Chronic inflammatory demyelinating polyneuropathy Etiology, clinical features, and diagnosis Author Richard Lewis, MD INTRODUCTION Chronic inflammatory

y demyelinating polyneuropathy (CIDP, also known as chronic inflammatory demyelinating polyradiculoneuropathy) is an acquired disorder of peripheral nerves and nerve roots. There have been descriptions of patients with disorders that would now be considered CIDP for over 75 years, and the landmark report of Austin in 1958 described two patients with relapsing disease and glucocorticoid response. The concept of CIDP as a distinct entity was introduced in 1975 when a review of the clinical, electrodiagnostic, and pathologic findings of 53 patients was presented [2]. While that publication did not include "demyelinating" in the title, subsequent reports have included it, and demyelination is now recognized as a cardinal feature of the disorder. The classification, etiology, clinical features, and diagnosis of CIDP will be reviewed here. Treatment and prognosis of this disorder are discussed separately. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".) CLASSIFICATION Whether CIDP is a disease or a syndrome remains controversial. The following neuropathies all have chronicity, demyelination, inflammation, or immune-mediation in common: CIDP Multifocal motor neuropathy (MMN) Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) Distal demyelinating neuropathy with IgM paraprotein, with or without anti-myelin associated glycoprotein (anti-MAG) Demyelinating neuropathy with IgG or IgA paraprotein (the terms paraprotein and monoclonal gammopathy of undetermined significance [MGUS] are used synonymously in this setting) POEMS syndrome (osteosclerotic myeloma: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) (see "POEMS syndrome (osteosclerotic myeloma)") Sensory predominant demyelinating neuropathy Demyelinating neuropathy with central nervous system demyelination Demyelinating neuropathy associated with systemic disorders, including: Hepatitis B or C HIV infection Lymphoma Diabetes mellitus Systemic lupus erythematosus or other collagen vascular disorders Thyrotoxicosis Organ or bone marrow transplants Inherited neuropathies Nephrotic syndrome Inflammatory bowel disease While there is no established consensus regarding the classification of all these neuropathies, there is general agreement that MMN, POEMS, and the MAG-related neuropathies are separate from CIDP and the other neuropathies on the basis of clinical, electrodiagnostic, and therapeutic distinctions. Most investigators consider the remaining disorders to be variants of CIDP since they have many clinical and electrodiagnostic features in common and treatment response with immunotherapy appears to be similar. The classification of inflammatory demyelinating neuropathies will continue to evolve as specific immune mechanisms are elucidated. Temporal continuum There is a temporal continuum between acute inflammatory demyelinating polyneuropathy (AIDP), the demyelinating form of Guillain-Barr syndrome, and CIDP. AIDP is a monophasic subacute illness that reaches its nadir within three to four weeks 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 [3,4] 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 [5], 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 Guillain-Barr syndrome, and CIDP is recognized only after relapses or progression occur over the ensuing few months. In addition to chronicity, other features may be useful to distinguish Guillain-Barr syndrome (including AIDP) from CIDP. The onset of Guillain-Barr syndrome is usually easily identified, while the precise onset of CIDP is typically less clear. (See "Clinical features and diagnosis of Guillain-Barr syndrome in adults".) Antecedent events are more frequent with Guillain-Barr syndrome 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. In contrast, most studies have found an antecedent event prior to CIDP in no more than 30 percent of patients. (See "Pathogenesis of Guillain-Barr syndrome in adults", section on 'Antecedent events'.) PATHOGENESIS Although the cause of CIDP and its variants is unknown, there is evidence to support the hypotheses that the disorder(s) are immunologically based and have multiple triggers [6,7]. Both the cellular and humoral components of the immune system appear to be involved in the pathogenesis of CIDP and its variants [6,8]. Cellular immunity involvement is supported by evidence of T-cell activation, crossing of the blood-nerve barrier by activated T-cells, and by expression of cytokines, tumor necrosis factor, interferons, and interleukins. Humoral immunity is implicated by the demonstration of immunoglobulin 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. However, the immunologic cause(s) of CIDP remain unclear, since specific provoking antigens have not been identified [8]. EPIDEMIOLOGY The estimated prevalence of CIDP in populations from the UK, Australia, Italy, Japan, and the US is 0.8 to 8.9 per 100,000 [9-14]. CIDP can affect all ages but is more common in older males. It is thought that the disease is more likely to be progressive in the older age group and relapsing-remitting in younger patients. No specific predisposing factors for CIDP have been identified. There have been conflicting studies on human leukocyte antigen (HLA) type associations, but no clear genetic predisposition has been found. In several case reports, treatment with tumor necrosis factoralpha inhibitors has been associated with the subsequent development of chronic demyelinating neuropathies [15]. CLINICAL MANIFESTATIONS The initial description of CIDP in 1975 pointed out the major cardinal features of the disorder [2]. The classic form of CIDP is fairly symmetric and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles, and this pattern is a hallmark of acquired demyelinating polyneuropathy [5]. Cranial nerve and bulbar involvement occur in 10 to 20 percent of patients. Most patients with CIDP also have sensory involvement and globally diminished or absent reflexes [2,16]. 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. Unlike the motor involvement, the sensory involvement tends to follow a distal to proximal gradient, although finger involvement is frequently seen as early as toe and foot involvement. Painful dysesthesias can occur in some patients. Constipation and urinary retention are not usually early symptoms of CIDP, but may occur in more severe cases. Back pain may be present. Symptoms of lumbar spinal stenosis and cauda

equine syndrome can occur rarely if there is marked nerve root hypertrophy, and may require surgical intervention. Most patients with 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 [16]. 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. Variants of CIDP The clinical variants of CIDP are distinguished by their presentation and include the Lewis-Sumner syndrome, sensory-predominant CIDP, distal acquired demyelinating sensory neuropathy, and CIDP with central nervous system (CNS) involvement. Lewis-Sumner syndrome The Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), presents with a much more striking multifocal picture, indistinguishable from other forms of mononeuropathy multiplex, with sensory and/or motor symptoms in individual nerve distributions [17,18]. Sensory-predominant CIDP The sensory-predominant form of CIDP is characterized clinically by sensory symptoms and signs with balance problems, pain, paresthesias, and dysesthesias. Despite the lack of weakness, the nerve conduction studies demonstrate significant motor conduction slowing and other demyelinating features [19]. Distal acquired demyelinating sensory neuropathy Distal acquired demyelinating sensory neuropathy (DADS) is usually more slowly progressive than typical CIDP, and is frequently associated with an IgM paraprotein [5,20]. DADS with IgM paraprotein, whether or not associated with anti-MAG, is usually considered to be distinct from CIDP because it tends to be resistant to the standard immunomodulatory therapies for CIDP. Approximately one-half of patients with DADS and IgM paraprotein also have anti-MAG antibodies, but it is unclear whether presence or absence of these antibodies alters the clinical features of this disorder. DADS without IgM paraprotein is generally considered to be variant of CIDP because it may respond to treatment with immunomodulatory therapies. CIDP with CNS involvement CIDP is occasionally associated with CNS involvement, including optic nerve disorders, hyperreflexia, Babinski signs, and MRI abnormalities of CNS demyelination. However, it is unclear whether these combined signs represent associated disease entities or coincidental occurrences of unrelated diseases [21]. Electrophysiology Peripheral nerve demyelination underlies the characteristic electrophysiologic features of CIDP, which are as follows: Partial conduction block Conduction velocity slowing Prolonged distal motor latencies Delay or disappearance of F waves Dispersion and distance dependent reduction of compound motor action potential (CMAP) amplitude Pathology The characteristic pathologic features of CIDP include segmental demyelination and remyelination, and onion bulb formation [2]. The term onion-bulb formation" refers to the appearance of affected nerves when viewed under the microscope in transverse section. As a result of repeated episodes of demyelination and remyelination, such nerves are enlarged due to whorls of overlapping and proliferating Schwann cell processes encircling bare axons. Some degree of axonal degeneration is usually present as well [22]. Varying degrees of interstitial edema and endoneurial inflammatory cell infiltrates, including lymphocytes and macrophages, are additional pathologic features of CIDP. The macrophages are thought to initiate the demyelination by unraveling and degrading the myelin [23]. Unfortunately, this is not commonly found on most biopsy specimens. While the exact mechanism of axonal degeneration in CIDP is not known, it has been considered to be a secondary bystander product of the inflammatory demyelinating process. DIAGNOSIS The diagnosis of CIDP should be considered in patients with symmetric or asymmetric polyneuropathy who have a progressive or relapsing-remitting clinical course for more than two months, particularly if the clinical features include positive sensory symptoms,

proximal weakness, areflexia without wasting, or selective loss of vibration or joint position sense [24]. While the initial diagnosis of CIDP is clinical, the diagnosis is confirmed by evidence from electrodiagnostic studies, and in some cases by cerebrospinal fluid analysis, nerve biopsy findings, and other laboratory investigations. Peripheral nerve demyelination must be demonstrated by either electrodiagnostic findings or by nerve biopsy. The clinical features that distinguish CIDP from chronic length-dependent (ie, axonal) peripheral neuropathies are the prominence of muscle weakness and the involvement of upper extremity and proximal muscles, as well as distal muscles. In contrast, axonal polyneuropathies are characterized by predominantly distal weakness. Furthermore, deep tendon reflexes are globally reduced or absent in CIDP, whereas only the ankle reflexes are diminished in typical axonal polyneuropathies. The features of CIDP point to the multifocal or generalized nature of the disease even at early stages of the illness. To confirm the diagnosis of CIDP, the clinician must be sure that the patient has a clinical picture that is consistent with the diagnosis and that the electrophysiology and/or other studies (CSF, nerve biopsy, MRI) have features suggesting a demyelinating neuropathy. A treatment trial may be indicated if the diagnosis remains unclear despite a thorough evaluation, since a positive response to immunotherapy may add supportive evidence to the diagnosis of CIDP. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".) Diagnostic criteria 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 Reduced deep tendon reflexes throughout Increased cerebrospinal fluid protein without pleocytosis Nerve conduction evidence of a demyelinating neuropathy Nerve biopsy evidence of segmental demyelination with or without inflammation 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 since 1989 [5,24-30]. Differences between these sets are related to definitions of the clinical picture, the requirements for nerve biopsy, electrodiagnostic criteria for demyelination, and the number of features 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. Two sets of criteria the Koski and the EFNS/PNS deserve special mention. Koski criteria The Koski criteria were derived by predictive modeling of the clinical data of 150 patients who were diagnosed by expert consensus as having CIDP or other polyneuropathies [29]. For the diagnosis of idiopathic CIDP, the Koski criteria require the following: Chronic polyneuropathy, progressive for at least eight weeks No serum paraprotein and no genetic abnormality and Either Recordable compound muscle action potentials in at least 75 percent of motor nerves and either abnormal distal latency or abnormal motor conduction velocity or abnormal F wave latency in >50 percent of motor nerves Or Symmetric onset or symmetric exam and weakness in all four limbs and proximal weakness in at least one limb Of note, while the Koski criteria combine clinical presentation and electrophysiologic abnormalities, either is sufficient to establish the diagnosis. One of the striking features of this classification method is that patients who have symmetric proximal and distal weakness are so likely to have CIDP that nerve conduction studies are primarily confirmatory. In an internal validation sample of 117 patients, the sensitivity and specificity of the Koski criteria were 83 percent (95% CI 69-93) and 97 percent (95% CI 89-99) respectively [29].

EFNS/PNS criteria While the Koski classification is an interesting and valuable approach, we believe that the CIDP guideline from the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS), published in 2006 and updated in 2010 (table 1), is the one most useful for clinical practice and patient care [24,30]. When independently validated, the 2006 EFNS criteria had a sensitivity and specificity of 81 and 97 percent, whereas the Koski criteria had a sensitivity and specificity of 63 and 99 percent [31]. The lower sensitivity of the Koski criteria was primarily due problems detecting atypical cases of CIDP such as multifocal variants. Additional evidence supporting the utility of the EFNS/PNS guideline comes from an earlier retrospective report that compared the performance of three proposed CIDP classification schemes the American Academy of Neurology (AAN) criteria [26], the modified AAN criteria [5], and the 2006 EFNS/PNS criteria [24] by applying them to data from 76 patients with symmetric neurologic deficits and electrophysiologic and/or histologic evidence of peripheral nerve demyelination [32]. The sensitivities for the diagnosis of CIDP differed markedly for the AAN, modified AAN, and EFNS/PNS criteria (0.52 versus 0.83 versus 0.95), while all three had similar specificities (0.94 versus 0.90 versus 0.96). Overall, the results favored use of the EFNS/PNS criteria with respect to diagnosis. The EFNS/PNS guideline defines CIDP as typical (ie, classic) or atypical [30]. Atypical CIDP encompasses variants of CIDP with predominantly distal weakness such as DADS, and variants with pure motor or pure sensory presentations. (See 'Variants of CIDP' above.) The EFNS/PNS diagnostic categories are determined by clinical, electrodiagnostic, and supportive criteria [30]. For definite CIDP, one must have a typical or atypical clinical picture with clear demyelinating electrodiagnostic changes in two nerves, or probable demyelinating features in two nerves plus at least one supportive feature (from cerebrospinal fluid analysis, nerve biopsy, MRI, or treatment response to immunotherapy). Diagnostic evaluation Electrodiagnostic testing is recommended for all patients with suspected CIDP [24,30]. Additional studies that may be indicated in select patients include: Cerebrospinal fluid analysis Nerve biopsy MRI of spinal roots, brachial plexus, and lumbosacral plexus Laboratory studies Evaluation for inherited neuropathies Electrodiagnostic testing A critical component of the CIDP evaluation, electrodiagnostic testing is used to determine if there is demyelination, which causes reduced conduction velocity, prolonged distal motor latencies, dispersion and distance-dependent reduction of compound motor action potential (CMAP) amplitude [28], and delay or disappearance of F waves. Most, but not all, patients with CIDP will have electrodiagnostic evidence of primary demyelination [33]. However, other focal or generalized nerve diseases (eg, diabetic neuropathy) can also result in slow conduction velocities or apparent block in neural conduction. As already mentioned, various sets of electrodiagnostic criteria for demyelinating neuropathy have been established to address this problem (table 1). While these criteria can be helpful to the clinician, none have ideal sensitivity and specificity [33]. Extensive studies of the upper limbs or all four limbs, rather than unilateral or lower limb studies, may improve the electrodiagnostic yield [34]. Cerebrospinal fluid analysis A lumbar puncture is supportive of the diagnosis of CIDP when the cerebrospinal fluid (CSF) protein is elevated and the CSF white cell count is normal (ie, the classic albuminocytologic dissociation). This finding is present in over 90 percent of patients with CIDP [25]. CSF protein 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/mm^3 should suggest a diagnosis other than CIDP. An exception to this general rule is that patients with HIV infection may have a cerebrospinal fluid pleocytosis, although the CSF white cell count in patients with CIDP and HIV infection is generally <50/mm^3 [26]. Nerve biopsy The diagnostic utility of nerve biopsy (typically of the sural nerve) for suspected CIDP is controversial [35-37]. 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. A major limitation of nerve biopsy is suboptimal sensitivity and specificity [24,30]. 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, sarcoidosis, and vasculitis. (See "An overview of amyloidosis", section on 'Neurologic abnormalities' and "Neurologic sarcoidosis" and "Clinical manifestations of vasculitic neuropathy" and "Diagnosis and treatment of vasculitic neuropathy".) The nerve selected for biopsy should be one that is clinically and electrophysiologically affected by the disorder [30]. However, care should be taken to choose a nerve that has either electrophysiologic or clinical evidence of functionality, as completely devastated 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 [30]. Supportive features for CIDP on nerve biopsy include the following [30]: Endoneurial edema Macrophage-associated demyelination Demyelinated and remyelinated nerve fibers Onion bulb formation (see 'Pathology' above) Endoneurial mononuclear cell infiltration Variation between fascicles MRI MRI with gadolinium of the 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 EFNS/PNS guideline [30]. The MRI results can also guide selection of abnormal nerves for biopsy [24]. Laboratory studies There are no blood tests that specifically point to CIDP. However, a number of studies are useful to look for disorders that are either associated with or mimic CIDP [30]. These include: Fasting serum glucose and/or oral glucose tolerance test Glycated hemoglobin Thyroid function studies Hepatitis profiles HIV antibody Serum and urine immunofixation electrophoresis to detect paraprotein Complete blood count Renal function tests Liver function tests Borrelia burgdorferi serology C reactive protein Antinuclear antibodies Extractable nuclear antigen antibodies Angiotensin converting enzyme Chest radiograph Skeletal survey, if a paraprotein is found. Genetic considerations Certain genetic disorders of peripheral nerve myelin have characteristics that can mimic the clinical or electrodiagnostic features of CIDP or its variants. These include: Hereditary neuropathy with liability to pressure palsies (see "Overview of hereditary neuropathies", section on 'Hereditary neuropathy with liability to pressure palsy') Charcot-Marie-Tooth (CMT) disease, particularly CMT1A, adult-onset CMT1B, and CMT1X (see "Hereditary primary motor sensory neuropathies, including Charcot-MarieTooth disease")

A careful family history and examination of parents and siblings is important if these disorders are a consideration [30]. Appropriate genetic testing should be considered in select patients, particularly for PMP22 gene duplication or deletion and connexin 32 mutations SUMMARY AND RECOMMENDATIONS Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired disorder of peripheral nerves and nerve roots. Whether CIDP is a disease or a syndrome remains controversial. (See 'Classification' above.) There is a temporal continuum between acute inflammatory demyelinating polyneuropathy (AIDP), the demyelinating form of Guillain-Barr syndrome, and CIDP. (See 'Temporal continuum' above.) Both the cellular and humoral components of the immune system appear to be involved in the pathogenesis of CIDP and its variants. However, the precise cause is unclear, since specific provoking antigens have not been identified. (See 'Pathogenesis' above.) The classic form of CIDP is fairly symmetric and motor involvement is greater than sensory. Weakness is present in both proximal and distal muscles. Most patients also have sensory involvement and globally diminished or absent reflexes. Sensory impairment in CIDP is usually greater for vibration and position sense than for pain and temperature sense. Cranial nerve and bulbar involvement occur in a minority. Most patients have a slowly progressive course, but a relapsing-remitting course is noted in at least one-third. (See 'Clinical manifestations' above.) Major clinical variants of CIDP include (see 'Variants of CIDP' above): Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also known as Lewis-Sumner syndrome A sensory-predominant form of CIDP Distal acquired demyelinating sensory neuropathy (DADS) The following criteria support the diagnosis of the classic form of CIDP (see 'Diagnosis' above and 'Diagnostic criteria' 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 Reduced deep tendon reflexes throughout Increased cerebrospinal fluid protein without pleocytosis Nerve conduction evidence of a demyelinating neuropathy Nerve biopsy evidence of segmental demyelination with or without inflammation While the initial diagnosis of CIDP is clinical, peripheral nerve demyelination must be demonstrated by either electrodiagnostic testing (table 1) or by nerve biopsy. Electrodiagnostic testing is recommended for all patients with suspected CIDP. Additional investigations that are often indicated include (see 'Diagnostic evaluation' above): Cerebrospinal fluid analysis Nerve biopsy MRI of the spinal roots, brachial plexus, and lumbosacral plexus Laboratory studies to look for disorders that are either associated with or mimic CIDP Evaluation for inherited neuropathies Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. AUSTIN JH. Recurrent polyneuropathies and their corticosteroid treatment; with fiveyear observations of a placebo-controlled case treated with corticotrophin, cortisone, and prednisone. Brain 1958; 81:157. 2. Dyck PJ, Lais AC, Ohta M, et al. Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 1975; 50:621.