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.

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.

A subcortical network of dysfunction in TLE measured by magnetic resonance spectroscopy.

OBJECTIVE: The goal of this work was to evaluate the relationship between neuronal injury/loss in the hippocampus, thalamus, and putamen in temporal lobe epilepsy (TLE) patients using (1)H magnetic resonance spectroscopic imaging. METHODS: (1)H spectroscopic images from the hippocampus and thalamus of controls and patients with TLE were acquired at 4 T. The spectroscopic imaging data were reconstructed using an automated voxel-shifting method based on anatomic landmarks providing four, six, and three loci for the hippocampus, thalamus, and putamen, respectively. For correlation analysis, the hippocampal and striatal loci were averaged to provide single estimates of the entire structure, whereas the thalamus was divided into two regions, an anterior and posterior measure, using the average of three loci each. RESULTS: The ratio of N-acetyl aspartate to creatine (NAA/Cr), a measure of neuronal injury/loss, was significantly reduced in both the ipsilateral and contralateral hippocampi and thalami. NAA/Cr in the ipsilateral hippocampus was significantly correlated with the ipsilateral and contralateral anterior and posterior thalami, putamen, and contralateral hippocampus. In control subjects, the hippocampi were only correlated with each other. CONCLUSIONS: The data demonstrate that there is significant neuronal injury/loss in both the ipsilateral and contralateral thalami in temporal lobe epilepsy patients, with greater impairment in the anterior portions of the ipsilateral thalamus. The degree of injury/loss in the ipsilateral and contralateral thalamus and putamen is directly correlated with that of the ipsilateral hippocampus. This is consistent with the hypothesis that the impairment and damage associated with recurrent seizures as measured by N-acetyl aspartate originating in the hippocampus results in injury and impairment in other subcortical structures.

Hippocampal 1H-MRSI correlates with severity of depression symptoms in temporal lobe epilepsy.

OBJECTIVE: To investigate the association of an indicator of hippocampal function with severity of depression symptoms in temporal lobe epilepsy. METHODS: We evaluated 31 patients with video/EEG-confirmed temporal lobe epilepsy using creatine/N-acetylaspartate ratio maps derived from a previously validated (1)H magnetic resonance spectroscopic imaging ((1)H-MRSI) technique at 4.1 T. We also assessed depression symptoms, epilepsy-related factors, and self-perceived social and vocational disability. We used conservative nonparametric bivariate procedures to determine the correlation of severity of depression symptoms with imaging and clinical variables. RESULTS: The extent of hippocampal (1)H-MRSI abnormalities correlated with severity of depression (Spearman rho = 0.65, p value < 0.001), but other clinical factors did not. CONCLUSION: The extent of hippocampal dysfunction is associated with depression symptoms in temporal lobe epilepsy and may be a more important factor than seizure frequency or degree of disability.

A developmental and genetic classification for malformations of cortical development.

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Racial disparities in the use of surgical treatment for intractable temporal lobe epilepsy.

OBJECTIVE: To compare the use of surgical treatment for epilepsy among different ethnic and racial groups with surgically remediable temporal lobe epilepsy (TLE). METHODS: The authors used multiple logistic regression analysis to model the use of anterior temporal lobectomy in a cross-sectional study of video-EEG monitoring discharge data among residents of Alabama and surrounding states discharged from the University of Alabama at Birmingham Hospital between July 1998 and January 2003 with a primary diagnosis of TLE. RESULTS: Of 432 patients diagnosed with TLE, 130 had evidence of mesial temporal sclerosis on MRI studies. Seventy patients underwent surgery; African Americans were less likely than non-Hispanic whites to undergo surgical treatment (odds ratio, 0.3; 95% CI, 0.2 to 0.8). After potential demographic (age, education, and sex), socioeconomic, medical insurance coverage, and clinical confounders (bitemporal seizure onset) were controlled, African Americans had a 60% less chance to receive surgery than non-Hispanic whites. CONCLUSIONS: There are disparities in the use of surgical treatment for temporal lobe epilepsy. Race appears to be an influential factor related to such disparities.

Chronic temporal lobe epilepsy: spatial extent and degree of metabolic dysfunction studied with magnetic resonance spectroscopy (MRS).

INTRODUCTION: Proton magnetic resonance spectroscopy ((1)H MRS) has been proposed as a lateralizing method for the presurgical evaluation of patients with medically intractable temporal lobe epilepsy (TLE). Studies have shown correlations between temporal lobe (TL) NAA and seizure frequency, and TL NAA/Cr and the duration of epilepsy in patients with TLE. This latter finding may suggest that progressive neuronal dysfunction may occur in both temporal lobes in patients with TLE, even when the seizures originate in only one temporal lobe. We analyzed our data in an attempt to find a possible correlation between extension of neuronal dysfunction based on NAA measures and duration of epilepsy. METHODS: We studied 45 consecutive patients with the diagnosis of TLE, who were referred for presurgical evaluation. Duration of epilepsy was defined as the interval between the age of seizure onset and the time of the MRS examination. All studies were performed in the inter-ictal state, prior to intracranial monitoring or resection. We performed two-tailed Pearson correlation analysis between ipsilateral NAA/Cr and extension of the abnormality (voxels involved) and the duration of the seizure disorder in years. RESULTS: The average duration of epilepsy in this group was 20 years. No significant correlation was found between duration of epilepsy and mean hippocampal NAA/Cr (r=-.131, p=.390); nor was a correlation found between duration of epilepsy in years or the extent of metabolic lesion (voxels involved) (r=-.264, p=.079). CONCLUSIONS: Hippocampal NAA/Cr does not correlate with duration of epilepsy in TLE. Our findings suggest that cross-sectional group measures of hippocampal neuronal function do not suggest damage progression.

Neurotoxicity following addition of intravenous valproate to lamotrigine therapy.

Reversible neurotoxic symptoms were observed in three adult patients with absence status epilepticus on lamotrigine (LTG) therapy after administration of an IV bolus followed by oral valproic acid (VPA). Neurotoxicity was likely related to elevated serum LTG levels, as improvement correlated with discontinuing or reducing LTG dosage.

Radiologic classification of malformations of cortical development.

Malformations of cerebral cortical development are common birth defects that can cause delayed development, epilepsy, focal neurologic deficits, and mental retardation. Rational classification of these disorders is essential for proper prognosis, genetic testing and counseling, and investigation of the underlying molecular causes. A rational approach to this classification is a framework based on whether these disorders are the result of abnormal cell proliferation or apoptosis, abnormal migration of immature neurons, or abnormal horizontal and radial orientation in the cortex. Superimposed on this framework are subclassifications that are based on topology of the malformation, associated central nervous system (CNS) or extra-CNS malformations, and results of molecular genetic testing. Characteristics that correlate with and enforce this system of classification can be identified by modern neuroimaging studies.

Malformations of cortical development and epilepsy.

Although once thought to be rare, malformations of cortical development are being increasingly recognized as the underlying cause of developmental delay in children and of epilepsy in children and young adults. Advances in neuroimaging and developmental neurobiology have created the tools by which these important malformations have been investigated. Through a symbiotic type of relationship, these investigations, and the search for a better understanding of these malformations, have led to advances in neuroimaging techniques and better understanding of both normal and abnormal brain development. In this review, the most common malformations or cortical development associated with epilepsy are discussed in regard to their clinical manifestations, classification, imaging appearance and basic neurobiology.

Classification system for malformations of cortical development: update 2001.

The many recent discoveries concerning the molecular biologic bases of malformations of cortical development and the discovery of new such malformations have rendered previous classifications out of date. A revised classification of malformations of cortical development is proposed, based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories have been created based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In many cases, the precise developmental and genetic features are uncertain, so classification was made based on known relationships among the genetics, pathologic features, and neuroimaging features. A major change since the prior classification has been the elimination of the separation between diffuse and focal/multifocal malformations, based on the recognition that the processes involved in these processes are not fundamentally different; the difference may merely reflect mosaicism, X inactivation, the influence of modifying genes, or suboptimal imaging. Another change is the listing of fewer specific disorders to reduce the need for revisions; more detail is added in other smaller tables that list specific malformations and malformation syndromes. This classification is useful to the practicing physician in that its framework allows a better conceptual understanding of the disorders, while the component of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Wisconsin Card Sorting performance in patients with temporal lobe epilepsy: clinical and neuroanatomical correlates.

PURPOSE: A sizable proportion of patients with temporal lobe epilepsy (TLE) display impairments on tests of executive function. Previous studies have suggested several factors that may explain such performance, including the presence of hippocampal sclerosis, electrophysiological disruption to extratemporal regions, and early age of seizure onset. However, no clear determinants have been found that consistently explain such executive dysfunction. The present study investigated the contribution of several clinical variables and temporal lobe neuroanatomic features to performance on the Wisconsin Card Sorting Test (WCST) in a series of patients with TLE. METHODS: Eighty-nine patients with lateralized TLE (47 left, 42 right) were examined. Seventy-two patients from this series underwent anterior temporal lobectomy (ATL). Regression analysis was used to examine the effects of age, education, age at seizure onset, seizure duration, seizure laterality, history of secondary generalized seizures, and MRI-based volumes of the right and left hippocampi on preoperative WCST performance (number of categories completed, perseverative errors). Further univariate analyses examined whether the presence of bilateral hippocampal sclerosis, mesial temporal lobe abnormalities beyond the hippocampus, or temporal neocortical abnormalities affected preoperative WCST performance. In addition, we examined whether becoming seizure free after ATL affected change in WCST performance. RESULTS: Overall regression analysis was not significant. However, an examination of individual partial correlations revealed that patients with a history of secondary generalized seizures performed more poorly on the preoperative WCST than did patients without such history. In addition, patients who were seizure free after ATL did not exhibit better WCST outcome than patients who did not become seizure free. The presence of bilateral hippocampal sclerosis, extrahippocampal mesial temporal atrophy, or temporal neocortical lesions did not affect WCST performance. CONCLUSIONS: These results indicate that the presence of temporal lobe structural abnormalities do not significantly affect executive function as measured by the WCST. The present study does suggests that the critical determinants of WCST performance in patients with TLE lie outside the temporal lobe and likely relate to metabolic disruption to frontostriatal neural network systems.

Investigation of executive function change following anterior temporal lobectomy: selective normalization of verbal fluency.

The nociferous cortex hypothesis predicts that electrophysiological normalization to distal extratemporal brain regions following anterior temporal lobectomy (ATL) will result in improvements in executive functioning. The present study examined the effects of seizure laterality and seizure control on executive function change. The authors administered the Wisconsin Card Sorting Test (WCST), Trails B, and the Controlled Oral Word Association Test to 174 temporal lobe epilepsy patients who underwent ATL. No significant changes were found on the WCST or Trails B tests, regardless of surgery side or seizure-free status. However, verbal fluency significantly improved in seizure-free patients. Findings were consistent with the nociferous cortex hypothesis suggesting selective executive function improvement following ATL. These findings are discussed in terms of recent research demonstrating extrahippocampal metabolic normalization following surgery.

Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes.

Mutations in the X-linked gene doublecortin lead to "double cortex" syndrome (DC) in females and to X-linked lissencephaly (XLIS) in males. Because most patients with DC and XLIS are sporadic, representing de novo doublecortin mutations, we considered that some of these patients could be somatic or germline mosaics. Among a population of 20 patients and their families, we found evidence for mosaic doublecortin mutations in 6 individuals. Germline mosaicism was identified in two unaffected women, each with two affected children. Additionally, one affected male with DC was found to be a somatic mosaic, which presumably spared him from the more severe phenotype of lissencephaly. The high rate of mosaicism indicates that there may be a significant recurrence risk for DC/XLIS in families at risk, even when the mother is unaffected.

Anterior cingulate gyrus epilepsy: the role of ictal rCBF SPECT in seizure localization.

PURPOSE: The goal of this report is to demonstrate the utility of ictal brain single photon emission tomography (SPECT) in a 39-year-old man with complex partial seizures arising from the anterior cingulate gyrus. Seizures originating from the anterior cingulate gyrus are difficult to localize because they have variable ictal semiology, are usually brief, and have rapid cortical propagation. METHODS: Clinical neurologic examination, electroencephalography, extended video-electroencephalography with scalp and sphenoidal electrodes, magnetic resonance imaging, computed tomography, and ictal brain SPECT with Tc-99m HMPAO were performed to identify the seizure focus. The patient's regional cerebral blood flow (rCBF) findings were compared with those of eight normal controls, and changes in rCBF were assessed by comparing the patient's ictal scan with those of normal controls at rest by using statistical parametric mapping (SPM). RESULTS: Clinical and neurologic evaluations failed to demonstrate the epileptogenic focus. Ictal rCBF brain SPECT showed a focal region of hyperperfusion in the anterior cingulate gyrus. By using SPM, the ictal blood flow increase in the right anterior cingulate gyrus (x, y, z, -6, 42, 24 mm) was found to be statistically significant when compared with normal controls (z score, 4.88, p < 0.001). Subdural EEG recordings with intracranial electrodes positioned over this location confirmed that the cingulate gyrus was the origin of the seizures, and surgical resection resulted in >90% seizure reduction. CONCLUSIONS: We concluded that ictal brain SPECT localization in conjunction with subdural electrode confirmation is a useful test in the presurgical evaluation of difficult to localize cingulate epilepsy.

Visual confrontation naming and hippocampal function: A neural network study using quantitative (1)H magnetic resonance spectroscopy.

Prior research on the relationship between visual confrontation naming and hippocampal function has been inconclusive. The present study examined this relationship using quantitative (1)H magnetic resonance spectroscopy ((1)H-MRS) to operationalize the function of the left and right hippocampi. The 60-item Boston Naming Test (BNT) was used to measure naming. Our sample included 46 patients with medically intractable, focal mesial temporal lobe epilepsy who had been screened for all pathology other than mesial temporal sclerosis. Statistics included Pearson correlations and neural network analysis (multilayer perceptron and radial basis function). Baseline BNT performance correlated significantly with left (1)H-MRS hippocampal ratios. Thirty-six per cent of the variance in baseline BNT performance was explained by a neural network model using left and right (1)H-MRS ratios(creatine/N-acetylaspartate) as input. This was elevated to 49% when input from the right hippocampus was lesioned mathematically. In a second model, left (1)H-MRS hippocampal ratios were modelled using measures of semantic and episodic memory as input (including the BNT). Explained variance in left (1)H-MRS hippocampal ratios fell from 60.8 to 3.6% when input from BNT and another semantic memory measure was degraded mathematically. These results provide evidence that the speech-dominant hippocampus is a significant component of the overall neuroanatomical network of visual confrontation naming. Clinical and theoretical implications are explored.

Statistically driven identification of focal metabolic abnormalities in temporal lobe epilepsy with corrections for tissue heterogeneity using 1H spectroscopic imaging.

1H spectroscopic imaging of N-acetyl-aspartate, creatine, and choline has proven to be a sensitive indicator for the lateralization of seizure foci in temporal lobe epilepsy. Previous studies have used right-left comparisons to identify the epileptogenic tissue assuming that alterations due to the disease process outweigh the effects of tissue heterogeneity. To evaluate the effectiveness of tissue heterogeneity corrected analyses, we evaluated three criteria for lateralization of the seizure focus: 1) a statistically driven method adjusted for tissue composition, 2) a single valued threshold, and 3) a single global index of the hippocampus. The statistically driven analysis lateralized all eight patients correctly, whereas the single threshold method incorrectly lateralized one case and the global index failed to identify a significant difference in two cases. These findings indicate that increased accuracy and sensitivity can be obtained by correcting for tissue heterogeneity when analyzing spectroscopy studies of temporal lobe epilepsy.

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.