REYE SYNDROME

Reye syndrome is a clinic-pathological entity, characterized by generalized loss of mitochondrial functions and presenting as acute rapidly progressive encephalopathy with protracted vomiting.

Epidemiology: Once a common cause of acute ence­phalopathy, the incidence of Reye syndrome has declined in recent years. It is most common between 4 and 12 years of age.

Etiology: Typical Reye syndrome is almost always associated with use of aspirin in a mild viral febrile illness, e.g. chickenpox or influenza. However, many Reye-like illnesses have been described with mitochondrial dysfunction and similar clinical course, but diverse etiology, e.g. (a) inherited urea-cycle defects, e.g. carbamoyl phosphate synthetase or ornithine carbamyl transferase deficiency, (b) other metabolic disorders, e.g. organic acidemia, and (c) toxin exposure, e.g. aflatoxins.

Pathogenesis of Reye syndrome revolves around the generalized mitochondrial injury, leading to decreased activity of hepatic mitochondrial enzymes and consequent impairment in fatty acid, carnitine and ammonia metabolism. Cerebral edema is the most important CNS pathology, secondary to hyper-ammonemia, glucopenia and hypoxic/ischemic injury.

TABLE 18.32: Clinical staging of Reye syndrome

Stage Features

I Lethargy, vomiting, abnormal liver function tests

II Delirium, hyperventilation, hyperreflexia

III Light coma, decorticate rigidity, pupillary reflex +

IV Deep coma, seizures, decerebrate rigidity, fixed-dilated pupils

V Deep coma, flaccidity, areflexia, apnea, isoelectric EEG

Clinically Reye syndrome presents after 5-7 days of prodromal viral illness with:

• Abrupt onset of intractable vomiting,

• Rapidly progressive delirium, stupor and coma, within few hours of vomiting.

• Mild/moderate hepatomegaly, though icterus is typically absent till late stages.

Diagnosis is based on a triad of—(a) preceding viral illness/aspirin intake, (b) protracted vomiting, and (c) typical neurological course (Table 18.32), supported by persistent hypoglycemia and absence of icterus.

Laboratory diagnosis is supported with—(a) elevated serum ammonia, (b) protracted hypoglycemia, (c) abnormal LFT including prolonged prothrombin time,

(d) normal CSF except elevated pressure, (e) generalized slowing on EEG and (f) microvesicular steatosis without inflammation or necrosis on liver biopsy.

Management of these cases includes:

• Control of cerebral edema with mannitol, steroids and hyperventilation. Phenobarbitone 2.5 mg/kg/ dose 8-12 hourly helps to decrease cerebral blood flow, reduce metabolic demands of brain and control seizures.

• General nursing care of a comatose child with constant monitoring.

• Fluid and electrolyte correction/maintenance.

• Treatment of hypoglycemia, acidosis and other complications, e.g. bleeding.

Outcome is good in early cases (grade I/II), though severe cases have high mortality (25-70%) or risk of neurological sequelae, e.g. mental retardation.

18.12.5 CEREBRAL MALARIA_________________________

Cerebral malaria-the commonest form of severe falci­parum malaria (Ch 10.33), should be considered in differential diagnosis of any case with rapidly pro­gressive febrile encephalopathy, specially without localizing signs.

Pathogenesis of cerebral malaria is multifactorial and probably relates to:

• mechanical vascular injury by parasitized RBCs with increased cytoadherence,

• toxic cellular injury due to immune-mediated release of inflammatory mediators, and

• co-existing metabolic abnormalities, e.g. hypo­glycaemia and lactic acidosis.

Cerebral edema is uncommon in cerebral malaria.

Clinically, these cases present with acute onset of:

• High fever with rapidly deepening coma,

• Recurrent generalized seizures in gt;80% cases,

• Symmetrical motor signs without focal deficit,

• Signs of brainstem dysfunction, e.g.

Diagnosis rests on WHO criteria, as follows:

• Unarousable coma for gt;6 hours;

• Confirmed falciparum parasitemia on peripheral smear or rapid diagnostic tests;

• Exclusion of other causes for CNS signs, e.g. febrile seizures, meningitis or hypoglycemia, etc.

CSF is normal except increased pressure and mild lymphocytosis. However, CSF lactate may be elevated (gt;25 mg/dl indicates poor prognosis).

Treatment of cerebral malaria includes:

• Specific therapy: Recent data as well as WHO recommendations support the use of IV artesunate over IV quinine in severe malaria, to avoid serious side-effects, e.g. hypoglycemia and hypotension. Further, it takes ~4 hours to achieve adequate quinine levels even after the loading dose.

Children weighing lt;20 kg should receive higher dose of artesunate (3 mg/kg/dose) than older ones (2.4 mg/kg/dose) at 12 hourly interval to ensure equivalent exposure to the drug, followed by switch­over to oral ACT as soon as possible for 3 days (see Table 10.56).

In endemic regions, first dose of IV artesunate may be given to suspected cases even before smear confirmation. If IV access is not possible, first dose of artesunate administered rectally before referral has shown to reduce the risk of death in severe malaria.

• Supportive therapy: Coexisting complications, e.g. hypoglycemia and acidosis are major killers in cerebral malaria and all suspected cases of cerebral malaria need intensive care with:

± Continuous monitoring for vital signs, depth of coma and complications, e.g. hypoglycemia, acidosis, dyselectrolytemia and anemia.

± Treatment of hypoglycemia with IV 25% dextrose (2 ml/kg bolus) followed by continuous Dextrose 5-10% infusions.

± Correction of fluid/electrolyte imbalance and metabolic acidosis.

± Correction of anemia with transfusions or preferably partial exchange transfusion, which also helps to reduce parasite load

± Control of seizures with anticonvulsants, e.g.

Anti-edema measures, e.g. steroids, mannitol, dextran, etc. have no proven role in treatment of cerebral malaria and are generally contraindicated. Role of other therapeutic modalities, e.g. pentoxyphylline, deferoxamine, prostacyclines, IV immunoglobulins, hyperbaric oxygen and anti-TNF antibodies is controversial and at best, experimental.

Prognosis: Mortality in untreated cases of cerebral malaria is ~20-30%, with bad prognostic indicators being— (i) age lt;3 years, (ii) deep coma, recurrent seizures and decerebrate rigidity, (iii) absent corneal reflex or retinal hemorrhages, and (iv) co-existing hypoglycemia, severe anemia or lactic acidosis. With adequate treatment, most cases respond dramatically with complete recovery, though late neurological sequelae, e.g. epilepsy, motor deficits and hearing/vision/ speech impairment may develop in lt;10% cases.

18.12.6