Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Charcot-Marie-Tooth disease may be confused with chronic inflammatory demyelinating polyneuropathy, resulting in inappropriate and hazardous treatments. Age at onset < 40 years, a family history of neuropathy, absence of nerve hypertrophy on magnetic resonance imaging, and poor response to intravenous immune globulin treatment should prompt a genetic evaluation.
SOURCE: Hauw F, Fargeot G, Adams D, et al. Charcot-Marie-Tooth disease misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: An international multicentric retrospective study. Eur J Neurol 2021; Jun 1. doi:10.1111/ENE.14950. [Online ahead of print].
Chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease (CMT) overlap. CIDP is an acquired, immune-mediated, inflammatory demyelinating neuropathy, classically manifesting as a symmetric motor-predominant neuropathy with proximal and distal weakness, responsive to immunomodulatory therapy, whereas CMT encompasses a group of genetic neuropathies, usually demyelinating in nature, with predominantly distal weakness, not amenable to specific treatment. CMT occasionally is misdiagnosed as CIDP. Which features might suggest a diagnosis of CMT rather than CIDP, and thus prevent inappropriate treatment?
Using European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria for the diagnosis of CIDP, an observational retrospective study was undertaken among 16 university hospitals in France, Switzerland, and Belgium to identify patients with definite or probable CIDP and to determine how many were misdiagnosed CMT patients. Among 1,104 CIDP patients, detailed data were collected on 56 patients whose CIDP diagnosis was challenged. CMT was considered, based on family history, pes cavus, electrodiagnostic (EDX) findings, and lack of response to intravenous immune globulin (IVIG) treatment. EDX studies were performed on both the upper and lower extremities, using standard methodology, with skin temperature kept between 32° C and 34° C. Conduction block required a 50% drop in proximal negative peak compound muscle action potential amplitude, as per EFNS/PNS criteria. Additional paraclinical investigations included serum antiganglioside antibody measurement, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI) of the brachial and lumbosacral plexus, nerve biopsy, and genetic analysis, comprising PMP22 gene deletion/duplication analysis. If PMP22 was negative, further analysis was performed with a panel of 127 genes involved in hereditary neuropathies in 20 patients, and a panel of 76 genes in five patients. CMT patients misdiagnosed as CIDP were compared to a group of 35 CIDP patients diagnosed using EFNS/PNS criteria, randomly selected among CIDP patients followed at Bicêtre University Hospital and Pitié-Salpêtrière University Hospital, Paris, France. Statistical analysis comprised the Wilcoxon-Mann-Whitney test, Chi-squared test, and Fisher test, with significance set at 0.05.
Among 1,104 patients diagnosed initially with definite or probable CIDP based on EFNS/PNS criteria, CMT was suspected in 56 patients (5%) and genetically confirmed in 35 patients (3.2%). Median age at onset in these 35 misdiagnosed patients was 39 years (range, 4 to 60 years), with onset before age 15 years in five patients (14%), and before age 40 years in 18 patients (51%). Consanguinity was present in four patients (11%), with a family history of neuropathy or an associated autoimmune condition in eight patients (23%). Pes cavus was present in 20 patients (57%), cranial nerve involvement in six patients (17%), upper limb onset in 16 patients (46%), and asymmetric onset in four patients (11%). Progressive neuropathy was present in 32 patients (91%) and a relapsing-remitting course was present in three patients (9%). Challenge to the CIDP diagnosis was suggested by a family history in six patients (17%), EDX findings in three patients (9%), lack of response to IVIG in two patients (6%), pes cavus in one patient (3%), and a combination of these in 19 patients (54%). Among 33 patients treated with IVIG, seven were considered to be responsive. PMP22 gene mutations were found in 12 patients (34%), MPZ gene mutations were found in 11 patients (31%), and 10 miscellaneous CMT gene mutations were found in the remaining 12 patients (34%). Compared to typical CIDP patients, CMT patients misdiagnosed as CIDP had earlier onset, often younger than age 40 years (18 vs. 2), often with childhood onset (7 vs. 0), with more frequent initial muscle atrophy and motor impairment at diagnosis. Proximal conduction block was less frequent in CMT, as was response to IVIG treatment. CSF protein above 0.5 g/L and MRI plexus abnormalities were more frequent in CIDP.
The diagnosis and treatment of CIDP has been updated recently by the EFNS/PNS and may further improve differentiating CIDP from CMT.1 At least two motor and two sensory nerves must be abnormal for a diagnosis of typical CIDP. An ultrasound demonstrating nerve enlargement in at least two sites in proximal median nerve segments or the brachial plexus may assist in diagnosis. If diagnostic criteria are met using clinical and EDX studies, neither CSF analysis nor nerve biopsy is necessary. First-line treatments strongly recommended by the task force include corticosteroids or IVIG, with IVIG recommended over plasma exchange because of its ease of administration. Subcutaneous IVIG is equivalent to IVIG for maintenance therapy but perhaps less so for induction treatment. Methotrexate, interferon beta 1a, and fingolimod are contraindicated in CIDP, whereas azathioprine, mycophenolate mofetil, or cyclosporine may be considered as alternatives to IVIG or as corticosteroid-sparing agents. Cyclophosphamide, cyclosporine, or rituximab may be considered for CIDP patients who are refractory to first-line therapy.
- Van den Bergh PY, van Doorn PA, Hadden RD, et al. European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force – second revision. J Peripher Nerv Syst 2021; Jun 4. doi: 10.1111/jns.12455. [Online ahead of print].