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AIAN REVIEW
Year : 2021  |  Volume : 24  |  Issue : 6  |  Page : 849-864
 

Neurological facets of scrub typhus: A comprehensive narrative review


1 Department of Neurology, Neo Hospital, Noida, Uttar Pradesh, India
2 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission15-Aug-2021
Date of Acceptance29-Oct-2021
Date of Web Publication17-Dec-2021

Correspondence Address:
Divyani Garg
Consultant Neurologist, Department of Neurology, Neo Hospital, Noida, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_739_21

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   Abstract 


Scrub typhus is one of the most frequent causes of acute febrile illness in South and South-east Asian countries. Neurological features accompany 20% of scrub typhus infections, and may affect the central or peripheral nervous system, and sometime, may even occur in combination. Of late, its recognition among clinicians has increased with widening detection of its cutaneous hallmark, called eschar. Multiple mechanisms underlie neurological involvement, including direct invasion (meningitis, encephalitis), vasculitis (myositis) or immune-mediated mechanisms (opsoclonus, myoclonus, optic neuritis, Guillain–Barre syndrome). Despite an immunological basis for several neurological manifestations, response to doxycycline is remarkable, although immune therapy may be necessary for severe involvement. Scientific literature on scrub typhus neurology chiefly emanates from case reports, case series and small studies, and a comprehensive review is warranted to aid clinicians in recognising neurological involvement. This review aims at enriching this gap, and summarises clinical features, laboratory findings, and treatment options for various neurological facets of scrub typhus.


Keywords: Neurology, opsoclonus, orientia tsutsugamushi, scrub typhus, vasculitis


How to cite this article:
Garg D, Manesh A. Neurological facets of scrub typhus: A comprehensive narrative review. Ann Indian Acad Neurol 2021;24:849-64

How to cite this URL:
Garg D, Manesh A. Neurological facets of scrub typhus: A comprehensive narrative review. Ann Indian Acad Neurol [serial online] 2021 [cited 2022 Jan 26];24:849-64. Available from: https://www.annalsofian.org/text.asp?2021/24/6/849/332692





   Introduction Top


Scrub typhus is a rickettsial illness caused by Orientia tsutsugamushi. It is due to the bite of the larval form of the Leptotrombidium mite, termed 'chigger' which is both reservoir and disease vector. The larval form survives by feeding on rats, which are reservoir hosts. Humans are infected when they come in contact with chiggers. Most descriptions of scrub typhus have emanated from a distinct geographical region, termed 'tsutsugamushi triangle.' This triangles extend from northern Japan and eastern Russia in the north, Pakistan and Afghanistan in the west and northern Australia in the south.[1] However, reports have also emerged from other regions such as South America and Africa, lately.[2] Above one billion individuals are at risk for scrub typhus in endemic areas.[3] Scrub typhus typically leads to an acute febrile illness, associated with thrombocytopenia, transaminitis and a sine qua non-cutaneous lesion at the site of the chigger bite, termed 'eschar.' This has a 'cigarette burn' appearance with an ulcer with a scab at the centre, and surrounding erythema or desquamation. The eschar occurs at specific sites of predilection, including axilla, submammary folds, gluteal cleft, inner thighs, abdomen, and lower back [Figure 1]. Orientia tsutsugamushi is an obligatory intracellular bacterium and replicates within endothelial cells and phagocytes. Hence, it has a predilection for affecting highly vascularised organs such as brain, lungs, and liver. Severity of infection is determined by immune status of the host, and the strain of O. tsutsugamushi, with Karp serotype being most prevalent in endemic regions.
Figure 1: Sites of distribution of eschar of scrub typhus on the human body

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Nervous system involvement occurs in up to one-fifth of the patients and is often prominent.[4] It may affect the central or peripheral nervous system. A diverse range of neurological features have been described, ranging from the more frequent meningitis and encephalitis, to rarer phenomenon such as opsoclonus, myoclonus, parkinsonism and Guillain–Barre syndrome (GBS).[5] The pathogenesis underlying neurological manifestations may be a combination of vasculitis or other immune phenomena triggered by the infection.

Despite the potentially serious consequences, scrub typhus remains eminently amenable to therapy in the form of doxycycline. The presentations are myriad and can easily be mistaken for other tropical neurological syndromes. Although there are individual case series and reports on the neurological presentations in scrub typhus, an updated review is lacking.

In this article, we aim to evaluate the clinical and epidemiological profile, treatment outcomes and potential pathogenetic mechanisms underlying neurological manifestations of scrub typhus.


   Methods Top


Search strategy

We searched three major electronic databases in an attempt to locate all reports of neurological manifestations of scrub typhus published until May 2021 in the electronic form.: MEDLINE (PubMed), Google Scholar and ScienceDirect were searched.

Search terms were “neurology,” “encephalitis,” “meningitis,” “meningoencephalitis,” “seizure,” “parkinsonism,” “opsoclonus,” “myoclonus,” “ophthalmoplegia,” “ocular flutter,” “ataxia,” “neuropathy,” “Guillain–Barre syndrome,” “myelopathy,” “myelitis,” “cranial neuropathy,” “facial palsy,” “central nervous system.” These terms were combined with “scrub typhus” and “Orientia tsutsugamushi.”

We included original articles, case series, case reports, letters to the editor, posters and bulletins published up to May 2021 in this review, which described neurological manifestations associated with scrub typhus infection among adults (>18 years). We restricted our search to articles in English. The two authors (DG, AM) independently screened titles and abstracts of all papers located in the initial search. From these articles, we extracted author name, year of publication, journal name, age and sex of the patients, type of neurological manifestation, day of illness on which neurological feature appeared, diagnostic method, neuroimaging and other evaluation details, treatment details and outcome.


   Results Top


Neurological features in scrub typhus can be classified as those involving the central nervous system (CNS), peripheral nervous system (PNS) and those with multi-axial involvement. Clinical, laboratory features and treatment modalities adopted have been described below.

Pathogenesis of neurological features

Approximately 20%–25% of patients with scrub typhus suffer from neurological complications, making this an important part of the clinical constellation.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88] Entry in to the CNS is via invasion of endothelial cells by O. tsutsugamushi. Endothelial cells are the primary cellular target. Subsequent endothelial cell activation leads to leukocyte adhesion and transmigration, platelet aggregation and cytokine release. In the lung, this uncontrolled activation causes excessive neutrophilic and monocytic infiltration, triggering acute respiratory distress syndrome (ARDS).[6] In the CNS, resultant vasculitis leads to a plethora of complications. Direct invasion of the CSF has been reported in some studies, leading to meningitis and meningo-encephalitis.[7] A third mechanism underlying neurological features is immune-mediated, due to type 2 hypersensitivity reaction targeting self-antigens. This explains certain late-onset manifestations such as opsoclonus, myoclonus, GBS and myelitis.

We have summarised these mechanisms in [Figure 2] and the timeline of development in [Figure 3].
Figure 2: Pathogenesis of neurological features of scrub typhus

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Figure 3: Timelines of evolution of neurological manifestations in scrub typhus

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Central nervous system involvement in scrub typhus

The most frequently occurring CNS manifestations include meningitis, meningo-encephalitis, encephalitis, encephalopathy and seizures. Less commonly, stroke, cerebellar involvement, opsoclonus, myoclonus, cranial neuropathies, parkinsonism, acute disseminated encephalomyelitis (ADEM), haemorrhagic encephalitis and myelitis have been reported [Table 1]. The word 'typhus' itself is derived from 'typhos' indicating stupor, inspired from the diverse range of CNS involvement. CNS involvement in scrub typhus is also a predictor of mortality.[8]
Table 1: Summary of studies describing central nervous system (CNS) involvement in association with scrub typhus

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In the largest prospective series, 79/189 (41.8%) patients diagnosed with scrub typhus had any form of CNS manifestations; 42 (22.2%) had altered sensorium, 12 (6.3%) had seizures, 39 patients were diagnosed to have aseptic meningitis based on CSF findings.[9]

Meningitis, encephalitis and encephalopathy

Meningitis and meningoencephalitis are the most frequent neurological features of scrub typhus, with data emanating from larger case series [Table 1]. Scrub typhus accounted for 18% of all CNS bacterial infections in Laos.[10] In a large series of patients from India, 37/323 (11.5%) patients with scrub typhus had CNS involvement.[11] In studies from India, 20%–25% cases with acute encephalitis had IgM/PCR positivity for scrub typhus although this effect is uncertain as IgM response in scrub typhus may persist for more than a year.[12],[13]

Patients with scrub typhus meningitis present with classical clinical features of meningeal involvement.[14] They report fever, headache, vomiting, neck stiffness and altered sensorium. Neck stiffness may be reported in up to 67% of patients.[5] Presence of altered sensorium/seizures including status epilepticus and focal deficits is seen in encephalitis.[15] The median duration from onset of fever may ranges from 3 to 22 days as per literature. In one rare case report, haemorrhagic conversion of encephalitis was reported and was postulated to be consequent to vessel wall fragility in vasculitic blood vessels.[16]

Scrub typhus yields a cerebrospinal fluid (CSF) picture akin to aseptic meningitis, with lymphocytic pleocytosis, mild to moderate protein elevation and normal or borderline low sugar levels. In endemic regions, bacterial and tubercular meningitis form close differentials. Some of the pointers towards scrub typhus as the underlying aetiology of meningitis compared to tuberculosis include a relatively shorter duration of illness, less severe neurological deficits at presentation, presence of hepatic involvement, thrombocytopenia and CSF parameters including lower degree of protein elevation and lymphocytosis.[17],[18] In comparison to acute bacterial meningitis, shorter duration of symptoms, higher levels of obtundation, absence of hepatic involvement, higher CSF pleocytosis, neutrophilic predominance in CSF and higher degree of protein elevation favour bacterial meningitis over scrub typhus meningitis.[4]

Although doxycycline is the treatment of choice for scrub typhus, several authors have noted the development of meningitis or meningoencephalitis during the course of doxycycline therapy. This may be due to the bacteriostatic action of doxycycline, relatively poor penetration through the blood–brain barrier and drug resistance. For this reason, some authors advocate the use of rifampicin alone or in addition to doxycycline for CNS involvement in scrub typhus. Minocycline has also been found to be effective in treatment of CNS scrub typhus with good response.[19] Overall, response to antimicrobial therapy is favourable with most patients responding well. However, since CNS involvement may also be mediated by immunological mechanisms apart from just direct invasion, this issue may not be related to doxycycline penetration alone.

Cranial nerve palsies

Individual as well as multiple simultaneous nerve involvement has been reported with scrub typhus [Table 1]. Involvement may be indirect, as a result of an immune-mediated process, such as optic nerve involvement in post-infectious optic neuritis, which is steroid-responsive. Multiple extraocular nerve involvement may occur as part of cavernous sinus inflammation or infection. The latter seem to respond well to antibiotic therapy alone. In a series of patients with meningitis due to scrub typhus, cranial nerve palsies were observed to respond to doxycycline therapy.[15] However, development after scrub typhus infection has been treated may raise concerns of post-infectious demyelination. Additional clues may be derived from CSF analysis, with albumin-cytological dissociation favouring inflammation over infection. Similarly, in patients with scrub typhus with lateral rectus palsy, only one patient presented with diplopia in concert with fever.[20] In the other two cases, it was detected on examination. Moreover, CSF was normal in two cases and showed mild elevation in protein in one patient, suggesting that the mechanism of involvement may be leptomeningeal inflammation or raised intracranial pressure or even microvasculitis-mediated nerve injury.

Hearing loss is a unique and interesting phenomenon noted in scrub typhus and is acute and reversible. It is believed to be present in nearly one-third of patients although only limited cases have been reported [Table 1].[21] The mechanism could be due to immune-mediated or vasculitis-related damage to the VIIIth nerve or demyelinating neuropathy involving the cochleovestibular nerve. In a histopathology study of louse-borne typhus, cochlear and retro-cochlear injury was noted.[22]

Opsoclonus-myoclonus syndrome

Scrub typhus has been recognised as a para-infectious cause of opsoclonus and/or myoclonus syndrome. First reported by Nam et al. in 2010,[23] it was subsequently described in isolated case reports [Table 1]. The largest data emanate from a retrospective series of 18 cases.[24] In this series, opsoclonus with/without myoclonus was a transient and self-limited phenomenon following onset of fever. All patients had complete resolution at three months of follow-up. The usual onset is in the second week following fever and hence, it is likely to be an immune-mediated phenomenon, although immune modulation seems not to be required for treatment. Neuroimaging is usually normal or may show associated meningeal involvement. CSF may reveal albumino-cytologic dissociation. It is important to recognise scrub typhus as a cause of this often dramatic neurological condition, particularly considering its high amenability to antibiotic therapy alone.

Cerebellar involvement

Scrub typhus can rarely cause acute cerebellitis. We identified seven case reports in the literature describing cerebellitis in association with scrub typhus [Table 1]. MRI revealed cerebellar lesions in three of these cases. Most of these patients showed resolution of symptoms with doxycycline alone. Pure cerebellitis in the absence of meningitis may also occur, as reported in four cases.[25–28] In this latter context, acute cerebellar ataxia due to Plasmodium falciparum malaria forms an important differential in tropical regions.

Parkinsonism

Parkinsonism is also uncommonly reported in scrub typhus. Three individual case reports have described parkinsonism occurring during the course of scrub typhus with complete improvement following initiation of doxycycline. Imaging (CT/MRI) was normal in all these patients. In two of these cases, myoclonus was associated with parkinsonism. This co-occurrence of myoclonus and parkinsonism has also been noted in a case series reported from southern India focussed on delineating details of opsoclonus in scrub typhus, suggesting a shared immunological mechanism. Of 18 patients with opsoclonus in this retrospective series, 6 (33%) were noted to have associated parkinsonism.[24] Although this completely resolved in five, persistent asymmetrical extrapyramidal features were noted in one patient at 12 weeks of follow-up. Whether Parkinson disease was uncovered by scrub typhus or triggered by it in this patient remains conjectural.

Transverse myelitis

Four patients with acute transverse myelitis have been reported. The onset of symptoms ranged from 4 to 14 days after onset of fever. MRI variably showed cervical, dorsal and lumbar cord enhancement and swelling. All patients were managed with steroids in conjunction with doxycycline. In one patient, initial doxycycline therapy alone was insufficient to stimulate improvement, prompting the clinicians to initiate steroids, triggering recovery. This favours an immunological basis underlying this presentation in scrub typhus. The grey matter of the spinal cord has been noted to have a specific predilection to be affected, which may be attributable to the high metabolic demands of spinal cord grey matter.[29]

Encephalomyelitis

Two cases of acute encephalomyelitis have been reported in association with scrub typhus.[30],[31] Both patients developed obtundation and quadriparesis accompanied by sixth and/or seventh cranial nerve involvement. One patient was treated with steroids apart from doxycycline but did not respond well. The second patient showed favourable response to doxycycline therapy alone.

Status epilepticus

Although seizures have been reported in 6.3–21.6% of patients with scrub typhus, status epilepticus (SE) is reported less commonly. In one study, 13 out of 66 (19.7%) patients with scrub typhus admitted at a tertiary centre in northern India had SE.[32] All responded to antiseizure medications (ASMs) and scrub typhus treatment. ASMs could be stopped within one year in all patients as all had normal MRI and resolution of EEG abnormalities. Non-convulsive SE has been reported in one patient with scrub meningo-encephalitis.[33]

Other central nervous system manifestations

Scrub typhus has been implicated as a cause of rapidly progressive cognitive impairment in one report.[34] However, causality was uncertain in this case report as baseline cognitive status of the patient prior to acute deterioration was uncertain. Cognitive issues persisted despite improvement in neuroimaging features after treatment for scrub typhus. In another case report, the development of posterior reversible encephalopathy syndrome (PRES) was also attributed to scrub typhus.[35] However, the mechanism was unclear and the authors attributed it to a precipitous decline in blood pressure. Hence, strength of causation remains weak in both these reports.

Peripheral nervous system involvement in scrub typhus

Plexus involvement

Plexus involvement in the setting of scrub typhus is rare. We found three reports of plexus involvement with scrub typhus. Two of these reported brachial plexopathy which responded well to medical therapy.[36],[37] One of these patients had presented with fever along with unilateral shoulder pain and shoulder weakness which resolved completely with doxycycline therapy [Table 2].
Table 2: Peripheral nervous system involvement in scrub typhus other than meningitis/encephalitis

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Radiculoneuropathy

We found 11 reports of acute radiculoneuropathy in association with scrub typhus.[38],[73],[74],[75],[76],[77],[78],[79],[80] The age ranged from 13 months to 74 years. The range of duration from onset to weakness was 3-16 days. Nerve conduction studies revealed both demyelinating and axonal patterns. There was one report of Miller Fisher syndrome.[38] Nearly all patients were managed with intravenous immunoglobulins. All patients showed improvement to complete resolution of weakness. The pathogenesis appears to be immune-mediated [Table 2].

Peripheral neuropathy

One patient with mononeuritis multiplex developing in association with scrub meningitis and acalculous cholecystitis has been reported.[81] This patient was managed with minocycline for 10 days with complete response.

Muscle involvement[82],[83],[84]

In one case series, 13 of 33 (39%) patients were noted to have muscle involvement, in the form of myalgia or muscle weakness, in combination with elevated CPK levels [Table 2].[83] All these patients reported severe and generalised myalgia. They had moderately elevated creatine phosphokinase (CPK) levels ranging from 287-3166 U/L. The electromyographic findings demonstrated short-duration polyphasic potentials. Muscle biopsy exhibited features of vasculitis. Treatment with doxycycline led to improvement in clinical symptoms as well as CPK levels.

In one other case report, myalgias and high CPK levels were associated with rhabdomyolysis and in another report, severe myocarditis accompanied muscle involvement.[82],[84] Both patients showed complete resolution with doxycycline alone.

Despite the demonstration of vasculitis on muscle biopsy in the series by Kalita et al., immunomodulation in terms of steroids seems not to be necessary for the management of myositis.[83]

Multi-axial involvement

Several case reports describe simultaneous or tandem involvement of central and peripheral nervous system including peripheral neuropathy/Guillain–Barre syndrome with stroke/myelitis/meningoencephalitis, multiple cranial nerve palsies and cerebellitis.[85],[86],[87],[88]

Diagnostic issues

The mainstay of diagnosis in scrub typhus is via serological testing.[89] In primary scrub typhus, IgM antibodies usually develop by the end of the first week and IgG antibodies develop by the second week. The diagnosis of scrub typhus among the reports included in this review included mainly Weil-Felix test, enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescent antibody (IFA) test. Since these tests are associated with nuances and pitfalls, it is essential to discuss their importance in the context of diagnosis of scrub typhus.

Since O. tsutsugamushi is an intracellular pathogen, it cannot be isolated through standard bacterial culture but requires cell culture. Hence, nucleic acid amplification tests form the mainstay of diagnosis. Weil-Felix test is the oldest diagnostic test available, and it is based on cross-reaction with proteus OXK strain. It is, however, hindered by low sensitivity and cross reacts with other rickettsial agents. IFA is considered to be the diagnostic gold standard. This test detects the presence of antibodies in the sera of infected individuals that bind to immobilised antigen, using fluorescein labelled anti-human immunoglobulin. IFA requires demonstration of four-fold rise in antibody titre in acute and convalescent phase sera, and no absolute value can be used for diagnosis. ELISA is frequently used, as it is widely available and requires less technical input compared to IFA. The antigen used is a 56 kDa antigen which combines with IgM antibodies against Karp, Kato, Gilliam and TA716 strains in acute infection. Immunochromatographic tests are rapid point-of-care tests, which also use the 56 kDa antigen of Karp, Kato and Gilliam strains and have variable sensitivity and specificity. Polymerase chain reaction (PCR) directly detects the organism with high sensitivity and specificity, even at low copy numbers. However, cost is a prohibitive element, especially in low-resource settings. In the studies included in the review, the diagnosis was made on the basis of ELISA in the majority of patients, followed by IFA. ELISA has very high sensitivity of 92%–97% and specificity of 94%–99%.[89] A false positive may arise with other acute febrile illnesses, such as dengue, leptospirosis and spotted fever. A purely clinical diagnosis, hinging on the presence of an eschar was made in a handful. Eschar, if present, has high specificity (98.9%), but its presence may be highly variable among patients.

Treatment considerations

Doxycycline (100 mg twice daily, oral/intravenous) is the treatment of choice. Azithromycin is an alternative agent. Most of the neurological manifestations of scrub typhus, including meningitis, encephalitis, myositis, cerebellar dysfunction responded to these antibiotics. However, some of those with an immune pathogenesis, such as transverse myelitis, Guillain–Barre syndrome and optic neuritis, required treatment with steroid therapy or intravenous immunoglobulins. It is noteworthy that even neurological features with likely immune mechanisms were reported to respond to antibiotic therapy alone, without the need for steroids, as in several cases of opsoclonus myoclonus, cerebellar dysfunction and parkinsonism. Other antibiotic treatment options include chloramphenicol, rifampicin and tetracycline.


   Conclusions Top


Our review informs comprehensive detailing of neurological facets related to scrub typhus described till date. Information was gleaned from individual case reports, case series, retrospective and prospective data. The pathogenesis of this wide array of manifestations is also unclear, and probably multifactorial. Among the most important observations is that most of these neurological manifestations respond exceedingly well to doxycycline or other appropriate antibiotics. Only few immune-mediated conditions such as post-infectious optic neuritis, cerebellitis, Guillain–Barre syndrome required immune therapy in the form of steroids. Other dramatic clinical conditions including opsoclonus-myoclonus, meningitis/encephalitis, and even ADEM responded promptly to antibiotic therapy. Or review highlights that scrub typhus must be enlisted high in the differential diagnosis list among patients in endemic areas presenting with acute febrile illness, especially in the setting of multi-organ dysfunction and presence of an eschar due to its eminently treatable yet potentially lethal nature.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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