Twenty-seven patients (36%) presented with neurological deterioration related to TB. Paradoxical TB-IRIS was diagnosed in 16/75 patients (21%). Thirteen out of 16 of these patients received corticosteroids. At 6-months follow-up, 15/16 patients were alive and one was lost to follow-up. All patients diagnosed with tuberculoma either had a negative-serum immunoglobulin G (IgG) serological analysis for toxoplasma species or showed a good response to antitubercular treatment in the absence of treatment for toxoplasmosis.
Eighteen patients (24%) presented with deterioration related to cryptococcal meningitis. Five patients (7%) presented with paradoxical CM-IRIS, of whom one received corticosteroids. At 6-months follow-up, four of these five patients were alive and one was lost to follow-up.
Nine patients (12%) presented with psychosis. An EFV-induced psychosis was the most likely cause in five. One patient was diagnosed with INH-induced psychosis and another was diagnosed with a reactive psychosis secondary to social stressors. A diagnosis of HIV-induced psychosis was presumed for two patients in whom no other cause could be identified.
At 6-months follow-up, 43 (57%) patients were alive, 17 (23%) were dead and 15 (20%) were lost to follow-up from the healthcare system (Table 1). The median interval from ART initiation, and presentation, to death was 67 days [interquartile range (IQR) 47–164 days] and 23 days (IQR 10–39 days), respectively.
This is, to our knowledge, the first prospective study describing the spectrum of neurological disorders occurring within the first year of ART. TB and cryptococcal meningitis together accounted for at least 60% of cases. This is likely owing to the high incidence of TB in our setting, and profound immunosuppression at ART initiation; in 2007, 19% of adults starting ART in the Western Cape province had CD4+ cell counts below 50 cells/μl, whereas the median CD4+ cell counts of patients starting ART in two of the referring clinics were 131 cells/μl .
Neurological deterioration is an important cause of clinical deterioration and death after starting ART. The referral rate of 23.3 cases per 1000 patient-years at risk is most likely an underestimate of the true incidence of neurological deterioration. Although significant neurological presentation related to a CNS cause results in referral to our facility, patients with mild symptoms or signs are not always referred; patients who are too confused or otherwise unwell to seek medical help may die at home; and patients may attend other hospitals or move out of the referral area. Furthermore, new or worsening peripheral neuropathy is a common cause for neurological deterioration after starting ART . However, as most peripheral neuropathies are managed at primary care level, we did not include these patients in our study. In this study, the challenges posed by the management of patients with neurological deterioration are reflected in poor outcome (23% died), and high rate of loss to follow-up (20%), at 6 months. In comparison, among all patients starting ART in our setting, mortality and loss to follow-up is considerably lower. The cumulative mortality rate during the first year of ART (from 2004 to 2007 in the largest ART clinics in our referral area) was 8%, and 3–5% of patients were lost to follow-up during the first year of ART . In a busy ART program, clinic attendance and adherence to ART require patient mobility, insight and motivation. Neurological deterioration makes this difficult, especially if there is inadequate treatment support from family or friends. Patients with psychosis or confusion may not have the insight to seek medical help and may default ART and other medical therapies. Furthermore, patients with weakness or other neurological impairment may be physically incapable of seeking medical care independently. This may contribute to the high loss to follow-up rate we observed.
In our setting, opportunistic infections, notably TB and cryptococcosis, were the most important causes for neurological deterioration during the first year of ART. Over a quarter of patients were related to paradoxical IRIS. Our study has particular relevance to ART programs in high TB prevalence regions. We highlight the challenges associated with the management of these in patients in resource-constrained settings.
V.A., F.T., G.M., D.J.P. and S.M. were involved in study design. V.A., F.T., G.M. and S.M. assessed study participants and extracted clinical data. A.B. performed statistical analysis. All authors contributed to writing of the manuscript. S.M. and D.J.P. were supported by funding via the Perinatal HIV Research Unit from the United States Agency for International Development (USAID) and PEPFAR. The Wellcome Trust supports G.M. and R.J.W. (081667, 084323, 088316). F.T. is funded by a Gilead HIV Clinical Cooperation Grant 2008. G.M. and D.J.P. are supported by a Fogarty International Center South Africa TB/AIDS Training Award (NIH/FIC 1U2RTW007373-01A1, 1U2RTW007370).
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