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

§  Perivenular areas of demyelination with reactive gliosis.

·         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 5^th and 9^th)

§  Hemifacial Spasm (Demyelination of CN 7^th)

§  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 plaque – hyperintense focal area on T2-weighted MRI (but only 1/3^rd appear as hypointense lesions on T1-weighted MRI → ‘Black Holes’)

§  ‘Dawson’sFingers’ – perivenular demyelination perpendicular to ventricles

§  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