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Some Forms of Epilepsy Could Be Autoimmune in Nature, Suggests Study Linking Parasitic Infection and Nodding Syndrome

Epilepsy Research - Fri, 02/17/2017 - 04:15

Some forms of epilepsy such as nodding syndrome, could be autoimmune in nature according to a study published in the journal Science Translational Medicine.

“The findings … suggest that therapies targeting the immune system may be effective treatments against this disorder and possibly other forms of epilepsy,” said the senior author of the study Dr Avindra Nath who is also the clinical director of the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), in a press release.

Nodding syndrome is a form of childhood epilepsy seen in certain areas of East Africa. It is characterised by head nodding, seizures, severe impairment in thinking ability and restricted growth.

The cause of the condition remained a mystery until now. The present study suggests that the condition might be caused by an immune response triggered by a parasitic worm called Onchocerca volvulus, which then attacks the body’s own nervous system.

For the study, Dr Nath and colleagues compared blood samples from children with nodding syndrome and children without, who all lived in the same village in Uganda. They found antibodies in the blood of children with nodding syndrome, which recognised proteins from the parasitic worm as well as a protein called leiomodin-1. Leiomodin-1 antibodies were also present in the fluid covering the brain and the spinal chord of the children with nodding syndrome.

Leiomodin-1 is highly expressed in human nerve cells grown in the laboratory and is also found in certain areas of the mouse brain. These areas of the brains are the counterparts of the areas in the children’s brain that were affected by nodding syndrome.

When the researchers treated normal nerve cells grown in the laboratory with serum from nodding syndrome patients, they saw that the nerve cells died suggesting that the serum of the children contains a factor that was toxic for nerve cells. In order to test whether this factor could be leiomodin-1 antibodies, the researchers treated the nerve cells with the antibody directly and obtained the same results: the nerve cells died. And when they treated the nerve cells with serum from which the leiomodin-1 antibodies had been removed, the nerve cells survived

The researchers concluded that nodding syndrome may be an auto-immune epileptic disorders triggered by infection with a parasitic worm. The antibodies that the body produces to fight off the parasite wrongly recognise a protein found in the nerve cells and attacks them.

According to the authors, more research is needed to better understand the role of leiomodin-1 in healthy people and people with epilepsy.

Author: Dr Özge Özkaya

What is Nodding Syndrome?  This information is from the WHO website
Nodding syndrome (NS) is a neurological condition with unknown etiology. It was first documented in the United Republic of Tanzania (URT) in the 1960s, then later in the Republic of South Sudan in the 1990s and in northern Uganda in 2007. Typically, NS affects children between the ages of 5 and 15 years old, causing progressive cognitive dysfunction, neurological deterioration, stunted growth and a characteristic nodding of the head. Despite numerous and extensive investigations in all three countries, very little is known about the cause of the disease.

To date, Nodding Syndrome is known to occur in the southern region of the United Republic of Tanzania (URT) (Mahenge mountains, Ulanga District), South Sudan (Western Equatoria State, Eastern Equatoria State, Central Equatoria State, and Lakes State) and northern Uganda (Pader, Kitgum and Lamwo districts, with new cases starting to present in Gulu, Amuru, Oyam and Lira districts).

Jilek et al (1962) first described several children with attacks of “head nodding” in Mahenge, a region in URT. The current burden of NS in URT is unknown but observations during case control studies in 2005 and 2009 in the Mahenge region do not suggest a notable increase in the number of cases relative to those detected in the late 1950s and early 1960s.

Samaritan Purse, a local NGO, described observations of head nodding among several children in southern Sudan in the Lui and Amadi villages of East Mundri County in the mid-1990s. A physician from Samaritan Purse reported the outbreak to WHO in 1997. The 2001-2002 investigations by WHO and partners estimated the prevalence of NS at 4.6% among a small population in Western Equatoria State, which appeared to have the highest burden of the illness. By 2003, an estimated 300 cases had been reported from this region. The Ministry of Health of South Sudan estimates the current burden of NS at between six and seven thousand cases, but no systematic large-scale prevalence study has been conducted. The Mundri region in the northeast of Western Equatoria is the presumed epicentre for the disease.

In 2008 and 2009, an illness consistent with NS was reported from Kitgum and Pader Districts in northern Uganda. As of February 2012, Uganda has reported over 3 000 cases of NS from the three districts of Kitgum, Lamwo and Pader. A community survey is underway in Uganda to determine the real burden of NS in the affected districts. Kaiser et al (2009) referred to a phenomenon of head nodding observed in the Kabarole District in Western Uganda as possibly constituting a feature of an epileptic syndrome caused by Onchocerca volvulus (O. volvulus).

The prevalence of both onchocerciasis and epilepsy in the areas affected by NS is high. The affected populations are impoverished and experience regular and prolonged periods of severe food shortages. In South Sudan and in northern Uganda, affected populations have a history of internal displacement and living in internally displaced persons (IDPs) camps.

Familial clustering has been observed in some families with NS patients, with more than one sibling with NS and/or siblings or relatives with other forms of epilepsy.

The age of onset in the vast majority of cases ranges between 5 and 15 years old, but cases have been reported in children as young as 2 years old and in adults up to 32 years old. There is no observed significant difference in the proportion of males to females among the affected, nor is there an observed seasonal variation.

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International study suggests Nodding syndrome caused by response to parasitic protein

Medical News Today - Fri, 02/17/2017 - 03:00
Researchers at the National Institutes of Health have uncovered new clues to the link between Nodding syndrome, a devastating form of pediatric epilepsy found in specific areas of east Africa, and...
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Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: Evidence for differential vulnerability of interneurons

Epilepsia - Thu, 02/16/2017 - 06:55
Summary Objective

Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b).

Methods

Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region.

Results

We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b.

Significance

The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic laminar arrangement are maintained despite the severe disturbance of cytoarchitecture. Moreover, it showed that Parvalbumin-positive, inhibitory interneurons are highly vulnerable in contrast to other interneuron subtypes, possibly related to the epileptic condition.

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Sub-type of Brain Cell Linked to Brains Tumours and Epilepsy

Epilepsy Research - Thu, 02/16/2017 - 05:33

The formation of a specific type of brain cell during the progression of brain tumours is also linked to the development of epileptic seizures, according to a study conducted on mice and published in the leading scientific journal Nature Neuroscience.  This knowledge can help scientists better understand how brain tumours cause epilepsy and potentially help them develop new approaches that can prevent or even treat the condition.

“We do not understand exactly how malignant cells cause seizures, or why seizures persist after tumor surgery,” said one of the senior authors of the study, Dr Jeffrey Noebels, professor of neurology, neuroscience, and molecular and human genetics at Baylor College of Medicine in Texas, in a press release.

Dr Noebels and colleagues were studying normal brain cells and in particular a type of brain cell called astrocytes. These are start-shaped cells that fulfil a broad range of roles including biochemically supporting other cell types in the brain cells, providing nutrients to the brain, and repairing the nervous tissue following injury. They are also crucial for the formation of synapses or connections between neurons.

Astrocytes are often considered to be just one type of cell, but researchers identified five distinct sub-types of astrocytes based on the molecules found on their surface. They thought that the different sub-types may be responsible of fulfilling different roles in the brain.

They then looked at the brain of a mouse model of glioma, or brain cancer. They saw that as the tumor grew, neighbouring cells became more excitable, and eventually the mice started to have seizures. This correlated with the emergence of one of the five sub-populations of astrocytes. Strikingly, this sub-population expressed a significant number of genes linked to epilepsy.

Dr Benjamin Deneen, associate professor at Baylor explained: “[A]s the tumor evolves, different subpopulations of astrocyte-like cells develop within the tumor and execute distinct functions that are related to two important tumor characteristics, synaptic imbalance that can lead to seizures, and tumor migration that can lead to tumor invasion of other tissues”.

Dr Noebels added he is excited that for the first time, it is possible to study the earliest effects of tumours on the brain before seizures even start. “These studies would be a major advance in patient care, allowing clinicians to bypass precious months spent searching for effective therapy to stop seizures. Because seizures themselves damage brain tissue, timely effective therapy is of the essence,” he concluded.

Author: Dr Özge Özkaya

What is an Astrocyte
The video below from the Khan Academy gives a good and accessible overview of astrocytes.

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Nodding syndrome caused by response to parasitic protein, international study suggests

Science Daily - Wed, 02/15/2017 - 14:59
New clues to the link between Nodding syndrome, a devastating form of pediatric epilepsy found in specific areas of east Africa, and a parasitic worm that can cause river blindness have now been uncovered by researchers. The study suggests that the mysterious neurological disease may be caused by an autoimmune response to the parasitic proteins.
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Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells

Epilepsia - Wed, 02/15/2017 - 11:05
Summary Objective

Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples.

Methods

PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues (EPI-ECs; n = 8), commercially available human brain microvascular endothelial cells (HBMECs; n = 8), and human hepatocytes (n = 3). PXR/GR messenger RNA (mRNA) levels in brain ECs was initially determined by complementary DNA (cDNA) microarrays. The expression of PXR/GR proteins was quantified by Western blot. PXR and GR silencing was performed in EPI-ECs (n = 4), and the impact on downstream CYP expression was determined.

Results

PXR/GR expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated mRNA and protein levels of PXR and GR were found in EPI-ECs versus control HBMECs. Hepatocytes, used as a positive control, displayed the highest levels of PXR/GR expression. We confirmed expression of PXR/GR in cytoplasmic-nuclear subcellular fractions, with a significant increase of PXR/GR in EPI-ECs versus controls. CYP3A4, CYP2C9, and CYP2E1 were overexpressed in EPI-ECs versus control, whereas CYP2D6 and CYP2C19 were downregulated or absent in EPI-ECs. GR silencing in EPI-ECs led to decreased CYP3A4, CYP2C9, and PXR expression. PXR silencing in EPI-ECs resulted in the specific downregulation of CYP3A4 expression.

Significance

Our results indicate increased PXR and GR in primary ECs derived from human epileptic brains. PXR or GR may be responsible for a local drug brain metabolism sustained by abnormal CYP regulation.

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Validating the shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy

Epilepsia - Wed, 02/15/2017 - 11:05
Summary Objective

The aim of this study was to validate the newly developed shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy.

Methods

Data came from 136 children enrolled in the Impact of Pediatric Epilepsy Surgery on Health-Related Quality of Life Study (PEPSQOL), a multicenter prospective cohort study. Confirmatory factor analysis was used to assess the higher-order factor structure of the QOLCE-55. Convergent and divergent validity was assessed by correlating subscales of the KIDSCREEN-27 with the QOLCE-55. Measurement equivalence of the QOLCE-55 was evaluated using multiple-group confirmatory factor analysis of children with drug-resistant epilepsy from PEPSQOL versus children with new-onset epilepsy from HERQULES (Health-Related Quality of Life in Children with Epilepsy Study).

Results

The higher-order factor structure of the QOLCE-55 demonstrated adequate fit: Comparative Fit Index (CFI) = 0.948; Tucker-Lewis Index (TLI) = 0.946; Root Mean Square of Approximation (RMSEA) = 0.060 (90% confidence interval [CI] 0.054–0.065); Weighted Root Mean Square Residuals (WRMR) = 1.247. Higher-order factor loadings were strong, ranging from λ = 0.74 to 0.81. Internal consistency reliability was excellent (α = 0.97, subscales α > 0.82). QOLCE-55 subscales demonstrated moderate to strong correlations with similar subscales of the KIDSCREEN-27 (ρ = 0.43–0.75) and weak to moderate correlations with dissimilar subscales (ρ = 0.25–0.42). The QOLCE-55 demonstrated partial measurement equivalence at the level of strict invariance – χ2 (2,823) = 3,727.9, CFI = 0.961, TLI = 0.962, RMSEA = 0.049 (0.044, 0.053), WRMR = 1.834.

Significance

The findings provide support for the factor structure of the QOLCE-55 and contribute to its robust psychometric profile as a reliable and valid measure. Researchers and health practitioners should consider the QOLCE-55 as a viable option for reducing respondent burden when assessing health-related quality of life in children with epilepsy.

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Accuracy of claims-based algorithms for epilepsy research: Revealing the unseen performance of claims-based studies

Epilepsia - Wed, 02/15/2017 - 11:05
Summary Objective

To evaluate published algorithms for the identification of epilepsy cases in medical claims data using a unique linked dataset with both clinical and claims data.

Methods

Using data from a large, regional health delivery system, we identified all patients contributing biologic samples to the health system's Biobank (n = 36K). We identified all subjects with at least one diagnosis potentially consistent with epilepsy, for example, epilepsy, convulsions, syncope, or collapse, between 2014 and 2015, or who were seen at the epilepsy clinic (n = 1,217), plus a random sample of subjects with neither claims nor clinic visits (n = 435); we then performed a medical chart review in a random subsample of 1,377 to assess the epilepsy diagnosis status. Using the chart review as the reference standard, we evaluated the test characteristics of six published algorithms.

Results

The best-performing algorithm used diagnostic and prescription drug data (sensitivity = 70%, 95% confidence interval [CI] 66–73%; specificity = 77%, 95% CI 73–81%; and area under the curve [AUC] = 0.73, 95%CI 0.71–0.76) when applied to patients age 18 years or older. Restricting the sample to adults aged 18–64 years resulted in a mild improvement in accuracy (AUC = 0.75,95%CI 0.73–0.78). Adding information about current antiepileptic drug use to the algorithm increased test performance (AUC = 0.78, 95%CI 0.76–0.80). Other algorithms varied in their included data types and performed worse.

Significance

Current approaches for identifying patients with epilepsy in insurance claims have important limitations when applied to the general population. Approaches incorporating a range of information, for example, diagnoses, treatments, and site of care/specialty of physician, improve the performance of identification and could be useful in epilepsy studies using large datasets.

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Potential New Target to Treat Epilepsy Identified

Epilepsy Research - Wed, 02/15/2017 - 07:47

A new study published in the leading scientific journal PNAS may shed light onto why people with the same type of epilepsy-causing mutation may have symptoms that vary so dramatically in severity.

Previous research has shown that mutations in a gene called SCN2A, which encodes for sodium channels found on the surface of cells, are the most common cause of genetic epilepsy. However people with the same mutation in the SCN2A gene may experience seizures of very different severity and frequency.

Researchers think that this might be due to the effect of other genes known as genetic modifiers, which may be different between people.

In the present study, a team led by Dr Alfred George Jr. at Northwest University in Chicago studied the variability in seizure severity using a mouse model of epilepsy. They compared mice that had different degrees of epilepsy severity even though they had the same mutation in the SCN2a gene. Importantly, the animals came from different laboratory strains and had different genetic backgrounds.

When they analysed the properties of the animals’ brain cells, the researchers found that the brain cells of the animals more severely affected by epilepsy were more excitable than those of animals less severely affected.

On further analysis, the researchers uncovered that sodium channels on the surface of these cells were behaving differently in more and less severely affected animals. This different “behaviour” was modulated by an enzyme called calcium/calmodulin protein kinase II (CaMKII).

When they blocked the activity of the CaMKII enzyme, the researchers saw that the hyper excitability of the nerve cells was suppressed.

They concluded that blocking CamKII activity could constitute a new approach to treat epilepsy.

In a press release, Dr George said: “Not only did the findings explain the varying severity of epilepsy, but they also revealed a previously under appreciated pathway by which brain sodium channels are regulated — something that could be exploited for therapy.”

The researchers are now working on finding out whether this result can be generalised to mutations on other genes and models of epilepsy.

Author: Dr Özge Özkaya

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Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma

Epilepsia - Mon, 02/13/2017 - 05:10
Summary

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+-permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+-permeable AMPA receptors due to dislocation of ADAR2.

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Reduced local input to fast-spiking interneurons in the somatosensory cortex in the GABAA γ2 R43Q mouse model of absence epilepsy

Epilepsia - Mon, 02/13/2017 - 05:05
Summary Objective

Absence seizures in childhood absence epilepsy are initiated in the thalamocortical (TC) system. We investigated if these seizures result from altered development of the TC system before the appearance of seizures in mice containing a point mutation in γ-aminobutyric acid A (GABAA) receptor γ2 subunits linked to childhood absence epilepsy (R43Q). Findings from conditional mutant mice indicate that expression of normal γ2 subunits during preseizure ages protect from later seizures. This indicates that altered development in the presence of the R43Q mutation is a key contributor to the R43Q phenotype. We sought to identify the cellular processes affected by the R43Q mutation during these preseizure ages.

Methods

We examined landmarks of synaptic development at the end of the critical period for somatosensory TC plasticity using electrophysiologic recordings in TC brain slices from wild-type mice and R43Q mice.

Results

We found that the level of TC connectivity to layer 4 (L4) principal cells and the properties of TC synapses were unaltered in R43Q mice. Furthermore, we show that, although TC feedforward inhibition and the total level of GABAergic inhibition were normal, there was a reduction in the local connectivity to cortical interneurons. This reduction leads to altered inhibition during bursts of cortical activity.

Significance

This altered inhibition demonstrates that alterations in cortical circuitry precede the onset of seizures by more than a week.

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Erratum

Epilepsia - Mon, 02/13/2017 - 04:50
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Epilepsy drug discovered in fish model shows promise in small pediatric clinical trial

Medical News Today - Mon, 02/13/2017 - 03:00
"Bench-to-bedside" describes research that has progressed from basic science in animal models that has led to therapies used in patients.
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Epilepsy drug discovered in fish model shows promise in small pediatric clinical trial

Science Daily - Fri, 02/10/2017 - 14:11
'Bench-to-bedside' describes research that has progressed from basic science in animal models that has led to therapies used in patients. Now, a study describes what could be considered a direct 'aquarium-to-bedside' approach, taking a drug discovered in a genetic zebrafish model of epilepsy and testing it, with promising results, in a small number of children with the disease.
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Adult motor phenotype differentiates Dravet syndrome from Lennox-Gastaut syndrome and links SCN1A to early onset parkinsonian features

Epilepsia - Fri, 02/10/2017 - 06:35
Summary

Distinguishing adult patients with Lennox-Gastaut syndrome from those with Dravet syndrome is challenging. We have previously reported that patients with Dravet syndrome present a very peculiar motor phenotype. Here we sought to confirm that this association was not linked to the chronic use of antiepileptic drugs or the many lifetime seizures. To this aim, we studied 14 adult patients with Lennox-Gastaut syndrome and 14 adults with Dravet syndrome because both conditions share similar seizure severity. We found that antecollis and parkinsonian gait were significantly more common in the Dravet group, thus suggesting that these features are part of the Dravet syndrome adult phenotype.

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Many older adults with epilepsy may not be receiving optimal care

Medical News Today - Fri, 02/10/2017 - 03:00
Many older adults with newly diagnosed epilepsy in the United States are being prescribed older anti-epileptic drugs (AEDs), and only half begin treatment with AEDs within the first 30 days of a...
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Side and Site of Brain Surgery Affects Psychological Outcome

Epilepsy Research - Wed, 02/08/2017 - 05:00

The side and site of epilepsy surgery affects its psychological outcome according to a new study published in the journal Epilepsy and Behavior.

This finding highlights the importance of considering psychological changes that may occur as a result of epilepsy surgery, on an individual patient basis.

According to the authors, further studies are needed to identify potential risk factors that may make the symptoms of surgery more severe. Further research could also help provide patients with counselling before surgery and identify those who may be most in need of psychological surveillance following surgery.

For the study, the team of researchers led by Dr Robyn Busch, a clinical psychologist at Cleveland Clinic Epilepsy Centre analysed 228 adults with epilepsy who underwent temporal lobe or frontal lobe brain surgery. The patients completed the Personality Assessment Inventory (PAI), which provides an objective assessment of adult psychological problems, both before and after surgery.

The researchers then compared the psychological outcome of the operation between people who had surgery on the left side of their brain versus those who had right-sided surgery.

They found that people with left temporal lobe epilepsy had higher PAI scores (i.e. more psychological problems) before the operation compared to those with left frontal lobe epilepsy. Following surgery, the psychological problems, which included anxiety and depression, usually improved although a small subset of patients reported that their symptoms became worse after surgery. The most frequent improvements were seen in those undergoing temporal lobe surgery.

The researchers concluded that the side and site of brain surgery in epilepsy are important factors in determining the psychological outcome of the operation in adults. They stress that it is important to identify the risk factors that may be associated with the worsening of the symptoms seen in a subset of patients after surgery.

It is estimated that 20 to 40% of people with epilepsy are diagnosed with at least one form of psychological disorder and this percentage can be as high as 70% in people with drug resistant epilepsy. Previous studies have shown that depression is more frequent in people with a seizure focus on the left side of the brain.

Author: Dr Özge Özkaya

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