Diffusion-Weighted MR Imaging in a Prospective Cohort of Children with Cerebral Malaria Offers Insights into Pathophysiology and Prognosis.

BACKGROUND AND PURPOSE: Validation of diffusion-weighted images obtained on 0.35T MR imaging in Malawi has facilitated meaningful review of previously unreported findings in cerebral malaria. Malawian children with acute cerebral malaria demonstrated restricted diffusion on brain MR imaging, including an unusual pattern of restriction isolated to the subcortical white matter. We describe the patterns of diffusion restriction in cerebral malaria and further evaluate risk factors for and outcomes associated with an isolated subcortical white matter diffusion restriction. MATERIALS AND METHODS: Between 2009 and 2014, comatose Malawian children admitted to the hospital with cerebral malaria underwent admission brain MR imaging. Imaging data were compiled via NeuroInterp, a RedCap data base. Clinical information obtained included coma score, serum studies, and coma duration. Electroencephalograms were obtained between 2009 and 2011. Outcomes captured included death, neurologic sequelae, or full recovery. RESULTS: One hundred ninety-four/269 (72.1%) children with cerebral malaria demonstrated at least 1 area of diffusion restriction. The most common pattern was bilateral subcortical white matter involvement (41.6%), followed by corpus callosum (37.5%), deep gray matter (36.8%), cortical gray matter (17.8%), and posterior fossa (8.9%) involvement. Sixty-one (22.7%) demonstrated isolated subcortical white matter diffusion restriction. These children had lower whole-blood lactate levels (OR, 0.9; 95% CI, 0.85-0.98), were less likely to require anticonvulsants (OR, 0.6; 95% CI, 0.30-0.98), had higher average electroencephalogram voltage (OR, 1.01; 95% CI, 1.00-1.02), were less likely to die (OR, 0.09; 95% CI, 0.01-0.67), and were more likely to recover without neurologic sequelae (OR, 3.7; 95% CI, 1.5-9.1). CONCLUSIONS: Restricted diffusion is common in pediatric cerebral malaria. Isolated subcortical white matter diffusion restriction is a unique imaging pattern associated with less severe disease and a good prognosis for full recovery. The underlying pathophysiology may be related to selective white matter vulnerability.

HIV and new onset seizures: slipping through the cracks in HIV care and treatment.

OBJECTIVES: The aim of the study was to describe patient characteristics and outcomes among HIV-positive adults presenting to a Zambian tertiary care hospital with new-onset seizures. METHODS: From July 2011 to June 2013, adults with seizures and a known or probable diagnosis of HIV infection were screened for a cohort study. Demographic and clinical data were obtained, including information on engagement in HIV services and in-patient mortality. Analyses were conducted to identify characteristics associated with poor engagement in care and death. RESULTS: A total of 320 of 351 screened adults were HIV-positive, with 268 of 320 experiencing new-onset seizures. Of these, 114 of 268 (42.5%) were female, and their mean age was 36.8 years. Seventy-nine of the 268 patients (29.5%) were diagnosed with HIV infection during the index illness. Among those who were aware of their HIV-positive status, 59 of 156 (37.8%) had disengaged from care. Significant functional impairment (Karnofsky score < 50) was evident in 44.0% of patients. Cerebrospinal fluid was not obtained in 108 of 268 (40.3%). In-patient mortality outcomes were available for 214 patients, and 47 of these 214 (22.0%) died during hospitalization. Patients with significant functional impairment were more likely to undergo lumbar puncture (P = 0.046). Women and the functionally impaired were more likely to die (P = 0.04 and < 0.001, respectively). CONCLUSIONS: Despite the availability of care, less than half of HIV-infected people with new-onset seizures were actively engaged in care and in-patient mortality rates were high. In the absence of clinical contraindication, lumbar puncture should be performed to diagnose treatable conditions and reduce morbidity and mortality. Continued efforts are needed to expand community-based testing and improve HIV care retention rates. Qualitative studies are needed to elucidate factors contributing to lumbar puncture usage in this population.

Central nervous system infections in travelers.

International travelers commonly contract infections while abroad, many of which are primary neurological diseases or have potential neurological sequelae. The implications of these neuroinfectious diseases extend beyond the individual, since returning travelers may contribute to the spread of infection in novel areas. In this review, we discuss signs, symptoms, treatments, and prophylaxes for these infections, as well as emerging trends with regard to neuroinfectious diseases of the returning traveler.

Brain imaging in normal kids: a community-based MRI study in Malawian children.

OBJECTIVE: To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults. METHODS: We identified a representative, community-based sample of children aged 9-14 years. Children were screened for neurodevelopmental problems. Demographic data, medical history and environmental exposures were ascertained. Eligible children underwent the Neurologic Examination for Subtle Signs (NESS) and a brain MRI. Descriptive findings and analyses to identify risk factors for MRI abnormalities are detailed. RESULTS: One hundred and two of 170 households screened had age-appropriate children. Two of 102 children had neurological problems - one each with cerebral palsy and epilepsy. Ninety-six of 100 eligible children were enrolled. Mean age was 11.9 years (SD 1.5), and 43 (45%) were boys. No acute MRI abnormalities were seen. NESS abnormalities were identified in 6 of 96 children (6%). Radiographic evidence of sinusitis in 29 children (30%) was the most common MRI finding. Brain abnormalities were found in 16 (23%): mild diffuse atrophy in 4 (4%), periventricular white matter changes/gliosis in 6 (6%), multifocal punctuate subcortical white matter changes in 2 (2%), vermian atrophy in 1 (1%), empty sella in 3 (3%) and multifocal granulomas with surrounding gliosis in 1 (1%). Having an abnormal MRI was not associated with age, sex, antenatal problems, early malnutrition, febrile seizures, an abnormal neurological examination or housing quality (all P values >0.05). No predictors of radiographic sinusitis were identified. CONCLUSION: Incidental brain MRI abnormalities are common in normal Malawian children. The incidental atrophy and white matter abnormalities seen in this African population have not been reported among incidental findings from US populations, suggesting Malawi-specific exposures may be the cause.

Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease.

BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret- CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret-. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret- group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy.

OBJECTIVE: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. METHODS: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. RESULTS AND RECOMMENDATIONS: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ~50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

Magnetic resonance imaging in Malawi: contributions to clinical care, medical education and biomedical research.

Advanced medical imaging technologies are generally unavailable in low income, tropical settings despite the reality that neurologic disorders are disproportionately common in such environments. Through a series of donations as well as extramural research funding support, an MRI facility opened in Blantyre, Malawi in July 2008. Resulting opportunities for studying common tropical disorders, such as malaria and schistosomiasis, in vivo are promising. The subsequent improvements in local patient care were expected and exceptional and include major revisions in basic care protocols that may eventually impact care protocols at facilities in the region that do not have recourse to MRI. In addition, advanced neuroimaging technology has energized the medical education system, possibly slowing the brain drain. Advanced technologies, though potentially associated with significant fiscal opportunity costs, may bring unexpected and extensive benefits to the healthcare and medical education systems involved.

The epidemiology of stroke in Pakistan: past, present, and future.

Stroke is a major public health problem in developing countries of South Asia. In this paper, we review the epidemiology of stroke in Pakistan. Most of the available data are based on hospital-centred case series addressing established stroke risk factors, stroke-related mortality and disability, functional status, and case fatality rates. There are limited population-based data regarding the prevalence of established stroke risk factors in the general population, and no epidemiologic studies have been conducted to specifically identify potential stroke risk factors unique to the region. The limited data that are available from Pakistan indicate that stroke epidemiology differs between Pakistan and Western populations - in Pakistan first stroke occurs at a younger age, particularly among women, and there is a higher proportion of haemorrhagic strokes. Besides the established stroke risk factors (e.g. hypertension, smoking, and diabetes) some potentially unique stroke risk factors related to life style and dietary habits such as huqqa smoking, use of dalda and desi ghee, and orally consumed forms of tobacco, may exist in Pakistan, and warrant further investigation. The shortage of trained stroke epidemiologists is a major limiting factor to the conduct of epidemiological stroke studies in Pakistan. Epidemiologic data are essential to guide health policy development aimed at decreasing the mortality and morbidity from stroke in Pakistan. To facilitate this process, medical professionals in Pakistan could participate in the World Health Organization's STEPwise approach to stroke surveillance, which provides a framework for data collection and comparison between and within populations.

Knowledge, attitudes, behaviors, and practices regarding epilepsy among Zambian clerics.

BACKGROUND: Epilepsy carries a high burden of social morbidity. An understanding of who propagates stigma and the determinants of stigmatizing attitudes is needed to develop effective interventions. Clerics represent an especially influential social group in Africa. Therefore, we conducted a survey of the knowledge, attitudes, behavior, and practices of Zambian clerics with respect to epilepsy. METHODS: We studied clerics in one large rural region as well as in the capital city. The rural survey was conducted door-to-door. In the urban areas, central administration for multiple denominations assisted in survey delivery. The survey, adapted from previously published instruments, included cleric-specific questions and demographic data. Composite scores for knowledge and tolerance were developed. Determinants of higher knowledge and tolerance were assessed. RESULTS: Almost all Zambian clerics know someone with epilepsy and have witnessed a seizure. More than 40% report having a family member with epilepsy. Unfortunately, this familiarity is not associated with more knowledge or tolerance for the condition. Younger clerics, urban dwellers, those with fewer children, and those with more years of formal education were significantly more tolerant. More knowledgeable clerics are more likely to recommend that a person with epilepsy seek care from a physician rather than a traditional healer. Formal education was the most important factor in determining tolerance toward epilepsy. CONCLUSIONS: Zambian clerics are very familiar with epilepsy, yet have relatively little knowledge of the etiology. Many view traditional healers as the appropriate care provider for epilepsy. To decrease stigma and improve the quality of advice offered by clerics to their congregations, educational programs focusing on the biomedical nature of the disorder are needed, particularly in rural regions.

IV tissue plasminogen activator use in acute stroke: experience from a statewide registry.

OBJECTIVE: To assess the use of IV recombinant tissue plasminogen activator (rt-PA) in a statewide hospital-based stroke registry and to identify factors associated with its use among eligible patients. METHODS: A modified stratified sampling scheme was used to obtain a representative sample of 16 hospitals. Prospective case ascertainment and data collection were used to identify all acute stroke admissions over a 6-month period. Subjects eligible for IV rt-PA were defined as those who arrived within 3 hours of onset, who had no evidence of hemorrhage on initial brain image, and who had no physician-documented reasons for non-treatment with IV rt-PA. Multivariate logistic regression was used to identify factors associated with IV rt-PA use. RESULTS: Of 2,566 stroke admissions, 330 (12.9%) met the eligibility criteria for rt-PA treatment, and of these 43 (13%) received IV rt-PA treatment. Among 2,236 admissions excluded from consideration, 21% had evidence of hemorrhage on initial imaging, 35% had unknown stroke onset times, 38% had an onset to arrival time >3 hours, and 6% had physician documented contraindications. Among eligible patients, being male, use of emergency medical services, and rapid presentation were associated with increased IV rt-PA use. CONCLUSIONS: Treatment with IV rt-PA was underutilized in this hospital-based stroke registry. The primary reason for nontreatment was delayed presentation. Reducing prehospital and in-hospital response times would help increase IV rt-PA use, as would greater emergency medical services use. Improving the documentation of onset times would help clarify the underlying causes of delayed presentation.

Do malpractice concerns, payment mechanisms, and attitudes influence test-ordering decisions?

Greater understanding is needed of nonclinical factors that determine neurologists' decisions to order tests. The authors surveyed 595 US neurologists and utilized demographic information, attitude scales, and clinical scenarios to evaluate the influence of nonclinical factors on test-ordering decisions. Greater test reliance, higher malpractice concerns, and receiving reimbursement for testing were all associated with a higher likelihood of test ordering. These findings have implications for training needs and suggest malpractice worries may inflate health care costs.

Quality of life measures in epilepsy: how well can they detect change over time?

OBJECTIVE: To evaluate the ability of health-related quality of life (HRQOL) measures to detect change over time in persons with epilepsy. BACKGROUND: The application of HRQOL measures in clinical trials has been limited by a dearth of information regarding their abilities to measure change over time (i.e., their responsiveness). To calculate responsiveness, one must categorize subjects as "changed" or "unchanged" by a priori criteria. METHODS: The authors analyzed data collected at baseline and at 28-week follow-up from an antiepileptic drug trial. Two different criteria for classifying subjects as changed or unchanged-one based on seizure frequency (where changed = attainment of seizure freedom) and one based on self-reported overall condition (where changed = improvement in overall condition)-were used. We compared responsiveness indices for two generic (Short Form [SF]-36 and SF-12) and two epilepsy-targeted (Quality of Life in Epilepsy [QOLIE]-89 and QOLIE-31) HRQOL measures. Two scoring procedures for the SF-36, one based on classic test theory and the other on item response theory (IRT), were compared. RESULTS: Effect sizes of the most responsive HRQOL measures were medium to large. The shorter epilepsy-targeted measure had similar responsiveness indices to those of the longer measure. Epilepsy-targeted measures were consistently more responsive than generic measures under the overall condition criterion, but for the seizure freedom criterion, IRT scoring of the SF-36 yielded responsiveness indices comparable to those of the epilepsy-targeted measures. CONCLUSION: Epilepsy-targeted health-related quality of life measures may be preferable to generic ones in longitudinal studies. Selection of a shorter epilepsy-targeted measure does not compromise responsiveness. Item response theory scoring should be applied to epilepsy-targeted HRQOL measures.

Seizures in rural Zambia.

PURPOSE: To describe the period prevalence of epilepsy and febrile seizures in a bush hospital and discuss the medical sequelae and social impact of seizures in this population. METHODS: For 13 weeks, an evaluation of inpatients was made at Chikankata Hospital in rural Zambia. Inpatients identified as having seizures, "fits," "spells," or "fainting," were evaluated by a medical records review, basic demographic data, a neurological history and physical examination, and a treatment history. A semistructured questionnaire was administered to evaluate the social impact of seizures and assess factors associated with delayed care seeking. RESULTS: Seizures composed 44% of all inpatient neurologic disease and resulted in 84 admissions. Epilepsy patients received treatment primarily from traditional healers; only 31% reported ever receiving antiepileptic drugs (AEDs). Among those who had received treatment, AEDs were frequently underdosed. Patients with epilepsy had significantly less education than their sex-matched siblings. Patients with untreated epilepsy for >2 years were more likely to have experienced serious burns or falls requiring hospitalization. Children with febrile seizures whose parents held supernatural beliefs regarding seizures were more likely to be treated with traditional medicines, had higher malarial parasite counts, and required longer hospitalizations than children with febrile seizures whose parents recognized the association between seizures and hyperthermia. CONCLUSIONS: Epilepsy and febrile seizures are responsible for a significant burden of disease in rural Zambia. Serious medical complications often result from seizures, especially if untreated for >2 years. Social stigma decreases educational opportunities and misperceptions regarding seizures may result in delayed care for children with febrile seizures. Some evidence suggests that epilepsy is underreported, underrecognized, and undertreated in this population.

Barriers to care for patients with neurologic disease in rural Zambia.

The awesome burden of treatable yet untreated neurologic disease in the developing world presents a humanitarian crisis to those of us with neurologic expertise from more privileged situations. Although increased economic resources are critically needed, a shortage of personnel to care for these patients is as great a problem. It is neither feasible nor desirable to propose training neurologists to work in these regions. However, COs could be selected to receive additional training and return to their home regions to serve as resources for referrals and as community educators. Such a training program would not require massive financial commitments. A handful of dedicated neurologists could conceivably accomplish this in 6- to 8-week training sessions. Ideally, educational materials, such as posters and pamphlets in both English and the native language of the various regions, would be provided at no cost. Existing textbooks in neurology are written for physicians and often focus on diagnostic evaluations and therapies far beyond the services available in developing countries. A text for practical use by COs and community health workers that discusses the application of available medicines and therapies for common neurologic problems would be invaluable. Similar books exist that address general medical and obstetrical problems (for example, Where There Is No Doctor: A Village Health Care Handbook). Where There Is No Neurologist could be developed as a primary teaching tool and a valuable reference for COs with neurologic expertise. Neuroscience researchers, clinical neurologists, and neurology residents from industrialized countries have much to offer and to gain by working in the Third World. Research to monitor the incidence and resource utilization of emerging problems such as stroke is needed to influence public policy. The economic burden and lost productivity caused by neurologic disease in this part of the world has not been appreciated or explored. Disease beyond the scope of Western experience manifests daily in places like Chikankata. Entities such as tabes neurosyphilis, which previous generations of neurologists used as the basis for their training, still abound in Zambia. Much personal satisfaction can be gained in providing care to this vulnerable and underserved population.