·
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 plaque –
hyperintense focal area on
T2-weighted MRI (but only 1/3
rd
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
·
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
