Francesca Izzi

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease.

IMPORTANCE Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. OBJECTIVES To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and β-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. DESIGN, SETTING, AND PARTICIPANTS We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex. EXPOSURE Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and β-amyloid 1-42 and polysomnographic assessment of sleep variables. MAIN OUTCOMES AND MEASURES Levels of orexin, tau proteins, and β-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. RESULTS Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration. CONCLUSIONS AND RELEVANCE Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.

Sleep disorders in adult-onset myotonic dystrophy type 1: a controlled polysomnographic study

Background:  Sleep disturbances and excessive daytime somnolence are common and disabling features in adult‐onset myotonic dystrophy type 1 (DM1).

Pedunculopontine nucleus stimulation influences REM sleep in Parkinson’s disease

OBJECTIVE: To investigate the sleep-wake cycle and the effects of cabergoline monotherapy in a homogenous group of de novo Parkinsons Disease (PD) patients without confounding comorbid factors. DESIGN AND PARTICIPANTS: Twelve de novo patients affected by idiopathic PD underwent two ambulatory polysomnographic (APSG)monitoring sessions. The first was performed at baseline, and the second recording one-month after stable treatment with cabergoline monotherapy. Subjective daytime sleepiness was evaluated by means of the Epworth Sleepiness Scale.Data obtained in PD patients at baseline were compared with those obtained in 12 age- and sex-matched healthy subjects. RESULTS: Diurnal sleep parameters did not show significant differences between controls and PD patients at baseline. In PD patients, no significant changes in diurnal sleep were observed between baseline and cabergoline treatment. Regarding nocturnal sleep, patients at baseline showed a significantly lower sleep efficiency and a significantly higher Wakefulness After Sleep Onset than controls. With respect to baseline, a significant increase in REM latency and a significant reduction in REM sleep were observed during cabergoline treatment. CONCLUSIONS: In the early stage of PD, the neurodegenerative process does not seem to be directly responsible for daytime somnolence, but it may be directly involved in the alteration of nocturnal sleep. Cabergoline monotherapy does not affect daytime sleep propensity and, despite clinical improvement, it may have negative effects on REM sleep.

Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

Purpose:  The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug‐naive patients affected by temporal lobe epilepsy (TLE).

Ketotic hyperglycemia and epilepsia partialis continua

Epilepsia partialis continua (EPC) may occur during nonketotic hyperglycemia but has not been described with diabetic ketoacidosis. The authors report a patient with EPC associated with ketotic hyperglycemia. Brain MRI showed two areas of abnormal signal intensity in the left precentral gyrus and in the right cerebellar hemisphere. Hyperglycemia may reduce seizure threshold because of the increase in γ-aminobutyric acid metabolism and may trigger epileptic discharges.

Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy

PURPOSE To evaluate the effects of topiramate (TPM) on interictal epileptiform abnormalities (IEA) and background activity by means of a computerized EEG analysis, in adult patients affected by focal epilepsy, with or without secondarily generalization, treated with TPM as adjunctive therapy or monotherapy. METHODS Twenty-four patients affected by symptomatic or cryptogenic focal epilepsy underwent long-term video-EEG recording before and after TPM addition (mean dose 175+/-25 mg per day). RESULTS TPM addition induced a significant reduction of both partial and secondarily generalized tonic-clonic (SGTC) seizures; treatment responder patients (seizure reduction > or = 50%) were 19 out of 24 patients (79.1%), of whom 5 were seizure-free. Quantitative analysis of IEA showed a significant decrease in the mean number of spikes/10 min during TPM therapy ( 4.2+/-4.2 versus 2.2+/-4.4; P<0.003 ). The analysis of spatial distribution of interictal spikes showed that such reduction was more evident at the level of the epileptogenic area rather than on the spreading component. Statistical analysis revealed only a significant decrease of mean relative power of alpha band in the EEG spectral content, recorded at rest in a group of 18 out of 24 epileptic patients during TPM therapy. In addition, during TPM treatment we observed a significant reduction in alpha reactivity without any important changes of alpha indexes (peak frequency and median frequency). CONCLUSION These findings suggest that TPM has a strong inhibitory effect on IEA, probably acting on the generating processes, and, if used at low dosage and gradually titrated, seems to have only mild interferences with EEG background activity.

Effect of cabergoline added to levodopa treatment on sleep-wake cycle in idiopathic Parkinson’s disease: an open label 24-hour polysomnographic study

Summary.Few studies focused on the effects of cabergoline on sleep-wake cycle in PD. Twelve patients affected by PD treated with levodopa as monotherapy underwent two 24-hour ambulatory polysomnographic (A-PSG) sessions twice: in baseline condition (levodopa as monotherapy) and after addition of cabergoline. In each condition, a subjective evaluation of sleep quality and daytime sleepiness was obtained by means of Parkinson’s disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale. The statistical analysis of sleep parameters revealed a significant increase of sleep efficiency and slow wave sleep under cabergoline. The PDSS total score showed a significant improvement of overall sleep quality after cabergoline. No significant changes in daytime sleepiness were observed. No patient referred and/or showed sleep attacks before and after addition of cabergoline. We hypothesize that the long-lasting effect of cabergoline may improve the objective quality of nocturnal sleep in PD patients complaining nocturnal motor disability without inducing daytime sleepiness.

CSF beta-amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis?

Narcolepsy is characterized by hypocretin deficiency due to the loss of hypothalamic orexinergic neurons, and is associated with both the human leucocyte antigen DQB1*06:02 and the T cell receptor polymorphism. The above relationship suggests autoimmune/inflammatory processes underlying the loss of orexinergic neurons in narcolepsy. To test the autoimmune/inflammatory hypothesis by means of cerebrospinal fluid (CSF) levels of beta‐amyloid1–42 and/or total tau proteins in a sample of narcoleptic patients, we analysed 16 narcoleptic patients and 16 healthy controls. Beta‐amyloid1–42 CSF levels were significantly lower in narcoleptic patients compared with healthy controls. We also documented pathologically low levels of CSF beta‐amyloid1–42 (<500 pg mL−1) in six of 16 narcoleptic patients (37.5%). We hypothesize that the significant decrease of the CSF beta‐amyloid1–42 levels in narcoleptic patients may support both the inflammatory/autoimmune hypothesis as the basis of the pathogenesis of narcolepsy and the prevalence of an ‘amyloidogenic’ pathway caused by the deficiency of the alpha‐secretases enzymes.

Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study and self-reported questionnaires.

There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep–wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients.

Cognitive and psychiatric effects of topiramate monotherapy in migraine treatment: an open study

Few data are available on cognitive and psychiatric effects of topiramate (TPM) monotherapy in migraine. Twenty patients affected by migraine were treated with TPM monotherapy. At the same time, twenty control subjects were selected. A comprehensive neuropsychological and behavioural battery of tests were performed at baseline (T0), at titration (T1) and in maintenance period (T2). Topiramate serum levels were also investigated at T1 and T2. On comparison with the control group, no cognitive and psychiatric differences were detected at baseline. A significant reduction of word fluency score (P < 0.05) was evident after TPM treatment, both at T1 and T2. No patient developed psychiatric adverse events. TPM induced an impairment of verbal fluency and no psychiatric adverse events, demonstrating selective negative cognitive profile in migraine therapy. Slow titration, low doses, lack of previous psychiatric disorders and/or familial history may explain our data.