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Thursday, 11 October 2012

MULTIPLE SCLEROSIS


·         Demyelinating disorder of CNS
·         M:F = 1:3
·         Age of onset- 20-40 yrs
·         Pathogenesis
§  Δiad-
1.       Inflammation
2.       Demyelination
3.       Gliosis
§  Stage of inflammation-
§  Perivenular cuffing with inflammatory mononuclear cells (T cells & macrophages) + infiltration of surrounding white matter
§  Disruption of blood brain barrier (but vessel wall is preserved, a contrast to vasculitis syndromes where vessel wall is damaged)
§  Stage of demyelination
§  Cell-mediated immunity- T-lymphocytes against Myelin Basic Protein (MBP)
§  Humoral immunity- Myelin specific antibodies
§  Stage of Gliosis/Scarring
§  Astrocytes proliferation + Partial remyelination of surviving naked axons by surviving oligodendrocytes appearing as ‘shadow plaques’
·         Histology
·         Risk factors-
§  Vit D deficiency
§  Genetic susceptibility
§  HLA DR2
§  IL2RA (Interleukin-2 receptor α gene)
§  IL7RA (Interleukin-7 receptor α gene)
§  High socioeconomic status
·         Clinical Manifestations
§  Weakness of the limbs
§  UMN type
§  Exercise induced weakness- characteristic
§  Spasticity (associated with)
§  Painful spasms
§  Spontaneous/Movement induced muscle spasms
§  Facial weakness
§  Due to lesion in pons.
§  Not associated with ipsilateral loss of taste sensation/retroauricular pain (a contrast to Bell’s palsy)
§  Cerebellar features
§  Ataxia
§  Dysarthria / Scanning speech
§  Vertigo
§  Sensory symptoms
§  Paresthesias (pins-needles, formications, burning pain)
§  Hypoesthesia (numbness)
§  Pain (50%)
§  Bladder dysfunction (>90%)
§  Detrusor hyperreflexia - impairment of suprasegmental inhibition. (urgency, nocturia, frequency)
§  Detrusor sphincter dyssynergia - loss of synchronization between detrusor and sphincter muscles. (hesitancy, urinary retention, overflow incontinence)
§  Constipation (30%)
§  Sexual Dysfunction
§  Cognitive Dysfunction and Depression
§  Optic neuritis
§  Diminished visual acuity
§  Desaturation/↓color vision in central field of vision.
§  Unilateral > Bilateral
§   Visual loss is usually preceded by periorbital pain (aggravated by eye movements)
§  Pallor of optic disk/optic atrophy
§  Visual blurring


§  Ancillary Symptoms
§  Heat Sensitivity-
·         Neurologic symptoms are produced when core body temperature rises.
·         Uhthoff’s symptom- Unilateral visual blurring during exercise or hot shower.
§  Lhermitte’s Symptoms- electric shock–like sensation (specially induced by flexion or other movements of the neck) radiating down the back into the legs
§  Trigeminal Neuralgia and Glossopharyngeal Neuralgia (demyelination of CN 5th and 9th)
§  Hemifacial Spasm (Demyelination of CN 7th)
§  Facial Myokymia – persistent rapid flickering contractions of facial muscles (due to lesions of brainstem or corticobulbar tracts)
·         Disease Patterns
1.       Relapsing/Remitting MS (85%)
§  Discrete attacks separated by intervals of near complete recovery
§  Risk of evolving to SPMS is ≈ 2% every year
§  Majority of RRMS progress to SPMS.

  
2.       Secondary Progressive MS
§  Always starts as RRMS, but with time there is gradual progression of baseline disability with time which is unassociated with acute attacks of MS
§  Thus, SPMS represents late stage of RRMS.



3.       Primary Progressive MS (15%)
§  There are no acute exacerbations/attacks of MS. Instead, from the onset there is a gradual progression of disability with time, which is usually rapid than SPMS.
  
4.       Progressive/Relapsing MS (5%)
§  Overlapping between PPMS and SPMS disease patterns.
  
·         Diagnosis
§  MRI with/without Gadolinium contrast
§  In Active lesions – BBB disrupted → Gd contrast leakage into surrounding brain parenchyma → enhancement on T1-weighted MRI
§  Residual MS plaquehyperintense focal area on T2-weighted MRI (but only 1/3rd appear as hypointense lesions on T1-weighted MRI → ‘Black Holes’)
§  Burden of Disease a.k.a. degree of Clinical Disability – correlates weakly with the total volume of T2 hyperintense lesions.
§  Evoked Potential testing
§  To assess function of afferent pathways (visual, auditory or somatosensory) and efferent pathways(motor)
§  CSF examination
§  ↑ mononuclear cells (mononuclear pleocytosis)
§  CSF total proteins normal/mildly ↑
§  ↑ level of intrathecally synthesized IgG (to distinguish between intrathecally derived IgG and Serum IgG which may have leaked into CSF due to disruption of BBB)
·         CSF IgG index = [IgG : Albumin]CSF ÷ [IgG : Albumin]Serum
·         CSF IgG synthesis rate
·         OligoclonalBanding (OCB) – detected by Agarose gel electrophoresis - ≥2 OCBs – seen in 75-90 % of MS patients.
·         Treatment
§  Degree of neurological impairment - Kurtzke Expanded Disability Status Score (EDSS)
§  Score < 3.5 – mostly seen in RRMS
§  Score > 5.5 – mostly seen in PPMS or SPMS
§  Treatment of Acute Attacks
§  Differentiate between ‘True-exacerbation’ and ‘Pseudo-exacerbation’
§  True-exacerbation or acute active disease – Glucocorticoids (mainstay)
§  Glucocorticoids avoided in ‘Pseudo-exacerbation’ [which may be due to temperature changes/fever/infection]
§  Reducing Biological Disease Activity via Disease Modifying Agents (FDA approved)
§  IFN-β (flu-like symptoms, hepatotoxicity) (not effective in SPMS without acute attacks)
·         IFN-β-1a (RRMS/SPMS with acute attacks)
·         IFN-β-1b (RRMS/SPMS with acute attacks)
§  Glatiramer acetate (RRMS)
§  Natalizumab (very effective in all forms, but ↑ risk of progressive multifocal leukoencephalopathy on long term therapy)
§  Fingolimod
§  Mitoxantrone (Cardiotoxicity, permanent amenorrhoea, acute leukemia)
§  Cladribine (to be approved by FDA)
§  Symptomatic Therapy


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