Cerebral malaria: ED presentation, evaluation, and management

Authors: Jessica Pelletier, DO (EM Education Fellow, Washington University in St. Louis, USA); Emmanuel Effa, MD (University of Calabar Teaching Hospital, Calabar, Nigeria); Akan Otu, MD (University of Calabar Teaching Hospital, Calabar, Nigeria); John George Johnson, MS-6 (Edward Francis Small Teaching Hospital, Banjul, the Gambia) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

The Case

A 5-year-old female presents to the ED after a first-time seizure. On arrival to the ED the patient is unresponsive to voice and painful stimuli but is still protecting her airway. Vital signs are notable for a heart rate (HR) 140 bpm, blood pressure (BP) 70/40 mmHg, respiratory rate (RR) 35 breaths/minute, temperature 39° C, and O2 saturation 96% on room air. On examination, she is noted to have dry mucous membranes, prolonged capillary refill, and skin tenting. She is tachycardic with a regular rhythm and no murmurs, rubs, or gallops, and lungs are clear to auscultation. Her abdomen is soft and nontender to palpation. On neurologic examination, the patient’s pupils are equally round and reactive, and she is normoreflexic. There are no obvious meningeal signs. Her Blantyre Coma Scale (BCS) score is 0. A glucose check at the bedside is within normal limits. 

While an intravenous (IV) line is placed to begin fluid resuscitation, collateral history is obtained from the patient’s mother. The patient has been febrile intermittently for the past 2 weeks and has complained of body aches. She has had no rhinorrhea, cough, vomiting, or diarrhea, but has been incredibly sleepy, with decreased oral intake. Tonight her mother noted her having a 4-minute generalized, tonic-clonic seizure and brought her to a local clinic for evaluation, where she was sent on to the regional referral hospital. The patient has no past medical or surgical history, does not take any medications, and there is no family history of seizure disorders. She lives in a rural area of Uganda and is not up-to-date on childhood vaccinations. Her family does not have running water or mosquito nets in the home.

The patient’s BP improves to 85/65 mmHg after IV fluid resuscitation with two 20 cc/kg boluses of crystalloid. Her fever breaks with rectally-administered paracetamol. 1 hour goes by, and the patient’s mental status is unchanged. 

What is the differential for the patient at this point?

A typical post-ictal state lasts seconds to minutes, after which time the patient should resume some degree of consciousness. This may be associated with hours of memory impairments, confusion, and sometimes Todd’s paralysis, followed by up to days or weeks of psychiatric symptoms.¹ Given that this patient is experiencing prolonged unconsciousness, there is concern that she is in a coma.² In adults, the Glasgow Coma Scale (GCS) can be used to quantify the level of consciousness. Methods for assessing the level of consciousness in children include the pediatric GCS, AVPU (Alert; Verbal response; response to Pain; Unresponsive),³ and the BCS.⁴ 

The differential at this point includes severe malaria (including cerebral malaria),^5-7 non-convulsive status epilepticus (NCSE)⁸ versus coma, possibly secondary to an infectious process such as meningitis or encephalitis (given the presentation with a fever). Toxic or metabolic encephalopathy could also contribute to altered mentation. Hypoglycemia has been ruled out at this point.

Back to the Case

Multiple doses of diazepam are administered given the concern for NCSE with no improvement in her level of consciousness. The patient develops bradypnea and hypoxia and is subsequently intubated and sedated. Diagnostic results are notable for a white blood cell (WBC) count of 3000 cells/μL, hemoglobin of 4 g/dL with a hematocrit of 12%, platelet count of 100,000/μL, lactate dehydrogenase of 500 U/L, total bilirubin of 4.6 mg/dL, a low haptoglobin of 20 mg/dL, an elevated anion gap metabolic acidosis with a bicarbonate level of 12 mEq/L, and lactate of 4 mmol/L. Computed tomography (CT) scan demonstrates no mass lesions or intracranial hemorrhage (ICH). Magnetic resonance imaging (MRI) is unavailable. Lumbar puncture (LP) demonstrates a cerebrospinal fluid (CSF) WBC of 0 cells/μl, glucose 2.9 mmol/l, protein 0.5 g/L, as well as a negative gram stain. Rapid malaria antigen testing is positive, and a peripheral blood smear notes Plasmodium falciparum malarial rings, with a 12% parasite load.

The patient is ultimately diagnosed with cerebral malaria and started on IV artesunate.

Note: This case was developed with inspiration from case reports^9-10 with laboratory results based on aggregate research data¹¹ and does NOT represent a true patient case.

Definition

Cerebral malaria is a condition on the spectrum of severe malaria that is typically caused by P. falciparum, with rare cases caused by P. vivax or P. knowlesi.¹² Severe malaria is defined as parasitemia in combination with ≥1 of the clinical features in Table 1.¹³ Cerebral malaria is defined as parasitemia in combination with unarousable coma.^12-13

Table 1. Severe falciparum malaria. Adapted from: World Health Organization (WHO). WHO Guidelines for Malaria.; 2023. Accessed June 11, 2023. https://www.who.int/publications/i/item/guidelines-for-malaria

BCS = Blantyre coma score, RR = respiratory rate, GCS = Glasgow Coma Score, SBP = systolic blood pressure

Epidemiology

As of 2022, there were 249 million cases of malaria around the globe, with 608,000 deaths.¹⁴ 93% of malaria cases and 94% of malaria deaths occur in Africa, and 67% of malaria deaths occur in children under age 5 years. Notably, 25% of all malaria cases occur in Nigeria, constituting the largest single-country burden. P. falciparum causes 99.7% of malaria cases in African countries. It should be noted that malaria infection during pregnancy is associated with low birth weight and adverse outcomes for the mother and fetus, including death.¹⁵

Pathophysiology

Five species of malaria parasite are capable of infecting humans, and they are transmitted via the Anopheles mosquito. Sporozoites enter the bloodstream and migrate to the liver and lymphatic system; after hepatocyte infiltration, the parasite replicates in the form of merozoites, which then re-enter the bloodstream to infect red blood cells (RBCs). Hemoglobin consumption by merozoites within RBCs leads to the development of gametocytes or trophozoites; the latter form schizonts which can rupture RBCs, leading to hemolytic anemia. Merozoite transmission in the bloodstream during this lifecycle is responsible for cyclical fevers seen in malaria infection.¹⁶

Cerebral malaria is thought to occur secondary to cerebral vascular occlusion and inflammation. RBCs infected with P. falciparum clog small blood vessels due to adherence to the endothelium. Non-infected RBCs and platelets can also form clumps and rosettes with infected RBCs, creating microvascular clots. From an inflammation perspective, autopsies reveal increased concentrations of pro-inflammatory cytokines in the brains of cerebral malaria patients. These changes subsequently lead to compromised integrity of the blood-brain barrier (BBB) which can lead to leaking of metabolites that are typically restricted from entering the brain tissue, with the subsequent development of cerebral edema. MRI studies have shown that cerebral edema is transient in cerebral malaria survivors, and persistent cerebral edema is associated with death.¹⁷ Children are more likely than adults to suffer from brain herniation, leading to respiratory and cardiac arrest.¹⁸

Clinical Presentation

Cerebral malaria patients typically present with encephalopathy or coma; however, they may also exhibit focal neurologic deficits,¹⁸ including ataxia, abnormal pupil or corneal reflexes, dysconjugate gaze, or decerebrate posturing. Patients may exhibit psychiatric symptoms, including paranoia, mania, and psychosis. This is usually preceded by headache and fever (often >40°C). A few aspects of the presentation differ between age groups – pediatric patients more often present with seizures than adults, and the coma comes on more gradually in adult patients.¹⁸ Patients with cerebral malaria should not have meningeal signs, such as neck stiffness, photophobia, and positive Kernig’s or Brudzinski’s signs; the presence of these signs should suggest an alternative diagnosis such as subarachnoid hemorrhage or meningitis.¹²

If tools for ophthalmologic examination are available, patients with cerebral malaria may be noted to have retinopathy. Retinopathy – consisting of retinal hemorrhages, vessel changes, and retinal whitening – has been shown to highly correlate with the presence of cerebral malaria in children.¹⁸

When taking a history from patients with suspected cerebral malaria, the clinician should inquire about the patient’s location of residence to determine whether they reside in a malaria-endemic region. A travel history to endemic areas and use of chemoprophylaxis should be elicited. For female patients of childbearing age, pregnancy status should be determined since pregnant women are at high risk for severe outcomes.¹⁶ Clinicians must identify whether patients have G6PD deficiency since treatment with antimalarials can lead to severe hemolysis in this population.¹⁹ Finally, the presence or absence of sickle cell disease should be elicited since the presence of sickle cell anemia places malaria patients at a higher mortality risk.²⁰

Diagnostic Testing

The gold standard diagnostic test for confirmation of the diagnosis of malaria is microscopic blood smear examination, both thin and thick. This usually requires Giemsa/Wright-Giemsa staining and laboratory staff must be trained in how to do the procedure. However, one major advantage is that it allows for differentiation between species of malaria.^21-22 In addition, blood smears can be falsely negative. In order to definitively rule out malaria, a patient with suspected infection must have three negative blood smears, each separated by 12-24 hours.²¹ 

Rapid diagnostic tests (RDTs) are much easier to perform, less expensive, and require less staff training than blood smears. They involve the application of blood to a sample card followed by the addition of a reagent, similar to the RDTs used at home to test for COVID-19. Unfortunately, microscopic confirmation of the malaria diagnosis is still needed in the setting of a positive RDT, since an RDT cannot differentiate which species of malaria is causing the infection or the parasitemia burden (which is a prognostic indicator).²¹

Finally, molecular detection methods such as polymerase chain reaction (PCR) are available and have the advantage of distinguishing the malarial parasite species. These methods are more sensitive than blood smears but can be prohibitively expensive, require advanced diagnostic equipment, and staff must be trained in their use.²¹

Malaria infection causes hemolytic anemia, and mortality increases significantly with a hemoglobin of less than 3 g/dL.²³ WBC results are typically normal or low in patients with malaria infection.²⁴ Thrombocytopenia is commonly seen.²⁵ Severe malaria infection may be characterized by multiorgan failure, with laboratory derangements specific to the organs involved.¹²

CT head should be obtained (if available) to rule out space-occupying lesions (such as brain abscess or intracranial hemorrhage) or signs of elevated intracranial pressure (ICP) (such as ventriculomegaly) that would preclude LP. Performing an LP in the presence of raised ICP can lead to brain herniation.²⁶ CT head may or may not demonstrate cerebral edema in patients with cerebral malaria.²⁷ MRI can be useful (if available) to help distinguish cerebral malaria from mimicking conditions, such as viral encephalitis. Findings on MRI in patients with cerebral malaria may include increased brain volume, cortical and subcortical swelling, white matter changes, microhemorrhages, and abnormal T2 and diffusion-weighted imaging (DWI) signals, among others.²⁸

Once a space-occupying lesion or obvious signs of elevated intracranial pressure (ICP) have been excluded via CT head imaging, an LP is necessary to exclude meningitis or encephalitis, which would require significantly different medication therapy as compared with cerebral malaria. When compared with viral encephalitis patients, cerebral malaria patients have been shown to have lower CSF WBC counts, glucose, and protein levels.¹¹ Gram stain and culture should be obtained to exclude bacterial meningitis. 

If available, continuous electroencephalogram (EEG) may be considered to help exclude NCSE, as this condition can mimic the comatose state associated with cerebral malaria. In addition, cerebral malaria can cause seizures – including NCSE – and these must be treated appropriately with antiepileptics if present in order to prevent further neurologic damage.²⁹ NCSE-induced seizures often start focal and subsequently generalize, which may be identified on EEG.¹⁸

Treatment

Basic resuscitation takes priority in treating patients with cerebral malaria. Given that these patients present with coma, they are at high risk for airway compromise. Intubation should be considered early in patients who are unable to protect their airway. From a breathing perspective, severe malaria can cause pulmonary edema, and this should be managed with oxygen therapy and non-invasive ventilatory support as needed (or invasive ventilation if severe). From a cardiac perspective, patients with severe malaria may present with shock from sepsis or hypovolemia and should receive appropriate IVF resuscitation. From a disability perspective, patients should be treated aggressively for seizures and should be placed on their side if not intubated to avoid aspiration. Fever should be aggressively managed to prevent hyperthermia.¹² These recommendations are outlined in Table 2.

Table 2. Supportive care for severe malaria patients in addition to anti-malarial therapy.^12,30 Adapted from: World Health Organization (WHO). WHO Guidelines for Malaria.; 2023. Accessed June 11, 2023. https://www.who.int/publications/i/item/guidelines-for-malaria

AED = antiepileptic drug, FFP = fresh frozen plasma, IV = intravenous, IVF = intravenous fluid, NG = nasogastric, NIPPV = non-invasive positive pressure ventilation, ORS = oral rehydration solution, PRBC = packed red blood cells

Patients in shock should be treated with broad-spectrum antibiotics in addition to antimalarials, and antibiotics should only be withdrawn if repeat RDT testing for malaria at 12-24 hours remains positive and other causes of illness have been ruled out.³⁰ The first-line medication therapy for all patients with cerebral malaria is IV artesunate for a minimum of 24 hours, followed by a transition to oral artemisinin-based combination therapy (ACT) once the patient can tolerate per os (P.O.) intake. First-line and second-line medication regimens are outlined in Table 3.

Table 3. Medication therapy for cerebral malaria.^12,31

IM = intramuscular, IV = intravenous, PO = per os (oral). *Can also be given rectally in children < 6 years. **Should only be administered into the thigh.³⁰

Patients with cerebral malaria or for whom cerebral malaria is on the differential should be referred to a facility where IV artemisinin is available and where personnel are trained in its administration. If this is not possible, artemisinin or artemether may be given intramuscularly (IM), and artemisinin may be given rectally in children less than 6 years of age.¹²

Therapy to reduce intracranial pressure (i.e. mannitol) has not been shown to be helpful, and dexamethasone has been shown to worsen patient outcomes in cerebral malaria (increasing recovery time and increasing the risk of gastrointestinal bleeding and seizures).¹² Prophylactic AEDs are not indicated;²² however, if EEG is unavailable and NCSE cannot be ruled out, they should be considered.

Prognosis

Cerebral malaria has a very poor prognosis, with a mortality rate of 100% if untreated and up to 25% even in appropriately treated patients.¹⁷ Hypoglycemia and acidosis are key indicators of higher mortality.³² Neurologic sequelae of cerebral malaria infection may include epilepsy, hemi- or quadriplegia, ataxia, language disorders, cognitive impairment, depression, personality disorders, dementia, and cortical blindness.¹⁸ 6-29% of cerebral malaria patients will have neurologic deficits after recovery, and children are at higher risk for this than adults.¹⁸

Special Notes

Rarely, patients who suffered from malaria infection – cerebral malaria or otherwise – may develop post-malaria neurological syndrome (PMNS), which has an incidence of 0.7 to 1.8 per 1000 and is 300 times more common in severe malaria patients.³³ PMNS is characterized by many of the same symptoms as cerebral malaria, including seizures, ataxia, confusion, and psychosis, but develops after disease resolution and after a period in which they have no symptoms. The asymptomatic period is usually 15 days. PMNS can be distinguished from cerebral malaria by the presence of a negative blood smear.¹⁸

Case Wrap-Up

The patient is treated with IV artemisinin and gradually regains consciousness. She is subsequently extubated. After a prolonged hospital stay, the patient is ultimately discharged with minimal neurologic sequelae. 

Pearls and Pitfalls

• Cerebral malaria is a severe, life-threatening form of malaria that often presents with coma, altered mentation, or psychiatric symptoms
• This condition should be on the differential for patients who live in or who have traveled to a malaria-endemic region
• Diagnosis is typically made via blood smear and RDT and exclusion of other causes for clinical presentation
• First-line therapy is IV artemisinin; if unavailable, there are alternatives
• Supportive care should be provided for complications such as seizures, shock, and any associated severe anemia
• This condition is fatal if untreated, and even treated patients may have high morbidity

Further Reading:

• https://www.emdocs.net/em3am-malaria/
• https://www.emdocs.net/em-cases-fever-in-the-returning-traveler/ 

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