Immune Mediated Neuropathies

Disease/Disorder

Definition

Immune-mediated neuropathies are a group of peripheral nerve disorders in which the immune system damages nerve components via innate and/or humoral immunologic responses (antibody formation, inflammatory cascade, complement activation) leading to demyelination or axonal degeneration.

This can result in sensory, motor, or autonomic deficits that can range from life-threatening to an asymptomatic, minimally progressive, monophasic process. Some are part of a larger systemic autoimmune disease, and others are an isolated peripheral nerve disorder.

Immune-mediated neuropathies are broadly classified into

Acute immune-mediated neuropathy¹ 

• Typical GBS 
• GBS Variants
  • Pharyngeal-cervical-brachial
  • Paraparetic 
  • Pure sensory 
  • Acute Inflammatory demyelinating polyradiculoneuropathy (AIDP)
  • Acute motor and sensory axonal neuropathy (AMSAN) 
  • Acute motor axonal neuropathy (AMAN) 
  • Acute pandysautonomic neuropathy²
• Miller Fisher Syndrome Spectrum (GQ1b antibody syndromes)
  • Miller Fisher Syndrome (MFS)  
  • Partial MFS 
  • GBS/MFS overlap syndrome 
  • Bickerstaff brainstem encephalitis 
  • Acute ophthalmoplegia (without ataxia) 

Chronic immune-mediated neuropathy³ 

• Typical Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
• CIDP Variants
  • Distal CIDP, also known as distal acquired demyelinating symmetric neuropathy (DADSN) 
  • Multifocal CIDP, also known as multifocal demyelinating neuropathy with persistent conduction block (MADSAM); Lewis-Sumner syndrome (LSS); multifocal inflammatory demyelinating neuropathy
  • Focal CIDP 
  • Sensory CIDP – often a transient clinical stage prior to manifestation of weakness
    • Sensory predominant CIDP  
  • Motor CIDP
    • Multifocal motor neuropathy (MMN) 
    • Motor predominant CIDP if conduction block present 
  • Acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP)⁴ 

Epidemiology including risk factors

The annual incidence of immune-mediated neuropathies (IN) varies among specific types with the most common being GBS and subtype AIDP, followed by CIDP, MMN, and POEMS syndrome.

Acute- GBS⁴

• Annual global incidence approximately 1–2 per 100,000 person-years.
  • Highest in Chile and Bangladesh possibly due to differences in exposure to infectious organisms. 
  • Lowest in Japan, China, Tanzania and Finland 
• Worldwide prevalence is about 100,000 people per year. 
• Incidence increases with age and reaches its peak between 50 and 70 years
• Males are about 1.5 times more likely to be affected than females
• The demyelinating subtype is predominant in all global regions tested, but AMAN and motor GBS are more frequent in Asia (especially Bangladesh) than Europe and America
• Spikes of GBS have been reported following infectious outbreaks, most notably in relation to Campylobacter jejuni^4,5 C. jejuni infections are particularly associated with AMAN and/or motor GBS with worse outcome.
  • Other associated pathogens include Epstein–Barr virus (EBV), cytomegalovirus (CMV), hepatitis E virus (HEV), Mycoplasma pneumoniae, Haemophilus influenzae, influenza A virus, and Zika virus, and COVID⁴ 
• Post-vaccine GBS: advantages of vaccination significantly outweigh any marginal elevation in the risk of post‐vaccine GBS⁴
  • ‘Swine flu’ campaign in the USA:  4.9–5.9 GBS cases per million vaccinations
  • Recombinant zoster vaccine (RZV): 3 cases per million vaccinations
  • Adenovirus‐vector SARS‐CoV‐2 vaccine (ChAdOx1 and Janssen): 5.7 cases per million first doses
  • H1N1 influenza A vaccination in 2009: 1–1.6 cases per million doses
• Other risk factors include autoimmune disorders, malignancy and surgery¹
  • Orthopedic or GI surgery
  • Stem cell transplant patients on tacrolimus prophylaxis 
  • Immune checkpoint inhibitors as cancer treatment – risk not assessed in controlled studies

Chronic- CIDP⁶

• Worldwide incidence ranges from 0.2 to 1.6 per 100,000 persons per year. 
• Worldwide prevalence ranges from 0.8–10.3 per 100,000 persons 
• Prevalence higher in males than females
• Increased with age, mean patient age of 57 years 
• Similar mortality rates to the general population 
• No clear risk factors, potential associations include autoimmune disease, diabetes, hypertension, and antecedent infection or vaccination
  • An antecedent infection, or vaccination, preceded a diagnosis of CIDP in 27% of patients 

Etiology and pathogenesis

The pathophysiology of GBS can be delineated into two pivotal stages: initiation by an immunological trigger, followed by immune‐mediated disruption of axons and/or myelin.

New guidelines no longer support a pathophysiological distinction between AIDP (primarily demyelinating) and AMAN (primarily axonal damage):  

• AMAN is due to reversible axonal conduction block at the nodes of Ranvier or the motor nerve terminal with or without axonal degeneration. 
• AIDP is due to segmental demyelination with or without secondary axonal degeneration, usually followed by recovery through regeneration of myelinating Schwann cells.

Immunobiological mechanisms¹ 

• Molecular mimicry resulting in autoantibodies: In most cases, GBS is a post-infectious disease: Campylobacter jejuni leads to GBS through molecular mimicry between its surface lipo‐oligosaccharide (LOS) and host peripheral nerve ganglioside triggering the production of cross‐reactive antibodies targeting gangliosides like GM1, GD1a, and GQ1b, resulting in axo-glial damage.
  • Mycoplasma pneumoniae is associated with anti‐galactocerebroside antibodies of the IgG isotype, more frequently in children. 
• Damage to membrane via complement activation against the autoantibodies and formation of the membrane attack complex (MAC), leading to aberrant influx of calcium into the axon, calpain activation, and ultimately damage to the node of Ranvier, the paranode, and the motor nerve terminals. Ganglioside antibody binding also leads to displacement of voltage‐gated sodium channels, cytoskeletal anchoring proteins, and cell adhesion molecules within the nodal and paranodal regions. 
• Innate and cellular immune mechanisms involving T cells, B cells, NK cells, dendritic cells, and macrophages contribute to axonal damage and demyelination. 
• At least 40% of GBS patients do not have identifiable serum or CSF autoantibodies possibly as not all antigenic targets have yet to be found. 
• Genetic factorsmight also play a role- studies have found associations between GBS and a necrosis factor (TNF) gene polymorphism, mannose‐binding lectin (MBL) gene mutation. 

CIDP is a collection of syndromes with immunopathological diversity that is not well understood and differs across demographics. Cellular, humoral and complement pathways play a key role in peripheral nerve damage in CIDP, but exact mechanisms have not been delineated.⁷

• CD4+ and CD8+ T cells and inflammatory cytokines have been found in biopsies of peripheral nerves and nerve roots. 
• Macrophage infiltration of nerves triggers myelin breakdown through phagocytosis. 
• B cell role not well understood- possibly deposition of IgG and IgM on the surface of Schwann cells and compact myelin in the peripheral nerves. 
• The role of the complement mechanism is not well understood, however complement capture and inhibition are among the mechanisms of action of immunoglobulins, and IVIg has been shown to be an effective treatment for CIDP. 

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

New onset/Acute⁸

• GBS is a self-limited acute neuropathy characterized by symmetric flaccid paralysis, areflexia and sensory deficits that start 1-3 weeks after infection.
• There are three phases
  • Acute phase: Symptoms develop over hours to weeks and reach a nadir within 4 weeks, often in less than 2 weeks.
  • Plateau phase: For days to weeks, the disease stabilizes without further worsening or improvement.
  • Recovery phase: Gradual improvement in function, strength, and mobility begins as early as 4 weeks but may take months to years to fully—or sometimes only partially—resolve.
• Typical CIDP may present acutely (A-CIDP), initially diagnosed as GBS and later reclassified when symptoms persist >8 weeks. 
• GBS Trajectory: About 80% of patients will walk independently and over 50% return to their previous baseline within a year. Up to 10% of patients require mechanical ventilation, and more than 10% have subsequent severe disability. Approximately 20% of patients who become ventilator‐dependent and 3–7% of all GBS patients die.
  • Negative prognostic factors include age >60 years, rapid onset (less than 7 days from onset of weakness to hospital admission), severe weakness, mechanical ventilation, preceding diarrhea, and findings of severe neuropathy on electrophysiology.
  • Death and disability rates vary significantly between developed and developing countries due to discrepancy in availability of treatments like IVIg and PLEX 

Chronic >8 weeks³

• Most Typical CIDP commonly presents with paresthesia and weakness in the distal limbs with gait disturbance. Steadily progressive symmetric proximal and distal muscle weakness, sensory loss, and decreased or absent deep tendon reflexes occurs over > 8 weeks, but course can be relapsing-remitting. Unlike in GBS, cranial nerves are less frequently affected and respiratory or autonomic involvement is exceptional. 

Essentials of Assessment

History and Physical Examination

• Acute (GBS)
  • Progressive bilateral weakness in GBS with difficulty in climbing stairs getting out of chair is most notable 1-2 days after onset of paresthesia.⁹
  • Cranial nerves including facial, bulbar, and ocular motor nerves are commonly involved in GBS (especially in MFS).
  • MFS may present with ophthalmoplegia, ataxia, and areflexia.⁹
  • Respiratory muscles are commonly affected, and up to 25% of patients may need artificial ventilation.
  • Autonomic complaints are common in GBS and variants.
  • Autonomic dysfunction such as cardiac arrhythmias, arterial hypertension or hypotension, abnormal sweating, GI dysmotility may occur in two-thirds of patients
  • Bowel or bladder complaints are rare.
• Chronic¹⁴
  • Weakness is proximal and distal in typical CIDP.
  • Fasciculations and cramps common in MMN (approximately 50%).
  • The typical presentation of anti-MAG neuropathy is that of distal, predominantly sensory large fiber ataxic neuropathy, like DADSN. Some patients may also exhibit a neurogenic tremor in the arms.¹⁰
• Muscle stretch reflexes are diminished in GBS and CIDP by definition, except for the AMAN variant, which can have increased reflexes in the recovery phase.

Differential diagnosis

• GBS: transverse myelitis, myasthenia gravis, botulism, carcinomatous or lymphomatous meningitis, toxin-related neuropathy, vasculitis-related neuropathy.
• CIDP
  • IgA, IgM, or IgG monoclonal gammopathies
  • Neuropathy related to human immunodeficiency virus (HIV), hepatitis C, Sjogren’s disease, lymphoma, ulcerative colitis and Crohn disease, melanoma and diabetes.
  • Secondary immune-mediated neuropathies are associated with vasculitic diseases such as polyarteritis nodosa (PAN), Wegener granulomatosis, Churg-Strauss syndrome (CSS), microscopic polyangiitis, temporal arteritis, drug-induced vasculitis, non-systemic vasculitis neuropathy), connective tissue disease, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren syndrome, systemic sclerosis, cryoglobulinemia), sarcoidosis, or malignancies.⁹

Electrodiagnosis

• Electrodiagnostics (EDX) are an important clinical tool for distinguishing demyelinating and axonal types.¹⁰
  • Electrodiagnostic criteria for demyelination
    • Partial motor conduction block and temporal dispersion reduced motor conduction velocity (60% of the normal mean),¹⁰ prolonged motor latencies, and F wave latencies⁹
    • Conduction block¹⁰
  • Typical EDX findings in GBS
    • Test results can be normal early in acute disease.
    • Prolonged F wave or loss of F wave and H reflex may be the only finding if the patient is tested early.¹¹
    • In AIDP, electrodiagnostic performed within 2-15 days after onset may shows motor conduction blocks (CB) in approximately 60% of patients. Conduction block resolves with the appearance of CMAPs with slow initial components and increased duration on stimulation proximal to the site of block, consistent with the remyelinating process.¹² The other abnormalities are prolonged motor distal latencies and decreased amplitudes.¹⁵
    • Serial NCS lead to reclassification of GBS subtypes in as many as 40% of patients, especially from AIDP to an axonal form. Thus, the classification may differ among studies that employ single or repeated NCS.¹²
    • AMAN: decreased distal CMAPs, prolonged distal motor latency (DML), CB, and conduction slowing in forearm segments in the first week.¹⁰
  • CIDP¹⁶
    • American Academy of Neurology Ad Hoc Subcommittee Criteria in 1991 (requiring 3 of 4 following criteria)
      • Reduced conduction velocities (CVs; e.g. <80% of the lower limit of normal [LLN] if the distal motor amplitude is normal, and <70% of LLN if the amplitude is substantially reduced)
      • Prolonged DMLs
      • Prolonged F-wave latencies (FLs; e.g.>125% of the upper limit of normal [ULN] if the distal motor amplitude is normal, and >150% of ULN if the amplitude is reduced for distal latencies and F-waves)
      • CB/temporal dispersion (TD); e.g. CB is >50% reduction of proximal/distal [p/d] amplitude and abnormal temporal dispersion is >130% increase of p/d duration)
    • European Federation of Neurological Societies/Peripheral Nerve Society Guideline in 2010
      • Definite: at least one of the following:
        • At least 50% prolongation of DML above ULN in two nerves
        • At least 30% reduction of motor CV below LLN in two nerves
        • At least 20% prolongation of F-wave latency above ULN in two nerves (>50% if amplitude of distal negative peak CMAP <80% of LLN)
        • Abnormal temporal dispersion (>30% duration increase between the proximal and distal negative peak CMAP) in at least two nerves
        • Absence of F-waves in two nerves if these nerves have amplitudes of distal negative peak CMAPs at least 20% of LLN + at least one other demyelinating parameter in at least one other nerve
        • Partial motor CB: at least 50% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP at least 20% of LLN, in two nerves, or in one nerve + at least one other demyelinating parameter in at least one other nerve, or
        • Distal CMAP duration of at least 9 ms in at least one nerve + at least one other demyelinating parameter in at least one other nerve
      • Probable
        • At least 30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding the posterior tibial nerve, if distal negative peak CMAP at least 20% of LLN, in two nerves, or in one nerve + at least one other demyelinating parameter in at least one other nerve
      • Possible
        • As in ‘I’ but in only one nerve
  • MMN
    • Presence of motor CB with weakness in 2 or more nerves outside common entrapment sites,
    • Absence of upper motor neuron signs or significant sensory loss, and with normal sensory nerve conduction in typical cases.¹
  • In anti-MAG neuropathy, patients often have a disproportionate prolongation of distal latencies compared with patients who have CIDP.¹

Laboratory studies and supplementary tests

• Autoantibodies are variably associated, immune-mediated clinical syndromes; the highest associations are:
  • Anti-GQ1b and GT1a IgG Ab in MFS
  • Anti-GM1 and GD1a IgG Ab in AMSAN and AMAN
  • Anti-GM1 IgM Ab in MMN
  • Anti-MAG in the DADSN
  • IgM monoclonal gammopathies may be associated with anti-MAG neuropathies¹⁰
  • Anti-Contactin 1 IgG Ab in CIDP (aggressive onset and initial axonal involvement with poor response to IVIG)
  • Anti- NF155 IgG Ab in CIDP (tremor, ataxia, and distal motor involvement)
  • Anti- NF 186 and NF 140 IgG Ab in CIDP (subacute onset, sensory ataxia, and conduction block with good response to IVIG and steroids)
  • Anti- GD3, GD1b, GT1b and GQ1b IgM Ab in CANOMAD and CANDA
• Campylobacter jejuni serology is positive in 44%-88% of GBS cases.¹³
• Elevated CSF protein and normal cell count are seen particularly in GBS, CIDP, and variants (except MMN).
• Approximately 90% of patients with anti-MAG neuropathy have elevated CSF protein concentration with normal CSF cell counts.¹⁰
• Newly discovered fluid biomarkers are demonstrating to be useful for diagnostic and prognostic characteristics in GBS
  • Neurofilament light chain (NfL), a neurofilament protein released in both serum and CSF, was found to be elevated in the serum of patients with GBS, especially in patients with preceding diarrhea. Higher levels correlate with more severe disease and prognosticate inability to run at 1 year. NfL was also found to be elevated in CIPD.^20,21
  • T-Tau is another biomarker, historically used as a CSF biomarker for Alzheimer’s disease, which has also been shown to be elevated in the plasma of patients with acute and chronic forms of immune mediated neuropathies including GBS, CIDP, and MMN ^[21]
• The discovery of new fluid biomarkers associated with various acute and chronic immune mediated neuropathies marks a shift towards faster and more accessible means of diagnosis with simple serum studies.
• Nerve biopsy can be useful to confirm vasculitic neuropathies. In patients with equivocal electrodiagnostic findings, nerve biopsies can help distinguish between primary demyelinating and axonal neuropathy.
  • Motor nerve biopsy can help distinguish between MMN and motor neuron disease
  • Sensory nerve biopsy can aid diagnosis of CIDP, anti-MAG neuropathy or POEMS syndrome³⁰
• Autonomic testing can confirm autonomic involvement.
• Pulmonary function tests and telemetry are necessary in severe cases that have autonomic and diaphragmatic involvement, particularly in GBS.

Imaging

• Imaging is useful primarily to exclude other diagnoses.
• MRI may demonstrate enhancement and enlargement of not only peripheral nerves, but also of the brachial and lumbar plexus, and cauda equina. MRI is more expensive and requires more advanced interpretation and may not be superior in detection compared to high resolution ultrasound.
• New guidelines from European Academy of Neurology (EAN) suggest to only consider use of imaging studies when GBS presents in atypical fashion.^4,14

Ultrasonography in CIDP

• Typical findings with prognostic implications
  • Combining nerve/fascicle size with echo intensity and histology at baseline, nerves show hypoechoic enlargement and onion bulbing, reflecting active inflammation; or showed nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue, possibly reflecting axonal degeneration; some showing almost no enlargement, reflecting “burned-out” or “cured” disease without active inflammation.
  • Based on nerve echogenicity, nerves were classified into 3 classes
    • Class 1: large nerves (increased cross-sectional area [CSA]), with hypoechoic segments, correlating with good responses to treatment.
    • Class 2: large nerve, with segments with increased nerve CSA and coexistence of hyper- and hypoechogenic enlarged (or normal) fascicles (fascicles with hyperechoic structure and other fascicles with hypoechoic structure).
    • Class 3: normal nerve size, but changes in echogenicity (nerve appears hyperechoic with reduced CSA, as in class 1 or 2). The hyperechoic rim of the epineurium is not clearly identified (blurred boundaries). Fascicles are not well visualized.
  • The results of the above-reported classification were correlated with clinical data, namely, age of patient, duration of disease, muscle strength, and lower and upper limbs disability score.
  • Increase in nerve vascularization was not correlated with clear clinical implication.¹⁷
• Ultrasonography in differential diagnosis
  • “Bochum ultrasound score” (BUS) included evaluation of cross-sectional area (CSA) in the a) ulnar nerve in the Guyon canal b) ulnar nerve in the upper arm c) radial nerve in the spiral groove and d) sural nerve between the lateral and medial heads of gastrocnemius muscle. 1 point allotted to each anatomical site¹⁸
  • Typical BUS finding suggestive of CIDP includes pathological CSA enlargement at all 4 anatomical sites compared to reference values. CIDP was highly suggestive in BUS score ≥ 2.
  • For BUS score ≤ 2, other anatomical sites such as median and ulnar nerves in the forearm and tibial nerve at ankle were evaluated. Pathological enlargement in at least 1 of the aforementioned sites was suggestive of MMN. If the above 3 sites were normal and BUS was ≤ 2, then median nerve in carpal tunnel and ulnar nerve at the elbow were evaluated. CSA enlargement in at least 1 of these sites was highly suggestive of MADSAM.
  • The study showed 88% sensitivity and 84.6% specificity in distinguishing CIDP from other diagnoses of symmetrical demyelinating polyneuropathies. MMN and MADSAM could both be diagnosed with a sensitivity of 100% and specificity of 83.3%.¹⁹

Early predictions of outcomes

GBS

• Early predictors of poor prognosis: older age (over 50), rapid onset of profound weakness, mechanical ventilation, distal compound muscle action potential (CMAP) amplitude less than 10% of normal¹¹
• Long-term outcomes are worse in AMAN, better in MFS than classic AIDP. Disability remains in 10% of patients.¹¹
• The Modified EGRIS tool is a recently updated model which was developed to predict whether patients with GBS will develop respiratory failure requiring intubation during hospital admission. In North America, the mEGRIS-Eu/NA is recommended, and uses 3 criteria: time from weakness onset to hospital admission, presence of facial/bulbar weakness, and MRC score (overall measure of strength from 6 muscle groups).²²

CIDP

• A recent multicenter study from Korea and the UK found that early treatment initiation within a year of symptoms onset was associated with better outcomes, especially in older adults, those with typical CIDP, and patients with a chronic onset.
• In contrast, higher pre-treatment disability levels and the presence of disabling comorbidities (rheumatological conditions, heart disease, diabetes, pre-existing neurological disease) were associated with worse long-term functional outcomes.²⁵

Medical Management and Rehabilitation Strategies

Current treatment guidelines

At different disease stages

• New onset/Acute demyelinating neuropathies
  • In GBS, treatment should begin within two weeks if possible.⁴
    • Immunomodulatory treatment consists of plasma exchange and IVIg.
    • The current evidence advises administering IVIg as a dose of 2g/kg over the course of 5 days, but severe cases of GBS should only receive one total course, as there is limited benefit with additional courses and carries increased risk of side effects, primarily vascular in nature such as thromboembolism.
    • Plasma exchange (PLEX) may be considered for ambulatory patients unable to run, in which 2 PLEX treatments can be administered within 2 weeks of disease onset, and up to five PLEX treatments may be considered in ambulatory patients with rapid deterioration, such as respiratory compromise or autonomic instability. Most common adverse effects include hypotension.
    • Overall the data does not show any superiority between IVIg over PLEX regarding efficacy, nor do the latest guidelines from European Academy of Neurology/Peripheral Nerve Society Guideline indicate a preference.
  • Multidisciplinary care for the prevention of potentially fatal complications such as respiratory failure, cardiac arrhythmias, infections, and thromboembolism.
  • Autonomic instability may necessitate admission to an intensive care unit (ICU) and telemetry; impending respiratory distress requires pulmonary function monitoring and mechanical ventilation.
• Chronic/stable
  • Current recommendations for CIPD treatment consist of oral/IV steroids or IVIg as first line treatment and are equally efficacious while PLEX as second line only due to high cost and logistical challenges in resource poor settings.³
    • Pulsed high dose oral steroids or IV steroids in short bouts are not considered superior to a lower dose 8-month oral taper, though clinical tolerance and adverse reactions are to be considered for longer therapy durations.³
    • Subcutaneous IG can be an alternative to IVIg for maintenance therapy and some studies showed the benefits as initial therapy.²³
    • Steroid-sparing agents such as azathioprine and mycophenolate mofetil can be used to facilitate the tapering of corticosteroids. High-dose IV cyclophosphamide can be tried for refractory patients.²⁴
    • Monoclonal antibodies such as rituximab, alemtuzumab, natalizumab. Rituximab can be beneficial in CIDP patients with Ab against node of Ranvier proteins such as contactin-1, contactin-associated protein 1, and NF-155
  • Others
    • Anti-MAG neuropathy: rituximab, or combination with fludarabine are often first-line treatments
    • MMN: IVIG is first-line therapy (level A).

Rehabilitation

• At least a third of people with immune-mediated neuropathies experience long-term activity limitations. Residual symptoms may be present many years after recovery from GBS syndromes or CIDP. Persistent residual disability and fatigue are the most common long-term consequences which adversely affect ADLs, IADLs, social and family activities.
• Goal is to stabilize, prevent complications related to immobilization such as venous thromboembolism, contracture, etc. and optimize function and prepare for further interventions at later disease stages.
• Inpatient rehabilitation may be necessary for patients with functional deficits. 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 is prescribed as necessary. Orthotics are often necessary, particularly ankle-foot orthotics¹⁶
• Neuropathic pain and mechanical pain can develop in CIPD due to loss in muscle bulk and tone, change in biomechanics, and general weakness, and may be as prevalent as up to 72% in some studies.
• The use of corticosteroids for primary disease treatment may additionally lead to a reduction in pain in many patients.
• To reduce pain and improve quality of life, the EAN/PNS also recommend consideration for the use of neuropathic agents such as GABAergic agents like pregabalin or gabapentin, tricyclic antidepressants, or serotonin-noradrenaline reuptake inhibitors.³
• Despite the lack of randomized controlled trials, expert consensus strongly supports rehabilitation therapies across all phases of GBS, acute and chronic, including physical therapy, occupational therapy, and speech therapy. When feasible, patients should attempt to complete therapy in a rehabilitation center.⁴

Coordination of care

• The 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

• Patients and families should be educated on the generally good prognosis of GBS and the potentially recurrent nature of CIDP.
• Educate regarding complications of treatment such as prednisone and other immunomodulating treatments.
• Prevention of the complications of immobilization in the outpatient setting will largely fall on caregivers.
• Patients and families should be educated on the of proper Assistive Devices (AD) and orthotic devices.

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

• Identifying that 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). GBS is best treated within two weeks of the onset of symptoms, sometimes necessitating empiric treatment.
• Of the several idiopathic neuropathies referred to tertiary centers, 10%-33% are later felt to be CIDP. CIDP should be in the differential of unexplained neuropathies.

Cutting Edge/Emerging and Unique Concepts and Practice

• Advances have been made in surrogate markers in patients with immune-mediated neuropathy with correlation with certain clinical phenotypes or response to specific treatment in CIDP.
• Personalized medicine is advancing for treatments tailored to specific subgroups of patients.
• Emerging therapeutic agents in the form of new biologic agents, monoclonal antibodies or fusion proteins offer target-specific therapy and are currently used in other autoimmune disorders.
• Recent research into new uses for existing immunomodulatory therapy has demonstrated success with the use of Eculizumab, a C5 inhibitor, when combined with IVIG, and demonstrated improvements in GBS disability scale and appeared to be well tolerated. More studies with larger cohorts are need prior to FDA approval for the use in GBS.  ^[27]
• In Anti-MAG neuropathy, there has been interest in other more targeted anti-B cell immunologics, agents stronger than Rituximab, such as Ocrelizumab and obinutuzumab, which may demonstrate benefit for individuals with Anti-MAG antibodies who have refractory cases to first line therapy.^28,29
• An integrative therapy study titled InspireGBs assessed the safety and preliminary effectiveness of an inspiratory muscle training protocol in GBS patients and found that it was safe, feasible, and potentially effective in improving inspiratory muscle strength.
• The are no studies specific to neurorehabilitation protocols for CIDP. Integration of individual rehabilitation treatments such as strengthening exercise (moderate evidence in patients with neuropathy) can be applied in conjunction with pharmacological treatment.²⁶

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Original Version of the Topic

Shawn Jorgensen, MD. Immune Mediated Neuropathies. 12/27/2012

Previous Revision(s) of the Topic

Samuel S. Murala, MD, Se Won Lee, MD. Immune Mediated Neuropathies. 3/6/2018

Se Won Lee, MD. Immune Mediated Neuropathies. 5/4/2022

Author Disclosure

Steven Lacombe, DO
Nothing to Disclose

Elim Cho, MD
Nothing to Disclose

Ziva Petrin, MD
Nothing to Disclose