Among the acquired immune-mediated polyneuropathies, the most common are acute inflammatory demyelinating polyradiculoneuropathy (AIDP), also referred to as Guillain-Barré syndrome (GBS), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most authorities classify GBS as a clinical spectrum encompassing AIDP, acute motor-sensory axonal neuropathy, and acute motor axonal neuropathy (AMAN). A variant of GBS, Fisher (formerly Miller-Fisher) syndrome, will not be addressed in depth.
Acquired demyelinating polyneuropathies may be associated with:1,2,3
- vaccinations (swine influenza, meningococcus, influenza, hepatitis B, rabies, tetanus toxoid)
- autoimmune disorders
- systemic lupus erythematosus and other collagen vascular diseases
- inflammatory bowel disease
- diabetes mellitus
- acquired immunodeficiencies
- solid organ and bone marrow transplantation and graft versus host disease
- lymphoma and monoclonal gammopathy of undetermined significance (MGUS)
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
- cholangiocarcinoma and melanoma, or as a paraneoplastic complication of carcinoma (small cell lung, pancreas, colon)
- toxins (procainamide, cyclosporine, and tacrolimus)
- recent surgery
- postpartum state
Antecedent illness, vaccination, or surgery is implicated in 60% to 70% of patients with AIDP.1 Associated pathogens include:2
- Campylobacter jejuni
- Epstein-Barr virus
- Mycoplasma pneumoniae
- hepatitis A, B, and C
- human immunodeficiency virus (HIV)
A trigger can be identified in <30% of CIDP patients, but respiratory and other infections, vaccinations, surgeries, blood transfusions, and even intrarticular steroid injections have been reported. In addition, pregnancy and infection have been reported to precede 20% to 30% of cases of CIDP exacerbation/relapse.1
Epidemiology including risk factors and primary prevention
AIDP is the leading cause of acute flaccid paralysis in developed countries, with an annual incidence of 0.6 to 2.7 per 100,000 persons. There is a 20% increase in the average rate of GBS for every 10-year increase in age beyond the first decade.5 GBS demonstrates a predominance toward men (relative risk, 1.78), notably atypical for an immunologic condition.5
In contrast, the peak incidence of CIDP occurs in middle age (40s-60s). The relapsing-remitting form presents more often among patients in their 20s, whereas older patients may present with a more chronic, insidiously progressive motor and sensory polyneuropathy. Prevalence varies widely because of variable adherence to diagnostic criteria, from 1 to 9 per 100,000 persons. CIDP presenting in childhood carries a lower incidence of 0.48 per 100,000 persons.4
The underlying etiology and pathophysiology are immunologic. Molecular mimicry between surface glycolipids of antigenic stimuli (infectious agents, vaccinations) and myelin epitopes may trigger an immune attack through both cellular and humoral mechanisms. Autoantibodies target gangliosides on the Schwann cell plasmalemma of peripheral nerve and roots, leading to activation of the complement cascade and resultant inflammatory infiltrate (macrophages), and ultimately to vesiculation of myelin.1,2
Postmortem studies confirm segmental demyelination in large and small motor and sensory nerves and spinal roots with signs of secondary axonal degeneration.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
AIDP presents abruptly and follows a monophasic course, with progressive bilateral symmetric weakness that develops over 12 to 28 days, then plateaus.2 Fifty percent of patients reach the nadir by 2 weeks, 80% by 3 weeks, and 90% by 4 weeks.1
In contrast, indistinct onset and progression of signs/symptoms beyond 8 weeks are characteristic of the indolent course of CIDP. Two patterns predominate: relapsing-remitting (20%-65%) and progressive.6 Comparisons with multiple sclerosis (MS) are apropos, with CIDP often coined as the peripheral analog of MS, sharing an immunologic etiology, demyelinating pathophysiology, and similar patterns of progression.
Distinguishing AIDP and CIDP
Clinically, the 8-week temporal delineation is often less clear, as CIDP may present with an acute onset, and AIDP may have sequelae persist beyond 8 weeks. Posterior column sensory signs (ataxia, vibratory or proprioceptive loss) or relapse/progression may favor CIDP, whereas autonomic involvement, facial weakness, preceding infection, and mechanical ventilation favor AIDP.7
Specific secondary or associated conditions and complications
Largely out of the scope of this review, other conditions along the clinical spectrum of CIDP include multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome, distal acquired demyelinating symmetric neuropathy (DADS), demyelinating neuropathy with IgG or IgA paraprotein (MGUS), distal demyelinating neuropathy with IgM paraprotein with or without anti-myelin associated glycoprotein (anti-MAG), POEMS syndrome, and others.
Patients with longstanding CIDP can develop symptoms of lumbar stenosis and cauda equina syndrome secondary to nerve root hypertrophy with resultant radiculopathy and/or myelopathy.
2. ESSENTIALS OF ASSESSMENT
Often AIDP symptoms are preceded by upper respiratory symptoms, diarrhea, vaccination, or surgery 3 days to 6 weeks prior to onset of neurologic symptoms. Initial symptoms include numbness, paresthesias, weakness, and pain and may be preceded by vague back or neck pain. Over 12 to 28 days, progressive bilateral symmetric weakness develops, then plateaus.2 Although weakness often starts in the lower limbs, leading to ascending paralysis, descending or simultaneous upper and lower limb involvement is seen in nearly half of patients and should raise the possibility of AIDP.1
Typical CIDP presents with progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities developing over ≥8 weeks.8 In typical CIDP, motor involvement is greater than sensory, and can be accompanied by tremor or cranial nerve/bulbar involvement (oculomotor and facial nerves are more commonly involved7). Variants of CIDP present with predominantly distal (DADS), asymmetric (MADSAM), or focal (localized to plexus or peripheral nerve) weakness, pure motor, or pure sensory patterns.8 Detrusor areflexia and loss of bladder sensation affect micturition in 25% of patients with CIDP.4
Characteristic exam findings in both groups include generalized hyporeflexia or areflexia, although 10% demonstrate normal or brisk reflexes.2 Facial weakness may be present, mimicking stroke/transient ischemic attack. Autonomic dysfunction is often present, yet frequently overlooked in AIDP.
In CIDP, motor findings predominate, with symmetric distal > proximal > facial weakness. Large-fiber nerve function (vibration and position sense) are notably impaired, with lesser losses in small-fiber function (touch, pinprick, and temperature). Imbalance and ataxic gait may be evident. Enlarged peripheral nerves can be palpated in 11%.1
Sensorimotor deficits result in difficulty with ambulation, gait instability and falls, and (more so in CIDP) difficulty rising from a chair. Impaired dexterity and fine motor skills create challenges with handwriting, personal hygiene, and dressing.
Laboratory workup for AIDP may include serologies for Epstein-Barr virus, cytomegalovirus, Campylobacter jejuni, human immunodeficiency virus, hepatitis, and West Nile virus. Lumbar puncture is performed if GBS is suspected. Cerebrospinal fluid (CSF) protein levels are elevated in 50% to 66% of GBS cases during week 1, increasing to 75% by week 3.2 A cytoalbuminemic dissociation with elevated CSF protein and normal white blood cell count is classically seen in GBS and CIDP.
Although anti-GQ1b and anti-GT1a immunoglobulin IgG autoantibodies are highly sensitive for the Fisher variant,2 glycolipid antibody testing has limited clinical utility in GBS.
Suggested laboratory workup for CIDP includes the following: serologies for infections, including HIV; hepatitis profiles; Lyme disease; serum IgG, IgA, and IgM; serum protein electrophoresis; urine protein electrophoresis; and possible anti-myelin-associated glycoprotein antibody (suggesting DADS). Elevated CSF protein >45 mg/dL6 with a lymphocyte count of < 10/mm3 is supportive for CIDP.4
Other etiologic workup may include C-reactive protein, erythrocyte sedimentation rate, thyroid function studies, fasting blood sugar or oral glucose tolerance testing, complete blood count, antinuclear antibodies, and renal or liver function tests, when applicable.
Peripheral nerve biopsies may be useful in exceptional cases of CIDP to document vasculitis and other pathologies when electrodiagnostic criteria for demyelination are not met.4 Typical findings in CIDP include onion bulbs, endoneurial edema, inflammation, and lymphocytic infiltrate. Segmental demyelination is seen on teased fiber preparations.
Lumbar magnetic resonance imaging with gadolinium may demonstrate hypertrophy and enhancement of nerve roots in CIDP. Peripheral nerve enlargement can be detected with neuromuscular ultrasound, characterized by increased nerve cross-sectional area, which correlates with conduction block, disease severity, and functional disability.9
Supplemental assessment tools
Diagnosis of AIDP and CIDP hinges on clinical features, electrodiagnosis, and spinal fluid examination. Common to electrodiagnostic workup of both AIDP and CIDP is the demonstration of primary demyelination, adhering to the following published criteria: (1) reduced motor nerve conduction velocity (NCV), (2) motor conduction block and/or abnormal temporal dispersion, (3) prolonged distal motor latency (DML), and (4) prolonged or absent F-wave responses. Criteria differ quantitatively between the 2 conditions in the percentage of change from normal values and the required number of abnormal parameters.10
No less than 12 sets of criteria have been published for CIDP,8,10-14 including the well-known Asbury and Cornblath electrodiagnostic criteria for demyelination11 and the American Academy of Neurology research criteria for CIDP, known for its high specificity. The 2010 Joint Task Force of the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) developed both clinical and electrodiagnostic guidelines designed to more appropriately balance specificity and sensitivity to the clinical arena.8
EFNS/PNS electrodiagnostic criteria for CIDP7
- Definite: at least 1 of the following:
- Prolongation of the DML ≥50% above the upper limit of normal (ULN) in 2 nerves.
- Reduction in motor NCV ≥30% below the lower limit of normal (LLN) in 2 nerves.
- Prolongation of F-wave minimal latency ≥30% above the ULN in 2 nerves (≥50% above the ULN if the distal compound muscle action potential [CMAP] amplitude is <80% of the LLN).
- Absence of F-waves in 2 nerves if their distal CMAP amplitudes are ≥20% of the LLN and at least 1 other demyelinating parameter in at least 1 other nerve.
- Partial motor conduction block in 2 nerves: ≥50% amplitude reduction of the proximal relative to the distal CMAP, if the distal CMAP is ≥20% of the LLN, or in 1 nerve and at least 1 other demyelinating parameter in at least 1 other nerve.
- Abnormal temporal dispersion in ≥2 nerves (>30% duration increase between the proximal and distal CMAP).
- Prolonged distal CMAP duration in at least 1 nerve and at least 1 other demyelinating parameter in at least 1 other nerve.
- Probable: ≥30% amplitude reduction of the proximal relative to the distal CMAP in 2 nerves if the distal CMAP amplitude is ≥20% of the LLN, or in 1 nerve and at least 1 other demyelinating parameter in at least 1 other nerve.
- Possible: as in the definite category, but in only 1 nerve. Several authors have expressed concern with this classification because of low specificity.
Strict compliance with published evidence-based diagnostic criteria is paramount, since one-third of CIDP patients in the US have reportedly been incorrectly diagnosed and possibly receiving inappropriate treatment.15
The Inflammatory Neuropathy Cause and Treatment (INCAT) overall disability sum score (ODSS) is a validated tool to quantify arm and leg disability using a score ranging from 0 (“no disability”) to 12 (“most severe disability score”) that can be useful to track the course of AIDP/CIDP and provide an objective measure of therapeutic response before and after various treatments.16
Early predictions of outcomes
Risk factors for poorer prognosis in AIDP include older age of onset (>50-60y), abrupt onset of profound weakness, mechanical ventilation, and distal CMAP amplitudes < 10% to 20% of the LLN. Neck flexion/extension and shoulder abduction correlate with diaphragmatic strength. Published prognostic scales exist that enable quantitative assessment of GBS prognosis based on clinical factors.2 Two thirds of GBS patients are unable to walk independently at the nadir of weakness. Respiratory insufficiency occurs in 25%, contributing to an overall mortality rate of 5%.1,2 Among severe cases, 20% remain nonambulatory 6 months after onset.2 Only about 15% of patients are free of residual deficit at 1 to 2 years. Five to ten percent have persistent disabling sensory or motor symptoms. Seven percent experience recurrence.2
In CIDP, favorable response to treatment correlates with a lack of associated conditions, absence of monoclonal proteins, and highly elevated CSF protein. Predominantly distal weakness portends a poorer prognosis.6 Children with CIDP tend to respond well to immunotherapy.
Reminiscent of MS, there is geographic variation among subtypes of GBS. Although AIDP is the most common presentation in Europe and North America, AMAN is the most common subtype in China and Japan. AMAN and AIDP occur with equal incidence in India.17
Social role and social support system
Patients with AIDP infrequently require long-term services, but they often require short-term assistance after discharge. Those with CIDP present with a spectrum of ongoing need related to their disease burden. Home-based infusion services are a safe patient-centered option for stable patients and are associated with improved patient satisfaction.18
Largely overshadowed by organizations supporting MS, ALS, and muscular dystrophy, only a few online resources exist, including the GBS/CIDP Foundation International, founded in 1980.
Although GBS was linked with mass immunizations for swine flu in 1976, no such association with influenza has subsequently been found.2,19 Risk of contracting GBS because of seasonal influenza vaccination is 1 in 1,000,000 persons. Whether or not to vaccinate patients previously afflicted with GBS remains controversial; however, recent Centers for Disease Control and Prevention guidelines suggest minimal risk of recurrence to be weighed against the sizeable burden of illness for influenza.19,20 Two large studies of over 20 million adolescents vaccinated against meningococcus found no increased risk of GBS.21 Ongoing surveillance continues through the Vaccine Adverse Event Reporting System.19
Studies have demonstrated diminished quality of life many years after diagnosis of CIDP. Long-term therapy with intravenous immunoglobulin has demonstrated improvements in health-related quality of life in patients with CIDP.22
3. REHABILITATION MANAGEMENT AND TREATMENTS
See ADIP/CIDP Part 2.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
CIDP associated with autoantibodies against newly-discovered paranodal proteins (IgG4 autoantibodies to neurofascin-155 and contactin 1) present with distinct phenotypes and tend to be responsive to B cell depletion therapy (rituximab) while more refractory to IVIg,23 reminiscent of IgG4-mediated anti-MuSK myasthenia gravis.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
- Amato AA, Dumitru D. Acquired neuropathies. In: Dumitru D, Amato AA, Zwarts M, eds. Electrodiagnostic Medicine. 2nd ed. Philadelphia, PA: Hanley & Belfus; 2001:937-960.
- Yuki N, Hartung HP. Guillain-Barré syndrome. N Engl J Med. 2012;366:2294-2304.
- Haber P, Sejvar J, Mikealoff Y, et al. Vaccine and Guillain-Barré syndrome. Drug Saf. 2009;32:309-323.
- Hahn AF, Hartung HP, Dyck PJ. Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia, PA: Elsevier; 2005:2221-2253.
- Sejvar JJ, Baughman AL, Wise M, et al. Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis. Neuroepidemiology. 2011;36;123-133.
- Peltier AC, Donofrio PD. Chronic inflammatory demyelinating polyradiculoneuropathy: from bench to bedside. Semin Neurol. 2012;32:187-195.
- Dionne A, Nicolle MW, Hahn AF. Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy. Muscle Nerve 2010; 41:202
- 8. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society–First Revision. J Peripher Nerv Syst. 2010;15:1-9.
- Di Pasquale A, Morino S, Loreti S, et al. Peripheral nerve ultrasound changes in CIDP and correlations with nerve conduction velocity. Neurology. 2015;84:803–809.
- Van Den Bergh PY, Piéret F. Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2004;29:565-574.
- Rajabally YA, Nicolas G, Piéret F, et al. Validity of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy: a multicenter European study. J Neurol Neurosurg Psychiatry. 2009;80:1364-1368.
- Griffin JW, Sheikh K. The Guillain-Barré syndromes. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia, PA: Elsevier; 2005:2197-2219.
- Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol. 1990;27 Suppl:S21-24.
- Koski CL, Baumgarten M, Magder LS, et al. Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Sci. 2009;277:1-8.
- Cornblath DR, Gorson KC, Hughes RA, et al. Observations on chronic inflammatory demyelinating polyneuropathy: a plea for a rigorous approach to diagnosis and treatment. J Neurol Sci. 2013;330:2–3
- Merkies ISJ, Schmitz PIM, van der Meché FGA, et al. Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies. Journal of Neurology, Neurosurgery & Psychiatry 2002;72:596-601.
- Meena AK, Khadilkar SV, Murthy JM. Treatment guidelines for Guillain-Barré syndrome. Ann Indian Acad Neurol. 2011;14(Suppl 1):S73-81.
- Katzberg HD, Rasutis V, Bril V. Home IVIG for CIDP: a focus on patient centered care, Can J Neurol Sci, 2013;40:384–8.
- Centers for Disease Control and Prevention. Fact sheet: Guillain-Barré syndrome (GBS) and Flu vaccine. Available at: https://www.cdc.gov/flu/protect/vaccine/guillainbarre.htm . Accessed November 8, 2017.
- Stratton K, Alamario DA, Wizemann T, et al. Immunization Safety Review: Influenza Vaccines and Neurological Complications. Washington, DC: Institute of Medicine, The National Academies Press; 2004.
- Yih WK, Weintraub E, Kulldorff M. (2012), No risk of Guillain–Barré syndrome found after meningococcal conjugate vaccination in two large cohort studies. Pharmacoepidemiol Drug Saf, 21: 1359–1360.
- Merkies IS, Bril V, Dalaka MC, et al. Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: the ICE Study. Neurology. 2009;72:1337-1344.
- Querol L, Rojas-García R, Diaz-Manera J, et al. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015; 2:e149.
Original Version of the Topic
Michele Arnold, MD. AIDP/CIDP Part 1: Evaluation and Diagnosis. 09/20/2013.
Michele Arnold, MD
Nothing to Disclose