Effects Of Recurrent Seizures Research Articles

An update on the seizures beget seizures theory.

Seizures beget seizures is a longstanding theory that proposed that seizure activity can impact the structural and functional properties of the brain circuits in ways that contribute to epilepsy progression and the future occurrence of seizures. Originally proposed by Gowers, this theory continues to be quoted in the pathophysiology of epilepsy. We critically review the existing data and observations on the consequences of recurrent seizures on brain networks and highlight a range of factors that speak for and against the theory. The existing literature demonstrates clearly that ictal activity, especially if recurrent, induces molecular, structural, and functional changes including cell loss, connectivity reorganization, changes in neuronal behavior, and metabolic alterations. These changes have the potential to modify the seizure threshold, contribute to disease progression, and recruit wider areas of the epileptic network into epileptic activity. Repeated seizure activity may, thus, act as a pathological positive-feedback mechanism that increases seizure likelihood. On the other hand, the time course of self-limited epilepsies and the presence of seizure remission in two thirds of epilepsy cases and various chronic epilepsy models oppose the theory. Experimental work showed that seizures could induce neural changes that increase the seizure threshold and decrease the risk of a subsequent seizure. Due to the complex nature of epilepsies, it is wrong to consider only seizures as the key factor responsible for disease progression. Epilepsy worsening can be attributed to the various forms of interictal epileptiform activity or underlying disease mechanisms. Although seizure activity can negatively impact brain structure and function, the "seizures beget seizures" theory should not be used dogmatically but with extreme caution.

Sıçanlarda Pentilentetrazol ile İndüklenen Akut Epilepsi Modelinde Valproik Asidin NO/cGMP Üzerindeki Etkileri

Epilepsy is a disease which causes neuronal damage and loss of consciousness in consequence of recurrent seizures. Nitric oxide as a neuromodulator in brain is a gas which can penetrate into cells. It has a significant role on physiological cases,pathology of many diseases such as inflammation and degenerative diseases. The purpose of this research is to search the activity of NO/cGMP pathway of valproic acid in an experimental acuteepileptic model which is induced with pentylenetetrazol in rats.18 adult male Wistar Albino rats were used in the study. The rats were randomly divided into 3 groups (n=6) as control group, pentylenetetrazol (PTZ+salin) 45 mg kg-1, valproic acid (PTZ+VPA) 150 mg kg-1. After 24 hours of PTZ application, all rats brain tissues were removed and then cortex and hippocampus were separated. While PTZ increased the hippocampus and cortex NO/cGMP levels compared to control (p <0.01), VPA decreased the hippocampusand cortex NO levels by comparison with PTZ (p <0.001). On the other hand, while VPA decreased cortex cGMP levels (p<0,05) it did not change cGMP levels in hippocampus (p> 0.05). This study has suggested that VPA can show antiepileptic activity via NO/cGMP pathway.

Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study

PurposeIt remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease. In this study we addressed the question of neuronal loss from intermittent seizures using kindled rats (no initial injury) and rats with limbic epilepsy (initial injury). MethodsSupragranular mossy fiber sprouting, hippocampal neuronal densities, and subfield area measurements were determined in rats with chronic limbic epilepsy (CLE) that developed following an episode of limbic status epilepticus (n = 25), in kindled rats (n = 15), and in age matched controls (n = 20). To determine whether age or seizure frequency played a role in the changes, CLE and kindled rats were further classified by seizure frequency (low/high) and the duration of the seizure disorder (young/old). ResultsOverall there was no evidence for progressive neuronal loss from recurrent seizures. Compared with control and kindled rats, CLE animals showed increased mossy fiber sprouting, decreased neuronal numbers in multiple regions and regional atrophy. In CLE, but not kindled rats: 1) Higher seizure frequency was associated with greater mossy fiber sprouting and granule cell dispersion; and 2) greater age with seizures was associated with decreased hilar densities, and increased hilar areas. There was no evidence for progressive neuronal loss, even with more than 1000 seizures. ConclusionThese findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear.

Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders.

SummaryObjectiveThe true prevalence of epileptic seizures and epilepsy in 22q11.2 deletion syndrome (22q11.2DS) is unknown, because previous studies have relied on historical medical record review. Associations of epilepsy with other neurodevelopmental manifestations (eg, specific psychiatric diagnoses) remain unexplored.MethodsThe primary caregivers of 108 deletion carriers (mean age 13.6 years) and 60 control siblings (mean age 13.1 years) completed a validated epilepsy screening questionnaire. A subsample (n = 44) underwent a second assessment with interview, prolonged electroencephalography (EEG), and medical record and epileptologist review. Intelligence quotient (IQ), psychopathology, and other neurodevelopmental problems were examined using neurocognitive assessment and questionnaire/interview.ResultsEleven percent (12/108) of deletion carriers had an epilepsy diagnosis (controls 0%, P = 0.004). Fifty‐seven of the remaining 96 deletion carriers (59.4%) had seizures or seizurelike symptoms (controls 13.3%, 8/60, P < 0.001). A febrile seizure was reported for 24.1% (26/107) of cases (controls 0%, P < 0.001). One deletion carrier with a clinical history of epilepsy was diagnosed with an additional type of unprovoked seizure during the second assessment. One deletion carrier was newly diagnosed with epilepsy, and two more with possible nonmotor absence seizures. A positive screen on the epilepsy questionnaire was more likely in deletion carriers with lower performance IQ (odds ratio [OR] 0.96, P = 0.018), attention‐deficit/hyperactivity disorder (ADHD) (OR 3.28, P = 0.021), autism symptoms (OR 3.86, P = 0.004), and indicative motor coordination disorder (OR 4.56, P = 0.021).SignificanceEven when accounting for deletion carriers diagnosed with epilepsy, reports of seizures and seizurelike symptoms are common. These may be “true” epileptic seizures in some cases, which are not recognized during routine clinical care. Febrile seizures were far more common in deletion carriers compared to known population risk. A propensity for seizures in 22q11.2DS was associated with cognitive impairment, psychopathology, and motor coordination problems. Future research is required to determine whether this reflects common neurobiologic risk pathways or is a consequence of recurrent seizures.

Termination of pregnancy in women with epilepsy — A retrospective single center study

Antiepileptic drugs (AEDs) are commonly prescribed to women of childbearing age. As 0.3%–0.7% of all pregnancies occur in women with epilepsy (WWE), the effect of recurrent seizures and teratogenicity on pregnancy outcome and the fetus have been widely studied. Most of these studies have focused on live births. A significant number of terminated pregnancies in WWE were ignored in past studies, thus reducing the calculated incidence of congenital malformations and possible influence of AED exposure. We scrutinized the medical records at our medical center for termination of pregnancy (TOP) in WWE for the years 2004–2016. Fifty-eight TOPs occurred in WWE during these years. Reasons for TOP included spontaneous abortions necessitating medical intervention (46.6%), patient's request (31.0%), medically recommended (10.3%), and unknown (12.1%).

The effect of recurrent seizures on cognitive, behavioral, and quality-of-life outcomes after 12 months of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy.

The purpose of this study was to determine whether seizure recurrence has a negative impact on cognition, psychological function, and health-related quality of life (HRQoL) over a 12-month period of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy. Seizure freedom (SF) was defined as no seizure recurrence during the 40-week maintenance period of medication. Neuropsychological tests, the Symptom Checklist-90 (SCL-90), and the Quality of Life in Epilepsy-31 (QOLIE-31) were administered at baseline and after 48 weeks of carbamazepine or lamotrigine monotherapy. Seventy-three patients successfully continued treatment until the 48-week follow-up time point. Fifty patients (68.5%) had SF, and the remaining 23 were not seizure-free (NSF). A seizure outcome group-by-time interaction was analyzed using a linear mixed model. A group-by-time interaction was identified for the total QOLIE-31 score (p<0.05) and score on two QOLIE-31 subscales (social function: p<0.001 and seizure worry: p<0.001), with a significant improvement over time only present in the SF group (all p<0.001). There was no significant group-by-time interaction for most cognitive function tests, with the exception of the serial clustering score (p<0.01) and number of recognition hits on the California Verbal Learning Test (p<0.05). Serial clustering did not differ between the SF and NSF groups at baseline, but was significantly more used in the NSF group than in the SF group at 48 weeks (p<0.01). There was no significant group-by-time interaction for any dimension of the SCL-90. Recurrent seizures had a significant effect on HRQoL, a subtle effect on cognitive performance, and no effect on psychological symptoms over one year in newly diagnosed or previously untreated adults with partial epilepsy.

Alternative Therapies for Epilepsyedited by DevinskyOrrin, SchachterSteven C.and PaciaSteven B., 232pp., Demos Medical, 2012, $49

edited by Orrin Devinsky, Steven C. Schachter, and Steven B. Pacia, 232pp., Demos Medical, 2012, $49 The treatment of epilepsy is complex and may entail more than prescribing antiepileptic drugs. It is estimated that one-third of people with epilepsy (PWE) continue to have seizures despite treatment with conventional antiepileptic drugs. Given the consequences of recurrent seizures, it is easy to understand why PWE seek other treatment options. In Alternative Therapies for Epilepsy , Devinsky et al. aim to provide an evidence-based resource regarding the use of complementary and alternative medicine (CAM) in epilepsy. In addition to discussing more accepted alternative treatments such as the ketogenic and modified Atkins diets, Devinsky et al. review the potential antiepileptic properties of everything from herbal remedies (ranging from traditional Chinese medicine to Ayurveda) to transcranial magnetic stimulation. Equally important, the review provides clinicians, nurses, patients, and their families with information on how such therapies may interact (both positively and negatively) with existing conventional treatments for epilepsy.

The Neuropsychological and Academic Substrate of New/Recent-Onset Epilepsies

To characterize neuropsychological and academic status in children, ages 8-18 years, with new-/recent-onset idiopathic generalized epilepsy (IGE) and idiopathic localization-related epilepsy (ILRE) compared with healthy controls. Participants underwent neuropsychological assessment, and parents were interviewed regarding their child's academic history. Cognitive scores for children with epilepsy were age- and sex-adjusted and compared with controls across both broad-band (IGE n = 41 and ILRE n = 53) and narrow-band (childhood/juvenile absence, juvenile myoclonic, benign epilepsy with centro-temporal spikes, and focal [temporal/frontal/not otherwise specified]) syndromes. Academic histories were examined, including problems antecedent to epilepsy onset and diagnosis. Children with new/recent-onset epilepsies exhibit considerable cognitive abnormality at baseline, including patterns of shared abnormalities across syndromes (eg, psychomotor slowing) as well as unique syndrome-specific cognitive effects (eg, executive function in IGE and language/verbal memory in ILRE) that are observed and sometimes exacerbated in specific IGE and ILRE syndromes. Academic difficulties are evident in approximately 50% of the children with epilepsy, affecting all syndrome groups to an equal degree. Patterns of shared and syndrome-specific cognitive abnormalities and academic problems are present early in the course of virtually all epilepsy syndromes examined here, including syndromes classically viewed as benign. This is the base upon which the effects of recurrent seizures, treatment, and psychosocial effects will be added over time.

Hormonal Consequences of Epilepsy

Epilepsy is a common disorder in childhood. The effects of recurrent seizures and the use of antiepileptic drugs (AEDs) during childhood and adolescence on reproductive endocrine health are poorly defined. We review effects of hormones on epilepsy and vice versa along with the effects of treatment (AEDs) on hormones in children.

Mechanisms of drug resistance

ABSTRACT Despite the use of new antiepileptic drugs, approximately one third of patients with epilepsy have seizures that cannot be controlled satisfactorily by medical treatment. Drug resistance may exist at the time of the first seizure or may develop later as result of the disease process. The mechanisms of these different scenarios are likely to be multifactorial, and may include alterations in brain uptake or brain targets of antiepileptic drugs. Such alterations may be constitutive (intrinsic), thus underlying de novo drug resistance in epilepsy, or induced, e.g ., as a consequence of recurrent seizures or disease progression. Alterations in drug efflux (“multidrug”) transporters and drug targets, such as voltage‐gated sodium channels, have been found in epileptogenic brain tissue from both patients with epilepsy, and rodent models of epilepsy. However, although the multidrug transporter and target hypotheses are biologically plausible, proof‐of‐principle is lacking for these hypotheses. An advantage of the multidrug transporter hypothesis is that it can be validated both experimentally and clinically by combining antiepileptic drugs with inhibitors of such transporters. Selective inhibitors of the major efflux transporter P‐glycoprotein are currently in clinical trials for reversing chemotherapy resistance in oncology and may soon be used to determine whether such inhibitors can prevent or reverse drug resistance in epilepsy.

Neuropsychiatric and Memory Issues in Epilepsy

Epilepsy is an extremely complex disorder characterized by marked variability in clinical presentation, etiology, diagnostic certainty, and therapeutic options. Neuropsychiatric and cognitive concomitant disorders are equally diverse and complex. Depression and anxiety, for example, may be preexisting conditions, occur only in peri-ictal or ictal states, or persist as constant interictal phenomena; both place additional burden on memory functions, which are further taxed by the effects of recurrent seizures, temporal lobe insult, and antiseizure medications. Such factors present considerable clinical challenges, particularly in outpatient settings. This article provides an overview of major psychiatric features of epilepsy and of issues regarding the nature of memory deficits in this neurologic population. The importance of identifying and treating potentially reversible causes of memory impairment and related forms of cognitive impairment is emphasized.

Magnetic Resonance Imaging of Familial Temporal Lobe Epilepsy.

Magnetic Resonance Imaging Evidence of Hippocampal Sclerosis in Asymptomatic, First-Degree Relatives of Patients with Familial Mesial Temporal Lobe Epilepsy Kobayashi E, Li LM, Lopes-Cendes I, Cendes F Arch Neurol 2002;59:1891–1894 Purpose To investigate the presence of hippocampal atrophy (HA) and other magnetic resonance imaging (MRI) signs of hippocampal sclerosis (HS) in asymptomatic relatives of patients with familial mesial temporal lobe epilepsy (FMTLE). Methods We invited first-degree, asymptomatic relatives of patients with FMTLE to participate in our MRI protocol. After informed consent, all participating individuals underwent an MRI examination. Hippocampal abnormality was determined by qualitative and volumetric analyses, using a standard protocol. Results We studied 52 asymptomatic individuals (27 men), with a mean age of 32 years (range, 7–71 years), from 11 families with FMTLE. Volumetric studies showed HA in 18 (34%) of 52 individuals: 11 had left HA, and seven had bilateral HA. In addition, careful visual analysis of T1- and T2-weighted images showed additional classic MRI signs of HS (such as abnormal T2 signal and/or abnormal internal structure) in 14 of these 18 individuals. There was no age difference between individuals with and without HA ( t test, P = 0.80). Conclusions Our findings indicate that MRI evidence of HS is not necessarily related to seizure severity and may occur in individuals who never had seizures. In addition, these observations strongly indicate that HS in FMTLE is not a consequence of recurrent seizures and is determined by a strong genetic predisposition. The determination of seizure severity in patients with FMTLE probably depends on the interaction of different factors, both genetic and environmental.

Refractory epilepsy: a progressive, intractable but preventable condition?

Intractable seizures are just one manifestation of ‘refractory epilepsy’, which can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behaviour and a restricted lifestyle. The biological basis of ‘refractoriness’ is likely to be multifactorial, and may include the severity of the syndrome and/or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Some of these deleterious changes may be a consequence of recurrent seizures. We hypothesize that ‘refractory epilepsy’ may be prevented by interrupting this self-perpetuating progression. There is increasing evidence that these patients can be identified early in the clinical course and, thus, be targeted early for effective therapeutic intervention. Failure of two first-line AEDs due to lack of efficacy or poor tolerability should prompt consideration of epilepsy surgery in a patient with a resectable brain abnormality. For the majority not suitable for ‘curative’ surgery, AEDs should be combined with the aim of achieving ‘synergism’. This strategy has the potential to improve outcome by preventing the insidious progression to intractable ‘refractoriness’ and a downward spiralling quality of life.

Evidence against permanent neurologic damage from nonconvulsive status epilepticus.

Nonconvulsive status epilepticus (NCSE) is much more common than is generally appreciated and is certainly underdiagnosed, but its long-term effects are largely undetermined and remain controversial. There is increasing experimental evidence that generalized convulsive status epilepticus produces lasting neuropathologic damage in the hippocampus, but experimental models often include provocation of status epilepticus (SE) by physical (e.g., electrical stimulation) and chemical (including excitotoxic) agents that may induce damage independent of the epileptiform discharges. Also, damage appears to be related to the intensity and duration of electrical stimulation. Such models usually include high-frequency discharges sustained over long periods, somewhat different from the electrical activity of typical human NCSE. Pathologic studies in humans pertain primarily to patients who have had generalized convulsive status epilepticus. Clinical studies of the effects of NCSE are mandatory, but conclusions are difficult to come by, in part because of diverse definitions of NCSE. An altered mental status is obligatory, but the pertinent EEG and medication response criteria are controversial. Response to medication can be delayed by many hours or even days. Absence SE appears to cause no lasting effects. Complex partial SE is less uniform. Most reported cases have returned to baseline neurologic function, but several well-described patients have had prolonged memory deficits. The significance of other deficits is difficult to interpret in light of concomitant vascular and other diseases causing neurologic dysfunction. Clinical series usually lack premorbid neurologic and neuropsychologic assessment. The few exceptions are complicated by preexisting mental retardation and other deficits, by the coexistence of progressive illness, by the later effects of recurrent seizures, and almost always by the confounding influence of anticonvulsant medications. Most morbidity appears attributable to the underlying illnesses rather than to the NCSE itself. It is possible that relatively infrequent cases of prolonged NCSE or those with the synergistic effect of concomitant systemic illness, focal lesions, or very rapid excitatory epileptiform discharges may suffer more long-lasting damage, but these observations are still preliminary. NCSE should be treated expeditiously because of the acute neurologic impairment of the patients, because of the attendant morbidity including physical injury, and because it may go on to generalized convulsions. There is reasonable concern about possible long-term effects, but permanent neurologic damage from NCSE has not yet been established as a mandate for urgent treatment.

Mossy fiber sprouting after recurrent seizures during early development in rats.

In some children, epilepsy is a catastrophic condition, leading to significant intellectual and behavioral impairment, but little is known about the consequences of recurrent seizures during development. In the present study, we evaluated the effects of 15 daily pentylenetetrazol-induced convulsions in immature rats beginning at postnatal day (P) 1, 10, or 60. In addition, we subjected another group of P10 rats to twice daily seizures for 15 days. Both supragranular and terminal sprouting in the CA3 hippocampal subfield was assessed in Timm-stained sections by using a rating scale and density measurements. Prominent sprouting was seen in the CA3 stratum pyramidale layer in all rats having 15 daily seizures, regardless of the age when seizures began. Based on Timm staining in control P10, P20, and P30 rats, the terminal sprouting in CA3 appears to be new growth of axons and synapses as opposed to a failure of normal regression of synapses. In addition to CA3 terminal sprouting, rats having twice daily seizures had sprouting noted in the dentate supragranular layer, predominately in the inferior blade of the dentate, and had a decreased seizure threshold when compared with controls. Cell counting of dentate granule cells, CA3, CA1, and hilar neurons, with unbiased stereological methods demonstrated no differences from controls in rats with daily seizures beginning at P1 or P10, whereas adult rats with daily seizures had a significant decrease in CA1 neurons. Rats that received twice daily seizures on P10-P25 had an increase in dentate granule cells. This study demonstrates that, like the mature brain, immature animals have neuronal reorganization after recurrent seizures, with mossy fiber sprouting in both the CA3 subfield and supragranular region. In the immature brain, repetitive seizures also result in granule cell neurogenesis without loss of principal neurons. Although the relationship between these morphological changes after seizures during development and subsequent cognitive impairment is not yet clear, our findings indicate that during development recurrent seizures can result in significant alterations in cell number and axonal growth.

Nonfebrile seizures.

Nonfebrile seizures.

Recurrent seizures in immature rats: effect on auditory and visual discrimination

The effect of recurrent seizures in developing rats on subsequent long-term behavior was studied. Fifteen day old rats received a convulsant dosage of flurothyl three times daily for five consecutive days. When the rats were fully mature, they underwent behavioral testing using the water maze and auditory quality or location discrimination. With serial flurothyl administration seizure duration increased progressively but latency to seizure onset did not change. Compared to controls, flurothyl-treated rats had impaired performance in the water maze and on auditory location, but not on quality discrimination. Histological examination showed no gross cell loss in the hippocampus. This study demonstrates that serial seizures in the developing brain cause detrimental effects on visual and auditory spatial learning.

Prevention as it pertains to epilepsy.

Prevention may be practiced at various levels in the hierarchy of epilepsy; at the level of epilepsy itself (epileptogenesis), the individual epileptic seizures (ictogenesis), or in the avoidance of the consequences of the epilepsies or their component seizures. Moreover, it also applies in the arena of psychosocial predicaments, the neurologic or other injurious side effects of recurrent seizures, and the unwanted side effects of drug therapy or surgery employed in management, where attention to the risk/benefit analysis of the treatment employed may greatly influence outcome not only of life itself but also its quality.

Morphometric effects of intermittent kindled seizures and limbic status epilepticus in the dentate gyrus of the rat

The effect of recurrent seizures on the hippocampus has been controversial for many years. To determine the effect different seizure paradigms had on the structure of the dentate gyrus, we conducted histological studies on the dentate gyrus (DG) from three groups of rats: (1) those that had experienced 1500 intermittent kindled seizures; (2) those that had experienced a single episode of limbic status epilepticus (SE); and (3) control rats that had been implanted with electrodes. When compared to controls the DG of SE rats was overall slightly, but non-significantly, smaller, but the DG of rats with 1500 kindled seizures was significantly larger. The decrease of size following SE was attributable to a significant atrophy of the molecular layer. The increase in area associated with kindling was the result of an enlargement of the molecular layer and the hilus. Absolute neuronal counts showed a decrease in the hilus after SE but no change following kindling, but both groups had decreased neuronal densities in the hilus when compared to controls. The decreased density after SE was secondary to neuronal loss, but the decrease in neuronal density following kindling was the result of the expansion of the hilar neuropil without change in the number of neurons. This study extends our previous findings in Ammon's horn and indicates that SE induces significant neuronal loss, but numerous intermittent kindled seizures have no effect on neuronal numbers in the DG.