Immune Mediated Neuropathies

Author(s): Shawn Jorgensen, MD

Originally published:12/27/2012

Last updated:12/27/2012

1. DISEASE/DISORDER:

Definition

  1. Immune mediated neuropathies are a diverse group of disorders caused by immune-mediated damage to peripheral nerves. These can range from a fulminant, life-threatening crisis to an asymptomatic, minimally progressive process. Some are part of a larger systemic autoimmune process, and others an isolated peripheral nerve disorder.
  2. The major groupings include
    1. Acute inflammatory neuropathies (Guillain-Barré syndrome, GBS)
    2. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
    3. Acute motor and sensory axonal neuropathy (AMSAN)
    4. Acute motor axonal neuropathy (AMAN)
    5. (Miller-Fisher syndrome (MFS)
    6. Other acute variants
  3. Chronic inflammatory neuropathy
    1. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
    2. Multifocal acquired demyelinating sensory and motorneuropathy (MADSAM)
    3. Multifocal motor neuropathy (MMN)
    4. Distal acquired demyelinating symmetrical (DADS)
    5. Neuropathies related to systemic immune disorders

Etiology

  1. Autoimmune injury to the peripheral nervous system is common to all diseases in this group. The GBS, CIDP and subtypes are primarily peripheral nerve disorders. Others are secondary to an immune process affecting nerve and other organ systems.

Epidemiology including risk factors and primary prevention

  1. AIDP
    1. The annual incidence is 1-4 per 100,000.1
    2. Risk factors include antecedent viral and bacterial infections, autoimmune disorders, malignancy and surgery.
    3. The swine flu vaccine was felt to be a potential risk factor in 1976; however, in 2009 the risk in China was lower in those vaccinated than in those who were not.
  2. Connection between Campylobacter jejuni and GBS is strong, particularly the AMAN variant (67%-92%).
  3. Male and female are equally affected for most disorders excepting 3:1 male predominance in MMN and 2:1 for MFS.

Patho-anatomy/physiology

  1. Any aspect of the peripheral nerve can be involved, but in some disorders the target is specific (myelin in AIDP, ganglia in autoimmune sensory ganglionopathies).
  2. The humeral and cell mediated arms of the immune system can be involved.
  3. Often molecular mimicry is involved: an epitope from an invading microbe or tumor cell is processed by the immune system, generating a specific response. Because of similarity between this epitope and nerve tissue, the tissue is attacked by the immune system.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

  1. new onset/acute
    AIDP can develop over hours to weeks, progressing for four weeks or less, but often less than two. Subacute neuropathies (ie. SIDP or subacute inflammatory demyelinating polyradiculoneuropathy) are defined as progressing for 4-8 weeks, and CIDP over 8 weeks.
  2. subacute
    Subacute and chronic variants can present acutely but continue to progress slowly or intermittently.
  3. chronic/stable
    Some chronic neuropathies have a relapsing-remitting course.
    Vasculitic nerve infarction presents with sudden pain and deficits in a peripheral nerve distribution. Multiple infarcts over time evolve into the mononeuropathy multiplex pattern.
    Other secondary immune-mediated neuropathies are chronic.
  4. pre-terminal NA

Specific secondary or associated conditions and complications

  1. GBS is often preceded by infection; most commonly Campylobacter jejuni (67%),2,3 cytomegalovirus (CMV), Epstein-Barr virus (EBV) or mycoplasma pneumonia.
  2. IDP can be seen with monoclonal gammopathies, human immunodeficiency virus (HIV) and hepatitis, lymphoma, ulcerative colitis and Crohn disease, and diabetes.
  3. Secondary immune mediated neuropathies are associated with vasculitic disease (polyarteritis nodosa (PAN), Wegener granulomatosis, Churg-Strauss syndrome (CSS), microscopic polyangiitis, temporal arteritis, drug-induced vasculitis, nonsystemic vasculitis neuropathy), connective tissue disease, rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), Sjögren syndrome, systemic sclerosis, cryoglobulinemia), sarcoidosis,4 or malignancies.

2. ESSENTIALS OF ASSESSMENT

History

  1. GBS often presents with rapid onset of ascending numbness and tingling followed by weakness.
  2. Cranial nerve dysfunction is seen in many conditions.
  3. Bowel or bladder complaints are rare.
  4. Autonomic complaints are common in GBS and variants.
  5. Nerve infarcts in vasculitic neuropathies are associated with abrupt pain, numbness, tingling and weakness in a peripheral nerve distribution.

Physical examination

  1. In generalized neuropathies, sensory and motor loss is generally symmetrical. Both large and small fibers are typically involved. Sensory ataxia is common in MFS and ganglionopathies. Weakness is proximal and distal in typical CIDP by most criteria.
  2. Mononeuropathy multiplex, motor loss and sensory loss is in affected peripheral nerve distribution.
  3. Fasciculations common in MMN.
  4. Muscle stretch reflexes are diminished in GBS and CIDP by definition, with the exception of the AMAN variant which can have increased reflexes in the recovery phase.
  5. Autonomic dysfunction is common in GBS and pure autonomic neuropathies.
  6. Cranial nerves are commonly involved in GBS, MFS and sarcoid neuropathies.

Laboratory studies

  1. Autoantibodies are variably associated, immune mediated clinical syndromes; highest associations are:
    1. anti-GQ1b in MFS
    2. anti-GM1 in MMN
    3. anti-MAG in the DADS
    4. anti-Hu in paraneoplastic ganglionopathies
  2. Campylobacter jejuni serology is positive in many GBS cases.
  3. Elevated CSF protein and normal cell count is seen particularly in GBS, CIDP and variants (excepting MMN).

Imaging

  1. Imaging is useful primarily to exclude other diagnoses. An MRI can show enhancement and enlargement of nerve roots and peripheral nerves in AIDP and CIDP.5 Chest imaging can detect small cell lung or other cancer in anti-Hu syndrome.

Supplemental assessment tools

  1. Electrodiagnostics:
    1. In acute autoimmune neuropathies, early electrodiagnostic testing is essential to demonstrate peripheral nerve dysfunction. Test results can be normal early in acute disease. The first abnormalities are prolonged motor distal latencies and decreased amplitudes.5
    2. In CIDP, nerve conduction studies demonstrate evidence of demyelination.
    3. In other disorders, electrodiagnostic testing will show the nature and distribution of the nerve injury.
  2. Nerve biopsy can be useful to confirm vasculitic neuropathies. It can also be used to confirm CIDP, although the diagnosis is usually based on clinical and laboratory data.
  3. Autonomic testing can confirm autonomic involvement.
  4. Pulmonary function tests and telemetry are necessary in severe cases that have autonomic and diaphragmatic involvement, particularly in GBS.

Early predictions of outcomes

  1. GBS
    1. Early predictors of bad prognosis: older age (over 50), rapid onset of profound weakness, mechanical ventilation, distal compound muscle action potential (CMAP) amplitude less than 10% of normal.
    2. Most patients have significant but incomplete recovery — up to 85% having some residual deficits, and up to 10% having disabling chronic sensory or motor symptoms.5
    3. Long term outcomes are worse in AMAN, better in MFS than classic AIDP.

Professional Issues

  1. Cost containment can be an issue, since intravenous immunoglobulin (IVIG) can be prohibitively expensive, with some conditions requiring treatment every two weeks. This is a particularly true when IVIG is the preferred first option in the absence of any definite benefit over less costly treatments.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

  1. According to the Practice Parameter: Immunotherapy for Guillain-Barré Syndrome developed by the Quality Standards Subcommittee of the American Academy of Neurology:
    1. In GBS, plasma exchange (PE) is recommended in non-ambulant patients within four weeks of treatment (level A, class 2) or ambulant within two weeks (level B, limited class 2).
    2. IVIG is recommended within 2 weeks for non-ambulant patients (level A).
    3. PE and IVIG are equivalent (class 1) and steroids are ineffective (level A ,class 1).6

At different disease stages

  1. new onset/acute
    1. includes potential curative interventions
      1. In GBS, treatment should begin within two weeks if possible, particularly in nonambulant patients as outlined above. Repeat courses of PE or IVIG are not helpful except in cases of relapse.4
      2. Autonomic instability may necessitate admission to an intensive care unit (ICU) and telemetry; impending respiratory distress requires pulmonary function monitoring and mechanical ventilation.
    2. symptom relief NA
    3. includes rehabilitation strategies intended to stabilize or optimize function or prepare for further interventions at later disease stages
      1. Rehabilitation measures are typical to those of other immobilized patients – venous thromboembolism, contracture, pressure ulcer, and pneumonia prophylaxis.
  2. subacute
    1. Patients need to monitor themselves for continuing evolution and relapses of acute processes.
    2. Aerobic conditioning, resistance exercises, gait training, transfers and activities of daily living are emphasized in physical and occupational therapy. Tilt table training may be necessary for orthostasis. Speech and language therapy are prescribed as necessary. Orthotics are often necessary, particularly ankle-foot orthotics (AFO), often temporarily in AIDP. Neuropathic pain requires treatment. Inpatient rehabilitation may be necessary for patients with acute, stabilized neuropathies with functional deficits.
  3. chronic/stable
    1. Primary treatments for CIDP are steroids, IVIG, and plasma exchange.
    2. Rehabilitation measures as above, carried out at home or in an outpatient setting.

Coordination of care

  1. Interdisciplinary approach involves neurology, physical medicine and rehabilitation, hospitalists and intensivists, as well as other specialists and disciplines (physical and occupational therapy, speech and language therapy, respiratory therapy, nursing, orthotists).

Patient & family education

  1. Patients and families should be educated on the generally good prognosis of GBS, and the potentially recurrent nature of CIDP and vasculitic neuropathies.
  2. Educate regarding complications of treatment such as prednisone and other immunomodulating treatments.
  3. Prevention of the complications of immobilization in the outpatient setting will largely fall on caregivers.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Identifying that a neuropathy is immune mediated is important because of the potential for treatment.

Early diagnosis of GBS is complicated by its variable presentation and the lack of reliable, objective testing within the first week of treatment (In the first week of the disease, CSF protein is normal in one-third of patients; 50% have normal CMAP amplitude).5 GBS is best treated within two weeks of onset of symptoms, sometimes necessitating empiric treatment.

Of “idiopathic” neuropathies referred to tertiary centers, 10%-33% are later felt to be CIDP.2 CIDP should be in the differential of unexplained neuropathies.

Anti-Hu syndrome needs to be excluded in patients presenting with a sensory ganglionopathy, since it often heralds an undiagnosed and potentially treatable small-cell lung cancer or other cancer.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

  1. Time to motor recovery, time until able to stand and functional independence measure (FIM) scores have been used to measure outcomes in GBS.
  2. The neuropathy impairment scale has been used in trials of anti-MAG neuropathy.

EMERGING/UNIQUE INTERVENTIONS

  1. Immunomodulating agents used in the transplant, rheumatological, and oncology setting are being used but are not yet an established standard of care.
  2. Different regimens of currently used drugs such as pulsed dose dexamethasone have shown efficacy in CIDP.7

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  1. In GBS, the optimum plasma exchange regimen has not been established.
  2. Many immunomodulating agents are used in chronic immune mediated neuropathies without the support of high quality trials.

REFERENCES

  1. Hughes RAC. The concept and classification of Guillain-Barré syndrome and related disorders. Rev Neurol (Paris). 1995;151:291-294.
  2. Alter M. The epidemiology of Guillain-Barré Syndrome. Ann Neurol. 1990;27 (suppl):7-12.
  3. Kieseier B, Kiefer R, Gold R, Bernhard H, Willison H, Hartung H. Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle Nerve. 2004;30:131-156.
  4. Latov N, et al. Diagnosis and treatment of chronic immune mediated neuropathies. J Clin Neuromusc Dis. 2006;7(3):141-157.
  5. Amato A, Russell J. Neuromusc Disord. New York, NY: McGraw Hill Medical; 2008.
  6. Hughes RA, Wijdicks EF, Barohn R, Benson E, Cornblath DR, Hahn AF, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;61(6):736-740.
  7. VanSchaik I, Eftimov F, van Doorn P, Brusse E, van den Burg L, van der Pol L, et al. Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(3):245-253.

Author Disclosure

Shawn Jorgensen, MD
Nothing to Disclose

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