Several neurological complications are associated with Plasmodium falciparum malaria, which can lead to life-threatening cerebral malaria. A few patients may experience a neurological syndrome after complete recovery from P. falciparum infection, called post-malaria neurological syndrome (PMNS). It is relatively rare, with various clinical symptoms, and its pathogenesis is not well understood.1
We describe 2 young adult patients, born in France, of African origin, with no medical histories. They presented a PMNS in the weeks following recovery from severe P. falciparum malaria. During convalescence, both patients developed generalized convulsion and lymphocytic meningoencephalitis, not associated with parasite recrudescence. They both totally recovered spontaneously.
The first patient was a 19-year-old man, born and living in France but originating from the Ivory Coast (IC). He traveled to the IC in August 2006 without taking any antimalarial prophylaxis. The day of his return, he began to develop a fever, cough, and headache. Five days after his return, P. falciparum malaria was diagnosed on a blood-film examination with 2.5% parasitemia. Acute complications included acute renal insufficiency and clouding of consciousness associated to thrombocytopenia and cytolysis. When transferred to the intensive care unit (ICU), he received intravenous quinine and blood transfusion and required mechanical ventilation because of respiratory distress syndrome, but he did not undergo hemofiltration. Parasitemia cleared by Day 6, and quinine was stopped on Day 12. The patient was extubated on Day 14 and discharged on Day 17. On Day 63, he reported dizziness and mood disorders and had a generalized convulsion leading to another hospitalization. In the ICU, he was intubated because of a Glasgow coma score of 6. His temperature was 39°C. Biochemical screening was normal, including blood electrolytes, urea, creatinine, and liver-function tests. C-reactive protein (CRP) was 163 mg/L. Repeated blood-film examinations for Plasmodium were negative. Lumbar puncture (LP) revealed a mild inflammation with 8 WBCs/μL, and protein and glucose levels were 0.38 g/L and 3.7 mM/L, respectively. Cerebrospinal fluid (CSF) cultures for bacteria, fungi, and mycobacteria were sterile. HIV testing was negative. Culture of blood, urine, and stool samples were sterile. There was no biological evidence of any autoimmune process. Brain CT scan and MRI were normal. An electroencephalogram (EEG) demonstrated slow-wave activity consistent with encephalopathy. Because of persistent fever, another LP was performed after 24 hours, revealing 31 RBCs/μL, 76 WBCs/μL, of which 100% were lymphocytes, and protein and glucose levels of 0.52 g/L and 4.1 mM/L, respectively, with a sterile culture. PCR for HSV, EBV, VZV, enterovirus, and Mycobacterium tuberculosis in CSF and serology for arbovirus in blood were negative. Nevertheless, the patient was treated initially with acyclovir for suspicion of herpetic meningoencephalitis (15 mg/kg/8 h according to French recommendations). He improved by Day 70 and was extubated. His mental status improved by Day 87, and he recovered fully with no neurological sequelae.
The second patient was a 17-year-old man, born and living in France, originating from Gambia where he traveled to in November 2006, without antimalarial prophylaxis. He had presented fever and behavior disorders 10 days after his return. Neuromalaria was diagnosed with a 9% parasitemia, which decreased rapidly with intravenous quinine, leading to Plasmodium clearance within 4 days. He was discharged from the hospital on Day 11. On Day 18, he was rehospitalized because of fever and confusion. At entry, his temperature was 39°C, and he had no detectable focus of infection. Results of usual biochemical screening were normal, CRP was 9 mg/L. CSF revealed 5 WBCs/μL, protein and glucose levels of 0.96 g/L and 3.5 mM/L, respectively, and culture for bacteria was sterile. A brain CT scan was normal. Despite a negative blood-film examination for malaria, confirmed retrospectively by a senior parasitologist, the patient was again treated with intravenous quinine for 2 days by the on-duty physician under the hypothesis of a relapsing neuromalaria and transferred to the ICU. He rapidly presented a clouding of consciousness and a generalized convulsion on Day 19 and was intubated. HIV testing was negative. Another LP revealed 630 RBCs/μL, 26 WBCs/μL, including 91% lymphocytes, a protein level of 1.88 g/L, a normal glucose level, a sterile culture, and negative PCR for HSV, EBV, CMV, and HHV6. An EEG showed signs of encephalopathy, and a MRI of the brain was normal. The patient was treated for a suspicion of herpetic meningoencephalitis by acyclovir for 3 weeks. He was extubated on Day 26 and initially had abnormal mental status. By Day 30, his mental status normalized, and he recovered with no neurological sequelae.
PMNS is defined as the acute onset of confusion, epileptic seizures, or any other neurological or psychiatric sign occurring with a latency of several days to weeks (generally within 2 months) after an episode of successfully treated P. falciparum malaria.1
PMNS can have many clinical presentations. The first description of a post-infectious neurological complication of malaria was delayed cerebellar ataxia (DCA), identified in Sri Lanka in 1984, and it has been described many times since then.2–5 In these cases, there was cerebellar impairment with no evidence of cerebral involvement, with complete recovery within 3 months.2 Other presentations were described, such as encephalomyelitis6 or encephalopathy,7 with different degrees of severity. The only prospective study, conducted in Vietnam,1 first defining PMNS, described 22 patients, 19 adults, and 3 children, having neurological or psychiatric symptoms occurring within 2 months after an acute and cured malaria, among 18,124 patients with a treated P. falciparum malaria: overall incidence was 0.7 to 1.8 per 1000.1 Schnorf and others7 proposed in 1998 a classification into 3 subtypes of PMNS: a mild and localized encephalopathy affecting the cerebellum and causing ataxia (called DCA), a diffuse but not severe encephalopathy causing confusion with or without epileptic seizures, and a severe generalized encephalopathy resembling an acute disseminated encephalomyelitis (ADEM), with usually a good response to steroid therapy.7,8 Limits between PMNS and ADEM are not very clear: ADEM is defined as an inflammatory demyelinating disease of the central nervous system, preceded by a viral or bacterial infection or vaccination and also described after P. falciparum infection.9,10 The characteristic lesions of ADEM are perivenular inflammation and surrounding demyelinization, with hyper-intense lesions depicted by brain MRI. In PMNS, brain MRI can be normal11 or show aspecific increased signal.12 In addition, PMNS can present as a neuropsychiatric manifestation.12,13 In the study conducted by Nguyen,1 68% of patients with PMNS had an acute confusional state and 27% had generalized convulsions,1 the CSF showed a leukocyte pleocytosis (> 5 cells/μL) with lymphocyte predominance in 36% of cases and a raised protein concentration (> 50 mg/dL) in 59% of cases. Median duration of the syndrome was 60 hours.
In our 2 patients, the presentation fit with the second subtype described by Schnorf and others. Systemic and CSF inflammation was found with no other etiological cause. Empiric treatment by acyclovir because of the lymphocytic meningoencephalitis could probably not explain the rapid improvement, as no other criteria for herpes meningoencephalitis was found. Both cases presented generalized convulsion, necessitating intubation and sedation, but they finally improved, with no use of corticosteroids.
The pathogenesis of PMNS is unknown. There is probably no structural lesion because of the quite rapid and complete resolution.1 It could be mediated immunologically, all the more as steroids seem efficient to cure patients.8 Indeed, a study showed immune activation during cerebellar dysfunction after P. falciparum malaria, with CSF cytokine concentrations more elevated in ataxic patients compared with a reduction after corticotherapy.3,10 Nevertheless, there is still a lack of evidence for antibody mediation concerning DCA.14 PMNS was associated with the use of oral mefloquine for Nguyen and others, suggesting a possible role of such medication.1 They concluded that it would be better not to use mefloquine after parenteral treatment of severe malaria. However, our patients did not receive mefloquine but quinine, which not only is an argument against the responsibility of mefloquine but also provides additional support for the importance of factors other than medical treatment, such as immunoinflammatory mechanisms.
Moreover, the cases of PMNS reported in the literature occurred mainly in patients with no or low semi-immunity (context of imported malaria in non-immune travelers11 or in regions hypoendemic for malaria1). Nevertheless, a few cases have been described in African patients.12,15,16 In our 2 cases, it is notable that both patients were young adults with no malaria immunity, despite their African origin, as they were born in and live in France.
In conclusion, from a clinical point of view, PMNS must be distinguished from relapse of malaria. In PMNS, there is a free interval between the cured malaria and the onset of neurological symptoms, and parasitemia is negative. In mild cases, symptomatic treatment seems to be sufficient with a spontaneous and favorable evolution, but in severe cases, corticosteroids are probably of interest to limit brain inflammation. Clinicians should be aware of PMNS so that appropriate investigations could be done to explore its pathogenesis, its clinical characteristics, and its relationship to other known post-infectious neurological syndromes, such as ADEM.
Address correspondence to Olivier Bouchaud, Department of Infectious and Tropical Diseases, Hôpital Avicenne, AP-HP, Bobigny, F-93000 France. E-mail:
Authors’ addresses: Virginie Prendki and Olivier Bouchaud, Department of Infectious and Tropical Diseases, Hôpital Avicenne, AP-HP, Bobigny, F-93000 France. Claire Elzière and Igor Onnen, Department of Neurology, Hôpital Avicenne, AP-HP, Bobigny, F-93000 France. Rémy Durand, Department of Parasitology, Hôpital Avicenne, AP-HP, Bobigny, F-93000 France. Aicha Hamdi and Yves Cohen, Department of Resuscitation, Hôpital Avicenne, AP-HP, Bobigny, F-93000 France. Yves Cohen and Olivier Bouchaud, Université Paris, 13 Paris Nord, Bobigny, F-93017 France, Tel: 33-1-48-95-54-21, Fax: 33-1-48-95-54-28, E-mail:
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