Reana Velizarova

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.

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.

Temporal intermittent delta 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.

Ethosuximide-induced de novo systemic lupus erythematosus with anti-double-strand DNA antibodies: A case report with definite evidence

To the Editors: Based on the number of reports, the risk of developing lupus-like syndrome can be considered low with carbamazepine and very low with ethosuximide, hydantoin, primidone, or trimethadione (Rubin, 2005). Other antiepileptic drugs incriminated are valproic acid, zonisamide (Antonov et al., 2004), and lamotrigine (Sarzi-Puttini et al.,2000). These drugs are classed among drugs possibly inducing lupus (Antonov et al., 2004). Drugs definitely capable of inducing lupus are hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinine, and minocycline (Antonov et al., 2004). Clinical symptoms appear several months after the introduction of the drug (Aminoff & Parent, 2008) and are usually mild with arthralgia, fewer or limited to the skin, and disappear quickly after the drug’s discontinuation. Although antinuclear antibodies are common, antibodies to native DNA (anti-double-strand DNA antibodies) are rarely present in drug-induced lupus (Rubin, 2005). We describe ethosuximide-induced de novo systemic lupus erythematosus (SLE) with an increase in anti-double-strand DNA antibodies. The woman had refractory absence epilepsy not controlled on valproate and lamotrigine. At age 8 years she had received ethosuximide and carbamazepine, and had experienced arthritis with an increase in anti-double-strand DNA antibodies. The drugs were stopped and the SLE was ascribed to carbamazepine. Because of numerous daily absence seizures, ethosuximide (1,000 mg/day) was prescribed again at age 24. Before treatment, antinuclear and anti-double-strand DNA antibodies were 30 UI/ml and 3.3 UI/ml, respectively. One month later, the patient had arthralgia and fever and the antinuclear antibodies were 80 UI/ml. Because the patient was very happy to be seizure-free, the drug was continued. Three weeks later, the antinuclear antibodies were 640 UI/ml and the anti-double-strand DNA antibodies were 33 UI/ml. Ethosuximide was stopped, with normalization of the antibodies and cessation of the arthralgia and fever. Drug-induced SLE has been diagnosed as a result of a combination of clinical and biologic signs. Because ethosuximide was rechallenged with recurrence of SLE at age 24, there is a definite association between the drug and the development of the disease. Although ethosuximide is less often prescribed, it is a potential cause of SLE.

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.

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.

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 patients 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.

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.

A new approach for the detection of the fourteen- and six-Hertz positive bursts (6–14 Hz): The lower temporal line

The fourteenand six-Hertz positive bursts consist of rhythmic, arch-formed waves at a rate of 6 Hz and/or 14 Hz, with alternating positive spiky components and a rounded negative phase. They occur during drowsiness, NREM and REM sleep (Tsuzuki, 1967; Okuma et al., 1968; Niedermeyer, 2005). Usually the bursts are seen symmetrically over the parieto-temporal areas, even though their predominance could shift from side to side. They appear in children after 3–4 years, are maximally expressed in the adolescents and young adults, and then progressively decrease in adulthood. From 2 January 2004 to 15 July 2010, 783 patients underwent long-term video-EEG monitoring in an inpatients neurology–neurosurgery unit over 24–48 h for assessment of epileptic or non-epileptic seizures and over 5–6 days for presurgical assessment of drug resistant focal epilepsies. Fourteenand six-Hertz positive bursts were found in 50 (6.4%). Compared to other age groups, patients aged 15–25 years were most likely to have this activity (62%) (Table 1). It has been reported that the fourteenand six-Hertz positive bursts occur in 0.5% of 35249 patients who underwent routine EEG recordings (Santoshkumar et al., 2009) vs 6.4% in our population with recordings lasting 24 h or more. Their identification depends mainly of the used recording techniques and the length of the sleep portion. The long-distance or referential montages to the contralateral ear are recommended (Niedermeyer, 2005). The international 10/20 system neglects the anterior temporal pole. In order to increase the yield of identifying interictal epileptiform discharges and to improve ictal EEG localization, we systematically use in our epilepsy center additional electrodes for all patients who undergo long-term video-EEG recordings. T1 and T2 (zygomatic electrodes) are placed 1 cm above and one-third of the distance along the line from the external auditory meatus to the lateral canthus of the eye (Silverman, 1965). TA1 and TA2 (Temporal– Anterior) are placed 1 cm above and two thirds of the same distance anterior to the auditory canal (Fig. 1). The electrodes are glued directly onto the scalp. The application of the lower line electrodes increases significantly the visualization of the fourteenand six-Hertz positive bursts. They have the highest amplitude over the temporal leads, formed with the additional temporal electrodes (T1, TA1, T2, TA2) especially with the bipolar derivations T2-T6 and T1-T5. The morphology is typical. Three cases are presented (Fig. 1). Based on our experience, this activity is mainly seen during REM sleep (Fig. 1). Their presence in REM sleep was described in the sixties (Tsuzuki, 1967; Okuma et al., 1968) but curiously forgotten by most of the authors. Niedermeyer (2005) in his review did not mention their presence in this stage. Probably, because most of the electroencephalographists read EEG with a bipolar montage. We demonstrated that the use of additional temporal electrodes, especially derivations T2-T6 and T1-T5 increase significantly the visualization of the 14–6 Hz bursts. These derivations are very useful to recognize easily this benign epileptiform variant.