Adriana Marbini

Restless legs syndrome and polyneuropathy.

Restless legs syndrome (RLS), diagnosed according to the International RLS Study Group criteria, was investigated in 97 consecutive patients with polyneuropathy and found in 29 patients. RLS patients were more often women (22 of 29 vs. 33 of 68; P = 0.015), mainly with sensory neuropathy of small fiber type (15 of 29 vs. 16 of 68; P = 0.009). Changes of sensory action potentials were significantly less severe in RLS patients. In the RLS group, acquired neuropathies, and in particular dysimmune neuropathies, were significantly more frequent (27/29 vs. 46/68; P = 0.009). Thus, RLS is frequent in acquired polyneuropathy of sensory type and mild entity, mainly in women.

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

Article abstract 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.

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

Abstract  As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A‐delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.

Immunohistochemical study of muscle biopsy in children with cerebral palsy

Muscle biopsy was examined in 20 children with cerebral palsy, using immunohistochemical methods for marker of denervation neural cell adhesion molecules (N-CAM) in addition to standard techniques. Histological and histochemical study showed mild myopathic changes, type 1 predominance, and type 1 and type 2 hypotrophy, in accord with previous observations. Immunohistochemical study showed N-CAM expression in most biopsies (15/20), usually in scattered fibers, whereas in four patients aged less than 6 years it was expressed in grouped fibers. Our study supports the hypothesis of motor unit remodeling as a consequence of spasticity, especially in early phases of the disease.

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.

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.

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.

Peripheral neuropathy in essential mixed cryoglobulinaemia.

The prevalence of various forms of peripheral neuropathy has not been previously assessed in large series of patients with essential mixed cryoglobulinaemia (EMC). Clinical and electrophysiological signs of peripheral neuropathy were observed in 21 of 37 EMC patients, consisting of polyneuropathy in 19, mononeuropathy or multiple mononeuropathy in eight, and both in six. The various forms of peripheral neuropathy occurred differently in the subgroups of EMC. Isolated polyneuropathy was more common with type II (eight of 10) than type III EMC (two of eight). Multifocal neuropathy, in association with polyneuropathy, was the most common form in type III EMC (five of eight). Patients with peripheral neuropathy and type II EMC were significantly older than type II EMC patients without neuropathy, regarding present age and age of onset of EMC. Patients with peripheral neuropathy and type III EMC tended to have higher values of ESR and IgM than type III EMC patients without neuropathy. Electrophysiological findings and sural nerve biopsy specimens (nine cases) showed prominent axonal changes. Vascular changes included vasculitis and alterations of the endoneurial microvessels in type II and type III EMC. Our findings suggest that distinct pathogenic factors are implicated in the subgroups of cryoglobulinaemic neuropathy, possibly inducing different types of vascular changes underlying polyneuropathy or, respectively, mononeuropathy and multiple mononeuropathy.

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.

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.