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Patient: Male, 25 Final Diagnosis: Charcot-Marie-Tooth 1 Symptoms: Muscular • spasticity Medication: Oxandrolone Clinical Procedure: Neural and muscle biopsies Specialty: Neurology Objective: Unusual setting of medical care Background: Anabolic steroids have the clinical effect of increasing protein synthesis in muscle and other tissues. The brain and spinal cord neurons have gonadal steroid receptors and various studies have shown at structural and molecular levels that androgenic steroids have a significant trophic effect on the brain and spinal cord. Case Report: We evaluated the effect of Oxandrolone (an FDA-approved anabolic steroid) at the dose of 20 mg/day for 3 months added to concomitant exercise strength training 3 times a week in a patient affected by a demyelinating disease, Charcot-Marie-Toot 1 (CMT1). After the treatment, an increase in muscular strength and walking capacity was observed. Muscle biopsy revealed a significant increase of type grouping of muscle fibers, an expression of regeneration and reinnervation processes. Conclusions: Data ensuing from this single case-report suggest that anabolic androgenic steroids have a potential neuroregenerative effect, with an inherent improvement in neuromuscular efficiency through an increased myelin synthesis at peripheral nervous system site.

We report the features of non-length dependent small fiber neuropathy (SFN) and compare them to those with distal length-dependent SFN. In a series of 224 consecutive neuropathy patients, we evaluated 44 patients with SFN diagnosed in the presence of both symptoms and signs. Eleven were classified as non-length dependent SFN. Disease associations were Sjögren's syndrome (two patients), impaired glucose tolerance, rheumatoid arthritis, hepatitis C virus, Crohn's disease, and idiopathic (five patients). In the 33 patients with distal SFN, the age of onset was significantly older and more had impaired glucose metabolism (16/33). In both groups, pain was mainly characterized as burning, but patients with non-length dependent SFN more often reported an "itchy" quality and allodynia to light touch.

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.

Involvement of sensory nerves in Charcot-Marie-Tooth (CMT) disease is well known, however, sensory symptoms are usually overlooked. To assess the frequency and features of sensory symptoms in a cohort of patients with CMT, we investigated in a prospective study 52 consecutive CMT patients, diagnosed on the basis of clinical, neuro- physiological, and genetic features and classified in CMT type 1 (CMT1) (20 patients, including 14 with CMT1A) and CMT type 2 (CMT2) (32 patients). Positive sensory symp- toms were reported by 28 patients (54%), including neuropathic pain in 6 patients. Pain, either neuropathic or nociceptive, was present in 29 patients (56%) and in 15 patients as a main symptom. Positive sensory symptoms were present in 24 of 32 CMT2 patients (75%) and in 4 of 20 CMT1 patients (20%) (p

It is well known that painful neuropathy of the small fiber type is frequent in Fabry disease, however it has been rarely investigated in childhood. We report an 11-year-old boy without known familial history of neuromuscular diseases, who complained of painful symptoms in the lower extremities by age 9. Initially pain was present only in association with fever, but during the last year it was triggered also by mild variations in the environmental temperature, so that the boy, to prevent pain, was forced to stay barefooted for most the time during spring and summer, and to wear at least two or three pairs of socks during winter. Physical and neurological examination was negative, except for several small red spots in the testes. Neurophysiological study was negative, but EMG showed motor unit potentials with possible myopathic pattern. Muscle biopsy was unremarkable, apart from endothelial cells containing electron dense lipid inclusions of regular lamellar structure, which were seen also in skin biopsy within fibroblasts, pericytes and endothelial cells. Intraepidermal nerve fiber density was within normal limits (5.5/mm at distal leg and 8.3/mm at proximal thigh), but prominent axonal swellings (possible predegenerative changes) were frequently seen. Diagnosis of Fabry disease was confirmed by deficiency of alfa-galactosidase. Symptomatic treatment with gabapentin was started, in addition to enzyme replacement therapy. Symptoms of small fiber neuropathy in Fabry disease may be present in early disease as an onset manifestation, and the occurrence of small fiber neuropathy during childhood strongly suggests a diagnosis of Fabry disease. Painful symptoms may occur before a significant intraepidermal nerve fiber loss is seen, and are probably correlated to predegenerative changes in the small sensory fibers.

Cryoglobulinemic neuropathy is probably the commonest form of vasculitic neuropathy in Mediterranean countries, as usually related to the widespread hepatitis C virus (HCV) infection. We describe the spectrum of manifestations in a large series of patients with cryoglobulinemic neuropathy, also analyzing the impact of comorbid factors, which are quite frequent in HCV-related mixed cryoglobulinemia. The cohort included 60 patients (10 men, 50 women) with peripheral neuropathy associated with mixed cryoglobulinemia as main or sole cause (type 2 in 36 cases, type 3 in 4, not typized in 20), HCV-related in all patients but 8 (3 men and 5 women). Median age of patients was 65 years (range 41–85), and median age at onset of neuropathy was 59 (range 40–84). Peripheral neuropathy represented an onset manifestation of mixed cryoglobulinemia in about half patients. The most frequent clinical pattern was pure sensory neuropathy in 40 patients, including 4 patients with prominent ataxia; sensory neuropathy was asymmetrical in distribution in 9 patients, and in 14 patients sensory action potentials (SAPs) of the sural nerve were normal, suggesting selective involvement of the small sensory fibers. The remaining patients had sensorimotor neuropathy (15 cases) and mononeuropathy multiplex (5 cases). Positive sensory symptoms and restless legs syndrome were the most common manifestations. Neurophysiological study showed axonal degeneration of varying severity in all patients. In 20 patients, additional causes of neuropathy were present, including type 2 diabetes (5 patients), glucose intolerance (6 patients), non-Hodgkin lymphoma (3 patients), and alcohol (2 patients). With respect with this subset of patients, in “pure” cryoglobulinemic neuropathy there was more often a pattern of sensory neuropathy (31/40 vs. 6/20; p = 0.001), with more frequent asymmetrical distribution (9 vs 0; p = 0.05) and small fiber involvement (11 vs 3). Severity of neuropathy, as judged on the basis of the Rankin scale and of neurophysiological changes, was similar in the two subgroups. Our study confirms that sensory neuropathy, often asymmetrical, is the most common clinical pattern in cryoglobulinemic neuropathy, and is consistently present in pure cryoglobulinemic neuropathy rather than in patients with other associated causes of neuropathy; in these latter, paradoxically, clinical and neurophysiological impairment seems not greater than in pure cryoglobulinemic neuropathy.

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 Sjogren9s 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.

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.

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.

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.

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.

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.

Peroneal muscular atrophy (PMA) associated with hereditary spastic paraparesis (HSP) is a nosologically ill-defined disease, which has been classified by Dyck as hereditary motor and sensory neuropathy type V (HMSN V). Nerve biopsy has been rarely reported in this condition. We examined sural nerve biopsies in four patients, demonstrating the following: severe myelinated fiber loss especially of large fibers, with moderate (one case) or prominent (one case) onion bulb formation; selective decrease of large fibers with moderate Schwann cell hyperplasia (one case); normal myelinated fiber population with minimal changes (one case). After reviewing previously reported cases we, conclude that in PMA with HSP sural nerve biopsy may show features either of hypertrophic type of PMA, of neuronal type, or of spinal type; thus, it seems inappropriate to allocate PMA with HSP in a unique subtype of HMSN. In addition, HSP may be not associated with peripheral neuropathy, and thus the classification in the HMSN group may be incongruous. A proper classification of PMA with HSP may be in the "complicated" forms of HSP according to Harding [Lancet I: 1151-1155 (1983)]; however, the nosology of this condition needs to be further elucidated, possibly on the basis of the underlying molecular genetic mechanisms of HSP and PMA.

To look for an association between restless legs syndrome (RLS) and type 2 diabetes in a case-control study; to analyze the characteristics of RLS in diabetic patients; and to identify possible risk factors for the development of RLS in diabetic patients.A case-control study.Diabetic outpatient clinic of a major university hospital.One hundred twenty-four consecutive outpatients with diabetes and 87 consecutive controls with a previous diagnosis of other endocrine disease.RLS was diagnosed using the criteria of the International RLS Study Group, and severity of RLS was assessed using the International RLS Study Group Rating Scale. Characteristics of RLS and several laboratory parameters were investigated in diabetic patients and controls affected by the sleep disorder. A clinical diagnosis of polyneuropathy was assessed to evaluate its role as a risk factor for RLS in diabetic patients.RLS was diagnosed in 22 diabetic patients (17.7%) and in only 5 controls (5.5%), 3 of whom had pituitary and 2 had adrenal gland disorders, and RLS was independently associated with type 2 diabetes (P0.04). Even if a clinical diagnosis of polyneuropathy was made in only 27% of diabetic patients affected by RLS, after multivariate logistic regression, the presence of polyneuropathy was the only variable associated with RLS in diabetics (odds ratio, 7.88; 95% confidence interval, 1.34-46.28; P0.02). RLS in diabetics showed a frequency of positive family history lower than that known for primary RLS, showed a late age of onset, and manifested itself after the diagnosis of diabetes was made.This is the first controlled study confirming a significant association between RLS and type 2 diabetes. In diabetic patients, polyneuropathy represents the main risk factor for RLS. However, polyneuropathy only partially explains the increased prevalence of RLS in type 2 diabetics. Clinical characteristics of RLS in diabetic patients are those of a secondary form.

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.

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

Cryoglobulinemia represents an emerging cause of peripheral neuropathy, especially in Southern Europe, in view of its relationship with hepatitis C virus infection. In a series of 100 consecutive referral patients with uncharacterized peripheral neuropathies, we systematically investigated cryoglobulinemia to assess its diagnostic yield. The most frequent diagnosis was hereditary neuropathy (33%), 29% were acquired neuropathies of different types, and no cause could be identified in 27%. Cryoglobulinemic neuropathy was diagnosed in 11 patients (7 women and 4 men), aged 54-77 (mean = 63.5 years), most presenting with sensory polyneuropathy, often asymmetrical. Cryoglobulin was also detected in 2 additional patients in whom a final diagnosis of non-Hodgkin lymphoma was made. Purpura was absent in 4 patients (and in 2 with lymphoma), or restricted to discrete manifestations in the remaining patients, which did not provide a clue to the diagnosis. Thus, search for cryoglobulin proves useful in a substantial number of undiagnosed peripheral neuropathies (11% to 13% in our series), even in the absence of typical skin lesions, and it is recommended as a first-line investigation in patients with unexplained neuropathy presenting in middle to older age.

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.

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.

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.

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.

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.

Clinical and electrophysiological signs of peripheral neuropathy were found in 10 of 46 patients (21.7%) with primary Sjogren'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 Sjogren'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.

We reviewed the files of outpatients with polyneuropathy or multiple mononeuropathy over a two-year period (2002–2003), to assess the relative incidence of small fiber sensory neuropathy (SFSN), diagnosed with clinical criteria. The cohort included a total of 97 patients (41 men, 56 women), age 11–85 years (median 64), 91 with polyneuropathy and 6 with multiple mononeuropathy. Twenty-seven patients with SFSN (27.8%) were identified (7 men, 20 women), age 11–76 years (median 62). SFSN was idiopathic in 8 cases, and secondary to other diseases in 19 cases, mainly diabetes or glucose intolerance (8 cases) and mixed cryoglobulinemia (6 cases). The most frequent manifestations of SFSN were burning feet (12 cases) and restless legs syndrome (12 cases). Duration of neuropathy was 2.2 + 2.06 years, whereas in the other patients with polyneuropathy was 9.02 + 13.6 (p = 0.011). Treatment with drugs for neuropathic pain was effective in 9 out of 16 cases (56.2%). In this series, SFSN diagnosed by minimal clinical criteria showed an unexpectedly high relative incidence among miscellaneous peripheral neuropathies. This can be due to overdiagnosis of SFSN, as we included patients diagnosed using minimal clinical criteria; on the other hand, the diagnostic sensitivity of additional tests (quantitative sensory examination and skin biopsy) is not definitive, thus diagnosis of SFSN is actually a frequent diagnostic challenge. The efficacy of treatment with drugs for neuropathic pain in many patients may provide further support for diagnosis.

Aquadynia is a rare phenomenon of water-induced pain through presumed neural mechanisms. We describe two women in whom bathing was regularly followed by pain in the lower limbs, as a unique symptom (case 1) and, respectively, in the clinical context of an axonal polyneuropathy (case 2). Case 1: A 71-year-old woman complained, by age 69, of pruritus and pinprick-like pain in the extremities that lasted about 20 minutes following bathing. Neurological examination and electroneurography were negative, as well as investigations for systemic diseases. Quantitative sensory testing (QST) showed abnormal cold-pain sensation. Treatment with gabapentin was not effective. Case 2: A 69-year-old woman affected with HCV-related cryoglobulinemia had numbness and aquadynia in the distal lower limbs and restless legs syndrome, in the last few months. Neurological examination showed absent ankle jerks, and decreased touch and vibration sense in the feet. Electroneurography demonstrated an axonal neuropathy. Aquadynia likely represents a manifestation of small fiber neuropathy. It is unclear whether it has to be viewed as a primary sensory phenomenon similar to allodynia, or a type of noradrenergic pain primarily due to autonomic dysfunction. Alteration of QST in case 1, and the association with obvious features of sensory neuropathy in case 2, may favour the sensory hypothesis.

Restless legs syndrome (RLS) is increasingly recognized as a manifestation of various forms of peripheral neuropathy, and in particular in association with amyloidosis, uremia, diabetes, cryoglobulinemia, and Charcot-Marie-Tooth disease type 2. A previous study demonstrated a 5% prevalence of RLS in unselected neuropathies, but did not elucidate factors influencing the occurrence, or not, of RLS in peripheral neuropathy. We studied a series of unselected neuropathic patients to assess the prevalence of RLS, and to define the features of peripheral neuropathy associated with RLS. In a population of 70 consecutive patients with various forms of peripheral neuropathy (polyneuropathy in 65 cases, multiple mononeuropathy in 5 cases) we found RLS in 20 cases (28.6%). In particular, RLS was more often associated with cryoglubolinemic neuropathy (5/13), diabetic neuropathy (4/12), Charcot-Marie-Tooth disease (4/18), and chronic idiopathic axonal polyneuropathy (2/6). RLS was usually associated with a neuropathy of axonal type, and the onset of RLS was 0–10 (median 1) years after the onset of neuropathy; in 9 cases, RLS was an initial manifestation of neuropathy. Patients with pure sensory or mainly sensory neuropathy had RLS more often than patients with other patterns of neuropathy (13/37 vs. 7/33). Severity of neuropathy, as judged by Rankin score, did not differ in patients with or without RLS (13/20 with Rankin grade 2 or more, vs. 36/50). Prevalence of RLS in our population of neuropathic patients was higher than previously reported. Thus RLS may be viewed as a quite common manifestation of peripheral neuropathy in general, although more common in some forms, and it represents a treatable neuropathic symptom. Mechanisms of RLS are elusive, however a role of sensory inputs is supported by its greater incidence in association with sensory neuropathies.

The assessment of severity of polyneuropathy is usually based on the findings of neurological and electrophysiological examination, which however do not reflect overall function. Health-related quality of life (HRQOL) measurements aim to measure the impact of a disease on the daily life of a patient, and are expecially useful in chronic diseases, however are seldom used in neuromuscular diseases. It was previously reported that HRQOL assessment may be useful in diabetic neuropathy, chronic idiopathic axonal polyneuropathy, and Charcot-Marie-Tooth disease. The aim of this study was to determine whether HRQOL is reduced in cryoglobulinemic polyneuropathy, and whether its measurements add useful information to the assessment of severity of polyneuropathy. We studied 12 patients (10 females, 2 males) with symptomatic cryoglobulinemic neuropathy (HCV-related in all patients but 1), confirmed by neurophysiological study, and 10 non-neuropathic patients (4 females, 6 males) with HCV-related mixed cryoglobulinemia. HRQOL was assessed using the self-administered 36-item Short Form Health Survey Questionnaire (SF-36). The neuropathy patients had lower scores (impaired HRQOL) than the other cryoglobulinemic patients on “physical functioning”, “pain”, and “vitality.” Both neuropathic and non-neuropathic patients with cryoglobulinemia rated worse than the reference population on “role limitation due to physical problems” and “general health perception.” We conclude that the severity of neuropathy may be measured with a general HRQOL instrument, which provides additional information about the impact of the disease on the general functioning of the patient, and it may be useful in rehabilitation and counseling of neuropathic patients.

Cryoglobulinemic neuropathy is probably the commonest form of vasculitic neuropathy, at least in Southern Europe. We studied 25 patients (19 females, 6 males) with symptomatic cryoglobulinemic neuropathy (HCV-related in all patients but 4) clinically evident, and confirmed by neurophysiological study. Cryoglobulin was type 2 in 17 cases, type 3 in 4 cases, and not characterized in 4 cases. Neuropathy was more often in form of asymmetrical (mainly) sensory polyneuropathy (11 cases); other forms included symmetrical sensory polyneuropathy (8 cases), sensorimotor polyneuropathy (2 cases), and mononeuropathy multplex (4 cases). Neuropathy was often the presenting manifestation of the disease (16 cases), usually in association with purpura (9 cases). Purpura was the commonest non-neurological manifestation (21 cases), and was especially severe in frequency and intensity in 11 cases. Purpura of relevant entity tended to be associated with more severe features of neuropathy, on clinical and neurophysiological grounds, and worsening course. Severe purpura was more often associated with asymmetrical neuropathy or mononeuropathy multiplex. Hepatic involvement, relevant in 7 cases and mild in 11 cases, did not correlate with the severity of neuropathic manifestations. Peripheral nerve involvement in mixed cryoglobulinemia has heterogeneous features, but factors conditioning its expression are poorly known. Our study suggests that the severity of neuropathy is correlated with purpura thus the pathogenic mechanisms of cutaneous and neurological manifestations may be interconnected.

Sensory ganglionopathy is a sensory neuropathy characterized by inflammatory infiltration of the sensory ganglia, including trigeminal ganglia, in association with Sjogren's syndrome, or idiopathic. We report a patient who had a peculiar presentation with dysphagia. A 76-year-old man presented with a 1-year history of dysphagia and weight loss, and facial dysesthesias. A diagnosis of amyotrophic lateral sclerosis was initially suspected, because of muscular atrophy and bulbar signs, however EMG showed only mild neurogenic changes, excluding signs of motor neuron involvement. Neurological examination showed absent corneal reflexes, moderate muscular wasting and mild weakness in the extremities, absent deep tendon reflexes in the legs, and sensory loss over the face and extremities. Electroneurographic study demonstrated absent blink reflex, and severely decreased or absent sensory action potentials in the limb nerves. Laboratory investigations, including CSF examination and search for anti-neural antibodies, were negative. A sicca syndrome was demonstrated by Schirmer test and salivary gland scintigraphy, and lower lip biopsy showed focal sialoadenitis according to the criteria of Greenspan et al (1974). A pure sensory or mainly sensory neuropathy with prominent trigeminal involvement is quite typical in the course of collagen diseases, and in particular in Sjogren's syndrome, supported by T cell infiltration in the dorsal root ganglia. In our case, the presence of sicca syndrome and focal sialoadenitis was consistent with the diagnosis of Sjogren's syndrome. We suggest that dysphagia, an atypical symptom in sensory ganglionopathy, may be related to involvement of the sensory ganglia of the glossopharyngeal and/or vagus nerve.

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.

A man with Fabry's disease, who died at 52, suffered from lancinating limb pains between the age of 20 and 27, and from severe arthralgia between 20 and 40. The sural nerve showed a severe loss of fibers (1,614 myelinated fibers/mm2), chiefly affecting the small myelinated fibers. Inclusions of both homogeneous and lamellated appearance were present in the perineurial cells, fibroblasts and vessel walls. Teased fibers displayed moderate remyelination, regeneration and the presence of globular focal myelin thickening. The transient time course of painful manifestations in this case is stressed in view of a possible pathogenesis of pain in Fabry's disease. It appears that small-fiber neuropathy is not directly related to the occurrence of pain symptoms, since the prevalent loss of small myelinated fibers was seen in the absence of actual pain. The small sensory neurons in the dorsal root ganglia, that are especially affected by lipid accumulation, probably give rise to abnormal discharges producing pain via the prevalence of the small-fiber versus the large-fiber input to the dorsal horn of the spinal cord (gate control theory). Thus pain fits may spontaneously abate, as in our case, if degeneration and loss of the small sensory neurons overstep a critical level.

An X-linked adult-onset neurogenic muscular atrophy, chiefly proximal, with late involvement of the distal musculature and medulla oblongata was present in 4 members of a single kindred. Associated in all patients were gynecomastia, impotence and essential tremor. Frederickson type IV hyperlipemia was present in 1 patient. Hormonal stimulation tests in 2 patients elicited a borderline low testicular response in the younger of the 2 and a pathological response in the older patient. On the evidence of these and previously reported cases, Kennedy disease would appear to be characterized by an X-linked proximal neurogenic amyotrophy of adult onset and by a testicular endocrine deficit.

The authors report the muscular and humoral immunological abnormalities found in a family with progressive external ophthalmoplegia (PEO) of the “pure” form. Serum circulating immune complexes as determined by the polyethylen glycol (PEG) test and double radial immunodiffusion (DRID) were positive for IgG in both cases studied and for IgM and Clq for the propositus. In the latter circulating auto-antibodies against smooth muscle were also present. Immunohistochemical studies on striated muscle of the propositus showed positive perivascular IgG and IgM staining and IgG in the sarcolemma-basement membrane complex. It is suggested that in this family a genetically inherited abnormal immune response to the muscular blood vessel wall has induced vascular injury and ultimately chronic ischemic muscular damage. This is consistent with the view that PEO is a clinical syndrome, i.e. the expression of various defects affecting primarily or secondarily the energy metabolism of the muscular tissue.

A review of cases of systemic vasculitis followed for one year in a rheumatology department resulted in the detection of 18 patients who on the clinical and electrophysiological evidence had symmetrical distal polyneuropathy. A moderate impairment of the motor conduction velocity was present in 7 patients, with electromyographic neurogenic changes in the distal lower limbs of all but one patient. The sensory action potential of the sural nerve was bilaterally absent in one case, and its amplitude was reduced in 14 out of 16 patients, with a decreased sensory conduction velocity in 9 cases. The sural nerve biopsy, performed in 6 patients, was prevalently suggestive of previous axonal degeneration. This investigation illustrates the spectrum of diffuse peripheral nerve involvement associated with systemic vasculitis. A variable impairment of the sensory action potential, ranging from slight decrease of amplitude to no response, is the most common finding. Conduction velocities appear to be relatively spared.

A neuromuscular disorder is reported in two brothers, aged 28 and 38 years, with glycogenosis type III. Both patients had proximal weakness, pseudohypertrophy of sternocleidomastoid. trapezius and quadriceps muscles, mild distal wasting and myopathic EMG changes. Pseudohypertrophy was more evident in the younger brother, whereas weakness was prominent in the older one. In the former, muscle biopsy revealed vacuolar myopathy and virtual absence of amylo-1,6-glucosidase enzyme. Few familial cases of debrancher deficiency neuromuscular disorder have been reported. Distal wasting has been considered a quite characteristic manifestation of the disease. It is also suggested that this particular kind of pseudohypertrophy may represent a distinctive feature of glycogenosis type III.

Localized nodular myositis (LNM) is a rare variant of polymyositis beginning with inflammatory nodules within muscles. Only seven cases have so far been reported in the literature. We describe a probable further case of LNM in a 67-year-old man with ischemic claudication of the left leg for three years who presented with painful nodules in the left gastrocnemius muscle and signs of systemic disease; a complete follow-up was not possible, because the patient died after only two months and autopsy was not performed. Muscle biopsy showed localized areas of necrotic and inflammatory pleomorphic changes, in keeping with the features of the other known cases. The ultrastructural findings (not previously reported in this disease) were characterized by marked changes of endomysial capillaries, with fibroblastic metamorphosis of the endothelial cells, and by the presence of filamentous inclusions in the myonuclei. The differential diagnosis of LNM from other localized muscle masses, chiefly from muscle infarct, is discussed.

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.

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.

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.