CEREBRAL MALARIA

Introduction to malaria

• MALARIA IS AN PRTOZOAL DISEASE TRANSMITTED BY BITE OF INFECTED FEMALE ANOPHELES MOSQUITOES.

• THE MOST IMPORTANT OF THE PARASITIC DISEASES OF HUMANS.

• IT IS TRANSMITTED IN 108 COUNTRIES CONTAINING 3 BILLION PEOPLE.

• AND CAUSES NEARLY 1 MILLION DEATHS EACH YEAR.• MALARIA HAS BEEN ELIMINATED FROM UNITED STATES,

CANADA, EUROPE AND RUSSIA ; HOWEVER ITS PREVELANCE ROSE IN MANY PARTS OF THE TROPICS.

MALARIA THREATENS 40% WORLD POPULATION

ETIOLOGY AND PATHOGENESIS• 5 SPECIES OF THE GENUS PLASMODIUM CAUSE

NEARLY ALL MALARIAL INFECTIONS IN HUMANS .• THESE ARE P.FALCIPARUM, P. VIVAX, P . OVALE, P.

MALARIAE, AND IN SOUTH EAST ASIA THE MONKEY MALARIAL PARASITE P. KNOWLESI

• ALLMOST ALL DEATHS ARE CAUSED BY FALCIPARUM MALARIA

• Although p. vivax and p. malariae had achieved the widest

global distribution, today p . Malariae has lost its predominance and p. vivax and p. falciparum are the most commonly encountered malaria parasites.

• P. vivax is now the most geographically widespread of the human malarias, estimated to account for 100-300 million clinical cases across much of asia , central and south america , the middle east and parts of africa , where 70-90% of the malaria burden of p. vivax species and the rest due to p.falciparum.

Malaria in India • The state of orissa, with a population of 36.7 million

contributes to 25% of the total annual malaria cases more than 40% of p. falciparum malaria cases and nearly 20-30% deaths caused by malaria in india , followed by meghalaya, mizoram, maharastra, rajastan, gujarat, karnataka, goa, southern madhya pradesh, chattisghar, and jharkhand that also report significant number of malarial cases and deaths.

• The proportion of p.vivax and p.falciparum varies in different parts of india although p. falciparum accounts for <10% of malaria cases in mostly indogangetic plains and northern hilly states , northwestern india , and southern tamil nadu , it causes 30-90% of the infections in the forested areas inhabited by ethnic tribes.

HOST RESPONSE• INITIALLY, THE HOST RESPONDS TO PLASMODIAL

INFECTION BY ACTIVATING NONSPECIFIC DEFENSE MECHANISMS.

• SPLENIC IMMUNOLOGIC AND FILTRATIVE CLEARANCE FUNCTIONS ARE AUGMENTED IN MALARIA, AND THE REMOVAL OF BOTH PARASITIZED AND UNINFECTED ERYTHROCYTES IS ACCELERATED.

• THE GENETIC DISORDERS LIKE SICKLE CELL DISEASE, HEMOGLOBINS C AND E, HEREDDITARY OVALOCYTOSIS, THE THALASSEMIAS, AND GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY CONFER PROTECTION AGAINST DEATH FROM FALCIPARUM MALARIA.

• IMMUNE INDIVIDUALS HAVE A POLYCLONAL INCREASE IN SERUM LEVELS OF IGM, IGG AND IGA.

CLINICAL FEATURES• NONSPECIFIC SYMPTOMS::LACK OF SENSE OF WELL BEING,

HEADACHE, FATIGUE, ABDOMINAL DISCOMFORT, AND MUSCLE ACHES FOLLOWED BY FEVER.

• HEADACHE IS MORE SEVERE IN MALARIA, THERE IS NO NECK STIFFNESS OR PHOTOPHOBIA AS OCCURS IN MENINGITIS.

• NAUSEA, VOMITTING, AND ORTHOSTATIC HYPOTENSION ARE COMMON.

• THE CLASSICAL MALARIAL PAROXYSMS, IN WHICH FEVER SPIKES, CHILLS, AND RIGORS OCCUR AT REGULAR INTERVALS.

• THE TEMPERATURE OF NONIMMUNE INDIVIDUALS AND CHILDREN OFTEN RISES ABOVE 40 C IN CONJUNCTION WITH TACHYCARDIA AND SOMETIMES DELIRIUM.

• ANAEMIA,PALPABLE SPLEEN AND LIVER AND MILD JAUNDICE ARE COMMON.

• In P.falciparum infection, fever can occur every third day,

or more frequently, even in a daily paroxysmal pattern. • The typical malarial paroxysm occurs in a sequence of

chills and fever followed by sweating, often described as cold, hot and wet stages respectively.

Comparision of the 5 plasmodium species causing human malaria• P.falciparum :: in india 30-90% cases in orissa,the

northeastern states chattisghar, jharkhand, MP, bihar and andamans.

• Pre-erythrocytic cycle :: 5-6 days• Incubation period :: 12 days• Exoerythrocytic phase :: absent• Merozoites per tissue schizont :: 40,000• Erythrocytic cycle :: 48 hours• Fever pattern :: tertian, subtertian• Relapses :: +• Period of recurrence :: short• Severe malaria :: 6%

• P.vivax :: in india, nearly 50% of total malaria burden;

predominant species in most parts other than P.falciparum dominant areas.

• Pre-erythrocytic cycle:: 8 days • Incubation period:: 13 days or upto 6-12 months• Merozoites per tissue schizont :: more than 10,000• Fever pattern :: tertian• Relapses:: ++ • Severe malaria :: 3%

• P.ovale::stray cases reported from kolkata, orissa, delhi,

gujarat, and assam• Pre-erythrocytic cycle:: 9 days• Incubation period:: 17 days or longer• Merozoites per tissue schizonts:: 15,000• Fever pattern :: tertian• Severe malaria :: very rare • Relapse:: ++

• P.malaria:: in india , 3-16% reported from some tribal

areas, particularly orissa.• Pre-erythrocytic cycle:: 13 days • Incubation period:: 28 days or longer• Merozoites per tissue schizonts :: 2000• Fever pattern :: quartan• Severe malaria :: very rare• Relapses::+++

PATHOGENESIS OF COMPLICATED PLASMODIUM FALCIPARUMERYTHROCYTE CHANGES IN P. FALCIPARUM MALARIA

• IN P.FALCIPARUM INFECTIONS, MEMBRANE

PROTRUBERANCES APPEAR ON THE ERYTHROCYTES SURFACE 12-15 HOUR AFTER THE CELL INVASION.

• THESE KNOBS EXTRUDE A HIGH MOLECULAR WEIGHT, ANTIGENICALLY VARIANT, STRAIN SPECIFIC ERYTHROCTE MEMBRANE ADHESIVE PROTEIN THAT MEDIATES ATTACHMENT TO RECEPTORS ON VENULAR AND CAPILLARY ENDOTHELIUM AND IS CALLED AS CYTOADHERENCE.

• SEVERAL VASCULAR RECEPTORS HAVE BEEN

IDENTIFIED, OF WHICH INTRACELLULAR ADHESION MOLECULE 1(ICAM 1) IS PROBABLY THE MOST IMPORTANT IN THE BRAIN, CHONDROITIN SULPHATE B IN THE PLACENTA, AND CD 36 IN MOST OTHER ORGANS

• THUS, THE INFECTED ERYTHROCYTES STICK INSIDE AND EVENTUALLY BLOCK CAPILLARIES AND VENULES.

• AT THE SAME STAGE, THESE P. FALCIPARUM INFECTED RBC MAY ALSO ADHERE TO UNINFECTED RBC’S TO FORM ROSETTES AND TO OTHER PARASITIZED ERYTHROCYTES.

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MANIFESTATION OF SEVERE FALCIPARUM MALARIA• COMA OR CEREBRAL MALARIA• ACIDEMIA/ACIDOSIS• SEVERE NORMOCHROMIC,NORMOCYTIC ANEAMIA• RENAL FAILURE• NON CARDIOGENIC PULMONARY OEDEMA/ ARDS• HYPOGLYCEMIA• HYPOTENSION/SHOCK• BLEEDING/DIC• CONVULSIONS• HEMOGLOBINURIA/black water fever.

DEFEINITION OF CEREBRAL MALARIA

• WHO DEFINITION:: UNROUSABLE COMA NOT ATTRIBUTABLE TO ANY OTHER CAUSE IN A PATIENT WITH FALCIPARUM MALARIA.

THE COMA SHOULD PERSIST FOR ATLEAST 30 MIN AFTER A GENERALISED CONVULSION TO DIFFERENTIATE FROM THE TRANSIENT POST ICTAL COMA.• EXCLUSION OF OTHER CAUSES OF COMA

( HYPOGLYCEMIA, BACTERIAL MENINGITIS, VIRAL ENCEPHALITIDES )

AETIOPATHOGENESISSEQUESTRATION OF CEREBRAL CAPILLARIES AND VENULES

MECHANICAL HYPOTHESISP.FALCIPARUM PARASITES IN BRAIN CAPILLARIES

SECTION OF BRAIN SHOWING BLOOD VESSELS BLOCKED WITH DEVELOPING P.FALCIPARUM PARASITES

• SELECTIVE CYTOADHERENCE RESULTS IN

ROSETTING• REDUCTION OF MICROVASULAR BLOOD FLOW• HYPOXIA

HUMORAL HYPOTHESIS• MALARIAL TOXIN• STIMULATES PRODUCTION OF TNF-ALPHA AND

CYTOKINES• STIMULATE ENDOTHELIAL CELLS• UNCONTROLLED PRODUCTION OF NITRIC OXIDE• COMA

Charecteristics of cerebral malaria• Coma is charecteristic and ominous feature of falciparum

malaria.• Onset may be sudden following seizures or gradual with

initial drowsiness, confusion, disorientation, delirium, or agitation.

• Extreme agitation is indication of poor prognosis in falciparum malaria.

• Diffuse symmetric encephalopathy; focal nuerological signs are unusual.

Cont..• On routine fundoscopy, 15% of patients have retinal hemorrhages. Other

fundoscopic abnormalities include discrete spots of retinal opacification, papilledema,cotton wool spots, and decolouration of a retinal vessels or segment of vessel.

• On examination :: patient is febrile and unrousable . Although some passive resistance to head flexion may be detected, signs of meningeal irritation is absent.

• Bruxism is present.• Brisk jaw reflex present.• Cranial nerves usually normal.• Pout reflex is common.• The corneal reflexes are preserved, except in deep coma.• Muscle tone may be increased or decreased; plantar reflexes may be flexor or

extensor.• Patients may have a increase in tone with extensor posture of decorticate or

decerebrate.• Ophisthotonus posture.

Post malarial neurological syndromes• Late neurological complications may occur following

recovery from cerebral malaria.These are psychosis, encephalopathy, parkinsonian rigidity, tremors, cerebellar dysfunction.

RELATIVE INCIDENCE OF SEVERE COMPLICATIONS OF FALCIPARUM MALARIA

COMPLICATION NONPREGNANT ADULTS

PREGNANT WOMEN

CHILDREN

ANEMIA + ++ +++

CONVULSIONS + + +++

HYPOGLYCEMIA + +++ +++

JAUNDICE +++ +++ +

RENAL FAILURE +++ +++ -

PULMONARY OEDEMA

++ +++ +

Features indicating poor prognosis• Clinical: marked agitation, hyperventilation(respiratory

distress),hypothermia(<36.5), bleeding, deep coma, repeated convulsions, anuria, shock.

• Laboratory : Biochemistry : Hypoglycemia, hyperlactatemia, acidosis, elevated serum creatinine, elevated total bilirubin, elevated liver enzymes, elevated muscle enzymes, elevated urate.

• Hematology : leukocytosis, severe anemia, decreased platelet count (<50000), prolonged prothrombin time, prolonged partial thromboplastin time, decreased fibrinogen.>5% neutrophils contain visible malarial pigment.

• Parasitology : Hyperparasitemia,>20% of parasites identified as pigment containing trophozoites and schizonts.

Relapse in malaria• A latent stage for Plasmodium spp. in the liver, for which

there is now extensive morphological and experimental confirmation, best explains both the relapse phenomenon and the long prepatent periods seen with some strains of Plasmodium vivax.

• These latent stages (hypnozoites) have been detected in three relapsing malarias and have been found to persist in the liver as uninucleate parasites for up to 229 days after sporozoite inoculation.

DIAGNOSIS OF FALCIPARUM MALARIA

• The thin blood smears should be rapidly air dried, fixed and stained.

• The thick blood smears ; the thick film has the concentrating advantage and thus increasing diagnostic sensitivity

STAGES OF P.FALCIPARUM

LAB DIANOSIS

• Fluorescence Microscopy (QBC)• Nucleic Acid Staining with acridine

• Parasite Count = (TLC / Cuml X Parasite / 100 WBC) / 100 = Parasite / Cuml of Blood

• Serology • Anti body detection• Antigen detection

• Biochemical Test - Optimal test (Parasite LDH)• PCR & Culture

Rapid malaria test

SD BIOLINE Malaria rapid test (P.f/p.v) is a qualitative immunochromatographic rapid test for detection of antibodies of all isotypes (IgG, IgM, IgA) specific to Plasmodium falciparum and Plasmodium vivax simultaneously in human serum, plasma or whole blood.

CEREBRAL INVOLVEMENT• Clinical

• CSF - Increased Lactic Acid and low glucose; mild increase in cell count(leukocyte pleocytosis with lymphocyte predominance) and raised protein concentration(>50 mg/dl)

• CT, MRI

THERAPEUTIC OPTIONS

•CHEMOTHERAPY•Quinine•Artemisinins - Artesunate

• - Arte- ether• - Arte - mether

Antimalarial drugs for severe malaria

Parentral antimalarial immediately on admission for atleast 24 hours

• First choice: artesunate

2.4mg/kg iv stat, after 12 hours and then once daily.

• Alternative: quinine

20mg/kg iv infusion stat, upto maximum of 1.4 g quinine can be given over 4 hours, then 10mg/kg 8 hourly iv/im, then orally for totally 7 days.• Alternative: artemether

3.2mg/kg im stat, then 1.6 mg/kg per day

Follow on complete treatment

• Full course of artesunate+SP or artesunate plus amodiaquine or artesunate plus clindamycin or doxycycline for 7 days.

• Doxycycline 3.5mg/kg od for 7 days (not in pregnancy and children<8 years)or clindamycin 10 mg/kg bd for 7 days.

• Full course of artemether+lumefantrine

Radical cure of malaria due to p.vivax and p.ovale

• Relapses can be prevented by primaquine (15mg daily for 14 days ), which destroys the hypnozoite phase in liver.

• Malaria in pregnancy : uncomplicated P.falciparum :• First trimester : quinine + clindamycin for 7

days(artesunate + clindamycin for 7 days if this fails or if nothing else available)

• Second and third trimesters : ACT being used in the country/region or artesunate + clindamycin for 7 days or quinine + clindamycin for 7 days.

• Severe malaria : parenteral artesunate, artemether, or quinine.

Chemoprophylaxis of malaria

Area Antimalaria tablets

Adult prophylactic dose

Regimen

Choloroquine resistance high

Mefloquine or doxycycline or malarone

250 mg100 mg1 tablet from 1-2 days before travelling to 1 week after return

One tablet weeklyDailyDaily

Chloroquine resistance moderate

Chloroquine plus proguanil

150 mg base 100 mg

2 tablets weekly2 tablets weekly

Chloroquine resistance absent

Chloroquine or proguanil

150 mg100 mg

2 tablets weekly1 or 2 tablets daily

SUPPORITIVE & ADJUNCTIVE THERAPY• Nursing Care• Catherization• Nasogastric tube• Fluid & Electrolyte• Monitor level of coma & vital signs• Antipyretics• Anticonvulsants• Reduction in ICT• Correction of Hypoglycemia• Exchange Transfusion• Increase Microcirculatory Flow - Pentoxyfylline• Desferrioxamine• Correction of - Anaemia, Acidosis,

Dehydration

NEWER HORIZON

•Inhibition of Endothelial Activity •- LMP 420 – inhibitor of TNF alpha & LT activity

•Vaccine Development

Prevention• Avoid mosquito bites.• Mosquito repellant.• Insecticide mosquito nets.• Preventive medicines: Chloroquine is taken weekly and is

the preferred drug for the few areas without chloroquine resistance, it's used in combination with proguanil in areas with a slightly higher risk of chloroquine-resistant malaria.Doxycycline and malorone.

• Both chloroquine and proguanil have no special risk for pregnant women and should be administered together.

Outcome of cerebral malaria• Cerebral malaria carries a mortality of about 20% in adults

as well as children and most deaths occur within 24 hours of admission, even before antimalarial drugs have had time to work.

• Cerebral malaria and transtentorial herniation leading to respiratory arrest and severe metabolic acidosis causing cardio respiratory arrest have been identified as some of causes of death.

• The mortality was 39.28% among pregnant women.

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