Abstract
Article abstract The authors report an association between acute inflammatory neuropathy and previously undiagnosed Charcot-Marie-Tooth 1A disease in a 15-year-old girl. Sural nerve biopsy study showed hypertrophic neuropathy with endoneurial infiltrates of macrophages and lymphocytes. This association may be coincidental, but a particular susceptibility to damage of these peripheral nerves cannot be excluded. This report confirms the importance of pes cavus as a sign of long-standing sensorimotor neuropathy.
Patients with Charcot-Marie-Tooth (CMT) disease are not known to be at increased risk for development of acute inflammatory neuropathy. We report a girl showing clinical and laboratory signs of acute inflammatory sensorimotor neuropathy. Further investigation showed that the patient also had previously undiagnosed and clinically silent CMT 1A disease.
Case report.
A 15-year-old girl was referred for sudden difficulty in walking caused by weakness of the lower limbs. She also complained of paresthesias in the four limbs, which was more accentuated distally. Twelve days after onset of this condition, the patient was unable to walk. There was no delay in developmental milestones; the patient was successful in school and had always been able to carry out all her daily activities. Neurologic examination showed severe quadriparesis with absent deep tendon reflexes, diffuse hypotonia and objectively moderate impairment of vibration and position sense (limited to lower limbs, distally), and slight distal hypotrophy of the legs. General examination showed bilateral pes cavus; scoliosis was not observed. CSF analysis revealed elevated protein levels (90 mg/dL) with normal cell count. Electrophysiologic study showed denervation of the distal muscles, severe reduction of sensory and motor conduction velocities, marked temporal dispersion of the “M” response, mostly after proximal stimulation, and an increase in the motor distal latencies (table). Signs of reinnervation were not detected.
Results of electrophysiologic studies
The diagnosis of acute inflammatory demyelinating neuropathy was made and the patient was treated with a series of six plasma exchanges every other day. Her neurologic condition was improved 4 weeks after the last plasmapheresis. At that time, neurologic examination showed slightly steppage gait, absent deep tendon reflexes, slight distal hypotrophy of the legs, and slight reduction of the vibration sense in the distal area of the lower limbs. Sural nerve biopsy showed severe reduction in the number of myelinated fibers. Large-diameter fibers were almost completely absent. Many axons with a thin myelin sheath were surrounded by concentrically arranged processes of Schwann cells, leading to “onion-bulb” formations (figure 1). The endoneurial vessels occasionally showed conspicuous infiltrates of mononuclear cells (figure 1), which were also scattered throughout the endoneurium. Ultrastructural examination confirmed the presence in the endoneurium of several lymphocytes and macrophages, the latter often appearing within onion bulbs, closely related to myelin sheaths (figure 2); this finding was particularly prominent, involving about 60% of the onion bulbs observed. A moderate subperineurial and endoneurial edema was also observed. Immunocytochemical study showed several endoneurial CD68+ and CD45RO+ cells. Seven months later, electrophysiologic study showed an absence of denervation, a decrease in the motor distal latencies, and a reduction in the temporal dispersion of the “M” responses. There was a partial increase of the conduction velocities, but these remained at very low values (see table).
Figure 1. Sural nerve biopsy: semithin section shows an inflammatory infiltrate in the wall of an endoneurial vessel. Two complex onion-bulb formations containing axons with a thin myelin sheath are also evident. (Toluidine blue stain, original magnification ×1,000.)
Figure 2. Sural nerve biopsy: inside of onion-bulb formation shows a mononuclear cell (M) near an axon (A) with an extremely thin myelin sheath, formed by few lamellae. (Transmission electron micrograph, original magnification ×10,000.)
On the basis of pes cavus, as well as biopsy and electrophysiologic findings that seemed incongruous with the diagnosis of acute neuropathy, we examined other family members. The father and a paternal aunt had pes cavus without any disability. Neurologic examination showed absence of deep tendon reflexes. In light of these features, we performed molecular genetic analysis to investigate for a hereditary sensorimotor neuropathy. A duplication was demonstrated in all three subjects, affecting the PMP22 gene, at the locus D17S122 (probe VAW409R3), according to standard procedures.1,2
Discussion.
The current case apparently fulfilled diagnostic criteria for inflammatory neuropathy. Clinical manifestations and CSF analysis were compatible with Guillain-Barré–type acute sensorimotor neuropathy, but the finding of hypertrophic neuropathy was more suggestive of recurrence of chronic inflammatory demyelinating neuropathy (CIDP). Results of electrophysiologic study were characteristic of a demyelinating disorder, but they showed some incongruous aspects; in fact, although some parameters such as temporal dispersion, denervation, and increase in the motor distal latencies were suggestive of Guillain-Barré syndrome, the conduction velocities were too low, pointing to a preexisting demyelinating disorder. The perivascular infiltrates and macrophage activation further suggested an inflammatory neuropathy. It was the presence since infancy of bilateral pes cavus, together with the lack of previously reported sensorimotor symptoms, that prompted us to examine other family members carefully and to investigate the possibility of a hereditary disorder, even in the absence of delayed motor milestones, usually encountered in childhood-onset hereditary sensorimotor neuropathy.
The diagnosis of neuropathies in childhood represents an important medical problem. Difficulty is mostly experienced in differentiating inherited demyelinating neuropathy from CIDP. In childhood, CMT disease and CIDP may overlap in clinical manifestations. A course without any apparent disability may occur in children with CMT disease; in fact, the girl described in the current case was slim and frail since infancy, but was regarded as absolutely normal. Furthermore, subjective sensory symptoms are also uncommon in CMT.
This report confirms that pes cavus should be regarded by the clinician as indicative of a long-standing neurodegenerative disorder. Although rare cases of hereditary sensorimotor neuropathy associated with chronic inflammatory demyelinating disorders of the central3-5 and peripheral6,7 nervous systems have been reported, there is no mention of acute inflammatory neuropathy occurring in a patient with CMT. Barbieri et al.8 described the occurrence of Guillain-Barré syndrome in a girl with nerve biopsy findings typical of tomaculous neuropathy. The current association may represent a coincidence. However, the high number of macrophages observed inside onion-bulb formations, closely related to myelinated axons, may suggest the susceptibility of these abnormal peripheral nerves to an inflammatory process.
Acknowledgments
Supported by a grant from the University of Siena (Ministry of University) to Dr. Malandrini and from National Research Council (Rome) to Dr. Federico.
Acknowledgments
The authors thank Ms. Marie Louise Basso for editing the manuscript.
- Received June 30, 1998.
- Accepted in final form November 28, 1998.
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