Severe Drug-resistant Epilepsy Research Articles

Epilepsy in newborns with tuberous sclerosis complex

BackgroundEpilepsy affects up to 90% of TSC patients and majority of them have seizure at the age of 3–5 months, after a period of latent epileptogenesis, but some develop epilepsy earlier. AimsThe aim of this work was to identify incidence, clinical characteristics, and risk factors for neonatal onset of epilepsy in a large cohort of TSC patients. MethodsA retrospective review of medical data of 421 TSC patients was performed. Patients who developed epilepsy within first 4 weeks of life were included in the study. Clinical and treatment data, EEG, MRI, and genetic analyses were assessed. ResultsEpilepsy was present in 366 (86.9%) patients. Twenty-one (5.7%) developed epilepsy as newborns. Mean follow-up was 44.86 (6–170) months. Six patients were seizure free and 15 had drug-resistant seizures at the end of follow-up. Mental retardation was found in 81% of patients. In 11 (52.4%) patients brain MRI revealed large malformations of cerebral cortex, meeting the criteria for focal cortical dysplasia (FCD). FCD was revealed in both TSC1 and TSC2 mutation cases. Other risk factors for neonatal epilepsy included: perinatal complications and congenital SEGAs. Presence of FCD was associated with more severe epilepsy and worse neuropsychological outcome. Epilepsy surgery resulted in improvement in seizure control. ConclusionsNeonatal onset of epilepsy in TSC is frequently associated with large malformations of cerebral cortex. Patients with FCD are at high risk of severe drug-resistant epilepsy and poor neuropsychological outcome. Early epilepsy surgery may be beneficial and should be considered in such cases.

Epilepsy and autistic manifestations in an Egyptian child with ring 14

Ring chromosomes are rare chromosomal disorders. Patients carrying a ring chromosome have different phenotypes depending on the degree of structural rearrangement. We observed an 8-year-old patient attending the clinic for autistic disorders. By cytogenetic analysis, we identified a de-novo ring chromosome 14. Our patient had a rare condition of developmental delay, behavioral hyperactivity, anxiety, and autistic traits in addition to severe drug-resistant epilepsy, indicating that these features might be part of a syndromic condition. In comparison with other ring 14 patients, the neurological features seen in this patient were extremely severe, in addition to having low-functioning autism. We believe that chromosome 14qter can have a role in the etiology of autism; therefore, cytogenetic analysis should be considered in autistic children.

IV Methylprednisolone for Intractable Epilepsy

Investigators at King Abdulaziz University, Jeddah, Saudi Arabia, report their experience with IV pulse methylprednisolone in the treatment of children with severe drug-resistant epilepsy.

Intrinsic epileptogenicity of dysplastic cortex: Converging data from experimental models and human patients

Focal cortical dysplasia (FCD) is a brain malformation associated with particularly severe drug-resistant epilepsy that often requires surgery for seizure control. The molecular basis for such enhanced propensity to seizure generation in FCD is not as yet elucidated. To investigate cellular and molecular bases of epileptogenic mechanisms and possible effect of severe epilepsy on the malformed cortex we have here performed a parallel analysis of a rat model of acquired cortical dysplasia previously established in our laboratory, i.e., the methylazoxymethanol/pilocarpine (MAM-PILO) rats, and surgical samples from patients with type IIB FCD. Data from the MAM-PILO rat model and human FCD samples reveal in both conditions: (1) that status epilepticus (SE) and/or seizures can further modify the cellular and molecular settings of the malformed cortex; (2) excitation/inhibition imbalance, and dysregulation of the N-methyl-d-aspartate/ membrane-associated guanylate kinase (NMDA/MAGUK) expression; (3) activation of cell death in neurons and glia. The data therefore highlight the mechanistic relevance of glutamate/NMDA hyperactivation in FCD epileptogenesis and suggest that epilepsy is a pathologic process capable of affecting structure and function of both neurons and glia.

FMRI and DTI assessment of patients undergoing radical epilepsy surgery

Hemispherectomy is effective for young patients suffered from unilateral cortical disease and severe drug-resistant epilepsy, but a major concern for hemispherectomy is the remaining brain functions and function recovery in patients after such surgery. In this study, seven patients were evaluated with clinical and imaging assessment pre- and post-surgery. Among them, four underwent anatomic hemispherectomy (AH) and three underwent subtotal hemispherectomy (functional hemispherectomy, FH). After the surgery, 71.4% (5/7) patients [(4/4) with AH and (1/3) with FH] became seizure free (Engel class I). Motor function of the paretic upper extremity unchanged in 4 patients and deteriorated in 3. Functional imaging results indicated that relocation of hand motor function (to the ipsilateral hemisphere) could take place before or after the surgery, or did not occur. Similar observations were made in the motor cortex activation on the paretic foot movement. In addition, both the affected and unaffected hemispheres underwent post-surgical changes in the corticospinal tracks (CST) in various degrees, but significant reinforcement of the CST in the remaining unaffected hemisphere was not evident. Further research is needed to reveal the true functional and structural changes of the remaining brain after surgery and to explore the mechanisms of such functional relocation and reorganization in patients underwent hemispherectomy.

Use of Botulinum Neurotoxin Injections to Treat Recurrent Shoulder Dislocations in a Patient with Severe Epilepsy

The treatment of a shoulder dislocation sustained during an epileptic seizure can be a challenge to the orthopaedic surgeon. Severe drug-resistant epilepsy with multiple seizures may cause repeated dislocations of the shoulder, resulting in damage to the joint capsule and the glenoid. Any attempt at reconstructive surgery of the shoulder requires complete control of the seizures and prevention of dislocations for at least three months following the surgical procedure. We report our experience with one patient who had recurrent dislocations of the right shoulder due to uncontrollable seizures; we treated this patient with botulinum neurotoxin type A to prevent the dislocations. The patient was informed that data concerning her case would be submitted for publication, and she provided consent. The case report was approved by our institutional review board. A twenty-three-year-old woman had been diagnosed with acute intermittent porphyria and severe epilepsy at the age of fourteen. She had had repeated tonic-clonic seizures, which were unresponsive to therapy with multiple drugs (sodium valproate, carbamazepine, vigabatrin, sulthiame, clonazepam, levetiracetam, and topiramate). She had undergone implantation of a vagus nerve stimulator, which did not control the seizures but did shorten the postictal period. At the age of sixteen, the patient had sustained anterior glenohumeral dislocations of both shoulders during a seizure. By the time she was referred to our care at the age of nineteen, she had a chronic dislocation of the left shoulder and recurrent dislocations of the right shoulder. A computerized tomography (CT) examination of the right shoulder …

A new form of alpha‐dystroglycanopathy associated with severe drug‐resistant epilepsy and unusual EEG features

We describe two unrelated girls with congenital muscular dystrophy associated with alpha-dystroglycan deficit with no identified genetic defect, both presenting severe drug-resistant epilepsy with predominant myoclonic seizures and an unusual similar EEG pattern. Severe epilepsy has been unusually described in patients with congenital muscular dystrophies, mainly associated with Walker-Warburg, Fukuyama and muscle-eye-brain diseases. [Published with video sequences].

Handicap et épilepsie

The purpose of this article is to familiarize radiologists with the different aspects of severe drug resistant epilepsy. These result in three levels of disability: the disease itself (seizures and their impact, underlying cause), social impact (restrictions, safety and precautions, education, activities of daily life) and issues related to the medical treatment (long term medication intake, side effects, complications). First, clinical and EEG diagnosis will be reviewed to move on to MRI with attention to technical and protocol considerations followed by the imaging features of specific entities causing severe drug resistant epilepsy : migration and gyration disorders, Rasmussen's encephalitis, Sturge Weber disease and post-ischemic sequelae. Finally, current data and the imaging features of hemispherotomy, a radical treatment for epilepsy, will be presented.

Pregabalin: Preliminary Experience in Intractable Childhood Epilepsy

Pregabalin is a new antiepileptic drug that acts at presynaptic calcium channels, modulating neurotransmitter release. We report on treating consecutive children with severe drug-resistant epilepsy in a prospective, open-label, add-on trial. Nineteen children (63% male) aged 4-15 years (mean, 9.7; S.D., 2.9) were included. Most (74%) had daily seizures that failed multiple drugs (mean, 5). Epilepsy was symptomatic in 58%, and 74% exhibited associated cognitive deficits. Seizures were mixed in nine (47%), and four (21%) manifested Lennox-Gastaut syndrome. Pregabalin was maintained at 150-300 mg/day. On pregabalin, one (6%) child became seizure-free, and seven (37%) had >50% seizure reduction. The percentage of children with daily seizures was reduced from 74% before pregabalin to 37% afterward (P < 0.002). Side effects were evident in six (32%) with somnolence, weight gain, dizziness, or behavioral change. The drug was withdrawn in five (26%) children for lack of efficacy, and in two (11%) for worsening of myoclonic epilepsy. We conclude that pregabalin is a useful addition in the treatment of refractory childhood epilepsy. The drug should be used with caution in myoclonic epilepsy. Controlled studies are needed to establish long-term efficacy and tolerability.

ECG changes in epilepsy patients.

To investigate the frequency of ECG abnormalities suggestive of myocardial ischaemia in patients with severe drug resistant epilepsy and without any indication of previous cardiac disease, assuming that these changes may be of significance for the group of epileptic patients with sudden unexpected death. Twelve patients with medically intractable epilepsy were investigated with simultaneous long ECG and EEG recordings while attending either epilepsy surgery investigational procedures or the investigational programme for diagnostic purposes, and one while having an episode of status epilepticus. The ECG recording failed in 1 patient. This patient had chest pain and minor yet morphologically conspicuous changes in the ECG, suggestive of myocardial infarction. He died in heart arrest. Eight epilepsy patients had episodes of ST segment depression in the ECG, many of which coincided with video- and EEG documented epileptic seizures. Two patients experiencing simple partial seizures and 1 patient experiencing absence seizures had no ST segment depressions in the ECG. One patient had an episode of status epilepticus secondary to brain damage and no ST segment deviation was seen during the ECG recording which continued until 3 h before the patient died. Patients with severe drug resistant epilepsy have episodes of ST segment changes, some of which are closely related to epileptic seizures. Further studies are needed to confirm the present results and to investigate the nature of these changes and document the effect of prophylactic treatment with cardioactive drugs to reduce the risk of sudden death.

Chirurgie des dysplasies corticales focales en région centrale

Taylor-type focal cortical dysplasias (TTFCD) represent a particular pathological entity responsible for severe drug-resistant epilepsy of extratemporal location. Epilepsy can be surgically cured if complete removal of the lesion can be performed. However, identification on imaging may be difficult and negative standard MRIs are not rare. The frequent location of TTFCD in the central region restrains the possibilities of complete resection. We report a series of patients operated on for intractable epilepsy associated with TTFCD in the central area. Between 2000 and 2006, of 34 consecutive patients with TTFCD, 17 had a lesion located in the central area. MRI was considered normal in eight, although in five a subtle gyral abnormality was disclosed on further analysis. A (18)FDG PET scan performed in 16 cases demonstrated focal hypometabolism in 15 that correlated with abnormalities on MRI when visible. SEEG performed in 13 cases revealed typical abnormalities for TTFCD in 10 cases. At resection, cortical and subcortical stimulations of the dysplastic cortex did not elicit a motor response. Postoperative motor or sensory deficit was observed in 13 patients--severe in four--which subsequently resolved completely in seven. Six patients had a minor permanent, motor or sensory deficit. Four patients were reoperated for seizure recurrence and residual dysplastic tissue was found at reoperation in three cases. Average postoperative follow-up was 3.7 years. Sixteen patients (94%) were in Engel Class I (65% in Class IA). This study suggests that surgical resection of central region TTFCD may be associated with favorable seizure outcome and no or minor functional permanent disability. In cases of seizure relapse, reoperation can be performed without further permanent deficit and lead to seizure-free outcome. Future techniques for intraoperative detection of these lesions could optimize their complete resection in functional areas.

Focal cortical dysplasia type 1b as a cause of severe epilepsy with multiple independent spike foci

To investigate the clinical picture, the neurophysiological pattern, and neuropathological features of a young woman with severe drug-resistant epilepsy of unknown cause. We used the patient’s clinical records from the age of 2 to 20 years including neurophysiological patterns recorded via both scalp and cortex electrodes and results of studies conducted on the brain neuropathological specimen. The patient, with severe mental/psychomotor retardation, suffered from severe epilepsy from an early age, characterized by daily seizures of multiple types (atypical absences, tonic, and complex partial seizures), high frequency, and intractability. The neurophysiological pattern indicated multiple independent spike foci (SE-MISF). When she was 16, a vagal nerve stimulator was implanted without success. Neither neuroimaging (brain MRI and ictal SPECT) nor surface EEGs identified unique loci of seizure onset, establishing her as a candidate for a complete callosotomy. When the patient was 19, before the callosotomy, invasive EEG (i.e., electrocorticography) using just a few electrodes in different lobes showed the presence of a distinctive pattern. The surgical specimen, taken very close to one of the activity sites, showed architectural abnormalities and neurons that were giant or immature but not dysmorphic, indicative of focal cortical dysplasia (FCD) type 1b. Twelve months after the callosotomy, according to the Engel score, the patient exhibited a large improvement in quality of life, without permanent complications from the interhemispheric disconnection. (1) Hidden FCD type 1b could represent a missing diagnosis in patients with SE-MISF in the absence of other causes for their seizures. (2) Complete callosotomy can be efficacious in patients with SE-MISF with hidden FCD type 1b.

Gamma Knife Surgery for Epilepsy Related to Hypothalamic Hamartomas

Drug-resistant epilepsy associated with hypothalamic hamartomas (HHs) can be cured by microsurgical resection of the lesions. Morbidity and mortality rates for microsurgery in this area are significant. Gamma knife surgery (GKS) is less invasive and seems to be well adapted for this indication. To evaluate the safety and efficacy of GKS to treat this uncommon pathological condition, we organized a multicenter retrospective study. Ten patients were treated in seven different centers. The follow-up periods were more than 12 months for eight patients, with a median follow-up period of 28 months (mean, 35 mo; range, 12–71 mo). All patients had severe drug-resistant epilepsy, including frequent gelastic and generalized tonic or tonicoclonic attacks. The median age was 13.5 years (range, 1–32 yr; mean, 14 yr) at the time of GKS. Three patients experienced precocious puberty. All patients had sessile HHs. The median marginal dose was 15.25 Gy (range, 12–20 Gy). Two patients were treated two times (at 19 and 49 mo) because of insufficient efficacy. All patients exhibited improvement. Four patients were seizure-free, one experienced rare nocturnal seizures, one experienced some rare partial seizures but no more generalized attacks, and two exhibited only improvement, with reductions in the frequency of seizures but persistence of some rare generalized seizures. Two patients, now seizure-free, were considered to exhibit insufficient improvement after the first GKS procedure and were treated a second time. A clear correlation between efficacy and dose was observed in this series. The marginal dose was more than 17 Gy for all patients in the successful group and less than 13 Gy for all patients in the “improved” group. No side effects were reported, except for poikilothermia in one patient. Behavior was clearly improved for two patients (with only slight improvements in their epilepsy). Complete coverage of the HHs did not seem to be mandatory, because the dosimetry spared a significant part of the lesions for two patients in the successful group. We report the first series demonstrating that GKS can be a safe and effective treatment for epilepsy related to HHs. We advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures.

Gamma Knife Surgery for Epilepsy Related to Hypothalamic Hamartomas

ABSTRACT OBJECTIVE Drug-resistant epilepsy associated with hypothalamic hamartomas (HHs) can be cured by microsurgical resection of the lesions. Morbidity and mortality rates for microsurgery in this area are significant. Gamma knife surgery (GKS) is less invasive and seems to be well adapted for this indication. METHODS To evaluate the safety and efficacy of GKS to treat this uncommon pathological condition, we organized a multicenter retrospective study. Ten patients were treated in seven different centers. The follow-up periods were more than 12 months for eight patients, with a median follow-up period of 28 months (mean, 35 mo; range, 12–71 mo). All patients had severe drug-resistant epilepsy, including frequent gelastic and generalized tonic or tonicoclonic attacks. The median age was 13.5 years (range, 1–32 yr; mean, 14 yr) at the time of GKS. Three patients experienced precocious puberty. All patients had sessile HHs. The median marginal dose was 15.25 Gy (range, 12–20 Gy). Two patients were treated two times (at 19 and 49 mo) because of insufficient efficacy. RESULTS All patients exhibited improvement. Four patients were seizure-free, one experienced rare nocturnal seizures, one experienced some rare partial seizures but no more generalized attacks, and two exhibited only improvement, with reductions in the frequency of seizures but persistence of some rare generalized seizures. Two patients, now seizure-free, were considered to exhibit insufficient improvement after the first GKS procedure and were treated a second time. A clear correlation between efficacy and dose was observed in this series. The marginal dose was more than 17 Gy for all patients in the successful group and less than 13 Gy for all patients in the “improved” group. No side effects were reported, except for poikilothermia in one patient. Behavior was clearly improved for two patients (with only slight improvements in their epilepsy). Complete coverage of the HHs did not seem to be mandatory, because the dosimetry spared a significant part of the lesions for two patients in the successful group. CONCLUSION We report the first series demonstrating that GKS can be a safe and effective treatment for epilepsy related to HHs. We advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures.

Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study)

Patients having a hypothalamic hamartoma frequently present epileptic attacks of laughter, and they later experience multiple additional seizure types, which invariably lead to a severe drug-resistant epilepsy. If this association is now well-known, relationships between the hypothalamic mass and the different types of seizures remain still mysterious. We report the case of a 16-year-old girl suffering from this peculiar epileptic picture, in whom a stereo-EEG study was performed, allowing us to record both the hamartoma, the neighboring hypothalamic structures, and other bilateral cortical areas. It showed that gelastic fits were strictly linked to ictal discharges which began and remained well localized in the hamartoma. Conversely, atonic seizures, which might result from a secondary epileptogenesis, admitted a widely extended bilateral frontal cortical origin, sparing the lesion, and slightly involving the posterior hypothalamus. Stereotactic radiosurgery of the hamartoma proved to be ineffective on both types of seizures, probably because of the too low dose of X-rays delivered (18 grays), as suggested by the absence of hypothalamic mass changes on MRI. Such data, never reported to our knowledge, seem able to contribute to a better understanding of this very peculiar epileptic syndrome, and perhaps to a better adapted therapeutic management.

Manifestations électrocliniques induites par la stimulation électrique intracérébrale par «chocs dans les épilepsies temporales

In patients with severe drug-resistant partial epilepsy, undergoing Stereo-EEG investigations, spatial definition of the "epileptogenic area" is mainly based on spontaneous seizures recordings, but also on seizures induced by intracerebral electrical stimulation (ES). Only "trains" ES (TES, 50 pps) are currently used with this aim; "shocks" ES (SES, 1 pps) are principally applied to localize motor pathways. We have shown, during a prospective study concerning 10 temporal lobe epileptic patients, that SES could frequently induce seizures, especially when stimulation is applied in the anterior part of the Ammon's horn. Even if its efficacy seems lower than by TES, this kind of stimulation, in the majority of the cases, does reproduce isolated ictal subjective symptomatology, allowing the visualization of the progressive organisation of ictal electrical discharges, and avoids "unexpected" ("false positive"?) clinical responses.

Intracerebral low frequency electrical stimulation: a new tool for the definition of the "epileptogenic area"?

Low Frequency (1 Hz) Electrical Stimulation (LFES) has been systematically utilized, during stereo-EEG investigations, in 24 consecutive young adult patients considered for surgical treatment of severe drug-resistant partial epilepsy. Ninety seizures (1-14/patient) identical to the spontaneous ones previously recorded were thus obtained in 19 patients (79%). LFES is less effective for induction of seizures than high frequency (50 Hz) stimulation (5.9% vs 22.9%), and it also provokes less "false positive" responses (1% vs 17%). The main "sensitive" structures to LFES are the hippocampus, the amygdala, and the hippocampal gyrus. However, seizures were also induced by stimulating the temporal lobe white matter, the temporal pole, and the temporal neocortex, as well as the orbito-frontal cortex (in the only patient with fronto-temporal epilepsy). The more frequently observed electrical pattern is a gradual increase of spikes and spikes and waves frequency, with or without occurrence of low voltage fast activity. The high percentage of early "subjective" manifestations similar to the spontaneous ones, the lack of major electrical artifact, and the good visualization of the spatial evolution of the induced-discharge, strongly suggest that LFES is of great help for defining the "epileptogenic area".

Vigabatrin in Childhood Epilepsy

Sixty-six children with various types of severe drug-resistant epilepsy were entered into a long-term, dose-rising study of vigabatrin after a 4-week run-in placebo period. All the children were receiving one to three other antiepileptic drugs, the doses of which were not changed during the 6-month dose titration phase. Following the introduction of vigabatrin, 11 patients became seizure free, and 28 responded with a greater than 50% reduction in seizure frequency. The following types of epilepsy responded favorably in order of decreasing efficacy: cryptogenic and symptomatic partial epilepsy, other symptomatic generalized epilepsy, and Lennox-Gastaut syndrome. However, three of nine patients with myoclonic epilepsy showed an increase in seizure frequency. Optimal responses were found with vigabatrin doses of 40 to 80 mg/kg/day, although no significant adverse effects were noted with doses of higher than 100 mg/kg/day. Thirty-eight responders continued on vigabatrin, 19 of whom have been treated for more than 1 year, with generally good efficacy. As a result of discontinuing concomitant antiepileptics, six patients are on monotherapy with vigabatrin, four of whom are seizure free. Vigabatrin tolerability was good, with 39 of 66 children reporting no adverse effects. Hyperkinesia was reported in 17 patients (26%), and two had to drop out of the study. All these patients had a history of hyperkinesia or mental retardation. In patients in whom vigabatrin dose was reduced because of hyperkinesia, a dose increase could later be instituted without recurrence of symptoms. There was no change in neurologic examination and no drug-related abnormalities in clinical laboratory data.(ABSTRACT TRUNCATED AT 250 WORDS)

Complementarite de la tomodensitometrie des biopsies stereo-taxiques etagees et de la stereo-electro-encephalographie (SEEG) dans la definition spatiale des lesions intracerebrales

This study concerns 180 patients (132 M; 48 F) (age: 2 to 69 years; m: 33 years) who underwent stereotactic procedures according to the methodology of Talairach and Szikla. Such procedures (stereotactic and stereoscopic angiography in all cases, and ventriculography in 81%) should permit a correct spatial definition of intracranial lesions. The informations provided by the angiography (normal in 7%) and by the ventriculography (normal in 11%) are complementary to those yielded by the TDM and permit an easier and safe stereotactic approach to the lesions. In 43% of patients the lesions were deep-seated (basal ganglia: 24; sellar region: 19; thalamo-peduncular: 13; brain stem: 6, etc.). The histological examination showed: low-grade gliomas in 43%; glioblastomas in 21%; non tumoral lesions in 17%. A precise diagnosis couldn't be obtained in 3.8%. The data provided by the stereo-EEG (in 11 patients suffering also of severe drug-resistant partial epilepsy) did not permit, alone, an histological diagnosis, excepted when electrodes explored a solid tumor. Two patients had a neurological impairment, and two died (one for extracerebral reasons). The authors consider that the TDM data and the informations given by the stereotactic procedures are complementary for obtaining valuable informations on the spatial organization of intracranial lesions and choosing the best treatment.