A total of 15,506 children were admitted to KDH during the three-year period. Of these, 5,767 had malaria as a primary diagnosis. Four hundred and twenty-six patients fulfilled the criteria for cerebral malaria, of whom nine had incomplete records and were excluded. Of the remaining four hundred and seventeen, 215 (51.6%) were males. The median age was 27 (IQR 15–41) months and median duration of fever prior to admission was two (IQR one – three) days. Overall, 163 children (39.1%) had AMP: 85 (20.4%) presented with AMP and an additional 78 (18.7%) developed AMP after admission. Of the 85 patients who had AMP on admission, 63 (74%) had further episodes after admission. Most AMP occurred spontaneously and manifested as decorticate posturing in 80 (49.1%), decerebrate posturing in 61 (37.4%) and opisthotonus in 22 (13.5%).
Presentation and risk factors for abnormal motor posturing at admission
Admission clinical characteristics of patients with AMP at admission, during admission or without AMP are summarized in Table (and clinical features of patients with and without AMP are in the attached Additional file 1
). Overall, patients with AMP were older: 48.1% of those three years or older had AMP compared to only 35.8% of children under three years, p
= 0.01. No association was observed between AMP and duration of illness, history of seizures or parasite density. No relationship was also observed between AMP and other markers of severity of illness at admission such as a history of multiple convulsions, profound coma, deep breathing, hypotension, hypoglycaemia, severe anaemia, hyponatraemia or hyperparasitaemia. No significant differences were found in the CSF white blood cell count, protein, sugar or CSF: blood sugar ratio. Using multiple logistic regression analysis, age three years or older was independently associated with a child presenting with AMP (adjusted OR 2.0 95% CI 1.7 – 2.4, p
< 0.001). Unlike decorticate or decerebrate posturing, opisthotonic posturing was also independently associated with severe acidosis, (adjusted OR 4.2 95% CI 3.2–5.6, p
Characteristics of patients with posturing
Abnormal motor posturing after admission
Of the 78 children who developed posturing after admission, 38 (49%) had decorticate, 30 (38%) decerebrate and 10 (13%) opisthotonic posturing. This distribution was similar to the overall distribution of AMP. Apart from being younger, no differences in admission characteristics and in particular, the duration of illness or coma, history of seizures, level of coma, parasite density, blood glucose, electrolytes, acid base status or haemodynamic state were observed when compared to those who presented with AMP (Table ).
The median time from admission to the time of AMP was 4.0 (IQR 1.9 – 8.8) hours. Fifty-two patients developed posturing within six hours and the remaining 26 patients had posturing after six hours (Figure ). Two children developed opisthotonus 32 and 55 hours after admission. No significant age, sex or clinical differences were observed between those who developed posturing before or after six hours. However, most of those who developed opisthotonic posturing after admission did so after more than six hours of admission: of the 26 patients who developed AMP after 6 hours, 6 (23.3%) had opisthotonic posturing compared to only four out of 52 (7.7%) with AMP within six hours of admission, (OR 2.0 95% CI 1.1 – 3.8). Features of RICP on funduscopy (congested retinal veins, blurred disc margins or overt papilloedema) were the only clinical feature predictive for the development of posturing after admission, (adjusted OR 1.9 95% CI 1.7 – 2.2, p < 0.001).
Time from admission to onset of posturing.
Clinical events after admission
Deterioration in consciousness observed during the four hourly assessments, recurrence of seizures and brainstem features of raised ICP were the most significant clinical events after admission. The level of consciousness deteriorated in over 50% of patients with AMP, within 24 hours of admission and often, just before further posturing episodes (Table ).
Abnormal motor posturing and features of intracranial hypertension
Several brainstem signs consistent with different stages of raised ICP were observed. Abnormalities of pupillary size and reaction, eye movements, disorders of conjugate gaze, and changes on funduscopy were the most common features (Table ). Motor abnormalities of tone and reflexes were also seen. Raised ICP was associated with all three types of posturing (Table ), although patients with decorticate posturing had earlier funduscopic features such as congested retinal veins, unlike those with decerebrate posturing who had papilloedema more frequently.
Brainstem features of raised ICP, seizures after admission and type of posturing
Thirty-two patients thought to have severe intracranial hypertension usually with papilloedema or clinical signs compatible with progressive herniation (23 of whom had AMP), were given mannitol (0.5 g/kg infused over 20 minutes up to a maximum of three doses). No further episodes of AMP were observed in 12 (52.2%) after the administration of mannitol. Fifteen of the 32 patients (46.9%) died and five (15.6%) showed severe neurological deficits. Fourteen of the 15 deaths occurred in patients with AMP.
Patients were assessed for features of transtentorial herniation based upon the Plum and Posner criteria adapted for children with cerebral malaria [5
]. Forty-eight patients (11.5%) fulfilled a criterion for herniation (Table ). Thirty three (68.8%) of these died compared to only 30 (8.1%) of those without features of herniation, (OR 12.4 95% CI 7.1 – 21.4, p
< 0.001). Most patients with AMP who died had features of herniation (19/31), with most deaths following a respiratory arrest.
Herniation syndromes and posturing
Seizures after admission
Clinical seizures were observed in 107/163 (65.6%) patients with AMP compared to 129/254 (50.8%) of those without AMP (Table ). Most patients with AMP had multiple short seizures, often lasting one to three minutes and 20% had five or more seizures witnessed over the duration of admission. Seizures were particularly common among those who developed AMP after admission, often involving the mouth, face and limbs and were twice as common as that in patients without AMP. An association was observed between the type of AMP and recurrence of seizures in the ward; no posturing 50.8%, decorticate posturing, 60.0%, decerebrate, 68.9% and opisthotonus, 77.3% (χ2 = 11.4, p = 0.01 for trend). The median number of witnessed seizures among patients with opisthotonus was three compared to one in patients with either decerebrate or decorticate posturing.
Thirty five of the 85 patients with AMP at admission received intravenous phenytoin. AMP recurred in 22/35 (62.9%) of those who received phenytoin compared to 41/50 (82.0%) of those who did not receive phenytoin, but this difference was not statistically significant.
Abnormalities on cerebral function analyser monitoring
Twenty-one of the 58 patients (36%) monitored with the CFAM had AMP, a proportion similar to that seen in whole group. Recordings were examined for evidence of seizure activity and changes in background electrical activity during AMP. Patients with AMP had elevated peaks in the amplitude of the background electrical activity, which were not seen in those without AMP. During posturing, transient increases in the amplitude of the electroencephalographic (EEG) background activity were observed (Figure ). These were most marked with opisthotonic posturing and more pronounced with decerebrate than with decorticate posturing. The mean peak-to-peak amplitude in patients with decorticate posturing increased to just below 100 μV (CFAM voltage readings are in a logarithmic scale starting at 1, 10 and 100 μV), while in decerebrate and opisthotonic posturing it exceeded 100 μV. There was no evidence of seizure activity during AMP in the areas monitored by EEG (left and right fronto-central: F3-C3, F4-C4; left and right parieto-occipital: P3-O1, P4-O2).
Cerebral function analyser monitoring tracings before and during opisthotonic posturing in a child with cerebral malaria.
Seizures, posturing and resolution of coma
Both seizures and AMP were associated with prolonged coma. The median time to full consciousness in patients with AMP was 32 (IQR 12–63) compared to 13 (IQR 4–26) hours in those without AMP. In patients who had seizures after admission, the median time to full consciousness was 26 (IQR 10.3–51.8) hours compared to nine (IQR 4–21.5) among those without seizures. On multiple linear regression analysis, time to full consciousness was significantly longer in both patients with AMP, (β = -21.4, t = -5.453, p < 0.001) and those with seizures after admission, (β = -20.9, t = -5.485, p < 0.001). Of the 374 patients alive 24 hours after admission, 163/232 (70.3%) without AMP had regained full consciousness compared to only 57/142 (40.1%) with AMP, p < 0.001. Prolonged periods of unconsciousness were particularly common in patients who developed AMP after admission when compared with those posturing at admission, 53.8 (SD 55.1) vs 30.8 (SD 33.8) hours, p = 0.002.
Independent risk factors for abnormal motor posturing
Logistic regression analysis was performed to determine the main risk factor for AMP in particular, features associated with raised ICP or seizures. Only features of raised ICP on funduscopy (adjusted OR 2.1 95% 1.2 – 3.7, p = 0.009) were independently associated with AMP. No independent association was observed with seizures. When the different types of AMP were considered separately, decorticate posturing was associated with raised ICP (adjusted OR 3.2 95% CI 1.5–6.9, p = 0.003) but not seizures (adjusted OR 1.3 95% CI 0.7–2.1, p = 0.378). However, decerebrate posturing was significantly associated with both raised ICP (adjusted OR 3.2 95% CI 1.4–7.1, p = 0.006) and seizures (adjusted OR 1.9 95% CI 1.0–3.5, p = 0.036). Similarly, opisthotonic posturing was also associated with both raised ICP (adjusted OR 3.4 95% CI 1.1–10.7, p = 0.035) and seizures (adjusted OR 2.9 95% CI 1.0–8.1, p = 0.049).
Out of the 417 children with cerebral malaria, 63 (15.1%) died and 39 (11.0%) of the 354 survivors had neurological deficits at discharge. The mortality in the 163 patients with AMP was 19.0% compared to 12.6% of 254 patients without AMP, p = 0.07. Primary respiratory arrest was the commonest cause of death among patients with AMP (19/31 [61.3%] compared to 12/32 [37.5%] in those without posturing, p = 0.06) and the median time from admission to death was four hours longer (15 hours IQR 3–48 vs 11.5 hours IQR 3–106) among patients with AMP. Mortality increased with the type of AMP: mortality was 12.6% among children without AMP, 16.3% in those with decorticate posturing, 19.7% with decerebrate posturing and 27.3% in those with opisthotonic posturing. Patients who developed AMP after admission had the worst outcome; 40% either died or had gross neurological deficits at discharge (Table ).
At discharge, of the 39 children with neurological deficits, motor impairments in 28 (18 with central hypotonia, six with paresis and four with ataxia), aphasia in 13, blindness in 12 and deafness in 6 were the most common impairments. These impairments were particularly common among patients with AMP: 22 (16.7%) compared to 17 (7.7%) of those without AMP, p = 0.009). Other neurological deficits observed in patients with AMP included labile emotions with frequent mood changes, persistent visual hallucinations, lip smacking, choreoathetosis and repeated episodes of confusion. Recurrence of seizures in the ward was also associated with both increased neurological deficits (16.6 vs 4.3%, OR 4.4 95% CI 1.9–10.2, p < 0.001) and mortality (18.2 vs 11.0%, OR 1.8 95% CI 1.0–3.2, p = 0.04).