Background Scrub typhus has become a leading cause of central nervous system (CNS) infection in endemic regions. As a treatable condition, prompt recognition is vital. However, few studies have focused on describing the symptomology and outcomes of neurological scrub typhus infection. We conducted a systematic review and meta-analysis to report the clinical features and case fatality ratio (CFR) in patients with CNS scrub typhus infection. Methods A search and analysis plan was published in PROSPERO [ID 328732]. A systematic search of PubMed and Scopus was performed and studies describing patients with CNS manifestations of proven scrub typhus infection were included. The outcomes studied were weighted pooled prevalence (WPP) of clinical features during illness and weighted CFR. Results Nineteen studies with 1,221 (656 adults and 565 paediatric) patients were included. The most common clinical features in CNS scrub typhus were those consistent with non-specific acute encephalitis syndromes (AES), such as fever (WPP 100.0% [99.5%-100.0%, I2 = 47.8%]), altered sensorium (67.4% [54.9–78.8%, I2 = 93.3%]), headache (65.0% [51.5–77.6%, I2 = 95.1%]) and neck stiffness 56.6% (29.4–80.4%, I2 = 96.3%). Classical features of scrub typhus were infrequently identified; an eschar was found in only 20.8% (9.8%-34.3%, I2 = 95.4%) and lymphadenopathy in 24.1% (95% CI 11.8% - 38.9%, I2 = 87.8%). The pooled CFR (95% CI) was 3.6% (1.5%– 6.4%, I2 = 67.3%). Paediatric cohorts had a CFR of 6.1% (1.9–12.1%, I2 = 77%) whilst adult cohorts reported 2.6% (0.7–5.3%, I2 = 43%). Conclusion Our meta-analyses illustrate that 3.6% of patients with CNS manifestations of scrub typhus die. Clinicians should have a high index of suspicion for scrub typhus in patients presenting with AES in endemic regions and consider starting empiric treatment whilst awaiting results of investigations, even in the absence of classical signs such as an eschar or lymphadenopathy.

S crub typhus is an acute febrile illness caused by an obligate intracellular gram-negative bacterium, Orientia tsutsugamushi. It is transmitted through chigger mites and is considered endemic to the tsutsugamushi triangle (covering Asia, northern Australia, and islands in the Indian and Pacific Oceans), although scrub typhus caused by other Orientia species has also been reported in Africa, France, the Middle East, and South America (1). A recent systematic review from hospital-based studies in India reported 25% of acute undifferentiated febrile illness was caused by scrub typhus. Most studies included were from southern India, but only 20% of included patients were <15 years of age (2). Although scrub typhus illness is typically self-limiting, neurologic complications are seen in 20%-25% of patients admitted to the hospital and are associated with high mortality rates (3,4). Scrub typhus can result in myriad neurologic manifestations, including meningitis, meningoencephalitis, encephalopathy, seizures, stroke, neuropathy, optic neuritis, myositis, myelitis, involuntary movements, and Guillain-Barré syndrome, all of which are well recognized in adults (3,4).Recent studies in India have identified O. tsutsugamushi as a major cause of acute encephalitis syndrome (AES) outbreaks, especially in northern states of the country, such as Uttar Pradesh, Bihar, West Bengal, and Assam (5-7). Outbreaks of AES pose a major public health problem in India, predominantly affecting children (8). The definition of AES used for syndromic surveillance is broad and includes all patients experiencing acute onset of fever and altered mental state (9,10). The clinical manifestation might be caused by encephalitis or meningitis (direct invasion of the