Multifocal cortical myoclonus and cerebral amyloid beta-peptide angiopathy.
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Aged↗
Biomedical subjects
F Scaravilli
Publications and source records attributed to F Scaravilli.
Magnetic resonance imaging, thallium-201 SPET scanning, and laboratory analyses for discrimination of cerebral lymphoma and toxoplasmosis in AIDS.
OBJECTIVES: To compare the results of magnetic resonance imaging (MRI) and thallium-201 (201Tl) SPET scanning with laboratory analyses including CSF DNA detection, brain biopsy, and necropsy in the discrimination of cerebral lymphoma and toxoplasmosis in patients with AIDS. METHODS: A retrospective study of 32 patients infected with HIV who had focal CNS lesions on MRI as a result of either lymphoma or toxoplasmosis. RESULTS: 18 patients had lymphoma, 12 had toxoplasmosis, and two had both. Toxoplasma IgG antibodies were detected in only seven patients--four with toxoplasmosis, two with lymphoma, and one with both diagnoses. Epstein-Barr virus DNA was detected in CSF of all six patients with lymphoma and none of two with toxoplasmosis. MRI showed multiple lesions in 23 patients, appearances did not discriminate between lymphoma and toxoplasmosis; nine patients had single lesions, of these eight had lymphoma (p = 0.044, two tailed Fisher's exact test) 201Tl SPET showed accumulation in 17 with lymphoma and six with toxoplasmosis (p = 0.034, two tailed Fisher's exact test). Of nine patients with single lesions on MRI and 201Tl SPET with focal accumulation eight had lymphoma. 201Tl SPET uptake ratios of > or = 2.9 were only seen with lymphoma. CONCLUSION: Knowledge of patients' toxoplasma serostatus does not aid discrimination between lymphoma and toxoplasmosis. Single lesions on MRI with focal accumulation of 201Tl strongly suggest lymphoma. Multiple lesions on MRI with 201Tl SPET uptake ratios > or = 2.9 also suggest lymphoma; uptake ratios less than 2.1 do not aid discrimination. Detection of Epstein-Barr virus DNA in CSF is highly sensitive and specific for cerebral lymphoma.
AIDS-Related Opportunistic Infections↗
HIV-associated brain pathology in the United Kingdom: an epidemiological study.
OBJECTIVES: To examine the epidemiology of HIV-associated neuropathology in the United Kingdom and to investigate whether the prevalence of different forms of HIV-associated brain pathology varies with exposure category. DESIGN: The study was a cross-sectional survey; data was analysed from the Medical Research Council National AIDS Neuropathology database. SETTING: Information was gathered from throughout England, Scotland and Wales. SUBJECTS: Individuals who died from AIDS in the United Kingdom and had a postmortem examination. The database comprised 7% of all AIDS deaths in the United Kingdom between 1982 and 1993. MAIN OUTCOME: Neuropathological diagnoses based on internationally accepted neuropathological terminology of AIDS-related brain lesions. RESULTS: HIV encephalitis was the most prevalent pathological diagnosis, occurring in 25.3% [95% confidence interval (CI), 21.0-29.6] of the study sample. Statistically significant independent associations for the occurrence of HIV encephalitis were found for injecting drug use (odds ratio, 6.86; 95% CI, 2.91-16.17), and age less than 30 years at death (odds ratio, 3.58; 95% CI, 1.99-6.44). Vascular lesions were significantly higher among blood product recipients, 95% of whom were haemophiliacs. CONCLUSIONS: This was the first epidemiological investigation of HIV-associated brain pathology in the United Kingdom. HIV encephalitis appeared to occur more frequently in injecting drug users and those who died younger. Whereas the findings must be interpreted cautiously, one hypothesis was that differences in the route of transmission may have affected the manifestation of HIV-associated brain damage.
AIDS Dementia Complex↗
Accumulation of beta-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities.
The pathogenesis of neuropsychological abnormalities in patients with human immunodeficiency virus type 1 (HIV-1) encephalitis is obscure because neurons are not the target of infection and severe neuronal loss occurs only late during the disease. Moreover, there is evidence indicating that HIV dementia is not a homogeneous entity and could partially reverse after treatment with zidovudine. The finding that impaired axonal flow, evidenced by beta-amyloid precursor protein immunoreactivity, could contribute to the neuropsychological deficits prompted the present study. Brains of patients with full-blown acquired immunodeficiency syndrome (AIDS) were studied and findings compared with those of normal and abnormal control subjects. The presence of HIV-1 DNA was investigated by nested polymerase chain reaction; axonal abnormalities were detected by beta-amyloid precursor protein, ubiquitin immunohistochemistry, and silver staining. Accumulation of beta-amyloid precursor protein was observed in all the HIV encephalitis brains studied; the appearance of the immunostaining varied from globular structures to bundles of parallel formations. In 2 AIDS brains without pathological abnormalities, only the latter pattern was detected. The brains with trauma were strongly reactive with beta-amyloid precursor protein antibody and the different reactivity within them correlated with posttrauma survival, only globular structures being detected in the older cases. No correlation was found between the different pattern of beta-amyloid precursor protein reactivity and dementia in AIDS patients. These results show that widespread axonal injury is a constant feature in AIDS brains and suggest that it could play a role in the pathogenesis of the neuropsychological abnormalities of these patients.
AIDS Dementia Complex↗
Familial Lafora body disease of late onset: report of four cases in one family and a review of the literature.
Lafora body disease is one cause of progressive myoclonus epilepsy. It typically presents in the second decade with generalized seizures, myoclonus and then intellectual decline. Death is usual within 10 years. Diagnosis may be made by biopsy of skin, muscle, liver or brain. We present four siblings who were normal until their mid-twenties, but then developed intellectual decline, followed by myoclonus. Although a rare form of Lafora body disease has been described that follows a more benign course, may be of later onset, and whose pathology is subtly different, this family is so far unique in terms of the late presentation of otherwise typical Lafora body disease.
Adult↗
Spontaneous epileptiform seizures but increased resistance to kindled seizures in a mutant Sprague-Dawley rat (mf/mf).
Approximately 30% of a breeding colony of Sprague-Dawley rats homozygous for an autosomal recessive mutation mf ("mutilated foot") associated with a peripheral sensory neuropathy have been found unexpectedly to suffer spontaneous epileptiform attacks. Seizures ranged from brief episodes of compulsive running to tonic-clonic convulsions lasting for up to 30 s, recurring at intervals of hours or days. EEG recordings during seizures showed high-voltage 8-10 Hz spike trains that abated over the ensuing 1-2 min. Interictal records were usually normal. Twice-daily kindling of the amygdala (200 microA sinewave for 1.0 s) was unexpectedly ineffective. Most of the rats that had suffered spontaneous seizures failed to develop kindled afterdischarges, even after 30 kindling stimulations. Other mf rats developed prolonged high-amplitude kindled afterdischarges that were arrested at stage 2 and failed to evolve into convulsive seizures. Hippocampal dentate granule cells of kindled mf rats, stained for zinc by Timm's method, showed significantly less mossy fibre sprouting than wild-type Sprague-Dawley rats after the same number of kindled afterdischarges. A minority of the mf rats tested (2 of 14) kindled normally. Auditory stimulation (n = 23) or stroboscopic flicker (n = 14) failed to elicit seizures or running fits in any mf rat. Peripheral neuropathy corresponding to that in the mf rat, with resistance to kindling and diminished mossy fibre sprouting, have also been reported in transgenic mice with defective p75NGFR neurotrophin receptors. A homologous genetic defect in the rat could account for most of the features of the mf phenotype.
Acoustic Stimulation↗
Axotomy-induced apoptosis in adult rat primary sensory neurons.
Neuronal death following unilateral axotomy of a sensory nerve has long been inferred from neuronal counts of dorsal root ganglion neurons, using the contralateral ganglia as a control. The counting methods used usually involved the counting of neuronal nucleoli and made assumptions about them which could conceivably be flawed. Very few studies have used direct observations of dying or degenerating neurons to address questions concerning the duration of the period of neuronal death or the mechanisms involved in this process. Here we describe a morphological, morphometric and histochemical study into the nature and duration of sensory neuron death following transection and ligation of the sciatic nerve at mid-thigh level in the adult rat. We show that at least some of this neuronal loss occurs by apoptosis as defined by morphological criteria and in situ end-labelling of damaged DNA. Absolute numbers of apoptotic neurons were counted from serial paraffin sections of ganglia and estimates of neuronal numbers obtained by disector analysis at 1, 2, 3 and 6 months after axotomy. Using this approach we show that axotomy-induced apoptosis begins at around 1 week and continues up to at least 6 months after axotomy.
Animals↗
Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain.
While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.
Cerebral Cortex↗
Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS.
The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.
Amyloid beta-Protein Precursor↗
Tropical diseases: a historical perspective.
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History, 15th Century↗
Trypanosomiasis.
African (sleeping sickness) and American (Chagas' disease) trypanosomiasis, caused by protozoa of the family Trypanosomatidae, are diseases that are endemic in parts of Africa and Latin America, respectively. Physicians in developed countries may occasionally see cases because of extensive travel and immigration from endemic countries. Although neurological involvement is common in both, its incidence and clinical presentation differ considerably. African trypanosomiasis, caused by subspecies of Trypanosoma brucei (T b rhodesiense, T b gambiense), is transmitted by the tsetse fly and causes meningoencephalitis, in which somnolence is a prominent feature. Parasites may reach the brain parenchyma through the choroid plexus or the Virchow Robin spaces. American trypanosomiasis, caused by Trypanosoma cruzi is transmitted by reduviid bugs. While lesions in the central nervous system are not prominent, except in the reactivated forms which occur in immunodeficient patients, the peripheral nerve, mainly the autonomic nervous system, is frequently involved, leading to the cardiomegaly and the digestive megaviscera. Congenital infections may also occur. In this paper we give an account of the epidemiology, clinical presentation and pathological features of these two protozoal infections based on human and experimental studies of both the central and peripheral nervous system.
Animals↗
Correlation of MRI and neuropathology in AIDS.
OBJECTIVE: To assess the correlation between findings on radiological and neuropathological examinations of the brain. METHODS: The formalin fixed brains of 19 patients who had died of AIDS were examined by MRI and neuropathology. RESULTS: The rate of identification of cerebral atrophy was similar radiologically and neuropathologically. However, only in half of these cases were the two examinations concordant in the diagnosis. Furthermore, in the 15 brains which had radiological diffuse white matter lesions, the underlying pathology was heterogeneous. CONCLUSIONS: The possible reasons for the inconsistencies, and their relevance to the interpretation of imaging studies, are discussed. The study suggests that the qualitative identification of atrophy in the postmortem brain is problematical and that diffuse white matter lesions seen on MRI are not indicative of a specific pathological process.
Acquired Immunodeficiency Syndrome↗
Comparison of magnetic resonance imaging with neuropathological findings in the diagnosis of HIV and CMV associated CNS disease in AIDS.
OBJECTIVES: To compare the results of clinical assessment and MRI with neuropathological findings in the diagnosis of HIV and cytomegalovirus (CMV) associated CNS disease. METHODS: A retrospective study of 35 patients infected with HIV who were examined at necropsy between four and 70 (median 20) days after neurological assessment and MRI. RESULTS: Of the 35 patients, 19 had diffuse white matter hyperintensity on T2 weighted MRI, six of whom also had focal lesions. Nine other patients had focal white matter lesions and seven had changes in cortical atrophy only. Necropsy in the 19 with diffuse white matter hyperintensity showed HIV leukoencephalopathy (HIVLEP) with encephalitis in 10, CMV encephalitis in three, both HIVLEP/HIV encephalitis and CMV encephalitis in one, lymphoma in three, and non-specific inflammation in two. Necropsy in the 16 other patients without diffuse white matter hyperintensity showed CMV encephalitis in six, HIV encephalitis (without HIVLEP) in two, CMV encephalitis and HIVLEP/HIV encephalitis in one, non-HIV associated abnormalities in five, herpes simplex encephalitis in one, and lymphoma in one. CMV DNA was detected in CSF of five of seven patients with CMV encephalitis and in two of two with CMV associated polyradiculopathy but without CMV encephalitis. Diffuse white matter hyperintensity on MRI had a sensitivity of 100%, a specificity of 66.6%, and a positive predictive value of 58% for diagnosis of HIVLEP. CONCLUSION: Diffuse white matter hyperintensity on MRI can be due to either HIV or CMV associated pathology or non-specific abnormalities.
Acquired Immunodeficiency Syndrome↗
Chronic encephalitis and epilepsy in adults and adolescents: a variant of Rasmussen's syndrome?
Chronic encephalitis and epilepsy (Rasmussen's encephalitis) is a rare progressive disorder of uncertain etiology that usually occurs in children, producing focal epilepsy, hemiparesis, and intellectual deterioration. We identified 13 patients in whom seizures developed in adolescence or adulthood with a pathologic picture of chronic encephalitis. The clinical characteristics were more variable than those occurring in children, with the patients falling into three groups: five patients developed seizures in adulthood, but otherwise showed many resemblances to the childhood form; five developed seizures in adolescence, with similar presentation but rather more benign course than in the younger patients; and three presented with clinical features initially suggestive of a tumor. Occipital onset to the seizures appeared to be more common than in the childhood form, and bilateral disease also occurred.
Adolescent↗
[Central nervous system infection due to varicella and zoster virus in AIDS].
We have reviewed 23 cases of varicella-zoster virus infection of the central nervous system in patients with the acquired immunodeficiency syndrome, previously reported in the literature, including 11 from our own series. This allowed us to identify 5 clinico-pathological patterns which could occur simultaneously. In most cases, viral proteins or viral genome were identified using immunocytochemistry or in situ hybridization. Multifocal encephalitis involves predominantly the white matter and is likely to be due to haematogenous spread of the infection. Ventriculitis may have variable appearance according to the course of the disease. In one incipient case, the ependymal lining appeared irregular with foci of infected ependymal cells some of which protruded into the ventricular lumen; in other instances, there was acute or chronic necrosis of the ventricular wall with marked vasculitis. Acute haemorrhagic meningo-myelo-radiculitis with necrotising vasculitis may be associated with ventriculitis and results from shedding of infected ependymal cells into the ventricular lumen and secondary seeding of the cerebrospinal fluid. Focal necrotising encephalitis or myelitis usually follows cutaneous herpes zoster in the corresponding dermatoma and is considered to result from neural spread from the diseased trigeminal or dorsal root ganglion. Vasculopathy involving leptomeningeal arteries and causing cerebral infarcts is associated with meningitis in most cases. These findings are in keeping with the observation in other immunocompromised patients, that varicella-zoster virus spread to the central nervous system may follow different routes. Our study tends to show that varicella-zoster virus infection of the central nervous system is more frequent in the acquired immunodeficiency syndrome than previously suspected and suggests this diagnosis must be considered systematically in cases of encephalitis, ventriculitis, focal myelitis, acute myeloradiculitis and cerebral infarcts in these patients, since an efficient treatment is available.
AIDS Dementia Complex↗
Early HIV-1 infection of the central nervous system.
There is a consensus of opinion that central nervous system (CNS) involvement takes place in a large proportion of patients with the acquired immune deficiency syndrome (AIDS). However, uncertainty still remains about how often and how early the CNS is infected during the early asymptomatic stage as some researchers still believe that low copy of human immunodeficiency virus type 1 (HIV-1) identified in the brains using polymerase chain reaction (PCR) represents HIV harboured in the infected cells trapped in cerebral blood vessels. In this review, the neurological abnormalities in HIV-1 positive pre-AIDS individuals are discussed from three points of view: neuropsychiatric and neurophysiological, involvement of cerebrospinal fluid (CSF) and brain pathology. In particular, our investigations of the brains of asymptomatic individuals have demonstrated that HIV-1 DNA was present in about half (17/36) of brains studied (copy numbers of HIV-1 DNA were detected and the possibility of contamination from the blood was calculated and excluded). Astro- (34/36) and micro- (31/36) gliosis and meningitis (11/36) were found. Immune activation, revealed by elevated expression of major histocompatibility complex (MHC) class II antigens, was previously demonstrated in the brains of patients with AIDS and was also present before the development of AIDS. Furthermore, demonstration of highly expressed cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, 4, 6) possibly explains the neuropathological changes and neuronal damage (confirmed by the demonstration of apoptotic neurons by in situ end labelling) seen in these brains. We conclude that HIV-1 is present in the brains of HIV-1 infected individuals at early stages of the infection and that HIV-1 induces brain damage in a direct as well as indirect way. This is a worrying conclusion which makes it mandatory to reconsider the time at which treatment must be applied in HIV-1 infection.
Animals↗
HIV-1 DNA in brains in AIDS and pre-AIDS: correlation with the stage of disease.
Seventeen asymptomatic individuals positive for human immunodeficiency virus type 1 (HIV-1) and 16 patients with acquired immunodeficiency syndrome (AIDS), all with polymerase chain reaction evidence of HIV-1 DNA, were selected for quantitative analysis to correlate the levels of HIV-1 DNA in brain tissue with the stage of infection. The AIDS patients either were clinically asymptomatic or presented various abnormalities. Neuropathological lesions were assessed by morphological and immunohistochemical methods. To determine the level of HIV-1 DNA, semiquantitative nested polymerase chain reaction was applied using a digoxigenin-labeled primer and chemiluminescence. Serial dilutions of standard HIV DNA were run in parallel with brain DNA samples. Among the 16 AIDS brains studied, 9 showed changes characteristic of HIV encephalitis/leukoencephalopathy while 1 showed focal pontine leukoencephalopathy and 6 showed no obvious neuropathological lesions. Abnormalities in pre-AIDS individuals included meningitis, microgliosis, and astrogliosis. Copy numbers of HIV-1 DNA in the brains of AIDS patients were higher than those in asymptomatic individuals (median, 135 vs 45 copies/150,000 cells). However, there was some degree of overlapping between the two groups, with some AIDS patients showing low figures while 3 asymptomatic individuals had high copy numbers. This suggests that the use of HIV-1 DNA load in the central nervous system as an indicator of progression of the disease should be restricted to large series and not single patients.
Acquired Immunodeficiency Syndrome↗
Mitochondrial DNA levels in the brain of HIV-positive patients after zidovudine therapy.
Previous studies have shown that the antiviral nucleoside analogue zidovudine (AZT) depletes levels of mitochondrial DNA (mtDNA) in muscle of patients on long-term therapy. In this study we found that in a similar group of eight HIV-positive patients receiving AZT there was no depletion of brain mtDNA. This finding suggests that AZT-related mtDNA depletion is not a contributing factor in the HIV encephalopathy that occurs in a proportion of HIV-positive patients receiving this antiviral agent.
AIDS Dementia Complex↗