Chronic anterior thalamus stimulation for intractable epilepsy

PURPOSE: A significant number of patients with epilepsy remain poorly controlled despite antiepileptic medication (AED) treatment and are not eligible for resective surgery. Novel therapeutic methods are required to decrease seizure burden in this population. Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. We investigated neuromodulation of the anterior thalamus by using deep-brain stimulation (DBS) in patients with intractable seizures. METHODS: Five patients with medically refractory epilepsy underwent stereotactic placement of and received stimulation through bilateral DBS electrodes in the anterior thalamus. RESULTS: Treatment showed a statistically significant decrease in seizure frequency, with a mean reduction of 54% (mean follow-up, 15 months). Two of the patients had a seizure reduction of > or =75%. No adverse effects were observed after DBS electrode insertion or stimulation. Unexpectedly, the observed benefits did not differ between stimulation-on and stimulation-off periods. CONCLUSIONS: DBS of the anterior thalamus is a safe procedure and possibly effective in patients with medically resistant seizures.     

Comparison of efficiency between VNS and ANT-DBS therapy in drug-resistant epilepsy: A one year follow up study

Vagus nerve stimulation (VNS) and anterior thalamic deep brain stimulation (ANT-DBS) have both been used for treatments of drug-resistant epilepsy (DRE). However, there is no comparative study on the effectiveness of two methods from one single center. 17 patients with DRE who underwent VNS therapy and 18 patients who underwent DBS were enrolled. A retrospective study was performed starting from baseline before operation extending to 12 months after operation. The seizure types, duration of epilepsy, age at implantation, failed numbers of antiepileptic drugs (AEDs) before operation, history of craniotomy, stimulation parameters and response rate were described. The analysis of liner regression on the age of onset, duration of epilepsy, numbers of AEDs, and the seizure reduction at 12 months after operation was applied. The mean seizure reduction in patients with DBS at 3, 6, 9 and 12 months after the operation was 57.22%, 61.61%, 63.94% and 65.28%, and that in cases with VNS was 36.06%, 39.94%, 45.24% and 48.35%, respectively. At 1 year after the operation, the patients with older operation age, focal seizures and older age of onset responded better to VNS; and those older operation age, focal generalized seizures, history of craniotomy and longer duration of disease responded better to DBS. The efficiency of ANT-DBS was higher than that of VNS at each follow up time point. Patients can choose the appropriate treatment according to the individual clinical characteristics.     

Lamotrigine can be beneficial in patients with Dravet syndrome

Dravet syndrome, a severe infantile epilepsy syndrome, is typically resistant to anti‐epileptic drugs (AED). Lamotrigine (LTG), an AED that is effective for both focal and generalized seizures, has been reported to aggravate seizures in Dravet syndrome. Therefore, LTG is usually avoided in Dravet syndrome. We describe two adults and a child with Dravet syndrome in whom LTG resulted in decreased seizure duration and frequency. This benefit was highlighted in each patient when LTG was withdrawn after 6 to 15 years, and resulted in an increased frequency of convulsive seizures together with longer seizure duration. A 25‐year‐old male required hospital admission for frequent seizures for the first time in 7 years, 6 weeks after ceasing LTG. Reintroduction of LTG improved seizure control, suggesting that in some patients with Dravet syndrome, LTG may be beneficial.     

Dravet syndrome - considerable delay in making the diagnosis

Objectives – To assess delay in diagnosis and clinical characteristics of Dravet syndrome based on the Dravet register at The National Centre for Epilepsy in Norway. Material and methods – Medical records of patients diagnosed with Dravet syndrome since 2007 were analysed. Results – Twenty‐two patients were identified. In 15, genetic screening disclosed mutations/deletions in the SCN1A gene. Average time from seizure onset to diagnosis was 7.4 years. Mean age at seizure onset was 6.7 months, nine had hemiconvulsions and 13 had generalized tonic‐clonic seizures. The seizures were precipitated by fever in 17, by external heating in three. During second year of life, multiple seizure types and cognitive and motoric stagnation occurred. No patients became seizure‐free with antiepileptic drugs. The effect of vagal nerve stimulation was disappointing. Conclusions – By making an early diagnosis, an extensive presurgical evaluation may be avoided, and the patient and their parents may be offered genetic guidance.     

Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus

Surgical treatment of intractable epilepsy with deep brain stimulation (DBS) has been shown to be of therapeutic benefit in some patients and with the recent publication of a randomised control study its use is likely to increase in the future. We describe a patient who developed a focal epileptic seizure within a few seconds of momentarily turning off the DBS stimulator in the nucleus ventralis oralis posterior, with which she was successfully treated for tremor. The seizure was the result of a newly diagnosed primary brain tumor. We suggest that the nucleus ventralis oralis posterior may be another thalamic target of DBS in epilepsy.     

Tuesday July 4, 200615:00–17:00Hall 1Discussion Group SessionNeurostimulation for epilepsy

¹ P. Boon (   ¹ Laboratory for Clinical and Experimental Neurophysiology (LCEN) and Department of Neuology, Ghent University Hospital, Belgium )
Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies of patients with medically refractory epilepsy. Only limited data on chronic thalamic and amygdalohippocampal stimulation are available. Chronic DBS in these structures requires resolving many conceptual and technical issues. There is little evidence based information on rational targets and stimulation parameters. Currently available depth EEG recording electrodes are unsuitable for chronic use. Inversely, the use of DBS electrodes for intracranial EEG recording and localization of the ictal onset zone prior to stimulation has only been reported by a few groups. Results from feasibility and pilot studies in the most recent literature will be presented. The experience with DBS in temporal lobe epilepsy using quadripolar DBS electrodes bilaterally implanted in the amygdalohippocampal region to identify and subsequently stimulate the ictal onset zone will be described. This work has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Various hypotheses on the possible mechanism(s) of action of DBS for epilepsy using EEG, cerebral blood flow and metabolic measures including results from animal experiments have recently been developed. Data from open pilot studies suggests that chronic DBS for epilepsy may be a feasible, effective and safe procedure that reduces interictal EEG abnormalities and seizures. Further trials with larger patient populations, controlled and randomised designs should be initiated.     

Successful use of fenfluramine as an add-on treatment for Dravet syndrome

Purpose: Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine‐like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome. Methods: Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add‐on therapy. Key Findings: Their ages at their last evaluation ranged from 3–35 years. The mean dosage of fenfluramine was 0.34 (0.12–0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1–19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure‐free for at least 1 year. In total, patients had been seizure‐free for a mean of 6 (1–19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow‐up; seizures reappeared in three of the seizure‐free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance. Significance: Compared with a recent long‐term follow‐up series in which a maximum of 16% of patients with Dravet syndrome were seizure‐free, our result of 70% of patients with Dravet syndrome remaining seizure‐free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.     

Does a SCN1A gene mutation confer earlier age of onset of febrile seizures in GEFS+?

SCN1A is the most clinically relevant epilepsy gene and is associated with generalized epilepsy and febrile seizure plus (GEFS+) and Dravet syndrome. We postulated that earlier onset of febrile seizures in the febrile seizure (FS) and febrile seizure plus (FS+) phenotypes may occur in the presence of a SCN1A mutation. This was because of the age-related onset of Dravet syndrome, which typically begins in the first year of life. We found that patients with FS and FS+ with SCN1A mutations had earlier median onset of febrile seizures compared to the population median. Patients with GABRG2 mutations had a similar early onset in contrast to patients with SCN1B mutations where onset was later. This study is the first to demonstrate that a specific genetic abnormality directly influences the FS and FS+ phenotype in terms of age of onset.     

Is thalamic deep brain stimulation synergistic with vagus nerve stimulation in drug-resistant genetic generalized epilepsy?

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a “rational polytherapy” may exist in some patients with GGE undergoing dual neuromodulation.     

Ketogenic diet as a successful early treatment modality for SCN2A mutation

SCN2A mutations have been described in a very broad spectrum of clinical phenotypes including benign (familial) neonatal/infantile seizures and early infantile epileptic encephalopathies (EIEE) as Ohtahara syndrome (OS), Dravet syndrome (DS), epilepsy of infancy with migrating focal seizures and West syndrome (WS). Treatment modalities for epilepsy caused by SCN2A mutations mainly consist of sodium channel blockers but ketogenic diet (KD) is also considered as an option of treatment for intractible seizures caused by SCN2A mutations. Because of the wide nature of the heterogeneity of mutations related to SCN2A gene, the clinical phenotypes vary in severity and treatment response to KD has been reported to be controversial.We present a patient diagnosed with OS associated with a novel SCN2A mutation (c.408G?>?A, p.Met136lle; OMIM®: 182390) who had a complete resolution of seizures and EEG abnormalities with KD commenced at 39?days of age.As far as we are aware our case is the youngest patient with SCN2A mutation treated with KD with complete resolution of epilepsy at an early age and has been seizure free of antiepileptic medications for a long duration.     

Neurostimulators in epilepsy

A review of electrical stimulation in patients with refractory epilepsy, including animal and human data, shows that there is anatomic and physiologic evidence supporting the role of the thalamus in epilepsy. The most recent reports in patients with refractory epilepsy suggest that deep brain stimulation and cortical electrical stimulation of the anterior thalamic nucleus and hippocampus may reduce seizure frequency in patients with refractory partial and secondarily generalized seizures. This has led to a multicenter, prospective randomized trial called the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE trial) that is currently being conducted at several centers in the United States. There is also a multicenter clinical trial for patients with refractory partial epilepsy treated with a cranially implanted responsive neurostimulator (RNS) system. Preliminary reports from the RNS system feasibility trial (the NeuroPace trial) suggest that electrographic seizures can be detected before they evolve into clinical seizures, and that electrical stimulation of the epileptogenic zone can then terminate the electrographic seizures. The preliminary data in patients using deep brain stimulation of the anterior thalamic nucleus and hippocampus, and cortical stimulation studies of the epileptogenic zone are promising and suggest a reduction in seizure frequency in some patients with refractory partial and secondarily generalized seizures. The exact mechanism of action and the best parameters used during electrical stimulation remain unknown and are the subject of ongoing research.     

Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy

Short-term deep brain stimulation (DBS) recently has been shown to be efficacious in refractory temporal lobe epilepsy. We (1) evaluated long-term DBS in medial temporal lobe structures in patients with normal magnetic resonance imaging (MRI) findings and (2) investigated the use of chronic DBS electrodes for the localization of the ictal onset zone before DBS. In three patients with complex partial seizures (CPSs), DBS electrodes were implanted in the amygdalohippocampal region to identify and subsequently stimulate the ictal onset zone. CPSs were compared before and after chronic DBS. Side effects were carefully monitored. DBS electrodes yielded high-quality electroencephalogram recordings showing unilateral seizure onset in medial temporal lobe structures. For all patients, unilateral amygdalohippocampal stimulation was performed. After a mean follow-up of 5 months (range, 3-6 months), all patients had a greater than 50% reduction in seizure frequency. In two patients, antiepileptic drugs could be tapered. None of the patients reported side effects. This open study demonstrates the feasibility of consecutive electroencephalographic recordings and DBS in medial temporal lobe structures using DBS electrodes. These results prompt further studies in a larger patient population to establish the efficacy and safety of chronic DBS as an alternative treatment for refractory temporal lobe epilepsy.     

The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome

Dravet syndrome is a rare form of epilepsy largely refractory to current antiepileptic medications. The only precedents of randomized placebo-controlled trials in Dravet syndrome are the two small trials that led to the approval of stiripentol. With the arrival of new clinical trials for Dravet syndrome, we sought to determine the characteristics of the patient population with Dravet syndrome in Europe today, which has possibly evolved subsequent to the approval of stiripentol and the ability to diagnose milder clinical cases via genetic testing. From May to June 2014, we conducted an online parent-reported survey to collect information about the demographics, disease-specific clinical characteristics, as well as current and past use of antiepileptic medications by European patients with Dravet syndrome. We present data from 274 patients with Dravet syndrome from 15 European countries. Most patients were between 4 and 8 years of age, and 90% had known mutations in SCN1A. Their epilepsy was characterized by multiple seizure types, although only 45% had more than 4 tonic–clonic seizures per month on average. The most common drug combination was valproate, clobazam, and stiripentol, with 42% of the total population currently taking stiripentol. Over a third of patients with Dravet syndrome had taken sodium channel blockers in the past, and most had motor and behavioral comorbidities. Our study helps define the current typical European patient with Dravet syndrome. The results from this survey may have important implications for the design of future clinical trials that investigate new treatments for Dravet syndrome.     

The core Dravet syndrome phenotype

Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic-clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70-80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years.     

Tiefe Hirnstimulation des Nucleus accumbens bei fokalen Epilepsien

Background

The study on stimulation of the anterior nucleus of the thalamus for epilepsy (SANTE) is so far the only clinical trial to provide class I evidence for the efficacy of deep brain stimulation (DBS) in partial epilepsy. Stratification of possible responders and potential contraindications are still lacking.

Aim

The rationale and the design of a double-blind and an open interventional study protocol for the nucleus accumbens (NAC) as a potential target for DBS in epilepsy are introduced in this article.

Material and methods

In both investigation protocols potential psychiatric alterations were collated using the Beck depression inventory (BDI) and the mini-international neuropsychiatric interview (MINI) as well as cognitive alterations using an extensive epilepsy-specific neurocognitive examination. Additionally the Liverpool seizure severity scale (LSSS) was used to objectify possible alterations in the severity of seizures. Determination of the quality of life was carried out using the quality of life inventory for epilepsy P-31. The patients completed a seizure calendar in which a differentiation was made and documented between simple focal, complex focal and generalized tonic-clonic seizures. The anti-ictal medication for all patients treated with DBS was left unaltered during the investigation period. The minimum requirement for admission to the 6-month interventional study investigation protocol was a seizure frequency of at least one debilitating seizure per month. The randomized controlled investigation protocol had a shorter observation period of only 3 months and required a minimum of three debilitating seizures per month.

Results

For the four patients who have so far been recruited into the interventional study protocol there was a tendency towards a reduction of the subjective severity of seizures after 6 months of NAC-DBS (p?=?0.068). Seizure frequency as well as psychiatric and neurocognitive outcome parameters remained unchanged.

Conclusion

These preliminary results suggest that the NAC might represent a suitable target for DBS in partial epilepsy in syndrome-oriented indications for focal epilepsy; however, the small patient numbers and the open design of this protocol warrant higher evidence class studies to confirm the results and identify possible responders and side effects.     

Suppression of hippocampal epileptic seizures in the kainate rat by Poisson distributed stimulation

Purpose: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresistant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Poisson distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE. Methods: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS‐ and depth electroencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high frequency stimulation (HFS) at 130 Hz. Stimulation intensity was 100 μA below the threshold for induction of epileptiform EEG activity. Results: Stimulation intensity was significantly lower for PDS (156 ± 20 μA) than HFS (207 ± 23 μA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduction in seizure frequency. In PDS‐improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS‐improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value. Discussion: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life.     

Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy

The authors describe long-term follow-up (mean, 5 years) in patients with anterior (AN) (n = 6) or centromedian (n = 2) thalamic deep brain stimulation (DBS) for epilepsy. Five patients (all AN) had > or = 50% seizure reduction, although benefit was delayed in two until years 5 to 6, after changes in antiepileptic drugs. DBS electrode implantation in AN patients was followed by seizure reduction 1 to 3 months before active stimulation, raising the possibility of a beneficial microthalamotomy effect.     

Vaccination and Occurrence of Seizures in SCN1A Mutation–Positive Patients: A Multicenter Italian Study

BackgroundThe relation between epileptic seizures and vaccinations is sometimes debated. In the present work, the impact of vaccination on seizure onset and clinical outcome of SCN1A mutation-positive patients is addressed.MethodsSeventy-two patients diagnosed with Dravet syndrome or generalized epilepsy with febrile seizure plus, carrying SCN1A mutations or not, were included. Details on vaccination type, temporal relationship between vaccination and seizure occurrence, seizure type at onset and during development, cognitive functioning, and vaccination completion was obtained by reviewing clinical records. Patients were divided into two groups based on the temporal window between vaccination and seizure onset (proximate group: <48 hours; distant group: >48 hours).ResultsVaccination-related seizures occurred in 25% of patients with SCN1A mutation and 18% of patients without the mutation (no significant difference). The proximate group showed an earlier age at seizure onset and a higher frequency of status epilepticus during development than did the distant group. No other significant differences were found. Subsequent vaccinations did not significantly alter the evolution of the disease.ConclusionsResults from this relatively small series provide evidence that vaccinations do not significantly affect clinical and cognitive evolution of Dravet syndrome and generalized epilepsy with febrile seizure plus patients even if they carry SCN1A mutations.     

Five‐year extended follow‐up status of 10 patients with Dravet syndrome treated with fenfluramine

Dravet syndrome (DS) is a rare and therapy‐resistant epilepsy syndrome. A retrospective analysis of add‐on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long‐term response. Herein we present the results of a subsequent 5‐year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure‐free for the entire 5 years, and an additional four patients experienced seizure‐free intervals of at least 2 years. Fenfluramine was generally well‐tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long‐term control of convulsive seizures by low‐dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.     

Refractory grand mal seizures with onset during infancy including severe myoclonic epilepsy in infancy.

In 1978, Dravet proposed a clinical entity called severe myoclonic epilepsy in infancy (SMEI). In the same year, a patient group, which was later called high voltage slow wave-grand mal syndrome (HVSW-GM), is reported in Japan. Both syndromes are very similar, except for seizure manifestation: generalized tonic-clonic convulsions (GTC) with myoclonic and other polymorphic seizures in SMEI vs. GTC only in HVSW-GM. To study the pathophysiology of these refractory epilepsies, the author formulated new clinical diagnostic criteria common to both syndromes as follows: GTC with onset before the age of 1 year as the principal seizure type; an epilepsy entity unclassifiable either as partial or generalized by all the clinical data including EEG findings; mental and motor dysfunction absent prior to seizure onset but appearing later; absence of epileptiform activities on EEG in the initial stage; stubborn refractoriness to conventional antiepileptic medication. Twenty-two patients meeting all of five clinical criteria above mentioned were recruited in the study. Detailed analysis of clinico-electrical features and long-term follow-up of these patients led the author to the conclusion that GTC in combination with seizures of other types will contribute to an unfavorable pathophysiological or prognostic conditions, and, especially when GTC exists in combination with myoclonic seizures, the severity of epilepsy will increase. The author claimed that the three clinical entities, SMEI, HVSW-GM, and their variant form, share certain characteristics in common and may constitute a unique epilepsy syndrome for which a new name of infantile refractory grand mal syndrome (IRGMS) was offered. This is a more basic concept with broader spectrum than SMEI, encompassing not only SMEI but also related borderlands like HVSW-GM. More recently, the author observed that early zonisamide medication within 1 year after seizure onset may improve seizure prognosis in IRGMS, by preventing the development of myoclonic seizures.