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General Principles of Autoimmune disorders
- 1. Direct (subacute)
- -Cell mediated: multifocal, episodic
- -Antibody mediated: diffuse, continuous or monophasic
- 2. Vasculitic
- -Large vessel injury: infarctions, acute
- -Microvascular injury: indolent, diffuse, subacute or chronic
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Multiple Sclerosis
- Clinical Presentation
- Epidemiology
- Clinical Presentation: Episodes of subacute onset (hours - days), with partial or full
- resolution (weeks - months), affect any part of CNS
- -UMN syndromes
- -Cranial neuropathies
- -autonomic dysfunction
- -optic neuritis
Multiple lesions in time and space
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Multiple Sclerosis
-Pathophysiology
-Diagnosis
- Pathophysiology:
- CD4 T cells react against myelin antigens and secrete cytokinesdemyelination, inflammationineffective remyelination impairs saltatory conductionDiagnosis:Imaging: T2 MRICSF: oligoclonal bands (IgG)Evoked potentials (slower conduction)
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Multiple Sclerosis
-Treatment
- Acute Relapse:IV glucocorticoids (decrease recovery time but don't change overall courseChronic Disease Modification:Glatiramer acetate
- InterferonsNatalizumabFingolimodSymptomatic Therapy:Neuropathic pain (caramazepine, gapapentin, duloxetine)Spasticity (baclofen, tizanidine)Urinary Urges (oxybutinin)Fatigue (amantadine, modafinil, methylfenidate)
Types:
- 1. Relapsing-Remitting
- 2. Secondary Progressive
- 3. Primarily Progressive (older, male > female)
- Epidemiology: more common in far northern and southern latitudes, strong
- genetic component, 2-3x more common in women, ages 20-40
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Multiple Sclerosis
-Pathophysiology
-Diagnosis
Pathophysiology:
- CD4 T cells react against
- myelin antigens and secrete cytokinesdemyelination, inflammationineffective remyelination
- impairs saltatory conduction
Diagnosis:
Imaging: T2 MRICSF: oligoclonal bands (IgG)
Evoked potentials (slower conduction)
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Multiple Sclerosis
-Treatment
Acute Relapse:
- IV glucocorticoids (decrease
- recovery time but don't change overall course
Chronic Disease Modification:
Glatiramer acetate InterferonsNatalizumabFingolimod
Symptomatic Therapy:
- Neuropathic pain (caramazepine,
- gapapentin, duloxetine)Spasticity (baclofen,
- tizanidine)Urinary Urges (oxybutinin)
Fatigue (amantadine, modafinil, methylfenidate)
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Glatiramer acetate
- MOA:
- -synthetic peptide similar to MBP, exact mechanism unknown
- Effects:
- -decreases relapses by 1/3
- -no neutralizing antibodies develop
- Adverse Effects:
- -delayed onset by months
- -injection site reactions
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Interferons
- MOA:
- -decrease expression of pro-inflammatory cytokines
- -reduce T cell migration across BBB
- -increases production of NGF
- Effects:
- -similar to glatiramer
- Adverse Effects:
- -injection site reaction
- -neutralizing antibodies
- -flu-like symptoms
- -liver dysfunction (rare)
- -depression (rare)
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Natalizumab
- MOA:
- -monoclonal antibody that inhibits alpha-4 integrins
- -prevents lymphocytes from entering CNS
- Effects:
- -decrease relapse by 60%
- -decrease MRI lesions by 90%
- Adverse Effects:
- -1/1000 risk of progressive multifocal leukoencephalopathy (PML)
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Fingolimod
- MOA:
- -binds S1P receptors
- -blocks lymphocytes from exiting LNs
- Effects:
- -only oral drug for MS
- -more effective than IFN
- Adverse Effects:
- -bradycardia
- -leukopenia
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Temporal Arteritis
- Clinical Presentation:
- -subacute to chronic HA, jaw claudication, nodular temporal artery, blindness
- Epidemiology:
- -most common in the elderly
- Pathophysiology:
- -chronic, granulomatous inflammation of large arteries (most often temporal
- artery)
- -initial T cell response against vascular wall antigen
- -segmental regions of nodular intimal thickening with lumen narrowing
- Diagnosis:
- -Clinical suspicion
- -ESR
- -temporal artery bx
- Treatment:
- -high dose glucocorticoids (prednisone)
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Guillain Barre Syndrome
- Clinical Presentation:
- -subacute onset progressive ascending paralysis
- -early mild sensory change
- -painful
- -typical LMN syndrome
- -autonomic dysfunction
- -out of degree areflexia
- -85% recover (usually 2-3 mo, some 6-18 mo)
- Epidemiology:
- -60% preceeded by URI or GI illness
- -relation to C. jejuni
- Pathophysiology:
- -T cells initiate response against myelin
- -segmental demyelination throughout PNS
- -the longer the nerves, the more lesions --> distal polyneuropathy
- Treatment:
- -ABCs
- -Plasmapheresis
- -IVIg
- -Glucocorticoids are NOT effective
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Myasthenia Gravis
- Clinical Presentation:
- -fluctuating weakness
- -weakness that worsens with exercise and improves with rest
- -affects small, constantly used muscles first (EOMs, hands)
- Epidemiology:
- -third decade for women
- -sixth decade for men
- -associated with thymoma or thymic hyperplasia
- Pathophysiology:
- -antibodies block AChR
- -increased degradation of AChRs
- -Abs cause C' mediated degradation of postsynaptic folds
- Diagnosis:
- -serum antibodies
- -decrementing response
- -pharmacologic challenge (edrophonium or tensilon)
- Treatment:
- -Anticholinesterase drugs
- -Chronic glucocorticoids
- -plasmapheresis
- -IVIg
- -thymectomy
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Paraneoplastic Disorders
-subacute to chronic progressive diffuse lesion
- 1. Cerebellar degeneration
- 2. Encephalomyelitis
- 3. Opsoclonus-myoclonus-ataxia
- 4. Subacute sensory neuropathy
- 5. Lambert-Eaton myasthenic syndrome
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Cerebellar Degeneration
- -onset: weeks to months
- -symmetrical ataxia, dysarthria, nystagmus
- -imaging: subtle enhancement of cerebellum
- -associated with ovarian and lung cancer
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Encephalomyelatis
- -subacute onset
- -often bilateral
- -medial temporal lobe
- -confusion, agitation, amnesia, dementia
- -associated with lung, prostate, lymphoid, ovarian, testicular CA
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Opsoclonus-myoclonus-ataxia
- -predominantly childhood syndrome
- -"bouncing eyes"
- -associated with Neuroblastoma
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Subacute sensory neuropathy
- -rapid onset polyneuropathy
- -small cell lung cancer, lymphoma
- -often rapidly leads to death, refractory to tx
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Lambert-Eaton myasthenic syndrome
- -NMJ dysfunction due to failure of
- vesicle fusion
- -anti-voltage gated Ca channel antibodies
- -improves with exercise (incrementing response)
- -small cell lung cancer
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Acute demyelinating encephalomyelitis (ADEM)
- -multifocal areas of myelin breakdown
- -monophasic (all lesions enhance on MRI)
- -typically follows an acute infection
- Clinical Presentation:
- -rapid subacute progression
- -HA, confusion, fever, ataxia
- Epidemiology:
- -children more commonly affected in adults
- -in adults can be associate with small pox vaccine
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Dermatomyositis
- Clinical Presenation:
- -muscle weakness
- -heliotrope rash
- -childhood variant is different
- Pathophysiology:
- -inflammatory infiltrates around small blood vessels and in perimysial CT
- -B cell mediated
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Poliomyositis
- Clinical Presentation:
- -painless symmetrical weakness
- Pathophysiology:
- -inflammation in the endomesium scattered throughout the fascicles
- -due to CD8 T cells
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