B. K. Kleinschmidt-DeMasters

Concussion in Sports: Guidelines for the Prevention of Catastrophic Outcome

Concussion (defined as a traumatically induced alteration in mental status, not necessarily with loss of consciousness) is a common form of sports-related injury too often dismissed as trivial by physicians, athletic trainers, coaches, sports reporters, and athletes themselves. While head injuries can occur in virtually any form of athletic activity, they occur most frequently in contact sports, such as football, boxing, and martial arts competition, or from high-velocity collisions or falls in basketball, soccer, and ice hockey. The pathophysiology of concussion is less well understood than that of severe head injury, and it has received less attention as a result. We describe a high school football player who died of diffuse brain swelling after repeated concussions without loss of consciousness. Guidelines have been developed to reduce the risk of such serious catastrophic outcomes after concussion in sports.

Varicella-zoster virus infections of the nervous system: Clinical and pathologic correlates

BACKGROUND Diseases that present with protean manifestations are the diseases most likely to pose diagnostic challenges for both clinicians and pathologists. Among the most diverse disorders caused by a single known toxic, metabolic, neoplastic, or infectious agent are the central and peripheral nervous system complications of varicella-zoster virus (VZV). METHODS The pathologic correlates of the neurologic complications of VZV infection, as well as current methods for detecting viral infections, are discussed and presented in pictorial format for the practicing pathologist. RESULTS Varicella-zoster virus causes chickenpox (varicella), usually in childhood; most children manifest only mild neurologic sequelae. After chickenpox resolves, the virus becomes latent in neurons of cranial and spinal ganglia of nearly all individuals. In elderly and immunocompromised individuals, the virus may reactivate to produce shingles (zoster). After zoster resolves, many elderly patients experience postherpetic neuralgia. Uncommonly, VZV can spread to large cerebral arteries to cause a spectrum of large-vessel vascular damage, ranging from vasculopathy to vasculitis, with stroke. In immunocompromised individuals, especially those with cancer or acquired immunodeficiency syndrome, deeper tissue penetration of the virus may occur (as compared with immunocompetent individuals), with resultant myelitis, small-vessel vasculopathy, ventriculitis, and meningoencephalitis. Detection of the virus in neurons, oligodendrocytes, meningeal cells, ependymal cells, or the blood vessel wall often requires a combination of morphologic, immunohistochemical, in situ hybridization, and polymerase chain reaction (PCR) methods. The PCR analysis of cerebrospinal fluid remains the mainstay for diagnosing the neurologic complications of VZV during life. CONCLUSIONS Varicella-zoster virus infects a wide variety of cell types in the central and peripheral nervous system, explaining the diversity of clinical disorders associated with the virus.

The Expanding Spectrum of Herpesvirus Infections of the Nervous System

Herpesviruses cause various acute, subacute, and chronic disorders of the central (CNS) and peripheral (PNS) nervous systems in adults and children. Both immunocompetent and immunocompromised individuals may be affected. Zoster (shingles), a result of reactivation of varicella zoster virus (VZV), is the most frequent neurologic complication. Other neurological complications include encephalitis produced by type I herpes simplex virus (HSV‐1), and less frequently HSV‐2, as well as by VZV and cytomegalovirus (CMV). Acute meningitis is seen with VZV and HSV‐2, and benign recurrent meningitis with HSV‐2. Combinations of meningitis/ encephalitis and myelitis/radiculitis are associated with Epstein Barr Virus (EBV); myelitis with VZV, CMV, EBV, and HSV‐2; and ventriculitis/encephalitis with VZV and CMV. Brainstem encephalitis due to HSV and VZV, and polymyeloradiculitis due to CMV are well documented. HHV‐6 produces childhood exanthem subitum (roseola) and febrile convulsions. Immunocompetent and immunocompromised hosts manifest different incidences and patterns of herpesvirus infections. For example, stroke due to VZV‐mediated large vessel disease (herpes zoster ophthalmicus) occurs predominantly in immunocompetent hosts, while small vessel disease (leukoencephalitis) and ventriculitis develop almost exclusively in immunocompromised patients. EBV‐associated primary CNS lymphomas also are restricted to immunosuppressed individuals. Recent large CSF PCR studies have shown that VZV, EBV, and CMV more frequently produce meningitis, encephalitis, or encephalopathy in immunocompetent hosts than was formerly realized. We review herpesvirus infections of the nervous system and illustrate the expanding spectrum of disease by including examples of a 75‐year‐old male on steroid treatment for chronic lung disease with fatal HSV‐2 meningitis and an 81‐year‐old male with myasthenia gravis, long‐term azathioprine use, and an EBV‐associated primary CNS lymphoma.

Decrease in the Numbers of Dendritic Cells and CD4+ T Cells in Cerebral Perivascular Spaces Due to Natalizumab

OBJECTIVE To extend our studies on the prolonged and differential effect of natalizumab on T lymphocyte numbers in the cerebrospinal fluid, we investigated the number and phenotypes of leukocytes and the expression of major histocompatibility complex (MHC) classes I and II in cerebral perivascular spaces (CPVS). We hypothesized that natalizumab reduces the number of antigen presenting cells in CPVS. DESIGN A case-control study in which inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining. SUBJECTS A patient with multiple sclerosis (MS) who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy. Controls included location-matched cerebral autopsy material of patients without disease of the central nervous system, patients with MS not treated with natalizumab, and patients with PML not associated with natalizumab therapy. RESULTS The absolute number of CPVS in the patient with MS treated with natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture. The expression of MHC class II molecules and the number of CD209+ dendritic cells were significantly decreased in the CPVS of the patient with MS treated with natalizumab. No CD4+ T cells were detectable. CONCLUSIONS Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in the cerebrospinal fluid.

Varicella zoster virus, a cause of waxing and waning vasculitis: the New England Journal of Medicine case 5-1995 revisited.

A 73-year-old man developed an ill-defined fatal vasculitis involving the central nervous system. The case report was published as a clinicopathologic exercise in February 1995 in The New England Journal of Medicine. [1] We restudied the pathologic material and found both varicella zoster virus (VZV) DNA and VZV-specific antigen, but not herpes simplex virus (HSV) or cytomegalovirus (CMV) DNA or HSV- or CMV-specific antigen, in three of the five cerebral arteries examined. The inflammatory response, disruption of the internal elastic lamina, and detection of viral antigen were patchy from one artery to another, as well as within a given artery. A search for VZV should be conducted in cases of vasculitis when both the central and peripheral nervous systems are involved, when focal narrowing is present in large arteries, when brain imaging reveals infarction in gray and white matter, both deep and superficial, and when white matter is disproportionally involved. Zosteriform rash is not required for diagnosis. NEUROLOGY 1996;47: 1441-1446

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimers disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.

N-Methyl-d-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease

The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate receptor that plays a pivotal role in synaptic mechanisms of learning and memory. We tested the hypothesis that NMDA receptor protein levels are abnormal in Alzheimers disease (AD). By immunoblotting, we assessed levels of both non-phosphorylated and phosphorylated receptor subunit proteins from four separate regions of 16 post-mortem brains. Three patient groups with thorough pre-mortem neuropsychological testing were evaluated, including AD, early AD (p-AD), and control patients. Protein levels and phosphorylation status of NMDA receptor subunits NR1, NR2A and NR2B were correlated with measurements of cognitive performance. Selective regional reductions in NMDA receptor subunit protein levels were found in AD compared to controls, but protein levels in the p-AD group were similar to controls. Reductions of NR1 (53%, P<0.05) and NR2B (40%, P<0.05) were identified in hippocampus. Reductions of NR2A (39%, P<0.05) and NR2B (31%, P<0.01) were found in entorhinal cortex. No reductions were noted in occipital cortex and caudate. Phosphorylated NR2A (30%, P<0.05) and NR2B (56%, P<0.01) were selectively reduced in entorhinal cortex in AD when compared to controls. Both phosphorylated and non-phosphorylated NMDA receptor protein levels in entorhinal cortex correlated with Mini-Mental Status Examination (MMSE) and Blessed (BIMC) scores. The losses of phosphorylated and non-phosphorylated NMDA receptor subunit proteins correlated with changes in synaptobrevin levels (a presynaptic protein), but not with age or post-mortem interval. Our results demonstrate that NMDA receptor subunits are selectively and differentially reduced in areas of AD brain, and these abnormalities correlate with presynaptic alterations and cognitive deficits in AD.

Epithelioid GBMs show a high percentage of BRAF V600E mutation

BRAF V600E mutation has been identified in up to 2/3 of pleomorphic xanthoastrocytomas (PXAs), World Health Organization grade II, as well as in varying percentages of PXAs with anaplastic features (PXA-A), gangliogliomas, extracerebellar pilocytic astrocytomas, and, rarely, giant cell glioblastoma multiforme (GC-GBMs). GC-GBMs and epithelioid GBMs (E-GBMs) can be histologically challenging to distinguish from PXA-A. We undertook this study specifically to address whether these 2 tumor types also showed the mutation. We tested our originally reported cohort of 8 E-GBMs and 2 rhabdoid GBMs (R-GBM) as well as 5 new E-GBMs (1 pediatric, 4 adult) and 9 GC-GBMs (2 pediatric, 7 adult) (n=24) for BRAF V600E mutational status. Twenty-one of 24 had sufficient material for IDH-1 immunostaining, which is usually absent in PXAs, PXA-As, and primary GBMs but present in secondary GBMs. Patients ranged in age from 4 to 67 years. BRAF V600E mutation was identified in 7/13 of E-GBMs, including 3 of our original cases; patients with mutation were aged 10 to 50 years. None of the 9 GC-GBMs or 2 R-GBMs manifested this mutation, including pediatric patients. The sole secondary E-GBM was the single case manifesting positive IDH-1 immunoreactivity. A high percentage of E-GBMs manifest BRAF V600E mutation, paralleling PXAs. All R-GBMs and GC-GBMs were negative, although larger multi-institutional cohorts will have to be tested to extend this result. BRAF V600E mutational analyses should be performed on E-GBMs, particularly in all pediatric and young-aged adults, given the potential for BRAF inhibitor therapy in this subset of GBM patients.

A Role for Chromosome 9p21 Deletions in the Malignant Progression of Meningiomas and the Prognosis of Anaplastic Meningiomas

Meningiomas display significant variability in terms of recurrence and survival rates, even within tumor grade. Although several recent modifications of the grading system have improved our ability to predict biologic behavior, additional prognostic markers are needed. Inactivation of the cell cycle regulator, p16 (CDKN2A), has recently been observed in a small subset of atypical and the majority of anaplastic meningiomas. To assess the potential clinical utility of this marker, we performed dual‐color FISH on 117 well‐characterized archival meningiomas using paired commercial probes to the chromosome 9 centromeric (CEP9) and p16 (9p21) regions. Benign meningiomas (N=42) were divided into non‐recurring versus recurring groups. Atypical meningiomas (N=52) consisted of proliferative and brain invasive subsets. The 23 anaplastic meningiomas were not further stratified. Deletion of p16 or monosomy 9 was seen in 17% of benign, 52% of atypical, and 74% of anaplastic meningiomas (p<0.001). No statistically significant differences were found among subsets of benign or subsets of atypical meningioma, though there were more recurrences in those with deletion. Despite potential effects on cell cycle regulation, p16 deletions were not restricted to meningiomas with a high proliferative index. Most importantly, p16 deletion was strongly associated with survival in the anaplastic meningioma cohort, with a risk ratio for death of 6.79 (p= 0.016). Conversely, absence of deletion identified a subset of anaplastic meningioma patients (26%) with prolonged survival. We conclude that chromosome 9p21 deletions are associated with malignant progression of meningiomas and poor prognosis in anaplastic meningiomas.

The patterns of varicella zoster virus encephalitis

Varicella zoster virus (VZV) encephalitis has become increasingly prevalent in the era of acquired immunodeficiency syndrome (AIDS), and a widening spectrum of pathological lesions has defined the disease in these and other severely immunosuppressed patients. VZV produces three distinct morphological patterns of brain damage. VZV can cause bland or hemorrhagic infarctions secondary to a large or medium vessel vasculopathy. Deep white matter, ovoid mixed necrotic, and demyelinative lesions occur as a consequence of small vessel vasculopathy, with demyelination dependent on the degree of additional oligodendrocyte infection. Distinctive Cowdry A intra-nuclear viral inclusions are rare in either large or small blood vessels or near infarctions, but are commonly found in glial cells at the edge of the smaller ovoid, demyelinative lesions. Ependymal and periventricular necrosis occurs as a result of vasculopathy of subependymal vessels and secondary infection of ependymal and other glial cells in the periventricular region. To clarify these patterns of VZV encephalitis and shed light on their pathogenesis, the authors have examined all cases of VZV encephalitis seen at our institution since 1984. Additionally, the authors review the extensive literature in an attempt to classify the patterns of VZV encephalitis into (1) large/ medium vessel vasculopathy with bland or hemorrhagic infarctions, (2) small vessel vasculopathy with mixed ischemic/demyelinative lesions, and (3) ventriculitis/periventriculitis. Although one of these three patterns often predominates clinically and radiographically, careful histological examination at autopsy shows mixed features in many cases.