Late onset myoclonic epilepsy in Down syndrome and dementia

Specific forms of epilepsy may be found at various ages in Down Syndrome (DS) and a sharp increase in the incidence of epilepsy with age has been documented. A specific type of myoclonic epilepsy associated with cognitive decline has been reported as “senile myoclonic epilepsy” or “late onset myoclonic epilepsy in DS” (LOMEDS). We report a new case of LOMEDS, documented by clinical and neurophysiological evaluation and psychometric assessment (DSDS and DMR). MF, male, affected by DS, was referred in 2004 at 40 years of age; he had no personal or familial history of epilepsy. Since one year, the patient presented cognitive deterioration, characterized by regression of language abilities, loss of memory, and loss of sphincters control. A brain TC showed mild brainstem and sub-cortical atrophy. In 2006, myoclonic jerks involving upper limbs occurred mainly after awakening. EEG showed a low voltage 8 Hz background activity with diffuse slow activity, intermingled with spikes or polyspikes, persisting during NREM sleep. MF was initially treated with clonazepam and after with topiramate, resulting in partial seizures control. MRI (2008) demonstrated diffuse brain atrophy, associated with marked ventricular enlargement. At the psychometric evaluation, onset of dementia was evident late in 2004, with transition to the middle stage in 2006. Last assessment (2009) showed the clinical signs of a late stage of deterioration, with loss of verbal abilities and autonomous ambulation. Using levetiracetam till 2,000 mg/die, myoclonic jerks decreased but are still present every day after awakening. On the EEG slow and poorly organized background activity with bilateral polyspike-wave discharges was recorded. Therefore, we documented a parallel progression of dementia and myoclonic epilepsy in a DS subject

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

BACKGROUND: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. OBJECTIVE: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). METHODS: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. RESULTS: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. CONCLUSION: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients

Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients

Introduction: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects.Methods: Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.Results: 365 patients were enrolled, and 289 patients with follow-up (age 67.7 & PLUSMN; 7.3 years, 237 males, mean follow-up 40 & PLUSMN; 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project.Conclusions: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Introduction Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naive patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 \ub1 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials

Motor-Behavioral Episodes in REM Sleep Behavior Disorder and Phasic Events During REM Sleep

Study Objectives: To investigate if sudden-onset motor-behavioral episodes in REM sleep behavior disorder (RBD) are associated with phasic events of REM sleep, and to explore the potential meaning of such an association. Design: Observational review analysis. Setting: Tertiary sleep center. Patients: Twelve individuals (11 males; mean age 67.6 ± 7.4 years) affected by Idiopathic RBD, displaying a total of 978 motor-behavioral episodes during nocturnal in-laboratory video-PSG. Interventions: N/A Measurements and Results: The motor activity displayed was primitive in 69.1% and purposeful/semi-purposeful in 30.9% of the motor-behavioral episodes recorded. Sleeptalking was significantly more associated with purposeful/semi-purposeful motor activity than crying and/or Incomprehensible muttering (71.0% versus 21.4%, P < 0.005). In 58.2% of the motor-behavioral episodes, phasic EEG-EOG events (rapid eye movements [REMs], α bursts, or sawtooth waves [STWs]) occurred simultaneously. Each variable (REMs, STWs, a bursts) was associated more with purposeful/semi- purposeful than with primitive movements (P < 0.05). Conclusions: Motor-behavioral episodes in RBD were significantly more likely to occur in association with phasic than with tonic periods of REM sleep. The presence of REMs, a bursts and STWs was found to be more frequent in more complex episodes. We hypothesize that motor-behavioral episodes in RBD are likely to occur when the brain, during REM sleep, is in a state of Increased instability (presence of α bursts) and experiencing stronger stimulation of visual areas (REMs)

The relationship between focal seizures and sleep: An analysis of the cyclic alternating pattern

Purpose:: The aim of this study was to examine the relationship between focal epileptic seizures and sleep through analysis of the cyclic alternating pattern (CAP). Methods:: We analyzed the recordings of a total of 56 nocturnal partial seizures (13 occurring as isolated events and 43 "in clusters" during a full-night ambulatory polysomnography) in 12 adult patients affected by localization-related focal epilepsy (7 males, 5 females; mean age 35 + 12.8 years; range 25-71). Results:: On exact binomial distribution analysis, seizures were more frequent in CAP than in non-CAP sleep, and in CAP phase A than in CAP phase B (p < 0.001). Seizures occurring in clusters were more frequently associated with CAP sleep (p < 0.05) than isolated seizures and first seizures of seizure clusters. Increase of CAP rate during the 30-min of sleep period after the occurrence of a seizure was documented in both cluster and isolated seizures. Conclusions:: Our data indicate that an intra-sleep condition of highly fluctuating vigilance constitutes the real substrate for the occurrence of epileptic seizures regardless of the NREM stage in which they occur. The occurrence of partial seizures during sleep appears to induce sleep instability, which may in turn result in the facilitation of clusters of seizures. Together, these data highlight the potential of sleep fragmentation to modulate intra-sleep seizure occurrence. (c) 2005 Elsevier B.V. All rights reserved

Kleine-Levin syndrome: report of a case with marked dysautonomic features

Kleine-Levin syndrome is a rare neurologic disorder of unknown etiopathogenesis, characterized by abrupt onset and remission of attacks of hypersomnia and cognitive dysfunctions. Psychiatric symptoms are frequently present, ranging from disinhibited sexual behavior and eating disorders to hallucinations, anxiety, mood alterations, and derealization. A vast range of attack-related dysautonomic signs and symptoms are reported but remain poorly described. We describe a patient with Kleine-Levin syndrome with sleep attacks dominated by marked dysautonomic features. We briefly review similar clinical cases and suggest that the hypothalamus may play a central role in the genesis of autonomic dysfunction in Kleine-Levin syndrome

Sleep paralysis in narcolepsy: more than just a motor dissociative phenomenon?

Sleep paralyses are viewed as pure motor phenomena featured by a dissociated state in which REM-related muscle atonia coexists with a wakefulness state of full consciousness. We present a 59-year-old man diagnosed with narcolepsy experiencing sleep paralysis, who failed to establish the boundaries between real experience and dream mentation during the paralysis: the patient's recall was indeed featured by uncertainty between real/unreal and awaken/dreaming. Hereby, we suggest that sleep paralysis may represent a more complex condition encompassing a dissociated state of mind together with the dissociative motor component. Neurophysiological data (spectral EEG analysis corroborated by cross-correlation analysis) reinforce the idea that the patient was in an intermediate state of mind between wake and REM sleep during the paralysis. The persistence of local impaired activity proper of REM sleep in cortical circuits necessary for self-reflective awareness and insight, in conflict with wakefulness-related activation of the remaining brain areas, could account for disrupted processing of afferent inputs in our patient, representing the underlying pathophysiologic substrate for patient's failure to establish the boundaries between real experience and dream mentation