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Cerebral MalariaCPTRobert B. Daroff, MC, USA; LTCJohnJ.Deller,Jr.,MC, USA;

CPT AlbertJ. Kastl,Jr., MSC, USA; and CPT W. WebsterBlocker,Jr.,MC, USA

During the ten-month period of this study, approxi-mately 1,200 cases of malaria due to Plasmodium falci-parum were seen at the 93rd Evacuation Hospital in SouthVietnam. Ofthese, 19 were cases of cerebral malaria thatevinced itself after therapy was begun. Although cerebralmalaria is often an alarming consequence of P falciparuminfection, early recognition andappropriate therapy affordan excellent prognosis.

Malariadue to Plasmodium falciparum (estivo-

autumnal, malignant tertian) is the mostfrequently encountered variety among US troopsserving in South Vietnam. A cerebral syndrome isa well-recognized complication of this type of malaria andmerits emphasis because of its often dramatic clinical presentation and itspotentially fataloutcome.

From January to November 1966, nineteen patients with "cerebral malaria"

secondary to P

falciparuminfection werediagnosed at the 93rd Evacuation Hospital, Long Binh, South Vietnam. Themajor clinical varieties of this syndrome are clarified, and five cases are reported depicting thespectrum. A treatment program which evolvedfrom this experience is outlined, and the pertinentliterature is reviewed.

Report ofCasesCase 1.A 19-year-old Negro man was admitted on Jan

13, 1966, with a two-weekhistory of pain in the right lowerquadrant of the abdomen. On admission, he was afebrile,but the abdominal pain persisted. On the ninth hospitalday, his temperature rose to 102 F (38.9 C). Temperaturesthereafter varied between 100 and 102 F (37.8 and 38.9 C),and on the 14thhospital day, a blood smear was positive forP falciparum. Therapy with quinine sulfate, 2 gm/day for12 days, and chloroquine phosphate, 300 mg/day for fivedays was instituted. On the 17th hospital day, hookwormova were found in the stool, and tetrachlorethylene wasgiven. As the patient remained febrile, pyrimethamine(25 mg, three times aday for threedays), and sulfadiazine(500 mg, four times a day forfivedays) were added on the19th and 20th hospital days. During this febrile interval,in the patient there developed a bitemporal, nonthrobbingheadache of increasing intensity that was exacerbated byhis lying down and relieved by his standing. Neurological

examination on the 27thhospital day disclosed a hyperre-flexia and hemihypalgesia of the right side and a rapid,sustained,b idirectional, horizontal jerk nystagmus. Lumbarpuncture revealed an opening pressure of 250 mm HL,0(with lower extremities extended andpatient relaxed) and

aclosing pressure of 100 mm H.,0. The fluid was clear andwithoutcells. Theglucose level was 71 mg/100 ml, and the

protein level was 24mg/100 ml. Nobacteria were found insmears or culture. Skull roentgenograms were normal. Theheadache began improving on the 32nd hospital day, andby the 38th hospital day, it hadcompletely resolved, andthe neurological signs were no longer present. Thepatientwas discharged asymptomatic on the 42nd hospital day".

CASE 2.A21-year-old Negro man was admitted onJune5, following ten days of chills, fever, malaise, arthralgias,low back pain, headache, nausea, vomiting, and diarrhea.Onadmission, histemperature was 103 F (39.4 C), andhewas alert and oriented. On the morning after admission, hewas afebrile but disoriented. Several hours later, his temperature rose to 104 F (40.0 C), and he became comatose.Hisblood smears werepositive for Pfalciparum.Quadrupledrugtherapy was given consisting ofchloroquine phosphateadministered intramuscularly (400 mg immediately and200 mg in six hours and then daily for six days) ; quininesulfate (2 gm in 24 hours intravenously for four days andthereafter orally for ten days) ; pyrimethamine (25 mgeveryeight hours forthreedays); and sulfadiazine (500 mgevery six hours for sevendays), bothinitiallyby nasogastrictube andthen orally. Inaddition, he was treated with oxygen; diphenylhydantoin sodium (400 mg/day) ; dextran 75(10 mg/kg of body weight the first day and then 5 ml/kgdaily for fourdays) ; and dexamethasone sodium phosphate(9 mg intravenously, daily for four days), followed by decreasing doses of prednisone orally for an additional eightdays.

On the third hospital day, the patient became afebrileandarousable but had agrand mal seizure. He was confusedand disoriented upon regaining consciousness, but he improved steadily thereafter, and his sensorium was clear onthe seventh

hospital day.Case 3.A 19-year-old white man was admitted on July14, with a 14-day history ofheadache, weakness, chills, andfever. On admission, his temperature was 102 F (38.9 C),and he was lethargic but mentally clear. His temperatureranged from 100 to 104 F (37.8 to 40.0C) before his malariasmears became positive on the third hospital day. At thattime, therapy was instituted with quinine sulfate given intravenously (2 gm/day). On the fifth hospital day, he wasafebrile and improved clinically. Although thepatient remainedafebrile, on the 11thhospitalday, heagain becamequite lethargic. He remained oriented but had difficultywith abstractions andsimple calculations. On the followingday, his temperature spiked to 105 F (40.6 C). His mentalstatus continued to deteriorate, and a generalized, rapid,moderate amplitude, resting tremor exaggerated with intentiondeveloped on the 15th hospital day. A

wrist-rollingquality was apparent, giving the tremor a rubral appear-

Fromthe 93rd EvacuationHospital,LongBinh, South Vietnam.Reprint requests to the University of California Medical Center,

Parnassus and Third avenues, San Francisco 94122 (Dr. Daroff).

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Table 1.Falciparum Cerebral Malaria in World War I ICompared to South Vietnam

Falciparum Malaria, Cerebral Systems, Incidence,Authors Sample No. of Cases No. of Cases %

Medical dept. General hospital,US Army2 Pacific Theater ... ... 1.2

Fitzhugh US and Allied troopset al1 in general hospital,

Pacific Theater 6.059 . . . 2.3Horn and US troops,

Karelitz13 Mediterranean Theater 397 6 1.5Hughes and British troops,

Bomford8 Africa 846 2 0.25Our US troops in the

series 93rd Evacuation Hospital,South Vietnam l,200t 19 1.6t

"Incidence of 2.3% was same for both US and Allied troops. Compare this with mortality note in samehospital in Table 2.

tFigure is close approximation.

anee,ie, an appearance of having arisen from a lesion ofthered nucleus. In addition to this, rapid, irregular, asynchronous, myoclonic extremity jerks were seen. No abnormalmovements were seenduringsleep, and no abnormalpalatal or ocular movements occurred. Thevalues for serumelectrolytes, including serumcalcium, were normal, and theintravenous administration of calcium did not improve the

myoclonus. Acompletecerebral malaria treatment program(outlined later) was started, and, in addition, the patientwasgiven trihexyphenidyl hydrochloride (10 mg/day). Hebecame afebrile on the 20th hospital day, but the tremorand myoclonus persisted. Several days later, his movementdisorder began to improve and by the 20th hospital day, ithad cleared completely.

Case 4.A 28-year-old white man was admitted on July22, with a history ofchills, fever, and headache of four tofivedays' duration. His temperature onadmission was 104 F(40.0C), and smears were positive for P falciparum. Treatment was instituted withquinine sulfate (2 gm/day) ; pyri-methamine (25 mg, three times aday for three days) ; anddapsone (25 mg/day for 14 days). Because of a hematocritreading of30%, 2 units of whole blood were administered.The patient soon became afebrile and asymptomatic, and

on Aug 1, he was transferred to the convalescent ward. Heremainedasymptomatic until Aug 12, when a headache developed. The followingday, he became febrile, dizzy, andhad a syncopal episode. On Aug 14, with a temperature of102 F (38.9 C), he had a grand mal seizure. Postictally, he

was confused. Diphenylhydantoin sodiumtherapy (400 mg/day) was started, but on the following day he had anothergrand mal seizure. For the next several days, he wasafebrile and mentally clear. On Aug 21, his temperaturewas 101 F (38.3 C),however, andalthough he wasoriented,he was concrete indealing with abstractions and had a disturbance in his ability to calculate. He became tremulous,and this rapidly progressed to severe restlessness, irritability, and choreiform movements. In addition, he had become disoriented and confused. Thecerebral malarial treatment program (outlined in Comment) was instituted. Inaddition, he was given calcium intravenously, trihexyphenidyl hydrochloride (10 mg/day), paraldehyde orally(8 cc every six hours), and chlorpromazine hydrochloride(200 mg four times aday). None of this therapy controlledhis restlessness and chorea. He remained awake for thenext three days and nights, and the restlessness, hyperac-tivity, and chorea increased. His temperature during thisperiod ranged from 100 to 101 F (37.8 to 38.3 C). Finally,on the morning of Aug 24, the anesthesiologist inducedsleep with thiopental sodium administered intravenously.The patient slept for four hours without abnormal movements and awakened feeling much better; the chorea returned, however, and increased throughout the day. Fivehundred milligrams of amobarbitol sodium administeredintravenously was required to induce sleep that evening.He gradually improved during the next week, and thesedative drugs were tapered to discontinuance. By Sept

1, he was mentally clear, and the neurological exami-

nation gave normal findings.Case 5.

-

A 19-year-oldwhite man was admitted onSept 16, with a four-day history ofheadache,chills, fever,nausea, andvomiting. Admission temperature was 102 F(38.9 C). He was lethargicbut oriented, and findingsfrom the physical examination were negative. Smearswere positive for P falciparum, and triple drug therapy with quinine sulfateadministered orally, pyri-methamine, and sulfisoxazolediolamine was started. Earlythefollowingmorning, thepa-

tient awakened confused, disoriented, and incontinent ofurine. His temperature was 103 F (39.4C). Quinine sulfatewas given intravenously and intramuscularly. Chloroquinephosphate therapy was started. He remained incontinentand confused throughout the day. His hematocrit readinghad fallento30%,and 4 unitsofwhole blood weregiven overthe next two days raising the hematocrit reading to 34%.Additional drug therapy included diphenylhydantoin sodium, dextran 75, and prednisone. Except for the disorientation and a right Babinski reflex, the neurological examination disclosed no abnormalities.

Lumbarpuncture disclosed anopeningpressureof290 mmH..O and a closing pressure of 210 mm H20. Protein was48 mg/100 ml; glucose, 70 mg/100 ml; and no cells wereobserved. No bacteria were found on smears or culture.Definite improvement was noted within 24 hours ofinstitution of cerebral malaria therapy, and by the fifth hospitalday, thepatient wasafebrile, oriented, and nolonger manifestedBabinski's reflex or any discernibleneurologic deficit.

Comment

The syndrome of "cerebral malaria" was diagnosed when a patient with confirmed parasitemiadisplayed signs of cerebral dysfunction which werenot readily explained by severe hyperpyrexia ordetectable metabolic abnormalities. Such simplediagnostic criteria have been applied to studies ofthis problem in the past and have resulted in afairly consistent picture of the spectrum of thiscomplication of P falciparum infection.13 Approximately 1,200 cases of falciparum malaria were seenat the 93rd Evacuation Hospital during the ten-month period of this study. The 19 cases of falciparum cerebral malaria in this series constitute anincidence of approximately 1.6%. The reportedfigures in US hospitals in World War II rangedfrom 1.2% to 2.3% (Table 1).

The clinical syndromes in cerebral malaria arevaried, and almost every neurological sign andsymptom has been described.4 Our 19 cases canbe broadly divided into five groupings: (1) disturbance of consciousness, (2) acute organic mental syndrome, (3) movement disorders, (4) focalneurological signs, and (5) acute personalitychanges.

Disturbanceof consciousness was the most commonly encountered neurological abnormality inboth our series and others."' Eight of our 19 caseswere in this group of which the patient in case 2

is an example. This disturbance ranged from ex-



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treme lethargy and stupor to frank coma. Somepatients hadunilateral extensor plantar responses,but no other focal signs, were present. Upon awakening, thepatients all demonstrated transientsignsof organic mental disturbance on mental-statustesting and in some instances by formal psycho-metrics.

Acute organic mental syndrome was present infour patients of which the patient in case 5 is anexample. Thepatients manifested obvious signs ofconfusion,disorientation, and intellectual deterioration withoutsignificantly depressed states of consciousness.

Movement disorders were seen in three patients(eg, cases 3 and4). Two hadextremitymyoclonus,and one had severe chorea. In addition, all threehad gross intention tremors. In no instance didthe addition of trihexyphenidyl hydrochloride, di-phenylhydantoin sodium, chlorpromazine hydrochloride, or calcium administered intravenouslyseem to affect the movements. General anesthesiawas resorted to in the patient in case 4 after 72sleepless hours. This clinical type of cerebral malaria is most dramatic in presentation although ithas received little mentionparticularly in the morerecent literature. Cases of severe chorea and myoclonus arereported in Anderson's classical review.4Masson described a characteristic "malarial tremor" of the upper extremities which was present atrest and worsened by intention." In the WorldWar II experience, descriptions of "generalizedtremors and mild tetany"7 and "severe musculartwitchings"8 may have represented myoclonus.

Focal neurological signs were encountered in

only a single instance. The patient in case 1 hada transient, unilateral hyperreflexia and hemisen-sory disturbance in association with increased intracranial pressure. We did not encounter patientswith frankhemiplegia andhemianopia. The occurrence of this type of focal abnormality in cerebralmalaria has been recently questioned" and attributed to misdiagnosis. However, there is ampleliterature to the contrary.1'3,4'10,11

Acutepersonality changes were seen three times.In two patients there developed a severe paranoidpsychosis, and another patient became delusionalbelieving that his wife and children were killed

bizarrelyby a flock of birds. In each

case, psychometric testing revealed signs of an organic mentaldisturbance. These patients all recovered withoutresidua and will be reported in detail elsewhere.

Almost withoutexception, the deaths in malariacases inWorld War II were due to cerebral involvement.212 No deaths were encountered in our seriesof 19 cases. Themortality statistics of the WorldWar II and other experiences are presented inTable 2. Themarked difference in survival betweenUSandAllied (mostly Chinese) troops, particularly in the same hospital, is explained by the factthat non-US troops were not sent to the hospitalunless they were gravely ill, which resulted in con

siderable delay in the institution of treatment.

Table 2.Mortality of Cerebral Malaria Due to P falciparum inPreviously Reported Series

Cerebral Malaria, No. Mortality,

Authors Sample of Cases Deaths %US Army US troops, 144 8 5.5

MediterraneanHorn and Same as above 6 0 0

Kareiitz13

Simpson and US

troops 12 0

0Sagebiel11Arbuse" US troops 7 3 43

Fitzhugh US troops, general 25 2 8et al1 hospital in Pa

cific Theater

Fitzhugh Allied troops in 68 28 41et al1 same hospital as

above

US Army2 US troops in Pa- ... ... 5cific Theatergeneral hospital

USArmy2 Chinese troops in ... ... 33same hospital asabove

USArmy2 US and Allied 57 27e 47troops

Hughes and British troops 2 0 0Bomfordv in Africa

Ewing21 New York city at 34 13 38turn of century

Rothe22 Children below 97 21 22

age 14 in KenyaRothe22 Adults in Kenya 3 0 0Present US troops at 93rd 19 0 0

series Evac HospS Vietnam

-Only one of the deaths was in an American soldier.

In our initial cases, completely normal resultsfrom cerebrospinal fluid examinations were obtained except for slight to moderate increasedpressure.We subsequently did not perform lumbarpunctures routinely. Previous reports vary, withsome authors sharing our experience,1'7"13 whileothers have reported pleocytosis and protein increase or both.310'11,14 Increased pressure was usual

ly found in the moreseverely illpatients.There is disagreement as to the basic pathological changes in cerebral malaria. Some feel thatthrombosis or plugging of intracerebral vessels bypigments, infected, clumped erythrocytes, andendothelial proliferation results in the cerebraldysfunction.' 1"15 Others deny actual vessel occlusion and blame the cerebral anoxic changes onstagnation, anemia, and particularly on the decreased oxygen-carrying capacity of the infectederythrocytes.1"1" Ridgon and Fletcher emphasizecerebral edema as the most constant and earliestchange.17 Perivascular hemorrhages are frequentlyseen.'517 The

complete recovery of our

patientssuggests that thepathophysiological process, whatever its exact nature, is completely reversible.

The treatment or cerebral malaria in WorldWar II was reasonably standard and consisted ofquinine sulfate administered intravenously eitheralone1'14'20 or in combination with quinacrine hydrochloride (Atabrine) administered intravenously.2Therapeutic lumbarpunctures were consideredof value to relieve increased intracranial pressure.1" Routine measures such as whole blood foranemia, sedation, and anticonvulsive treatmentwere used when needed.At the93rd Evacuation Hospital, the treatment

of uncomplicated falciparum malaria changed as



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experience increased. If mild cerebral signs developed, no alteration in basic drug therapy wasmade, which in most instances consisted of tripletherapy using quinine sulfate, 650 mg every eighthours for 14 days; pyrimethamine, 25 mg threetimes daily for three days; and sulfadiazine, 500mg four times daily for seven days. The earlier

patients also received chloroquine phosphate, 600mg initially and then 300 mg daily for five days.Once drug therapy was started, it was continuedfor a complete course, and thus it is unlikely thatthe reversible signs of central nervous system involvement were attributable to drug therapy.

When the signs of cerebral malaria were moresevere, additional adjunctive therapy was instituted. If the patient was comatose or vomiting,quinine sulfate was givenintravenously andchloroquine phosphate was given intramuscularly. Pyrimethamine and sulfadiazine were given by naso-gastric tube as soon as feasible. If the hematocrit

readingdroppedbelow

30%, a minimum of 4 units

of whole blood was given. Diphenylhydantoin sodium, 400mg/day, was given to everypatient, andsedatives were used when indicated.In the mostseverely ill patients, dextran 75 and

dexamethasone sodium phosphate were used andfelt to be important to the patient's recovery. Theformer agent wasgiven at the rate of 1 unit every12 hours for 72 hours in the hope of favorablyeffecting intravascularsludging, and the latterdrugwas used in a dosage of 3.0 mg every eight hoursuntil clinical improvement was obvious in anticipation of its effect in reducing cerebral edema.

Although rare cases of permanent sequelae havebeen noted,1 our experience parallels that of Fitzhugh et al1 and Simpson and Sagebiel14 whostressed that the survivors of cerebral malaria arefree of residual disability. Clinically, our patientsseem to havecompletely recovered. In an effort todetermine whether subtle residual signs of an organic mental disturbance remained, a formal battery ofpsychometric tests, consisting of a WechslerAdult Intelligence scale, Wechsler Memory scale,Bender-Gestalt, and Rorschach test were given tonine patients during the acute or subacute phaseandrepeated again during the convalescentperiod.Initial test results were consistent with mild to

moderate organic dysfunctioning. Retest dataclearly indicated a disappearance of the organicpattern.

The performance of these patients (and that ofa matched control group) has been statisticallyanalyzed and will subsequently be reported. Thedata supported our clinical impression that therewas no organic residua in our patients with cerebral malaria.

Genericand Trade Names of DrugsChloroquine phosphateAralen Phosphate.Py rimethamineDaraprim.Diphenylhydantoin sodiumDenyl Sodium, Dilantin Sodium,

Diphentoin, Diphenylan Sodium.Dexamethasone sodium phosphateDecadron Phosphate, Respi-

haler Decadron. Hexadrol Phosphate, Turbinaire DecadronPhosphate.

PrednisoneDeltasone, Deltra, Meticorten, Paracort,Cotone, Lisa-

cort, Metasone, Delta-Dome.Trihexyphenidyl hydrochlorideArtane, Pipanol, Tremin.DapsoneA vlosulfon.Chlorpromazine hydrochlorideThorazine Hydrochloride.Thiopental sodiumPentothal Sodium.Amobarbitol sodiumA my tal Sodium, Tlamo.Sulfisoxazole diolamineGantrisin Diolamine, Suladrin.QuinacrinehydrochlorideA tabrine Hydrochloride.

References

1. Fitzhugh, T., Jr.; Pepper, D.S.; and Hopkins, H.U.: TheCerebral Form of Malaria, bulletin 83, US Army Medical Dept,1944, pp 39-48.

2. "Activities of Medical Consultants," in Internal Medicine inWorld War II, vol 1, Dept of the Army, Office of the SurgeonGeneral, 1961.

3. Levine, H.D.: "Clinical Aspects of Malaria," in InternalMedicine in World War II, vol2, Dept of the Army, Office of the

Surgeon General, 1961, pp479-492.4. Anderson, W.K.: Malarial Psychosis and Neurosis, Edin-burgh: OxfordUniversity Press, 1927, p 395.

5. Most, H., andMeleney, H.E.: Falciparum Malaria, JAMA124:71-76 (Jan 8) 1944.

6. Masson, C.B.: Effectof Malaria on the NervousSystem WithSpecial Reference to the Malarial Psychosis, AmerJ Med Sci 168:334-371 (Sept) 1924.

7. Arbuse, D.I.: Neuropsychiatric Manifestations in Malaria,US Naval Med Bull 45:304-309 (Aug) 1945.

8 Hughes, S.B., and Bomford, R.R.: Clinical Features andTreatment of Malaria in British Troops in West Africa, Brit MedJ 1:69-73 (Jan 15) 1944.

9. Hutton, P.W.: Neurological Disease in Uganda, E Afr MedJ 33:209-223 (June) 1956.

10. Brill, N.Q., and Pellicano, V.L.: Estivoautumnal MalariaWith Frontal Lobe Syndrome, JAMA 121:1150-1152 (April 3)1943.

11. Dhayagude, R.G., and Purandare, N.M.: Autopsy Study ofCerebral Malaria With Special Reference to MalarialGranuloma,Arch Path 36:550-558 (Dec) 1943.

12. Russell, P.F., et al: Practical Malariology, ed 2, London:Oxford University Press, 1963, p 387.

13. Horn, H.,and Karelitz, S.: Clinical Experience With Ma-laria at a General Hospital During Summer and Fall of 1943,MedBull North Afr Theat Op 1:2-11 (April) 1944.

14. Simpson, W.M., and Sagebiel, J.L.: Cerebral Malaria: AReport of 12 Cases Encountered at US Naval Base Hospital, USNaval Med Bull 41:1596-1602 (Nov) 1943.

15. Arieti, S.: Histopathologic Changes in Cerebral Malariaand Their Relation to Psychotic Sequels, Arch Neurol Psychiat56:79-104 (July) 1946.

16. Kean, B.H., and Smith, J.A.: Death Due to Estivo-Autum-nal Malaria, Amer J Trop Med 24:317-322 (Sept) 1944.

17. Rigdon, R.H., and Fletcher, D.E.: Lesions in theBrain As-sociated With Malaria, Arch NeurolPsychiat 53:191-198 (March)1945.

18. Clark, H.C., and Tomlinson, W.J.: "The Pathological An-atomy of Malaria," in Mark, F. Boyd (ed.): Malariology, Phila-delphia: W.B. SaundersCo., 1949, vol 2, pp 874-903.

19. Belding, D.C.:Textbook of Parasitology, ed 3, New York:Appleton-Century-Crofts Inc., 1965.

20. Gillespie, J.O.: "Malaria in the Defense of Bataan," in Pre-ventive Medicine in World WarII, vol 6, Dept of Army, Office oftheSurgeonGeneral, 1961, pp 497-511.

21. Ewing, J.: Contribution to the Pathological Anatomy ofMalarial Fever, J Exp Med 6:119-180, 1901-1905.

22. Rothe, H.: One Hundred Cases of Cerebral Malaria, E AfrMedJ 33:405-407 (Oct) 1956.


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