Rita Bella

Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels

Nitric oxide (NO) is hypothesized to play a role in the immunopathogenesis of multiple sclerosis (MS). Increased levels of NO metabolites have been found in patients with MS. Peroxynitrite, generated by the reaction of NO with superoxide at sites of inflammation, is a strong oxidant capable of damaging tissues and cells. Inducible NO synthase (iNOS) is up‐regulated in the CNS of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In this study, Western blots of cerebrospinal fluid (CSF) from patients with MS demonstrated the presence of iNOS, which was absent in CSF from control subjects. There was also NOS activity present in both MS and control CSF. Total NOS activity was increased (by 24%) in the CSF from MS patients compared with matched controls. The addition of 0.1 mM ITU (a specific iNOS inhibitor) to the samples did not change the activity of the control samples but decreased the NOS activity in the MS samples to almost control levels. The addition of 1 mM L‐NMMA (a nonisoform specific NOS inhibitor), completely inhibited NOS activity in CSF from control and MS subjects. Nitrotyrosine immunostaining of CSF proteins was detectable in controls but was greatly increased in MS samples. There were also significant increases in CSF nitrate + nitrite and oxidant‐enhanced luminescence in MS samples compared with controls. Additionally, a significant decrease in reduced glutathione and significant increases in oxidized glutathione and S‐nitrosothiols were found in MS samples compared with controls. Parallel changes in NO metabolites were observed in the plasma of MS patients, compared with controls, and accompanied a significant increase of reduced glutathione. These data strongly support a role for nitrosative stress in the pathogenesis of MS and indicate that therapeutic strategies focussed on decreasing production of NO by iNOS and/or scavenging peroxynitrite may be useful in alleviating the neurological impairments that occur during MS relapse.

Absence of Response to Early Transcranial Magnetic Stimulation in Ischemic Stroke Patients Prognostic Value for Hand Motor Recovery

BACKGROUND AND PURPOSE Transcranial magnetic stimulation (TMS) has been proposed as a prognostic tool in stroke patients. Most of the previous studies agree in considering the presence of motor-evoked potentials (MEPs) in the first days after a stroke as an indicator of good outcome. In the present study, we have assessed the prognostic value of the absence of response to early TMS on hand motor recovery in stroke patients with complete hand palsy at onset due to ischemia in the area of the middle cerebral artery. METHODS Fifteen patients submitted to TMS within 48 hours of stroke onset (defined as day 1) and again after 1 year. They were also evaluated clinically on day 1 by a scale derived from the Medical Research Council (MRC) and by the National Institutes of Health (NIH) stroke scale; they were reevaluated by the same scales and by Barthel Index on day 365. RESULTS On day 1, all the patients had complete hand palsy and no response to TMS; their NIH scores showed great variability. After 1 year, 6 of 15 patients regained small and prolonged MEPs, together with a very poor and not functionally useful motor recovery. NIH scores were significantly improved. Barthel Index scores showed large interindividual differences and were not correlated with MRC scores. CONCLUSIONS We conclude that in patients with complete hand palsy, the absence of response to TMS in the first hours is predictive of absent or very poor, not useful, hand motor recovery.

Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations

Auditory hallucinations are experienced by 60-80% of person with schizophrenia and can often cause significant distress behavioural dyscontrol. The application of rTMS in the left temporoparietal cortex could modulate the neuronal activation and reduce the occurrence of auditory disperceptions. Sixteen schizophrenic patients (treated with atypical antipsycothic drugs) reporting auditory hallucinations were included in the study. Low frequency rTMS (1 Hz) was performed at the 90% of resting motor threshold (MT), during 4 sessions in four consecutive days for 15 minutes each application. Eight patients received active stimulation, while eight patients received sham stimulation. Scale for the assessment of positive symptoms (SAPS), scale for the assessment of negative symptoms (SANS) and a scale to asses the severity of the auditory hallucinations (SAH) were administered at the beginning and at regular intervals during the follow-up. The present study confirms the reduction in auditory hallucinations by means of rTMS. The main finding was the long-term reduction in auditory hallucinations in the active group, with a return to the baseline in the sham group. The negative symptomatology improved only in the later sessions and lasted during the follow-up. The improvements in auditory hallucinations and positive symptomatology increased and lasted during the follow-up till the end-point. These data suggest that this approach may lead to an alternative somatic intervention for auditory hallucination in patients with schizophrenia.

Transcranial magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity

To study the possible changes of cortical excitability in the Alzheimer disease (AD) by transcranial magnetic stimulation (TMS) and to evaluate their eventual correlation with its stage twenty-one AD patients and 18 normal controls underwent TMS. Motor threshold, amplitudes of motor evoked potentials (MEPs), central motor conduction time (CMCT) and silent period (SP) were considered. The motor threshold in AD patients was lower than in normal subjects with a significant correlation between the stage of cognitive severity. The amplitude of MEPs was increased and the SP duration was reduced in AD patients. No significant differences were obtained for CMCT. These findings could suggest a correlation between increased motor cortical excitability and cognitive severity. Moreover, the increased cortical excitability could represent a key to understand the mechanism of AD and may have implication for novel treatment strategies.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self‐assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI‐S), and the Mini‐Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI‐S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Transcranial magnetic stimulation after pure motor stroke

OBJECTIVES The objective of this study was to assess the sensitivity of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in demonstrating the possible subclinical impairment of the corticospinal pathway after recovery, in patients with a clinical history of pure motor stroke (PMS) due to a single lacunar infarct detectable by magnetic resonance imaging (MRI). METHODS MEPs were recorded from the first dorsal interosseous muscle of 20 healthy subjects and 40 patients, 6 months or more after PMS onset. Patients were evaluated clinically by means of the NIH stroke scale, the Medical Research Council (MRC) scale and the Barthel Index. The patients with full hand strength recovery and the normal controls were also tested by means of the 9-hole peg test. RESULTS Motor threshold (MT), MEP amplitude and central motor conduction time (CMCT) of the affected side were significantly different from those of the normal side and of the control subjects. MT, MEP amplitude and CMCT obtained after stimulation of the affected hemisphere were significantly correlated with the MRC scale values of the affected hand. Eighty-six percent of patients with persistent hand strength deficit showed MEP abnormalities. In 21 patients with complete clinical recovery, a significant increase in MT and decrease in MEP amplitude on the affected side were observed. CONCLUSIONS After PMS, neurophysiological changes may persist despite complete clinical recovery. TMS represents a sensitive tool that enables to demonstrate objectively the clinical and subclinical impairment of the corticospinal pathway.

Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease

Abstract The association between elevated plasma levels of homocysteine (Hcy) and nutritional status has been shown in Alzheimer disease (AD) patients and also in vascular dementia (VaD). Moreover, a previous study provided evidence that the relation between a high Hcy level and low vitamin B12 and folate levels in AD patients is due to biochemical damage, rather than a nutritional deficit. The purpose of this study was to investigate the relationship between plasma Hcy levels and vitamins involved in its metabolism in AD and VaD. Twenty-two VaD patients, 22 AD patients and 24 healthy subjects were studied for Hcy, vitamin B12, vitamin B6 and folate. All patients and control subjects were comparable for age, educational level, nutritional and socioeconomic status. None of them showed macrocytic anemia or impaired renal function. Hcy was significantly increased in VaD patients (26.0±6.58 µmol/l) as compared to controls (10.7±3.0 µmol/l) and AD patients (22.3±4.51 µmol/l; p<0.001); however, AD patients also showed increased levels of Hcy. Folates were significantly reduced in both VaD (10.8±2.81 nmol/l) and AD (10.0±2.72 nmol/l; p<0.001) patients, while vitamin B12 showed significantly reduced levels only in AD patients (392.1±65.32 pmol/l; p=0.02). Vitamin B6 was not significantly different in the three groups. Increased levels of Hcy associated with low vitamin B12 plasma levels were found only in AD patients. This observation led us to consider that vitamin B12 metabolism does not represent the direct consequence of the nutritional status and suggests that neuronal damage results in a functional vitamin B12 deficiency, as emphasized by recent reports. New therapeutic strategies are necessary, considering that available pharmaceutical forms of vitamin B12 are not utilized by neurons in oxidative stress conditions.

Motor cortex excitability in Alzheimer disease: one year follow-up study

Seventeen patients affected by Alzheimer disease (AD) underwent two transcranial magnetic stimulation (TMS) studies separated by an interval of 12 months, in order to monitor possible changes in motor cortex excitability. After the first examination, all patients were treated with cholinesterase inhibitor drugs. Motor threshold (MT), amplitude of motor evoked potentials and central motor conduction time were considered. After one year, the mean MT values showed a decrease significantly correlated with the severity of cognitive involvement, evaluated by means of the Mini Mental State Examination (MMSE). The difference in MT between the two recording sessions showed no significant correlation with the difference in MMSE score. One year of treatment with cholinesterase inhibitor drugs did not stop the progressive increase in motor cortex excitability. Serial analysis of TMS might represent a method to monitor the rate of change in motor cortex excitability in patients with AD.

Transcranial magnetic stimulation in Alzheimer’s disease: a neurophysiological marker of cortical hyperexcitability

Recently, neuropathological studies have shown an important motor cortex involvement in Alzheimer’s disease (AD), even in its early stages, despite the lack of clinically evident motor deficit. Transcranial magnetic stimulation (TMS) studies have demonstrated that cortical excitability is enhanced in AD patients. This cortical hyperexcitability is believed to be a compensatory mechanism to execute voluntary movements, despite the progressive impairment of associative cortical areas. At present, it is not clear if these motor cortex excitability changes might be the expression of an involvement of intracortical excitatory glutamatergic circuits or an impairment of inhibitory cholinergic and, to a lesser extent, gabaergic activity. Although the main hypothesis for the pathogenesis of AD remains the degeneration of the basal forebrain cholinergic neurons, the development of specific TMS protocols, such as the paired-pulse TMS and the study of the short-latency afferent inhibition, points out the role of other neurotransmitters, such as gamma-amino-butyric acid, glutamate and dopamine. The potential therapeutic effect of repetitive TMS in restoring or compensating damaged cognitive functions, might become a possible rehabilitation tool in AD patients. Based on different patterns of cortical excitability, TMS may be useful in discriminating between physiological brain aging, mild cognitive impairment, AD and other dementing disorders. The present review provides a perspective of these TMS techniques by further understanding the role of different neurotransmission pathways and plastic remodelling of neuronal networks in the pathogenesis of AD.

Oral acetyl-l-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study

BACKGROUND Fatigue is frequently reported in hepatic encephalopathy (HE) and may be related to hyperammonemia. Acetyl-L-carnitine (ALC) offers neuroprotective benefits and improves mitochondrial energetics and function. OBJECTIVE This study evaluated the effect of exogenous ALC on physical and mental fatigue, fatigue severity, and physical activity in patients with mild and moderate hepatoencephalopathy (HE1 and HE2, respectively). DESIGN A total of 121 patients with overt HE were recruited to the study and were subdivided into 2 groups according to their initial HE grade [HE1 (n = 61) or HE2 (n = 60)]. Thirty-one patients with HE1 and 30 with HE2 received 2 g ALC, and 30 patients with HE1 and 30 patients with HE2 received placebo twice a day for 90 d. All patients underwent clinical and laboratory assessments and automated electroencephalogram analysis. RESULTS At the end of the study period, the ALC-treated patients in the HE1 group showed significantly better improvement than did the placebo group in mental fatigue score (-1.7 compared with -0.3; P < 0.05), the fatigue severity scale (-6.4 compared with 2.3; P < 0.001), 7-d Physical Activity Recall questionnaire score (17.1 compared with -2.5; P < 0.001), and Short Physical Performance Battery (2.1 compared with 0.2; P < 0.001); the HE2 group showed significantly better improvement in the fatigue severity scale (-8.1 compared with -5.1; P < 0.001) and 6-min walk test (19.9 compared with 2.3; P < 0.05). Significant decreases in NH(4)(+) were observed in both groups (P < 0.001). CONCLUSION Patients with HE treated with ALC showed a decrease in the severity of both mental and physical fatigue and an increase in physical activity. This trial was registered at clinicaltrials.gov as NCT01223742.