Neuronal Cytomegaly Research Articles

Histological and neuroimaging comparison of SMART syndrome versus focal neuronal gigantism.

Two of the rarest radiation-induced adverse effects are focal neuronal gigantism (FNG) and SMART syndrome (stroke-like migraine attacks after radiation therapy). Both conditions develop years, and sometimes decades, after receipt of therapeutic radiation to the brain. To date, there are only 3 previously reported cases of FNG, all of which describe cortical thickening, enlarged "hypertrophic" neurons, and neuronal cytological changes. No detailed studies exist of histological features of SMART or the comparison between FNG and SMART. In this study, we contrast histological and neuroimaging features of 3 FNG vs. 4 SMART cases, the latter diagnosed by a neuroradiologist, neurooncologist, and/or neurosurgeon. We confirm the cortical thickening, dyslamination, neuronal cytomegaly, and gliosis in FNG vs. cortical architectural preservation and normal neuronal cytology in SMART, although both showed gliosis, scattered neurons with cytoplasmic accumulation of tau and neurofibrillary protein and variable co-existence of other radiation-induced lesions. Both conditions lacked significant inflammation or consistent small vessel hyalinization throughout the entire resection specimen. The absence of pathognomonic histologic alterations in SMART cases suggests underlying vascular dysregulation. Despite differing histology, some overlap may exist in neuroimaging features. Molecular assessment conducted in 2 cases of FNG was negative for significant alterations including in the MAPK pathway.

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.

Distinct clinicopathologic subtypes of cortical dysplasia of Taylor

Two pathologic subtypes based on the presence or absence of balloon cells have been described in cortical dysplasia of Taylor (CDT). To determine whether the pathologic subtype has any distinct clinical or MRI features that are relevant to management. The histopathologic, clinical, and MRI features of 34 children with CDT who underwent epilepsy surgery at Miami Children's Hospital from 1990 to 2001 were investigated. Bizarre neuronal cytomegaly was the primary pathologic feature of 15 patients with the dysplasia-only subtype, and 19 cases showed additional characteristics including balloon cells and marked white matter abnormalities. Both groups presented with severe intractable epilepsy of very-early-onset, multiple daily seizures, cognitive disability, and focal neurologic deficits. The dysplasia-only subtype had higher rates of neonatal onset, hemiparesis, and severe mental retardation (p < 0.05). The MRI features of focal cortical thickening with associated cortical T2 signal change showed excellent sensitivity (94%) and reasonable specificity (73%) for the diagnosis of the balloon cell subtype. The overall surgical outcome was 59% seizure freedom at 2 years. Children with cortical dysplasia of Taylor type have in common a very-early-onset, severe epilepsy with neurologic co-morbidity. Patients with the non-balloon cell pathologic subtype have a more severe phenotype. A trend toward a better outcome in the balloon cell group suggests that preoperative identification of these subtypes may impact surgical planning.

Absence of allelic loss in cytomegalic neurons of cortical tuber in the Eker rat model of tuberous sclerosis.

The Eker rat is an animal model of tuberous sclerosis caused by a mutation in the Tsc2 gene encoding a tumor suppressor protein, tuberin. According to Knudson's two-hit theory, renal carcinomas and other tumors develop in various organs. Although the incidence of brain lesions is lower in the Eker rat than in human tuberous sclerosis, a cortical tuber was recently found in the cerebrum of an Eker carrier. In this study, we examined whether neuronal cytomegaly in the Eker rat tuber is caused by deletion of the normal Tsc2 allele and resultant loss of tuberin, as is the case with the majority of renal carcinomas. A combination of laser capture microdissection and semi-nested polymerase chain reaction demonstrated the presence of the wild-type Tsc2 allele in the cytomegalic neurons isolated individually. Immunohistochemistry also detected positive tuberin immunoreactivity in many of these giant neurons. These findings were in sharp contrast to those of renal carcinoma cells deriving from allelic loss. Our results provide evidence that many if not all cytomegalic neurons of a cortical tuber occur in the absence of allelic loss.

Surgical pathology of drug‐resistant partial epilepsy: A 10‐year‐experience with a series of 327 consecutive resections

ABSTRACT Herein we reviewed the histopathological findings in 327 consecutive surgical specimens from patients with pharmaco‐resistant epilepsy (PRE). Three major pathological groups (78.3% of all cases) were identified: Ammon's horn sclerosis (85 cases as an isolated lesion plus 18 as one part of a dual pathology), tumors (94 cases), and malformations (77 cases). Tumors, often associated with cortical dysplasias (CDs), were all of low histological grade and included 61 dysembryoplastic neuroepithelial tumors (DNTs), 29 gangliogliomas, and 4 pleomorphic xanthoastrocytomas (PXAs). Among the malformations were observed 52 CDs, 13 cavernomas, 8 cortical tubers, and 4 cysts. The remaining findings consisted of 16 scars (mostly posttraumatic) and 4 Rasmussen's encephalitis. Fifty‐one (15.6%) specimens contained non‐specific changes, and histological samples from 215 patients with presurgical implantation of electrodes revealed iatrogenic changes. All these figures are in agreement with the most recent and comparable series, and confirm the high incidence of DNTs that appear clearly as the most common tumoral entity in PRE. Our data also support the hypothesis of a close histogenetic relationship between DNT, ganglioglioma, and PXA, with a putative common origin from pluripotential progenitor CD34 positive cells of the subpial granular layer. As for CDs, our study confirms the clinical relevance of two main subtypes: severe CD (or Taylor's type CD) with neuronal cytomegaly and balloon cells, and non‐Taylor's type CDs with a better outcome. Eventually, this series demonstrates that most patients have significant histopathological lesions, among which, aspects that are relevant to the diagnostic surgical pathologist are highlighted [published with a complete image database on CD‐Rom].

Clinicopathological findings in patients who have undergone epilepsy surgery in the first year of life.

Epilepsy presenting early in childhood may be associated with a neurologically devastating clinical course and have significant implications for the child's development. There are limited published data regarding the clinicopathological features of patients who have undergone epilepsy surgery in the first year of life and the role such surgery may have in reducing seizure frequency. This study retrospectively reviews the clinicopathologic features of eight patients from a tertiary care setting who underwent surgery for epilepsy in the first year of life. Eight infants, including seven males and one female, underwent surgery for epilepsy at 3-11 months of age (median 7.5 months). Age at the time of seizure onset ranged from birth to 2 months. Epileptogenic foci were localized by electroencephalographic and radiographic studies to the right side in five patients and left side in three patients. Histopathological findings in excised tissues included cortical dysplasia (n = 7), hemimegalencephaly (n = 3), and Sturge-Weber syndrome (n = 1). Dysplasia was marked by abnormalities in cortical lamination and neuronal orientation (n = 7), neuronal cytomegaly (n = 6), increased molecular layer neurons (n = 5) and balloon cells (n = 2). One patient was known to have epidermal nevus syndrome. Two patients required additional surgery for continued seizures. At last known follow up, all but one patient, who died in the postoperative period, were alive with no or decreased seizures at postoperative intervals of 3-60 months (median 13 months). Surgery can potentially ameliorate epilepsy in patients less than 1 year of age. Most of the patients in this series had cortical dysplasia as the underlying pathology of their epilepsy.

Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections.

c Background.—Surgical management of intractable epilepsy continues to be important in select cases to achieve seizure control. Design.—This study retrospectively reviews the pathologic findings in 133 consecutive cases of extratemporal lobe epilepsy experienced during a 17-year period. Results.—The study group consists of 133 patients (78 males) who underwent extratemporal lobe resection for epilepsy at a mean age of 21.1 years (range, 3 months to 57 years). In 50 patients (37.6%), cortical dysplasia (neuronal migration abnormalities) was identified. The most common patterns of dysplasia observed included diffuse architectural disorganization in 46 cases, neuronal cytomegaly in 30 cases, increased numbers of molecular layer neurons in 30 cases, and balloon cells in 18 cases. Tumors were identified in 37 cases (27.8%) and included 13 astrocytomas, 7 gangliogliomas, 6 dysembryoplastic neuroepithelial tumors, 6 glioneuronal hamartomas, 4 oligodendrogliomas, and 1 oligoastrocytoma (mixed glioma). Twenty-four resections (18%) showed evidence of remote ischemic damage or infarct. Neuronal heterotopia was identified in 59 resection specimens (44.4%). Other less common findings included vascular malformations in 4 patients (3.0%), Sturge-Weber malformations in 3 patients (2.3%), and Rasmussen encephalitis in 2 patients (1.5%). Two patients were known to have tuberous sclerosis. In 23 resection specimens (17.3%), no significant pathologic finding was identified. Coexistent cortical dysplasia and tumor were seen in 10 cases and coexistent dysplasia and infarct or remote ischemic damage in 11 cases. Conclusion.—This series demonstrates that most patients with extratemporal lobe epilepsy have significant histopathologic findings, which most frequently include cortical dysplasia, tumor, or evidence of remote ischemic damage or infarct. Coexistent pathologic findings were present in a significant minority of cases (16.5%). (Arch Pathol Lab Med. 2000;124:545‐549)

Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections.

Surgical management of intractable epilepsy continues to be important in select cases to achieve seizure control. This study retrospectively reviews the pathologic findings in 133 consecutive cases of extratemporal lobe epilepsy experienced during a 17-year period. The study group consists of 133 patients (78 males) who underwent extratemporal lobe resection for epilepsy at a mean age of 21.1 years (range, 3 months to 57 years). In 50 patients (37.6%), cortical dysplasia (neuronal migration abnormalities) was identified. The most common patterns of dysplasia observed included diffuse architectural disorganization in 46 cases, neuronal cytomegaly in 30 cases, increased numbers of molecular layer neurons in 30 cases, and balloon cells in 18 cases. Tumors were identified in 37 cases (27.8%) and included 13 astrocytomas, 7 gangliogliomas, 6 dysembryoplastic neuroepithelial tumors, 6 glioneuronal hamartomas, 4 oligodendrogliomas, and 1 oligoastrocytoma (mixed glioma). Twenty-four resections (18%) showed evidence of remote ischemic damage or infarct. Neuronal heterotopia was identified in 59 resection specimens (44.4%). Other less common findings included vascular malformations in 4 patients (3.0%), Sturge-Weber malformations in 3 patients (2.3%), and Rasmussen encephalitis in 2 patients (1.5%). Two patients were known to have tuberous sclerosis. In 23 resection specimens (17.3%), no significant pathologic finding was identified. Coexistent cortical dysplasia and tumor were seen in 10 cases and coexistent dysplasia and infarct or remote ischemic damage in 11 cases. This series demonstrates that most patients with extratemporal lobe epilepsy have significant histopathologic findings, which most frequently include cortical dysplasia, tumor, or evidence of remote ischemic damage or infarct. Coexistent pathologic findings were present in a significant minority of cases (16.5%).

Histopathologic findings in 37 cases of functional hemispherectomy.

Hemispherectomy procedures are performed in patients for whom focal cortical resection would be predicted to produce a significant reduction in seizures. The functional hemispherectomy procedure consists of disconnecting the hemispheres while attempting, in some cases, to preserve parenchyma. This study retrospectively reviews the histopathologic findings in 37 cases of functional hemispherectomy performed between 1990 and 1998 at a major epilepsy center. Procedures were performed in 20 males and 17 females who ranged in age from 3 months to 37 years (mean age, 9.6 years). In all but two cases, more than half or all the material submitted for pathologic testing was examined histologically. Cortical dysplasias or hemimegalencephaly were identified in 14 patients. The most common patterns of dysplasia observed included architectural disorganization (n = 13), increased molecular layer neurons (n = 11), and neuronal cytomegaly (n = 11). One patient was known to have epidermal nevus syndrome. Six patients had Sturge-Weber syndrome. Remote infarct/ischemic damage was identified as the etiology of seizures in six patients; four of these patients had mild associated secondary cortical architectural abnormalities. Three patients demonstrated pathology consistent with Rasmussen's encephalitis; one additional patient had chronic encephalitis changes, not otherwise specified. In two cases, changes consistent with hippocampal sclerosis were identified; additionally, hippocampal neuronal loss and gliosis was focally identified in three patients. Most of these patients had coexistent cortical dysplasia or radiographic evidence of remote infarct. One specimen demonstrated areas of infarct following resection of an arteriovenous malformation. In two specimens, significant histopathologic findings were not identified; both of these patients had radiographic evidence of remote infarct. The spectrum of pathologic conditions that may be encountered in the setting of a functional hemispherectomy is varied and in this study most frequently included cortical dysplasia, Sturge-Weber syndrome remote infarct, and Rasmussen's encephalitis.

Neuronal migration disorders in cerebral palsy

We retrospectively analyzed 58 autopsy cases of cerebral palsy which were clinically diagnosed at the Aichi Prefecture Colony Hospital. Most of the cases of cerebral palsy had brainweights that were 60-70% of the normal brainweight for their ages. However, approximately 20% of the brains were not small, especially in cases over 20 years of age. The brains of cerebral palsy cases showed wide morphological variation, and were classified into thinned cerebral mantle type (10 cases), hydrocephalus type (three cases) and microgyria-pachygyria type (45 cases). Macroscopic morphometric analysis was performed in the brains of the microgyria-pachygyria type using the coronal whole brain sections through the mammillary bodies stained with Klüver-Barerra (KB) stain, and compared with the brains of four cases of the Fukuyama type congenital muscular dystrophy (FCMD), two cases of lissencephaly, and nine cases of non-neural diseases as controls. The morphometric values of the coronal sections in the cerebral palsy cases showed diminished white matter with more dilatated ventricles compared with the control brains. This tendency was stronger in the brains of spastic cerebral palsy cases than in the brain of athetotic cerebral palsy cases. Cerebral palsy, in terms of the morphological complexity of the cerebrum as determined by the morphometric analysis, was situated between FCMD and lissencephaly. Although microscopic analysis of cerebral palsy brains was limited to 19 cases, there were four brains with heterotopic gray matter, three brains with cortical folding, a sign of cortical dysplasia, and three brains with neuronal cytomegaly. In addition, more than half of the brains showed disorganization of lamination in the cortex with disorientation of neurons. These findings suggest that some cases of cerebral palsy may result from disrupted neuronal migration during cortical development.

Tuberous sclerosis-related gene expression in normal and dysplastic brain.

Cortical dysplasia (CD) broadly defines a complex cerebral malformative lesion associated clinically with intractable, pharmacoresistant epilepsy (including infantile spasms), especially in infants and children. In CD, the spectrum of structural brain abnormalities includes (at a minimum) neuronal dyslamination and (in severe cases) neuronal cytomegaly with cytoskeletal alterations and the presence of gemistocyte-like 'balloon cells'. In some CD variants, the neuropathological features are essentially indistinguishable from those of a tuber of tuberous sclerosis (TSC). Two genes associated with the autosomal dominant, multi-system disorder TSC have recently been cloned: TSC2 (on chromosome 16p13.3) encodes the protein tuberin and TSC1 (on 9q34) encodes hamartin. Tuberin has been immunolocalized to neurons and possibly astrocytes in normal brain and CD/TSC tubers, and is widely expressed in normal viscera; loss of heterozygosity and tissue culture studies suggest it functions as a growth suppressor. The TSC1 gene has been cloned within the last year and hamartin as yet has no well-defined cellular function, though its protein product may also function as a growth suppressor. This article focuses on the cellular pathogenesis of CD and TSC brain lesions and how the two may be biologically related. Studies of how TSC1 and TSC2 function in normal and dysplastic cerebral neocortex may provide a paradigm for understanding the neurobiology of other genes that determine epilepsy-associated cerebral malformations (e.g. lissencephaly, double cortex).

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.