Non-length-dependent small fibre neuropathy. Confocal microscopy study of the corneal innervation.

BACKGROUND: It has been recently observed that small fibre neuropathy (SFN) may present as distal symmetrical polyneuropathy and with atypical non-length-dependent pattern. OBJECTIVE: To describe a small series of patients with non-length-dependent SFN, investigating corneal innervation with corneal confocal microscopy (CCM). METHODS: Evaluation of the corneal nerve fibre density using CCM in six women with non-length-dependent SFN. The patients were characterised by sensory disturbance involving proximal regions of the limbs, face and trunks, and the diagnosis was confirmed by the findings of decreased intraepidermal nerve fibre density on skin biopsy. RESULTS: Six women, aged 35-64, had non-length-dependent SFN, related to Crohn disease, impaired glucose tolerance and Sjögren's syndrome, or idiopathic (three cases). In all patients, CCM demonstrated decreased corneal nerve fibre density (12.5-23.4/mm(2); normal, >30.6/mm(2)). CONCLUSION: Non-length-dependent SFN may represent an intriguing diagnostic problem because of its puzzling presentation and the need for special investigations for its confirmation. In this perspective, CCM may provide a useful, non-invasive tool to complement the diagnostic workup.

Clinical spectrum of cryoglobulinaemic neuropathy.

BACKGROUND AND OBJECTIVE: Cryoglobulinaemic neuropathy (CN) is probably common, as it is usually related to HCV infection. The aim of this study was to delineate the clinical spectrum of CN in a large series and to investigate the factors influencing its expression. METHODS: Seventy one consecutive patients (12 men, 59 women), diagnosed as having CN on the basis of clinical features of neuropathy, clinical and serological findings of mixed cryoglobulinaemia, and exclusion criteria, were identified during a six year period. All patients underwent clinical examination, and electrophysiological and laboratory investigations. RESULTS: Results of the patients with "pure" CN (n = 54) and those with comorbidities (n = 17) were evaluated separately. Of the former 76% had sensory neuropathy (including selective small fibre sensory neuropathy (SFSN) in 14 patients), 15% had sensorimotor polyneuropathy, and 9% had mononeuritis multiplex. The pattern of distribution was similar in the patients with comorbidities. In 30/54 patients, CN was the first manifestation of cryoglobulinaemia. Patients with mild cryoglobulinaemic syndrome had sensory neuropathy more frequently than patients with active syndrome (p < 0.001), in particular SFSN (p < 0.001). The latter group had more severe features, with significantly more cases of reduced or absent motor (p = 0.028) and sensory action potentials (p < 0.001), and a tendency towards higher Rankin scores (p = 0.06). CONCLUSIONS: Sensory neuropathy, often in the form of SFSN, is by far the commonest form of CN. Cryoglobulinaemia should be vigorously investigated in the diagnosis of sensory neuropathy, especially in older women. Activity of the cryoglobulinaemic syndrome is a major factor influencing the clinical expression and severity of CN.

Small fibers peroneal mononeuropathy in a patient with Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune epithelitis characterized by lymphocytic infiltration of exocrine glands and epithelia in multiple sites. One third of the patients present with peripheral nervous system involvement. We describe the case of a woman aged 62 affected by a peroneal nerve mononeuropathy with painful disturbances secondary to a prevalent involvement of small fibers as demonstrated by electrophysiological investigations and skin biopsy. Asymmetric peripheral nerve involvement is not uncommon in SS, though, to our knowledge, it has never been reported of a mononeuropathy involving primarily small fibers.

Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2.

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.

Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance.

Neuropathy has been frequently reported in patients with IgG monoclonal gammopathy of undetermined significance (MGUS) but it is still unclear whether this association has clinical or pathogenetic relevance. In order to clarify the possible role of IgG MGUS in the neuropathy we correlated the clinical and electrophysiological features of the neuropathy with the duration and anti-neural activity of the M-protein in 17 patients with neuropathy and IgG MGUS. Ten patients (59%) had a chronic demyelinating neuropathy clinically indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) while 7 (41%) had a predominantly sensory axonal or mixed neuropathy. In 80% of patients in the CIDP-like and 28% in the sensory group the IgG M-protein became manifest several months to years after onset of the neuropathy. Antibodies to one or more neural antigens (including tubulin, a 35KD P0-like nerve myelin glycoprotein, GD1a, GM1 and chondrotin sulfate C) were found in 40% of patients with CIDP-like and 43% with sensory neuropathy but also in 37% patients with IgG MGUS without neuropathy. Neuropathy associated with IgG MGUS is probably less heterogeneous than previously considered suggesting that this association may not be merely casual. The evidence for primary pathogenetic role of IgG M-proteins in the neuropathy remains however elusive.

Charcot-Marie-Tooth disease type 2 with restless legs syndrome.

In a series of 44 consecutive patients with Charcot-Marie-Tooth disease (CMT), we found restless legs syndrome (RLS) in 10 of 27 CMT type 2 (CMT2) patients (37%) and in none of 17 CMT type 1 patients (p = 0.004). In the CMT2 patients, RLS was associated with positive sensory symptoms (10/10 versus 10/17; p = 0.026). This finding supports the view that a disorder of sensory input plays a role in the pathogenesis of RLS. Symptomatic treatment may benefit these patients.

Congenital myopathy with mosaic fibers and interlacing sarcomeres: a new structural myopathy.

A 44-year-old man presenting with dyspnoic attacks was found to be affected with congenital myopathy, rigid spine, restrictive respiratory insufficiency and cardiomyopathy. Muscle biopsy showed type 1 fiber predominance (65.7%) and hypotrophy, and characteristic changes in 43.9% of the type 1 fibers, consisting in alternating pale and dark staining on alkaline ATPase reacted sections in a mosaic pattern. Ultrastructural examination demonstrated bands of myofibrils at right angles or skew to the remaining myofibrils transversing the fibers. Myofibrillar disarray was always associated with loss of the Z-discs and actin filaments, and often with aggregation of mitochondria. The muscle biopsy findings in this patient suggest a new entity of congenital myopathy with clinical features of rigid spine, cardiomyopathy and restrictive respiratory insufficiency, characterized by peculiar abnormalities of ATPase staining in a mosaic pattern and, ultrastructurally, by zones of disorientation of the sarcomeres.

Sarcoid neuromyopathy with selective involvement of the intramuscular nerves.

A 35-year-old man affected with pulmonary sarcoidosis had a 12-year history of fatigue and pain in the limbs, with normal neurological examination, except for diffusely absent deep tendon reflexes. Muscle biopsy samples showed multiple noncaseating granulomas, most prominent around the intramuscular nerves, with predominance of CD4+ cells. Intramuscular nerve bundles surrounded by granulomas were immunolabelled with laminin alpha1, alpha2, beta1 and gamma1 chain, and collagen IV. Sural nerve biopsy samples were normal. This patient showed a unique histopathological pattern of sarcoid neuromyopathy characterized by distribution of granulomas or infiltrating cells around intramuscular nerve fibers. The clinical picture, restricted to nonspecific symptoms of fatigue and myalgia, and loss of deep tendon reflexes, correlated well with the selective localization of sarcoid lesions in contiguity with the intramuscular nerves. To our knowledge, this peculiar clinico-pathological correlation has not been reported previously.

Isolated neuritis of the sciatic nerve in a case of Lyme disease.

Lyme disease is an infectious disease caused by the spirochete Borrelia burgdorferi. The course of the disease is divided into three stages, the second of which may include various types of peripheral nervous system disturbances. We report the case of a patient with persistent deficits caused by the prevalent involvement of the sciatic nerve, confirmed by electrophysiological and neuropathological findings. The most significant bioptic results were axonal degeneration and perivascular inflammation. Damage to a single peripheral nerve as the dominant clinical expression during the course of Lyme disease is an unusual finding that has been rarely described in the literature.

Immunohistochemical study of merosin-negative congenital muscular dystrophy: laminin alpha 2 deficiency in skin biopsy.

We studied the immunohistochemical expression of laminin subunits alpha 2, alpha 1, beta 1 in muscle and skin biopsy samples from three patients with congenital muscular dystrophy (CMD), and from ten control patients investigated for various neuromuscular disorders. Merosin alpha 2 chain was not detectable in the basement membrane of muscle fibers, or in the nerve endings, cutaneous nerves, and corium in the skin of the CMD patients, whereas it was clearly expressed in the skin biopsy samples from control patients, especially in the nerve endings of the arrector pili muscles. Laminin alpha 1 chain was expressed in the corium, in the muscle fiber membranes of arrector pili muscles and in cutaneous nerve fibers, perineurium and blood vessels in controls and in CMD patients. Laminin beta 1 chain was faintly expressed in the corium, and a diffuse labeling was detected on arrector pili muscle with enhanced expression at nerve endings, intracutaneous nerves and capillaries, with similar findings in all biopsy specimens. For merosin-negative CMD patients, skin biopsy may provide a diagnostic alternative to muscle biopsy since merosin deficiency can be demonstrated in the skin neural structures, and in particular in the nerve endings of the arrector pili smooth muscles.

Cryoglobulinaemic neuropathy manifesting with restless legs syndrome.

In a series of 12 patients with essential mixed cryoglobulinaemia (EMC) and peripheral neuropathy as main feature of the disease, restless legs syndrome (RLS) was a major manifestation in four women, aged 55-65 years. In one patient RLS was a presenting manifestation of the disease, and in another patient the diagnosis of EMC was made investigating RLS and polyneuropathy, although prior rheumatological symptoms were retrospectively recognized. All patients with RLS had symmetrical sensory polyneuropathy, but non-RLS patients had also other forms of peripheral neuropathy, and symmetrical sensory polyneuropathy only in two of eight cases (P=0.03). Neurophysiological study showed that sensory action potentials of the sural nerve were more often inelicitable in non-RLS patients (six of eight) than in RLS patients (none of three). Sural nerve biopsy had no distinctive features in three RLS patients, with regard to other patients with cryoglobulinaemic neuropathy. RLS seems not uncommon in cryoglobulinaemic neuropathy, and significantly associated with symmetrical sensory polyneuropathy, whereas patients with other subtypes of cryoglobulinaemic neuropathy do not develop RLS; thus, a disorder of the sensory inputs may be important in the pathogenesis of RLS. The occurrence of RLS, especially in middle-aged women, should prompt investigations for peripheral neuropathy focusing on cryoglobulinaemic neuropathy.

Immunohistochemical localization of utrophin and other cytoskeletal proteins in skin smooth muscle in neuromuscular diseases.

We investigated the immunohistochemical distribution of cytoskeletal proteins in smooth muscles of 15 patients with Duchenne muscular dystrophy (DMD), 8 patients with Becker muscular dystrophy (BMD), 28 patients with various neuromuscular diseases, and 2 normal controls, performing skin and muscle biopsies. Dystrophin immunostaining confirmed absent reaction in the arrector pili muscles of DMD patients, faint positive reaction in BMD patients, and strong dystrophin reaction in patients with other neuromuscular diseases and normal controls. Immunostaining of utrophin was positive with variable intensity in the arrector pili muscles in all DMD patients. In BMD patients, utrophin was faintly expressed in the arrector pili muscles in 2 cases, and negative in the other 5 patients. In the other cases of neuromuscular diseases and in normal controls, immunostaining for utrophin was negative in the arrector pili muscles. Staining of the capillary endothelial cells and muscular vessel walls was seen in normal controls, as well as in DMD, BMD, and other neuromuscular diseases. Vinculin, vimentin and desmin were expressed both in arrector pili smooth muscles and in vessel walls of patients with dystrophinopathy and other neuromuscular diseases, as well as in normal controls. Thus utrophin is normally expressed in the smooth muscle of the vessels and its expression does not vary in neuromuscular diseases. On the contrary, in the arrector pili smooth muscle utrophin is not expressed in normal controls but it is in dystrophinopathies, paralleling the findings in striated muscle, which expresses utrophin in a reciprocal manner with respect to dystrophin.

X-linked bulbar and spinal muscular atrophy, or Kennedy disease: clinical, neurophysiological, neuropathological, neuropsychological and molecular study of a large family.

We report the clinical, neurophysiological, neuropsychological, neuropathological and molecular findings in a large family with X-linked bulbar and spinal muscular atrophy (X-BSMA). Molecular study, performed in 28 family members, showed an increase in the number of CAG repeats in 6 affected males (including 2 presymptomatic patients), and in 10 females, of whom 5 were obligate carriers. All symptomatic patients showed, besides the typical manifestation of X-BSMA, neurophysiological signs of sensory nerve involvement, and abnormal findings in neuropsychological tests. Sural nerve biopsy, performed in two patients, was consistent with axonal atrophy and slow-rate degeneration, with secondary demyelination. Neurophysiological alterations were also present in 6 out of 8 carriers, consisting of neurogenic EMG changes in 3 cases and abnormal sensory action potentials (SAP) and reduced conduction velocity of the sural nerve in 3 cases. Abnormalities of at last two neuropsychological tests were found in 6 out of 8 carriers. Alterations of the sensory nerves in X-BSMA patients have been previously reported in some cases; however, we demonstrate for the first time sensory nerve involvement also in carriers. Evidence of central nervous system involvement, with neuropsychological impairment in all symptomatic patients and in some carriers, is another feature of this family, not previously reported in X-BSMA. In spite of the variable phenotypic features, the number of CAG repeats ranged from 40 to 44 in the affected patients, indicating that phenotypic expression was not related to the size of the mutation, but was probably age-related.

Epidemiological survey of amyotrophic lateral sclerosis in the province of Reggio Emilia, Italy: influence of environmental exposure to lead.

We carried out a retrospective incidence, prevalence and mortality survey of amyotrophic lateral sclerosis (ALS) in the province of Reggio Emilia, northern Italy. Based on 79 patients, the mean incidence per year for the period 1980 through 1992 was 1.5 cases per 100,000. On December 31st, 1992, the prevalence rate was 5.4 per 100,000. In the 10-year period of 1983-1992 the average mortality rate was 1.3 per 100,000 per year. The average age at onset was 61.3 +/- 10.2, the average survival period thereafter was 26.3 months +/- 17.7; 27.3 +/- 17.6 for classic ALS, 19.5 +/- 8.4 for progressive bulbar palsy and 36.3 +/- 41.4 for pseudopolyneuritic ALS. The incidence rate, recorded in public health district No.12, an area with documented lead pollution since the 1970s, was standardized to the sex and age of the population of the province. Its incidence and prevalence rate were comparable to the rates found in the remaining area of the province.

Dystrophin expression in skin biopsy immunohistochemical. Localisation of striated muscle type dystrophin.

Dystrophin is normally localized in smooth muscle fibers of various organs in experimental animals, and it has been shown to be defective in the smooth muscle fibers of the mdx mouse, including the myoepithelial cell layer of the sweat glands. We investigated dystrophin localization, using three antisera raised against different domains of skeletal muscle type of dystrophin, in the smooth muscle structures of the skin, using immunohistochemical methods with monoclonal antibodies against dystrophin, in 24 patients with various neuromuscular diseases, and in a normal control. Skin biopsy showed a strong dystrophin reaction in the arrector pili muscles and in the myoepithelial cells of the sweat glands of patients with congenital muscular dystrophy, polymyositis, distal myopathy, putative Duchenne muscular dystrophy carriers, myoglobinuria, neurogenic atrophy and in a normal control. A faint positive dystrophin reaction was seen in four patients with Becker muscular dystrophy, whereas it was absent in 3 patients with Duchenne muscular dystrophy. As our data suggest that immunohistochemical dystrophin expression in smooth muscle structures of the skin is similar to that observed in striated muscle, skin biopsy may represent an alternative way to ascertain dystrophin deficiency.

Peripheral neuropathy associated with primary Sjögren's syndrome.

Clinical and electrophysiological signs of peripheral neuropathy were found in 10 of 46 patients (21.7%) with primary Sjögren's syndrome, symmetric polyneuropathy in seven (mainly sensory in five, mainly autonomic in two), sensory neuronopathy in two patients, and mononeuropathy multiplex in one patient. Peripheral neuropathy was the presenting manifestation in five patients (10.9%). Onset of the disease after 50 years was significantly more common in the polyneuropathy group (six of seven) than in non-neuropathic patients with primary Sjögren's syndrome (14 of 36; p = 0.034). No other difference in clinical or laboratory variables between neuropathic and non-neuropathic patients with primary Sjogren's syndrome was found. Neurophysiological study showed variable findings predominantly suggesting an axonopathy. Nerve biopsy showed moderate remyelination and regeneration in four patients, and fibre loss, mainly of large size, in three. Necrotising vasculitis was not seen but alterations of the endoneurial microvessels were prominent.

Hereditary sensory and autonomic neuropathy with ataxia and late onset.

We report two brothers affected by a dominantly inherited form of hereditary sensory and autonomic neuropathy (HSAN), characterized by clinical features of sensory ataxia, and by late onset in the 6th decade. Sural nerve biopsy in the proband showed almost complete loss of myelinated fibers, and relative sparing of unmyelinated fibers. This family showed an atypical presentation of HSAN, which is usually characterized by acrodystrophic manifestations of infantile or juvenile onset. Although a few reports of HSAN presenting with late onset and/or ataxia appeared, this is the first report of a family with dominant HSAN characterized by late onset sensory ataxia.

Acute sensory and autonomic neuropathy: possible association with coxsackie B virus infection.

This report describes a 26 year old woman with a Coxsackie B virus infection complicated by an acute pandysautonomic and sensory neuropathy. Electrophysiological studies suggested an axonal neuropathy. A sural nerve biopsy performed early in the disease showed axonal degeneration with a virtual absence of unmyelinated fibres and moderate loss of myelinated fibres, mainly affecting the small fibres; this differs from previous reports. An immune-mediated or direct virus action might explain the pathogenesis of this unusual evolution of a viral infection.