John F. Kerrigan

Electrical Stimulation of the Anterior Nucleus of the Thalamus for the Treatment of Intractable Epilepsy

Summary:  Purpose: Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open‐label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data.

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.

Endoscopic resection of hypothalamic hamartomas for refractory symptomatic epilepsy.

Background: Hypothalamic hamartomas (HHs), rare developmental abnormalities of the inferior hypothalamus, often cause refractory, symptomatic, mixed epilepsy, including gelastic seizures. We present 37 patients with HH who underwent transcortical transventricular endoscopic resection. Methods: Between October 2003 and April 2005, 42 consecutive patients with refractory epilepsy who underwent endoscopic resection of HH were studied prospectively. The endoscope was held by an articulated pneumatic arm and tracked with a frameless stereotactic neuronavigation system. Data collection and follow-up were performed by personal interview. Five patients were excluded. The remaining 37 patients (22 males, 15 females; median age 11.8 years; range 8 months to 55 years) had frequent and usually multiple types of seizures. Results: Postoperative MRI confirmed 100% resection of the HH from the hypothalamus in 12 patients. At last follow-up (median 21 months; range 13–28 months), 18 (48.6%) patients were seizure free. Seizures were reduced more than 90% in 26 patients (70.3%) and by 50% to 90% in 8 patients (21.6%). Overall, the mean postoperative stay was shorter in the endoscopic patients compared with our previously reported patients who underwent transcallosal resection (mean 4.1 days vs 7.7 days, respectively; p = 0.0006). The main complications were permanent short-term memory loss in 3 patients and small thalamic infarcts in 11 patients (asymptomatic in 9). Conclusions: Endoscopic resection of hypothalamic hamartoma (HH) is a safe and effective treatment for seizures. Its efficacy seems to be comparable to that of transcallosal resection of HH, but postoperative recovery time is significantly shorter.

Interobserver agreement in the interpretation of EEG patterns in critically ill adults.

Summary: The significance of rhythmic and periodic EEG patterns in critically ill patients is unclear. A universal terminology is needed to facilitate study of these patterns, and consistent observer agreement should be demonstrated in its use. The authors evaluated inter- and intraobserver agreement using the standardized terminology (Hirsch et al., J Clin Neurophysiol 2005;22:128–135) recently proposed by the American Clinical Neurophysiology Society. Trained electroencephalographers viewed a series of 10-second EEG samples from critically ill adults (phase I), a set of ≥20-minute EEGs from the same patient cohort (phase II), and then reevaluated the first sample set (phase III). The readers used the proposed terminology to “score” each EEG. For each possible term, interobserver agreement (phases I and II) and intraobserver agreement (phase III) were calculated using pairwise kappa (&kgr;) values. Moderate agreement beyond chance was seen for the presence/absence of rhythmic or periodic patterns and for localization of these patterns. Agreement for other terms was slight to fair. Inter- and intraobserver agreement were consistently lower for optional terms than mandatory terms. Even when standardized terminology is used, the description of rhythmic and periodic EEG patterns varies significantly. Further refinement of the proposed terminology is required to improve inter- and intraobserver agreement.

Electrophysiological properties of human hypothalamic hamartomas

The hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures, which are usually refractory to medical therapy. The mechanisms of epileptogenesis operative in this subcortical lesion are unknown. In this study, we used standard patch‐clamp electrophysiological techniques combined with histochemical approaches to study individual cells from human HH tissue immediately after surgical resection. More than 90% of dissociated HH cells were small (6–9μm soma) and exhibited immunoreactivity to the neuronal marker NeuN, and to glutamic acid decarboxylase, but not to glial fibrillary acidic protein. Under current‐clamp, whole‐cell recordings in single dissociated cells or in intact HH slices demonstrated typical neuronal responses to depolarizing and hyperpolarizing current injection. In some cases, HH cells exhibited a “sag‐like” membrane potential change during membrane hyperpolarization. Interestingly, most HH cells exhibited robust, spontaneous “pacemaker‐like” action potential firing. Under voltage‐clamp, dissociated HH cells exhibited functional tetrodotoxin (TTX)–sensitive Na+ and tetraethylammonium‐sensitive K+ currents. Both GABA and glutamate evoked whole‐cell currents, with GABA exhibiting a peak current amplitude 10‐fold greater than glutamate. These findings suggest that human HH tissues, associated with gelastic seizures, contained predominantly small GABAergic inhibitory neurons that exhibited intrinsic “pacemaker‐like” behavior. Ann Neurol 2005;58:371–382

Fumaric aciduria: Clinical and imaging features

Fumaric aciduria (fumaric acidemia, fumarase deficiency) is a rare inborn error of metabolism caused by deficient activity of fumarate hydratase, one of the constituent enzymes of the Krebs tricarboxylic acid cycle. We describe the clinical and imaging features of this disease arising from a consanguineous pedigree in 8 patients in the southwestern United States. Thirteen patients have been previously described in the medical literature. Our patients presented with an early infantile encephalopathy with profound developmental retardation and hypotonia, and most experienced seizures. Previously unreported characteristics described here include structural brain malformations, dysmorphic facial features, and neonatal polycythemia. Magnetic resonance imaging showed multiple abnormalities, including diffuse polymicrogyria, decreased cerebral white matter, large ventricles, and open opercula. Fumaric aciduria should be included in the differential diagnosis of inborn errors of metabolism that cause cerebral malformations and dysmorphic features. The possibility that inborn errors of energy metabolism may cause structural malformations deserves increased recognition. Ann Neurol 2000;47:583–588

The Histopathology of Hypothalamic Hamartomas: Study of 57 Cases

Hypothalamic hamartomas (HHs) are rare developmental tumors that cause seizures or pituitary axis dysfunction, usually beginning in childhood. We analyzed HH tissue from 57 patients whose tumors were resected through recently developed transcallosal interforniceal and transventricular endoscopic surgical approaches. All cases were composed of abnormally distributed but cytologically normal neurons and glia, including fibrillary astrocytes and oligodendrocytes. Neuronal elements predominated in most cases, but a relative increase in astrocytic elements was seen with increasing age. All had various sized nodular foci of neurons as well as areas of diffusely distributed neurons with interspersed glial cells. Smaller neurons predominated, and most cases had only a few interspersed large ganglion cells. Immunohistochemistry demonstrated extensive production of synapse-associated proteins. Immunohistochemistry for phosphorylated and nonphosphorylated neurofilament and &agr;-internexin demonstrated staining patterns consistent with mature neurons. In contrast to cortical dysplasia, atypical large ganglion-like balloon cells were almost never seen. In summary, although their number and distribution vary, mature smaller neurons were the most prominent and most consistent histologic feature of HH. Nodules of these small neurons were a universal feature of the microarchitecture of HH lesions associated with epilepsy. Characterization of these neurons may aid in understanding the mechanism of seizure development in HH.

Treatment of refractory status epilepticus with hemispherectomy.

Summary:  A 7‐year‐old boy with left hemiparesis secondary to right hemispheric cortical dysplasia was admitted to the hospital with increasing numbers of seizures. Magnetic resonance imaging showed a small dysplastic right hemisphere with abnormally thickened gyri and an apparently normal left hemisphere. Previous video‐electroencephalogram (EEG) monitoring showed bilateral independent spikes and generalized slow spike‐and‐wave episodes on EEG and [18F]fluorodeoxyglucose (FDG) positron emission tomography scan demonstrated scattered areas of regional hypometabolism bilaterally; therefore hemispherectomy was not undertaken at that time. During this hospital stay, nonconvulsive status epilepticus developed and was refractory to multiple medical therapies including pentobarbital (PTB) coma. Burst‐suppression pattern during PTB coma appeared to be generalized spike and wave, but when EEG was reviewed with increased time resolution spikes suggested a right hemisphere origin. The patient underwent bilateral intracarotid amobarbital spike‐suppression test that showed only minimal suppression of epileptiform discharges with injection of the left carotid, but complete suppression of spike activity after right‐sided carotid injection. A right hemispherectomy was performed with complete cessation of status epilepticus. Postoperative EEG showed no epileptiform discharges. Patient follow‐up was limited to 12 months after surgery. The patient had regained the ability to walk unaided and was seizure free with a single antiepileptic medication. This case illustrates a potentially life‐saving procedure for refractory status epilepticus and several techniques including a spike‐suppression test to aid in prediction of cessation of seizures after hemispherectomy.

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.

GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas.

Purpose: The human hypothalamic hamartoma (HH) is a rare, intrinsically epileptogenic lesion associated with gelastic seizures, but the underlying mechanisms remain unclear. Here, we examined the role of GABAA receptors in surgically resected HH tissue.