Discussion:-
There have been few attempts to study scrub typhus in Nepal. In 1981, a high probability of scrub typhus was identified in Nepal by detecting high antibody titers (10%) in healthy adults. IgM antibodies to O. tsutsugamushi were positive in samples from various regions, including 30 districts in Nepal. Positive cases have been found in different ecological regions of Nepal 9.
Humans are infected by the bite of the larvae of the leptothrombidium mite. From the bite site, bacteria are distributed throughout the body via blood and lymph. It induces endothelial injury, leukocyte perivascular infiltration, increased vascular permeability, and an vasculitic response with severe microvascular thrombosis leading to organ damage 1,10. Classically, scrub typhus presents with fever, headache, cough, myalgia, arthralgia, lymphadenopathy, and maculopapular rash that begins from the trunk and spreads to the limbs11–13. The ’eschar’, which are thought to be the hallmark of the disease, are the bites of these chiggers that creates wound similar to ’cigarette burns’ 1,10. ”Characteristic” symptoms of scrub typhus have been occasionally reported, with the characteristic crust occurring in only 20% of patients and lymphadenopathy in 24%. Nevertheless, the eschar occurs more frequently in adults, and conversely, and conversely organanomegaly can occur in children. However, the absence of these signs should not rule out scrub typhus infection, as these features are present in only 1 in 4-5 patients with confirmed CNS scrub typhus. Given its potential impact on long-term morbidity, clinicians should be alert to the possibility of acute convulsive activity in children with central nervous system scrub typhus 14. The microbe has an increased propensity of infecting organs that are highly vascularized, like the liver, brain, heart, and lungs 11. Hence, beginning from 2nd week, the infection, if untreated, progresses to complications like acute diffuse encephalomyelitis, encephalopathy, meningitis, cranial nerve palsies, congestive heart failure, vasculitis, myocarditis, pneumonia, acute respiratory distress syndrome, acute renal failure, gastrointestinal bleeding, alterations in liver functions and pancreatitis 11–13,15. Among the complications, myocarditis and encephalitis are the most life-threatening ones16. Doxycycline is the drug of choice and azithromycin is the drug of choice for children and pregnant women17.
Despite the growing number of clinical studies addressing the neurological complications of tsutsugamushi disease, there are surprisingly few studies to clarify the underlying mechanisms of neuroinvasion and neuroinflammation 8. Spread of bacteria from the periphery to the central nervous system occurs by hematogenous spread 18,19.
Although the exact mechanism of entry into the central nervous system is unknown, there is evidence that direct entry may occur through damage to the microvascular endothelium or disruption of the blood-brain barrier through transcellular translocation of bacteria, which can occur independently or by way of macrophages that have engulfed the bacterium. After entering the central nervous system, it activates specific transcription factors, such as the nuclear factor kappa B, which causes inflammation [14]. Orientia tsutsugamushi has an endothelial cell tropism and invades dendritic cells, monocytes and tissue macrophages. Endothelial invasion causes vascular injury with intestinal perivascular mononuclear infiltration leading to complications 20.
Several neurological syndromes have been reported in association with scrub typhus. Literature review reveals case reports of acute transverse myelitis, myoclonus, parkinsonism, and acute disseminated encephalomyelitis 21–23. Solitary or multiple cranial neuropathy is a well-known neurological manifestation of scrub typhus infection 2. Cranial nerve disorders such as facial paralysis, sensorineural hearing loss, trigeminal neuralgia, and diplopia due to abduction paralysis were observed24–27. Few authors suggest that scrub typhus should be considered as a differential diagnosis in all patients with aseptic meningitis with renal or hepatic impairment living in endemic areas28. They found that the CSF profile mimics tuberculous meningitis or viral meningitis. CSF had predominantly lymphocytic pleocytosis, elevated protein with low or normal glucose.
As per the definition, acute encephalitis syndrome presents with the fever in association with seizure, altered mental status and the focal neurological signs like ataxia, aphasia, cranial nerve palsy or hemiparesis 12. Our patient presented with the symptoms of fever, headache, vomiting, and altered mental status associated with the signs of bilateral lateral rectus palsy, dysphagia, regurgitation of food, dysarthria, and left-sided UMN type facial palsy that is suggestive of acute encephalitis syndrome with cranial nerve palsy.
The Neuroimaging findings for meningoencephalitis due to scrub typhus are quite limited. There have been reports of radio imaging findings of lesions on a white matter involving the subcortical, periventricular deep white matter, corpus callosum, cerebellar peduncles, brain stem, and basal ganglia, as well as grey matter lesion and microhemorrhages29. Kar et. al(2014) have reported the presence of diffuse cerebral edema along with T2-weighted and FLAIR hyperintensities in the putamen and thalamus, suggesting brain parenchymal involvement12. The diagnosis of encephalitis in our case was further supported by the multiple mildly increased T2DM/FLAIR signal in the midbrain, pons, and left middle cerebellar peduncle.