CMT, in Costly Error, Can Be Mistaken for Similar Rare Disorder

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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A sizable number of people at 16 hospitals in three European countries were wrongly diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) and treated for that disorder, only to learn through later genetic testing that they actually had Charcot–Marie–Tooth disease (CMT), a study reported.

Its researchers spotted features specific to CMT that might encourage clinicians to consider this rare genetic disease in suspected cases, including age at onset, motor symptoms, and response to CIDP treatment.

They also noted the considerable healthcare costs, in addition to the human cost, of these particular misdiagnoses, as treating CIDP in these 35 people was far more expensive than giving them the genetic test that correctly identified their CMT-causing mutations.

The study, “Charcot-Marie-Tooth disease misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: an international multicentric retrospective study,” was published in the European Journal of Neurology.

CMT, also known as hereditary motor and sensory neuropathy, is a group of disorders characterized by damage to the nerves that transmit signals between the brain and spinal cord, and the rest of the body. As a result, patients typically experience weakness in the legs, ankles, and feet.

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People with CIDP, another rare nerve disorder, show symptoms similar to CMT, which can make its diagnosis difficult. Differentiating between the two disorders is vital for proper treatment.

Despite its low prevalence, CIDP also has a significant economic burden, primarily because of its treatments, including intravenous immunoglobulin (IVIg), are costly.

Researchers sought to analyze the clinical features of people with CMT wrongly diagnosed with CIDP at 16 university hospitals in Belgium, France, and Switzerland, and to estimate the costs associated with those diagnoses.

“Surprisingly, studies investigating CMT misdiagnosis are scarce, and the frequency of CMT patients misdiagnosed as CIDP has not been systematically investigated until now,” the scientists wrote.

Medical records of 1,104 people diagnosed with definite or probable CIDP, according to the European Federation of Neurological Societies/Peripheral Nerve Society criteria, at those hospitals were examined.

CMT was suspected in 56 (5%) of these 1,104 CIDP cases. Reasons that led the investigators to question the initial diagnosis were the patients’ family history, data from muscle and nerve electrical activity tests, lack of response to IVIg treatment, the existence of pes cavus (high foot arch), or a combination of these features.

Genetic testing confirmed that 35 patients (3.2%) had received an incorrect CIDP diagnosis — and, the researchers added, three of them had participated in Phase 3 clinical trials for CIDP.

Twelve (34%) of these patients had mutations in the PMP22 gene (which causes different forms of CMT), 11 (31%) in the MPZ gene, and 12 (34%) patients had mutations in 10 other CMT genes. Causative mutations in more than 100 genes are known for CMT, the study noted.

Compared with a group of 35 CIDP patients serving as controls, researchers found that CMT patients were younger at disease onset — a median age for 39 for CMT and 56 for CIDP — and initial symptoms more often included “significant” motor weakness (80% vs. 29%) and hearing loss (14% vs. 0%).

CMT patients also had fewer irregularities than did those with CIDP on imaging scans of the brachial plexus, a network of nerves that sends signals from the spinal cord to the arms and hands. The quantity of cerebrospinal fluid proteins, those in the fluid that surrounds the brain and spinal cord, was lower in CMT patients.

Most of these patients (94% or 33 people) received IVIg treatment, and two (6%) were treated with corticosteroids. The mean duration of IVIg therapy was 17 months, and analysis showed that IVIg treatment response was lower in CMT patients relative to the CIDP group (20% vs. 69%).

Researchers next calculated the total expenses associated with the in-hospital IVIg infusions, documenting a total of 548 IVIg sessions given over those months. Each infusion session consisted of a 2 g/kg dose delivered over three-to-five days. The total cost of IVIg treatment was estimated at €4.56 million (nearly $5.4 million) for these 35 patients.

“Indirect costs due to nonmedical treatment, medical aids, transport, premature retirement, disability, unemployment, and sick leave were not included in our estimation, suggesting that the total cost of misdiagnosis is likely much higher,” the investigators wrote.

In comparison, genetic testing in France is estimated to cost €2,440, so that genetic tests for CMT if given all 1,104 patients would have cost an estimated €2.7 million, “which is significantly lower than the cost of treating 35 misdiagnosed patients with IVIg,” the researchers wrote.

“When considering the previous observations, one may suggest that prioritizing for CMT genetic analysis patients younger than 40 years who present with at least one additional ‘red flag’ (i.e., family history of neuropathy, motor weakness at first presentation, hearing impairment, absent response to treatment, normal plexus brachial imaging, and normal CSF content) may be a cost-effective strategy,” they concluded.

However, “prospective cost-effectiveness studies are needed to evaluate whether CMT should be systematically investigated in all patients with suspected CIDP or only in a subgroup of patients,” the researchers added.

Study limitations noted by its authors included a lack of genetic testing in the control group of CIDP patients, and across most of the entire 1,104 initial patient group, so that the real frequency of CMT in this study may be higher than 3.2%.