A case of motor neuron involvement in Gaucher disease.

Gaucher disease (GD) is a genetic disorder characterized by an accumulation of glucosylceramide in cells in the monocyte-macrophage system. We describe a case of a 33-year-old man with a previous diagnosis of type 3 GD who displayed a progressive weakening of the limbs followed by upper motor neuron involvement. A diagnosis of definite Amyotrophic Lateral Sclerosis was made. This is the first reported case of concurrent Gaucher disease and the ALS phenotype in the same patient.

PNKP deficiency mimicking a benign hereditary chorea: The misleading presentation of a neurodegenerative disorder.

PNKP gene encodes for a kinase/phosphatase involved in DNA damage response, controlled and stabilized by ATM phosphorylation. PNKP deficiency, thus far described in 40 subjects, has been associated with a complex neurological phenotype encompassing microcephaly, seizures, developmental delay, ataxia, oculomotor apraxia and polyneuropathy. We report a new case expanding the clinical phenotype of this rare disorder. This 25 years old girl presented with chorea at the age of 2 years and remained stable up to the adult age when the emergence of fatigability and asthenia of lower limbs prompted a new examination disclosing a sensory-motor axonal demyelinating neuropathy. Clinical exome sequencing revealed two previously described variants in PNKP gene. This case highlights the phenotypic variability of PNKP associated disorders, showing that an early onset apparently non progressive chorea can be the presenting symptoms of this rare condition.

Modulation of human corticospinal excitability by paired associative stimulation in patients with amyotrophic lateral sclerosis and effects of Riluzole.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes an impairment in both the upper and lower motor neurons. The recent description of numerous non-motor signs points to an involvement of the neocortex networks that is more complex than was previously believed. Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation, can enhance motor output in the contralateral hand through an NMDA-mediated sensorimotor mechanism. OBJECTIVE: To describe the effects of PAS on ALS patients before and after Riluzole intake compared with healthy subjects. METHODS: PAS was used to detect differences between 24 newly-diagnosed ALS patients and 25 age-matched healthy controls. MEP amplitude from the abductor pollicis brevis was considered before PAS, immediately after (T0) and after 10 (T10), 20 (T20), 30 (T30) and 60 (T60) minutes. Statistical significance was calculated using RM-ANOVA. RESULTS: In healthy controls, PAS significantly increased MEP amplitude at T10, T20 and T30 (p < 0.05). In ALS patients, a significant increase in MEP amplitude was also observed after 60 min (p < 0.05), thus demonstrating NMDA-mediated enhanced facilitatory plasticity. After two weeks of riluzole intake, no MEP amplitude increase was evident after PAS at any time point. In three monomelic-onset ALS patients, a long lasting sensorimotor facilitation was evident only in the hemisphere corresponding to the affected side and appeared in the opposite hemisphere when the patients manifested contralateral symptoms. CONCLUSIONS: PAS may be considered a useful tool when investigating NMDA-mediated neocortical networks in ALS patients and the modulation of such networks after anti-glutamatergic drug intake.

Vitamin D in amyotrophic lateral sclerosis.

Vitamin D supplementation has been proposed as a potential treatment to delay amyotrophic lateral sclerosis (ALS) progression. The aims of this study were to compare retrospectively vitamin D blood levels in ALS patients with those in healthy subjects; to correlate vitamin D blood levels with clinical functions in patients; and to evaluate whether administration of vitamin D could modify the clinical progression of the disease. Vitamin D blood levels were evaluated in 57ALS patients and in 57 healthy subjects. In the ALS patients the following clinical variables were evaluated every 3 months: Medical Research Council scale (MRC) score; revised ALS functional rating scale (ALSFRS-R) score; forced vital capacity (FVC). Twentyfour patients were treated with high doses of cholecalciferol. No significant differences were found between the vitamin D blood levels in the ALS patients (18.8 ± 12.2) and the healthy subjects (20.7 ± 10.1). The vitamin D levels in the ALS patientsdid not correlate with recorded clinical parameters. No clinical differences in terms of ALSFRS-R, MRC or FVC were found between the treated and the untreated patients over time. In ALS, as in other chronic neurological diseases, levels of vitamin D in blood appeared reduced, but no difference was found between the levels in ALS patients and in healthy subjects. Oral vitamin D supplementation in ALS patients was not associated with better prognosis in comparison with untreated ALS patients. Further prospective controlled studies are needed to clarify the effect of vitamin D on the progression of ALS disease.

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.

Effects of daily tadalafil on lower urinary tract symptoms in young men with multiple sclerosis and erectile dysfunction: a pilot study.

PURPOSE: Men affected by multiple sclerosis often experience neurogenic overactive bladder (OAB), lower urinary tract symptoms and erectile dysfunction (ED). The aim of the study was to investigate modifications of urinary and sexual functions after administration of daily tadalafil (TAD) 5 mg. METHODS: Twenty men were enrolled in a single-blind, 4-week prospective study while 10 men without treatment served as controls. Primary outcomes were changes from baseline of International Prostate Symptom (IPSS), OAB questionnaire (OAB-q-short form) and International Index of Erectile Function (IIEF-5) scores. To evaluate the influence of bladder filling on somatic reflexes, we studied variations of the H-reflex evoked by electrical stimuli applied to the tibial nerve at the popliteal fossa and recorded from the soleus muscle. Also testosterone/estradiol (T/E) ratio was measured before and after treatment. RESULTS: In TAD group, an improvement in IPSS (p < 0.001), OAB-q (p < 0.001) and IIEF-5 (p < 0.001) scores was found. Also, an increase in Q max (p < 0.01) and T/E ratio (p < 0.01) was found with a concomitant reduction in post-void residual volume (p < 0.001) without any changes in the H-reflex. CONCLUSIONS: The study demonstrates for the first time that daily TAD in patients with multiple sclerosis improves storage symptoms, post-void residual volume, steroid hormone pattern and ED without urodynamic changes.

Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS.

We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.

Heterogeneity of root and nerve ultrasound pattern in CIDP patients.

OBJECTIVE: The few published ultrasound (US) studies on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report diffusely increased cross-sectional area (CSA) of nerves. The data are, however, heterogeneous and correlations with clinical history or disease severity are lacking. METHODS: Thirty-four patients with CIDP underwent US nerve evaluation by two neurologists blinded to clinical data. US nerve pattern for each patient was defined by a third neurologist blinded to clinical data. Three US classes were identified based on CSA and echogenicity: large nerves with hypoechoic nerves/fascicles (class 1); large nerves with heterogeneous hypo- and hyperechoic fascicles (class 2); normal size nerve but abnormal hyperechoic array (class 3). RESULTS: In all patients, US nerve changes were observed: in most of the cases, enlarged nerves or nerve segments were observed. The three 'classes' of US nerve changes significantly correlated (R: 0.68, p<0.001) with disease duration, but not with age or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. CONCLUSIONS: US may be of adjunctive diagnostic value in CIDP assessment. Nerve morphological changes may mirror the underlying pathophysiological mechanisms and seem to correlate with disease duration. SIGNIFICANCE: These results offer the possibility of exploring the use of US to assess CIDP disease activity and treatment.

Depression, pain and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study.

The complications related to amyotrophic lateral sclerosis (ALS) include pain. A higher risk of depression and a negative effect on quality of life (QoL) might be expected in ALS patients with pain. The aims of this study were to evaluate the prevalence of pain in ALS patients, to compare measures of depression and QoL in patients with and without pain, and to study the influence of depression scores and pain on the QoL of ALS patients with pain. Forty ALS patients were enrolled, and 36 were included in the analysis. Seventy-two percent of patients reported pain. Pain intensity was significantly related to a worsening of QoL (p<.05). This effect was no longer significant after considering depression scores as a covariate. Depression scores significantly decreased QoL (p<.02) and this effect remained significant after considering pain intensity as a covariate (p<.05). Our study suggests that pain is frequent in ALS patients and that depressive symptoms are significantly related to poorer QoL. Clinicians should pay more attention to both pain and depressive symptoms in ALS patients considering their effect on QoL.

Dysphagia in amyotrophic lateral sclerosis: prevalence and clinical findings.

OBJECTIVES: To characterize swallowing deficits in amyotrophic lateral sclerosis (ALS); investigate the delay in dysphagia onset; estimate correlations between dysphagia severity and patients' functional status; identify the symptom(s) most likely to predict dysphagia. MATERIALS AND METHODS: A group of 49 consecutive patients with ALS, 14 with bulbar onset and 35 with spinal onset, underwent swallowing evaluation including bedside and fiberoptic endoscopic examination to detect dysphagia. RESULTS: Patients with dysphagia were more likely than those without to have bulbar onset ALS (P = 0.02); more severely impaired chewing (P = 0.01); and tongue muscle deficits (P = 0.001). The only variable measured at first examination significantly associated with dysphagia was a more than mild tongue muscle deficit. The only variable useful in predicting dysphagia was a chewing deficit. In 10 of the 49 patients studied, swallowing evaluation disclosed an impaired cough reflex. CONCLUSIONS: Dysphagia in patients with ALS correlates significantly with bulbar onset and with oral swallowing impairment. Fiberoptic swallowing evaluation is a useful tool for detecting swallowing deficits and laryngeal sensitivity in patients with ALS. An impaired cough reflex is an unexpected finding in many patients with ALS.

H-coil repetitive transcranial magnetic stimulation for pain relief in patients with diabetic neuropathy.

BACKGROUND: Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to study changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H-coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower-limb representation relieves pain in patients with diabetic neuropathy. METHODS: Patients were randomly assigned to receive daily real or sham H-coil rTMS for 5 consecutive days. After a 5-week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex). RESULTS: Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p=0.01), and so did RIII reflex area (p<0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS-induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well. CONCLUSIONS: Deep H-coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.

Chronic treatment with rivastigmine in patients with Alzheimer's disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic stimulation.

OBJECTIVE: To investigate changes in cortical excitability and short-term synaptic plasticity we delivered 5 Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in 11 patients with mild-to-moderate Alzheimer's disease (AD) before and after chronic therapy with rivastigmine. METHODS: Resting motor threshold (RMT), motor evoked potential (MEP), cortical silent period (CSP) after single stimulus and MEP facilitation during rTMS trains were tested three times during treatment. All patients underwent neuropsychological tests before and after receiving rivastigmine. rTMS data in patients were compared with those from age-matched healthy controls. RESULTS: At baseline, RMT was significantly lower in patients than in controls whereas CSP duration and single MEP amplitude were similar in both groups. In patients, rTMS failed to induce the normal MEP facilitation during the trains. Chronic rivastigmine intake significantly increased MEP amplitude after a single stimulus, whereas it left the other neurophysiological variables studied unchanged. No significant correlation was found between patients' neuropsychological test scores and TMS measures. CONCLUSIONS: Chronic treatment with rivastigmine has no influence on altered cortical excitability and short-term synaptic plasticity as tested by 5 Hz-rTMS. SIGNIFICANCE: The limited clinical benefits related to cholinesterase inhibitor therapy in patients with AD depend on factors other than improved plasticity within the cortical glutamatergic circuits.

Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans.

Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face- and foot-laser evoked potentials (LEPs) and foot-cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot-LEPs (P<0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS (P<0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions. Our data suggest that anodal tsDCS over the thoracic spinal cord might impair conduction in the ascending nociceptive spinal pathways, thus modulating LEPs and increasing pain tolerance in healthy subjects.

Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological study.

In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P>0.50), but a longer delay since symptom onset than those without (P<0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P<0.0001), NCS data did not differ between groups (P>0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P<0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.

Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome.

Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS. We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Abeta-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Adelta-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Adelta-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Abeta-fibres, spontaneous constant pain arises from damage to nociceptive Adelta-fibres.

Intracortical excitability in patients with relapsing-remitting and secondary progressive multiple sclerosis.

We designed this study to investigate possible correlations between variables measuring primary motor cortex excitability detected by single and paired-pulse transcranial magnetic stimulation (TMS) and the severity of clinical manifestations in patients with multiple sclerosis (MS). Thirty patients with MS in remission, 16 with relapsing-remitting (RR), 14 with secondary progressive disease (SP) and 17 healthy subjects participated in the study. In each subject, the central motor conduction time (CMCT) was calculated, and single-pulse and paired-pulse TMS at 3 and 10 ms interstimulus intervals was delivered over the primary motor cortex of the dominant hemisphere to measure the amplitude of motor-evoked potentials (MEPs), motor threshold (MTh), intracortical inhibition (ICI) and facilitation (ICF). Correlations were determined between the patients' TMS findings and magnetic resonance imaging (MRI) (lesion load) and clinical features (expanded disability status scale, EDSS score). EDSS scores were significantly higher in SPMS than in RRMS patients. The MTh was significantly higher, and the MEP was significantly smaller in SPMS patients than in RRMS patients and control subjects. All patients had longer CMCTs than healthy subjects. In all patients, paired-pulse TMS elicited an inhibited test MEP at the 3-ms ISI and a facilitated test MEP at the 10 ms ISI. Post hoc analysis showed that ICI was significantly lower in SPMS patients than in those with RRMS and healthy subjects. EDSS scores correlated significantly with TMS measures (MEP, ICI, CMCT and MTh), but not with MRI lesion load. It was found that intracortical excitability as measured with TMS differs according to the clinical course of MS; it remains normal in patients with low EDSS scores and is altered in patients with high EDSS scores.

Dissociation between cutaneous silent period and laser evoked potentials in assessing neuropathic pain.

In this study we investigate whether the cutaneous silent period (CSP)-an inhibitory response evoked in hand muscles by painful digital nerve stimulation-is useful for assessing nociceptive pathway function in patients with neuropathic pain. In 40 patients with peripheral neuropathy (21 without and 19 with neuropathic pain) we recorded the CSP in the abductor digiti minimi after fifth digit stimulation and also recorded laser evoked potentials (LEPs) after stimulation applied to the ulnar territory of the hand. Although the LEP amplitude was significantly lower in patients with pain than in those without (P < 0.005), the CSP duration did not differ between groups (P > 0.50). Pain intensity correlated significantly with LEP amplitudes (P < 0.005) but not with CSP duration (P > 0.5). Our findings indicate that the CSP is not useful for assessing nociceptive pathway function in patients with neuropathic pain.

Psychophysiological aspects of voluntary skilled movement after stroke: a follow-up study.

OBJECTIVES: The aim of the study was to follow the psychophysiological evolution of a self-paced voluntary skilled movement in hemiparetic subjects after ischemic stroke by means of a skilled performance task (SPT). The task consisted in starting a sweep of an oscilloscope trace by pushing one button with the left index finger (trigger point), and in stopping it within a central area on the oscilloscope screen, between 40 and 60 ms (correct performance) after the start of the sweep, by pushing the other button with the right index finger. A SPT yields a considerable amount of information on the electrophysiological components, which reflect pre-programming activity (Bereitschaftspotential--BP), control strategies (Skilled Performance Positivity--SPP) and behavioural response (Correct Performances). The study was also aimed at detecting any longitudinal changes in the psychophysiological pattern, as evaluated by the clinical examination and specific motility scales, that parallel motor recovery. METHODS: Movement related potentials (MRPs) were recorded in 12 control subjects and 9 patients in the acute phase, before the start of neurorehabilitation (time 0), when the patients were able to execute an index finger press with the affected hand. The patients (mean age = 62.33 years, SD = 8.17) presented a mild to moderate central arm paresis caused by a first-ever unilateral supratentorial and subcortical ischemic lesion. The subsequent recordings were carried out respectively 3, 9 and 12 months later. RESULTS: At the first recording, hemiparetic patients achieved a significantly lower percentage of correct performances and had a lower BP amplitude than controls (p < 0.001); SPP was absent. The number of correct performances did not improve significantly during the subsequent recordings. BP amplitude showed a mild increase in the second, third and fourth recordings (p < 0.05), while SPP amplitude revealed a slight improvement at the second and a marked improvement at the third and fourth recordings, when there was no longer a statistically significant difference from controls. CONCLUSIONS: Our findings point to an early recovery of pre-programming activity and a delayed improvement in control activity. The delayed development of control activity in the absence of procedural learning, i.e. skill learning through practice, forces patients to exploit attentional strategies to compensate for their procedural learning impairment. SPT shows that the efficacy of physical therapy aimed at motor ability recovery in hemiparetic patients does not keep up with the slow recovery process of an automatic motor level.