Occurrence and characterization of Pain in immune-mediated neuropathies: a multicentre prospective study.

BACKGROUND: pain is a common symptom of peripheral neuropathies that may severely affect patients' Quality of Life. Pain questionnaires, based on verbal descriptors, are a useful way to investigate it. METHODS: we performed a multicentre study through validated measures to characterize pain in a sample of consecutive patients affected by immune-mediated neuropathies. RESULTS: ninety-three patients were enrolled in 16 Italian centres. Based on the numeric rating scale, almost half of the patients complained of moderate pain and one-third of the patients severe pain. Overall, up to 50% of our patients with immune-mediated neuropathies complained of neuropathic pain. The most common neuropathic symptoms were paraesthesia/dysesthesia and superficial spontaneous pain. Surprisingly, also patients with neuropathies commonly thought to be painless (such as multifocal motor neuropathy) reported discomfort and painful symptoms. CONCLUSIONS: pain questionnaires should be considered in the clinical evaluation of immune-mediated neuropathies, also when evaluating therapy efficacy, because they may provide clinicians with useful information on painful symptoms and patients' quality of life.

Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.

The aim of this study was to investigate the role of Brain Derived Neurotrophic Factor (BDNF) and inflammatory factors in the development of cognitive dysfunctions in Multiple Sclerosis (MS). We correlated peripheral blood mononuclear cell (PBMC) production of BDNF, Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin (IL)-6 and IL-10 with performances on specific neuropsychological tasks in a selected series of MS patients. We studied a sample of 30 patients with relapsing-remitting (RR)MS, segregated by gender and matched for age, education, disease duration, type of immunomodulating therapy, degree of disability and overall cognitive status. We found that low BDNF levels were correlated with increased time of execution on a divided attention and visual scanning task whereas high levels of IL-6 were correlated with low Mini Mental State Examination scores. We did not observe any significant correlations between IL-10, TNF-alpha levels and cognitive performances in our patients. In conclusion our study shows a correlation between low BDNF and high IL-6 production by PBMCs and poorer performances in cognitive tasks in RRMS patients suggesting a possible role of these factors in cognitive impairment in MS.

Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation.

Multiple sclerosis attacks triggered by hyperprolactinemia.

Multiple sclerosis (MS) is a T-cell autoimmune disease of the central nervous system (CNS). Predominance of women in autoimmune diseases suggests that sex hormones may play a role in disease susceptibility. A possible role for prolactin, a neuroendocrine peptide with powerful immunomodulatory properties, is suggested in MS. We describe the case of a 32-year-old man affected by relapsing-remitting MS who experienced the first MS clinical event during the development of a prolactin-secreting adenoma and the only two MS relapses during adenoma recurrence. Prolactin may have facilitated the inflammatory process and triggered MS clinical attacks, suggesting a role of prolactin in immunomodulation and therefore in autoimmune disease course.

Associative motor cortex plasticity: direct evidence in humans.

Previous studies have shown that paired associative stimulation (PAS) protocol, in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex at intervals that produce an approximately synchronous activation of cortical networks, enhances the amplitude of motor evoked potentials (MEPs) evoked by cortical stimulation. Indirect data support the hypothesis that the enhancement of MEPs produced by PAS involves long-term potentiation like changes in cortical synapses. The aim of present paper was to investigate the central nervous system level at which PAS produces its effects. We recorded corticospinal descending volleys evoked by single pulse TMS of the motor cortex before and after PAS in 4 conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. The descending volleys evoked by TMS represent postsynaptic activity of corticospinal neurones that can provide indirect information about the effectiveness of synaptic inputs to these neurones. PAS significantly enhanced the amplitude of later descending waves, whereas the earliest descending wave was not significantly modified by PAS. The present results show that PAS may increase the amplitude of later corticospinal volleys, consistent with a cortical origin of the effect of PAS.

"Dropping objects": a potential index of severe carpal tunnel syndrome.

Patients affected by carpal tunnel syndrome (CTS) often report finding themselves "dropping objects". This symptom is perceived as a severe and frustrating problem. We investigated the occurrence of "dropping objects" in a sample of 532 patients affected by CTS, studied with a multidimensional protocol (clinical, neurophysiological, and patient-oriented). To ensure that the definition of "dropping objects" was index of abnormality, we evaluated a control group interviewing 200 subjects. In order to evaluate if "dropping objects" was an index of more severe CTS impairment, we compared the severity measures between the patients with and without this condition. Severity of CTS multidimensionally assessed was significantly greater in patients with a history of dropped objects than those without. Moreover, "dropping objects" was more frequent in females, older patients, and in those patients with more functional impairment. The occurrence of "dropping objects" in CTS patients seems to be an index of CTS severity.

Natural history of Charcot-Marie-Tooth 2: 2-year follow-up of muscle strength, walking ability and quality of life.

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, no therapies are available at the moment but clinical trials are ongoing. For that reason it is very important to know the natural history of the disease. We report the results of the natural history of clinical features and quality of life (QoL) in patients with CMT2. Twenty patients were enrolled. At recruitment and at follow-up (2 years), all patients underwent neurological evaluation, QoL and disability assessments. The study-end evaluation took place 20-28 months after the baseline evaluation. During the 2-year follow-up period, CMT2 patients showed a mild reduction of strength of distal muscles of upper limbs and proximal muscles of lower limbs, a worsening sensory function and a mild increase in walking disability. However, there was no relevant worsening of QoL, except for a mild deterioration of one mental health domain.

T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis.

In pregnant women affected by multiple sclerosis (MS) we observed increased percentages of CD4(+)CD25(+)Foxp3(+) T regulatory cells at the 1st and the 2nd trimester of gestation that was associated with a decreased T-bet expression in CD4(+) T cells. In women showing clinical relapse and/or new lesions at MRI after delivery we found, a higher expression of T-bet, pSTAT1 and pSTAT3 in CD4(+), CD8(+) T cells and CD14(+) cells, associated with an increase of IFNgamma and IL17 production by PBMC at the 3rd trimester of gestation and after delivery. Our data suggest that the expansion of circulating CD4(+)CD25(+)Foxp3(+) regulatory T cells and the lower expression of T-bet in CD4(+) T cells may account for the decreased MS activity during pregnancy. The expression of T-bet, pSTAT1 and pSTAT3 in peripheral blood CD4(+) and CD8(+) T cells and monocytes could be useful to identify MS patients who will develop a relapse after delivery.

T-bet and pSTAT-1 expression in PBMC from coeliac disease patients: new markers of disease activity.

Coeliac disease (CD) is considered a T cell-mediated autoimmune disease, and up-regulation of T-bet and phosphorylated signal transducers and activators of transcription (pSTAT)1, key transcription factors for the development of T helper type 1 (Th1) cells, has been described in the mucosa of patients with untreated CD. Using transcription factor analysis, we investigated whether T-bet and pSTAT1 expressions are up-regulated in the peripheral blood of CD patients and correlate with disease activity. Using flow cytometry, we analysed T-bet, pSTAT1 and pSTAT3 expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes from peripheral blood of 15 untreated and 15 treated CD patients and 30 controls, and longitudinally in five coeliac patients before and after dietary treatment. We evaluated using enzyme-linked immunosorbent assay (ELISA), interferon (FN)-gamma, interleukin (IL)-17 and IL-10 production by peripheral blood mononuclear cell (PBMC) cultures. T-bet expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes and IFN-gamma production by PBMC was higher in untreated than in treated CD patients and controls. pSTAT1 expression was higher in CD4(+)T cells, B cells and monocytes from untreated than from treated CD patients and controls. pSTAT3 was increased only in monocytes from untreated patients compared with CD-treated patients and controls. The data obtained from the longitudinal evaluation of transcription factors confirmed these results. Flow cytometric analysis of pSTAT1 and T-bet protein expression in peripheral blood mononuclear cells could be useful and sensible markers in the follow-up of CD patients to evaluate disease activity and response to dietary treatment.

Does exposure to extremely low frequency magnetic fields produce functional changes in human brain?

Behavioral and neurophysiological changes have been reported after exposure to extremely low frequency magnetic fields (ELF-MF) both in animals and in humans. The physiological bases of these effects are still poorly understood. In vitro studies analyzed the effect of ELF-MF applied in pulsed mode (PEMFs) on neuronal cultures showing an increase in excitatory neurotransmission. Using transcranial brain stimulation, we studied noninvasively the effect of PEMFs on several measures of cortical excitability in 22 healthy volunteers, in 14 of the subjects we also evaluated the effects of sham field exposure. After 45 min of PEMF exposure, intracortical facilitation produced by paired pulse brain stimulation was significantly enhanced with an increase of about 20%, while other parameters of cortical excitability remained unchanged. Sham field exposure produced no effects. The increase in paired-pulse facilitation, a physiological parameter related to cortical glutamatergic activity, suggests that PEMFs exposure may produce an enhancement in cortical excitatory neurotransmission. This study suggests that PEMFs may produce functional changes in human brain.

Levodopa therapy reduces DNA damage in peripheral blood cells of patients with Parkinson's disease.

Oxidative stress seems to play a major role in the pathogenesis of neurodegeneration. In Parkinson's disease (PD) patients, the dopaminergic neurons are subjected to oxidative stress resulting from reduced levels of antioxidant defenses such as glutathione and high amount of intracellular iron. Levodopa (LD) is widely used for the symptomatic treatment of PD, but its role in oxidative damage control is still unclear. The aim of this study was to analyze the presence of DNA damage in peripheral blood lymphocytes (PBL) of PD patients, during a washout and a controlled LD dosage and to evaluate the oxidative damage fluctuation after LD intake. The standard and the Fpg-modified version of Comet assay were applied in analyzing DNA damage in PBL from blood samples of nine PD patients and nine matched controls. Due to the limited number of patients we cannot reach definite conclusions even if our data confirm the accumulation of DNA lesions in PD patients; these lesions decrease after LD intake.

LTD-like plasticity induced by paired associative stimulation: direct evidence in humans.

Paired associative stimulation (PAS), in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex, may produce a long lasting change in cortical excitability. At an interstimulus interval slightly shorter than the time needed for the afferent inputs to reach cerebral cortex (10 ms), motor cortex excitability decreases. Indirect data support the hypothesis that PAS at this interval (PAS10) involves LTD like-changes in cortical synapses. The aim of present paper was to investigate more directly PAS10 effects. We recorded corticospinal descending volleys evoked by single pulse TMS before and after PAS10 in two conscious subjects who had a high cervical epidural electrode implanted for pain control. These synchronous volleys provide a measure of cortical synaptic activity. PAS10 significantly reduced the amplitude of later descending waves while the earliest descending wave was not modified. Present results confirm the cortical origin of the effect of PAS10.

Low-frequency repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex.

Previous studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) suppresses motor-evoked potentials (MEPs) evoked by single pulse TMS. The aim of the present paper was to investigate the central nervous system level at which rTMS produces a suppression of MEP amplitude. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after 1 Hz rTMS in five conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. One of the patients had Parkinson's disease and was studied on medication. Repetitive TMS significantly suppressed the amplitude of later I-waves, and reduced the amplitude of concomitantly recorded MEPs. The earliest I-wave was not significantly modified by rTMS. The present results show that 1 Hz rTMS may decrease the amplitude of later descending waves, consistent with a cortical origin of the effect of 1 Hz rTMS on MEPs.

The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (TMS). When applied to motor cortex it leads to after-effects on corticospinal and corticocortical excitability that may reflect LTP/LTD-like synaptic effects. An inhibitory form of TBS (continuous, cTBS) suppresses MEPs, and spinal epidural recordings show this is due to suppression of the I1 volley evoked by TMS. Here we investigate whether the excitatory form of TBS (intermittent, iTBS) affects the same I-wave circuitry. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after iTBS in three conscious patients who had an electrode implanted in the cervical epidural space for the control of pain. As in healthy subjects, iTBS increased MEPs, and this was accompanied by a significant increase in the amplitude of later I-waves, but not the I1 wave. In two of the patients we tested the excitability of the contralateral cortex and found a significant suppression of the late I-waves. The extent of the changes varied between the three patients, as did their age. To investigate whether age might be a significant contributor to the variability we examined the effect of iTBS on MEPs in 18 healthy subjects. iTBS facilitated MEPs evoked by TMS of the conditioned hemisphere and suppressed MEPs evoked by stimulation of the contralateral hemisphere. There was a slight but non-significant decline in MEP facilitation with age, suggesting that interindividual variability was more important than age in explaining our data. In a subgroup of 10 subjects we found that iTBS had no effect on the duration of the ipsilateral silent period suggesting that the reduction in contralateral MEPs was not due to an increase in ongoing transcallosal inhibition. In conclusion, iTBS affects the excitability of excitatory synaptic inputs to pyramidal tract neurones that are recruited by a TMS pulse, both in the stimulated hemisphere and in the contralateral hemisphere. However the circuits affected differ from those influenced by the inhibitory, cTBS, protocol. The implication is that cTBS and iTBS may have different therapeutic targets.

Natural history of CMT1A including QoL: a 2-year prospective study.

The Italian CMT study group performed a multicentre, multidimensional, longitudinal 2-year follow-up study using validated measurements of neurological impairment, disability and quality of life. The aim of the study was to evaluate the natural history of clinical features, disability and QoL in patients with CMT1A. On clinical examination, CMT1A patients showed a significant reduction in muscle strength and sensory function during the 2-year follow-up period. However, there was no worsening of QoL or disability, nor was depression observed. The discrepancy between the evolution of clinical features and the evolution of QoL and disability may be due to the development of compensatory strategies that help patients cope with the slow progression of the disease. Our observations provide information which may be useful when designing clinical trials in CMT.

Cognitive impairment in myotonic dystrophy type 1 (DM1): a longitudinal follow-up study.

OBJECTIVE: To characterize the progression of the cognitive involvement in patients affected by myotonic dystrophy type 1 (DM1) by a longitudinal neuropsychological follow-up study. METHODS: In a previous study we documented an ageing-related decline of frontal and temporal cognitive functions in juvenile/adult forms of DM1, irrespectively of the n(CTG) in leukocytes and the severity of muscle weakness. Here we present the results of a neuropsychological follow-up study performed in 34 out of 70 DM1 patients previously studied. Patients were divided into four groups according to their genotype (E1:50-150; E2:150-500; E3:500-1000; E4: >1000 CTG). The neuropsychological test battery included MMSE, memory, linguistic, level, praxis, attentional and frontal-executive tasks. Statistical analysis was performed by One way MANOVA with repeated measures analysis and by Wilcoxon match paired test. RESULTS: The whole group of patients showed a significant deterioration in linguistic functions, together with a tendency towards decline in executive abilities, confirming a predominant involvement of cognitive functions subserved by fronto-temporal areas. We found no significant correlation between the progression of cognitive decline and the n(CTG) in leukocytes. Moreover, we observed that patients belonging to E2 group, with the highest mean age, got scores lower than E3 patients, with particular regard both to linguistic and executive tasks. CONCLUSIONS: These data support our previous hypothesis that the cognitive damage is confined to frontotemporal functions in adult DM1 patients, with a tendency towards a decline with aging.

IN-RATIO: a new test to increase diagnostic sensitivity in ulnar nerve entrapment at elbow.

OBJECTIVE: Motor conduction velocity may yield false-negative results in mild ulnar nerve entrapment at elbow (UNE). There is evidence that the clinical heterogeneity of UNE may be due to the different involvement of fascicles. We hypothesized that, if fibres to FDI are more damaged than fibres to ADM, a relative slowing of motor conduction velocity (CV) at the segment across the elbow recording from FDI (FDI-CV) versus CV at the same segment recording from ADM (ADM-CV) would occur. METHODS: We calculated the ratio between FDI-CV and ADM-CV (IN-RATIO) in 60 consecutive UNE patients, 40 norms, and 16 patients with lower cervical radiculopathy. The UNE sample consisted of (1) patients with neurophysiological evidence (UNE NF+), (2) patients without neurophysiological evidence (UNE NF-). We evaluated the possible usefulness of the IN-RATIO to increase sensitivity in diagnosing UNE. RESULTS: The IN-RATIO was lower in the UNE NF- than in norms (p<0.001) and cervicobrachialgia sample (p=0.02). We found that if the IN-RATIO is

Modulating cortical excitability in acute stroke: a repetitive TMS study.

OBJECTIVE: Changes in cerebral cortex excitability have been demonstrated after a stroke and are considered relevant for recovery. Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate cerebral cortex excitability and, when rTMS is given as theta burst stimulation (TBS), LTP- or LTD-like changes can be induced. The aim of present study was to evaluate the effects of TBS on cortical excitability in acute stroke. METHODS: In 12 acute stroke patients, we explored the effects of facilitatory TBS of the affected hemisphere and of inhibitory TBS of the unaffected hemisphere on cortical excitability to single-pulse transcranial magnetic stimulation (TMS) on both sides. The effects produced by TBS in patients were compared with those observed in a control group of age-matched healthy individuals. RESULTS: In patients, both the facilitatory TBS of the affected motor cortex and the inhibitory TBS of the unaffected motor cortex produced a significant increase of the amplitude of MEPs evoked by stimulation of the affected hemisphere. The effects observed in patients were comparable to those observed in controls. CONCLUSIONS: Facilitatory TBS over the stroke hemisphere and inhibitory TBS over the intact hemisphere in acute phase enhance the excitability of the lesioned motor cortex. SIGNIFICANCE: TBS might be useful to promote cortical plasticity in stroke patients.

In vivo functional evaluation of central cholinergic circuits in vascular dementia.

OBJECTIVE: Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of motor cortex. This test, named short latency afferent inhibition (SAI) has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in Alzheimer disease (AD) patients, a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. The objective of present study was to evaluate central cholinergic circuits in patients with Vascular Dementia (VaD). METHODS: We evaluated SAI in a group of patients with VaD and compared the data with those from a group of AD patients and a control group of age-matched healthy individuals. RESULTS: Mean SAI was normal in VaD patients while it was significantly reduced in AD patients. The analysis of individual data showed abnormal SAI in 75% of AD and in only 25% of VaD. CONCLUSIONS: SAI is normal in most of VaD patients in contrast with AD patients. This test might be used for the functional evaluation of central cholinergic circuits in VaD patients. SIGNIFICANCE: SAI testing may represent a useful additional tool for the evaluation of patients with VaD however, further studies are required in order to evaluate whether this method can be used for the differential diagnosis between pure VaD and different forms of dementia.

Myasthenia gravis: an unrecognized cause of head drop in Parkinson's disease.

Head drop is characterized by marked anterior flexion of the cervical spine, caused by weakness of the neck extensors or by increased tone of the flexor muscles. We report a woman with Parkinson's disease and head drop not due to cervical dystonia (a common cause of antecollis in parkinsonisms). Clinical, radiological, and neurophysiological features together with responsiveness to anticholinesterases and plasma exchanges indicated the possibility of a concomitant myasthenia gravis.