Neurological disorder and psychosocial aspects of cerebral malaria: what is new on its pathogenesis and complications? A minireview.

Recently, malaria is remain considered as the most prevalent infectious disease, affecting the human health globally. High morbidity and mortality worldwide is often allied with cerebral malaria (CM) based disorders of the central nervous system, especially across many tropical and sub-tropical regions. These disorders are characterised by the infection of Plasmodium species, which leads to acute or chronic neurological disorders, even after having active/effective antimalarial drugs. Furthermore, even during the treatment, individual remain sensitive for neurological impairments in the form of decrease blood flow and vascular obstruction in brain including many more other changes. This review briefly explains and update on the epidemiology, burden of disease, pathogenesis and role of CM in neurological disorders with behaviour and function in mouse and human models. Moreover, the social stigma, which plays an important role in neurological disorders and a factor for assessing CM, is also discussed in this review.

Neurodevelopmental Impairments 1 Year After Cerebral Malaria.

: media-1vid110.1542/5972295739001PEDS-VA_2018-1026Video Abstract BACKGROUND AND OBJECTIVES: Cerebral malaria (CM) causes significant mortality and morbidity in sub-Saharan African children. Reliable morbidity estimates are scarce because of methodological variability across studies. We describe the incidence, course, and severity of neurodevelopmental impairments in survivors of CM and the associated patient characteristics to inform epidemiologic estimates of malaria morbidity rates and prevention and treatment efforts. METHODS: We conducted an exposure-control study of 85 survivors of CM and 100 age-matched patients in a control group who were enrolled at hospital discharge and assessed after 1, 6, and 12 months using caregiver interviews and standardized developmental, cognitive, and behavioral measures. RESULTS: Developmental or cognitive impairment (<10th percentile of the control distribution) and/or new onset of caregiver-reported behavior problems occurred in 53% of case patients compared with 20% of the patients in the control group (odds ratio 4.5; 95% CI: 2.4 to 8.6; P < .001). In case patients, developmental or cognitive impairment at the 12-month assessment was associated with HIV-positive status and short stature at presentation, more prolonged fever and coma during admission, and severe atrophy or multifocal abnormalities being found on MRI at the 1-month assessment. CONCLUSIONS: One-half of survivors of CM were neurodevelopmentally impaired at the 1-year assessment. With these results, we support prevention trials of acute, neuroprotective interventions and the allocation of resources to evaluation, education, and rehabilitation efforts to reduce the significant long-term burden of CM-associated impairments on families and their communities.

Cerebral Malaria Causes Enduring Behavioral and Molecular Changes in Mice Brain Without Causing Gross Histopathological Damage.

Malaria, parasitic disease considered a major health public problem, is caused by Plasmodium protozoan genus and transmitted by the bite of infected female Anopheles mosquito genus. Cerebral malaria (CM) is the most severe presentation of malaria, caused by P. falciparum and responsible for high mortality and enduring development of cognitive deficits which may persist even after cure and cessation of therapy. In the present study we evaluated selected behavioral, neurochemical and neuropathologic parameters after rescue from experimental cerebral malaria caused by P. berghei ANKA in C57BL/6 mice. Behavioral tests showed impaired nest building activity as well as increased marble burying, indicating that natural behavior of mice remains altered even after cure of infection. Regarding the neurochemical data, we found decreased α2/α3 Na+,K+-ATPase activity and increased immunoreactivity of phosphorylated Na+,K+-ATPase at Ser943 in cerebral cortex after CM. In addition, [3H]-Flunitrazepam binding assays revealed a decrease of benzodiazepine/GABAA receptor binding sites in infected animals. Moreover, in hippocampus, dot blot analysis revealed increased levels of protein carbonyls, suggesting occurrence of oxidative damage to proteins. Interestingly, no changes in the neuropathological markers Fluoro-Jade C, Timm staining or IBA-1 were detected. Altogether, present data indicate that behavioral and neurochemical alterations persist even after parasitemia clearance and CM recovery, which agrees with available clinical findings. Some of the molecular mechanisms reported in the present study may underlie the behavioral changes and increased seizure susceptibility that persist after recovery from CM and may help in the future development of therapeutic strategies for CM sequelae.

Exploring neurodevelopmental outcome measures used in children with cerebral malaria: the perspectives of caregivers and health workers in Malawi.

BACKGROUND: Progress has been made in tackling malaria however there are still over 207 million cases worldwide, the majority in children. As survival rates improve, numbers of children with long-term neurodisabling sequelae are likely to increase. Most outcome studies in cerebral malaria (CM) have focused only on body function and structure and less on outcomes within the broader framework of the International Classification of Functioning and Disability (ICF). The aim of this study was to utilise qualitative methods to identify relevant clinical outcomes in CM to support formulation of a core outcome set relevant to CM and other acquired brain injuries for use in future clinical trials. METHODS: In depth interviews with parent/caregivers (CGs) of children with/without previous CM (N = 19), and in depth interviews with health professionals (N = 18) involved in their care were conducted in community and clinical settings in and around Blantyre, Malawi. Interviews were audio taped, transcribed, translated and a thematic content analysis was conducted. Themes were categorised and placed firstly in an iterative framework derived from the data but then within the ICF framework. RESULTS: Outcomes perceived as important to carers and professionals fulfilled each level of the ICF. These included impairment in body function and structure (contractures, impaired mobility, visual problems, seizures, cognitive function and feeding); activity and participation outcomes (learning, self-care, relationships in school, play and activities of daily living). Other issues emerging included the social and emotional implications of CM on the family, and balancing care of children with neurodisability with demands of daily life, financial pressures, and child protection. Themes of stigma and discrimination were described; these were perceived to negatively influence care, participation and integration of carer and child into the community. CONCLUSIONS: Outcomes considered important for parents/caregivers and professionals working with children post CM cross all aspects of the ICF framework (impairment, functioning and participation). Outcomes emphasised by families and carers in cross-cultural settings must be given adequate attention when conducting clinical studies in these settings.

Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties. In the present work, we evaluated the effects of CBD in a murine model of CM. Female mice were infected with Plasmodium berghei ANKA (PbA) and treated with CBD (30mg/kg/day - 3 or 7days i.p.) or vehicle. On 5th day-post-infection (dpi), at the peak of the disease), animals were treated with single or repeated doses of Artesunate, an antimalarial drug. All groups were tested for memory impairment (Novel Object Recognition or Morris Water Maze) and anxiety-like behaviors (Open field or elevated plus maze test) in different stages of the disease (at the peak or after the complete clearance of the disease). Th1/Th2 cytokines and neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) were measured in the prefrontal cortex and hippocampus of experimental groups. PbA-infected mice displayed memory deficits and exhibited increase in anxiety-like behaviors on the 5dpi or after the clearance of the parasitemia, effects prevented by CBD treatment. On 5dpi, TNF-α and IL-6 increased in the hippocampus, while only IL-6 increased in the prefrontal cortex. CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6). Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.

Cerebral malaria retinopathy predictors of persisting neurocognitive outcomes in Malawian children.

BACKGROUND: Neuropsychological sequelae from pediatric cerebral malaria (CM) have been well-documented. Although malaria-specific retinopathy during acute illness has become a defining criterion for CM, its relationship to neurocognitive sequelae has not been documented. This relationship is important if malaria-specific retinopathy reflects the possible brain neuropathogenesis leading to long-term neurocognitive deficits. METHODS: From 2008 to 2012, 49 Malawian children 4.5-12 years of age surviving retinopathy-positive CM (CM-R) were tested 1-6 yrs after illness with the Kaufman Assessment Battery for Children, 2 edition, the tests of variables of attention and the Achenbach Child Behavior Checklist. In an observational study of a cohort of cerebral malaria survivors, these neurocognitive and behavioral outcomes were statistically related to types and severity of retinopathy measures, while controlling for age, sex, body mass index, socioeconomic status and time interval between illness and testing. RESULTS: Worse scores for hemorrhages, papilledema, optic disk hyperemia, retinal whitening of macula and foveal annulus were associated with poorer Kaufman Assessment Battery for Children, 2 edition mental processing index and global scale scores. Disk hyperemia was also predictive of tests of variables of attention D prime overall attention performance (inattention) and commission errors (impulsivity). Few associations were found between retinopathy scores and Achenbach Child Behavior Checklist (emotional and behavioral) outcomes. CONCLUSIONS: We are the first to report the relationship between severity of malaria-specific retinopathy during acute illness in CM survivors and persisting neurocognitive problems. These findings support earlier studies documenting that severity of retinopathy during acute illness is medically prognostic in CM survivors. We extend these findings to include long-term neurocognitive outcomes.

Neurocognitive sequelae of cerebral malaria in adults: a pilot study in Benguela Central Hospital, Angola.

OBJECTIVE: To characterize the neurocognitive sequelae of cerebral malaria (CM) in an adult sample of the city of Benguela, Angola. METHODS: A neuropsychological assessment was carried out in 22 subjects with prior history of CM ranging from 6 to 12 months after the infection. The obtained results were compared to a control group with no previous history of cerebral malaria. The study was conducted in Benguela Central Hospital, Angola in 2011. RESULTS: CM group obtained lower results on the two last trials of a verbal learning task and on an abstract reasoning test. CONCLUSIONS: CM is associated to a slower verbal learning rate and to difficulties in the ability to discriminate and perceive relations between new elements.

Brain-derived neurotrophic factor and the course of experimental cerebral malaria.

The role of neurotrophic factors on the integrity of the central nervous system (CNS) during cerebral malaria (CM) infection remains obscure, but the long-standing neurocognitive sequelae often observed in rescued children can be attributed in part to the modulation of neuronal survival and synaptic plasticity. To discriminate the contribution of key responses in the time-sequence of the pathogenic events that trigger the development of neurocognitive malaria syndrome we defined four stages (I-IV) of the neurological progression of CM in C57BL/6 mice infected with Plasmodium berghei ANKA. Upregulation of ICAM-1, VCAM-1, e-selectin and p-selectin expression was detected in all cerebral regions before parasitized red blood cells (pRBC) accumulation. As the severity of symptoms increased, BDNF mRNA progressively diminished in several brain regions, earliest in the thalamus-hypothalamus, cerebellum, brainstem and cortex, and correlated with a four-stage disease sequence. Immunohistochemical confocal microscopy revealed changes in the BDNF distribution pattern, suggesting altered axonal transport. During CM progression, molecular markers of neurological infection and inflammation in the parasite and the host, respectively, were accompanied by a switch in the brain constitutive proteasome to the immunoproteasome, which could impede normal protein turnover. In parallel with BDNF downregulation, NCAM expression also diminished with increased CM severity. Together, these data suggest that changes in BDNF availability could be involved in the pathogenesis of CM.

Effects of experimental cerebral malaria in memory, brain-derived neurotrophic factor and acetylcholinesterase activity [correction for acitivity] in the hippocampus of survivor mice.

Malaria is the most important human parasitic disease and cerebral malaria (CM), its main neurological complication, is characterized by neurological and cognitive damage in both human and animal survivors. The brain-derived neurotrophic factor (BDNF) appears to be involved with activity-dependent synaptic plasticity. There is great interest regarding its role in learning and memory as well as acetylcholinesterase activity (AChE) that is implicated in many cognitive functions and probably plays important roles in neurodegenerative disorders. In the present work, we evaluated BDNF protein levels and AChE activity in the hippocampus and habituation in an animal model of CM using C57BL/6 mice after fifteen days of the induction. The results demonstrated that there was a decrease in BDNF levels in the hippocampus of C57BL/6 mice infected with PbA when compared with C57BL/6 non-infected mice and C57BL/6 non-infected mice that received treatment with chloroquine. However, no difference was observed in AChE activity in the hippocampus. When habituation was evaluated there was memory impairment in the C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). In conclusion, we believe that the decreased BDNF levels in the hippocampus may be related with memory impairment without alterations on AChE activity.

Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome.

Cerebral malaria is the most severe neurological complication of infection with Plasmodium falciparum. With >575,000 cases annually, children in sub-Saharan Africa are the most affected. Surviving patients have an increased risk of neurological and cognitive deficits, behavioral difficulties, and epilepsy making cerebral malaria a leading cause of childhood neurodisability in the region. The pathogenesis of neurocognitive sequelae is poorly understood: coma develops through multiple mechanisms and there may be several mechanisms of brain injury. It is unclear how an intravascular parasite causes such brain injury. Understanding these mechanisms is important to develop appropriate neuroprotective interventions. This article examines possible mechanisms of brain injury in cerebral malaria, relating this to the pathogenesis of the disease, and explores prospects for improved neurocognitive outcome.

Impaired everyday memory associated with encephalopathy of severe malaria: the role of seizures and hippocampal damage.

BACKGROUND: Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage. METHODS: An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition. RESULTS: CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures. DISCUSSION: The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.

Immediate neuropsychological and behavioral benefits of computerized cognitive rehabilitation in Ugandan pediatric cerebral malaria survivors.

OBJECTIVE: Our earlier studies on Ugandan children surviving cerebral malaria showed cognitive deficits mainly in attention and memory. We now present the first study in sub-Saharan Africa to investigate the feasibility and potential benefits of computerized cognitive rehabilitation training on neuropsychological and behavioral functioning of children surviving cerebral malaria. METHODS: A randomized trial in which 65 children admitted 45 months earlier with cerebral malaria were recruited at Mulago Hospital, Kampala, Uganda. For 8 weeks, 32 of the children received weekly training sessions using Captain's Log cognitive training software and the other 33 were assigned to a nontreatment condition. Pre- and postintervention assessments were completed using CogState, a computerized neuropsychological battery, measuring visuomotor processing speed, working memory, learning, attention and psychomotor speed and the Child Behavior Checklist measuring internalizing problems, externalizing problems, and total problems. RESULTS: Preintervention scores were similar between both groups. Treatment effects were observed on visuospatial processing speed [group effect (standard error) 0.14 (0.03); p < .001], on a working memory and learning task [0.08 (0.02); p < .001], psychomotor speed [0.14 (0.07); p = .04], and on internalizing problems [-3.80 (1.56); p = .02] after controlling for age, sex, school grade, quality of the home environment, and weight for age z scores. Similar treatment effects were observed when no adjustments for the above covariates were made. CONCLUSIONS: Computerized cognitive training long after the cerebral malaria episode has immediate benefit on some neuropsychological and behavioral functions in African children. The long-term benefit of this intervention needs to be investigated.

Household decision-making process and childhood cerebral malaria in The Gambia.

Mortality from childhood cerebral malaria remains unacceptably high in endemic regions. This survey was conducted between June and December 2001 among 69 primary caregivers of children admitted for cerebral malaria in Bansang Hospital, Central River Division (CRD), The Gambia to describe decision-making process at the family level that could have impact on malaria mortality. Thirty two percent of children presented in coma after 24 h of onset of illness. The eldest person in the compound or the father was responsible for taking decision on when hospital treatment was necessary in 85% of the cases. Mothers who were the primary caregivers made such decisions only in 7% of the cases. Cultural norms in a community are important factors affecting preferences at the household level and could influence important medical decisions. This survey suggests that patriarchs and/or fathers are important target groups for health education and project implementation programs.

The effect of Plasmodium falciparum on cognition: a systematic review.

OBJECTIVE: Systematic review to investigate the relationship between Plasmodium falciparum infection and cognitive function. METHOD: We searched MEDLINE, EMBASE and PsycINFO, and hand-searched journals and PhD theses. The inclusion criteria were (1) use of standardized tests for the specific populations and/or appropriate controls; (2) clear differentiation between children and adults. Eighteen studies were eligible, of which three gave information on all cognitive domains considered in the review. RESULTS: Deficits in attention, memory, visuo-spatial skills, language and executive functions may occur after malaria infection. These deficits are not only caused by cerebral falciparum malaria, but also appear to occur in less severe infections. P. falciparum seems to affect the brain globally, not in a localised fashion. Outcome depends on both biological and social risk factors. CONCLUSION: Future research should seek to establish the extent of these cognitive deficits using culturally appropriate techniques and well-defined criteria of disease.

Risk factors for persisting neurological and cognitive impairments following cerebral malaria.

BACKGROUND: Persisting neurological and cognitive impairments are common after cerebral malaria. Although risk factors for gross deficits on discharge have been described, few studies have examined those associated with persistent impairments. METHODS: The risk factors for impairments following cerebral malaria were determined by examining hospital records of 143 children aged 6-9 years, previously admitted with cerebral malaria, who were assessed at least 20 months after discharge to detect motor, speech and language, and other cognitive (memory, attention, and non-verbal functioning) impairments. RESULTS: The median age on admission was 30 months (IQR 19-42) and the median time from discharge to assessment was 64 months (IQR 40-78). Thirty four children (23.8%) were defined as having impairments: 14 (9.8%) in motor, 16 (11.2%) in speech and language, and 20 (14.0%) in other cognitive functions. Previous seizures (OR 5.6, 95% CI 2.0 to 16.0), deep coma on admission (OR 28.8, 95% CI 3.0 to 280), focal neurological signs observed during admission (OR 4.6, 95% CI 1.1 to 19.6), and neurological deficits on discharge (OR 4.5, 95% CI 1.4 to 13.8) were independently associated with persisting impairments. In addition, multiple seizures were associated with motor impairment, age <3 years, severe malnutrition, features of intracranial hypertension, and hypoglycaemia with language impairments, while prolonged coma, severe malnutrition, and hypoglycaemia were associated with impairments in other cognitive functions. CONCLUSIONS: Risk factors for persisting neurological and cognitive impairments following cerebral malaria include multiple seizures, deep/prolonged coma, hypoglycaemia, and clinical features of intracranial hypertension. Although there are overlaps in impaired functions and risk factors, the differences in risk factors for specific functions may suggest separate mechanisms for neuronal damage. These factors could form the basis of future preventive strategies for persisting impairments.

Developmental impairments following severe falciparum malaria in children.

OBJECTIVE: Neurological deficits are reported in children after cerebral malaria (CM) but little is known about the prevalence and characteristics of persisting neurocognitive consequences. The prevalence of developmental impairments following other complications of falciparum malaria, such as multiple, prolonged or focal seizures, is not known. Thus, our objective was to investigate the long-term developmental outcome of CM and malaria with complicated seizures (M/S). METHODS: We followed up a cohort of children previously exposed to CM or M/S and children unexposed to either condition. All children between 6 and 9 years of age, exposed to CM, and an equal number of children exposed to M/S were identified from databases of hospital admissions from 1991 to 1998. The unexposed group was randomly selected from a census database. The children's performance was measured using assessments of cognition, motor, speech and language, hearing and vision. A parental questionnaire was used to identify children with epilepsy. RESULTS: CM group scores were significantly lower than unexposed group scores on the assessments of higher level language (adjusted mean difference -1.63, 95% CI: -2.99 to -0.27), vocabulary (-0.02, 95% CI: -0.04 to -0.01), pragmatics (OR 2.81, 95% CI: 1.04-7.6) and non-verbal functioning (-0.33, 95% CI: -0.61 to -0.06). The areas of significantly reduced functioning for the M/S group were concentrated on phonology (OR 2.74, 95% CI: 1.26-5.95), pragmatics (OR 3.23, 95% CI: 1.2-8.71) and behaviour (OR 1.8, 95% CI: 1.0-3.23). The performance of the active epilepsy group was significantly poorer than that of the group without epilepsy on the tests of comprehension, syntax, pragmatics, word finding, memory, attention, behaviour and motor skills. CONCLUSIONS: CM and M/S are associated with developmental impairments. If these impairments persist, this may have implications for least 250,000 children in Sub-Saharan Africa each year. Active epilepsy significantly increases the risk of cognitive and behavioural problems in children with a history of severe malaria.

Somatosensory discrimination deficits following pediatric cerebral malaria.

Pathologic studies of central nervous system damage in human falciparum malaria indicate primary localization in the cerebral white matter. We report a sensory-perceptual investigation of 20 Ghanaian children with a recent history of cerebral malaria who were age-, gender-, and education-matched with 20 healthy control subjects. Somatosensory examinations failed to show any evidence of hemianesthesia, pseudohemianesthesia, or extinction to double simultaneous tactile stimulation. While unilateral upper limb testing revealed intact unimanual tactile roughness discrimination, bimanual tactile discrimination, however, was significantly impaired in the cerebral malaria group. A strong negative correlation (r = -0.72) between coma duration and the bimanual tactile roughness discrimination test was also found. An inefficiency in the integrity of callosal fibers appear to account for our findings, although alternative subcortical mechanisms known to be involved in information transfer across the cerebral hemispheres may be compromised as well.

Delayed neuropsychiatric effects of malaria in Ghana.

This study investigated the long-term emotional and cognitive effects of malaria infection in a sample of community resident nonmigratory Ghanaian adults, comparing 142 individuals with a documented history of clinical falciparum malaria and 30 controls without a lifetime medical diagnosis of malaria. Results were based on self-report inventory and interview-based approaches to assessment of emotional status as well as individual administration of the Mini-Mental State Examination. Our findings indicated the presence of an enduring, albeit subclinical, mixed anxiety-depression syndrome after medical recovery from falciparum malaria. There were, however, no significant neurocognitive deficits associated with malaria status on the objective screening instrument, nor were there reports of subjective attention, concentration, memory, or other cognitive complaints by self-report. Malaria may be a risk factor for psychiatric morbidity. We therefore recommend a search for effective malaria prevention and intervention strategies to avert the more serious clinical manifestations of mental disorder likely to evolve in this imminently lethal infectious disease.