Table 1
Search Strategy.
| PubMed | (“Scrub Typhus”[Mesh] OR “Orientia tsutsugamushi”[tiab] OR “tsutsugamushi disease”[tiab] OR “scrub typhus”[tiab] OR “Orientia infection”[tiab] OR (rickettsial[tiab] AND “scrub typhus”[tiab])) AND (“Movement Disorders”[Mesh] OR “Neurologic Manifestations”[Mesh] OR “movement disorder”[tiab] OR neurological[tiab] OR neurology[tiab] OR “gait disorder”[tiab] OR tremor[tiab] OR myoclonus[tiab] OR ataxia[tiab] OR parkinsonism[tiab] OR dystonia[tiab] OR chorea[tiab] OR ballism[tiab] OR hemiballismus[tiab] OR hemiballism[tiab] OR opsoclonus[tiab] OR hyperkinesia[tiab] OR hypokinesia[tiab] OR extrapyramidal[tiab] OR “tic disorder”[tiab] OR tics[tiab] OR stereotypy[tiab] OR stereotypies[tiab] OR automatisms[tiab] OR akathisia[tiab] OR blepharospasm[tiab] OR rigidity[tiab] OR dyskinesia[tiab]) |
| Embase | (“scrub typhus”/exp OR “orientia tsutsugamushi”:ti,ab OR “tsutsugamushi disease”:ti,ab OR “scrub typhus”:ti,ab OR “orientia infection”:ti,ab OR (rickettsial:ti,ab AND “scrub typhus”:ti,ab)) AND (“movement disorder”/exp OR “neurologic manifestation”/exp OR “movement disorder”:ti,ab OR neurological:ti,ab OR neurology:ti,ab OR “gait disorder”:ti,ab OR tremor:ti,ab OR myoclonus:ti,ab OR ataxia:ti,ab OR parkinsonism:ti,ab OR dystonia:ti,ab OR chorea:ti,ab OR ballism:ti,ab OR hemiballismus:ti,ab OR hemiballism:ti,ab OR opsoclonus:ti,ab OR hyperkinesia:ti,ab OR hypokinesia:ti,ab OR extrapyramidal:ti,ab OR “tic disorder”:ti,ab OR tics:ti,ab OR stereotypy:ti,ab OR stereotypies:ti,ab OR automatisms:ti,ab OR akathisia:ti,ab OR blepharospasm:ti,ab OR rigidity:ti,ab OR dyskinesia:ti,ab) |
| Scopus | (TITLE-ABS-KEY(“scrub typhus” OR “Orientia tsutsugamushi” OR “tsutsugamushi disease” OR “Orientia infection” OR (rickettsial AND “scrub typhus”))) AND (TITLE-ABS-KEY(“movement disorder” OR “movement disorders” OR neurological OR neurology OR “gait disorder” OR tremor OR myoclonus OR ataxia OR parkinsonism OR dystonia OR chorea OR ballism OR hemiballismus OR hemiballism OR opsoclonus OR hyperkinesia OR hypokinesia OR extrapyramidal OR “tic disorder” OR tics OR stereotypy OR stereotypies OR automatisms OR akathisia OR blepharospasm OR rigidity OR dyskinesia)) |
| Google Scholar | (“scrub typhus” OR “Orientia tsutsugamushi” OR “tsutsugamushi disease”) AND (“movement disorder” OR tremor OR myoclonus OR ataxia OR parkinsonism OR dystonia OR chorea OR opsoclonus OR dyskinesia OR hyperkinesia OR extrapyramidal) |
Figure 1
PRISMA 2020 flow diagram summarizing study selection: 1046 records identified, 449 duplicates removed, 597 screened, 125 assessed, and 58 studies included, comprising 49 case reports and 9 cohort studies.
Table 2
Baseline characteristics and clinical features of patients with scrub typhus–associated movement disorders (n = 55).
| VARIABLES | VALUE |
|---|---|
| Age (in years) | NA: 3 Mean: 31.8 Median: 28 Range: 3–73 IQR: 28.5 |
| Sex | Male: 34 (61.8%) Female: 20 (36.4%) NA: 1 (1.8%) |
| Country-wise distribution of published articles (n = 49) | India: 42 (85.7%) South Korea: 3 (6.1%) China: 1 (2.0%) Nepal: 1 (2.0%) Sri Lanka: 1 (2.0%) Taiwan: 1 (2.0%) |
| Diagnostic Serology/CSF | NA: 1(1.9%) IgM ELISA: 30 (55.6%) IgM ELISA + Weil–Felix/combo: 6 (11.1%) Weil–Felix test: 4 (7.4%) Indirect immunofluorescence assay (IFA): 4 (7.4%) PCR (molecular test): 3 (5.6%) Rapid antibody test: 2 (3.7%) Next-generation sequencing (NGS): 1 (1.9%) Other serology (unspecified): 4 (7.4%) |
| Duration of illness | ≤5 days: 18 (32.7%) 6–10 days: 23 (41.8%) 11–15 days: 6 (10.9%) >15 days: 4 (7.3%) Not reported: 4 (7.3%) |
| Type of Movement Disorder/Ataxia | Opsoclonus and related ocular motor disorders: 23 (41.8%) Cerebellar ataxia and cerebellar syndromes: 19 (34.5%) Parkinsonism: 7 (12.7%) Myoclonus and related hyperkinetic disorders: 4 (7.3%) Other movement disorders (ballismus, dystonia, opisthotonus, akinetic mutism): 4 (7.3%) |
| Associated Neurological Findings* | Other cerebellar signs (nystagmus, dysmetria, hypotonia; excluding ataxia): 18 (32.7%) Extrapyramidal signs (bradykinesia, rigidity, tremor): 12 (21.8%) Seizures/status epilepticus: 6 (10.9%) Cranial nerve palsies/brainstem involvement: 8 (14.5%) Meningeal signs/raised intracranial pressure: 9 (16.4%) Pyramidal signs (spasticity, quadriparesis, hyperreflexia): 7 (12.7%) Peripheral neuropathy/sensory deficits: 3 (5.5%) |
| Other Clinical Features | Fever: 55 (100%) Headache: 20 (36.4%) Vomiting/GI symptoms: 20 (36.4%) Myalgia/Arthralgia/Malaise: 10 (18.2%) Altered sensorium, confusion, drowsiness, akinetic mutism: 14 (25.5%) Liver involvement (transaminitis/hepatomegaly/jaundice): 17 (30.9%) Thrombocytopenia/Coagulopathy/Bleeding: 6 (10.9%) Rash/Petechiae/Erythema: 4 (7.3%) Respiratory involvement/ARDS: 6 (10.9%) Renal involvement/AKI: 6 (10.9%) Papilledema/Photophobia/Meningeal signs: 4 (7.3%) Lymphadenopathy/Episcleritis: 3 (5.5%) Hypotension/Shock/MODS: 4 (7.3%) Other neurological signs (rigidity, tremor, imbalance): 5 (9.1%) |
| Presence of a characteristic eschar | Present: 21 (38.2%) Absent: 17 (30.9%) Not reported/Not mentioned/Not specified: 17 (30.9%) |
[i] *Movement disorder categories represent the primary motor syndrome, whereas associated neurological findings denote additional examination signs; therefore, categories are not mutually exclusive.
Table 3
Clinical investigations, treatment, and outcomes in scrub typhus–associated movement disorders (n = 55).
| VARIABLES | VALUES |
|---|---|
| Blood investigations | Thrombocytopenia: 27 (49.1%) Elevated liver enzymes/transaminitis/hyperbilirubinemia: 23 (41.8%) Leukocytosis/leukopenia/lymphocytosis: 16 (29.1%) Hyponatremia/electrolyte imbalance: 6 (10.9%) Renal dysfunction/elevated urea-creatinine: 6 (10.9%) Elevated inflammatory markers (CRP, ESR, ferritin): 7 (12.7%) Anemia/hypoalbuminemia: 5 (9.1%) Normal findings: 3 (5.5%) Not reported: 7 (12.7%) |
| CSF findings | Lymphocytic pleocytosis ± elevated protein: 26 (47.3%) Elevated protein with normal or few cells (albumin-cytologic dissociation): 5 (9.1%) Normal CSF findings: 10 (18.2%) Low glucose (with pleocytosis/protein elevation): 4 (7.3%) Acellular CSF: 2 (3.6%) Not performed/Not reported: 8 (14.5%) |
| Neuroimaging Findings | Normal imaging: 34 (61.8%) Cerebellar involvement (hyperintensity, edema, enhancement): 7 (12.7%) Basal ganglia/thalamic/brainstem lesions: 4 (7.3%) Leptomeningeal enhancement/pachymeningeal enhancement: 3 (5.5%) Intracranial hemorrhage/SAH/IVH: 1 (1.8%) Gliosis/demyelination/chronic changes: 3 (5.5%) Other findings (calcified granuloma, hydrocephalus, ARDS findings only): 3 (5.5%) |
| Treatment | Antibiotics only (mainly doxycycline ± azithromycin/ceftriaxone): 27 (49.1%) Antibiotics + corticosteroids (dexamethasone/methylprednisolone): 10 (18.2%) Antibiotics + immunotherapy (IVIG and/or steroids): 5 (9.1%) Antibiotics + symptomatic/supportive therapy (antiepileptics, ICP control, etc.): 8 (14.5%) Supportive/symptomatic therapy only: 2 (3.6%) Not reported: 3 (5.5%) |
| Response on movement disorder | Complete resolution of movement disorders: 37 (67.3%) Partial improvement with residual signs (e.g., mild tremor, persistent ataxia, parkinsonism): 9 (16.4%) Gradual or near-complete improvement over weeks to months: 4 (7.3%) Spontaneous resolution without specific therapy: 2 (3.6%) No improvement/fatal outcome: 1 (1.8%) Not reported: 2 (3.6%) |
| Outcome | Complete recovery/full resolution: 38 (69.1%) Near-complete recovery with minimal residual signs: 6 (10.9%) Partial recovery with persistent deficits: 5 (9.1%) Spontaneous resolution: 1 (1.8%) Death: 1 (1.8%) Not reported/insufficient details: 4 (7.3%) |
| Duration of follow up | ≤2 weeks: 10 (18.2%) 2–4 weeks: 8 (14.5%) 1–3 months: 10 (18.2%) 4–6 months: 2 (3.6%) ≥1 year: 5 (9.1%) Not reported/not specified: 20 (36.4%) |
[i] ARDS – Acute Respiratory Distress Syndrome; CRP – C-Reactive Protein; CSF – Cerebrospinal Fluid; ESR – Erythrocyte Sedimentation Rate; ICP – Intracranial Pressure; IVH – Intraventricular Hemorrhage; IVIG – Intravenous Immunoglobulin; SAH – Subarachnoid Hemorrhage.
Table 4
Proposed Mechanisms of Movement Disorders in Scrub Typhus (n = 55).
| MECHANISM | DESCRIPTION | CASES (N) | PERCENTAGE (%) |
|---|---|---|---|
| Immune-mediated/para-infectious response | Antibody-mediated cross-reactivity, cytokine release, and neuroinflammation triggered by O. tsutsugamushi, leading to opsoclonus–myoclonus, cerebellitis, basal ganglia dysfunction, or post-infectious encephalitis. | 21 | 38.2% |
| Endothelial invasion and vasculitis | Direct invasion of vascular endothelium causes vasculitis, perivasculitis, cytokine storm, and microglial activation, leading to parenchymal injury, cerebellar involvement, or intracerebral hemorrhage. | 10 | 18.2% |
| Combined immune and vascular injury | Interaction of antibody-mediated injury with vasculitic endothelial damage, often producing mixed features like opsoclonus with vasculitic lesions or cerebellitis with microvascular injury. | 6 | 10.9% |
| Direct CNS invasion and neuronal damage | Direct penetration of the pathogen into brain tissue (thalamus, brainstem, basal ganglia) causing structural neuronal damage and subsequent movement disorders. | 3 | 5.5% |
| Autoimmune demyelination/ADEM-like response | Molecular mimicry and cytokine-mediated inflammation lead to CNS demyelination, Guillain–Mollaret triangle disruption, or hypertrophic olivary degeneration. | 4 | 7.3% |
| Disruption of specific neuronal circuits | Dysfunction of omnipause neurons, Purkinje cells, or saccadic burst neurons in the pontine reticular formation and cerebellar fastigial nucleus results in opsoclonus, ocular flutter, or abnormal motor control. | 8 | 14.5% |
| Cytokine-mediated dopaminergic disruption | Pro-inflammatory cytokines (e.g., IL-8, MCP-1, MIP-1α/β) activate microglia and damage dopaminergic neurons, contributing to parkinsonism and related movement disorders. | 3 | 5.5% |
[i] ADEM – Acute Disseminated Encephalomyelitis; CNS – Central Nervous System; IL-8 – Interleukin-8; MCP-1 – Monocyte Chemoattractant Protein-1; MIP-1α – Macrophage Inflammatory Protein-1 alpha; MIP-1β – Macrophage Inflammatory Protein-1 beta; OMS – Opsoclonus–Myoclonus Syndrome.
Figure 2
Mechanisms linking Orientia tsutsugamushi infection to movement disorders, including CNS invasion, neuroinflammation, immune activation, and blood–brain barrier disruption, leading to opsoclonus and myoclonus.