cerebral malaria presentation

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INTRODUCTION

Issues related to clinical manifestations and diagnosis of malaria will be reviewed here. Technical aspects of laboratory tools for diagnosis of malaria are discussed further separately.

The epidemiology, pathogenesis, diagnosis, and treatment of malaria are discussed separately:

● (See "Malaria: Epidemiology, prevention, and control" .)

● (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" .)

On This Page

• Incubation Period
• Uncomplicated Malaria
• Severe Malaria
• Malaria Relapses
• Other Manifestations of Malaria

Infection with malaria parasites may result in a wide variety of symptoms, ranging from absent or very mild symptoms to severe disease and even death. Malaria disease can be categorized as uncomplicated or severe (complicated) . In general, malaria is a curable disease if diagnosed and treated promptly and correctly.

All the clinical symptoms associated with malaria are caused by the asexual erythrocytic or blood stage parasites. When the parasite develops in the erythrocyte, numerous known and unknown waste substances such as hemozoin pigment and other toxic factors accumulate in the infected red blood cell. These are dumped into the bloodstream when the infected cells lyse and release invasive merozoites. The hemozoin and other toxic factors such as glucose phosphate isomerase (GPI) stimulate macrophages and other cells to produce cytokines and other soluble factors which act to produce fever and rigors and probably influence other severe pathophysiology associated with malaria.

Plasmodium falciparum- infected erythrocytes, particularly those with mature trophozoites, adhere to the vascular endothelium of venular blood vessel walls and do not freely circulate in the blood. When this sequestration of infected erythrocytes occurs in the vessels of the brain it is believed to be a factor in causing the severe disease syndrome known as cerebral malaria, which is associated with high mortality.

Following the infective bite by the Anopheles mosquito , a period of time (the “incubation period”) goes by before the first symptoms appear. The incubation period in most cases varies from 7 to 30 days. The shorter periods are observed most frequently with P. falciparum and the longer ones with P. malariae .

Antimalarial drugs taken for prophylaxis by travelers can delay the appearance of malaria symptoms by weeks or months, long after the traveler has left the malaria-endemic area. (This can happen particularly with P. vivax and P. ovale , both of which can produce dormant liver stage parasites; the liver stages may reactivate and cause disease months after the infective mosquito bite.)

Such long delays between exposure and development of symptoms can result in misdiagnosis or delayed diagnosis because of reduced clinical suspicion by the health-care provider. Returned travelers should always remind their health-care providers of any travel in areas where malaria occurs during the past 12 months.

  Top of Page

The classical (but rarely observed) malaria attack lasts 6–10 hours. It consists of

• A cold stage (sensation of cold, shivering)
• A hot stage (fever, headaches, vomiting; seizures in young children); and
• Finally a sweating stage (sweats, return to normal temperature, tiredness).

Classically (but infrequently observed) the attacks occur every second day with the “tertian” parasites ( P. falciparum , P. vivax , and P. ovale ) and every third day with the “quartan” parasite ( P. malariae ).

More commonly, the patient presents with a combination of the following symptoms:

• Nausea and vomiting
• General malaise

In countries where cases of malaria are infrequent, these symptoms may be attributed to influenza, a cold, or other common infections, especially if malaria is not suspected. Conversely, in countries where malaria is frequent, residents often recognize the symptoms as malaria and treat themselves without seeking diagnostic confirmation (“presumptive treatment”). Physical findings may include the following:

• Elevated temperatures
• Perspiration
• Enlarged spleen
• Mild jaundice
• Enlargement of the liver
• Increased respiratory rate

Diagnosis of malaria depends on the demonstration of parasites in the blood, usually by microscopy. Additional laboratory findings may include mild anemia, mild decrease in blood platelets (thrombocytopenia), elevation of bilirubin, and elevation of aminotransferases.   Top of Page

Severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient’s blood or metabolism. The manifestations of severe malaria include the following:

• Cerebral malaria, with abnormal behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities
• Severe anemia due to hemolysis (destruction of the red blood cells)
• Hemoglobinuria (hemoglobin in the urine) due to hemolysis
• Acute respiratory distress syndrome (ARDS), an inflammatory reaction in the lungs that inhibits oxygen exchange, which may occur even after the parasite counts have decreased in response to treatment
• Abnormalities in blood coagulation
• Low blood pressure caused by cardiovascular collapse
• Acute kidney injury
• Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites
• Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia

Severe malaria is a medical emergency and should be treated urgently and aggressively.

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks (“relapses”) after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ( “hypnozoites” ) that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack.

• Neurologic defects may occasionally persist following cerebral malaria, especially in children. Such defects include trouble with movements (ataxia), palsies, speech difficulties, deafness, and blindness.
• Recurrent infections with P. falciparum may result in severe anemia. This occurs especially in young children in tropical Africa with frequent infections that are inadequately treated.
• Malaria during pregnancy (especially P. falciparum ) may cause severe disease in the mother, and may lead to premature delivery or delivery of a low-birth-weight baby.
• On rare occasions, P. vivax malaria can cause rupture of the spleen.
• Nephrotic syndrome (a chronic, severe kidney disease) can result from chronic or repeated infections with P. malariae .
• Hyperreactive malarial splenomegaly (also called “tropical splenomegaly syndrome”) occurs infrequently and is attributed to an abnormal immune response to repeated malarial infections. The disease is marked by a very enlarged spleen and liver, abnormal immunologic findings, anemia, and a susceptibility to other infections (such as skin or respiratory infections).

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• Published: 24 July 2012

Infectious disease

Pathogenesis of cerebral malaria—a step forward

• Sudhanshu S. Pati 1 &
• Saroj K. Mishra 1  

Nature Reviews Neurology volume  8 ,  pages 415–416 ( 2012 ) Cite this article

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• Central nervous system infections
• Gene therapy
• Pathogenesis

Cerebral malaria is a potential, severe outcome of Plasmodium falciparum infection, but the molecular basis of this complication has been unclear. Three recent studies have identified specific var genes encoding the malaria parasite ligand that binds to human brain endothelial cells, pointing to therapeutic targets for cerebral malaria.

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Sudhanshu S. Pati & Saroj K. Mishra

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Pati, S., Mishra, S. Pathogenesis of cerebral malaria—a step forward. Nat Rev Neurol 8 , 415–416 (2012). https://doi.org/10.1038/nrneurol.2012.144

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Unexpected severe malaria in a postoperative patient, New York, USA

• Alan Bulbin 1 ,
• Julia Shen 1 ,
• Carol Liotta-Bono 1 &
• Tahir Ahmad 1  

BMC Infectious Diseases volume  24 , Article number:  404 ( 2024 ) Cite this article

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Severe malaria is not routinely considered when evaluating a febrile patient in the postoperative setting. Common bacterial infections, along with adverse drug reactions, are the usual differential concerns. We present a case of severe malaria emerging unexpectedly eight days after routine craniotomy.

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When encountered within the first 48 hours, post-surgical fever is usually from non-infectious causes. Beyond this, the differential diagnosis includes bacterial infections such as surgical site/wound, urinary tract, and pneumonia. The possibility of hypersensitivity reactions to newly introduced drugs should also be considered [ 1 ]. Malaria has been reported in the postoperative setting, but typically only from endemic regions or returned travelers [ 2 , 3 ]. Malaria has rarely been acquired via transfusion following open heart surgery [ 4 ]. However, case reports of autochthonous malaria emerging postoperatively are lacking.

Case Presentation

SC is a 65 year old male with prior history of hypertension and hyperlipidemia, maintained on long term aspirin therapy, who suffered a mechanical fall with head trauma on September 15, 2023. He presented to a New York City hospital, was found to have a left subdural hematoma, leading to left craniotomy, and surgical evacuation on September 18th. He transferred to our institution on September 21st for postoperative management. His subsequent hospital course was without incident. He recovered well from his surgery, remained fever free; CBC and liver enzymes all were normal. He did not require a blood transfusion. Metformin was initiated for newly diagnosed diabetes, along with levetiracetam for seizure prophylaxis, while maintained on losartan, metoprolol, and atorvastatin. He was discharged home on September 24th.

The patient returned to our Emergency Department (ED) on October 1st with fever, malaise, and dark urine progressing over four days. On presentation, vital signs were as follows: temperature 100.8 °F, pulse 92 beats/min, blood pressure 98/62 mm Hg, and oxygen saturation 100% on room air. He was alert and oriented. The physical exam otherwise was unremarkable; the left craniotomy incision was clean and dry; skin demonstrated no rashes or lesions. Laboratory results demonstrated elevated lactic acid and liver enzymes, mild hyponatremia and thrombocytopenia. White blood cell count and hemoglobin values were normal. No eosinophilia was noted (Table  1 ). Computerized Tomography (CT) imaging of head, chest, abdomen, pelvis and Magnetic Resonance Imaging (MRI) of brain did not reveal any acute process.

Initial treatment in the ED included IV fluids, antipyretics and antibiotics (vancomycin and piperacillin-tazobactam). Neurosurgery assessment determined no clinical signs of meningitis, brain abscess, cerebral edema or infection from his recent cranial surgery. The subdural hematoma was improved.

Over the next day, the patient experienced high fevers (peak of 104 °F) as well as progressive anemia, thrombocytopenia, and an uptrend in bilirubin (Table  1 ). Hematology was consulted; the peripheral blood smear was reviewed, revealing many ring form intraerythrocytic organisms, concerning for babesiosis vs. malaria.

The patient lives in a developed area of suburban Yonkers, New York. The nearest wooded area is two miles from his home, where deer have been seen, although he denied any known tick bites. His only travel was to Miami Beach and the Florida Keys eight weeks prior to his brain injury (Fig.  1 ). He works as a food vendor, selling fruits and vegetables at a large market in Hunts Point, New York. He reported mosquito bites both at home and work. He was working up to September 15th, when he fell at home. He has no history of substance use or needle sharing. He has no history of prior malaria.

Based on the report from Hematology, with guidance from Infectious Disease, antibiotic coverage was switched to azithromycin 500 mg daily, doxycycline 100 mg twice daily, and atovaquone 750 mg twice daily on October 2nd.

A formal thick and thin blood smear was sent to our reference lab on October 2nd. The next day, the report confirmed Plasmodium falciparum detected with > 15% parasitemia. A diagnosis of severe malaria was made, and available atovaquone-proguanil (Malarone™) 250 − 100 mg (4 tablets) daily was initiated. Intravenous Artesunate was ordered via the commercial supplier, which arrived on October 4th, and was immediately started. The patient completed two full doses of atovaquone-proguanil while awaiting the arrival of Artesunate.

Artesunate was initiated at a dose of 2.4 mg/kg/dose (180 mg) IV every 12 h x 3 doses at 0, 12 and 24 h over October 4th and October 5th. On October 6th, Artesunate 180 mg IV daily was continued. A repeat blood smear from October 5th, after two doses of both atovaquone-proguanil and Artesunate, revealed a significant decrease in parasitemia to 0.3%.

By day 3 of therapy (October 6th ), the patient’s fever curve improved, total bilirubin had normalized with AST, ALT and LDH slowly declining (Table  1 ). Thrombocytopenia was improving as well, and the patient felt better overall. Repeat blood smear on October 6th showed further improvement in parasitemia to 0.1%. Due to these improvements, the decision was made to limit Artesunate to one more daily dose for a total of 4 days and convert the patient back to atovaquone-proguanil to complete the oral course. Artesunate was stopped on October 7th, and the last dose of atovaquone-proguanil was administered October 8th (Fig.  1 ). A final blood smear on October 8 showed no intraerythrocytic parasites.

There were no immediate adverse events related to malaria treatment. The patient tolerated therapy well and was discharged home on October 9th. On the day of discharge, the patient’s labs continued to normalize (Table  1 ).

Timeline of Events and Sequence of Therapy

This case of P. falciparum malaria was completely unexpected. The patient developed fever eight days after surgery without any suspicious travel history. Initial concerns of a routine postoperative bacterial infection were promptly excluded. The possibility of a drug reaction from levetiracetam was considered in view of liver injury, but no rash or eosinophilia was seen. Ultimately, the high fever, typical progression of laboratory parameters, including evidence of hemolysis, and intraerythrocytic parasites seen on the peripheral blood smear led to the diagnosis of malaria, as later confirmed on formal thick and thin smear.

The initial peripheral smear finding on October 2nd was the first alert to a possible bloodborne pathogen. However, malaria was still difficult to consider, especially in a patient with no relevant travel history. Locally acquired Babesiosis is more commonly encountered in our region/experience. Due to low volume, our centralized microbiology laboratory does not perform formal malaria smears, opting to send specimens to an offsite reference lab (Quest Diagnostics®).

As of October 3rd, the malaria diagnosis was confirmed and reported to the New York State Department of Health (NYSDOH) as required. However, the source of infection was difficult to determine. The patient had been hospitalized, and upon discharge, did not leave his house during the two weeks prior to his febrile presentation on October 1st.

Cases of malaria locally acquired in Florida have been reported [ 5 ], but his travel to South Florida was eight weeks prior. Moreover, the cases reported in Florida were all from Plasmodium vivax and identified only in Sarasota County [ 5 ]. The incubation period for the different forms of malaria can be variable, but P. falciparum (as diagnosed in our patient) is typically associated with shorter incubation times of 7–20 days [ 6 ]. His work selling international fruits and vegetables raised the possibility of “baggage” malaria, meaning presumed occupational exposure from an infectious mosquito imported via the shipped produce directly. Otherwise, local exposure from a New York resident anopheles mosquito vector should be considered. Finally, the possibility of nosocomial malaria could be questioned. Cases of hospital-acquired malaria with breaks in standard precautions have been reported [ 7 , 8 ]. These reports highlight the possible link between a non-traveler and a malaria-infected returned traveler, if hospitalized together. This is even more relevant if genomic typing between the two match [ 7 , 8 ].

The Center for Disease Control and Prevention (CDC) malaria treatment guidelines include prompt and aggressive treatment with parenteral Artesunate for patients with manifestations of severe malaria [ 9 ]. Severe malaria symptoms may include impaired consciousness/coma, hemoglobin < 7 g/dL, acute kidney injury, acute respiratory distress syndrome, circulatory collapse/shock, acidosis, jaundice, disseminated intravascular coagulation, and/or parasite density of ≥ 5% [ 9 ]. Our patient initially was found to have > 15% parasite density. If Artesunate is not immediately available, treatment with any other active agent should be initiated.

Our patient received doxycycline, atovaquone, and then combination atovaquone-proguanil while awaiting the arrival of Artesunate.

Artesunate is an intravenous antimalarial agent that is metabolized to dihydroartemisinin (DHA) [ 10 ]. Artesunate and DHA are activated by heme iron binding, resulting in oxidative stress, inhibition of protein and nucleic acid synthesis, and a decrease in parasite growth and survival [ 10 ]. It is dosed at 2.4 mg/kg/dose at 0 h, 12 h, and 24 h, followed by once daily for up to a total of 7 days depending on patient response [ 9 ]. After intravenous therapy is completed, it is recommended to complete a full course with an oral regimen [ 9 ]. Artesunate is generally well tolerated, but can cause hypersensitivity reactions (hypotension, anaphylaxis, dyspnea, urticaria, and rash) during administration, as well as delayed hemolytic anemia after treatment [ 10 ]. All persons treated for severe malaria with intravenous Artesunate should be monitored weekly for up to four weeks after treatment initiation for evidence of hemolytic anemia [ 9 ].

Despite being completely unexpected, with no typical travel history, the clinical and laboratory parameters ultimately led to the diagnosis of severe P. falciparum malaria in our postoperative patient. Artesunate was ordered and delivered via the manufacturer within less than 24 hours. The patient was discharged after a satisfactory clinical response with clearance of parasitemia. He remains relapse free with no evidence of hemolytic anemia.

We believe this is a case of locally acquired malaria (autochthonous) as outlined above. In these situations, it is vital NYSDOH and CDC investigate and discover the source of infection to detect a possible malaria outbreak. The investigation is ongoing. They report a possible nosocomial exposure involving a returned traveler at the outside hospital. As of February 22, 2024, our last communication with NYSDOH Bureau of Communicable Disease Control, there have been no additional community-associated or work-related malaria cases identified.

Data availability

Relevant patient-specific data included in manuscript. No additional raw data.

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Alan Bulbin, Julia Shen, Carol Liotta-Bono & Tahir Ahmad

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Contributions

Dr. Alan Bulbin (Infectious Disease) contributed to study conception/design, patient assessment, treatment, data analysis and writing/editing of draft case report. Dr. Julia Shen: Draft manuscript preparation and editing, patient treatment. Dr. Carol Liotta-Bono: Draft manuscript preparation and editing, patient treatment. Dr. Tahir Ahmad: Patient assessment, treatment. All authors reviewed the final version of manuscript.

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Correspondence to Carol Liotta-Bono .

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Written Informed consent was obtained from the patient to participate and publish. Ethics Committee approval obtained. See Related files for copies of written informed consent and Ethics/Institutional Review Board (IRB) approval.

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Bulbin, A., Shen, J., Liotta-Bono, C. et al. Unexpected severe malaria in a postoperative patient, New York, USA. BMC Infect Dis 24 , 404 (2024). https://doi.org/10.1186/s12879-024-09272-6

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Published : 15 April 2024

DOI : https://doi.org/10.1186/s12879-024-09272-6

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Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi

• Arabella Borgstein 1   nAff6 ,
• Bo Zhang 2 ,
• Colin Lam 3 ,
• Montfort Bernard Gushu 1 ,
• Alice Wangui Liomba 1 ,
• Albert Malenga 1 ,
• Paul Pensulo 1 ,
• Andrew Tebulo 1 ,
• Dylan S. Small 2 ,
• Terrie Taylor 1 , 4 &
• Karl Seydel   ORCID: orcid.org/0000-0001-9859-9549 1 , 4 , 5  

Malaria Journal volume  21 , Article number:  60 ( 2022 ) Cite this article

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Cerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi.

This retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome.

A total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007–1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986–1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983–0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993–1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090–1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973–1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome.

Conclusions

In Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome.

Cerebral malaria (CM) is the gravest manifestation of severe malaria and results in the highest mortality rates encountered in this disease [ 1 , 2 ]. It is defined by peripheral asexual Plasmodium falciparum parasitaemia and coma (Blantyre coma score ≤ 2) persisting for more than 2 h after a seizure and with no other identifiable cause [ 3 ]. In malaria-endemic areas children are more vulnerable than adults, with 5% of all paediatric deaths being attributed to CM, making it the third major cause of death in children under the age of 5 worldwide [ 4 ]. Even with timely and appropriate care, mortality due to CM remains between 10 and 20% [ 3 ]. In survivors, there can be serious neurological sequelae that leave children with permanent cognitive impairments [ 5 ].

Neurological sequelae have been reported in 9–23% of paediatric CM survivors at discharge [ 6 , 7 , 8 ]: 21–23% have been found to develop cognitive deficits or epilepsy in the months after discharge [ 9 , 10 ] and neurodevelopmental impairments have been reported to accumulate for up to one year after hospital discharge. As a result, more than 50% of CM survivors eventually develop some form of deficit [ 11 ]. These neurosequelae can manifest in a variety of ways including compromised hearing, sight or speech, motor abnormalities, paralysis, learning and memory defects, disruptive behaviours, and epilepsy [ 12 , 13 , 14 ]. In sub-Saharan Africa, the appropriate resources for support, treatment, and rehabilitation of children with these sequelae are scarce. In addition, these disabilities still carry heavy societal stigma and can have devastating repercussions on children and their families within their communities.

Although there has been substantial research on the factors associated with malaria mortality, factors associated with neurosequelae have been less well documented [ 11 ]. A study in The Gambia showed that post-CM deaths were associated with hypoglycaemia and acidosis, whereas neurological sequelae were associated with repeated seizures and deep prolonged coma [ 15 ]. This suggests that neurological disability could be associated with prolonged duration of symptoms and that the causal pathways of mortality and sequelae may be different. No research has considered the delay of presentation to medical care—with its associated extended duration of symptoms—and its direct impact on clinical outcome in CM. Actions taken before a child reaches the hospital, such as the rapidity of care-seeking by the parents or guardians and the availability of treatment options at the local level, may be critical to disease outcome. Death and sequelae may have different pathogenic pathways and this concept has been little explored.

To address these questions, data from a longstanding study of CM were used to investigate the contribution of coma duration prior to admission (a proxy measure for delay to presentation at hospital and receipt of treatment) to the distinct clinical outcomes of full recovery, sequelae, or death. The data spanned 20 years of research in a central government hospital of Malawi. The exposure variables were chosen based on a previous Malawi-based study investigating contributors to mortality which found lactate to be the only independent predictor of death [ 16 ]. In this previous study coma duration was included in the variables of interest; however, the outcomes were binary only (survival or death) without consideration of survival with sequelae. The study found that HIV status was not related to mortality although it has been shown to be a known risk factor for complicated malaria, positive status being associated with an increase in incidence and severity and decrease in treatment success [ 17 , 18 , 19 , 20 ]. Other previous studies have revealed that age and duration of coma symptoms are risk factors for cognitive impairment post-CM [ 9 , 10 , 11 , 21 , 22 ]. In addition to these exposure variables, pre-treatment with artesunate or non-artesunate based therapies was included given the recent emergence of readily available artemisinin-based combination therapy (ACT) in the community.

Data analysed were previously collected by the Blantyre Malaria Project (BMP) in the Paediatric Research Ward (PRW) of Queen Elizabeth Central Hospital (QECH), the largest government-run tertiary care hospital in Malawi. Only patients meeting the following definition of CM were included; Blantyre coma score ≤ 2 with no other identifiable cause of coma and P. falciparum parasitaemia on a peripheral blood smear.

Patients were given the maximum level of high-dependency care available and treated with antimalarial medication, antipyretics, antibiotics, and anticonvulsants according to the national guidelines at the time. Ethical approval for the study was provided by the institutional review boards at the University of Malawi College of Medicine in Blantyre, Malawi, and Michigan State University.

On admission, written informed consent was obtained from the parent or guardian of each child to authorize the collection and analysis of samples as well as access to deidentified data. Two rapid tests, Uni-Gold Recombigen HIV-1/2 (Trinity Biotech) and Determine HIV-1/2 (Inverness Medical), were used to diagnose infection with HIV, with a tiebreaker used if discrepant (Capillus, Trinity Biotech). Blood lactate levels were measured on admission using a Lactate Pro 2 point of care detector (Arkray Inc). A lumbar puncture was performed to rule out meningitis.

History of the disease episode was determined using a questionnaire completed by the nurse in consultation with the primary caregiver at the time of admission. This included details of symptom onset, when and where medical attention was sought and whether any medication was given prior to arrival at the hospital. Children were screened on admission for any pre-existing neurological condition; if present they were excluded from the study.

Clinical outcomes were determined by research clinicians at the time of discharge or death. Details of neurological sequelae were selected from a list (cognitive impairment, paresis, ataxia, aphasia, blindness, deafness, or behavioural changes), or, if not included in the list, described.

The statistical analysis included all subjects with a recorded outcome at discharge (full recovery, sequelae, or death). Missing data for other variables was imputed using multiple imputation with chained equations and five imputed datasets were created [ 23 ]. A proportional odds assumption was used to test the equality of the association between explanatory variables and outcome (full recovery, sequelae, and death) and assessed using a Brant test [ 24 ]. A multinomial regression was then fit to quantify the association between each variable and outcome. All analyses were performed on each imputed dataset and results were then pooled using standard methods [ 25 ]. Statistics were performed using the statistical computing software, R [ 26 ].

To understand the factors contributing to delayed presentation to medical care, the clinical notes of patients with coma duration of 24 h or longer (15% of the sample) were examined between 2002 and 2019.

Between 2001 and 2021, a total of 1663 children with cerebral malaria between the ages of 6 months and 14 years were admitted to the PRW (Table 1 ).

Associations with outcomes

A proportional odds assumption tested the hypothesis that the five variables evaluated had comparable effects on the three clinical outcomes. The proportional odds assumption was rejected at p = 0.05 level using an omnibus Brant test with a Chi-square statistic of 22.15 (6 degrees of freedom, p-value = 0.001) (Additional file 1 : Table S1).

Given the rejection of the proportional odds hypothesis, the contribution of each of the variables was then explored using a multinomial regression (Table 2 ). Longer coma duration prior to admission (OR 1.023, p-value = 0.006) was strongly associated with neurological sequelae, but not with death (OR 1.00, p-value = 0.961). This trend is highlighted in Fig.  1 . Although the odds ratios appear minimal, this is partially due to the choice of units of hours. Were the consequences of a six-hour delay to have been considered rather than the delay of a single hour, the OR would increase to 1.14. Age was significantly and inversely associated with sequelae (OR 0.990, p = 0.004) but was not associated with death (OR 0.998, p = 0.335). Higher lactate levels were strongly correlated with death (OR 1.125, p < 0.001), but were not associated with sequelae (OR 1.016, p = 0.475). Being HIV positive and receiving prior treatment were not significantly associated with any outcome.

A cumulative distribution showing the effect of coma duration prior to presentation on the three clinical outcomes. As is also shown in the statistical analysis, longer coma duration is associated with higher rates of sequelae, compared to full recovery or death

• Delay to presentation

Detailed patient histories were available from 2002 to 2019. Clinical notes of patients presenting with coma duration of 24 h or longer, and with sequelae at discharge were examined. Of these, fifty-seven had histories which included comments on delay to presentation. Delays were categorized in 1 of the following four categories (Table 3 ): institutional delay, family action, transport problems or unknown. Most of the analysed cases (54%) gave their reason for delay as being rooted in an institutional cause (Fig.  2 , Table 3 ). Another 19% attributed their delay to the actions taken by the child’s parent or guardian and 8% to issues with transportation. For 19% no reasons could be identified.

Proportions of primary reasons for delay to presentation in patients with coma duration ≥ 24 h prior to admission

Most families and communities in rural sub-Saharan Africa have little or no access to educational or rehabilitation resources and are ill-equipped to care for disabled children. If a child survives CM with severe, or even mild neurological deficits, their entire family may be subject to stigma, discrimination, and social isolation from their community [ 27 ]. In countries such as Malawi—where most of the population live below the poverty line—financial strain, cultural pressure and the burdens of daily life leave little capacity to cope with additional adversity. As well as alienating the family from their community, stigma and discrimination have been shown to have a detrimental effect on post-CM care of the patient [ 12 ].

There is an increasing awareness of the burden of neurological sequelae post-CM [ 28 , 29 , 30 ] however there remains a knowledge gap as to its pathogeneses, causes and clinical associations [ 2 ]. Previous studies have revealed that age, seizure frequency, prolonged fever and duration of coma symptoms are risk factors for cognitive impairment post-CM [ 9 , 10 , 11 , 21 , 22 ]. In this study coma duration prior to admission and younger age were identified as two significant drivers of neurosequelae in CM survivors (Fig.  2 ).

CM is typically more common in younger children. Other studies have also shown younger age to be associated with worse outcomes in CM survivors, children under the age of 5 showing considerably greater developmental delays one month after discharge, as well as more abnormal MRIs and associated impairment in cognitive ability, attention, and associative memory [ 21 , 22 ]. Younger brains may be more vulnerable to CM as critical events in brain growth and development occur between birth and age 5 years [ 28 ]. It is uncertain, however, whether the increased neuroplasticity at this age facilitates more rapid recovery from injury, contributes to more serious and sustained neurological damage, or both [ 31 , 32 , 33 ].

As the disease is frequently lethal, patients with CM should be given the highest level of available attention, preferably in an intensive care unit or local equivalent [ 3 , 14 ]. Immediate anti-malarial medication, antipyretics, and anticonvulsants should be administered, with ACT being regarded as the “first-line of defence” in the outpatient setting [ 5 ]. Clinical trials have established artemisinin-based combinations as being superior to other anti-malarials [ 34 , 35 ] and they are now widely recommended as first-line drugs for treatment of malaria [ 3 ]. Although prior treatment with ACT did not affect clinical outcome in this study, it showed a trend toward decreasing sequelae, which was not seen with mortality. The lack of a statistically significant result could be due to the relatively recent introduction of outpatient ACT, which limited the number of cases in the analysis.

Lactic acidosis is frequently observed in patients with severe malaria and is a prognostic factor for both mortality and poor outcome, [ 6 , 36 , 37 , 38 , 39 ] with prolonged periods of hyperlactataemia possibly leading to neuronal dysfunction as well as death [ 2 ]. A number of factors could potentially contribute to lactic acidosis in this setting, including parasite metabolism, aerobic glycolysis by activated immune cells, anaerobic glycolysis in hypoxic cells and tissues due to parasite sequestration and anaemia, and impeded clearance of lactate in the liver or kidneys [ 39 ]. Studies in Ghana and Thailand showed that dichloroacetate decreased lactate levels but did not specifically decrease overall mortality in severe malaria cases [ 38 , 40 ]. In one study in South Africa, HIV positive patients with severe malaria were significantly more likely to have lactic acidosis than HIV negative patients [ 17 ]. Positive HIV status is a known risk factor for complicated malaria, increasing incidence and severity, as well as reducing the likelihood of successful treatment [ 17 , 18 , 19 , 20 ]. Although blood lactate concentration was strongly associated with mortality in this study, the effect of HIV on outcome was not significant when controlling for lactate levels.

Despite the advantages of readily available and effective medication, these benefits cannot be fully realised if children are delayed in reaching medical care. Extended coma duration prior to admission at hospital is an indicator of this delay to presentation in CM patients. Determinants of delay in seeking treatment for uncomplicated malaria have been studied in Ethiopia, Nigeria, Equatorial Guinea, and Tanzania [ 41 , 42 , 43 , 44 , 45 ], and the primary contributors are household duties and dynamics, socioeconomic status, and transportation problems. In Tanzania, diagnosis and treatment of uncomplicated malaria within 24 h of the onset of symptoms reduced progression to severe malaria and was associated with decreased mortality [ 41 ]. These previous studies considered uncomplicated malaria, whereas this is the first to investigate the effect of coma duration prior to admission on clinical outcomes in CM specifically.

Coma duration prior to hospitalization surfaced as the most significant variable associated with sequelae in this analysis. A prolonged delay prior to appropriate hospital care could be due to multiple reasons. More than half of the patients whose comas lasted for ≥ 24 h prior to admission to hospital were linked to an institutional cause associated with the health care system and referral routes (Fig.  2 , Table 3 ).

When considering the effect of delay to presentation on clinical outcome, it was originally hypothesised that a longer delay would lead to higher rates of both mortality and sequelae. On finding that there was a distinct contrast in the way the two outcomes were influenced, the differences between them became a point of interest for the study and two additional hypotheses were considered:

Clinical outcome evolves on a spectrum, from infection to death, with full recovery and variable states of survival with neurosequelae in between. This hypothesis assumes that all outcomes would be influenced by the same driving factors.

There are different causal pathways leading to full recovery, sequelae, and death, each with their own distinct drivers. This hypothesis assumes that the outcomes have independent pathways.

The results from the multinomial regression analysis suggested that the variables of interest influenced death and neurological sequelae differently, supporting the second hypothesis.

This study has the advantage of using data from one of the longest standing studies of the pathogenesis of CM, spanning 20 years and including over 1600 well-characterized cases from a single study site. Nevertheless, there were some limitations. Over the course of the study, both the standard of living and health care system in Malawi changed. Increased availability of transport could have made it easier for patients to reach hospital faster, for instance. Increased numbers of staff and more district health care centres may have led to more prompt treatment prior to arriving at the referral hospital. These are potential confounders. In addition, the determination of sequelae was made at discharge only, thus failing to capture both sequelae that developed over time, and the resolution of any sequelae seen at discharge. Extensive follow up data are being collected on a subset of these patients and further analysis will be informative. Data on time to presentation was collected via questionnaire completed by the parent or guardian in conjunction with research staff. Reporter bias might be inherent, with parents or guardians tending to minimize the amount of time that they delayed prior to taking action. In addition, the individual providing the history at the hospital may not be the same as the one present during the initial phases of the disease: for example, aunts and grandmothers often accompany the patient to the hospital when the mother is occupied at home with housework and care for the patient’s siblings. In addition, the parents or guardians may have an inaccurate perception of ‘coma’. These all lead to the measure of ‘coma duration prior to admission’ being a variable to be interpreted with care. In addition, there are possibly a subset of children that die quickly prior to reaching QECH. It is currently impossible to document these cases given the diagnostic and reporting capabilities in the more rural referral areas. This could lead to a selection bias in the cases being considered at the referral hospital. Each of these weaknesses would decrease the effect on outcome, however the presence of a striking differential effect of coma duration on sequelae and mortality emphasizes that there is still value in considering this variable. Finally, only a small number of comprehensive patient histories were available to determine reasons for delay to presentation, with fifty-seven of these having a coma duration of 24 h or longer.

This study sheds light on how a delay to presentation at hospital is significantly associated with the clinical outcome of children with CM. It highlights a novel distinction between the pathogenic processes leading to death and sequelae that warrants further investigation. Although the treatment and understanding of CM has improved, there are still barriers to full recoveries. It is critical that children are given medical attention in a timely manner. Beyond parents and guardians taking action to present to health care quickly, it is the responsibility of the country, the health care system, health care workers and institutions to facilitate this rapid presentation. Efforts in the education of caregivers as well as careful public health measures could target these delays and in turn, lead to a decrease in the burden of sequelae in CM survivors.

Availability of data and materials

The datasets used and analysed in this study are available from the first author or corresponding author on reasonable request.

Abbreviations

• Cerebral malaria

Human immunodeficiency virus

Artemisinin-based combination therapy

Blantyre Malaria Project

Paediatric Research Ward

Queen Elizabeth Central Hospital

World Health Organization

Interquartile range

Confidence interval

Magnetic resonance imaging

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Acknowledgements

The authors wish to acknowledge all the nurses and clinicians involved over the span of this study, responsible for the excellent nursing care that takes place on the Paediatric Research Ward. The clinical detailed histories, often taken by clinical officers, have been crucial to this analysis. In addition, we would like to acknowledge the parents and guardians that have put their faith in our staff to care for their children. We thank the Malawi Fund at Michigan State University for financial contributions to the publication costs.

This work was supported by the National Institutes of Health (RO1AI34969 to TET).

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Arabella Borgstein

Present address: St. George’s University of London/University of Nicosia Medical School, Nicosia, Cyprus

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Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi

Arabella Borgstein, Montfort Bernard Gushu, Alice Wangui Liomba, Albert Malenga, Paul Pensulo, Andrew Tebulo, Terrie Taylor & Karl Seydel

Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, USA

Bo Zhang & Dylan S. Small

Bronx High School of Science, Bronx, NY, USA

Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA

Terrie Taylor & Karl Seydel

Malawi-Liverpool-Wellcome Trust Research Programme, Kamuzu University of Health Sciences, Blantyre, Malawi

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AB: Study design, data collection, data analysis, writing of the manuscript. BZ: Data analysis. CL: Data analysis. MBG, AL, AM, PP, AT: Patient enrolment and characterization. TT: Study conceptualization, patient enrolment and characterization, data review, editing the manuscript. DS: Study design, data analysis. KS: Study design, patient enrolment and characterization, data analysis, writing and editing of the manuscript. All authors read and approved the final manuscript.

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Additional file 1: table s1..

Analysis with multiply imputed datasets: results of the pooled Brant test.

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Borgstein, A., Zhang, B., Lam, C. et al. Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi. Malar J 21 , 60 (2022). https://doi.org/10.1186/s12936-022-04080-2

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Received : 10 October 2021

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DOI : https://doi.org/10.1186/s12936-022-04080-2

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