Long-term outcomes after new onset seizure in children living with HIV: A cohort study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure. METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality. RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence. SIGNIFICANCE: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures. PLAIN LANGUAGE SUMMARY: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.

BACKGROUND: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures. RESULTS: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures. CONCLUSIONS: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.

Mental health and adaptive functioning among school-aged children living with HIV in Zambia.

Background: The number of children living with HIV (CLWHIV) has been increasing, reflected by lower mortality. However, this change is coupled with higher rates of morbidity, where CLWHIV face considerable challenges, including neurocognitive delays and mental health and behavioral functioning challenges. Despite Sub-Sahara accounting for the highest number of CLWHIV, there is still limited research on the effects of HIV on child mental health and adaptive functioning. Method: Mental health and adaptive functioning were assessed in 120 children. The sample included 62 CLWHIV and 58 demographically-matched HIV-uninfected children aged 6-12 years. Mental health was assessed using the Connors, while adaptive functioning was assessed using the Vineland Adaptive Behavioral Scale (VABS). Results: Scores obtained were within average ranges for mental health (T-score 40-59) and adaptive functioning standard scores (70-115). However, CLWHIV had significantly higher mental health problems than uninfected children in executive functioning and aggressiveness (p < 0.05). CLWHIV had lower adaptive functioning scores on the VABS Communication domain although these differences were not significant. In the Daily Living Skills domain, CLWHIV had significantly higher scores than the HIV-uninfected children (p < 0.05). There were no significant differences in the Socialization subdomain. Furthermore, CLWHIV had significantly higher scores on the Maladaptive Behavior scales of the VABS' internalizing and externalizing subdomains. Conclusion: Challenges to mental health and adaptive functioning are still pervasive among CLWHIV. These findings support the need to develop support mechanisms for CLWHIV to help address mental health and adaptive functioning problems, especially as they progress into adolescence.

Mortality & recurrent seizure risk after new-onset seizure in HIV-positive Zambian adults.

BACKGROUND: Recurrent seizure risks in HIV-positive people with new-onset seizure are largely unknown, making it challenging to offer optimal recommendations regarding antiepileptic drug (AED) initiation. Existing outcomes data is limited, and risk factor identification requires a diagnostic assessment, which is often unavailable in regions heavily effected by HIV, like sub-Saharan Africa. METHODS: HIV-positive Zambian adults with new-onset seizure were enrolled in a prospective cohort study to determine seizure recurrence and risk factors for recurrence. Seizure etiology was evaluated, and recurrent seizures and medication usage were assessed during clinic visits. Due to unexpectedly high mortality rates, predictors of death were evaluated using proportional hazards with Gray's test to compare cumulative incidence functions for recurrent seizure across groups adjusting for the competing outcome of death. RESULTS: 95 patients were enrolled (mean age 37 years, 43% female, 83% with Karnofsky > 50) and followed for a mean of 293 days (median 241 (IQR: 29-532)). At presentation, 50 (53%) were in status epilepticus. The majority (91, 85%) had advanced HIV disease and 65 (68%) were not on combined antiretroviral therapy (cART). After extensive workup, seizure etiology remained unknown in 16 (17%). Average time to cART initiation after enrollment was 61 days. During follow up, 37 (39%) died and 23 (24%) had recurrent seizure. Most deaths (25/37, 68%) occurred in the first 60 days post-index seizure. Individuals with advanced HIV were more likely to die (HR: 19.1 [95% CI: 1.1-333.4]) as were those whose seizure etiology remained unknown (HR: 2.2 [95% CI: 1.1-4.4]). Among participants that survived from enrolment to the end of data collection on 10 May 2013 (n = 58), 20 (34%) experienced recurrent seizures. CONCLUSIONS: New-onset seizure among HIV-positive Zambian adults is associated with high mortality despite good functional status prior to presentation. Advanced HIV infection and failure to identify an underlying seizure etiology are associated with greater mortality. Recurrent seizures occur in over a third of survivors within only 2 years of follow-up. This provides evidence to support AED initiation after first seizure in HIV-positive individuals with advanced HIV disease at the time of presentation though the risks of AED-cART interactions remain a concern and warrant further study.

New-onset seizure in HIV-infected adult Zambians: A search for causes and consequences.

OBJECTIVE: To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence. METHODS: A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks of index seizure obtained clinical, laboratory, and neuroimaging data to determine seizure etiology. Participants were followed to identify risk factors for seizure recurrence. Risk factors for mortality were examined as mortality rates were unexpectedly high. RESULTS: Eighty-one patients with CSF for analysis were enrolled and followed for a median of 306 days (interquartile range 61-636). Most (91%) were at WHO stage III/IV and 66 (81%) had a pre-seizure Karnofsky score ≥50. Prolonged or multiple seizures occurred in 46 (57%), including 12 (15%) with status epilepticus. Seizure etiologies included CNS opportunistic infections (OI) in 21 (26%), hyponatremia in 23 (28%), and other infections in 8 (10%). OIs included Cryptococcus (17%), JC virus (7%) and 5% each for tuberculosis, cytomegalovirus, and varicella-zoster virus. No etiology could be identified in 16 (20%). Thirty (37%) patients died during follow-up and 20 (25%) had recurrent seizures with survival being the only identifiable risk factor. CONCLUSIONS: HIV-infected adults with new-onset seizure in Zambia often have advanced HIV disease with OI being the most frequent seizure etiology. Seizure recurrence is common but no risk factors for recurrence other than survival were identified. These findings suggest an urgent need for immune reconstitution in this population. Initiating treatment for seizure prophylaxis where only enzyme-inducing antiepileptic medications are available could threaten antiretroviral efficacy.

Do neuropsychological test norms from African Americans in the United States generalize to a Zambian population?

Healthy Zambian adults (N = 324) were evaluated to determine to what degree a Western neuropsychological (NP) test battery, with African American norms adjusted for age, gender, and education could be used in healthy Zambians, including 157 men (48.46%) and 167 women (51.54%) with an average age of 38.48 (SD = 12.80) years and an average education level of 11.02 (SD = 2.58) years. The NP battery included tests of attention/working memory, executive function, verbal fluency, processing speed, verbal and visual episodic memory, and fine motor skills. The Zambian Achievement Test (ZAT) and the U.S. Wide Range Achievement Test-4 (WRAT-4) reading subtest also were administered to assess literacy and quality of education. Similar to findings in Western countries, the Zambian results show substantial age and education effects on most tests and smaller, less consistent effects of gender. Beyond the basic demographic effects, urban/rural background had small effects on some cognitive variables, and the ZAT (but not WRAT-4) reading level was a robust predictor of performance on many NP tests, even when other background characteristics were controlled. Women in the United States tend to outperform men on tests of processing speed and episodic memory. However, Zambian women showed modest but statistically significant disadvantages versus their male counterparts. The results show that tests developed in the United States may be used in Zambia. Nevertheless, development and use of local cultural norms remains very important and is a must. New demographically corrected norms were developed for the cohort that was examined.

Acute EEG findings in HIV-infected Zambian adults with new-onset seizure.

OBJECTIVE: To describe acute EEG findings in HIV-infected adults with new-onset seizure, assess baseline clinical characteristics associated with EEG abnormalities, and evaluate the relationship between EEG abnormalities and recurrent seizure. METHODS: Eighty-one HIV-infected adults with new-onset seizure had EEG recordings during their index admission. Baseline characteristics assessed included HIV stage, seizure semiology, serum and CSF studies, neuroimaging, cognitive function based on the Zambian Mini-Mental State Examination and International HIV Dementia Scale, and psychiatric symptoms using the Shona Symptom Questionnaire. We evaluated the relationship between baseline characteristics and EEG abnormalities. Patients were followed for seizure recurrence, and the association between acute EEG abnormalities and seizure recurrence was assessed. Death was a secondary outcome. RESULTS: Fifty-five patients had abnormal EEGs (68%): 18 (22%) had interictal spikes (12) or a recorded seizure (6). Among baseline clinical characteristics, more advanced HIV disease (p = 0.039) and any imaging abnormality (p = 0.027) were associated with abnormal EEGs. Cortical (p = 0.008) and white matter (p = 0.004) abnormalities were associated with slow posterior dominant rhythm. Patients were followed for a median of 303 days (interquartile range 103-560). Twenty-four (30%) died and 23 (28%) had recurrent seizures. EEG abnormalities were not associated with recurrent seizure. There was a nonsignificant association between seizures recorded during EEG and death (67% vs 26%, p = 0.051). CONCLUSIONS: EEG abnormalities are common in this population, particularly in patients with imaging abnormalities and advanced HIV. Acute EEG abnormalities were not associated with recurrent seizure, but high mortality rates during follow-up limited this analysis.

Cognitive impairment and psychiatric morbidity in HIV+ Zambians with new-onset seizure.

A prospective cohort study of new-onset seizure in people with human immunodeficiency virus (HIV) in Zambia is ongoing to determine the incidence of subsequent epilepsy and risk factors for epileptogenesis in this population. At enrollment, we evaluated this cohort for cognitive impairment and psychiatric morbidity. Over 50% of participants had cognitive impairment and significant psychiatric morbidity. Most participants had advanced HIV disease based on CD4+ T-cell count and World Health Organization stage, but we found no association between cognitive impairment or psychiatric morbidity and HIV disease staging.

Neuroimaging abnormalities and seizure recurrence in a prospective cohort study of zambians with human immunodeficiency virus and first seizure.

In HIV-positive individuals with first seizure, we describe neuroimaging findings, detail clinical and demographic risk factors for imaging abnormalities, and evaluate the relationship between imaging abnormalities and seizure recurrence to determine if imaging abnormalities predict recurrent seizures. Among 43 participants (mean 37.4 years, 56% were male), 16 (37%) were on antiretroviral drugs, 32 (79%) had advanced HIV disease, and (28) 66% had multiple seizures and/or status epilepticus at enrollment. Among those with cerebrospinal fluid studies, 14/31 (44%) had opportunistic infections (OIs). During follow-up, 9 (21%) died and 15 (35%) experienced recurrent seizures. Edema was associated with OIs (odds ratio: 8.79; confidence interval: 1.03-236) and subcortical atrophy with poorer scores on the International HIV Dementia Scale) (5.2 vs. 9.3; P=0.002). Imaging abnormalities were not associated with seizure recurrence or death (P>0.05). Seizure recurrence occurred in at least a third and over 20% died during follow-up. Imaging was not predictive of recurrent seizure or death, but imaging abnormalities may offer additional diagnostic insights in terms of OI risk and cognitive impairment.