Neurological manifestations of malaria : an update.
Several neurological complications are associated with complicated and severe falciparum malaria. Cerebral malaria is one of the most dreaded complication. The children are particularly more vulnerable to have this complication. Despite availability of several potent antimalarial drugs in recent past, the mortality status has not changed. A large number of survivors are left with disabling neurological sequelae. Few patients may experience post-malaria neurological syndrome after recovery from complicated falciparum infection. Various psychiatric syndromes have been described either as early manifestation of cerebral malaria or part of post malaria neurological syndrome. From Indian 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 be differentiated from febrile convulsions. Falciparum malaria is also associated specifically with convulsions in uncomplicated patients of malaria. Several isolated case reports of various other neurological syndromes like peripheral neuropathies, various movement disorders, myelopathies and stroke like syndrome have been described. However association of these neurological manifestations with malaria remains doubtful.
Malaria is a common parasitic disease caused by a protozoan from the genus 'Plasmodium' of which there are four human species : Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and Plasmodium malaria. Every year malaria causes clinical illness in over 300-500 million people globally and over 1 million people die from it every year. In India the incidence of malaria, since 1982, is about 2 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 are particularly at risk. Increasing drug resistance in several parts of our country has further aggravated the 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 potentially life threatening neurological complication. In this article an updated account of cerebral malaria and other important neurological manifestations of the disease have been discussed.
Cerebral malaria is characterized by unarousable coma. Loss of consciousness can develop very rapidly, most of the patients being in deep coma by the time they reach the hospital. Convulsions are frequent, especially in children. Few patients may have status epilepticus. For the diagnosis of cerebral malaria, coma should persist for more than 30 minutes after a generalized seizure to differentiate it from 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 its modification Blantyre scale in children is useful in categorizing the level of unconsciousness in cases with cerebral malaria.
A variety of neuro-ophthalmological signs could be elicited. Dysconjugate gaze (internuclear ophthalmoplegia) is a common finding. Corneal and conjuctival reflexes are usually intact, the pupils are symmetrical and react normally to light. The eyes are usually divergent with normal doll's eye movement. Papilloedema is rare but retinal haemorrhages are sometimes seen.,,,
Cerebral malaria is also known as 'symmetric encephalopathy' because of presence of symmetrical upper motor neurone signs. Muscle tone is increased and tendon reflexes are usually brisk with patellar and ankle clonus, along with extensor plantar responses. Abdominal reflexes are usually absent. Extensor posturing suggesting brainstem dysfunction, either due to cerebral malaria or profound hypoglycaemia, is a common and important sign. In advanced stages decerebrate and decorticate 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 death is not apparent most of the time. Progressive deterioration of brainstem function may lead to cardiac and respiratory arrest.,
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.,, 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 the white matter. These haemorrhages result from the rupture of endarterioles proximal to the occlusive plugs of parasitized red blood cells., High levels of cytokine 'tissue necrosis factor' (TNF) have been found in the plasma of patients with malaria. Recent observations suggest that TNF upregulates the nitric oxide synthetase activity. It is possible that large amount of nitrous oxide is produced locally at the sites of sequestered parasites. This nitrous oxide diffuses across the wall of the affected cerebral vessels into the brain, where it interferes with the activity of calcium influx mechanisms, inducing coma in a manner analogous to some anaesthetics.,
In majority of the cases, examination of thick and thin films of the peripheral blood will reveal malarial parasites. 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 or low parasitaemia. Lumbar puncture should routinely be performed to rule out possibility of bacterial meningitis.
For the treatment of cerebral malaria, antimalarial drugs are given by intravenous infusion to clear the parasitaemia in the shortest possible period. Quinine is currently considered the drug of choice. If an intravenous preparation of quinine is not readily available, quinidine gluconate can be used to initiate treatment. The practice of using intravenous route is often difficult to practice in children and in the setting of rural health centres. One recent study has confirmed efficacy of intramuscular administration of quinine in children with cerebral malaria. Another important point in the management is to achieve therapeutic plasma concentrations of antimalarial drugs as quickly as possible. 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. When the patients start taking orally, antimalarial drugs should be administered by this route [Table I]. Artemether and artesunate are two derivatives of traditional Chinese antimalarial drug qinghaosu (artemisinin). These derivatives are most rapidly acting and potent of all the antimalarial drugs. Two recently published reports of controlled studies comparing quinine with artemether proved superiority of later drug in children as well as in adults., Artemisinin derivatives are simple to administer by intramuscular route and have no apparent local or systemic side effects [Table I]. Quinine causes hypotension if given too quickly by intravenous injection, and it also prolongs ventricular repolarization (prolongation of QT interval) seen in electrocardiography. The intramuscular administration of quinine is often painful and causes local tissue damage, which sometimes results in abscess formation and occasionally may produce tetanus. In experimental studies on primates, artemether produced an unusual and selective pattern of damage to certain brain-stem nuclei (auditory)., The study done by Hein et al 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 groups of patients : (1) young patients especially children with severe disease; (2) patients treated with quinine 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 because all these clinical features also occur in cerebral malaria itself. Deterioration in consciousness may be 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 be given to prevent hypoglycaemia.,, Use of dexamethasone is contra indicated in cerebral malaria. In a controlled study there was no evidence of benefit, but the duration of unconsciousness was prolonged, and there was an increased incidence of infection and gastrointestinal bleeding in dexamethasone treated group. Similarly, mannitol has no place in the management of cerebral malaria, because usually there is no evidence of cerebral oedema. The successful use of exchange transfusion has been reported in patients of severe falciparum malaria. Exchange transfuion can be recommended for patients having parasitaemia exceeding 10%, and who are severely ill.
Cerebral malaria is often associated with other serious systemic complications. In addition to hypoglycaemia, hyperpyrexia, severe anaemia, shock, renal failure and pulmonary oedema may contribute to coma. 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 coma score.,, Deaths from cerebral malaria usually occur within first 24 hours of admission to the hospital, but occasional late deaths are also encountered. Some patients make a rapid recovery but deterioration in conscious level and recurrent episodes of convulsions and hypoglycaemia may occur after 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. These sequelae are more common in children., In a large series from India including 185 adult patients, Bajiya and Kochar 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 4 patients. 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 symptoms were still present. In a recent study van Hensbroek et al observed that in children the incidence of sequelae was 20% at the time of discharge but only 4% of patients had detectable deficit when examined 6 months later. The most frequent sequelae were paresis and ataxia, often found in combination with other neurological abnormalities. Cognitive and behavioural abnormalities were observed in 2% of survivors assessed at one month. These abnormalities ranged from mild attention disorders to grossly abnormal patterns of behaviour with hallucinations and aggressive attacks. In approximately 1% of children, gross developmental regression was seen. These severely handicapped children were often blind, deaf, aphasic and paretic. 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 to elucidate the cause of neurological sequelae and intracranial hypertension. Four children with subsequent serious neurological sequelae had widespread low density areas suggestive of ischaemic damage. Their follow-up scans showed either severe cerebral atrophy and/or infarction. The neurological sequelae observed were hemiparesis, hemidystonia, learning problems, cortical blindness and spastic quadriparesis, in variable combinations. One patient was in persistent vegetative state.
Varied psychiatric manifestations have been described as a part of cerebral malaria or after recovery from unconsciousness. Malarial psychosis develops because of encephalopathy in patients with cerebral malaria. It manifests as paranoid and manic syndromes in acute stage; depression being a late sequelae. Confusional states, delirium with hallucinations, transient amnesia and schizophrenic picture have been also described. Infrequently, permanent personality disturbances and dementia like picture have been observed. Agitation and confusion may develop after patient has recoverd from coma. These psychiatric manifestations may be presenting feature in patients with acute uncomplicated malaria especially in association with hyperpyrexia. Neuropsychiatric manifestions are also caused by antimalarial drugs.,,,
Seizures in malaria
Convulsions occur in 40% of adult patients and majority of children with cerebral malaria. Generalized convulsions are more common than partial seizures. Possible causes of these convulsions include cerebral hypoxia associated with cerebral malaria, fever, hypoglycaemia, other metabolic disturbances such as lactic acidosis, antimalarial drugs, eclampsia in pregnant women and Reye'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. Recently, van Hensbroek et al established a link between repeated convulsions and development of long-term neurological sequelae and emphasized the need to control the convulsions early. Convulsions should be 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 by the vascular invasion of the organisms. It may be difficult to distinguish febrile convulsions and those resulting form cerebral malaria in children. Vivax malaria is also a frequent cause of typical febrile convulsions in endemic areas.,
Post-malaria neurological syndrome
Post-malaria neurological syndrome is a discrete, transient neurological syndrome seen after recovery from severe infection. 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 neurological or psychiatric symptoms within two months of acute illness. 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 neurological syndrome. In one patient it followed uncomplicated malaria, and in 21 patients it followed severe malaria. Thirteen patients had an acute confusional state or psychosis, six had one or more generalised 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. 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. Dominant cerebellar involvement could be part of cerebral malaria. Cerebellar signs resolve along with cerebral manifestations. A syndrome of delayed cerebellar ataxia has frequently been reported from Sri Lanka in which there is an acute, self limiting, isolated ataxia without any evidence of cerebral involvement. Severe gait and truncal ataxia are striking features suggesting that the disease predominantly affects midline cerebellar structures. The majority of patients have afebrile period before the onset of cerebellar symptoms. 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.,,, 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 symptomatic response has been noted with oral clonazepam.,
Other neurological manifestations in uncomplicated malaria Postural hypotension is common in uncomplicated malaria and is exacerbated by the quinoline antimalarial drugs. Febrile patients, both adults and children should be kept in horizontal position and great care must be taken if they get up rapidly from beds. Mothers should be discouraged from carrying febrile babies vertically immediately after parenteral quinine or chloroquine has been given.
Malarial polyneuritis, once frequent, is now rare. Malaria can give rise to Guillian-Barre syndrome like presentation, mononeuritic syndromes such as facial palsy, trigeminal neuralgia, retrobulbar optic neuritis 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 associated with bleeding from multiple sites. He had disseminated intravascular coagulation and subsquent thrombocytopaenia and hypofibrinogenaemia., In addition, several isolated case reports described extrapyramidal syndromes, asteriexis, upper motor neuron quadriparesis, cranial nerve involvement and periodic paralysis in patients of uncomplicated malaria. However, association of these neurological manifestations with malaria remains doubtful.,,
Neurological manifestations due to antimalarial drugs
Chloroquine is usually very well tolerated. However, it may rarely produce transient neuropsychiatric syndrome or cerebellar dysfunction. Prolonged administration of this drug may cause a vacuolar myopathy. In one report chloroqine has been shown to precipitate acute intermittent porphyria. The quinine and quinidine may be associated with cinchonism (nausea, tinnitus and high-tone deafness). Mefloquine, a new antimalarial drug recently made available in India, is associated with serious but self-limiting neuro-psychiatric reaction. Occurrence of confusion has been reported in 0.5 to 1.0 percent of Europeans and Africans, but only 0.1% of south-east Asian patients. Lately, a case of 'central anticholinergic syndrome' associated with mefloquine treatment has been described. In an epileptic patient mefloquine should be avoided as it has potent epileptogenic effect as well. Similarly, van Hensbroek et al in a comparative study of artemether and quinine in children with cerebral malaria observed increased incidence of convulsions in artemether treated group. Ataxia and slurring of speech have been described after artesunate treatment for falciparum malaria.
Neurological manifestations are important aspect of clinical features of complicated as well as uncomplicated malaria. Neurological involvement is more frequent with falciparum malaria because of its unique characteristics leading to micro-vascular involvement. Both central and peripheral nervous system 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. Use of newer drugs has been recommended for drug resistant malaria patients. Due to widespread availability and indiscriminate use (which has already started) there is a fear that resistance may develop to these drugs as well. Judicious use of antimalarial drugs will go a long way to prevent devastating neurological sequelae and neurological complications of malaria. We should adhere to the recommendations of WHO for proper use of these newer and potent antimalarial drugs.