Autoimmune and Demyelinating Diseases Flashcards
What are the two ways in which we typically develop auto-antibodies in neurologic autoimmune disease?
Both are ways of exposing normally “hidden” epitopes
- Release of nervous system antigens into circulation
- Allowing immunologic cells access in to the nervous system which they don’t usually have
If auto-antibodies are present, is this always a cause of disease?
No. Oftentimes, autoantibodies are simply used as a marker of autoimmune disease, but may not be directly pathogenic. They should correlate with disease severity, however.
How are corticosteroids effective in myasthenia gravis? How should you give them?
In addition to having immunosuppressive activity, they are also thought to upregulate the synthesis of acetylcholine receptors.
Start low and go slow to avoid acute exacerbation
Is plasmapheresis highly selective for the antibody you want to remove? Why or why not?
No -> it is similar in principle to dialysis, and uses filtration by molecular weight. Many things other than antibodies are removed from the serum, and it’s fairly nonspecific
How does giving pooled IVIg thought to work?
- Suppressed endogenous antibody production by over-loading the system with antibodies
- Giving human IVIg is thought to add exogenous antibodies which can bind the idiotypes causing autoimmune disease (it is normal to produce anti-antibodies)
What are the Kock-Witebsky Postulates of autoimmune disease?
- Circulating antibodies are present and titers are related to disease activity
- Passive transfer of antibodies should reproduce all major pathogenic effects (reproduce in animal models)
- Immunization with putative antigen should produce the disease in healthy animals
What causes myasthenia gravis and what groups of people tend to get it?
Autoantibodies to acetylcholine receptors at the NMJ
Older men and younger women get it
Newborns can also get it via passive immunization by mother, but resolves quickly after birth
What is the pattern of muscle weakness and daily change in MG?
Eye muscles are usually affected first because they are constantly moving
Muscle weakness is worse as the day progresses -> due to ACh depletion
Give three tests which can be used in the bedside diagnosis of MG?
- Arm abduction time - patient holds arms out as long as possible, MG holds usually <2 min
- Edrophonium test
- Ice pack test - cooling inhibits AChE, will improve ptosis if present
How does the Edrophonium test work and what is the best way to measure response?
Response to edrophonium occurs in 30-60 seconds and subsides in 4-5 minutes. Make sure to have atropine incase dangerous bradycardia occurs.
Typically works better if patient has diplopia -> improvement of diplopia. Weakness improvement is subjective and nonspecific
What other antibody than anti-AChR commonly occurs in MG patients who are negative for that antibody?
anti-muscle specific tyrosine kinase (MuSK)
What finding is seen for repetitive stimulation EMG in MG and why?
Decrement of signal is >10% between 1st and 5th compound motor AP at 3 Hz
-> repeat stimulation causes depletion of ACh in neuromuscular junction (normal). Decreased AChR concentration (pathologic) leads to some muscles not firing, so that compound active potential is decremented over repeat stimulations.
What is the most sensitive EMG test for neuromuscular junction disease in general and how does it work?
Single fiber electromyography (SFEMG)
- hook up electrodes to a single motor unit with two fibers coming from it.
- healthy individuals will have a normal delay based on the distance apart between two motor fibers
- diseased individuals will have varying delay times between firing of 1 & 2 because the response is unpredictable
- > “jitter pattern” on EMG
Are anti-AChR antibodies common, and is there any genetic control over who gets MG?
Yes - anti-AChR happens in many elderly patients without any myasthenic disease
Genetic control is proprosed to some extent because anti-AChR antibodies are associated with several HLA types.
What two things are thought to induce anti-AChR antibodies?
- Thymoma - thymus has many similar antibodies to NMJ
2. Penicillamine
What drugs are first-line in the treatment of MG?
- Pyridostigimine - AChE which is a quaternary amine and does not cross BBB
- Prednisone +/- azathioprine, giving azathioprine to reduce required prednisone dosage
What surgical and hematologic treatments are useful for MG? When is the surgical treatment done?
- Thymectomy - done when thymoma is present or patient is <45 years (thymus antigens probably contributing, and it involutes in older patients)
- Plasmapheresis / IVIg
What causes Lambert-Eaton Myasthenic Syndrome (LEMS) and what is usually associated?
anti-VGCC antibodies (presynaptic voltage gated calcium channels)
Usually associated with small cell lung cancer (paraneoplastic syndrome)
How do the clinical symptoms of LEMS (aside from EMG studies and reflexes) differ from MG?
- Bulbar and respiratory muscles are less frequently affected than MG, and gait is more affected
- Associated with more autonomic dysfunction (not purely neuromuscular ACh release that’s inhibited)
What autonomic dysfunction is common in LEMS?
Dry mouth, sexual impotence, and sometimes sphincter dysfunction
How is reflex activity different between MG and LEMS?
MG - reflexes unaffected since it only requires a single twitch and muscles won’t be tired
LEMS - more severely affected, because muscle use gets better after multiple twitches
What EMG finding is characteristic of LEMS? Whats the pathophys behind this?
Repetitive stimulation increments response by >25% after 10-15 seconds of maximal effort. >100% is diagnostic.
- > repetitive contractions lead to more calcium sequestration in mitochondria and smooth ER -> calcium release from these is not dependent on VGCC, so contraction strength will be greater with more repetitive contractions as ACh release is increased
- > Calcium eventually lost by mitochondria / SR at rest.
How does treatment of LEMS differ from MG?
LEMS - less responsive to pyridostigmine
Add: Fampridine (3,4-diaminopyridine) -> enhances calcium entry by inhibiting K+ channels, prolonging repolarization
-> may be CNS-toxic and cause seizures
What is the most common subtype of Guillain-Barre snydrome? What nerve types are affected and where are they affected most?
Acute inflammatory demyelinating polyneuropathy (AIDP)
Autoimmune destruction of peripheral myelin (Schwann cells) -> affects both sensory and motor nerves -> especially proximally / distally where the blood-nerve barrier is the weakest
What is the CSF finding in AIDP & why was this important?
Albuminocytologic dissociation -> elevated CSF protein with normal WBC count. Important because it differentiated from polio which had similar clinical findings but is associated with increased WBCs as well.
