Special Issue on Epilepsy and Seizures
Batool F. Kirmani
Director, Scott and White Epilepsy Center
Associate Professor of Neurology
Texas A & M HSC College of Medicine
Temple, TX, USA
Kan Ding1*, Yunhua Gong2, Puneet Gupta1, Alan Frol3, Roderick McColl4, Mark Agostini1, Pradeep Modur1, Paul Van Ness1 and Ramon Diaz-Arrastia1,2
Purpose: Cognitive impairment is commonly observed in patients with Temporal Lobe Epilepsy (TLE). Recently, volumetric analysis showed widespread cortical and subcortical atrophy in patients with TLE. In this study, we hypothesized that the diffuse atrophy in TLE with and without Mesial Temporal Sclerosis (MTS) was associated with cognitive impairment.
Methods: To investigate atrophy patterns in TLE, we studied 40 patients with TLE and MTS and 34 patients with TLE without MTS determined by gross visual inspection of structural Magnetic Resonance Imaging (MRI). Volumetric analysis was performed using Free Surfer software. The relationship between volume/cortical thickness and performance on neuropsychological tests was evaluated in 33 patients.
Results: Whole brain volume loss and widespread sub-cortical regional atrophy was noted in both TLE with and without MTS regardless of lateralization of seizure onset. Bilateral hippocampus atrophy was seen in both TLE with and without MTS. However, hippocampal volume loss was asymmetrical with more prominent ipsilateral atrophy in the TLE patients with MTS and symmetrical bilaterally in these without MTS. Widespread neocortical thinning was noted in all TLE patients. In TLE without MTS, the cortical thinning pattern was similar in patients with left and right seizure onset. In TLE with MTS, patients with left MTS had more diffused contralateral cortical involvement compared to these with right MTS. One-to-one structural-functional association was only found in immediate and delayed memory performance in all groups. In addition to left hippocampal volume, the cortical thickness in the inferior frontal gyrus and bilateral amygdala also had additional predictive value to performance in memory tests.
Conclusions: The results of this study confirmed widespread regional atrophy in the TLE patients with and without MTS. It also provided evidence that extra-hippocampal atrophy (i.e., in prefrontal regions and amygdala) contributes to memory impairment in medically intractable TLE.
Gabriel Maisonnave Arisi1,2#, Maira Licia Foresti1,2#, Andrés Montañez1 and Lee A. Shapiro1,2,3*
Minocycline is an antibiotic agent that has been shown to have neuroprotective properties in animal models of ischemia, Huntington’s disease and Parkinson’s disease. However, data are lacking regarding the neuroprotective effects of minocycline treatment following pilocarpine-induced status epilepticus. Rats were treated with 25 mg/kg minocycline 2 hours after the onset of pilocarpine-induced SE. The hippocampus was examined for neuronal loss and microglia proliferation. The rats were monitored for the development of spontaneous recurrent seizures.
Minocycline treatment was found to reduce seizure-induced neuronal loss in the hippocampus. Although minocycline treatment did not significantly inhibit microglia activation, a modest reduction in microglial cell number was related to greater neuroprotection. Finally, a single-dose of minocycline did not prevent the occurrence of spontaneous behavioral seizures. Taken together, the findings suggest that Minocycline treatment is neuroprotective after SE.
Sanjib Mukherjee1,2,3, Paul C Bricker1,2,3 and Lee A Shapiro1,2,3*
Traumatic Brain Injury (TBI) is one of the few known etiological factors contributing to the development of Post-Traumatic Epilepsy (PTE). An understanding of the mechanisms involved in the development of PTE is vital because PTEs are amongst the most difficult to treat, and are often resistant to first and second line anti- epileptic treatment regimens. TBI-induced inflammation, neuroplasticity and neuropathology in the hippocampus have been observed in animal models of TBI. Components of these alterations have been implicated in TBI-pathogenesis and the epileptogenic development of PTE. However, the early time course of these changes is not fully elucidated. This study was designed to examine inflammation and neuropathology in the hippocampus in a rat Fluid Percussion Injury (FPI) model of PTE. Cytokine analysis in the hippocampus, as well as astrocyte morphology was assessed to determine early inflammatory changes after TBI. To examine early seizure-promoting neuropathology, we performed stereological analysis of parvalbumin-labeled interneurons in the hippocampus at 24 hrs after TBI. The results demonstrate that FPI in rats results in early hippocampal inflammation, but not a loss of parvalbumin-labeled interneurons.
Diana Mungall Robinson1,2, Jose Aceves3, Ekokobe Fonkem1,4 and Batool F Kirmani1,2*
Abstract: Psychogenic non-epileptic spells are a form of conversion disorder which is characterized by “seizure like episodes” often misdiagnosed as epilepsy. These are frequently seen in adults with female predominance but occur also in children. The gold standard, for a definitive diagnosis, is inpatient video-EEG monitoring in a specialized epilepsy monitoring unit to capture these episodes. There is paucity of literature about psychogenic non-epileptic spells in children and adolescents resulting in delay of diagnosis, oftentimes by several months. In this review, we discuss the current available literature about the incidence, clinical semiology, diagnosis and management of PNES in this subgroup of patients.
Joseph Pham1, Darin Garret1, Batool Kirmani2,3 and Ekokobe Fonkem1,3
Abstract: Lacosamide is a new antiepileptic drug that was has been approved as an adjunctive treatment of partial-onset seizures but also has potential in brain tumor-related epilepsy. The medication’s novel mechanism of action of selectively enhances slow inactivation of sodium channels and does not affect the rate of recovery. Lacosamide is available in both oral and intravenous preparation for ease of use and have has 100% bioavailability. Lacosamide is not metabolized by nor induces the activity of cytochrome P450. There is no significant interactions with other antiepileptic or chemotherapy drugs. Seizure control rate is very good with 50% respond rate range between 54-78%. The side effects of lacosamide are usually well tolerated, most commonly and include dizziness, blurry vision, nausea and vomiting. Although there are only a small number of retrospective studies of lacosamide in brain tumor patients with seizure, the results are promising. Lacosamide is an excellence choice as an add-on agent for brain-tumor patients with epilepsy resistant to one or more first line AEDs.
Jared F Benge1,2,3*, Michael Therwhanger J3 and Batool Kirmani1,3
Abstract: The neuropsychological consequences of Frontal Lobe Epilepsy (FLE) are not as well characterized as those of temporal lobe epilepsy. In the past 5 years though, new advances in behavioral assessment and imaging techniques have begun to more fully elucidate the cognitive, behavioral, and emotional sequelae of these conditions, especially in children. This review summarizes the recent advances in understanding the neuropsychology of FLE, and points out future directions for growth in this rapidly evolving area.
Leslie E. Perry1 and Jennifer L. DeWolfe2*
Abstract: The relationship between epilepsy and sleep is complex and dynamic. Sleep complaints and concomitant sleep disorders are common in people with epilepsy. Seizures and antiepileptic drugs can alter sleep architecture.There have been conflicting findings on the impact of sleep deprivation on seizures; however there is evidence to support the improved specificity of epilepsy diagnosis when a negative routine EEG is followed with a sleep-deprived study. The timing of seizure occurrence may be influenced by seizure onset localization; however much remains to be investigated regarding the impact of circadian rhythms and sleep patterns on seizure control. Lastly, epilepsy surgery has been shown to improve sleep quality in patients who remain seizure free. There have been advances in epilepsy and sleep research in light of newer investigational techniques, improved awareness of comorbid sleep disorders and the increasing prevalence of surgically-cured epilepsy patients. This article reviews the impact of sleep hygiene and obstructive sleep apnea on seizures, sleep deprivation on seizures, the circadian pattern on seizures, and finally the impact of epilepsy surgery on sleep.
Abstract: Pure word deafness is a disorder of auditory verbal comprehension without dysfunction of speaking, reading, or writing. This rare symptom arises from bilateral lesions in the temporal lobes or disconnection between the primary auditory cortex and Wernicke’s area. I present a right-handed 33-year-old woman who presented with pure word deafness and complex auditory hallucination with intermittent amnesia. She had no generalized convulsion. There was no intracranial lesion on plain or gadolinium-enhanced magnetic resonance imaging. Electroencephalogram revealed theta waves in the left temporal-occipital region followed by high-amplitude slow wave burst during hyperventilation. Carbamazepine completely ameliorated the pure word deafness and auditory hallucination. This is the first report of pure word deafness resulting from primary complex partial seizure. The epileptic focus might lie along the auditory word processing pathway between the left auditory cortex and Wernicke’s area.
Fructuoso Ayala-Guerrero*, Azalea Reyes and Graciela Mexicano
Abstract: Epilepsy is one of the most frequent neurological alterations affecting significantly the quality of life of the individuals who suffer it. Temporal Lobe Epilepsy (TLE) is one of the most severe types of epilepsies commonly presented in the world population. It is characterized by neuronal damage in regions of the limbic system, such as the amygdala and the hippocampus (mesial temporal lobe sclerosis). These lesions provoke alterations in cognitive processes, including learning and memory.
Since epilepsy is a highly prevalent disease in the world population, experimental models have been implemented to investigate its physiopathology and test the effectiveness of anticonvulsive drugs.
The Kainic Acid (KA) model to produce TLE in rats and phenobarbital (PB) as antiepileptic drug were used in this study. Four groups of rats trained on a spatial task were used and once they met the learning criteria, one group was administered with saline solution, the second group with PB, the third with KA, and the last group with PB+KA. Results indicate that the epileptic seizures induced by KA produced deficits on reference (p<0.01) and working memories (p<0.001). PB administered 30 minutes prior KA inhibited the development of status epilepticus, protected against alterations of reference memory and minimized those of working memory. These findings suggest that reference and working memories are a part of different functional systems.
Li Cui1, Zhen He1,2*, Sherry A Ferguson2 and Merle G Paule2
Abstract: In a clinical study conducted a decade ago, it was proposed that different versions of the gene encoding phosphodiesterase 4D, cAMP-specific (pde4d) confer different risks for ischemic stroke. Today, however, there continues to be unresolved global discussion of this issue. This short review summarizes the results of clinical genomic and basic research studies. In the acute phase following experimentally-induced stroke, the microvascular expression of PDE4D is increased in association with increased blood-brain-barrier (BBB) permeability and neuronal death. Treatment with PDE4 inhibitors ameliorates BBB dysfunction and reduces cerebral ischemic damage. Accordingly, experimental approaches using Pde4d knock-out animals for addressing the role of PDE4D in cerebral ischemia are logical next steps. The results of such studies may determine whether or not enhanced PDE4D expression after cerebral ischemia exacerbates stroke outcome and, thus, may provide at least partial resolution to this issue. More importantly, such an approach may provide enhanced opportunities in the search for stroke therapies.
Brian D Moseley*
Abstract: Sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Despite its growing recognition amongst clinicians caring for patients with epilepsy, the exact pathophysiologic mechanisms behind SUDEP have not yet been fully elucidated. However, autonomic effects of seizures are thought to most likely to contribute to sudden unexpected death. Such autonomic effects may affect the heart. These include peri-ictal tachycardia, bradycardia, asystole, repolarization abnormalities, and/or reduced heart rate variability. Respiration may also be affected by seizures, with resulting hypoventilation, apnea, and hypoxemia. More recently, postictal generalized EEG suppression (PGES) has been hypothesized to be an electrophysiologic marker of increased SUDEP risk. If the cortical neuronal inhibition suggested by PGES affects deeper subcortical and brainstem structures, it may interfere with respiratory drive and result in apnea, putting patients at risk for sudden death. Given that SUDEP occurs less frequently than any peri-ictal autonomic disturbance in isolation, it is possible that death only occurs when several precipitating factors come together in a “perfect storm.” Increasing our understanding of SUDEP will require further exploration of ictal and interictal autonomic dysfunction in patients with seizures. It is only through such research that we may one day understand SUDEP enough to fully prevent it.
Hülya Ertasoğlu Toydemir1 and Ayse Destînâ Yalcin2
Abstract: Both incidence and prevalence of epilepsy are high among the elderly patients. Epilepsy in the elderly differs in etiology, clinic features and prognosis. The most common etiological factor of epilepsy in the elderly is cerebrovascular diseases. Although most of the seizures in elderly patients are of focal onset, with or without secondary generalization, the presentation of seizures may be nonspecific. The diagnosis of epilepsy in the elderly patients may be difficult because of subtle semiological findings, co-morbid diseases, medications and age-related cognitive difficulties. A detailed history, a comprehensive neurological examination, routine laboratory tests, EEG and neuroimaging modalities are the cornerstones of diagnostic evaluation. Treatment of epilepsy in the elderly requires an understanding of the etiologies, medical and psychological aspects of this age group and should be based on careful assessment of risk/benefit profiles of antiepileptic drugs. The choice of antiepileptic drugs is also determined by side-effects, tolerability, drug interactions and pharmacokinetic profiles.
Daniel S Weisholtz* and Barbara A Dworetzky
Abstract: Psychosis is a significant comorbidity for a subset of patients with epilepsy, and may appear in various contexts. Psychosis may be chronic or episodic. Chronic Interictal Psychosis (CIP) occurs in 2-10% of patients with epilepsy. CIP has been associated most strongly with temporal lobe epilepsy. Episodic psychoses in epilepsy may be classified by their temporal relationship to seizures. Ictal psychosis refers to psychosis that occurs as a symptom of seizure activity, and can be seen in some cases of non-convulsive status epilepticus. The nature of the psychotic symptoms generally depends on the localization of the seizure activity. Postictal Psychosis (PIP) may occur after a cluster of complex partial or generalized seizures, and typically appears after a lucid interval of up to 72 hours following the immediate postictal state. Interictal psychotic episodes (in which there is no definite temporal relationship with seizures) may be precipitated by the use of certain anticonvulsant drugs, particularly vigabatrin, zonisamide, topiramate, and levetiracetam, and is linked in some cases to “forced normalization” of the EEG or cessation of seizures, a phenomenon known as alternate psychosis. Seizures and psychosis may also co-occur secondary to another neurologic disorder, such as a traumatic brain injury, brain tumor, or limbic encephalitis. When a patient with epilepsy develops psychosis, the clinician should attempt to determine the cause, as treatment approach may vary. In this article, we review the various forms of epilepsy-related psychosis and discuss a rational approach to the evaluation and management of patients with epilepsy and psychosis.
Krisztian Kovacs S, Fabio Leonessa, Jamie Grimes and Geoffrey S F Ling*
Abstract: It is recognized that explosive blast Traumatic Brain Injury (TBI) may be a significant risk factor for seizure and consequently Post-Traumatic Epilepsy (PTE). This has importance clinically as the manifestation of seizures following a blast exposure may be the only objective clinical sign that a victim may have suffered cellular and structural brain injury. The mechanisms by which explosive blast damages brain remain unclear. Characterizing blast TBI neuropathology will provide the basis for a deeper understanding of this condition thereby facilitating development of meaningful therapies. The evidence to date reveals that explosive blast TBI leads to the neuropathological features of axonal injury as evidenced by focal and diffuse axonal degeneration and axonal swelling detected by silver staining and beta-Amyloid Precursor Protein (APP). Silver stained and immunfluorescent Fluoro-jade reactive neurons consistent with neuronal degeneration and apoptotic bodies of cell death are also observed. Electron microscopy reveals neuron cell body chromatolysis and pycnosis as evidences of neuronal cell degeneration as well as swollen degenerating nerve fibers. These findings are mainly distributed in long fiber tracts, such as the corticospinal tract and visual pathways (including the optic tract and its deep nuclear structures such as the lateral geniculate body and superior colliculus), cerebellar white matter structures, the hippocampus and the brainstem. The neuropathological features of neuronal cell degeneration and cell loss and astrogliosis, particularly in hippocampal structures, have been shown in other clinical conditions with seizures and PTE, which supports the risk of this disorder following explosive blast TBI.
Kengo Maeda1*, Nobuhiro Ogawa1 and Yutaka Tadano2
Abstract: Cases in which epilepsy and atrio-ventricular (AV) block coexist are unusual. A 31-year-old man presented with syncope. Holter ECG showed the second-degree AV block and the longest cardiac pause was 6.3 seconds. Even after receiving pacemaker, he repeated consciousness cloudiness. Electroencephalogram revealed spike and waves on the left temporal region, suggesting complicated with complex partial seizure. There was no pathogenic mutation in KCNA1 encoding Kv1.1 potassiume channel of which deficient mice displayed both epilepsy and AV block. Epileptic discharge in the left temporal region could result in bradycardia and sometimes it might be a cause of sudden unexpected death in epilepsy. Neurologists and cardiologists should pay attention to this rare disorder.