Chronic inflammatory demyelinating polyneuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated disorder of the peripheral nervous system characterized by progressive symmetrical weakness, sensory impairment, and areflexia due to segmental demyelination of peripheral nerves and nerve roots.[1] The condition typically evolves over a period exceeding eight weeks, differentiating it from acute inflammatory neuropathies such as Guillain-Barré syndrome.[1] CIDP exhibits a male predominance with a 2:1 ratio and increases in incidence with age, with a mean onset around 60 years, though it can affect children.[1] Estimated prevalence ranges from 0.8 to 8.9 per 100,000 individuals, while pooled incidence is approximately 0.33 per 100,000 person-years.[1][2] Most cases are idiopathic, though associations with infections, connective tissue diseases like systemic lupus erythematosus, and viral infections such as HIV or hepatitis C have been reported.[1] Pathophysiologically, it involves T-cell and macrophage-mediated inflammation targeting myelin sheaths, leading to demyelination, attempted remyelination, and potential secondary axonal loss.[1] Clinically, patients present with proximal and distal motor weakness, paresthesias, numbness, and hyporeflexia, with sensory deficits more pronounced for vibration and proprioception than pain or temperature.[1] Diagnosis relies on clinical history, electrodiagnostic studies demonstrating prolonged motor latencies and conduction blocks, cerebrospinal fluid analysis showing elevated protein without pleocytosis, and sometimes nerve biopsy confirming demyelination.[3] The 2021 European Federation of Neurological Societies/Peripheral Nerve Society criteria offer 83% sensitivity and 94% specificity.[1] First-line treatments include intravenous immunoglobulin (IVIG) at 2 g/kg induction, corticosteroids, or plasma exchange, with most patients responding and approximately 40% achieving remission; maintenance therapy often involves steroid-sparing immunosuppressants like azathioprine.[1][3] Despite effective therapies, diagnostic challenges persist, with misdiagnosis rates up to 54%, particularly in atypical variants.[1]
Historical background
Initial descriptions and recognition
Cases consistent with chronic inflammatory demyelinating polyneuropathy (CIDP) were reported as early as the mid-20th century, often described as recurring or relapsing forms of neuritis distinct from acute conditions like Guillain-Barré syndrome (GBS). In 1958, J.H. Austin detailed patients with a fluctuating motor-sensory neuropathy characterized by progressive weakness, sensory loss, elevated cerebrospinal fluid (CSF) protein, and responsiveness to corticosteroid therapy, though without definitive pathological correlation at the time.[4] These early observations highlighted chronic progression over weeks to months, contrasting with GBS's rapid onset within four weeks, but lacked systematic distinction or inflammatory evidence from nerve biopsies.[5] Parallel advancements in animal modeling supported recognition of immune-mediated mechanisms underlying chronic demyelination. In 1955, Byron H. Waksman and Raymond D. Adams induced experimental allergic neuritis (EAN) in rabbits by injecting homogenized peripheral nerve tissue emulsified with Freund's adjuvant, resulting in inflammatory infiltrates, segmental demyelination, and clinical paralysis mimicking human polyneuropathies.[6] This model, refined through the 1950s and 1960s across species like guinea pigs and mice, demonstrated T-cell driven immune attacks on myelin sheaths, providing causal evidence for inflammation's role in peripheral nerve demyelination and influencing interpretations of human biopsy findings showing perivascular infiltrates and onion-bulb formations.[7] The formal identification of CIDP as a distinct entity occurred in 1975, when Peter J. Dyck and colleagues at Mayo Clinic analyzed 53 patients from a cohort of chronic idiopathic polyneuropathies, defining it as a symmetric sensorimotor disorder with progression exceeding eight weeks, proximal and distal weakness, areflexia, elevated CSF protein without pleocytosis, and nerve conduction slowing.[8] Pathological examination of sural nerve biopsies in 26 cases revealed prominent segmental demyelination with macrophage-mediated myelin stripping and endoneurial inflammation, though axonal degeneration affected about 25% of fibers; this differentiated CIDP from purely axonal or hereditary neuropathies and emphasized its immune-inflammatory nature akin to EAN.[5] Initially termed "chronic inflammatory polyradiculoneuropathy," the condition was noted for potential steroid responsiveness, though not universally, solidifying its separation from acute monophasic GBS.[8] ![CIDP histopathology showing teased fiber preparation with segmental demyelination][float-right]Evolution of understanding and criteria
Following the initial recognition of chronic inflammatory demyelinating polyneuropathy (CIDP) in the 1970s, advancements in the 1980s and 1990s emphasized electrophysiologic techniques to differentiate demyelinating from axonal pathology. Nerve conduction studies (NCS) identified key demyelinating features, including prolonged distal motor latencies, reduced conduction velocities exceeding 30% below lower limits of normal, prolonged F-wave latencies, and conduction block or temporal dispersion in motor nerves, contrasting with axonal loss marked primarily by reduced compound muscle action potential amplitudes without such slowing.[9] These criteria helped refine CIDP classification by quantifying multifocal demyelination, though early sets varied in stringency and often required biopsy confirmation for ambiguous cases.[10] In 2010, the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) published standardized diagnostic guidelines, integrating obligatory clinical features (progressive or relapsing weakness and sensory deficits over at least 2 months), supportive electrodiagnostic evidence of demyelination in at least three nerves, and optional cerebrospinal fluid protein elevation or nerve pathology.[11] These criteria achieved high sensitivity (up to 99% for definite CIDP) by allowing probable or possible diagnoses with fewer abnormalities, facilitating earlier intervention while reducing misclassification of mimics like diabetic neuropathy.[12] The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines updated these by simplifying clinical requirements to definite temporal evolution (progressive or relapsing course over 8 weeks) and proximal/distal involvement, introducing a "possible CIDP" category for atypical presentations with incomplete electrophysiology.[13] Enhancements included stricter specificity for variants like distal acquired demyelinating symmetric neuropathy and sensory-predominant forms, alongside recommendations for autoantibody testing in seronegative or treatment-refractory cases.[14] Discoveries in the 2010s of autoantibodies targeting nodal and paranodal proteins, such as contactin-1 and neurofascin-155/186, informed criteria revisions by delineating subsets with paranodal disruption, often showing poor intravenous immunoglobulin response but distinct electrophysiologic patterns like uniform conduction slowing.[15] These findings, validated in meta-analyses, prompted inclusion of serological testing in guidelines to subclassify cases beyond traditional demyelination metrics, though prevalence remains low (around 10-20% in typical CIDP).[16]Clinical presentation
Core signs and symptoms
Chronic inflammatory demyelinating polyneuropathy (CIDP) manifests primarily through progressive, symmetric weakness affecting both proximal and distal muscles of the upper and lower limbs, typically evolving over at least 8 weeks to distinguish it from acute forms like Guillain-Barré syndrome.[13] This weakness often begins in the legs, leading to difficulty rising from a chair, climbing stairs, or walking, and may progress to involve the arms with impaired fine motor tasks such as buttoning clothing.[1] Sensory disturbances, including numbness, tingling, and impaired vibration and position sense due to large-fiber involvement, accompany the motor deficits in most cases, though sensory symptoms are generally milder than motor ones.[17] Deep tendon reflexes are typically absent or markedly reduced throughout, reflecting widespread nerve root and peripheral nerve dysfunction.[18] Fatigue is a frequent complaint, exacerbating functional limitations and contributing to reduced quality of life, independent of the degree of weakness.[19] Gait instability arises from leg weakness and sensory ataxia, increasing fall risk and often necessitating assistive devices early in the course.[20] Pain, when present, is usually neuropathic and less dominant than in axonal neuropathies, affecting a subset of patients with burning or aching sensations in affected limbs.[19] Cranial nerve involvement occurs infrequently, with facial weakness reported in approximately 5-20% of cases, while bulbar or oculomotor deficits are rare.[21] Autonomic features, such as orthostatic hypotension or urinary dysfunction, appear in a minority of patients, around 25% showing mild involvement, based on clinical cohort data.[21] These core symptoms reflect the immune-mediated demyelination targeting motor and sensory nerves, with empirical evidence from diagnostic cohorts confirming their predominance in typical CIDP.[13][17]Variants and atypical forms
Lewis-Sumner syndrome, also designated as multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, manifests with asymmetric, multifocal sensory and motor impairments that simulate mononeuropathy multiplex, frequently accompanied by conduction blocks on electrophysiological testing and potential evolution toward a symmetric CIDP phenotype over time.[22][1] This variant affects 6-15% of CIDP cases and exhibits a less favorable response to first-line therapies compared to typical CIDP, with approximately 56% responsiveness to intravenous immunoglobulin (IVIG) and 50% to prednisone.[22][1] The distal acquired demyelinating symmetric (DADS) variant features symmetric, length-dependent distal sensory or sensorimotor deficits, distinguished by markedly prolonged distal motor latencies and frequent association with IgM paraproteins in up to 50% of instances, including anti-myelin-associated glycoprotein (MAG) antibodies.[22][1] Idiopathic DADS subtypes respond to standard immunomodulatory treatments like IVIG or plasma exchange in 70-80% of patients, whereas paraprotein-associated forms (DADS-M) demonstrate poorer outcomes with these agents and improved disability scores following rituximab administration.[22] Paranodal autoantibody-mediated forms, primarily involving IgG4 antibodies targeting contactin-1 (CNTN1, prevalence 2.2-8.7%) or neurofascin-155 (NF155, 4-18%), are marked by early disease onset, prominent sensory ataxia, tremor, and conduction blocks, alongside axonal involvement and resistance to IVIG or corticosteroids.[22][1][23] These subtypes, classified under autoimmune nodopathies, respond more effectively to rituximab or cyclophosphamide in refractory scenarios, reflecting distinct nodal/paranodal disruption distinct from classic cellular immune mechanisms in typical CIDP.[22][23]Etiology
Genetic and predisposing factors
Chronic inflammatory demyelinating polyneuropathy (CIDP) exhibits limited evidence of strong heritable components, with familial clustering occurring rarely and often confounded by misdiagnosis of underlying genetic neuropathies such as hereditary neuropathy with liability to pressure palsies or Charcot-Marie-Tooth disease.[24][25] Large-scale analyses indicate that CIDP susceptibility likely involves polygenic influences rather than monogenic inheritance, as twin studies and pedigree analyses show no consistent Mendelian patterns.[26] Human leukocyte antigen (HLA) associations have been investigated, revealing modest and inconsistent links; for instance, HLA-DR2 and HLA-DR3 alleles appear elevated in some cohorts, particularly among females for DR2, with relative risks not exceeding twofold in affected populations.[27][28] Other reports highlight HLA-DRB1*13 or DR3/DQ2 haplotypes in specific ethnic groups, but replication across studies is limited, and no allele confers high-penetrance risk.[29][30] Genome-wide association studies (GWAS), including the first large-scale effort in 2024 analyzing over 500 CIDP cases, have identified suggestive loci such as one at 20q13.33 in females but no genome-wide significant variants replicated across sexes or ancestries, underscoring weak polygenic contributions to onset.[31][32] Functional validation of candidate genes remains pending, with pathways implicating immune regulation but lacking causal confirmation.[26] Predisposing comorbidities amplify empirical risk, notably diabetes mellitus, present in up to 20% of CIDP cases versus population baselines, potentially via hyperglycemia-induced nerve vulnerability and immune dysregulation.[33][34] Monoclonal gammopathy of undetermined significance (MGUS), especially IgG or IgA subtypes, co-occurs in 10-20% of patients, correlating with atypical phenotypes and treatment resistance, likely through paraprotein-mediated immune perturbation without direct causality established.[33][35] These associations highlight multifactorial susceptibility but do not imply determinism, as most affected individuals lack such factors.Triggers including infections
Antecedent infections precede the onset of chronic inflammatory demyelinating polyneuropathy (CIDP) in approximately 10% of cases, with higher rates observed among younger patients; these events often involve gastrointestinal or respiratory pathogens that trigger immune dysregulation.[36] Documented infections include Campylobacter jejuni, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV), mirroring patterns seen in Guillain-Barré syndrome (GBS) but leading to a protracted course rather than acute monophasic illness.[37] In a European collaborative study of 397 CIDP patients, infectious episodes were self-reported within 3 months prior to symptom onset in 38 cases (9.6%), predominantly viral upper respiratory infections or gastroenteritis.[38] The temporal association typically involves a latency period of 1-8 weeks post-infection, during which immune activation escalates into peripheral nerve targeting; acute-onset CIDP variants, comprising 16-20% of cases, may emerge within this window, progressing beyond the 8-week GBS cutoff.[39] Longitudinal cohort data indicate that such post-infectious triggers correlate with relapsing-remitting patterns in susceptible individuals, though causality remains inferential due to retrospective reporting biases and lack of prospective pathogen isolation in most series.[36] Molecular mimicry is hypothesized as a key mechanism, wherein microbial antigens cross-react with peripheral nerve components like gangliosides or myelin proteins, initiating autoreactive T- and B-cell responses; epitope similarity between C. jejuni lipooligosaccharides and human GM1 gangliosides, well-established in GBS, extends plausibly to CIDP subsets with shared pathophysiology.[37] However, direct epitope mapping studies in CIDP are limited, with evidence primarily extrapolated from acute demyelinating neuropathies rather than chronic cohorts, underscoring the need for targeted serological and sequencing analyses to confirm mimicry-driven triggers.[40]Associations with vaccinations and immune challenges
Case reports have documented instances of chronic inflammatory demyelinating polyneuropathy (CIDP) onset or exacerbation following influenza vaccination, though such events remain rare and temporally associated without established causation. The 2012 Institute of Medicine (IOM) review identified three reports of CIDP post-influenza vaccine, concluding that evidence was inadequate to accept or reject a causal relationship due to limited data and confounding factors like underlying predisposition.[41] Similarly, studies on symptom worsening in established CIDP patients post-flu vaccination reported rates around 20% in small cohorts, but these did not confirm vaccine-induced de novo disease.[42] With the rollout of COVID-19 vaccines, clusters of CIDP cases emerged shortly after administration, primarily linked to mRNA (e.g., Pfizer-BioNTech, Moderna) and viral vector platforms. By July 2024, at least 32 peer-reviewed case reports described CIDP following COVID-19 vaccination, often fulfilling diagnostic criteria like electrodiagnostic evidence of demyelination and temporal proximity (within weeks).[43] These included pediatric cases and variants with autoantibodies (e.g., anti-NF186), but causality remains debated, with molecular mimicry hypothesized as a potential immune trigger in susceptible individuals.[44][45] Empirical data from surveillance systems underscore the rarity of these associations. Vaccine Adverse Event Reporting System (VAERS) records indicate sporadic CIDP reports post-vaccination, with incidence estimates below 1 per million doses for COVID-19 vaccines, far lower than background rates of CIDP (approximately 1-9 per 100,000 annually).[46] The U.S. National Vaccine Injury Compensation Program (NVICP) has adjudicated claims using criteria adapted from Brighton Collaboration standards for demyelinating neuropathies, awarding compensation in select CIDP cases post-influenza or other vaccines where temporal and clinical evidence supported vaccine-table injury, such as $4.4 million in a GBS-to-CIDP progression claim.[47] These awards reflect no-fault adjudication rather than definitive proof of causation, prioritizing empirical patterns over population-level risks.[48] Overall, while immune challenges from vaccines may unmask or precipitate CIDP in predisposed individuals via dysregulated responses, large-scale studies find no elevated population risk, emphasizing the need for individualized assessment.[49]Pathophysiology
Immune-mediated mechanisms
The peripheral nervous system maintains immune privilege through the blood-nerve barrier (BNB), which restricts immune cell access to nerve tissues; its breakdown in CIDP initiates autoimmune infiltration.[50] Activated T cells and their secreted cytokines disrupt endothelial tight junctions in the BNB, allowing entry of inflammatory cells into the endoneurium.[51] This loss of barrier integrity, observed across CIDP subtypes via enhanced permeability and protein leakage, sets the stage for localized immune responses targeting myelin sheaths.[52] T-cell infiltration follows BNB compromise, with CD4+ and CD8+ T cells accumulating at sites of nerve inflammation in CIDP patients.[53] These cells contribute to the inflammatory milieu by releasing proinflammatory cytokines, including elevated TNF-α levels detected in cerebrospinal fluid (CSF) and serum during active disease phases.[54] [55] TNF-α correlates with clinical severity, promoting further recruitment of immune effectors and amplifying tissue damage through sustained activation of local immune cascades.[56] Macrophages, recruited subsequent to T-cell driven inflammation, execute primary demyelination via segmental stripping of myelin sheaths, as evidenced in sural nerve biopsies from CIDP cases.[57] Electron microscopy reveals macrophages extending processes into intact Schwann cell myelin lamellae, selectively stripping segments without initial Schwann cell injury, leading to conduction block.[58] [51] This macrophage-mediated mechanism predominates in typical CIDP pathology, distinguishing it from primary axonal damage and underscoring cellular immunity's role in perpetuating chronic demyelination.[59]Role of autoantibodies and complement
In subsets of chronic inflammatory demyelinating polyneuropathy (CIDP), autoantibodies of the IgG class target proteins at the node of Ranvier and paranodal regions, such as neurofascin-155 (NF155), disrupting axo-glial interactions essential for myelin stability and nerve conduction.[60] These antibodies, detected in approximately 10% of CIDP cases, bind to the NF155-contactin-1 complex at paranodal loops of Schwann cells, impairing the adhesion between axons and myelin sheaths.[1] IgG4-predominant forms predominate in anti-NF155-positive CIDP, often correlating with atypical features like tremor and poor response to intravenous immunoglobulin (IVIG), though IgG3 subclasses against pan-neurofascin isoforms have been linked to more aggressive disease courses and complement recruitment.[61][62] Complement activation amplifies humoral pathology in CIDP, with deposition of components like C3 fragments and the membrane attack complex (MAC) observed in sural nerve biopsies from affected patients.[63] A 2025 immunohistochemical analysis of 55 sural nerve specimens from CIDP and variant cases revealed marked complement involvement, including C3d and MAC immunoreactivity colocalizing with demyelinated fibers, suggesting innate immune escalation beyond adaptive autoantibody effects.[64] This deposition promotes macrophage recruitment and demyelination, independent of cellular infiltrates in some subsets, and aligns with therapeutic rationale for complement inhibitors in refractory disease.[65] IgG3 autoantibodies, by virtue of their ability to fix complement via C1q binding, may preferentially drive this pathway in fulminant or treatment-resistant presentations, contrasting with non-complement-activating IgG4 forms.[62] Empirical data from cohort studies indicate such subclass-specific activation correlates with IVIG non-response, underscoring humoral-complement interplay in disease persistence.[61]Cellular and molecular processes in demyelination
In CIDP, demyelination primarily involves macrophage-mediated stripping of myelin sheaths from axons, executed through direct penetration of the Schwann cell-axon unit, resulting in focal disruption of compact myelin. This process targets internodal regions, leading to segmental demyelination characterized by widened nodes of Ranvier and exposure of paranodal structures, which impairs saltatory conduction and manifests as conduction blocks due to Schwann cell dysfunction.[58][1] Schwann cells respond to demyelination by dedifferentiation, proliferation, and attempted remyelination, forming nascent sheaths that are often thinner and shorter than normal, as observed in nerve biopsies showing excessive myelin folding and incomplete internodal lengths. However, chronic immune pressure reduces Schwann cell plasticity, hindering effective repair and contributing to persistent conduction abnormalities, with histopathological evidence of ongoing cycles of demyelination and partial remyelination in teased fiber preparations.[66][67] Serial nerve biopsy data reveal recurrent demyelinating events interspersed with abortive remyelination, evidenced by increased onion bulb formations—concentric arrays of dedifferentiated Schwann cells—correlating with relapsing clinical courses and failure to achieve stable conduction restoration. These molecular alterations, including disrupted expression of myelin proteins like P0 and PMP22 in regenerating Schwann cells, underscore the inefficiency of repair mechanisms under sustained inflammatory conditions.[57][68] Prolonged demyelination in untreated CIDP triggers secondary axonal degeneration, initiated by Wallerian-like breakdown distal to demyelinated segments, with biopsy studies documenting axonal loss in up to 83.7% of cases and clinical observations indicating accumulation of irreversible damage within months of onset if immunomodulation is delayed. Empirical thresholds suggest that axonal integrity deteriorates significantly after 6-12 months of unchecked disease activity, shifting the pathology from potentially reversible demyelination to permanent neuropathy.[69][70]Diagnosis
Clinical and electrophysiological criteria
The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) requires fulfillment of standardized criteria outlined in the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline, which emphasize clinical features of motor involvement, electrophysiological demonstration of acquired demyelination in peripheral nerves, and exclusion of alternative disorders such as hereditary neuropathies, monoclonal gammopathies, or diabetic polyneuropathy.[13] These criteria simplify prior classifications by reducing diagnostic certainty levels to CIDP or possible CIDP, prioritizing objective evidence of multifocal demyelination over treatment response to minimize misdiagnosis risks.[71] For typical CIDP, clinical inclusion mandates a progressive or relapsing course over at least 8 weeks, featuring symmetric proximal and distal muscle weakness in upper and lower limbs, with sensory ataxia optional but areflexia or hyporeflexia required in all extremities.[13] Proximal weakness distinguishes typical cases from distal-predominant variants and is essential for confirming motor nerve root involvement.[72] Cerebrospinal fluid (CSF) analysis supports diagnosis when protein exceeds 45 mg/dL (0.45 g/L) without pleocytosis (<10 cells/μL), though normative values may rise to >60 mg/dL in patients over 50 or with comorbidities like diabetes.[13] Electrophysiological confirmation demands abnormalities in at least two motor nerves indicative of demyelination, including:- Distal motor latency prolongation ≥50% above the upper limit of normal (ULN),
- Motor conduction velocity reduction ≥30% below the lower limit of normal (LLN),
- Prolonged F-wave latency ≥20% above ULN (or ≥50% if compound muscle action potential [CMAP] amplitude <80% LLN),
- Conduction block with ≥50% CMAP amplitude reduction across a stimulated segment (or ≥30% for tibial nerve) without excessive temporal dispersion, or
- Absent F-waves in two nerves if CMAP ≥20% LLN, combined with one other demyelinating parameter.[13]