NEUROLOGICAL MANIFESTATIONS O F MALARIA GUSTAVO
C. ROMÁN * — NIMAL
SENANAYAKE
**
SUMMARY — The involvement of the nervous system in malaria is reviewed in this paper. Cerebral malaria, the acute encephalopathy which complicates exclusively the infection by Plasmodium falciparum commonly affects children and adolescents in hyperendemic areas. Plugging of cerebral capillaries and venules by clumped, parasitized red cells causing sludging in the capillary circulation is one hypothesis to explain its pathogenesis. The other is a humoral hypothesis which proposes nonspecific, immune-mediated, inflammatory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. Cerebral malaria has a mortality rate up to 50%, and also a considerable longterm morbidity, particularly in children. Hypoglycemia, largely in patients treated with quinine, may complicate the cerebral symptomatology. Other central nervous manifestations of malaria include intracranial hemorrhage, cerebral arterial occlusion, and transient extrapyramidal and neuropsychiiatric manifestations. A self-limiting, isolated cerebellar ataxia, presumably caused by immunological mechanisms, in patients recovering from falciparum malaria has been recognized in Sri Lanka. Malaria is a common cause of febrile seizures in the tropics, and it also contributes to the development of epilepsy in later life. Several reports of spinal cord and peripheral nerve involvement are also available. A transient muscle paralysis resembling periodic paralysis during febrile episodes of malaria has been described in some patients. The pathogenesis of these neurological manifestations remains unexplored, but offers excellent perspectives for research at a clinical as well as experimental level. K E Y WORDS: malaria, Plasmodium falciparum, nervous system. Manifestações neurológicas da malária Manifestações neurológicas da malária RESUMO — O envolvimento do sistema nervoso central pela malária é revisto neste artigo. Malária cerebral, a encefalopatia que complica exclusivamente a infecção pelo Flasmodium Plasmodium falciparum, atinge essencialmente crianças e adolescentes em áreas hiperendêmicas. Uma das hipóteses para a sua patogênese consiste no desvio dia circulação capilar por obstrução de capilares e vénulas cerebrais por eritrocitos parasitados. Outra, a teoria humoral, propõe que a resposta inflamatória, inflamatoria, imunomediada e inespecífica, liberta substâncias vasoativas capazes de produzir alterações endoteliais e de permeabilidade. Malária cerebral tem taxa de mortalidade até 50% e também considerável morbidade a longo prazo, particularmente em crianças. A sintomatologia cerebral pode ser complicada por hipoglicemia, principalmente em doentes tratados com quinino. Outras manifestações incluem hemorragia intracraniana, neuropsiquiátrica. Em oclusão arterial cerebral e sintomatologia transitória extrapiramidal e neuropsiquiátriea. Sri Lanka, alguns doentes em recuperação têm mostrado ataxia cerebelar, autolimitada, provavelmente devida a mecanismos imunes. Malária é causa frequente de convulsões febris nos trópicos e contribui para o desenvolvimento posterior de epilepsia. Envolvimento medular e dos nervos periféricos também têm sido descritos. Durante episódios febris, alguns doentes têm apresentado paralisia transitória semelhante à paralisia periódica. A patogênese das manifestações neurológicas na malária continua por ser esclarecida e oferece excelentes perspectivas de investigaçção tanto clínica como experimental. PALAVRAS CHAVE: malária, Plasmodium falciparum, sistema nervoso. * M.D., F.A.C.P., Chief, Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, USA; ** M.D., F . R . C P . , Professor of Medicine, Department of Medicine, Faculty of Medicine, University of Peradeniya, Paradeniya, Sri Lanka, and Visiting Scientist Neuroepidemiology Branch, NINDS, NIH, Bethesda, USA. Dr. Gustavo C. Román — Neuroepidemiology Branch - Federal Wisconsin Avenue - Bethesda, Maryland 20892 - USA.
Building,
Room
Ilk
- 1550
Malaria is rising again as the most important parasitic disease in the world. Several factors have been responsible for this resurgence. First, resistance of the parasite to antimalarial drugs and of the arthropod vectors to insecticides. Second, socio-economic factors which have resulted in migration, irrigation, deforestation, and also violence and warfare which have forced populations into new areas and have prevented the implementation of malaria control campaigns. Malaria can be a life-threatening disease with involvement of many organs and systems. In this review, however, we focus on the neurological manifestations.
CEREBRAL,
MALARIA
Cerebral malaria is an acute encephalopathy that complicates exclusively the infection by Plasmodium falciparum. Reported frequencies of cerebral malaria in malarial infections vary from 0 . 0 1 % to 1 6 % . It affects children and young adults in hyperendemic areas, and also nonimmune adults traveling from non-endemic areas, commonly when preventive treatment is interrupted. Pregnant women are at risk because of the decreased immunity during pregnancy. There is concern that acquired immune deficiency syndrome (AIDS) may predispose to cerebral malaria in the tropics. 2 4
Pathophysiology — Macroscopically, the most striking findings are moderate cerebral edema and diffuse petechial hemorrhages preferentially involving the white matter of brain 35. Some degree of slate-grey discoloration of the cerebral cortex due to malarial pigment (hemozoin) is present. Microscopically, these petechial hemorrhages show the typical appearance of ring hemorrhages occurring predominantly around white matter arterioles, the sine qua non of cerebral malaria. These are most likely the result of an immune mediated vasculopathy leading to alteration of endothelial permeability, perivascular edema, diapedesis of leukocytes and erythrocytes, necrosis of the vessel wall and intravascular microthrombosis 36. Perivascular demyelination and intravascular aggregates of parasitized erythrocytes and thrombosis of capillaries have also been reported . 1
The pathogenesis of cerebral malaria remains an unsolved riddle 30. Observa tions of plugging of cerebral capillaries and venules by clumped, parasitized red blood cells, as well as demonstration of blood sludging in the capillary circulation in malarial infections have provided the basis for a «mechanical» hypothesis. This cytoadherence is mediated by knobs which protrude from the surface of parasitized red cells. Attach ment of knobs on endothelial cells surface receptors is probably mediated by host molecules such as OKM5 and thrombospondin 29. Lack of response to corticoids has been interpreted either as an indication that damage of the blood-brain barrier with vasogenic edema is not a major pathogenic element, or that the role of inflammation mediated by cytokines or free oxygen radicals is limited and unaffected by dexamethasone treatment 38. The «humoral» hypothesis is based on the fact that most patho genic mechanisms in mammalian malaria are nonspecific, immune-mediated, inflamma tory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. It has been demonstrated that obstruction of cerebral circulation occurs before plugging of the cerebral vessels by high para sitemia 19. Serum T N F concentrations are significantly increased in children dying with cerebral malaria 13. The recent findings of early lesions of endothelial cells, basal lamina, and astrocytes resulting in damage of blood-brain barrier in the murine model, probably due to T N F effect, further confirm the importance of vascular lesions in cerebral malaria 27. Neither mechanical obstruction nor isolated immune responses by themselves are capable of explaining the pathogenesis of cerebral malaria; the answer, very likely, will be found in the interaction of these elements. Clinical Manifestations — Cerebral malaria may present abruptly or develop as a late complication in the progressive worsening of falciparum malaria with multisystem involvement. Typically, the patient presents with fever, severe headache, and delirium progressing to an acute febrile stupor, with hyperthermia reaching 40 ° C to 42 °C. There is rapid worsening from stupor to coma with fluctuations. Decerebrate and decorticate rigidity may occur. Fundi may show retinal hemorrhages. Generalized seizures occur in about 4 0 % of adult patients and in most children. Partial seizures may occur, and transient focal neurological signs are occasionally seen. Tendon refle xes and muscle tone are variable; brisk reflexes, extensor plantar responses, and ankle clonus may be elicited in half the patients; areflexia is a poor prognostic sign.
Cutaneous and abdominal reflexes are usually absent. Neck rigidity is frequent, and the Kernig's sign may be positive. Other forms of presentation of cerebral malaria include a clinical picture of psychomotor agitation and delirium that resembles acute alcohol intoxication or an acute psychotic episode. Diagnosis — Cerebral malaria must be differentiated from other causes of stupor and coma in the tropics. A lumbar puncture should be done to exclude conditions such as meningitis. In cerebral malaria, the cerebrospinal fluid ( C S F ) is generally under normal pressure, with a few lymphocytes and a slight increase in protein content in half the patients. A presumptive diagnosis can be made by demonstrating malarial parasites in peripheral blood. The degree of invasion of the peripheral red cells by falciparum trophozoites cannot always be correlated with the severity of the cerebral involvement. Therefore, it is important to treat the patient on clinical sus picion alone. Treatment — Treatment should be started as soon as possible, since there is a highly significant correlation between delayed chemotherapy and mortality. The recom mended treatment is chloroquine 5 m g / k g diluted in 10 ml/kg isotonic fluid by i.v. infusion over 4-6 hr every 12 hr to a total dose of 25 mg/kg. In chloroquine resis tance, treatment should be started with quinine, with a loading of dose 16,7 mg/kg diluted in 10 ml/kg isotonic fluid by i.v. infusion over 4 h r , then 8.4 mg/kg over 4 hr, 8 hourly until patients can swallow. Then quinine tablets approximately 8.4 mg/kg 8 hourly is given to complete 7 days of treatment . Deep intramuscular injections may be given if intravenous treatment is impossible. The patient must be in bed to avoid postural hypotension. Hypoglycemia should be corrected and monitored fre quently. Corticosteroids cannot be recommended because their use is accompanied by increased mortality 39. Lowering intracranial pressure by lumbar puncture or by osmotic agents agents such as urea or mannitol may be beneficial . Fever should be controlled with acetaminophen and physical means. Aspirin should not be used because of its antiplatelet effects. Anemia should be corrected with packed red cells. Appropriate fluid and electrolyte balance is mandatory. Metabolic acidosis due to hypotension and shock should be corrected. A single i.m. injection of phenobarbitone (3.5 mg/kg) is effective in preventing seizures in cerebral malaria 40. Gram-negative sepsis is common in patients with severe malaria, and appropriate antibiotic therapy should be considered. Treatment with qinghaosu from Artemisia annual L. appears promising ! 5 . 5
22
Prognosis — Mortality rates of cerebral malaria in children, reported mainly from African countries, vary from 6 % to over 5 0 % . It also causes considerable longterm morbidity, particularly in children, up to 2 1 % of patients reported to having neuro logical sequelae 6. In a study of 308 Gambian children, the mortality rate was 1 4 % . Of those who survived, 32 ( 1 2 % ) had residual neurological deficits, the commonest being hemiplegia (23 cases), cortical blindness ( 1 1 ) , aphasia ( 9 ) , and cerebellar ataxia ( 6 ) . Factors predisposing to sequelae included prolonged coma, protracted convulsions, and severe anaemia. The possibility of some of the children who made a good recovery having subtle neurological defects such as intellectual impairment cannot be discounted 6. 2 0
OTHER CEREBRAL.
MANIFESTATIONS
Intracranial hemorrhages — Cerebral hemorrhages causing focal neurological signs such as hemiplegia and aphasia are known to occur in association with malaria. Paralysis associated with cerebral hemorrhages has been described in a rodent model of m a l a r i a In this model the mechanism is immunopathological, and T N F seems to be a critical mediator. A single case of subarachnoid hemorrhage has been reported. He also had numerous retinal hemorrhages . Retinal hemorrhages are an important sign of prognostic significance in cerebral malaria. 12
21
Cerebral arterial occlusion — Some of the focal neurological signs complicating cere bral malaria have been shown to be due to arterial occlusion 6. In an unusual case of malaria which presented like a cerebral tumor, the postmortem examination revealed thrombosis of individual brainstem vessels and perivascular hemorrhages in the cere bellar cortex 37. Extrapyramidal manifestations — Extrapyramidal manifestations may be seen in asso ciation with cerebral malaria, some as late sequelae. Clinical syndromes reported
include tonic-dyskinetic posturing, myoclonia, chorea, and athetoid movements. Even Parkinson's syndrome with its typical posture, facies and tremor has been observed during convalescence 37 Three patients with falciparum malaria reported from India developed cog-wheel rigidity, coarse tremor at rest, and slowness of movements. The signs disappeared completely in 1 to 2 weeks 2. There is also a report of a patient who developed opsoclonus and hand tremor during the course of P. falciparum infection 28. k
Benign intracranial hypertension — A report is available of a young African woman with resistant malaria who presented with typical features of raised intracranial pres sure including bilateral florid papilledema, diagnosed as benign intracranial hyper tension 23. Neuropsychiatrie manifestations — In cerebral malaria, acute psychiatric disturbances including schizophrenic-like and manic syndromes, depression of the exogenous or endogenous types, acute malignant anxiety, amok and confusional states, hallucinatory delirium, amnesia, twilight states, have been described 37. in 6 Indian patients who presented with acute personality disorders, some of the manifestations were disorien tation, hysterical features, paranoid ideas, hallucinations, aggressive behavior, and depression. All the patients had P. falciparum in the peripheral blood which was treated with antimalarial drugs. The psychiatric features completely resolved in about 4 weeks n . Although there is no evidence of a specific malarial psychosis, the organic nature of the malarial psychoses has been well established. The occurrence of schizophrenia-like conditions may indicate malaria triggering off a latent endo genous psychosis 37. HYPOGLYCEMIA
Some patients with falciparum malaria develop hypoglycemia, causing coma, decerebrate posturing and seizures. Up to 5 2 % of African c h i l d r e n and about half the pregnant women with falciparum malaria treated with q u i n i n e have been found to have hypoglycemia. Pregnant women with mild malarial infections can become hypoglycemic without symptoms, but have severe fetal distress or even death in utero 25. The hypoglycemia may develop hours, or even days after admission 34. In the pathogenesis, quinine-induced hyperinsulinemia is probably the principal mecha nism . Consumption of glucose by the parasite, and increased peripheral utilization of glucose may be contributory 25. 41
18
4 2
Clinical features characteristic of hypoglycemia, such as tremulousness, sweating, mydriasis, and tachycardia may not be present 25. Hypoglycemia must be suspected and specifically excluded by performing a blood glucose estimation in any patient who has fits, impaired consciousness or unexplained neurological symptoms or signs. Intravenous dextrose corrects hypoglycemia in children without difficulty 34. in qui nine-treated adults, hyperinsulinemia may cause recurrent hypoglycemia despite con tinuous infusion of dextrose. A somatostatin analogue SMS 201/995 has proved effective in Thailand 26. DELAYED CEREBELLAR
ATAXIA
Cerebellar involvement is a known but rare feature in malaria which has gene rally been considered a part of a global encephalopathy associated with cerebral malaria 8,17. A syndrome of isolated cerebellar ataxia following falciparum malaria has been recognized in Sri Lank in otherwise well, conscious patients, with no features of cerebral malaria. The ataxia occurs as the fever subsides, usually after an afebrile period of 2 to 4 days. T h e delay between onset of fever and the ataxia is 3 to 4 weeks. Unsteadiness on walking is the first and the most noticeable symptom. The disability is maximum on the 2nd or the 3rd day, but in some cases the symptoms progress up to 2 weeks. Some patients may be bedridden because of the ataxia. On examination, abnormal heel-to-toe walking is a constant feature. Other cerebellar signs may be present to a varying degree. C S F examination, electroencephalogram, and computed tomographic brain scan are normal. Treatment consists of antimalarial drugs to clear any parasitemia, symptomatic drugs, and physiotherapy. Complete recovery is usually takes a few weeks or up to 4 months 32. This condition has later been reported from other parts of Sri Lanka 9, and from different parts of the world 7,io. The selective involvement of the cerebellar system, the delay in onset of the ataxia, and the favorable response in some patients treated with prednisolone , 3 2
favor an immune mechanism in the pathogenesis. The self-limiting course with full recovery suggests a demyelinating process, similar to those described following certain viral infections. A recent investigation has shown significantly high serum concen trations of TNFa, interleuikin 6 and interleukin 2, and elevated C S F cytokine in these patients (HJ de Silva, personal communication) providing further evidence for an immunological basis for the neurological symptoms. EPILEPSY
Epilepsy has long been recognized as a late sequel of cerebral malaria. Gene ralized tonic-clonic seizures as well as partial motor seizures have been recorded 37. Pathological examination of the brain in fatal cases, in late stages, have shown the malaric granuloma of Durck formed by astroglial reaction 36 it is conceivable that these lesions may act as epileptogenic foci in those who survive, giving rise to chronic epileptic seizures. FEBRILE
SEIZURES
Malaria is a common cause of febrile seizures in children in the tropics. A study in Congo showed that 9.6% of all children admitted to Brazzaville General Hospital between 1981-1983 presented with seizures 33. Status epilepticus occurred 13.6% of the cases, and 6 7 % of these were related to benign malaria. Febrile seizures occurred in 7 3 . 5 % of all cases, and 8 1 % of them were related to malaria. Approximately 6 0 % of all seizure disorders between 1 month and 6 years of age in a large general hospital were related to benign or malignant forms of malaria, and seizures were the reason for admission in 1 0 % of all children in that age group . In Nigeria, 5 0 % of cases of febrile convulsions are due to malaria. Even in the adult Nigerian, the commonest trigger of epileptic seizure is chloroquine-responsive febrile illness, due to malarial infections 24. 4
SPINAL CORD
DISORDERS
Spinal syndromes of malaria are thought to resemble those of amyotrophic lateral sclerosis, funicular myelosis, spastic spinal paralysis and tabes dorsalis; in part they have been interpreted as late sequelae. In contrast to true tabes dorsalis, the typical Argyll-Robertson pupil is not seen. In cases of simultaneous cerebral and spinal disease, the clinical condition may resemble disseminated encephalomyelitis, e.g. spastic gait, tremor, and occasionally nystagmus and speech disorders. On treat ment with quinine these symptoms are reported to regress 37. PERIPHERAL
NEUROPATHY
Early literature refers to cases of neuritis, polyneuritis, Landry's paralysis, and cranial nerve palsies in association with malarial infections 37. «Irritative» phenomena with sharp or stinging pain in the distribution of a peripheral nerve, followed by a sensation of «drawing» in the muscles with muscle contraction, intense hyperalgesia, and increased sweating have been reported . More recent cases include Guillain-Barre type polyneuropathy developing 2 to 3 weeks following vivax or falciparum malaria 3,14. 16
PERIODIC
PARALYSIS
Transient muscular paralysis resembling periodic paralysis has been observed during febrile episodes of malaria in 3 Sri Lankan patients 31. Following a rigor, the weakness first appeared in the lower limbs, and soon spread to the rest of the body causing paralysis affecting the entire body except for the respiratory muscles. The patients remained conscious during the attack. Signs of improvement appeared in 4 to 6 h r , and the recovery was complete in 8 to 10 hr, the muscles which were affected first being the last to recover. Two of the patients showed a mixed infection of P. vivax and P. falciparum in the peripheral blood films, while the other had only P. vivax. The transient rise of serum potassium concentration due to lysis of red cells and intense muscular contraction during rigors, and the muscular exertion itself caused by the rigo** during the febrile episodes of malaria were suggested as the mechanism underlying the muscle paralysis. A genetic predisposition which make only some individuals susceptible, may explain the general rarity of the phenomenon.
CONCLUSIONS
Involvement of the nervous system in malaria is a complex phenomenon ranging from the lethal encephalopathy to the relatively mild forms of cerebellar involvement. Some of the manifestations, for instance the spinal syndromes and the neuritides, would be difficult to justify as being causally related to plasmodial infections, unless the symptoms disappear or are significantly ameliorated by antimalarial therapy when other causes are excluded. The pathogenesis of the nervous system involvement in malaria remains unexplored, but offers excellent perspectives for research at clinical as well as experimental level. REFERENCES 1. 2. 3. 4.
5. 6. 7. 8. 9. 10.
11. 12.
13.
14. 15.
16. 17. 18. 19. 20.
21. 22.
23.
A i k a w a M. H u m a n c e r e b r a l m a l a r i a . A m J T r o p M e d H y g 1988, 3 9 : 3 - 1 0 . A r y a T V S , A w a s t h i R , R h u t a n i J . E x t r a p y r a m i d a l s y n d r o m e in f a l c i p a r u m m a l a r i a . J A s s o c P h y s i c i a n s I n d i a 1989, 37:393-394. A v a s t h i G, A g g a r w a l S P . P l a s m o d i u m f a l c i p a r u m m a l a r i a a s s o c i a t e d w i t h G u i l l a i n - B a r r e s y n d r o m e . J I n d i a n M e d A s s o c 1985, 8 3 : 3 6 0 - 3 6 3 . B i t t e n c o u r t P R M , G r a c i a CM, L o r e n z a n a P . E p i l e p s y a n d p a r a s i t o s i s of t h e c e n t r a l nervous system. I n P e d l e y T A , M e l d r u m B S ( e d s ) : R e c e n t A d v a n c e s in E p i l e p s y , vol 4. E d i n b u r g h : C h u r c h i l l L i v i n g s t o n e , 1988, p 123-159. B r a d l e y D J , Newbold C I , Wtarrell DA. In Weatherall D J , Ledingham JGG, Warrell D A ( e d s ) : O x f o r d T e x t b o o k of M e d i c i n e . O x f o r d : U n i v e r s i t y P r e s s , 1987, p 5474-5502. B r e w s t e r D R , K w i a t k o w s k i D, W h i t e N J . N e u r o l o g i c a l s e q u e l a e o f c e r e b r a l m a l a r i a in children. L a n c e t 1990, 336:1039-1043. C h i n e P , W o i m a n t F , C o r a b i a n u O, F a y a d a C, H a g u e n a u M. Isolated cerebellar syn d r o m e : a n a t y p i c a l f o r m o f c e r e b r a l m a l a r i a . J N e u r o l N e u r o s u r g P s y c h i a t r y 1991, 54:655. C h i t k a r a A J , A n a n d N K , Saini L . C e r e b e l l a r s y n d r o m e in m a l a r i a . Indian Pediatr 1984, 2 1 : 9 0 8 - 9 1 0 . De Silva H J , G a m a g e R , H e r a t h H K , P e i r i s J B , A b e y s e k e r a D T . A self-limiting midline cerebellar syndrome. I s f a l c i p a r u m m a l a r i a t h e c a u s e ? T r o p D o c t 1988, 1 8 : 5 - 6 . G i r a r d P M , d e B r o u c k e r T , F r y e r DG, N e t t e r J M , S a i m o t AG, C o u l a u d J P . C e r e b e l l a r s y n d r o m e in m i l d P l a s m o d i u m f a l c i p a r u m m a l a r i a . T r a n s R S o c T r o p M e d H y g 1988, 82:204. Gopinathan V P , Thampi U R , Ganguly SB. N e u r o p s y c h i a t r y m a n i f e s t a t i o n s of f a l c i p a r u m m a l a r i a . J I n d i a n M e d A s s o c 1982, 7 8 : 1 5 5 - 1 5 7 . G r a u G E , F a j a r d o L F , P u i g u e t P F , Allet B , L a m b e r t P H , Vassalli P . T u m o r necrosis f a c t o r ( c a c h e c t i n ) a s a n e s s e n t i a l m e d i a t o r in m u r i n e c e r e b r a l m a l a r i a . S c i e n c e 1987, 237:1210-1212. G r a u G E , T a y l o r T E , M o l y n e u x M E , W i r i m a J J , V a s s a l l i P , H o n a m e l M, L a m b e r t P H . T u m o r n e c r o s i s f a c t o r a n d d i s e a s e s e v e r i t y in c h i l d r e n w i t h f a l c i p a r u m m a l a r i a . N E n g l J M e d 1989, 320:1586-1591. G u e r r e i r o C A M , F a c u r e N O , Goncjalves F L J r , D a S i l v a L J , R a m o s MC, P e d r o R D e J . P o l i r r a d i c u l o n e u r i t e e m a l a r i a . A r q N e u r o p s i q u i a t r 1985, 4 3 : 2 1 4 - 2 1 6 . G u o q i a o L , X i n g b o G, R u i J , Z i c a i W , X u a x i a n g J , Z i y a n L . C l i n i c a l s t u d i e s on t r e a t m e n t of cerebral m a l a r i a with qinghaaosu and its derivatives. J T r a d i t Chi Med 1982, 2 : 1 2 5 - 1 3 0 . H a r v e y AM. A t y p e of n e u r i t i s a s s o c i a t e d w i t h m a l a r i a l f e v e r . Bull J o h n s Hopkins H o s p 1944, 7 5 : 2 2 5 - 2 3 1 . I l l a n g a s e k e r a V L , D e S y l v a S. A c u t e c e r e b e l l a r s y n d r o m e in f a l c i p a r u m m a l a r i a . Ceylon M e d J 1976, 2 1 : 1 3 0 - 1 3 2 . L o o a r e e s u w a n S Phillips R E , W h i t e N J , Silamut A, Philips R E , W a r r e l l DA. Quinine a n d s e v e r e f a l c i p a r u m m a l a r i a i n l a t e p r e g n a n c y . A c t a L e i d e n 1987, 5 5 : 1 3 9 - 1 4 9 . M a e g r a i t h B , F l e t c h e r A . T h e p a t h o g e n e s i s of m a m m a l i a n m a l a r i a . A d v P a r a s i t o l 1972, 10:49-75. Molyneux M E , T a y l o r T E , W i r i m a J J , B o r g s t e i n A. Clinical f e a t u r e s a n d p r o g n o s t i c i n d i c a t o r s i n p a e d i a t r i c c e r e b r a l m a l a r i a : a s t u d y of 131 c o m a t o s e M a l a w i a n c h i l d r e n . Q J M e d 1989, 7 1 : 4 4 1 - 4 5 9 . M u r u g a v e l K , S a r a v a n a p a v a n a n t h a n S, A n p a l a h a n A , J a m e s R F . S u b a r a c h n o i d h a e m o r r h a g e i n P l a s m o d i u m f a l c i p a r u m m a l a r i a . P o s t g r a d M e d J 1989, 65:236-237. N e w t o n C R J C , K i r k h a m F J , W i n s t a n l e y P A , P a s v o l G, P e s h u N , W a r r e l l D A , M a r s h K. I n t r a c r a n i a l p r e s s u r e i n A f r i c a n children, w i t h c e r e b r a l m a l a r i a . L a n c e t 1991, 337:573-576. Okelo G B A . Benign intracranial hypertension associated with resistant Plasmodium f a l c i p a r u m m a l a r i a i n f e c t i o n : a c a s e r e p o r t . E A f r M e d J 1985, 6 2 : 3 6 3 - 3 6 4 .
24. 25. 26.
27.
28. 29.
30. 31. 32. 33. 34.
35.
36. 37. 38.
39.
40. 41. 42.
O s u n t o k u n B O . M a l a r i a a n d t h e n e r v o u s s y s t e m . A f r J M e d Sci 1983, 12:165-172. Phillips R E . H y p o g l y c a e m i a is an i m p o r t a n t complication of falciparum malaria. Q J M e d 1989, 2 6 6 : 4 7 7 - 4 8 3 . P h i l l i p s R E i , W a r r e l l D A , L o o a r e e s u w a n S, T u r n e r R C , B l o o m S R , Q u a n t r i l l D , M o o r e AR. Effectiveness o f S M S 201-995, a s y n t h e t i c l o n g - a c t i n g s o m a t o s t a t i n a n a l o g u e , in t r e a t m e n t of quinine induced hyperinsulinaemia. L a n c e t 1986, 1 : 7 1 3 - 7 1 6 . P o l d e r T W , E l i n g W M C , J e r u s a l e m C R , W i j e r s - R o u w M. A c y t o c h e m i c a l s t u d y of c e r e b r o v a s c u l a r l e s i o n s in m i c e i n f e c t e d w i t h P l a s m o d i u m b e r g h e i . J N e u r o l Sci 1991, 101-24-34. P o u n g v a r i n N, P r a d i t s u w a n R . O p s o c l o n u s in m a l a r i a : t h e f i r s t r e p o r t in t h e l i t e r a t u r e . J M e d A s s o c T h a i 1990, 7 3 : 4 6 2 - 4 6 6 . R o b e r t s D D , S c h e r w o o d J A , S p i t a l n i k S L , Plantón L J , H o w a r d R J , D i x i t V M , F r a z i e r W A , M i l l e r L H , G i n s b u r g V. Thrombospondin binds falciparum m a l a r i a parasitized erythrocytes and m a y mediate cytoadherence. N a t u r e 1985, 3 1 8 : 6 4 - 6 6 . R o m a n GC. C e r e b r a l m a l a r i a : t h e u n s o l v e d r i d d l e . J N e u r o l Sci 1991, 1 0 1 : 1 - 6 . S e n a n a y a k e N, W i m a l a w a n s a S J . P e r i o d i c p a r a l y s i s c o m p l i c a t i n g m a l a r i a . P o s t g r a d Med J 1981, 5 7 : 2 7 3 - 2 7 4 . S e n a n a y a k e N. Delayed cerebellar a t a x i a : a new complication of f a l c i p a r u m m a l a r i a ? B r M e d J 1987, 294:1253-1254. S e n g a P , M a y a n d a H F , N z i n g o u l a S. P r o f i l e of s e i z u r e s in i n f a n t s a n d y o u n g c h i l d r e n in B r a z z a v i l l e ( C o n g o ) . A n n P e d i a t r 1985, 3 2 : 4 7 7 - 4 8 0 . Taylor T E , Molyneux ME, Wirima J J , Fletcher KA, Morris K. Blood glucose concen t r a t i o n s in M a l a w i a n c h i l d r e n b e f o r e a n d d u r i n g p a r e n t e r a l q u i n i n e t r e a t m e n t f o r s e v e r e f a l c i p a r u m m a l a r i a . » N E n g l J M e d 1988, 319:1040-1047. T o r o G, R o m á n G, d e R o m a n L N . P a l u d i s m o . I n T o r o G, R o m á n G, d e R o m á n L N (eds): Neurología Tropical: Aspectos Neuropatologicos de la Medicina Tropical. Bo g o t a : E d i t o r i a l P r i n t e r C o l o m b i a n a , 1983, p 106-113. T o r o G, R o m á n GC. C e r e b r a l m a l a r i a : a d i s s e m i n a t e d v a s c u l © m y e l i n o p a t h y . A r c h N e u r o l 1978, 3 5 : 2 7 1 - 2 7 5 . V i e t z e G. Malaria a n d other protozoal diseases. In Vinken P J , B r u y n G W (eds): H a n d b o o k o f C l i n i c a l N e u r o l o g y , vol 35. A m s t e r d a m : N o r t h - H o l l a n d , 1978, p 143-160. W a r r e l l D A , L o o a r e e s u w a n S, P h i l l i p s R E , W h i t e M J , W a r r e l l M J , C h a p e l H , A r e e k u l M, T h a r a v a n i j S. F u n c t i o n , of t h e b l o o d - c e r e b r o s p i n a l fluid b a r r i e r in h u m a n c e r e b r a l m a l a r i a : rejection of the permeability hypothesis. A m J T r o p M e d H y g 1986, 35:882-889. W a r r e l l D A , L o o a r e e s u w a n S, W a r r e l l M J , K a s e m s a m P , I n t r a p a s e r t R , B u n n a g D, Harinasuta T. D e x a m e t h a s o n e p r o v e s d e l e t e r i o u s in c e r e b r a l m a l a r i a : a double-blind t r i a l in 1 0 0 c o m a t o s e p a t i e n t s . N E n g l J M e d 1982, 3 0 6 : 3 1 3 - 3 1 9 . W h i t e N J , L o o a r e e s u w a n S, P h i l l i p s R E , C h a n t h a v a n i c h P , W a r r e l l D A . S i n g l e dose p h e n o b a r b i t o n e p r e v e n t s c o n v u l s i o n s in c e r e b r a l m a l a r i a . L a n c e t 1988, 2 : 6 4 - 6 6 . W h i t e N J , Miller K D , M a r s h K , B e r r y CD, T u r n e r R C , Williamson D H , B r o w n J . H y p o g l y c a e m i a in A f r i c a n c h i l d r e n w i t h s e v e r e m a l a r i a . L a n c e t 1987, 1:708-711. W h i t e N J , W a r r e l l DA, C h a n t h a v a n i c h P , e t al. Severe hypoglycemia and hyperinsulin e m i a in f a l c i p a r u m m a l a r i a . N E n g l J M e d 1983, 3 0 9 : 6 1 - 6 6 .
C. ROMÁN * — NIMAL
SENANAYAKE
**
SUMMARY — The involvement of the nervous system in malaria is reviewed in this paper. Cerebral malaria, the acute encephalopathy which complicates exclusively the infection by Plasmodium falciparum commonly affects children and adolescents in hyperendemic areas. Plugging of cerebral capillaries and venules by clumped, parasitized red cells causing sludging in the capillary circulation is one hypothesis to explain its pathogenesis. The other is a humoral hypothesis which proposes nonspecific, immune-mediated, inflammatory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. Cerebral malaria has a mortality rate up to 50%, and also a considerable longterm morbidity, particularly in children. Hypoglycemia, largely in patients treated with quinine, may complicate the cerebral symptomatology. Other central nervous manifestations of malaria include intracranial hemorrhage, cerebral arterial occlusion, and transient extrapyramidal and neuropsychiiatric manifestations. A self-limiting, isolated cerebellar ataxia, presumably caused by immunological mechanisms, in patients recovering from falciparum malaria has been recognized in Sri Lanka. Malaria is a common cause of febrile seizures in the tropics, and it also contributes to the development of epilepsy in later life. Several reports of spinal cord and peripheral nerve involvement are also available. A transient muscle paralysis resembling periodic paralysis during febrile episodes of malaria has been described in some patients. The pathogenesis of these neurological manifestations remains unexplored, but offers excellent perspectives for research at a clinical as well as experimental level. K E Y WORDS: malaria, Plasmodium falciparum, nervous system. Manifestações neurológicas da malária Manifestações neurológicas da malária RESUMO — O envolvimento do sistema nervoso central pela malária é revisto neste artigo. Malária cerebral, a encefalopatia que complica exclusivamente a infecção pelo Flasmodium Plasmodium falciparum, atinge essencialmente crianças e adolescentes em áreas hiperendêmicas. Uma das hipóteses para a sua patogênese consiste no desvio dia circulação capilar por obstrução de capilares e vénulas cerebrais por eritrocitos parasitados. Outra, a teoria humoral, propõe que a resposta inflamatória, inflamatoria, imunomediada e inespecífica, liberta substâncias vasoativas capazes de produzir alterações endoteliais e de permeabilidade. Malária cerebral tem taxa de mortalidade até 50% e também considerável morbidade a longo prazo, particularmente em crianças. A sintomatologia cerebral pode ser complicada por hipoglicemia, principalmente em doentes tratados com quinino. Outras manifestações incluem hemorragia intracraniana, neuropsiquiátrica. Em oclusão arterial cerebral e sintomatologia transitória extrapiramidal e neuropsiquiátriea. Sri Lanka, alguns doentes em recuperação têm mostrado ataxia cerebelar, autolimitada, provavelmente devida a mecanismos imunes. Malária é causa frequente de convulsões febris nos trópicos e contribui para o desenvolvimento posterior de epilepsia. Envolvimento medular e dos nervos periféricos também têm sido descritos. Durante episódios febris, alguns doentes têm apresentado paralisia transitória semelhante à paralisia periódica. A patogênese das manifestações neurológicas na malária continua por ser esclarecida e oferece excelentes perspectivas de investigaçção tanto clínica como experimental. PALAVRAS CHAVE: malária, Plasmodium falciparum, sistema nervoso. * M.D., F.A.C.P., Chief, Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, USA; ** M.D., F . R . C P . , Professor of Medicine, Department of Medicine, Faculty of Medicine, University of Peradeniya, Paradeniya, Sri Lanka, and Visiting Scientist Neuroepidemiology Branch, NINDS, NIH, Bethesda, USA. Dr. Gustavo C. Román — Neuroepidemiology Branch - Federal Wisconsin Avenue - Bethesda, Maryland 20892 - USA.
Building,
Room
Ilk
- 1550
Malaria is rising again as the most important parasitic disease in the world. Several factors have been responsible for this resurgence. First, resistance of the parasite to antimalarial drugs and of the arthropod vectors to insecticides. Second, socio-economic factors which have resulted in migration, irrigation, deforestation, and also violence and warfare which have forced populations into new areas and have prevented the implementation of malaria control campaigns. Malaria can be a life-threatening disease with involvement of many organs and systems. In this review, however, we focus on the neurological manifestations.
CEREBRAL,
MALARIA
Cerebral malaria is an acute encephalopathy that complicates exclusively the infection by Plasmodium falciparum. Reported frequencies of cerebral malaria in malarial infections vary from 0 . 0 1 % to 1 6 % . It affects children and young adults in hyperendemic areas, and also nonimmune adults traveling from non-endemic areas, commonly when preventive treatment is interrupted. Pregnant women are at risk because of the decreased immunity during pregnancy. There is concern that acquired immune deficiency syndrome (AIDS) may predispose to cerebral malaria in the tropics. 2 4
Pathophysiology — Macroscopically, the most striking findings are moderate cerebral edema and diffuse petechial hemorrhages preferentially involving the white matter of brain 35. Some degree of slate-grey discoloration of the cerebral cortex due to malarial pigment (hemozoin) is present. Microscopically, these petechial hemorrhages show the typical appearance of ring hemorrhages occurring predominantly around white matter arterioles, the sine qua non of cerebral malaria. These are most likely the result of an immune mediated vasculopathy leading to alteration of endothelial permeability, perivascular edema, diapedesis of leukocytes and erythrocytes, necrosis of the vessel wall and intravascular microthrombosis 36. Perivascular demyelination and intravascular aggregates of parasitized erythrocytes and thrombosis of capillaries have also been reported . 1
The pathogenesis of cerebral malaria remains an unsolved riddle 30. Observa tions of plugging of cerebral capillaries and venules by clumped, parasitized red blood cells, as well as demonstration of blood sludging in the capillary circulation in malarial infections have provided the basis for a «mechanical» hypothesis. This cytoadherence is mediated by knobs which protrude from the surface of parasitized red cells. Attach ment of knobs on endothelial cells surface receptors is probably mediated by host molecules such as OKM5 and thrombospondin 29. Lack of response to corticoids has been interpreted either as an indication that damage of the blood-brain barrier with vasogenic edema is not a major pathogenic element, or that the role of inflammation mediated by cytokines or free oxygen radicals is limited and unaffected by dexamethasone treatment 38. The «humoral» hypothesis is based on the fact that most patho genic mechanisms in mammalian malaria are nonspecific, immune-mediated, inflamma tory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. It has been demonstrated that obstruction of cerebral circulation occurs before plugging of the cerebral vessels by high para sitemia 19. Serum T N F concentrations are significantly increased in children dying with cerebral malaria 13. The recent findings of early lesions of endothelial cells, basal lamina, and astrocytes resulting in damage of blood-brain barrier in the murine model, probably due to T N F effect, further confirm the importance of vascular lesions in cerebral malaria 27. Neither mechanical obstruction nor isolated immune responses by themselves are capable of explaining the pathogenesis of cerebral malaria; the answer, very likely, will be found in the interaction of these elements. Clinical Manifestations — Cerebral malaria may present abruptly or develop as a late complication in the progressive worsening of falciparum malaria with multisystem involvement. Typically, the patient presents with fever, severe headache, and delirium progressing to an acute febrile stupor, with hyperthermia reaching 40 ° C to 42 °C. There is rapid worsening from stupor to coma with fluctuations. Decerebrate and decorticate rigidity may occur. Fundi may show retinal hemorrhages. Generalized seizures occur in about 4 0 % of adult patients and in most children. Partial seizures may occur, and transient focal neurological signs are occasionally seen. Tendon refle xes and muscle tone are variable; brisk reflexes, extensor plantar responses, and ankle clonus may be elicited in half the patients; areflexia is a poor prognostic sign.
Cutaneous and abdominal reflexes are usually absent. Neck rigidity is frequent, and the Kernig's sign may be positive. Other forms of presentation of cerebral malaria include a clinical picture of psychomotor agitation and delirium that resembles acute alcohol intoxication or an acute psychotic episode. Diagnosis — Cerebral malaria must be differentiated from other causes of stupor and coma in the tropics. A lumbar puncture should be done to exclude conditions such as meningitis. In cerebral malaria, the cerebrospinal fluid ( C S F ) is generally under normal pressure, with a few lymphocytes and a slight increase in protein content in half the patients. A presumptive diagnosis can be made by demonstrating malarial parasites in peripheral blood. The degree of invasion of the peripheral red cells by falciparum trophozoites cannot always be correlated with the severity of the cerebral involvement. Therefore, it is important to treat the patient on clinical sus picion alone. Treatment — Treatment should be started as soon as possible, since there is a highly significant correlation between delayed chemotherapy and mortality. The recom mended treatment is chloroquine 5 m g / k g diluted in 10 ml/kg isotonic fluid by i.v. infusion over 4-6 hr every 12 hr to a total dose of 25 mg/kg. In chloroquine resis tance, treatment should be started with quinine, with a loading of dose 16,7 mg/kg diluted in 10 ml/kg isotonic fluid by i.v. infusion over 4 h r , then 8.4 mg/kg over 4 hr, 8 hourly until patients can swallow. Then quinine tablets approximately 8.4 mg/kg 8 hourly is given to complete 7 days of treatment . Deep intramuscular injections may be given if intravenous treatment is impossible. The patient must be in bed to avoid postural hypotension. Hypoglycemia should be corrected and monitored fre quently. Corticosteroids cannot be recommended because their use is accompanied by increased mortality 39. Lowering intracranial pressure by lumbar puncture or by osmotic agents agents such as urea or mannitol may be beneficial . Fever should be controlled with acetaminophen and physical means. Aspirin should not be used because of its antiplatelet effects. Anemia should be corrected with packed red cells. Appropriate fluid and electrolyte balance is mandatory. Metabolic acidosis due to hypotension and shock should be corrected. A single i.m. injection of phenobarbitone (3.5 mg/kg) is effective in preventing seizures in cerebral malaria 40. Gram-negative sepsis is common in patients with severe malaria, and appropriate antibiotic therapy should be considered. Treatment with qinghaosu from Artemisia annual L. appears promising ! 5 . 5
22
Prognosis — Mortality rates of cerebral malaria in children, reported mainly from African countries, vary from 6 % to over 5 0 % . It also causes considerable longterm morbidity, particularly in children, up to 2 1 % of patients reported to having neuro logical sequelae 6. In a study of 308 Gambian children, the mortality rate was 1 4 % . Of those who survived, 32 ( 1 2 % ) had residual neurological deficits, the commonest being hemiplegia (23 cases), cortical blindness ( 1 1 ) , aphasia ( 9 ) , and cerebellar ataxia ( 6 ) . Factors predisposing to sequelae included prolonged coma, protracted convulsions, and severe anaemia. The possibility of some of the children who made a good recovery having subtle neurological defects such as intellectual impairment cannot be discounted 6. 2 0
OTHER CEREBRAL.
MANIFESTATIONS
Intracranial hemorrhages — Cerebral hemorrhages causing focal neurological signs such as hemiplegia and aphasia are known to occur in association with malaria. Paralysis associated with cerebral hemorrhages has been described in a rodent model of m a l a r i a In this model the mechanism is immunopathological, and T N F seems to be a critical mediator. A single case of subarachnoid hemorrhage has been reported. He also had numerous retinal hemorrhages . Retinal hemorrhages are an important sign of prognostic significance in cerebral malaria. 12
21
Cerebral arterial occlusion — Some of the focal neurological signs complicating cere bral malaria have been shown to be due to arterial occlusion 6. In an unusual case of malaria which presented like a cerebral tumor, the postmortem examination revealed thrombosis of individual brainstem vessels and perivascular hemorrhages in the cere bellar cortex 37. Extrapyramidal manifestations — Extrapyramidal manifestations may be seen in asso ciation with cerebral malaria, some as late sequelae. Clinical syndromes reported
include tonic-dyskinetic posturing, myoclonia, chorea, and athetoid movements. Even Parkinson's syndrome with its typical posture, facies and tremor has been observed during convalescence 37 Three patients with falciparum malaria reported from India developed cog-wheel rigidity, coarse tremor at rest, and slowness of movements. The signs disappeared completely in 1 to 2 weeks 2. There is also a report of a patient who developed opsoclonus and hand tremor during the course of P. falciparum infection 28. k
Benign intracranial hypertension — A report is available of a young African woman with resistant malaria who presented with typical features of raised intracranial pres sure including bilateral florid papilledema, diagnosed as benign intracranial hyper tension 23. Neuropsychiatrie manifestations — In cerebral malaria, acute psychiatric disturbances including schizophrenic-like and manic syndromes, depression of the exogenous or endogenous types, acute malignant anxiety, amok and confusional states, hallucinatory delirium, amnesia, twilight states, have been described 37. in 6 Indian patients who presented with acute personality disorders, some of the manifestations were disorien tation, hysterical features, paranoid ideas, hallucinations, aggressive behavior, and depression. All the patients had P. falciparum in the peripheral blood which was treated with antimalarial drugs. The psychiatric features completely resolved in about 4 weeks n . Although there is no evidence of a specific malarial psychosis, the organic nature of the malarial psychoses has been well established. The occurrence of schizophrenia-like conditions may indicate malaria triggering off a latent endo genous psychosis 37. HYPOGLYCEMIA
Some patients with falciparum malaria develop hypoglycemia, causing coma, decerebrate posturing and seizures. Up to 5 2 % of African c h i l d r e n and about half the pregnant women with falciparum malaria treated with q u i n i n e have been found to have hypoglycemia. Pregnant women with mild malarial infections can become hypoglycemic without symptoms, but have severe fetal distress or even death in utero 25. The hypoglycemia may develop hours, or even days after admission 34. In the pathogenesis, quinine-induced hyperinsulinemia is probably the principal mecha nism . Consumption of glucose by the parasite, and increased peripheral utilization of glucose may be contributory 25. 41
18
4 2
Clinical features characteristic of hypoglycemia, such as tremulousness, sweating, mydriasis, and tachycardia may not be present 25. Hypoglycemia must be suspected and specifically excluded by performing a blood glucose estimation in any patient who has fits, impaired consciousness or unexplained neurological symptoms or signs. Intravenous dextrose corrects hypoglycemia in children without difficulty 34. in qui nine-treated adults, hyperinsulinemia may cause recurrent hypoglycemia despite con tinuous infusion of dextrose. A somatostatin analogue SMS 201/995 has proved effective in Thailand 26. DELAYED CEREBELLAR
ATAXIA
Cerebellar involvement is a known but rare feature in malaria which has gene rally been considered a part of a global encephalopathy associated with cerebral malaria 8,17. A syndrome of isolated cerebellar ataxia following falciparum malaria has been recognized in Sri Lank in otherwise well, conscious patients, with no features of cerebral malaria. The ataxia occurs as the fever subsides, usually after an afebrile period of 2 to 4 days. T h e delay between onset of fever and the ataxia is 3 to 4 weeks. Unsteadiness on walking is the first and the most noticeable symptom. The disability is maximum on the 2nd or the 3rd day, but in some cases the symptoms progress up to 2 weeks. Some patients may be bedridden because of the ataxia. On examination, abnormal heel-to-toe walking is a constant feature. Other cerebellar signs may be present to a varying degree. C S F examination, electroencephalogram, and computed tomographic brain scan are normal. Treatment consists of antimalarial drugs to clear any parasitemia, symptomatic drugs, and physiotherapy. Complete recovery is usually takes a few weeks or up to 4 months 32. This condition has later been reported from other parts of Sri Lanka 9, and from different parts of the world 7,io. The selective involvement of the cerebellar system, the delay in onset of the ataxia, and the favorable response in some patients treated with prednisolone , 3 2
favor an immune mechanism in the pathogenesis. The self-limiting course with full recovery suggests a demyelinating process, similar to those described following certain viral infections. A recent investigation has shown significantly high serum concen trations of TNFa, interleuikin 6 and interleukin 2, and elevated C S F cytokine in these patients (HJ de Silva, personal communication) providing further evidence for an immunological basis for the neurological symptoms. EPILEPSY
Epilepsy has long been recognized as a late sequel of cerebral malaria. Gene ralized tonic-clonic seizures as well as partial motor seizures have been recorded 37. Pathological examination of the brain in fatal cases, in late stages, have shown the malaric granuloma of Durck formed by astroglial reaction 36 it is conceivable that these lesions may act as epileptogenic foci in those who survive, giving rise to chronic epileptic seizures. FEBRILE
SEIZURES
Malaria is a common cause of febrile seizures in children in the tropics. A study in Congo showed that 9.6% of all children admitted to Brazzaville General Hospital between 1981-1983 presented with seizures 33. Status epilepticus occurred 13.6% of the cases, and 6 7 % of these were related to benign malaria. Febrile seizures occurred in 7 3 . 5 % of all cases, and 8 1 % of them were related to malaria. Approximately 6 0 % of all seizure disorders between 1 month and 6 years of age in a large general hospital were related to benign or malignant forms of malaria, and seizures were the reason for admission in 1 0 % of all children in that age group . In Nigeria, 5 0 % of cases of febrile convulsions are due to malaria. Even in the adult Nigerian, the commonest trigger of epileptic seizure is chloroquine-responsive febrile illness, due to malarial infections 24. 4
SPINAL CORD
DISORDERS
Spinal syndromes of malaria are thought to resemble those of amyotrophic lateral sclerosis, funicular myelosis, spastic spinal paralysis and tabes dorsalis; in part they have been interpreted as late sequelae. In contrast to true tabes dorsalis, the typical Argyll-Robertson pupil is not seen. In cases of simultaneous cerebral and spinal disease, the clinical condition may resemble disseminated encephalomyelitis, e.g. spastic gait, tremor, and occasionally nystagmus and speech disorders. On treat ment with quinine these symptoms are reported to regress 37. PERIPHERAL
NEUROPATHY
Early literature refers to cases of neuritis, polyneuritis, Landry's paralysis, and cranial nerve palsies in association with malarial infections 37. «Irritative» phenomena with sharp or stinging pain in the distribution of a peripheral nerve, followed by a sensation of «drawing» in the muscles with muscle contraction, intense hyperalgesia, and increased sweating have been reported . More recent cases include Guillain-Barre type polyneuropathy developing 2 to 3 weeks following vivax or falciparum malaria 3,14. 16
PERIODIC
PARALYSIS
Transient muscular paralysis resembling periodic paralysis has been observed during febrile episodes of malaria in 3 Sri Lankan patients 31. Following a rigor, the weakness first appeared in the lower limbs, and soon spread to the rest of the body causing paralysis affecting the entire body except for the respiratory muscles. The patients remained conscious during the attack. Signs of improvement appeared in 4 to 6 h r , and the recovery was complete in 8 to 10 hr, the muscles which were affected first being the last to recover. Two of the patients showed a mixed infection of P. vivax and P. falciparum in the peripheral blood films, while the other had only P. vivax. The transient rise of serum potassium concentration due to lysis of red cells and intense muscular contraction during rigors, and the muscular exertion itself caused by the rigo** during the febrile episodes of malaria were suggested as the mechanism underlying the muscle paralysis. A genetic predisposition which make only some individuals susceptible, may explain the general rarity of the phenomenon.
CONCLUSIONS
Involvement of the nervous system in malaria is a complex phenomenon ranging from the lethal encephalopathy to the relatively mild forms of cerebellar involvement. Some of the manifestations, for instance the spinal syndromes and the neuritides, would be difficult to justify as being causally related to plasmodial infections, unless the symptoms disappear or are significantly ameliorated by antimalarial therapy when other causes are excluded. The pathogenesis of the nervous system involvement in malaria remains unexplored, but offers excellent perspectives for research at clinical as well as experimental level. REFERENCES 1. 2. 3. 4.
5. 6. 7. 8. 9. 10.
11. 12.
13.
14. 15.
16. 17. 18. 19. 20.
21. 22.
23.
A i k a w a M. H u m a n c e r e b r a l m a l a r i a . A m J T r o p M e d H y g 1988, 3 9 : 3 - 1 0 . A r y a T V S , A w a s t h i R , R h u t a n i J . E x t r a p y r a m i d a l s y n d r o m e in f a l c i p a r u m m a l a r i a . J A s s o c P h y s i c i a n s I n d i a 1989, 37:393-394. A v a s t h i G, A g g a r w a l S P . P l a s m o d i u m f a l c i p a r u m m a l a r i a a s s o c i a t e d w i t h G u i l l a i n - B a r r e s y n d r o m e . J I n d i a n M e d A s s o c 1985, 8 3 : 3 6 0 - 3 6 3 . B i t t e n c o u r t P R M , G r a c i a CM, L o r e n z a n a P . E p i l e p s y a n d p a r a s i t o s i s of t h e c e n t r a l nervous system. I n P e d l e y T A , M e l d r u m B S ( e d s ) : R e c e n t A d v a n c e s in E p i l e p s y , vol 4. E d i n b u r g h : C h u r c h i l l L i v i n g s t o n e , 1988, p 123-159. B r a d l e y D J , Newbold C I , Wtarrell DA. In Weatherall D J , Ledingham JGG, Warrell D A ( e d s ) : O x f o r d T e x t b o o k of M e d i c i n e . O x f o r d : U n i v e r s i t y P r e s s , 1987, p 5474-5502. B r e w s t e r D R , K w i a t k o w s k i D, W h i t e N J . N e u r o l o g i c a l s e q u e l a e o f c e r e b r a l m a l a r i a in children. L a n c e t 1990, 336:1039-1043. C h i n e P , W o i m a n t F , C o r a b i a n u O, F a y a d a C, H a g u e n a u M. Isolated cerebellar syn d r o m e : a n a t y p i c a l f o r m o f c e r e b r a l m a l a r i a . J N e u r o l N e u r o s u r g P s y c h i a t r y 1991, 54:655. C h i t k a r a A J , A n a n d N K , Saini L . C e r e b e l l a r s y n d r o m e in m a l a r i a . Indian Pediatr 1984, 2 1 : 9 0 8 - 9 1 0 . De Silva H J , G a m a g e R , H e r a t h H K , P e i r i s J B , A b e y s e k e r a D T . A self-limiting midline cerebellar syndrome. I s f a l c i p a r u m m a l a r i a t h e c a u s e ? T r o p D o c t 1988, 1 8 : 5 - 6 . G i r a r d P M , d e B r o u c k e r T , F r y e r DG, N e t t e r J M , S a i m o t AG, C o u l a u d J P . C e r e b e l l a r s y n d r o m e in m i l d P l a s m o d i u m f a l c i p a r u m m a l a r i a . T r a n s R S o c T r o p M e d H y g 1988, 82:204. Gopinathan V P , Thampi U R , Ganguly SB. N e u r o p s y c h i a t r y m a n i f e s t a t i o n s of f a l c i p a r u m m a l a r i a . J I n d i a n M e d A s s o c 1982, 7 8 : 1 5 5 - 1 5 7 . G r a u G E , F a j a r d o L F , P u i g u e t P F , Allet B , L a m b e r t P H , Vassalli P . T u m o r necrosis f a c t o r ( c a c h e c t i n ) a s a n e s s e n t i a l m e d i a t o r in m u r i n e c e r e b r a l m a l a r i a . S c i e n c e 1987, 237:1210-1212. G r a u G E , T a y l o r T E , M o l y n e u x M E , W i r i m a J J , V a s s a l l i P , H o n a m e l M, L a m b e r t P H . T u m o r n e c r o s i s f a c t o r a n d d i s e a s e s e v e r i t y in c h i l d r e n w i t h f a l c i p a r u m m a l a r i a . N E n g l J M e d 1989, 320:1586-1591. G u e r r e i r o C A M , F a c u r e N O , Goncjalves F L J r , D a S i l v a L J , R a m o s MC, P e d r o R D e J . P o l i r r a d i c u l o n e u r i t e e m a l a r i a . A r q N e u r o p s i q u i a t r 1985, 4 3 : 2 1 4 - 2 1 6 . G u o q i a o L , X i n g b o G, R u i J , Z i c a i W , X u a x i a n g J , Z i y a n L . C l i n i c a l s t u d i e s on t r e a t m e n t of cerebral m a l a r i a with qinghaaosu and its derivatives. J T r a d i t Chi Med 1982, 2 : 1 2 5 - 1 3 0 . H a r v e y AM. A t y p e of n e u r i t i s a s s o c i a t e d w i t h m a l a r i a l f e v e r . Bull J o h n s Hopkins H o s p 1944, 7 5 : 2 2 5 - 2 3 1 . I l l a n g a s e k e r a V L , D e S y l v a S. A c u t e c e r e b e l l a r s y n d r o m e in f a l c i p a r u m m a l a r i a . Ceylon M e d J 1976, 2 1 : 1 3 0 - 1 3 2 . L o o a r e e s u w a n S Phillips R E , W h i t e N J , Silamut A, Philips R E , W a r r e l l DA. Quinine a n d s e v e r e f a l c i p a r u m m a l a r i a i n l a t e p r e g n a n c y . A c t a L e i d e n 1987, 5 5 : 1 3 9 - 1 4 9 . M a e g r a i t h B , F l e t c h e r A . T h e p a t h o g e n e s i s of m a m m a l i a n m a l a r i a . A d v P a r a s i t o l 1972, 10:49-75. Molyneux M E , T a y l o r T E , W i r i m a J J , B o r g s t e i n A. Clinical f e a t u r e s a n d p r o g n o s t i c i n d i c a t o r s i n p a e d i a t r i c c e r e b r a l m a l a r i a : a s t u d y of 131 c o m a t o s e M a l a w i a n c h i l d r e n . Q J M e d 1989, 7 1 : 4 4 1 - 4 5 9 . M u r u g a v e l K , S a r a v a n a p a v a n a n t h a n S, A n p a l a h a n A , J a m e s R F . S u b a r a c h n o i d h a e m o r r h a g e i n P l a s m o d i u m f a l c i p a r u m m a l a r i a . P o s t g r a d M e d J 1989, 65:236-237. N e w t o n C R J C , K i r k h a m F J , W i n s t a n l e y P A , P a s v o l G, P e s h u N , W a r r e l l D A , M a r s h K. I n t r a c r a n i a l p r e s s u r e i n A f r i c a n children, w i t h c e r e b r a l m a l a r i a . L a n c e t 1991, 337:573-576. Okelo G B A . Benign intracranial hypertension associated with resistant Plasmodium f a l c i p a r u m m a l a r i a i n f e c t i o n : a c a s e r e p o r t . E A f r M e d J 1985, 6 2 : 3 6 3 - 3 6 4 .
24. 25. 26.
27.
28. 29.
30. 31. 32. 33. 34.
35.
36. 37. 38.
39.
40. 41. 42.
O s u n t o k u n B O . M a l a r i a a n d t h e n e r v o u s s y s t e m . A f r J M e d Sci 1983, 12:165-172. Phillips R E . H y p o g l y c a e m i a is an i m p o r t a n t complication of falciparum malaria. Q J M e d 1989, 2 6 6 : 4 7 7 - 4 8 3 . P h i l l i p s R E i , W a r r e l l D A , L o o a r e e s u w a n S, T u r n e r R C , B l o o m S R , Q u a n t r i l l D , M o o r e AR. Effectiveness o f S M S 201-995, a s y n t h e t i c l o n g - a c t i n g s o m a t o s t a t i n a n a l o g u e , in t r e a t m e n t of quinine induced hyperinsulinaemia. L a n c e t 1986, 1 : 7 1 3 - 7 1 6 . P o l d e r T W , E l i n g W M C , J e r u s a l e m C R , W i j e r s - R o u w M. A c y t o c h e m i c a l s t u d y of c e r e b r o v a s c u l a r l e s i o n s in m i c e i n f e c t e d w i t h P l a s m o d i u m b e r g h e i . J N e u r o l Sci 1991, 101-24-34. P o u n g v a r i n N, P r a d i t s u w a n R . O p s o c l o n u s in m a l a r i a : t h e f i r s t r e p o r t in t h e l i t e r a t u r e . J M e d A s s o c T h a i 1990, 7 3 : 4 6 2 - 4 6 6 . R o b e r t s D D , S c h e r w o o d J A , S p i t a l n i k S L , Plantón L J , H o w a r d R J , D i x i t V M , F r a z i e r W A , M i l l e r L H , G i n s b u r g V. Thrombospondin binds falciparum m a l a r i a parasitized erythrocytes and m a y mediate cytoadherence. N a t u r e 1985, 3 1 8 : 6 4 - 6 6 . R o m a n GC. C e r e b r a l m a l a r i a : t h e u n s o l v e d r i d d l e . J N e u r o l Sci 1991, 1 0 1 : 1 - 6 . S e n a n a y a k e N, W i m a l a w a n s a S J . P e r i o d i c p a r a l y s i s c o m p l i c a t i n g m a l a r i a . P o s t g r a d Med J 1981, 5 7 : 2 7 3 - 2 7 4 . S e n a n a y a k e N. Delayed cerebellar a t a x i a : a new complication of f a l c i p a r u m m a l a r i a ? B r M e d J 1987, 294:1253-1254. S e n g a P , M a y a n d a H F , N z i n g o u l a S. P r o f i l e of s e i z u r e s in i n f a n t s a n d y o u n g c h i l d r e n in B r a z z a v i l l e ( C o n g o ) . A n n P e d i a t r 1985, 3 2 : 4 7 7 - 4 8 0 . Taylor T E , Molyneux ME, Wirima J J , Fletcher KA, Morris K. Blood glucose concen t r a t i o n s in M a l a w i a n c h i l d r e n b e f o r e a n d d u r i n g p a r e n t e r a l q u i n i n e t r e a t m e n t f o r s e v e r e f a l c i p a r u m m a l a r i a . » N E n g l J M e d 1988, 319:1040-1047. T o r o G, R o m á n G, d e R o m a n L N . P a l u d i s m o . I n T o r o G, R o m á n G, d e R o m á n L N (eds): Neurología Tropical: Aspectos Neuropatologicos de la Medicina Tropical. Bo g o t a : E d i t o r i a l P r i n t e r C o l o m b i a n a , 1983, p 106-113. T o r o G, R o m á n GC. C e r e b r a l m a l a r i a : a d i s s e m i n a t e d v a s c u l © m y e l i n o p a t h y . A r c h N e u r o l 1978, 3 5 : 2 7 1 - 2 7 5 . V i e t z e G. Malaria a n d other protozoal diseases. In Vinken P J , B r u y n G W (eds): H a n d b o o k o f C l i n i c a l N e u r o l o g y , vol 35. A m s t e r d a m : N o r t h - H o l l a n d , 1978, p 143-160. W a r r e l l D A , L o o a r e e s u w a n S, P h i l l i p s R E , W h i t e M J , W a r r e l l M J , C h a p e l H , A r e e k u l M, T h a r a v a n i j S. F u n c t i o n , of t h e b l o o d - c e r e b r o s p i n a l fluid b a r r i e r in h u m a n c e r e b r a l m a l a r i a : rejection of the permeability hypothesis. A m J T r o p M e d H y g 1986, 35:882-889. W a r r e l l D A , L o o a r e e s u w a n S, W a r r e l l M J , K a s e m s a m P , I n t r a p a s e r t R , B u n n a g D, Harinasuta T. D e x a m e t h a s o n e p r o v e s d e l e t e r i o u s in c e r e b r a l m a l a r i a : a double-blind t r i a l in 1 0 0 c o m a t o s e p a t i e n t s . N E n g l J M e d 1982, 3 0 6 : 3 1 3 - 3 1 9 . W h i t e N J , L o o a r e e s u w a n S, P h i l l i p s R E , C h a n t h a v a n i c h P , W a r r e l l D A . S i n g l e dose p h e n o b a r b i t o n e p r e v e n t s c o n v u l s i o n s in c e r e b r a l m a l a r i a . L a n c e t 1988, 2 : 6 4 - 6 6 . W h i t e N J , Miller K D , M a r s h K , B e r r y CD, T u r n e r R C , Williamson D H , B r o w n J . H y p o g l y c a e m i a in A f r i c a n c h i l d r e n w i t h s e v e r e m a l a r i a . L a n c e t 1987, 1:708-711. W h i t e N J , W a r r e l l DA, C h a n t h a v a n i c h P , e t al. Severe hypoglycemia and hyperinsulin e m i a in f a l c i p a r u m m a l a r i a . N E n g l J M e d 1983, 3 0 9 : 6 1 - 6 6 .
