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Neurological manifestations of malaria : an update. 

Garg RK, Karak B, Misra S 

Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India.  

Correspondence Address: Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India.  

» Abstract 

Several neurological complications are associated with complicated and severe falciparum malaria.Cerebral malaria is one of the most dreaded complication. The children are particularly morevulnerable to have this complication. Despite availability of several potent antimalarial drugs in recentpast, the mortality status has not changed. A large number of survivors are left with disablingneurological sequelae. Few patients may experience post-malaria neurological syndrome after

recovery from complicated falciparum infection. Various psychiatric syndromes have been describedeither as early manifestation of cerebral malaria or part of post malaria neurological syndrome. FromIndian subcontinent several patients of delayed cerebellar ataxia have also been described following

recovery from clinical malaria. In paediatric patients, convulsions of cerebral malaria need to bedifferentiated from febrile convulsions. Falciparum malaria is also associated specifically withconvulsions in uncomplicated patients of malaria. Several isolated case reports of various otherneurological syndromes like peripheral neuropathies, various movement disorders, myelopathies andstroke like syndrome have been described. However association of these neurological manifestationswith malaria remains doubtful.

How to cite this article: 

Garg R K, Karak B, Misra S. Neurological manifestations of malaria : an update. Neurol India 1999;47:85-91

How to cite this URL: 

Garg R K, Karak B, Misra S. Neurological manifestations of malaria : an update. Neurol India [serial online] 1999

[cited 2013 Mar 21];47:85-91. Available from: http://www.neurologyindia.com/text.asp?1999/47/2/85/1647 

» Introduction 

Malaria is a common parasitic disease caused by a protozoan from the genus 'Plasmodium' of whichthere are four human species : Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale andPlasmodium malaria. Every year malaria causes clinical illness in over 300-500 million people globallyand over 1 million people die from it every year. In India the incidence of malaria, since 1982, is about2 million cases per year, representing 40% of total number of cases outside Africa. The proportion of falciparum malaria is between 35 to 43%, which affects both young and old persons, but children areparticularly at risk.[1]Increasing drug resistance in several parts of our country has further aggravatedthe problem of management. Several neurological manifestations of malaria have been reported.Cerebral form of malaria because of severe falciparum infection is the most common and potentiallylife threatening neurological complication. In this article an updated account of cerebral malaria andother important neurological manifestations of the disease have been discussed.

Cerebral Malaria

Cerebral malaria is characterized by unarousable coma. Loss of consciousness can develop very

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rapidly, most of the patients being in deep coma by the time they reach the hospital. Convulsions arefrequent, especially in children. Few patients may have status epilepticus. For the diagnosis of cerebralmalaria, coma should persist for more than 30 minutes after a generalized seizure to differentiate itfrom post-ictal coma. Localizing signs are observed infrequently, but in severe cases there may be

generalized hypertonia, opisthotonous, posturing and bruxism. Glasgow coma scale in adults and itsmodification Blantyre scale in children is useful in categorizing the level of unconsciousness in caseswith cerebral malaria.

A variety of neuro-ophthalmological signs could be elicited. Dysconjugate gaze (internuclearophthalmoplegia) is a common finding. Corneal and conjuctival reflexes are usually intact, the pupilsare symmetrical and react normally to light. The eyes are usually divergent with normal doll's eyemovement. Papilloedema is rare but retinal haemorrhages are sometimes seen.[2],[3],[4],[5] 

Cerebral malaria is also known as 'symmetric encephalopathy' because of presence of symmetricalupper motor neurone signs. Muscle tone is increased and tendon reflexes are usually brisk withpatellar and ankle clonus, along with extensor plantar responses. Abdominal reflexes are usuallyabsent. Extensor posturing suggesting brainstem dysfunction, either due to cerebral malaria or

profound hypoglycaemia, is a common and important sign. In advanced stages decerebrate anddecorticate rigidity are frequently present and often associated with sustained upwards deviation of eyes, extension of neck, pouting of lips and periodic sterterous breathing pattern. The cause of deathis not apparent most of the time. Progressive deterioration of brainstem function may lead to cardiac

and respiratory arrest.[2],[4] 

In these patients small cerebral vessels are packed with parasitized red blood cells. The degree of 

sequestration of parasitized erythrocytes in the cerebral microvasculature correlates with the depth of coma.[6],[7],[8] Electron-dense knobs are present on the surface of parasitized red blood cells, close to

their point of contact with endothelial cells. Numerous patechial ring haemorrhages are seen in thewhite matter. These haemorrhages result from the rupture of endarterioles proximal to the occlusiveplugs of parasitized red blood cells.[9],[10] High levels of cytokine 'tissue necrosis factor' (TNF) havebeen found in the plasma of patients with malaria.[11] Recent observations suggest that TNF

upregulates the nitric oxide synthetase activity. It is possible that large amount of nitrous oxide isproduced locally at the sites of sequestered parasites. This nitrous oxide diffuses across the wall of theaffected cerebral vessels into the brain, where it interferes with the activity of calcium influxmechanisms, inducing coma in a manner analogous to some anaesthetics.[12],[13] 

In majority of the cases, examination of thick and thin films of the peripheral blood will reveal malarialparasites. The presence of malarial pigment in monocytes is a useful indicator of the diagnosis of malaria, especially in anaemic children and in patients with severe malaria associated with absent orlow parasitaemia.[14]Lumbar puncture should routinely be performed to rule out possibility of bacterialmeningitis.[2] 

For the treatment of cerebral malaria, antimalarial drugs are given by intravenous infusion to clear theparasitaemia in the shortest possible period. Quinine is currently considered the drug of choice. If anintravenous preparation of quinine is not readily available, quinidine gluconate can be used to initiatetreatment.[15]The practice of using intravenous route is often difficult to practice in children and in thesetting of rural health centres.[16] One recent study[17] has confirmed efficacy of intramuscularadministration of quinine in children with cerebral malaria. Another important point in themanagement is to achieve therapeutic plasma concentrations of antimalarial drugs as quickly aspossible. This can be done by giving initial loading dose; which can safely be given in patients with

renal and hepatic dysfunction and in pregnant women.[18] When the patients start taking orally,antimalarial drugs should be administered by this route [Table I]. Artemether and artesunate are twoderivatives of traditional Chinese antimalarial drug qinghaosu (artemisinin). These derivatives aremost rapidly acting and potent of all the antimalarial drugs.[19] Two recently published reports of controlled studies comparing quinine with artemether proved superiority of later drug in children aswell as in adults.[17],[20] Artemisinin derivatives are simple to administer by intramuscular route andhave no apparent local or systemic side effects[21][Table I]. Quinine causes hypotension if given too

quickly by intravenous injection, and it also prolongs ventricular repolarization (prolongation of QTinterval) seen in electrocardiography. The intramuscular administration of quinine is often painful andcauses local tissue damage, which sometimes results in abscess formation[15] and occasionally may

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produce tetanus.[22] In experimental studies on primates, artemether produced an unusual andselective pattern of damage to certain brain-stem nuclei (auditory).[23],[24] The study done by Hein etal[17] showed significantly prolonged recovery time from coma in patient treated with artemether.

Hypoglycaemia is an important complication of falciparum malaria. It occurs in three different groupsof patients : (1) young patients especially children with severe disease; (2) patients treated withquinine or quinidine, as a result of a quinine-induced hyperinsulinaemia; (3) pregnant women, either

on admission or following quinine treatment. The clinical picture includes deteriorating consciousness,generalized seizures, extensor posturing, shock and coma. The diagnosis is easily overlooked becauseall these clinical features also occur in cerebral malaria itself .[25] Deterioration in consciousness maybe the only sign. On suspicion, the possibility of hypoglycaemia should be confirmed by biochemical

testing, especially in the high risk groups. In an unconscious patient, glucose should regularily begiven to prevent hypoglycaemia.[2],[3],[26] Use of dexamethasone is contra indicated in cerebral

malaria. In a controlled study there was no evidence of benefit, but the duration of unconsciousnesswas prolonged, and there was an increased incidence of infection and gastrointestinal bleeding indexamethasone treated group.[27] Similarly, mannitol has no place in the management of cerebralmalaria, because usually there is no evidence of cerebral oedema.[28] The successful use of exchange

transfusion has been reported in patients of severe falciparum malaria. Exchange transfuion can berecommended for patients having parasitaemia exceeding 10%, and who are severely ill.[29] 

Cerebral malaria is often associated with other serious systemic complications. In addition to

hypoglycaemia, hyperpyrexia, severe anaemia, shock, renal failure and pulmonary oedema maycontribute to coma.[3] The prognosis of cerebral malaria is poor, even under optimal conditions of care.Mortality in children still ranges from 10 to 30% depending upon the initial comascore.[30],[31],[32] Deaths from cerebral malaria usually occur within first 24 hours of admission to thehospital, but occasional late deaths are also encountered. Some patients make a rapid recovery butdeterioration in conscious level and recurrent episodes of convulsions and hypoglycaemia may occurafter an initial period of apparent improvement.

Despite adequate treatment, 10% to 18% of survivors develop neurological sequelae in the form of psychosis, ataxia, hemiplegia, cortical blindness, aphasia and extrapyramidal syndrome. Thesesequelae are more common in children.[30],[33] In a large series from India including 185 adultpatients, Bajiya and Kochar[31]observed neurological sequelae in 13 (10.5%) of the 123 survivors.These neurological sequelae were in the form of psychosis in 5 patients and cerebellar ataxia in 4patients. Extrapyramidal rigidity and hemiplegia were also seen in 2 patients each. All of them

recovered fully at the end of the month. However, in three patient with psychosis, mental symptomswere still present.[31] In a recent study van Hensbroek et al[34] observed that in children the incidence

of sequelae was 20% at the time of discharge but only 4% of patients had detectable deficit whenexamined 6 months later. The most frequent sequelae were paresis and ataxia, often found incombination with other neurological abnormalities. Cognitive and behavioural abnormalities wereobserved in 2% of survivors assessed at one month. These abnormalities ranged from mild attentiondisorders to grossly abnormal patterns of behaviour with hallucinations and aggressive attacks. Inapproximately 1% of children, gross developmental regression was seen. These severely handicappedchildren were often blind, deaf, aphasic and paretic.[34]Depth and duration of coma, and multiple

convulsions were independent risk factors for these sequelae.

Computed tomography was performed on 14 Kenyan children recovering from cerebral malaria toelucidate the cause of neurological sequelae and intracranial hypertension. Four children withsubsequent serious neurological sequelae had widespread low density areas suggestive of ischaemic

damage. Their follow-up scans showed either severe cerebral atrophy and/or infarction. Theneurological sequelae observed were hemiparesis, hemidystonia, learning problems, cortical blindnessand spastic quadriparesis, in variable combinations. One patient was in persistent vegetative state.[35] 

Psychiatric manifestations

Varied psychiatric manifestations have been described as a part of cerebral malaria or after recoveryfrom unconsciousness. Malarial psychosis develops because of encephalopathy in patients withcerebral malaria. It manifests as paranoid and manic syndromes in acute stage; depression being alate sequelae. Confusional states, delirium with hallucinations, transient amnesia and schizophrenic

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picture have been also described. Infrequently, permanent personality disturbances and dementia likepicture have been observed. Agitation and confusion may develop after patient has recoverd fromcoma. These psychiatric manifestations may be presenting feature in patients with acuteuncomplicated malaria especially in association with hyperpyrexia. Neuropsychiatric manifestions arealso caused by antimalarial drugs.[36],[37],[38],[39] 

Seizures in malaria

Convulsions occur in 40% of adult patients and majority of children with cerebralmalaria.[3] Generalized convulsions are more common than partial seizures. Possible causes of theseconvulsions include cerebral hypoxia associated with cerebral malaria, fever, hypoglycaemia, other

metabolic disturbances such as lactic acidosis, antimalarial drugs, eclampsia in pregnant women andReye's syndrome in children. The use of a single intramuscular injection of phenobarbital sodium (10-15 mg/kg body weight) on admission may reduce the incidence of convulsions.[40] Recently, vanHensbroek et al[34] established a link between repeated convulsions and development of long-term

neurological sequelae and emphasized the need to control the convulsions early. Convulsions shouldbe treated with paraldehyde 0.1 mg/kg of body weight intramuscularly. Diazepam may also be used.

Chronic remote symptomatic epilepsy may be related to the development of astrocytosis caused bythe vascular invasion of the organisms. It may be difficult to distinguish febrile convulsions and thoseresulting form cerebral malaria in children. Vivax malaria is also a frequent cause of typical febrile

convulsions in endemic areas.[41],[42] 

Post-malaria neurological syndrome

Post-malaria neurological syndrome is a discrete, transient neurological syndrome seen after recoveryfrom severe infection. Criteria for inclusion under this syndrome are : recent symptomatic malarialinfection with parasites cleared from blood, full recovery of consciousness in cases of cerebral malariaand the development of new neurological or psychiatric[8] symptoms within two months of acuteillness.[43] Mai et al in a series of 18124 treated patients of falciparum malaria (1176 of whom had

severe infection), reported 19 adults and 3 children with subsequent post-malaria neurologicalsyndrome. In one patient it followed uncomplicated malaria, and in 21 patients it followed severemalaria. Thirteen patients had an acute confusional state or psychosis, six had one or moregeneralised seizure, two had generalised convulsions followed by a long period of acute confusion,while one patient developed fine tremors. The syndrome was self limiting and in few cases it was

associated with the use of oral mefloquine.[43] Cerebellar syndromes in malaria

Cerebellar involvement is the most consistent neurological manifestation of complicated as well as of uncomplicated malaria. Purkinje cells are susceptible to damage due to hyperpyrexia. The patients of uncomplicated malaria can also develop cerebellar syndrome.[44] Dominant cerebellar involvementcould be part of cerebral malaria. Cerebellar signs resolve along with cerebral manifestations.[45] Asyndrome of delayed cerebellar ataxia has frequently been reported from Sri Lanka[46] in which thereis an acute, self limiting, isolated ataxia without any evidence of cerebral involvement. Severe gait andtruncal ataxia are striking features suggesting that the disease predominantly affects midlinecerebellar structures. The majority of patients have afebrile period before the onset of cerebellarsymptoms. It is always associated with Plasmodium falciparum infection. The exact mechanism of delayed cerebellar ataxia is unknown, however, there is some evidence to suggest involvement of immunological factors in the pathogenesis.[46],[47],[48],[49] In few case reports, dramatic syndrome of opsoclonus-myoclonus in relation to malaria has also been described. Activation of some neurotropic

virus resulting in this syndrome has been suggested as possible mechanism. An excellent symptomaticresponse has been noted with oral clonazepam.[50],[51] 

Other neurological manifestations in uncomplicated malaria Postural hypotension is common inuncomplicated malaria and is exacerbated by the quinoline antimalarial drugs. Febrile patients, bothadults and children should be kept in horizontal position and great care must be taken if they get uprapidly from beds. Mothers should be discouraged from carrying febrile babies vertically immediatelyafter parenteral quinine or chloroquine has been given.[15] 

Malarial polyneuritis, once frequent, is now rare. Malaria can give rise to Guillian-Barre syndrome like

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presentation, mononeuritic syndromes such as facial palsy, trigeminal neuralgia, retrobulbar opticneuritis and involvement of ulnar, circumflex and lateral popliteal nerves. The existence of malaria-induced polyradiculoneuritis has been questioned because pathogenesis is not precisely understood.The possibilities include parasitic emboli obstructing the vasa nervosum, liberation of neurotoxin from

the parasite and / or metabolic or nutritional disturbances.[52-54] There are several reports of subarachnoid haemorrhage from India. In one patient, subarachnoid haemorrhage was associatedwith bleeding from multiple sites. He had disseminated intravascular coagulation and subsquent

thrombocytopaenia and hypofibrinogenaemia.[55],[56] In addition, several isolated case reportsdescribed extrapyramidal syndromes, asteriexis, upper motor neuron quadriparesis, cranial nerveinvolvement and periodic paralysis in patients of uncomplicated malaria. However, association of theseneurological manifestations with malaria remains doubtful.[4],[57],[58] 

Neurological manifestations due to antimalarial drugs

Chloroquine is usually very well tolerated. However, it may rarely produce transient neuropsychiatricsyndrome or cerebellar dysfunction. Prolonged administration of this drug may cause a vacuolarmyopathy. In one report chloroqine has been shown to precipitate acute intermittentporphyria.[59] The quinine and quinidine may be associated with cinchonism (nausea, tinnitus andhigh-tone deafness). Mefloquine, a new antimalarial drug recently made available in India, isassociated with serious but self-limiting neuro-psychiatric reaction. Occurrence of confusion has beenreported in 0.5 to 1.0 percent of Europeans and Africans, but only 0.1% of south-east Asian

patients.[60] Lately, a case of 'central anticholinergic syndrome' associated with mefloquine treatmenthas been described.[61] In an epileptic patient mefloquine should be avoided as it has potentepileptogenic effect as well. Similarly, van Hensbroek et al[20] in a comparative study of artemether

and quinine in children with cerebral malaria observed increased incidence of convulsions inartemether treated group. Ataxia and slurring of speech have been described after artesunatetreatment for falciparum malaria.[62] 

» Conclusion 

Neurological manifestations are important aspect of clinical features of complicated as well asuncomplicated malaria. Neurological involvement is more frequent with falciparum malaria because of 

its unique characteristics leading to micro-vascular involvement. Both central and peripheral nervoussystem is likely to be affected. Neurological side effects of antimalarial drugs add to the spectrum of neurological manifestations. Whole spectrum of antimalarial drugs is now available in our country. Useof newer drugs has been recommended for drug resistant malaria patients. Due to widespreadavailability and indiscriminate use (which has already started) there is a fear that resistance maydevelop to these drugs as well. Judicious use of antimalarial drugs will go a long way to preventdevastating neurological sequelae and neurological complications of malaria. We should adhere to therecommendations of WHO for proper use of these newer and potent antimalarial drugs.

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