Variations of the perforin gene in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

Perforin (PRF) has a key role in the function of cytotoxic T and natural killer cells. Rare variations of PRF1 predispose to autoimmunity. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, involving defective lymphocyte apoptosis. The aim of this study was to investigate the role of PRF1 in CIDP. The entire coding region of PRF1 was sequenced in 94 patients and 158 controls. We found three missense variations leading to amino acid substitutions and one nonsense variation resulting in a premature stop codon. All variations would decrease PRF activity. Their overall frequency was significantly higher in patients than in controls (odds ratio (OR)=4.47). The most frequent variation was p.Ala91Val (OR=3.92) previously associated with other autoimmune diseases. Clinical analysis showed that PRF1 variations were more frequent in relapsing patients and in patients displaying axonal damage. These data suggest that PRF1 variations may influence CIDP development and course.

Neurophysiology of the pelvic floor in clinical practice: a systematic literature review.

Neurophysiological testing of the pelvic floor is recognized as an essential tool to identify pathophysiological mechanisms of pelvic floor disorders, support clinical diagnosis, and aid in therapeutic decisions. Nevertheless, the diagnostic value of these tests in specific neurological diseases of the pelvic floor is not completely clarified. Seeking to fill this gap, the members of the Neurophysiology of the Pelvic Floor Study Group of the Italian Clinical Neurophysiology Society performed a systematic review of the literature to gather available evidence for and against the utility of neurophysiological tests. Our findings confirm the utility of some tests in specific clinical conditions [e.g. concentric needle electromyography, evaluation of sacral reflexes and of pudendal somatosensory evoked potentials (pSEPs) in cauda equina and conus medullaris lesions, and evaluation of pSEPs and perineal sympathetic skin response in spinal cord lesions], and support their use in clinical practice. Other tests, particularly those not currently supported by high-level evidence, when employed in individual patients, should be evaluated in the overall clinical context, or otherwise used for research purposes.

Prevalence of subclinical neuropathy in diabetic patients: assessment by study of conduction velocity distribution within motor and sensory nerve fibres.

Nerve conduction velocity distribution (CVD) study is a newly-developed electrodiagnostic method for detecting alterations in the composition of nerve fibres according to their conduction velocity. The presence of subclinical neuropathy was evaluated in 138 diabetic patients by CVD study of four motor nerves (external popliteal and ulnar nerves bilaterally) and two sensory nerves (median nerve bilaterally), and the data obtained were compared with standard electrophysiological parameters in the same nerve segments. CVD studies revealed an altered distribution pattern in 106 of 129 evaluable patients for motor nerves (82%) and in 67 of 115 evaluable patients for sensory nerves (58%), while standard examination gave abnormal findings in 92 of 137 patients (67%) and in 33 of 118 patients (11%), respectively. Of the patients adequately evaluated by both techniques, 21 of 129 patients (16%) revealed altered CVD data unaccompanied by slowing of maximum nerve conduction velocity, and 37 patients of 101 (37%) showed similar findings for sensory nerves. Subclinical alterations of motor and sensory nerve CVD were not significantly related to age or to metabolic control expressed as glycated haemoglobin levels; a significantly longer duration of disease was found in patients with motor and mixed subclinical neuropathy with respect to non-neuropathic patients. The CVD study allowed us to detect subclinical abnormalities of motor and sensory nerve fibres; often this is a more sensitive method than the standard electrodiagnostic study. This method can be very useful as a diagnostic tool and in research in the study of the progression of diabetic neuropathy.

Electrophysiological observations on the palmomental reflex in normal neonates.

The authors report normative data on the electrical response (EMG response) recorded from the mentoneal muscles by repetitive mechanical stimulation of the thenar eminence surface of the hand in 18 neonates, 1 to 6 days old: the so-called palmomental reflex (PMR) or palm-chin reflex. PMR potentials showed in most cases great variability in amplitude and duration but not in latency, and they were present in all but one of the cases. The PMR was monolateral in one case only. Evoked potentials from the scalp were also recorded after electrical stimulation of the thenar eminence. The afferent branch of the PMR is constituted of impulses originating mainly from median nerve, skin and muscle receptors. Such impulses may reach facial motor nuclei following corticofugal pathways throughout a long-loop circuit.

Sympathetic skin response versus maximum motor and sensory conduction velocity to detect subclinical neuropathy in non-insulin-dependent diabetics.

Conventional motor (MCV) and sensory conduction velocity (SCV) of the ulnar (UN), peroneal (PN) and median nerves (MN) and the areas of sympathetic sudomotor response (SSR) recorded from the middle finger were measured on both sides in 20 normal and 20 non-insulin-dependent diabetic (NIDD) subjects. Conventional statistical tests (t test, linear correlation coefficient r) and discrimination analysis were applied to the above electrophysiological parameters. To evaluate the capability of the tests to separate NIDD diseased from normal nerves, the results were represented as generalized distances, i.e., difference between mean discriminant normalized combinations adjusted for intra-group variability. The r values were 0.92 (P less than 0.01) for the UN, 0.40 (P greater than 0.05) for the PN, and 0.86 (P less than 0.01) for the MN sensory action potential (SAP) amplitudes. No significant differences were found for normalized latencies. The r values of the SSR areas were 0.62 (P less than 0.01) at the right and 0.77 (P less than 0.01) at the left, homolaterally to the side of stimulation. SR and MCV generalized distances were 1.35 and 1.39, respectively. The discriminating power of SSR, MCV and SCV considered together was higher (2.40) than that of MCV and SCV (1.70). Since motor, sensory and autonomic alterations often did not coexist in NIDD, it was possible to find at least one type of involvement in most of the diabetic subjects.

The palmomental reflex from mechanical stimulation in normal man: normative data.

The authors report normative data on the electrical response (EMG response) recorded from the mentoneal muscles by repetitive mechanical stimulation of the palmar and dorsal surface of the hand in 23 normal adults: the palmomental reflex (PMR). An early and late response was observed in 11 cases. The PMR potentials showed great variability in latency, amplitude and duration and were present in about 70% of the subjects in whom the PMR was undetectable by visual inspection. In 3 cases the reflex was also observed contralaterally to the side of stimulation. The afferent branch of the normal PMR is constituted of impulses originating mainly from the median nerve skin and muscle receptors. Such impulses could reach facial motor nuclei either through short-(paucisynaptic) or long-loop (thalamocortical) circuits.

Muscle compound motor action potentials from esophago-vertebral electrical stimulation of the spinal cord in the normal awake man.

In 15 normal alert subjects, electrical stimulation of the spinal cord at various levels by a nasopharyngeal probe (cathode) and a vertebral surface electrode (anode) was performed with different orientation of the stimulating dipole. Maximum spinal cord compound motor action potentials (SCCMAPmax) simultaneously recorded from homologous muscles of the upper arm of both sides were not significantly different in amplitude and latency. By stimulating the spinal cord at the cervico-dorsal level it was possible to obtain simultaneous recordings of SCCMAP from muscles of the upper and lower limbs and trunk at a stimulus intensity of 50-70 mA. Stimulating the spinal cord and the peripheral nerve at Erb's point it was also possible to calculate motor propagation velocity of the peripheral nerve of limb-girdle muscles. Central latency of the F wave exceeded by 0.5 to 0.7 ms that of the SCCMAP, suggesting that esophago-vertebral stimulation is able to directly excite the motor neurons. By threshold current intensity, it is possible to obtain a threshold SCCMAP (SCCMAPth) of the same latency as SCCMAPmax and different in shape, duration and amplitude from the CMAP obtained by cortical stimulation with threshold magnetic stimuli. SCCMAPth was different in shape from the motor unit action potential activated at weak voluntary effort, SCCMAPth latency and amplitude were unchanged after voluntary homo- and contralateral activation.

Electrophysiology of the palmomental reflex in normal and parkinsonian subjects.

The palmomental reflex (PMR), obtained by mechanical stimulation of the skin of the thenar and hypothenar eminences of the hand and recording the surface EMG response from the chin muscles homolateral and contralateral to the side of stimulation, was studied in normal subjects and in a group of akinetic parkinsonians, both de novo and treated. PMR was present in most subjects of both groups. No differences regarding the incidence of the PMR homolateral to stimulation of the thenar eminence was found between controls and patients, and it was non-habituating in both groups. When the hypothenar eminence was stimulated, the PMR was present in about half of the subjects of both groups. PMR was present contralaterally in both normal and patients, whereas bilateral PMR prevailed in parkinsonians. Latency and duration of the reflex were significantly shorter in parkinsonians than in controls. The data are discussed in the light of the pathophysiology of the PMR putative pathways in normal subjects and in Parkinson's disease.

Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical neuropathy. I. Motor nerve.

A computer-assisted collision method to evaluate motor conduction velocity distribution of the ulnar and external peroneal nerves in normal subjects and in insulin-dependent and non-insulin-dependent diabetics without clinical signs of neuropathy is described. Distribution curves were sigmoidally (bimodally) shaped in normal and in insulin- and non-insulin-dependent subjects. In insulin-dependent patients, motor conduction velocity of the peroneal nerves was globally impaired, whereas of the ulnar nerves it was normal. In non-insulin-dependent patients, slower conduction velocity was involved in both nerves.

Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical signs of neuropathy. II. Sensory nerve.

A new computer-assisted method to evaluate sensory conduction velocity distribution and dispersion of the digital nerve of the middle finger in normal subjects and in type I and type II diabetic subjects without any neurological impairment is reported. Distribution curves were exponentially shaped in normal and in diabetic subjects. In insulin-dependent diabetics, only slower conduction velocity fibers were involved, whereas no significant difference was observed between the non-insulin-dependent diabetic group and the control group.

Short and long latency cortical potentials evoked by electrical stimulation of the oesophageal mucosa in normal alert humans.

Cerebral responses from the oesophagus were investigated in 16 normal male and female volunteers ranging in age from 20 to 54 years. The stimulus was applied by a naso-oesophageal probe equipped with bipolar ring electrodes. Short and long latency EP (SLEP and LLEP) were observed in all the subjects examined. SLEP consisted in a low threshold potential of 30 to 70 microV amplitude, biphasic or triphasic in shape and of approximately 5 to 10 ms duration; mean latency at the largest peak was 4.5 +/- 1.7 at 25 cm from the nostrils. Early components at about 2.5-3.5 ms and of small amplitude are also present. Recording from the neck at C7 with a common non-cephalic reference, SLEP components occurred from 2 to 6 ms earlier than that from the scalp, suggesting an oligo-synaptic transmission of the excitement via ganglion and lemniscal pathways to the cortex. SLEP was always followed by a complex potential formed of a succession of negative and positive waves with latencies ranging from 20 to 300 ms: the LLEP. This LLEP was usually not very stable and reproducible during the course of successive recordings and in the same subject because it tended to adjust. Preliminary observations concerning the topographical cortical distribution of oesophageal evoked potentials show a circumscribed localization of the SLEP in the parieto-temporal region of the hemisphere whereas LLEP was more widespread. It is the authors' opinion that oesophageal evoked potentials are generated both by the excitation of myelinic fibres with a wide range of conduction speed and of amyelinic fibres from the oesophageal mucosa and the paraoesophageal peripheral nerves of vagal origin.

White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) offers a unique window on the connectivity changes, extending beyond the basal ganglia, which accompany the cognitive symptoms of Parkinson disease (PD). The primary purpose of this study was to assess the microstructural damage to cerebral white matter occurring in idiopathic PD. MATERIALS AND METHODS: Our sample included patients with PD without dementia (n = 10; Hoehn and Yahr stages I and II; Unified Parkinson Disease Rating Scale, 20.5 +/- 8.3; and Mini-Mental State Examination, 28.3 +/- 1.5) and age-matched healthy control subjects (n = 10). DTI was performed on a 1.5T scanner, and mean diffusivity (MD) and fractional anisotropy (FA) maps were obtained. Regions of interest (ROIs) were drawn on the major fiber bundles as well as on gray matter nuclei. RESULTS: In patients, the MD was increased at borderline significance in the substantia nigra but was unaltered in the thalamus, globus pallidus, putamen, and in the head of the caudate nucleus. The FA and MD were unaltered in the corticospinal tract in the midbrain and at the level of the internal capsule, and in the splenium of the corpus callosum. By contrast, the MD was increased and the FA was decreased in the genu of the corpus callosum and in the superior longitudinal fasciculus; in the cingulum, only the MD was altered. The observed changes were not significantly lateralized. CONCLUSIONS: Widespread microstructural damage to frontal and parietal white matter occurs already in the early stages of PD.

A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) disrupt neuronal mitochondrial DNA synthesis, resulting in antiretroviral toxic neuropathy (ATN). Acetyl-L-carnitine (ALCAR) enhances neurotrophic support of sensory neurones, potentially providing symptom relief and nerve regeneration. OBJECTIVE: The objective of the study was to assess the safety and efficacy compared to placebo of intramuscular ALCAR in HIV-positive patients with symptomatic distal symmetrical polyneuropathy. METHODS: Ninety patients were enrolled and randomized to receive ALCAR [500 mg twice a day (bid); n=43] or placebo (n=47) intramuscularly twice daily for 14 days followed by 42 days of oral ALCAR 1000 mg bid. Assessment of pain was obtained using the Visual Analogue Scale (VAS), Total Symptom Score (TSS), Clinical Global Impression of Change, McGill Pain Questionnaire (MPQ), and the need for rescue analgesics. RESULTS: There was no statistically significant difference in changes in VAS over 14 days between groups for the intent-to-treat (ITT) population, but for the efficacy-evaluable (EE) population ALCAR treatment produced a significantly greater reduction in pain compared with placebo (P=0.022). The proportion of patients with an improvement in TSS over 14 days was greater in the ALCAR group compared with the placebo group, but the differences were not statistically significant. During the open-label phase, patients experienced an improvement in pain, as measured by the VAS, TSS and McGill Pain Questionnaire. CONCLUSION: ALCAR, administered twice a day intramuscularly to HIV-1-infected patients with symptomatic ATN, significantly reduced weekly mean pain ratings on the VAS compared with placebo. Treatment with oral ALCAR improved symptoms for the patient group as a whole. Intramuscular and oral ALCAR was generally safe and well tolerated.

Treatment of morbid obesity by intraparietogastric administration of botulinum toxin: a randomized, double-blind, controlled study.

OBJECTIVE: The stomach is the main target organ for bariatric surgery, but no medical treatment has been developed to increase satiety and decrease food intake via gastric pathways. The aim of our study was to investigate whether or not the intraparietogastric administration of botulinum toxin A (BTX), able to modify the motility patterns of the stomach, could be useful for treatment of obesity. DESIGN: Double blind controlled study. SUBJECTS: Twenty-four morbidly obese patients (mean weight (s.e.m.) 116.1+/-4.89 kg, mean body mass index (BMI) 43.6+/-1.09 kg/m(2)) were blindly randomized to receive 200 IU BTX or placebo into the antrum and fundus of the stomach by intraparietal endoscopic administration. MEASUREMENTS: We evaluated weight loss, BMI changes, satiety score, the maximal gastric capacity for liquids and the gastric emptying time (octanoic acid breath test). RESULTS: The two groups were homogeneous for anthropometric characteristics. Eight weeks after treatment, BTX patients had significantly higher weight loss (11+/-1.09 vs 5.7+/-1.1 kg, P<0.001) and BMI reduction (4+/-0.36 vs 2+/-0.58 kg/m(2), P<0.001) and a higher satiety score on a visual analogic scale (7.63+/-0.38 vs 4.72+/-0.44, P<0.001) than controls. Furthermore, BTX patients showed a significantly greater reduction in maximal gastric capacity for liquids (266.6+/-48 vs 139+/-31, P<0.001) and a greater prolongation in gastric emptying time (+18.93+/-8 vs -2.2+/-6.9 min, P<0.05). No significant side effects or neurophysiologic changes were found. CONCLUSIONS: Topical intragastric BTX was effective in reducing food intake and body weight in morbidly obese patients.

Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies.

The results of 7 open-label clinical studies on oxcarbazepine (OXC) in different neuropathic pain conditions, sharing the same protocols, were pooled together in order to evaluate whether the results obtained in the individual trials were confirmed in the pooled analysis of this larger sample, providing more evidence for efficacy and tolerability of OXC in these conditions. Eligible patients (>18 years old) with a diagnosis of neuropathic pain were enrolled in seven open-label trials, consisting of a one-week prospective Screening Phase followed by an eight-week Treatment Phase. Treatment with OXC was initiated at 150 mg/day, and the daily dose was increased by 150 mg/day on a 2-3 day basis to the maximum tolerated dose over four weeks, up to 1800 mg/day. The primary outcome measure was the change in the actual pain rating assessed on the visual analogue scale (VAS) between the end of the Screening Phase and the end of the Treatment Phase. One hundred and thirty-six patients were enrolled in the trials. The mean VAS score dropped from 77.13 at the end of the Screening Phase to 38.41 at the end of the trial for a mean reduction of 50.2%. The percentage of responders (mean VAS score reduction > or = 50%) was 49.2%. OXC was well tolerated, with the most common adverse events consisting of vertigo, tremor, somnolence, hypotension and nausea. The results of this analysis suggest that OXC administered as monotherapy is an efficacious and safe option for the symptomatic treatment of pain associated with neuropathies.

Propranolol, clonidine, urapidil and trazodone infusion in essential tremor: a double-blind crossover trial.

Accelerometric tremorgrams were recorded from 25 subjects affected by essential tremor and analysed by a Berg-Fourier frequency analyser before and during venous infusion of the following drugs: propranolol (beta-blocker), clonidine (alpha-presynaptic adrenergic agonist), urapidil (alpha-postsynaptic blocker), trazodone (adrenolytic agent) and placebo. The washout interval between infusions was 3 days. Recordings and data analyses were performed in a double-blind crossover trial. Tremor was classified as: at rest; postural (arms hyperextended); and intention (finger-nose test). Analysis of the results showed that propranolol and clonidine reduced significantly (P = 0.01 and P = 0.009, respectively) the power spectrum of postural tremor, but left at rest and intention tremors unchanged. No significant effects on the tremor power spectrum were observed after placebo, urapidil or trazodone administration. None of the drugs had any effect on tremor frequency.

An electrophysiological method to assess the distribution of the sensory propagation velocity of the digital nerve in normal and diabetic subjects.

We report a new computer-assisted collision method to evaluate sensory conduction velocity (SCV) distribution in the digital nerve of the middle finger in normal subjects and in insulin-dependent diabetic subjects without any neurological impairment. Distribution curves were monomodally shaped in controls, indicating a greater proportion of fibers with relatively slow conduction velocity and a lesser proportion of fibers with faster velocity. In most diabetic nerves, a monomodal trend of the SCV distribution indicated a definite reduction in high and intermediate SCV. In a small proportion of nerves, the SCV distribution tended to be bimodal, with an absolute maximum corresponding to lower velocities and a relative maximum to intermediate-fast velocities. Slowing of the intermediate velocity, or loss of fibers of intermediate velocity, can be hypothesized to represent the early electrical evidence of a subclinical polyneuropathy in insulin-dependent diabetic subjects.

High prevalence of human T cell lymphotropic virus type II infection in patients affected by human immunodeficiency virus type 1--associated predominantly sensory polyneuropathy.

The etiopathogenesis of peripheral neuropathy (PN) that frequently affects human immunodeficiency virus (HIV) type 1-positive patients remains undefined. Forty-seven HIV-1-positive patients with PN (8 with inflammatory demyelinating polyneuropathy and 39 with predominantly sensory polyneuropathy [PSP]) and 266 controls with symptomatic HIV-1 infection without PN were screened for antibodies to human T cell lymphotropic virus (HTLV) types I and II. The prevalence of antibodies to HTLV-II was significantly higher in patients with PSP than in controls (30.8% vs. 8.3%; P < .001). All seropositive patients with PN had HTLV-II DNA in their peripheral blood mononuclear cells by polymerase chain reaction (PCR) analysis. PCR analysis of tissues from 1 patient with PSP who died during the study showed HTLV-II proviral sequences in the femoral nerve and basal nuclei. These results support the hypothesis that HTLV-II represents an etiologic factor in the pathogenesis of a considerable proportion of PSP in patients infected with HIV-1.