Setting: A tertiary care teaching hospital in India. Objective: To report a syndromic approach to acute encephalitis syndrome (AES) and propose a cost-effective model. Study design: AES patients were categorized by the presence or absence of myalgia/rash into systemic and neurological AES. The patients with systemic AES were investigated for dengue, scrub typhus, leptospira, chikungunya, and malaria, and those with neurological AES were investigated for herpes and Japanese encephalitis (JE). Sensitivity and specificity of syndromic categorization were tested, and cost effectiveness was calculated. Results: There were 210 patients with infectious AES; neurological in 45 and systemic in 165. Specific etiology could be found in 130 (62%) patients, and after excluding 36 patients with co-infections, 94 patients were tested for sensitivity and specificity. Twenty patients had neurological AES (herpes 12, JE 8), and 74 systemic (scrub typhus 42, dengue 20, malaria 6, leptospira 6). The absence of myalgia/rash categorized neurological AES with 100% specificity. In neurological AES, thalamic involvement predicted JE with 100% specificity. In systemic AES, differentiation could not be made between etiologies based on hypotension, thrombocytopenia, and muscle, liver, and kidney dysfunction. In these patients, MRI and acyclovir therapy were warranted, saving cost. By targeted investigations and treatment, the cost was reduced by 70%. Conclusions: A syndromic approach to AES and goal-directed investigations and treatment substantially reduces the cost of management.

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