Methanol outbreak in Norway 2002-2004: epidemiology, clinical features and prognostic signs.

OBJECTIVES: Knowledge on methanol poisoning does mainly come from clinical studies. We therefore report epidemiological, clinical and prognostic features from the large methanol outbreak in Norway in 2002-2004 where the new antidote fomepizole was the primary antidote in use. DESIGN AND SUBJECTS: Combined prospective and retrospective case series study of 51 hospitalized patients who were confirmed poisoned with methanol, of whom nine died. In addition, eight patients died outside hospital. Most patients were admitted in a late stage and because of symptoms. Treatment consisted of alkali, fomepizole (71%) and haemodialysis (73%). RESULTS: The median serum methanol was 25.0 mmol L-1 (80 mg dL-1) (range 3.1-147.0 mmol L-1), median pH was 7.20 (6.50-7.50), and median base deficit 22 mmol L-1 (range 0-31). The most frequent clinical features reported were visual disturbances (55%), dyspnoea (41%), and gastrointestinal symptoms (43%). Twenty-four per cent were comatose on admission, of whom 67% died. There was a trend towards decreasing pCO2 with decreasing pH amongst the patients surviving. The opposite trend was demonstrated in the dying; the difference was highly significant by linear regression analyses (P<0.001). CONCLUSIONS: Methanol poisoning still has a high morbidity and mortality, mainly because of late diagnosis and treatment. Respiratory arrest, coma and severe metabolic acidosis (pH<6.90, base deficit>28 mmol L-1) upon admission were strong predictors of poor outcome. Early admission and ability of respiratory compensation of metabolic acidosis was associated with survival.

Prevalence of hypertension in HIV-positive patients on highly active retroviral therapy (HAART) compared with HAART-naïve and HIV-negative controls: results from a Norwegian study of 721 patients.

Highly active antiretroviral therapy (HAART) may induce dyslipidemia, insulin resistance and body fat distribution similar to that seen in the metabolic syndrome. Hypertension is often a part of the classic metabolic syndrome, but few studies are published about hypertension in HIV-positive patients on HAART. The aim of this study was to compare the prevalence of hypertension in HIV-positive patients on HAART with that in HIV-positive/HAART-naïve patients and HIV-negative controls. The cross-sectional study included 283 unselected HIV-positive ambulatory patients, 219 who were on HAART and 64 who were HAART-naïve. Age- and gender-matched controls (n=438) were randomly selected from a simultaneous health survey of the general population. The prevalence of hypertension was 21% in patients on HAART, 13% in HAART-naïve patients (P=0.20), and 24% in HIV-negative controls (P=0.28). Among several possible risk factors for hypertension, only body mass index (BMI) was found to be a confounder. BMI was similar in HAART-treated and HAART-naïve patients but elevated in controls compared to HAART-treated patients. After adjustment for BMI, the prevalence of hypertension in HIV-negative controls was slightly lower than that in patients on HAART (P=0.29). The results demonstrated a prevalence of hypertension in patients on HAART similar to that in HIV-negative controls. The prevalence of hypertension was somewhat higher in patients on HAART compared to HAART-naïve patients, but the difference was not statistically significant. Considering the marked drop in mortality following antiretroviral therapy, we conclude that the possible influence of HAART on the prevalence of hypertension appears to be a minor problem.

Early psychomotor slowing predicts the development of HIV dementia and autopsy-verified HIV encephalitis.

OBJECTIVES- To ask if slowed motor speed predicts later human immunodeficiency virus (HIV) dementia and HIV encephalitis. METHODS- In 100 deceased acquired immunodeficiency syndrome (AIDS) patients prior results from repeated testing of the movement reaction time test were correlated with later clinical signs of HIV dementia and with neuropathological signs of HIV encephalitis. Autopsy was performed in 72 patients. RESULTS- Movement reaction time 1-2 years prior to death, or at the time of clinical AIDS diagnosis predicted both development of HIV dementia (P<0.05) and HIV encephalitis at autopsy (P<0.01). CONCLUSION- Testing for early psychomotor slowing may be used to identify patients at risk of HIV dementia and HIV encephalitis.

Dementia in AIDS patients in Oslo; the role of HIV encephalitis and CMV encephalitis.

In a well-defined population of adult AIDS patients from Oslo, we studied the correlation between clinical dementia and autopsy results. The study included 91% of all adult AIDS patients from Oslo who died between 1983 and 1996. The autopsy rate was 73% (167/229). Twenty-three percent of patients had definite dementia and 24% possible dementia. In more than half of the patients with definite dementia multinucleated giant cells were present in the brain tissue, suggesting that the dementia was due to HIV encephalitis. Diffuse damage of white matter also showed a significant association with clinical dementia. When found alone it tended to occur in symptomatic patients with a short survival time from onset of dementia until death. This indicates that diffuse damage of white matter may be an early stage of HIV encephalitis. CMV encephalitis was found in 28 cases (17%). Of these, 20 were classified as definitely or possibly demented. In 14 of these 20 cases we detected no multinucleated giant cells, suggesting that CMV caused or contributed to the dementia. Multiple logistic regression supported an association between CMV and conditions clinically classified as HIV dementia. We conclude that HIV encephalitis is the major cause of dementia in AIDS patients, but that CMV encephalitis as a cause of dementia has been underestimated.

Varicella infection in a renal transplant recipient associated with abdominal pain, hepatitis, and glomerulonephritis.

A 36-year-old renal transplant patient developed 9 years after a successful transplantation a fatal secondary varicella infection. The disseminated varicella infection was associated with hepatitis with liver necrosis, disseminated intravascular coagulation and fibrinolysis and glomerulonephritis. To our knowledge this is the first description of glomerulonephritis associated with varicella infection in a renal transplanted patient. The autopsy showed morphologically a mesangial glomerulonephritis with minor proliferative activity and extensive deposits by electronmicroscopy, mainly in the mesangium. The ongoing immunosuppression may have modified the mesangial cell response to the deposition of immune complexes.

Association between apolipoprotein E genotypes and cancer risk in patients with acquired immunodeficiency syndrome.

The apolipoprotein E (apoE) genotype was determined in 197 deceased acquired immunodeficiency syndrome (AIDS) patients treated at Ullevaal Hospital in Oslo, Norway. A full autopsy had been performed on all. Cancer had developed in 71 individuals, mainly lymphomas (46) and Kaposi's sarcomas (18). The apoE genotype distribution was consistent with Hardy-Weinberg equilibrium, and allele frequencies were in the typical Scandinavian range (6.9% apoE2; 75.6% apoE3; and 17.5% apoE4). Cancer cases had a significantly higher frequency of apoE4 alleles than noncancer cases (24.6% and 13.5%, respectively) and a lower frequency of apoE2 alleles (3.5% versus 8.7%). Background factors, such as survival from AIDS diagnosis, could not explain these differences. Our study thus indicates that apoE genotype affects the development of cancers among AIDS patients.

Slowed reaction time in HIV-1-infected patients without AIDS.

OBJECTIVES: To investigate if HIV-1-infected patients without acquired immunodeficiency syndrome (AIDS) have cerebral dysfunction as reflected by impaired reaction times compared to patients with chronic hepatitis C. MATERIAL AND METHODS: Forty-one HIV-1-infected patients not fulfilling the AIDS criteria, were tested with three reaction time tests and compared to controls with chronic hepatitis C, matched according to gender and age. RESULTS: HIV-1-infected individuals had, in mean, 5-47 ms longer reaction time than patients with hepatitis C (statistically significant in two of three tests). All but 9 HIV-1-infected individuals had, however, reaction times within the normal range defined by the control group (mean +/- 2 SD). No correlation was found between reaction time and immune status measured as CD4-cell count. CONCLUSION: This study indicates that a subgroup of HIV-1-infected individuals have slower reaction time compatible with cerebral deterioration early in the course of the infection.

Early changes in peripheral blood T cell subsets induced by antiretroviral treatment of human immunodeficiency virus-1 positive individuals.

Human immunodeficiency virus (HIV)-1 infection causes a gradual decline in peripheral blood CD4+ T cells. Shortly after the primary infection, an expansion of the activated memory CD8+ T-cell pool is also observed paralleling increased levels of plasma viraemia. In the present study we investigated the immediate effects of zidovudine therapy on peripheral blood T-cell subsets during the first 3 weeks of therapy in a group of HIV-1 positive individuals receiving influenza vaccine. HIV-1 positive individuals who received vaccine, but no treatment, were included as controls. Both the number of CD4+ and CD8+ T cells increased during the first week of therapy in parallel with a decline in plasma viraemia. The majority of CD4+ T cells contributing to this expansion expressed CD28, CD45RO and Fas, whereas the expanded CD8+ T cells were predominantly CD28-, CD45RO+, CD38+, Fas+ and Fas+ (CD95). We propose that the increase in the number of activated memory T cells observed in peripheral blood immediately after the onset of antiretroviral treatment is most likely caused by the redistribution of cells from various lymphoid organs in response to decreased levels of viral load in these compartments. The degree of T-cell redistribution is probably dependent on the magnitude of virus suppression.

HIV dementia and apolipoprotein E.

The effect of apolipoprotein E genotypes on the occurrence of HIV dementia and HIV encephalitis was studied in a sample of 132 AIDS patients in whom clinical data on dementia was available and full autopsy had been performed. There was no statistically significant correlation between risk of HIV dementia or HIV encephalitis in relation to apolipoprotein E genotypes, even after correction for length of survival with AIDS and antiretroviral treatment.

The impact of primary central nervous system lymphoma in AIDS patients: a population-based autopsy study from Oslo.

This study comprises the 255 adult AIDS patients treated at Ullevål hospital 1983-1995. These patients, fulfilling the Centers of Disease Control (CDC) clinical criteria for AIDS, correspond to 91% of all adult AIDS cases in Oslo. By the end of the study period, 44 patients were alive and 211 had died. Full autopsy was performed on 153 (73%) of the deceased. Supplementary analyses were carried out on the 344 patients (225 deceased) fulfilling the U.S. definition of AIDS, which includes CD4 cell counts below 200 cells/mm3. In the autopsy group, histologically verified non-Hodgkin B-cell lymphoma was found in 29 cases (19%). Nineteen of these (12%) had primary central nervous system (PCNS) lymphoma. Survival curves indicate that PCNS lymphoma constitutes a small risk early in the AIDS stage, but it has a serious impact on long-term survival. For patients not contracting other fatal diseases, one fourth are estimated to die of PCNS lymphoma within about 3 years. Comparison of clinical diagnoses and autopsy results show that PCNS lymphoma has been difficult to separate from other CNS disorders, which probably has caused marked underestimation of the incidence in previous assessments. We conclude that PCNS lymphoma is a major threat to long-term survival in AIDS victims.

[Cerebral CT findings in AIDS]. / Cerebrale CT-funn ved AIDS.

A cerebral CT was performed in 82 of 525 AIDS patients, with positive findings in 46 cases. These findings included cerebral atrophy in 28 cases, pathological demyelinisation in two, progressive multifocal leukoencephalopathy in one, toxoplasmosis in 11, lymphomas in seven, infarction in one and one subdural haematoma. The radiological findings are correlated to pathology and clinical symptoms. The authors point out the importance of these findings for correct interpretation of the CT scans.

High incidence and aggressive growth of non-AIDS-defining cancers among AIDS patients in Oslo.

The spectrum of cancers advanced by AIDS is disputed. To supplement the register-based investigations, we have studied the occurrence of non-AIDS-defining malignancies in a closely followed population of AIDS patients. The population comprises 255 patients fulfilling CDC's clinical AIDS definition, representing 91% of all adult AIDS patients from Oslo 1983-1995. Full autopsy was performed on 73% of the 211 fatal cases. Adding patients with CD4 cell counts below 200 cells/mm3 to match the US AIDS definition, the population increases to 344, including 225 deceased. The expected number of cancer cases was calculated from age- and sex-specific cancer incidence rates for Oslo 1988-1992. The number of non-AIDS-defining cancers was six (clinical CDC criteria) or eight (US AIDS definition), compared to expected numbers of 0.54 and 1.0, respectively. At autopsy, four of eight cases showed extensive tumor dissemination with involvement of the heart. These observations suggest that (at least some) non-AIDS-defining cancers occur at increased rates and show aggressive growth pattern in AIDS.

Reduced Global Cerebral Blood Flow in Non-Demented HIV Positive Patients.

Twelve non-demented HIV positive men with different degrees of immunodeficiency were examined with single photon emission computed tomography (SPECT). Reduction in relative global cerebral blood flow was found in HIV positive patients compared to healthy HIV negative controls (p = 0.014). In the patients there was also a change in cerebral flow distribution, with lower global flow compared to central flow (p = 0.01), most pronounced in patients with early disease. In the patients with advanced HIV disease the relative cerebral blood flow was lower than in the controls in 108 of 116 (93%) regions investigated.

Risk of toxoplasmic encephalitis in AIDS patients: indications for prophylaxis.

To establish the indications for primary prophylaxis against toxoplasmic encephalitis in the Norwegian HIV-positive population, we estimated the incidence of toxoplasmic encephalitis, and related the degree of immunodeficiency and the presence of IgG antibodies against Toxoplasma gondii (T. gondii) to the development of toxoplasmic encephalitis. This retrospective study includes all HIV-positive patients at our hospital from April 1983 to October 1994 (n = 705). A total of 238 patients had AIDS, which represents almost 90% of all AIDS patients in Oslo. Autopsy was done in over 70% of the patients who died during this period; 19 patients developed toxoplasmic encephalitis (8.0%). The median CD4 cell count was 75 x 10(6) cell/I (range 0-280) at the time of diagnosis of toxoplasmic encephalitis. T. gondii serology was studied in 698 (99.0%) of the patients, and was found positive for 17.8%. Of the patients with toxoplasmic encephalitis 18/19 had IgG antibodies against T. gondii and of the 40 AIDS patients who had anti-T. gondii IgG, 18 (45%) developed toxoplasmic encephalitis. We conclude that there is indication for prophylactic treatment of HIV positive patients who have IgG antibodies against T. gondii and who have fewer than 200 x 10(6) CD4 cells/I.

Changing incidence of HIV-induced brain lesions in Oslo, 1983-1994: effects of zidovudine treatment.

OBJECTIVE: To investigate the relation between HIV-induced brain lesions, zidovudine (ZDV) treatment and survival length in a well-defined population of HIV-positive patients. METHODS AND PATIENTS: Ulleval Hospital has the responsibility for treating all AIDS patients from the city of Oslo except haemophiliac patients. The patient population in this autopsy study comprised all adult AIDS patients in Oslo who were treated at our hospital and died during 1983-1994 (n = 171). This represents 86% of all adult AIDS patients from Oslo who died during the same period. Full autopsy, including neuropathological examination of the brain and spinal cord, was performed on 128 (75%) of those who died. RESULTS: No significant differences were found between autopsy and non-autopsy cases with regard to sex, age, risk groups, survival length or ZDV treatment. In the autopsy material, multinucleated giant cells (MGC) in brain tissue were found in 29 cases and diffuse damage of white matter in 52 cases. Analysis shows that ZDV (600 mg per day) reduced the incidence of these brain lesions, but only if continued until death. A second finding was an increased incidence of HIV-induced brain lesions for those with long-term survival. Together these observations may explain a substantial part of the time-trend in the incidence of MGC in Oslo. MGC were frequent (40%) during the first years of the epidemic, although survival length was short in this period. The incidence fell markedly around the time ZDV was introduced and later remained low in those using ZDV until death. The incidence of MGC has, however, increased during the later years, the new cases mainly occurring in patients who had discontinued ZDV use. CONCLUSION: If continued until death, ZDV can reduce the incidence of HIV-induced brain lesions in AIDS patients. When ZDV treatment is terminated a rapid increase occurs in the incidence of HIV encephalitis.

Total reaction time: a new approach in early HIV encephalopathy?

In an attempt to develop better methods for diagnosis, screening and serial assessment of HIV-1-associated cognitive/motor complex, we have added a motor component to tests of reaction time, defining the new parameter as total reaction time. Thirty-four non-drug-using, HIV-positive men underwent four different tests of total reaction time. All four tests reached a level of statistical significance, both for a group of patients with early disease and for a group of patients with symptoms, compared with a control group. Total reaction time had a better discriminatory ability than standard reaction time, particularly for patients with early disease. It is suggested that neuropsychological studies of HIV-1-associated cognitive/motor complex should include tests of total reaction time.

Five different tests of reaction time evaluated in HIV seropositive men.

In an attempt to develop a short neuropsychological test battery five different tests of reaction time were assessed according to their ability to discriminate between HIV seropositive men and healthy controls. In all tests a patient group with clinical symptoms was slower than the control group. In the complex reaction time test, which has a large cognitive aspect, even a clinically "asymptomatic" group was slower than the control group. The movement test, a new test with a large motor component, identified most slow responders, defining approximately half of the patients with clinical symptoms and one third of the "asymptomatic" patients as such. A test battery consisting of three tests is suggested for serial assessment and screening.

Calprotectin in cerebrospinal fluid of the HIV infected: a diagnostic marker of opportunistic central nervous system infection?

The calprotectin level in the cerebrospinal fluid (CSF) of 15 HIV positive patients with symptoms from the central nervous system (CNS) was measured. All 5 patients with opportunistic infections had levels above the reference range and all 10 patients with HIV associated encephalopathy had levels within the reference range. Thus, the calprotectin level in CSF can be of diagnostic value in differentiating between HIV associated encephalopathy and opportunistic infection in the HIV positive patient with symptoms from the CNS.