Our study provides a detailed analysis of non-traumatic neurological syndromes among HIV-infected patients in northeastern Iran, addressing a critical gap in understanding the burden of neurological complications in this context. Neurological syndromes accounted for 22.73% of hospital admissions among HIV-infected patients, aligning with global estimates that suggest up to 70% of HIV-positive individuals may experience such complications [4].
The prognosis for HIV-infected patients with neurological syndromes was particularly poor. Kaplan-Meier survival curves showed a steep decline in survival rates in those with neurological syndromes, with a 36-month survival rate of 36.30%. The log-rank test confirmed that patients with neurological syndromes faced significantly higher mortality than those hospitalized with other conditions. Similar trends have been documented globally: in Brazil, a cohort study found a 12% in-hospital mortality and 31% one-year mortality [10], while studies in Ethiopia, China, and Poland reported mortality rates of 13–59% for HIV-infected patients with neurological syndromes [11,12,13].
Our data emphasize the severe consequences of late presentation of HIV-infected patients with neurological syndromes. Notably, 17% of patients with neurological syndromes died within the first 24 h of admission, contributing to half of all in-hospital deaths. Delayed HIV diagnosis, advanced disease at the time of admission, and the absence of antiretroviral therapy (ART) were the potential contributors to this outcome. Only 26.61% of HIV-infected individuals in the cohort were on ART, and CD4 counts were documented in less than 40% of patients prior to admission. Among patients with neurological syndromes, 16% were newly diagnosed with HIV, only 44% were receiving ART, and the median CD4 count at admission was 67/µL. This mirrors findings from studies in Brazil, China, and Indonesia, where median CD4 counts were similarly low [10, 12, 14], highlighting the need for better ART coverage and earlier HIV diagnosis to prevent such severe complications. Similarly, in another study conducted in Iran, 92.3% of HIV/AIDS patients with neurological syndromes who died had no history of ART, and only one patient had received ART for two months before death. In contrast, among survivors, 62.1% were not receiving ART. The average CD4 count in that cohort was 59 cells/µL [15]. Additionally, a retrospective cohort study in Italy found that before the introduction of highly active antiretroviral therapy (HAART), the median CD4 count at disease onset was 38 cells/µL, rising to 77 cells/µL during the HAART era. Among 1,043 HIV-infected patients, 27 of 53 individuals with neurological complications in the pre-HAART era were on ART prior to diagnosis, compared to 19 of 61 in the HAART era [16]. Another study conducted in Germany among HIV/AIDS patients with neurological manifestations reported that the mean CD4 count increased from 214 cells/µL between 1995 and 1996 to 335 cells/µL between 1997 and 1998, while ART coverage rose from 2.4 to 3.79% over the same period [17]. These findings highlight the importance of early HIV testing, timely initiation of ART, and enhanced management protocols for patients with neurological symptoms to improve outcomes. A multidisciplinary approach and comprehensive healthcare policies aimed at expanding ART coverage are crucial. Such efforts can help prevent severe complications, improve prognosis, and reduce mortality associated with HIV-related neurological syndromes.
Comorbidities like intravenous drug use (IVDU), hepatitis C, and diabetes mellitus further complicated patient outcomes. IVDU, reported in 44.8% of patients, was not only associated with a higher prevalence of certain infections, such as infective endocarditis and CNS abscesses, but also contributed to worse overall prognoses (OR: 2.22, 95%CI:1.18–4.18) potentially due to poor adherence to ART and increased susceptibility to opportunistic infections. The high prevalence of IVDU among HIV-infected patients has also been reported in studies from other countries. For example, Matinella (2015) found that 51.7% of HIV-infected patients with neurological manifestations in Verona, Italy had a history of IVDU [16], while Janocha-Litwin (2022) reported that 47% of patients in Poland had similar histories [13]. Chronic hepatitis C, found in 11.7% of patients, likely exacerbated neurological outcomes through systemic inflammation and hepatic encephalopathy, compounding the complexity of diagnosing and managing HIV-associated neurological syndromes. Similarly, diabetes mellitus, though less prevalent (3.4%), could have contributed to accelerated neurovascular complications and increased vulnerability to infections due to immune dysregulation. These comorbidities often necessitated multidisciplinary management strategies, highlighting the need for integrated care approaches to address both the direct effects of HIV on the CNS and the indirect contributions of comorbid conditions. The median age of 40 years in our cohort reflects the younger age range of HIV-infected patients with neurological complications, comparable to other studies in Ethiopia, Poland, and Germany [11, 13, 17]. This relatively young age may have influenced the prevalence of certain syndromes while reducing age-related complications like cerebrovascular diseases.
Our findings underscore a wide range of clinical presentations. Altered consciousness was the most frequent symptom (59.6%), followed by limb paresis (44.4%), fever (38.9%), and clinical seizures (24.1%). Notably, central nervous system (CNS) involvement was present in 93.3% of cases, and nervous system infections accounted for 33.3% of neurological syndromes, with toxoplasma encephalitis, CNS tuberculosis, and bacterial brain abscess being common diagnoses. However, 25% of cases had neurological conditions of unknown etiology, suggesting substantial diagnostic challenges. These cases included single or multiple brain space-occupying lesions of unknown cause in 8.3%, and encephalitis and encephalopathy of unknown cause in 8.3% and 5%, respectively. The high proportion of neurological syndromes of unknown cause in our cohort may be attributed to the late presentation and advanced stages of HIV infection, where many patients were either too critically ill to undergo necessary diagnostic tests or died before evaluations could be completed. Additional challenges may include limited access to advanced neuroimaging, molecular diagnostics, and specialized laboratory tests in resource-constrained settings. Improving diagnostic accuracy requires addressing these limitations through better infrastructure, increased availability of diagnostic tools (e.g., MRI and CT scans, cerebrospinal fluid (CSF) multiplex PCR panels, and next-generation sequencing for pathogen detection), and standardized diagnostic protocols tailored for HIV-infected populations. Training healthcare providers in recognizing and managing neurological complications in HIV and ensuring timely referral to specialized centers can also play a crucial role.
These results align with studies in Brazil, Ethiopia, and China, where toxoplasma encephalitis and CNS tuberculosis were prevalent [10,11,12]. Previous research in Iran has also shown a high prevalence of toxoplasma encephalitis and CNS tuberculosis among HIV-infected patients with neurological infections [15, 18]. A retrospective cohort study in Germany identified cryptococcal meningitis (0.9% and 0.2%), PML (0.6% and 0.5%), CMV encephalitis (1.2% and 1.5%), toxoplasma encephalitis (0.9% and 0.7%), and primary CNS lymphoma (0.5% and 0.2%) as common neurological manifestations among HIV/AIDS patients [17]. In Italy, a study involving 1,043 HIV-infected patients found neurotoxoplasmosis, PML, primary CNS lymphoma, severe HIV-associated neurocognitive disorder, cryptococcal encephalitis, and lesions of unknown origin as the most prevalent conditions [16]. A Polish cohort study of 476 HIV-infected patients reported neurotoxoplasmosis, cryptococcal neuroinfection, PML, and neurosyphilis as common CNS conditions [13]. Similarly, a Dutch study of 363 HIV-infected patients with suspected CNS infection found that 34 had CNS infections, including PML (17%), cryptococcal meningitis, toxoplasma encephalitis, and other conditions like CMV encephalitis and neurosyphilis (11% each) [4].
In regions with widespread access to ART, the incidence of opportunistic infections affecting the nervous system has significantly decreased, largely due to improved HIV management. Socioeconomic factors, healthcare systems, and cultural differences also play a role in the reduced burden of these infections in high-income areas. However, the epidemiology of HIV-associated neurological complications is shifting. As opportunistic infections decline, there is an increase in primary HIV-related neurological disorders and adverse outcomes linked to ART. Furthermore, the aging HIV-infected population faces a rising prevalence of age-related neurological conditions, such as stroke and cognitive decline. This trend highlights the complex interplay between aging and HIV, as older adults are more susceptible to both long-term effects of the virus and age-associated neurological challenges. Addressing these issues requires tailored prevention and management strategies to improve outcomes for this vulnerable population [19]. As a result, healthcare providers must remain vigilant in addressing both the direct neurological consequences of HIV and the complications arising from age-related conditions to ensure comprehensive care for older patients living with HIV.
In our study, male sex, drug addiction—especially intravenous drug use (IVDU)—and the presence of neurological syndromes were significant predictors of increased mortality in HIV-infected patients, as shown by univariable analysis (OR 3.95, 95% CI 2.21–7.05 for male sex; OR 3.34, 95% CI 1.62–6.89 for drug addiction; OR 2.07, 95% CI 1.11–3.86 for neurological syndromes). Elevated heart rate at admission (p = 0.03) and older age (p = 0.03) were also linked to higher mortality risk. Although a trend suggested increased mortality with lower CD4 counts, it did not reach statistical significance (P = 0.05), likely due to the high proportion of unknown CD4 values, which may have limited the analysis’s power. In multivariable analysis, only heart rate on admission (OR: 1.03, 95% CI: 1.02–1.05) and altered consciousness on admission (OR: 8.32, 95% CI: 2.48–27.87) were significant predictors of mortality.
Interestingly, factors such as diabetes mellitus, HIV status, and ART did not show statistically significant associations with mortality in our cohort, which contrasts with findings from some previous studies. However, when comparing our results with other research, altered consciousness consistently emerged as a key predictor of mortality, as seen in studies from Brazil [10], Ethiopia [11], and Pakistan [20]. Two previous studies from Iran also identified significant mortality predictors among HIV-infected patients with neurological syndromes. One, involving 43 patients, reported that male sex, lower CD4 counts, and hepatitis C virus (HCV) co-infection were key predictors of mortality [18]. Another found that altered consciousness and low CD4 count were major factors associated with mortality [15]. These findings align with our results, where male sex and altered consciousness were significant predictors of death.
Our study had several limitations that could impact the interpretation of our findings. One key limitation is the retrospective nature of this study, which inherently restricts our ability to draw causal conclusions. Another limitation is that our findings are specific to hospitals in northeastern Iran, making it difficult to generalize these results to other regions or populations in Iran or elsewhere. Variations in healthcare infrastructure, access to treatment, and patient demographics could influence the burden and outcomes of neurological syndromes in different settings. Furthermore, while our study examined various factors associated with mortality, we were unable to account for potential biases in patient selection. For example, patients who presented with severe neurological complications may have been more likely to be admitted to specialized units, introducing selection bias that may not fully represent the entire population of HIV-infected individuals. Importantly, missing data—such as the time from HIV diagnosis to neurological admission—may limit our ability to interpret the influence of disease chronicity or delays in care on outcomes. This gap could have affected the assessment of prognosis and hindered efforts to identify time-sensitive predictors of mortality. Finally, diagnostic limitations may have played a role. The study highlights that 25% of cases had unknown etiologies, which may be partly due to late presentation and the advanced stage of disease in many patients. The lack of resources to perform comprehensive evaluations could have resulted in underdiagnosis or misdiagnosis, further limiting the clarity of our findings.
Future research directions
To address these limitations and build upon our findings, we recommend future research focusing on prospective, multicenter studies that could provide more robust data on the progression and outcomes of neurological complications in HIV-infected individuals. Longitudinal research is essential to examine how early detection, timely treatment, and adherence to ART impact long-term neurological health and survival rates. Additionally, future studies should incorporate targeted interventions to assess their effectiveness in improving patient outcomes and quality of life. Such research could help refine strategies for prevention, diagnosis, and treatment, ultimately contributing to better management of HIV-related neurological syndromes and improved patient survival.