Myasthenia Gravis meets Koch’s postulates



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Etiology

Clinical Features

Diagnosis

Treatment

Myasthenia Gravis

-meets Koch’s postulates

-circulating Abs to AChR

-passive transfer to animals w/human serum

-autoimmune model in rabbits

-severity fluctuates w/circulating Ab titers & responds to plasmapheresis


-weakness/muscle fatigability

-affected distribution variable, often asymmetric

-eye muscles 1st affected in 60%, eventually in 90%

-diurnal variation

-reflexes preserved

-sensation unaffected




Bedside:

-arm abduction or ptosis time < 5 min demonstrates fatigability

-tensilon test demonstrates reversal of sx w/enhanced synaptic transmission

-edrophonium 2 mg test, then 4-8mg at 1 min

-response in 30-60 sec & subsides in 4-5 min

-need to have atropine on hand, non-specific, need objective criteria

Lab:

-Anti-AChR Ab – 85-90% (+), highly specific



-repetitive stimulation on EMG causes decrement due to later stimuli releasing less ACh

-decrement >10% at 3Hz, 50% (+) in mild, 80% (+) in moderate/severe, highly specific

-jitter on SFEMG reflects variable synaptic transmission

-95% (+) in generalized weakness, 84% (+) in ocular myasthenia, non-specific


-Ab’s to AChR w/o MG in 18% of elderly Japanese, 7% elderly w/raised anti-thyroid Ab titer, pt’s w/tardive dyskinesia or non-myasthenic thymoma & identical twins of MG patients

-assoc w/several HLA types – HLA type correlates w/clinical features (age of onset, Ab titer, thymus path)

-Thymoma & penicillamine can induce MG and Ab’s to AChR

-AChR Ab’s vary in epitope & in affinity for junctional vs. extra-junctional receptors

-attempts to link AChR Ab’s to viruses & bacteria have been unsuccessful (no cross-reactivity)


-pyridostrigmine (AChE inhibitor)

-prednisone ± azathioprine

-thymectomy

-plasmapheresis



Lambert-Eaton Myasthenic Syndrome (LEMS)

-circulating Ab’s w/interfere w/ACh release by binding presynaptic VGCC

-passive transfer to animals

-autoimmune animal model

-severity fluctuates w/circulating Ab titers, responds to plasmapheresis



-weakness/muscle fatigability like MG but bulbar & resp. muscles less frequently involved, gait usually affected

-autonomic dysfunction (dry mouth, sexual impotence, sometimes sphincter dysfxn)

-reflexes often depressed, can restore after brief activity

-60% assoc w/small cell lung cancer



-dx similar to MG

-less responsive to Tensilon testing


-Anti-VGCC Ab – 45-65% (+), highly specific

-repetitive stimulation on EMG ↑ as presynaptic terminal accumulates calcium

-↑ >25% after 10-15 sec maximal effort = highly suggestive, ↑ >100% = diagnostic


-search for/treat tumor

-pyridostigmine (Mestinon) less effective than in MG

-3,4-diaminopyridine (Fampridine)enhances calcium entry by inhibiting

K channels (but often toxic)

-plasmapheresis

-prednisone, azathioprine

-IVIg may be effective


Polymyositis, Dermatomyositis

-most common inflammatory myopathies (0.5-1/100,000)

-clinically & pathologically distinct




DM: presents more acutely, systemic sx more often
PM: autoimmune model
-severity responds to plasmapheresis & IVIg in DM, possibly in PM

-circulating Ab’s to myosin & nuclear Ag’s present, but not disease specific; circulating immune complexes & cytokines may also be a factor
-progressive symmetric weakness of limb girdle & neck flexor muscles, dysphagia

-↑ CPK, muscle enzymes

-EMG w/”irritative” myopathy

-segmental myonecrosis & regeneration w/mononuclear inflammatory exudates

-DM: erythematous dermatitis on neck, upper trunk, & extensor surfaces of PIP, MCP, elbow, & knee; nailbed infarcts; heliotrope discoloration of upper eyelids; periorbital edema; vasculopathic changes

-PM: Ag-directed cytoxicity by CD8+ T cells



-prednisone 1mg/kg/day PO

-azathioprine 100-250 mg/day PO

-MTX, weekly IV or PO, doses ↑ until effective or 50mg/week

-cyclosporine 125-200mg PO BID

-plsamapheresis, esp. in DM

-IVIg, esp. in DM



Guillain-Barre Syndrome

(GBS, AIDP)

-acute monophasic

-“ascending” neuropathy, but any multifocal/asymmetric pattern of onset possible


-intraneural injection of pt sera causes demyelination in rats, but systemic transfer does not

-autoimmune animal model (experimental allergic neuritis = EAN)



-early loss of reflexes

- sensory & motor involved, often early ataxia

-often assoc w/recent febrile or GI illness

-circulating immune complex (not Ab’s) & cytokines




-acute “ascending” multifocal or asymmetric pattern of neuropathy; both sensory & motor involved

-hyporeflexia or areflexia

-spinal fluid w/ <10 WBC, usu ↑ protein

-nerve conduction study w/prolonged distal latencies, slowed conductions, or prolonged F-waves




-plasmapheresis or IVIg can shorten/reduce severity of acute phase

-tx should not be started >3 weeks after onset unless there is clear progression

-tx should be started asap in pt’s who can’t walk unassisted

-Tx course 5-10 days

-steroid therapy NOT helpful


AMAN & AMSAN

-circulating Ab’s to GM1b & GaINAc-GD1a, and cross react w/lipopolysaccharides of campylobacter jejuni

-c. jejuniacute motor neuropathy in chickens

-AMAN recovery usu rapid & complete despite axonal disease

-AMSAN recovery is slow & less complete



AMAN:

-clinical presentation like AIDP, but only motor nerves affected

-nerve conduction studies show axonal drop-out w/o significant slowing of conduction

-Mexico, seasonally in N. China

-occurs after c. jejuni diarrheal disease
AMSAN:

-clinical presentation like AIDP (both motor & sensory involvement)

-nerve conduction studies show axonal drop-out w/o significant slowing of conduction

-low frequency in Europe and N. America

-also assoc. w/ c. jejuni diarrheal disease





Multifocal Motor Neuropathy (w/conduction block) (MMN)

-asymmetric slowly progressive weakness, often beginning in arms, w/atrophy & fasciculations

-may resemble ALS but w/o UMN sx

-systemic transfer of sera causes electrophysiologic defect, but not overt disease

-no animal model



-nerve conduction study shows focal slowing & conduction block

-80-90% have high anti-GM1 ganglioside titers (partially specific)

-circulating Ab identified, but not associated w/disease activity


-IVIg

-not plasmapheresis or steroids



Chronic Inflammatory Demyelinating Polyneuropathy (CIPD)

-systemic transfer of sera from pt’s to marmosets causes electrophysiologic defect, but not overt disease

-immunization of rabbits w/galactocerebroside causes relapsing remitting demyelinative neuropathy similar to CIDP in humans



-resembles AIDP w/slower onset (>8 weeks) followed by chronic relapsing & remitting course

-usu no clear antecedent illness

-nerve conduction study shows prolonged distal latencies, slowed conductions, & prolonged F-waves, often non-uniform distribution

-no circulating Ab’s, but circulating immune complexes & cytokines may be a factor

-tissue binding of Ab’s is of questionable significance


-IVIg

-plasmapheresis

-prednisone 1mg/kg/day PO

-cyclosporine 125-200mg BID PO



Dysproteinemic Neuropathy

Myeloma w/ osteosclerosis:

-nearly ½ have neuropathy, often w/POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin thickening & hyperpigmentation)

- demyelinating neuropathy

-neuropathy improves w/treatment of myeloma


Myeloma w/o osteosclerosis

-5% have neuropathy

-axonal neuropathy

-does NOT improve w/treatment of myeloma


CIDP-MGUS

-clinically resembles CIDP, often w/more prominent sensory involvement

-may not respond to usual tx for CIDP
Anti-MAG Ab (CIDP-MGUS with IgM K antibody directed against MAG)

-sera causes neuropathy on passive transfer to chickens

-nerve biopsy shows myelin wide-spacing

-may respond to plasmapheresis & IVIg






Paraneoplastic Syndromes

Paraneoplastic Cerebellar Degeneration (PCD)

-circulating & intrathecal Ab’s bind cerebellar purkinje cells

-anti-Yo Ab’s assoc. w/ovarian, uterine, & breat neoplasms

-plasma exchange rarely beneficial, but usu. tried late in disease course


Paraneoplastic Opsoclonus-Myoclonus (flurries of multidirectional rapid eye movements , “dancing eyes and dancing feet”)

-circulating Ab’s NOT identified in kids w/neuroblastoma and adults w/variety of tumors

-anti-Ri Ab high titer in pt’s w/breast tumors, and cross-reacts w/tumor cell and neuronal nuclei

-opsoclonus-myoclonus may resolve w/treatment of tumor or w/prednisone


Paraneoplastic Encephalitis & Sensory Neuronopathy

-circulating anti-neuronal Ab’s, esp. anti Hu

-common in pt’s w/small cell carcinoma

-plasma exchange rarely beneficial






Stiff-Man Syndrome







-circulating Ab’s to the GABA-synthesizing enzyme glutamic acid decarboxylase in 60%

-patient sera can inhibit enzyme activity in vitro





-response to plasmapheresis & IVIg is debated

Multiple Sclerosis

-interaction b/w genetically susceptible individuals & geographic exposure:

1) incidence ↑ w/latitude

2) risk correlates with geographic location before age 15

3) prevalence varies among races

4) incidence correlates w/ HLA type

-MHC locus on chr 6

-MHC class II HLA-DR2

haplotype DR15, DQ6)

5) concordance 25.9% in MZ twins and 2.5% in DZ twins


-chronic demyelinating disease of adults

-multifocal development and accumulation of plaques of demyelination in CNS




-no specific circulating Ab’s identified, but ↑ titers to variety of viruses (mumps, HSV, rubella, vaccinia) suggests immune system deregulation
-↑ intrathecal Ab’s (oligoclonal bands), but no specific Ag identified
-β-interferons effective in ↓ severity & frequency of exacerbations

-interfere w/actions of interferon gamma, which provokes exacerbations

-binds specific cell receptorssynthesis of >24 proteins that contribute to viral resistance
-Glatiramer (Copaxone) effective in MS patients and in experimental allergic encephalomyelitis (EAE)

-mixture of random polymers of 4 aa’s: L-alanine, L-glutamic acid, L-lysine, L-tyrosine

-effect probably related to inhibition of immune response to myelin basic protein & other myelin Ag’s

-at least partially cross-reacts w/myelin basic protein on a cellular and humoral level




-no significant response to most immunosuppressive therapies, but high dose methylprednisolone may shorten acute exacerbations

Neuromyelitis optica (Devic’s Disease)




-inflammatory demyelinating disease w/generally poor prognosis that selectively targets optic nerves and spinal cord



* similar to and commonly misdiagnosed as MS
-NMO-IgG is a specific marker autoAb; distinguishes neuromyelitis optica from MS

-binds at or near BBB






Pediatric autoimmune neuropsychiatric disorders assoc. w/strep infection

(PANDAS)







-Sydenham’s chorea is a post-strep autoimmune disorder
-implicates post-infectious autoimmunity in a subset of pt’s w/childhood onset tics & OCD

-assoc. w/anti-basal ganglia Ab’s







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