Focal cortical dysplasia (FCD) is often characterized by minor structural changes that may go unrecognized by standard radiological analysis. Visual assessment of morphological characteristics of FCD ...and sulci harbouring them is difficult due to the complexity of brain convolutions. Our purpose was to elucidate and quantify the spatial relationship between FCD lesions and brain sulci using automated sulcal extraction and morphometry. We studied 43 consecutive FCD patients using high-resolution MRI. Lesions were classified into small and large using qualitative (detection on initial clinical assessment of conventional MRI) and quantitative (volume) criteria. Sulci were identified and labelled automatically using an algorithm based on a congregation of neural networks. Segmented FCD lesions and sulci were then simultaneously visualized in 3D. We measured mean and maximum depth of sulci related to each FCD and of the corresponding sulci in 21 healthy controls. In addition, we calculated sulcal depth within the FCD neighbourhood. Twenty-one (21/43 = 49%) patients had small FCD lesions (volume range: 128–3093 mm3). Among them, 17 (81%) had been overlooked during initial radiological evaluation and were subsequently identified using image processing. Eighteen (18/21 = 86%) small FCD lesions were located at the bottom of a sulcus. Two others were related to the walls of two sulci and one was located at the crown of a gyrus. Mean and maximum depth of sulci related to the FCD was higher than that of the corresponding sulci in controls (P < 0.008). Sulcal depth within lesional neighbourhood had larger mean depth than that of the entire sulcus (P < 0.0002). Evidence that small FCD lesions are preferentially located at the bottom of an abnormally deep sulcus may be used to direct the search for developmental abnormalities, particularly in patients in whom large-scale MRI features are only mildly abnormal or absent.
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A ...is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.
Aim
Polymicrogyria (PMG) is one of the most common forms of cortical malformation yet the mechanism of its development remains unknown. This study describes the histopathological aspects of PMG in a ...large series including a significant proportion of fetal cases.
Method
We have reviewed the neuropathology and medical records of 44 fetuses and 27 children and adults in whom the cortical architecture was focally or diffusely replaced by one or more festooning bands of neurons.
Results
The pial surface of the brain overlying the polymicrogyric cortex was abnormal in almost 90% of cases irrespective of the aetiology. This accords with animal studies indicating the importance of the leptomeninges in cortical development. The aetiology of PMG was highly heterogeneous and there was no correlation between cortical layering patterns and aetiology. PMG was almost always associated with other brain malformations.
Interpretation
The inclusion of many fetal cases has allowed us to examine the early developmental stages of PMG. The study indicates the significance of surface signals responsible for human corticogenesis and the complex interaction between genetic and environmental factors leading to this common endpoint of cortical maldevelopment.
What this paper adds
Fetal cases allow study of the early developmental stages of polymicrogyria (PMG).
PMG is commonly associated with pial disruption, regardless of aetiology.
Abnormal festooning of the cortical neuronal band can occur well before normal cortical folding is expected to start.
PMG is very often associated with other brain malformations.
This article is commented on by Ten Donkelaar on page 7 of this issue.
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of ...Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, ...and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations corrected.Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
The authors report long-term follow-up seizure outcome in patients who underwent corpus callosotomy during the period 1981-2001 at the Montreal Neurological Institute.
The records of 95 patients with ...a minimum follow-up of 5 years (mean 17.2 years) were retrospectively evaluated with respect to seizure, medication outcomes, and prognostic factors on seizure outcome.
All patients had more than one type of seizure, most frequently drop attacks and generalized tonic-clonic seizures. The most disabling seizure type was drop attacks, followed by generalized tonic-clonic seizures. Improvement was noted in several seizure types and was most likely for generalized tonic-clonic seizures (77.3%) and drop attacks (77.2%). Simple partial, generalized tonic, and myoclonic seizures also benefited from anterior callosotomy. The extent of the callosal section was correlated with favorable seizure outcome. The complications were mild and transient and no death was seen.
This study confirms that anterior callosotomy is an effective treatment in intractable generalized seizures that are not amenable to focal resection. When considering this procedure, the treating physician must thoroughly assess the expected benefits, limitations, likelihood of residual seizures, and the risks, and explain them to the patient, his or her family, and other caregivers.
Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion, and little information is available. The aim of this study was to compare seizure outcomes at the ...5-year follow-up in patients with medically refractory unilateral mesial TLE (MTLE) due to hippocampal sclerosis (HS) who were treated using a cortical amygdalohippocampectomy (CorAH) or a selective AH (SelAH).
The authors obtained data from 100 adult patients who underwent surgery for MTLE. Fifty patients underwent a CorAH and 50 underwent an SelAH. Seizure control achieved with each technique was compared using the Engel classification scheme.
Overall, at the 5-year follow-up, favorable (Engel Classes I and II) seizure outcomes were noted in 82 and 90% of patients who had undergone CorAH and SelAH, respectively. Furthermore, 40% of the patients who had undergone a CorAH and 58% of those who had undergone an SelAH were seizure free (Engel Class Ia). There was no statistically significant difference between the 2 surgical approaches in terms of seizure outcome at the 5-year follow-up (p = 0.38).
Both CorAH and SelAH can lead to similar favorable seizure control in patients with MTLE/HS. However, the authors suggest that the transcortical selective approach has the great advantage of minimizing or completely abolishing the impact of dividing several venous and arterial adhesions which are tedious, time consuming, and, at times, associated with some degree of cerebral swelling.
Hypothalamic hamartomas may be associated with gelastic seizures, focal seizures, and a generalized epileptic encephalopathy, with severe seizures and cognitive and behavior decline. Despite earlier ...views to the contrary, good evidence now exists that all these clinical features are caused, directly or indirectly, by the hamartoma. Resection of these lesions was long regarded as too hazardous and unlikely to benefit seizure control. It is now clear that hypothalamic hamartomas can be effectively treated with a variety of surgical approaches with sustained seizure control and often seizure freedom. Qualitative observations suggest that behavior and cognition also improve with treatment, but quantitative validation is required. The specific approach should be tailored according to the surgical anatomy of the lesion and the experience of the surgeon. Choices include a transcallosal approach (good for intraventricular lesions), a pterional approach (useful for interpeduncular lesions), a transventricular endoscopic approach, or destruction of the lesion with radiofrequency probes or gamma knife radiosurgery. The previously dismal outlook for children with severe seizures associated with this lesion has now dramatically changed. These insights may have implications for other epileptic encephalopathies of childhood.
To examine the specificity of thalamic atrophy in epilepsy.
Thalamic volume measurements were carried out using high-resolution MRI in 40 patients with pharmacologically intractable temporal lobe ...epilepsy (TLE), 16 patients with extratemporal lobe epilepsy (ETE), and 17 with idiopathic generalized epilepsy (IGE). Thalamic volumes of patients were compared with those of 21 neurologically normal control subjects. Volumes were correlated with duration of epilepsy. The effect of prolonged febrile seizures and generalized seizures on thalamic volumes was examined.
Compared with normal control subjects, patients with TLE had a reduction in thalamic volume ipsilateral to the seizure focus. Thalamic volumes in patients with ETE and IGE were not significantly different from those of normal control subjects. In TLE patients, thalamic volumes ipsilateral to the seizure focus were negatively correlated with duration of epilepsy. Patients with a history of prolonged febrile seizures had more severe thalamic atrophy ipsilateral to the seizure focus than those without febrile seizures.
Thalamic atrophy ipsilateral to the seizure focus is found in TLE but not in other forms of focal epilepsy or IGE. In TLE, thalamic atrophy is correlated with duration of disease. Patients with a history of prolonged febrile seizures had smaller thalamic volumes ipsilateral to the seizure focus than those without.
Purpose: Considering the epileptogenic effect of cavernoma‐surrounding hemosiderin, assumptions are made that resection only of the cavernoma itself may not be sufficient as treatment of symptomatic ...epilepsy in patients with cavernous malformations. The purpose of this study was to test the hypothesis whether seizure outcome after removal of cavernous malformations may be related to the extent of resection of surrounding hemosiderin‐stained brain tissue.
Methods: In this retrospective study, 31 consecutive patients with pharmacotherapy‐refractory epilepsy due to a cavernous malformation were included. In all patients, cavernomas were resected, and all patients underwent pre‐ and postoperative magnetic resonance imaging (MRI). We grouped patients according to MRI findings (hemosiderin completely removed versus not/partially removed) and compared seizure outcome (as assessed by the Engel Outcome Classification score) between the two groups.
Results: Three years after resection of cavernomas, patients in whom hemosiderin‐stained brain tissue had been removed completely had a better chance for a favorable long‐term seizure outcome compared with those with detectable postoperative hemosiderin (p = 0.037).
Conclusions: Our study suggests that complete removal of cavernoma‐surrounding hemosiderin‐stained brain tissue may improve epileptic outcome after resection of cavernous malformations.
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