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Neuropathology > Autoimmune Disease > Flashcards

Autoimmune Disease Flashcards

1
Q

AI diseases in neurology

Gen list

A 
Myasthenia gravis 
Lambert-Eaton 
Polymyositis and dermatomyositis 
Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré) 
Chronic inflammatory demyelinating polyneuropathy (CIDP) 
Multifocal motor neuropathy (MMN) 
Acute motor axonal neuropathy (AMAN) 
Dysproteinemic neuropathy

Paraneoplastic neuropathy
Paraneoplastic cerebellar degeneration
Paraneoplastic limbic encephalitis
Paraneoplastic retinal degeneration Stiff-man syndrome
Multiple sclerosis
Neuromyelitis Optica
Pediatric AI neuropsychiatric disorders assoc with strep infection (PANDAS)

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2
Q

Why are there so many neurologic AI diseases

A

Autoimmune disease occurs when the immune system fails to recognize antigens as “self”

Many nervous system antigens are usually inaccessible to the immune system

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3
Q

AI neurologic diseases

mech

A

(1) Production of antibody that can cross-react with nervous system antigens may not be inhibited, so antibodies directed against infections and other external antigens may cause disease by such cross-reaction. This is called molecular mimicry.
(2) Diseases which disrupt the blood-brain or blood-nerve barrier may lead to formation of antibodies against normally “hidden” epitopes, either by release of nervous system antigens into circulation or by allowing immunologic cells access in to the nervous system. These antibodies may be pathogenic or may be simply markers of disease.

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4
Q

Immunosuppressive therapy in neurology

list

A

(1) IV steroids (methylprednisolone)
(2) PO steroids (prednisone)
(3) Azathioprine
(4) Methotrexate
(5) Cyclosporine
(6) Mycophenylate
(7) Plasmapheresis
(8) IVIg

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5
Q

Plasmapheresis

Gen mech

A

Plasmapheresis is similar in principle to dialysis, and uses filtration by molecular weight. It removes all plasma components in approximately equal
proportions unless semiselective adsorption is used to enhance removal of certain antibodies and other proteins (eg. complement components). It is also known as plasma exchange (PE).

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6
Q

Plasmapheresis

Which compenents are removed

A

(1) antibodies
(2) immune complexes
(3) complement components
(4) cytokines
(5) hormones
(6) clotting factors
(7) soluble toxins

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7
Q

IVIg

Use in AI neurologic disease

A

IVIg is pooled human immunoglobulins. It may suppress endogenous antibody production by “over-loading” the system with antibodies, although it has also been proposed that there are networks of “anti-idiotypic antibodies” which regulate or neutralize certain circulating antibodies.

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8
Q

Koch-Witebsky postulates

list

A

Circulating antibodies are present and titers are related to disease activity
Passive transfer of antibodies should reproduce all major pathogenic effects
Immunization with the putative antigen should produce the disease in healthy animals

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9
Q

Etiology of Myasthenia Gravis

A

(1) Circulating antibodies to acetylcholine receptors (AChR) are present
(2) Passive transfer to animals with human serum has been demonstrated
(3) There is an autoimmune animal model in rabbits
(4) Disease severity fluctuates with circulating antibody titers, and responds to plasmapheresis

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10
Q

Myasthenia gravis

epidemiology

A

Affects females > males
Can occur at any age
a. Neonatal commonly is due to transfer of maternal antibodies
Peak incidence in females is 10-40 years old
Peak incidence in males is 50-70 years old
Prevalence 4-9 per 100,000

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11
Q

Myasthenia Gravis

Clinical presentation

A

a. Weakness and muscle fatigability
b. Distribution of affected muscles is variable and often asymmetric
c. Eye muscles are first to be affected in 60%, eventually involved in 90%
d. Diurnal variation
e. Reflexes preserved
f. Sensation is unaffected

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12
Q

Bedside dx of myasthenia Gravis

A

Arm abduction time or ptosis time

Tensilon test

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13
Q

MG

Arm abduction time or ptosis time

A

Arm abduction time (patient holds their arms straight out in front of them as long as possible) or ptosis time (patient maintains and upward gaze until the upper eyelids droop) < 5 minutes demonstrates fatiguability

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14
Q

MG

Bedside dx

Tensilon test

A

The tensilon test demonstrates reversal of symptoms with enhancement of synaptic transmission.

Edrophonium 2 mg test dose, then 4-8 mg at 1 minute
Response occurs in 30-60 seconds and subsides in 4-5 minutes
Need to have atropine on hand
Non-specific
Need objective criteria

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15
Q

Lab dx of MG

A

Anti-AChR antibody: 85-90% positive Highly specific 40% of MG patients without AChR antibodies have muscle-specific tyrosine kinase (MuSK) antibodies
Repetitive stimulation on EMG cause a decrement due to later stimuli releasing less acetylcholine: Decrement >10% at 3 Hz 50% positive in mild cases, 80% positive if moderate to severe Highly specific
Jitter on SFEMG (single fiber electromyography) reflects variable synaptic transmission: 95% positive when there is generalized weakness 84% positive in ocular myasthenia Non-specific

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16
Q

Antibodies to AChR without MG

A

Antibodies to AChR without myasthenia gravis occur in 18% of elderly Japanese, in 7% of elderly patients with raised anti-thyroid antibody titer, in patients with tardive dyskinesia or non-myasthenic thymoma and in identical twins of myasthenia gravis patients

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17
Q

What can induce MG and antibodies to AChR?

A

Thymoma and Penicillamine

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18
Q

AChR antibodies

Vary in…

A

Epitope and affinity for junctional vs extra-junctional receptors

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19
Q

MG

Tx

A

Pyridostigmine (acetylcholinesterase inhibitor, anti-AChE) to enhance cholinergic transmission
Prednisone azathioprine
Thymectomy
Plasmapheresis (= plasma exchange) or IVIg

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20
Q

LEMS

etiology

A

(1) Caused by circulating antibodies which interfere with ACh release by binding presynaptic voltage gated calcium channels (VGCC)
(2) Passive transfer to animals has been demonstrated
(3) Disease severity fluctuates with circulating antibody titers, and responds to plasmapheresis

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21
Q

LEMS

Clinical features

A

(1) Weakness and muscle fatigability similar to myasthenia gravis, but bulbar and respiratory muscles are less frequently involved and gait is usually affected
(2) Autonomic dysfunction (dry mouth, sexual impotence, sometimes sphincter dysfunction) is common
(3) Reflexes are often depressed but can be restored after a brief period of activity
(4) 60% of cases are associated with small cell lung cancer

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22
Q

LEMS

dx

A

LEMS is less responsive to Tensilon testing

Anti-VGCC antibody can be measured (45-65% positive, Highly specific)

Repetitive stimulation on EMG increments as the presynaptic terminal accumulates calcium -
Increment >25% after 10-15 seconds maximal effort is highly suggestive, increment >100% is diagnostic

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23
Q

LEMS

tx

A

(1) Search for and treat tumor
(2) Pyridostigmine (Mestinon) is less effective than in myasthenia gravis
(3) 3,4-diaminopyridine (Fampridine), which enhances calcium entry by inhibition of potassium channels, is beneficial but often toxic
(4) Plasmapheresis is effective, IVIg may be effective (5) Prednisone and azathioprine are effective

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24
Q

PM and DM

chars

A

Polymyositis and dermatomyositis are the most common of the inflammatory myopathies (0.5-1.0/100,000)

An autoimmune mechanism is widely accepted for both. PM and DM are clinically and pathologically distinct

25
Q

DM

Clinical findings

A

DM includes erythematous dermatitis over the neck, upper trunk, & extensor surfaces of the PIP, MCP, elbow and knee joints; nailbed infarcts; heliotrope discoloration of the upper eyelids; and periorbital edema

DM has more vasculopathic findings on muscle biopsy

26
Q

PM and DM

mech

A

Circulating antibodies to myosin and nuclear antigens are present but not disease specific, circulating immune complexes and cytokines may also be a factor

Antigen-directed cytoxicity implicated by CD8+ T cells in PM

27
Q

PM and DM

tx

A

Disease severity responds to plasmapheresis and IVIg in DM, and possibly in PM

28
Q

GBS (AIDP)

Clinical presentation

A

Often described as “ascending” neuropathy, but any multifocal or asymmetric pattern of onset is possible
Early loss of reflexes
Both sensory and motor involvement, often early ataxia

29
Q

GBS (AIDP)

Mech

A

Often associated with a recent febrile or gastroenteric illness

Pathogenic circulating antibodies have never been demonstrated, but circulating immune complexes and cytokines may be a factor. Tissue binding of antibodies can be demonstrated but is of questionable significance

30
Q

GBS (AIDP)

tx

A

Disease severity responds to plasmapheresis and IVIg

31
Q

GBS (AIDP)

etiology

A

Herpes viruses (CMV), Mycoplasma pneumoniae, Campylobacter jejuni have been associated

Anti-ganglioside antibodies, especially GM1 and GQ 1b

Experimental allergic neuritis (EAN) resembles AIDP but involves immunization against P2 protein in peripheral myelin, which does not occur in human AIDP

32
Q

Fisher Syndrome

Sx/mech

A

Ataxia, areflexia, ophthalmoplegia (& unreactive pupils)

Fisher syndrome involves antibodies against the ganglioside GQ1b, which is concentrated in oculomotor fibers and is also present on sensory ganglia. These antibodies can interfere with quantal release at neuromuscular junctions.

33
Q

AMAN

Clinical presentation/nerve conduction studies/strongly correlated with

A

(1) Clinical presentation is similar to AIDP, but only motor nerves are affected
(2) Nerve conduction studies show axonal drop-out without significant slowing of conduction
(3) AMAN has been reported in Mexico, and occurs seasonally in northern China
(4) AMAN is strongly correlated with Campylobacter jejuni infection

34
Q

AMSAN

chars

A

(1) Clinical presentation is similar to AIDP, with both motor and sensory nerves affected
(2) Nerve conduction studies show axonal drop-out without significant slowing of conduction
(3) AMSAN occurs a low frequency in Europe and North America
(4) AMSAN has also been associated with Campylobacter jejuni diarrheal disease

35
Q

AMAN & AMSAN

etiology

A

Circulating antibodies to GM1b and GalNAc-GD1a have been demonstrated, and cross-react with lipopolysaccharides (LPSs) of Campylobacter jejuni
C. jejuni inoculation can produce an acute motor neuropathy in chickens
Recovery is usually rapid and complete despite axonal disease AMAN
Recovery is slow and less complete in AMSAN

36
Q

MMN (with conduction block)

Clinical presentation/nerve conduction studies

A

Asymmetric slowly progressive weakness, often beginning in the arms, with fasciculations and atrophy. May resemble ALS but without upper motor neuron symptoms

Nerve conduction study shows focal slowing and conduction block

37
Q

MMN

Antibody/tx

A

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

MMN responds to IVIg, but not plasmapheresis or steroids

38
Q

CIDP

Clinical features

A

(1) Clinically CIDP resembles AIDP with a slower onset (>8 weeks) followed by a chronic relapsing and remitting course
(2) Usually there is no clear antecedent illness

39
Q

CIDP

dx

A

Nerve conduction study shows prolonged distal latencies, slowed conductions and prolonged F-waves, often in a non-uniform distribution
Pathogenic circulating antibodies have never been demonstrated, but circulating immune complexes and cytokines may be a factor. Tissue binding of antibodies can be demonstrated but is of questionable significance
Systemic transfer of sera from patients to marmosets causes electrophysiologic deficits but not overt disease

40
Q

CIDP

Immunization of rabbit/tx

A

Immunization of rabbits with galactocerebroside causes a relapsing remitting demyelinative neuropathy similar to CIDP in humans

Disease severity responds to plasmapheresis and IVIg

41
Q

Myeloma with osetosclerosis

chars

A

nearly half have neuropathy, often with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein & skin thickening & hyperpigmentation)

neuropathy is demyelinating

neuropathy improves with treatment of the myeloma

42
Q

Myeloma without osteosclerosis

chars

A

few (~5%) have neuropathy

neuropathy is axonal

neuropathy does not improve with treatment of the myeloma

43
Q

CIDP-MGUS

chars

A

clinically resembles CIDP, often with more prominent sensory involvement

may not respond to usual treatment for CIDP

44
Q

Anti-MAG and GALOP

chars

A

Anti-MAG (myelin associated glycoprotein) antibody
Gait Ataxia Late-Onset Polyneuropathy
CIDP-MGUS with a IgM K antibody directed against MAG or GALOP protein
Sera causes neuropathy on passive transfer to chickens
Nerve biopsy shows myelin wide-spacing
May respond to plasmapheresis and IVIg

45
Q

PCD

pathogenesis

A

(1) Circulating and intrathecal antibodies have been identified which bind cerebellar
Purkinje cells
(2) Best characterized are anti-Yo antibodies associated with ovarian, uterine and breast neoplasms
(3) The role of these antibodies in pathogenesis is unknown
(4) Plasma exchange is rarely beneficial, but usually has been tried late in the disease course

46
Q

Paraneoplastic opsoclonus-myoclonus

Gen description

A

flurries of multidirectional rapid eye movements, “dancing eyes and dancing feet”

47
Q

Paraneoplastic opsoclonus-myoclonus

chars

A

(1) Circulating antibodies have not been identified in children with neuroblastoma and adults with a variety of tumors
(2) Anti-Ri antibody is found in high titer in patients with breast tumors, and cross-reacts with tumor cell and neuronal nuclei
(3) The role of these antibodies in pathogenesis is unknown
(4) Opsoclonus-myoclonus may resolve with treatment of the tumor or with prednisone therapy

48
Q

Paraneoplastic Encephalitis and Sensory Neuronopathy

chars

A

(1) Circulating anti-neuronal antibodies have been identified, especially anti-Hu
(2) These syndromes commonly occur in small cell carcinoma patients
(3) The role of these antibodies in pathogenesis is unknown
(4) Plasma exchange is rarely beneficial

49
Q

Stiff-Person syndrome

pathogenesis
A) Circulating antibodies to the GABA-synthesizing enzyme glutamic acid decarboxylase are present in 60%

A

(1) In paraneoplastic SPS, the circulating antibodies are directed against two other components in the GABAergic synapse: amphiphysin and gephyrin
(2) In up to 65% of SPS patients, there are circulating anti-GABARAP (gamma- aminobutyric acid receptor–associated protein) antibodies that inhibit the GABA receptor expression

50
Q

Stiff-Person syndrome

tx

A

Responds to steroids, response to plasmapheresis and IVIg is debated

51
Q

Multiple Sclerosis

Char by…

A

Multiple sclerosis is a chronic demyelinating disease of adults characterized by multifocal development and accumulation of plaques of demyelination in the CNS

52
Q

MS

Autoimmune chars

A

(1) No specific circulating antibodies have been identified, although increased titers to a variety of viruses including mumps, HSV, rubella and vaccinia are seen suggesting immune system dysregulation
(2) Increased intrathecal antibodies are seen (oligoclonal bands), but no specific antigen has been identified
(3) There is no significant response to most immunosuppressive therapies, although high dose methylprednisolone may shorten acute exacerbations

53
Q

MS

epidemiology

A

Epidemiological evidence suggests an interaction between genetically susceptible individuals and a geographic exposure

a. Multiple sclerosis incidence increases with latitude
b. Multiple sclerosis risk correlates with geographic location prior to age 15
c. Multiple sclerosis prevalence varies among races
d. Multiple sclerosis incidence correlates with HLA type
e. Multiple sclerosis concordance is 25.9% in monozygotic twins and 2.5% in dizygotic twins

54
Q

MS

HLA

A

MHC locus on chromosome 6

MHC class II HLA-DR2 haplotype DR15, DQ6

55
Q

MS

Tx

interferons

A

Beta-interferons are effective in reducing the severity and frequency of exacerbations

a. Beta-interferons are thought to interfere with the actions of interferon gamma, which appears to provoke exacerbations
b. Following binding to specific cellular receptors, interferons lead to synthesis of over 2 dozen proteins that contribute to viral resistance

56
Q

Glatiramer

Used for…

A

Glatiramer (Copaxone) is effective in multiple sclerosis patients and in experimental allergic encephalomyelitis (EAE)

a. Glatiramer is a mixture of random polymers of four amino acids, L-alanine, L-glutamic acid, L-lysine, and L-tyrosine
b. The effect is probably related to inhibition of the immune response to myelin basic protein and possibly other myelin antigens
c. Glatiramer has been shown to at least partially cross-react with myelin basic protein on a cellular and humoral level

57
Q

Natalizumab

Used for…

A

Natalizumab is effective treatment of relapsing forms of multiple sclerosis.

Natalizumab is a monoclonal antibody directed against alpha(4) integrin and results in at least partial blockade of immune-cell adhesion to vascular endothelium and subsequent tissue migration of lymphocytes, preventing inflammatory cells from crossing the blood-brain barrier.

58
Q

Pediatric AI neuropsychiatric disorders assoc with strep infection (PANDAS)

chars

A

A) Sydenham’s chorea is a post-streptococcal autoimmune disorder
B) PANDAS implicates post-infectious autoimmunity in a subset of patients with childhood onset tics and obsessive–compulsive disorder (OCD)
C) PANDAS is associated with the presence of anti-basal ganglia antibodies

Neuropathology (29 decks)

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