Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.

PURPOSE: Prior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas. PATIENTS AND METHODS: We correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival. RESULTS: Of 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overall median survival for patients with high versus low MGMT levels was 8 and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6 months, respectively (P=.008). Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months (n=40). The overall hazards ratio (risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19; age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60 years (1.11). Multivariate analysis showed that MGMT was independent of other known prognostic factors (age, performance status, histology). CONCLUSION: The MGMT level in tumor tissue specimens may be a predictive marker of survival in patients with malignant astrocytoma that is independent of other previously described prognostic variables.

The relationship of astrocytes and macrophages to CNS demyelination after experimental herpes simplex virus infection.

Corneal inoculation of mice with herpes simplex virus type I (HSV) produces central nervous system (CNS) demyelination 7 to 8 days after infection. The demyelination originates at the junction between PNS and CNS in the trigeminal root entry zone. The pathogenesis for this selective demyelination is unknown. Immunosuppression with cyclophosphamide reduces the extent of demyelination, but does not eliminate the lesion entirely. This report concerns the electron microscopic evaluation of the events preceding demyelination. The astrocytes forming the CNS junction are heavily infected 62 hours after corneal inoculation before myelin breakdown. These cells then undergo lysis, releasing viral and cellular debris. Perivascular monocytes appear in the CNS at this time, and proceed to phagocytize the dying cells. These monocytes may be important in transferring antigenic information to the cell-mediated immune system, which responds by producing extensive CNS demyelination by 6 to 7 days postinfection.

Schwann cell remyelination in experimental herpes simplex encephalitis at the trigeminal root entry zone.

Inoculation of mice on the cornea with herpes simplex virus, type I, results in demyelination of central nervous system (CNS) axons at the trigeminal root entry zone. This study examined the process of remyelination in this area. Between eight and 15 days after corneal infection, increasing numbers of Schwann cells appeared on the CNS side of the trigeminal root entry zone, where they encircled the demyelinated CNS axons. Remyelination of CNS axons by Schwann cells began between 12 and 15 days and increased during the following weeks. Remodeling of remyelinated internodes continued during the nine weeks of observation. No infectious virus could be cultured 15 days after infection, although latent virus was recovered from the dorsal root ganglia at this time. The disruption of astrocytes on the CNS side of the trigeminal root entry zone during the early stages of infection and the proximity of Schwann cells to the CNS trigeminal root entry zone appear to be important factors affecting CNS remyelination.

Central nervous system susceptibility to herpes simplex infection.

Four days after inoculation of herpes simplex virus (HSV) on the rabbit cornea, distinctive and reproducible lesions appear in the trigeminal root entry zone. These viral lesions, situated in the central nervous system (CNS) portion of the root, consist of severe myelin destruction accompanied by mononuclear cell infiltration and partial sparing of axons. Immunofluorescent study demonstrated abundant viral antigen, and by electron microscopy viral nucleocapsids were found to be numerous within astrocytes and were rarely found in other cell types. In contrast, the adjacent peripheral nervous system (PNS) tissue appears unaffected by the presence of virus. The mechanism for this marked difference in response of the central nervous system and the peripheral nervous system may depend upon the susceptibility of astrocytes to viral infection and replication. The selective nature of the lesion provides an easily reproducible model for further investigation of the response of nervous system tissue to HSV.

Peripheral nervous system demyelination with herpes simplex virus.

Inoculation of the cornea or footpad with herpes simplex virus Type I (HSV) has been shown to produce subsequent encephalitis or myelitis respectively. Although Schwann cells become infected, there is no destruction or demyelination in the peripheral nervous system (PNS). Demyelination only occurs in the central nervous system. Previous studies have shown that the Schwann cells infected with HSV do not produce enveloped viral particles. The studies presented here demonstrate that microinjection of HSV into the sciatic nerve of mice causes focal mononuclear cell infiltration and demyelination seven days after injection. The Schwann cells in this model produced enveloped virus. These studies demonstrate that when HSV is introduced into the extracellular space of the PNS, demyelination occurs.

Porphyrin-laser photodynamic induction of focal brain necrosis.

A noninvasive photodynamic method has been developed to produce focal brain necrosis using porphyrin activated in vivo with laser light. After peripheral injection of the photosensitive porphyrin derivative, Photofrin I, mice were irradiated on the posterior lateral aspect of the head through the intact depilated scalp with 632 nm argon-dye laser light. Animals were studied at one, two and seven days after irradiation. Blood-brain barrier damage was detected by the intravenous injection of Evans blue, horseradish peroxidase and heterologous immunoglobulins. At one and two days after irradiation, the lesions were characterized by extravasation of immunoglobulin and Evans blue, and by edema, ischemia and infiltration by monocytes. On the seventh day after irradiation, the lesion was smaller than it had been two days after irradiation, and had reactive changes at its edges and coagulative necrosis at its center. Extravasation of Evans blue and immunoglobulin was markedly reduced by the seventh day after irradiation, but uptake of horseradish peroxidase by macrophages located at the periphery of the lesion was evident.

An infant with Cushing's disease due to an adrenocorticotropin-producing pituitary adenoma.

An 8-month old male with Cushing's disease is presented; his clinical presentation and appearance were typical of infants with glucocorticoid excess. Concentrations of cortisol, 17-hydroxyprogesterone, and adrenal androgens were strikingly elevated. High doses of dexamethasone did not suppress the excretion of urinary free cortisol or 17-hydroxycorticoids, and administration of ACTH elicited no further rise in plasma cortisol. Responses of LH, FSH, and PRL to iv LRF and TRF were appropriate for age, but neither TSH nor ACTH rose significantly. Plasma ACTH values were elevated to 700 pg/ml. An intracranial mass lesion superior and anterior to the sella turcica was demonstrated by computerized axial tomography and angiography. An inoperable pituitary adenoma was a massive surrounding fibroblastic reaction was found at craniotomy. The pathological diagnosis of an ACTH-producing pituitary adenoma was confirmed by immunohistochemistry and by the in vitro secretion of ACTH by cells cultured from the tumor.

Myoclonus in Alzheimer disease. A confusing sign.

Myoclonus in association with dementia of later adult life has been considered almost pathognomonic of Creutzfeldt-Jakob disease. However, myoclonus may also be seen with Alzheimer disease, and when the myoclonus occurs as an early manifestation of Alzheimer disease, distinction from Creutzfeldt-Jakob disease may prove difficult.

Acquired toxoplasmosis. A neglected cause of treatable nervous system disease.

The neurological manifestations of six cases of acquired central nervous system toxoplasmosis are compared with the 39 well-documented cases from the literature. Half of the patients had underlying systemic diseases (18 malignant neoplasms, two renal transplants, three collagen vascular diseases) treated with intensive immunosuppressive therapy. The remainder had primary toxoplasmosis. Three major neurological patterns were seen: (1) diffuse encephalopathy with or without seizures, (2) meningoencephalitis, and (3) singular or multiple progressive mass lesions. Routine neurological diagnostic studies were not helpful. The Sabin-Feldman dye test or IgM indirect fluorescent antibody test or both were effective in confirming the diagnosis. Twenty-seven patients died without a clinical diagnosis of toxoplasmosis. The diagnosis was made terminally in four additional patients. Thirteen of fourteen patients who received a full course of sulfadiazine or pyrimethamine or both did well. Toxoplasmosis should be considered in the immunosuppressed patient who appears with neurological involvement.

Unilateral megalencephaly: hamartoma or neoplasm?

The clinical and pathologic findings in three cases of unilateral megalencephaly, showing a spectrum of mild to severe involvement, are presented. The first case demonstrated an increase in neuronal size and mild gliosis and is contrasted with the second and third cases, which showed a progressive enlargement and bizarre appearance of neurons associated with an increase in number and size of astrocytes. The relationship of these cases to developmental and neoplastic disease in the brain is discussed.

Brain pyruvate carboxylase and the pathophysiology of biotin-dependent diseases.

Given the cerebellar symptomatology of biotin-dependent diseases and other lactic acidoses, we hypothesized that cerebellar pyruvate carboxylase activity might be differentially low or especially sensitive to cofactor deprivation. Accordingly, pyruvate carboxylase activity was measured in selected areas of normal and biotin-deficient rat brain. Control cerebellar hemisphere and vermis specific activities were identical, and slightly higher than cerebral and brainstem activities. In biotin-deficient rats, hepatic pyruvate carboxylase activity was 3% of control, whereas pyruvate carboxylase activities of all brain sections were 53 to 71% of control. Brain histology was normal. Cerebellar pyruvate carboxylase activity is therefore not distinctly low or labile and is in fact preferentially maintained despite severe cofactor deprivation.

Evidence for preganglionic pupillary involvement in superficial siderosis.

A 36-year-old man presented with spinal myoclonus, ataxia, hearing loss, and unilateral pupillary dilation. MRI demonstrated hemosiderin deposition along the superficial surfaces of the brain, brainstem, cerebellum, and spine. The pupillary changes were localized to the preganglionic oculomotor nerve. In contrast to vasculopathic oculomotor nerve palsies, superficial siderosis may cause selective involvement of the superficially located pupillary fibers.

Continuous cataplexy in a patient with a midbrain tumor: the limp man syndrome.

A patient with glioblastoma of the rostral brainstem and hypothalamus exhibited bilateral internuclear ophthalmoplegia and vertical nystagmus; he suffered episodes of cataplexy, narcolepsy, and sleep paralysis. A peculiar fluctuation of posture and tone ("limp man syndrome") proved to be a manifestation of continuous cataplexy, as documented by H-reflex recordings. This is the first report of a remarkable movement disorder caused by continuous, fluctuating, partial cataplexy, and is the second report of an association between cataplexy and a tumor of the rostral brainstem.

Calciphylaxis mimicking dermatomyositis: ischemic myopathy complicating renal failure.

BACKGROUND: Among the complications of chronic renal failure is a syndrome of medial calcification of small- to medium-sized arteries associated with ischemic necrosis of the skin and other organ systems, leading to gangrene and a poor prognosis. The syndrome has been reviewed in the renal, dermatologic, and surgical literature under the term calciphylaxis, which describes a postulated pathogenetic mechanism whereby sensitization to an endogenous or exogenous substance (such as parathyroid hormone) predisposes to calcium deposition after exposure to a challenging agent. Myopathy has rarely been reported as the presenting feature, and the syndrome has not been discussed in the neurologic literature. METHODS: We report two patients with renal failure and systemic calciphylaxis who presented to our hospital with myopathic complaints and signs suggesting dermatomyositis. We also discuss possible disease mechanisms and treatment. CONCLUSIONS: Because early treatment (including aggressively lowering the calcium and phosphate levels and parathyroidectomy) may improve the outcome, early recognition of the syndrome of calciphylaxis is essential.

Macrophage response to herpes simplex encephalitis in immune competent and T cell-deficient mice.

Corneal inoculation of Nude (athymic) mice and Balb/c mice with herpes simplex virus Type I produces a brainstem encephalitis with demyelination of the trigeminal root entry zone. The extent of CNS demyelination is less in the immune-deficient athymic mice 7 days after infection compared to the immune-competent Balb/c mice. Both groups demonstrate a macrophage response and beginning myelin disruption approximately 3 days after corneal infection when herpes viral particles are first observed within central nervous system cells. Five to seven days after infection when differences in the extent of demyelination between the immune-competent and immune-deficient animals become evident, the Balb/c mice demonstrate T cells and increasing numbers of macrophages at the trigeminal root entry zones. These findings suggest an interaction between macrophages and T cells which leads to an extension of the demyelination in the immune competent Balb/c mice and that lack of T cells is important in limiting demyelination in Nude (athymic) mice.

Augmentation of adoptively transferred experimental allergic encephalomyelitis by administration of a monoclonal antibody specific for LFA-1 alpha.

We investigated the effect of an anti-leukocyte function antigen 1 (LFA-1 alpha) monoclonal antibody, M17/4.2, on murine relapsing experimental allergic encephalomyelitis (EAE). In vitro investigations demonstrated that M17/4.2 inhibited proliferation with concanavalin A or myelin basic protein. Control mice treated with phosphate buffered saline (PBS) developed a mild to moderate disease at 7-10 days followed by a long-term relapsing clinical course. With administration of M17/4.2, the time of disease onset was unchanged; however, the severity of the disease was greatly augmented, resulting in early mortality. The pathology correlated well with the clinical course. M17/4.2 mice showed more inflammation and demyelination than PBS or anti-CD4 treated mice. Therefore, this anti-LFA-1 specific monoclonal antibody augmented EAE.

Chimeric cytotoxin IL2-PE40 inhibits relapsing experimental allergic encephalomyelitis.

IL2-PE40 is a chimeric protein composed of human interleukin-2 (IL2) genetically fused to a modified form of Pseudomonas exotoxin lacking the cell recognition domain. IL2-PE40 is cytotoxic for IL2 receptor-bearing lymphocytes in culture and can inhibit activation of T cells in vivo. IL2-PE40 can significantly diminish antigen-stimulated proliferation of lymphocytes sensitized to myelin basic protein. Intraperitoneal administration of IL2-PE40 not only markedly inhibits the clinical manifestations of adoptively transferred relapsing experimental allergic encephalomyelitis but also dramatically reduces both inflammation and demyelination characteristic of the disease.

Contrasting effects of anti-adhesion molecule therapy in experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis.

An augmentation of experimental allergic encephalomyelitis (EAE) was observed when monoclonal antibody (mAb) to intercellular adhesion molecule 1 (ICAM-1) was administered after adoptive transfer. Clinical disease was more severe in the ICAM-1 specific mAb-treated EAE mice and included prominent ataxia compared to the PBS-treated controls or Theiler's murine encephalomyelitis virus (TMEV) infected mice treated with ICAM-1 specific mAb. Neuropathologic evaluation demonstrated a distinctly different distribution of lesions in the anti-ICAM-1-treated EAE mice which featured prominent demyelination and inflammation in the cerebellum, brainstem and cerebrum. These structures were minimally involved in the control mice and mAb treatment did not alter the neuropathology in TMEV-infected mice. These results indicate that anti-ICAM-1 can alter trafficking of lymphocytes and mononuclear cells in EAE but not TMEV-induced demyelinating disease.

Acalvaria: a unique congenital anomaly.

Acalvaria is a rare malformation usually regarded as a postneurulation defect. It consists of absence of the calvarial bones, dura mater and associated muscles in the presence of a normal skull base and normal facial bones. The condition is frequently confused by prenatal ultrasonography with anencephaly or an encephalocele. Whereas the cerebral hemispheres are absent in anencephaly, the cranial contents in acalvaria are generally complete, though some neuropathological abnormality is often present. The presumed pathogenesis of acalvaria is faulty migration of the membranous neurocranium with normal placement of the embryonic ectoderm, resulting in absence of the calvaria but an intact layer of skin over the brain parenchyma. We describe 2 cases of acalvaria, one misdiagnosed ultrasonographically as an occipital encephalocele prenatally. The brain in one fetus demonstrated semilobar holoprosencephaly and micropolygyria, but in the other, was structurally and histologically normal with the exception of hydrocephalus.

Aprosencephaly and cerebellar dysgenesis in sibs.

Aprosencephaly is a rare, lethal malformation sequence of the central nervous system that has been attributed to a postneuralation encephaloclastic process. We describe autopsy findings consistent with aprosencephaly in 2 fetuses conceived from a consanguineous mating (first cousins). Both showed anencephalic manifestations; however, the crania were intact, with fused sutures. The neuropathologic findings were essentially identical. Each fetus had complete absence of the telecephalon and pyramidal tracts, rudimentary diencephalic and mesencephalic structures, primitive cerebellar hemispheres, posterolateral clusters of primitive neural cells in the medullas suggesting an abnormality of neural migration, a normally-formed spinal cord, and retinal dysplasia within normally-formed globes. In addition, both fetuses manifested a peculiar perivascular mesenchymal proliferation seen only within the central nervous system. The similarity of these cases, coupled with parental consanguinity, suggests a primary malformation in brain development due to the homozygous representation of a mutant allele. We hypothesize that these patients may represent a defect in a gene important in brain development, the nature of which has yet to be elucidated.