Evidence of increased restless legs syndrome occurrence in chronic and highly disabling migraine.

The existence of an association between migraine and restless legs syndrome (RLS) has recently been reported, although the possible implications of this for migraine clinical presentation remain poorly understood. The objectives of this study were to determine RLS frequency in a population of migraineurs compared with healthy subjects and to assess RLS occurrence in episodic versus chronic migraine patients; the relationship between migraine-related disability and RLS comorbidity was also evaluated. Two hundred and seventy-seven consecutive migraineurs (ICHD-II, 2004) were enrolled and compared with 200 controls; migraine was episodic in 175 and chronic in 102 patients. RLS (IRLSSG criteria, 2003) was present in 22.7% of the total sample of migraineurs and in 7.5% of the controls (p<0.0001). RLS occurred significantly more frequently in chronic compared with episodic migraineurs (34.3% vs 16%, respectively, p=0.0006); a significant association between RLS diagnosis and moderate-severe migraine-related disability was also documented (p=0.0003). In conclusion, the results of the present study not only confirm the higher occurrence of RLS in migraine patients compared with the general population, but also suggest that RLS (the condition itself, or the disruption of sleep patterns often found in patients affected by RLS) might affect migraine clinical presentation, being associated with chronic and highly disabling migraine. These findings could have important therapeutic and prognostic implications in clinical practice.

Event-based prospective memory in newly diagnosed, drug-naive Parkinson's disease patients.

The present study investigated memory for intention in individuals with Parkinson's disease (PD) who were newly diagnosed and not yet treated to avoid the effect of therapy as a potential confounding variable. A comprehensive neuropsychological battery and an event-based prospective memory task were administered to 41 subjects with de novo PD and 40 control subjects. Separate scores were computed for correct execution of intended action (prospective component) and recall of intention (retrospective component). PD patients performed marginally worse (p = .053) than controls on the prospective component of the task. On the other hand, the performance of the two groups was comparable for the retrospective component. Neuropsychological findings revealed lower performance of the PD group in episodic memory and in some measures of executive functions. These results suggested a subtle prospective memory dysfunction present at the initial stage of PD, which may be related to disruption of fronto-striatal circuitry.

Clock T3111C and Per2 C111G SNPs do not influence circadian rhythmicity in healthy Italian population.

A possible relationship between human circadian rhythmicity and polymorphisms in clock genes have been documented. However, these data are controversial, and studies both corroborating and denying them have been reported. T3111C Clock polymorphism had been associated with the human evening preference, however, this association has not been confirmed. Moreover, C111G Per2 polymorphism has been associated with the "morning larks" chronotype in one study, not yet replicated. We have, therefore, performed this study to evaluate whether Per2 C111G and Clock T3111C polymorphisms might influence sleep circadian rhythmicity in a sample of 219 Italian volunteers. A possible interaction between these polymorphisms was also investigated. No differences in Per2 C111G and Clock T3111C allele and genotype frequencies were found, and none of the combined Clock T3111C-Per2 C11G genotypes resulted more frequent in one group compared to the others. Present results do not support a role of these polymorphisms in the circadian phenotypes.

Reproducibility of BOLD localization of interictal activity in patients with focal epilepsy: intrasession and intersession comparisons.

OBJECT: Simultaneous EEG-fMRI recordings allow the identification of haemodynamic changes induced by neuronal activity during ictal or interictal epileptiform events (IEDs). We evaluated the reproducibility of continuous EEG-fMRI (cEEG-fMRI) in patients with focal epilepsy. MATERIALS AND METHODS: We studied 15 patients with focal epilepsy (8 cryptogenic and 7 symptomatic) and frequent interictal abnormalities. Each patient underwent two cEEG-fMRI acquisitions (runs) in the same day (session) and 8 patients repeated the examination after one month. cEEG-fMRI reproducibility was defined by the existence of partially overlapping clusters between activation maps obtained from different runs. RESULTS: We detected IEDs in 40 out of 46 EEG-fMRI runs and a related significant BOLD-response in all 40 runs. A prevalent positive BOLD response was detected in 12 patients and a prevalent negative response in 3 subjects. Statistical maps included a mean of 10 significant clusters. Nearly 30% of clusters were reproducible in both intrasession and intersession comparisons, with a mean overlap of 30%. Reproducibility did not differ between positive and negative BOLD-responses. DISCUSSION: Among the reproducible clusters, those with the highest percentage of overlap were concordant with the EEG electric field in all patients and they were localized in the same lobe as the brain lesion in patients with symptomatic epilepsy. We hypothesize that reproducible clusters could be more consistently related to the irritative zone than non-reproducible ones. CONCLUSION: The evaluation of cluster reproducibility could improve our knowledge of IED-related BOLD response. Moreover, it could enhance the reliability of cEEG-fMRI to identify the irritative zone in focal epileptic patients.

Lithium delays progression of amyotrophic lateral sclerosis.

ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.

Macro-EMG and MUNE changes in patients with amyotrophic lateral sclerosis: one-year follow up.

OBJECTIVE: We assessed changes in Motor Units (MU) and extent of MU loss using macro-electromyography (macro-EMG) and Motor Unit Number Estimation (MUNE). METHODS: We applied these techniques to a sample of 61 Amyotrophic Lateral Sclerosis (ALS) patients basally (T0) and after 4 (T1), 8 (T2), and 12 (T3) months. Macro Motor Unit Potentials (macro-MUPs) were derived from Biceps Brachii (BB) muscle; MUNE was performed both in BB and Abductor Digiti Minimi (ADM) muscles of the same side. RESULTS: Macro-MUPs area resulted in progressive increase at T1, T2, and T3 with respect to T0. Fiber density (FD) at T3 decreases a bit than at T2. Functioning MUS number decreased in both the muscles throughout the entire follow-up with respect to T0 and the rate of MU decrease was similar in both the muscles, but steeper distally. CONCLUSIONS AND SIGNIFICANCE: Macro-EMG increase and FD decrease suggest that a process of MU rearrangement begins to fall after 8 months of disease course. Combined use of macro-EMG and MUNE techniques in ALS patients allows to track over time changes in muscle MU features and number in face of progressive anterior horn cells death during disease's evolution.

Parkinson's disease and pathological gambling: results from a functional MRI study.

Seven patients with a diagnosis of Parkinson's disease (PD) and pathological gambling (PG) and 7 PD patients without PG were investigated by functional MRI and a block-design experiment with gambling-related visual cues alternating with neutral stimuli and rest periods. Compared with PD/non-PG, in PD/PG patients, several areas of increased cue-related blood oxygen level dependent (BOLD)-response were observed including bilateral anterior cingulate cortex, medial and superior frontal gyri, and precuneus, right inferior parietal lobule, and ventral striatum. The over activation of cingulate cortex and ventral striatum in PD/PG patients after the craving task is similar to that reported in addicted patients, whereas the activation of the parietal structures is probably related to the attentional network.

Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is known to occur after solid organ transplantation, and is caused by immunosuppressive agents such as tacrolimus. PRES onset usually occurs within the first 2months after liver transplantation. Clinical findings include seizures, headache, focal neurological deficits, visual disturbances, and altered mental status. These are associated with characteristic imaging features of subcortical white matter lesions on brain MRI. Atypical localizations of this posterior leukoencephalopathy have been reported. Expeditious recognition of the syndrome may lead to a complete recovery. Abnormalities of EEG during follow-up might be associated with unfavorable seizure outcome, even when neuroimaging changes resolve. We report a case of late-onset PRES with atypical localization following liver transplantation. The patient developed epilepsy despite resolution of MRI lesions at 8 months of follow-up. EEG was a prognostic factor of seizure persistence, suggesting an incomplete recovery of brain lesions in contrast to neuroimaging findings.

Further insight on A-wave in acute and chronic demyelinating neuropathies.

A-wave is a late motor response that maintains the same characteristics of latency, amplitude and shape with every electrical stimuli at a proper given intensity. The presence of A-waves was reported both in chronic (CIDP) and acute (AIDP) forms of inflammatory demyelinating polyradiculoneuropathy. It is attributed to the effect of either sprouting phenomena or ephaptic/ectopic discharge. In the first condition it could be a sign of functional recovery, while in the second it could represent an early indicator of demyelination. Aims of our research were to investigate retrospectively the presence of the A-waves, establishing whether its frequency is more common in CIDP or AIDP. Data from 77 patients, 57 male and 20 female, mean age 60.7 years (SD 15.4), were recovered from clinical records and their neurophysiological tests retrieved for reanalysis. Our results seem to indicate that A-waves can represent an early sign of acute pathology of peripheral nervous system.

Insulinoma presenting as idiopathic hypersomnia.

We report the case of a 32-year-old woman with a history of increased sleep need and difficulty waking up; the diagnosis of idiopathic hypersomnia was hypothesized. During ambulatory polysomnography (PSG), the patient presented an episode characterized by loss of consciousness and jerking of the four limbs. A video-PSG monitoring was performed and the patient showed unresponsiveness and drowsiness at 7 a.m. During the episode, EEG showed theta-delta diffuse activity, and blood glucose level was 32 mg dl(-1). The diagnosis of insulinoma was then assumed; CT scan showed a hypodense mass into the pancreatic tail, and a partial pancreasectomy was performed. The described symptoms disappeared, and 5 years later the findings of a complete clinical and neurophysiological examination were negative. The clinical picture of insulinoma presenting with paroxysmal disorders has been previously described; however, whereas hypersomnia is uncommon, in the current case it represents the main symptom. Clinicians should keep in mind that neuroglycopenia should be considered in the differential diagnosis of patients with hypersomnia, particularly if the clinical scenario does not conform to standard criteria.

Is there a primary role of the mitochondrial genome in Alzheimer's disease?

The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic Alzheimer's disease (AD). Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of amyloid beta, which in a vicious cycle reinforces mtDNA damage and oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, and despite the cognitive impairment frequently reported in patients with mtDNA mutation, no causative mutation in the mtDNA have been linked to AD. Indeed, results of studies on the role of mtDNA polymorphisms or haplogroups in AD are controversial. In this minireview, we summarize the actual knowledge about the involvement of mtDNA in AD pathology.

Lack of alpha 1b-adrenergic receptor protects against epileptic seizures.

PURPOSE: The role of alpha 1b-adrenergic receptor (alpha 1b-AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress alpha 1b-AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of alpha 1b-AR leads to anticonvulsant and neuroprotective effects. However, the lack of alpha 1b-AR antagonists does not allow testing of this hypothesis. METHODS: The development of alpha 1b-AR knockout (KO) mice led us to measure seizure susceptibility and neurodegeneration following systemic excitotoxins in these mice. RESULTS: We found that alpha 1b-AR KO mice are markedly resistant to kainate- and pilocarpine-induced seizures. Moreover, when marked seizure duration and severity are obtained by doubling the dose of chemoconvulsants in alpha 1b-AR KO, neuronal degeneration never occurs. CONCLUSIONS: These data indicate that alpha 1b-AR per se plays a fundamental role in the mechanisms responsible for seizure onset, severity, and duration, whereas the brain damage observed in alpha 1b-AR-overexpressing mice is likely to be a secondary phenomenon. In fact, the absence of alpha 1b-AR confers resistance to neurotoxicity induced by seizures/chemoconvulsants. These data, although confirming a pivotal role of alpha 1b-AR in modulating seizure threshold and neuronal death, offer a novel target, which may be used to develop novel anticonvulsants and neuroprotective agents.

Creutzfeldt-Jakob disease with E200K PRNP mutation: a case report and revision of the literature.

Creutzfeldt-Jakob disease (CJD) is typically characterized by rapidly progressive dementia and myoclonus, and it is caused by a conformational change of the prion protein. The heritable forms are associated with mutation in the gene encoding the prion protein (PRNP). We report a 63-year-old Italian woman harboring the E200K PRNP mutation. Electroencephalogram, cerebrospinal fluid analysis, PRNP gene sequencing, histopathologic examination, immunohistochemical studies, and Western blotting analysis confirmed the diagnosis of CJD. Pyramidal involvement was the first sign and the prominent clinical feature. Later on, she developed also myoclonus, ataxia, spastic tetraplegia, and at last dementia with akinetic mutism. Usually, signs of degeneration of the pyramidal tracts occur in a small number of patients as the disease advances. Our report supports the variability of the clinical expression of the E200K genetic CJD. Further studies are needed to understand the molecular basis underlying the phenotypic variability among patients carrying this mutation.

Functional magnetic resonance imaging in episodic cluster headache.

We have investigated the cerebral activation centre in four patients with episodic cluster headache (CH) with functional magnetic resonance imaging (f-MRI). The patients underwent MRI scans for anatomical and functional data acquisition in the asymptomatic state, during a headache attack and after subcutaneous administration of sumatriptan. Anatomical images were acquired by means of 3D-MPRAGE sequences and f-MRI images were obtained by means of echo-planar imaging. Data was analysed using the BrainVoyager QX version 1.7.81 software package. In all patients, the data showed significant hypothalamic activation of the hypothalamus ipsilateral to the pain side, attributable to a headache attack. Overall, we have demonstrated the anatomical location of central nervous system activation by means the first f-MRI study in CH patients. f-MRI offers a good balance of spatial and temporal resolution, and this method of study appears appropriate for investigating the pathogenetic aspects of primary headaches. Positron emission tomography and f-MRI may be regarded as little or no importance in a clinical context, they do, however, offer great potential for the exploration of headache physiopathology and the effects of pharmacological treatment.

Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.

Activation of brain metabolism and fos during limbic seizures: the role of locus coeruleus.

The noradrenergic nucleus Locus Coeruleus (LC) densely innervates limbic structures. In rats, the damage to LC by the neurotoxin DSP-4, converts episodic limbic seizures induced by bicuculline infusion in the anterior piriform cortex (APC) into self-sustaining status epilepticus (SE). SE induced by this approach is similar to SE induced by co-infusing cyclothiazide and bicuculline into APC in rats bearing an intact LC. As opposed to other commonly used rat SE models (e.g. systemic kainate or pilocarpine), this approach allows one to analyze the effects of SE on brain regions which are solely due to spreading of seizure activity, rather than to direct effect of systemic chemoconvulsant. We evaluated the expression of Fos protein (an immediate early gene product), and the local cerebral metabolic rates for [14C] 2-deoxyglucose (lCMRglc), in rats following SE induced either by cyclothiazide+bicuculline or by DSP-4+bicuculline. We demonstrated that regional Fos expression after SE does not parallel the increase in lCMRglc, in LC-lesioned rats. In DSP-4+bicuculline rats there is an overall lower expression of the protein as compared with the cyclothiazide+bicuculline or bicuculline alone groups; even more, such a difference co-exists with an higher lCMRglc in the DSP-4+bicuculline-treated rats in some regions, as compared with the other groups. These data show that LC neurons play an important role in determining immediate early genes expression even in conditions of strong pathological activation, such as limbic SE. This might have relevant effects in the plastic mechanisms related with epileptogenesis.

Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study.

STUDY OBJECTIVES: To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors. DESIGN: Prospective, multicenter, case-control epidemiologic survey. SETTINGS: Twenty sleep centers certified by the Italian Association of Sleep Medicine. PATIENTS: Eight hundred and sixty-one patients affected by MS and 649 control subjects. INTERVENTIONS: N/A. MEASURES AND RESULTS: Data regarding demographic and clinical factors, presence and severity of RLS, the results of hematologic tests, and visual analysis of cerebrospinal magnetic resonance imaging studies were collected. The prevalence of RLS was 19% in MS and 4.2% in control subjects, with a risk to be affected by RLS of 5.4 (95%confidence interval: 3.56-8.26) times greater for patients with MS than for control subjects. In patients with MS, the following risk factors for RLS were significant: older age; longer MS duration; the primary progressive MS form; higher global, pyramidal, and sensory disability; and the presence of leg jerks before sleep onset. Patients with MS and RLS more often had sleep complaints and a higher intake of hypnotic medications than patients with MS without RLS. RLS associated with MS was more severe than that of control subjects. CONCLUSIONS: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability. These results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS. As it does in idiopathic cases, RLS has a significant impact on sleep quality in patients with MS; therefore, it should be always searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.

Predictive value of nigrostriatal dysfunction in isolated tremor: a clinical and SPECT study.

The overlap among tremor disorders is wide and complex because essential tremor patients may present resting tremor coexisting with postural tremor, while postural may coexist with resting tremor in Parkinson's disease. We investigated dopamine transporter binding in 61 subjects presenting with isolated atypical tremors defined as unilateral either postural, resting, or mixed (i.e. resting and postural) tremor, without rigidity or bradykinesia, by means of 123I-FPCIT SPECT imaging at baseline. Patients were followed-up clinically for 28.4 +/- 7.2 months. Twenty-five patients with baseline normal SPECT continued to present only tremor at follow-up. Among 36 patients with abnormal SPECT, 23 (64%) developed PD, while the remaining 13 continued to present only tremor at follow-up. The value of 123I-FPCIT SPECT in predicting the evolution to PD was very high in a way independent from the first clinical presentation of tremor (Rest tremor, P = 0.015; Mixed tremor, P = 0.015; Postural tremor, P = 0.039; chi-square test). Our data suggest that the clinical presentation of isolated tremors is insufficient to allow a precise early-stage diagnosis, whereas the detection of presynaptic nigrostriatal dopaminergic dysfunction could lead to diagnosis of atypical tremor disorders at a very early stage. We suggest this disorder to be labeled as "isolated tremor with dopaminergic presynaptic dysfunction".

Mitochondrial DNA haplogroups do not influence the Huntington's disease phenotype.

Various lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of Huntington's disease (HD). However, the precise role of mitochondria in the neurodegenerative cascade leading to HD is still unclear. Mitochondrial DNA (mtDNA) haplogroups-specific polymorphisms were previously related to several neurodegenerative diseases. The length of CAG repeat seems to be related to the clinical features of HD, such as age of onset and progression of motor impairment. The basis for the impaired cognitive functions and for the mood changes is less clear. Aim of this study was to determine whether mtDNA polymorphism(s) play the role of "modifier gene(s)" in this disease. In this work we have genotyped predefined European mtDNA haplogroups in 51 patients with HD and 181 matched controls. The frequency of the haplogroups and haplogroup clusters did not differ between the two groups, and no correlation with gender, age of onset and disease status was observed. No significant difference was observed between different haplogroups and haplogroup clusters in the cognitive or motor progression of the disease. Our study does not support any association between mtDNA haplogroups and HD.

Autosomal dominant psychiatric disorders and mitochondrial DNA multiple deletions: report of a family.

BACKGROUND: Psychiatric problems, including bipolar affective disorder (BD) and schizophrenia, are common in mitochondrial diseases (MD) and frequently precede the diagnosis of mitochondrial dysfunction. However, they are rarely the only persistent manifestation of a MD and they are usually associated with other neurological or non-neurological features. CASE REPORT: Here, we describe an Italian family with multiple deletions of mtDNA in muscle, in which BD, schizophrenia, and depression recurred over several generations in the absence of other major signs of mitochondrial dysfunction. CONCLUSION: In patients with positive family history of psychiatric problems, the possibility of MD should be kept in mind, even in absence of other canonical features of mitochondrial encephalomyopathies.