Oxford Handbook of Clinical Immunology and Allergy (3 edn)
Contents
5 Autoimmunity of the nervous system
-
Published:February 2013
Annotate
Cite
Myasthenia gravis (MG)
Presentation
Patients complain of double vision, muscle weakness, and fatigue (worse later in the day).
Ptosis and diplopia are typical signs.
Examination reveals generalized fatiguable muscle weakness.
It is a heterogeneous condition with varying ages of presentation.
Diagnosis of a neuromuscular junction defect can be confirmed by electrophysiological tests and the Tensilon® test (see Box 5.1).
| Tests for diagnosis . | Test for monitoring . |
|---|---|
Tensilon (edrophonium) test | AchRAb |
AchRAb | |
Striated muscle antibodies | |
MuSK antibodies |
| Tests for diagnosis . | Test for monitoring . |
|---|---|
Tensilon (edrophonium) test | AchRAb |
AchRAb | |
Striated muscle antibodies | |
MuSK antibodies |
Immunogenetics
In younger patients there is an association with HLA-A1, B8, and DR3, and a strong female predominance.
Disease can also be induced by penicillamine, and is mostly found in those who are HLA-Bw35/DR1 positive.
Immunopathology
Muscle weakness is due to impaired action of acetylcholine (ACh) at the muscle endplate.
The cause is unknown but the disease is strongly associated with thymomas (benign and malignant), thymic hyperplasia, and other autoimmune diseases such as SLE, polymyositis, haemolytic anaemia, and thyroid disease (especially in those <40 years old).
Prevalence is 2–10/100 000.
Patients with thymoma are usually older and both sexes are affected equally; about 10% have thymomas, but removal of the tumour does not always affect the course of the disease.
Autoantibodies
IgG anti-ACh-receptor (AChRAb) is detected in 75–95% of patients.
10% are seronegative.
50% with pure ocular myasthenia are seronegative.
The disease is caused by direct receptor blockade, complement-mediated endplate damage, and enhanced recycling of the receptor off the endplate surface membrane.
AChRAb levels are variable, but high titres are found in those <40 years old with thymic hyperplasia.
Antibodies are IgG isotype and therefore can be transmitted across the placenta, causing neonatal myasthenia.
The presence of striated muscle antibodies is a marker for the presence of a thymoma. These includes antibodies to the ryanodine receptor and titin antibodies.
Cardiac arrythmias may occur in the presence of anti-cardiac muscle antibodies.
Antibodies to MuSK (muscle-specific tyrosine kinase) have been shown in a proportion of patients with AChRAb negative MG.
MuSK is a receptor tyrosine kinase that is restricted to the neuromuscular junction.
Patients with these antibodies are typically female, with bulbar disease, who may be difficult to treat with immunosuppression.
Antibodies to MuSK interfere with agrin-triggered stimulation of MuSK.
Treatment
Treatment is with oral anti-cholinesterases.
Immunosuppressive therapy may be required: prednisolone (1–1.5mg/kg) alone or with azathioprine is the treatment of choice.
Mycophenolate mofetil, cyclophosphamide, methotrexate, and ciclosporin have all been used.
Thymectomy may be required to prevent local extension and exclude malignancy.
Plasma exchange may be helpful in myasthenic crisis, but must be coupled with other immunosuppressive therapy.
High-dose IVIg (hdIVIg) has also been demonstrated to be helpful in acute crises.
Lambert–Eaton myasthenic syndrome (LEMS)
Presentation
LEMS is an idiopathic or paraneoplastic syndrome.
It is associated with small cell lung cancer (SCLC) as a paraneoplastic phenomenon (1–3% of cases).
Some cases occur without cancer (especially in children) and are associated with HLA-B8, DR3.
Proximal muscle weakness is marked, but bulbar and ocular muscles are spared.
Associated with other autoimmune diseases, especially thyroid and vitiligo.
Immunopathology
There is a decrease of voltage-gated calcium channels (VGCC) on presynaptic nerve terminals caused by an autoantibody reactive with the channels, particularly the P/Q-type.
Some patients have antibodies to synaptotagmin.
Patients with LEMS may also have antibodies to AchR.
Autoimmune aetiology has been established by demonstration of passive transfer of disease.
Treatment
Treatment of the tumour with chemotherapy may give temporary benefit.
3,4-diaminopyridine (blocks potassium channels) or guanidine may be needed to control the weakness.
Plasma exchange or hdIVIg may be of significant (but temporary) benefit.
In both non- and paraneoplastic forms, prednisolone is an option combined with azathioprine in non-paraneoplastic LEMS.
Acquired neuromyotonia (Isaac’s disease) and stiff person syndrome (SPS)
Acquired neuromyotonia (Isaac’s disease)
Presentation
This syndrome is marked by acquired spontaneous and continuous muscle contraction.
Patients develop stiffness, twitching, cramps, sweating, and other autonomic problems.
Immunopathology
Some cases are due to autoantibodies against voltage-gated potassium channels (VGKC) at presynaptic nerve terminals.
Treatment
Treated with phenytoin, carbamazepine, or immunosuppression.
Stiff person syndrome
Presentation
It causes a fluctuating and progressive muscular rigidity, which is painful.
Men are more commonly affected than women.
Up to a third of patients will develop diabetes, and there may be features of autoimmune glandular disease.
In approximately 10% of patients, SPS develops as a paraneoplastic disorder associated with breast cancer.
Immunopathology
This rare neurological syndrome is associated with anti-GAD antibodies.
The finding of the autoantibody ties in with the neurological conclusion that GABAergic neurons, which regulate muscle tone, are involved.
Autoantibodies
Anti-GAD antibodies are found in >60% of patients with SPS (see Chapter 18).
Anti-amphiphysin antibodies are sometimes elevated in blood and CSF of patients with paraneoplastic SPS and, rarely, in non-neoplastic SPS.
There is some evidence that the autoantibodies are pathogenic in some cases of paraneoplastic SPS.
Treatment
Muscle relaxants such as diazepam, baclofen, vigabatrin, and valproate are used.
HdIVIg has been shown to be effective in a single trial in non-paraneoplastic SPS.
Immunosuppression is frequently attempted.
There are case reports of complete remission with rituximab (anti-CD20).
Morvan’s syndrome
Rare syndrome of neuromyotonia, hyperhidrosis, insomnia, and delirium.
Autoimmune aetiology; may be associated with thymoma (and solid tumours).
Associated with antibodies to VGKC and to CASPR2
May respond to corticosteroids, plasmapheresis, hdIVIg, and thymectomy.
Rasmussen encephalitis
This rare syndrome usually presents in children, with hemiparesis and intractable focal epilepsy, dementia, and cerebral atrophy.
In some cases associated with autoantibodies to glutamate R3 receptors and the synaptic protein munc-18. A subset is associated with antibodies to the NMDA receptor.
It may respond to hdIVIg.
PANDAS
PANDAS—paediatric autoimmune neuropsychiatric disorders associated with Streptococcus).
Syndrome with dramatic onset of symptoms including motor and vocal tics. Possibly similar to Sydenham’s chorea, but no evidence of cardiac involvement. Basal ganglia affected.
May be a genetic susceptibility to this syndrome after group A streptococcal infection linked to expression of B-cell antigen D8/17.
May respond to hdIVIg.
Paraneoplastic autoimmune neurological syndromes
Paraneoplastic cerebellar degeneration
Associated with carcinoma of the breast and carcinoma of the ovary.
Anti-Yo antibodies, directed against the cytoplasm of cerebellar Purkinje cells and recognizing two antigens of molecular weights 34 and 62kDa, are found.
Associated with Hodgkin’s lymphoma:
anti-Tr antibodies
anti mGluR1.
Associated with SCLC, without LEMS:
antibodies to P/Q VGCC
anti-PCA2 (also causes encephalomyelitis)
Zic4 (often in association with anti-Hu and anti-CV2/CRMP5).
Associated with germ cell tumours, breast and colon cancer:
antibodies to Ma.
May be treated with immunosuppression, tumour removal, and hdIVIg.
Paraneoplastic neurological syndrome of ataxia and myoclonus (opsoclonus–myoclonus)
This has been described in patients with carcinoma of the breast, gynaecological cancer, and SCLC.
Patients may have anti-Yo or an anti-neuronal nuclear antibody, anti-Ri.
Can be treated with immunosuppression, tumour removal, and hdIVIg.
Paraneoplastic ataxic sensory neuropathy or paraneoplastic encephalomyelitis
This can occur in patients with small cell carcinoma of the lung, although less commonly patients may have anaplastic, bronchial, or squamous carcinoma of the lung, or reticuloendothelial neoplasms.
Anti-Hu is an anti-neuronal nuclear antibody (ANNA), recognizing a group of proteins of molecular weight 35–40kDa.
Anti-Hu is one of the autoantibodies now known to penetrate intact cells containing the Hu antigen in their nucleus, indicating that it may have a primary pathogenic role.
Other antibodies associated with paraneoplastic encephalomyelitis include anti-Zic and anti-Ma (brainstem encephalitis).
Paraneoplastic tranverse myelitis with SCLC is associated with anti-Hu, anti-CV2/CRMP5, or anti-amphiphysin antibodies.
Paraneoplastic autonomic neuropathy is associated with anti-Hu, anti-CV2/CRMP5, and antibodies to ganglionic AChR.
Many other target antigens have been identified, but they occur extremely rarely.
Demyelinating diseases 1: multiple sclerosis (MS)
Clinical presentation
The pattern of illness is difficult to predict; it may be chronic and progressive, or relapsing and remitting.
The progressive form of the disease leads to disability.
It affects any age, but predominantly the young, and has a 2:1 female predominance.
Clinical presentations are highly variable and include visual disturbance (optic neuritis), ataxia, weakness, and sensory signs, which usually resolve completely over a few days, at least in initial attacks.
Immunogenetics
MHC susceptibility loci have been identified, although these differ in different racial groups.
DR2, DQ1, and DQ6 seem to be particularly important; DRB1*1501 is the strongest HLA association.
Other genetic susceptibility loci are located on chromosomal regions 19q35 and 17q13.
Monozygotic twin concordance is only 25–30%.
Immunopathology
The cause of MS is unknown, although there are strong indications that it is triggered by infection.
the disease seems to involve abnormal T cells reactive to myelin basic protein.
Macrophages and microglia are involved, with local release of inflammatory cytokines and upregulation of MHC class II antigens.
Plasma cells also localize to lesions, increasing local synthesis of IgG.
There is selective destruction of myelin sheath and demyelination.
Animal studies show that the disease can be transferred with CD4+ T cells.
CSF may contain membrane attack complexes of complement.
Cytokines may be involved (TNF, IFNs, and IL-2).
Autoantibodies
Autoantibodies to myelin oligodendrocyte glycoprotein (MOG) may occur.
Some patients with a typical MS pattern of demyelination may demonstrate anti-nuclear antibodies and antibodies to dsDNA, without other features of SLE.
Conversely, some patients who clearly have SLE develop MS-like symptoms and signs.
Investigations
There are no specific diagnostic immunological tests.
Examination of serum and CSF demonstrates increased intrathecal immunoglobulin synthesis, with a CSF IgG-to-albumin ratio >22%.
Isoelectric focusing and immunoblotting demonstrate the presence of oligoclonal IgG bands, but these are not specific for MS, as they are also found in neurosarcoid, neurosyphilis, acute viral infections of the CNS, SLE, and Sjögren’s syndrome.
Other helpful tests include evoked potentials (visual, auditory, peripheral).
MRI scanning shows typically placed demyelinating lesions.
Rarely, patients with MS develop a uveitis as well as an optic neuritis. This may be associated with autoantibodies to the retinal S-antigen.
Treatment
Acute attacks may respond to high-dose steroids, but chronic steroid therapy does not prevent relapses.
Cytotoxic agents mitoxantrone, cladribine, azathioprine, and cyclophosphamide have also shown some benefit.
β-interferon (1a and 1b) (8mU on alternate days subcutaneously) has shown considerable promise in decreasing the relapse rate in the relapsing–remitting form. Utility of therapy may be limited by anti-interferon antibodies.
Drugs have significant immunomodulatory effects, including reducing T-cell proliferation, decreasing induced MHC class II antigen expression, and reducing the production of inflammatory cytokines (TNF-α and γ-IFN).
The effect can be monitored by measuring the production of myxoma resistance protein A (MxA).
Natalizumab (Tysabri®) is an MAb against α4-integrin, and has been shown to be useful in MS. Concerns have been raised about possible association with progressive multifocal leucoencephalopathy (PML).
Other biologicals in trial include daclizumab (anti-IL-2R), rituximab (anti-CD20), and alemtuzumab (anti-CD52).
Glatiramer is an immunomodulatory drug comprising synthetic polypeptides. It also reduces attack rate in relapsing–remitting disease.
Fingolimod is a sphingosine analogue that modulates the sphingosine-1-phosphate receptor and alters lymphocyte migration. Benefit has been identified; possibly best for newly diagnosed patients.
Fumarate (also used in skin disease) has been shown to reduce new lesions.
Evidence for the use of hdIVIg is sparse.
TNFα blockade is not helpful.
Demyelinating diseases 2: Guillain–Barré syndrome (GBS) and variants
Clinical presentation
An inflammatory demyelinating peripheral neuropathy that frequently follows 1–3 weeks after infection, particularly with Campylobacter jejuni.
Begins with ascending weakness, which may progress with alarming rapidity and involve bulbar and respiratory muscles, including the diaphragm, leading to respiratory failure.
Sensory symptoms are mild.
There may be marked autonomic instability.
Demyelination may progress for up to 4 weeks before remyelination begins.
Recovery may be very prolonged.
There are a number of variants to this classical presentation and progression, including acute motor axonal neuropathy, acute motor sensory axonal neuropathy, and the Miller Fisher variant with ophthalmoplegia, ataxia, and areflexia.
Immunopathology and autoantibodies
Antibodies to membrane gangliosides (glycolipids including GM1, LM1, and GD1b) are detected in sera from up to 40% of patients with GBS.
These antibodies interfere with nerve conduction and have been shown to activate phagocytes via IgG receptors.
Antibodies to GQ1b are present in 90–100% of cases of the Miller Fisher variant and seem to be specific for this condition, possibly related to the very high expression of this antigen in the third cranial nerve.
Anti-GM1 antibodies are known to cross-react with lipopolysaccharides from C.jejuni.
Treatment
Treatment is best undertaken with plasmapheresis or hdIVIg, which appear to be equally effective if begun early.
There is a suggestion that the relapse rate may be higher with hdIVIg.
Steroids are of no benefit, and may make symptoms worse.
The Miller Fisher variant appears to be relatively benign and resolves without treatment.
Demyelinating diseases 3: chronic inflammatory demyelinating polyneuropathy (CIDP), related conditions, and Devic’s syndrome (neuromyelitis optica)
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Clinical features
CIDP resembles a chronic form of GBS.
Characterized by mainly distal weakness and areflexia as well as marked sensory signs.
There is usually no history of antecedent infection.
Investigations
The diagnosis is confirmed by the course, exclusion of other diseases, and typical electrophysiological studies compatible with demyelination.
Complement-fixing IgG and IgM antibodies may be demonstrated in affected nerves.
Autoantibodies to the gangliosides GM1, LM1, and GD1b can be found in some patients.
Treatment
Steroids, cytotoxic agents, plasmapheresis, and hdIVIg have all been used successfully.
If hdIVIG is to be given, current practice is to give three courses at monthly intervals and a further three courses if there is benefit.
Treatment is then discontinued, to see whether patients maintain remission.
Some patients require long-term hdIVIg therapy.
Related conditions
Other related conditions that may have an autoimmune basis include amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block.
Multifocal motor neuropathy with conduction block is associated with high-titre polyclonal antibodies to GM1. Plasma exchange may not be effective.
Treatment is the same as for CIDP.
Devic’s syndrome (neuromyelitis optica)
Comprises attacks of optic neuritis and myelitis but, unlike MS, there is no brainstem, cerebellar, or cognitive involvement.
Seen mainly in Asians and Africans, but not Caucasians.
May be associated with SLE, Sjögren’s syndrome, P-ANCA+ vasculitis, or mixed connective tissue disease.
Can be triggered by varicella or HIV infection.
Autoantibodies to aquaporin 4 (channel for water transport in astrocytes) are frequently found and are diagnostic.
Demyelination is complement-mediated and therefore distinct from MS.
Demyelinating diseases 4: paraproteinaemic neuropathy and paraproteinaemic myopathy
Paraproteinaemic neuropathy
Demyelinating polyneuropathies may be associated with paraproteins of all classes.
Anti-myelin-associated glycoprotein neuropathy is particularly associated with IgM paraproteins directed against myelin-associated glycoprotein (MAG), a 100kDa glycoprotein of central and peripheral nerves.
The light chain of the monoclonal protein is invariably lambda.
Paraproteinaemic neuropathies may be associated with:
Waldenström’s macroglobulinaemia.
type II cryoglobulinaemia.
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) (see also Chapter 4).
Skin changes tend to be a sclerodermatous thickening.
Endocrine diseases include diabetes, thyroid disease, gonadal failure, and hyperprolactinaemia.
Lymph nodes may show the changes of Castleman’s syndrome, or angiofollicular lymph node hyperplasia (with ‘onion-skin’ lesions), which is itself also associated with a polyneuropathy. The lesion is not thought to be malignant.
IL-6 levels are said to be raised, explaining the plasma-cell abnormalities.
CIDP associated with MGUS: a monoclonal gammopathy of uncertain significance will be found in approximately 10% of patients for whom no diagnosis has been identified.
A severe motor and sensory polyneuropathy is seen in up to 50% of patients with osteosclerotic myeloma and can be the presenting feature of the illness.
Treatment
Treatment of paraproteinaemic neuropathies should include treatment of the underlying plasma-cell clone with steroids, melphalan, or chlorambucil.
Plasmapheresis and hdIVIg are useful as for CIDP.
Paraproteinaemic myopathy
Anti-decorin (BJ) antibodies have been associated with myopathy associated with Waldenström’s macroglobulinaemia (specificity of the paraprotein).
Vasculitic neuropathy and Degos’s disease
Vasculitic neuropathy
Systemic causes
Behçet’s disease
Giant cell arteritis (GCA)
Takayasu’s arteritis
Wegener’s granulomatosis
Churg–Strauss syndrome
Cogan’s syndrome
Kawasaki’s disease
Henoch–Schönlein purpura in children
Polyarteritis nodosa
Systemic lupus erythematosus
Rheumatoid arthritis
Clinical features
Clinical deficits arise from nerve ischaemia or infarction.
Patients may present with a variety of symptoms including mononeuritis multiplex, asymmetric neuropathy, and a distal polyneuropathy.
Investigations
Nerve biopsy shows a vasculitis of the epineurial arterioles, focal or multifocal fibre loss, and areas of segmental demyelination and remyelination.
Investigation should follow the guidance in Chapter 13.
Treatment
Steroids are the mainstay of treatment with or without the addition of cytotoxics.
Cyclophosphamide appears to be the most effective treatment.
Degos’s disease
See Chapter 13.
A vasculitic syndrome in which cerebral infarction is a major feature.
Associated with the presence of anti-cardiolipin antibodies and a lupus anticoagulant.
Activated T cells (virally triggered) may be the pathogenic mechanism.
Neuropathy associated with Sjögren’s syndrome (SS)
Clinical features
Patients may present with a number of neurological conditions
chronic and slowly progressive sensorimotor neuropathy
sensory neuropathy
neuronopathy
mononeuritis multiplex
multiple recurrent cranial neuropathies
subacute demyelinating polyradiculopathy.
Autoantibodies
An IgG antibody can be detected against Ro and La in approximately 50% of patients.
See Chapter 12 for details of investigation of suspected SS.
Treatment
Response to treatments has generally been disappointing.
Steroids, immunosuppression, plasma exchange, and hdIVIG have all been used.
Autoimmune encephalopathies
Encephalopathies have been associated with the following.
Sjögren’s syndrome: this is not well-established.
Hashimoto’s thyroiditis with high levels of anti-thyroid antibodies.
α-enolase has been identified as an auto-antigen in this syndrome
Treatment is with corticosteroids and hdIVIg.
Coeliac disease in association with occipital lobe epilepsy and intracranial calcification has been described. Seizure control may improve with a strict gluten-free diet.
Coeliac disease may also be associated with a cerebellar syndrome which may respond to gluten withdrawal.
Claims have been made that this syndrome is associated with IgG antigliadin rather than endomysial or tissue transglutaminase antibodies. Evidence is weak
Synapsin I has been identified as a possible target of cross-reactive antigliadin antibodies.
Primary angiitis of the central nervous system (PACNS)
| Month: | Total Views: |
|---|---|
| October 2022 | 1 |
| June 2024 | 2 |
