Improved seizure burden and cognitive performance in a child treated with responsive neurostimulation (RNS) following febrile infection related epilepsy syndrome (FIRES).

Responsive neurostimulation (RNS) is an emerging therapy for patients with refractory focal epilepsy who are not candidates for surgical resection, with limited published experience in the pediatric population. We report a case of refractory multifocal epilepsy following febrile infection related epilepsy syndrome (FIRES) in which surgical resection was not feasible due to multifocal independent seizures and risk of cognitive deficit, and RNS was pursued. Relevant RNS data and neuropsychological testing results were reviewed. By eight months after implantation, decreased frequency and severity of clinical seizures were noted, and RNS data revealed decreased "long episodes," reduced spread of electrographic seizures, and fewer detections. Neuropsychological assessment, though potentially confounded by stimulant medication, revealed significant improvement in multiple cognitive domains, particularly working memory and processing speed, at six months. These findings illustrate success in detecting and aborting seizures, and additionally suggest a neuromodulatory effect of RNS stimulation. Our case demonstrates feasibility, efficacy and safety of RNS in a pediatric patient with FIRES, with evidence to also suggest cognitive improvement.

[Gelastic seizures as the presenting symptom of infarction of the cingulate gyrus]. / Crisis gelasticas como forma de presentacion de un infarto del giro cingulado.

INTRODUCTION: Gelastic seizures are infrequent epileptic seizures in which the main manifestation is inappropriate laughter. They have a variety of causations. A search of the literature did not reveal any cases of pathological laughter that was clearly related with strokes, although there a numerous reports of non-epileptic pathological laughter as a prodromal symptom in stroke patients (fou rire prodromique). We report the case of a patient with infarcted cingulate gyrus who progressed with gelastic seizures at onset and during the course of the clinical process. CASE REPORT: An 81-year-old female who suddenly presented bouts of difficulties in verbal expression with disconnection from the milieu that were accompanied by fits of unmotivated and uncontrollable laughter that lasted less than five minutes. Following the attacks, her level of consciousness had dropped. In some of the attacks there were also involuntary movements of the upper limbs. Resonance imaging revealed the existence of an acute ischaemic lesion in the left territory of the cingulate gyrus and an electroencephalogram revealed the existence of epileptogenic activity in the left-hand anterior temporal and frontal regions. CONCLUSIONS: The clinical profile, the results of the complementary examinations and the response to the antiepileptic treatment allow us to state that in the episode reported in this patient we are dealing with gelastic seizures related to an acute ischaemic lesion in the left cingulate gyrus.

TITLE: Crisis gelasticas como forma de presentacion de un infarto del giro cingulado.Introduccion. Las crisis gelasticas son crisis epilepticas poco frecuentes en las que la risa inapropiada es la manifestacion principal. Su etiologia es diversa. No hemos encontrado en la bibliografia ningun caso de risa patologica claramente epileptica relacionada con ictus, aunque hay multiples descripciones de risa patologica no epileptica como sintoma prodromico en pacientes con ictus (fou rire prodromique). Presentamos un caso de infarto del giro cingulado que curso con crisis gelasticas al inicio y durante la evolucion del proceso clinico. Caso clinico. Mujer de 81 años, que bruscamente presento episodios de dificultad para la expresion verbal con desconexion del medio, acompañados de accesos de risa inmotivada e incontrolable de duracion inferior a cinco minutos. Tras los episodios, tenia bajo nivel de consciencia. Coincidiendo con alguno de ellos, se observaron tambien movimientos involuntarios de los miembros superiores. La resonancia desvelo la existencia de una lesion isquemica aguda del territorio del giro cingulado izquierdo y el electroencefalograma puso de manifiesto la existencia de actividad epileptogena frontal y temporal anterior izquierda. Conclusiones. El perfil clinico, los resultados de las exploraciones complementarias y la respuesta al tratamiento antiepileptico permiten afirmar que los episodios descritos en esta paciente corresponden a crisis gelasticas relacionadas con una lesion isquemica aguda del giro cingulado izquierdo.

Cerebellar white matter changes in patients with newly diagnosed partial epilepsy of unknown etiology.

OBJECTIVE: We hypothesize that pre-existing susceptible structures in the brain may be associated with the development of newly diagnosed partial epilepsy of unknown etiology. METHODS: Twenty-two patients with newly diagnosed partial epilepsy of unknown etiology and 36 healthy controls were enrolled in this study. In addition, we included 24 patients with chronic partial epilepsy of unknown etiology as a disease control group. We analyzed whole-brain T1-weighted MRIs using FreeSurfer 5.1. The volumes of the hippocampus, amygdala, thalamus, caudate, putamen, pallidum, brainstem, cerebellar gray and white matter, as well as cerebral gray and white matter were compared between the groups. We also analyzed the changes in brain volumes associated with the chronicity of epilepsy in the patients with chronic epilepsy compared to newly diagnosed epilepsy. RESULTS: The volume of cerebellar white matter in patients with newly diagnosed epilepsy was significantly smaller than that which was observed in the healthy controls (p=0.0001). This finding was also observed in patients with chronic epilepsy (p<0.0001). Cerebral white matter volume was negatively correlated with the duration of epilepsy (r=-0.4, p=0.04). CONCLUSION: These findings support our hypothesis that cerebellar white matter changes may constitute a pre-existing susceptible structure in the brain that is associated with the development of partial epilepsy of unknown etiology. In addition, cerebral white matter was the structure that was the most vulnerable to the progression of epilepsy.

Amygdala opioid receptors mediate the electroacupuncture-induced deterioration of sleep disruptions in epilepsy rats.

BACKGROUND: Clinical and experimental evidence demonstrates that sleep and epilepsy reciprocally affect each other. Previous studies indicated that epilepsy alters sleep homeostasis; in contrast, sleep disturbance deteriorates epilepsy. If a therapy possesses both epilepsy suppression and sleep improvement, it would be the priority choice for seizure control. Effects of acupuncture of Feng-Chi (GB20) acupoints on epilepsy suppression and insomnia treatment have been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot). Therefore, this study was designed to investigate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi acupoints on sleep disruptions in rats with focal epilepsy. RESULTS: Our result indicates that administration of pilocarpine into the left central nucleus of amygdala (CeA) induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep. High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints, in which a 30-min EA stimulation was performed before the dark period of the light:dark cycle in three consecutive days, further deteriorated pilocarpine-induced sleep disruptions. The EA-induced exacerbation of sleep disruption was blocked by microinjection of naloxone, µ- (naloxonazine), κ- (nor-binaltorphimine) or δ-receptor antagonists (natrindole) into the CeA, suggesting the involvement of amygdaloid opioid receptors. CONCLUSION: The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints exhibits no benefit in improving pilocarpine-induced sleep disruptions; in contrast, EA further deteriorated sleep disturbances. Opioid receptors in the CeA mediated EA-induced exacerbation of sleep disruptions in epileptic rats.

Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients.

Hypothalamic hamartomas present with isolated fits of ictal laughter (gelastic epilepsy) or a combination of gelastic and other types of seizures. Many of these patients also suffer from cognitive decline, neuropsychiatric comorbidities and precocious puberty. Although there is a large body of anecdotal evidence about hypothalamic hamartomas and gelastic seizures, many questions still remain to be answered. For instance, which specific hypothalamic regions are most affected by the location of hamartomas causing laughing versus other types of seizures? Does the neuroanatomical localization of the lesions differ in cases with only gelastic seizures or a combination of gelastic and other types of seizures? Does the location of the lesions correlate with the presence of precocious puberty, and does the type of lesion influence the severity or the type of seizures? In a retrospective review of clinical and structural neuroimaging data from 100 cases of gelastic epilepsy and hypothalamic hamartoma, we aimed to address these questions by analysing the clinical presentation and the neuroanatomical features of the hypothalamic lesions in these patients. Our findings suggest that in all 100 cases, lesions were centred at the level of the mammillary bodies in the posterior hypothalamus. Compared with the patients with pure gelastic seizures (n = 32), those with gelastic and other types of seizures (n = 68) had significantly longer duration of epilepsy (P < 0.001), whereas age of seizure onset, the volume of lesions and the proximity to the mammillary bodies were not different between the two groups. In contrast, patients with cognitive or developmental impairment and those with precocious puberty had significantly larger lesions involving the anterior and posterior hypothalamus.

Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: Correlation with other seizure and epilepsy models.

Chronic electrical stimulation via corneal electrodes can rapidly yield large numbers of kindled mice with a seizure phenotype reflective of secondarily generalized partial seizures. The corneal kindled mouse model has been found to be a highly sensitive and efficient screening model for antiepileptic drug (AED) discovery. The present study further evaluates the utility of the corneal kindled mouse model as a tool for rapid screening of investigational AEDs. Results obtained with nine AEDs (valproic acid, lamotrigine, phenytoin, carbamazepine, levetiracetam, vigabatrin, topiramate, tiagabine, and ezogabine) with varying mechanisms of action and clinical spectrums, as well as six investigational compounds were evaluated in the corneal kindled mouse. ED(50) values are compared to those obtained in the hippocampal kindled rat, the mouse maximal electroshock (MES) model, the 6Hz partial psychomotor seizure model, and the subcutaneous pentylenetetrazol (scPTZ) test. The results obtained in the corneal kindled mouse demonstrate a positive correlation with those attained employing established preclinical models: MES (r² = 0.9511), scPTZ (r² = 0.9697), 6Hz (r² = 0.9519), and hippocampal kindling (r² = 0.9037). The demonstrated predictive ability of the corneal kindled mouse model supports its use in the early evaluation of investigational AEDs.

Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures.

Hypothalamic hamartomas (HHs) are congenital, benign masses in the hypothalamus and tuber cinereum that may cause central precocious puberty and gelastic seizures. Nodules of small neurons are thought to be a universal feature of the microarchitecture of HH lesions associated with epilepsy. Here we describe the case of a 5-year-old boy with gelastic seizures who underwent resection of a HH that contained nodules of glial cells, but only few, randomly distributed neurons. HHs that contain few or no neurons have only been reported thus far in cases associated with precocious puberty. This case demonstrates that few solitary neurons in HHs can drive the development of gelastic seizures, and nodules of small neurons may not be a universal feature of HHs associated with epilepsy. This finding is clinically important since hypothalamic hamartomas with rare neurons can easily be misdiagnosed as pilocytic astrocytomas or subependymomas if their presence is overlooked. A neuronal stain is helpful in making the correct diagnosis in these cases.

[Late revelation of homocysteinuria: clinical, biological and progressive aspects]. / Homocystéinurie à révélation tardive : aspect clinique, biologique et évolutif.

UNLABELLED: Homocysteinuria is a metabolic disorder with defect in genes encoding for methionine metabolism enzymes. The clinical features consist in: ophthalmic, neurological, orthopedic and vascular manifestations. It is generally diagnosed in childhood. Vascular involvements characterize adult's forms. We report one case. OBSERVATION: A 26-year-old man, who has lentis ectopia and a recent epilepsy, was hospitalized for deep vein thrombosis. Regarding the marfanoid phenotype and the high level homocysteinemia (231 micromol/L), homocysteinuria was suspected. Amino acid chromatography and reduced CBS activity were used to confirm the diagnosis. Vitamin enriched diet with vitamin B6 and folates has reduced slightly the homocysteine level. CONCLUSION: Homocysteinuria must be diagnosed early since a simple vitamin supply could ameliorate prognosis and decrease complications.

Outcome and predictors of interstitial radiosurgery in the treatment of gelastic epilepsy.

BACKGROUND: Gelastic epilepsy due to hypothalamic hamartomas is usually a severe condition encompassing both epileptic seizures and an epileptic encephalopathy associated with behavioral and cognitive impairments. Here we report the effects of interstitial radiosurgery in the treatment of this generally pharmacoresistant epilepsy syndrome. METHODS: Twenty-four consecutive patients (3-46 years of age, 7 women, mean age 21.9 years, mean duration of epilepsy 17.6 years) with gelastic epilepsy due to MR-ascertained hypothalamic hamartoma and a minimum follow-up period of 1 year were included in this evaluation. Treatment was performed by interstitial radiosurgery using stereotactically implanted (125)I seeds. Effects of treatment on seizure frequency and possible side effects were assessed prospectively. Factors influencing outcome and side effects were analyzed statistically. RESULTS: After a mean 24-month follow-up period following the last radiosurgical treatment, 11/24 patients were seizure free or had seizure reduction of at least 90% (Engel class I and II), in some cases only after repeated treatment. The duration of epilepsy prior to radiosurgery negatively influenced outcome. Treatment was well tolerated in most patients. Headache, fatigue, and lethargy were transient side effects associated with the development of brain edema extending from the implantation site in five patients. Four patients had a weight gain of more than 5 kg which was severe in two patients. The majority of those patients whose cognitive functions initially deteriorated showed subsequent recovery of cognitive functions, but episodic memory in two patients showed persistent decline at 1 year follow-up. Longer disease duration increased the risk for cognitive side effects, and larger hamartoma size and eccentric seed positioning increased the risk for radiogenic brain edema. Neither perioperative mortality nor neurologic impairments, visual field defects, or endocrinologic disturbances were encountered following treatment. CONCLUSION: Interstitial radiosurgery was efficacious in significantly improving gelastic epilepsy in about half of the patients treated in this series. Weight gain may occur as a side effect, whereas other severe side effects reported following microsurgical removal of the hamartoma were absent. The study results strongly suggest early causal treatment, as chances for seizure control are higher and the risk for cognitive side effects is lower in patients with shorter disease duration.

[Case of an 81-year-old woman with theophylline-associated seizures followed by partial seizures due to vitamin B6 deficiency].

We report an 81-year-old woman who suffered from theophylline-associated seizures followed by partial seizures due to vitamin B6 deficiency. She developed complex partial seizures. She had been treated with theophylline for two months because of chronic bronchitis. Brain diffusion-weighted magnetic resonance imaging (MRI) showed high intensity lesions in unilateral cerebral cortex and thalamus. Electroencephalogram presented periodic lateralized epileptiform discharges (PLEDs), and single photon emission computed tomography (SPECT) using 123I-IMP revealed increased blood flow in the same side of the cerebrum. We diagnosed as theophylline-associated seizures though blood theophylline concentration disclosed its therapeutic dose, and her symptom improved after theophylline was discontinued. She developed partial seizures again, after she suffered from diarrhea for two days. Laboratory examination showed that serum vitamin B6 was under the limitation of measurement, and intravenous supplementation of vitamin B6 stopped her seizures immediately. Theophylline may induce seizures independent of its blood concentration, and vitamin B6 deficiency may exist in the case of theophylline-associated seizures.

Palatal tremor, focal seizures, repeated miscarriages and elevated anti-thyroid antibodies.

Neurological manifestations of thyroid autoimmunity are heterogeneous and nonspecific. The most frequently adopted name for this entity is Hashimoto's encephalopathy although this eponym has been recently contested. In the absence of specific clinical features, diagnosis is suggested by the presence of elevated levels of anti-thyroid antibodies in the appropriate clinical context. We describe a patient with recurrent focal seizures, palatal tremor and elevated anti-thyroid antibodies but no encephalopathy. Her past medical history was marked by recurrent miscarriages. The markedly elevated thyroid antibodies, the temporal relationship between neurological symptoms and hypothyroidism, and the absence of another explanation to her symptoms suggest a causal role of thyroid autoimmunity. In the clinical setting of recurrent spontaneous miscarriages, elevated levels of anti-thyroid antibodies and neurological deficits not attributed to another disease entity, Hashimoto's encephalopathy should be suspected.

SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy.

SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra). The specific mechanism by which SV2A binding leads to seizure protection has not yet been fully elucidated. However, a functional correlation between SV2A binding affinity and anticonvulsant potency has been observed in the mouse audiogenic seizure model. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies. As expected, there was a high degree of correlation between anticonvulsant potency and SV2A binding affinity in the mouse audiogenic seizure model (r(2)=0.77; p<0.001). A similar correlation was also observed in the mouse corneal kindling (r(2)=0.80; p<0.01) and in the rat model of generalized absence epilepsy (GAERS) (r(2)=0.72; p<0.01). Moreover, there were no significant differences between the slopes and intercepts of regression lines in these models. Interestingly, the protective potencies in these three epilepsy models were also well correlated with each other. As such, protective doses of a given SV2A ligand in one model could be easily predicted based on the data obtained in another model. Taken together, these results support the concept that SV2A protein is an important target for both partial and generalized epilepsies and thereby relevant for the generation of new antiepileptic drugs with potential broad-spectrum efficacy.

Anticonvulsant effects of transcranial direct-current stimulation (tDCS) in the rat cortical ramp model of focal epilepsy.

PURPOSE: Weak direct currents induce lasting alterations of cortical excitability in animals and humans, which are controlled by polarity, duration of stimulation, and current strength applied. To evaluate its anticonvulsant potential, transcranial direct current stimulation (tDCS) was tested in a modified cortical ramp-stimulation model of focal epilepsy. METHODS: The threshold for localized seizure activity (TLS) was determined in freely moving rats by applying a single train of rising bipolar pulses through a unilateral epicranial electrode. After tDCS, TLS was determined repeatedly for 120 min at intervals of 15 min. The first group of animals received two sessions of cathodal tDCS at 100 microA, one for 30 and one for 60 min. A third session consisted of 60 min of anodal tDCS. A second group received cathodal tDCS at 200 microA for 15 and for 30 min, as well as anodal tDCS for 30 min. RESULTS: Sixty minutes of cathodal tDCS at 100 microA resulted in a TLS increase lasting for >or=2 h. When the intensity was increased to 200 microA, a similar lasting TLS elevation occurred after a stimulation of just 30-min duration. In contrast, anodal tDCS at identical stimulation durations and current strengths had no significant effect on TLS. CONCLUSIONS: The anticonvulsive effect induced by cathodal tDCS depends on stimulation duration and current strength and may be associated with the induction of alterations of cortical excitability that outlast the actual stimulation. The results lead to the reasonable assumption that cathodal tDCS could evolve as a therapeutic tool in drug-refractory partial epilepsy.

Partial seizure provoked by hyperbaric oxygen therapy: possible mechanisms and implications.

Hyperbaric oxygen treatment (HBO2) is used commonly for treatment of bone and soft-tissue radiation necrosis. It may be a potential therapy for radiation necrosis seen after brain irradiation. HBO2 risks include generalized tonic-clonic convulsions. We report a patient after resection of anaplastic astrocytoma and 5,580 cGy of total external-beam radiation treatments with brain radiation necrosis who underwent HBO2 therapy and developed a partial seizure during treatment. Mechanisms and implications are discussed.

Endoscopic disconnection for hypothalamic hamartoma with intractable seizure. Report of four cases.

Although intractable epilepsy associated with hypothalamic hamartoma (HH) can be controlled by microsurgical resection of the lesion, excision of deep-seated lesions is often associated with morbidity and mortality. Endoscopic disconnection is less invasive and seems to be well suited for this indication. The authors discuss the role of endoscopic-assisted surgery in the management of HH-induced seizures. Four patients with HH-related intractable gelastic seizure underwent endoscopic disconnection surgery. Postoperatively, all patients exhibited improvement. Two patients became seizure free immediately after endoscopic disconnection surgery, one patient with a widespread seizure focus involving the motor strip continued to experience rare complex partial seizures but gelastic seizures ceased, and one experienced a reduced frequency of seizures but persistence of some generalized seizures. Three patients suffered postoperative disconnection-like syndrome, which continued 3 to 7 days and spontaneously disappeared. The authors advocate the endoscopic disconnection surgery as a safe and effective treatment for HH-related epilepsy by blocking the spread of epileptic discharges from the lesion.

[Voluminous hypothalamic hamartoma in a 5-month-old boy: Epilepsy and surgery]. / Voluminoso hamartoma hipotalámico en un niño de 5 meses: epilepsia y cirugía.

The authors report the case of 5-month-old boy with a hypothalamic hamartoma and persistent gelastic seizures in spite of a wide combination of different antiepileptic drugs. It was decided to carry out only partial removal of the tumor for decompression and to decreasing the activity of the epileptogenic focus. Surgical therapy revealed as a valid option in the treatment of the uncontrollable gelastic seizures.

Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.

BACKGROUND: Hypothalamic hamartoma with gelastic seizures (HHGS) is an uncommon, often unrecognized, epileptic syndrome with onset of symptoms during childhood. AIM: In order to study the occurrence, clinical symptoms and different investigations of HHGS in Swedish children and adolescents, a nationwide survey was undertaken. Methods. Twelve patients, three females, aged 5 to 19 years were identified and their hospital records reviewed. MRI examinations were reinvestigated. RESULTS: Gelastic seizures were noted before the age of six months in seven patients in at least three as early as the neonatal period. During the course of disease one or more other seizure types developed in 11 patients. Behaviour disorder became subsequently obvious in ten patients, and mental retardation was diagnosed in seven. Precocious puberty was diagnosed in five patients. A total of 46 MRI examinations were performed in 11 patients, revealing hypothalamic tumors, eight of which were drooping with a broad base. Interictal and ictal EEG examinations were pathological in 10 patients with nonspecific results. Nonspecific results were also found on SPECT and PET performed in six and two patients, respectively. Available antiepileptic drugs had little or no effect on gelastic seizures, but some effect on other seizure types. Precocious puberty was treated with a GnRH-agonist. Neurosurgical treatment of the hypothalamic hamartoma, performed in three patients, had a rather good outcome concerning gelastic seizures and behaviour. Vagal nerve stimulation in five patients had no effect. CONCLUSIONS: Review of the literature and experience from this group's own cases confirms that early diagnosis of HHGS is important. Hypothalamic hamartoma should be considered in any child with laughing attacks. MRI investigation is compulsory, and neurosurgery the most important treatment.