Clinical manifestations

Presentation and course

Incubation periods vary with malarial species ranging from 8 to 40 days, the shortest period being for Plasmodium falciparum (8 to 15 days). The clinical manifestations of malaria depend on the infecting parasite and the immune status of the host. Children account for around 15% to 20% of all malaria cases and need to be considered separately from adults because they have different risk factors for developing malaria. Children also have a higher risk of developing severe disease because they are more likely to be nonimmune to malaria.

Uncomplicated malaria. All symptoms and signs of uncomplicated malaria are nonspecific and similar with other febrile conditions. Fever, headache, fatigue, malaise, and musculoskeletal pain constitute the most frequent clinical features in malaria. In endemic areas, hepatosplenomegaly, thrombocytopenia, and anemia are frequently associated with malaria, particularly in children (37).

Severe and complicated malaria. Severe and complicated malaria is caused by Plasmodium falciparum. It is characterized by a set of clinical and laboratory parameters, which in patients with malaria are associated with an increased risk of death (Table 1) (99; 100).

Table 1. Features of Severe Malaria*

Cerebral malaria. Cerebral malaria is the most severe neurologic complication of Plasmodium falciparum malaria. Cerebral malaria is characterized by unarousable coma (Blantyre coma scale lower than 3; Glasgow coma scale lower than 11). To fulfill the strict diagnostic criteria of cerebral malaria, the patient must remain comatose for more than six hours after seizure to distinguish the coma from postictal altered sensorium. Loss of consciousness can develop very rapidly; most of the patients are in deep coma by the time they reach the hospital or immediately after hospitalization. Glasgow coma scale in adults and Blantyre scale (Table 2) in children are useful in categorizing the level of unconsciousness.

Seizures are more common in pediatric patients with cerebral malaria than in adults. In Malawi, for example, 82% of childhood cases had a history of convulsions, and almost one fourth of these had seizures within 3 hours of admission. Generalized tonic-clonic seizures occur in more than 40% of adult patients. Partial seizures are uncommon. About one third of acute seizures in children with cerebral malaria do not manifest as convulsions but as changes such as eye deviation or salivation (24).

Table 2. Blantyre Coma Scale

Cerebral malaria is also known as “symmetric encephalopathy” because of the presence of symmetrical upper motor neuron signs. Localizing signs are observed infrequently, but in severe cases there may be generalized hypertonia, opisthotonos, posturing, and bruxism. Tendon reflexes are usually brisk with patellar and ankle clonus along with extensor plantar responses. Abdominal reflexes are usually absent (67; 68; 33; 99; 47; 57).

Abnormal motor posturing is a common feature of cerebral malaria in children. It is associated with features of raised intracranial pressure and recurrence of seizures, although intracranial hypertension may be the primary cause (47). Extensor posturing suggesting brainstem dysfunction, either due to cerebral malaria or profound hypoglycemia, is a common and important sign. In advanced stages, decerebrate and decorticate rigidity are frequently present and often associated with sustained upward deviation of eyes, extension of neck, pouting of lips, and periodic stertorous breathing pattern. The cause of death is not apparent most of the time. Progressive deterioration of brainstem function may lead to cardiac and respiratory arrest (57).

Malarial retinopathy. Malarial retinopathy consists of a set of retinal abnormalities that are unique to severe malaria and common in children with cerebral malaria. The presence of malarial retinopathy can be used to differentiate children whose comas are caused by Plasmodium falciparum from those with other causes for altered mental status. Its presence and severity are related to risk of death and length of coma in survivors. A large autopsy study of Malawian children who died of cerebral malaria suggested that the presence of malarial retinopathy was higher than any other clinical or laboratory feature in distinguishing malarial from nonmalarial coma. It was also noted that two components of malarial retinopathy are unique to severe malaria: white-centered retinal hemorrhages and vascular changes in the form of retinal vessel whitening. Color of retinal vessels changes from red to orange and subsequently to white. Areas of retinal whitening in the form of patchy opacification are found between vessels. In fact, these patchy areas are areas of capillary nonperfusion. White-centered hemorrhages can be detected with a direct ophthalmoscope through dilated pupils. A large increase in retinal hemorrhages was associated with death (08). Retinal hemorrhages, in cerebral malaria, usually occur in the inner and middle layers of the retina. Retinal hemorrhages may also be of large size and involve all retinal layers and can be associated with subretinal hemorrhage and retinal detachment. Histopathologically, retinal hemorrhages in cerebral malaria are similar to ring hemorrhages seen in the brain parenchyma (98). The malarial retinopathy is thought to represent microvascular obstruction of retinal vessels, as can be demonstrated in affected retinas by fluorescein angiography (07; 59). Children with retinopathy-negative cerebral malaria share a common clinical phenotype with lower rates of mortality compared with those who have malarial retinopathy (77).

Hypoglycemia. Hypoglycemia is a common feature in severe malaria. It is often overlooked because all clinical features of hypoglycemia (anxiety, dyspnea, tachycardia, sweating, coma, abnormal posturing, and generalized seizures) are also typical of severe malaria itself. If left untreated, this clinical picture may evolve into deteriorating consciousness, generalized convulsions, extensor posturing, shock, and coma. In some patients, deterioration in the level of consciousness may be the only sign. Hypoglycemia especially occurs in three different sets of patients with severe disease: young children; patients treated with quinine or quinidine, resulting in quinine-induced hyperinsulinemia; and pregnant women, either on admission or following quinine treatment. All high-risk-group patients should regularly be tested for blood sugar levels (67; 68; 33; 99; 47).

Postmalaria neurologic syndrome. Postmalaria neurologic syndrome is a self-limiting postinfective encephalopathy that occurs after recovery from Plasmodium falciparum malaria. Neuropsychiatric manifestations of postmalaria neurologic syndrome are wide ranging, including an acute confusional state or acute psychosis, cerebellar ataxia, generalized convulsions, motor aphasia, or fine tremor. Criteria for inclusion under this syndrome are: recent symptomatic malarial infection with parasites cleared from blood, full recovery of consciousness in cases of cerebral malaria, and the development of new neurologic or psychiatric symptoms within two months of acute illness. Nguyen and associates, in a series of 18,124 treated patients of falciparum malaria (1176 of whom had severe infection), reported 19 adults and three children with subsequent postmalaria neurologic syndrome. One patient followed with uncomplicated malaria, and 21 patients followed with severe malaria. Thirteen patients had an acute confusional state or psychosis, six had one or more generalized seizures, two had generalized convulsions followed by a long period of acute confusion, and one patient developed fine tremors (70). The syndrome was self-limiting, and in a few cases, it was associated with the use of oral mefloquine (39). A self-limiting cerebellar ataxia of delayed onset up to several weeks after an acute episode of falciparum or vivax infection has also been described (03; 84; 89).

Castaldo and coworkers reviewed 151 published cases of postmalaria neurologic syndrome and noted that the majority of them occurred following severe plasmodium falciparum infection (17). They identified four distinct patterns of postmalaria neurologic syndrome. In 37% of cases, a classical postmalaria neurologic syndrome presented with self-limiting encephalopathy. The next most common presentation was delayed cerebellar ataxia, seen in 36% of cases. Acute inflammatory demyelinating polyneuropathy (18%) and acute disseminated encephalomyelitis (8%) were other manifestations of postmalaria neurologic syndrome (17).

Prognosis and complications

Most survivors with cerebral malaria regain consciousness within 2 to 3 days, although it may occasionally take more than a week. Mortality in untreated severe falciparum malaria is almost 100%. Most deaths from severe malaria occur within a few hours of hospitalization. Early treatment with parenteral antimalarial drugs can reduce number of deaths by 15% to 20% (100). In African children, most deaths occur with brainstem signs after a respiratory arrest, suggesting transtentorial herniation or cardiorespiratory arrest in association with severe metabolic acidosis. Adults often die with renal failure or pulmonary edema. Mortality is particularly high in pregnant patients (47).

Age is an independent risk factor for a fatal outcome of malaria. In a study of 1050 patients with severe malaria, the mortality was observed to increase in a stepwise pattern. Mortality was 6.1% in children (age, younger than 10 years) in comparison to 36.5% in patients aged older than 50 years. Compared with adults aged 21 to 50 years, the decreased risk of death among children and the increased risk of death among patients aged older than 50 years was independent of the variation in presenting manifestations. Even presenting manifestations in severe malaria depend on age. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. However, the incidences of coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome (30). In a study, acidosis, cerebral involvement, renal impairment, and chronic illness were independent predictors for a poor outcome in African children with severe malaria. Mortality was markedly increased in cerebral malaria combined with acidosis (94).

Prognosis in Plasmodium falciparum can be predicted from impaired consciousness, repeated convulsions, respiratory distress, substantial bleeding, and shock. Parasitemia of more than 500,000 parasites/mm³ as well as more than 5% of neutrophils that contain malaria pigment adversely affect the prognosis (96). High cerebrospinal fluid and venous lactate levels (more than 45 mg/dL), low cerebrospinal fluid sugar, hypoglycemia (blood sugar less than 40 mg/dL), involvement of liver (serum bilirubin > 2.5 mg/dL, elevated aminotransferase levels > three times normal) and kidney (serum creatinine > 3 mg/dL), and acidosis (pH less than 7.25, plasma bicarbonate less than 15 mmol/L) also influence mortality (03; 96). Papilledema and retinal edema outside the posterior vascular arcades are also associated with poor outcome in cerebral malaria (56).

Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria. Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits compared with 5.8% of community children. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits (12). Children who suffer retinopathy-positive cerebral malaria at preschool age are at greater risk of developmental delay, particularly with respect to language development (13). Risk factors for persisting neurologic and cognitive impairments following cerebral malaria include multiple seizures, deep or prolonged coma, hypoglycemia, and clinical features of intracranial hypertension. Although impaired functions and risk factors overlap, the differences in risk factors for specific functions may suggest separate mechanisms for neuronal damage (46). In one study, 132 children with retinopathy-positive cerebral malaria and 264 age-matched, non-comatose controls were followed up for a median of 495 days; 12 of 132 cerebral malaria survivors developed epilepsy versus none of 264 controls (11). Twenty-eight patients of 121 cerebral malaria survivors developed new neurologic disabilities, characterized by gross motor, sensory, or language deficits, compared with two of 253 controls. Risk factors for epilepsy in children with cerebral malaria included a higher maximum temperature and acute seizures. Male sex was a risk factor for new neurologic disabilities. Sequelae such as hemiplegia or monoplegia, cortical blindness, and behavioral disturbances are common in children who have suffered prolonged deep coma, repeated convulsions, brainstem dysfunctions, and hypoglycemia (93).

Cerebral malaria is considered a potential cause of epilepsy in tropical areas (69). It is important to terminate convulsions lasting more than five minutes because seizures are associated with prolonged coma and increased risk of neurologic sequelae and death. Prolonged convulsions are also associated with neurologic deficits in children who survive severe malaria (72). An increased prevalence of epilepsy was seen in children previously admitted with cerebral malaria compared with the unexposed group (15). A group of authors evaluated the changes in the incidence of seizures with the reduction of malaria in an endemic area (49). The overall incidence of acute symptomatic seizures over the period was 651/100,000 per year, and it was 400/100,000 per year for acute complex symptomatic seizures (convulsive status epilepticus, repetitive or focal) and 163/100,000 per year for febrile seizures. From 2002 to 2008, the incidence of all acute symptomatic seizures decreased by 809/100,000 per year (69.2%), with 93.1% of this decrease in malaria-associated seizures. It was concluded that in endemic areas, falciparum malaria is the most common cause of seizures and the risk for seizures in malaria decreases with age. The reduction in malaria has decreased the burden of seizures that are attributable to malaria.

In a prospective study of 149 children in Kampala, Uganda, aged between 6 months and 12 years who survived cerebral malaria, Clark and colleagues investigated the association of clinical factors, including the depth of coma, number of clinical seizures, and EEG features during hospitalization with mortality and long-term neurocognitive outcomes (21). The study found that higher Blantyre or Glasgow coma scores (BCS and GCS), increased background voltage on EEG, and the presence of normal reactivity on EEG were linked with decreased mortality. A notable observation was that children who experienced more than four seizures upon admission had a greater likelihood of long term neurologic deficits. Furthermore, both the number of seizures and certain EEG characteristics were independently associated with better cognitive outcomes. Particularly in children under five years of age, the number of seizures and the presence of vertex sharp waves were linked to better cognitive performance after hospitalization. Additionally, a faster dominant EEG frequency correlated with improved attention, whereas higher average background voltage and a faster dominant background frequency were tied to better associative memory (21).

Patients surviving retinopathy-positive cerebral malaria are at high risk for the development of epilepsy, developmental disabilities, and behavioral abnormalities. Even children with retinopathy-negative cerebral malaria are at high risk for long-term neurologic outcomes. In retinopathy-negative cerebral malaria survivors, a Blantyre Coma Scale score of 1 or lower on admission was associated with an adverse outcome (78).

Biological basis

Etiology and pathogenesis

Malaria is caused by protozoa of the genus Plasmodium. It is transmitted by female Anopheles mosquitoes.

Four species of malaria parasite cause clinical disease in humans. Plasmodium falciparum is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax. A few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. In addition to a mosquito bite, malaria transmission may occur by blood transfusion, from contaminated needles, and from the placenta. A series of 11 patients showed that Plasmodium vivax could cause both sequestration-related and nonsequestration-related complications of severe malaria infections (50).

The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been suggested (01; 51).

Life cycle

Liver stage. When an infective Anopheles mosquito bites a human host, sporozoites are injected and carried via blood circulation to the liver, where extra-erythrocytic schizonts and latent hypnozoites develop. In about 1 to 2 weeks, these schizonts rupture and release many thousands of mononucleated merozoites. This replicative stage is often called exoerythrocytic schizogony.

Blood stage. Merozoites released from the infected liver cells invade erythrocytes. The young trophozoite is often called a ring form due to its morphology in Giemsa-stained blood smears. As the parasite increases in size this “ring” morphology disappears, and it is called a trophozoite. Nuclear division marks the end of the trophozoite stage and the beginning of the schizont stage. Later, the host erythrocyte containing multinucleated schizont ruptures and releases the merozoites. These merozoites invade new erythrocytes and initiate another round of schizogony. Each merozoite enters a new erythrocyte (but not the liver cell) and starts the next erythrocytic cycle. This stage is often called erythrocytic schizogony.

Sexual stage. Some merozoites differentiate into gametocytes, the sexual forms, which are ingested by female Anopheles mosquitoes. Sexual development in the mosquito results in midgut oocysts that mature to form infectious sporozoites in the salivary glands of mosquitoes. The oocysts undergo an asexual replication, called sporogony, which culminates in the production of several thousand sporozoites. Some of these sporozoites will be expelled into the human as the mosquito takes a blood meal.

Why does only Plasmodium falciparum cause cerebral malaria? A failure to control blood Plasmodium falciparum parasitemia and subsequent sequestration of parasites to brain microvasculature are thought to be key events in cerebral malaria pathogenesis. Three benign malarial parasites, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, show a predilection for either older red blood cells or for reticulocytes and produce a parasitemia that rarely exceed 2% of total red blood cells. In contrast, Plasmodium falciparum parasitizes red blood cells of patients of all ages. Secondly, in the life cycle of Plasmodium falciparum a large number of merozoites are produced. Thus, there may be a very high level of parasitemia in falciparum malaria. In Plasmodium falciparum infection, only ring forms are present in the peripheral blood; other stages of the life cycle remain sequestered in the internal organs of body and escape host defense mechanisms. So, severe and complicated malaria is produced by Plasmodium falciparum infection (33; 68; 99).

Pathogenic mechanisms causing cerebral malaria. The pathophysiology of cerebral malaria is not completely understood but likely involves multiple factors and complex interactions between the host and parasite. The cytoadhesion of Plasmodium falciparum-infected erythrocytes to the endothelial cells lining the microvasculature, which clogs the microvessels of various organs, is now thought to be a key event in the pathogenesis of severe forms of malaria including cerebral malaria. Sequestration is the process by which erythrocytes infected with the mature forms of the malaria parasite Plasmodium falciparum disappear from circulation and accumulate within venules and capillaries of various organs and tissues. Parasite-induced sequestration of infected and uninfected erythrocytes is mediated through cytoadherence, rosette formation, autoagglutination, and reduced red cell deformability (47). The phenomenon of Plasmodium falciparum-infected red blood cells binding uninfected red blood cells is known as “rosetting.”

Cytoadherence appears to be mediated by the electron-dense protuberances on the surface of the infected erythrocyte. These “knobs” are expressed during the trophozoite and schizont stages and are formed as a result of parasite proteins exported to the erythrocyte membrane. Among human Plasmodium species, knobs are restricted to Plasmodium falciparum, and there is also a good correlation between animal Plasmodium species that express knobs and exhibit sequestration. Electron microscopy also shows that the knobs are contact points between the infected erythrocyte and the endothelial cell (86).

A major variant surface antigen, Plasmodium falciparum erythrocyte membrane protein-1, expressed on the surface of the infected erythrocyte, mediates cytoadherence to several endothelial receptors. Cytoadherence is mediated in part by electron-dense knobs containing the adhesion Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1), which protrudes from the surface of parasitized red blood cells. PfEMP-1 proteins are coded for by variable “var” genes and vary antigenically over time, allowing parasites to evade the host immune response. The proteins appear to bind specifically to vascular receptors including CD36 (71), which is expressed at all times, and intracellular adhesion molecule-1 (ICAM-1) and endothelial selectin (E selectin), which have increased expression in the cerebral vessels of patients with cerebral malaria (09; 92).

Cerebral malaria is characterized not only by the cytoadherence of Plasmodium falciparum-infected erythrocytes, but also by morphological and functional alterations of brain microvascular endothelial cells subsequent to their interactions with circulating cells, such as platelets, monocytes, lymphocytes, and dendritic cells. During cerebral malaria, host cells, in particular immune cells, are found recruited and activated at the site of sequestration, where they release various soluble molecules. Among these, cytokines play a major role in cerebral malaria pathogenesis. Cytokines (notably interferon-gamma, tumor necrosis factor, and lymphotoxin) and chemokine receptors are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in cerebral malaria (23).

One of the earliest events in cerebral malaria pathogenesis appears to be a mild increase in the permeability of the blood-brain barrier to protein. Diffuse breakdown of the blood-brain barrier is considered because of a reduction in the paracellular brain microvascular endothelial cells junction proteins (91). Studies have also shown a role for CD8+T cells in mediating damage to the microvascular endothelium, and this damage can result in the leakage of cytokines, malaria antigens, and other potentially harmful substances across the blood-brain barrier into the cerebral parenchyma. It has been suggested that this, in turn, leads to the activation of microglia and the activation and apoptosis of astrocytes. The role of hypoxia in the pathogenesis of cerebral malaria has also been suggested. There may be local reduction of oxygen consumption in the brain as a consequence of vascular obstruction, cytokine-driven changes in glucose metabolism, and cytopathic hypoxia (44).

Nitric oxide and cytokines released during the immune activation process may also contribute to disease severity and accelerate cytoadherence (26). However, nitric oxide was also shown to have a protective rather than pathological role in African children with malaria, as evident by inverse correlation between nitric oxide synthesis and disease severity (05). In a study, a new NOS2 promoter polymorphism was associated with increased nitric oxide production and protection from cerebral malaria and severe malarial anemia in Tanzanian and Kenyan children (42). Complement activation, although profoundly increased in complicated malaria, was not related to disease severity (95). Autoimmune mechanisms may play a role in postmalarial cerebellar syndrome, as raised cytokine levels have been demonstrated in serum and cerebrospinal fluid of such cases (28).

A disseminated vasospasm theory has been suggested for the pathogenesis of cerebral malaria. A diffuse vasospasm is triggered by inflammatory mediators produced locally in the vascular bed, in response to the sequestered infected red blood cells. Vascular obstruction by clumps of infected blood cells, platelets, and uninfected red blood cells tightly adhering to endothelium is less likely to be rapidly reversible without leaving irreversible neurologic damage, which occurs in a minority of patients with cerebral malaria (31; 35).

Metabolic factors. One study provides evidence that axonal injury is associated with malaria coma and suggests a potential role of severe anemia, acidosis, and hyperparasitemia in the pathogenesis of pediatric cerebral malaria. In this study two neuronal markers were analyzed; the microtubule-associated protein tau for degenerated axons and S-100B for astrocytes. The level of tau proteins in the CSF was significantly elevated in children with cerebral malaria compared with either malaria with prostration or malaria with seizures but normal consciousness. Elevated tau was also found to be associated with impaired delivery of oxygen (severe anemia), severe metabolic acidosis manifesting as respiratory distress (increased respiratory rate and deep acidotic breathing), and higher parasite densities. Elevated S-100B in children was associated with an increased risk of repeated seizures (60).

Pathology. On autopsy, brain specimens usually show engorgement of cerebral capillaries and venules with parasitized red blood cells, which frequently contain mature schizonts. Numerous petechial ring hemorrhages result from rupture of endarterioles proximal to the occlusive plug of parasitized red blood cells. There is frequently perivascular demyelination and destruction of neurons. Reactive astroglial foci (granuloma of Durck) may occasionally be observed in advanced cases (75). Taylor and associates conducted autopsies in 31 children with clinical diagnoses of cerebral malaria. They found that 23% of the children had actually died from other causes. These patients had postmortem evidence of an alternative cause for coma, including Reye syndrome, hepatic necrosis, and ruptured arteriovenous malformation. The remaining patients had parasites sequestered in cerebral capillaries, and 75% of those had additional intra- and perivascular pathology. Retinopathy was the only clinical sign distinguishing malarial from nonmalarial coma (88). Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria suggested that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria than in patients with noncerebral malaria (76). Sequestration of parasitized red blood cells and cerebral malaria was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death.

Marked brain swelling resulting in severely increased brain volume has been found a major risk factor for mortality. A study was conducted in 168 children with cerebral malaria (85). Increased brain volume was noted in the 25 children who died in comparison to the 143 survivors (84% vs. 27%; P< 0.001). Brain swelling was more prominent in the peripontine areas. Brain swelling subsides spontaneously over 24 to 48 hours among survivors.

Epidemiology

In 2021, the global malaria landscape witnessed both concerning trends and pandemic-induced challenges. An estimated 247 million cases of malaria were reported worldwide, with a potential range of 224 to 276 million cases, showcasing the substantial burden the disease continues to pose. Accompanying this, the global death toll reached an estimated 619,000 malaria-related deaths. This marked a divergence from the decreasing trend observed between 2000 and 2019, where malaria cases dwindled from 82.3 to 57.2 cases per 1000 population at risk. However, the year 2020 brought an unforeseen hurdle with the COVID-19 pandemic, which led to a staggering surge of 13 million cases—the highest annual increase recorded. This surge was attributed to disruptions in healthcare systems during COVID-19 pandemic. Remarkably, the pandemic-induced disruptions resulted in an additional 13.4 million cases, amplifying the malaria burden further. Despite the overall decline in malaria deaths from 897,000 in 2000 to 568,000 in 2019, 2020 witnessed a disconcerting 10% spike, reaching 625,000 deaths globally. The subsequent year, 2021, displayed a slight reduction in malaria-related deaths. Worryingly, the pandemic also precipitated 63,000 deaths due to interrupted essential malaria services between 2019 and 2021.Geographically, the malaria crisis disproportionately affected the WHO African Region, accounting for a staggering 95% of all reported cases and 96% of deaths. Children under five years old constituted a significant portion, with 78.9% of deaths occurring in this age group. Four African countries (Nigeria, Republic of Congo, Mozambique, and United Republic of Tanzania) account for over half of global malaria related deaths. In the WHO African Region, in 2018, Plasmodium falciparum accounted for 99.7% of estimated malaria cases. Parasite resistance to artemisinin drugs has been detected in parts of Cambodia and Thailand (105; 106; 107; 108).

Five United States residents have been diagnosed with locally acquired malaria—four in Florida and one in Texas, marking the first such cases since 2003. All are under treatment and recovering (87).

Travelers from malaria-free regions going to areas where there is malaria transmission are highly vulnerable (they have little or no immunity) and often suffer because of delayed or wrong malaria diagnosis when returning to their home country. From 1995 through 2004, 7944 cases of malaria among American civilians were reported to Centers for Disease Control and Prevention. Of these, 4959 (62%) were acquired in sub-Saharan Africa; 1310 (19%) in Asia; 1271 (16%) in the Caribbean and Central and South America; and 273 (3%) in other parts of the world. During this period, 43 fatal malaria infections occurred among American civilians; 38 (88%) were caused by Plasmodium falciparum, of which 34 (80%) were acquired in sub-Saharan Africa (06). In 2006, the Centers for Disease Control and Prevention reported 1564 cases of malaria among persons in the United States. This is an increase of 2.4% from the 1528 cases reported for 2005. Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale were identified in 39.2%, 17.6%, 2.9%, and 3.0% of cases, respectively. Based on estimated volume of travel, the highest estimated relative case rates of malaria among travelers occurred among those returning from West Africa. A large number of patients reported that they had not followed a chemoprophylactic drug regimen recommended by the Centers for Disease Control and Prevention. Six deaths were reported; five of the persons were infected with Plasmodium falciparum and one with Plasmodium malariae (58). In the United States, malaria cases can occur through exposure to infected blood products, congenital transmission, or local mosquito-borne transmission (90).

In one published study, the incidence, clinical phenotypes, and outcomes of neurologic involvement in African children with acute falciparum malaria have been reported. Out of 58,239 admitted pediatric patients (1992 to 2004), 19,560 (33.6%) children had malaria as the primary clinical diagnosis. Neurologic involvement was observed in 9313 (47.6%) children. Important neurologic manifestations were seizures (37.5%), agitation (2.8%), prostration (20.6%), and impaired consciousness or coma (13.2%). Factors independently associated with neurologic involvement included past history of seizures, fever lasting two days or less, delayed capillary refill time, metabolic acidosis, and hypoglycemia. Mortality was higher in patients with neurologic involvement. At discharge, 2.2% (159 of 7281) of patients had neurologic deficits. (48).

HIV-infected nonimmune adults are at increased risk of severe malaria. This risk is associated with a low CD4+ T cell count. Patients infected with HIV are more likely to experience renal failure, acidosis, and severe anemia compared to patients without HIV (22). Infection with HIV has been shown to cause more clinical malaria and higher parasitemia in patients living in perennial transmission areas and higher rates of severe malaria episodes and mortality in areas where malaria is transmitted with seasonal frequency. Patients infected with HIV also have higher rates of malaria treatment failures (41). In patients with HIV on zidovudine or efavirenz, amodiaquine-containing artemisinin-based combination regimens should be avoided (102).

Prevention

Chemoprophylaxis is especially important for persons from malaria-free countries who visit areas endemic for malaria. In endemic areas, unprotected nonimmune persons can develop a serious and life-threatening disease. The currently used drugs for chemoprophylaxis are chloroquine (300 mg base once weekly), proguanil/atovaquone (proguanil 100 mg and atovaquone 250 mg; one tablet daily, starting 1 day before exposure), pyrimethamine/dapsone, mefloquine (250 mg base once weekly), and doxycycline (100 mg daily, starting 1 to 2 days before exposure) (Table 3). Intermittent preventive treatment is now a recommended approach to the prevention of malaria in pregnancy. Intermittent preventive therapy involves the administration of full, curative-treatment doses of an effective antimalarial drug at predefined intervals during pregnancy (06; 27).

Table 3. Type of Malaria Risk and Recommended Prevention Methods in International Travelers

Because no prophylactic regimen is completely reliable, personal protection is encouraged, such as the use of repellents containing 30% to 40% of N, N-diethyl-m-toluamide, bed nets impregnated with pyrethroid insecticides, and protective clothing. Vaccines against the pre-erythrocytic stages of malaria hold great promise as a future effective intervention tool against malaria. According to a 2011 report, the RTS,S/AS01 vaccine was shown to provide protection against both clinical and severe malaria in African children (02). In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% in the intention-to-treat population and 55.8% in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% in the intention-to-treat population and 47.3% in the per-protocol population.

Primaquine is a potent gametocidal agent: even a single dose (0.5 mg/kg) can substantially reduce the transmissibility of Plasmodium falciparum infection. A trial has suggested that a higher dose of primaquine (7.0 mg per kilogram over 14 days) is more effective in preventing relapse of P. vivax malaria (19). Although primaquine induces hemolysis in the presence of glucose-6-phosphate dehydrogenase deficiency, still a single and low dose (0.25 mg/kg) primaquine is effective, safe, and well tolerated in reducing transmissibility (80). In malaria-naive adults, administration of the long-acting monoclonal antibody CIS43LS has been found effective in preventing malaria after controlled infection (34).

Differential diagnosis

In developing countries where Plasmodium falciparum malaria is endemic, viral encephalitis and cerebral malaria are also prevalent, and frequently parasitemia with Plasmodium falciparum is common in asymptomatic patients. In patients with suspected cerebral malaria, a lumbar puncture should always be performed to rule out bacterial meningitis. Other differential diagnoses include heat stroke, enteric encephalopathy, metabolic encephalopathies, cerebral venous thrombosis and eclampsia. Neuroimaging, if available, should always be performed to rule out intracerebral bleeding, cerebral edema, and cerebral or medullary herniation.

Because clinical features of malaria are nonspecific, immediate treatment may be needed in obtunded patients who have just returned from malaria-endemic areas if careful search and lumbar puncture fail to indicate alternative causes of meningitis and encephalitis (109). Absence of parasites on a single blood smear does not exclude malaria.

Acute disseminated encephalomyelitis, an immune-mediated demyelinating syndrome, can cause clinical manifestations mimicking cerebral malaria. This syndrome is characterized by fever, headache, fatigue, focal neurologic deficits, bilateral optical neuritis, convulsions, symptomatic psychosis, coma, and characteristic magnetic resonance imaging changes (52).

Diagnostic workup

Examination of thick blood films under light microscopy for a minimum of 100 high-power fields is the standard malaria diagnostic technique. As few as 10 to 20 parasites/µL blood can be detected by an experienced pathologist using this technique. A thin film should be carefully reviewed for species identification. For determining disease severity and treatment monitoring, densities of the asexual forms, in parasite number/µL, should always be reported. In suspicious cases with initial thick film negative, blood smears should be repeated every 12 hours for two days. In addition to microscopy, polymerase chain reaction and rapid immunochromatographic diagnostic tests are alternate diagnostic tools that are not routinely available. Assays based on the polymerase chain reaction are highly sensitive, can be used for unambiguous species identification and, thus, may increasingly complement or even replace light microscopy in developed countries (40).

In comatose children with suspected cerebral malaria, lumbar puncture should always be performed to diagnose other CNS co-infections. An investigation noted that lumbar puncture is a safe procedure even in children with signs of raised intracranial pressure (64).

Neuroimaging abnormalities on computed tomography are common in patients with cerebral malaria. In adult patients, computed tomography findings may conform to four characteristic patterns: a normal scan, isolated diffuse cerebral edema, diffuse cerebral edema with bilateral thalamic hypoattenuation, and diffuse cerebral edema with bilateral thalamic and cerebellar hypoattenuation. Areas of petechial hemorrhage, which are the hallmark of cerebral malaria at pathologic examination, are not seen on computed tomography (74). Yadav and colleagues reported the imaging findings in three patients with cerebral malaria who presented with altered sensorium (110). Magnetic resonance imaging using a 1.5-Tesla unit was carried out. Focal hyperintensities in the bilateral periventricular white matter, corpus callosum, occipital subcortex, and bilateral thalami were noticed on T2-weighted and fluid-attenuated inversion-recovery sequences. The lesions were more marked in the splenium of the corpus callosum. In reports imaging findings consistent with posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome have also been demonstrated (79; 111).

In a report from Blantyre, Malawi, Moghaddam and colleagues noted that in pediatric patients of cerebral malaria, areas of diffusion restriction are common (61). In approximately 72% (194 out of 269) of patients with cerebral malaria, diffusion-weighted MRI demonstrated at least one area of diffusion restriction. Bilateral subcortical white matter, corpus callosum, deep gray matter, cortical gray matter, and posterior fossa were commonly involved structures. Isolated subcortical diffusion restriction was associated with less severe disease and a good prognosis.

Sahu and colleagues observed a distinctly different neuroimaging patterns in pediatric and adult patients of cerebral malaria (83). The authors performed quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) assessment and noted that in nonfatal cases reversible, hypoxia-induced cytotoxic edema dominantly affected the white matter in children, whereas changes dominantly affected basal ganglia in adults. A different imaging pattern was noted in fatal cases as well. In adults, there was hypoxia induced global decrease in apparent diffusion coefficient. There were no evidence of brain swelling and brain stem herniation in adults. In pediatric fatal cases, an increase in brain volume was demonstrated. Increase in brain volume led to brainstem herniation and death (83). Subsequently, Mohanty and colleagues demonstrated that imaging brain abnormalities are common in adults with severe noncerebral malaria and a subset of patients with uncomplicated malaria (62). On MRI, Mohanty and colleagues demonstrated abnormalities in brain tissue apparent diffusion coefficient values. Patients with low apparent diffusion coefficient values indicated cytotoxic edema, a pattern similar to cerebral malaria. High apparent diffusion coefficient values, suggestive of mild vasogenic edema, were noted both in patients with severe noncerebral malaria (without coma) and patients with uncomplicated malaria. Increased creatinine in severe noncerebral malaria was considered responsible for cytotoxic edema of the brain.

Management

According to World Health Organization recommendations, universal diagnostic testing of malaria should be a mandatory step in the management of malaria. This will help in the fight against malaria as it will allow for the targeted use of artemisinin-based combination therapy for those who actually have malaria. This will help to reduce the emergence and spread of drug resistance. It will also help identify patients who do not have malaria so that alternative diagnoses can be made and appropriate treatment provided (104).

Choice of antimalarial drugs depends on species, parasite density, clinical severity, and possibility of drug resistance. To counter drug resistance to antimalarial monotherapy and improve outcome in patients with uncomplicated falciparum malaria, World Health Organization has recommended usage of a combination of multiple antimalarial drugs. Artemisinin-based combination therapies are now considered the treatment of choice for uncomplicated falciparum malaria (100) (Tables 4 and 5).

Table 4. Treatment of Malaria Recommended by World Health Organization

In the United States, where artemisinin derivatives are not available, patients with Plasmodium malariae, Plasmodium ovale, and chloroquine-sensitive Plasmodium falciparum and Plasmodium vivax may be treated with chloroquine (Table 5). The United States Food and Drug Administration, on May 26, 2020, approved artesunate injection for treatment of severe malaria. Artesunate injections are available from CDC through an expanded-use investigational new drug protocol.

Table 5. Treatment of Malaria in the United States

Because Plasmodium vivax and Plasmodium ovale have persistent, latent hypnozoites in the liver, a radical treatment with primaquine is also required to prevent relapses. In uncomplicated cases of chloroquine-resistant Plasmodium falciparum infection, quinine sulfate should be given orally with tetracycline. A single dose of sulfadoxine and pyrimethamine may replace tetracycline for infection acquired in some parts of Africa. If resistance to sulfadoxine-pyrimethamine is suspected, use doxycycline is recommended. Tetracycline and doxycycline are contraindicated in pregnant women and children under 8 years old. Combination therapies for multidrug-resistant Plasmodium falciparum infection include sulfadoxine plus pyrimethamine given to adults as a single dose of three tablets, and proguanil plus atovaquone given to adults as four tablets once daily for three days (Tables 4 and 5).

Patients with complicated falciparum malaria should immediately receive parenteral antimalarial drugs. It is essential that therapeutic concentrations of antimalarial drugs are established as soon possible. Quinine and artemisinin derivatives are widely available for parenteral use. The treatment of choice for severe or complicated malaria in both adults and children is intravenous artesunate (53; 32). Intravenous quinine should be started if artesunate is not available. Patients treated with intravenous quinine should be monitored for hypoglycemia. In primary health centers where facilities are limited, rectal artemether is effective and well tolerated and could be used as treatment for cerebral malaria. Intramuscular quinine is as safe and effective as intravenous quinine. In the United States, where artemisinin derivatives and intravenous quinine are not available, quinidine is the intravenous medication of choice for complicated falciparum malaria. The potential cardiac toxicity of quinine and quinidine necessitates that patients receive these medications as intravenous infusions, never as a bolus, with continuous ECG monitoring. Infusion rates should be reduced if the QT interval is prolonged by more than 25% of the baseline value (36). Compared with quinine, the artemisinins reduce parasite counts faster, and there is now evidence from Asia that they reduce mortality in adults with severe malaria. Artesunate substantially reduces mortality in African children with severe malaria as well. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria (29). Intravenous administration of artesunate can be associated with delayed hemolysis known as “post-artemisinin delayed hemolysis (PADH).” PADH occurs 1 to 3 weeks after initiation of artemisinin-based treatment. Delayed hemolysis leads to a decline in hemoglobin levels (82).

Exchange transfusion has been recommended for nonimmune adult patients with parasite densities >30% as it reduces parasitemia and improves red-cell flow, but there is no conclusive evidence that it reduces mortality (47; 100; 102) (Tables 4 and 5). Erythropoietin has been shown to improve the outcome in a murine model of cerebral malaria. High plasma levels of erythropoietin in children with cerebral malaria were associated with a better outcome (16).

Table 6. Supportive Treatment in Patients with Severe Falciparum Malaria

Supportive treatment in patients with severe falciparum malaria is also equally important (Table 6). Patients with recurrent seizures have traditionally been treated with phenobarbital or phenytoin, as one would treat a patient with status epilepticus. Phenobarbital prophylaxis for seizures is not recommended in children with cerebral malaria, however, because a large study in Kenyan children demonstrated a higher mortality rate in children who received phenobarbital prophylaxis than in children who did not receive the drug as prophylaxis. It is unclear whether giving anticonvulsant drugs routinely to people with cerebral malaria will improve the outcome of treatment and prevent death. Routine use of phenobarbital in cerebral malaria is associated with fewer convulsions but possibly more deaths. Lorazepam may be a useful alternative anticonvulsant to stop convulsions in children with severe malaria because it has a longer duration of action than diazepam and can be given by other routes, such as intramuscularly (65). Levetiracetam has now emerged as a safer treatment option for seizures in pediatric patients than phenobarbital (10).

Dehydration and hypovolemia in children with cerebral malaria should be corrected with intravenous fluids. Patients with symptomatic anemia (such as those with congestive heart failure) should receive a blood transfusion. It is recommended that blood transfusion should be given if the hemoglobin level is 5 mg/dL or lower. Lactic acidosis can be corrected by aggressive management of malarial infection, volume replacement if the patient is dehydrated, and blood transfusion. Lactic acidosis resolves in many children with this approach alone. Some experts recommend the use of sodium bicarbonate if the patient's blood pH is less than 7.1. Hypoglycemia can be corrected with a 50% dextrose intravenous bolus. Blood glucose measurements should be performed every 30 minutes for 4 hours or until the blood glucose level is stable, and then every 4 hours until the patient regains full consciousness. Mannitol is often used as adjunct therapy for cerebral malaria, but the World Health Organization does not recommend it (67; 68; 33; 99; 100; 102; 47).

Outcomes

Mortality from untreated severe falciparum malaria, including cerebral malaria, is virtually 100%. Prompt treatment with parenteral antimalarial drugs and other supportive management may bring the mortality down to 10% to 20% (104). Children who survive cerebral malaria are at increased risk of long-term neurologic adverse outcome, including epilepsy (20). Approximately one-half of pediatric survivors of cerebral malaria remain neurodevelopmentally impaired at the 1-year assessment (54).

Special considerations

Pregnancy

Pregnant women are at high risk of malaria. Pregnant women, particularly during the first pregnancy, are prone to severe infection with high parasitemia, severe anemia, hypoglycemia, pulmonary edema, and fetal complications. Maternal mortality is approximately 50%, which is higher than in nonpregnant adults (100). Artemisinin-based treatment regimens are safe and effective in the second and third trimester of pregnancy (25). Plasmodium falciparum infections during pregnancy in Africa frequently do not result in fever and, therefore, remain undetected and untreated. Meta-analyses of intervention trials suggest that successful prevention of these infections reduces the risk of severe maternal anemia by 38%, low birthweight by 43%, and perinatal mortality by 27%. Plasmodium vivax is common in Asia and the Americas and, unlike Plasmodium falciparum, does not cytoadhere in the placenta. Yet, it is associated with maternal anemia and low birthweight (27). The World Health Organization recommends that all pregnant women in malaria-endemic areas sleep under an insecticide treated bed-net and receive at least two doses of intermittent preventive treatment with an efficacious antimalarial in the second and third trimesters. Chemoprophylaxis with chloroquine is no longer recommended. The recommended drug for intermittent preventive treatment is sulfadoxine-pyrimethamine (66). Despite maternal peripheral and placental parasitemia, congenital malaria is rare but possible (45). Infants born to placenta-infected mothers were more likely to develop a malaria infection between 4 and 6 months of age (55).