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Review article
Malformations of cortical development and epilepsies:
Ingmar Blümcke, Harry V Vinters, Dawna Armstrong, Eleonora Aronica, Maria Thom, Roberto Spreafico
become a successful treatment option for many of these patients. A broad spectrum of malformations of cortical development (MCD) can be histopathologically identified in resective surgical brain samples. Here, we discuss neuropathological findings and available classification systems in children and adult patients. Particular emphasis will be paid to the classification system for focal cortical dysplasias (FCD), which can be histopathologically distinguished as type I and II. Also mild forms of cortical malformations (mMCD) may be present, including heterotopic neurons in white matter location. However, different cohorts of epilepsy patients may present with similar histopathological findings and clinico-pathological correlations are not always comparable with respect to outcome prediction. We will, therefore, discuss also the difficulties to classify some FCD variants. Notwithstanding, the underlying pathomechanisms in all FCD entities need to be specified. A comprehensive approach taking all currently available data into consideration will be mandatory to further develop our current understanding of FCDs, and to continuously improve our concept for a reliable classification system.
Imaging of malformations of cortical development
Nadia Colombo, Noriko Salamon, Charles Raybaud, Çigdem Özkara, A James Barkovich
zones, neuronal migration and cortical organization. With the improvement and increased utilization of modern imaging techniques, MCD have been increasingly recognized as a major cause of seizure disorders. The advent of Magnetic Resonance Imaging (MRI), in particular, has revolutionized the investigation and the treatment of patients with epilepsy. High-resolution MRI may elucidate the type, the extension and the localization of MCD; therefore, in a group of patients suffering from drug-resistant partial epilepsy (DRPE), MRI greatly contributes to the identification of subjects who are suitable for surgical treatment. In the recent past, many efforts were addressed to establish the MRI diagnostic criteria for a peculiar group of MCD, namely focal cortical dysplasias (FCD), histopathologically distinguished as types I and II. Some subtle FCD, which were previously cryptic to imaging investigation, can now be recognized by MRI, however their detection and specification remains challenging. This review will re-visit the neuroimaging findings, including structural MRI, PET, co-registered PET/MRI, MEG and diffusion tensor imaging (DTI) of FCD types I and II. Three major issues will be discussed: 1) the morphological MRI features of the FCDs, 2) the utility of PET and MEG and the use of co-registration methods and 3) diffusion tensor imaging (DTI) as a future modality of investigation, which may add additional informations regarding the microstructure of the grey matter (GM) and white matter (WM) in cortical dysplasia.
Basic mechanisms of MCD in animal models
Giorgio Battaglia, Albert J Becker, Joseph LoTurco, Alfonso Represa, Scott C Baraban, Steven N Roper, Annamaria Vezzani
frequently gangliogliomas. The neuropathological findings are variable but suggest aberrant proliferation, migration, and differentiation of neural precursor cells as essential pathogenetic elements. Recent advances in animal models for MCDs allow new insights in the molecular pathogenesis of these epilepsy-associated lesions. Novel approaches, presented here, comprise RNA interference strategies to generate and study experimental models of subcortical band heterotopia and study functional aspects of aberrantly shaped and positioned neurons. Exciting analyses address impaired NMDA receptor expression in FCD animal models compared to human FCDs and excitatory imbalances in MCD animal models such as lissencephaly gene ablated mice as well as in utero irradiated rats. An improved understanding of relevant pathomechanisms will advance the development of targeted treatment strategies for epilepsy-associated malformations.
Original article
Paradoxical ictal EEG lateralization in children with unilateral encephaloclastic lesions
Eliana Garzon, Ajay Gupta, William Bingaman, Americo C Sakamoto, Hans Lüders
underwent hemispherectomy during 2003-2005, scalp video-EEG and brain MRI of six children with an ictal scalp EEG pattern discordant to the clinical and imaging data were reanalyzed. Medical charts were reviewed for clinical findings and seizure outcome.ResultsAge of seizure onset was 1 day-4 years. The destructive MRI lesion was an ischemic stroke in 2, a post-infectious encephalomalacia in 2, and a perinatal trauma and hemiconvulsive-hemiplegic syndrome in one patient each. Ictal EEG pattern was characterized by prominent ictal rhythms with either 3-7 Hz spike and wave complexes or beta frequency sharp waves (paroxysmal fast) over the unaffected (contralesional) hemisphere. Scalp video-EEG was discordant, however, other findings of motor deficits (hemiparesis; five severe, one mild), seizure semiology (4/6), interictal EEG abnormalities (3/6), and unilateral burden of MRI lesion guided the decision for hemispherectomy. After 12-39 months of post-surgery follow up, five of six patients were seizure free and one has brief staring spells.ConclusionWe describe a paradoxical lateralization of the EEG to the “good” hemisphere in children with unihemispheric encephaloclastic lesions. This EEG pattern is compatible with seizure free outcome after surgery, provided other clinical findings and tests are concordant with origin from the abnormal hemisphere.
Everyday cognition in temporal lobe and frontal lobe epilepsy
Deborah A Cahn-Weiner, Dana Wittenberg, Carrie McDonald
The hypothesis was that patients with TLE would demonstrate relatively more impairment on a test of everyday memory, while patients with FLE would demonstrate relatively more impairment on a test of everyday executive function. The five Daily Living subtests of the Neuropsychological Assessment Battery (NAB) were administered to twenty-five patients with TLE and nine patients with FLE. The two groups were matched on all demographic variables. The hypothesis was not confirmed: the TLE and FLE patient groups did not demonstrate a double dissociation in memory and executive daily functioning. Rather, both groups were significantly impaired in daily memory functioning, while their executive daily functioning test scores were within normal limits. Relative deficits were also noted in attention in the TLE group and in language in the FLE group, suggesting that despite having focal lesions, functional impairments may be seen in a broad range of daily activities in these patient groups. Generalizability of the findings is limited due to the small number of subjects and because the everyday cognition measures employed may not have been adequately sensitive. Future studies are needed with larger sample sizes to provide a better understanding of how cognitive impairment in epilepsy is associated with deficits in daily functioning.
Predictors and prognosis of status epilepticus treated with intravenous sodium valproate
Somsak Tiamkao, Kittisak Sawanyawisuth
death. Methods. Patients were included with a diagnosis of SE who had received intravenous sodium valproate (VPAiv) during 2005-2007 at Srinagarind Hospital, Khon Kaen University, Thailand. Logistic regression analysis with a stepwise approach was used to evaluate the predictors of seizure control and death. Results. Thirty-two cases were diagnosed as SE with VPAiv treatment; 12 and 20 patients received VPAiv as the first- and second-line therapy, respectively. SE ceased in nine out of 12 patients (75%) and in seven out of 20 (35%) patients with VPAiv as the first- and second-line therapy, respectively. No serious cardiovascular compromise was recorded. The first-line therapy of VPAiv was the only factor that was significantly related to seizure control with an adjusted odds ratio [OR] of 5.571; 95% confidence interval [CI] of 1.128-27.523. Initial leukocytosis and hypotension were significantly associated with death (adjusted OR: 22.765, 95% CI: 1.176-440.640 and adjusted OR: 37.591, 95% CI: 3.035-465.571, respectively). Conclusion. For SE patients who received VPAiv treatment, the first-line VPAiv was effective. Initial leukocytosis and hypotension were factors that correlated with death.
Gene expression changes in an animal model of in utero irradiation-induced cortical dysplasia
Girish K Hiremath, Cristiane Q Tilelli, Yaomin Xu, Banu Gopalan, Imad M Najm
such information may help target therapeutics more effectively, our aim was to perform a gene expression analysis of an animal model of cortical dysplasia induced by in utero irradiation. Methods. Nine offspring from irradiated animals, and nine age-matched controls were sacrificed at post-natal day 60. Cortical and hippocampal regions were separated, and total ribonucleic acid (RNA) was extracted using a commercially available kit (Qiagen
<sup>®</sup>). RNA was then subjected to a gene expression analysis using an oligonucleotide microarray platform (Illumina
<sup>®</sup>). After statistical analysis, genes were considered differentially expressed when a p value less than 0.001 was observed. Real-time, quantitative polymerase chain reaction (RT-qPCR) was used to confirm microarray results for three genes via the Livak method. Results. Twenty three genes from cortical tissue met criteria for altered gene expression. Six genes from cortex seemed relevant to the pathogenesis of CD. Two genes that promoted cell survival (connective tissue growth factor and peroxiredoxin) were upregulated. One gene that promoted excitotoxic neurodegeneration (latrophilin-2) was downregulated. Two genes involved in glutamate (protein kinase C-α) and AMPA receptor recycling (NEEP-21) were downregulated. One gene, (Shank-1) involved in the control of dendritic maturation, was downregulated. Conclusion. Gene expression analysis in this animal model revealed some of the potential mechanisms by which CD may lead to the phenotype of intractable epilepsy. The downregulation of genes that are involved in glutamate and AMPA receptor recycling may lead to increased excitability. Disinhibition of aberrant dendritic branching, resulting from a downregulation of Shank-1, may also result in an increase in sprouting, excitation and/or hypersynchrony. Finally, genes promoting cell survival, either directly (connective tissue growth factor, peroxiredoxin) or indirectly (latrophilin-2) may allow CD tissue to survive the excitotoxic injury that it produces, thus allowing it to perpetuate the epileptic condition over time.
Changes in white matter microstructure in patients with TLE and hippocampal sclerosis
Susanne Knake, David H Salat, Eric Halgren, Mark A Halko, Douglas N Greve, P Ellen Grant
temporal neocortex, the ipsilateral frontal lobe or the contralateral hippocampus, although structural MRI only shows unilateral involvement of the hippocampal formation. We used whole-head diffusion Tensor Imaging (DTI) to delineate a network that facilitates propagation of interictal epileptiform and seizure activity in this patient group. Methods. Isotropic 2 mm DTI was performed at 3 Tesla in 12 patients with medically intractable left TLE due to HS and compared to 12 controls. Whole-brain maps of fractional anisotropy (FA) were compared using a voxel based t-test to search for regions affected in patients with HS. This preliminary analysis was complementary to a set of anatomically guided region of interest (ROI) analyses that were manually defined on each individual’s FA map. Results. Left HS patients showed FA decreases in the temporal lobe white matter bilaterally, the ipsilateral frontal lobe white matter (WM) and in the genu and trunk of the corpus callosum. ROI analysis identified a significant FA decrease in left HS subjects in the affected hippocampus, WM of the ipsilateral parahippocampal gyrus and the genu and trunk of the corpus callosum. Conclusion. WM alterations occur bilaterally in the temporal lobe and in the ipsilateral superior frontal gyrus in left HS. The etiology and significance of these changes are unclear but the role of these regions in epileptogenesis and for pathways of epileptic spread should be further investigated.
Anatomo-electro-clinical correlations
Functional hemispherectomy in adults with intractable epilepsy syndromes: a report of 4 cases
Bernhard J Steinhoff, Anke Maren Staack, Sofia Bilic, Uwe Kraus, Andreas Schulze-Bonhage, Josef Zentner
with catastrophic epilepsies and pre-existing severe hemiparesis. It is accepted that mainly patients at young ages with more or less complete loss of their hand function are suitable candidates for FH. However, we feel that FH should be considered also in some adults with devastating unilateral epilepsy syndromes. Patients and methods. We report four cases of adults who underwent FH because of their intractable epilepsy syndromes. Three of the four patients had reduced but not complete loss of hand function. Careful weighing-up of the risk-benefit ratio still led to the decision to perform FH in order to achieve complete seizure relief. Results. All patients had a surgical outcome of Engel class I; one of them suffered from post-operative psychogenic non-epileptic seizures which were treated successfully by psychotherapy. No clinically relevant complications occurred. Conclusion. We wish to point out that FH is a possible surgical option in cases with catastrophic epilepsies in adulthood. Patients and relatives should strongly consider that the likelihood of at least partially, impaired hand function or other surgery-related additional handicaps may be outweighed by the chance of freedom of seizures in a limited number of patients. In all of our cases, patients and relatives agreed that the surgical outcome led to a marked improvement of quality of life and that it had been the right decision to proceed with FH in spite of the expected negative impacts of the operation. Video examples of the pre- and post-surgical hand function of one sample patient are enclosed. [Published with video sequences]
Invited editorial comment
Huh? Hemispherectomy in adults?
Selim Benbadis, Fernando Vale, François Dubeau, Michael Duchowny
Clinical commentary
Complex partial status epilepticus revealing anti-NMDA receptor encephalitis
Caroline Bayreuther, Véronique Bourg, Jean Dellamonica, Michel Borg, Gilles Bernardin, Pierre Thomas
viral disease, followed by memory loss, psychiatric features, seizures, disturbed consciousness, prominent abnormal movements and autonomic imbalance. Association with ovarian teratoma is common. Neurological outcome can be good, especially when surgery is performed at an early stage. Here, we report a case of anti-NMDA receptor encephalitis associated with ovarian teratoma presenting with inaugural complex partial status epilepticus. The nature of abnormal movements at early stages was unclear and abnormal movements were misinterpreted as the recurrence of partial epileptic seizures. Despite its rarity, all clinicians treating epilepsy and movement disorders should be familiar with anti-NMDA receptor encephalitis, that appears to be a very severe but curable disease. [Published with video sequences]
Anti-NMDA receptor encephalitis: a video case report
Angelo Labate, Sarosh R Irani, Angela Vincent, Antonio Gambardella, Emilio Le Piane, Vittoria Cianci, Umberto Aguglia
and hyperkinetic movements are very commonly seen as initial symptoms of paraneoplastic encephalitis. Interestingly, our patient showed stereotypical movements predominantly located to lower limbs, mimicking a psychogenic seizure. This latter feature further extends the clinical spectrum of dyskinetic movements of anti-NMDAR encephalitis. [Published with video sequences]
Panayiotopoulos syndrome with coincidental brain lesions
A Destina Yalçın, Hülya Ertaşoğlu Toydemir, Lale Gündoğdu Çelebi, Hulki Forta
Methods. Our study was based on patients from the Epilepsy Outpatient Clinic of Şişli Etfal Education Hospital in Istanbul, where a prospective study of Panayiotopoulos syndrome was initiated in 1995. Records of our Epilepsy Outpatient Clinic revealed 53 patients with Panayiotopoulos syndrome. Among them were three with cranial lesions identified by MRI. Results. The onset of the seizures in our patients ranged between five and eight years. The seizures included mainly autonomic symptoms such as nausea, vomiting, pallor, mydriasis, urinary and fecal incontinence, and rarely hypersalivation. Autonomic partial status was detected in one patient. The personal history of our patients revealed head trauma in two and difficult birth history in one patient. Two patients described simple febrile seizures. All patients had occipital spike or spike-wave complexes in their EEGs. The background activity was normal. From the cranial MRI, one patient had a neuroepithelial cyst, the second patient had a right occipital encephalomalasic lesion and the third patient had an arachnoid cyst located in the cisterna magna associated with colpocephaly. Seizure frequency was low in general. All patients except for one received carbamazepine treatment 450-600 mg/day. None of our patients had seizures under antiepileptic treatment. Conclusions. Children with Panayiotopoulos syndrome may have static MRI brain findings which are likely to be coincidental and do not affect prognosis.
