Search

The recent identification of the somatic GNAQ mutation (c.548G > A) provides insight into the pathogenesis of Sturge–Weber syndrome (SWS). Although the primary SWS brain pathology is the leptomeningeal angiomatosis (LMA), cerebral cortical and white matter abnormalities play a prominent role in the disease manifestations. In some cases, SWS brain involvement is present even without detectable LMA on magnetic resonance imaging (MRI). To expand our understanding of the etiology of SWS brain pathology, surgical SWS brain specimens from nine children (age: 0.8–7.5 years) were carefully separated into LMA and (non-LMA) brain tissue; the latter did not contain any vascular malformation. A custom Competitive Allele-Specific TaqMan PCR (castPCR) assay to detect the mutation in GNAQ was performed in these separated specimens. The mutation was present in all nine LMA and seven of the nine non-LMA brain tissues. LMA tissues were significantly enriched by the mutation, as compared with non-LMA brain (mean: 7.2 ± 2.1% and 1.2 ± 0.4%, respectively; p = 0.008). These results demonstrate that the somatic GNAQ mutation in SWS is not confined to the venous vascular malformation but can directly (although less severely) affect underlying brain parenchyma, not directly affected by LMA, and possibly contribute to SWS brain pathology. Future studies should identify the specific cell type(s) affected by the mutation in the SWS-affected brain parenchyma.

To identify the role of acute surgical intervention in the treatment of refractory status epilepticus (RSE). Retrospective review of consecutive patients who underwent epilepsy surgery from 2006 to 2015 was done to identify cases where acute surgical intervention was employed for the treatment of RSE. In addition, the adult and pediatric RSE literature was reviewed for reports of surgical treatment of RSE. Nine patients, aged 20–68 years, with various etiologies were identified to have undergone acute surgical resection for the treatment of RSE, aided by electrocorticography. Patients required aggressive medical therapy with antiepileptic drugs and intravenous anesthetic drugs for 10–54 days and underwent extensive neurodiagnostic testing prior to resective surgery. Eight out of nine patients survived and five patients were seizure-free at the last follow-up. The literature revealed 13 adult and 48 pediatric cases where adequate historical detail was available for review and comparison. We present the largest cohort of consecutive adult patients who underwent resective surgery in the setting of RSE. We also reveal that surgery can be efficacious in aborting status and in some can lead to long-term seizure freedom. Acute surgical intervention is a viable option in prolonged RSE and proper evaluation for such intervention should be conducted, although the timing and type of surgical intervention remain poorly defined.

SummaryObjective We reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms. Methods Data were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded. Results Mean age at surgery was 5.1 (range 0.2–19) years, with mean postsurgical follow-up of 45.3 (6–120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2–8), which decreased to 1.2 (0–4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated

Many 3rd-trimester stillbirths are unexplained, including the time course of the illness. Histologic acute thymic involution (ATI), when graded, correlates with duration of acute illness (grade 0, 72 hours). Histologic brain injury is also common in stillbirth. We investigated ATI in unexplained stillbirth and correlated it with neuropathologic injury by identifying 58 autopsies of unexplained, 3rd-trimester stillborns (preterm, n = 24; term, n = 34) that included brain examination and graded ATI from 0 (resting state) to 4 (pronounced lymphodepletion). Gray matter injury (GMI) and white matter injury (WMI) were classified as older, recent, or absent, and ATI was correlated with GMI, WMI, thymic weight, and clinical data. Nine cases (16%) had ATI grade 0–1; 19 (33%), grade 2; 24 (41%), grade 3; and 6 (10%), grade 4. Older GMI and WMI were present in 39 (67%) and 10 (17%) stillborns, respectively. Higher ATI grade correlated significantly with older GMI ( P < 0.001) and WMI ( P = 0.014). The ATI grade was higher in the small-for-gestational stillborns compared with the appropriate- or large-for-gestational stillborns ( P = 0.017) but did not correlate significantly with gestational age or other clinical or demographic factors evaluated. The ATI grades 2–4 were found in 84% of the stillborns, consistent with onset of acute illness between 24 and >72 hours before demise. Higher ATI grade correlated significantly with older brain injury, suggesting similar time of onset and shared underlying pathophysiologic events, the specific nature of which remains unclear.

Increasing evidence demonstrates the immunosuppressive kynurenine pathway’s (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[ 11 C]-methyl- l -tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.

PET of amino acid transport and metabolism may be more accurate than conventional neuroimaging in differentiating recurrent gliomas from radiation-induced tissue changes. α-(11)C-methyl-l-tryptophan ((11)C-AMT) is an amino acid PET tracer that is not incorporated into proteins but accumulates in gliomas, mainly because of tumoral transport and metabolism via the immunomodulatory kynurenine pathway. The aim of this study was to evaluate the usefulness of (11)C-AMT PET supplemented by tracer kinetic analysis for distinguishing recurrent gliomas from radiation injury.Twenty-two (11)C-AMT PET scans were obtained in adult patients who presented with a lesion suggestive of tumor recurrence on conventional MRI 1-6 y (mean, 3 y) after resection and postsurgical radiation of a World Health Organization grade II-IV glioma. Lesional standardized uptake values were calculated, as well as lesion-to-contralateral cortex ratios and 2 kinetic (11)C-AMT PET parameters (volume of distribution [VD], characterizing tracer transport, and unidirectional uptake rate [K]). Tumor was differentiated from radiation-injured tissue by histopathology (n = 13) or 1-y clinical and MRI follow-up (n = 9). Accuracy of tumor detection by PET variables was assessed by receiver-operating-characteristic analysis.All (11)C-AMT PET parameters were higher in tumors (n = 12) than in radiation injury (n = 10) (P ≤ 0.012 in all comparisons). The lesion-to-cortex K-ratio most accurately identified tumor recurrence, with highly significant differences both in the whole group (P0.0001) and in lesions with histologic verification (P = 0.006); the area under the receiver-operating-characteristic curve was 0.99. A lesion-to-cortex K-ratio threshold of 1.39 (i.e., a 39% increase) correctly differentiated tumors from radiation injury in all but 1 case (100% sensitivity and 91% specificity). In tumors that were high-grade initially (n = 15), a higher lesion-to-cortex K-ratio threshold completely separated recurrent tumors (all K-ratios ≥ 1.70) from radiation injury (all K-ratios1.50) (100% sensitivity and specificity).Kinetic analysis of dynamic (11)C-AMT PET images may accurately differentiate between recurrent World Health Organization grade II-IV infiltrating gliomas and radiation injury. Separation of unidirectional uptake rates from transport can enhance the differentiating accuracy of (11)C-AMT PET. Applying the same approach to other amino acid PET tracers might also improve their ability to differentiate recurrent gliomas from radiation injury.

Dysembryoplastic neuroepithelial tumors (DNTs) are typically hypometabolic but can show increased amino acid uptake on positron emission tomography (PET). To better understand mechanisms of amino acid accumulation in epileptogenic DNTs, we combined quantitative α-[(11)C]methyl-L: -tryptophan (AMT) PET with tumor immunohistochemistry. Standardized uptake values (SUVs) of AMT and glucose were measured in 11 children with temporal lobe DNT. Additional quantification for AMT transport and metabolism was performed in 9 DNTs. Tumor specimens were immunostained for the L: -type amino acid transporter 1 (LAT1) and indoleamine 2,3-dioxygenase (IDO), a key enzyme of the immunomodulatory kynurenine pathway. All 11 tumors showed glucose hypometabolism, while mean AMT SUVs were higher than normal cortex in eight DNTs. Further quantification showed increased AMT transport in seven and high AMT metabolic rates in three DNTs. Two patients showing extratumoral cortical increases of AMT SUV had persistent seizures despite complete tumor resection. Resected DNTs showed moderate to strong LAT1 and mild to moderate IDO immunoreactivity, with the strongest expression in tumor vessels. These results indicate that accumulation of tryptophan in DNTs is driven by high amino acid transport, mediated by LAT1, which can provide the substrate for tumoral tryptophan metabolism through the kynurenine pathway, that can produce epileptogenic metabolites. Increased AMT uptake can extend to extratumoral cortex, and presence of such cortical regions may increase the likelihood of recurrent seizures following surgical excision of DNTs.

Introduction Whipple's disease (WD) is a rare multisystemic infectious disease that can involve a variety of organs namely the gastrointestinal tract, lymphatic system, heart and nervous system. Myorhythmia is a hallmark of WD. Isolated CNS involvement is very rare. Case We present a 50 year-old African-American woman with rapid cognitive decline, visual hallucinations, insomnia, dysarthria, and gait unsteadiness. She subsequently developed pendular nystagmus and gaze paresis. Serial brain MRI scans showed T2 hyperintense lesions in the left striatum and right parahippocampal gyrus. FDG-PET scan showed marked increase of glucose uptake in the left putamen. Serum and CSF PCR for Tropheryma whipplei was negative. Stereotactic biopsy of the lesion and tissue PCR was consistent with WD. Review of literature A systematic review identified 24 cases of isolated intracranial presentation of WD since 1975. Cases with systemic and extracranial manifestations were excluded. Discussion In patients with rapidly progressive cognitive decline with negative workup for common etiologies, there should be a high index of suspicion for WD. Diagnosis of WD remains a challenge as traditional methods commonly fail to culture T. whipplei. PET scans can help in identifying areas of inflammation that can be biopsied. Our case proves that a negative serum and CSF PCR should not exclude CNS WD and a brain biopsy of the lesion with PCR assay should be performed when possible.

Recently, we reported hippocampal and temporal lobe abnormalities in 5 toddlers with sudden unexplained death in childhood (SUDC). The association of these anomalies with a high incidence (40%) of individual/family histories of simple febrile seizures in the cases raised concern that febrile seizures can be associated with death. In a series of 64 toddlers with sudden death, we tested the hypothesis that an SUDC subset is characterized by hippocampal and temporal lobe maldevelopment and an individual and/or family history of simple familial seizures. Cases of sudden and unexplained death in children aged 1.0 to 5.9 years (median 1.7 years) were divided into groups based upon a history of febrile or nonfebrile seizures, familial febrile seizures, and autopsy classification of cause of death. Forty-nine of the 64 cases (77%) were classified as SUDC, of which 40% had an individual/family history of febrile seizures. Of the 26 SUDC cases with available hippocampal sections, 62% (16/26) had hippocampal and temporal lobe anomalies, including 82% (9/11) of cases with an individual/family history of febrile seizures. Cases with these anomalies were all found dead during a sleep period, typically in the prone (87%) position. We conclude that a potential new entity may account for the majority of SUDC in toddlers, defined by sleep-related death in the prone position, individual/family history of febrile seizures, and hippocampal and temporal lobe anomalies. The mechanism of death appears analogous to sudden death in (temporal lobe) epilepsy, with a putative unwitnessed seizure during sleep leading to airway occlusion and death. This study mandates further research into the potential link between simple febrile seizures and death.

Occasionally children undergoing cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest develop a postoperative syndrome of acute chorea. The authors report the neuropathological findings in two such children surgically treated for congenital heart disease. Examination of the brain showed neuronal loss, reactive astrocytosis and degeneration of myelinated fibers (without frank necrosis) in the globus pallidus, primarily the outer segment, with sparing of other regions commonly susceptible to hypoxic-ischemic necrosis. The localization and relative mildness of the brain damage suggest a susceptibility of the globus pallidus to injury in this setting and implicate disruption of pallidal pathways in the pathogenesis of post-cardiac surgery choreic syndrome.

Background To assess gliomas using image-based estimation of cellularity, we utilized isotropic diffusion spectrum imaging (IDSI) on clinically feasible diffusion tensor imaging (DTI) and compared it with amino acid uptake measured by α[11C]methyl-L-tryptophan positron emission tomography (AMT-PET). Methods In 10 patients with a newly-diagnosed glioma, metabolically active tumor regions were defined in both FLAIR hyperintense areas and based on increased uptake on AMT-PET. A recently developed independent component analysis with a ball and stick model was extended to perform IDSI in clinical DTI data. In tumor regions, IDSI was used to define tumor cellularity which was compared between low and high grade glioma and correlated with the glioma proliferative index. Results The IDSI-derived cellularity values were elevated in both FLAIR and AMT-PET-derived regions of high-grade gliomas. ROC curve analysis found that the IDSI-derived cellularity can provide good differentiation of low-grade from high-grade gliomas (accuracy/sensitivity/specificity of 0.80/0.80/0.80). . Both apparent diffusion coefficient (ADC) and IDSI-derived cellularity showed a significant correlation with the glioma proliferative index (based on Ki-67 labeling; R = 0.95, p

Background. Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using a-[ 11 C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas. Methods. Forty-seven patients with MRI-detected meningioma (n ¼ 16) and glioma (n ¼ 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3 ′ evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas. Results. Meningioma grade showed a positive correlation with AMT k3 ′ tumor/cortex ratio (r ¼ 0.75, P ¼ .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3 ′ ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3 ′ ratios (P ¼ .001). Conclusions. PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.

Mutations in the major peripheral nervous system (PNS) myelin protein, myelin protein zero (MPZ), cause Charcot-Marie-Tooth Disease type 1B (CMT1B), typically thought of as a demyelinating peripheral neuropathy. Certain MPZ mutations, however, cause adult onset neuropathy with minimal demyelination but pronounced axonal degeneration. Mechanism(s) for this phenotype are unknown. We performed an autopsy of a 73-year-old woman with a late-onset neuropathy caused by an H10P MPZ mutation whose nerve conduction studies suggested severe axonal loss but no demyelination. The autopsy demonstrated axonal loss and reorganization of the molecular architecture of the axolemma. Segmental demyelination was negligible. In addition, we identified focal nerve enlargements containing MPZ and ubiquitin either in the inner myelin intralaminar and/or periaxonal space that separates axons from myelinating Schwann cells. Taken together, these data confirmed that a mutation in MPZ can cause axonal neuropathy, in the absence of segmental demyelination, thus uncoupling the two pathological processes. More important, it also provided potential molecular mechanisms as to how the axonal degeneration occurred: either by disruption of glial-axon interaction by protein aggregates or by alterations in the molecular architecture of internodes and paranodes. This report represents the first study in which the molecular basis of axonal degeneration in the late-onset CMT1B has been explored in human tissue.

Previous studies have demonstrated that lesions of the anterior horn motor neurons are the primary pathology in patients with paralysis due to West Nile virus (WNV) infection. To characterize recovery and identify prognostic factors for the recovery of paralysis, we investigated 11 patients with electrophysiology testing and muscle biopsy, and one with autopsy. We found that limb weakness was markedly asymmetric and differed between upper and lower extremities, suggesting focal or segmental involvement of the spinal cord anterior horn. This was supported by segmental depletion of spinal motor neurons at autopsy. Clinical recovery was variable during a 21-month follow-up period. To explain variability, we performed motor unit number estimation (MUNE) in six patients. MUNE values and strength were correlated in tested muscles. We also detected motor nerve terminal damages in muscle biopsies, suggesting another possible mechanism for transient weakness and variable recovery. We conclude that the type of pathological lesions may vary in paralytic WNV infection, and different degrees or combinations of motor neuron loss and motor nerve terminal changes may account for the observed degrees of weakness and recovery.

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. α-[11C]Methyl-l-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution ( VD') and the metabolic rate constant ( k'3) were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood–brain barrier, while k'3values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k'3. In contrast, oligodendrogliomas showed high VD' values but lower k'3as compared with normal cortex. In astrocytic tumors, low grade was associated with high k'3and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders.

Summary Objective Cortical resections in epilepsy surgery tend to be larger in children, compared to adults, partly due to underlying pathology. Some children show unilateral multifocal seizure onsets involving much of the hemisphere. If there were a significant hemiparesis present, hemispherectomy would be the procedure of choice. Otherwise, it is preferable to spare the primary sensorimotor cortex. We report the results of “subtotal” hemispherectomy in 23 children. Methods All children (ages 1 year and 4 months to 14 years and 2 months) were operated on between 2001 and 2013 at Children's Hospital of Michigan (Detroit). Patients were evaluated with scalp video–electroencephalography (EEG), magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) scans, and neuropsychological assessments when applicable. Subsequently, each case was discussed in a multidisciplinary epilepsy surgery conference, and a consensus was reached pertaining to candidacy for surgery and optimum surgical approach. The actual extent of resection was based on the results from subdural electrocorticography (ECoG) monitoring. The surgical outcome is based on International League Against Epilepsy (ILAE) classification (class 1–6). Results Among the 23 patients, 11 had epileptic spasms as their major seizure type; these were associated with focal seizures in 3 children. MRI showed focal abnormalities in 12 children. FDG-PET was abnormal in all but one subject. All except two children underwent chronic subdural ECoG. Multiple subpial transections were performed over the sensorimotor cortex in three subjects. On histopathology, various malformations were seen in 9 subjects; the remainder showed gliosis alone (n = 12), porencephaly (n = 1), and gliosis with microglial activation (n = 1). Follow-up ranged from 13 to 157 months (mean = 65 months). Outcomes consisted of class 1 (n = 17, 74%), class 2 (n = 2), class 3 (n = 1), class 4 (n = 1), and class 5 (n = 2). Significance Extensive unilateral resections sparing only sensorimotor cortex can be performed with excellent results in seizure control. Even with the presence of widespread unilateral epileptogenicity or anatomic/functional imaging abnormalities, complete hemispherectomy can often be avoided, particularly when there is little hemiparesis.

With advances in therapy, more neonates with severe congenital anomalies are surviving, albeit some with neurologic disorders, possibly related to antenatal low brain blood flow. This autopsy series reports antenatal brain injury in neonates expiring due to severe anomalies, and provides correlation with umbilical cord blood gas and acid-base analysis.We identified autopsies of third trimester neonates expiring shortly following delivery due to severe anomalies or malformations. Brain injury classified as "older" included periventricular leukomalacia, gliosis and karyorrhectic neurons, and "recent" included red neurons and reactive glial changes.We identified 22 cases (nine term, 13 preterm). 16 (73%) had brain injury, including 11 with older injury. Cord arterial blood was analyzed in 17, and six had pH7 or base deficit12 mmol/L. Four out of 5 (80%) neonates with neuronal necrosis compared to two out of 12 (17%) without had a pH7 or base deficit12 mmol/L (p = 0.03). Five out of nine (56%) neonates with white matter injury compared to one out of 8 (13%) without had pH7 or base deficit12 mmol/L (p = NS).Antenatal brain injury is frequent in neonates with severe congenital anomalies. Severely abnormal cord blood analysis results correlate significantly with neuronal necrosis and show a trend toward white matter injury; however, the absence of these abnormal results does not preclude the presence of brain injury.

Our purpose was to determine whether maternal rat seizure activity was associated with fetal histopathologic brain changes and whether magnesium sulfate reduced these changes.Electrodes were stereotaxically implanted into the hippocampus of nonpregnant rats 1 week before breeding. Pregnant rats were randomly assigned to 1 of 4 groups: (1) sodium chloride solution and no seizure (n = 2), (2) magnesium sulfate and no seizure (n = 2), (3) sodium chloride solution and seizure (n = 5), and (4) magnesium sulfate and seizure (n = 5). On gestational days 9, 11, 13, 15, 17, and 19, subcutaneous doses of sodium chloride solution or magnesium sulfate were administered to all rats every 20 minutes for 4 hours (loading-maintenance-loading), followed by seizure induction. On gestational day 20, the rats were perfused with formalin and fetuses were delivered via cesarean. Fetuses were perfused with formalin, brains were obtained and embedded in paraffin, and the forebrain and hindbrain were sectioned in the coronal plane and stained with hematoxylin and eosin. A neuropathologist masked to the protocol performed histopathologic grading of each section, including extent and nature of cellular damage. Eleven brain regions were examined in each section. Scores were expressed as mean +/- SD. Kruskal-Wallis analysis of variance was used, and P.05 was considered significant.We evaluated 26 fetal brains in group 1, 9 in group 2, 72 in group 3, and 45 in group 4. Fetuses in the sodium chloride solution-and-seizure group (group 3) presented significantly higher grades of neuronal damage in the hippocampus (group 1, 0.50 +/- 0. 88; group 2, 0.22 +/- 0.66; group 3, 1.01 +/- 1.17; and group 4, 0. 48 +/- 0.72) and in the tegmentum region (group 1, 1.0 +/- 1.0; group 2, 0.8 +/- 1.0; group 3, 1.7 +/- 0.7; and group 4, 1.5 +/- 0. 8) (P.05, group 3 compared with others). Isolated and patchy neuronal injury with shrinkage of cells, nuclear pyknosis, and karyorrhexis were the main histologic findings.Maternal rat seizure activity was associated with histologic brain injury in the fetus. Maternal administration of magnesium sulfate before seizure prevented or significantly decreased this effect.

Purpose: To date, numerous retrospective studies have suggested that the addition of brachytherapy to the conventional treatment of malignant gliomas (MG) (surgical resection followed by radiotherapy ± chemotherapy) leads to improvements in survival. Two randomized trials have suggested either a positive or no survival benefit with implants. Critics of retrospective reports have suggested that the improvement in patient survival is due to selection bias. A recursive analysis by the RTOG of MG trials has stratified MG patients into 6 prognostically significant classes. We used the RTOG criteria to analyze the implant data at Wayne State University to determine the impact of selection bias. Methods and Materials: Between July 1991 and January 1998, 75 patients were treated with a combination of surgery, radiotherapy, and stereotactic I-125 implant as primary MG management. Forty-one (54.7%) were male; 34 (45.3%) female. Median age was 52 years (range 4–79). Twenty-two (29.3%) had anaplastic astrocytoma (AA); 53 (70.7%), glioblastoma multiforme (GBM). Seventy-two patients had data making them eligible for stratification into the 6 RTOG prognostic classes (I–VI). Median Karnofsky performance status (KPS) was 90 (range 50–100). There were 14, 0, 14, 31, 12, and 1 patients in Classes I to VI, respectively. Median follow-up time for AA, GBM, and any surviving patient was 29, 12.5, and 35 months, respectively. Results: At analysis, 29 (40.3%) patients were alive; 43 (59.7%), dead. For AA and GBM patients, 2-year and median survivals were: 58% and 40%; 38 and 17 months, respectively. For analysis purposes, Classes I and II, V and VI were merged. By class, the 2-year survival for implanted patients compared to the RTOG data base was: I/II—68% vs. I—76%; III—74% vs. 35%; IV—34% vs. 15%; V/VI—29% vs. V—6%. For implant patients, median survival by class was (in months): I/II—37; III—31; IV—16; V/VI—11. Conclusion: When applied to MG patients receiving permanent I-125 implant, the criteria of the RTOG recursive partitioning analysis are a valid tool to define prognostically distinct survival groups. As reflected in the RTOG study, a downward survival trend for the implant patients is seen from “best to worse” class patients. Compared to the RTOG database, median survival achieved by the addition of implant is improved most demonstrably for the poorer prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with I-125 implant and would contradict the notion that the patients most eligible for implant are those gaining the most benefit from the treatment. In light of the contradictory results from two randomized studies and given the present results, further randomized studies with effective stratification are required since the evidence for a survival benefit with brachytherapy (as seen in retrospective studies) is substantial.

Background. Previously, we demonstrated the high accuracy of alpha-[ 11 C]methyl-L-tryptophan (AMT) PET for differentiating recurrent gliomas from radiation injury. The present study evaluated the prognostic value of increased AMT uptake in patients with previously treated high-grade glioma. Methods. AMT-PET was performed in 39 patients with suspected recurrence of World Health Organization grades III– IV glioma following surgical resection, radiation, and chemotherapy. Mean and maximum standardized uptake values (SUVs) and unidirectional AMT uptake (K) were measured in brain regions suspicious for tumor and compared with the contralateral cortex (ie, background). Optimal cutoff thresholds for 1-year survival prediction were determined for each AMT parameter and used for calculating the prognostic value of high (above threshold) versus low (below threshold) values for post-PET overall survival (OS). Results. In univariate analyses, 1-year survival was strongly associated with 3 AMT parameters (SUVmax, SUVmean, and tumor-to-background K-ratio; odds ratios: 21.3 – 25.6; P ≤ .001) and with recent change in MRI contrast enhancement (odds ratio: 14.7; P ¼ .02). Median OS was 876 days in the low- versus 177 days in the high-AMT groups (log-rank P , .001). In multivariate analyses, all 3 AMT parameters remained strong predictors of survival: high AMT values were associated with unfavorable 1-year survival (binary regression P ≤ .003) and shorter overall survival in the whole group (Cox regression hazard ratios: 5.3 –10.0) and in patients with recent enhancement change on MRI as well (hazard ratios: 7.0–9.3; P ≤ .001). Conclusion. Increased AMT uptake on PET is highly prognostic for 1-year and overall survival, independent of MRI contrast enhancement and other prognostic factors in patients with a previously treated high-grade glioma.

To determine whether transient acute maternal hypoxemia during the end of pregnancy may cause neuronal damage in fetal rat brains.Nine pregnant rats (4 study and 5 controls) at 16-17 gestational days were studied. The study rats were placed in a chamber and breathed a gas mixture of 11.8% oxygen, 4.95% CO2, and nitrogen for either 1 or 2 h, while the control animals breathed room air. Tail venous blood was collected and gases were evaluated at the beginning and conclusion of the exposure periods. After 72 h of recovery, at 19-20 days' gestation, the fetal cardiovascular systems were perfused with saline and formalin. The brains were embedded in paraffin, sectioned in coronal plane, and stained with hematoxylin and eosin Histologic assessment of sections was performed by a neuropathologist blinded to the protocol. Statistical analysis of the data was performed using analysis of variance and the chi-square test.Exposure to the gas mixture resulted in decreased maternal pO2 from 39.9 +/- 7.6 mm Hg in the control group to 28.8 +/- 2.0 mm Hg in the 2-hour hypoxia group (p0.05). No significant changes in maternal pH or pCO2 status have been noted. A total of 34 fetal rat brains served as controls and 26 brains as the hypoxia study group There was a significant increase in isolated neuronal damage, including necrosis and shrinkage of cells, with karyorrhexis (fragmentation and breakage of the nucleus) in the hippocampus, basal ganglia, thalamus, and hypothalamus in the hypoxemia rats as compared with controls.Transient maternal hypoxemia may cause neuronal necrosis in vulnerable regions of the fetal rat brain, including the hippocampus, basal ganglia, thalamus, and hypothalamus.

Medial temporal lobe epilepsy is commonly associated with hippocampal atrophy on MRI and hippocampal sclerosis on histopathological examination of surgically-resected specimens. Likewise, it is well-established that prolonged seizures and status epilepticus can lead to hippocampal edema as noted on MRI. In this paper, the authors present an unusual patient with prolonged refractory status epilepticus, due to limbic encephalitis associated with anti-GAD antibody, who underwent palliative epilepsy surgery. Bilateral hippocampal edema was noted on preoperative MRI. Histologic evaluation confirmed presence of acute necrosis and neuronal loss in the left hippocampal formation. Follow-up MRI several months after surgery demonstrated severe atrophy of the contralateral right hippocampus. This is the first clear histopathological evidence that hippocampal atrophy following status epilepticus is the result of acute neuronal necrosis and cell loss.

Pretreatment delineation of infiltrating glioma volume remains suboptimal with current neuroimaging techniques. Gadolinium-enhanced T1-weighted (T1-Gad) MR images often underestimate the true extent of the tumor, while T2-weighted images preferentially highlight peritumoral edema. Accumulation of α-[(11)C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) has been shown in gliomas. To determine whether increased uptake on AMT-PET would detect tumor-infiltrated brain tissue outside the contrast-enhancing region and differentiate it from peritumoral vasogenic edema, volumes and spatial concordance of T1-Gad and T2 MRI abnormalities as well as AMT-PET abnormalities were analyzed in 28 patients with newly-diagnosed WHO grade II-IV gliomas. AMT-accumulating grade I meningiomas were used to define an AMT uptake cutoff threshold that detects the tumor but excludes peri-meningioma vasogenic edema. Tumor infiltration in AMT-accumulating areas was studied in stereotactically-resected specimens from patients with glioblastoma. In the 28 gliomas, mean AMT-PET-defined tumor volumes were greater than the contrast-enhancing volume, but smaller than T2 abnormalities. Volume of AMT-accumulating tissue outside MRI abnormalities increased with higher tumor proliferative index and was the largest in glioblastomas. Tumor infiltration was confirmed by histopathology from AMT-positive regions outside contrast-enhancing glioblastoma mass, while no or minimal tumor cells were found in AMT-negative specimens. These results demonstrate that increased AMT accumulation on PET detects glioma-infiltrated brain tissue extending beyond the contrast-enhanced tumor mass. While tryptophan uptake is low in peritumoral vasogenic edema, AMT-PET can detect tumor-infiltrated brain outside T2-lesions. Thus, AMT-PET may assist pretreatment delineation of tumor infiltration, particularly in high-grade gliomas.

PURPOSE PET studies with α[C-11]methyl-L-tryptophan (AMT) have shown decreased serotonin synthesis based on a decrease of the unidirectional uptake rate (K-complex) in neuropsychiatric conditions such as autism and depression. Increased AMT K-complex in tumors can indicate increased tryptophan metabolism via the immunosuppressive kynurenine pathway. Moreover, apparent AMT volume of distribution (VD') reflects net tryptophan transport from blood to tissue. We evaluated if kinetic parameters (K-complex, VD') of AMT, measured by PET, can predict the proliferative activity of glioma, and if these AMT parameters are altered in the remote cortex. METHODS We evaluated dynamic AMT PET images of 30 adult patients with grade 2 to 4 gliomas according to the World Health Organization's classification to determine tumoral AMT VD' and K-complex values, which were correlated with tumor proliferative activity as assessed by the Ki-67 labeling index in resected tumor specimens. We also compared cortical VD' and K-complex values between patients with glioma and healthy controls. RESULTS Both VD' and K-complex values were significantly higher in gliomas than in the contralateral cortex (VD', P < 0.001; K-complex, P < 0.001). Tumoral VD' values and tumor/cortex VD' ratios, but not the K-complex, showed strong positive correlations with the proliferative activity of glioma (P ≤ 0.001). The contralateral frontal cortex showed decreased AMT VD' and K-complex in patients with glioma compared with those in controls (P ≤ 0.01). CONCLUSIONS Increased net amino acid transport into tumor tissue, quantified by PET, can serve as an imaging marker of the proliferative activity of glioma. The data also suggest a glioma-induced down-regulation of cortical serotonin synthesis, likely mediated by shunting of tryptophan from serotonin synthesis to kynurenine metabolism.

We report the neuropathologic findings and clinicopathologic associations in 63 3rd trimester singleton stillborn fetuses. All were ≥28 weeks estimated gestational age (EGA) with complete autopsies, including placental examination. Fetuses with chromosomal abnormalities, major congenital anomalies, and intrapartum demise were excluded. The cases were divided into those with abruption ( n = 12) and those with unexplained fetal demise ( n = 51). The latter group was then subdivided by gestational age with 3 subgroups (preterm 28 to Established or recent injury involving gray or white matter was seen in 88% of the fetuses with unexplained demise versus 42% with abruption ( P = 0.001). The most common form of brain injury was established gray matter damage, seen in 65% of the fetuses with unexplained demise versus 25% with abruption ( P = 0.021), the most common pattern being established pontosubicular neuronal necrosis plus established neuronal necrosis in other sites. There was no significant difference in the frequency of brain injury between the SGA fetuses and AGA/LGA fetuses or between the unexplained stillbirth preterm and term subgroups, and there was no unequivocal correlation between placental lesions and brain lesions. Brain injury, most frequently established gray matter damage, is seen in the majority of stillborn infants with unexplained demise, indicating that the brain injury predates the period immediately before death.

We reviewed the records of 98 consecutive patients, 18 years of age or younger, with pathologically confirmed supratentorial astroglial neoplasms at the Children's Hospital, Boston, to evaluate the importance of seizures in their presentation and natural history. Tumors were diagnosed using the WHO criteria as pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas, glioblastomas, giant cell glioblastomas, oligoastrocytomas and gangliogliomas. Our results were as follows. (1) Fifty percent of children had seizures as part of their presentation and 30% had seizures as their only presenting phenomenon. (2) The seizures varied in nature, but complex (55%) or simple (28%) partial seizures were by far the most common types, occurring in 77% of cases. (3) Preoperative electroencephalography (EEG) accurately lateralized to the tumor side in 88% of the cases and localized to the correct lobe in 56%. (4) Tumors involving cerebral cortex significantly correlated with seizures at presentation as compared to noncortical locations; 59% of patients with cortical tumors presented with seizures, and only 15% of patients with noncortical tumors experienced seizures. Lesions in the temporal and frontal lobes had the highest incidence of seizures. (5) Patients with gangliogliomas and oligoastrocytomas had the highest incidence of seizures, 88 and 86%, respectively, whereas patients with anaplastic astrocytoma had the lowest incidence, 21%. (6) Histopathologic calcification was associated with seizures at presentation approaching significance (p = 0.06). (7) Seizures at presentation were significantly associated with good prognosis (p = 0.02).

Plasma cell granuloma (PCG) is an uncommon non-neoplastic mass lesion of unknown etiology. It is characterized by a polyclonal proliferation of chronic inflammatory cells, mostly mature plasma and other mononuclear cells. PCGs arising in the central nervous system are particularly rare. We report two additional cases of intracranial PCG exclusively involving the brain parenchyma. A 47 year-old woman, presenting with partial motor seizures and fluent aphasia, underwent complete excision of a well-demarcated, enhancing left parietal mass. The second patient was a 56 year-old man presenting with headaches and right-sided weakness who underwent stereotactic biopsy of an ill-defined, heterogeneously enhancing lesion in the left basal ganglia. Immunohistochemical analysis of surgical specimens showed polyclonal plasma cells and mature lymphocytes but no etiological agent. A histopathologic diagnosis of intracranial PCG was made in both cases. PCG should be part of the differential diagnosis of enhancing mass lesions of the brain. The etiology and natural history of these tumor-like lesions is not fully understood. Complete surgical excision appears to be curative. Lesions where total resection is not possible may benefit from adjuvant treatment including corticosteroids and possibly radiation therapy.

Hydrolethalus syndrome is a rare autosomal recessive (AR) disorder characterized by polyhydramnios, CNS abnormalities, cleft lip/palate, micrognathia, and polydactyly. Its molecular basis is unknown and prenatal diagnosis is challenging due to phenotypic overlap with several other midline malformation syndromes. A 34-year-old G3P2, nonconsanguinous, married, African-American woman was referred at 19 weeks of gestation after ultrasound findings of "multiple congenital anomalies." A previous pregnancy had been terminated following ultrasound findings of polyhydramnios, cleft lip/palate, polydactyly, severe hydrocephalus, and a Dandy-Walker malformation (DWM). Level II ultrasound evaluation of the current pregnancy demonstrated all of the anomalies which had been present in her previous pregnancy. Karyotype of amniocytes was 46,XX. Autopsy following pregnancy termination confirmed ultrasound findings. The pedigree, sonographic, and autopsy findings in this case were most consistent with hydrolethalus syndrome, although other AR multiple midline malformation syndromes were considered. Our case was detected by 19 weeks. Confident differential diagnosis is difficult for the geneticist and even more so for the sonologist given the technical limitations of ultrasound. It is uncertain whether these mendelian midline malformation syndromes represent slightly different phenotypic expressions of a common genetic defect or are manifestations of allelic and or locus heterogeneity. We suggest that for prenatal diagnostic purposes, in the absence of knowledge of the molecular basis of these disorders, the fine distinctions are not crucial as long as their mendelian inheritance is recognized and presence or absence of manifestations which make them severe are ascertained.

PURPOSE DNA ploidy status, completeness of surgical resection, use of chemotherapy, adequacy of radiation therapy, metastatic stage, sex, and age at diagnosis were evaluated as predictors of relapse in 58 patients with cerebellar medulloblastoma. METHODS Flow cytometry (FCM) and/or image analysis (IA) were used to characterize tumor DNA ploidy. Twelve tumors (21%) were found to be aneuploid, 11 (19%) tetraploid, and 35 (60%) diploid. RESULTS The most significant predictors of relapse in univariate analyses were the adequacy of radiation (> or = 50 Gy) (P = .02), metastatic staging (P = .05), completeness of resection (P = .085), and DNA ploidy status (diploid/tetraploid v aneuploid; P = .11). When the 52 patients who received > or = 50 Gy were included in a multivariate Cox model analysis, those with diploid/tetraploid tumors had fewer recurrences than those with aneuploid tumors (relative risk, 0.33; 95% confidence interval, 0.12 to 0.89; P = .03). Patients with complete resections (P = .07), or with stage M0 disease (P = .06) had fewer recurrences than other patients, but these factors were not independent predictors of outcome. DNA ploidy status was correlated with age; 10 of the 12 aneuploid tumors were found in children ages 3 to 10 years. Age, sex, and the use of chemotherapy were not prognostically significant in these analyses. CONCLUSION The adequacy of radiation dose and DNA ploidy were the most important prognostic factors in this series. Contrary to previous reports, when corrected for adequacy of treatment, DNA aneuploidy was associated with a poor outcome. By multivariate analyses, DNA ploidy was an independent variable, even when controlling for extent of surgical resection and metastatic stage.

Benign histiocytic proliferations are identified by their component cells and classified as either Langerhans cell histiocytosis or non-Langerhans cell histiocytosis. We report a 58-year-old Caucasian woman who presented with diabetes insipidus and was found to harbor a large suprasellar mass. Histopathological analysis was consistent with non-LCH. The differential diagnoses included juvenile xanthogranuloma, adult-onset xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, and Erdheim-Chester disease. Immunohistochemical examination demonstrated a proliferation of large lipid-laden histiocytic cells which were positive for CD68, negative for S100 protein, and showed only faint, background staining for CD1a. We present a case of an autopsy-confirmed non-Langerhans cell histiocytosis limited to the central nervous system and evaluated with both immunohistochemical and ultrastructural studies. Based on the multifocality, anatomic distribution, and immunostaining features, a diagnosis of Erdheim-Chester disease was made. This is only the second reported case of Erdheim-Chester disease with intracranial involvement but absence of extracerebral manifestations. Given the overlapping clinicopathologic, radiographic, and immunohistochemical profiles, differentiating between these rare histiocytic disorders can often present a significant diagnostic challenge. A systematic approach using all available clinical, laboratory, radiographic, histologic, immunohistochemical and ultrastructural data is essential for proper discrimination between the numerous histiocytoses.

BACKGROUND: Vulvodynia, defined as vulvar pain or burning in the presence of normal vulvar appearance, is common and is associated with chronic pain syndromes and psychiatric disorders. CASE: A postmenopausal woman complained of vulvar burning. Causes for vulvar burning including yeast infection, estrogen deficiency, and contact dermatitis were excluded. Vulvovaginal examination was normal. Subsequently, she complained of headaches, insomnia, and depression. She developed ataxic gait with rapidly progressive dementia. Brain biopsy confirmed the diagnosis of Creutzfeldt-Jakob disease, and 3 weeks later she lapsed into coma and died. CONCLUSION: This report is unique in that a rare disease, known to result in neuronal damage, mimicked symptoms of vulvodynia in its initial phase. This supports the hypothesis that vulvodynia is a neuropathic syndrome originating in the nervous system.

Tryptophan catabolism via the kynurenine pathway, mediated by indoleamine 2,3-dioxygenase (IDO), is a mechanism involved in tumor immunoresistance. Positron emission tomography (PET) with α-[11C]methyl-L-tryptophan (AMT) can quantify transport and metabolism of tryptophan in infiltrating gliomas and glioneuronal tumors. In the present study, we investigated whether increased tryptophan metabolism in brain tumors measured by PET is related to expression of IDO in resected brain tumor specimens. IDO expression was assessed by immunohistochemistry in tumor specimens from 15 patients (median age, 34 years) with primary brain tumors who underwent AMT PET scanning before tumor resection. Patterns of IDO expression were compared between low- and high-grade tumors and also to AMT transport and metabolism measured on PET. IDO immunoreactivity was seen in tumor cells in six of seven low-grade tumors but only in one of eight high-grade tumors (p = 0.01); three of these latter tumors showed endothelial staining only. Low-grade neoplasms showed lower transport rate (p

In 1948 Cahan and others reported 11 cases of sarcoma that arose in radiated bone, mostly in children treated for tuberculosis. They studied only cases that met certain inclusion criteria: 1) there must have been histologic or radiographic evidence of the nonmalignant nature of the initial condition; 2) the sarcoma that arose must have arisen in the area included in the radiotherapeutic beam; 3) there must have been a relatively long, asymptomatic period of latency between radiation and development of the sarcoma; and 4) the sarcoma must be proved histologically. Since Cahan’s report, these criteria have often been cited as requirements for considering a case to represent radiationinduced malignancy. Since the 1980s there has been considerable interest in stereotactic radiosurgery and other forms of focused radiation therapy for nonmalignant conditions. One of the concerns raised by radiation treatments for acoustic neuroma, which has somewhat limited their use, is the potential for radiation to induce other intracranial tumors, including malignancies. Because such cases are rare, it has been difficult to establish a reliable estimate of their occurrence to guide selection of treatment and patient counseling. We report a case that we feel should be taken into consideration when estimating the risk of radiation-induced malignancy. Institutional Review Board approval was obtained. A 58-year-old woman presented to the emergency department complaining of increasing ataxia for the past two weeks. She also noted numbness and tingling in the right face and body, diplopia, blurred vision, nausea, and vomiting for the same period. On the morning of admission she experienced a severe pressure headache at the right mastoid process, which spread to include the left side within a few hours. The past medical history was significant for microsurgical excision of a right acoustic neuroma two years previously. This was conducted as a two-stage procedure at another center. A few months postoperatively she received an osseointegrated implant for single-sided deafness. The patient’s family history was negative for cancer, schwan

Preliminary studies suggest that alpha[ 11 C]methyl-l-tryptophan positron emission tomography can detect the epileptic focus within malformations of cortical development. We determined the sensitivity and specificity of alpha-[ 11 C]methyl-l-tryptophan positron emission tomography in identifying epileptic focus in children with intractable, neocortical epilepsy with and without malformations of cortical development. Seventy-three epileptic children were classified into lesional and nonlesional groups, and compared regarding focal increased alpha-[ 11 C]methyl-l-tryptophan uptake. The sensitivity and specificity of focal increased alpha-[ 11 C]methyl-l-tryptophan uptake, using intracranial electroencephalogram localization of seizure onset as the standard, were compared between lesional and nonlesional groups. The specificity of alpha-[ 11 C]methyl-l-tryptophan positron emission tomography for detecting seizure onset lobe was equally high in lesional (97%) and nonlesional groups (100%), whereas sensitivity was higher in the lesional than the nonlesional group (47% versus 29%; P = 0.047). The incidence of alpha-[ 11 C]methyl-l-tryptophan uptake abnormality was higher in the lesional than the nonlesional group ( P 0.01). Alpha-[ 11 C]methyl-l-tryptophan positron emission tomography localized and visualized epileptogenic regions in 25% of patients with nonlocalizing magnetic resonance imaging. Although overall sensitivity of alpha-[ 11 C]methyl-l-tryptophan positron emission tomography in identifying neocortical epileptic focus is modest, specificity is extremely high. When an alpha-[ 11 C]methyl-l-tryptophan focus is detected, it likely represents the epileptogenic region to be resected.

Sudden unexplained death in childhood (SUDC) is the sudden death of a child older than 1 year of age that remains unexplained after review of the clinical history, circumstances of death, and autopsy with appropriate ancillary testing. We report here 5 cases of SUDC in toddlers that we believe define a new entity associated with hippocampal anomalies at autopsy. All of the toddlers died unexpectedly during the night, apparently during sleep. Within 48 hours before death, 2 toddlers had fever, 3 had a minor upper respiratory tract infection, and 3 experienced minor head trauma. There was a history of febrile seizures in 2 (40%) and a family history of febrile seizures in 2 (40%). Hippocampal findings included external asymmetry and 2 or more microdysgenetic features. The incidence of certain microdysgenetic features was substantially increased in the temporal lobes of these 5 cases compared with the temporal lobes of 39 (control) toddlers with the causes of death established at autopsy ( P < 0.01). We propose that these 5 cases define a potential subset of SUDC whose sudden death is caused by an unwitnessed seizure arising during sleep in the anomalous hippocampus and producing cardiopulmonary arrest. Precipitating factors may be fever, infection, and/or minor head trauma. Suggested risk factors are a history of febrile seizures and/or a family history of febrile seizures. Future studies are needed to confirm these initial findings and to define the putative links between sudden death, hippocampal anomalies, and febrile seizures in toddlers.

We report morphological data on brains of four African, Loxodonta africana, and three Asian elephants, Elephas maximus, and compare findings to literature. Brains exhibit a gyral pattern more complex and with more numerous gyri than in primates, humans included, and in carnivores, but less complex than in cetaceans. Cerebral frontal, parietal, temporal, limbic, and insular lobes are well developed, whereas the occipital lobe is relatively small. The insula is not as opercularized as in man. The temporal lobe is disproportionately large and expands laterally. Humans and elephants have three parallel temporal gyri: superior, middle, and inferior. Hippocampal sizes in elephants and humans are comparable, but proportionally smaller in elephant. A possible carotid rete was observed at the base of the brain. Brain size appears to be related to body size, ecology, sociality, and longevity. Elephant adult brain averages 4783 g, the largest among living and extinct terrestrial mammals; elephant neonate brain averages 50% of its adult brain weight (25% in humans). Cerebellar weight averages 18.6% of brain (1.8 times larger than in humans). During evolution, encephalization quotient has increased by 10-fold (0.2 for extinct Moeritherium, approximately 2.0 for extant elephants). We present 20 figures of the elephant brain, 16 of which contain new material. Similarities between human and elephant brains could be due to convergent evolution; both display mosaic characters and are highly derived mammals. Humans and elephants use and make tools and show a range of complex learning skills and behaviors. In elephants, the large amount of cerebral cortex, especially in the temporal lobe, and the well-developed olfactory system, structures associated with complex learning and behavioral functions in humans, may provide the substrate for such complex skills and behavior.

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of α-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones ( P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery. ( J Child Neurol 2005;20:429—438).

Skin biopsy is a minimally invasive procedure and has been used in the evaluation of non-myelinated, but not myelinated nerve fibres, in sensory neuropathies. We therefore evaluated myelinated nerves in skin biopsies from normal controls and patients with Charcot-Marie-Tooth (CMT) disease caused by mutations in myelin proteins. Light microscopy, electron microscopy and immunohistochemistry routinely identified myelinated dermal nerves in glabrous skin that appeared similar to myelinated fibres in sural and sciatic nerve. Myelin abnormalities were observed in all patients with CMT. Moreover, skin biopsies detected potential pathogenic abnormalities in the axolemmal molecular architecture previously undetected in human neuropathies. Finally, myelin gene expression at both mRNA and protein levels was evaluated by real-time PCR and immunoelectron microscopy. Peripheral myelin protein 22 (PMP22) was increased in CMT1A (PMP22 duplication) and decreased in patients with hereditary neuropathy with liability to pressure palsies (PMP22 deletion). Taken together, our data suggest that skin biopsy may in certain circumstances replace the more invasive sural nerve biopsy in the morphological and molecular evaluation of inherited and other demyelinating neuropathies.

Summary: Purpose: Hemimegalencephaly (HMEG) is characterized by unilateral hemispheric enlargement and severe cytoarchitectural abnormalities that are highly associated with intractable epilepsy. No studies have defined alterations in neurotransmitter-receptor subunit gene expression in HMEG. We hypothesize that a differential expression of excitatory amino acid and γ-aminobutyric acid (GABA)A-receptor subunit messenger RNAs (mRNAs) exists in HMEG. Methods: The expression of mRNAs encoding 20 neurotransmitter-receptor subunits, synthetic enzymes, and uptake sites as well as select additional candidate genes was defined in HMEG samples (n = 8) compared with homotopic control cortex specimens by using targeted complementary DNA (cDNA) arrays. Expression of GLT-1 (a glial glutamate transporter), EAAC-1 (neuronal glutamate transporter), and NMDA2B was corroborated by immunohistochemical, Western, and ligand-binding assays. Results: Differential expression of 11 neurotransmitter-related mRNAs was demonstrated in HMEG compared with control cortex. For example, expression of GLT-1 and GluR6 mRNAs was enhanced, whereas diminished expression of the neuronal glutamate transporter EAAC-1, GABAAα2, GABAAγ2, GABAAγ3, NMDA2B, GluR1, GluR2, GluR4, and GluR5 subunits occurred. Reduced NMDA2B subunit mRNA expression in HMEG was confirmed by receptor ligand-binding assays by using the NMDA2B-receptor antagonist ifenprodil, which revealed barely detectable levels of NMDA2B binding compared with that in control cortex. Conclusions: Selective alterations occur in distinct neurotransmitter-receptor and -uptake sites in HMEG. Differential expression of neurotransmitter-receptor and -uptake sites in HMEG may contribute to epileptogenesis in HMEG.

To examine the relationships between age at onset and duration of seizure disorder with severity of hippocampal sclerosis (HS) and cognitive functioning in patients with HS and unilateral temporal lobe epilepsy.Twenty-six subjects had left temporal lobe seizure onset; 20 had right temporal onset. Measures were age at seizure onset, duration of seizure disorder divided by age (seizure duration), history of febrile convulsion (FC), ratio of the smaller hippocampal volume to the larger (HF) as determined by volumetric MRI, and pathologic HS grade.Results showed that pathologic HS grade and HF were positively related to seizure duration, and negatively related to seizure onset. When subjects were divided into onset prior to age 10 versus later, subjects with earlier onset had higher mean pathologic HS grade and smaller (more asymmetric) mean HF. When subjects were divided into seizure duration0.5 (i.e., less than half current lifetime) vs greater, subjects with seizure durationor =0.5 had higher mean pathologic HS grade and lower mean HF. There was also evidence for earlier age at seizure onset and longer seizure duration being associated with worse performance on neuropsychological measures. FC was not related to either seizure duration or age at seizure onset, but patients with a history of FC showed higher pathologic HS grade and lower HF. A history of FC was not related to cognitive functioning.Unilateral HS patients with earlier seizure onset and longer duration of epilepsy have more severe HS and greater hippocampal volume asymmetry. This suggests that HS may be a progressive disorder with risk for cognitive dysfunction.

OBJECTIVE AND IMPORTANCE: Intravascular papillary endothelial hyperplasia (IPEH) is an atypical proliferation of endothelium that results in abnormal organization for thrombus formation. Intracranial IPEH is a rare entity and has not been reported to arise from within an intracranial aneurysm. Furthermore, the elapsed time during which acquired intracranial IPEH develops has not been previously documented. CLINICAL PRESENTATION: In this case report, a patient with facial and neck pain was noted to have an enhancing mass lesion lateral to the medulla in magnetic resonance imaging scans. Angiography revealed a vascular mass adjacent to the posteroinferior cerebellar artery. Normal magnetic resonance imaging and magnetic resonance angiographic findings had been obtained for the patient 29 months earlier. INTERVENTION: During surgery, a thrombosed, 2.5-cm, posteroinferior cerebellar artery aneurysm was resected and noted to contain florid IPEH. There has been no evidence of recurrence in 1 year of follow-up monitoring. A literature search revealed 13 cases of intracranial IPEH, in which recurrence was observed for incompletely resected lesions. CONCLUSION: IPEH can develop in a relatively short time, can present as a hypervascular mass lesion or within an intracranial aneurysm, and should be completely resected to prevent recurrence.

Objective: To determine whether severe maternal hypoxia affects fetal rat physical characteristics and causes neuronal damage, and whether magnesium sulfate can decrease these effects. Methods: At 17 days gestation, rats were randomly assigned to one of four groups that received saline injections and room air (n = 6), magnesium sulfate and room air (n = 5), saline and hypoxia (n = 5) or magnesium sulfate and hypoxia (n =5). Maternal magnesium sulfate or saline injections were given for 4 hours. In groups 3 and 4 this was followed by a hypoxia chamber protocol that included a gas mixture of 9% oxygen and 3% carbon dioxide for 2 hours. After 72 hours of recovery, fetuses were delivered abdominally, perfused transcardially, and brains removed intact. Fetal body and brain weight and size were measured. Brains were embedded in paraffin, sectioned, and stained. A neuropathologist masked to the protocol performed histologic grading of brain regions. Results: Exposure to the hypoxia chamber resulted in decreased maternal oxygen tension and pH (from 82.8 ± 20.0 to 49.2 ± 14.4 mmHg, and from 7.37 ± 0.05 to 7.20 ± 0.04, respectively; P < .005). Magnesium sulfate administration resulted in higher magnesium levels in blood (from 1.52 ± 0.2 to 3.77 ± 0.7 mg/dL; P < .001). The hypoxia protocol resulted in a significant decrease in fetal body and brain size, but not weight. Hypoxia also caused an increase in the proportion of fetal rats that had brain injury, including shrinkage of cells and karyorrhexis in the hippocampus and thalamus (from 0% to 38.1% and 38.9%, respectively; P < .05). Magnesium sulfate reduced these effects on fetal brain histopathology and size. Conclusion: Severe maternal rat hypoxia resulted in significant fetal neuronal damage and decreased fetal body and brain size. Maternal magnesium sulfate administration reduced the effect of hypoxia on fetal brain histopathology and size without affecting body size.

In vitro and in vivo parameters of flumazenil (FMZ) binding were measured in spiking and nonspiking neocortex identified by intraoperative elcctrocorticography in epileptic patients who underwent cortical resection for seizure control. In vitro measures of receptor affinity (KD), number (Bmax) and laminar distribution for [3H]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [11C]-FMZ binding measured with positron emission tomography (PET) (n = 19). The Bmax was higher in the 38 spiking tissues as compared to the 12 nonspiking tissues ( P = .012). Paired comparison of spiking versus nonspiking binding in the 12 patients from whom nonspiking tissue was available showed increases in both KD ( P = .037) and Bmax ( P = .0047) in spiking cortex. A positive correlation was found between KD and Bmax values for 38 patients (r = 0.55, P < .0001), the magnitude of the KD increase being twice that of the Bmax increase. In addition, there was a significant correlation between the asymmetry indices of the in vivo FMZ binding on PET and in vitro KD of spiking cortex (n = 19, r = 0.52, P = .02). The laminar distribution of [3H]-FMZ showed increased FMZ binding in cortical layers V-VI in spiking cortex compared to nonspiking and control cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increased Bmax in spiking cortex was accompanied by a larger decrease in the affinity of FMZ for the receptor suggesting that decreased FMZ binding in the epileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.

A consanguineous couple had 3 pregnancies in which prenatally diagnosed hydrocephalus was observed (in 1 female and 2 male fetuses). This case appears to represent an autosomal recessive form of hydrocephalus, given the consanguinity, affected sibs of both genders, and no evidence for intrauterine infection, chromosome abnormality, or neural tube defect.

Background The complex clinical and radiological picture of leptomeningeal spread of tumor is well recognized as a problem of systemic cancer but is less frequent in primary cerebral glioma, particularly as a presenting picture. While brain ischemia and infarction may occur in patients with subarachnoid tumor, the mechanism for these complications remains unclear. Angiographic and pathological demonstrations of direct vascular involvement by disseminated glioma are particularly sparse. We report a patient presenting with multiple infarctlike lesions with postmortem evidence of direct vascular involvement by glioma. Case Description A 54-year-old woman presenting with seizures, headache, and changes in mental status was found to have vascular narrowing in cerebral blood vessels and ischemic lesions on neuroimaging studies of the brain, interpreted as cerebral vasculitis. A brain biopsy showed leptomeningeal glioma. Postmortem examination demonstrated a glioblastoma arising around the right sylvian fissure with extensive subarachnoid dissemination of tumor. The leptomeningeal tumor caused vascular narrowing by encasement, direct vascular wall invasion, and thrombosis and was associated with underlying infarctlike foci of parenchymal necrosis. Conclusions This case demonstrates an unusual presentation of glioblastoma clinically and radiographically mimicking cerebral vasculitis, and it illustrates a variety of mechanisms for tumor-produced vascular compromise.

The biological nature of optic gliomas is controversial, with some considering them benign hamartomatous lesions, and others believing them to be true neoplasms. We evaluated the use of colloid silver impregnation of nucleolar organizer region-associated proteins (AgNORs) in making this distinction. Thirty-one optic gliomas, 14 optic nerve meningiomas, and a single case of giant cell glioblastoma multiforme (monstrocellular glioma) of the optic chiasm were stained for AgNORs and counted in a masked fashion. The optic gliomas contained 2.01 +/- 0.09 AgNORs per nucleus, similar to that of optic nerve meningiomas (2.15 +/- 0.15) and our previously reported counts for diffuse fibrillary astrocytoma (2.22 +/- 0.10), and significantly more than that of reactive astrocytosis (1.18 +/- 0.02). Six of the seven optic gliomas examined had compound AgNORs, a feature associated with malignancy in other tumour types. AgNOR counts did not correlate with clinical features, including those seen during the post-operation course. These data suggest that optic gliomas may be true neoplasms, and not benign hamartomas.

The intrauterine onset of convulsive syndromes has been documented only rarely, and previous reports have lacked detailed neuropathologic description. This report details a case of severe, intractable myoclonic encephalopathy, which, on the basis of severely abnormal paroxysmal fetal movement patterns confirmed by antenatal ultrasound, appears to have been of antenatal onset. The infant suffered an early demise and at autopsy showed features of a severe brain dysgenesis with polymicrogyria and superadded encephaloclastic features. Despite an extensive evaluation, the etiology of this condition remains elusive in our case. This case demonstrates that closer analysis of the qualitative features of fetal movements by, for instance, real-time ultrasound could aid in the antenatal diagnosis of neurologic, particularly convulsive, syndromes. ( J Child Neurol 1993;8:164-170).

A newborn with bilateral uncal herniation secondary to acute bacterial meningitis is reported. The findings of previous neuropathologic studies of neonatal bacterial meningitis are reviewed and the factors most likely responsible for the relative rarity of herniation in this disease in newborns are discussed.