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.
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.
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.
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.
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
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.
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).
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.
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),
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,
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.