CIDP Diagnosis Criteria: An Expert Guide for Accurate Identification and Management

Introduction

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is a complex, immune-mediated neurological disorder targeting the peripheral nerves and nerve roots. This condition is characterized by inflammation leading to segmental demyelination and subsequent remyelination. Classically, CIDP manifests as a symmetrical, predominantly motor weakness accompanied by sensory impairments, particularly affecting proprioception and vibration sense more profoundly than pain and temperature. Areflexia is also a common finding. While many cases of CIDP are idiopathic, it’s crucial to recognize that various underlying conditions can trigger its onset. The diagnostic process for CIDP can be intricate, often leading to both underdiagnosis and overdiagnosis, highlighting the critical need for precise diagnostic criteria and prompt intervention. Accurate and timely diagnosis is paramount to initiate effective treatment, mitigate potential mortality, and reduce long-term morbidity associated with this debilitating condition. Fortunately, various treatment modalities are available that can significantly improve patient outcomes.

This continuing education article aims to provide a comprehensive overview of CIDP, encompassing its pathophysiology, clinical presentation, evaluation, diagnosis, and treatment strategies. We will place particular emphasis on the Cidp Diagnosis Criteria currently utilized in clinical practice. Furthermore, this activity underscores the indispensable role of an interprofessional healthcare team in delivering holistic patient care. By staying abreast of the latest advancements and evidence-based practices, healthcare professionals can optimize outcomes and enhance the quality of life for individuals affected by this challenging neurological disorder.

Objectives:

• Apply current CIDP diagnosis criteria to effectively differentiate chronic inflammatory demyelinating polyradiculoneuropathy from other neurological conditions with overlapping symptoms.
• Determine the appropriate and strategic use of electrodiagnostic studies in confirming a CIDP diagnosis and accurately assessing peripheral nerve demyelination.
• Develop comprehensive long-term management plans for chronic inflammatory demyelinating polyradiculoneuropathy, carefully considering maintenance therapies alongside their associated risks and benefits.
• Enhance coordination and communication among interprofessional team members to foster positive outcomes for patients definitively diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy.

Etiology of CIDP

While the majority of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) cases are classified as idiopathic, meaning their exact cause remains unknown, there are instances where preceding infections, particularly respiratory and gastrointestinal infections, have been reported. However, a specific causative organism has yet to be identified by researchers. Furthermore, CIDP has been linked to various systemic illnesses, including systemic lupus erythematosus, HIV infection, and hepatitis B or C. The prevailing theory suggests a multifactorial etiology involving both T-cell-mediated and humoral immune mechanisms that ultimately target myelin within the peripheral nervous system. Evidence supports the notion that activated T-cells breach the blood-nerve barrier, triggering the release of cytokines, tumor necrosis factor, interferons, and interleukins. The presence of immunoglobulin (Ig) and complement deposition on myelinated nerve fibers further substantiates the involvement of humoral immunity in the pathogenesis of CIDP.

Clinically, CIDP presents in diverse forms. Approximately 50% of patients follow a typical or classical course, characterized by progressive, symmetrical sensory deficits and motor weakness that develops over at least eight weeks. Atypical variants, on the other hand, encompass seropositive CIDP (marked by the presence of specific antibodies), sensory predominant, motor predominant, Lewis-Sumner syndrome (also known as multifocal acquired demyelinating sensory and motor polyneuropathy, or MADSAM), and distal acquired demyelinating symmetric (DADS) neuropathy.

Intriguingly, about 10% of individuals with CIDP exhibit autoantibodies directed against nodal and paranodal proteins. These autoantibodies are predominantly of the IgG4 subclass, which typically do not activate the complement system. The primary target proteins appear to be neurofascin (NF) isoforms and contactin-1 (CNTN1), located at or near the nodes of Ranvier. Specific proteins targeted in CIDP include:

• Neurofascin-155 (NF155): A paranodal protein expressed by glial cells.
• Neurofascin-140 (NF140) and Neurofascin-186 (NF186): Neuronal proteins found at nodes and axon initial segments.
• Contactin-associated protein 1 (CASPR1) and CNTN1.

NF155 antibodies are found in 4% to 18% of CIDP patients and target Schwann cells in the paranodal region. NF186 antibodies, less common (under 2%), target the nodal region of the axon. Anti-CNTN1 antibodies are present in 2.2% to 8.7% of patients. Patients with anti-CNTN1 antibodies often present with predominantly motor neuropathy and signs of axonal damage.

The pathogenesis of CIDP associated with autoantibodies to nodal proteins is considered distinct from classical CIDP, and ongoing research aims to further refine their classification. Notably, these variant forms often show a diminished response to initial treatments like corticosteroids and intravenous immunoglobulins (IVIG) compared to typical CIDP. Studies on human leukocyte antigen (HLA) types in CIDP have yielded conflicting results, with some suggesting associations with HLA Dw3, DRw3, A1, and B8, while others find no conclusive genetic link.

Epidemiology of CIDP

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) exhibits a higher prevalence in males compared to females, with a reported ratio of approximately 2:1. Recent meta-analysis data indicates a crude incidence rate of 0.3 cases per 100,000 individuals. The overall prevalence ranges from 0.8 to 8.9 per 100,000 people, with a notable increase in incidence associated with advancing age. While the average age of onset reported in studies is around 60 years, CIDP can occur across the lifespan, including in children. Variations in clinical presentations and inconsistencies in diagnostic criteria used globally contribute to the observed variability in incidence and prevalence rates. Juvenile CIDP is more likely to present with a relapsing course and motor-dominant features.

Pathophysiology of CIDP

The prevailing pathophysiological mechanism in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) involves an immunologic antibody-mediated reaction coupled with the infiltration of the endoneurium by T-cells and macrophages. This immune response leads to segmental demyelination and subsequent remyelination of peripheral nerves. Activated T-cells and macrophages function as antigen-presenting cells, further promoting the demyelination process. T-helper (Th)17 cells are found in elevated numbers in both peripheral blood and cerebrospinal fluid (CSF) of CIDP patients. Nerve involvement in CIDP is typically patchy, with demyelination primarily occurring in the paranodal regions, near the nodes of Ranvier. Impairment of Schwann cells, which are crucial for regenerating myelin sheaths, is also a key component of CIDP pathology. A potential decline in regulatory and naive T cells, often associated with increased age, may also contribute to the disease process. Furthermore, heightened natural killer cell activity has been observed in CIDP.

Although CIDP is primarily characterized as a demyelinating neuropathy, axonal degeneration is frequently present. This is likely a secondary consequence of the chronic inflammatory demyelinating process. Affected nerves often become enlarged due to the presence of overlapping Schwann cells attempting to cover denuded axons.

Histopathology of CIDP

Microscopic examination of nerve tissue in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) reveals characteristic features, including interstitial edema and inflammatory cell infiltrates composed of lymphocytes and macrophages. Demyelination and remyelination are considered hallmark histopathological findings of CIDP. Teased fiber analysis, a specialized technique, demonstrates these features in 48% to 68% of patients, while approximately 21% show a mixed pattern of demyelination and axonal changes. The cyclical process of demyelination and remyelination results in the formation of “onion bulbs,” which are concentrically oriented Schwann cells surrounding thinly myelinated fibers, readily observable in transverse sections of nerve biopsies.

Nerve biopsies further reveal the presence of inflammatory T-cells and macrophages, along with localized edema and fibrosis within the nerve tissue. Ultrastructural studies provide detailed insights, showing macrophages extending cellular processes between myelin lamellae, leading to the degradation of myelin components. In specific CIDP variants, such as distal acquired demyelinating symmetric polyneuropathy (DADS) associated with anti-myelin-associated glycoprotein (anti-MAG) antibodies, demyelination is predominantly observed along large myelinated axons. This is characterized by separation of myelin lamellae and deposition of IgM and C3d on myelin sheaths. Some histological studies also highlight an increased presence of macrophage clusters around blood vessels within the endoneurium.

History and Physical Examination in CIDP

Typical Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), a symmetrical sensorimotor polyneuropathy, accounts for 50% to 60% of all CIDP cases. The disease course is generally slow and progressive, although approximately one-third of patients may experience a relapsing-remitting pattern.

A thorough patient history is essential for evaluating potential CIDP. Key areas to explore include:

• Limb Weakness: Assess the distribution (proximal, distal, symmetric, asymmetric) and progression (acute, subacute, chronic) of weakness.
• Fluctuating Symptoms: Inquire about symptom variability over weeks to months, which can be suggestive of CIDP.
• Functional Impairment: Specifically ask about difficulties with daily activities such as climbing stairs, rising from a seated position, lifting objects overhead, and ambulation.
• Falls: Document the frequency and circumstances of falls, as these can be indicative of balance and motor deficits.
• Fine Motor Skills: Assess for impairments in fine motor tasks like buttoning clothes, manipulating small objects, or writing.
• Grip Strength: Inquire about difficulty opening doors or jars, which may reflect proximal arm weakness.
• Foot Drop: Ask about tripping or shuffling gait, which can be caused by foot drop.
• Sensory Symptoms: Elicit information about paresthesias (tingling, numbness) or burning sensations in the extremities.

The physical examination should be comprehensive, with a particular focus on the following:

• Musculoskeletal Assessment:
  • Muscle Weakness: Evaluate both proximal and distal muscle strength, noting if weakness is disproportionately greater than sensory loss.
  • Symptom Progression: Document the temporal course of symptoms, noting gradual progression over months. Approximately 15% may experience a more steady, non-relapsing progression.
  • Symmetry: Assess for equal involvement of proximal and distal muscles.
  • Tremor: Observe for the presence of tremor, which can occur in some CIDP variants.
  • Foot Drop: Specifically assess for and document foot drop.
  • Muscle Tone: Assess muscle tone, which may be normal or decreased, with potential signs of hypotonia, atrophy, and fasciculations in advanced cases.
• Reflexes: Crucially, assess tendon reflexes in all extremities. Absent or reduced reflexes (areflexia or hyporeflexia) are a key diagnostic feature of typical CIDP.

Serial physical examinations and meticulously documented longitudinal patient history, particularly before and after immunomodulatory treatment, are clinically invaluable in confirming a CIDP diagnosis and monitoring treatment response.

Atypical Chronic Inflammatory Demyelinating Polyradiculoneuropathy Variants:

Recognizing atypical variants is crucial for accurate CIDP diagnosis. These include:

• Distal Acquired Demyelinating Symmetric (DADS) Neuropathy Variant: Characterized by distal, length-dependent, symmetric sensory or sensorimotor neuropathy with significantly prolonged distal motor latencies. Often associated with an IgM paraprotein.
• Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM) Variant (Lewis-Sumner Syndrome): Presents with asymmetric, mixed sensorimotor clinical symptoms, affecting 6% to 15% of patients. Conduction block is a hallmark electrophysiological finding in this variant.
• Proximal Radiculopathy Variant (Brachial or Lumbosacral Plexopathy): Involves bilateral motor-sensory deficits following a root plexus distribution, predominantly affecting either the upper or lower extremities depending on the affected plexus.
• Pure Motor Variant: A relapsing-remitting focal or diffuse motor weakness, affecting 7% to 10% of patients, with minimal or no sensory involvement.
• Pure Sensory Variant: Predominantly lower extremity dysesthesias, with or without sensory ataxia, affecting 5% to 35% of patients.
• Chronic Immune Sensory Polyradiculopathy Variant: Clinically similar to the pure sensory variant, but with predominant sensory ataxia due to dorsal column nerve conduction disruption.
• Chronic Ataxic Neuropathy with Ophthalmoparesis, IgM paraprotein, Cold Agglutinin, and Disialosyl Ganglioside Antibodies (CANOMAD): A distinct, rarer variant characterized by ataxia and additional features listed in the name.

Diagnosis and Evaluation of CIDP

Diagnosing CIDP can be challenging due to its varied clinical presentations. Accurate identification is paramount, however, because CIDP is a treatable condition. Early diagnosis and treatment are critical to halting disease progression and preventing irreversible axonal damage. It’s important to note that overdiagnosis of CIDP is a significant concern, with some studies suggesting that nearly 50% of cases may be misdiagnosed.

Laboratory Evaluation in CIDP Diagnosis:

Currently, no single laboratory test can definitively confirm a CIDP diagnosis. Instead, laboratory investigations serve as crucial adjuncts to exclude alternative diagnoses that mimic CIDP or conditions that may be associated with it. For all patients suspected of having CIDP, the following laboratory tests are recommended:

• Glucose Metabolism Assessment: Fasting serum glucose or oral glucose tolerance test to rule out diabetes, a common cause of neuropathy.
• Glycated Hemoglobin (HbA1c): Provides a longer-term assessment of glucose control, further evaluating for diabetes.
• Serum Calcium: To assess for hypercalcemia, which can cause neurological symptoms.
• Serum Creatinine: To evaluate renal function, as renal impairment can be associated with certain neuropathies.
• Complete Blood Count (CBC): To assess general hematological status and rule out infection or other systemic conditions.
• Serum Aminotransferase Levels (ALT, AST): Liver function tests to screen for liver disease, which can sometimes be associated with neuropathy.
• Thyroid Function Studies (TSH, Free T4): To rule out hypothyroidism, another potential cause of neuropathy.
• Serum Protein Electrophoresis (SPEP) and Immunofixation: Essential to detect monoclonal gammopathies, which can be associated with CIDP-like neuropathies.
• Serum Free Light Chain (FLC) Assay: A more sensitive test for monoclonal gammopathies than SPEP in some cases.

SPEP and FLC assay are particularly important because neuropathies associated with monoclonal gammopathy of undetermined significance (MGUS) can clinically resemble typical CIDP. Furthermore, monoclonal gammopathies can be associated with neuropathies that mimic CIDP, such as anti-MAG IgM neuropathy; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes); multiple myeloma; or AL-amyloidosis.

Additional laboratory tests may be considered based on individual patient circumstances and clinical suspicion:

• Serology for Borrelia burgdorferi: Lyme disease serology to rule out Lyme neuropathy in endemic areas or when clinically indicated.
• C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR): Markers of inflammation, which may be elevated in inflammatory neuropathies.
• Antinuclear Antibodies (ANA): To screen for autoimmune connective tissue diseases like lupus.
• Angiotensin-Converting Enzyme (ACE): To assess for sarcoidosis, a systemic inflammatory disease that can affect nerves.
• Hepatitis B and C Serology: To rule out hepatitis-associated neuropathy.
• HIV Antibody Test: To screen for HIV-associated neuropathy.
• Chest Radiograph: May be indicated to evaluate for underlying malignancy or sarcoidosis.
• Genetic Testing for Inherited Neuropathies: Consideration for genetic testing to rule out hereditary neuropathies, especially if family history is suggestive or atypical features are present.
• Clinical Testing for Nodal and Paranodal Antibodies: Specialized antibody testing (e.g., anti-NF155, anti-CNTN1) may be considered in atypical CIDP variants or cases refractory to standard treatments.
• Anti-MAG Antibody Testing: Specifically test for anti-MAG antibodies in the presence of an IgM gammopathy, as this is associated with a distinct demyelinating neuropathy.

CIDP Diagnostic Criteria: EFNS/PNS Guidelines (2021)

Several sets of CIDP diagnosis criteria exist, reflecting the evolving understanding of this complex disorder. The European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) 2021 diagnostic criteria are widely accepted and demonstrate high diagnostic accuracy, with 83% sensitivity and 94% specificity.

The 2021 EFNS/PNS guidelines initiate the diagnostic process by classifying patients with suspected CIDP into “typical CIDP” or “CIDP variant” (atypical) categories based on their presenting symptoms and physical examination findings.

Typical Chronic Inflammatory Demyelinating Polyneuropathy: Required Criteria (EFNS/PNS 2021)

For a CIDP diagnosis of typical CIDP, the following clinical criteria must be met:

1. Progressive Weakness and Sensory Dysfunction: Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction affecting two or more limbs, developing over a period of two months or longer. Cranial nerves may also be affected.
2. Areflexia or Hyporeflexia: Absent or reduced tendon reflexes in all extremities.

Chronic Inflammatory Demyelinating Polyneuropathy Variants: Criteria (EFNS/PNS 2021)

To be classified as a CIDP variant, one of the following clinical presentations must be present. Tendon reflexes may be normal in unaffected limbs in variant forms:

1. Predominantly Distal Presentation (Distal CIDP): Symptoms primarily affecting distal limbs, as seen in distal acquired demyelinating symmetric neuropathy (DADS).
2. Asymmetric Presentation (Focal or Multifocal CIDP): Asymmetric symptoms, as observed in multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) or Lewis-Sumner syndrome.
3. Focal Presentation (Focal CIDP): Symptoms localized to a specific area, such as involvement of one or more peripheral nerves in a single upper or lower limb.
4. Pure Motor Presentation (Motor CIDP): Predominantly or exclusively motor symptoms without significant sensory involvement.
5. Pure Sensory Presentation (Sensory CIDP): Predominantly or exclusively sensory symptoms, such as dysesthesias or sensory ataxia.

Following clinical classification, electrodiagnostic studies are essential to further refine the CIDP diagnosis. Combining electrophysiological findings with clinical features yields varying levels of diagnostic certainty. Earlier guidelines used designations of “definite,” “probable,” and “possible” CIDP. However, the 2021 guidelines simplify this to “CIDP” and “possible CIDP.”

Electrophysiological Findings in CIDP Diagnosis

Nerve conduction studies (NCS) are a cornerstone of CIDP diagnosis. Clinicians typically perform NCS on the median, ulnar (below elbow), peroneal (below fibular head), and tibial nerves on at least one side of the body. These studies help differentiate between demyelinating and axonal neuropathic processes. It is crucial to remember that axonal damage can occur secondary to demyelination and does not necessarily exclude a CIDP diagnosis. If initial electrodiagnostic criteria for definite CIDP are not met, repeat studies at a later date may be considered, as demyelinating features may evolve over time.

Motor Nerve Conduction Criteria for CIDP Diagnosis (EFNS/PNS 2021)

To meet electrodiagnostic criteria for demyelination in motor nerves, at least one of the following parameters must be present in at least two nerves:

• Distal Latency Prolongation: At least a 50% prolongation of motor distal latency above the upper limit of normal (ULN) in two or more nerves.
• Conduction Velocity Reduction: At least a 30% reduction of motor conduction velocity below the lower limit of normal (LLN) in two or more nerves.
• F-wave Latency Prolongation or Absence:
  • At least a 20% prolongation of F-wave latency above the ULN in two or more nerves, or more than 50% if the distal compound muscle action potential (CMAP) amplitude is less than 80% of the LLN.
  • Absence of F waves in two or more nerves, if these nerves have distal CMAP amplitudes 20% or greater of the LLN, plus at least one other demyelinating parameter meeting definite criteria in one or more other nerves.
• Partial Motor Conduction Block: A greater than 30% amplitude reduction of the proximal negative peak CMAP relative to the distal negative peak CMAP, if the distal CMAP amplitude is 20% or greater of the LLN, in two or more nerves, or in one nerve plus one or more other demyelinating parameters meeting definite criteria in one or more other nerves.
• Abnormal Temporal Dispersion: A greater than 30% increase in duration between the proximal and distal negative peak CMAP in two or more nerves.

Sensory Nerve Conduction Criteria for CIDP Diagnosis (EFNS/PNS 2021)

Sensory nerve conduction abnormalities are supportive of a CIDP diagnosis, but specific criteria are less strictly defined than for motor nerves in the EFNS/PNS guidelines. Abnormalities may include reduced sensory nerve action potential (SNAP) amplitudes or slowed sensory conduction velocities.

Supporting Information for CIDP Diagnosis (EFNS/PNS 2021)

In addition to clinical and electrodiagnostic findings, supportive information can strengthen a CIDP diagnosis. This includes:

• Objective Response to Immunotherapy: A clear clinical improvement following treatment with IVIG, plasma exchange, or corticosteroids significantly supports the diagnosis of CIDP.
• Magnetic Resonance Imaging (MRI): While not routinely recommended for CIDP diagnosis, MRI of the nerve roots and plexus can be helpful in certain cases, particularly when “possible CIDP” is considered. Enlargement or increased signal intensity of nerve roots on T2-weighted MRI sequences can increase the likelihood of CIDP.
• Nerve Biopsy: Nerve biopsy is not routinely required for CIDP diagnosis. It may be considered in cases where clinical, laboratory, imaging, and electrodiagnostic studies are inconclusive, or to exclude other conditions like amyloidosis, vasculitis, or hereditary neuropathies.

Summary of Diagnostic Certainty Levels Based on EFNS/PNS 2021 Criteria

The EFNS/PNS guidelines use a tiered approach to diagnostic certainty, moving away from “definite,” “probable,” and “possible” and focusing on “CIDP” and “possible CIDP” categories.

• Typical Chronic Inflammatory Demyelinating Polyneuropathy (CIDP):

  • Meets clinical criteria for typical CIDP AND motor conduction criteria for demyelination in two or more nerves AND sensory conduction abnormalities in two or more nerves.

• Possible Typical Chronic Inflammatory Demyelinating Polyneuropathy:

  • Meets clinical criteria for typical CIDP AND motor conduction criteria for demyelination in one nerve AND sensory conduction abnormalities in two or more nerves.
  • Meets clinical criteria for typical CIDP AND motor conduction abnormalities that do not fully meet CIDP motor conduction criteria in one nerve AND sensory conduction abnormalities in two or more nerves AND objective response to treatment AND one or more other supportive criteria (MRI, nerve biopsy).

• Variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP):

  • Distal CIDP:
    • CIDP: Meets clinical criteria for distal CIDP AND motor conduction criteria for demyelination in two or more upper limb nerves AND sensory conduction abnormalities in two or more nerves.
    • Possible Distal CIDP: Meets clinical criteria for distal CIDP AND motor conduction criteria for demyelination in one upper limb nerve AND sensory conduction abnormalities in one nerve OR clinical criteria for distal CIDP AND motor conduction criteria for demyelination in two lower limb nerves only AND sensory conduction abnormalities in two nerves (cannot be upgraded to CIDP with supportive criteria).
  • Multifocal or Focal CIDP:
    • CIDP: Meets clinical criteria for multifocal or focal CIDP AND motor conduction criteria for demyelination in two nerves AND sensory conduction abnormalities in two nerves.
    • Possible Multifocal or Focal CIDP: Meets clinical criteria for multifocal or focal CIDP AND motor conduction criteria for demyelination in one nerve AND sensory conduction abnormalities in two nerves OR focal CIDP fulfilling clinical criteria with motor conduction criteria in one nerve AND sensory conduction abnormalities in one nerve (cannot be upgraded to CIDP with supportive criteria).
  • Motor CIDP:
    • CIDP: Meets clinical criteria for motor CIDP AND motor conduction criteria for demyelination in two nerves AND normal sensory conduction in four or more nerves.
    • Possible Motor CIDP: Meets clinical criteria for motor CIDP AND motor conduction criteria for demyelination in one nerve OR Possible motor CIDP with 2 or more supportive criteria.
  • Sensory-Predominant CIDP:
    • CIDP: Meets clinical criteria for sensory-predominant CIDP AND sensory conduction abnormalities in two nerves AND motor conduction criteria fulfillment in two nerves.
    • Possible Sensory-Predominant CIDP: Meets clinical criteria for sensory-predominant CIDP AND conduction abnormalities in two nerves OR motor conduction criteria fulfillment in one nerve.

Exclusion Criteria for CIDP Diagnosis

Certain conditions must be excluded to confirm a CIDP diagnosis. Exclusion criteria include:

• Identifiable Causes of Neuropathy: Neuropathy clearly attributable to Borrelia burgdorferi infection (Lyme disease), diphtheria, or exposure to drugs or toxins known to cause demyelinating neuropathy.
• Hereditary Demyelinating Neuropathy: Evidence of hereditary demyelinating neuropathy, such as Charcot-Marie-Tooth disease type 1 (CMT1).
• Anti-MAG IgM Neuropathy: IgM monoclonal gammopathy with high titers of anti-MAG antibodies, as this represents a distinct clinical entity.

Treatment and Management of CIDP

First-line treatment options for CIDP include corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (plasmapheresis). Due to the potential for long-term adverse effects with corticosteroids, IVIG and plasma exchange are often favored as primary therapies, especially for chronic management. IVIG is generally easier to administer than plasma exchange. Both plasma exchange and IVIG may induce a more rapid therapeutic response compared to glucocorticoids.

Corticosteroids can be particularly beneficial for patients with a more gradual onset of CIDP, where a rapid response may be less critical. Corticosteroids may also be more likely to induce remission in some patients. They are also useful for patients who experience relapses despite ongoing IVIG or other maintenance therapies. Steroid-sparing immunosuppressive agents, such as azathioprine, cyclosporine, tacrolimus, and mycophenolate mofetil, may be considered for long-term maintenance therapy to minimize corticosteroid exposure and side effects. Treatment is typically continued until symptom resolution or stabilization. Encouragingly, nearly 40% of patients with CIDP may achieve remission or even a cure.

Corticosteroids for CIDP

• Studies have shown no significant difference in efficacy between high-dose monthly dexamethasone and daily oral prednisone for CIDP treatment.
• Corticosteroids are generally less expensive and easier to administer compared to IVIG or plasma exchange.

Intravenous Immunoglobulin (IVIG) for CIDP

• The relapse rate following initial treatment with IVIG is approximately 45%, which is comparable to the relapse rate associated with corticosteroids (around 50%).
• Chronic administration of IVIG and corticosteroids has been shown to slow the median time to clinical deterioration in CIDP.
• Dosing Regimen: IVIG is typically administered as an initial induction dose of 2 g/kg of body weight, given over 2 to 5 days, or alternatively as 0.4 g/kg/day over 5 consecutive days. This is followed by a maintenance dose of 1 g/kg every 3 to 4 weeks for a period of 2 to 3 months to assess treatment efficacy.
  • Treatment efficacy is monitored by documenting disability scales and quantitative grip strength measurements at each follow-up appointment. Commonly used disability scales include the Inflammatory Rasch-Built Overall Disability Scale (I-RODS) and the Inflammatory Neuropathy Cause and Treatment Disability Scale (INCAT).
• Immunomodulatory Mechanisms of IVIG: IVIG exerts its therapeutic effects in CIDP through several complex immunomodulatory mechanisms, including:
  • Inhibition of innate immune cell activation.
  • Neutralization of pathogenic autoantibodies.
  • Inhibition and abrogation of activated complement.
  • Induction of autophagy in peripheral blood mononuclear cells.
  • Modulation of fragment crystallizable receptors (FcR).
  • Reduction of T helper 17 (Th17) cell proliferation and interleukin 17 (IL-17) secretion (pro-inflammatory cytokines).
  • Decrease in pro-inflammatory cytokine production overall.
  • Increase in regulatory T-cell (Treg) expansion, promoting immune tolerance.
• Adverse Effects of IVIG: Potential side effects of IVIG therapy include infusion reactions (fever, chills, hypotension), thrombotic events (increased risk of blood clots), and aseptic meningitis.

Plasma Exchange (Plasmapheresis) for CIDP

Plasma exchange, while effective in CIDP, is often limited by its availability, the need for repeated venous access or indwelling catheters, and logistical complexity. Plasma exchange is often reserved for severe cases of CIDP or for patients who have not responded adequately to corticosteroids and IVIG. A typical course of plasma exchange involves 5 to 10 sessions administered over 2 to 4 weeks. Plasma exchange may provide a faster initial clinical response compared to IVIG or corticosteroids. However, the relapse rate after plasma exchange can be high, reported at approximately 67%. Potential adverse effects include hypotension, catheter-related complications (infection, thrombosis), hypocalcemia, allergic reactions to albumin infusions (used as replacement fluid), and citrate toxicity (due to the anticoagulant used during the procedure).

Steroid-Sparing Agents for Maintenance Therapy in CIDP

Currently, there are no definitive clinical guidelines specifying the optimal duration of maintenance therapy for CIDP. A typical duration of maintenance therapy is around 6 months, but this can vary depending on individual patient needs and disease course. For patients requiring prolonged therapy and who are at increased risk of developing serious adverse effects from long-term corticosteroids or IVIG, steroid-sparing immunosuppressive agents can be valuable. These agents include methotrexate, cyclosporine, cyclophosphamide, rituximab, and mycophenolate mofetil. However, the evidence supporting the use of these agents in CIDP is primarily derived from smaller case studies or anecdotal reports, with limited large-scale randomized controlled trials.

Mycophenolate mofetil, either alone or in combination with prednisone, is used to treat various autoimmune conditions, including CIDP. Similar to azathioprine, it can cause bone marrow suppression and is contraindicated in pregnant women.

Approximately 25% of patients with CIDP are refractory (non-responsive) to first-line treatments (corticosteroids, IVIG, plasma exchange). In these cases, further investigations are warranted to re-evaluate the CIDP diagnosis, consider atypical CIDP variants, or explore other causes of acquired demyelinating chronic neuropathies. Targeted therapies, such as rituximab and alemtuzumab, may be considered as alternative treatment options for refractory CIDP.

Rehabilitation plays a crucial role in the comprehensive management of CIDP. Occupational therapy, physical therapy, and physiatry interventions are essential to optimize functional status and improve quality of life for individuals with CIDP. These multidisciplinary approaches aim to enhance mobility, strength, coordination, and independence in daily activities.

Differential Diagnosis of CIDP

The differential diagnosis for CIDP is broad and includes various neurological conditions that can mimic its clinical presentation. Key differential diagnoses include:

• Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) – Guillain-Barré Syndrome (GBS)
• Multifocal Motor Neuropathy (MMN)
• Distal Acquired Demyelinating Symmetric (DADS) neuropathy with monoclonal IgM gammopathy and anti-MAG antibodies
• Chronic Ataxic Neuropathy with Ophthalmoplegia, IgM paraprotein, Cold Agglutinins, and Disialosyl antibodies (CANOMAD)
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes), or osteosclerotic myeloma
• Demyelinating neuropathy induced by tumor necrosis factor-alpha (TNF-α) blockers and checkpoint inhibitors (immunotherapy-related neuropathy)
• Infectious neuropathies due to Lyme disease, diphtheria, hepatitis B or C, or HIV
• Charcot-Marie-Tooth (CMT) disease, particularly CMT type 1
• Hereditary neuropathy with liability to pressure palsies (HNPP)
• Transthyretin (TTR) familial amyloid polyneuropathy
• Pyridoxine (Vitamin B6) toxicity (abuse)
• Toxic and metabolic neuropathies
  • Diabetic lumbosacral radiculopathy-plexopathy
  • Non-diabetic lumbosacral radiculopathy-plexopathy
  • Chemotherapy-induced demyelinating neuropathy
• Peripheral Nervous System (PNS) lymphoma
• Systemic amyloidosis

Prognosis of CIDP

The prognosis for CIDP is variable. Approximately two-thirds of patients with CIDP exhibit an initial favorable response to at least one standard therapy, including IVIG, glucocorticoids, or plasma exchange. However, a subset of patients (around 10% to 15%) may show resistance to all these first-line treatments. Despite treatment, nearly 40% of patients with CIDP may achieve a state of cure or remission, although some may experience persistent residual deficits that do not respond further to immunotherapies.

Recent studies indicate that a significant proportion of patients (e.g., 54% in one study from South England) experience severe disability at some point during their CIDP disease course. Over time, the risk of relapse increases. Once patients are clinically stable and no longer worsening, clinicians may consider tapering immunosuppressive therapy cautiously. A study by Dyck et al. involving 40 patients demonstrated that 72% required ongoing immunosuppressive treatment, while 27% achieved remission off treatment.

Complications of CIDP

Misdiagnosis of CIDP remains a significant concern, with some studies suggesting that approximately 54% of known cases are initially misdiagnosed. These patients may undergo prolonged immunosuppressive therapy without clinical benefit and with exposure to potential side effects. Even with available immunosuppressive therapies, most patients with CIDP experience some degree of persistent disability. Furthermore, patients may develop treatment-related complications, including hypertension, thromboembolic events, increased susceptibility to infections, bone marrow suppression, nephrotoxicity, and an increased risk of malignancies, such as lymphoma.

Additional disease-related complications of CIDP can include aspiration pneumonia, atelectasis, and respiratory failure due to swallowing difficulties and respiratory muscle weakness. Autonomic nervous system involvement can lead to gastrointestinal motility abnormalities, bladder dysfunction, orthostatic hypotension, and cardiac conduction defects.

Deterrence and Patient Education for CIDP

CIDP is a chronic neurological disorder causing progressive weakness and sensory loss in the arms and legs. Patient education is crucial. Patients should be informed about the relapsing-remitting or progressive nature of the disease and the importance of early diagnosis and treatment to prevent disability. Misdiagnosis of CIDP is common and can lead to unnecessary medical costs and exposure to potentially toxic therapies. Referral to a neuromuscular specialist center is essential to confirm the CIDP diagnosis and ensure appropriate management.

Patients and caregivers need to understand the variability of CIDP symptoms and the potential need for long-term management with a neurology and neuromuscular specialist. While various medication options are available, each carries its own risks and benefits. Despite the chronic nature of CIDP, potential medication side effects, and associated healthcare costs, patients should be reassured that many individuals experience significant improvement with therapy, and a substantial proportion (up to 40%) achieve remission.

Pearls and Other Key Issues in CIDP

Key points to remember regarding CIDP:

• CIDP is an immune-mediated disorder affecting the myelin sheath of peripheral nerves.
• It can have a monophasic, progressive, or relapsing-remitting course and develops over more than 8 weeks, distinguishing it from acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and Guillain-Barré syndrome (GBS) variants.
• Typical CIDP symptoms are symmetrical and affect both proximal and distal muscles, with sensorimotor involvement. Electrophysiological studies show a demyelinating pattern, including distal latency prolongation, conduction velocity reduction or block, prolonged or absent F-waves, temporal dispersion, and increased CMAP duration.
• Atypical CIDP variants include DADS neuropathy, chronic immune sensory polyradiculopathy, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), focal or diffuse brachial or lumbosacral plexopathy, pure motor CIDP, and pure sensory CIDP.
• The pathophysiology involves a chronic immune response targeting myelin components, with coordinated activation of innate macrophages and adaptive immune mechanisms, including humoral and cell-mediated immunity.
• Typical CIDP symptoms include symmetric large-fiber and small-fiber paresthesias, paraparesis, diffuse muscle fatigue, and areflexia.
• Atypical symptoms can include asymmetric allodynia, painful cervical or lumbar radiculomyelopathies, multiple cranial nerve neuropathies, bulbar and autonomic symptoms, tremor, and spasticity.
• Uncontrolled diabetes mellitus may be a risk factor for developing CIDP.
• The differential diagnosis is broad and includes toxic, metabolic, systemic, infectious, iatrogenic, hereditary, and neoplastic neuropathies, as well as multifocal motor neuropathy.
• Supportive ancillary tests can include CSF analysis (showing albuminocytologic dissociation), gadolinium-enhancing hypertrophy of nerve roots on MRI, delayed somatosensory evoked potentials, or nerve biopsy demonstrating demyelination and remyelination.
• Treatment includes acute and chronic immunomodulatory therapies such as IVIG, plasma exchange, prednisone, mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, and, in refractory cases, rituximab.
• Complications of therapy can include infusion reactions, headaches, infections, renal failure, and hypercoagulability.
• Prognosis is variable and depends on factors such as age, clinical course, responsiveness to treatment, and electrophysiological findings.
• Aggressive rehabilitation is crucial for long-term functional recovery in patients with CIDP.

Enhancing Healthcare Team Outcomes in CIDP Management

The diagnosis and management of CIDP are complex and require a collaborative interprofessional healthcare team. This team should include neurology, primary care physicians, physical medicine and rehabilitation specialists, pain management specialists, physical therapists, occupational therapists, psychiatrists, social workers, neuromuscular specialists, and case management staff. Effective interprofessional communication is essential for optimal patient care.

Healthcare professionals must possess a comprehensive understanding of CIDP, including its variable presentations and the nuances of CIDP diagnosis criteria, particularly for variant forms. A strategic approach to evidence-based guidelines and individualized treatment plans is crucial. Ethical considerations must guide decision-making, ensuring respect for patient autonomy in treatment choices.

Aggressive immunomodulatory therapy combined with physical neurorehabilitation is essential for achieving long-term favorable outcomes. Barriers to clinical improvement can include social determinants of health, inadequate pain control, and aggressive clinical variants of CIDP. Each team member’s expertise and seamless interprofessional communication are vital for collaborative decision-making and holistic patient-centered care.

Care coordination is paramount to ensure efficient and seamless patient care throughout the CIDP journey, from initial diagnosis to treatment and ongoing follow-up. Effective coordination minimizes medical errors, reduces delays in care, and enhances patient safety, ultimately leading to improved outcomes and patient satisfaction for individuals affected by CIDP.

Review Questions

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References

1.Kuwabara S, Misawa S. Chronic Inflammatory Demyelinating Polyneuropathy. Adv Exp Med Biol. 2019;1190:333-343. [PubMed: 31760654]

2.Lehmann HC, Burke D, Kuwabara S. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2019 Sep;90(9):981-987. [PubMed: 30992333]

3.Reynolds J, Sachs G, Stavros K. Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): Clinical Features, Diagnosis, and Current Treatment Strategies. R I Med J (2013). 2016 Dec 01;99(12):32-35. [PubMed: 27902997]

4.Burns TM. Chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol. 2004 Jun;61(6):973-5. [PubMed: 15210544]

5.Hagen KM, Ousman SS. The immune response and aging in chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroinflammation. 2021 Mar 22;18(1):78. [PMC free article: PMC7983397] [PubMed: 33752693]

6.Doneddu PE, Dentoni M, Nobile-Orazio E. Atypical chronic inflammatory demyelinating polyradiculoneuropathy: recent advances on classification, diagnosis, and pathogenesis. Curr Opin Neurol. 2021 Oct 01;34(5):613-624. [PMC free article: PMC9914159] [PubMed: 34267052]

7.Kieseier BC, Mathey EK, Sommer C, Hartung HP. Immune-mediated neuropathies. Nat Rev Dis Primers. 2018 Oct 11;4(1):31. [PubMed: 30310069]

8.Ogata H, Yamasaki R, Hiwatashi A, Oka N, Kawamura N, Matsuse D, Kuwahara M, Suzuki H, Kusunoki S, Fujimoto Y, Ikezoe K, Kishida H, Tanaka F, Matsushita T, Murai H, Kira J. Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann Clin Transl Neurol. 2015 Oct;2(10):960-71. [PMC free article: PMC4603379] [PubMed: 26478896]

9.Mathey EK, Garg N, Park SB, Nguyen T, Baker S, Yuki N, Yiannikas C, Lin CS, Spies JM, Ghaoui R, Barnett MH, Vucic S, Pollard JD, Kiernan MC. Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies. J Neuroimmunol. 2017 Aug 15;309:41-46. [PubMed: 28601286]

10.Doppler K, Appeltshauser L, Wilhelmi K, Villmann C, Dib-Hajj SD, Waxman SG, Mäurer M, Weishaupt A, Sommer C. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry. 2015 Jul;86(7):720-8. [PubMed: 25694474]

11.Vallat JM, Sommer C, Magy L. Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol. 2010 Apr;9(4):402-12. [PubMed: 20298964]

12.Rodríguez Y, Vatti N, Ramírez-Santana C, Chang C, Mancera-Páez O, Gershwin ME, Anaya JM. Chronic inflammatory demyelinating polyneuropathy as an autoimmune disease. J Autoimmun. 2019 Aug;102:8-37. [PubMed: 31072742]

13.Kiefer R, Kieseier BC, Stoll G, Hartung HP. The role of macrophages in immune-mediated damage to the peripheral nervous system. Prog Neurobiol. 2001 Jun;64(2):109-27. [PubMed: 11240209]

14.Dimachkie MM, Barohn RJ. Chronic inflammatory demyelinating polyneuropathy. Curr Treat Options Neurol. 2013 Jun;15(3):350-66. [PMC free article: PMC3987657] [PubMed: 23564314]

15.Latov N. Diagnosis and treatment of chronic acquired demyelinating polyneuropathies. Nat Rev Neurol. 2014 Aug;10(8):435-46. [PubMed: 24980070]

16.McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain. 1987 Dec;110 ( Pt 6):1617-30. [PubMed: 3427403]

17.Jha S, Ansari M, Sonkar K, Paliwal V. Unusual features in chronic inflammatory demyelinating polyneuropathy: Good outcome after prolonged ventilatory support. J Neurosci Rural Pract. 2011 Jul;2(2):171-3. [PMC free article: PMC3159356] [PubMed: 21897683]

18.Kuwabara S, Misawa S, Mori M. Atypical chronic inflammatory demyelinating polyneuropathies. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):121. [PubMed: 30297522]

19.Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology. 2015 Aug 11;85(6):498-504. [PubMed: 26180143]

20.Van den Bergh PYK, van Doorn PA, Hadden RDM, Avau B, Vankrunkelsven P, Allen JA, Attarian S, Blomkwist-Markens PH, Cornblath DR, Eftimov F, Goedee HS, Harbo T, Kuwabara S, Lewis RA, Lunn MP, Nobile-Orazio E, Querol L, Rajabally YA, Sommer C, Topaloglu HA. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. [PubMed: 34085743]

21.Goedee HS, van der Pol WL, van Asseldonk JH, Franssen H, Notermans NC, Vrancken AJ, van Es MA, Nikolakopoulos S, Visser LH, van den Berg LH. Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies. Neurology. 2017 Jan 10;88(2):143-151. [PubMed: 27927940]

22.Di Pasquale A, Morino S, Loreti S, Bucci E, Vanacore N, Antonini G. Peripheral nerve ultrasound changes in CIDP and correlations with nerve conduction velocity. Neurology. 2015 Feb 24;84(8):803-9. [PubMed: 25632087]

23.Katzberg HD, Latov N, Walker FO. Measuring disease activity and clinical response during maintenance therapy in CIDP: from ICE trial outcome measures to future clinical biomarkers. Neurodegener Dis Manag. 2017 Apr;7(2):147-156. [PubMed: 28112008]

24.Hiwatashi A, Togao O, Yamashita K, Kikuchi K, Momosaka D, Nakatake H, Yamasaki R, Ogata H, Yoneyama M, Kira JI, Honda H. Simultaneous MR neurography and apparent T2 mapping in brachial plexus: Evaluation of patients with chronic inflammatory demyelinating polyradiculoneuropathy. Magn Reson Imaging. 2019 Jan;55:112-117. [PubMed: 30266626]

25.Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ. Distal acquired demyelinating symmetric neuropathy. Neurology. 2000 Feb 08;54(3):615-20. [PubMed: 10680792]

26.Rajabally YA, Chavada G. Lewis-sumner syndrome of pure upper-limb onset: diagnostic, prognostic, and therapeutic features. Muscle Nerve. 2009 Feb;39(2):206-20. [PubMed: 19145651]

27.Kimura A, Sakurai T, Koumura A, Yamada M, Hayashi Y, Tanaka Y, Hozumi I, Yoshino H, Yuasa T, Inuzuka T. Motor-dominant chronic inflammatory demyelinating polyneuropathy. J Neurol. 2010 Apr;257(4):621-9. [PubMed: 20361294]

28.Rajabally YA, Wong SL. Chronic inflammatory pure sensory polyradiculoneuropathy: a rare CIDP variant with unusual electrophysiology. J Clin Neuromuscul Dis. 2012 Mar;13(3):149-52. [PubMed: 22538310]

29.Oh SJ, Joy JL, Kuruoglu R. “Chronic sensory demyelinating neuropathy”: chronic inflammatory demyelinating polyneuropathy presenting as a pure sensory neuropathy. J Neurol Neurosurg Psychiatry. 1992 Aug;55(8):677-80. [PMC free article: PMC489203] [PubMed: 1326601]

30.Dyck PJ, Litchy WJ, Kratz KM, Suarez GA, Low PA, Pineda AA, Windebank AJ, Karnes JL, O’Brien PC. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 1994 Dec;36(6):838-45. [PubMed: 7998769]

31.Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev. 2017 Jan 13;1(1):CD010369. [PMC free article: PMC5468847] [PubMed: 28084646]

32.van Lieverloo GGA, Peric S, Doneddu PE, Gallia F, Nikolic A, Wieske L, Verhamme C, van Schaik IN, Nobile-Orazio E, Basta I, Eftimov F. Corticosteroids in chronic inflammatory demyelinating polyneuropathy : A retrospective, multicentre study, comparing efficacy and safety of daily prednisolone, pulsed dexamethasone, and pulsed intravenous methylprednisolone. J Neurol. 2018 Sep;265(9):2052-2059. [PMC free article: PMC6132640] [PubMed: 29968199]

33.Yasir M, Goyal A, Sonthalia S. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 3, 2023. Corticosteroid Adverse Effects. [PubMed: 30285357]

34.Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, Merkies IS, van Doorn PA., ICE Study Group. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008 Feb;7(2):136-44. [PubMed: 18178525]

35.Eftimov F, Vermeulen M, van Doorn PA, Brusse E, van Schaik IN., PREDICT. Long-term remission of CIDP after pulsed dexamethasone or short-term prednisolone treatment. Neurology. 2012 Apr 03;78(14):1079-84. [PubMed: 22442436]

36.Lunn MP, Ellis L, Hadden RD, Rajabally YA, Winer JB, Reilly MM. A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. J Peripher Nerv Syst. 2016 Mar;21(1):33-7. [PubMed: 26757367]

37.Lehmann HC, Hartung HP. Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies. J Neuroimmunol. 2011 Feb;231(1-2):61-9. [PubMed: 21056913]

38.Markvardsen LH, Harbo T. Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs. J Neurol Sci. 2017 Jul 15;378:19-25. [PubMed: 28566163]

39.van Schaik IN, Bril V, van Geloven N, Hartung HP, Lewis RA, Sobue G, Lawo JP, Praus M, Mielke O, Durn BL, Cornblath DR, Merkies ISJ., PATH study group. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018 Jan;17(1):35-46. [PubMed: 29122523]

40.Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol. 2018;9:1299. [PMC free article: PMC6008653] [PubMed: 29951056]

41.Mehndiratta MM, Hughes RA, Pritchard J. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2015 Aug 25;2015(8):CD003906. [PMC free article: PMC6734114] [PubMed: 26305459]

42.Mehndiratta MM, Hughes RA. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD003906. [PubMed: 22972066]

43.RMC Trial Group. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol. 2009 Feb;8(2):158-64. [PubMed: 19136303]

44.Hadden RD, Sharrack B, Bensa S, Soudain SE, Hughes RA. Randomized trial of interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 1999 Jul 13;53(1):57-61. [PubMed: 10408537]

45.Kuntzer T, Radziwill AJ, Lettry-Trouillat R, Naegeli C, Ochsner F, Erne B, Steck AJ, Bogousslavsky J. Interferon-beta1a in chronic inflammatory demyelinating polyneuropathy. Neurology. 1999 Oct 12;53(6):1364-5. [PubMed: 10522905]

46.Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther Adv Neurol Disord. 2012 Nov;5(6):359-73. [PMC free article: PMC3487533] [PubMed: 23139706]

47.Mauermann ML, Sorenson EJ, Dispenzieri A, Mandrekar J, Suarez GA, Dyck PJ, Dyck PJ. Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry. 2012 May;83(5):480-6. [PubMed: 22396441]

48.Lozeron P, Mariani LL, Dodet P, Beaudonnet G, Théaudin M, Adam C, Arnulf B, Adams D. Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy. Neurology. 2018 Jul 10;91(2):e143-e152. [PubMed: 29907605]

49.Dalakas MC. Chronic idiopathic ataxic neuropathy. Ann Neurol. 1986 Jun;19(6):545-54. [PubMed: 3014995]

50.Mygland A, Monstad P, Vedeler C. Onset and course of chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2005 May;31(5):589-93. [PubMed: 15742374]

51.Dyck PJB, Tracy JA. History, Diagnosis, and Management of Chronic Inflammatory Demyelinating Polyradiculoneuropathy. Mayo Clin Proc. 2018 Jun;93(6):777-793. [PubMed: 29866282]

52.Dyck PJ, Taylor BV, Davies JL, Mauermann ML, Litchy WJ, Klein CJ, Dyck PJ. Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. Muscle Nerve. 2015 Oct;52(4):488-97. [PMC free article: PMC4621010] [PubMed: 25976871]

53.Min DI, Monaco AP. Complications associated with immunosuppressive therapy and their management. Pharmacotherapy. 1991;11(5):119S-125S. [PubMed: 1745617]

Disclosures:
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