C. Crisci

Quantification of myelinated endings and mechanoreceptors in human digital skin

We used immunohistochemistry and confocal microscopy applied to fingertip punch biopsy to study glabrous skin innervation in 14 healthy subjects. In addition to epidermal nerve fibers, we quantified mechanoreceptors and their myelinated afferents. Using digital images and dedicated software, we calculated caliber, internodal and nodal length, and G‐ratio of the last four internodes of the myelinated endings. In our skin samples, we found a mean density of 59.0 ± 29.3 myelinated endings per square millimeter with a mean diameter of 3.3 ± 0.5μm and an internodal length of 79.1 ± 13.8μm. These findings indicate that Aβ fibers undergo drastic changes in their course from the nerve trunk to the target organ, with repeated branching and consequent tapering and shortening of internodal length. Our work demonstrates that skin biopsy can give information on the status of large myelinated endings as well as unmyelinated sensory and autonomic nerves. Since distal endings are primarily involved in distal axonopathy, skin biopsy can be more suitable than sural nerve biopsy to detect early abnormalities. In addition to diagnostic applications, this technique allows clarification of the mode of termination of Aβ fibers and their relationship with mechanoreceptors, leading to relevant electrophysiological speculations. Ann Neurol 2003

Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis

OBJECTIVES A case of a 10-year-old girl with congenital insensitivity to pain with anhidrosis (CIPA) is reported. METHODS AND RESULTS Parents referred several hyperpyretic episodes without sweating occurring since birth, and insensitivity to pain, noticed when the child was 2 years old. Her body had many bruises and scars, bone fractures and signs of self-mutilation. Neurological examination was normal except for insensitivity to pain. Her IQ was 52. Electrical and tactile sensory nerve conduction velocities were normal. The patient was unable to detect thermal stimuli. Histamine injection evoked a wheal but not a flare; pilocarpine by iontophoresis did not induce sweat. Microneurography showed neural activity from A-beta sensory fibers while nociceptive and skin sympathetic C fiber nerve activity was absent. No small myelinated fibers and very rare unmyelinated fibers were found in the sural nerve. Immunohistochemistry showed a lack of nerve fibers in the epidermis and only few hypotrophic and uninnervated sweat glands in the dermis. CONCLUSIONS The lack of innervation of the skin (C and A-delta fibers) appears to be the morphological basis of insensitivity to pain and anhidrosis, and is consistent with the loss of unmyelinated and small myelinated fibers in the sural nerve biopsy.

Small fibers involvement in Friedreich's ataxia.

Although the involvement of large myelinated sensory fibers in Friedreichs ataxia (FA) is well documented, an impairment of unmyelinated fibers has not been described. We demonstrate an involvement of cutaneous unmyelinated sensory and autonomic nerve fibers in FA patients. We performed a morphological and functional study of cutaneous nerve fibers in 14 FA patients and in a population of control subjects. We used immunohistochemical techniques and confocal microscopy applied to punch skin biopsies from thigh, distal leg, and fingertip, and compared the density of epidermal nerve fibers (ENFs) with the results of mechanical pain sensation and thermal and tactile thresholds performed on hand dorsum, thigh, distal leg, and foot dorsum. We observed in our patients a statistically significant loss of ENFs, a reduced innervation of sweat glands, arrector pilorum muscles and arterioles, and an impairment of thermal and tactile thresholds and mechanical pain detection.

Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich’s ataxia

OBJECTIVE To verify if GAA expansion size in Friedreich’s ataxia could account for the severity of sensory neuropathy. METHODS Retrospective study of 56 patients with Friedreich’s ataxia selected according to homozygosity for GAA expansion and availability of electrophysiological findings. Orthodromic sensory conduction velocity in the median nerve was available in all patients and that of the tibial nerve in 46 of them. Data of sural nerve biopsy and of a morphometric analysis were available in 12 of the selected patients. The sensory action potential amplitude at the wrist (wSAP) and at the medial malleolus (m mal SAP) and the percentage of myelinated fibres with diameter larger than 7, 9, and 11 μm in the sural nerve were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) expanded allele in each pair. Pearson’s correlation test and stepwise multiple regression were used for statistical analysis. RESULTS A significant inverse correlation between GAA1 size and wSAP, m mal SAP, and percentage of myelinated fibres was found. Stepwise multiple regression showed that GAA1 size significantly affects electrophysiological and morphometric data, whereas duration of disease has no effect. Conclusion—The data suggest that the severity of the sensory neuropathy is probably genetically determined and that it is not progressive

Friedreich's ataxia: electrophysiological and histological findings

ABSTRACT‐ Electromyography was performed, and motor and sensory nerve conduction velocities were measured in 19 patients definitely affected by Friedreichs ataxia. Biopsy of the sural nerve was also performed in 9 patients.

POEMS syndrome: follow-up study of a case.

We report here the case of a 20-year-old man with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M proteins, skin changes). This rare syndrome followed a 3-year history of a syndrome that mimics a chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment with cyclophosphamide induced regression of the syndrome and improved peripheral nerve conduction.

Is early onset cerebellar ataxia with retained tendon reflexes identifiable by electrophysiologic and histologic profile?. A comparison with Friedreich's ataxia

An electrophysiologic and histologic study was performed on 18 patients affected by early onset cerebellar ataxia with retained tendon reflexes (EOCA). Sensory and motor conduction velocity (SCV, MCV) was measured along peripheral nerves in all patients, somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) were recorded in 13; cortical stimulation (CS) in 12, and sural nerve biopsy in 4 patients were also performed. The results as a whole allow a division of EOCA patients into 2 groups: with (7 patients) and without (11 patients) peripheral neuropathy. Among EOCA patients with neuropathy a differential diagnosis with Friedreichs disease patients was not possible according to BAEPs and CS, while SSEPs could differentiate 2 out 5 patients in whom they were performed.

A family with tomaculous neuropathy mimicking Charcot-Marie-Tooth disease

The appearance of Guillain-Barré syndrome in a 9-year-old girl led to the detection of a hereditary neuropathy in her family. This neuropathy showed clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease. Only nerve biopsy performed in a sister of the proband allowed diagnosis of tomaculous neuropathy which presented unusual clinical, electrophysiological and bioptic aspects.

Tactile stimulation and mechanoreceptors in sensory neuropathies

Abstract Meissner corpuscles are supposed to play a primary role in generating tactile responses. To verity this hypothesis, we combined electrophysiological and morphological methods. In a group of twelve patients affected by congenital or acquired neuropathies, electrical and tactile evoked potentials were near-nerve recorded along the median nerve. The density of Meissner corpuslces was calculated in the fingertip, exactly in the same area stimulated by the tactile probe. Using immunohistochemical techniques we determined in the skin specimens the density of normal and atrophic Meissner corpuscles and of myelinated nerve fibers per square millimeter. We demonstrated that tactile potentials depend exclusively on number of normal Meissner corpuscles, while electrical potentials are also correlated with atrophic receptors. Tactile stimulation is a more suitable method than electrical stimulation to discriminate between functional and not functional mechanoreceptive units.

Electrophysiological contribution to understanding the pathophysiology of Friedreich's ataxia

Abstract Friedreichs ataxia (FA) is the most frequent early onset recessive ataxia. Ataxia clinical progression is slow, but the majority of patients is wheelchair-bounded before 30 years of age. Some studies suggested that the peripheral sensory neuropathy was a dynamic process that could explain the clinical worsening. In 1983 an electrophysiological and histological study showed peripheral nerve axonal degeneration unrelated to disease duration or severity. A follow-up study confirmed that symptom progression is independent from peripheral neuropathy that is not progressive. A defective developmment of the largest neurons of the dorsal ganglion was supposed. When the unstable GAA expansion in the X25 gene was identified as the responsible mutation in the majority of FA patients, genotype-phenotype correlation studies were performed. A direct correlation between GAA expansion and involvement of peripheral nerve sensory fibers and central somatosensory pathway was shown. Disease duration correlates with pyramidal, auditory and visual pathway involvement, while the GAA expansion size has no effect.