Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases.

BACKGROUND: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. CASE REPORT: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5-6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. CONCLUSION: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

The prevalence of narcolepsy in Catalunya (Spain).

Previous studies have estimated an overall prevalence for narcolepsy between 15 and 70 cases per 100 000 inhabitants. We aimed to estimate the prevalence of narcolepsy in Catalunya (Catalonia), a north-east region of Spain (7 424 754 inhabitants), on 31 December 2014 by identifying all living subjects diagnosed with narcolepsy. First, we identified patients diagnosed by one of the 13 sleep, paediatric or neurological departments that perform tests regularly to diagnose narcolepsy. In a second phase, we searched for additional patients with narcolepsy in a clinical database of the primary health-care system. Clinical files were reviewed and narcolepsy diagnosis validated according to the Brighton Collaboration case definitions. Three hundred and twenty-five patients had a validated diagnosis of narcolepsy in the specialized centres (mean age: 44.6 years, range: 6-89; male: 60.3%; 85% with narcolepsy type 1), including 17.8% cases in Brighton, definition level 1, 62.5% in level 2, 15.4% in level 3 and 4.3% in level 4a. The overall prevalence for narcolepsy was 4.4; 3.7 for narcolepsy type 1 and 0.7 cases per 100 000 inhabitants for narcolepsy type 2. Fifty-six additional narcoleptic patients were identified in the primary health-care system, increasing the overall prevalence to 5.2 cases per 100 000 inhabitants. Prevalence rates for narcolepsy type 1 increased from childhood to adulthood, but in subjects aged more than 50 years there was a substantial drop in prevalence rates, suggesting the presence of a significant pool of undiagnosed cases in this population. Narcolepsy can be considered a rare neurological disorder in Catalunya.

Effect of lacosamide on depression and anxiety symptoms in patients with focal refractory epilepsy: A prospective multicenter study.

INTRODUCTION: Depression is the main psychiatric comorbidity in epilepsy with an estimated prevalence between 20% and 55% and one of the main determinants of quality of life. The aim of this study was to investigate the effect of lacosamide (LCM) on mood and anxiety symptoms in patients with focal onset seizures (FOS). The secondary objective was to evaluate if the potential modifications in variables were related to seizure control or to the intrinsic effect of LCM. MATERIAL AND METHODS: We performed a prospective multicenter study in 8 tertiary epilepsy centers in adults with FOS in which LCM was initiated as add-on therapy. Patients' mood and quality of life were evaluated through questionnaires and scales such as the Beck Depression Inventory-II (BDI-II), the State-Trait Anxiety Inventory (STAI-S/T), the Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy-10 (QOLIE-10). Initiation of psychotropic medication was not allowed during the observation period. Patients with diagnosis of major depression or bipolar disorder were excluded. Evaluations were scheduled before LCM treatment, at 3 and 6months. RESULTS: Forty-nine patients were included (51% female) with an average age of 39.5years (range 18-65). At the start of treatment with LCM, 65.3% of the patients were on treatment with one antiepileptic drug (AED). Based on BDI-II, 38.8% of patients had depressive symptoms and 46.9% according to HADS Depression (HADS-D), 63.3% of patients presented pathological levels of anxiety (STAI-S/T), and 44.9% according to HADS Anxiety (HADS-A). Quality of Life in Epilepsy-10 showed that 57.1% of patients had a relevant reduction in their quality of life. After LCM, the score on the BDI-II depression scale decreased significantly (p<0.001). Based on the STAI and HADS-anxiety scales, patients who had a pathological anxiety at baseline, significantly improved. The QOLIE-10 improved significantly over the observation period (p<0.001). At 6months, 28.3% of patients were seizure-free (67.4% were responders). The improvements on depression and anxiety scores were not statistically related to seizure control. CONCLUSION: Lacosamide seems to have a positive effect on depressive and anxiety symptoms. Although the efficacy of LCM in seizure control was demonstrated, the antidepressant and anxiolytic effect on mood and anxiety seems to be an independent factor.

Exploring the presence of narcolepsy in patients with schizophrenia.

BACKGROUND: There are several case reports of patients with narcolepsy and schizophrenia, but a systematic examination of the association of both disorders has not been done. The aim of this work is to assess the frequency of narcolepsy with cataplexy in a large consecutive series of adult patients with schizophrenia and schizoaffective disorder. METHODS: We screened 366 consecutive patients with schizophrenia or schizoaffective disorder with a sleep questionnaire and the Epworth Sleepines scale (ESS) exploring narcoleptiform symptoms. Those who screened positive were assessed by a sleep specialist, and offered an HLA determination. CSF hypocretin-1 determination was proposed to those who were HLA DQB1*06:02 positive. RESULTS: On the screening questionnaire, 17 patients had an ESS score ≥11 without cataplexy, 15 had cataplexy-like symptoms with an ESS score < 11, and four had an ESS score ≥11 plus cataplexy-like symptoms. Of those, 24 patients were evaluated by a sleep specialist. Five of these 24 were HLA DQB1*06:02 positive, and three of these five subjects underwent lumbar puncture showing normal hypocretin-1 levels. CONCLUSIONS: Our results suggest that narcolepsy with cataplexy is not an unrecognized disease in adult patients with schizophrenia or schizoaffective disorder.

Medically refractory epilepsy in autism.

PURPOSE: Epilepsy and electroencephalographic abnormalities are frequent in idiopathic autism, but there is little information regarding treatment-resistant epilepsy (TRE) in this group. We sought to define the clinical and electrophysiologic characteristics and treatment outcomes in these patients. METHODS: We retrospectively reviewed clinical and laboratory data of patients with idiopathic autism evaluated at NYU Epilepsy Center during a 20-year period. KEY FINDINGS: One hundred twenty-seven patients had idiopathic autism and at least one epileptic seizure; 33.9% had TRE and 27.5% were seizure free. The remaining 38.6% of patients had infrequent seizures or insufficient data to categorize. Patients with TRE had a significantly earlier onset of seizures than seizure-free patients, and a trend for more developmental regression and motor and language delays. Three patients had surgical resection (two had limited improvement and one had no improvement) and one had an anterior callosotomy (no improvement). Vagus nerve stimulator (VNS) implantation provided limited improvement (2 patients) and no improvement (7). SIGNIFICANCE: This study found that TRE is common in idiopathic autism and more common with early age of seizure onset. Relatively few patients underwent surgical resection due to multifocal partial epilepsy, comorbid generalized epilepsy, or limited impact of ongoing partial seizures given other problems related to autism. Our small sample suggests that surgical and VNS outcomes in this group are less favorable than in other TRE populations.

Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.

PURPOSE: To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD). METHODS: This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. RESULTS: Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. CONCLUSION: PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Non-random temporal distribution of sleep onset REM periods in the MSLT in narcolepsy.

STUDY OBJECTIVES: The diagnosis of narcolepsy is supported by the presence of two or more sleep onset REM periods (SOREMPs) in the multiple latency sleep test (MSLT). The distribution of SOREMPs throughout the MSLT has not been systematically studied in narcolepsy. We studied the temporal distribution of SOREMPs in the MSLT of a large series of narcoleptics and calculated the effects of age and the diagnostic value of shorter versions of the test. PATIENTS: 129 patients consecutively diagnosed with narcolepsy (73.4% with cataplexy) underwent nocturnal polysomnography followed by a five-nap MSLT. RESULTS: 429 SOREMPs were recorded in 645 MSLT naps (66.5%). The probability of presenting SOREMPs in the fourth nap (3:30 pm) was significantly lower than in the remaining naps: 22.4% SOREMPs in the first nap, 20.5% in the second, 20.5% in the third, 16% in the fourth and 20.5% in the fifth nap (p<0.034). Patients older than 29 years had less SOREMPs than the younger ones (p:0.045). Shortening the MSLT to three or four naps decreased the capability of the test to support the diagnosis of narcolepsy in 14.7 and 10% respectively. CONCLUSION: The temporal distribution of SOREMPs in the MSLT is not even in narcolepsy, with the fourth nap having the lowest probability of presenting a SOREMP. This should be taken into account when evaluating the results of the MSLT, and particularly when using shorter versions of the test.

Biot's breathing in a woman with fatal familial insomnia: is there a role for noninvasive ventilation?

We present the case of a 48-year-old woman suffering from fatal familial insomnia (FFI)--a rare prion disease--who developed Biot's breathing and secondary respiratory failure during the early stages of the illness. Once hypercapnia was detected a trial of nocturnal noninvasive ventilation (NIV) was offered with important improvement of arterial blood gases (ABG), and subjective good quality of sleep. To our knowledge, this is the first report in the medical literature of the use of NIV in the management approach of this devastating disease. Its impact on the prognosis and survival of these patients, however, is yet to be elucidated.

Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: a multicentric observational study.

INTRODUCTION: Treatment of status epilepticus (SE) has not changed in the last few decades, benzodiazepines plus phenytoin being the most common first line treatment. Intravenous levetiracetam (ivLEV) is a new antiepileptic drug with interesting properties for SE. MATERIAL AND METHODS: Efficacy and effectiveness of ivLEV in SE were assessed in an observational, multicentric and retrospective study. Efficacy was defined as cessation of seizures in the 24h subsequent to starting ivLEV, with no need of any further antiepileptic drug. All patients were treated following the standard protocol (benzodiazepines plus phenytoin or valproate). ivLEV was used as add-on therapy, except in those cases with contraindication for the standard protocol, when it was administered earlier. RESULTS: 40 patients were included, 57% men, with a mean age of 63 years. The most common type of SE was partial convulsive (90%). ivLEV was effective in approximately half of the patients (57.5%), in a mean time of 14.4h. ivLEV was used as add-on treatment in 26 patients (after benzodiazepines plus phenytoin, valproate or both) with an efficacy of 46.1%, and as early treatment (pretreatment with benzodiazepines or nothing) in 14 patients with an efficacy of 78.5% (p 0.048). Adverse events were observed in 15% of patients. CONCLUSIONS: ivLEV was an effective antiepileptic drug for SE, but its efficacy depends on the timing of its administration, being more effective when used as early treatment, and less effective as add-on treatment.

Obstructive sleep apnea in narcolepsy.

STUDY OBJECTIVES: Narcolepsy and obstructive sleep apnea syndrome (OSAS) are two conditions associated with excessive daytime sleepiness (EDS). They may coexist in the same patient but the frequency of this association and its clinical significance is unknown. The presence of obstructive sleep apnea (OSA) in a narcoleptic patient may interfere with the diagnosis of narcolepsy. The aim of the study was to determine the prevalence of OSA in narcolepsy. DESIGN AND SETTING: University hospital sleep clinic series of narcoleptic patients diagnosed with nocturnal polysomnography and multiple sleep latency test. Patients were systematically interviewed evaluating narcoleptic and OSAS features and their response to continuous positive airway pressure (CPAP) treatment when applied. PATIENTS: One hundred and thirty-three patients with narcolepsy. RESULTS: Thirty-three patients (24.8%) had an apnea-hypopnea index greater than 10 with a mean index of 28.5+/-15.7. Ten of them were initially diagnosed only with OSAS and the diagnosis of narcolepsy was delayed 6.1+/-7.8years until being evaluated in our center for residual EDS after CPAP therapy. In the remaining 23 patients, narcolepsy and OSA were diagnosed simultaneously. Cataplexy occurred with similar frequency in both groups. EDS did not improve in 11 of the 14 patients who were treated with CPAP. The presence of OSA was associated with male gender, older age and higher body mass index. CONCLUSIONS: OSA occurs frequently in narcolepsy and may delay the diagnosis of narcolepsy by several years and interfere with its proper management. In patients with OSA, cataplexy should be actively looked for to exclude the presence of narcolepsy. Treatment with CPAP does not usually improve EDS in narcoleptics with OSA.