Sleep-Disordered Breathing, Quality of Sleep and Chronotype in a Cohort of Adult Patients with Bardet-Biedl Syndrome.

OBJECTIVE/BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare but well-recognized ciliopathy with high genetic and phenotypic heterogeneity. Cardinal features include obesity, diabetes and high blood pressure (HBP), which are often associated with sleep-disordered breathing. Also, the high prevalence of blindness due to retinal dystrophy could affect circadian sleep-wake rhythms. We characterized in this cohort of adult BBS patients sleep-disordered breathing, sleep quality, daytime sleepiness and chronotype. PATIENTS AND METHODS: Thirty-two patients with genetically confirmed BBS were included in this observational single center study. Overnight respiratory polygraphy was performed for sleep apnea syndrome (SAS) in 30 patients. Quality of sleep, daytime sleepiness, fatigue and chronotype were assessed in 25 patients using Pittsburgh sleep quality index (PSQI), 14-day sleep diary (SD), Epworth sleepiness scale (ESS), Pichot fatigue scale (PFS) and Horne and Ostberg morningness-eveningness questionnaire (MEQ). RESULTS: Patients' mean age was 32±11 years and mean BMI 32.6±7.7 kg/m2. Eleven (35%) patients had HBP and 7 (22%) diabetes. Moderate to severe sleep apnea syndrome (SAS) was present in 5 (17%) and was not associated with altered sleep, daytime sleepiness or fatigue. Most of the patients (63%) evaluated their sleep as of good quality (PSQI ≤ 5). Median scores of sleep quality, daytime sleepiness and fatigue were normal (PSQI of 3.0 [2.0-6.0], ESS of 9.0 [6.0-13.0] and PFS of 8.0 [3.0-13.0], respectively). Predominant chronotypes according to MEQ were either "intermediate" (57%) or "moderate morning" (29%). None had a free running sleep-wake cycle. 14-day SD revealed overall few awakenings at night and low daytime napping. CONCLUSIONS: Given the cardiovascular risk factors, systematic screening for SAS should be considered in BBS patients, regardless of sleep and daytime vigilance complaints. None of these highly visually impaired patients had a circadian sleep-wake rhythm disorder. Further objective assessments are needed to better characterize sleep and circadian rhythms in BBS patients.

Zonisamide for refractory juvenile absence epilepsy.

PURPOSE: To examine the clinical effect of zonisamide (ZNS) in patients with drug-resistant juvenile absence epilepsy (JAE). METHODS: Between 2006 and 2010, 13 JAE patients were successively treated with add-on ZNS. Safety and efficacy were assessed according to the patient and caregiver reports at visits every 3 months. Response rate was defined as a 50% or greater reduction in seizure frequency. RESULTS: Mean age was 42 years. No patient had been seizure free for a period ≥12 months before ZNS. The mean follow-up was 34 months. The mean dosage of ZNS was 388 mg. ZNS was effective for absence seizures (AS) in all patients (more than 50% AS reduction). Four patients reached seizure reduction on 550-600 mg/day. Three (23%) had a reduction in AS frequency >75% and five (38.5%) between 50% and 75%. Seizure freedom was achieved in five patients (38.5%) (three patients with AS only and two with AS plus generalized tonic-clonic seizures (GTCS)). Before ZNS, four patients had AS evolving to absence status. After ZNS, three of them were in the seizure-free group, the later never experienced this type of complication. Among seven patients with AS plus GTCS, two of them did not report any improvement in the frequency of GTCS (29%). CONCLUSION: This observational post-marketing study confirms the broad-spectrum activity of ZNS that includes GTCS, myoclonic seizures and now AS. This study provides evidence that add-on ZNS is efficient and well tolerated in adult patients with refractory JAE, even at high doses.

Sleep before and after temporal lobe epilepsy surgery.

PURPOSE: Patients with epilepsy often complain of non-restorative sleep. This is the consequence of the acute effect of seizures and the chronic effect of epilepsy responsible for disrupting sleep architecture. Other factors such as antiepileptic drugs (AEDs), also play a role in the alteration of sleep organization. The aim of this study was to evaluate the specific effect of seizures and interictal epileptiform abnormalities (IEAs) on sleep, in particular to see whether reducing seizure frequency by epilepsy surgery might improve sleep organization in these patients. METHODS: Eleven patients with refractory mesial temporal lobe epilepsy, who underwent surgical treatment and who were seizure free at the follow-up, were included in the study. Treatment with AEDs was not significantly modified before the second year of follow-up. Patients were evaluated before surgery, at 1-year and 2-year follow-up visits with a videoEEG monitoring (24h/24). At each follow-up visit, interictal epileptiform abnormalities and sleep macrostructure parameters were assessed. RESULTS: All patients showed a reduction of their IEAs. At 1-year follow-up, total sleep time and REM sleep increased significantly (p=0.032 and p=0.006, respectively). At 2-year follow-up, an important increase of REM sleep was observed (p=0.028). Most significant variations were noted 1 year after surgery. No significant variations were observed between the first and the second year after surgery. CONCLUSIONS: Surgical treatment of temporal lobe epilepsy may improve sleep macrostructure by reducing the number of seizures and of IEAs. These results indirectly confirm the role of epilepsy in disrupting sleep organization chronically.

Worsening of negative myoclonus by lamotrigine in a case of idiopathic focal epilepsy of children with long-term follow-up.

We report the case of a 5-year-old boy, first referred in 1995, with benign epilepsy with centro-temporal spikes (BECTS) with proximal negative myoclonus as the only seizure type who experienced severe aggravation of seizures when lamotrigine (25 mg/d) was prescribed in association to valproate (400 mg/d). Lamotrigine was stopped and progressively the drops of the legs disappeared within 6 months but valproate was continued. The overall prognosis was benign, confirmed by long-term follow-up until age 20, inkeeping with the diagnosis of BECTS. There was a clear relationship between introduction of lamotrigine and the detrimental effect and the condition improved dramatically when lamotrigine was stopped. Thus lamotrigine may aggravate BECTS in certain conditions and should be used with proper care in this indication.

Dravet syndrome: the long-term outcome.

Few studies focused on the long-term outcome of Dravet syndrome in adulthood are available in the literature, but all are concordant. In this article, we consider the outcomes of 24 patients followed at the Centre Saint-Paul, Marseille, up to the age of 50, and compare them to the patients reported in the literature. Five patients (20.8%) died, at a mean age of 24.8 years, one by status epilepticus, three by sudden unexpected death in epilepsy (SUDEP), and one of unknown cause. Epileptic seizures tend to become less frequent and less severe after childhood. Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its impact on seizure frequency and severity is milder than in infancy. Generalized convulsive seizures, mostly reported as generalized tonic-clonic seizures (GTCS), were the only seizure type observed in almost all of the patients, often with a focal onset. They are less frequent than in childhood and mostly nocturnal. Some of these major convulsive seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in some cases by a tonic vibratory state or clonic movements (Oguni et al., Brain Dev 2001;23:736-748; Akiyama et al., Epilepsia 2010;51:1043-1052). Other seizures like myoclonic seizures, atypical absences, and complex partial seizures (CPS) are less common in adulthood: Among our 24 patients, only 6 had atypical absences, and one myoclonic and one complex focal seizures. Electroencephalography (EEG) also changes with age but is still multiple and heterogenous, interictally and ictally. Photosensitivity and pattern sensitivity also showed a tendency to disappear before the age of 20. Motor abnormalities are common. Cerebellar features, including ataxia, dysarthria, intention tremor, and eye movement disorder, become more prominent. Walking is markedly impaired, often due to orthopedic signs such as kyphosis, kyphoscoliosis, flat feet, or claw feet. This symptomatology was minor during childhood and worsened during and after adolescence, despite physiotherapy. Mental retardation ranged from moderate to severe, with predominance of language impairment, and some patients had a major personality disorder, labeled autistic or psychotic. Dependency in adulthood is nearly constant: Only 3 of our 24 adult patients lived independently.

Valproate treatment after liver transplant in a patient with Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a well-defined epileptic encephalopathy highly drug resistant. The first-line treatment option is valproate (VPA), usually in combination with lamotrigine. VPA has been linked to serious hepatotoxicity. We report a 22-year-old liver transplanted patient with LGS successfully treated with VPA in combination with phenobarbital (100 mg/d; blood level: 36 mg/l), lamotrigine (125 mg/d; blood level: 4.81 mg/l) and topiramtate (175 mg/d), as well as immunosuppressive, antiviral, anti-anemic, hypo-phosphoric and alkaline medication. On VPA 1000 mg/d, the seizure frequency decreased significantly. Taking into consideration the patient's good tolerance and the normal liver function, VPA was increased to 1500 mg/d. At this dose the daily drop attacks and generalized tonic-clonic seizures totally ceased. The patient presented only some tonic seizures around awakening. During many years, VPA was avoided in this patient because of its potential hepatotoxicity. However the good functioning of the transplanted liver permitted its introduction. VPA can be used safely in liver transplanted patients under the strict control of the hepatic function.

Focal epilepsy as first symptom in CADASIL.

Recurrent transient ischemic attacks, migraine and dementia represent the principal symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). During the course of the disease, about 10% of patients may experience epileptic seizures, mainly related to the presence of an ischemic stroke. We present a 30-year-old woman with new-onset focal epilepsy leading to the diagnosis of CADASIL. The neuropsychological testing revealed no cognitive impairment. Interictal EEG demonstrated spikes and polyspikes with low amplitude over the right occipital region during NREM sleep. MRI showed white-matter hyperintensities on both hemispheres with confluent lesions at the right parieto-occipital junction, with juxtacortical components. Like in multiple sclerosis, we can suppose that this type of white matter lesions, close to the cortex, may be causative of seizures.

Temporal intermittent δ activity: a marker of juvenile absence epilepsy?

PURPOSE: To report three cases of juvenile absence epilepsy (JAE) with temporal intermittent, asynchronous delta activity over the temporal regions. METHODS: Long term video-EEG using the international 10/20 system and supplementary anterior-inferior temporal electrodes. Cohort of 1123 patients included in our active file seen at least one time over one year. RESULTS: Among 23 patients with JAE (2% of our active file), temporal intermittent rhythmic delta activity (TIRDA) was observed in 3 (13%). Moreover, this activity was never observed in 80 patients with juvenile myoclonic epilepsy. None of the three patients had inadequate antiepileptic drug for idiopathic generalized epilepsy. Case 1 had no antiepileptic drug. Case 2 was treated with valproate (1000 mg/day) and case 3 with levetiracetam (1500 mg/day). These delta activities were activated by hyperventilation and drowsiness. They decreased in NREM sleep and reappeared in REM sleep. The frequency was around 3 Hz. These changes were not frequently recorded in any given patient. CONCLUSION: The presence of TIRDA in the clinical and EEG context is very suggestive of JAE as posterior delta waves are of childhood absence epilepsy but with a more anterior location over the temporal lobe. This pattern was not described before probably because in this easily diagnosed and treated type of IGE, few patients have long-term video-EEG and also because a wrong diagnosis of focal epilepsy can be made. This pattern must be known to avoid the risk of treating this epilepsy by inappropriate antiepileptic drugs.

Unilateral continuous subclinical paroxysmal activity: an unusual finding in a patient with recurrent absence status.

We report a patient with a history of rare generalised tonic-clonic seizures and recurrent absence status who was diagnosed with a rare variant of idiopathic generalised epilepsy and absence status epilepsy. No other pathology was identified and MRI was normal. During a follow-up of 17 years, we recorded a single unilateral continuous, strictly subclinical, paroxysmal activity which lasted for at least several hours. No control was observed under treatment with phenobarbital, lamotrigine and topiramate. Absence status was aggravated with carbamazepine and generalised tonic-clonic seizures were not controlled with ethosuximide. Total seizure control was only possible with sodium valproate, which caused weight gain, and the patient has remained seizure-free for the past 10 years under 1,000 mg/d valproate and 200 mg/d topiramate. The recorded unilateral, long-lasting, subclinical spike-and-wave discharge is quite unusual for idiopathic generalised epilepsy and, in our opinion, occupies a transitional position between generalised and focal activity.

[Juvenile myoclonic epilepsy with recurrent myoclonic status: efficacy of valproate]. / Epilepsie myoclonique juvénile avec états de mal myocloniques récurrents: efficacité du valproate.

Juvenile myoclonic epilepsy (JME) is characterized by a specific pharmacological sensitivity. JME is controlled by certain antiepileptic drugs but may be aggravated by others. Valproate is the treatment of choice of this epilepsy. Among the "newer" antiepileptic drugs those that appear to be useful are lamotrigine, topiramate, zonisamide and levetiracetam. We present a patient with JME who experienced myoclonic status epilepticus every months not controlled with lamotrigine monotherapy (200 mg/d), not controlled with levetiracetam monotherapy (1000 mg/d). Addition of valproate (500 mg/d) to levetiracetam fully controlled the seizures and levetiracetam was reduced to 500 mg/d. The patient is presently seizure free.

Familial generalized epilepsy in Bulgarian Roma.

AIMS: Gypsy communities constitute cultural and frequently inbred genetic isolates. Several genetic neurological disorders have been identified in these communities. Epilepsy appears as a fairly frequent medical condition among Bulgarian Gypsies, and many patients can be related to large pedigrees that may then be studied by conventional genetic linkage analyses. PATIENTS AND METHODS: We identified two large Wallachian Gypsy families from the Plovdiv and Varna regions of Bulgaria, with detailed clinical questionnaires and examination, and EEG recordings for many. Genetic linkage analysis was performed using microsatellite markers spaced across the human genome. RESULTS: Although phenotypes were not always easy to identify, epilepsy appears in both families as a dominant, or pseudo-dominant trait, with the characteristics of idiopathic generalized epilepsy with onset at various ages, with infrequent, generalized tonic-clonic seizures, some associated with fever in childhood, but without sensitivity to fever in later life. While few markers yielded LOD scores > 2, no locus showed significant linkage, assuming autosomal dominant or recessive modes of inheritance. CONCLUSION: Idiopathic generalized epilepsy, with a marked familial character, has not been reported to date in Bulgarian Gypsies. Both pedigrees studied here present with an identifiable epilepsy type inherited as a Mendelian trait. Despite the current lack of significant linkage, these families may constitute interesting ground for further genetic studies, on condition that more patients and families can be recruited. [Published with supplemental data on DVD].