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Two syndromes affecting cognitive and motor function in the setting of AIDS have been described as HIV encephalopathy (HIVE) and progressive multifocal leukoencephalopathy (PML). HIVE is characterized by the presence of microglial nodules with accompanying astrocytosis. PML is a fatal demyelinating disease of the white matter induced by the human papovavirus JCV which causes cytolytic destruction of glial cells. In addition to the effect of HIV-1 induced immune suppression, HIV may act directly as a co-factor for stimulation of JCV replication in AIDS patients, in part due to Tat-induced activation of JCV gene transcription. Since Tat has been implicated in CNS pathogenesis, we examined its localization in CNS specimens from HIV infected patients with HIVE and PML as well as controls. Based on the observation of CC chemokine induction in monocytes by Tat, we also examined the cellular localization of the CC chemokine Macrophage Inflammatory Protein-1alpha (MIP-1alpha) and its cognate receptor CCR-5 in these samples. In HIVE, Tat was primarily localized in astrocytes and microglia, within the nodular lesions. In PML, a marked increase in the number of Tat positive astrocytes was observed. In both HIVE and PML, prominent expression of MIP-1alpha and CCR-5 was found within areas containing histopathological lesions. CCR-5 positivity of microglia was localized primarily to nodular lesions in HIVE. In PML, increased numbers of cells with monocyte/microglial morphology were observed relative to HIVE. The increased MIP-1 alpha positivity, and potentially other chemokines, may contribute to the pathogenesis of PML in the setting of HIV infection. Tat may play an important role in the pathogenesis of both HIV associated CNS disease states, acting indirectly through cytokine and chemokine dysregulation.

Cerebellar disorders associated with HIV infection are typically the result of discrete cerebellar lesions resulting from opportunistic infections such as toxoplasmosis and progressive multifocal leukoencephalopathy or primary CNS lymphoma. Clinical symptoms and pathologic abnormalities related to the cerebellum may also be observed with HIV dementia. A primary cerebellar degeneration with HIV has not previously been reported. Ten patients were identified over an 8-year period at five medical centers. All patients had clinical, laboratory, and radiologic evaluations, and three had neuropathologic examinations. Patients presented with progressively unsteady gait, slurred speech, and limb clumsiness. Examination revealed gait ataxia, impaired limb coordination, dysarthria, and abnormal eye movements. Cognition, strength, and sensory function remained normal. CD4 lymphocyte counts varied between 10 and 437 cells/mm3. Neuroimaging studies showed prominent cerebellar atrophy. Neuropathology showed focal degeneration of the cerebellar granular cell layer and unusual focal axonal swellings in the brainstem and spinal cord. Cultures, histopathology, and immunochemical studies showed no conclusive evidence of infection. We report a syndrome of unexplained degeneration of the cerebellum occurring in association with HIV infection.

Chronic inflammation may contribute to neuropsychological impairments in individuals with HIV, and modulation of this inflammatory response by opiate receptor ligands is important in light of the prevalence of drug use in HIV populations. Exogenous MOR and KOR agonists have differential effects on central nervous system (CNS) immunity and, while some data suggest KOR agonists are immunosuppressive, the KOR agonist dynorphin has been shown to stimulate human monocyte chemotaxis. In this study, we examined mRNA levels of endogenous opioid receptors OPRK1 and OPRM1, prodynorphin (PDYN), macrophage scavenger receptor CD163, and microglia/macrophage marker CD68 in the caudate and anterior cingulate of postmortem brains from HIV-positive and HIV-negative subjects. Brain tissues of HIV-infected (n = 24) and control subjects (n = 15) were obtained from the Manhattan HIV Brain Bank. Quantification of the gene mRNA was performed using SYBR Green RT-PCR. CD68 and CD163 were increased in HIV-positive (HIV+) compared to HIV-negative (HIV-) individuals in both brain regions. There were higher OPRK1 (P

Pure autonomic failure (PAF; also known as idiopathic orthostatic hypotension or Bradbury-Eggleston syndrome) is an uncommon sporadic disorder, characterized by autonomic failure without other neurological deficits and histopathologically by cell loss in intermediolateral columns and sympathetic ganglia. Few postmortem studies of patients with PAF have been reported in the literature, and none have demonstrated Lewy bodies in distal axons, although this has been described as a feature in Parkinson's disease with autonomic failure. We report a patient with PAF who had orthostatic hypotension and urinary symptoms for 15 years prior to death at the age of 63 years. Postmortem findings included typical and atypical Lewy bodies in the substantia nigra, locus ceruleus, substantia innominata, and sympathetic ganglia, as well as in autonomic axons in the epicardial fat, autonomic nerve fascicles in periadrenal adipose tissue, and autonomic nerves in the muscularis of the urinary bladder. Sites of autonomic nerve involvement correlated with clinical symptomatology, and thus were a valuable observation in the complete autopsy. Systemic autopsy results should be reviewed carefully in patients with PAF, as Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies.

Abnormalities in cerebral glucose metabolism have been demonstrated in patients with AIDS dementia complex (ADC), with increased consumption in early disease and decreased utilization in late stages. The basis of these changes is unknown. Accordingly, a pilot study was undertaken to determine whether levels of cerebral glucose transporters GLUT1 and GLUT3 were altered by HIV disease. Frontal gray and white matter membrane preparations from patients with HIV encephalitis (HIVE), HIV infection without parenchymal neuropathology, and non-infected controls were utilized in quantitative immunoblots to measure GLUT1 and GLUT3. Results were expressed as a ratio of glucose transporter to structural protein actin. Within-group patient variability was great, precluding statistically significant differences between groups for any one brain region. However, when data for gray and white matter was pooled, results obtained statistical significance, with levels of GLUT1 increasing in HIV infection without neuropathology, and declining with HIVE. Increased GLUT1 in HIV infection without parenchymal neuropathology may be important in the biology of increased glucose consumption described with early ADC. With progression to HIVE, reduced levels of glucose transporters may contribute to late stage hypometabolism.

A case is described of an elderly woman who presented with headaches, hypopituitarism, and visual disturbances and was found to have idiopathic granulomatous hypophysitis, a rare lesion of the pituitary gland. Preoperative magnetic resonance imaging demonstrated a well-circumscribed lesion, which was isointense on both T1- and T2-weighted imaging and enhanced uniformly with administration of gadolinium contrast enhancement, not unlike a macroadenoma. The present case and 12 other cases from the literature are reviewed.

Primary central nervous system lymphoma has undergone a remarkable increase in incidence over the last decade, both in immunosuppressed and immunocompetent individuals. Its clinicopathologic evaluation requires knowledge of current hematopathologic systems for lymphoma classification, as well as specific understanding of unique central nervous system determinants. In immunocompromised individuals, the tumor has a constant association with Epstein-Barr virus. The form of Epstein-Barr virus in these tumors appears to be predominantly latent, however, the precise mechanism relating virus to tumor pathogenesis is still unclear. In immunocompetent patients, risk factors and oncogenic associations are completely unknown. Critical to the formation of these tumors is the trafficking of B-cells, whether pre- or post-transformation, across the blood-brain barrier. These B-cell migrations may require perturbations to the barrier that originate in or around neural parenchyma, such as localized injury or infection.

✓ Cystic epithelial lesions of the sellar and parasellar region are classified on the basis of histology and location into Rathke's cleft cysts, epithelial cysts, epidermoid cysts, dermoid cysts, and craniopharyngiomas. A retrospective review of the clinical presentation, radiological findings, and histology was performed on 19 such lesions, and a survey of the literature pertinent to the classification, clinical presentation, and embryology of these lesions was conducted. Presentation was nonspecific and not predictive of histology. Imaging studies were generally useful in distinguishing these tumors, with the exception of Rathke's cleft cysts, suprasellar epidermoid cysts, and craniopharyngiomas, which frequently could not be differentiated. On microscopic examination, most lesions fit into distinct categories; however, overlap was common among all and some could not be definitively categorized by histological criteria. Evidence supportive of an ectodermal ancestry for sellar and parasellar epithelial-lined cystic lesions is presented. Based on the current findings and a review of the literature, it is suggested that these lesions represent a continuum of ectodermally derived cystic epithelial lesions.

Hyperinfection with Strongyloides stercoralis is rare in acquired immunodeficiency syndrome (AIDS), despite endemicity in areas where infection with human immunodeficiency virus is highly prevalent. We autopsied two patients with AIDS and disseminated Strongyloides and describe their central nervous system findings. The microscopic patterns of brain infection were dissimilar in the two patients, and reflected histology in systemic viscera. In one patient, a granulomatous response accompanied filariform larvae in all locations, including granulomatous ependymitis in brain. Additionally in the brain, larvae without tissue reaction were seen. In the second patient, the absence of tissue response to larvae was body wide, and isolated parasites were found in centrum semiovale. The occurrence of these patients in a region where Strongyloides is not endemic suggests that this infection may be more prevalent in AIDS than formerly suspected.

Objective To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era. Design Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models. Setting Six US academic medical centers. Patients One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study. Main Outcome Measures The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey. Results We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95% confidence interval, 1.8-2.5] per 10 years), lower CD4 nadir (1.2 [1.1-1.2] per 100-cell decrease), current CART use (1.6 [1.3-2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3-2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir. Conclusions Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.

A case of OS of the T6 vertebra in a 58-year-old man is presented. Diagnosis was obtained by an open biopsy. The clinical and radiographic findings were described. The topic of vertebral OS was discussed at length. We emphasize the fact that OS of the spine is rare and that those cases not associated with Paget's disease or previous radiation therapy are even rarer.

Objective To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. Design Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. Results The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. Conclusions Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.

Fourier-transform infrared spectroscopy (FT-IR) was applied to the study of tissue sections of human colorectal cancer. Pairs of tissue samples from colorectal cancer and histologically normal mucosa 5-10 cm away from the tumor were obtained from 11 patients who underwent partial colectomy. All cancer specimens displayed abnormal spectra compared with the corresponding normal tissues. These changes involved the phosphate and C-O stretching bands, the CH stretch region, and the pressure dependence of the CH2 bending and C = O stretching modes. Our findings indicate that in colonic malignant tissue, there are changes in the degree of hydrogen-bonding of (i) oxygen atoms of the backbone of nucleic acids (increased); (ii) OH groups of serine, tyrosine, and threonine residues (any or all of them) of cell proteins (decreased); and (iii) the C = O groups of the acyl chains of membrane lipids (increased). In addition, they indicate changes in the structure of proteins and membrane lipids (as judged by the changes in their ratio of methyl to methylene groups) and in the packing and the conformational structure of the methylene chains of membrane lipids. The cell(s) of the malignant colon tissues responsible for these spectral abnormalities is unknown. Cultured colon adenocarcinoma cell lines displayed similarly abnormal FT-IR spectra. The diagnostic potential of the observed changes is discussed.

Forty-two patients with large pitutary tumors were studied with magnetic resonance imaging scans. Based on the operative findings, the tumors were divided into two groups, Tumors in Group 1 (n = 35) were soft or partially necrotic and were easily removed by suction and curettage, Tumors in Group 2 (n = 7) were firm and required sharp dissection or use of the laser for removal. Tumors were divided into two groups based on the long TR signal: a) isointense in comparison with white matter, or b) hyperintense in comparison with white matter. All 7 firm tumors (Group 2) had an isointense signal on long TR sequences. Thirty-two of 35 soft tumors showed a hyperintense signal on long TR sequences, and 3 an isointense signal. Based on these results, we recommend a transsphenoidal approach for the initial operation in patients with large pituitary tumors. If the tumor is largely isointense on the magnetic resonance imaging scan, we discuss with the patient preoperatively the possibility (70% in this series) that the tumor may be too firm to remove in a single transsphenoidal procedure. In these circumstances, a second, transcranial, procedure may be required to decompress the suprasellar structures adequately.

HIV associated neurological diseases include HIV dementia, peripheral neuropathies and progressive multifocal leukoencephalopathy (PML). In the studies presented here, we examined the abnormal accumulation of monocytes/macrophages in the CNS in patients with HIV dementia complex (HIVD), AIDS without dementia, and seronegative controls. Our results demonstrate substantial increases in both perivascular macrophages and ramified parenchymal microglia in HIVD. Although these mononuclear phagocytes were positive for proliferating cell nuclear antigen (PCNA), they do not appear to be proliferating as determined by the paucity of Ki-67 staining. Using antibody to HIV-P24 antigen, PCNA expression co-localized in cells productively infected with HIV-1. Additional cells were negative for HIV-1 P24, but positive for PCNA expression, possibly suggesting the role of secreted factors. These results suggest dysregulation of DNA repair pathways in HIVD, with potential relevance to the JCV activation and the development of PML in the setting of AIDS.

Forty-four patients with cervical spondylotic myelopathy who underwent a ventral surgical approach were evaluated with respect to the results of surgery. The neurological status of the patients was categorized according to the modified Japanese Orthopedic Association scale (0-18). Three patients had a functional score of 8, one patient 9, five patients 10, five patients 11, seven patients 12, seven patients 13, seven patients 14, and nine patients had a functional score of 15, preoperatively. Twenty-three patients underwent a one-level corpectomy, 15 patients a two-level corpectomy, and six patients underwent a three-level corpectomy. Forty-one (93.1%) of the 44 patients underwent ventral cervical plate fixation. Complications among the 44 patients included graft-and instrumentation-related complications in seven cases, iliac crest donor-site infection in three cases, and respiratory complications in three cases. The follow-up periods ranged between 7 and 60 months (mean 42.3 months). Overall, the fusion rate was 97.72%. Three patients showed no functional change (6.8%), two patients were worse (4.5%), and 39 patients (88.6%) showed functional improvement in their score between +1 and +6 points (mean 2.16 points). There was no statistically significant difference in the functional improvement score in patients younger or older than 60 years old. The mean improvement in the functional score was found to be +2.857 ± 1.352, +2.400 ± 1.454, and +0.5000 ± 1.871 following one-level corpectomy, two-level, and three-level corpectomies, respectively. There were statistically significant differences in the neurological improvement observed between patients with one-level corpectomy and three-level corpectomy (p < 0.01), as well as between those with two-level and three-level corpectomy (p < 0.05). There was no statistically significant difference in the neurological outcome between patients with one-level and two-level corpectomy (p > 0.05). The results of this study demonstrate a high rate of solid bone fusion and a high rate of functional (neurological) improvement. Five patients underwent reoperation, predominantly for instrumentation failure. The use of instrumentation dictates careful consideration of the risk/benefit ratio associated with its use in each case.

The MR images and CT scans of 14 patients with surgically verified pyogenic cerebral abscesses were reviewed. The MR findings correlated well with those seen on CT and were believed to be sufficiently characteristic to allow early and accurate diagnosis with MR alone. These features include (1) peripheral edema producing mild hypointensity on short TR/short TE and marked hyperintensity on long TR/intermediate to long TE scans; (2) central necrosis with abscess fluid hypointense relative to white matter and hyperintense relative to CSF on short TR/short TE scans and hyperintense relative to gray matter on long TR/intermediate to long TE scans (the fluid had concentric zones of varying intensity in seven cases, a finding not previously identified in other lesions); (3) extraparenchymal spread (intraventricular or subarachnoid), which was detected more easily on MR than on CT and was manifested by increased intensity relative to normal CSF on both short TR/short TE and long TR/intermediate TE scans; and (4) visualization of the abscess capsule, which was iso- to mildly hyperintense relative to brain on short TR/short TE scans and iso- to hypointense relative to white matter on long TR/intermediate to long TE scans. On the long TR scans, the relative hypointensity of the rim allowed for visualization of the typical morphologic features of the capsule, which in turn aided in differentiation of abscesses from other lesions (as it does on CT). To investigate the cause of the capsular intensity, pathologic studies of the capsules were reviewed when available (10 cases). Fibrosis was identified in all mature abscess capsules, but the combination of the intensities seen on short TR/short TE and long TR/intermediate to long TE scans as well as the temporal changes in intensity were believed to be incompatible with fibrosis as a cause of the capsular changes. Intensity patterns were suggestive of hemorrhage, but neither acute nor chronic hemorrhage was identified on routine H and E stains, while iron stain revealed scant hemorrhage in only two of the eight patients in whom these stains were used. We believe the capsular intensity (in particular the hypointense rims on long TR scans) may reflect paramagnetic T1, and to a greater extent T2, shortening, possibly due to the presence of heterogeneously distributed free radicals that are products of the respiratory burst produced by actively phagocytosing macrophages in the capsule wall. Distinctive MR features of pyogenic abscesses should afford early and accurate diagnosis.

An insulin-containing ovarian carcinoid was found at the autopsy of a 63-year-old woman with a 12-year history of episodic hyperinsulinemic hypoglycemia. In terms of histology, the carcinoid displayed both insular and trabecular patterns and contained a small focus of mucinous cystadenoma. Beta secretory granules were demonstrated by electron microscopy, and immunoreactivity for insulin was demonstrated in tumor cell cytoplasm by immunohistochemistry. Additional autopsy findings included a solitary parathyroid adenoma and a microscopic focus of pituitary hyperplasia. This is the first recorded case of insulin production by a primary ovarian neoplasm. The patient's constellation of endocrine findings may represent a variant of the syndrome of type I multiple endocrine neoplasia.

A 22-year-old Haitian man had a 15-month course of progressive meningitis accompanied by multiple cerebral infarcts. Multiple areas of stenosis and occlusion in all branches of the circle of Willis, and hypertrophy of collateral perforating vessels at the base of the brain in a "puff of smoke" appearance typical of moyamoya disease were seen on cerebral angiogram 5 months before the patient died. At autopsy, the patient had meningovascular syphilis and a necrotizing encephalitis with massive treponemal invasion of the brain, the pathology of late-stage degenerative, or "quaternary", neurosyphilis. The patient was also infected with human immunodeficiency virus (HIV). Retrovirus-like particles 100 nm in diameter with dense cores were seen by electron microscopy. Nucleic acid obtained from the patient's brain contained sequences homologous to HIV DNA as determined by dot blot hybridization. The moyamoya-like radiologic appearance of neurosyphilis has not been previously described. The autopsy finding of quaternary neurosyphilis in a patient with HIV infection supports the hypothesis that retrovirus may alter the natural history of syphilitic infection.

• Three patients with the acquired immunodeficiency syndrome (AIDS) had combined infections of the central nervous system, with both herpes simplex virus (HSV) and cytomegalovirus (CMV). All three had a diffuse ventriculoencephalitis documented at postmortem examination. The presence of HSV type 1 and CMV was confirmed microscopically with immunohistochemistry. The clinical importance of these three patients is that they establish the presence of concomitant HSV and CMV encephalitis in acquired immunodeficiency syndrome, and suggests the possibility of therapeutic intervention with antiviral drugs that have activity against HSV and/or CMV.

Human herpesvirus 8 (HHV-81, the Kaposi9s sarcoma (KS)-associated herpesvirus, is closely related to the transforming Epstein-Barr virus (EBV) and may be detected in AIDS-related, EBV-containing, body-cavity-based lymphomas. Accordingly, we analyzed 27 EBV-positive, AIDS-related CNS lymphomas for HHV-8 sequences. Only one tumor yielded HHV-8 sequences; this tumor arose in a patient with concomitant systemic lymphoma and a history of KS. We conclude that HHV-8 is unlikely to have a major role in the pathogenesis of AIDS-related, EBV-associated CNS lymphomas.

We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.

Article abstract The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.

T-cell lymphoma may involve the CNS as either a primary or secondary neoplasm. This report describes 8 patients with either primary or secondary T-cell malignancies in the CNS. Five patients presented with symptoms and signs of CNS disease that included seizures, visual impairment, cranial nerve palsies, sensory and motor deficits, gait ataxia, and paraparesis. Three of them had primary parenchymal CNS lymphoma, and 2 had epidural lymphoma that originated in adjacent bone marrow. Three patients were neurologically asymptomatic, but had leptomeningeal tumor and focal parenchymal infiltration at postmortem examination. Histologically, 4 lymphomas were large cell, 3 were mixed large and small cell, and 1 could not be classified by the working formulation for non-Hodgkin's lymphomas. The clinical and pathologic manifestations of T-cell lymphoma in the CNS may be diverse. This report demonstrates that neurologic abnormalities may be the presenting signs of either primary CNS or systemic T-cell lymphoma.