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Objective: To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48., Design: In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count > or =200 cells/microl and a plasma HIV-1 RNA level 10,000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml)., Results: Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/microl, with 150 cells/microl in the zidovudine/lamivudine arm, and from 290 cells/microl, with 310 cells/microl in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level <50 copies/ml at week 12 and 48, respectively. The CSF indinavir concentration ranged from 50 to 170 ng/ml., Conclusion: The long-term HIV-1 suppression observed in this study is remarkable, as adding a single antiretroviral agent to a failing regimen goes against current notions of adequate therapy.

Heterozygosity for a 32-bp deletion in the CCR5 gene (CCR5 Delta32), which encodes the coreceptor for macrophage-tropic non-syncytium-inducing (NSI) human immunodeficiency virus type 1 (HIV-1) variants, results in a lower CCR5 expression and reduced NSI HIV-1 replication. Because infection of macrophages and microglial cells by NSI HIV-1 is considered to be instrumental for the development of AIDS dementia complex (ADC), we studied whether the CCR5 Delta32 heterozygous genotype correlated with a reduced frequency of ADC. Two (4.1%) of 49 patients with ADC versus 27 (14. 5%) of 186 AIDS patients without ADC were heterozygous for CCR5 Delta32 (P=.05). In contrast, a point mutation in the first transmembrane domain of CCR2 (CCR2 64I) did not show this protective effect (P=.57). The reduced prevalence of the CCR5 Delta32 allele among patients with ADC may indicate a reduced or absent reservoir of macrophage-tropic NSI HIV-1 in the brain of CCR5 Delta32 heterozygotes.

Objectives: To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients., Design and Methods: Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight control subjects was processed for iNOS immunocytochemistry, NADPH-diaphorase activity staining as an index of NOS activity, and in situ end-labelling to detect cell death., Results: iNOS-positive cells were present in the white matter of 14 out of 16 AIDS and ADC patients, whereas two out of eight control subjects showed iNOS-positive cells. iNOS immunoreactivity was exclusively localized in activated macrophages and microglial cells that both showed NADPH-diaphorase activity. In addition, NADPH-diaphorase activity, not related to iNOS immunoreactivity, was observed in astrocytes in both white and grey matter of AIDS and ADC patients. All AIDS and ADC patients, and only one control subject showed characteristic features of apoptotic cell death., Conclusions: Different forms of NOS are present in microglial cells and astrocytes of AIDS and ADC patients but are largely absent in control subjects. Although more NOS-expressing cells occur in ADC than in AIDS patients, apoptotic cell death was found in both patient groups to the same extent. We postulate that NO production in brains of AIDS patients results in cumulative cortical cell loss, which becomes neurologically evident at later stages of disease and is expressed as ADC.

A 30-year-old AIDS-patient with cryptococcal meningitis developed subacute bilateral visual loss associated with high cerebrospinal fluid (CSF) pressure. With immediate CSF drainage the blindness was reversible. The importance of prompt CSF drainage in AIDS-related cryptococcal meningitis with visual failure is stressed.

Paired serum and cerebrospinal fluid (CSF) samples from 10 AIDS patients with and 10 without AIDS dementia complex (ADC) were studied, in an attempt to uncover ADC-associated variation in V3 sequences. Sequences were obtained from four of the patients with and eight of those without ADC. Comparison of the sequences using a resampling technique revealed a significant ADC-associated difference occurring at several amino acid positions. Results from serum and CSF sequences were comparable. These differences may indicate that the virus found in ADC and that in non-ADC patients have different biological properties. Comparison of serum versus CSF sequences within samples from both ADC and non-ADC patients, using the same resampling technique, revealed no clear distinctions. In some patients, the sequence populations in serum and CSF were completely distinct, while in others, there was no difference in distribution. These patterns were not associated with ADC.

The number of immunocytochemically identified vasopressin (AVP) and oxytocin (OXT) neurons was determined morphometrically in the paraventricular nucleus of the hypothalamus of 20 acquired immunodeficiency syndrome (AIDS) patients and 10 controls. The AIDS group consisted of 14 homosexual males (age range 25-62 years), four of whom had a probable HIV-1 associated dementia complex, and six non-demented heterosexuals (four males and two females, age range 21-73 years). Ten males without a primary neurological or psychiatric disease served as a control group. The number of OXT-expressing neurons in the paraventricular nucleus of both groups of AIDS patients was approximately 40% lower than that of the controls. In contrast, the three groups showed no significant differences in the number of AVP-expressing neurons in the paraventricular nucleus. Since there were no significant differences in the number of AVP and OXT cells between the homosexual and heterosexual subjects with AIDS, the morphological difference in the paraventricular nucleus seems to be related to AIDS and not to sexual orientation. No inflammatory changes were found in the paraventricular nucleus area. The selective changes in the OXT neurons of the paraventricular nucleus may be the basis for part of the neuroendocrine, autonomic dysfunction or vegetative symptoms in AIDS.

This study was carried out to determine clinical features, abnormalities on CT scan and MRI, and course in patients with HIV-I-related progressive multifocal leukoencephalopathy (PML). There were 14 patients with a presumptive diagnosis of PML among 500 HIV-I infected patients with neurological complaints, examined between September 1982 and May 1991 in the University Medical Centre in Amsterdam by a neurologist. In these 14 patients clinical features, imaging abnormalities and course of the disease were analysed retrospectively. All patients presented with progressive focal neurological abnormalities. Cerebrospinal fluid analysis revealed aspecific abnormalities in 5/13 patients. CT scanning of the brain showed hypodense areas in the white matter, without mass effect and with contrast enhancing in only one patient. MR Imaging of the brain showed high signal intensity areas in white matter and in gray matter (10/13), without mass effect, and with contrast enhancement in two. Specimens for neuropathological examination were obtained from 7 patients; in all these cases the diagnosis of PML was confirmed. In patients with AIDS a presumptive diagnosis of PML can be based on clinical features, brain imaging abnormalities and course. However neuropathological confirmation remains the gold standard. Usually the course in these patients was steadily progressive. Most patients died within one year.

Objective: We conducted a comparison of itraconazole versus amphotericin B plus flucytosine in the initial treatment of cryptococcal meningitis in patients with AIDS and established the efficacy of itraconazole as maintenance treatment., Design: The trial was a prospective, randomized, and non-blinded study., Setting: The study was performed at an academic centre for AIDS, Amsterdam, The Netherlands., Patients, Participants: Twenty-eight HIV-1-seropositive men with a presumptive diagnosis of cryptococcal meningitis, randomized between 5 February 1987 and 1 January 1990, were included for analysis., Interventions: Oral itraconazole (200 mg twice daily), versus amphotericin B (0.3 mg/kg daily) intravenously plus oral flucytosine (150 mg/kg daily) was administered for 6 weeks followed by maintenance therapy with oral itraconazole (200 mg daily) to all patients., Main Outcome Measures: Outcome measures were a complete or partial response, recrudescence and relapse., Results: A complete response was observed in five out of the 12 patients who completed 6 weeks of initial treatment with itraconazole versus all 10 patients who completed treatment with amphotericin B plus flucytosine (P = 0.009). A partial response was observed in seven out of the 14 patients assigned to itraconazole. During maintenance therapy, recrudescence (n = 6) or relapse (n = 1) occurred in seven out of the 12 patients initially assigned to itraconazole, whereas two relapses occurred among nine patients initially treated with amphotericin B plus flucytosine (P = 0.22); recurrence of clinical symptoms was significantly related to a positive cerebrospinal fluid culture at 6 weeks (P = 0.003)., Conclusion: Itraconazole is less effective compared with amphotericin B plus flucytosine in achieving a complete response in initial therapy in AIDS patients with cryptococcal meningitis.

We retrospectively assessed the efficacy of maintenance therapy with pyrimethamine alone in 38 patients with AIDS and central nervous system (CNS) toxoplasmosis. The diagnosis was based on clinical presentation and compatible CT scan abnormalities with subsequent response to therapy. Survival analysis was performed by the product limit method of Kaplan-Meier. Fourteen patients received maintenance therapy with 25 mg pyrimethamine per day (group 1), and 24 patients were treated with 50 mg per day (group 2). The median survival from initiation of maintenance therapy until death or end of the study for the entire study population was 32 weeks. Median survival in group 1 was 28 weeks, as compared with 36 weeks in group 2 (p = 0.34). Relapses occurred in 12 patients, six in group 1 and six in group 2. There was no significant difference in failure-free survival between the two treatment groups (p = 0.09). One patient in group 1 and two patients in group 2 experienced severe toxicity, requiring discontinuation of therapy. All three patients relapsed and died. Two patients in group 2 who stopped treatment on their own initiative also had relapses. Thus, all five patients who discontinued therapy had relapses. Five of 13 patients in group 1 and two of 20 patients in group 2 relapsed during continuous therapy with pyrimethamine (p = 0.13); these seven patients responded to reintroduction of combination therapy (n = 6) or treatment with 50 mg pyrimethamine per day (n = 1). The results of our retrospective analysis suggest that maintenance therapy with oral pyrimethamine, 50 mg per day, in AIDS patients with CNS toxoplasmosis is effective.

Six AIDS patients with progressive cytomegalovirus (CMV) polyradiculomyelitis were treated with ganciclovir in an open study. The diagnosis was based on the presence of a distinct clinical syndrome with progressive flaccid paraparesis, preserved proprioception and urinary retention with specific cerebrospinal fluid (CSF) findings. Ganciclovir therapy, 5-10 mg/kg per day, instituted 3-6.5 weeks after onset of symptoms, was ineffective in four patients with severe paraparesis. One patient developed CMV polyradiculomyelitis while receiving ganciclovir and further deteriorated during foscarnet therapy. One patient however, showing minor paresis of one leg, improved after institution of ganciclovir therapy 1 week after onset of symptoms. It is concluded that a presumptive diagnosis of CMV polyradiculomyelitis can be made on the basis of distinct clinical findings and CSF pleocytosis with predominance of polymorphonuclear leukocytes in patients with AIDS. Ganciclovir therapy does not appear to be beneficial for patients with advanced paresis in the doses used. Further investigations are needed in order to determine if early intervention with ganciclovir, when paresis is mild, or higher doses in advanced paresis, might be of some benefit.

Cytomegalovirus (CMV) polyradiculomyelitis was diagnosed in 4 of 241 consecutive neurologically assessed human immunodeficiency virus type (HIV-1) seropositive patients. CMV-related neurologic disease was suspected on clinical grounds and was subsequently confirmed by CMV culture from cerebrospinal fluid (CSF) and/or CMV in situ hybridization on specific specimens. All four patients showed CSF pleocytosis with predominance of polymorphonuclear leukocytes (PMNs). Retrospective analysis of the results of CSF examination, performed in 143 of 241 patients with neurologic symptoms, showed pleocytosis in 58 of 143 patients. Predominance of PMNs was found in seven patients, including the four with CMV polyradiculomyelitis. It is concluded that in HIV-1 seropositive patients with a clinical diagnosis of polyradiculomyelitis, a predominance of PMNs in CSF could be an indication that the condition is CMV related. This should lead to early diagnosis and institution of specific antiviral therapy.

Neurological complications in patients with Acquired Immuno Deficiency Syndrome (AIDS) are frequent and in addition to central nervous system syndromes, involvement of the peripheral nervous system is increasingly seen. We evaluated the indications and results of myelographic examination in six AIDS-patients with signs of peripheral nervous system disease, out of 200 AIDS-patients with neurological complications. Five of these patients had a polyradiculopathy, with proven cytomegalovirus (CMV) infection in four cases. There were two abnormal myelographic examinations with findings of cauda equina nerve root involvement, both in patients with proven CMV-polyradiculopathy. These abnormal findings had no direct therapeutic consequences. Myelography is not essential for establishing the diagnosis, which is based on cerebrospinal fluid (CSF) analysis, but may be indicated to exclude a spinal cord or nerve root compressive lesion.

Human immunodeficiency virus type-1 (HIV-1) antigen was assayed in paired serum/cerebrospinal fluid (CSF) specimen from 85 adults and 58 children with acquired immunodeficiency syndrome and was compared with clinical neurological status. A quantitative comparison of HIV-1 antigen levels in matched serum and CSF specimens indicated that HIV-1 antigen expression in these compartments is independent and is correlated with acquired immunodeficiency syndrome dementia complex in adults and progressive encephalopathy in children. In a longitudinal study (n = 47), 16 patients tested positive for HIV-1 antigen in the CSF before (n = 2) or coincident (n = 14) with neurological deterioration. Six patients who tested positive for HIV-1 antigen in the CSF remained neurologically normal for a median duration of follow-up of 11 months. Six of 25 patients who tested negative for HIV-1 antigen in the CSF, subsequently showed neurological deterioration. These data indicate that HIV-1 antigen expression in the CSF is not useful in predicting neurological deterioration.

Objective: To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment., Design: Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988., Setting: An academic centre for AIDS., Patients: 196 Patients with AIDS and neurological symptoms examined from 1982 to 1988., Interventions: Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D)., Main Outcome Measures: Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid., Results: The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive., Conclusions: The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.