Neuromuscular Notes: Taking the Mis- out of CIDP Diagnosis

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune demyelinating sensorimotor neuropathy affecting 1.0 to 8.9 persons per 100,000.^1,2 Typical clinical manifestations include symmetric proximal and distal limb weakness with acral sensory deficits that evolve over 2 or more months along with diminished or absent tendon reflexes. Atypical variants of CIDP typically manifest clinically with predominantly distal asymmetric pure motor or pure sensory deficits.³

A High Rate of Misdiagnosis

In 2015, a pivotal study reported that 47% of people in the US who were referred to a tertiary care center for a diagnosis of CIDP did not meet minimum standards for CIDP diagnosis.⁴ This has brought attention and significant concern to the issue of CIDP misdiagnosis. Most individuals misdiagnosed with CIDP in this study actually had length-dependent axonal polyneuropathy. Other diagnoses included motor neuron disease, small fiber neuropathy, diabetic neuropathy, inclusion body myositis, antiMAG neuropathy, multifocal motor neuropathy, or fibromyalgia. Of particular interest are the 22% of misdiagnosed individuals who ultimately had chronic pain syndromes that did not meet any of the clinical or electrophysiologic diagnostic criteria for CIDP. Concern has been raised that this high rate of misdiagnosis may be unique to the US; results of a study evaluating the rate of misdiagnosis of CIDP in the Netherlands are eagerly awaited.⁵

This degree of misdiagnosis is concerning. Expert consensus-derived guidelines for the diagnosis and treatment of CIDP were published in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). These guidelines recommended intravenous immunoglobulin (IVIG), steroids, or therapeutic plasma exchange as first-line treatment. People who are misdiagnosed with CIDP may receive lengthy courses of unnecessary treatment and be exposed to treatment risks without a reasonable prospect of benefit. Inappropriate treatment increases healthcare costs. Unnecessary use of IVIG can lead to shortages for correctly diagnosed individuals who rely on this treatment.

Diagnostic Criteria

Both clinical and electrophysiologic data are important for confirming a CIDP diagnosis. Relying only on either clinical or electrophysiologic data (or other test results) in isolation can lead to an inaccurate diagnosis. Although other criteria exist, the 2010 EFNS/PNS guidelines are recommended and accepted for clinical use (Table).³ The sensitivity of the EFNS/PNS criteria is 81% to 99% and the specificity is 61% to 97%, which together provide a good balance compared with previously described criteria.^6-8 However, a recent cross-sectional quantitative survey study evaluating current practice patterns for CIDP showed that only 13% of community practices use the EFNS/PNS guidelines. Additionally, 27% of university-affiliated sites and 51% of nonuniversity-affiliated sites reported they do not routinely use any specific guidelines when diagnosing CIDP. Significant variability in treatment approaches was also seen, including lower doses than recommended for loading and maintenance of IVIG.⁹

Education Is Needed

These findings highlight the need for education with respect to diagnosis and management of CIDP. The importance of adhering to the EFNS/PNS guidelines for diagnosis should be emphasized at the early stages of medical training. Awareness of the guidelines also needs to be raised amongst general and subspecialist neurologists. Beyond diagnosis, it is important to educate providers about setting prognostic expectations with patients at the start of treatment and about management considerations including monitoring clinical exam findings and objective outcome measure metrics such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, the inflammatory Rasch-built Overall Disability Scale, and grip dynamometry.^10-12

Objective Measures Are Essential

It should be emphasized that objective outcome measure metrics are essential in the management of CIDP. In 1 study, 85% of people with CIDP who were being treated reported some benefit of treatment; however, only 19% of patients reported objective improvement in strength and sensation.⁴ These findings highlight that if only subjective measures are used to guide CIDP treatment decisions, there is an increased risk for unnecessary or prolonged treatment. If a person diagnosed with CIDP does not objectively respond to treatment after an adequate trial, switching to an alternate treatment and re-evaluating the diagnosis should be considered. Secondary axonal injury may occur with longstanding CIDP and is unlikely to respond to treatment, leading to potential overtreatment if subjective measures are used exclusively.

Atypical Presentations Create Challenges

Clinically, there is relatively high accuracy in typical CIDP diagnosis if the pattern of weakness is symmetric and more proximal than distal with diminished or absent reflexes and progression over an 8-week period.⁸ The difficulty in clinical diagnosis often involves atypical CIDP that include 1) predominantly distal weakness and sensory changes (eg, distal acquired demyelinating symmetric neuropathy), 2) asymmetric weakness (eg, multifocal acquired demyelinating sensory and motor neuropathy), and 3) focal, or rarely, pure motor or pure sensory demyelinating neuropathy. In these atypical presentations, additional data should be collected to help support the diagnosis. Electrophysiologic data should meet the 2010 EFNS/PNS criteria (Table) and cerebrospinal fluid (CSF) analysis, imaging studies, and nerve biopsy can be helpful in some cases.

Cerebrospinal Fluid Analysis. Detection of albuminocytologic dissociation with a white blood cell count less than 10 / mm3 and an elevated spinal fluid protein are diagnostic of CIDP. However, not all laboratories use the same reference standards for the upper limit of normal CSF protein levels, although approximately 85% use 45 mg/dL. This cutoff value, however, cannot be universally applied to all individuals because CSF protein levels can be affected by age, with 60 mg/dL considered the upper limit of normal for people more than age 50. Using a higher age-dependent cutoff value was reported to reduce the sensitivity of CSF analysis (from 95% to a range of 84% to 86%) but did not affect the overall CIDP detection rate.¹³ Additionally, other autoimmune conditions, diabetes and spinal stenosis can contribute to an elevated spinal fluid protein. Thus, a spinal fluid analysis should be interpreted with care and not used in isolation to make the diagnosis of CIDP.

Imaging Studies. Gadolinium enhancement on MRI or hypertrophy of the cauda equina, lumbosacral or cervical nerve roots, or brachial or lumbar plexii can provide support for the diagnosis of CIDP.³ Ultrasound imaging demonstrating focal nerve enlargement at a noncompressive site can also support diagnosis of CIDP.¹⁴

Nerve Biopsy. Classic findings on peripheral nerve biopsy supporting CIDP diagnosis include onion bulb formation and macrophage-associated demyelination and remyelination, although the evidence for this is class IV.³ Nerve biopsy is rarely pursued because the absence of expected findings does not exclude the diagnosis, and the procedure can be complicated by wound healing issues, permanent numbness in the distribution of the biopsied nerve, and potentially painful neuroma formation.

Unique Variants

A subset of people with CIDP harbor autoantibodies that target proteins at the node of Ranvier. These paranodal and nodal autoantibodies are associated with certain clinical phenotypes and treatment response profiles that differ from typical CIDP. Specifically, people with antineurofascin 155, antineurofascin 140/186, and anticontactin antibodies have CIDP that is typically less responsive to IVIG and steroids and possibly more responsive to rituximab.¹⁵

Summary

The accuracy of CIDP diagnosis can be improved by gathering appropriate clinical, electrophysiologic, and other supportive data and by applying the contemporary EFNS/PNS diagnostic criteria. Because there is no serologic biomarker for CIDP yet, diagnosis continues to rely on careful assessment and interpretation of the data at initial presentation with continual reassessment using validated outcome measures.