Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

Metabolic networks in epilepsy by MR spectroscopic imaging.

OBJECTIVE: The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients. MATERIALS AND METHODS: A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying. RESULTS: We extract two independent factors that explain the data's variability in control and MTLE patients. In controls, these factors characterize a 'thalamic' and 'dominant subcortical' function. The MTLE patients also exhibit a 'thalamic' factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia. CONCLUSIONS: These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.

Abnormalities of cortical thickness in postictal psychosis.

Postictal psychosis (PIP), the occurrence of psychotic episodes following a seizure, is a common and serious comorbidity in patients with epilepsy. Yet, the anatomical correlates remain poorly defined. Here, we used quantitative MRI morphometry to identify structural abnormalities in the cortex of patients with PIP relative to patients with epilepsy without PIP and age- and gender-matched normal healthy controls. Comparison of patients with epilepsy and PIP with patients with epilepsy without PIP revealed increased cortical thickness in the right lateral prefrontal cortex, right anterior cingulate cortex, and right middle temporal gyrus. The PIP group was distinguished from the EC and NC groups by thicker cortex in the right rostral anterior cingulate cortex and thinner cortex in the right angular gyrus and the left middle temporal region. Findings indicate that PIP is associated with thickening of the right anterior cingulate cortex, which may serve as a marker for patients at risk for developing PIP.

COVID-19 Severity and Stroke: Correlation of Imaging and Laboratory Markers.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) appears to be an independent risk factor for stroke. We hypothesize that patients who develop stroke while hospitalized for severe COVID-19 will have higher inflammatory markers and distinct stroke imaging patterns compared with patients positive for COVID-19 with out-of-hospital stroke onset and milder or no COVID-19 symptoms. MATERIALS AND METHODS: This is a retrospective case series of patients positive for COVID-19 on polymerase chain reaction testing with imaging-confirmed stroke treated within a large health care network in New York City and Long Island between March 14 and April 26, 2020. Clinical and laboratory data collected retrospectively included complete blood counts and creatinine, alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer levels. All CT and MR imaging studies were independently reviewed by 2 neuroradiologists who recorded stroke subtype and patterns of infarction and intracranial hemorrhage. RESULTS: Compared with patients with COVID-19 with outside-of-hospital stroke onset and milder or no COVID-19 symptoms (n = 45, 52.3%), patients with stroke already hospitalized for severe COVID-19 (n = 41, 47.7%) had significantly more frequent infarctions (95.1% versus 73.3%, P = .006), with multivascular distributions (56.4% versus 33.3%, P = .022) and associated hemorrhage (31.7% versus 4.4%, P = .001). Patients with stroke admitted with more severe COVID-19 had significantly higher C-reactive protein and ferritin levels, elevated D-dimer levels, and more frequent lymphopenia and renal and hepatic injury (all, P < .003). CONCLUSIONS: Patients with stroke hospitalized with severe COVID-19 are characterized by higher inflammatory, coagulopathy, and tissue-damage biomarkers, supporting proposed pathogenic mechanisms of hyperinflammation activating a prothrombotic state. Cautious balancing of thrombosis and the risk of hemorrhagic transformation is warranted when considering anticoagulation.

Corpus callosum area and brain volume in autism spectrum disorder: quantitative analysis of structural MRI from the ABIDE database.

Reduced corpus callosum area and increased brain volume are two commonly reported findings in autism spectrum disorder (ASD). We investigated these two correlates in ASD and healthy controls using T1-weighted MRI scans from the Autism Brain Imaging Data Exchange (ABIDE). Automated methods were used to segment the corpus callosum and intracranial region. No difference in the corpus callosum area was found between ASD participants and healthy controls (ASD 598.53 ± 109 mm(2); control 596.82 ± 102 mm(2); p = 0.76). The ASD participants had increased intracranial volume (ASD 1,508,596 ± 170,505 mm(3); control 1,482,732 ± 150,873.5 mm(3); p = 0.042). No evidence was found for overall ASD differences in the corpus callosum subregions.

Familial diffuse cortical dysplasia.

Two brothers are described with a syndrome characterized by mental retardation, atypical absence, atonic and generalized tonic-clonic seizures, and bilateral symmetrical slow spike and wave discharges on electroencephalograms. Magnetic resonance imaging revealed dysplastic cortex probably representing pachygyria primarily over the parietal regions bilaterally in both patients. The presence of an identical clinical, electroencephalographic, and cortical developmental abnormality on imaging studies in these brothers suggests that a genetic mechanism may play a role in some developmental disorders of the cerebral cortex.

Predictive value of magnetic resonance imaging in temporal lobe epilepsy surgery.

The predictive value of magnetic resonance imaging (MRI) was assessed by a prospective study of 34 patients selected for surgical treatment of temporal lobe epilepsy. The MRIs were interpreted using standardized visual diagnostic criteria and the imaging findings were correlated with the surgical outcome. Lateralized MRI abnormalities were found in 25 (74%) of 34 patients. Significant associations were found between either the presence of a restricted foreign-tissue lesion or hippocampal atrophy and an excellent surgical outcome. An abnormal MRI had an 82% predictive value and a normal MRI had a 56% predictive value for surgical success. A history of febrile convulsions and the presence of hippocampal atrophy best predicted outcome (predictive value, 86%). These results suggest that specific MRI findings in candidates for temporal lobe epilepsy surgery are predictive of surgical outcome. The information provided by MRI may be of value for counseling patients prior to surgical intervention.

Magnetic resonance spectroscopic imaging in temporal lobe epilepsy: neuronal dysfunction or cell loss?

BACKGROUND: Magnetic resonance spectroscopy (MRS) has demonstrated consistent metabolic abnormalities in temporal lobe epilepsy. The reason for decreases in N-acetylated compounds are thought to be related to neuronal hippocampal cell loss as observed in hippocampal sclerosis. However, mounting evidence suggest that the N-acetylated compound decreases may be functional and reversible. OBJECTIVE: To establish whether the metabolic changes measured by MRS correlate to hippocampal cell loss in temporal lobe epilepsy. SUBJECTS AND METHODS: We prospectively performed quantitative hippocampal MR imaging volumetry and MRS imaging in 33 patients with intractable mesial temporal lobe epilepsy who were undergoing surgery. A neuronal-glial ratio of cornu ammonis and fascia dentata was obtained and correlated while validating the pathologic analysis by comparisons with specimens of age-matched autopsy control-case hippocampus (n = 14). RESULTS: The neuronal-glial ratio of the patient group was statistically significantly lower than in the control group for the cornu ammonis region (P<.001). Correlations of hippocampal volumes with cornu ammonis and neuronal-glial ratios revealed a significant interdependence (P<.01). However, correlations of the resected hippocampal creatine-N-acetylated compound ratio with the cornu ammonis or fascia dentata neuronal-glial ratios showed no significant interdependence (P>.8). CONCLUSIONS: Our findings support the concept that the metabolic dysfunction measured by MRS imaging and the hippocampal volume loss detected by MR imaging volumetry do not have the same neuropathologic basis. These findings suggest that the MRS imaging metabolic measures reflect neuronal and glial dysfunction rather than neuronal cell loss as previously assumed.

Gray matter heterotopia.

Gray matter heterotopia are common malformations of cortical development. From a clinical perspective, affected patients are best divided into three groups: subependymal, subcortical, and band heterotopia (also called double cortex). Symptomatic women with subependymal heterotopia typically present with partial epilepsy during the second decade of life; development and neurologic examinations up to that point are typically normal. Symptoms in men with subependymal heterotopia vary, depending on whether they have the X-linked or autosomal form. Men with the X-linked form more commonly have associated CNS and visceral anomalies; their development is typically abnormal. Symptomatic men with the autosomal variety have clinical courses similar to symptomatic women. Both men and women with subcortical heterotopia typically have congenital fixed neurologic deficits and develop partial epilepsy during the second half of the first decade of life. The more extensive the subcortical heterotopia, the greater the deficit; bilateral heterotopia are almost invariably associated with severe developmental delay or mental retardation. In general, band heterotopia are seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die in utero or have a much more severe brain anomaly. Symptoms in affected women vary from normal to severe developmental delay or mental retardation; the severity of the syndrome is related to the thickness of the band of arrested neurons. Nearly all affected patients that come to medical attention have epilepsy, with partial complex and atypical absence epilepsy being the most common syndromes. Some of the more severely affected patients develop attacks.

The epileptic spectrum in the congenital bilateral perisylvian syndrome. CBPS Multicenter Collaborative Study.

We studied the frequency, clinical and EEG characteristics, and outcome of the epileptic syndrome in 31 patients with a congenital neurologic syndrome characterized by pseudobulbar palsy, cognitive deficits, and bilateral perisylvian polymicrogyria. Seizures were present in 27 of 31 patients (87%) and usually began between the ages of 4 and 12 years; they commonly consisted of atypical absence, atonic/tonic, and generalized tonic-clonic seizures. Partial attacks were present in 26%. EEG demonstrated generalized spike and wave abnormalities and, less frequently, multifocal discharges, predominantly in centro-parietal regions. Seizures were poorly controlled in 65%, with the remaining patients well controlled. Seven patients underwent callosotomy, which resulted in seizure improvement. This study indicates that the epileptic spectrum in this syndrome is broad but follows predictable patterns. Callosotomy is a valuable treatment strategy in those with intractable drop attacks.

Hippocampal sclerosis without detectable hippocampal atrophy.

Six patients from three centers had MRI and pathologic evidence of hippocampal sclerosis but no detectable hippocampal atrophy. Loss of normal internal structure and T1- and T2-weighted signal abnormalities allowed the MRI diagnosis of unilateral hippocampal sclerosis when hippocampal volume measurements were normal and symmetric. Although accurate hippocampal volume measurements will determine the most severely affected side in most cases, volume measurements or atrophy alone will not always detect all MRI-visible pathology. Additional detailed MRI assessment is required before structural abnormality of the hippocampus is excluded on the basis of volume measurements.

Diffusion mapping applied to mesial temporal lobe epilepsy: preliminary observations.

OBJECTIVE: To evaluate whether diffusion mapping could lateralize intractable seizures in mesial temporal lobe epilepsy (MTLE) patients. BACKGROUND: Animal seizure models show acute postictal depression of the apparent diffusion coefficient of water (ADCw), interictal normalization, then chronic elevation. METHODS: The hippocampal plane was imaged with five diffusion weightings along each axis. Three orthogonal ADCw maps were averaged to produce an isotropic ADCw map. RESULTS: In all eight MTLE patients, ADCw was elevated by a mean of 10+/-3% (p<0.01, paired t-test) interictally in the ipsilateral hippocampus, where side of seizure focus was determined electrographically with corroboration by volumetric MRI studies. Measured ADCw values in phantoms and five normal brains agree with published values. CONCLUSIONS: Brain tissue with interictally increased ADCw may represent an epileptogenic region with neuronal loss, gliosis, and expanded extracellular space (hippocampal sclerosis). Thus, diffusion mapping may confirm seizure lateralization.

Congenital porencephaly and hippocampal sclerosis. Clinical features and epileptic spectrum.

We studied clinical features and seizure localization in 14 patients with porencephaly and intractable seizures. Perinatal complications were present in nine patients, childhood febrile convulsions in two, congenital hemiparesis in 12, and intellectual impairment in seven. Ten patients had psychoparetic complex partial seizures (CPS), three had sensorimotor simple partial seizures, and one had generalized tonic-clonic seizures. Surface EEG showed temporal onset in nine patients (one bitemporal) and extratemporal onset in four. MRI showed porencephaly in the distribution of the middle cerebral artery in eight patients, posterior cerebral in three, internal carotid in one, and multiple vessels in two. MR-based volumetry revealed hippocampal formation atrophy in 13 patients (eight unilateral and five bilateral) and amygdalar atrophy in 10 patients (nine unilateral and one bilateral). Hippocampal formation atrophy was concordant with CPS semiology in 10 patients (71%) and with EEG temporal localization in nine patients. Two patients had pathologic confirmation of mesial temporal sclerosis and were seizure free after temporal lobectomy. We conclude that mesial temporal sclerosis often coexists with porencephaly and is the likely seizure focus in the presence of concordant electroclinical data. This recognition implies that effective surgical intervention can be offered to certain patients with porencephaly-related seizure disorders. The dual pathology and association with perinatal cerebral vascular occlusion suggest a common ischemic pathogenesis.

Proton spectroscopic imaging at 4.1 tesla in patients with malformations of cortical development and epilepsy.

We used proton magnetic resonance spectroscopic imaging (MRSI) at 4.1 tesla in patients with malformations of cortical development (MCDs) and epilepsy. We compared the spectroscopic results with normative data using 2 SDs (95% confidence) above normal values for detection of significant abnormalities for creatine-N-acetylated compounds (Cr/NA) ratio and choline-N-acetylated compounds (Cho/NA). The results were correlated with clinical, EEG, and histologic findings. Patients with focal cortical dysplasia showed significant metabolic abnormalities in correspondence with the structural lesions, whereas patients with heterotopia and polymicrogyria demonstrated no subcortical MRSI abnormalities. Significant correlations were found between the metabolic abnormalities and the frequency of seizures but not with the degree of interictal EEG discharges. Quantitative neuronal and glial cell counts revealed no statistically significant correlation between cell loss and the abnormal metabolic ratios in those who underwent surgery. These preliminary findings suggest that MRSI-based metabolic abnormalities in patients with MCDs are variable and are likely to be associated with complex cellular mechanisms involving the regulation of NA, total Cr content, and Cho.

Focal transmantle dysplasia: a specific malformation of cortical development.

We report 18 patients who presented prior to age 20 years with epilepsy or fixed neurologic deficits. MRI showed signal abnormality extending from the cortex to the superolateral wall of the lateral ventricle. Histology showed cortical disorganization, neuronal cytomegaly, balloon cells, indistinct cortical gray matter-white matter junctions, and variable accompanying astrogliosis. We propose that this transmantle dysplasia is a specific anomaly resulting from abnormal stem cell development.

Temporal lobe developmental malformations and epilepsy: dual pathology and bilateral hippocampal abnormalities.

Temporal lobe developmental malformations (TLDM) with focal cortical dysplasia and balloon cells may coexist with mesial temporal sclerosis. The true incidence of this dual pathology is unknown. Our aim was to assess the frequency of amygdala (AM)-hippocampal abnormality in a homogeneous population with this specific developmental malformation. MRI-based volumetry of the AM and hippocampal formation (HF) in 30 patients with unilateral TLDM and intractable partial epilepsy was performed. A volume normalization process defined a normal range of HF and AM volumes in control subjects, and enabled the detection of bilateral volume loss. Normalized volumes detected HF atrophy in 26 patients (nine unilateral and 17 bilateral) and AM atrophy in 18 patients (three unilateral and 15 bilateral). Visual analysis detected unilateral HF abnormality in 21 patients and bilateral abnormality in two. When compared with a group of patients with temporal lobe epilepsy and pure hippocampal sclerosis (N = 92), where volumetry revealed bilateral HF atrophy in 18%, a significant difference in the frequency of bilateral HF atrophy was found (p < 0.0001). Dual pathology is frequent in patients with TLDM (87%), and the AM-HF abnormality is often bilateral (57%). Our data suggest that more widespread and potentially epileptogenic lesions coexist with visibly detectable unilateral TLDM. This has implications for the selection of patients for temporal lobe surgery and may influence surgical strategies.

In vivo 31P nuclear magnetic resonance spectroscopy of human temporal lobe epilepsy.

We performed localized 31P nuclear magnetic resonance (NMR) 1H-image-guided in vivo spectroscopy to study regional high-energy phosphate levels in the brains of normal controls and in patients with intractable unilateral temporal lobe epilepsy. We did not observe differences in intracellular pH between controls and patients. The phosphocreatine/inorganic phosphate ratio was reduced by 50% in the epileptogenic temporal lobe compared with controls (p less than 0.005) and by 35% when compared with the unaffected contralateral temporal lobe (p less than 0.05). We did not observe differences in the ratio of phosphomonoesters to phosphodiesters between controls and patients. These findings suggest that in vivo 31P NMR spectroscopy yields a distinctive interictal metabolic profile in patients with intractable unilateral temporal lobe epilepsy and may permit noninvasive lateralizing evidence of the seizure focus.

Relative utility of 1H spectroscopic imaging and hippocampal volumetry in the lateralization of mesial temporal lobe epilepsy.

OBJECTIVES: To determine the relative utility of 1H MRSI and hippocampal volumetry for the lateralization of mesial temporal lobe epilepsy (MTLE) in patients with intractable epilepsy. BACKGROUND: MTLE is the most common partial-onset seizure disorder in patients undergoing temporal lobe epilepsy surgery. MR volumetry and spectroscopy are reliable preoperative imaging techniques for the lateralization of MTLE. METHODS: We analyzed the 1H MRSI and hippocampal formation volumes preoperatively in 30 consecutive patients who had undergone temporal lobectomy. RESULTS: Volumetry correctly lateralized the side of surgery in 93% of patients and 1H MRSI did so in 97% of patients. Incorrect lateralization occurred by volumetry in two patients and by 1H MRSI in one patient. Concordance between all MRI modalities was 73%. Pearson's analysis revealed no correlation between the degree of hippocampal volume loss and the creatine-to-N-acetylated-compounds ratio. CONCLUSIONS: Volumetry and 1H MRSI correctly lateralized most patients with MTLE and complement each other in final lateralization. The lack of correlation between the severity of volume loss and the degree of metabolic disturbance suggests that the techniques examine distinct pathophysiologic processes in MTLE.

Amygdala atrophy and seizure outcome after temporal lobe epilepsy surgery.

Surgical outcome in hippocampal atrophy (n = 44) and amygdalohippocampal atrophy (n = 14) were compared. Hippocampal atrophy had better seizure-free outcome than amygdalohippocampal atrophy (80% versus 50%, p = 0.043). Severity of hippocampal atrophy correlated with duration of epilepsy in patients with hippocampal atrophy (r = 0.4, p = 0.007), but not in those with amygdalohippocampal atrophy, suggesting that these two groups may have a different pathogenesis.

Multimodality MRI in mesial temporal sclerosis: relative sensitivity and specificity.

Our objectives were to determine the relative sensitivity and specificity of different MRI sequences and analysis techniques for the detection of mesial temporal sclerosis (MTS). Mesial temporal sclerosis is the most common pathologic finding in patients undergoing temporal lobe epilepsy surgery. Magnetic resonance imaging is the most reliable preoperative imaging technique for the detection of MTS. We analyzed the abnormalities in preoperative MRIs of 44 consecutive patients who had undergone temporal lobectomy and who had pathologic confirmation of MTS. Techniques included inversion recovery (IR); T1-weighted, volume-acquired images; hippocampal T2 relaxometry (HT2); volumetric assessment; and visual analysis. Sensitivity was 86% with IR, 90% with T1-weighted qualitative visual analysis, and 97% with quantitative volumetry. Pathologic prolongation of HT2 (> 2 SD of normal) was present in 79%. Analysis of variance showed statistically significant differences in sensitivity between HT2, volumetric measurements (p < 0.01), and qualitative visual atrophy (p < 0.05). Concordance between all MRI modalities was 68%. Inversion recovery and qualitative analysis lateralized the side of surgery in 93%. The combination of IR and T1-weighted images correctly identify MTS in most patients. Hippocampal volumetry provided localization in an additional small number of patients.