Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Task-shifting to optimize outpatient neurological care in Zambia.

OBJECTIVE: To investigate opportunities for task shifting to decongest an outpatient neurology clinic in Zambia by describing current patient flow through the clinic and potential nodes for intervention using process mapping. BACKGROUND: Zambia has a population of approximately 18 million people with 4 full-time adult neurologists, as of 2018, who all practice at the University Teaching Hospital (UTH), the main tertiary care center in the country. As a result of this provider-to-patient ratio, the outpatient neurology clinic is overcrowded and overbooked. Task-shifting programs have shown to improve efficiency, access and quality of care through the use of less specialized healthcare workers in low- and middle-income countries (LMIC). METHODS: We evaluated patient flow in the UTH neurology outpatient clinic through the development and analysis of a process map. The characteristics of the clinic population between 2014 and 2018 were retrospectively reviewed from the clinic register. Between July and August 2018, we prospectively collected appointment lag times and time each patient spent waiting at various points in the clinic process. We conducted interviews with clinic staff and neurologists to generate a detailed process map of current pathways to care within the clinic. We then devised task-shifting strategies to help reduce patient wait times based on the overview of clinic process mapping and patient demographics. RESULTS: From 2014 to 2018, there were 4701 outpatients seen in the neurology clinic. The most common neurological diagnoses were epilepsy (39.2%), headache (21.5%) and cerebrovascular disease (16.7%). During prospective data collection, patients waited an average of 57.8 (SD 73.4) days to be seen by a neurologist. The average wait time from arrival in the clinic to departure was 4.0 (SD 2.5) h. The process map and interviews with clinic staff revealed long waiting times due to a paucity of providers. Nurses and clerks represent an influential stakeholder group, but are not actively involved in any activity to reduce wait times. A large proportion of follow-up patients were stable and seen solely to obtain medication refills. CONCLUSIONS: Epilepsy, headache, and stroke make up the largest percentage of outpatient neurological illness in Zambia. Targeting stable patients in these diagnostic categories for a task-shifting intervention may lead to substantially decreased patient wait times. Potential interventions include shifting clinical follow-ups and medication refills to less specialized healthcare workers.

Prevalence and Risk Factors of Distal Symmetric Polyneuropathy Among Predominantly Non-Hispanic Black, Low-Income Patients.

BACKGROUND AND OBJECTIVES: Distal symmetric polyneuropathy (DSP) is a disabling, often painful condition associated with falls and reduced quality of life. Non-Hispanic Black people and people with low income are underrepresented in existing DSP studies; therefore, it is unknown whether data accurately reflect the prevalence, risk factors, and burden of disease in these populations. METHODS: Patients older than 40 years presenting to an outpatient internal medicine clinic predominantly serving Medicaid patients in Flint, Michigan, were enrolled in a cross-sectional study. Demographics, clinical characteristics, including medication use, anthropomorphic measurements, fasting lipids, and hemoglobin A1c were collected. DSP was defined using the modified Toronto Clinical Neuropathy Score (mTCNS). Multivariable logistic regression was performed to model DSP and undiagnosed DSP as a function of potential risk factors age, metabolic syndrome, and race. DSP burden was measured using Peripheral Neuropathy Quality of Life Instrument-97. RESULTS: Two hundred participants were enrolled, and 169 (85%) completed all data collection. The population was 55% female of mean age (SD) 58.2 years (10.4) and 69% non-Hispanic Black. Among the population, 50% had diabetes, 67% had metabolic syndrome, and 47% had a household income <$20,000. DSP was present in 73% of the population, of which 75% were previously undiagnosed. Neuropathic pain was documented in 57% of participants with DSP. DSP based on mTCNS criteria was associated with older age (odds ratio [OR] 1.1 [95% confidence interval (CI) 1.03-1.2]) and metabolic syndrome (OR 4.4 [1.1-18.1]). Non-Hispanic Black participants had lower odds of DSP (OR 0.1 [0.01-0.4]) than non-Hispanic White and Hispanic participants. DSP burden was high, including increased pain, health-related worry, and poorer quality of life (all p < 0.001). DISCUSSION: DSP is extremely common and often underrecognized in this predominantly non-Hispanic Black, low-income population and leads to substantial disease burden. Metabolic syndrome is a highly prevalent, modifiable risk factor in this population that should be managed to lower DSP prevalence.

Genetic Neuromuscular Disorders and Health Services Access, Utilization, and Needs in Zambia.

BACKGROUND: Medical and rehabilitative advances increasingly transform management of rare genetic neuromuscular diseases (GNMDs) for children in the global north. Lack of information about GNMDs and related health care needs in sub-Saharan Africa threatens to widen pre-existing health disparities. METHODS: This is a cross-sectional study of probands enrolling in a study of GNMDs at the University Teaching Hospital in Lusaka, Zambia, a member of the International Consortium for Genomic Medicine in Neuromuscular Disease. Probands/caregivers were interviewed about utilization of medical, rehabilitative, and other support services by a research assistant. A neuromuscular neurologist and/or physiotherapist examined each case and completed an independent questionnaire regarding health service utilization for each proband. Diagnoses were made on available clinical and electrophysiologic data. Molecular findings were unavailable at the time of this analysis. RESULTS: Among 50 probands, 52% were male with median age 12 (absolute range 2 months to 54 years). Motor neuron diseases (n = 16; 32%), muscle disorders (n = 20; 40%), and inherited polyneuropathies (n = 5; 10%) were most common. Six (15%) cases had insufficient clinical data to classify the GNMDs. Outside of primary care, patient/caregiver-reported access to recommended health services (n = 34; 69%) was challenging. Large disparities in current utilization of health care services versus clinician-recommended services are reported. CONCLUSIONS: Paradigms to improve access to diagnostics and therapeutic interventions are needed for GNMDs in Zambia. Multidisciplinary clinics may improve access and utilization of needed health services. Qualitative and other research focused on improving referrals, access, and quality of available health services are greatly needed.

Consensus Competencies for Postgraduate Fellowship Training in Global Neurology.

BACKGROUND AND OBJECTIVES: Use a modified Delphi approach to develop competencies for neurologists completing ≥1 year of advanced global neurology training. METHODS: An expert panel of 19 United States-based neurologists involved in global health was recruited from the American Academy of Neurology Global Health Section and the American Neurological Association International Outreach Committee. An extensive list of global health competencies was generated from review of global health curricula and adapted for global neurology training. Using a modified Delphi method, United States-based neurologists participated in 3 rounds of voting on a survey with potential competencies rated on a 4-point Likert scale. A final group discussion was held to reach consensus. Proposed competencies were then subjected to a formal review from a group of 7 neurologists from low- and middle-income countries (LMICs) with experience working with neurology trainees from high-income countries (HICs) who commented on potential gaps, feasibility, and local implementation challenges of the proposed competencies. This feedback was used to modify and finalize competencies. RESULTS: Three rounds of surveys, a conference call with United States-based experts, and a semistructured questionnaire and focus group discussion with LMIC experts were used to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across 8 domains: (1) cultural context, social determinants of health and access to care; (2) clinical and teaching skills and neurologic medical knowledge; (3) team-based practice; (4) developing global neurology partnerships; (5) ethics; (6) approach to clinical care; (7) community neurologic health; (8) health care systems and multinational health care organizations. DISCUSSION: These proposed competencies can serve as a foundation on which future global neurology training programs can be built and trainees evaluated. It may also serve as a model for global health training programs in other medical specialties as well as a framework to expand the number of neurologists from HICs trained in global neurology.

Epilepsy care challenges in developing countries.

PURPOSE OF REVIEW: This review discusses recent literature relevant to the diagnosis and treatment of epilepsy in developing countries with particular attention to underlying causes, natural history, and advances made toward optimizing systems of care and bridging the treatment gap. RECENT FINDINGS: Prospective data suggest that cerebral malaria-induced brain injury may explain the high prevalence of epilepsy in malaria-endemic regions. Population-based mortality studies support the long proposed hypothesis that seizure-related deaths contribute to excessive premature mortality. WHO guidelines have the potential to improve care, but macrolevel barriers related to pharmaceutical regulation and distribution continue to contribute to the treatment gap. Evidence-based guidelines endorsed by the WHO and American Academy of Neurology regarding the optimal management of comorbid epilepsy and HIV may raise awareness regarding critical drug interactions between antiepileptic drugs and antiretrovirals, but are also problematic as the treatment regimen and diagnostic facilities routinely available in developing countries will prevent most healthcare providers from following the recommendations. SUMMARY: New insights into the causes, natural history and best care practices for epilepsy in developing countries are available but without prioritization and action from policy makers, the present treatment gap will likely to persist.

A qualitative study of patient, caregiver, doctor and nurse views of factors influencing lumbar puncture uptake in Zambia.

BACKGROUND: Uptake of lumbar puncture (LP) remains low in regions with a high prevalence of central nervous system (CNS) infections like Zambia. Efforts to improve uptake are hindered by limited understanding of factors influencing LP uptake. METHODS: Semistructured qualitative interviews were conducted with patients with suspected CNS infection, caregivers, doctors and nurses at the University Teaching Hospitals in 2016. Questions focused on LP experiences, knowledge, the consent process and health system barriers to LP among patients with an LP indication. Interviews were transcribed, translated to English and analysed using a thematic approach. RESULTS: We recruited 24 adult patients, 36 caregivers of adult patients, 63 caregivers of paediatric patients, 20 doctors and 30 nurses (173 in total). LP barriers arose from both patients/caregivers and health providers and included community apprehension about LP, proxy (family) consensus consent practices, competing clinical demands, wariness of patient/caregiver responses, limitations in consumables and time to complete the LP. This could result in consent not being obtained correctly. LP enablers included patient/caregiver perceived LP utility, provider comfort with LP and in-person counselling. CONCLUSIONS: LP uptake is a complex sociocultural process influenced by patient, healthcare and community-level factors. Interventions to improve uptake must address multiple barriers to be successful.

Predictors of in-hospital and 90-day post-discharge stroke mortality in Lusaka, Zambia.

BACKGROUND: Factors associated with stroke mortality are understudied in sub-Saharan Africa but have implications for designing interventions that improve stroke outcomes. We investigated predictors of in-hospital and 90-day post-discharge stroke mortality in Lusaka, Zambia. METHODS: Data from consecutive adults admitted with stroke at University Teaching Hospital in Lusaka, Zambia between October 2018 and March 2019 were retrospectively reviewed for clinical in-hospital outcomes. Vital status at 90-days post-discharge was determined through phone calls. Factors associated with stroke mortality were included in multivariable logistic regression models utilizing multiple imputation analysis to determine independent predictors of in-hospital and 90-days post-discharge mortality. RESULTS: In-hospital mortality was 24%, and 90-day post-discharge mortality was 22% among those who survived hospitalization. Hemorrhagic and unknown strokes, ICU care, seizures, and aspiration pneumonia were significantly associated with in-hospital mortality. Among these, hemorrhagic stroke (OR 2.88, 95% CI 1.27-6.53, p = 0.01) and seizures (OR 29.5, 95% CI 2.14-406, p = 0.01) remained independent predictors of in-hospital mortality in multivariable analyses. Ninety-day post-discharge mortality was significantly associated with older age, previous stroke, atrial fibrillation, and aspiration pneumonia, but only older age (OR 1.04, 95% CI 1.01-1.06, p = 0.007) and aspiration pneumonia (OR 3.93, 95% CI 1.30-11.88, p = 0.02) remained independently associated with 90-day mortality in multivariable analyses. CONCLUSION: This Zambian stroke cohort had high in-hospital and 90-day post-discharge mortality that were associated with several in-hospital complications. Our data indicate the need for improvement in both acute stroke care and post-stroke systems of care to improve stroke outcomes in Zambia.

A qualitative study of factors resulting in care delays for adults with meningitis in Zambia.

BACKGROUND: Meningitis causes significant mortality in regions with high comorbid HIV and TB. Improved outcomes are hindered by limited understanding of factors that delay adequate care. METHODS: In-depth interviews of patients admitted to the University Teaching Hospital with suspected meningitis, their caregivers, doctors and nurses were conducted. Patient/caregiver interviews explored meningitis understanding, treatment prior to admission and experiences since admission. Provider interviews addressed current and prior experiences with meningitis patients and hospital barriers to care. A conceptual framework based on the Three Delays Model identified factors that delayed care. RESULTS: Twenty-six patient/caregiver, eight doctor and eight nurse interviews occurred. Four delays were identified: in-home care; transportation to a health facility; clinic/first-level hospital care; and third-level hospital. Overcrowding and costly diagnostic testing delayed outpatient care; 23% of patients began with treatment inside the home due to prior negative experiences with biomedical care. Admission occurred after multiple clinic visits, where subsequent delays occurred during testing and treatment. CONCLUSIONS: Delays in care from home to hospital impair quality meningitis care in Zambia. Interventions to improve outcomes must address patient, community and health systems factors. Patient/caregiver education regarding signs of meningitis and indications for care-seeking are warranted to reduce treatment delays.

Lumbar Puncture-Related Knowledge, Attitudes, and Practices among Patients, Caregivers, Doctors, and Nurses in Zambia.

Lumbar puncture (LP) is underused for neuroinfectious disease diagnosis in Zambia, but reasons for poor uptake remain speculative. This cross-sectional study assessed LP knowledge, attitudes, and practices among patients/caregivers and healthcare workers (HCWs) and predictors of LP completion. Patients with suspected central nervous system infection, caregivers, and HCWs at the University Teaching Hospitals in 2016 were eligible. Questions adapted from the existing literature were used for a LP knowledge score. Predictors of knowledge scores were assessed independently for patients/caregivers and HCWs. Predictors of LP completion were assessed using multivariable logistic regression. Among 123 patients/caregivers, LP knowledge was poor. Pediatric caregivers were more likely than adult patients/caregivers to report LP could be replaced by neuroimaging (90% versus 78%, P < 0.001) and cause paralysis (57% versus 39%, P = 0.01). There were no significant predictors of the knowledge score among patients/caregivers. Among HCWs, 28% said LP makes patients clinically worse, and 60% reported it could cause paralysis. The increased knowledge score was associated with greater wealth (P = 0.03) and personally knowing someone who underwent LP (P < 0.001). Lumbar puncture was completed on 67/112 (57%) patients and was associated with an increased knowledge score (OR: 1.62 [95% CI: 1.19-2.23]). Pediatric patients (OR: 0.18 [95% CI: 0.07-0.47]) and those with a fear of paralysis (OR 0.29 [95% CI: 0.11-0.77]) were less likely to undergo LP. Improving LP-related knowledge may improve uptake. Healthcare workers sense of LP risk may also play a role in encouraging/discouraging use.

Evaluating the diagnostic capacity of a single-question neuropathy screen (SQNS) in HIV positive Zambian adults.

A single-question neuropathy screen (SQNS) is routinely included in the enrolment data for people commencing antiretroviral therapy in publically funded clinics in Zambia. The authors assessed the sensitivity, specificity, positive and negative predictive value of this SQNS against the Brief Peripheral Neuropathy Screen (BPSN) in detecting HIV-associated sensory neuropathy in patients recruited from a rural and an urban hospital in Zambia. The SQNS was asked followed by conduct of the BPNS by the neurology resident assisted by a Zambian healthcare worker/translator. 77 patients (48 (62.3%) urban and 29 (37.7%) rural) were enrolled. 13 subjects were excluded due to altered mental status. The mean age was 33.7 years (range 15-53 years; SD±7.81). The SQNS was 95.7% sensitive and 80.0% specific, with 88.2% positive predictive value and 92.3% negative predictive value. Age, geographical location, gender and WHO stage were all unrelated to the performance of the SQNS (p>0.05). Despite its reliance on symptoms alone, this study suggests that the SQNS may be a valid research tool for identifying HIV-associated neuropathy among advanced stage HIV patients in Zambia.

Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial.

BACKGROUND: This study evaluates the effects of retinol on intestinal barrier function, growth, total parasites, and Giardia spp infections in children in northeastern Brazil. SUBJECTS AND METHODS: The study was a double-blind, randomized placebo-controlled trial (http://clinicaltrials.gov; register no. #NCT00133406) involving 79 children who received vitamin A 100,000-200,000 IU (n = 39) or placebo (n = 40) at enrollment, 4, and 8 months and were followed for 36 months. Intestinal barrier function was evaluated using the lactulose:mannitol ratio test. Stool lactoferrin was used as a marker for intestinal inflammation. RESULTS: The groups were similar with regard to age, sex, nutritional parameters (z scores), serum retinol concentrations, proportion of lactoferrin-positive stool samples, and intestinal barrier function. The lactulose:mannitol ratio did not change during the same time of follow-up (P > 0.05). The proportion of lactoferrin-positive samples evaluated at 1 month did not change between groups (P > 0.05). Total intestinal parasitic, specifically new, infections were significantly lower in the vitamin A treatment compared with control group; these were accounted for entirely by significantly fewer new Giardia infections in the vitamin A treatment group. The cumulative z scores for weight-for-length or height, length or height-for-age z scores, and weight-for-age did not change significantly with vitamin A intervention for 36 months of follow-up. CONCLUSIONS: These data showed that total parasitic infection and Giardia spp infections were significantly lower in the vitamin A treatment group when compared with the placebo group, suggesting that vitamin A improves the host's defenses against Giardia infections.

A case of combined central and peripheral demyelination in Zambia.

Overlap syndromes, where otherwise distinct autoimmune processes of the central and peripheral nervous systems are present in the same patient, are uncommon and have not been previously reported in sub-Saharan Africa. We present a case of a 32-year-old man who was found to have both clinically isolated syndrome and chronic inflammatory demyelinating polyneuropathy, highlighting the importance of continued efforts to establish the prevalence of demyelinating disease in the region given the limited treatment options currently available for autoimmune disease.

Is folate deficiency a common cause of distal symmetric polyneuropathy in Zambian clinics?

OBJECTIVES: To evaluate the odds of vitamin B12 and folate deficiencies among Zambian clinic attendees with distal symmetric polyneuropathy (DSP) and age, sex, and HIV matched controls. METHODS: Cases were adults from clinics in urban/peri-urban Zambia. Controls were enrolled among persons not seeking personal medical care, such as a caregiver or person collecting antiretrovirals without a medical complaint. Participants underwent structured interviews, physician examination, and assessments of complete blood count, renal and liver profiles, serum vitamin B12 and folate, erythrocyte folate, plasma total homocysteine and methylmalonic acid. HIV testing and CD4 counts were performed when appropriate. RESULTS: Among 107 consenting matched case-control pairs, 65% were female, 52% HIV positive, with mean age of 47.6 (SD 13.5) years. Among HIV positive participants, mean CD4 count was 484 (SD 221) and 482 (SD 236) for cases and controls, respectively (p = .93). DSP symptoms and severity did not differ by HIV status (p's > 0.05). Height, history of tuberculosis treatment, alcohol use, education, asset index, dietary diversity, and nutritional supplement use did not differ between cases and controls (p's > 0.05). DSP cases had at least 3:1 odds of having low serum folate (p = .0001), severely low erythrocyte folate (p = .014), and elevated total homocysteine (p = .001) levels compared to controls. Markers of vitamin B12 deficiency were not associated with case status (p's > 0.05). CONCLUSION: Markers of folate deficiency are highly associated with DSP among Zambian clinic attendees. Future studies should consider a broader range of comorbid nutritional deficiencies, and strategies for interventions.

Electrodiagnostic consultations in Zambia: Referral characteristics and neuromuscular disorders.

INTRODUCTION: Research on neuromuscular disorders in sub-Saharan Africa is scarce. We aimed to delineate referral characteristics and the neuromuscular disorders observed among electrodiagnostic (EDX) consultations in a tertiary care setting in Zambia. METHODS: EDX records were reviewed for all specialist-performed studies after the establishment of the laboratory. The frequency of demographic, medical characteristics, and final EDX impressions are presented. RESULTS: Among 108 referrals, 52% were male, 84% were adults (mean age 44 years). Referrals were predominantly outpatients (85%) and sent by neurologists (68%). HIV infection was common (12%). Diabetes was rare (3%). Overall, 77% of studies were abnormal. Polyneuropathy was the most common abnormal EDX finding, followed by motor neuron disease. DISCUSSION: A diverse range of neuromuscular diseases was evaluated among EDX referrals in Zambia. Though labor and expertise intensive, access to EDX consultation can enhance clinical care and facilitate research and surveillance of neuromuscular disorders in the region.

Factors associated with distal symmetric polyneuropathies in adult Zambians: A cross-sectional, observational study of the role of HIV, non-antiretroviral medication exposures, and nutrition.

BACKGROUND: Non-antiretroviral (ART) drug exposures and poor nutrition may be important modifiable risk factors for distal symmetric polyneuropathies (DSP) in sub-Saharan Africa. METHODS: We conducted a cross-sectional study of DSP prevalence and factors associated with DSP among clinic attendees in urban and rural Zambia. All participants underwent neurologist-performed examination. Laboratory investigations seeking comorbid risk factors for DSP were performed for DSP cases. RESULTS: We identified 31/137 (22.6%) HIV+ and 21/177 (11.9%) HIV- DSP cases. DSP prevalence did not differ by urbanicity, although rural participants were significantly more likely to have one asymptomatic DSP sign. Low dietary diversity, history of syphilis, history of tuberculosis, and prior metronidazole and ciprofloxacin use were associated with DSP amongst HIV+ cases, while age and education were associated with DSP in HIV- participants (all p-values < 0·05). In a multivariate logistic regression model, HIV (p = 0·0001) and age (p < 0·0001), and ciprofloxacin exposure (p = 0·01) remained independently associated with DSP. While diabetes was rare, supoptimal micronutrients levels were common among DSP cases regardless of HIV status. CONCLUSIONS: While HIV infection is strongly associated with DSP in Zambia, history of non-ART drug exposures and low dietary diversity are also important determinants of DSP in HIV+ individuals. Treatable micronutrient deficiencies were common.

Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning.

OBJECTIVE: To identify the impact of supplemental zinc, vitamin A, and glutamine, alone or in combination, on long-term cognitive outcomes among Brazilian shantytown children with low median height-for-age z-scores. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in children aged three months to nine years old from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for cognitive testing (total of 167 children) were: (1) placebo, n = 25; (2) glutamine, n = 23; (3) zinc, n = 18; (4) vitamin A, n = 19; (5) glutamine+zinc, n = 20; (6) glutamine+vitamin A, n = 21; (7) zinc+vitamin A, n = 23; and (8) glutamine+zinc+vitamin A, n = 18. Neuropsychological tests were administered for the cognitive domains of non-verbal intelligence and abstraction, psychomotor speed, verbal memory and recall ability, and semantic and phonetic verbal fluency. Statistical analyses were performed using SPSS, version 16.0. ClinicalTrials.gov: NCT00133406. RESULTS: Girls receiving a combination of glutamine, zinc, and vitamin A had higher mean age-adjusted verbal learning scores than girls receiving only placebo (9.5 versus 6.4, p = 0.007) and girls receiving zinc+vitamin A (9.5 versus 6.5, p = 0.006). Similar group differences were not found between male study children. CONCLUSIONS: The findings suggest that combination therapy offers a sex-specific advantage on tests of verbal learning, similar to that seen among female patients following traumatic brain injury.