Continuing Education Activity

Chronic inflammatory demyelinating polyradiculoneuropathy is an immune-mediated polyneuropathy marked by nerve roots and peripheral nerve inflammation, characterized by segmental demyelination and remyelination. Typical chronic inflammatory demyelinating polyradiculoneuropathy presents with symmetric, motor-predominant weakness and sensory impairment, notably affecting vibration and position sense more than pain and temperature sense, often accompanied by areflexia. While idiopathic cases are common, various diseases may trigger chronic inflammatory demyelinating polyradiculoneuropathy. Diagnosis challenges can lead to misdiagnosis or overdiagnosis, emphasizing the need for prompt identification and treatment to prevent mortality and prolonged morbidity. Treatment options are available and can improve the outcome of this condition.

This continuing education activity discusses chronic inflammatory demyelinating polyradiculoneuropathy's pathophysiology, clinical presentation, evaluation, diagnosis, and treatment. The activity underscores the vital role of the interprofessional team in comprehensive patient care, aiming to enrich healthcare professionals' understanding. Staying updated on advancements and best practices enables professionals to optimize outcomes and enhance the quality of life for individuals grappling with this complex neurological disorder.

Objectives:

• Apply current diagnostic criteria to distinguish between chronic inflammatory demyelinating polyradiculoneuropathy and related neurological disorders.

• Determine the appropriate use of electrodiagnostic studies in confirming the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy and assessing peripheral nerve demyelination.

• Develop strategies for long-term management of chronic inflammatory demyelinating polyradiculoneuropathy, considering maintenance therapies and their potential risks and benefits.

• Coordinate among interprofessional team members to facilitate positive outcomes for patients diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy.

Introduction

First described in 1890, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder affecting the peripheral nervous system and nerve roots.[1][2] Characterized by symmetric weakness in both proximal and distal muscles, CIDP is a subset of chronic acquired demyelinating polyneuropathies (CADP). 

CIDP can manifest in various clinical forms, with "typical" or "classical" presentations involving a progressive motor-predominant peripheral neuropathy and sensory impairment, particularly affecting position and vibration sense more than pain and temperature. Notably, CIDP is closely linked to acute inflammatory demyelinating polyradiculoneuropathy (AIDP), the demyelinating variant of Guillain-Barré syndrome (GBS).

Distinguishing between these 2 diseases is aided by assessing the progression timeline and the presence of relapses. Proper diagnosis is crucial for initiating appropriate treatment and managing the condition effectively.

CIDP may have atypical variants with different immunopathogeneses and treatment responses. The condition can be monophasic, relapsing, or progressive, and symptoms must persist for at least 8 weeks to establish the diagnosis.[3][4] Progressive or relapsing symptoms over this duration, electrodiagnostic studies revealing pathologic evidence of peripheral nerve demyelination, and the responsiveness to immunomodulatory treatments helps establish the diagnosis of CIDP.[4]

Etiology

Most cases of CIDP are idiopathic, although preceding infections are reported in some instances, with respiratory and gastrointestinal infections noted. However, researchers have not yet identified a causative organism. CIDP is also associated with various illnesses such as systemic lupus erythematosus, HIV, and hepatitis B or C. Multiple factors are believed to trigger T-cell-mediated and humoral immune mechanisms that target myelin in the peripheral nervous system.[2] Evidence exists of activated T-cells crossing the blood-nerve barrier and inducing the expression of cytokines, tumor necrosis factor, interferons, and interleukins. Immunoglobulin (Ig) and complement deposition on myelinated nerve fibers provide evidence of humoral immunity involvement.

About 50% of cases follow a typical or classical course as described above, with progressive, symmetric sensory deficits and motor weakness (with symptoms progressive over at least 8 weeks). Atypical variants include the following: seropositive (positive for antibodies), sensory predominant, motor predominant, Lewis-Sumner syndrome (ie, multifocal acquired demyelinating sensory and motor polyneuropathy, MADSAM), and distal acquired demyelinating symmetric (DADS) neuropathy.[5][6]

Approximately 10% of patients with CIDP exhibit autoantibodies against nodal and paranodal proteins. The autoantibodies are primarily of the IgG4 subclass that do not activate complement. The target proteins most likely affected are neurofascin (NF) isoforms and contactin-1 (CNTN1) located at or near the node of Ranvier. The specific proteins targeted in patients with CIDP include the following:

• Neurofascin-155 (NF155), a paranodal protein expressed by glial cells
• Neurofascin-140 (NF140) and Neurofascin-186 (NF186), neuronal proteins present at nodes and axon initial segments
• Contactin-associated protein 1 (CASPR1) and CNTN1 [7]

NF155, present in 4% to 18% of patients diagnosed with CIDP, is expressed on Schwann cells in the paranodal region, while NF186, found in less than 2% of patients, is expressed on the nodal region of the axon.[8] Antibodies against CNTN1 are present in 2.2% to 8.7% of patients.[9][10] Individuals with anti-CNTN1 antibodies typically present with predominant motor neuropathy and axonal damage. 

Pathogenesis in patients with autoantibodies to nodal proteins is considered distinct from classic CIDP, and ongoing research further delineates their classification. Additionally, these variants differ from typical CIDP in that they generally exhibit a poor response to initial treatment with corticosteroids and intravenous immunoglobulins (IVIG).[7] Studies reveal conflicting information regarding human leukocyte antigen (HLA) types. Some studies report that HLA Dw3, DRw3, A1, and B8 are more likely present in patients with CIDP than in healthy cohorts, while others report no actual genetic link. 

Epidemiology

CIDP affects males more than females, with a ratio of 2:1. According to a recent meta-analysis, the crude incidence rate is 0.3 per 100,000 patients. The overall prevalence varies from 0.8 to 8.9 per 100,000 people, with an increased incidence associated with advancing age. While the mean age reported in studies is 60, the condition can also occur in children. The diverse clinical presentations and global variations in diagnostic criteria contribute to the variability in incidence and prevalence rates.[7][11] Juveniles are more likely to present with relapsing and motor-dominant CIDP.[5] 

Pathophysiology

The presumed mechanism involves an immunologic antibody-mediated reaction and infiltration of the endoneurium by T-cells and macrophages, resulting in segmental demyelination and remyelination of peripheral nerves.[12] Activated T-cells and macrophages act as antigen-presenting cells, promoting demyelination.[13] T-helper (Th)17 cells are especially found in high numbers in peripheral blood and the CSF. Nerve involvement is patchy, with demyelination occurring paranodal near the nodes of Ranvier. Schwann cell impairment in regenerating myelin sheaths is part of the CIDP pathology. A decline in regulatory and naive T cells may also be part of the pathology, which is also associated with increased age.[5] Increased natural killer cell activity has also been described.

Although CIDP is primarily demyelinating, axonal degeneration is commonly present, likely a secondary effect of the inflammatory demyelinating process. Affected nerves become enlarged due to overlapping Schwann cells covering bare axons.

Histopathology

Microscopic examination reveals interstitial edema and inflammatory cell infiltrates, including lymphocytes and macrophages. Demyelination and remyelination are the hallmark characteristics of CIDP and are visualized on teased fibers analysis in 48% to 68% of patients, while 21% exhibit mixed demyelination and axonal changes.[14] The recurrent demyelination and remyelination result in "onion bulbs’' or concentrically oriented Schwann cells surrounding thinly myelinated fibers noted on the transverse section.[15] 

Nerve biopsies reveal inflammatory T-cells and macrophages along with local edema and fibrosis.[7][13] Ultrastructural studies exhibit macrophages extending their processes between myelin, leading to the degradation of its components. In CIDP variants, such as distal acquired demyelinating symmetric polyneuropathy (DADS) with anti-myelin-associated glycoprotein (anti-MAG) antibodies, demyelination is noted along large myelinated axons with separation of the myelin lamellae and depositions of IgM and C3d on myelin sheaths.[15] Some histologic studies also show increased macrophage clusters around blood vessels of the endoneurium.[5] 

History and Physical

Typical CIDP is a symmetric sensorimotor polyneuropathy encompassing 50% to 60% of all cases. The disease is generally slowly progressive, although approximately one-third of patients may experience a relapsing-remitting course.[16]

Obtaining a thorough patient history is essential in evaluating for CIDP. This includes inquiring about the following:

• Limb weakness
• Fluctuating symptoms over weeks to months
• Challenges with tasks such as climbing or descending stairs, rising from a seated position or lifting objects overhead
• Ambulating difficulties
• Frequent falls
• Fine motor skill impairments, like buttoning clothes
• Difficulty opening doors or jars
• Tripping or shuffling feet due to foot drop
• Paresthesias or burning in extremities 

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

• Musculoskeletal
  • Proximal and distal muscle weakness exceeding the extent of sensory loss
  • Symptoms gradually progress over months
    • Approximately 15% experience a more steady progression
  • Equal involvement of proximal and distal muscles
  • Presence of tremor
  • Foot drop
  • Muscle tone may be normal or decreased, with signs of hypotonia, atrophy, and fasciculations

• Neurological
  • Cranial nerve or bulbar involvement was observed in 10% to 20% of cases
    • Diplopia, facial muscle paralysis, oropharyngeal involvement
  • Absent or diminished reflexes
  • Predominance of large-fiber neuropathy versus small-fiber neuropathies
  • Sensory involvement affects position and vibration more than pain and temperature
    • Typically worse distally
  • Ataxia
  • Cervical and lumbar radiculopathy
  • Minimal autonomic involvement, especially in early disease
    • Dysarthria, dysphagia, dyspnea, dysrhythmias, hypotension or hypertension, anhidrosis or hyperhidrosis, urinary retention, impotence, and constipation are possible
  • Allodynia
  • Sensory deficits following a stocking-glove distribution
  • Positive Romberg sign due to damage to large nerve fibers that convey proprioception 
  • Bilateral phrenic nerve palsy [17]

A meticulous longitudinal patient history recorded over time and serial physical examinations conducted before and after immunomodulatory treatment can be clinically valuable in confirming the diagnosis of CIDP.

Atypical Chronic Inflammatory Demyelinating Polyradiculoneuropathy Variants [2][18]

• Distal acquired demyelinating symmetric (DADS) neuropathy variant: Distal length-dependent symmetric sensory or sensorimotor neuropathy with markedly prolonged distal motor latencies, often associated with an IgM paraprotein.

• Multifocal acquired demyelinating sensory and motor neuropathy variant: Asymmetric, mixed sensorimotor clinical symptoms. Affects 6% to 15% of patients. Conduction block is most typical for this type of CIDP.

• Proximal radiculopathy variant (brachial or lumbosacral plexopathy): Bilateral motor-sensory deficits that follow a root plexus distribution, predominant in 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.

• Pure sensory variant: A lower extremity predominant dysesthesias with or without sensory ataxia affecting 5% to 35% of patients.

• Chronic immune sensory polyradiculopathy variant: Clinically similar to the pure variant except that the sensory ataxia is predominant due to dorsal column nerve conduction disruption.

• Chronic ataxic neuropathy: Associated with ophthalmoparesis, IgM paraprotein, cold agglutinin, and disialosyl ganglioside antibodies.

Evaluation

Diagnosing CIDP can be challenging due to its varied clinical presentations, underscoring the importance of accurate identification given its treatability. Early diagnosis and treatment can arrest disease progression and prevent axonal damage; however, nearly 50% of cases may be a result of overdiagnosis.[19] 

Laboratory Evaluation

No laboratory tests definitively confirm the diagnosis of CIDP. Instead, laboratory tests serve as adjuncts to rule out alternative diagnoses that mimic or may be associated with CIDP. All patients with suspected CIDP should undergo the following:[11][15]

• Fasting serum glucose or oral glucose tolerance test
• Glycated hemoglobin (HbA1C)
• Serum calcium
• Serum creatinine
• Complete blood count
• Serum aminotransferase levels
• Thyroid function studies
• Serum protein electrophoresis (SPEP) and immunofixation 
• Serum free light chain (FLC) assay

All patients should undergo SPEP and FLC assay since neuropathies associated with monoclonal gammopathy of undetermined significance may behave like typical CIDP. Monoclonal gammopathies may also be associated with neuropathies mimicking CIDP, such as anti-MAG IgM neuropathy; polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome; multiple myeloma; or AL-amyloidosis.

Additional laboratory tests to consider based on specific patient circumstances include the following:

• Serology for Borrelia burgdorferi 
• C-reactive protein
• Antinuclear antibodies (ANA)
• Angiotensin-converting enzyme
• Hepatitis B and C serology
• HIV antibody
• Chest radiograph
• Evaluation for inherited neuropathies 
• Clinical testing for nodal and paranodal antibodies
• Test for anti-MAG in the presence of an IgM gammopathy 

Numerous sets of diagnostic criteria exist to diagnose CIDP. The diagnosis requires a combination of clinical, electrodiagnostic, and supportive information. The European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) 2021 diagnostic criterion has 83% sensitivity and 94% specificity.[20] The 2021 guidelines begin the diagnostic process by classifying patients with suspected CIPD as "typical CIDP" or "CIDP variant" (atypical) based on their symptoms and physical examination findings. 

Typical Chronic Inflammatory Demyelinating Polyneuropathy [20]

Required criteria

1. Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of 2 or more limbs, developing over 2 months or longer; cranial nerves may be affected 
2. Absent or reduced tendon reflexes in all extremities 

Chronic Inflammatory Demyelinating Polyneuropathy Variants [20]

One of the following criteria must be present. Tendon reflexes may be normal in the unaffected limbs.

1. Predominantly distal as with distal acquired demyelinating symmetric neuropathy 
2. Asymmetric symptoms as seen in multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome
3. Focal symptoms, such as involvement of 1 or more peripheral nerves in an upper or lower limb
4. Pure motor symptoms
5. Pure sensory symptoms 

Following classification as typical or a CIPD variant, clinicians should conduct electrodiagnostic studies. These studies, combined with the patient's symptoms and physical examination findings, offer varying levels of diagnostic certainty. Previous guidelines contained definite, probable, and possible CIDP designations. However, the most recent guidelines now only include CIDP and possible CIDP.

Electrophysiological Findings 

Clinicians perform nerve conduction tests on the median nerve, ulnar nerve below the elbow, peroneal nerve below the fibular head, and tibial nerves on one side of the body. These electrophysiological studies aid in distinguishing between a demyelinating and an axonal process. It is important to note that axonal damage can be either primary or secondary to demyelination and does not exclude CIDP. If initial electrodiagnostic criteria for definite CIDP are inconclusive, a repeat study at a later date may be considered.

Motor nerve conduction criteria 

Affected patients must have at least 1 of the following demyelinating parameters:

• At least 50% prolongation of motor distal latency above the upper limit of normal in 2 nerves

• At least 30% reduction of motor conduction velocity below the lower limit of normal in 2 nerves

• At least 20% prolongation of F-wave latency above the upper limit of normal in 2 nerves, or more than 50% if the amplitude of the distal negative peak compound muscle action potential (CMAP) is less than 80% of the lower limit of normal

• Absence of F waves in 2 nerves, if these nerves have amplitudes of distal negative peak CMAPs 20% or greater of the lower limit of normal, plus at least 1 other demyelinating parameter meeting any of the definite criteria in 1 or more other nerves

• Partial motor conduction block, defined by a greater than 30% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP is 20% or greater of the LLN, in 2 nerves, or 1 nerve plus 1 or more other demyelinating parameters meeting any of the definite criteria in 1 or more other nerves.

• Abnormal temporal dispersion, defined by a greater than 30% duration increase between the proximal and distal negative peak CMAP in 2 or more nerves

• Distal CMAP duration or interval between onset of the first negative peak and return to baseline of the last negative peak, increase in 1 or more nerves plus at least 1 other demyelinating parameters meeting any of the definite criteria in 1 or more other nerves [20]

Sensory nerve conduction criteria

• Prolonged distal latency, reduced sensory nerve action potential (SNAP) amplitude, or slowed conduction velocities in 2 or more nerves.[20] After electrodiagnostic testing, patients with possible CIPD can obtain a definitive diagnosis of typical or variant CIPD if 2 additional supporting criteria are met. 

Supporting information 

• Objective response to treatment: A clinical response to treatment with IVIG, plasma exchange, or corticosteroids supports the diagnosis of CDIP.

• Nerve ultrasound: Nerve enlargement of at least 2 sites in proximal median nerve segments or the brachial plexus.[21][22][23]

• Magnetic resonance imaging: Current guidelines do not recommend using magnetic resonance imaging (MRI) to diagnose CIDP unless the patient falls into probable CIPD. The enlargement or increased signal intensity of nerve roots on T2-weighted MRI sequences increases the likelihood of CIPD.[24]

• Cerebral spinal fluid analysis: Albuminocytologic dissociation is characteristic. Between 85% to 90% of patients with CIDP will have elevated protein and mild pleocytosis of fewer than 10 cells/mm³. A leukocyte count more than 10 cells/mm³ should raise suspicion for alternate diagnoses. Elevated cerebral spinal fluid (CSF) protein is considered ancillary testing more than a diagnostic criterion; therefore, a normal CSF protein does not exclude the diagnosis.[3] CSF analysis is unnecessary unless diagnostic criteria are not met.

• Nerve biopsy: Nerve biopsy is not a routinely required diagnostic test. Clinicians should consider a nerve biopsy when clinical, laboratory, imaging, and electrodiagnostic studies do not provide a definitive diagnosis. Nerve biopsy can exclude other causes of neuropathy, such as amyloidosis, vasculitis, and toxic or hereditary neuropathies.[3]

Summary of Diagnostic Criteria 

Typical chronic inflammatory demyelinating polyneuropathy

• Clinical criteria with motor conduction criteria in 2 or more nerves and sensory conduction abnormalities in 2 nerves

• Possible typical CIDP with 2 or more supportive criteria

Possible typical chronic inflammatory demyelinating polyneuropathy

• Clinical criteria with motor conduction criteria in 1 nerve and sensory conduction abnormalities in 2 nerves

• Clinical criteria with motor conduction abnormalities not fulfilling CIDP motor conduction criteria in 1 nerve and sensory conduction abnormalities in 2 nerves and objective response to treatment and 1 other supportive criterion

Variant chronic inflammatory demyelinating polyneuropathy

• Distal CIDP
• Clinical criteria with motor conduction criteria in 2 upper limb nerves and sensory conduction abnormalities in 2 nerves
• Possible distal CIDP with 2 or more supportive criteria

• Possible distal CIDP
• Clinical criteria with motor conduction criteria in 1 upper limb nerve and sensory conduction abnormalities in 1 nerve
• Clinical criteria with motor conduction criteria in 2 lower limbs nerves only and sensory conduction abnormalities in 2 nerves (possible distal CIDP only, cannot be upgraded by supportive criteria)

In the initial electrodiagnostic changes noted in the DADS variant, the sensory conduction is affected, with some overlap of posterior column deficits, as seen in the chronic immune sensory polyradiculopathy variant. Often, clinicians note conduction deficits in motor potentials. More than 50% of the patients generate IgM gamma antibodies against anti-MAG in the CSF.[25]

• Multifocal or focal CIDP
• Clinical criteria with motor conduction criteria in 2 nerves and sensory conduction abnormalities in 2 nerves
• Possible multifocal or focal CIDP with 2 or more supportive criteria [26]

• Possible multifocal or focal CIDP
• Clinical criteria with motor conduction criteria in 1 nerve and sensory conduction abnormalities in 2 nerves
• Focal CIDP fulfilling clinical criteria with motor conduction criteria 1 nerve and sensory conduction abnormalities in 1 nerve (possible focal CIDP only, cannot be upgraded by supportive criteria)

• Motor CIDP
• Clinical criteria with motor conduction criteria in 2 nerves and normal sensory conduction in 4 nerves
• Possible motor CIDP with 2 or more supportive criteria [27]

• Possible motor CIDP
  • Possible motor CIDP with 2 or more supportive criteria

• Motor-predominant CIDP
  • The same as motor CIDP but with sensory conduction abnormalities 2 nerves [27]

• Possible sensory CIDP
• Clinical criteria with sensory conduction criteria
• Motor conduction must be normal in 4 or more nerves

• Sensory-predominant CIDP
• Clinical criteria with sensory conduction abnormalities in 2 nerves and motor conduction criteria fulfillment in 2 nerves.
• Pure sensory conduction abnormalities are rare. Most often, there is evidence of motor-axonal demyelination in advanced stages.[28][29] 

• Possible sensory-predominant CIDP
  • Conduction abnormalities in 2 nerves or motor conduction criteria fulfillment in 1 nerve.

Exclusion Criteria

Clinicians can exclude the diagnosis of CIDP if Borrelia burgdorferi, diphtheria, or drug or toxin exposure likely causes the patient's neuropathy. Additional exclusion criteria are the presence of hereditary demyelinating neuropathy and IgM monoclonal gammopathy with high titers of anti-MAG antibodies.

Treatment / Management

First-line treatment options for CIDP include corticosteroids, IVIG, and plasma exchange.[14] Due to the potential long-term adverse effects of corticosteroids, serial IVIG and plasmapheresis are the primary therapies.[30] IVIG is easier to administer than plasma exchange. Both plasma exchange and IVIG may have a more rapid response than that of glucocorticoids.

Corticosteroids are particularly beneficial for patients with a more subtle onset as a rapid treatment response may be less critical, and they are more likely to achieve remission. Corticosteroids are also helpful for patients who continue to experience relapses despite ongoing IVIG or other maintenance therapy. Steroid-sparing immunosuppressive agents such as azathioprine, cyclosporine, tacrolimus, and mycophenolate may be utilized for maintenance therapy. Treatment is generally continued until symptom resolution or stabilization; nearly 40% of patients will achieve remission or cure. 

Corticosteroids 

• The usual induction dose of prednisone is 60 to 100 mg/day. Tapering begins after steroid-sparing medications reach a steady state.[31]

• Studies reveal no difference between high-dose monthly dexamethasone and daily oral prednisone.[32]

• Corticosteroids are less expensive and easier to use.

• Adverse effects of corticosteroids are hypertension, diabetes, moon facies, osteoporosis and fractures, myopathy, sleep and mood disturbances, cataracts, skin and hair changes, immunosuppression, adrenal insufficiency, and risk of infections.[33]

Intravenous Immune Globulin

• The 2008 Immune Globulin Intravenous for CIDP (ICE) trial is the most extensively reported CIDP treatment study. It exhibits the effectiveness and safety of using IVIG as both initial and maintenance therapy, effectively preventing frequent relapses.[34] 

• The relapse rate with IVIG is approximately 45%, whereas the relapse rate associated with corticosteroids is approximately 50%.[35]

• Chronic administration of IVIG and corticosteroids slows the median time to deterioration.

• Dosing: IVIG is administered as an initial induction dose of 2 g/kg over 2 to 5 days or 0.4 g/kg/d over 5 days, followed by a maintenance dose of 1 g/kg every 3 to 4 weeks for 2 to 3 months to determine efficacy.
  • Clinicians monitor efficacy by documenting a disability scale and a quantitative grip measure at each 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). 

• Once clinicians establish efficacy, IVIG therapy stops until the patient experiences clinical deterioration. The corresponding interval determines their future treatment interval. The patient will then be given the IVIG with a subsequent 20% reduction in dose each time until a final dosing schedule is determined. The typical dose is 1.4 g/kg at a mean interval of 4.3 weeks, but some patients can go as low as 0.4mg/kg.[36]

• The immunomodulating mechanisms of IVIG can be summarized as follows:[37]
• Inhibition of innate immune cell activation
• Neutralization of autoantibodies
• Inhibition and abrogation of activated complement
• Induction of autophagy in peripheral blood mononuclear cells
• Modulation of fragment crystallizable receptors (FcR)
• Decrease of T helper 17 (Th17) cell proliferation and interleukin 17 (IL-17) secretion
• Decrease in proinflammatory cytokine production
• Increase in regulatory T-cells (Treg) expansion

• The Polyneuropathy And Treatment with Hizentra (PATH) study reveals the safety and efficacy of subcutaneous IG for maintenance therapy of CIDP over 24 weeks. The study reveals equal efficacy with fewer generalized adverse effects and increased adherence compared to IVIG.[38][39]

• Some adverse effects of IVIG are infusion reactions, fever, chills, hypotension, thrombotic events, and aseptic meningitis.[40]

Plasma Exchange

Plasma exchange, while effective, is often limited by availability and requires repeat venous access or indwelling catheters. Clinicians frequently reserve plasma exchange for severe cases or patients unresponsive to corticosteroids and IVIG.[41] A typical course involves 5 to 10 sessions over 2 to 4 weeks, with a faster response than IVIG or steroids. The relapse rate is high at approximately 67%. Potential adverse effects are hypotension, catheter-related complications, risk of catheter-related infection, hypocalcemia, allergic reaction to albumin infusions, and citrate toxicity.[42]

Steroid Sparing Agents for Maintenance Therapy

• No clinical guidelines exist regarding the duration of maintenance therapy. Approximately 6 months is the usual duration of maintenance therapy. 

• Patients requiring chronic therapy with a high risk of developing serious adverse effects from corticosteroids or IVIG can use other immunosuppressive agents such as methotrexate, cyclosporine, cyclophosphamide, rituximab, and mycophenolate. Most data supporting these therapies comes from smaller case studies or anecdotal reports.

• Azathioprine dosed at 2 mg/kg offers unclear benefits. Methotrexate 15 mg/wk has shown no benefit and is associated with severe adverse effects compared to placebo.[43] Similarly, intramuscular interferon–β–1A at 30 µg/wk, 30 µg twice weekly, and 60 µg twice weekly show no benefit when compared to IVIG.[44][45]

• Mycophenolate mofetil alone or combined with prednisone treats various autoimmune conditions, including CIDP. Like azathioprine, it can cause bone marrow suppression and is contraindicated in pregnant females.[31][46]

• Approximately 25% of patients are refractory to first-line treatment. These patients require further investigations to evaluate for CIDP variants or other causes of acquired demyelinating chronic neuropathies. Targeted therapies such as rituximab and alemtuzumab are potential alternatives in such cases.

Involvement of occupational therapy, physical therapy, and physiatry can play a crucial role in achieving optimal functional status for individuals with CIDP. These multidisciplinary approaches aim to improve mobility, strength, coordination, and independence in daily activities, enhancing patients' overall quality of life.

Differential Diagnosis

Differential diagnosis for CIDP includes the following:

• AIDP
• Multifocal motor neuropathy 
• DADS with monoclonal IgM gammopathy and anti-MAG
• Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies 
• POEMS syndrome, or osteoclastic myeloma [47]
• Demyelinating neuropathy due to tumor necrosis factor-α blockers and checkpoint inhibitors
• Infectious neuropathy due to Lyme disease, diphtheria, hepatitis B or C, or HIV
• Charcot-Marie-Tooth (CMT) disease, especially CMT1
• Hereditary neuropathy with liability to pressure palsies
• Transthyretin (TTR) familial amyloid polyneuropathy [48]
• Pyridoxine (B6) abuse [49]
• Toxic and metabolic neuropathy
  • Diabetic lumbosacral radiculopathy-plexopathy
  • Non-diabetic lumbosacral radiculopathy-plexopathy
  • Chemotherapy-induced demyelinating neuropathy 
• PNS lymphoma
• Systemic amyloidosis

Prognosis

Approximately two-thirds of patients with CIDP show an initial favorable response to any single standard therapy, including IVIG, glucocorticoids, or plasma exchange.[11][50] However, resistance to all these treatments may be observed in approximately 10% to 15% of patients. Additionally, nearly 40% of patients with CIDP attain a state of cure or remission, although some may continue to have lingering deficits that remain unresponsive to immunotherapies.

A recent study from South England reveals that 54% of patients experience severe disability as a result of CIDP at some point in their disease. Over time, the risk of relapse increases. Clinicians can taper the immunosuppressive therapy once patients have stabilized and are no longer worsening.[51] A study involving 40 patients by Dyck et al demonstrates that 72% required immunosuppressive treatment while 27% achieved remission off treatment.[52]

Complications

Approximately 54% of known cases are misdiagnosed as CIDP.[19] These patients undergo long-term immunosuppressive therapy with minimal to no benefit. Despite the availability of several immunosuppressive therapies, most patients with CIDP have some form of disability. Furthermore, patients may suffer from several treatment-related side effects such as hypertension, thromboembolic events, increased risk of infection, bone marrow suppression, nephrotoxicity, and malignancies such as lymphoma.[46][53]

Additional disease-related complications are aspiration pneumonia, atelectasis, and respiratory failure due to swallowing and breathing dysfunction. Autonomic function involvement may cause gastrointestinal motility abnormalities, bladder function, orthostatic hypotension, and cardiac conduction defects.

Deterrence and Patient Education

CIDP is a neurological disorder that causes progressive weakness and reduced sensation in the arms and legs. The underlying pathophysiology results from recurrent demyelination and remyelination of nerves. Misdiagnosis of CIDP is common and results in high medical costs and exposure to potentially toxic therapies. Referral to a center with expertise in neuromuscular medicine may be essential to confirm the diagnosis.  

Patients should be informed about the variability of symptoms and the potential necessity of consulting with a neurology and neuromuscular specialist. Patients and caregivers need to understand that CIDP may follow a relapsing-remitting or progressive course, emphasizing the significance of early diagnosis and treatment to prevent disease progression and disability. While various medication options exist, each carries its own set of risks and benefits. Despite the long duration of the disease, medication side effects, and associated expenses, patients should be encouraged by the fact that many patients experience significant improvement with therapy, and up to 40% achieve remission.

Pearls and Other Issues

Key facts to keep in mind about CIDP include the following:

• CIDP is an immune-mediated disorder affecting the myelinated structures of the peripheral nervous system.

• It can be monophasic, progressive, or relapse-remitting and develops over more than 8 weeks, which distinguishes it from AIDP and GBS variants. 

• The symptoms are typically symmetric, affecting proximal and distal sensorimotor patterns, with a demyelinating nerve conduction pattern that includes a focal or multifocal distal latency prolongation, decreased or blocked conduction, prolonged or absent F-wave latency, temporal dispersion, and increased duration.

• Atypical variants include DADS, chronic immune sensory polyradiculopathy, multifocal acquired demyelinating sensory and motor neuropathy, focal or diffuse brachial or lumbosacral plexopathy, pure motor, and pure sensory CIDP.

• The pathophysiology includes a chronic, maladaptive self-targeting of myelinated components of the neurons by the coordinated activation of innate macrophages and adaptive immune systems, including humoral and cell-mediated mechanisms.

• Typical symptoms include symmetric large-to-small fiber paresthesias, paraparesis, diffuse muscle fatigue, and areflexia.

• Atypical symptoms are asymmetric allodynia, painful cervical or lumbar radiculomyelopathies, multiple cranial nerve neuropathies, bulbar and autonomic symptoms, tremors, and spasticity.

• Uncontrolled diabetes is a potential risk factor for developing CIDP.

• Alternate differential diagnoses are toxic, metabolic, systemic, infectious, iatrogenic, hereditary, neoplastic, and multifocal motor neuropathies.

• Supporting ancillary tests include CSF with albumino-cytologic dissociation, gadolinium-enhancing hypertrophy of the neuroaxis, delayed somatosensory evoked potentials, or muscle biopsy with unequivocal evidence of demyelination and remyelination.

• Treatment includes acute and chronic immunomodulatory therapies such as serial IVIG, plasmapheresis, prednisone, mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, and, in exceptional cases, rituximab.

• Complications of therapy include infusion reactions, headaches, infections, renal failure, and hypercoagulability.

• Prognosis is variable and can depend on age, clinical course, responsiveness to treatment, and electrophysiological findings.

• Aggressive rehabilitation is instrumental for the long-term recovery of patients with CIDP.

Enhancing Healthcare Team Outcomes

The diagnosis and management of CIDP are complex, requiring an interprofessional inpatient and outpatient team that includes neurology, primary care, physical medicine and rehabilitation, pain management, physical therapy, occupational therapy, psychiatry, social workers, neuromuscular specialists, and case management staff. Healthcare professionals must possess the necessary knowledge to diagnose and manage CIDP. This knowledge includes the variable presentations and nuances of the diagnostic criteria for CIDP variants. A strategic approach to evidence-based guidelines and individual treatment plans is essential. Ethical considerations must guide decision-making, respecting patient autonomy in treatment choices.

Aggressive immunomodulatory therapy and physical neurorehabilitation are essential for a long-term favorable outcome. Barriers that may hinder clinical improvement include social determinants of health, pain control, and aggressive clinical variants. Each team member must contribute expertise and provide seamless interprofessional communication, allowing for collaborative decision-making. By embracing knowledge, strategy, ethics, and communication, healthcare professionals can provide patient-centered care, ultimately reducing the number of misdiagnoses and morbidity associated with CIDP. Effective interprofessional communication fosters a collaborative environment where information is shared, questions are encouraged, and concerns are addressed promptly.

Lastly, care coordination is pivotal in ensuring seamless and efficient patient care. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must work together to streamline the patient's journey, from diagnosis through treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of those affected by CIDP.