Version May 2024
INTRODUCTION — Chronic inflammatory demyelinating polyneuropathy (CIDP; also known as chronic inflammatory demyelinating polyradiculoneuropathy) is an acquired, immune-mediated neuropathy affecting peripheral nerves and nerve roots, typically characterized by a relapsing-remitting or progressive course of symmetric weakness of proximal and distal muscles. CIDP is identified by electrodiagnostic and/or pathologic features of demyelination and responsiveness to immunomodulatory treatments.
The classification, etiology, clinical features, and diagnosis of CIDP will be reviewed here. Treatment and prognosis of CIDP are discussed separately. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)
An approach to the patient with polyneuropathy more broadly and an overview of immune-mediated neuropathies are also presented separately. (See "Overview of polyneuropathy" and "Immune-mediated neuropathies".)
EPIDEMIOLOGY — The reported prevalence of CIDP ranges from 0.7 to 10.3 cases per 100,000 people [1]. There is a predominance in males, with a sex rate ratio ranging from 1.5 to 4. CIDP primarily affects adults and the incidence rises with advancing age. The typical age of onset is not well established, but some studies have reported mean ages of presentation in the sixth decade [2,3]. CIDP may also occur in children [4,5]. No specific predisposing risk factors for CIDP have been clearly identified [6]. There have been conflicting studies on human leukocyte antigen (HLA) type associations, but no clear genetic predisposition has been found.
PATHOGENESIS
Immunologic basis — Although the cause of CIDP and its variants is unknown, there is evidence to support the hypothesis that the disorder(s) are immunologically mediated and can have multiple triggers. Both the cellular and humoral components of the adaptive immune system appear to be involved in the pathogenesis of CIDP and its variants [7-10].
●Cellular immunity involvement is supported by evidence of T cell activation, crossing of the blood-nerve barrier by activated T cells, and expression of cytokines, tumor necrosis factor, interferons, and interleukins.
●Humoral immunity is implicated by the demonstration of immunoglobulin (Ig) and complement deposition on myelinated nerve fibers, and by passive transfer experiments that induce conduction block and demyelination by injecting serum or purified IgG from CIDP patients into rats.
The specific immunologic triggers or cause(s) of CIDP in the majority of patients remain unclear, however [9]. The significance of autoantibodies to nodal and paranodal proteins in a subset of patients with CIDP is discussed below. (See 'Nodal and paranodal antibodies' below.)
Neuropathologic findings — The characteristic pathologic features of CIDP include segmental demyelination and remyelination of peripheral nerves, which may result in onion bulb formation [11]. The term "onion bulb formation" refers to the appearance of affected axons when viewed under the microscope in transverse section. As a result of repeated episodes of demyelination and remyelination, affected nerve fibers are enlarged due to whorls of overlapping and proliferating Schwann cell processes encircling bare axons.
Nerve involvement is patchy, with inhomogeneous involvement over the length of a nerve. Demyelination tends to occur paranodally, near nodes of Ranvier. Varying degrees of interstitial edema and endoneurial inflammatory cell infiltrates, including lymphocytes and macrophages, are seen microscopically. The macrophages are thought to initiate the demyelination by unraveling and degrading myelin [12]. However, macrophages are not prominent on most clinical biopsy specimens.
Although CIDP is a primarily demyelinating disorder, some degree of axonal degeneration is usually present as well [13]. The mechanism of axonal degeneration in CIDP is not known but has been considered to be a secondary bystander product of the inflammatory demyelinating process.
Nodal and paranodal antibodies — In approximately 10 percent of patients with a clinical diagnosis of CIDP, autoantibodies against nodal and paranodal proteins have been identified and are considered to be pathogenic [6,14,15]. The majority are IgG4 subclass antibodies directed at proteins at or near the node of Ranvier, including neurofascin (NF) isoforms and contactin 1 (CNTN1). The pathogenesis of the neuropathy in these patients appears to be distinct from classic CIDP, and classification is evolving [16]. Some of the antibodies have also been described in patients with other neuropathies, and further understanding of the specificity and clinical relevance is needed [17,18].
Specific targets described in patients with CIDP include:
●NF 155, a paranodal protein expressed by glial cells [15,17,19-22]
●NF140 and NF186, neuronal proteins present at nodes and axon initial segments [23]
●CNTN1 and contactin-associated protein 1 (CASPR1) [14,24,25]
NF and contactin are critical structural elements of the paranodal loop attachment to the axolemma. The antibodies appear to target paranodal proteins and may disrupt the axonal-glial junctions, leading to nerve conduction slowing and conduction block [25-27]. Biopsies from patients with these antibodies have not shown findings typical for CIDP, such as onion bulb formation and macrophage-mediated demyelination. Clinical phenotypes also appear to differ from typical CIDP. (See 'Neurofascin antibody-mediated' below and 'Contactin 1 antibody-mediated' below.)
CLINICAL FEATURES
Typical CIDP (symmetric sensorimotor) — Typical CIDP is the most common subtype and accounts for at least 50 to 60 percent of all cases [6,28]. Typical CIDP is a fairly symmetric sensorimotor polyneuropathy characterized by proximal and distal muscle weakness that exceeds the extent of sensory loss. The presentation is usually one of gradually progressive symptoms over the course of several months or longer. Some patients present with more rapidly progressive symptoms, resembling acute inflammatory demyelinating polyneuropathy (AIDP) and which have been termed "acute-onset CIDP" [29]. However, by definition, the diagnosis of CIDP is dependent on progression or relapse of the disease over greater than eight weeks. (See 'Acute inflammatory demyelinating polyneuropathy' below.)
Weakness is present in a non-length-dependent pattern, affecting both proximal and distal muscles in similar degrees. This pattern is a hallmark of an acquired demyelinating polyneuropathy [30]. Proximal muscle weakness may cause difficulty climbing or descending stairs, rising from a seated position, and lifting objects overhead. Patients may have trouble walking and report frequent falls. Signs and symptoms of distal muscle weakness may include scuffing or tripping over the feet due to "foot drop," difficulty with fine motor tasks like buttoning, and difficulty opening doors or jars. Cranial nerve and bulbar involvement occur in 10 to 20 percent of patients. Tremor has been reported as a common symptom in several studies [31,32].
Although less prominent than motor symptoms, most patients with typical CIDP also have sensory involvement and globally diminished or absent reflexes [11,33]. Sensory impairment in CIDP is usually greater for vibration and position sense than for pain and temperature sense, reflecting the involvement of larger myelinated fibers. This commonly results in gait ataxia because of impairment of proprioception (sensory ataxia) and can be mistaken for posterior column spinal cord involvement. Unlike motor involvement, sensory involvement tends to be worse distally, with finger involvement frequently seen as early as toe and foot involvement. Painful dysesthesias can occur. Back pain may also be present. Symptoms of lumbar spinal stenosis and cauda equina syndrome can occur rarely if there is marked nerve root hypertrophy, and these problems may require surgical intervention.
Autonomic involvement in typical CIDP is generally mild and limited in distribution [34]. Constipation and urinary retention are not usually early symptoms but may occur in more severe cases.
Most patients with typical CIDP exhibit a slowly progressive course, but a relapsing-remitting course is noted in at least one-third and may be more common in younger patients [33]. The advent of early treatment for CIDP has made the temporal progression of the disease more difficult to characterize, since remissions may be related to therapy rather than to the natural course of the disease. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis", section on 'Prognosis'.)
CIDP variants and related conditions — Several variants of CIDP are distinguished by their clinical presentation and/or pathogenic mechanism. The forms of CIDP recognized as variants by the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) criteria include [16]:
●Multifocal CIDP
●Focal CIDP
●Motor CIDP
●Sensory CIDP
●Distal CIDP
The boundaries of these variants are not always clearly defined and may continue to evolve [28]. In particular, the classification of the neuropathies caused by autoantibodies against nodal and paranodal proteins (neurofascin, contactin) is evolving as they are not clearly demyelinating, and treatment responses are different than those for typical and atypical CIDP. (See 'Nodal and paranodal disorders' below.)
Asymmetric sensorimotor (multifocal) — The Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), is a well-described atypical variant of CIDP that accounts for 5 to 10 percent of CIDP cases [6,28]. Patients present with a strikingly asymmetric, multifocal picture, indistinguishable from other forms of mononeuropathy multiplex, resulting in sensory and motor signs and symptoms in individual nerve distributions [35,36]. Symptoms may start in any nerve distribution. Some patients may have autonomic symptoms, neuropathic pain, and cranial nerve involvement [28]. Some patients present with focal CIDP with symptoms restricted to a single limb or nerve [36].
Focal — The focal form of CIDP is an uncommon presentation that features sensorimotor deficits typically isolated to the brachial or lumbosacral plexus [37,38].
Pure motor — A pure motor variant of CIDP has been reported in a small number of cases [39,40]. Involvement of motor nerves and sparing of sensory fibers is present on clinical and electrodiagnostic evaluations. Weakness tends to be relatively symmetric and may involve any part of the body, including motor cranial nerves [28]. This is a very rare variant and must be distinguished from lower motor neuron-predominant amyotrophic lateral sclerosis and multifocal motor neuropathy (in which the motor nerve involvement tends to be more focal). (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Progressive muscular atrophy'.)
Pure sensory — The pure sensory form of CIDP is characterized clinically by symptoms and signs consistent with large fiber sensory dysfunction, including balance problems, pain, paresthesias, and dysesthesias. Symptoms may start anywhere in the body except in a length-dependent fashion (which would be more consistent with the distal variant) [28]. (See 'Distal and sensory predominant' below.)
There is no clinical weakness or autonomic dysfunction, and electrodiagnostic studies show no motor conduction abnormality in this variant [16]. If nerve conduction studies demonstrate significant motor conduction slowing and other demyelinating features, the subtype is called sensory predominant CIDP [41].
Distal and sensory predominant — Distal-acquired demyelinating symmetric neuropathy (DADS; or distal CIDP) refers to a distal and sensory-predominant variant of CIDP, which is usually more slowly progressive than typical CIDP. Patients typically present with length-dependent, symmetric sensory or sensorimotor dysfunction in the lower extremities with sparing of proximal limbs, trunk, and face [28]. Involvement of the upper limbs may occur later (eg, more than one year after disease onset). Additional features in some patients include ataxia, neuropathic pain, cramps, fatigue, autonomic symptoms, and tremor. As in other variants of CIDP, reflexes are typically absent.
Patients with a clinical phenotype of DADS are more likely to have a monoclonal gammopathy than patients with other CIDP variants, and approximately 50 percent of those with monoclonal IgM also have anti-myelin-associated glycoprotein (anti-MAG) antibodies [30,42]. With further hematologic evaluation, these patients are typically classified as having either monoclonal gammopathy of clinical significance (MGCS) or Waldenström macroglobulinemia [43], signaling a disease mechanism that differs from CIDP. Therefore, DADS with monoclonal IgM, particularly when associated with anti-MAG, is usually considered to be distinct from CIDP and tends to be resistant to the standard immunomodulatory therapies for CIDP. (See "Immune-mediated neuropathies", section on 'Distal sensory and motor acquired symmetric neuropathy'.)
DADS without monoclonal IgM is generally considered to be a variant of CIDP because it may respond to treatment with immunomodulatory therapies.
Proximal (polyradiculopathy) — A proximal variant of CIDP consisting of inflammatory demyelination confined to dorsal (sensory) nerve roots has been reported [44,45]. This variant, referred to as "chronic immune sensory polyradiculopathy" (CISP), presents clinically with a symmetric sensory ataxia with marked vibration and proprioceptive deficits, indicative of large fiber sensory dysfunction.
Because the disease process spares peripheral nerve myelin distal to the nerve roots (in contrast with sensory-predominant CIDP and DADS), sensory and motor nerve conduction studies are normal, and additional studies are crucial to making the diagnosis. Evidence of dorsal nerve root involvement is demonstrated by enlarged and enhancing nerve roots on magnetic resonance imaging (MRI), abnormal somatosensory evoked potentials (SSEPs), and elevated cerebrospinal fluid (CSF) protein. Other causes of polyradiculopathy must also be excluded (eg, infectious, granulomatous, neoplastic). (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes".)
A variant in which both sensory and motor nerve roots are involved has been described and is likely closely related to CISP, termed "chronic immune sensorimotor polyradiculopathy" (CISMP) [46,47].
The inclusion of CISP or CISMP as variants of CIDP has been questioned by some experts because studies have not clearly demonstrated a demyelinating pathophysiology [16].
Nodal and paranodal disorders — Patients with autoantibodies to neurofascin (NF) 155, contactin 1 (CNTN1), and other nodal/paranodal constituents have clinical features that overlap with CIDP. Physiologically, nodal and paranodal disorders can have conduction changes as seen in CIDP, but pathologically, the autoimmune nodopathies are not clearly demyelinating. In addition, they typically do not respond to typical immunomodulatory treatments used for CIDP. In a cohort of 401 patients with CIDP and 21 patients with an autoimmune nodopathy, those with an autoimmune nodopathy were less likely to respond to IVIG than patients with CIDP (39 versus 80 percent) and more likely to require other therapies (84 versus 34 percent) [48]. Because of these distinctions, the 2021 European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) CIDP guidelines did not include the nodo-/paranodopathies as variants of CIDP [16].
Neurofascin antibody-mediated — Patients with autoantibodies to NF 155 appear to be younger and more likely to have sensory ataxia and prominent tremor compared with those with antibody-negative CIDP [15,17,19-22]. The symptoms can cause severe dysfunction.
In a series of five patients with autoantibodies targeting NF140 and NF186, four patients presented with subacute sensory ataxia, and nerve conduction studies were consistent with a demyelinating neuropathy in three patients (definite CIDP) and axonal neuropathy in two (probable CIDP) [23]. Associated conditions included nephrotic syndrome in two patients and IgG4-related retroperitoneal fibrosis in one patient.
As IgG4 antibodies, NF autoantibodies do not activate complement. Similar to other IgG4 disorders (eg, anti-muscle-specific tyrosine kinase [anti-MuSK] myasthenia gravis), these patients do not typically respond to intravenous immune globulin (IVIG) but can be responsive to B cell depletion therapy (eg, rituximab) [20,49]. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)
Contactin 1 antibody-mediated — Autoantibodies of the IgG4 class to CNTN1 or contactin-associated protein 1 (CASPR1) are found in a small subset of patients with CIDP symptoms [14,24,25]. The clinical phenotype is not fully established but is often severe and predominantly motor with early axonal involvement. As with neurofascin antibody-mediated disease, this condition is also due to an IgG4 antibody and may be responsive to B cell depletion therapy (eg, rituximab) and refractory to IVIG.
DIFFERENTIAL DIAGNOSIS — CIDP is one of several neuropathies that share demyelination and immune mediation in common, and there is a lack of consensus on classification and nomenclature. In some cases, the distinction is primarily temporal; in others, pathogenic or therapeutic differences form the basis for the distinction. Certain genetic neuropathies are associated with peripheral nerve demyelination, and although not immune mediated, they are important mimics of CIDP.
Acute inflammatory demyelinating polyneuropathy — There is a temporal continuum between acute inflammatory demyelinating polyneuropathy (AIDP), which is the demyelinating form of Guillain-Barré syndrome (GBS), and CIDP. The time course of progression and the occurrence of relapses are used to distinguish between these entities:
●GBS commonly reaches its nadir within three to four weeks but does not progress beyond eight weeks [29].
CIDP continues to progress or has relapses for greater than eight weeks.
"Subacute inflammatory demyelinating polyneuropathy" (SIDP) is the term used by some authors for disease that reaches its nadir between four and eight weeks [50,51].
●GBS is typically monophasic, but up to two relapses in the first eight weeks from onset can occur. Three or more relapses in the first eight weeks is highly suggestive of acute onset CIDP. Relapses closer to the eight-week time period are more suggestive of CIDP.
This arbitrary temporal delineation of inflammatory demyelinating polyneuropathy can occasionally be difficult to ascertain in practice. Only observation of the patient over time can clarify whether the clinical course is that of AIDP or CIDP [30], and therapeutic interventions are likely to be initiated before a patient reaches a specific time point that distinguishes between these entities. As an example, some patients with CIDP have a subacute onset resembling that seen in GBS, and CIDP is recognized only after relapses or progression occur over the ensuing few months.
In addition to chronicity, other clinical features may be useful to distinguish GBS (including AIDP) from CIDP.
●The onset of GBS is usually easily identified, while the precise onset of CIDP is typically less clear. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)
●Antecedent events are more frequent with GBS than in CIDP. Approximately 70 percent of AIDP cases are preceded by an infectious illness, vaccination, or surgery by three to four weeks prior to the onset of clinical symptoms. By contrast, most studies have found an antecedent event prior to CIDP in no more than 30 percent of patients. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Antecedent events'.)
●Prominent sensory signs (ie, sensory ataxia and impaired vibration and pinprick sensation) favor CIDP [52].
●Cranial nerve involvement is more common in GBS.
●The need for ventilator support favors GBS [52].
●Autonomic involvement in the form of labile hypertension, heart rhythm disorders, and gastrointestinal dysmotility also favors GBS.
Other chronic demyelinating neuropathies — Classic CIDP and its variants are not the only forms of chronic demyelinating neuropathy. While there is no established consensus regarding the classification of these neuropathies, there is general agreement that several forms are distinct from CIDP on the basis of clinical, electrodiagnostic, and therapeutic differences. These include:
●Multifocal motor neuropathy (MMN). (See "Multifocal motor neuropathy".)
●Distal acquired demyelinating symmetric neuropathy (DADS) with monoclonal IgM gammopathy and anti-myelin-associated glycoprotein antibodies (anti-MAG). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)
●Other IgM-associated demyelinating neuropathies, such as CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies). CANOMAD is a chronic disorder with clinical features similar to the Miller Fisher variant of GBS. One of the disialosyl gangliosides is GQ1b. In CANOMAD, the GQ1b antibody is an IgM antibody; in Miller Fisher syndrome, it is an IgG antibody. Other IgM antibodies associated with neuropathy include GD1a and GD1b, both of which tend to cause a sensory-predominant disorder. (See "Immune-mediated neuropathies", section on 'CANOMAD syndrome'.)
●POEMS syndrome (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes). (See "POEMS syndrome".)
●Demyelinating neuropathy associated with medications such as tumor necrosis factor-alpha blockers [53] and checkpoint inhibitors [54]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease' and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Checkpoint inhibitor-associated neuropathies'.)
Of note, CIDP has been reported in association with a variety of systemic illnesses, including Lyme disease, hepatitis B or C, HIV infection, systemic lupus erythematosus and other collagen vascular disorders, thyroid disease, nephrotic syndrome, solid organ or bone marrow transplantation, and inflammatory bowel disease. The associations are not necessarily causative, and in some cases, the systemic illness is associated with increased risk for more than one type of neuropathy. The presence of a comorbid systemic illness is therefore cause for increased diagnostic scrutiny but is not otherwise incompatible with a diagnosis of CIDP, assuming all other electrodiagnostic features are consistent. Some authors have identified an association of diabetes mellitus as a risk for CIDP [55,56], but others have not [57,58]. Accurate interpretation of abnormalities in nerve conduction studies performed in patients with diabetes may impact the assessment of this association [59]. Even though demyelinating changes on nerve conduction studies can occur in diabetic neuropathy, rapidly progressive weakness and sensory ataxia in a diabetic patient with demyelinating changes on nerve conduction studies should raise the possibility of CIDP.
Genetic mimics of CIDP — Certain genetic disorders of peripheral nerve myelin have characteristics that can mimic the clinical or electrodiagnostic features of CIDP or its variants. Most genetic neuropathies are symmetric length dependent but can involve proximal muscles when severe. These include:
●Charcot-Marie-Tooth (CMT) disease, particularly CMT1A, adult-onset CMT1B, CMT1X, and recessive cases such as CMT4 (eg, CMT4C due to SH3 domain and tetratricopeptide repeats 2 [SH3TC2] genetic variants), can cause multifocal, nonuniform slowing and conduction block. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)
●Hereditary neuropathy with liability to pressure palsies, which causes conduction slowing at compression sites. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy'.)
●Transthyretin (TTR) familial amyloid polyneuropathy (FAP) due to variants in the TTR gene is typically axonal but occasionally can manifest as a demyelinating polyneuropathy with features that overlap with CIDP, particularly sporadic, late-onset (>50 years) forms of the disease [60]. Clues that may alert the clinician to the possibility of TTR-FAP include prominent pain, dysautonomia, distal upper limb motor deficits, extension of small fiber sensory loss above the wrist, and absence of ataxia. Sequencing of the TTR gene can confirm the diagnosis. This is of particular importance as new therapies for FAP are available. (See "Genetic factors in the amyloid diseases", section on 'Transthyretin'.)
A careful family history and examination of parents and siblings are important if these disorders are a consideration, although absence of a family history does not rule out a genetic cause [61]. Appropriate genetic testing should be considered in select patients, particularly for peripheral myelin protein 22 (PMP22) gene duplication or deletion, connexin 32, and TTR.
DIAGNOSTIC EVALUATION — While the initial suspicion for CIDP is clinical, the diagnosis is confirmed by evidence of peripheral nerve demyelination, which must be demonstrated by electrodiagnostic findings or rarely by nerve biopsy, and exclusion of other disorders that may cause or mimic CIDP. (See 'Differential diagnosis' above.)
We suggest using one of the published sets of diagnostic criteria for CIDP to guide the evaluation, improve diagnostic accuracy, and avoid misdiagnosis [62]. We prefer the 2021 European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) criteria for this purpose. (See 'Diagnosis' below and 'EAN/PNS criteria' below.)
History and neurologic examination — The diagnosis of CIDP should be considered in patients presenting with a progressive or relapsing-remitting polyneuropathy involving both motor and sensory axons along with areflexia, particularly when weakness predominates and affects proximal and distal muscles simultaneously and symmetrically. Symptom progression or relapses must be present for at least eight weeks. The diagnosis can be more difficult in patients presenting with multifocal or sensory-predominant symptoms that characterize the less common, atypical CIDP variants. (See 'Typical CIDP (symmetric sensorimotor)' above and 'CIDP variants and related conditions' above.)
Elements of the history and examination that should raise suspicion for an alternative diagnosis include the presence of weakness in the respiratory muscles; clear asymmetric pattern of weakness; severe tremor, ataxia, or muscle weakness at disease onset; prominent autonomic dysfunction; prominent pain; and no improvement after one or more effective therapies (eg, glucocorticoids, intravenous immune globulin [IVIG]) [6].
Electrodiagnostic testing — Electrodiagnostic testing (nerve conduction studies of both sensory and motor nerves, electromyography [EMG]) should be performed in all patients with suspected CIDP and is a critical component of the evaluation [16].
The characteristic electrophysiologic features of CIDP are those of peripheral nerve demyelination (table 1), which include:
●Partial conduction block (see "Overview of nerve conduction studies", section on 'Conduction block')
●Conduction velocity slowing (see "Overview of nerve conduction studies", section on 'Demyelination'):
•Prolonged distal motor latencies
•Delay or disappearance of F waves (see "Overview of nerve conduction studies", section on 'F wave')
●Temporal dispersion and distance-dependent reduction of compound motor action potential (CMAP) amplitude [63]
The overwhelming majority of patients with CIDP will have electrodiagnostic evidence of primary demyelination [64]. However, other focal or generalized nerve diseases (eg, diabetic neuropathy) can also result in slow conduction velocities or apparent block in neural conduction. For example, because of significant clinical and electrodiagnostic overlap, careful assessment and adherence to criteria is needed to discriminate between patients with diabetic neuropathy and the distal acquired demyelinating symmetric neuropathy (DADS) variant of CIDP. Additionally, it may be difficult to determine conduction slowing in patients who have severe axonal loss. Evaluating nerves that supply more proximal and less severely denervated muscles may be helpful in finding the conduction abnormalities. (See 'EAN/PNS criteria' below.)
Various sets of electrodiagnostic criteria for demyelinating neuropathy have been established to address these and other complexities (table 1). While these criteria can be helpful to the clinician, none have ideal sensitivity and specificity [16,64]. Extensive studies of the upper limbs or all four limbs, rather than unilateral or lower limb studies, may improve the electrodiagnostic yield [65]. Cranial nerve conduction studies (eg, blink reflex) showing conduction slowing can also be useful for diagnosis.
Laboratory studies — There are no laboratory test findings that specifically point to CIDP. The purpose of testing is to look for disorders that are either associated with or mimic CIDP [16]. In most cases, laboratory evaluation in patients with suspected CIDP should include the following:
●Fasting serum glucose and/or oral glucose tolerance test
●Glycated hemoglobin (HbA1C)
●Serum calcium and creatinine
●Complete blood count
●Liver function tests
●Thyroid function studies
●Serum protein electrophoresis (SPEP) and immunofixation
●Serum free light chain (FLC) assay
Additional tests in selected patients, including those with atypical presentations, may include [16]:
●Borrelia burgdorferi serology
●C-reactive protein
●Antinuclear antibodies (ANAs)
●Angiotensin-converting enzyme
●Hepatitis panel (for types B and C)
●HIV antibody
●Chest radiograph
●Skeletal survey and vascular endothelial growth factor (VEGF) level, if a monoclonal gammopathy is found (see "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Evaluation' and "POEMS syndrome")
●Evaluation for inherited neuropathies such as Charcot-Marie-Tooth (CMT) disease or transthyretin (TTR) familial amyloid polyneuropathy (FAP) (see 'Genetic mimics of CIDP' above)
Antibody testing should be done selectively. Testing for anti-myelin-associated glycoprotein (anti-MAG) is recommended if an IgM gammopathy is identified. Neurofascin and contactin 1 antibody testing is not widely available at commercial laboratories but may be available by contacting certain research laboratories directly [66].
Lumbar puncture — Cerebrospinal fluid (CSF) analysis is performed for patients with suspected CIDP when the clinical and electrophysiologic findings are nondiagnostic. Albuminocytologic dissociation is a hallmark of CIDP and represents supportive evidence in the EAN/PNS diagnostic criteria [16]. (See 'EAN/PNS criteria' below.)
CSF protein is elevated (>45 mg/dL) and the CSF white cell count is normal (ie, the classic albuminocytologic dissociation) in over 80 percent of patients with CIDP [67-69]. An elevated CSF protein level in patients with diabetes mellitus should be attributed to CIDP if greater than 100 mg/dL. Additionally, using a higher threshold for CSF protein elevation (>60 mg/dL) in patients over age 50 can improve the specificity of CSF analysis in CIDP [70]. In most cases, the CSF protein level is >100 mg/dL, and elevations as high as 10 times the upper limits of normal are occasionally seen in patients with CIDP.
An increased CSF white cell count of >10 cells/mm3 should suggest a diagnosis other than CIDP, such as infection (eg, Lyme), inflammation (eg, sarcoidosis), or neoplasm (eg, lymphoma, leukemia). An exception to this general rule is that patients with HIV infection may have a CSF pleocytosis, although the CSF white cell count in patients with CIDP and HIV infection is generally <50/mm3 [71].
Additional testing in selected patients
Neuroimaging — Magnetic resonance imaging (MRI) with gadolinium of the spine (including spinal roots, cauda equina), brachial plexus, lumbosacral plexus, and other nerve regions can be used to look for enlarged or enhancing nerves. MRI abnormalities are useful as supportive criteria for CIDP in the EAN/PNS guidelines [16]. The MRI results can also guide selection of abnormal nerves for biopsy.
MRI is usually reserved for atypical cases, often when clinical and electrophysiologic findings are focal (such as multifocal CIDP), and to rule out other causes of neuropathy and infiltrative pathology [72]. MRI of the spine is particularly important if chronic immune sensory polyradiculopathy (CISP) or chronic immune sensorimotor polyradiculopathy (CISMP) are being considered, as these are rare disorders with clinical features that overlap with structural, infectious, and infiltrative causes of polyradiculopathy. (See 'Proximal (polyradiculopathy)' above.)
The sensitivity and specificity of MRI of the nerves in CIDP is not well established, and large studies with relevant controls have not been performed. In studies using a range of MRI techniques, most commonly brachial plexus MRI, nerve enlargement or enhancement is seen in approximately 40 to 80 percent of patients with CIDP [6,73,74].
Nerve ultrasound — When appropriate expertise is available, neuromuscular ultrasound can also be used to detect nerve hypertrophy in patients with acquired and hereditary forms of chronic demyelinating neuropathies. Although the findings are not specific for CIDP, they may help indicate regions of involvement. (See "Diagnostic ultrasound in neuromuscular disease", section on 'Findings in neuropathy'.)
Nerve biopsy — The diagnostic utility of nerve biopsy (typically of the sural nerve) for suspected CIDP is controversial [75-77], and nerve biopsy is not done on most patients with suspected CIDP, especially those with typical electroclinical findings. Nerve biopsy is used mainly when other studies fail to clearly establish the diagnosis of CIDP, particularly when electrophysiologic criteria for demyelination are not met or there is high suspicion for an infiltrative or vasculitic process.
A major limitation of nerve biopsy is suboptimal sensitivity and specificity [61]. CIDP is a multifocal disorder, and motor nerve fibers tend to be more affected than sensory nerves (the usual nerves used for biopsy). As a result, the biopsy sample may not demonstrate the demyelination. In addition, the inflammatory component of CIDP may not be prominent and thus may not be apparent on biopsy.
Despite these drawbacks, nerve biopsy can provide solid evidence of demyelination. In addition, biopsy occasionally reveals other neuropathies that mimic CIDP, such as those due to amyloidosis [78], sarcoidosis, and vasculitis [79]. (See "Overview of amyloidosis", section on 'Neurologic abnormalities' and "Neurologic sarcoidosis" and "Clinical manifestations and diagnosis of vasculitic neuropathies".)
The nerve selected for biopsy should be one that is clinically and electrophysiologically affected by the disorder [61]. However, care should be taken to choose a nerve that has either electrophysiologic or clinical evidence of functionality, as completely degenerated nerves usually convey limited information. Typically, the sural nerve is biopsied, but other candidate nerves include the superficial peroneal, superficial radial, and gracilis motor nerve. Electron microscopy and teased fiber analysis of nerve biopsy specimens is highly desirable [61].
Supportive features for CIDP on nerve biopsy include endoneurial edema, macrophage-associated demyelination, demyelinated and remyelinated nerve fibers, onion bulb formation, endoneurial mononuclear cell infiltration, and inhomogeneous involvement of different fascicles and different areas within the same fascicle [61]. (See 'Neuropathologic findings' above.)
Role of treatment trial — A treatment trial may be indicated if the diagnosis remains unclear despite a thorough evaluation. Clear improvement using objective clinical measures or electrodiagnostic testing after a three-month trial with first-line immunotherapy may add supportive evidence to the diagnosis of CIDP. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)
DIAGNOSIS — There is general agreement that the following criteria support the diagnosis of the classic form of CIDP:
●Progression over at least two months
●Weakness more than sensory symptoms
●Symmetric involvement of arms and legs
●Proximal muscles involved along with distal muscles
●Widespread reduction or loss of deep tendon reflexes
●Increased cerebrospinal fluid (CSF) protein without pleocytosis
●Nerve conduction evidence of a demyelinating neuropathy
●Nerve biopsy evidence of segmental demyelination with or without inflammation
●Gait ataxia secondary to large fiber sensory loss
However, there is still no gold-standard set of diagnostic criteria for the electrophysiologic identification of demyelination, or for the clinical diagnosis of CIDP and its variants, even though multiple sets of diagnostic criteria have been published [16,28,30,61,63,64,67,71,80-85]. Differences between sets of criteria are related to variations in definitions of the clinical features, the requirements for nerve biopsy, electrodiagnostic assessment of demyelination, and the number of individual criteria required to make the diagnosis. The plethora of criteria sets for CIDP illustrate the difficulty of developing precise standards for problems that have multiple variations.
We believe that the European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines, revised in 2021, are the most useful for clinical practice and patient care (table 1) [16,61,86]. Retrospective studies comparing diagnostic criteria for CIDP have confirmed the accuracy of the EAN/PNS criteria [87,88]. When independently validated in a retrospective study, the original criteria from 2006 had a sensitivity and specificity of 81 and 97 percent, respectively [89]. Similarly, the 2021 revised criteria were found to have a sensitivity of 83 percent and specificity of 94 percent in a retrospective cohort of patients with suspected CIDP and an objective treatment response [90]. Further studies will help determine the optimal approach for defining atypical CIDP variants [28].
EAN/PNS criteria — The 2021 EAN/PNS guidelines are the 2nd revision of the European Federation of Neurological Societies (EFNS)/PNS guidelines. The 2021 guidelines define CIDP as typical (ie, classic) or variant form [16]. The diagnosis of CIDP is based upon clinical, electrodiagnostic (mandatory), and supportive criteria:
●Clinical inclusion criteria for typical CIDP require both of the following:
•Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of at least two limbs, developing over two months or longer; cranial nerves may be affected
•Absent or reduced tendon reflexes in all extremities
●Clinical inclusion criteria for CIDP variants require one of the following, but otherwise as in typical CIDP. However, tendon reflexes may be normal in unaffected limbs:
•Predominantly distal (distal acquired demyelinating symmetric neuropathy [DADS]); or
•Asymmetric (multifocal acquired demyelinating sensory and motor neuropathy [MADSAM], Lewis-Sumner syndrome); or
•Focal (eg, involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in one upper or lower limb); or
•Pure motor; or
•Pure sensory
●Clinical exclusion criteria:
•Neuropathy probably caused by B. burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure
•Hereditary demyelinating neuropathy
•Prominent sphincter disturbance
•Diagnosis of multifocal motor neuropathy (MMN)
•IgM monoclonal gammopathy with high titer antibodies to myelin-associated glycoprotein (MAG)
•Other causes for a demyelinating neuropathy including POEMS syndrome, osteosclerotic myeloma, and diabetic and nondiabetic lumbosacral radiculoplexus neuropathy; peripheral nervous system lymphoma and amyloidosis may occasionally have demyelinating features
●Electrodiagnostic criteria for CIDP include parameters to identify motor and sensory conduction abnormalities that suggest demyelination (table 1).
●Supportive criteria:
•Elevated CSF protein with leukocyte count <10/mm3
•Magnetic resonance imaging (MRI) showing gadolinium enhancement and/or hypertrophy of the cauda equina, lumbosacral or cervical nerve roots, or the brachial or lumbosacral plexuses
•Ultrasound of peripheral nerve revealing nerve enlargement in at least two sites
•Abnormal sensory electrophysiology in at least one nerve:
-Normal sural with abnormal median (excluding median neuropathy at the wrist from carpal tunnel syndrome) or radial sensory nerve action potential (SNAP) amplitudes; or
-Conduction velocity <80 percent of lower limit of normal (<70 percent if SNAP amplitude <80 percent of lower limit of normal); or
-Delayed somatosensory evoked potentials (SSEPs) without central nervous system (CNS) disease
•Objective clinical improvement following immunomodulatory treatment
•Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination by electron microscopy or teased fiber analysis
The EAN/PNS diagnostic categories (ie, degrees of certainty) are determined by the combination of clinical, electrodiagnostic (table 1), and supportive criteria as follows [16]:
●Possible CIDP:
•Typical or atypical CIDP by clinical inclusion criteria, and
•No clinical exclusion criteria, and
•CIDP by electrodiagnostic criteria in one nerve (table 1)
or
•Typical or atypical CIDP by clinical inclusion criteria, and
•No clinical exclusion criteria, and
•Possible CIDP by electrodiagnostic criteria in one nerve (table 1), and
•Objective response to treatment, and
•One other supportive criterion
●CIDP:
•Typical or atypical CIDP by clinical inclusion criteria, and
•No clinical exclusion criteria, and
•CIDP by electrodiagnostic criteria in two nerves (table 1)
or
•Possible CIDP (as above), and
•Two or more additional supportive criteria
DIAGNOSTIC PITFALLS — Both clinical experience and data from retrospective studies suggest that over-diagnosis of CIDP is common, involving one-third to nearly one-half of patients so labeled [62,91]. Furthermore, many of those with an erroneous diagnosis of CIDP are exposed to the potential toxicities and costs of long-term treatment with intravenous immune globulin (IVIG) and glucocorticoids [62,91].
Patients with atypical features or diagnostic uncertainty should be referred to a neuromuscular specialist with expertise in the diagnosis of peripheral nerve disorders. The GBS/CIDP Foundation International has identified clinical centers of excellence around the world that specialize in the diagnosis and treatment of Guillain-Barré syndrome (GBS) and CIDP.
Problems leading to a misdiagnosis of CIDP in these reports included the following [62,91,92]:
●Failure to focus on symptoms and signs that characterize CIDP
●Technically inadequate or misinterpreted electrodiagnostic studies (eg, a lax electrodiagnostic interpretation of demyelination)
●Failure to adhere to diagnostic criteria
●Over-emphasis on a minimally elevated cerebrospinal fluid (CSF) protein level in a patient whose syndrome does not otherwise meet criteria for CIDP
●Excessive reliance on subjective measures of patient-reported treatment response
As an example, in a report of 59 consecutive patients referred to an expert center with a diagnosis of CIDP made elsewhere, the proportion who failed to meet diagnostic criteria was 47 percent [62]. The correct diagnoses in these cases were heterogeneous and included diabetic polyneuropathy, multifactorial neuropathy, multifocal motor neuropathy (MMN), and hereditary neuropathy, but a number of patients had non-neuropathic disorders such as amyotrophic lateral sclerosis and fibromyalgia.
Of note, none of the patients in this report who were misdiagnosed with CIDP satisfied the diagnostic inclusion criteria for typical CIDP, while 44 percent fulfilled the clinical inclusion criteria for atypical CIDP without meeting electrodiagnostic criteria [62]. This finding suggests that the diagnosis of atypical CIDP is particularly challenging and requires astute interpretation of electrodiagnostic and laboratory data, as well as rigorous adherence to diagnostic criteria.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired neuropathy affecting peripheral nerves and nerve roots. The characteristic pathologic features of CIDP include segmental demyelination and remyelination of peripheral nerves, resulting in onion bulb formation. The disorder is immunologically mediated but the precise cause is unclear in most cases. (See 'Pathogenesis' above.)
●Typical presentations – Typical CIDP is characterized by a symmetric, motor-predominant peripheral neuropathy that causes both proximal and distal weakness, sensory impairment that is usually greater for vibration and position sense than for pain and temperature sense, and areflexia. The course can be progressive or relapsing-remitting. (See 'Typical CIDP (symmetric sensorimotor)' above.)
●Atypical presentations and related conditions – Other forms of CIDP distinguished by specific features include (see 'CIDP variants and related conditions' above):
•Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also known as Lewis-Sumner syndrome
•Focal form of CIDP
•Pure motor form of CIDP
•Sensory-predominant form of CIDP
•Distal form of CIDP
•Proximal CIDP
•Nodal and paranodal disorders
●Differential diagnosis – CIDP is one of several neuropathies that share demyelination and immune mediation in common. Other causes in the differential diagnosis of CIDP include acute inflammatory demyelinating polyneuropathy (AIDP), other chronic demyelinating neuropathies (eg, multifocal motor neuropathy), and some genetic neuropathies associated with peripheral nerve demyelination (eg, Charcot-Marie-Tooth disease). (See 'Differential diagnosis' above.)
●Diagnostic evaluation – The clinical diagnosis of CIDP is confirmed by electrodiagnostic findings showing characteristic peripheral nerve demyelination (table 1). (See 'Electrodiagnostic testing' above.)
Additional testing is used to support clinical and electrodiagnostic results:
•Screening laboratory studies and lumbar puncture for cerebrospinal fluid analysis are typically performed for all patients to exclude alternative causes of symptoms. (See 'Laboratory studies' above and 'Lumbar puncture' above.)
•Neuroimaging with MRI and/or ultrasound is reserved for patients with atypical presentations when initial diagnostic testing is inconclusive and to exclude structural or infiltrative causes to symptoms. (See 'Neuroimaging' above and 'Nerve ultrasound' above.)
•Nerve biopsy may be performed when other studies fail to clearly establish the diagnosis of CIDP or when there is high suspicion for an infiltrative or vasculitic process. (See 'Nerve biopsy' above.)
●Diagnostic criteria – The following general criteria support the diagnosis of the classic form of CIDP (see 'Diagnosis' above):
•Progression over at least two months
•Weakness more than sensory symptoms
•Symmetric involvement of arms and legs
•Proximal muscles involved along with distal muscles
•Widespread reduction or absence of deep tendon reflexes
•Gait ataxia secondary to large fiber sensory loss
•Increased cerebrospinal fluid (CSF) protein without pleocytosis
•Nerve conduction evidence of a demyelinating neuropathy
•Nerve biopsy evidence of segmental demyelination with or without inflammation
To improve diagnostic accuracy and avoid misdiagnosis, we suggest utilizing one of the published sets of diagnostic criteria for CIDP; we prefer the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) criteria for this purpose. (See 'Diagnosis' above and 'EAN/PNS criteria' above.)
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