Scrub typhus-associated movement and gait disorders: A systematic review with principal component analysis and in silico mechanistic modelling.

Abstract

Background: Orientia tsutsugamushi, the causative agent of scrub typhus, is increasingly recognised for its neurological complications. Among these, movement and gait disorders are poorly understood. We systematically examined their clinical spectrum and explored underlying mechanisms through in-silico protein-protein interaction modelling.

Methods: A systematic review was conducted following PRISMA guidelines, including studies published up to 5 November 2024. Principal component analysis was used to identify clinical patterns among neurological features. In-silico protein-protein interaction modelling was used to examine potential cross-reactivity between Orientia tsutsugamushi proteins and human targets proteins.

Results: Among 76 cases, 50 presented with either isolated or combined movement disorders, most commonly opsoclonus (64.0%, 32/50), with the opsoclonus-myoclonus combination predominating (59.4%, 19/32). Other hyperkinetic features included tremor (4.0%, 2/50) and distinct forms of myoclonus (without opsoclonus) (8.0, 4/50%). Parkinsonism was present in 26.0% (13/50) of cases. Gait disorders, excluding parkinsonian gait and instability due to myoclonus, were well-characterised in 27 patients, one of whom had concomitant opsoclonus and cerebellar ataxia. Ataxic gait was the predominant pattern, observed in 96.3% (26/27), primarily cerebellar in origin. Principal component analysis revealed five principal components reflecting distinct clinical clusters: cerebellar dysfunction, tremor and parkinsonism, sensory ataxia and spinal involvement, myoclonus (diaphragmatic/action/segmental), and prolonged recovery and cranial nerve involvement. In-silico analyses revealed high-confidence interactions between bacterial epitopes and host proteins, including fibronectin-1 and Golgi-associated molecules, suggesting mechanisms of immune-mediated injury and neuroinflammation.

Conclusions: Scrub typhus may lead to a range of movement and gait disorders through neuroimmune mechanisms and molecular mimicry. Principal component analysis offered a data-driven framework to classify these manifestations, highlighting clinically relevant patterns. Early recognition and targeted treatment are critical to improving outcomes. Future studies should validate the molecular targets identified and evaluate immunomodulatory strategies for therapeutic intervention.