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یکشنبه 3 تیر‌ماه سال 1386
مولتیپل اسکلروز


Multiple Sclerosis and Other Demyelinating Diseases


The peripheral nervous system (PNS) is spared.

Multiple sclerosis (MS) is characterized by a triad of inflammation, demyelination, and gliosis (scarring);

Lesions of MS are typically disseminated in time and location.

MS is second only to trauma as a cause of neurologic disability in early to middle adulthood



lesions (plaques) vary in size from 1 or 2 mm to several centimeters

Unlike vasculitis, the vessel wall is preserved


Surviving oligodendrocytes or those that differentiate from precursor cells may partially remyelinate the surviving naked axons, producing so-called shadow plaques


Although sparing of axons is typical of MS, partial or total axonal destruction can also occur


axonal loss is a major cause of irreversible neurologic disability in MS.


Nerve conduction in myelinated axons occurs in a saltatory mannerà faster conduction velocities (~70 m/s) than the slow velocities (~1 m/s) produced by continuous propagation in unmyelinated nerves


Conduction block occurs when the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath


A temporary conduction block often follows a demyelinating event before the sodium channels (originally concentrated at the nodes) have had a chance to redistribute themselves along the naked axon. This redistribution ultimately allows the continuous propagation of nerve action potentials through the demyelinated segment


Variable conduction block can occur with raised body temperature or metabolic alterations and may explain clinical fluctuations (typical of MS) that vary from hour to hour or in association with fever or exercise.



در خانمها 2 برابر! - بین 20 تا 40 سالگی در خانمها زودتر- در خانمها پیش آگهی بهتر

Twice as common in women as in men.(f/m =2)

age of onset is typically between 20 and 40 years (slightly later in men than in women).

prevalence increases with increasing distance from the equator


NO association of trauma or stress with either MS onset or exacerbation

 A genetic susceptibility to MS exists


(MHC) on chromosome 6p21 (encoding proteins involved in presenting peptide antigens to T cells) is the most important MS

MS susceptibility is associated with the class II region of the MHC, specifically with the DR2 (DRB1*1501) allele


Other genetic regions implicated in MS susceptibility are located on chromosomal regions 19q35 and 17q13.


Membrane attack complexes (from complement-mediated antibody damage) can be detected in CSF, and elevated CSF immunoglobulin (synthesized locally) is characteristic of MS


Oligoclonal immunoglobulin is also detected in other chronic inflammatory conditions, including infections, and thus is not specific to MS.


proinflammatory TH1 cytokines such as interleukin (IL) 2, tumor necrosis factor (TNF) α, and interferon (IFN) γ are thought to be central to MS pathogenesis


there is a large reservoir of subclinical disease activity in MS, especially during the early stages of the disease.


High antibody titers against many viruses have been reported in serum and CSF of MS patients, including measles, herpes simplex, varicella, rubella, Epstein-Barr, and influenza C and some parainfluenza strains. Most recently human herpes virus type 6 (HHV-6) and Chlamydia pneumoniae have been implicated, although a causal role for any infectious agent in MS remains unproven.





Sensory loss


Optic neuritis





ضعف اندامها معمولا از نوع نورون محرکه فوقانی:

Exercise-induced weakness is a characteristic symptom of MS. The weakness is of the upper motor neuron type.

اسپاستیسیته بیش از 30%- در پاها -:دردناک

More than 30% of MS patients have moderate to severe spasticity, especially in the legs. accompanied by painful spasms.

نوریت اپتیک عموما تک چشمی- با بستن یک چشم از بین نمی رود- همراه با درد پری اربیتال-نقص آوران مردمک:

Optic neuritis (ON) generally presents as diminished visual acuity, dimness, or decreased color perception (desaturation) in the central field of vision.

generally monocular. Periorbital pain (aggravated by eye movement) often precedes or accompanies the visual loss. An afferent pupillary defect  may be found.


Visual blurring in MS may result from ON or diplopia.

 Visual blurring that resolves when either eye is covered is due to diplopia

دوبینی در اثر افتالموپلژی بین هسته ای یا فلج عصب 6 دوطرفه :

Diplopia may result from internuclear ophthalmoplegia (INO) or from palsy of the 6th cranial nerve (rarely the 3rd or 4th).


A bilateral INO is particularly suggestive of MS.


Other common gaze disturbances in MS include: (1) a horizontal gaze palsy, (2) a “one and a half” syndrome (horizontal gaze palsy plus an INO), and (3) acquired pendular nystagmus.


علائم حسی وجود سطح حسی مؤید منشاء نخاعی است :

Sensory symptoms  include  paresthesias (e.g., tingling, prickling sensations, formications, “pins and needles,” or painful burning) and hypesthesia (e.g., reduced sensation, numbness or a “dead” feeling). Unpleasant sensations (e.g., feelings that body parts are swollen, wet, raw, or tightly wrapped). Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) suggests that the spinal cord is the origin of the sensory disturbance. It is often accompanied by a bandlike sensation of tightness around the torso.


درد-50% :

 Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur anywhere on the body and can change locations over time.


آتاکسی- معمولا ترمور مخچه ای یا درگیری صدا به صورت تکلم بریده بریده:

Ataxia usually manifests as cerebellar tremors. Ataxia may also involve the head and trunk or the voice, producing a characteristic cerebellar dysarthria (scanning speech). Difficult to determine.


اختلال عملکرد مثانه و روده- اختلال عملکرد مثانه 90%- یبوست 30% :

Bladder and bowel dysfunction. During normal reflex voiding, relaxation of the bladder sphincter (α-adrenergic innervation) is coordinated with contraction of the detrusor muscle in the bladder wall (muscarinic cholinergic innervation). Bladder-stretch (during filling) activates this reflex, which is inhibited by supraspinal (voluntary) input.


bladder dysfunction are present in >90% of MS patients and, in a third, dysfunction results in weekly or more frequent episodes of incontinence.


Detrusor hyperreflexia, due to impairment of suprasegmental inhibition, causes urinary frequency, urgency, nocturia, and uncontrolled bladder emptying.


 Detrusor sphincter dyssynergia, due to loss of synchronization, producing hesitancy. It can also lead to urinary retention, large postvoid residual volumes, overflow incontinence, and recurrent infection.


Constipation occurs in >30% of patients. Fecal urgency or bowel incontinence is less common (15%) but can be socially debilitating.


اختلالات شناختی:

Cognitive dysfunction can include memory loss, impaired attention, difficulties in problem-solving, slowed information processing, and problems shifting between cognitive tasks.


Euphoria actually uncommon, occurring in <20% of patients.

افسردگی  50تا 60% خودکشی 7.5 برابر:

Depression, 50 to 60% of patients.

 Suicide in MS patients is 7.5-fold more common.

خستگی 90%- شایعترین علت برای ناتوانی مرتبط با کار:

 Fatigue is experienced by 90% of patients and is moderate or severe in half.

 Fatigue (either alone or with other symptoms) is the most common reason for work-related disability in MS.

 Fatigue can be exacerbated by elevated temperatures, by depression, by expending exceptional effort to accomplish basic activities of daily living, or by sleep disturbances (e.g., from frequent nocturnal awakenings to urinate).

 MS-related fatigue may be maximum during mid-afternoon or continuous throughout the day, and it is often difficult to treat.

اختلال عملکرد جنسی:

Sexual dysfunction is common in MS. Adductor spasticity (in women) can also interfere with intercourse, and urinary incontinence (in either men or women) can be problematic.


ضعف عضلات صورت- عدم از دست رفتن حس چشایی در همان طرف یا درد پشت گوش (برخلاف فلج بل):

Facial weakness due to a lesion in the intraparenchymal pathway of the 7th cranial nerve may resemble idiopathic Bell's palsy.

 Unlike Bell's palsy, facial weakness in MS is generally not associated with ipsilateral loss of taste sensation or retroauricular pain.


سرگیجه با منشاء ساقه مغز:

Vertigo may appear suddenly and resemble acute labyrinthitis.


 A brainstem rather than end-organ origin is suggested by:

 1-the presence of coexisting trigeminal or facial nerve involvement;

 2-vertical nystagmus; or

 3-nystagmus that has no latency to onset,

 4-no direction reversal, and

 5- doesn't fatigue.


Hearing loss uncommon.


Ancillary Symptoms


Heat sensitivity à neurologic symptoms produced by an elevation of the body's core temperature. For example, transient unilateral visual blurring or loss may occur during a hot shower or with physical exercise (Uhthoff's symptom)

از دست رفتن بینایی یا تاری دید به هنگام دوش آب گرم یا فعالیت بدنی =                   Uhthoff's symptom  


Lhermitte's symptomà

is the electric shock -- like sensation (evoked by neck flexion or other movement) that radiates down the back into the legs. Rarely, radiates into the arms -- generally self-limited but may persist for years +  also other disorders of the cervical spine (e.g., cervical spondylosis).

احساس شوک الکتریکی متعاقب فلکسیون گردن که به پشت به سمت پاها انتشار می یابد.                                              


Paroxysmal symptoms à

brief duration (30 s to 2 min), high frequency (5 to 40 episodes per day),-- during episodes:  consciousness (NL) & background electroencephalogram (NL) -- a self-limited course (generally lasting weeks to months) -- precipitated by hyperventilation or movement -  include Lhermitte's symptom; tonic contractions of a limb, face, or trunk (tonic seizures); paroxysmal dysarthria/ataxia; paroxysmal sensory disturbances; -- probably result from spontaneous discharges, arising at the edges of demyelinated plaques, and spreading ephaptically to adjacent white matter tracts.

علائم حمله ای با مدت کوتاه (30 ثانیه تا 2 دقیقه) و فرکانس بالا (5 تا 40 اپیزود در روز)-در طی حملات، هوشیاری بیمار و EEG نرمال هستند- سیر خودمحدود دارند.


Trigeminal neuralgia 5th, hemifacial spasm 7th, and glossopharyngeal neuralgia 9th when the demyelinating lesion involves the root entry (or exit) zone of the 5th, 7th, and 9th cranial nerve, respectively.

درگیری ناحیه ورود (یا خروج) اعصاب 5 ، 7 و 9 مغزی --› نورالژی تریژمینال5، اسپاسم همی فاسیال7، نورالژی گلوسوفارنژیال9


Trigeminal neuralgia (tic douloureux)

is a very brief lancinating facial pain often triggered by an afferent input from the face or teeth. Most cases of trigeminal neuralgia are not MS-related.


Atypical features àonset before age 50 years, bilateral symptoms, objective sensory loss, or nonparoxysmal pain à MS is responsible.

شروع نورالژی تریژمینال (تیک دولورره) در سنین کمتر از 50 سالگی، دوطرفه بودن علائم، اختلال حسی در محدوده عصب که توسط پزشک گزارش شود یا غیرحمله ای بودن درد، --›  به نفع مولتیپل اسکلروز است.

Facial myokymia

consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the orbicularis oculus) or a contraction that slowly spreads across the face. It results from lesions of the corticobulbar tracts or brainstem course of the facial nerve.

میوکیمی صورت: انقباضات سریع و پایدار عضلات صورت (بخش تحتانی عضله حلقوی دور چشم)                                    


DISEASE COURSE                                                                                           سیر بیماری:       


  • Relapsing/remitting MS (RRMS) à 85% of MS cases at onset –discrete attacks that generally evolve over days to weeks (rarely over hours). Often, complete recovery over the ensuing weeks to months. When ambulation is severely impaired during an attack, approximately half will fail to improve. Between attacks, neurologically stable.

نوع عودکننده/تخفیف یابنده: 85% موارد- بین حملات از نظر نورولوژیک پایدار


  • Secondary progressive MS (SPMS) àAlways begins as RRMSàa steady deterioration in function + acute attacks (which may continue or cease during the progressive phase). a greater amount of fixed neurologic disability than RRMS. Approximately 50% of patients with RRMS will have developed SPMS after 15 years, the great majority of RRMS ultimately evolves into SPMS. SPMS represent a late-stage of the same underlying illness as RRMS.

نوع پیشرفت ثانویه: همیشه به صورت RRMS شروع می شود- زوال پایدار همراه با حملات حاد 50% بیماران RRMS بعد از 15 سال دچار SPMS می شوند-همان مرحله نهایی RRMS  است.


  • Primary progressive MS (PPMS) à~15% of cases. These patients do not experience attacks but only a steady functional decline from disease onset. Compared to RRMS, the sex distribution is more even, the disease begins later in life (mean age, ~40 years), and disability develops faster.


نوع پیشرونده اولیه:15% - بدون حملات-توزیع جنسی یکنواخت تر-سیر نزولی عملکردی از آغاز- شروع دیرتر (40سالگی) - و آغاز سریعتر ناتوانی


  • Progressive/relapsing MS (PRMS) àoverlaps PPMS and SPMS and accounts for ~5% of MS patients. Like PPMS, a steady deterioration in their condition from disease onset. However, like SPMS, occasional attacks superimposed upon their progressive course. The early stages of RPMS are indistinguishable from those of PPMS (i.e., until the first clinical attack).

نوع پیشرونده/عود کننده: 5%- نزول پایدار عملکرد همراه با حملات گاهگاهی که بر آن سوار می شوند- در مراحل ابتدایی غیر قابل افتراق از PPMS است.






No definitive diagnostic test for MS.


Diagnostic criteria: for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically NONcontiguous white matter tracts of the CNS .


 Symptoms must last for >24 h and occur as distinct episodes that are separated by a month or more.

سمپتوم ها باید به مدت حداقل 24 ساعت و به صورت اپیزودهای مجزا با فاصله حداقل یک ماه رخ دهند.                                           

1-At least one of the two required signs must be present on neurologic examination.  

  2-The second may be documented by certain abnormal paraclinical tests such as MRI or evoked potentials (EPs).


In patients who experience gradual progression of disability for ≥6 months without superimposed relapses, documentation of intrathecal IgG and visual EP testing may be used to support the diagnosis.


A confirmatory MRI must have either four lesions involving the white matter or three lesions if one is periventricular in location. Acceptable lesions must be >3 mm in diameter.

درMRI به طور معمول ضایعه بالای 3 mm، ولی در افراد بالای 50  سال ضایعه باید بالای 5 mm  باشد.

برای افراد بالای 50 سال:                                                                                                   

 For patients older than 50 years, two of the following criteria must also be met:

(a) lesion size >5 mm,

(b) lesions adjacent to the bodies of the lateral ventricles, and

(c) lesion(s) present in the posterior fossa.



TABLE 359-2 Diagnostic Criteria for MS

1.     Examination must reveal objective abnormalities of the CNS.

2.     Involvement must reflect predominantly disease of white matter long tracts, usually including (a) pyramidal pathways, (b) cerebellar pathways, (c) medial longitudinal fasciculus, (d) optic nerve, and (e) posterior columns.

3.     Examination or history must implicate involvement of two or more areas of the CNS.

a. MRI may be used to document a second lesion when only one site of abnormality has been demonstrable on examination. A confirmatory MRI must have either four lesions involving the white matter or three lesions if one is periventricular in location. Acceptable lesions must be >3 mm in diameter. For patients older than 50 years, two of the following criteria must also be met: (a) lesion size >5 mm, (b) lesions adjacent to the bodies of the lateral ventricles, and (c) lesion(s) present in the posterior fossa.

b. Evoked response testing may be used to document a second lesion not evident on clinical examination.

4.     The clinical pattern must consist of (a) two or more separate episodes of worsening involving different sites of the CNS, each lasting at least 24 h and occurring at least 1 month apart, or (b) gradual or stepwise progression over at least 6 months if accompanied by increased IgG synthesis or two or more oligoclonal bands. MRI may be used to document dissemination in time if a new T2 lesion or a Gd-enhancing lesion is seen 3 or more months after a clinically isolated syndrome.

5.     The patient's neurologic condition could not better be attributed to another disease.


1.     Definite MS: All five criteria fulfilled.

2.     Probable MS: All five criteria fulfilled except (a) only one objective abnormality despite two symptomatic episodes or (b) only one symptomatic episode despite two or more objective abnormalities.

3.     At risk for MS: Criteria 1, 2, 3, and 5 fulfilled; patient has only one symptomatic episode and one objective abnormality.




Magnetic Resonance Imaging

MRI: characteristic abnormalities are found in >95% of patients


An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) into the parenchyma.


Gd-enhancement persists for up to 3 months, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on spin-echo (T2-weighted) and proton-density images.


Lesions are frequently oriented perpendicular to the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson's fingers).


Lesions in the anterior corpus callosum are helpful diagnostically because this site is usually spared in cerebrovascular disease!!!

ضایعات قدامی کورپوس کالوزوم در MRI از نظر تشخیصی کمک کننده اند زیرا این ناحیه در بیماری عروقی مغزی درگیر نمی شود.

The total volume of T2-weighted signal abnormality (the “burden of disease”) shows a significant (albeit weak) correlation with clinical disability.

Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted imaging. Black holes may be a better marker of irreversible demyelination and axonal loss than T2 hyperintensities, although even this measure depends upon the timing of the image acquisition (e.g., most acute Gd-enhancing T2 lesions are T1 dark).


Evoked Potentials

an abnormal visual EP in some circumstance would permit a diagnosis of clinically definite MS

Abnormalities on one or more EP modalities occur in 80 to 90% of MS patients.


 EP abnormalities are not specific to MS, although a marked delay in the latency of a specific EP component (as opposed to a reduced amplitude) is suggestive of demyelination

تاخیر قابل ملاحظه در فاز نهفته جزء خاصی از پتانسیل برانگیخته،  مؤید دمیلیناسیون می باشد.


Cerebrospinal Fluid

In MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG

The total CSF protein is usually normal or slightly elevated.

 Two or more oligoclonal banding (OCB)s are found in 75 to 90% of patients with MS. OCBs may be absent at the onset of MS, and in individual patients the number of bands present may increase with time.

 It is important that paired serum samples be studied to exclude a peripheral (i.e., non-CNS) origin of any OCBs detected in the CSF.

A mild CSF pleocytosis (>5 cells/µL) is present in ~25% of cases, usually in young patients with RRMS.

در موارد زیرشاید بیمار MS نباشد:

 A pleocytosis of >75 cells/µL,

 The presence of PMN leukocytes,

 Or a protein concentration of >1.0 g/L (>100 mg/dL) in CSF


 Should raise concern:

                                That the patient may NOT have MS!!!


No single clinical sign or test is diagnostic of MS.

مطرح شدن تشخیصی به غیر از MS به خصوص در موارد زیر:

 The possibility of an alternative diagnosis should always be considered, particularly when:

(1) symptoms are localized exclusively to the posterior fossa, craniocervical junction, or spinal cord;

(2) the patient is <15 or >60 years of age;

(3) the clinical course is progressive from onset;

(4) the patient has never experienced visual, sensory, or bladder symptoms; or

(5) laboratory findings (e.g., MRI, CSF, or EPs) are atypical.


Similarly, uncommon or rare symptoms in MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe muscular atrophy, peripheral neuropathy, episodic loss of consciousness, fever, headache, seizures, or coma) should increase concern about an alternative diagnosis.

 Diagnosis is also difficult in patients with a rapid or explosive (stroke-like) onset or with mild symptoms and a normal neurologic examination.

موارد زیر باید در تمام بیماران مشکوک به MS خواسته شوند:

 an ESR, serum B12 level, ANA, and VDRL

should probably be obtained in all patients with suspected MS !!!


Most patients with MS experience progressive neurologic disability.

 15 years after onset, only 20% of patients have no functional limitation; half will have progressed to SPMS and will require assistance with ambulation.

 25 years after onset, >80% of MS patients will have reached this level of disability.


Certain clinical features suggest a more favorable prognosis:               پیش آگهی خوب:

1- Patients with ON or sensory symptoms at onset,

2- patients who recover completely from early attacks,

3- patients <40 years at onset (but not beginning in childhood),

4- women,

5- patients with RRMS,

6- patients with fewer than 2 relapses in the first year of illness,

7- and patients with minimal impairment after 5 years do better than patients without these clinical features.


By contrast more likely to become disabled:                                          پیش آگهی بد:

1-patients with truncal ataxia,

2-action tremor,

3-pyramidal symptoms, or

4-a progressive disease course.


 A purely progressive disease course carries a graver outlook at all disease stages than accompanied by occasional relapses.


The likelihood of benign MS thought to be <20% and never develop neurologic disability.


In patients with their first demyelinating event (i.e., a clinically isolated syndrome), the brain MRI provides prognostic information. With three or more typical T2-weighted lesions, the risk of developing MS after 10 years is 70 to 80%. Conversely, with a normal brain MRI, the likelihood of developing MS is <20%. Similarly, two or more Gd-enhancing lesions at baseline is highly predictive of future MS, as is the appearance of either new T2-weighted lesions or new Gd enhancement ≥3 months after the episode.


25-year survival is only 85% of expected. Death can occur during an acute MS attack, although this is distinctly rare.

 More commonly, death occurs as a complication of MS (e.g., pneumonia in a debilitated individual).


Effect of Pregnancy                                                                                                      تاثیر حاملگی: 

Pregnant MS patients experience

 Fewer attacks than expected during gestation (especially in the last trimester)

 But more attacks than expected in the first 3 months post-partum.

as a whole (i.e., 9 months pregnancy plus 3 months post-partum), the overall disease course is unaffected.

در طی حاملگی به خصوص سه ماهه آخر، حملات بیماری کمتر؛ ولی در 3 ماه اول پس از زایمان حملات بیشتر بیماری رخ می دهد-› پس سیر کلی بیماری طی حاملگی تحت تاثیر قرار نمی گیرد.


Disease-modifying therapy is generally discontinued during pregnancy, although the actual risk from the interferons and glatiramer acetate appears to be quite low.




Most patients with EDSS scores <3.5 have RRMS, walk normally, and are not disabled; by contrast, patients with EDSS scores >5.5 have progressive MS (SPMS or PPMS) and are gait-impaired and occupationally disabled.


Acute Attacks or Initial Demyelinating Episodes


 1-new disease activity or a

 2-“pseudoexacerbation” resulting from an increase in ambient temperature, fever, or an infection. In such instances, glucocorticoid treatment is inappropriate.


 Glucocorticoids are used to manage either first attacks or acute exacerbations. They provide short-term clinical benefit by reducing the severity and shortening the duration of attacks. As a result, mild attacks are often not treated.

گلوکوکورتیکوئیدها جهت درمان اولین حملات یا تشدید حاد بیماری استفاده می شوند. اثر بلندمدتشان نامعلوم است پس در حملات خفیف بیماری استفاده نمی شوند.

Glucocorticoid: intravenous methylprednisolone, 500 to 1000 mg/d for 3 to 5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60 to 80 mg/d and gradually tapered over 2 weeks. Outpatient treatment is usually possible. If intravenous therapy is unavailable or inconvenient, oral glucocorticoids can be substituted.

Side effects of short-term glucocorticoid therapy include:

( fluid retention, potassium loss, weight gain, gastric disturbances, acne, and emotional lability.)

 Concurrent use of a low-salt, potassium-rich diet and avoidance of potassium-wasting diuretics is advisable.


کربنات لیتیوم جهت درمان بی خوابی و حساسیت عاطفی در بیمارانی که کورتون می گیرند، استفاده می شود.

 Lithium carbonate (300 mg orally bid) may help to manage emotional lability and insomnia associated with glucocorticoid therapy.

 Patients with a history of peptic ulcer disease may require cimetidine (400 mg bid) or ranitidine (150 mg bid).

تعویض پلاسما :

Plasma exchange (7 exchanges: 54 mL/kg or 1.1 plasma volumes per exchange, every other day for 14 days) may benefit patients with fulminant attacks of demyelination (not only MS) that are unresponsive to glucocorticoids. However, because the cost is high, and the evidence of efficacy is preliminary, plasma exchange should be considered only in selected cases.

تعویض پلاسما زمانی استفاده می شود که بیماری به کورتون مقاوم باشد.

درمانهای تعدیل کننده بیماری برای اشکال عود کننده مولتیپل اسکلروز:

Disease-Modifying Therapies for Relapsing Forms of MS (RRMS SPMS with Exacerbations)

Four such agents are approved in the United States:

(1) IFN-β1a (Avonex),

(2) IFN-β1a (Rebif);

(3) IFN-β1b (Betaseron); and

(4) glatiramer acetate (Copaxone).


 Each of these treatments is also used in SPMS patients who still experience attacks, because SPMS can be difficult to distinguish from RRMS and the clinical trials suggest that such patients also derive therapeutic benefit.

 Mitoxantrone (Novantrone), an immune suppressant, because of its potential toxicity, it is generally reserved for patients with progressive disability who have failed other treatments.



IFN-β is a class I interferon originally identified by its antiviral properties. Efficacy in MS, however, probably results from immunomodulatory properties including:

(1) downregulating expression of MHC molecules on antigen-presenting cells;

(2) inhibiting proinflammatory and increasing regulatory cytokine levels;

(3) inhibition of T cell proliferation; and

(4) limiting the trafficking of inflammatory cells in the CNS.


 Glatiramer acetate is a synthetic, random polypeptide composed of four amino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine). Its mechanism of action may include:

(1) induction of antigen-specific suppressor T cells;

(2) binding to MHC molecules, thereby displacing bound MBP; or

(3) altering the balance between proinflammatory and regulatory cytokines.


IFN-β:   reduces the attack rate. It also improves disease severity.


 IFN-β should be considered in patients with either RRMS or SPMS with superimposed relapses. In patients with SPMS but without relapses, efficacy has not been established.

 Higher IFN-β doses --slightly greater efficacy-- induce neutralizing antibodies, may reduce the clinical benefit.


Glatiramer acetate also reduces the attack rate (whether measured clinically or by MRI) in RRMS.

 Glatiramer acetate may also benefit disease severity measures, although this is less well established than for the relapse rate. Therefore, glatiramer acetate should be considered in RRMS patients. However, its usefulness in progressive disease is entirely unknown.




FIGURE 359-4 Therapeutic decision making for MS.



Many experts currently believe that very early treatment with a disease-modifying drug is appropriate for most MS patients.

It is reasonable to delay initiating treatment in patients with:

(1) normal neurologic exams;

(2) a single attack or a low attack frequency; and

(3) a low burden of disease as assessed by brain MRI.

Untreated patients need to be followed closely with periodic brain MRI scans;


Most treated patients with relapsing forms of MS receive IFN-β as first-line therapy.


 Common side effects of IFN-β therapy include flulike symptoms (e.g., fevers, chills, and myalgias) and mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia). Rarely, more severe hepatotoxicity may occur. Subcutaneous IFN-β also causes reactions at the injection site (e.g., pain, redness, induration, or, rarely, skin necrosis). Side effects can usually be managed with concomitant nonsteroidal anti-inflammatory medications and with the use of an auto-injector.


For a patient doing well on therapy, the presence of antibodies should not matter. Conversely, for a patient doing poorly on therapy, alternative treatment should be considered, even if there are no detectable antibodies.


With glatiramer acetate approximately 15% of patients experience one or more episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety after injection. This systemic reaction is unpredictable, brief (duration <1 h), and tends not to recur.



Mitoxantrone (Novantrone), an anthracenedione, exerts its antineoplastic action by:

(1) intercalating into DNA and producing both strand breaks and interstrand cross-links,

(2) interfering with RNA synthesis and,

(3) inhibiting topoisomerase II (involved in DNA repair).


 mitoxantrone is indicated for use in SPMS, in PRMS, and in patients with worsening RRMS (defined as patients whose neurologic status remains significantly abnormal between MS attacks).


عوارض جانبی  Mitoxantrone   مشکلات قلبی، آمنوره، لوکمی حاد ، طول مدت درمان کمتر از 2-3 سال :

 1- cardiac problems (e.g., cardiomyopathy, reduced left ventricular ejection fraction, and irreversible congestive heart failure). a cumulative dose >140 mg/m2 is not recommended. At currently approved doses (12 mg/m2 every 3 months), the maximum duration of therapy can be only 2 to 3 years.

 2- >40% of women will experience amenorrhea, may be permanent.

 3- risk of acute leukemia.

 میتوگزانترون برای درمان موارد مقاوم استفاده می شود و نه به عنوان خط اول درمان!!!

mitoxantrone should not be used as a first-line agent in either RRMS or relapsing SPMS. It is reasonable to consider mitoxantrone in selected patients with a progressive course who have failed other approved therapies.

درمانهای تعدیل کننده بیماری در مبتلایان به SPMS بدون عود:

Disease-Modifying Therapies for SPMS without Relapses

High-dose IFN-β probably has a beneficial effect in patients with SPMS who are still experiencing acute relapses. IFN-β is probably ineffective in patients with SPMS who are not having acute attacks.



No currently available therapies have shown any promise for treating PPMS at this time.


سایر روشهای درمانی برای RRMS و SPMS:

Off-Label Treatment Options for RRMS and SPMS

Azathioprine used primarily in SPMS. marginally effective at lowering relapse rates.


Methotrexate : slow the progression of upper extremity dysfunction in SPMS. Because of the possibility of developing irreversible liver damage, some experts recommend a blind liver biopsy after 2 years of therapy.

Cyclophosphamide: for treatment-refractory patients who are (1) otherwise in good health, (2) ambulatory, and (3) <40 years of age. Because cyclophosphamide can be used for periods in excess of >3 years, it may be preferable to mitoxantrone in these circumstances.

* سیکلوفسفامید را می توان بیش از 3 سال استفاده کرد و  بیمار کمتر از  40 سال داشته باشد.

Intravenous immunoglobulin (IVIg), administered in monthly pulses (up to 1 g/kg) for up to 2 years, appears to reduce annual exacerbation rates.


Methylprednisolone administered in one study as monthly high-dose intravenous pulses, reduced disability progression.


درمان علامتی:

Symptomatic Therapy

1-Potassium channel blockers (e.g., 4-aminopyridine,; and 3,4-di-aminopyridine) may be helpful for weakness, especially for heat-sensitive symptoms. At high doses they may cause seizures.

* مسدودکننده های کانال پتاسیم جهت درمان ضعف عضلانی به کار می روند! به خصوص در انواع حساس به گرما!


2-Ataxia/tremor is often intractable.

Clonazepam, 1.5 to 20 mg/d;

mysoline, 50 to 250 mg/d;

propranalol, 40 to 200 mg/d; or

ondansetron, 8 to 16 mg/d may help.

Wrist-weights occasionally reduce tremor in the arm or hand. Thalamotomy or deep brain stimulation has been tried with mixed success.


3-Spasticity and spasms may improve with physical therapy, regular exercise, and stretching. Avoidance of triggers (e.g., infections, fecal impactions, bed sores) is extremely important.

 Effective medications include

lioresal (20 to 120 mg/d),

diazepam (2 to 40 mg/d),

tizanidine (8 to 32 mg/d),

dantroline (25 to 400 mg/d), and

cyclobenzaprine hydrochloride (10 to 60 mg/d).

For severe spasticity, a lioresal pump (delivering medication directly into the CSF) can provide substantial relief.



4-Pain is treated with


(carbamazepine, 100 to 1000 mg/d;

phenytoin, 300 to 600 mg/d; or

gabapentin, 300 to 3600 mg/d),


(amitriptyline, 25 to 150 mg/d;

nortryptiline, 25 to 150 mg/d;

desipramine, 100 to 300 mg/d; or

venlafaxine, 75 to 225 mg/d), or

Antiarrhythmics (mexiletine, 300 to 900 mg/d).


5-Bladder dysfunction management is best guided by urodynamic testing.

 Evening fluid restriction or frequent voluntary voiding may help detrusor hyperreflexia. If these methods fail,

propantheline bromide (10 to 15 mg/d),

oxybutinin (5 to 15 mg/d),

hycosamine sulfate (0.5 to 0.75 mg/d), or

tolteridine tartrate (2 to 4 mg/d) may help.

Coadministration of pseudoephedrine (30 to 60 mg) is sometimes beneficial.


6-Detrusor/sphyncter dyssynergia may respond to:

 phenoxybenzamine (10 to 20 mg/d) or

 terazosin hydrochloride (1 to 20 mg/d).

Loss of reflex bladder wall contraction may respond to bethanecol (30 to 150 mg/d). However, both conditions often require catheterization.


7-Urinary tract infections should be treated promptly. Patients with large postvoid residual urine volumes are predisposed to infections. Prevention by urine acidification (with cranberry juice or vitamin C) inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to colonization by resistant organisms. Intermittent catheterization may help to prevent recurrent infections.


8-Treatment of constipation includes high-fiber diets and fluids. Natural or other laxatives may help. Fecal incontinence may respond to a reduction in dietary fiber.


9-Depression should be treated. Useful drugs include the

selective serotonin reuptake inhibitors:

 (fluoxitine, 20 to 80 mg/d, or

  sertraline, 50 to 200 mg/d); the

tricyclic antidepressants:

 (amitriptyline, 25 to 150 mg/d,

  nortryptiline, 25 to 150 mg/d, or

  desipramine, 100 to 300 mg/d);

and the non-tricyclic antidepressants (venlafaxine, 75 to 225 mg/d).


10-Fatigue may improve with assistive devices, help in the home, or successful management of spasticity. Patients with frequent nocturia may benefit from anticholinergic medication at bedtime.

 Primary MS fatigue may respond to:

 amantadine (200 mg/d),

 pemoline (37.5 to 75 mg/d),

 methylphenidate (5 to 25 mg/d), or

 modafinil (100 to 400 mg/d).


11-Cognitive problems may respond to the cholinesterase inhibitor donepezil hydrochloride (10 mg/d).


12-Paroxysmal symptoms respond dramatically to

 low-dose anticonvulsants:

(acetazolamide, 200 to 600 mg/d;

 carbamazepine, 50 to 400 mg/d;

 phenytoin, 50 to 300 mg/d; or

 gabapentin, 600 to 1800 mg/d).


13-Heat sensitivity may respond to heat-avoidance, air conditioning, or cooling garments.


14-Sexual dysfunction may be helped by lubricants to aid in genital stimulation and sexual arousal. Management of pain, spasticity, fatigue, and bladder/bowel dysfunction may also help. Sildenafil (50 to 100 mg) taken 1 to 2 h before sex is now the standard treatment for maintaining erections.


Promising Experimental Therapies

Numerous clinical trials are currently underway. These include: (1) combination therapies; (2) higher-dose IFN-β than currently prescribed; (3) monoclonal antibodies against α4-integrin to prevent adhesion of lymphocytes to endothelial surfaces, against CD52 to induce global lymphocyte depletion, or against CD20 to deplete B cells selectively; (4) use of statins as immunomodulators; (5) estriol to induce a pregnancy-like state; (6) bone marrow transplants; and (7) schwann cell transplants.

he value of combination therapy is unknown.



CLINICAL VARIANTS OF MS                                                                                          MSواریانتهای بالینی


سندرم دویک یا نورومیلیت اپتیکا

1-Neuromyelitis optica (NMO), or Devic's syndrome:

 consists of separate attacks of acute ON and myelitis.

 ON may be unilateral or bilateral and precede or follow an attack of myelitis by days, months, or years.

 In contrast to MS, patients with NMO do not experience brainstem, cerebellar, and cognitive involvement, and the brain MRI is typically normal !!!


MRI مغز به طور معمول نرمال است ! درگیری ساقه مغز ، مخچه یا درگیری شناختی ندارند!

3 یا تعداد بیشتری از سگمانهای نخاع دچار ناحیه کانونی افزایش یابنده ای از تورم و کاویتاسیون در MRI می شوند.


 A focal enhancing region of swelling and cavitation, extending over three or more spinal cord segments, is typically seen on MRI. Histopathology of these lesions may reveal areas of necrosis and thickening of blood vessel walls.

 Uncommon in Caucasians.

 A syndrome with diverse causes. Some patients have a systemic autoimmune disorder, often SLE, Sjögren's syndrome, p-ANCA  associated vasculitis, or MCTD. In others, onset may be associated with acute infection with varicella-zoster virus or HIV. More frequently, however, NMO is idiopathic and probably represents an MS variant.


Acute attacks are usually treated with high-dose glucocorticoids as for MS exacerbations. plasma exchange has also been used empirically for acute episodes that fail to respond to glucocorticoids. Immunosuppressants or interferons are sometimes used in the hope that further relapses will be prevented.

MS حاد یا واریانت ماربرگ:

2-Acute MS (Marburg's variant):

 is a fulminant demyelinating process that progresses to death within 1 to 2 years!!!

* یک پروسه فولمینانت که در عرض 1 تا 2 سال به مرگ بیمار منتهی می شود بدون فروکش کردن بیماری- بیوپسی یا اتوپسی

 Typically, there are no remissions.

 Diagnosis : biopsy or at autopsy, revealing widespread demyelination, axonal loss, edema, and macrophage infiltration. Discrete plaques may also be seen.

Antibody-mediated process in the demyelinating lesions.

high-dose glucocorticoids, plasma exchange, and cyclophosphamide have been tried, with uncertain benefit.

انسفالومیلیت گسترده حاد (ADEM) :


ADEM has a monophasic course and is frequently associated with antecedent immunization (postvaccinal encephalomyelitis) or infection (postinfectious encephalomyelitis).


The hallmark of ADEM is the presence of widely scattered small foci of perivenular inflammation and demyelination.

* شاه علامت ADEM وجود کانونهای کوچک پراکنده از التهاب دور وریدچه ای و دمیلیناسیون است.


In its most explosive form, acute hemorrhagic leukoencephalitis of Weston Hurst, the lesions are vasculitic and hemorrhagic, and the clinical course is devastating.


Postvaccinal :   administration of smallpox and certain rabies vaccines.

Postinfectious : viral exanthems of childhood. Infection with measles virus is the most common antecedent (1 in 1000 cases).


Worldwide, measles encephalomyelitis is still common, although use of the live measles vaccine has dramatically reduced its incidence in developed countries.

An ADEM-like illness rarely follows vaccination with live measles vaccine (1 to 2 in 106 immunizations).


 ADEM is now most frequently associated with varicella (chickenpox) infections (1 in 4000 to 10,000 cases).

It may also follow infection with rubella, mumps, influenza, parainfluenza, and infectious mononucleosis viruses and with Mycoplasma.


An autoimmune response to MBP can be detected in the CSF from many patients with ADEM. This response has been most clearly established after rabies vaccination and infection with measles virus.



 In severe cases, onset is abrupt, and progression rapid (hours to days).

 In postinfectious ADEM, the neurologic syndrome generally begins late in the course of the viral illness as the exanthem is fading.

 Fever reappears, and headache, meningismus, and lethargy progressing to coma may develop.    Seizures are common.

 Signs of disseminated neurologic disease are consistently present (e.g., hemiparesis or quadriparesis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss and brainstem involvement).


In ADEM due to chickenpox, cerebellar involvement is often conspicuous.

* در ADEM ناشی از آبله مرغان ، درگیری مخچه ای آشکار است.


CSF protein is modestly elevated [0.5 to 1.5 g/L (50 to 150 mg/dL)].

Lymphocytic pleocytosis, generally 200 cells/µl, occurs in 80% of patients. Occasional patients have higher counts or a mixed polymorphonuclear-lymphocytic pattern during the initial days of the illness. Transient CSF oligoclonal banding has been reported.

MRI may reveal extensive gadolinium enhancement of white matter in brain and spinal cord.



The diagnosis is easily established when there is a history of recent vaccination or exanthematous illness. In severe cases with predominantly cerebral involvement, acute encephalitis due to infection with herpes simplex or other viruses may be difficult to exclude.

 The simultaneous onset of disseminated symptoms and signs is common in ADEM and rare in MS. Similarly, meningismus, drowsiness or coma, or seizures suggest ADEM rather than MS.

 Unlike in MS, in ADEM optic nerve involvement is generally bilateral and transverse myelopathy complete.

MRI findings that may support a diagnosis of ADEM include extensive and relatively symmetric white matter abnormalities and Gd enhancement of all abnormal areas, indicating active disease and a monophasic course.


ADEM: سابقه واکسیناسیون یا بیماری اگزانتمی وجود دارد- آغاز همزمان و گسترده علایم و نشانه ها (نادر در MS) وجود مننژیسموس، خواب آلودگی یا کوما (در MS نادر است) درگیری 2طرفه عصب اپتیک و میلوپاتی عرضی کامل ( برخلاف MS)


Initial treatment is with high-dose glucocorticoids as for exacerbations of MS. Patients who fail to respond may benefit from a course of plasma exchange or intravenous immunoglobulin.


Measles encephalomyelitis is associated with a mortality rate of 5 to 20%, and most survivors have permanent neurologic sequelae. Children who recover may have persistent seizures and behavioral and learning disorders.


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