiziologică, mai degraba decat patologica, într-o perioada atat
de scurta este putin probabil ca recuperarea se fie rezultatul remielinizari, recuperarea este probabil
rezultatul remisiunii edemului si a modificarilor inflamatorii acute intra- si perilezionale. Remielinizarea
apare probabil, dar este un proces lent, partial, efectele sale se exprima printr-o incetinire a conducerii
nervoase, care daca este prezenta la un ochi cu vedere normala, poate fi responsabilă de reducerea
fuziunii la scintilatie si a perceptiei stimulilor vizuali multipli—astfel se explica reducerea in intensitate
(desaturarea) a culorii rosii, semn tipic de nevrita optica

-multe dintre placi vizibile IRM nu sunt însoțite de simptome corespondente, ori pt ca a existat o
remielinizare completa in aceste placi, suficienta pt a a sustine functionarea clinica, fie in stadiul acut
placa reprezinta mai degraba edemul decat demielinizarea

-Inducerea temporara prin caldura sau exercitiu fizic a unor simptome, cum ar fi incetosarea unilaterala a
vederii ( Fenomen Uhthoff), sau parestezii si slabiciunea unui membru (cazi cu apa fierbinte)-- trasatura
tipica. In fibrele nervoase demielinizate conducerea impulsurilor este sensibila la cresterile de
temperatura. O crestere de doar 0.5 C poate bloca transmisia electrica in fibrele putin mielinizate sau
demielinizate.

-Hiperventilatia incetineste conducerea raspunsului evocat, efect rar perceput de pacient

-Sensibilitatea regiunilor demielinizante si remielinizante la modificari subtile metabolice sau de mediu,

explica instalarea rapida a simptomelor, fluctuatii ale SM, in lipsa unui sdr inflamator in laborator.

-Fumatul, oboseala, hiperventilatie, cresterea temperaturii ambientale pot inrautati pe termen scurt
functionarea neurologica, pot fi confundate cu un puseu al bolii.

Manifestari clinice
Semne și simptome precoce

· Slăbiciunea sau paresteziile/ambele în unul sau mai multe membre simptomul inițial la
jumătate dintre pacienți.

· Simptome de amorteli ale extremitatiilor si senzatii de corset la nivelul

trunchiului/membrelor -rezultatul implicării cordoanelor posterioare ale MS

· Simptomele apar în decurs de ore, zile, uneori fiind atat de neînsemnate incat sunt ignorate,
mai puțin frecvent atat de acute si evidente, ca aduc aduc pacientul la urgență

· Sindroamele variază de la discreta inabilitate sau control deficitar al unuia sau ambelor
membre inferioare, pana la parapareza spastica sau ataxica

· ROT pastrate, ulterior devin hiperactive

13
 · RCP in extensie

· Diferite grade de afectare a sensibilității profunde si superficiale

· Pacientul cu SM se prezinta cu simptome la un picior, dar cu semen la amandoua

· Sindroame tipice pentru SM, care pot fi si manifestări inițiale

1. Nevrita optica

2. Mielita transversa

3. Ataxia cerebeloasa

4. Sdr de trunchi cerebral (vertij, durere sau parestezii faciale, disartria,

diplopie).

· Cand aceste sindroame nu sunt insotite de alte trasaturi ale SM, sunt denumite sindrom
clinic izolat.

· Flexia gatului induce o furnicatura, cu senzatie de curent electric, ce iradiaza pe umeri si

spate, mai rar pe fața anterioară a coapselor semnul Lhermitte (probabil poate fi atribuit unei
sensibilități crescute a axonilor demielinizati la intinderea si presiunea induse in MS prin
flexia gatului, dar apare și în alte condiții , de ex . spondiloza cervicala

· La 20% instalarea simptomatologiei neurologice complete era o chestiune de minute, într-

un nr similar chestiune de ore

· La 30% simptomele au evoluat lent, timp de cateva zile

· La 20% de-a lungul catorva luni

· La 10% debut insidios, lent, cu progresie continua, de-a lungul a luni sau ani

· Patternul tipic recurent remisiv este mai frecvent la pacienții mai tineri de 40 de ani

· Procesul inflamator din SM nu afectează alte organe sau sisteme in afara SNC.

Nevrita optica (nevrita retrobulbara; papilita + Cap44, Pg 1257)

· La aprox. 25% din pacienți cu SM este manifestarea initiala

· Pe parcursul unei perioade de ore sau zile, apare pierderea partiala sau totala a vederii la un
ochi

14
· Mulți pacienți cu 1-2 zile înaintea afectarii vederii, acuza durere orbitara, agravata de miscari
oculare si de palparea GO

· rar, scaderea vederii progresează continuu de-a lungul catorva saptamani, mimând o leziune
compresiva sau tumora intrinsecă a nervului optic

· poate fi identificat un scotom implicand aria maculara sau pata oarba (cecocentral)

· poate surveni o largă varietate de defecte de camp vizual, rar hemianopsica (uneori
homolaterala)

· La unii pacienti sunt implicati ambii nervi optici, fie simultan, sau mai frecvent la distanța de
câteva zile, saptamani

· 1 din 8 pacient va avea atacuri repetate

· La o zecime dintre pacienti, lărgirea sau edemul papilei nervului optic (papilita). Apariția
papilitei depinde de proximitatea unei leziuni demielinizante fata de papila nervului optic.
Papilita poate fi diferentiata de edemul papilar determinat de HIC, prin pierderea severă si acută
a AV, ce o însoțește doar pe papilita.

· Mai frecvent, papila nervului optic apare normală nevrita retrobulbara

· Manifestări subtile ale afectarii n.optic, defect al componentei aferente a reflexului pupilar,
atrofia fibrelor nervoase retiniene sau mansonarea venelor retiniene si un răspuns anormal la
potențiale evocate vizual (Cap.2), trebuie luate in considerare la pacienții care nu se plang de
afectarea vederii, dar sunt suspectati de SM.

· Pierderea substanțială a vederii, exista o diminuare a răspunsului pupilar la lumina (paralizie

pupilara aferenta) si instabilitate a răspunsului pupilar direct, dar pupila nu este dilatata in lumina
ambientala

· daca nevrita optica este unilaterala, reflexul fotomotor consensual de la ochiul normal este
păstrată. (demielinizarea n.oculomotor comun in traiectul sau intranevraxiala se asociază cu
midriaza fixa)

· PEV și tomografia în coerență optică detectarea nevritei

· Aproape jumătate dintre pacienți cu nevrita optică recuperează complet, majoritatea celor
rămași se amelioreaza semnificativ, chiar daca inițial a existat o pierdere profundă a vederii si
ulterior o paloare a discului optic.

· Durere in GO este de scurta durata. Durerea persistentă impune o evaluare promptă pt

afectiune locală

15
· Discromatopsia (perceptia desaturata a culorilor) si efectul Pulfrich ( un obiect, de ex. pendul
oscilează perpendicular față de direcția privirii pacientului, apare miscandu-se într-un mod
tridimensional, circular)—persista frecvent

· Ameliorarea se începe de obicei in primele doua saptamani de la debut, ca si in majoritatea

simptomelor acute de SM, probabil mai devreme cu corticosteroid. Ameliorarea poate continua
timp de cateva luni

· Mai mult de jumătate dintre pacienți cu nevrita optica vor dezvolta si alte semne de SM.
Riscul de aparitia SM este mai mic, dacă nevrita a fost in copilărie. Majoritatea dezvolta semne
primii 5 ani de la atacul inițial.

· La multi pacienti, nevrita optica izolata, IRM evidentiaza leziuni ale subst. albe—
diseminarea, desi asimptomatica, a survenit deja, stabilind diagnosticul de SM.

· Recurenta nevritei optice crește șansele de a dezvolta SM. Riscul de SM recurent remisiv
este mai scăzut dacă IRM cerebral nu evidentiaza leziuni demielinizante.

· Nevrita optica poate fi si o manifestare a encefalomielitei postinfectioase

· Neuropatia optică este o boala demielinizanta, dar se știe ca o leziune vasculara sau
compresia nervului optic de către o tumora sau mucocel, pot determina scotom central sau
cecocentral, ce nu poate fi diferențiat de efectele nevritei optice

· Poate exista o forma speciala cronică de nevrite optice recurente rezultatul unui proces
granulomatos nedefinit, de ex. sarcoidul

· Uveitele si mansonarea venelor retiniene, apar mai frecvent la pacienții cu SM. Mansonarea
venelor retiniene este cauzată de un infiltrat cu cel.T, identic cu cel din plăcile tipice, dar este
neobisnuit, deoarece retina nu contine fibre mielinizate

· Nevrita optică este o trasatura comuna în boala Devic

UpToDate: Optic neuritis is an inflammatory, demyelinating condition that causes acute,

usually monocular, visual loss.

Most cases of acute demyelinating optic neuritis occur in females (two-thirds) and
typically develop in patients between the ages of 20 and 40 years.

The most common pathologic basis for optic neuritis is inflammatory demyelination of
the optic nerve. The pathology is similar to that of acute multiple sclerosis (MS) plaques
in the brain, with perivascular cuffing, edema in the myelinated nerve sheaths, and
myelin breakdown. Inflammation of the retinal vascular endothelium can precede

16
demyelination and is sometimes visibly manifest as retinal vein sheathing . Myelin loss
exceeds axonal loss.

It is believed that the demyelination in optic neuritis is immune mediated, but the
specific mechanism and target antigen(s) are unknown. Systemic T cell activation is
identified at symptom onset and precedes changes in the cerebrospinal fluid (CSF)
Systemic changes also normalize earlier (within two to four weeks) than central
changes. T cell activation leads to the release of cytokines and other inflammatory
agents. B cell activation against myelin basic protein is not seen in peripheral blood but
can be demonstrated in the CSF of patients with optic neuritis

Optic neuritis is usually monocular in its clinical presentation. In approximately 10

percent of cases, symptoms occur in both eyes, either simultaneously or in rapid
succession Bilateral optic neuritis is more common in children younger than 12 to 15
years old;. Because bilateral symptoms are relatively uncommon, they should suggest
an alternative cause of optic neuropathy. However, subclinical visual deficits in acuity,
contrast sensitivity, color vision, and visual field in the contralateral eye can often be
elicited by detailed visual testing in patients with clinically monocular disease Because
these deficits usually resolve along with the clinical deficits in the symptomatic eye, it is
unlikely that these findings represent prior episodes of optic neuritis.

The two most common symptoms of optic neuritis are vision loss and eye pain:

●Vision loss typically develops over a period of hours to days, peaking within one to two
weeks. Continued deterioration after that time suggests an alternative diagnosis .

● Eye pain occurred in 92 percent of patients in the ONTT and often worsened with eye
movement. The onset of pain generally coincided with the visual acuity loss and improved
along with it.

Other common visual symptoms and signs include:

●An afferent pupillary defect always occurs in optic neuritis if the other eye is uninvolved
and otherwise healthy. This is demonstrated by shining a light alternately in one eye and
then the other and finding that the direct response to light is more sluggish in the affected
eye.

●The visual field defect in optic neuritis is typically characterized as a central scotoma
However, in the ONTT, almost all types of visual field defects were seen, including diffuse
vision loss and altitudinal, arcuate, hemianopic, and cecocentral defects. Nonetheless, a
defect that extends to the periphery should suggest a compressive lesion, while an
altitudinal defect, particularly an inferior altitudinal defect, is more common in anterior
ischemic optic neuropathy Visual field defects usually resolve;

17
 ●Papillitis with hyperemia and swelling of the disk, blurring of disk margins, and distended
veins is seen in one-third of patients with optic neuritis (picture 1) [7]. Two-thirds of these
patients have retrobulbar neuritis with a normal funduscopic examination. Papillitis is
more common in children less than 14 years old and in certain ethnic populations,
Peripapillary hemorrhages are rare in optic neuritis but are a common accompaniment to
papillitis due to anterior ischemic optic neuropathy

Patients with optic neuritis due to myelin oligodendrocyte glycoprotein (MOG) antibody-
associated disease (MOGAD) frequently have bilateral papillitis, which may be mistaken
for papilledema .

● Photopsias (flickering or flashes of light) are often precipitated with eye movement and
were reported by 30 percent of patients

● Loss of color of vision out of proportion to the loss of visual acuity is specific to optic
nerve pathology. Abnormal color vision by Ishihara plates was found in 88 percent of
involved eyes in the ONTT;

● Other signs of ocular inflammation may be observed by the ophthalmologist on

funduscopic or slit lamp examination. Perivenous sheathing or periphlebitis retinae can be
seen in approximately 12 percent of patients with optic neuritis and implies a high risk for
multiple sclerosis (MS) Uveitis, cells in the anterior chamber, and/or pars planitis are
uncommonly seen in optic neuritis and are more typical of infections and other autoimmune
disease

Diagnosis — In general, optic neuritis is a clinical diagnosis based upon the history and
examination findings. Because important findings on funduscopic examination help
differentiate typical from atypical cases of optic neuritis, an ophthalmologic examination
should be considered an essential feature of the clinical evaluation.

Magnetic resonance imaging (MRI) study of the brain and orbits with gadolinium contrast
provides confirmation of the diagnosis in most cases and also provides an assessment
of the risk of subsequent multiple sclerosis (MS).

Patients with recurrent or bilateral optic neuritis and those who present with additional
neurologic signs or symptoms should undergo further evaluation to determine if the optic
neuritis is due to a broader neurologic disease such as neuromyelitis optica spectrum disorder
(NMOSD) or myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD)

Lumbar puncture — Lumbar puncture is not an essential diagnostic test in optic neuritis but
should be considered in atypical cases (eg, those with bilateral presentation, <15 years in age,
or symptoms suggesting infection)

Other CSF findings in optic neuritis can include:

●Myelin basic protein in approximately 20 percent

18
 ●Immunoglobulin G (IgG) synthesis in 20 to 36 percent

●Oligoclonal bands (OCB) in 56 to 69 percent

The presence of OCB implies a higher risk of developing MS

Other testing — When there are relevant clues to an alternative diagnosis , measurement of
the erythrocyte sedimentation rate, antinuclear antibodies, and angiotensin converting enzyme
levels and serologic and CSF tests for Lyme disease and syphilis should be obtained

Visual evoked response — A delay in the P100 of the visual evoked response (VER) is the
electrophysiologic manifestation of slowed conduction in the optic nerve as a result of axonal
demyelination [48]. This test is not usually helpful in the diagnosis of acute optic neuritis, unless
there is a suspicion that the visual loss is functional.

Optical coherence tomography — Optical coherence tomography (OCT) measures the

thickness in the retinal nerve fiber layer and detects thinning in most (85 percent) of patients
with optic neuritis These abnormalities are also common in patients with MS who do not have a
clinical history of optic neuritis [54]. While lower values correlate with impaired visual outcome,
the utility of OCT as a prognostic tool is limited in that abnormal values do not show up until
early swelling disappears. In one study, OCT was less sensitive than VER in detecting
subclinical optic neuritis

Antibody testing — Serum NMO antibody testing (both aquaporin-4 autoantibody and MOG
antibody) is suggested for individuals with recurrent optic neuritis, particularly if the MRI brain is
negative for any abnormal T2/FLAIR lesions outside of the affected optic nerve(s)

Patients with recurrent optic neuritis appear to be particularly at risk for NMOSD or MOGAD.
This is particularly true for patients with a normal brain MRI and those with optic neuritis events
in rapid succession or with a presentation of severe vision loss .

Mielita acuta (mielita transversala) (+Cap 44, pg 1255; pg 1266)

-denumire generala pt o leziune inflamatorie-demielinizanta a maduvei spinarii cu evolutie acuta

- poate fi in majoritatea cazurilor o expresie a SM - in acest caz leziunea maduvei este analoga
nevritei optice
- in SM afectarea maduvei spin este asimetrica, incompleta, implica numai o parte a tracturilor
lungi ascendente si descendente - paraplegia si pierderea totala a sensibilitatii este neobisnuita
Clinic: - paraplegie sau parapareza sinetrica sau asimetrica, rapid progresiva (ore, zile),
parestezii ascendente, tulb de sensibilitate profunda la MI, nivel de sensibilitate la niv
trunchiului, disfunctie sfincteriana, semn Babinski bilat
LCR: - numar modest de limfocite, cresterea proteinelor totale, dar la debut pot fi normale

19
⅓ de pacienti - boala infectioasa care precede semnele neurologice (caz in care mai degraba
discutam despre boala demielinizanta monofazica postinfectipoasa)
IRM: nu sunt constante - leziuni de demielinizare focala la niv mad spin
- poate exista priza de contrast la administrare de gadoliniu
- Leziunile sunt indistinctibile de cele di mielita postinfectioasa
- Daca e SM - IRM cerebral - leziuni pot fi prezente dar nu in totdeauna
Unele cazuri evolueaza catre mielopatie necrotica cu sau fara neuropatie optica
<½ dintre pacienti au leziuni demielinizante asimptomatice in alta parte ale SNC sau vor
dezvolta dovezi clinice de diseminare in primii 5 ani
Mielita recurenta - la un nivel al maduvei spinarii, fara alte semne de demielinizare pe IRM;
unii pot sa aiba si benzi oligoclonale in LCR; - este o forma recurenta de SM spinala in care
diseminarea cerebrala este rara
Mielita recurenta izolata sau mielopatia apare in: lupus eritematos, sarcoidoza, sindr Sjogren,
boala mixta de tesut conjuctiv, sindromul anticorpilor antifosfolipidici, sau in prezenta altor
autoanticorpi; sau in asociere cu fistulele vasculare durale si medulare si malformatiile
arteriovenoase
- O situatie similara poate sa apara si in cazul nevritei optice (atacuri repetate limitate la
niv n.optic)

Mielita inflamatorie non-infectioasa (scleroza multipla si mielita transversal acuta si

subacuta) - Cap 44. Pg 1255
- Afectiunile care apartin acestei catergorii se prezinta cu leucomielita acosiata ori cu
demielinizare ori cu necroza unor regiuni medulare
- Raspuns imun anormal - uneori determinat de infectie alterori de SM
Sindroame clinice diverse, denumiri: mielita acuta transvera, mielita post-infectioasa, mielita
post-vaccinala, SM acuta, neuromielita optica, mielita necrozanta
Mielopatiile sunt caracterizate prin diverse grade de distrugere inflamatorie, agregate limfocitare
perivenulare medulare - sunt clasificate separat

❖ Mielitele post-infectioase si post-vaccinale

- relatia temporala cu infectia virala sau cu vaccinarea - apar semne neurologice la cateva
zile
- evolutie monofazica - un singur puseu - urmat de recuperare variabila, fara recurente
- pot imlica ata creierul cat si maduva spinarii, caz in care boala este denumita ADEM -
acute disseminated encephalomyelitis - encefalomielita acuta diseminata
-mult probabi mielita post-infectioasa este de natura autoimuna
Tablou clinic: deficit motor si parestezii la nivelul picioarelor si al membrelor inferioare
(mai putin frecvent la maini si brate), care se dezvolta tipic in cateva zile, progresia
ascendenta a simptomelor senzitive, de la picior catre trunchi
- Parestezii care apar la nivelul picioarelor si al membrelor inferioare, care
simuleaza o polineuropatie reprezinta simptome initiale frecvente
20
 - In primele zile pot aparea tulb sfincteriene, durere de spate - dar pot aparea si mai
tarziu
- Asimetria usoara a simptomelor si semnelor, nivel senzitiv la niv trunchiului,
semn Babinski - indica ca afectiunea este o mielopatie, servesc ca si DD pentru
polineuropatie rapid progresiva ca in Guillain Barre
- Pot fi prezente sau absente: durere toraco-lombara de intensitate variabila, cefalee,
redoare de ceafa
- ½ din cazuri pacientul identifica o afectiune infectioasa recenta banala de cai
aeriene sup, febra, care remite cand apar semnele neurolgice
- Boala evolueaza pe parcursul catorva zile, uneori o zi, sau 1-2 saptamani
- Mai frecvent apar sindroame corticospinale sau spinotalamice incomplete care
afecteaza mai mult o jumatate a mduvei spinarii decat jumatatea cealalta
- Un episod acut de mielita post-infectioasa nu poate fi de obicei diferentiat de un
prim puseu de SM, dar prezenta unei infectii pledeaza pt prima
LCR: 10-50/mm3 de limfocite si alte celule mononucleare, usoara crestere a proteinelor,
glucoza normala, dar celulele pot fi si absente; de obicei nu sunt benzi oligoclonale
IRM: discrete anomalii de semnal pe secventele T2-ponderate si captare minima de
gadoliniu la niv de 2-3 segmente spinale; poate sa aiba si edem, dar IRM poate fi normal
Sunt frecvente variantele clinice ale sindromului:
- afectiune aproape pur parestezica cu disfunctie de cordoane posterioare;
- parapareza simetrica cu analgezie sub un nivel situat pe trunchi, dar fara afectarea
sensibilitatii profunde (sindrom asociat mai tipic cu infarctul in teritoriul arterei
spinale anterioare);
- Sindrom de afectare senzitiva variabila care implica un membru inferior si
regiunea genitala ipsilateral
- Doar o mielopatie lombosacrata sau sacrata (sindrom de con medular cu anestezie
in sa si tulb sfincetriene)
- Sindrom incomplet Brown Sequard
In trecut asociat cu exantemele frecente (rujeola, rubeola, varicela), dar acum toate virusurile
umane au fost asociate cu infectii care au precedat mielite acute, ader cel mai frecvent: virusurile
ADN - Ebstein Barr sau citomegalovirus; ocazional: virusul hepatitei B, varicele, enterovirusuri,
rinovirusuri; sindurul precipitant bacetrian: Mycoplasma (dar mai degraba determina reactie
autoimuna post-infectioasa)(de exemplu Campylobacter jejuni, care determina Guillain-Barre, nu
determina mielita)
- Mai putin de jumatate dintre cazuri au prezentat alte semne de SM dupa 10-20 de ani
- Exista o forma izolata de mielita recurenta - declansat uneori de infectie
- Modificari patologice in mielita postinfectioasa: multiple arii de demielinizare aflate
subpial si perivenular, cun inflitrate limfocitare si cu alte celule mononucleare
perivasculare si meningeale si microglii situate para-adventiceal (nu sunt diferite fata de
SM)
Tratament: dupa debutul simptomelor nu este clara valoarea niciunui tratament
21
 - Corticosteroizi in doze mari
- Schimb plasmatic, IvIg fara rezultate certe, dar poate fi benefic
Prognostic bun, mielita se amelioreaza invariabil, uneori surprinzator, dar exista exemple
cu defucut restant
- Prezenta durerii la niv regiunii mediotoracice sau debut sever si brisc al
simptomatologiei indica de obicei un prognostic nefavorabil

❖ Mielita demielinizanta acuta din SM

-leziunile care apar in SM prezinta multe dintre caracteristicile mielitei post-infectioase,

insa manifestarile clinice ale SM tind sa evolueze mai lent, 1-3 saptamani sau mai mult
- asociere in infectii anterioare nu este observata frecvent
- aparitia puseelor ulterioare sau a leziunilor suplimentare pe IRM sau dupa efectuarea
potentialelor evocate vizuale - indica ca afectiunea de baza este de demielinzare cronica
Tablou clinic tipic: amorteala care progreseaza uni- sau bilateral de la nivelul
segmentelor sacrate catre picioare, fata anterioara a coapselor si superior la nivelul
trunchiului, asociind cu deficit motor variabil, de obicei asimetric si apoi paralizia
membrelor inferioare; este afectata si vezica urinara
- Tulb senzitivo-motorie se poate extinde si brahial, la niv trunchiului s epoate
prezenta nivel de sensibilitate
LCR: limfocitoza usoara, cai sin in mielita postinfectioasa, dar poate fi normal; in
primul puseu benzile oligoclonale pot fi absente
IRM: in SM modificarile spinale ocupa doar cateva segmente spinale adiacente, in
mielita post-infectioasa are o extensie mai mare pe verticala (Isti is azt mondta, hogy
cervicalis mielitisben legalabb 3 segmens erintett, mig SM-ben altalaban 2 segmens)
SM spinala este relativ nedureroasa, nu asociaza febra, pacientul de obicei se
amelioreaza, semnele reziduale sunt variabile
Tratament: corticosterozii pot determina regresia simptomatologiei, ocazional cu
recadere la intreruperea medicatiei (dupa 1-2 saptamani); unii pacienti par sa nu raspunda
la trat, sau pot prezenta si agravare continua sub trat; Schimb plasmatic, IvIg pot avea
beneficii in cazuri individuale- mai ales in debut explosiv

Pg 1266 Scleroza multipla spinala: - parapareza ataxica este printre cele mai frecvente
manifestari
- Afectare asimetrica membrelor, semne de afectare cerebrala, nervul optic, trunchi
cerebral si cerebel confirma dg de SM
- Poate aparea afectare spinala pura
- Faza secundar progresiva a SM spinale este consecinta atacurilor demielinizante
recurente; mult probabil progresia se coreleaza cel mai bine cu atrofia medulara
progresiva, nu cu leziunile demielinizante
22
 - DD: afectiuni discale cervicale, spondiloza cervicala, tumori cervicale;
- LCR (pleiocitoza minora si anomalii oligoclonale IgG); 70-90% pe IRM alte
leziuni ale substantei albe medulare si cerebrale

UpToDate: Transverse myelitis

Immunopathogenesis — The immunopathogenesis of TM is varied and reflects the rather diverse spectrum of this
disease from idiopathic to disease-associated myelitis. Traditionally, the majority of TM cases were thought to be
characterized by perivascular infiltration by monocytes and lymphocytes in the lesion [1]. Axonal degeneration was
also reported [1]. Pathologic heterogeneity and the involvement of both gray and white matter suggest that TM is not
a pure demyelinating disorder but rather a mixed inflammatory disorder that affects neurons, axons, and
oligodendrocytes and myelin. TM has been reported after vaccination.
Associated and causative conditions — Idiopathic TM usually occurs as a postinfectious complication and appears
to result from an autoimmune process. Alternatively, secondary TM can be directly associated with infectious,
systemic inflammatory, or multifocal central nervous system disease.

●Central nervous system autoimmune disorders that can cause TM include the following:

•Multiple sclerosis – TM can occur as part of the spectrum of multiple sclerosis. In some cases, TM is the
initial demyelinating event (a clinically isolated syndrome [CIS]) that precedes clinically definite multiple
sclerosis.

•Neuromyelitis optica spectrum disorder (NMOSD) – TM manifesting as a longitudinally extensive spinal

cord lesion spanning three or more vertebral segments is one of the characteristic manifestations,
along with optic neuritis, of neuromyelitis optica spectrum disorder. However, neuromyelitis optica
spectrum disorder can also cause TM involving fewer segments. The most common autoantibody identified
in NMOSD is the anti-aquaporin 4 (AQP4) antibody.

•Acute disseminated encephalomyelitis (ADEM) – TM may be seen in patients with ADEM, a

demyelinating disease of the central nervous system that typically presents as a monophasic disorder with
multifocal neurologic symptoms and encephalopathy. Brain involvement is required to make a diagnosis of
ADEM.

•Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) – This disorder is associated

with a variety of manifestations related to central nervous system demyelination that include relapsing and
bilateral optic neuritis, transverse myelitis, brainstem encephalitis, and ADEM. MOGAD is more common
in children than adults and can mimic the NMOSD syndrome seen in patients with the anti-AQP4 antibody.
●Systemic inflammatory autoimmune disorders have been associated with TM, but some conditions are
more common than others.

The systemic inflammatory autoimmune disorders more commonly associated with TM include the following:
•Sarcoidosis •Sjögren syndrome •Systemic lupus erythematosus

Less commonly associated systemic inflammatory autoimmune disorders include:•Ankylosing spondylitis

•Antiphospholipid antibody syndrome •Behçet disease •Mixed connective tissue disease •Rheumatoid arthritis
•Systemic sclerosis

23
●Infections including but not limited to enteroviruses (commonly enterovirus D68 and EV71), West Nile virus,
herpes viruses, HIV, human T-cell leukemia virus type 1 (HTLV-1), Zika virus [48], neuroborreliosis (Lyme),
Mycoplasma, and Treponema pallidum (table 1 and table 2). In general, infectious causes of spinal cord dysfunction
are rare, but outbreaks of acute flaccid myelitis (AFM) serve as a reminder of the myelitis outbreaks seen during
poliovirus outbreaks.

●Paraneoplastic syndromes – Paraneoplastic myelopathy can present as a rapidly progressive spastic paresis with or
without bowel and bladder dysfunction. It often occurs in association with involvement of other areas of the nervous
system; examples include encephalitis, sensory neuronopathy, chorea, and optic neuropathy. However,
paraneoplastic myelopathy can also occur as an isolated syndrome. The most commonly associated antibodies are
anti-Hu, anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, antiamphiphysin antibodies
(table 3). The usual culprit is small cell lung cancer (SCLC).

Determining if the myelopathy is inflammatory — If a compressive myelopathy is ruled out, the clinician should
determine whether the myelopathy is inflammatory or noninflammatory. Spine MRI; CSF analysis

Determining the cause of TM

CNS inflammatory demyelinating disorders — Clinical and imaging evidence of multifocal involvement
within the central nervous system (CNS) raise suspicion for TM associated with multiple sclerosis, neuromyelitis
optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), or acute
disseminated encephalomyelitis (ADEM) (table 5).

●Brain MRI – Brain MRI with and without gadolinium is recommended to evaluate for the presence of
brain and/or optic nerve lesions suggestive of multiple sclerosis, NMOSD, MOG antibody disorders, or ADEM.

●Autoantibody testing – For patients with suspected TM of unknown etiology, we test for serum anti-
aquaporin-4 (AQP4) IgG autoantibodies (associated with NMOSD) and anti-MOG IgG autoantibodies (associated
with MOGAD).

●CSF findings – Oligoclonal bands in CSF are found in 85 to 95 percent of patients with multiple sclerosis
but are more frequently absent in patients with anti-AQP4 antibody-mediated NMOSD or ADEM.

Search for inflammatory disorders

Infectious causes

Paraneoplastic syndromes

Deficiency syndromes

DD: Noninflammatory conditions that may mimic TM include the following

●Vascular myelopathies •Anterior spinal artery infarction; •Spinal-dural arteriovenous fistula; •Fibrocartilaginous
embolism

●Metabolic and nutritional myelopathies: •Vitamin B12 deficiency; •Vitamin E deficiency; •Copper deficiency;
•Nitrous oxide toxicity •Neurolathyrism and neurocassavism

24
●Neoplasms: •Intramedullary primary spinal cord tumor; •Primary central nervous system lymphoma; •Intravascular
lymphoma

●Radiation myelopathy

Secondary transverse myelitis

Acute flaccid myelitis

Guillain-Barré syndrome

TREATMENT Acute idiopathic TM — We suggest high-dose intravenous glucocorticoid treatment for patients
with acute idiopathic TM. Glucocorticoid treatment should be initiated as soon as possible; there are relatively few
contraindications. Thus, a clinician does not need to wait for the workup to be complete before initiating therapy.
Our preferred regimens are methylprednisolone (30 mg/kg up to 1000 mg daily) or dexamethasone (120 to 200 mg
daily for adults) for three to five days. Continued treatment with glucocorticoids or more aggressive regimens is
based upon the clinical course and radiologic parameters.

Alte manifestări clinice ale atacurilor acute

- Alte manifestari precoce ale SM sunt: instabilitatea mersului, simptome de afectarea
trunchiului cerebral (diplopie, vertij, varsaturi), parestezii sau amorteala unui intreg
membru sup sau inf, durere faciala simuland nevralgia de trigemen (tic douloureaux);
tulb de mictiune
- Vertij de tip central - smen initial frecvent, dar apare si in cazuri definite
- In numar restrans apar: hemiplegia, sindr dureroase, pareza faciala, surditate, crize
epileptice
- Poate sa apara mai multe simptome aproape simultan
- Un sindrom relativ izolat- la femei mai varstnice - mielopatia cervicala lent progresiva cu
slabiciune musculara si ataxie (dificil de diferential de spondiloza)
- Nistagmus si ataxia cu/fara slabiciune musculara si spasticitatea membrelor (implicarea
tracturilor cerebeloase si corticospinale)
- Ataxia de tip cerebelos- vorbire scandata, instabilitate ritmica a capului si
trunchiului, tremor intentional a membrelor sup si inf, tulb de coordonarea
miscarilor voluntare a mersului
- Triada Charcot: nistagmus, vorbire scandata, tremor intentional
- In SM cu evolutie indelungata poate sa apara forma severa de ataxie cerebeloasa-
la cea mai mica tentativa de miscare apare prematur un tremor ataxic violent
(leziune mul probabil la niv tegmentului mezencefalic si implica tracturile dento-
rubro-talamice)
- Ataxia cerebeloasa poate fi combinata cu ataxia senzitiva- din cauza afectarii
cordoanelor posterioare a maduvei spinarii sau lemniscurilor mediale de la niv
trunchiului cerebral

25
 - Diplopia - frecvent; rezultatul afectarii fasciculelor longitudinale mediale determinand-
oftalmoplegie internucleara; in SM aceasta afectiune este de obicei bilaterala (spre
deosebire de infarctele pontine mici, care cauzeaza o oftalmoplegie internucleara unilat.)
- Prezenta oftalmoplegiei internucleare bilaterale la un adult tanar este practic
diagnostica pentru SM
- Ocazional oftalmoplegia internucleara este combinata cu pareza miscarilor
conjugate pe orizontala in cealalta directie - sindrom unu si jumtatate (dar e mai
frecvent in AVC)
- Mai putin frecvent alte paralizii ale privirii
- Manifestari aditionale ale afectarii trunchiului cerebral: miokimia sau paralizia muschilor
faciali, surditate, tinnitus, vertij, varsaturi, rar stupor si coma
- Hipoestezie sau anestezie faciala tranzitorie sau nevralgie de trigemen la adult
tanar trebuie sa sugereze diagnosticul de SM
- Durere lombara joasa sacaitoare este o acuza obisnuita; rar durere ascutita, cu caracter de
arsura, imprecis localizata, sau durere radiculara lancinanta la membru sau trunchi

Simptome si semne ale bolii clinic definite

Un numar de sindroame clinice survin cu regularitate atunci cand diagnosticul de SM a devenit

virtual o certitudine
- ½ din pacienti vor avea un tablou mixt sau de tip generalizat cu semne ce denota
afectarea nervilor optici, trunchiului cerebral, cerebelului si maduvei spinarii - cordon
posterior si tract corticospinal
- 30-40% din pacienti vor prezenta grade variate de ataxie spastica si tulburari de
sensibilitate profunda - deci o forma spinala a bolii
- Cea mai comuna manifestare- parapareza spastica asimetrica cu un grad de tulburare de
sensibilitate mioartrokinetica si vibratorie la MI
- 5% din pacienti - forma predominant cerebeloasa cu afectarea trunchiului cerebral si a
cerebelului
- 80% alte forme mixte si spinale
-un grad de deteriorare cognitiva, un declin progresiv la 50% din pacienti cu SM cu evolutie
indelungata: scaderea atentiei, viteza de procesare si capacitatea executiva diminuate, tulburare
de memorie, cu pastrarea limbajului si a altor functii intelectuale - trasaturi din “dementa
subcorticala” (Cap21.)
- pierderea memoriei de stocare, dementa globala sau o stare confuzional-psihotica in
stadii avansate in cazuri limitate
- declinul cognitiv se coreleaza cu scaderea volumului substantei albe, subtierea corpului
calos si atrofia cerebrala masurate pe IRM
- euforia, o buna dispozitie patologica - “o indiferenta stupida”, “un optimism morbid”,
“la belle indifference” - poate face parte din sindromul pseudobulbar

26
 - un numar mare de pacienti sunt deprimati, irascibili si colerici; depresie 25-40%
- tulb cognitiva- dementia subcorticala, dar demielinizarea cortexului este din ce in ce
mai mult recunoscuta ca o posibila baza a dementei din SM - pierderea volumului substantei
cenusii pare sa fie la fel de predictiva pentru dementa ca pierderea sustantei albe centrale
- disfunctia vezicii urinare - disuria, mictiuni imperioase, polachiuria, incomntinenta urinara -
apar de obicei cand e implicata maduva spinarii; disfunctie erectila
- retentia urinara - afectare segmentelor sacrate - mai putin frecvente
- atacuri paroxistice de deficit neurologic - cu o durata de cateva secunde sau minute, care se
repeta uneori de mai multe ori pe zi - manifestari rare dar bine cunoscute, pe parcursul fazei
recurent remisive
- cele mai comune: disartria, ataxia, durerea si disestezia paroxistica la nivelul unui
membru, fosfene, pruritul paroxistic sau “crizele epileptice” tonice - sub forma spasmului in
flexie (distonic) a mainii, pumnului si cotului cu extensia membrului inferior;
- simptomele paroxistice, spasmele tonice, pot avea ca trigger stimuli senzitiv, sau pot fi
provocate prin hiperventilatie (rar simptome de debut -mana distonica si spasme la MS - placa
acuta in capsula interna controlaterala), in cazuri avansate spasmele pot implica toate memrele
- aceste simptome tranzitorii apar brusc, pot sa reapara pa parcursul mai multor zile sau
saptamani, ulterior se remit complet
- uneori e dificil de diferentiat daca e o exacerbare sau o noua leziune, mai ales daca
leziunea originala era asimptomatica
- Simptomele si semnele pot progresa fara aparitia de noi placi
- Carbamazepina - control eficient al atacurilor spontane
- Atecazolamida - blocheaza spasmele tonice dureroase induse de hiperventilatie
-Oboseala neobisnuit de severa este un alt simptom caracteristic al SM
- cel mai frecvent este tranzitorie, si apare cand pacientul este febril sau cand exista
dovezi de activitate a bolii;
- dar poate fi si persistenta - depresia poate avea un rol in aceste cazuri refractare, dar
antidepresivele nu amelioreaza oboseala
- medicamente pentru ameliorarea oboselii: modafilin, amantadin
- Nevralgie trigeminala tipica (tic douloureaux) la pacienti tineri
Pareza faciala periferica tip Bell nu este aproape niciodata semn de SM
-Durere brahiala, toracica sau lombosacrata, manifestata in principal prin disestezii termice si
dureroase
-simptome distonice si paroxistice - dar nu sunt tipice
- frecvența crizelor epileptice variaza larg, dar mai ales in boli avansate
-aparitia comei in timpul recaderilor scelrozei multiple cu evolutie indelungata urmata de deces
Factori precipitanti ai atacurilor acute
Cele mai frecvente: infectiile, traumatismele si sarcina - dar niciunul nu a fost asociat
convingator
- Unele afectiuni febrile (ex infectie de tract urinar), pot exacerba simptomele preexistente

27
 - Incidenta infectiilor virale respiratorii, urinare sau gastrointestinale care preced debutul
bolii sau exacerbarile viaza larg intre 5-50%
- Rolul potential al traumatismelor este dificil de apreciat

Variante de scleroza multipla

Scleroza multipla acuta si psueod-tumorala (tumefianta) (varianta Marburg)

Rar, SM are o evolutie rapid progresiva si agresiva

Asociere de semne de afectare: cerebrala, spinala, si trunchi cerebral - survine pe parcursul
catorva saptamani - pacientul devine stuporos, comatos/ decerebrat, semne evidente de nervi
cranieni si cai corticospinale - deces in cateva saptamani - luni
- Autopsie- leziuni macroscopice - placi acute foarte intense de SM; multe placi sunt de
aceeasi varsta evolutiva, condfluenta mai multor zone de demielinizare perivenoasa
- LCR- raspuns celular fara benzi oligoclonale
- Putini pot ameliora dupa cativa luni, cativa pacienti au ramas stabili 25-30 de ani, dar pot
sa aiba si recaderi tipice pt SM
Placi acute de mari dimensiuni cu efect de masa asociat si priza de contrast - ce simuleaza
imagistic o tumora - SM forma tumefianta
- O leziune tumefianta poate surveni si independent in cazurile noi de boala sau de boala
deja confirmata, evoluand asemanator ca si SM tipic

Radiopaedia: The Marburg variant of multiple sclerosis, also known as acute, fulminant, or malignant
multiple sclerosis, is characterized by extensive and fulminant acute demyelination, often resulting in death within
one year after the onset of clinical signs.

MRI Extensive confluent areas of tumefactive demyelination are seen with mass effect and defined rings and
incomplete ring enhancement

Differential diagnosis Possible imaging differential considerations include: Baló concentric sclerosis (BCS) ; acute
disseminated encephalomyelitis (ADEM) - similar, although Marburg is usually more severe

Tumefactive multiple sclerosis is a term used to describe patients with established multiple sclerosis who develop
large aggressive demyelinating lesions, similar/identical in appearance to those seen in sporadic tumefactive
demyelinating lesions (TDL). TDL is now considered to be a separate entity, lying on a spectrum between multiple
sclerosis and postinfectious demyelination/acute disseminated encephalomyelitis (ADEM) 1-3.

Tumefactive demyelinating lesion (TDL), also sometimes referred to as monofocal acute inflammatory
demyelination (MAID), is a locally aggressive form of demyelination, usually manifesting as a solitary lesion (or
sometimes a couple of lesions) greater than 2 cm that may mimic a neoplasm on imaging.

On imaging, they usually present with relatively little mass effect or surrounding edema, contrast enhancement in an
open-ring pattern, high ADC values, and low relative cerebral blood volume (rCBV).

28
Clinical presentation Patients present with symptoms atypical for multiple sclerosis such as focal neurologic
deficits, seizures, and/or aphasia 5. Most do not progress to multiple sclerosis. In some instances, patients can
deteriorate rapidly and succumb to illness (e.g. acute malignant Marburg variant of MS).

CT- Tumefactive demyelinating lesions appear as a large hypoattenuating lesion with ill-defined ring enhancement,
central necrosis, perilesional edema and minimal mass effect 7.

MRI - The International Magnetic Resonance Imaging in MS Collaboration categorizes the different MRI
appearances of tumefactive demyelination:

ring-enhancing

diffusely infiltrative

Megacystic

Balo-like

Tumefactive demyelinating lesions tend to be large but with relatively little mass effect or surrounding edema.
Centrally located dilated veins have also been observed within these lesions

Differential diagnosis

high-grade glioma (e.g. GBM)

CNS lymphoma

cerebral infective process: cerebritis or cerebral abscess

Boala Balo si boala Schilder

Scleroza concentrica Balo -prezenta de benzi alternante de distructie si conservare a mielinei

intr-o serie de inele concentrice ce reprezinta arii alternante de pierdere si conservare a mielinei
- De obicei se regaseste in cadrul fazei acute a bolii, dar poate sa apare in cazuri izolate de
SM cronica recurenta
Radiopaedia: Baló concentric sclerosis is a rare and severe monophasic demyelinating disease, considered
a subtype of multiple sclerosis, appearing as a rounded lesion with alternating layers of high and low
signal intensity on MRI, giving it a characteristic 'bullseye' or 'onion bulb' appearance
- although it is usually monophasic, most closely resembling acute Marburg type multiple
sclerosis, with rapid progression and sometimes fulminant course

Scleroza difuza sau boala Schilder - emisferele cerebrale sunt afectat de demielinizare difuza si
masiva;
- Cazuri mai frecvente in copilsrie si adolescenta
- Reactie inflamatorie evidenta cu relativa crutare a axonilor
- Schilder a denumit encefalita periaxiala difuza/ encefalita periaxiala sclerotica

29
 - Putem face abstractie de leucodistrofiile metabolice ereditare si alte afectiuni ale
substantei albe caracteristice copilariei
- Boala poate avea o evolutie similara SM, fie stabila si fara remisiuni, fie punctata de serii
de episoade de agravare rapida
- LCR - modificrai similare celor din SM cronica recurenta
- Deces dupa cateva luni sau ani, dar unii pot supravietui sau mai mult
- DD: neoplasm cerebral difuz (gliomatoza sau limfom), adrenoleucodistrofia,
leucoencefalopatia multifocala progresiva

Radiopaedia: Schilder disease, also known as diffuse myelinoclastic sclerosis or diffuse cerebral
sclerosis, is considered a variant of multiple sclerosis, and represents an extremely rare progressive
demyelinating process that begins in childhood

Scleroza multipla asociata cu neuropatia periferica

- Au existat pacienti care au avut si polineuropatie sau mononeuropatie multiplex
- Mult probabil o coincidenta cu alte boli subiacente (boala Lyme, SIDA)
- Dar o demielinizare autoimuna ar putea afecta maduva spinarii si nervii periferici, luand
forma unei poliradiculoneuropatii cronice inflamatorii
- Simptomele rediculare/neuropatice, motorii si/senzitive pot rezulta din afectarea fibrelor
mielinizate din zona medulara de intrare a radacinilor nervoase sau a fibrelor eferente din
substanta alba ventrala

Modificari de laborator in scleroza multipla tipica

Lichidul cefalorahidian
⅓ din pacienti, mai ales cu debut acut sau exacerbare - poate exista o pleiocitoza cu
mononucleare (de obicei sub 50 celule/mm3, 6-20)
- In caz sever de neuromielita optica, sau afectare severa de trunchi, nr celulelor poate fi
>100 celule/mm3, chiar si 1000 (leucocite polimorfonucleare)
- Pleiocitoza poate fi singura masura a activitatii bolii
-proteinele gama globulinice din LCR sunt sintetizate la niv SNC - migreaza la electroforeza cu
gel de agar sub forma de populatii anormale distincte - benzi oligoclonale - mai larg utilizat pt
confirmarea diagnosticului
-determinarea benzilor oligoclonale IgG - mai multe benzi in LCR la >90% din cazuri cu
SM; dar apar si la pacienti cu sifilis, Lyme si panencefalita sclerozanta subacuta
- demonstrarea benzilor oligoclonale in LCR dar nu in sange - importante pt diagnostic;
insa nu in totdeauna sunt prezente la primul atac, sau in stadii mai tardive
- prezenta benzilor la primul atac este predictiva pt o evolutie cronica cu recaderi
- benzile sunt considerate prezente daca există mai mult de o banda
-in mielopatie necrotica si in boala Devic benzile sunt de obicei absente

30
-40% din pacienti continutul total de proteine in LCR este crescut - dar usor, >100 mg/dl este
neobisnuita, trebuie considerat alt diagnostic
-masusrare IgG si indexul IgG in LCR (semnaleaza proportia gama globulinelor in raport cu
proteinele totale din LCR) - test pozitiv inseamna >12% din proteinele totale - mai putin folosit
- LCR la multi pacienti contine concentratii mari de MBP (myelin basic protein) in timpul
exacerbarilor acute, nivel mai scazut in SM lent progresiv sau in remisiuni; alte leziuni (infarct)
pot creste MBP
- la pacienti cu SM clinic definita vor fi modificari - celule, proteine totale, gama globuline,
benzi oligoclonale

Imagistica
-ex IRM cel mai util test auxiliar - identificarea placilor asimptomatice si simptomatice - de la
niv emisferelor cerebrale, trunchi cerebral, nervi optici si maduva spinarii
- Chiar daca sunt o multitudine de leziuni cerebrale, astea tind sa fie asimptomatice; in schimb
leziunile de la niv maduvei spinarii sunt aproape intotdeauna simtomatice
Modificari IRM caracteristice leziunilor de SM:
- Placi SM hiperintense pe secventele T2-ponderate, mai evidente pe T2-FLAIR
- T2 sensibile pt detectarea leziunilor dintrunchi, cerebel si maduva spinarii
- Leziunile acute tind sa demonstreze exspansiune tisulara din cauza edemului car apare ca
o hipointensitate T1, hiperintensitate T2
- Leziunile cronice sunt contractate si hiperintense T2
- Prezenta hipointensitatii T1 depinde de gradul de remielinizare - daca e absenta sau
insuficienta - centrul da aspectul de “gauri negre”; hipointensitate T1 este invers
proportionala cu gradul de remielinizare
- leziuni individuale pe IRM nu garanteaza SM
- leziuni multifocale, bine demarcate, ovale sau liniare, orientate radial, adiacente
suprafetei ventriculilor- denota de obicei forma recurent remisiva de SM; orientarea
radiala corespunde traiectului venulelor incorporate in subtsnta alba cerebrala
- Imagini sagitale - leziunile se extind de la nivelul corpului calos sub forma filiforma -
“degetele Dawson”
- apar si leziuni subcorticale si infratentoriale, mai frecvent la niv tracturilor de substanta
alba ca pedunculii cerebrali si cerebelosi si fasciculul longitudinal medial
- Leziunile SM nu respecta teritoriile vasculare cerebrale si nu au o forma triunghiulara
tipica infarctelor cerebrale embolice
- Difuzia in SM este variabila
Alterarea barierei hematoencefalice survine precoce - hiperintensitate anormala T1 (priza de
contrast) dupa administrare de gadoliniu - care poate dura mai multe saptamani
- Apect caracteristic - forma de C incomplete sau al unui inel deschis de priza de contrast
patologica (util la diferentiere de abces, neoplasm), segmentul deschis al inelului este cel
mai frecvent situat medial

31
 - In cazuri avansate de SM leziunile periventriculare pot deveni confluente, de obicei la
polii ventriculilor
- Rar o leziune acuta intinsa poate avea efect de masa si o margine circulara de priza de
contrast (- similar cu un glioblastom -) leziune tumefianta
Pentru diagnostic SM - “diseminare in timp si spatiu”
- La un pacient cu un singur episod clinic, descoperirea leziunilor asimptomatice cu IRM
duce la stabilirea diagnosticului
- Diagnosticul poate fi revelat pe un singur IRM: unu sau mai multe leziuni acute (cu priza
de contrast), si leziuni aditionale fara priza de contrast
- Unele leziuni asimptomatice pot fi identificate la niv maduvei
- Examinari IRM seriate ce arata leziuni hiperintense T2 ce se acumuleaza in timp sunt
sugestive pt diagnostic
Atrofia cerebrala progresiva - reflecta pierderea ata celulelor gliale, dar mai ales degenerarea
valeriana si pierderea de axoni initiate in faza acuta a inflamatiei si in faza mai cronica
- Apreciata prin masuratori volumetrice ale cortexului, nucleilor profunzi si substantei albe
pe IRM - este o trasatura SM
- Demonstrabila ata in faza acuta cat si in cea tardiva - coreleaza bine co dizabilitatea
cognitiva
Leziunile spinale - ocupa numai o portiune a suprafeteoi transverse a maduveii, mai frecvent
situate la niv tracturilor de substanta alba, intr-o regiune subpiala
- Se extind rareori longitudinal, pe o distanta mai mare de 3 segmente, spre deosebire de
leziunile din neuromielita optica
- Leziunile acute pot cauza expansiunea focala a maduvei spinarii, pot avea priza de
contrast,
- leziunile cronice tind sa produca atrofie
Focarele periventriculare hiperintensitati T” intalnite si in alte patologii, chiar si persoane
normale; spre deosebire de SM aceste leziuni sunt orientate paralel cu suprafata ventriculara, au
contur mai net decat leziunile din SM, de obicei atribuite modificarilor micorvasculare
CT - poate sa demonstreze leziuni cerebrale, dar cu sensibilitate scazuta;
- Placile acute pot aparea ca leziuni cu priza de contrast inelara simuland un abces sau o
tumora
- Unele leziuni reiventriculare devin neevidentiabile radiologic dupa tratament cu steroizi

Radiopaedia

● T1
○ lesions are typically iso- to hypointense (T1 black holes)
○ callososeptal interface may have multiple small hypointense lesions (Venus necklace) or
the corpus callosum may merely appear thinned 11
○ hyperintense lesions are associated with brain atrophy and advancing disease 18
● T2
○ lesions are typically hyperintense

32
 ○ acute lesions often have surrounding edema
● SWI
○ central vein sign: at higher field strengths most plaques have been shown to be
perivenular (at 3 T, 45% of lesions; at 7 T, 87% of lesions) 19
● FLAIR
○ lesions are typically hyperintense
○ a very early sign is called ependymal dot-dash sign 16
○ when these propagate centrifugally along the medullary venules and are arranged
perpendicular to the lateral ventricles in a triangular configuration (extending radially
outward - best seen on parasagittal images), they are termed Dawson's fingers
○ FLAIR is more sensitive than T2 in the detection of juxtacortical and periventricular
plaques, while T2 is more sensitive to infratentorial lesions
● T1 C+ (Gd)
○ active lesions show enhancement
○ enhancement is often incomplete around the periphery (open ring sign)
● DWI/ADC
○ active plaques may demonstrate high or low ADC (increased or decreased diffusion)
10,11,22

○ also typically open ring in morphology

Potentiale evocate vizuale si alte teste:

-cand datele clinice indica o sinura leziune la niv SNC, cum e si in stadiile incipiente sau in
forma spinala - alte teste fiziologice si radiologice pot demonstra prezenta leziunilor
asimptomatice
-potentiale evocate vizuale, auditive, somestize,, intarzierea perceptiei la stimulare vizuala,
electroculografie, reflexe de clipire modificate, modificare a fuziunii la scintilatie a imaginii
vizuale (flicker fusion test)
- la 70% din pacienti cu caracteristici SM clinic definite, si la 60% cu SM probabil sau posibil -
anomalii ale raspunsurilor evocate vizuale
Tomografia in coerenta optica (OCT) - imagini bi sau tridimensionale ale nervului optic si a
retinei - afiseaza peierdere axonala si subtierea retinei care contribuie la evaluarea nevritei optice
si a atrofiei optice; folosit pt urmarirea evolutiei nevritei optice
Valoarea predictiva a testarii serologice pt anticorpi anti-oligodendrocite si anti-mielina ramane
de stabilit
Importanta anticorpilor anti-aquaporina (NMO)in boala Devic

Criterii de diagnostic pentru SM

33
 Tratamentul sclerozei multiple

-SM recurent remisiva, tipica, ce se asociază cu inflamatie episodica, este forma cu cel mai bun
răspuns la imunomodulatoare

-nu exista nicio corelație certă între nr de pusee si dizabilitate finală

Corticosteroizi:

-recuperarea după un atac, inclusiv un puseu de nevrita optica, pare sa fie accelerată la tratament
cu corticosteroizi

-un nr de pacienți cu exacerbări acute nu răspund la acest tratament

-nu exista dovezi ca steroizii au efect semnificativ asupra evolutiei bolii sau ca ei previn
recaderile

-într-un studiu cu metilprednisolon iv 1g/zi, timp de 5 zile pe luna timp de 5 ani, s-a observat o
reducere a dizabilitatii precum si a gradului de atrofie cerebrală si a volumului total de leziuni in
hiposemnal T1 pe IRM (zivadinov)

-pentru un atac doza de corticosteroizi, doza inițială crescută este mai eficienta

-Metiloprednisolon iv (un bolus de 500 pana la 1000 mg zilnic pentru 3-5 zile) urmata de doze
orale crescute de prednison (60-80 mg zilnic si scazand la un dozaj mai mic pe o perioada de 12
pana la 20 zile) este in general eficientă pentru a opri sau a scurta o exacerbare acuta/subacuta a
SM sau a nevritei optice

-daca nu se poate administra metilprednisolon parenteral, acesta poate fi inlocuit cu

metilprednisolon oral ( 48mg in doza unica timp de 1 saptamani, urmat de 24 mg/zi timp de 1
saptamana, iar in final de 12 mg/zi timp de 1 saptamana) sau doza echivalenta de prednison

-administrarea de corticosteroizi pe perioada scurta in general produce putine efecte adverse, unii
pacienti acuza insomnie, simptome depresive, maniacale

-cei care necesita tratament oral cu o durata mai mare de cateva saptamani, sunt susceptibili la
efecte adverse date de nivelul crescut de cortizol, inclusiv modificarile cosmetice la nivelul fetei,

34
trunchiului caracteristice sdr Cushing, HTA, hiperglicemi, control slab al diabetului,
osteoporoza, necroza avasculara de cap femural, cataracta, hemoragie gastrointestinala, activarea
tuborculozei, sau a unei infectii cu Pneumocystis.

-un studiu limitat a arata un oarecare beneficiu pentru pacientii cu forma recurent-remisiva, al
administrarii lunare de imunoglobulina iv (0.2 g/kg) timp de 2 ani.

We recommend high-dose, short-term glucocorticoid therapy for patients with an acute MS

exacerbation that results in neurologic symptoms and increased disability or impairments in
vision, strength, cerebellar function, or significant sensory disturbances. Before starting therapy,
acute infection (particularly of the urinary tract) should be ruled out, and any active infection
should be treated, since glucocorticoids are immunosuppressive and may exacerbate infection.

Intravenous methylprednisolone — Three- to seven-day courses of intravenous

methylprednisolone, 500 to 1000 mg daily, with or without a short prednisone taper, are used
most commonly Our preferred regimen is intravenous methylprednisolone 1000 mg daily for
five days, though this may be truncated for minor relapses where patients have symptomatic
relief with fewer than five treatments.

Oral prednisone — An alternative is a three- to seven-day course of oral methylprednisolone,

1000 mg daily, or oral prednisone, 1250 mg daily, with or without a short taper. Our preferred
regimen is oral methylprednisolone (1000 mg) without an oral taper

Adverse effects — Short-term high-dose glucocorticoid therapy is associated with relatively

few side effects in most patients, although mental status changes, increased susceptibility to
infection, and gastric disturbance are potential complications. Psychiatric adverse effects can
include increased depressive, manic, and hypomanic symptoms . To mitigate these adverse
effects, strategies include the prophylactic use of a proton pump inhibitor in the morning and/or
low-dose clonazepam at night while on glucocorticoid treatment. Patients with diabetes mellitus
may need to be hospitalized to monitor glucose levels.

An increased incidence of fractures has been reported in patients undergoing repeated

glucocorticoid therapy; baseline and yearly bone density scans are recommended for these
individuals.

Plasma exchange — We suggest treatment with PLEX for patients with acute, severe
neurologic deficits caused by MS attacks who have a poor response to treatment with high-dose
glucocorticoids.- One author uses PLEX particularly for patients with large, tumefactive lesions
causing severe deficits such as hemiplegia, paraplegia, quadriplegia, coma, aphasia, or acute
severe cognitive dysfunction, and for patients with optic neuritis and severe visual impairment

● Administration – PLEX is administered daily or every other day for a total of three to
seven treatments

35
 ● Adverse effects complications from PLEX are uncommon and generally mild; rarely
patients may experience potentially severe complications such as anaphylaxis, catheter
infection and thrombosis, bleeding, hypotension, cardiac arrhythmias, and a toxic reaction
to the citrate used in the procedure

Tratamentul nevritei optice

-prednison oral a crescut discret riscul de noi episoade de nevrita optica, conform unor
studii

-folosirea metilprednisolon iv accelereaza viteza recuperarii pierderii de vedere

Oral prednisone is generally not used.

● Intravenous methylprednisolone accelerated the recovery of visual function

●Intravenous methylprednisolone also reduced the risk of conversion to MS within the first
two years in comparison with either placebo or oral prednisone

●The oral prednisone arm of the study was found to have a higher two-year risk of
recurrent optic neuritis in either eye.

While subsequent small randomized trials have suggested that high-dose oral
corticosteroids (methylprednisolone 500 mg; prednisone 1250 mg) might have similar
efficacy to intravenous agents in regard to vision outcomes, their small size precludes
definitive conclusions, and their relatively short follow-up did not address the potential risk
of recurrent optic neuritis that was observed in the ONTT

Alternative treatments used for acute neuroimmunologic disease include intravenous immune
globulin (IVIG) and plasma exchange. These do not have established efficacy in the treatment
of optic neuritis.

Interferon-beta:

· Interferonul si glatiramerul acetat in mica masura modifica evolutia naturala a SM

recurent remisiv

· IFN-β-1b, un produs nonglicolizat al celulei bacteriene, cu o secventa de aminoacizi

identica cu cea a IFN-β natural

36
 · adm sc la 2 zile pentru o perioada de pana la 5 ani, scade frecventa si severitatea puseelor
cu aproape o treime, dar si nr de leziuni noi sau in crestere dimensionala (incarcatura
lezionala) pe IRM seriate

· Tratamentul SM recurent-remisiv cu IFN-β-1a este probabil cel mai eficient, doza 30mcg
sau 6.6 milioane de unitati.

· o problema legat de acest medicament este, formarea de anticorpi impotriva

medicamentului. Frecventa cu care acest ac apar creste cu frecventa administrarii
interferonului. Dupa cativa ani, ac sunt prezenti la 30 % dintre pacienti, care isi
administreaza zilnic, la 18% care si-l administreaza in zile alternative, la 5% la cei cu
administrare saptamanala. Conform unor date prezenta acestor ac scade eficienta
interferonului

· Efectele adverse sunt modeste, simptome pseudo-gripale, transpiratii, stare generala

proasta, care incep la cateva ore dupa injectie si persista pana la 14 ore. Sunt reduse de
administarea pre- si post tratament de antiinflamatoare nesteroidiene si tind sa scada cu
folosirea cu consecventa a produsului. In cazuri severe, 10 mg prednison, cu o ora anterior,
cateva ore dupa, si din nou la 6-8 ore de la injectare pot fi eficiente. Unii nu tolereaza
interferonul. Unii migrenosi acuza exacerbarea cefaleei. Poate exista o tendinta la depresie.
Rar, apare sdr de efractie capilara sistemica, la pacienții cu gamapatie monoclonala. Dacă se
administrează cu o frecventa mai mare de o data pe saptamana, se poate observa o creștere a
enzimelor hepatice

· Studiul CHAMPS, interferon la cei cu nevrita optica prim episod+ doua leziuni pe IRM
compatibile cu SM, pe o perioada de 3 ani, s-a observat o reducere modesta a progresiei
clinice sau a puseelor de la 37 la 28%

Interferons — Interferons are cytokines that modulate immune responsiveness through

various mechanisms. Indications and efficacy — All are indicated for the treatment of
relapsing forms of MS, including clinically isolated syndromes, RRMS, and active secondary
progressive multiple sclerosis (SPMS).

●Interferon beta-1b

●Interferon beta-1a - available in several different formulations, including intramuscular,

subcutaneous, and pegylated preparations.

•Intramuscular interferon beta-1a –30 mcg once a week

•Subcutaneous interferon beta-1a –22 mcg or 44 mcg of subcutaneous interferon beta-1a three times
per week for two years. Relapse was less frequent with sc. beta-1a, however, treatment with
subcutaneous interferon beta-1a was associated with a substantially higher rate of developing

37
 neutralizing antibodies. Most of these studies too suggest that IFNB treatment for MS does not
prevent long-term disability, though a minority suggests otherwise.

Adverse effects— Injection site reactions are common with IFNB therapy and can include injection
site necrosis. Flu-like symptoms are also common and may be treated with ibuprofen, acetaminophen,
and glucocorticoids [160]. Although depression has been reported as a possible adverse effect of
IFNB therapy. There is a relatively high prevalence of mainly asymptomatic liver dysfunction
(transaminitis) associated with IFNB therapy. Other: leukopenia and anemia. A partially reversible
polyneuropathy was described in a small series Rare cases of thrombotic microangiopathy have been
linked to the use of IFNB therapy.

Dosing and monitoring:

●Interferon beta-1b (Betaferon) – Recombinant interferon beta-1b is administered at 0.25 mg (1

mL) every other day subcutaneously by self-injection. Generally, the drug is started at 0.0625 mg
(0.25 mL) every other day and increased over a six-week period to 0.25 mg (1 mL) every other day.

●Intramuscular interferon beta-1a (Avonex) –is dosed at 30 mcg once weekly. To minimize flu-
like symptoms, one strategy is to start with 7.5 mcg (week 1) then increase dose in increments of 7.5
mcg once weekly (during weeks 2, 3, and 4) up to the recommended dose (30 mcg once weekly).

●Subcutaneous interferon beta-1a (Rebif) - is given as a dose of 22 mcg three times weekly or 44
mcg three times weekly [173]. Dose titration schedules for each target dose follow:

Target dose 44 mcg three times weekly:

•Initial dose 8 mcg three times weekly for weeks 1 and 2

•Increase to 22 mcg three times weekly for weeks 3 and 4

•Increase to 44 mcg three times weekly for week 5 and thereafter

Target dose 22 mcg three times weekly:

•Initial dose 4.4 mcg three times weekly for weeks 1 and 2

•Increase to 11 mcg three times weekly for weeks 3 and 4

•Increase to 22 mcg three times weekly for week 5 and thereafter

●Monitoring – Periodic monitoring of complete blood count, liver function, and thyroid function.

●Neutralizing antibodies and response markers – The development of neutralizing antibodies (NAbs)
may limit the effectiveness (in 34%) of interferons as measured by MRI activity, relapses, and disease
progression. In the setting of high disease activity, therapy should be changed independent of Nab or
MxA results. For patients who have NAb titers, a switch to a non-IFNB therapy would be indicated.

38
Glatiramer (Copaxone):

· Copolymerul I (glatiramer acetat), care a fost sintetizat pentru a simula actiunile proteinei
bazice a mielinei, un presupus autoantigen in SM, se adm. sc 20 mg zilnic

· Nu se formeaza ac fata de glatiramer acetat

-scade frecventa puseelor, scade severitatea bolii (apreciata cu incarcare de leziuni in

secventa T2), incetinirea progresiei catre invaliditate

-spre deosebire de interferon beta, poate fi utilizata la pacientii cu depresie

· reactii posibile: eritem facial, constrictie toracica, dispnee, palpitatii si anxietate, reactii la
locul injectarii. In caz de reactii urticariene extinse-trebuie oprit

Glatiramer acetatei is a mixture of random polymers of four amino acids. The mixture is
antigenically similar to myelin basic protein, a component of the myelin sheath of nerves. In
addition, glatiramer is a potent inducer of specific T helper 2 type suppressor cells that migrate
to the brain and lead to bystander suppression; these cells also express anti-inflammatory
cytokines.

Indications and efficacy- is indicated for the treatment of relapsing forms of MS, including
clinically isolated syndromes, RRMS, and active SPMS.

Adverse effects — Side effects of glatiramer acetate include local injection site reactions and,
less commonly, transient systemic postinjection reactions such as chest pain, flushing, dyspnea,
palpitations, and/or anxiety . Neutralizing antibodies to glatiramer acetate have been detected in
some studies but their clinical significance is unknown Desensitization to glatiramer acetate has
been successfully performed in patients with either systemic allergic reactions or recurrent local
reactions. Serious adverse effects due to glatiramer are uncommon, but cases of hepatotoxicity,
some severe, have been reported

Dosing and monitoring — is administered by subcutaneous injection. There are two different
doses, which are not interchangeable:

● 20 mg daily or

● 40 mg three times a week

No laboratory monitoring is necessary.

Medicamente imunosupresoare convenționale:

→ substanțe care modifica reactivitatea imuna

39
 → azathioprine, ciclofosfamida, iradiere limfoida totala, transplant medular -au fost folosite
in unele cazuri si au îmbunătățit evolutia la unii pacienți

→ riscurile folosirii îndelungate a medicamentelor imunosupresoare, inclusiv posibilitatea

apariției unei neoplazii, infecții -face imposibilă folosirea lor pe scala larga

→ pt faza cronica, progresiva a bolii, a fost observat discreta intarziere a progresiei bolii
dupa o administrare de 2 ani a prednisonului si ciclofosfamidei, din cauza toxicitatii severe
nu se utilizează

→ un studiu cu SM cronic progresiv, doze mici, saptamanale de metotrexat oral—ușoară

îmbunătățire si scaderea volumului leziunilor cerebrale pe IRM. avand in vedere ca acest
medicament este relativ bine tolerat, are o utilitate in cazuri progressive altminteri netratabile

→ mitoxantrona (imunosupresor si citotoxic extins)—efect usor benefic in forma progresiva

→ mycofenolat si medicamente similare folosite cu rate variabile de succes

→ aceste medicamente sunt utilizate din ce in ce mai putin frecvent

Anticorpi monoclonali:

1. Natalizumab (Tysabri):

· este un anticorp monoclonal îndreptat împotriva alfa integrinei pentru a bloca

adeziunea limfocitelor si a monocitelor la celulele endoteliale si migrarea lor prin peretele
vascular, blochează pătrunderea celulelor in parenchimul SNC

· a fost folosit in poliartrita reumatoida si in boala Crohn fistulizanta

· reduce nr de recaderi (reduce activitatea bolii clinic si radiologic) si încetinire a

acumulării de leziuni pe IRM

· La pacienti cu SM recurrent remisiv, reducere cu 68% a puseelor, cu 80% a leziunilor noi

sau in crestere pe IRM si o reducere cu 96% a leziunilor cu priza de gadolinium pe IRM dupa
un an.

· 2% reactie anafilactica

· administrare lunara intravenoasa, lipsa efectelor secundare acute

-se adm iv o data pe lun

40
 · poate sa apara Leucoencefalopatie multifocala progresiva (LEMP)—este posibila
insanatosirea daca medicamentul este intrerupt prompt si eliminat prin schimb plasmatic (a
inversat evolutia LEMP si a determinat disparitia virusului JC din LCR. La scurt timp dupa
schimb plasmatic poate sa apara sdr inflamator de reconstituire imuna, ameliorat de catre
corticosteroizi) Absenta virusului JC in urina si a ac serici impotriva JC fac improbabila
aparitia LEMP , insa sunt cazuri rare care contrazic acest fapt. Cei care au ac anti-virus JC,
riscul depinde de durata utilizarii natalizumabului (mai ales dupa 24 luni) si de utilizarea
anterioara sau concomitenta de medicatie imunosupresoare. Daca ambii factori sunt prezent
riscul de LEMP 11 la 1000

-Natalizumab is a recombinant monoclonal antibody directed against the alpha-4 subunit of

integrin molecules, thereby blocking integrin association with vascular receptors and limiting
adhesion and transmigration of leukocytes. In patients with MS, natalizumab treatment is
associated with a diminished migratory capacity of immune cells and a prolonged decrease in
lymphocyte counts in the cerebrospinal fluid.

Indications and efficacy — one of several disease-modifying therapies (DMTs) that effectively
reduce the relapse rate for patients with RRMS. Natalizumab is indicated as monotherapy for
the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndromes,
RRMS, and active secondary progressive multiple sclerosis (SPMS).

Adverse effects- treatment is associated with a risk of developing progressive multifocal

leukoencephalopathy (PML), a rare, potentially fatal neurologic disease caused by reactivation
of JC virus (JCV) infection.

The most frequent adverse events associated with natalizumab treatment include infusion-
related symptoms (headache, flushing, erythema, nausea, and dizziness), fatigue, infections
(mainly urinary tract and lower respiratory tract infections), arthralgia, gastroenteritis, vaginitis,
extremity pain, depression, and rash . Other than PML, opportunistic infections are rarely
associated with natalizumab therapy; they have included cases of herpes zoster, herpes
meningitis, herpes simplex virus encephalitis, and tuberculosis. Hepatoxicity, including clinically
significant liver injury, and thrombocytopenia have been reported in postmarketing data
Neonatal thrombocytopenia has been reported in newborns exposed to natalizumab in utero.

Natalizumab is contraindicated in patients who have or have had PML, and in patients with a
previous hypersensitivity reaction to natalizumab. Because of the risk of PML, natalizumab
should not be used for patients who may have impaired immunity, such as hematologic or
rheumatologic conditio+ns associated with compromised cell-mediated immunity The risk of
natalizumab-associated PML for an individual patient varies according to the following factors

●Anti-JCV antibody status

●Prior immunosuppressant treatment

● Duration of natalizumab exposure

41
Dosing and monitoring-* in piv, i cura la 4 saptamani

Administration — Natalizumab is given as a 300 mg IV infusion over one hour, every four
weeks. . Patients should be observed for any signs or symptoms consistent with hypersensitivity
reaction during the infusion and for one hour after the infusion is complete. Natalizumab should
be discontinued in patients who develop hypersensitivity reactions.

Among patients treated with natalizumab who are seropositive for JCV antibody, the risk of PML
may be reduced by converting the dosing interval to every six or eight weeks rather than every
four weeks, without a loss in efficacy.When there is suspicion for PML, natalizumab should be
discontinued

Before starting – Leukocyte and neutrophil counts should be within or close to the normal
range. We suggest stopping glucocorticoids and other immunomodulators for at least one
month prior to starting natalizumab. Cholestyramine may be used to accelerate the removal of
teriflunomide. A longer washout period (up to three months or more) is suggested for
azathioprine, methotrexate, mycophenolate, mitoxantrone, and cyclophosphamide . A baseline
brain MRI scan should be obtained prior to initiating therapy with natalizumab, since it is useful
in comparison with later MRI scans for detecting changes suggestive of PML.

Risk management program – For patients treated with natalizumab, rigorous clinical and
neuroimaging follow-up is essential in order to detect the onset of symptoms and signs
related to PML as opposed to those related to MS . Clinicians must evaluate patients at
three and six months after natalizumab treatment is started, and at least every six months
thereafter.

Antibodies to natalizumab – Antibodies to natalizumab are not routinely obtained in

clinical practice, but limited data suggest they may be useful in select patients with
infusion reactions or poor response to natalizumab. However, it is more common in these
scenarios to switch to a different DMT rather than obtain natalizumab antibody studies.
Antibodies to natalizumab developed in approximately 9 percent of patients in the
AFFIRM and SENTINEL trials, and were persistently positive in approximately 6 percent ű
When compared with antibody negativity, persistent anti-natalizumab antibody positivity
was associated with reduced clinical effectiveness of natalizumab treatment and with an
increased incidence of infusion reactions. The authors of the study suggest testing for
antibodies after six months of natalizumab therapy in patients who have continued clinical
MS activity or persistent infusion reactions and stopping natalizumab if antibody positivity
is confirmed by retesting after three more months.

Surveillance for PML — PML is rare in the first year of natalizumab therapy even among those
who are seropositive at baseline for anti-JCV antibodies. In patients with a negative or low JCV
antibody level, most studies suggest that approximately 97 percent remain low over an 18-
month period. However, the risk increases with in patients who are seropositive for anti-JCV
antibodies and longer duration of natalizumab therapy

42
 JCV antibody testing – We suggest testing for anti-JCV antibodies at baseline and
every six months while on natalizumab therapy. For patients who are seropositive and
without prior immunosuppressive treatment, determination of anti-JCV antibody levels, as
measured by the anti-JCV antibody index, may improve the accuracy of PML risk
stratification. The index allows quantification of anti-JCV antibody levels for individual
patients, and is calculated by normalizing the optical density of the anti-JCV antibody
serum sample with a calibrator. In contrast to testing for anti-JCV antibodies, testing for
JCV DNA in blood or urine appears to have no utility for determining the risk of PML. The
authors have noted with some frequency that despite ordering JCV antibody testing,
some commercial labs have erroneously run the JCV polymerase chain reaction (PCR)
instead. Therefore, it is important to verify that the correct test (the anti-JCV antibody
assay) was done when results come in.

JCV antibody status – The JCV antibody status, JCV antibody index, history of prior
immunosuppressant exposure, and duration of natalizumab exposure can be used to
estimate the risk of PML and to guide decisions concerning natalizumab therapy

For patients who remain seronegative for anti-JCV antibodies, the estimated
risk of PML is <1:10,000, suggesting relative safety of continuing natalizumab
as indicated for MS.

For patients who are seropositive or seroconvert to positive anti-JCV status,

and have with no prior use of immunosuppressant medications, the estimated
risk of PML varies with the strength of the seropositive response or the
antibody index; higher antibody levels are associated with a higher risk.

With an anti-JCV antibody index <0.9, the estimated risk of PML is <1:10,000 for
months 1 to 24 and 1:748 for >24 months of natalizumab exposure Suggested
monitoring involves repeating the anti-JCV antibody index every six months and
a brain MRI every 12 months of natalizumab exposure. At a minimum, clinicians
should counsel the patient about the risks of continuing natalizumab therapy
beyond 24 months, although it should be cautioned that PML risk is cumulative
rather than only beginning at the 24-month period.

With an anti-JCV antibody index of ≥0.9, the estimated risk of PML is <1:1062
for months 1 to 24 and 1:101 for >24 months of natalizumab exposure
Suggested monitoring involves repeating the MRI scan at 12 months and
then every 6 months beginning at 18 months of natalizumab exposure. For
patients with an index of ≥0.9, we suggest stopping natalizumab after 24 months of
treatment and transitioning to another DMT because of the mounting risk of PML.

Neurologic assessment – Clinical vigilance and neurologic follow-up is an important

aspect of monitoring for the signs and symptoms of PML. In general, MS relapses are
characterized by subacute onset, typically occurring over hours to days, with eventual

43
 stabilization and resolution, and typical presentations that include diplopia, optic neuritis,
and myelopathy. By contrast, PML is characterized by even slower onset over several
weeks to months, progressive disease, and presentations that include aphasia, behavioral
and neuropsychiatric abnormalities, cortical visual deficits, hemiparesis, and seizures.

MRI monitoring – Some PML cases have been discovered prior to any symptoms, and
imaging (ie, brain MRI) follow-up is very important. A baseline brain MRI scan should be
obtained prior to initiating therapy with natalizumab. For patients who are JCV antibody-
positive, screening for PML with brain MRI more frequently, as often as every three to four
months, may be advised, although practice preferences vary widely among MS experts.
For patients who are negative for JCV antibodies at baseline and at one year, we suggest
repeating the MRI scan every 12 months for PML monitoring

New MRI lesion – Any anti-JCV positive patient on natalizumab who develops a new MRI
lesion while should be evaluated for the possibility of PML. Important issues are the
specific characteristics of the lesion and the length of time on natalizumab. Radiologists
must be informed that patients are on natalizumab and at risk for PML, as the initial
lesions of PML may be indistinguishable from a new demyelinating lesion due to MS.
However, the presence of punctate hyperintense T2 lesions and cortical gray matter
involvement suggest PML rather than new MS-related lesions, while periventricular
location and focal appearance (as opposed to a diffuse, confluent irregular, or infiltrative
appearance) suggest new MS-related lesions rather than PML. Cerebrospinal fluid
analysis for JCV polymerase chain reaction (PCR) DNA is mandatory in these patients,
though different laboratories have different sensitivities, and the PCR may be negative in
early case of PML.

2. Ocrelizumab a recombinant human anti-CD20 (a B-cell marker) monoclonal antibody

that binds to a different, but overlapping, CD20 epitope than rituximab, another anti B cell
monoclonal antibody. It was designed to optimize B cell depletion by modification of the Fc
region, which enhances antibody-dependent cell-mediated cytotoxicity and reduces
complement-dependent cytotoxicity compared with rituximab; the latter has shown efficacy in
small trials and has been widely used in some MS centers for years.-reduce nr leziuni noi pe
IRM

Indications and efficacy — indicated for relapsing forms of MS including, RRMS, clinically
isolated syndrome (CIS), and active SPMS; it is also indicated for primary progressive MS

Adverse effects — The most common adverse effects of ocrelizumab are infusion reactions,
upper and lower respiratory tract infections, and skin infections

In the postmarketing setting, the following infections and immune-mediated conditions have
been reported in patients treated with ocrelizumab:

● Serious infections caused by herpes simplex virus and varicella zoster virus (VZV)

● Hepatitis B reactivation

44
 ● PML that developed in patients on ocrelizumab who had not received natalizumab or
prior immunomodulatory medications, and who did not have conditions resulting in
compromised immune system function

●Immune-mediated colitis

There may be an increased risk of malignancy, including breast cancer, with ocrelizumab..

Ocrelizumab is contraindicated in patients with active hepatitis B virus infection and those with
a history of life-threatening infusion reaction to ocrelizumab.

Dosing — The initial dose of ocrelizumab is a 300 mg IV infusion, followed two weeks later by a
second 300 mg IV infusion. Subsequently, ocrelizumab is given as 600 mg IV infusion every six
months, beginning six months after the first 300 mg dose. The drug should be given under close
medical supervision with access to medical support should severe infusion reactions develop.
Premedication is recommended with both methylprednisolone 100 mg IV (or equivalent
glucocorticoid) approximately 30 minutes prior to each ocrelizumab infusion and with an
antihistamine (eg, diphenhydramine) approximately 30 to 60 minutes prior to each ocrelizumab
infusion to reduce the frequency and severity of infusion reactions; an antipyretic (eg,
acetaminophen) can be added as well. Infusions should be delayed, if there is active infection, until the
infection resolves. Some mild infusion reactions can be treated with additional doses of
methylprednisolone and/or antihistamine.

Quantitative levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M

(IgM) should be obtained at baseline; the label recommends consulting with immunology
experts for patients with low immunoglobulin levels before starting ocrelizumab. Patients must
be screened for hepatitis B virus before starting ocrelizumab. We also screen at baseline for
hepatitis C, tuberculosis, HIV, and obtain a complete blood count, lymphocyte subsets, and a
metabolic panel. Repeat screening for these factors depends upon individual patient
characteristics, such as hepatitis risk factors, prior vaccination, and level of hepatitis B surface
antibody (anti-HBs) as a positive response to vaccination.

Patients should receive all necessary live or live-attenuated vaccines at least four weeks before
starting ocrelizumab and non-live vaccines at least two weeks before starting ocrelizumab. Live-
attenuated and live vaccines are not recommended during ocrelizumab treatment or after
discontinuation until B-cell repletion occurs.

3. Alemtuzumab:

-ac monoclonal îndreptat împotriva antigenului CD-52 exprimat pe limfocitele T si B,

reduce nr de celule B circulante si pt o perioada mai lunga pe cele T

-este folosit într-un ciclu anual de adm iv de 5 zile consecutive

-poate produce purpura trombocitopenica idiopatica si tiroidita autoimuna

(hiper-/hipotiroidism)

45
Alemtuzumab — a humanized monoclonal antibody that causes depletion of CD52-expressing
T cells, B cells, natural killer cells, and monocytes.

Indications and efficacy — is indicated for the treatment of relapsing forms of MS, including
RRMS and active SPMS. Because of its safety profile, alemtuzumab is not recommended for
the treatment of clinically isolated syndromes. Alemtuzumab is generally reserved in the United
States for patients with highly active RRMS who have had an inadequate response to two or
more DMTs, or where other DMTs cannot be used. The drug is contraindicated in patients with
HIV infection, active infection, or known hypersensitivity to alemtuzumab..

Adverse effects — The main side effects are infusion reactions, infections, and autoimmune
disorders. Infusion reactions occur in approximately 90 percent of patients and are
characterized by headache, rash, nausea, and fever. Infections, though generally not severe,
were observed in two-thirds or more of the patients treated with alemtuzumab. Herpes viral
infections occurred in 16 to 18 percent, leading to a change in the protocol of the in-progress
CARE-MS trials with the addition of prophylactic acyclovir treatment during alemtuzumab
infusion and for 28 days after infusion. Thyroid autoimmunity was seen in 16 to 18 percent of
patients at two years after alemtuzumab treatment and in 30 percent with longer follow-up ITP

The prescribing label warns of an increased risk of autoimmunity (ITP, thrombotic

thrombocytopenic purpura [TTP], antiglomerular basement membrane disease, autoimmune
encephalitis), infusion reactions, thyroid disorders, hemophagocytic lymphohistiocytosis, adult-
onset Still disease, acquired hemophilia A, infections, and malignancies (thyroid cancer,
melanoma, lymphoproliferative disorders). .

Dosing and monitoring — Necessary immunizations must be completed at least six weeks
before the start of treatment with alemtuzumab. Patients without a history of VZV infection or
vaccination for VZV should be tested for antibodies to VZV, and VZV vaccination should be
considered for patients who are antibody-negative, with postponing alemtuzumab treatment for
six weeks after VZV vaccination. Patients should be screened for tuberculosis and advised to
avoid potential sources of Listeria monocytogenes.

To monitor for early signs of potentially serious adverse events, laboratory testing is
recommended at baseline and periodically thereafter until 48 months after the last treatment
course of alemtuzumab for the following:

● Urine protein to creatinine ratio prior to initiation of treatment

●Complete blood count (CBC) with differential prior to treatment and at monthly
intervals thereafter

●Serum creatinine levels prior to treatment and at monthly intervals thereafter

●Urinalysis with urine cell counts prior to treatment and at monthly intervals
thereafter

46
 ●Thyroid function testing (eg, thyroid stimulating hormone level [TSH]) prior to
treatment and every three months thereafter

●Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total

bilirubin levels prior to initiation and periodically thereafter

Baseline and yearly skin examination are recommended to monitor for melanoma.

Alemtuzumab is administered via IV infusion at 12 mg daily for five consecutive days (total 60
mg) at the start of treatment followed 12 months later by 12 mg daily for three consecutive days
(total 36 mg) . Subsequent treatments (12 mg daily for three consecutive days, total dose 36
mg) are given as needed at least 12 months after the last dose of a previous treatment course.
Premedication with glucocorticoids (1 g of methylprednisolone) for the first three days of therapy
is indicated. Infusions should be administered in a medical setting capable of managing
anaphylaxis, serious infusion reactions, and myocardial, cerebrovascular, or pulmonary adverse
reactions, and patients should be observed for at least two hours after each infusion.

Alemtuzumab therapy requires monitoring (for infusion reactions, symptoms of ITP, and
symptoms of nephropathy) and prophylaxis for herpes virus infections (oral acyclovir 200 mg
twice daily) during treatment and continuing for at least two months after completion of a
treatment course, or until the CD4+ count is >200 cells/microL, whichever occurs later ].
Prolonged surveillance (for 48 months after the last dose) for bone marrow suppression,
infections, and autoimmune disorders such as ITP is also necessary. Patients should be
educated about the symptoms of ITP and should report them immediately if they develop.

4. Ofatumumab — a monoclonal antibody that targets CD20 (a protein expressed on the

surface of normal B lymphocytes) and causes selective B cell depletion.

Indications and efficacy — for the treatment of adults with relapsing forms of MS, including
clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive
disease.

Adverse effects — The most common adverse effects observed with ofatumumab are upper
respiratory tract infection, headache, injection-related reactions, and local injection site
reactions. The potential for reduction in immunoglobulins may increase the risk of recurrent
infections or opportunistic infections.

Contraindicated in patients with active hepatitis B virus infection. Animal data suggest a risk of
fetal harm. The label recommends use of an effective method of contraception during
ofatumumab treatment and for six months after discontinuation.

Dosing and monitoring — is given by subcutaneous injection, starting with 20 mg

administered at weeks zero, one, and two. Subsequently, the dose is 20 mg per month starting
at week four. Before the first dose, patients should be screened for hepatitis B virus and tested
for quantitative serum immunoglobulins. Patients should receive all recommended
immunizations at least four weeks before starting ofatumumab. Administration should be

47
delayed in patients with active infection until the infection resolves. Live or live-attenuated
vaccines are not recommended during treatment and after stopping treatment until B cell
repletion occurs.

5.Rituximab:

-ac monoclonal care tinteste limfocitele CD20, eliminand celulele B, eficient in reducerea
puseelor si a acumulării de leziuni IRM

Indications and efficacy — Rituximab has been widely used off-label to treat MS in some
centers for years. Data from randomized controlled trials supporting the effectiveness of
rituximab for RRMS are limited but convincing, and nonrandomized studies and the positive
trials for ocrelizumab increase confidence that rituximab is beneficial.

Adverse effects — Potential adverse effects include infusion reactions,

hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia.

Rare cases of PML have been reported in patients treated with rituximab for other indications.
However, it is unknown if rituximab increases the risk of PML, since rituximab is often used to
treat patients who have an underlying risk factor for PML.

Dosing and monitoring — Patients must be screened for hepatitis B virus before starting
rituximab. We also screen at baseline for hepatitis C, tuberculosis, HIV, and obtain a complete
blood count, lymphocyte subsets, levels of IgG, IgA, and IgM, and a metabolic panel. In
addition, patients should ideally receive all necessary immunizations at least six weeks prior to
starting rituximab.

Immunoglobulin levels should be monitored prior to each infusion cycle.

Rituximab dosing varies:

● Induction with two 1 g infusions separated by a two-week interval, followed by 1 g

infusion given every six months

●1 g infusion given every six months with a reduction in the dose and/or infusion
frequency after one or two years

●500 mg infusion given every six months

Rituximab should be given under close medical supervision with access to medical support to
manage possible severe infusion reactions. Premedication is recommended using both
methylprednisolone 100 or 125 mg IV (or equivalent glucocorticoid) approximately 30 minutes
prior to each rituximab infusion, and with an antihistamine (eg, diphenhydramine) approximately
30 to 60 minutes prior to each rituximab infusion, to reduce the frequency and severity of
infusion reactions; an antipyretic (eg, acetaminophen) can be added as well. Infusions should
be delayed if there is active infection until the infection resolves.

48
Terapii orale:

1. Fingolimod:

-medicament imunosupresor care interfera cu migrarea limfocitelor din ganglioni limfatici,

efect scurt asupra incarcarii lezionale, asupra frecventelor puseelor

-se adm oral odata pe zi

-duce la limfopenie, ingradind limfocitele la nivelul ganglionilor limfatici si produce

adenopatii

-este necesara intreruperea in cazuri rare, din cauza unei bradicardii extreme su BAV,
edem macular, infectii herpetice, cresterii enzimelor hepatice

S1PR modulators — Fingolimod, siponimod, ozanimod, and ponesimod are sphingosine 1-

phosphate receptor (S1PR) modulators used for the treatment of MS

Fingolimod — is sphingosine analogue that modulates the S1PR and thereby alters
lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes

Indications and efficacy — Fingolimod is indicated for the treatment of relapsing forms of MS,
including clinically isolated syndromes, RRMS, and active SPMS.

Adverse effects — The most common adverse effects are headache, elevated liver enzymes,
diarrhea, cough, flu, sinusitis, back pain, abdominal pain, and pain in the arms or legs.
Fingolimod treatment has been associated with an increased risk of bradyarrhythmia and
atrioventricular block (potentially fatal), macular edema, liver injury, diminished respiratory
function, tumor development, and opportunistic infections ű The immunomodulating and
lymphocytopenic effects of fingolimod increase the risk of viral and fungal infection, including
varicella zoster virus (VZV) infections, cryptococcal meningoencephalitis, and disseminated
cryptococcus. Rare cases of PML have been reported patients with and without prior
immunosuppressant treatment All reported cases occurred after 19 months of fingolimod
treatment.

Contraindicated in patients with recent (within six months) myocardial infarction, unstable angina,
stroke, transient ischemic attack (TIA), or heart failure, a history of second- or third-degree
atrioventricular block or sinus node dysfunction (unless treated with a pacemaker), a prolonged QT
interval ≥500 milliseconds at baseline, and treatment with anti-arrhythmic drugs We suggest not using
fingolimod to treat patients who have diabetes because they are at increased risk for macular
edema, which has been reported in association with fingolimod treatment. In addition, the trials
of fingolimod excluded patients with diabetes.

Dosing and monitoring — Before starting fingolimod, patients should have the following :

● Complete blood count and liver function test results within six months

49
 ● Electrocardiogram (ECG)

● Ophthalmologic examination

● Varicella serology, and VZV vaccination if antibody negative, for patients without a
confirmed history of chicken pox or prior vaccination; fingolimod should not be started
until one month after vaccination

● Females of childbearing potential should be informed of risk for adverse fetal outcomes;
however, a higher rate of fetal abnormalities was not detected among infants exposed to
fingolimod in pregnancy registries

In addition, we suggest a skin examination at baseline to screen for evidence of precancerous

skin lesions.

The dose of oral fingolimod is 0.5 mg once daily. The first dose, and doses following therapy
interruption longer than 14 days, should be given in a setting where symptomatic bradycardia
can be managed

.At treatment initiation, baseline pulse and blood pressure should be measured. These
measurements should be repeated hourly for six hours after the first dose while the patient is
observed for signs of bradycardia or atrioventricular block, and an ECG should be obtained at
the end of the six-hour observation period.

During fingolimod treatment (and for two months after stopping), patients should be monitored
for symptoms and signs of infection, and live attenuated vaccines should be avoided.
Ophthalmologic examination should be repeated three to four months after starting fingolimod,
and routinely in patients with diabetes mellitus or a history of uveitis. Pulmonary function testing
with spirometry and diffusion lung capacity for carbon monoxide should be obtained if indicated
clinically, and liver function tests should be monitored for patients with symptoms suggestive of
hepatic dysfunction.

Fingolimod is a possible teratogen and should be stopped two months prior to conception.

2.Siponimod:

- a S1PR modulator that is similar to but more selective than fingolimod.

Indications and efficacy: for the treatment of adults with RRMS, active SPMS, and clinically
isolated syndromes.

Adverse effects — The most common adverse are headache, hypertension, and increased
transaminase levels.- Siponimod cause a dose-dependent decrease in peripheral lymphocyte
counts by approximately 20 to 30 percent. Potential adverse effects include infections, macular
edema, bradyarrhythmia, decreased pulmonary function, liver toxicity, cutaneous malignancies,
increased blood pressure, and fetal harm.

50
Contraindicated for patients with a CYP2C9*3/*3 genotype (which causes substantially
elevated siponimod plasma levels), or those with recent myocardial infarction, unstable angina,
stroke, TIA, or advanced heart failure. It is also contraindicated for patients with Mobitz type II
second-degree or third-degree atrioventricular block, or sick sinus syndrome unless patient has
a functioning pacemaker. Caution is suggested for concomitant use with other anti-neoplastic,
immune-modulating, or immunosuppressive therapies.

Dosing and monitoring — Prior to starting treatment, patients should be tested for CYP2C9
genotype, complete blood count, liver function, and presence of antibodies to VZV; antibody-
negative patients should receive varicella vaccination . In addition, patients should have
baseline ophthalmic evaluation of the fundus and cardiac evaluation, including ECG, to look for
conduction system abnormalities. A skin examination at baseline and periodically thereafter is
recommended to monitor for precancerous skin lesions.

The starting dose of siponimod is 0.25 mg daily. The first dose should be monitored for patients
with sinus bradycardia, first- or second-degree (Mobitz type I) atrioventricular block, or a history
of myocardial infarction or heart failure. For patients with a CYP2C9*1/*3 or *2/*3 genotype, the
drug is titrated over a five-day period up to the maintenance dose of 1 mg daily; for patients with
a CYP2C9*1/*1, *1/*2, or *2/*2 genotype, the drug is titrated over a six-day period to the
maintenance dose of 2 mg daily. Liver function and blood pressure should be monitored during
treatment.

3.Cladribine: an immunosuppressive purine antimetabolite agent that targets lymphocyte

subtypes, appears to reduce the relapse rate in patients with RRMS.

Indications and efficacy — for the treatment of adults with relapsing forms of MS, including
RRMS and active SPMS

Adverse effects — The most common adverse reactions are upper respiratory tract infections,
headache, and lymphocytopenia . There is also an increased risk of life-threatening infection
and tumor development. Lymphocytopenia, generally mild to moderate.

Cladribine is contraindicated in patients with malignancy and active chronic infections. It is

contraindicated in pregnancy, breastfeeding, and for females and males of reproductive
potential who do not plan to use effective contraception during treatment and for six months
after the last dose in each treatment course.

Dosing and monitoring — Prior to starting cladribine, patients must be screened to exclude
infections, malignancy, and pregnancy, and a baseline brain MRI should be obtained . Zoster
vaccination is recommended before treatment for patients who are seronegative for VZV.
Vaccination with the recombinant zoster vaccine is recommended before or during treatment for
patients who are seropositive for VZV.

The recommended cumulative dosage of oral cladribine is 3.5 mg/kg of body weight divided into
two yearly treatment courses (1.75 mg/kg per treatment course). p Each treatment course is

51
divided into two treatment cycles of four or five days separated by approximately four weeks.
Lymphocyte counts must be monitored before, during, and after treatment.

Fumarates — Fumarates may have neuroprotective and immunomodulatory properties through

activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

4. Dimethyl fumarate — oral fumarate that is metabolized to monomethyl fumarate, its active
metabolite.

Indications: is indicated for the treatment of relapsing forms of MS, including clinically isolated
syndromes, RRMS, and active secondary progressive multiple sclerosis (SPMS).

Adverse effects — The most common side effects of dimethyl fumarate were flushing and
gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain.

There are case reports of patients taking dimethyl fumarates for MS or psoriasis who developed
progressive multifocal leukoencephalopathy (PML), including those with and without
lymphocytopenia. Other reported adverse events include anaphylaxis and angioedema, herpes
zoster and other serious opportunistic infections, hepatotoxicity, and lymphopenia

Dimethyl fumarate is contraindicated for patients with known hypersensitivity to dimethyl

fumarate.

Dosing and monitoring — Treatment with dimethyl fumarate may decrease lymphocyte
counts, so patients should have a complete blood count obtained before starting the medication,
at no longer than six months after starting, and at least every six months or as clinically
indicated during the course of treatment.

Dimethyl fumarate should be discontinued if lymphocytopenia develops, although the exact

cutpoint that defines an unacceptably low count is not established. Another concern associated
with dimethyl fumarate is liver injury manifested by elevated serum aminotransferase and
bilirubin levels, with onset from a few days to several months after starting treatment Therefore,
serum aminotransferase, alkaline phosphatase, and total bilirubin levels should be obtained
prior to and during treatment as clinically indicated; the drug should be discontinued if clinically
significant liver injury occurs.

The starting dose for oral dimethyl fumarate is 120 mg given twice daily. After seven days, the
dose should be increased to 240 mg given twice daily. It is available in 120 and 240 mg
preparations. Taking the medication with food may decrease the rate of gastrointestinal upset.

5. Teriflunomide — The immunomodulator teriflunomide is the active metabolite of

leflunomide that inhibits pyrimidine biosynthesis and disrupts the interaction of T cells with
antigen presenting cells

52
Indications: indicated for the treatment of relapsing forms of MS, including clinically isolated
syndromes, RRMS, and active SPMS.

Adverse effects — The most common adverse effectswere headache, diarrhea, nausea, hair
thinning, and elevated alanine aminotransferase (ALT) levels Uncommon but potentially serious
adverse effects include hepatotoxicity, bone marrow suppression, immunosuppression,
infections, hypersensitivity and serious skin reactions, peripheral neuropathy, increased blood
pressure, and interstitial lung disease

Teriflunomide is contraindicated in patients with severe hepatic impairment, pregnancy,

hypersensitivity to teriflunomide, or current leflunomide treatment.

Dosing and monitoring — Patients should be brought up to date with all immunizations before
initiating therapy with teriflunomide. Live vaccines should not be given concurrently. Before
starting teriflunomide, patients should be screened for latent tuberculosis infection. Blood
pressure should be monitored before starting treatment and periodically thereafter.

The recommended dose of oral teriflunomide is 7 mg or 14 mg once daily

Recommended laboratory testing includes transaminase and bilirubin levels at baseline, and
ALT levels monthly for at least six months after starting treatment. A complete blood cell count
(CBC) should be obtained within six months before starting treatment; further CBCs should be
done if signs and symptoms of infection develop. Some experts repeat the CBC and a
comprehensive metabolic panel (which includes liver and kidney function) every six months
during therapy.

Due to the risk of teratogenicity, teriflunomide is contraindicated for females who are pregnant
or trying to conceive, and females of childbearing age must have a negative pregnancy test
before starting the drug. Teriflunomide is also found in semen

Laquinimod — Laquinimod is a synthetic immunomodulatory compound – a selective

aryl hydrocarbon receptor inhibitor – with high oral bioavailability In patients with RRMS
oral laquinimod treatment led to statistically significant though modest reductions in the
annual relapse rate.

Radiopaedia: The aim of treatment is twofold: to curtail progression (disease-modifying agents)

and symptomatic relief.

Steroids, disease-modifying therapies, and autologous hematopoietic stem cell transplantation

are all used. Although discussion of individual agents and therapies is well beyond the scope of
this article, it is worth being aware of the main agents available and their mechanism of action
20
:

● interferon beta: inhibition of T-lymphocyte proliferation

53
 ● glatiramer acetate (Copaxone): immunomodulation
● teriflunomide (Aubagio): reduces both T-cell and B-cell activation and proliferation
● dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity): immunomodulation
● fingolimod (Gilenya), siponimod (Mayzent) and ozanimod (Zeposia): prevents
lymphocyte migration out of lymph nodes and into CNS
● natalizumab (Tysabri): inhibits binding of lymphocytes to endothelium
● cladribine (Mavenclad): purine analog that targets lymphocytes
● ocrelizumab (Ocrevus) and ofatumumab (Kesimpta): anti-CD20 monoclonal antibodies
● alemtuzumab (Lemtrada): immunomodulation of T-cell and B-cell function
● mitoxantrone (Novantrone): reduces T-cell and B-cell proliferation and reduces T-cell
activation

Prognosis is variable and depends on the pattern of disease a patient has (e.g. primary
progressive carries a worse prognosis than relapsing-remitting). In general, patients with
relapsing-remitting MS will progress to secondary progressive disease in 10 years and will
require ambulatory aids (e.g. cane/wheelchair/frame) in another 5 to 15 years. Approximately
half of the affected individuals will no longer be independently ambulatory after 20 years. Overall
life expectancy is also reduced, by 7 to 14 years

Masuri generale

1. Fatigabilitatea este o acuza frecventa, in mod deosebit în legătură cu atacurile acute, răspunde
într-o oarecare masura la amantadina (100mg dimineata si la pranz), modafinil (200 pana la 400
mg), sau pemoline (20-75 mg dimineata), metilfenidat, dextroamfetamina.. Exista o serie de
substanțe care imbunatatesc conducerea prin fibre centrale demielinizate, si care s-a sugerat ca
ameliorează fatigabilitatea si mersul. ( de ex. 4-aminopiridina)
2. Tulburările funcției vezicii urinare dificil de abordat. Dacă disfunctia majoră este legată de
retentie de urina Clorura de betanecol, este utila. In aceste situații monitorizarea și reducerea
volumului urinar rezidual sunt importante, pt prevenirea infecției. Unii pacienți beneficiază de
cateterizare intermitenta. Mai frecvent apar mictiunile imperioase si polakiurie (vezica spastica)--
in acest caz Propantelina sau Oxybutynin (Ditropan) pot relaxa muschiul detrusor. Se
recomanda utilizarea acestor medicamente intermitent
3. Constipatia severa: clisme spatiale, program de antrenament al intestinului
4. Disfunctia sexuala: sildenafil si medicamente similare
5. Durerea-tratamentul durerii (Cap.8). Carbamazepina si Gabapentina sunt utile in reducerea
simptomelor paroxistice
6. In caz de paralizie spastica severă si spasme dureroase ale flexorilor MI, injectie locala de toxina
botulinica, baclofen (oral, apoi intratecal printr-un cateter permanent si o pompa implantata)
Injectarea selectiva a a toxinei botulinice in muschi cu gradul cel mai mare de hipertonie este a
solutie timpurie. Cei cu grade mici de spasticitate beneficiază de trat oral cu baclofen. O
alternativa la baclofen este tizanidina. Dacă asta eșuează, administrarea intratecala continua de
baclofen prin pompa pt oferi ameliorarea pe o perioada indelungata
7. Tremor sever (tremor intentional/postural), dizabilitant, apare la cele mai mici mișcări ale
membrelor, daca este unilateral poate fi abordat chirurgical prin talamotomie ventrolaterala sau

54
 stimulator implantat (ca in B. Parkinson). Tremorul postural poate fi îmbunătățit cu izoniazida
(300 mg/zi, crescut saptamanal cu cate 300 mg, pana la o doza de 1200 mg/zi) in combinatie cu
100 mg piridoxina/zi, cu monitorizarea atentă a enzimelor hepatice din cauza izoniazidei. Un
succes variabil se poate obține cu carbamazepina sau clonazepam.
8. Depresia -nu este un antidepresiv superior celuilalt
9. Probleme cognitive-Donepezil nu s-a dovedit util

-vaccinurile nu sunt interzise

-copolymer, oxigen hiperbar, dieta saraca in grasimi, fara gluten, suplimentarea dietei cu acid
linoelic

Encefalomielita acuta necrozanta hemoragica (Leucoencefalita acuta hemoragica a lui

Weston Hurst)

· Cea mai fulminanta forma de boala demielinizanta, capătul sever al spectrului ADEM

· Afecteaza in principal adulti tineri si copii

· Este precedata de o infecție respiratorie cu durata variabila (1-14zile), uneori cauzata de

M. pneumonie, mai frecvent urmarea unei infectii obisnuite sau de cauza nedeterminata

· Simptomele neurologice apar in mod brusc, debutand cu cefalee, febra, redoare de ceafa
si confuzie. Acestea sunt urmate de rapid de semne de afectare a uneia sau ambelor emisfere
cerebrale si trunchi cerebral-crize focale, hemiplegie/tetraplegie, paralizie pseudobulbara si
coma, ce se adanceste progresiv

· Leucocitoza periferica atingand 30.000 celule/mm3, VSH crescut

· LCR hipertensiv, celularitate variază ca nr de la cateva limfocite la pleiocitoza cu PMN

de pana la 3000 celule/mm3, hematii prezente în nr variabil, proteinorachie crescuta,
glicorahie normala

· Dg. ex. CT si IRM: evidentiaza leziuni bilaterale, asimetrice, mari, confluente,

edematoase, cu o multitudine de hemoragii punctiforme in substanta cenusie si alba.

55
 Dimensiunea leziunilor, caracterul lor hemoragic si întinderea edemului înconjurător le
disting de ADEM postinfectios tipic. Sunt similare din mai multe puncte de vedere, cu
exceptia severitatii lor

· Multe cazuri au final fatal in 2 pana la 4 zile, in alte cazuri supraviețuirea este mai lungă

· A fost observat o recurență a bolii la un interval de 2 ani la unul din pacienți

· DD: abces cerebral, epiem subdural, encefalomalacia embolica focala, encefalita acuta, in
special cauzata de HS tip 1

· Constatarile anatomo-patologice sunt distinctive. La secționarea creierului, substanta alba

este distrusa aproape pana la stadiul de lichefiere. Tesutul afectat este roz sau galben-cenusiu
si presărat cu multiple hemoragii petesiale. Modificări similare sunt de obicei si la nivelul
trunchiului cerebral, pedunculi cerebelosi, maduva spinarii (o forma de mielita acuta
necrozanta si b. Devic)

· La ex. histologica: necroza intinsa a vaselor mici si a tesutului cerebral din jurul vaselor,
cu infiltrare celulara intensam multiple hemoragi mici, reactie inflamatorie meningeala de
intensitagte variabila.

· Aspectul anatomo-patologic se aseamana cu encefalomielita diseminata prin distributie

perivasculara, cu caracteristicile aditionale de necroza mai extinsa, tendinta leziunilor de
forma focare mari in emisferele cerebrale. Leziunile vasculare duc la exudarea caracteristica
a fibrinei din peretele vascular si tesutul inconjurator

· Unii pacienti care prezinta o afectare mielitica exploziva, sa sufere o leziune necrozanta
similara

· S-a observat raspuns partial la steroizi

· Etiologia este nelamurita

· Similaritatea modificarilor histopatologice cu cele din ADEM, sugereaza ca cele doua

boli sunt forme inrudite ale aceluiasi proces de baza.

· Dintre putinii pacienti care si-au revenit, unii au dezvoltat apoi SM tipica.

Tratamentul boli Hurst:

· Corticosteroizi intravenos in doze mari

· Folosirea schimbului plasmatic si a IVIG este in curs de investigare, a avut succes in

cazuri izolate raportate, cand au fost administrate precoce

56
 Boala grefa-contra gazda

· inflamatie cerebrala, legata de transplantul de maduva osasa

· La distanta de luni, ani dupa transplant, pot aparea subacut hemipareza, crize, modificari
comportamentale, ataxie, ce pot fi atribuite LEMP, o infectie virala a subst. albe (Cap-33) sau
alt proces viral cunoscut ca putand sa apara in context de imunosupresie

· Ex. IRM arata leziuni ale subs. albe care sunt in concordanta cu dispozitia
periventriculara caracteristica SM sau cu a unei leucoencefalopatii mai confluente

· unele raporturi subliniaza vasculita usoara in terioriul leziunilor din subst alba

· pacienti prezinta erupti eritematoasa, maculara, sensibila la palpare, care este tipica bolii
acute grefa-contra-gazda

· rar, pot exista complicatii neuromusculare

57