Myasthenia Gratis, Guillain-Barre Syndrome & Multiple Sclerosis

Question 1

myasthenia gravis keywords

Answer 1

autoimmune, anti-body mediated disorder dysfunction at the neuromuscular junction

Question 2

epidemiology of myasthenia gravis

Answer 2

0. 3-2.8/100,000 per year
   - occurs at all ages
   - women < 40; men > 60
   - young women w/ HLA-DR14 higher incidence
   - increased familial risk –> 4.5% for siblings and first degree relative

Question 3

pathophysiology of MG

Answer 3

-immunological attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (antibody mediated; T cell dependent) auto-antibodies attack AChR, reducing the number of available receptors over time

Question 4

signs & symptoms of MG

Answer 4

hallmark=fluctuating degree and variable combination of weakness in ocular, bulbar (cough, gag & swallowing - being able to clear secretions), limb and respiratory muscles CN 3, 4, 5, 6, 7, 10, 12 ptosis, diplopia, difficulty in chewing/swallowing, respiratory difficulties, limb weakness (CN 5, 7, 9, 10, 12) weakness may be localized or generalized symptoms often fluctuate in intensity during the day, generally worse in afternoon/evening

Question 5

diagnosis of MG

Answer 5

physical exam: sustained upward gaze, deep breath test, neck extension and flexion, arm abduction time, EOM, visual fields, pupillary reaction Labs: AChR-Ab, MuSK-Ab

Diagnostics: NIF (negative inspiratory force) & FVC, CT chest to r/o thymoma, EMG (as outpatient), tension test (as outpatient, sensitive by not confirmatory, can allow you to follow progress generally happens with other autoimmune disorders: RA, LSE, DM I, Graves

Question 6

management/treatment of MG

Answer 6

symptomatic and immunosuppressive treatment

• pyridostigmine (Mestinon): cholinesterase inhibitor with potentially bothersome muscarinic side effects (diarrhea and oral secretions)
• corticosteroids (Prednisone) add if still having symptoms with Mestinon
• non steroidal immunosuppression (azathioprine, cyclosporine, mycophenolate, mofetil, methotrexate, tacrolimus)
• can use these alone when steroids are contraindicated or refused by patients
• there are significant side effects when used in conjunction w/ corticosteroids,
• can be used in conjunction when steroid response inadequate
• can be used at the same time if steroids unable to be weaned due to symptom relapse
• considerations: serious adverse effects and drug interactions with cyclosporine

Question 7

what do you do for refractory MG

Answer 7

have to think about this when on 2 or all 3 and still having symptoms (Mestinon, steroids, non steroidal immunosuppression) -

• IVIG, PLEX, cyclophosphamide, Rituximab
• Considerations: IVIG cannot be used in RENAL failure, efficacy less in mild/ocular MG, can be used as maintenance if IS contraindicated, PLEX more effective in MuSK-MG surgery….
• non-thymomatous MG to avoid or minimize dose/duraiton of immunotherapy -no current evidence to support thymectomy in MuSK, LRP4 or again antibodies
• otherwise thymectomy should be performed unless elderly or multiple co-morbidities.

Question 8

what do you do for a myasthenic crisis?

Answer 8

• supportive care: pyridostigmine, steroids, immunotherapy.
  
  • can uptitrate but generally keep them on same dose and give IVIG.
  • can treat with stress dose steroids if going to have surgery
  • respiratory: daily NIF/FVC - often have to intubate
  • IVIG (2g/kg over 5 days)
    
    • prior to administration check for IgA deficiency - if they have a deficiency then they will have a stronger reaction to IVIG & should have pre-treatment w/ tylenol & benadryl
    • some report migrainous headache following infusion -> migraine cocktail (avoid fluoroquinolone, Zpac, Magnesium as they can worse symptoms of MG)

Question 9

why do people go into myasthenic crisis?

Answer 9

infection, not responding to their meds, stress, too tired, medications aren’t enough

Question 10

plasmapheresis for myasthenic crisis?

Answer 10

course of 7-14 days

contraindications: limited access, hemodynamically unstable, hypocalcemia, heparin allergy

Question 11

psych help for myasthenic crisis

Answer 11

anxiety can be limiting factor to extubation and improvement. must treat aggressively and consider anxiolytics, anti-depressants and neuroleptic agents -lots of patients will end up with trachs b/c they aren’t strong enough to wean. -promote sleep, minimize stress, avoid extreme temperatures

Question 12

what are the outcomes for MG

Answer 12

• slow progressive disease which may have a fatal outcome owing to respiratory complications such as aspiration PNA
• requires commitment to balance of medications, activity and stress to optimize lifestyle and prevent crisis.

Question 13

key words for Guillain-Barre syndrome?

Answer 13

• immune mediated disorder of PNS
• inflammatory response on peripheral myelin resulting in myelin degeneration

Question 14

epidemiology of Guillain-Barre

Answer 14

1 to 2 / 100,000 per year (slightly more common than MG)

• can occur at any age, most common in 50s.
• incidence increases by 20% with every decade
• equally among men & women, but males > females for hospitalization

Question 15

what about GBS variants?

Answer 15

• 16 clinical variant subtypes
• acute inflammatory demyelinating polyradicularneuropathy. This is the dominate subtype in Europe & North American with 90% of cases
• acute motor axonal neuropathy. this is the dominate subtype in China & japan

Question 16

what is the dominate GBS subtype in China and Japan?

Answer 16

acute motor axonal neuropathy

Question 17

what is the dominate GBS in Europe and North American

Answer 17

acute inflammatory demyelinating polyradiculoneuropathy.

Question 18

what is the AIDP and miller-fisher variants of GBS?

Answer 18

-focal inflammatory response against myelin-producing Schwann cells or peripheral myelin causing segmental myelin degeneration of nerve.

Question 19

what is motor and motor sensory variants of GBS?

Answer 19

-axon is affected with inflammatory response, with primary immune response directed at nodes of Ranvier leading to functional axonal involvement with conduction block.

Question 20

what do the subtypes of GBS look like?

Answer 20

Question 21

what is the pathophysiology of GBS?

Answer 21

• acute or subacute polyradiculoneuropathy
• antecent infections are common and thought to trigger immune response leading to acute polyradiculoneuropathy

Question 22

what is the most commonly identified precipitant for GBS?

Answer 22

campylobacter jejuni. it’s linked with worst prognosis, with slower recover & greater residual neurologic deficit.

Question 23

what are other antecedent infections for GBS?

Answer 23

upper respiratory infection - influenza like virus HIV, CMV, EBV

Question 24

what are clinical features of GBS

Answer 24

• progressive, fairly symmetric muscle weakness with absent or depressed DTR
• weakness varies from mild difficulty walking to complete paralysis of extremity, facial, respiratory & bulbar (cough/gag, difficulty with secretions) muscles
• weakness usually begins in legs
• paresthesias of hands and feet >80%, sensory abnormalities are mild -ventilatory support required in approximately 30%
• dysautonomia in approximately 70%
• progresses over period of about 2 weeks. by 4 weeks after initial symptoms, 90% have reached nadir

Question 25

what is dysautonomia?

Answer 25

tachycardia (most common), bradycardia, hypertension followed by hypotension, urinary retention, ileum.

Question 26

why does dysautonomia happen?

Answer 26

because of sympathetic over activity and parasympathetic under activity

Question 27

how do you diagnose GBS

Answer 27

• initial diagnosis based on clinical presentation
• physical exam: ascending paralysis, areflexia, progressive weakness

Question 28

what labs do you get for GBS?

Answer 28

• Lumbar puncture to rule out infection.
• albuminocytologic dissociation –> no WBC and high protein (which would rule in GBS)
• EMG > 3 weeks = prognostic
• antibodies: they will distinguish variants

Question 29

what are red flag to diagnosis of GBS & should question other etiologies with the listed clinical findings/lab values

Answer 29

• fever at onset
• severe pulmonary dysfunction with limited weakness at onset
• severe sensory signs w/ limited weakness at onset
• persistent bowel or bladder dysfunction or dysfunction at onset
• sharp sensory level
• marked persistent asymmetry of weakness labs
• increased number of mononuclear cells in CSF
• polymorphonuclear cells in CSF

Question 30

what is management for GBS

Answer 30

• supportive care
• daily NIF/FVC (1/3 of patients require mechanical ventilation)
• telemetry
  
  • dysautonomia is significant cause of death. usually occurs in severe cases at peak of deficit.
• monitor for ileum and urinary retention
• hyponatremia r/t SIADH or natriuresis
• DVT prophylaxis
• enteral nutrition
• IVIG (2g/kg over 5 days)

Question 31

outcomes for GBS

Answer 31

• mortality d/t disease related or secondary complications d/t prolonged disease course (PNA or ileum generally)
• recovery is slow
• 80% walk independently at 6 months, 84% at 1 year
  
  • if if they can’t walk by 6 months, not likely that they will walk again
• after 1 year full recovery of motor strength in about 60%
• about 20% of those who become vent dependent will die

Question 32

key words for MS (multiple sclerosis)

Answer 32

inflammation, demyelination and axonal degeneration

Question 33

epidemiology of MS

Answer 33

• 2.5 million worldwide (570,000 in US)
• women>men
• mean age at onset: 28-31 years
• white (northern european) more susceptible than Asian, African and American Indian
• Prevalence increased the further away from the equater

Question 34

what is the epidemiology of two different types of MS

Answer 34

1. relapsing remitting MS: earlier onset 25-29 years old
2. primary progressive MS: mean age 39-41 years

Question 35

pathophysiology of MS

Answer 35

• cause is unknown. most accepted theory: immune-mediated inflammatory disease characterized by auto reactive lymphocytes, later dominated by microglial activation and chronic neurodegeneration
• alternate theories:
  
  • immune etiology d/t chronic viral infection;
  • non immune noninflammatory etiology d/t genetically determined and neuroglia degenerative process and chronic cerebrospinal venous insufficiency

Question 36

clinical features of MS

Answer 36

• fatigue
• weakness
• numbness, tingling, unsteadiness in a limb
• tremors
• spastic paraparesis or stiffness
• retrobulbar optic neuritis diplopia
• dysequilibrium
• sphincter disturbance such as urinary urgency or hesitancy
• symptoms may disappear after a few days/weeks, although examination often reveals a residual deficit.

Question 37

what are the differential diagnosis for MS

Answer 37

• infectious disease
• inflammatory & immune mediated disease
• genetic disorders
• spinal cord conditions
• ischemic conditions (ischemic strokes)
• cancer
• CNS disorderes
• demyelinating disorders
• dietary deficiency

Question 38

3 types of MS

Answer 38

1. relapsing-remiting - 85%
   
   • do well initially
   • months to years from initial symptoms until new symptoms develop or recur
   • increasing disability with weakness, spasticity an ataxia of the limbs, impaired vision, urinary incontinence
2. primary progressive (10-15%)
   
   • steadily progressive with disability at a relative early stage
   • more often when age of onset > 40
3. secondary progressive
   
   • relapsing remitting converts to gradual progressive
   • 50% within 10 years, 80% within 20 years, 90% after 25 years.

Question 39

how is the initial diagnosis made of MS?

Answer 39

• McDonalds criteria
  
  • symptomatic attacks + brain/spinal cord lesions on MRI
• MRI with white matter lesions: 4 key areas of the CNS (periventricular, juxtacortical, infratentorial and spinal cord)
• this MRI can be repeated if have more/worsening symptoms->likely new/worsening lesions will be visible CSF with lymphocytosis, increased protein, elevated IgG and oligoclonal bands

Question 40

management & treatment of MS

Answer 40

• IV methylprednisone 1 gram daily x 3 days followed by PO prednisone x 1 week then taper.
• long term steroids provide no benefit to prevent future relapses relapsing disease
• injectibles (beta-interferon, glatiramer, and natalizumab) show evidence of reducing frequency of attackes
• oral therapies (dimethyl fumarate fingolimod, and teriflunomide) less established but offer excellent efficacy at reduced rates of relapse

Question 41

management & treatment of severe progressive MS disease

Answer 41

• limited evidence supports immunosuppressive therapy such as rituximab, cyclophosphamide, azathioprine, methotrexate plasmapheresis is sometimes helpful in severe relapse when unresponsive to corticosteroids
• IVIG may reduce the rate of clinical attack in replace-remitting disease but studies have been inadequate to provide treatment recommendations symptomatic treatment
• spasticity->baclofen, gabapentin, tizanidine
• neurogenic bladder: oxybutinin
• fatigue: amatadine, modafinil (neurostimulants)
• neuropathic pain: pregab

Question 42

lifestyle modifications for MS

Answer 42

-sleep, health-well balanced diet, stress reduction, regular exercise -overheating can aggravate symptoms

Question 43

outcomes for MS

Answer 43

• partial recovery from acute exacerbations is expected
• relapses may occur without warning
• no means of preventing progression
• some disability is likely to result eventually
• about half of all patients are without significant disability 10 years after onset of symptoms.