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African Journal of Neurological Sciences
Pan African Association of Neurological Sciences
ISSN: 1015-8618
Vol. 17, Num. 1, 1998
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CEREBRAL MALARIA: CLINICAL FEATURES AND DIAGNOSIS
The African Journal of Neurological Sciences Vol 17 No.1,
1998
Cerebral malaria: clinical features and diagnosis.
SCHMUTZHARD E.
Department of Neurology - University Hospital - Innsbruck -
Austria
Code Number: NS98001
SUMMARY
Celebral Malaria is the most important course of
P.falciparum infection with mortality rates of up to 50%. The
clinical criteria consist of unarousable coma, exclusion of other
encephalopathies and the confirmation of P.falciparum infection.
Beside unarousable coma in up to 80% epileptic seizures are
observed in cerebral malaria. Frequently other organs are involved
parallel dysfunction. The golden standard of therapy for severe
P.falciparum malaria, incl. cerebral malaria, is intravenous
quinine dihydrochloride. Although anticonvulsive therapy is
recommended, there is no real scientific proof that such therapy in
cerebral malaria given prophylactically will improve the outcome.
The same applies to low molecular weight dextrane, full scale
heparinisation or dexamethasone, pentoxifylline, given as adjuctive
therapy, possibly provides a therapeutic value in cerebral
malaria.
Besides the mortality rate, neurological sequelae until recently
often denied, can occur on average in up to 7% of patients with
cerebral malaria, protracted convulsions prolonged coma and severe
anemia being frequently associated with the development of
neurological sequelae.
RESUME
La paludisme cerebral est la plus importante complication de
l'infection a P. Fqfciparum. Sa mortalite depasse 50%. Les
criteres cliniques reposent sur un coma profond, l'elimination
d'autres encephalopathies et la confirmation de l'infection
Par P. falciparum. Au cours du coma, on observe don 80%
des cas des crises d'epilepsie. D'autres organes sont consrnes en
fonction de l'atteinte cerebrale. La regle d'or du traitement du
paludisme a P. falciparum et du paludisme cerebral est le
dihydrochloride de quinine intaveineux. Bien que le traitement
anticonvulsif soit recommended il n'y a pas de preuve scientifique
que dans ce cas un tel traitement soit benefique. Il en va de meme
pour la dextrane de faible poids moleculaire, l'heparinisation a
dose elevee ou la dexamethasone. La pentoxifylline en traitement
d'appoint du paludisme cerebral presenterait un certain interet. En
plus de la mortalite des sequelles neurologiques souvent contestees
encore recemment peuvent apparaitre. 7% des patients
atteints de paludisme cerebral avec coma profond, convulsions
prolongees et une anemic importante sont frequemment atteints de
sequelles neurologiques.
KEY WORDS: Cerebral Malaria - diagnosis clinical features.
INTRODUCTION
Malaria represents the leading parasitic disease in today's
world (1). Half of the population of the globe is at risk to
malaria and the infected population may exceed 300 million (2). Per
year more than one million die from malaria, most of them from
cerebral manifestation (3). Cerebral malaria (C.M.) is the most
important course of Plasmodium falciparum infection with mortality
rates of up to 50% (4-6).
However it is not merely a disease of tropical countries, it is
seen in all its clinical aspects in all parts of the world,
frequently taking a more serious course in northern countries due
to delay of diagnosis and specific therapy (7,8).
DEFINITION:
Celebral malaria is an acute febrile and mainly diffuse
encephalopathy, occurring in a patient infected with Plasmodium
falciparum (9).
The World Health Organisation Malaria Action Programme proposed
three criteria for the diagnosis of cerebral malaria:
* unarousable come (motor response to noxious stiumuli in non
localizing or absent)
* exclusion of other encephalopathies
* confirmation of Plasmodium infection. Asexual forms of P.
falciparum must be demonstrated in peripheral blood smear or bone
marrow smear during life or in a brain smear after death (10).
There is frequently severely impaired function of other organs.
Parameters with indirect influence onto the brain function are:
Metabolic, circulatory functions may be severly disturbed,
additionally there might be acute pulmonary edema and hematological
dysfuntion as well as severe impairment of coagulation (11-14).
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF CEREBRAL MALARIA
Cerebral malaria is the most severe and common complication
affecting up to 7% of all P. falciparum malaria cases (3,5,6, 15).
Twenty to fifty percent of deaths from P. falciparum malaria are
reported to be due to the involvement of the central nervous system
(3,5, 15). In non-immune individuals C.M. occurs at all ages, but
in holoendemic areas it mainly strikes children less than five
years old, the peak frequency being between the second and third
year of age (3-6). A seasonal distribution of C.M. can be observed,
in particular in rural tropical areas with a clear peak in
incidence at the end of the rainy season (3-6).
Incubation Period.
Incubation period, or the interval between the infecting
mosquito bite and the elevation of temperature above 37.8, is 11-14
days in P. falciparum infection. It correlates directly with the
primary hepatic phase of the infection following sporozoite
invasion of the hepatic cells. However, the incubation period is
quite variable, depending on the infecting parasite strain, the
type, dose and frequency of any chemoprophylactic agents taken by
the patient and the type of exposure to malaria (mosquito,
transfusion, congenital). Initial attacks of P. falciparum may be
suppressed for weeks to months (16). During 1980 and 1981 the
interval between entry into the United States and onset of P.
falciparum disease exceeded 1 month in one quarter of the patients
(17). Incubation periods have also varied widely in reported cases
of transfusion malaria ranging from 4.to 17 days (18). In congenial
malaria the onset of symptoms usually occurs 3 to 8 weeks after
birth (16).
Presenting Features:
Prodome:
Initially patients often complain of unspecific symptoms,
even days before the onset of the paroxysm: malaise, headache,
myalgia and fatigue are easily mistaken for beginning viral illness
(16). Children usually experience an abrupt onset, frequently with
hyperpyrexia, headache, restlessness and vomiting. Within hours but
sometimes much slower features of CNS involvement set in (3-6,
16).
Paroxysms:
Characteristic malaria paroxysms have 3 stages
*rigor and chill
*highly elevated body temparature (<40 C)
*defervescence - profuse sweating.
Duration of paroxysms usually is 3 to 6 hours. In malignant
falciparum malaria however an asynchronous cycle of parasite
multiplication leads to continuous, remittent or irregular fever,
typical paroxysms occurring only in a minority of patients.
Table 1: LIST OF DISEASE PROCESS IN CEREBRAL MALARIA
Intection by: |
Mosquito bite in endemic area |
|
|
Blood Transfusion |
|
|
Congenital: |
|
Incubation Period: |
Mosquito bite: |
11-14 Days. up to months |
|
Translusion: |
4 - 17 Days |
|
Congenital: |
3 - 8 Weeks |
Unspecific prodromal signs and symptoms: |
Fever Paroxysms: |
Not always present |
|
Encephalopathy: |
Mainly diffuse. |
|
|
rarely localizing signs. |
|
|
imparement of conciousness (unarousable coma and
convulsions) |
|
Extracerebral manifestations aggravating the
encephaolpathy: |
|
anemia-hypoxemia-hypoxia |
|
|
thromboctopenia |
|
|
renal failure |
|
|
hepatic failure |
|
|
fluid and electrolyte disbalance |
|
|
pulmonary edema |
|
|
cardia failure |
|
|
hypotension |
|
|
bleeding and clotting disturbances |
|
CNS- Involvement:
Cerebral malaria is defined as febrile and mainly diffuse
encephalopathy, impairment of conciousness being a prominent
feature. Unarousable coma may be preceded by severe headache,
confusion, drowsiness and in many instances convulsions. It is not
possible to differentiate the immediate postictal state from
beginning cerebral malaria, but if coma persists for more than six
hours after a convulsion in a child with P. falciparum malaria then
cerebral malaria should be diagnosed (10).
Neurological signs of C .M. are those of symmetrical upper motor
neuron and brain stem disturbances including dysconjugate gaze,
decerebrate and decorticate postures ( 3-6, 15 ) resembling and
frequently paralleling the development of midbrain syndrome (6). In
a series of 66 Tanzanian children, 73% presented - at the time of
admission - with unarousable coma and 15% had an organic
psychosyndrome with confusion, disorientation and restlessness.
Almost a quarter showed localizing signs. Two thirds of the
children had generalized or - rarely - focal seizures frequently
heralding the development of coma, i.e.C.M. (6). In 52 of 65
Malawian children (80%)convulsions have been observed before
admission (19). In Thai patients seizures were estimated to occur
in one third of the mainly adult C.M. patients (15). Meningeal
irritation is rare, as are extrapyramidal or cerebellar signs (36,
15). Infrequently retinal hemorrhages and exudates are observed
(20), Hyperpyrexia and splenomegaly are frequently extracranial
physical findings. Less often hepatomegaly is present, frequently
associated with severe anemia and high output congestive heart
failure (16). In advanced disease severe anemia, icterus, renal
failure, acute pulmonary oedema, heart failure, bleeding tendencies
and spontaneous hemorrhages (e.g. from the upper gastrointestinal
tract) and hypoglycemia complicate the course of P. falciparum (10,
21). A mainstay in diagnostic C.M. is to take careful history, in
particular as to exposure of the parasite-descendance from or
travelling to endemic areas as - in rare instances - transfusion of
infected blood.
ROLE OF TESTING IN DIFFERENTIAL DIAGNOSIS:
The diagnosis of C.M. - principally a clinical one
based on the definition excluding all other causes is deemed to
be "definite" if asexual forms of P. falciparum are found in the
peripheral blood smear. Thick blood films are stained with Field's
A and B stain and thin films with Leishman's stain, Giemsa staining
being equally appropriate and superior for speciation (10,22).
Although a higher density of parasites appears in circulation
during fever paroxysms as schizonts burst and release merozoites it
is important that blood films are obtained several times daily and
for several days to establish the diagnosis in patients with low
density infections, which do not preclude cerebral involvement
(10,16,22). Mixed infections can occur if more than 2% of the
erythrocytes are infected. P. falciparum should be suspected (22).
Gametocytes of P. falciparum are distinct and crescent -
shaped.
Quantification of parasitemia should be done: parasites are
counted against 200 leucocytes in thick film, or as percentage of
500-red blood cells in thin film (22). While high
parasite-densities can be equated with severity the reverse is not
always true, particulady in non-immune individuals. Any parasitemia
above 250.000/m1 or more than 5% of red cells has to be considered
as medical emergency. Serum antiplasmodial antibodies
(immunoglobulins A,M and G class) synthesized in P. falciparum
malaria have no place in the diagnosis of cerebral malaria (23).
Lumbar puncture has to be done to exclude meningitis and
encephalitis, although meningeal irritation is uncommon in C.M..
Cell count and protein content in CFS is usually within normal
limits as well as opening pressure, although recent reports (24)
indicate that patients with poor outcome tend to have elevated
opening pressure in spinal tap. The search for even more
sensitivity and specificity in diagnosing life-threatening malaria
has lead to the development of diagnostic DNA probes for P.
falciparum (25,26). The golden standard however is still the direct
parasitological diagnosis by means of blood smear examination.
NATURAL HISTORY OF SEVERE P. FALCIPARUM MALARIA
A primary attack of P. lalciparum in a non immune patient is
short, severe and often fatal if not treated (approximately 25%).
Up to 7% develop C.M., its mortality rate ranging from 2 to 38%,
the average in 15 published series being 18.6% (282/1513) (19).
If the patient survives, in an untreated infection the illness
usually subsides within several weeks.
Recrudescence of latent blood stages occur for up to one year,
rarely longer. Contrary to other plasmodium species, there is no
latent hepatic phase in P. falciparum malaria. Neurological long
term sequelae do exist, convulsions and localizing signs being the
most prominent features (7%=106/1513)(9).
DISEASE SPECIFIC SEVERITY SCALES
In C .M. initial neurological findings and the degree of
parasitemia determine the severity and, hence, the course of
disease.
Molyneux et al adapted the Glasgow Coma scale for cerebral
malaria children with a minimum of O and a maximum of 5 points (4
or less is abnormal). It uses motor and crying responses to pain
and includes the ability to watch (5).
The same authors developed a bedside prognostic index based on
age. coma scoring, absence of corneal reflexes. signs of
decerebration, witnessed convulsions, blood-glucose, white blood
cell count and parasitemia, positive predictive value for an
unfavorable outcome was 83%, sensitivity was 66% (5).
The level of parasitemia parallels the severity of CNS affection
as well as involvement of other organs and metabolic derangements
leading to secondary affection of the central nervous system.
Parasitemia in more than 5% of erythrocytes is considered a medical
emergency. The parasitemia is expressed in thin films in terms of
percentage of erythrocytes being parasitized. In using thick film
methos that parasites are counted against 500 leucocytes (22).
ACUTE TREATMENT DECISIONS
Table 2: Classes of antimalarials
There are a number of classes of antimalarials, each of which
may have an effect on a different stage of the parasite and
different species:
* I. Cinhona alkaloids (quinine, quinidine)
*2. 4-Aminoquinolines (chloroquine, amodiaquine)
*3 Diaminopyrimidgs (pyrimethamine)
*4 Sulphonamides and sulphonea (sulfadoxing,
- sultametopyrazing, sulfaleng, dapsone)
*5 Tetracyclines (tetracycline. minocycline)
*6 Quinoline methanols (mefioquine)
*7 Scsquiterpene factones (artemisinine=qinghaosu)
*8 Phenanthrene methanols (halofantrine)
9 8-Aminoquinolines (primaquine)
10 Biguanidcs (proguanil, chlorproguanil. cycloguanil)
11 Other antibiotica and antimalarials
* those which can be of use for cerebral malaria are marked with
an asterix modified according to Holtmann, 1986 (27)
Adjunctive therapy:
-Exchange blood transtusion
-Anticonvulsive therapy
-Antipyretics
-Fluid and electrolyte therapy
-Treatment of complications
Anaemia
lactic acidosis
renaal failure
pulmonary oedma
Hoptension - cardiac failure
Disseminated, intravascular coagulation
gram negative septicaemia
Aspiration pneumonia
TNF synthesis inhibitors
??herapin
??low molecular weight dextran
??epinephrine
??: denotes unproven therapeutic recommendations
Table 2 denotes the classes of antimalarials with specific
reference to it's cerebral manifestations (27). Rapid reduction and
clearing of parasitemia require blood schizontocidal drugs, i.e.
antimalarials which are effective against the erythrocytic, asexual
stage of the parasite..Antiimalarial treatment has to be initiated
at the earliest possible point of disease. Intravenous quinine
dihydrochloride has been and still is the golden standard of
therapy for severe P. falciparum malaria inclusive C.M. (28). A
loading dose of 20 mg salt/kg body weight is given over 4 hours by
intravenous infusion, maintenance dosage is 10mg salt/kg body
weight by i.v. infusion (2-4 hours duration at 8 hours intervals
(29). At least seven days "treatment" should be completed. Where
available, intensive care monitoring and appropriate nursing care
are mandatory. The blood glucose concentration is checked
frequently to avoid hypoglycemia. Acute renal failure prompts early
dialysis; exchange blood transfusion, if considered in case of
severe parasitemia, is recommended as early as possible.
Convulsions, being an important cause of morbidity and mortality
and being associated with poor prognosis (10,30) are to be
contained as strictly as possible, however there is no real
scientific proof that anticonvulsive therapy in cerebral malaria
given prophylactically will improve the outcome (31 ). Neither low
molecular weight dextrane, heparinization or dexamethasone have
been proven efficacious in C.M. (32,33), pentoxifylline therapy,
however suggests a possible therapeutic value in C.M. (34).
Outcome:
Neurological sequelae, until recently often denied (15)
occur in an avarage of 7% of patients with cerebral malaria
(3-6,19,30). Death rates range trom 5 to 38% with an avarage of
18,6%. Epileptic seizures, both focal and generalized, and focal
neurological signs, like hemiplegia or aphasia, are most frequently
observed, in few cases blindness, cerebellar ataxia and diffuse
psychoorganic syndrome and even decerebrate state (35) might ensue.
The development of neuroplical sequelae is associated with
protracted convulsions, proplonged coma and sever anaemia (19).
Some of these deficits resolved at least partially even months
after the acute disease.
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Copyright 1998 Pan African Association of Neurological
Sciences
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