Cerebral malaria and epilepsy

Malaria, one of the most common parasitic diseases worldwide, is responsible for more than one million deaths among African children every year. Its neurological form, known as cerebral malaria (CM) is a potential cause of epilepsy in malaria-endemic regions of the world, primarily made up for the most part by the sub-Saharan Africa. Herein, we review recent African studies that examine the association between CM and epilepsy. Three studies suggest a modestly strong association between CM and epilepsy. Furthermore, there appears little doubt that this association is causal. Speculative considerations that may explain this causal association are discussed in this review. Additional research is however required in order to determine the clinical and electrographic behavior, the underlying structural and molecular basis, and course and outcome of this condition.     

Cerebral calpain in fatal falciparum malaria

Disruption of axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria (CM). Calpains are calcium (Ca2+)-activated cysteine proteases which have been implicated in axonal injury in neurological diseases of various aetiologies. In this study we examined the association between mu- and m-calpain, the specific inhibitor calpastatin, and axonal injury in post mortem brain tissue from patients who died from severe malaria. Calpains were associated with axons labelled for the beta-amyloid precursor protein that detects impaired axonal transport. Elevated levels of calpastatin were rarely observed in injured axons. There were increased numbers of neurones with mu-calpain in the nuclear compartment in severe malaria cases compared with non-neurological controls, and increased numbers of glia with nuclear mu-calpain in CM patients compared with non-CM malaria cases and non-neurological controls. There was marked redistribution of calpastatin in the sequestered Plasmodium falciparum-infected erythrocytes. Responses specific to malaria infection were ascertained following analysis of brain samples from fatal cases with acute axonal injury, HIV encephalitis, and progressive multifocal leucoencephalopathy. Our findings implicate a role for calpains in the modulation of disease progression in CM.     

Cerebral malaria. A disseminated vasculomyelinopathy.

Neuropathologic examination of 19 fatal cases of cerebral malaria and a review of the literature showed that the epidemiologic, clinical, and pathologic features of this entity suggest consideration of cerebral malaria as a form of disseminated vasculomyelinopathy, a hyperegic reaction of the CNS to the antigenic challenge of Plasmodium falciparum infection. Experimental evidence also substantiates this view The initial event seems to be vasculopathy, with alteration of the endothelial permeability, followed by brain edema, perivascular infiltrates and ring hemorrhages, perivascular demyelination, and gliosis (malarial granuloma) in the late stages. This chain of events could be interrupted early in its course by corticosteroids. Parenteral dexamethasone should then be seriously considered at the first signs of involvement of the CNS during P falciparum malaria along with the standard forms of antimalarial therapy.     

Cerebral malaria: A diagnostic dilemma: A case report

The following report describes an adolescent patient with falciparum malaria, who was initially seen in a florid psychotic state. Formulation of a diagnosis necessitated differentiation among three diagnostic possibilities: a coincidental functional psychosis, cerebral malaria, or cerebral malaria acting as the precipitating factor for a functional psychosis in a predisposed personality.     

Cerebral malaria: what is known and what is on research

Malaria is still the world's major important parasitic disease and is responsible for the death of more people than any other communicable disease except tuberculosis. A major change in recent years has been the recognition that severe malaria, predominantly caused by Plasmodium falciparum, is a complex multi-system disorder presenting with a range of clinical features. Some surviving patients have an increased risk of neurological and cognitive deficits, behavioural difficulties and epilepsy, making cerebral malaria a leading cause of childhood neurodisability in the malaria transmission area. It is unclear how an intravascular parasite causes such brain injury. Understanding of these mechanisms is important to develop appropriate neuroprotective interventions. However, due to the high specificity of P. falciparum to the human host and to the fact that clinical studies in human are not always feasible, our knowledge about this syndrome mainly comes from autopsy studies which can only give us a limited view of this deadly syndrome. Efforts developed by the scientific community have shown that development of severe malaria probably results from a combination of parasite-specific factors such as adhesion and sequestration to the vascular endothelium, the release of bioactive molecules, together with host inflammatory responses and metabolic acidosis. Recent studies have shown that endothelial cells could play a central role in the onset of the severe malaria. Indeed, adhesion of parasitized erythrocytes to these cells could drive their activation, which could participate in the trigger of an immune response and haemostatic derangements. Moreover, death of endothelial cells could be at the origin of the blood-lung/brain barrier breakdown. Despite the efforts to find new mechanisms, which explain the physiopathology of severe malaria, research progress is slowed down by the lack of experimental models, which reproduce this complex multi-system disorder. In absence of a vaccine so far, the rapid diagnosis of the disease, an efficient treatment, a correct management and nursing care are the only weapons to control mortality due to P. falciparum. It is important to note that in the future, the treatment of severe malaria may involve adjuvant treatments in addition to a potent antimalarial drug. In the present review, we summarize both what is known and practically useful for a physician, and the most promising and current topics of research.     

Cerebral malaria and sequelar epilepsy: first matched case-control study in Gabon

PURPOSE: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas. The purpose of this article was to evaluate the relationship between CM and epilepsy in Gabon. METHODS: A matched case-control study was carried out on a sample of subjects aged six months to 25 years and hospitalized between 1990 and 2004 in three hospitals in Libreville, Gabon. Cases were defined as patients suffering from epilepsy and confirmed by a neurologist. Controls were defined as patients without epilepsy. The exposure of interest was CM according to WHO criteria. RESULTS: In total, 296 cases and 296 controls were included. Of these, 36 (26 cases and 10 controls) had a CM history. The adjusted odds ratio (aOR) to develop epilepsy after CM was 3.9 [95% CI: 1.7-8.9], p<0.001. Additional risk factors were identified: family history of epilepsy: aOR=6.0 [95% CI: 2.6-14.1], p<0.0001, and febrile convulsions: aOR=9.2 [95% CI 4.0-21.1], p<0.0001. CONCLUSIONS: This first case-control study on that issue suggests that epilepsy-related CM is an underrecognized problem. It emphasizes the need for further studies to better evaluate the role of convulsions during CM.     

Cerebral malaria -- a neurovascular pathology with many riddles still to be solved

Cerebral malaria (CM), one of the most common fatal complications of the heterogenous syndrome named severe malaria, is indubitably a post-infectious neurovascular pathology, as evidenced by histopathological analyses. This neurological syndrome is characterised 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 CM, 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 CM pathogenesis. Indeed, cerebral complications appear to be due to an imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokines (notably interferon-gamma, tumour necrosis factor, lymphotoxin) and chemokine receptors (notably CCR5) are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in CM. In return, glial cells can influence blood-borne elements, and thereby worsen the pathology. Numerous problems remain to be solved, especially the sequence of pathological events, namely the order in which the circulating cells sequester on the endothelial wall. A better understanding of the molecular mechanisms involved in CM pathogenesis is needed if we are capable of preventing cerebral complications and improving the quality of patient management.     

Imported cerebral malaria

Cerebral malaria is one of the most serious complications of Plasmodium falciparum infection. Its diagnosis may sometimes be difficult. We report the case of a 63-year-old woman who presented with abdominal pain and nausea, rapidly followed by delirium and stupor, a few days after a travel in Africa. No prophylactic measures were prescribed. The main clinical features concerning cerebral malaria, diagnostic tools and therapeutic measures are discussed.     

Coagulopathy in malaria

Blood coagulation activation is frequently found in patients with malaria. Clinically apparent bleeding or disseminated intravascular coagulation (DIC) is associated with very severe disease and a high mortality. Protein C, protein S, and antithrombin levels were found to be low in P. falciparum, but were normal in P. vivax infection. Plasma levels of plasminogen activator inhibitor-1 were high in cases of P. falciparum infection whereas tissue plasminogen activator levels were low. Elevated plasma levels of von Willebrand factor (vWF) and vWF propeptide, thrombomodulin, endothelial microparticles have been reported in P. falciparum-infected patients. It has been demonstrated that severe P. falciparum infection is associated with acute endothelial cell (EC) activation, abnormal circulating ultralarge vWF multimers, and a significant reduction in plasma ADAMTS13 function. These changes may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease. It has also been shown that P. falciparum-parasitized red blood cells (pRBCs) induce tissue factor (TF) expression in microvascular ECs in vitro. Recently, loss of endothelial protein C receptor (EPCR) localized to sites of cytoadherent pRBCs in cerebral malaria has been demonstrated. Severe malaria is associated with parasite binding to EPCR. The cornerstone of the treatment of coagulopathy in malaria is the use of effective anti-malarial agents. DIC with spontaneous systemic bleeding should be treated with screened blood products. Study in Thailand has shown that for patients who presented with parasitemia > 30% and severe systemic complications such as acute renal failure and ARDS, survival was superior in the group who received exchange transfusion. The use of heparin is generally restricted to patients with DIC and extensive deposition of fibrin, as occurs with purpura fulminans or acral ischemia. Antiplatelet agents interfere with the protective effect of platelets against malaria and should be avoided.     

脑淀粉样血管病变与脑微出血

脑淀粉样血管病（CAA）是造成血压正常的老年人自发性皮质．皮质下脑内出血的重要原因。由于很多病例无症状,对共诊断及预防受到很大限制。研究显示,脑微出血（CMB）和CAA的发生与预后密切相关,本研究仅对CAA与CMB的相关性做一综述。     

脑血管支架成形术后脑高灌注综合征

目的 探讨脑动脉支架成形术后高灌注综合征（cerebral hyperperfusion syndrome,CHS）的发病机制及 临床表现。 方法 回顾性分析中国人民解放军第306医院4例脑动脉狭窄支架成形术后发生CHS患者的临床资料。 结果 本组4例CHS中男性3例,女性1例,年龄43～77岁。2例行颈动脉狭窄支架成形术（carotid artery stenting,CAS）,1例行CAS及椎动脉支架置入术,1例行基底动脉狭窄支架成形术。发生CHS症状时间 在术后1 h～3 d。症状为头痛3例,右侧肢体偏瘫1例,视物不清1例,意识障碍1例,头计算机断层扫描 （computed tomography,CT）提示脑实质出血2例,蛛网膜下腔出血1例,脑水肿1例。经降压、脱水等治 疗后,3例均恢复良好,1例死亡。 结论 脑动脉支架成形术后CHS是一种少见及严重的疾病,需提高认识,尽早诊断,尽早治疗。