Andres M. Kanner

Depression in Epilepsy: A Neurobiologic Perspective

Depression is the most frequent psychiatric comorbidity in patients with epilepsy. By the same token, patients with depression are at higher risk of developing epilepsy than are controls. Such bidirectional relations raise the question of whether both disorders share common pathogenic mechanisms, presenting with common neurotransmitter abnormalities and involvement of the same neuroanatomic structures. In this article, some of the available data in support of this hypothesis are reviewed.

Depression in Epilepsy Is Much More Than a Reactive Process

Patients with epilepsy have a higher prevalence of depressive disorders than the general population, but the relation between seizure rates and depression has not been adequately studied. We used the Beck Depression Inventory to evaluate depressive symptoms in 143 consecutive epilepsy patients from outpatient clinics. Patients who were seizure free for more than 6 months were considered not intractable. Thirty-six percent were neither intractable nor depressed, 43% had intractable epilepsy and were not depressed, 10% had intractable epilepsy and were depressed, and 11% did not have intractable epilepsy and were depressed. Patients with epilepsy have a higher prevalence of depression than does the general population, but the intractability of the seizure disorder does not seem to be an independent risk factor for the occurrence of depression. No relation occurs between the severity of depression and monthly seizure rate.

Deep brain stimulation for intractable epilepsy: which target and for which seizures?

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. METHODS: We report an open-label pilot study of intermittent electrical stimulation of the ANT in five patients (three men, two women; age range, 24–47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 msec; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline. RESULTS: Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic–clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters. CONCLUSIONS: Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.

The Pharmacology of Parenteral Valproate.

PURPOSE: Valproate sodium injection (VPA; Depacon) is an intravenous form of VPA for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. METHODS: Subjects with epilepsy were randomized in a 2:1 ratio to receive ≤15 mg/kg of VPA infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma VPA concentrations of 50– 100 μg/mL. Primary safety end points were the changes in the 5-min and minimum blood pressures (BPs) after first infusion. RESULTS: One hundred twelve subjects were treated (3.0-mg/kg/min group: n = 72; 1.5-mg/kg/min group: n = 40). No significant treatment differences were detected for changes in the primary BP end points. Two subjects in the 3.0-mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h after the first infusion. CONCLUSIONS: VPA injection dosages ≤15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population.

Landau-Kleffner Syndrome.

The presenting characteristics of 18 (11 female, seven male) children with Landau-Kleffner syndrome (LKS) were studied with respect to course and outcome of their condition at a mean length of 67 (SD 46) months’ follow up. All had regression of receptive language (mean age of onset 4 years 9 months) and electrical status epilepticus in sleep (ESES). Length of ESES correlated strongly with length of period between onset of illness and onset of recovery (p 0.006) and also with eventual receptive (p 0.001) and expressive (p 0.007) language. Behavior during the acute phase was severely affected in nine children and associated with frontal lobe discharges in awake electroencephalograms (EEGs) (p 0.004). Age at onset was not correlated with outcome. All children had impaired short-term memory at follow up. Three children had language outcome within the normal range. No child with ESES lasting longer than 36 months had normal language outcome. These data lend support for intervention in ending ESES by 36 months using multiple subpial transection (MST) if steroids are ineffective or cause unacceptable side effects.

Unraveling the secrets of sudden death in epilepsy: is it possible?

PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality for patients with epilepsy. Cardiac factors may be involved and were evaluated in this study. METHODS: EEG and ECG data for 21 patients with definite (n = 6) or probable (n = 15) SUDEP were compared with data from a group of 43 patients with refractory partial epilepsy. ECG abnormalities and heart rate (HR) changes were correlated with clinical data. RESULTS: Fourteen patients died in their sleep; two were awake. Ictal maximal HR (90 seizures from 16 of 21 patients) was significantly higher in SUDEP (mean, 149 beats/min, BPM) than in comparison patients (mean, 126 BPM; P < 0.001). Greater increases in HR were associated with seizures arising from sleep (78 BPM increase) than from wakefulness (47 BPM; P < 0.001) in SUDEP, as compared with the non-SUDEP group (52 BPM in sleep, 43 BPM in wakefulness; P = 0.27). Ictal cardiac repolarization and rhythm abnormalities occurred in 56% of SUDEP (including two atrial fibrillation, two ventricular premature depolarizations, two marked sinus arrhythmia, two atrial premature depolarizations, one junctional escape, one ST-segment elevation), and 39% of comparison patients (P = 0.39). No specific seizure onset (laterality or lobe) was associated with SUDEP. CONCLUSIONS: This study reveals, for the first time, evidence of increased autonomic stimulation (as measured by HR) associated with seizures, particularly in sleep, in patients with SUDEP, as compared with a clinically similar group of patients with refractory epilepsy. COMMENTARY

Subarachnoid Hemorrhage as a Cause of Epilepsy.

PURPOSE: To determine the frequency, predictors, and impact on outcome of epilepsy developing during the first year after subarachnoid hemorrhage (SAH). METHODS: The authors prospectively analyzed 247 of 431 patients with SAH treated over a period of 5 years who were alive with follow-up at 12 months. Epilepsy was defined as two or more unprovoked seizures after hospital discharge. RESULTS: New-onset epilepsy occurred in 7% (n = 17) of patients; an additional 4% (n = 10) had only one seizure after discharge. Independent predictors of epilepsy included subdural hematoma [odds ration (OR 9.9; 95% confidence interval (CI), 1.9–52.8] and cerebral infarction (OR, 3.9; 95% CI, 1.4–11.3). Unlike those without seizures, patients who developed epilepsy failed to experience functional recovery on the modified Rankin Scale (mRS) between 3 and 12 months after SAH. At 12 months, epilepsy was independently associated with severe disability (score ≥ 3) on the mRS (OR, 10.3; 95% CI, 2.5–42.0), increased instrumental disability on the Lawton Instrumental Activities of Daily Living scale (OR, 4.9; 95% CI, 1.1–22.2), reduced quality of life on the Sickness Impact Profile (OR, 4.5; 95% CI, 1.1–18.0), and increased state anxiety on the Spielberger Anxiety Inventory (OR, 4.8; 95% CI, 1.1–20.4). Epilepsy was not associated with cognitive impairment, depression, or subjective life satisfaction. CONCLUSIONS: Epilepsy occurred in 7% of patients with SAH, was predicted by subdural hematoma and cerebral infarction, and was associated with poor functional recovery and quality of life. Our findings indicate that focal pathology, rather than diffuse injury from hemorrhage, is the principal cause of epilepsy after SAH. COMMENTARY

Does Epilepsy Surgery Convert Medical Intractable Temporal Lobe Epilepsy to a Medically Treatable Seizure Disorder

Retrospectively, we analyzed preand postoperative (po) antiepileptic drug (AED) treatment in relation to longterm annual seizure outcome in the Zurich selective amygdalohippocampectomy (AHE) series. In 376 patients [hippocampal sclerosis (HS), n = 185; other lesions (lesional), n = 191] with a follow-up of more than 1 year, in the last available outcome (lao), 60% were seizure and aura free [International League Against Epilepsy (ILAE) class 1]. During the year before surgery, in the HS group, a mean of 2.3 ± 0.8 AEDs were taken. The percentage of patients without AEDs increased to 36.1% in the po years 1–5 [po year 5: HS (n = 133) 27.8%; lesional (n = 111) 45.9%]. In po years 7–11, this percentage was between 40% and 43% [po year 10: HS (n = 75) 29.3%; lesional (n = 65) 55.4%]. In the ILAE class 1a, at po year 5, 63 of 85 (74.1%) patients had discontinued AED intake. At lao, 36.2% of patients were off AEDs, and an additional 18.9% had a “substantial” reduction (i.e., from polytherapy to monotherapy, or a reduction of the existing monotherapy by at least 66% compared with the year before AHE). The relapse rate was similar for patients who were free of disabling seizures (a) for 1 year and without AEDs (17.1%), (b) immediately after surgery with or without AEDs (18.4%), and (c) had a substantial AED reduction over the entire follow-up period (18.9%). The rate of regained full seizure control, however, was significantly better for group (b) compared with (c) (77% vs. 53%); 10.9% of patients showed the “running down phenomenon” (i.e., had seizures during the first po year, but then became seizure free for 1 or more years). The percentage of patients free of “disabling” seizures, who did not follow the medical advice to discontinue/reduce AEDs, is about 30% after po year 10. In po year 15, this figure was 4.2 times higher for HS versus lesional patients. We conclude that the time of discontinuation of AEDs after AHE should be tailored based on the results of the presurgical evaluation, the early po seizure outcome, the histopathologic findings, the intraoperative electrocorticography findings, and the po EEG. In an optimal constellation, substantial AED reduction with the goal of a monotherapy can be advised after 1 year and discontinuation 2 years after surgery.

Thalamic Dysfunction in Idiopathic Generalized Epilepsy: New Findings of Old News

Experimental work in animal models of generalized epilepsy and clinical data in humans with idiopathic generalized epilepsy (IGE) indicate that the thalamocortical circuitry is involved in the generation of epileptic activity. The purpose of this study was to evaluate in vivo the chemical and structural integrity of the thalamus in patients with IGE. Thalamic proton magnetic resonance spectroscopic imaging (1H-MRSI), measuring Nacetylaspartate (NAA), choline-containing compounds, and creatine (Cr) was performed in 20 IGE patients and in a group of age-matched healthy subjects. Additionally, 1H-MRSI measurements were taken in the insular cortex, the posterior temporal lobe white matter, and the splenium of the corpus callosum. MRI volumetric analysis of the thalamus was performed in all patients. At the time of the examination, seizures were well controlled in 10 IGE patients and poorly controlled in 9. One patient was newly diagnosed and had the MRI and MRSI examination before starting the antiepileptic medication. In IGE patients, 1H-MRSI showed a reduction of mean thalamic NAA/Cr ratio compared with normal controls; no difference was found in NAA/Cr in the other examined areas. No difference in NAA/Cr was found between patients whose seizures were well controlled and those in whom seizures were not controlled. No correlation was seen between thalamic NAA/Cr and mean number of spike-and-wave complexes. We found a significant negative correlation between thalamic NAA/Cr and duration of epilepsy. The mean thalamic volume in patients with IGE was not different from that in normal controls. These results show evidence of progressive thalamic neuronal dysfunction in patients with IGE, supporting the notion of abnormal thalamocortical circuitry as a substrate of seizure generation in this form of epilepsy. The thalamic dysfunction may occur regardless of amount of spikeand-wave activity.

The Various Neuropathological "Faces" of Temporal Lobe Epilepsy.

PURPOSE: This study is a retrospective analysis of the pathology of the hippocampus from patients with medically intractable temporal lobe epilepsy. We attempted to relate neuronal density, immunohistochemistry, electrophysiologic data, and surgical outcome. METHODS: Immunostaining patterns for neuropeptide Y, somatostatin, substance P, and dynorphin defined the immunohistochemical characteristics of the hippocampi. Neuronal densities were determined by microscopic cell counts. Sharp electrode recordings from dentate granule cells determined measures of inhibition and excitation. RESULTS: Patient hippocampi without evidence of sclerosis generally resembled autopsy controls on the basis of neuronal densities of hippocampal subfields and patterns of immunostaining. The nonsclerotic hippocampi were divisible into two subgroups on the basis of neuronal-density correlations between hippocampal subfields, the excitability of dentate granule cells, etiology, and surgical outcome. Hippocampi with sclerosis were divisible into those with significant neuronal loss confined to area CA1 and those with neuronal loss throughout the hippocampus and dentate gyrus. In the former, the dentate gyrus resembled in morphology the nonsclerotic hippocampi but with slightly increased excitability of the dentate granule cells. The hippocampi with more extensive neuronal loss had changes in immunostaining patterns associated with the dentate gyrus, correlated with significant hyperexcitability of dentate granule cells. The surgical outcome, with the exception of one group, was good in approximately 70% to 90%. CONCLUSIONS: Hippocampi from patients with intractable temporal lobe epilepsy can be assigned to several groups on the basis of pathophysiology. Different pathologies may represent differing causative mechanisms of intractable temporal lobe epilepsy and be predictive of surgical outcome.