Neurocognitive impairment and gray matter volume reduction in HIV-infected patients.

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV.

Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders.

HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out. Fifty-eight HIV+ adults underwent a medical and neurocognitive evaluation within 1 year of death. DNA was obtained from occipital cortex and analyzed with the Illumina Infinium Human Methylation 450K platform. Biological age determined via the epigenetic clock was contrasted with chronological age to obtain a measure of age acceleration, which was then compared between those with HAND and neurocognitively normal individuals. The HAND and neurocognitively normal groups did not differ with regard to demographic, histologic, neuropathologic, or virologic variables. HAND was associated with accelerated aging relative to neurocognitively normal individuals, with average relative acceleration of 3.5 years. Age acceleration did not correlate with pre-mortem neurocognitive functioning or HAND severity. This is the first study to demonstrate that the epigenetic age of occipital cortex samples is associated with HAND status in HIV+ individuals pre-mortem. While these results suggest that the increased risk of a neurocognitive disorder due to HIV might be mediated by an epigenetic aging mechanism, future studies will be needed to validate the findings and dissect causal relationships and downstream effects.

Epstein Barr virus encephalitis: clinical diversity and radiological similarity.

Clinico-radiological features of two patients with cerebrospinal fluid polymerase chain reaction-positive Epstein Barr virus (EBV) encephalitis have been reported. Both the patients presented with fever and altered sensorium, one had visual hallucination, decerebration followed by visual loss and the other had downward ocular deviation and orofacial and upper limb choreiform movement. Magnetic resonance imaging (MRI) revealed parieto-occipital involvement in both the patients. Follow-up MRI at one month was normal in one and revealed regression of lesion in the other. Both the patients, however, had severe neurologic sequelae at 18 months' follow-up. EBV encephalitis may have diverse clinical presentation with characteristic parieto-occipital involvement.

Brain tumor as an unusual presentation of posttransplant lymphoproliferative disorder.

OBJECTIVES: Posttransplant lymphoproliferative disorder following solid organ transplant is a lifethreatening form of posttransplant malignancy. Its occurrence is typically associated with Epstein-Barr virus and profound immunosuppressive therapy. We describe a case of posttransplant lymphoproliferative disorder in the brain parenchyma, 4 years after renal transplant. CASE REPORT: A 23-year-old man was evaluated for generalized headache 4 years after receiving a deceased donor renal transplant. After initial immunosuppression with tacrolimus and prednisolone, mycophenolate mofetil was added for maintenance immunosuppression. A tumor in the right occipitoparietal lobe was detected by magnetic resonance imaging and excised. Immunohistochemical testing of the tumor revealed B-cell marker and Epstein-Barr virus. After surgery, the dosage of immunosuppressive drugs was reduced, and the patient was treated with chemotherapy and radiotherapy. Our patient is well after treatment. CONCLUSIONS: Reduction in immunosuppressive therapy is an important component of treatment for Epstein-Barr virus-positive posttransplant lymphoproliferative disorder and may lead to remission in early disease. If reduced immunosuppression fails to control early disease, cytotoxic chemotherapy, surgery and radiotherapy, antiviral therapies, and cell-based therapies are other options for treatment.

Diaschisis in chronic viral encephalitis with Koshevnikov syndrome.

The authors report a 61-year-old man with chronic viral encephalitis and Koshevnikov syndrome occurring 42 months after initial symptom of right hemiparesis. Serial computed tomography of the brain showed changes in the attenuation of the left temporal lobe lesion over time. Magnetic resonance images of the brain showed enlargement of left temporoparietooccipital lobes with cortical gyral enhancement on T1-weighted images following intravenous administration of gadolinium-DTPA. 99mTc-HMPAO single-photon emission computerized tomography showed increased radioactivity and hyperperfusion in the left temporoparietal region with paradoxically decreased local tissue perfusion at the contralateral right hemisphere. Follow-up magnetic resonance images of the brain 4 years later showed atrophy of bilateral cerebral hemispheres. We postulate that a "transcallosal diaschisis" with subsequent degeneration is a possible mechanism. A brain biopsy from the left temporal lobe lesion showed pictures compatible with viral encephalitis probably herpes simplex encephalitis.

Herpes simplex encephalitis with occipital localization in an infant: a different route of entry in the brain system?

Herpes simplex encephalitis classically involves the periventricular white matter in infants and the mesial temporal lobes, inferior frontal lobes, and insula in older children and adults. However, the increasing use of polymerase chain reaction to detect viral DNA in the cerebrospinal fluid has allowed the expansion of the spectrum of radiologic findings possibly associated with herpes simplex encephalitis. This study presents a rare case of a previously healthy infant with herpes simplex encephalitis with occipital involvement and permanent visual impairment. Possible pathogenic mechanisms are discussed.

Severe ataxia as a complication of human parvovirus B19 acute encephalitis in a child.

Human parvovirus B19 generally causes erythema infectiosum in childhood, but it can be associated with unusual findings, particularly in immunocompromised patients. This is a report about an immunocompetent 4-year-old female child affected with acute encephalitis by parvovirus B19, documented by polymerase chain reaction performed on cerebrospinal fluid, who was treated with intravenous immunoglobulins and dexamethasone and who developed a cerebellar syndrome with ataxia, dysmetria, and dysarthria. To the best of the authors' knowledge, this may be the first report of human parvovirus B19 encephalitis complicated by severe ataxia in childhood.

An occipital lobe epileptogenic focus in a patient with West Nile encephalitis.

Although most human cases of West Nile (WN) fever are benign, approximately 1% produce severe neurological illness. Meningitis and/or encephalitis comprise 75% of hospitalized cases with seizures in 10-15%. Occipital lobe seizures, often mimicking other primary seizure types due to extra-occipital spread, is uncommon in adults and especially so from an infectious origin. A case of WN encephalitis presenting with a simple partial seizure, focal motor, resulting from an occipital epileptogenic focus is reported. The atypical epileptogenic location of the case and the observed frequency of seizures in WN encephalitis suggest that this virus is particularly irritative to cortical neuronal networks. Thus when seizures especially with atypical EEG patterns present during an acute febrile illness in the warmer months, WN encephalitis should be considered.

Prevalence and distribution of human herpesvirus 7 in normal brain.

Although it has been recognised that human herpesvirus 7 (HHV-7) establishes latent infection in CD4+ T lymphocytes and productive infection in salivary glands, recent data suggest that its in vivo tropism may be more widespread. In this study, the prevalence and distribution of HHV-7 in brain tissues of 30 consecutive post-mortems were examined by nested polymerase chain reaction. For each post-mortem, 10 fresh autopsy tissue samples were collected respectively from the cerebellum, frontal, temporal, parietal, and occipital lobes of both cerebral hemispheres. These patients were aged from 20-95 years (mean = 61.4, SD = 20.2) with a male:female ratio of 2:1. Three patients died of intracranial haemorrhage, the others died of causes unrelated to the central nervous system. Overall, 5% (15/300) of the brain tissue samples were positive for HHV-7 DNA. The positive rates with respect to anatomical positions were similar (0-3/30). When analysed by patient, 36.7% (11/30) were HHV-7 DNA positive. The viral DNA-positive and -negative groups did not show a significant difference in gender or age distribution. The majority (81.8%) of viral DNA-positive patients had HHV-7 DNA detected at only one anatomical position; only two patients had viral DNA detected simultaneously at three anatomical sites. These results suggest that HHV-7 persists in brain tissues of a substantial proportion of the adult population, and in most individuals, its distribution is probably confined to one site rather than pervasive. Further studies to elucidate the role of this ubiquitous virus in neuropathology are warranted.

Comparison of PCR-amplified JC virus control region sequences from multiple brain regions in PML.

The authors report a 14-year-old boy with Wiskott-Aldrich syndrome complicated by progressive multifocal leukoencephalopathy after allogeneic bone marrow transplantation. Several therapeutic approaches were attempted, but there was no response. The patient died 2 months after the onset of neurologic symptoms. We detected three distinct, rearranged regions of JC virus in the cerebellum, occipital lobe, and brainstem. These findings suggest that the brain lesions had three independent origins.

Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain.

The presence of human herpesvirus 6 (HHV-6) in brain tissues of 40 consecutive post-mortem cases was examined. For each case, autopsy samples were collected from the cerebellum, frontal, temporal, parietal and occipital lobes of both sides of the brain. HHV-6 DNA was detected by nested polymerase chain reaction and characterised into variants A and B. Overall, 97/400 (24.3%) samples were positive for HHV-6 DNA with 16 being variant A and 81 being variant B, but none of the samples harboured both variants. When analysed by patient, 34/40 (85%) had HHV-6 DNA detected in the brain. The viral DNA positivity did not show significant variation with gender and age. Four patients harboured variant A, 23 harboured variant B, and seven had both variants at different positions. The results indicate that both HHV-6A and HHV-6B are neurotropic and human brain may be another site for latency. HHV-6B was detected in brain tissues of a majority (75%) of the studied population and with a widespread distribution within the brain. Although the observed prevalence of HHV-6A in brain is lower (27.5%), in view of its lower seroprevalence, the neuroinvasive potential of variant A may be comparable to that of variant B. Although both variants are potential pathogens for the nervous system, the fact that they can exist, probably for most of the time, as commensals in human brain needs to be considered when interpreting their roles in neuropathology.