Approach

Diagnosis is based on patients meeting defined clinical criteria. Multiple clinical, electrophysiologic, and laboratory criteria have been suggested with varying degrees of sensitivity and specificity.[1][23][24][25]​​​​​​​​ While most sets of criteria have specificities approaching 100%, sensitivities are around 60% to 70%.[23][24][26]​​​​​​ More recent criteria are less restrictive than earlier sets, resulting in higher sensitivities (80% to 85%) while retaining high specificities. Sensitivity may be higher if two sets of criteria with different parameters are combined.[27] Motor conduction block in a noncompressible site is highly sensitive.[26] Testing more nerves and proximal sites may improve sensitivity.[28][29]​​​​​​​ Fulfilling the criteria for established diagnostic guidelines may predict a higher treatment response rate than that for patients who do not fulfill these criteria.[30]

Diagnostic criteria were updated in the second revision of the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline on CIDP (published in 2021) in order to increase specificity, and these criteria are considered the most useful for clinical practice and patient care. Diagnostic categories (based on level of diagnostic certainty) are CIDP and possible CIDP.[1]​ These criteria update and replace criteria from the 2010 first revision of the guideline.[31]

Despite good sensitivity and specificity of diagnostic criteria for CIDP, misdiagnosis is common, particularly for patients with CIDP variants. This can be due to poorly performed or misinterpreted nerve conduction studies, or nonadherence to electrodiagnostic criteria, and can lead to delay in effective treatment.[1][2][16]

Typical features of CIDP include a chronic progressive or relapsing/remitting or stepwise course over at least 8 weeks, resulting in symmetric proximal and distal weakness, sensory loss in all four limbs, and hyporeflexia or areflexia in all four limbs. Predominantly distal weakness (known as distal acquired demyelinating symmetric neuropathy), asymmetric weakness, focal weakness, and subacute presentation over 4-8 weeks are alternative presentations indicating CIDP variants.[1] Electrodiagnostic evidence of demyelination is mandatory to make the diagnosis of CIDP.

Clinical evaluation

CIDP can occur at any age, with most common age of onset being between 40 and 60 years, and it is more common in men.​[1][2][5][15]

Drug or toxin exposure that is likely to have caused the neuropathy (e.g., diphtheria, buckthorn, amiodarone, tacrolimus) may rule out a diagnosis of CIDP.[32][33]​​ Hereditary demyelinating neuropathy based on family history, foot deformity, retinitis pigmentosa, optic atrophy, hearing loss, liability to pressure palsy, self-mutilation, significant central nervous system (CNS) manifestations, or presence of significant bowel or bladder sphincteric complaint may also point to an alternative diagnosis.[34][35][36]

Routine neurologic examination is required. Weakness is seen in nearly all patients, and gait difficulty is common. Hyporeflexia or areflexia and sensory dysfunction (numbness, paresthesias) are hallmarks of CIDP.[1]​​[3][16]​​​ Pain may be a feature; the prevalence of pain due to CIDP at any time during the disease course was estimated as 46% in one systematic review.[37]

Rarely, patients present with only sensory symptoms, typically distal paresthesias and dysesthesias, but may have sensory ataxia, which can also lead to gait difficulty.[1][38][39]​​ Other uncommon manifestations include dyspnea, vision loss, cranial nerve complaints (e.g., facial weakness, dysarthria, or dysphagia), erectile dysfunction, orthostatic hypotension, and urinary incontinence, urgency, or hesitancy; however, these are also symptoms and signs of alternative diagnoses.[40]​​[41]​​ Nerve hypertrophy may be detected in a few patients. CNS findings such as papilledema or spasticity have been reported, but are quite rare. Pure motor presentation may also occur.​​[1]

Investigations

Nerve conduction studies should be performed for all patients with suspected CIDP. Supportive investigations for diagnosis include cerebrospinal fluid (CSF) analysis, imaging studies with ultrasound or magnetic resonance imaging (MRI), response to treatment, and nerve biopsy; these may be helpful when electrodiagnostic studies are inconclusive or result in a diagnosis of "possible CIDP" in patients who meet the clinical criteria for CIDP.[1]

Electrodiagnostic evaluation

  • Electrodiagnostic evidence of demyelination is mandatory to make the diagnosis and should be ordered for all patients with a clinical suspicion of CIDP. The most important test is nerve conduction studies.

  • Diagnostic criteria are mainly based on finding a combination of slowed conduction velocities, prolonged distal latencies, prolonged F-wave latencies, and conduction block in one or more motor nerves.[1]

  • Sensory criteria are now also included in electrodiagnostic criteria.[1]

  • Patients with a suggestive history and neurologic examination, and supportive criteria consistent with a diagnosis of CIDP, should not be excluded from treatment if they do not fulfill electrophysiologic criteria, as long as nerve conduction studies show some evidence of demyelination. Furthermore, especially for patients with CIDP variants, sensitivity may be improved by studying more than four motor nerves, utilizing proximal stimulation in the upper limbs, and including sensory nerves and somatosensory evoked potentials.[1] Nerve conduction studies should be repeated if doubt still exists about the diagnosis.

  • For patients with pure sensory CIDP, nerve conduction studies may show only mild abnormalities not meeting typical electrodiagnostic criteria; elevated CSF protein, abnormal somatosensory evoked potentials, and demyelination on nerve biopsy may be present.[38][39]

  • In one study of patients referred to a tertiary care center for refractory CIDP, one of the main reasons for therapeutic failure was an incorrect alternative diagnosis. The importance of nerve conduction studies was emphasized, as many patients with alternative diagnoses (e.g., amyotrophic lateral sclerosis, idiopathic neuropathy, small-fiber neuropathy) had no demyelinating features and clinically lacked distal leg weakness, vibratory sensory loss, and widespread areflexia. CIDP mimics were also often misdiagnosed.[42]

CSF evaluation

  • CSF analysis should be considered for patients with suspected CIDP when clinical and electrophysiologic testing is not definitively diagnostic. It is also advised if infection or lymphoproliferative disease is suspected or possible.[1]

  • In >90% of patients with CIDP, CSF analysis typically shows albuminocytologic dissociation: elevated protein levels with a normal leukocyte count (<10 leukocytes/mm³). CSF protein levels of >45 mg/dL are abnormal; levels of >100 mg/dL are not unusual, and much higher levels can be found. However, cautious interpretation is needed, especially for patients with diabetes mellitus or spinal stenosis, and in young or older patients.[1][43][44][45]

  • Cell counts of >10 leukocytes/mm³ should raise suspicion of infection or malignancy. Cell counts may be up to 50 leukocytes/mm³ in HIV infection.[46][47]

  • ​​​The sensitivity of CSF analysis for detecting CIDP variants is unknown.[1][48]

Imaging

For patients who fulfill clinical and electrodiagnostic criteria for a diagnosis of CIDP, imaging is not needed for diagnosis and therefore is not recommended.[1]

Before concluding that abnormalities on imaging are supportive of a diagnosis of CIDP, other diseases should be considered and excluded. These include multifocal motor neuropathy, demyelinating Charcot-Marie-Tooth disease, IgM paraproteinemic neuropathy (especially with anti-myelin-associated glycoprotein [MAG] antibodies), polyneuropathy-organomegaly-endocrinopathy-M-protein-skin changes (POEMS) syndrome, diabetic radiculoplexus neuropathy, amyloid neuropathy, neuralgic amyotrophy, leprosy, neurofibromatosis, and neurolymphomatosis.[1]

Nerve ultrasound

  • Nerve ultrasound is recommended as a diagnostic tool for adult patients who fulfill the diagnostic criteria for possible CIDP.[1]

  • The most common finding on ultrasound is multifocal nerve enlargement.[1][49][50]​​ This can help to distinguish CIDP from Charcot-Marie-Tooth disease type 1, in which nerves are usually diffusely enlarged.[51][52]

  • The presence of multifocal nerve enlargement correlates with electrodiagnostic findings.[49][50][53] One study showed motor nerve conduction velocity to be inversely correlated with cross-sectional area in nerve segments with electrodiagnostic evidence of demyelination.[53] Nerves with increased cross-sectional area were seen in patients with a more severe course of CIDP as manifest by longer disease duration, lower Medical Research Council (MRC) sum score, higher Inflammatory Neuropathy Cause and Treatment (INCAT) score, and progressive disease.[53][54]

  • Diagnosis may be more likely if there is nerve enlargement of at least two sites in proximal median nerve segments/and or the brachial plexus (mimics must be excluded).[1]

  • Ultrasound may be used to assess treatment response.[55]​ Enlarged nerves may become smaller or normalize with remission of disease.[56] Patients with active CIDP that is refractory to treatment will generally have enlarged nerves without significant change over time.[56]

  • There is a lack of evidence on the use of ultrasound in pediatric patients.[1]

MRI

  • MRI spine and plexus with and without contrast may be considered for adult patients when electrodiagnostic studies are inconclusive or for those who fulfill diagnostic criteria for possible CIDP, and when ultrasound is unavailable or unclear.​[1]

  • Without gadolinium enhancement, hypertrophy of lumbosacral or cervical nerve roots or of the lumbosacral or brachial plexus is the most common abnormality. Rarely, hypertrophy involves cranial nerves; it is more common in longstanding disease with a relapsing-remitting course. Enhancement may be present and suggests inflammation.[1][57]​​​

  • There is a lack of evidence on the use of MRI in pediatric patients.[1]

Clinical trial of therapy

  • Most patients with CIDP will have a response to treatment with a first-line monotherapy (intravenous immune globulin, corticosteroids, or plasma exchange).[1][58][59][60]​​​​​​ If the first monotherapy is ineffective, an alternative first-line agent should be tried.

  • Lack of at least a partial response to one or two first-line immunosuppressive agents should lead to consideration of an alternative diagnosis: for example, autoimmune nodopathies.[1]

Nerve biopsy

  • Nerve biopsy is of limited diagnostic value, and is unnecessary for most patients.[3]​ It should only be performed in certain circumstances, mainly if the diagnosis is unclear and alternative diagnoses have not been fully excluded after nerve conduction studies, lumbar puncture, laboratory investigations, and imaging (if indicated). It may be helpful in cases where electrodiagnostic studies are inconclusive.[1][61]​​​ Biopsy should also be considered If there is a high suspicion of an infiltrative process such as seen in lymphoma, malignancy, amyloidosis, or sarcoidosis.[1]

  • Although the sural or superficial peroneal nerve is often biopsied, a biopsy from a clinically affected nerve will be more informative.[4][21]

  • Classic findings include unequivocal or predominant evidence of segmental demyelination, remyelination, or onion bulb formation by electron microscopy or teased fiber analysis. Demyelination often occurs paranodally or near nodes of Ranvier. Inflammatory cells (may or may not be present) are typically both epineurial and endoneurial.[1][3][6][41]​​​​​

  • Evidence of axonal degeneration is common, and includes axonal loss and myelin ovoid formation.​[6][21][22][40]​​

Other laboratory tests

  • Enzyme-linked immunosorbent assay (ELISA) or Western blot can be used to detect autoantibodies. A small subset of patients have antibodies against nodal or paranodal proteins, which are usually of the IgG4 subclass; these include contactin-1 (CNTN1), neurofascin-155 (NF155), contactin-associated protein 1 (Caspr1), and neurofascin isoforms NF140/186.[62][63]​​​ Such patients are classified as having an autoimmune nodopathy, which presents with a distinct phenotype including rapid onset, ataxia, tremor, and poor response to intravenous immune globulin and corticosteroids.[1] Response to cyclophosphamide or rituximab has been reported.[64][65][66]

  • A range of tests is recommended to identify other potential conditions (e.g., HIV, diabetes mellitus, monoclonal gammopathy, malignancy, hepatitis, sarcoidosis, systemic lupus erythematosus, mixed connective tissue disease) or to establish an alternate diagnosis if the criteria for CIDP are not met.[1]

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