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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 19-24

Neurological manifestations in scrub typhus from a case series in Southern India


Department of General Medicine, MVJ MC and RH, Hoskote, Karnataka, India

Date of Submission23-Jun-2020
Date of Decision05-Jul-2020
Date of Acceptance02-Aug-2020
Date of Web Publication03-Feb-2021

Correspondence Address:
Dr. Shreyashi Ganguly
MVJ MC and RH, Hoskote, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_46_20

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  Abstract 


Scrub typhus is an acute febrile illness caused by Orientia tsutsugamashi. CNS is the most crucial target in other rickettsial diseases and historically, the neurological disease burden was considered low in scrub typhus. However, there is growing evidence in literature that O. tsutsugamushi does invade the CSF and CNS invasion may be seen in 2–5 % cases of tsutsugamushi disease. O. tsutsugamushi parasitises endothelial cells both in the periphery as well as in the brain. The disease is characterized by focal or disseminated vasculitis and perivasculitis. Scrub typhus has protean manifestations. CNS involvement is rare but it should be considered as an important differential in the setting of known areas of scrub typhus outbreak. Meningoencephalitis with or without focal neurological deficits is the commonest clinical picture. However, the neurological manifestations can be highly variable. In our case series out of 81 patients who were diagnosed with scrub typhus, only 5 patients had neurological manifestations. All patients presented with altered sensorium. GCS was decreased in all patients. It was <10 in 60% cases. Neck rigidity and signs of meningeal irritation was present in 80% cases. There was no sign of papilloedema, cranial nerve involvement, focal neurological deficits. 2 of the patients had seizure which was GTCS in semiology. CSF in all cases showed lymphocytic predominance (between 150 and 400 cells/ mm3) with high protein and low to normal CSF sugar levels. NCCT brain was normal. MRI brain showed meningeal enhancement in 60% cases. Additionally, hyperintense signal on T2 was observed in 60% cases. Confirmation of the case requires serological evidence. CSF and neuroimaging picture are not pathognomonic. In the setting of acute fever, headache along with eschar or macular rash, scrub typhus must be ruled as a cause of neurological manifestations, such as altered sensorium, and seizure.

Keywords: Cerebrospinal fluid findings, meningoencephalitis, neurological manifestations, neurotropic effects of scrub typhus, scrub typhus


How to cite this article:
Kamath V, Ganguly S, Himabindu B. Neurological manifestations in scrub typhus from a case series in Southern India. APIK J Int Med 2021;9:19-24

How to cite this URL:
Kamath V, Ganguly S, Himabindu B. Neurological manifestations in scrub typhus from a case series in Southern India. APIK J Int Med [serial online] 2021 [cited 2021 Feb 28];9:19-24. Available from: https://www.ajim.in/text.asp?2021/9/1/19/308648




  Introduction Top


Scrub typhus is an acute febrile illness caused by Orientia tsutsugamashi, belonging to the Rickettsiaceae family. Scrub typhus is transmitted to humans by the bite of larval stage of trombiculid mites. It is endemic to a part of world known as the “tsutsugamushi triangle” which extends from Northern Japan and far Eastern Russia in the North to Northern Australia in the South and to Pakistan and Afghanistan in the West.[1] In Asia, the median seroprevalence of scrub typhus is about 22.2%.[1]

Scrub typhus has protean manifestations which can mimic conditions such as pneumonia, meningoencephalitis (ME), acute hepatitis, acute renal failure, diarrhea, and occasionally joint pains. The disease is characterized by fever, headache, myalgia, cough, injected conjunctiva, and gastrointestinal symptoms. An eschar at the site of chigger bite, regional lymphadenopathy, and a maculopapular rash may provide a clue to diagnosis. Studies from India and other Asian countries show that the prevalence of eschar vary from <10% to 90%.[2] An eschar at the site of bite is seen in 50% of patients with primary infection and 30% of patients with recurrent infection.[2] The severity of the symptoms varies widely, depending on the susceptibility of the host, and the virulence of the bacterial strain. With an early diagnosis and management, most patients recover without specific complications. However, clinical presentations of ST could be fatal if the diagnosis is delayed. At the extremes of age, with greater bacterial load, untreated case-fatality rate can vary from 7% to 30%.[3]

Some patients may have pulmonary, renal, central nervous system (CNS), and cardiac involvement. CNS is the most crucial target in other rickettsial diseases. The neurological disease burden was considered low in scrub typhus; however, there is growing evidence in literature that O. tsutsugamushi does invade the cerebrospinal fluid (CSF) and CNS invasion may be seen in 2%–5% cases of tsutsugamushi disease.[3]


  Mechanism of Central Nervous System Involvement Top


O. tsutsugamushi parasitises endothelial cells both in the periphery and in the brain.[4] The mechanism of cellular invasion may involve interaction between cell surface heparan sulfate proteoglycans and bacterial lectins. Binding to neutrophils and macrophages as well as nonprofessional phagocytes, including fibroblasts and endothelial cells, is seen.[4] After internalization into the cell, the organism escapes from phagosomes by an unknown mechanism. It then proliferates in the cytoplasm. Infection of host cells triggers a response, including the activation of the transcription factors nuclear factor-γB (NF-κB) (in macrophages) and NF-κB and AP-1 (in endothelial cells). This leads to the subsequent expression of chemokine genes for macrophage inflammatory protein (MIP)-1α/β, MIP-2, and monocyte chemotactic protein (MCP)-1 in macrophages and MCP-1, interleukin-8, and regulated on activation normal T expressed and secreted in endothelial cells. O. tsutsugamushi was shown to induce apoptosis in an endothelial cell line.[4] If the organism is able to overwhelm and also actively suppress cytokine production by infected macrophages cell-to-cell spread through budding of membrane-coated bacteria from infected cells occurs. Dissemination of bacteria from the periphery to the CNS is hematogenous. The organism can be found in circulating mononuclear cells and has prolonged microbial survival in leukocytes. As such, phagocyte-facilitated infection could play a role in CNS invasion.[4]


  Pathological Features Top


The disease is characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen, and CNS. The pathological findings in CNS in scrub typhus include diffuse or focal mononuclear cell exudates in leptomeninges and the presence of typhus nodules (cluster of microglial cells) that are distributed throughout brain substance. A large study showed that CNS was involved at least slightly in almost all patients suffering from scrub typhus; however, focal neurological deficit occurred rarely.

CNS manifestation can include:

  1. Meningitis/ME: Meningitis/ME has been reported in 14%–83% of patients with scrub typhus[3],[4]
  2. Acute disseminated encephalomyelitis[3],[4],[5],[6]
  3. Cranial nerve involvement: Sixth nerve is the most commonly involved.[7] Bilateral simultaneous seventh nerve palsy has been described.[8] The involvement of the second, third, and eighth cranial nerves has been documented in patients with scrub typhus[6]
  4. Cerebellitis[3],[4],[5],[6]
  5. Cerebrovascular accident[3],[4],[5],[6]
  6. Cerebral venous thrombosis[3],[4],[5],[6]
  7.  Parkinsonism More Details?[9]
  8. Opsoclonus and myoclonus?[10]
  9. Transverse myelitis and longitudinally extensive transverse myelitis[3],[4],[5],[6]
  10. Guillain–Barré syndrome[3],[4],[5],[6]
  11. Plexopathy and peripheral neuropathy?[10]
  12. Neuroleptic malignant syndromelike presentation[3],[4],[5],[6]
  13. Psychiatric manifestations.[3],[4],[5],[6]



  Case Series Top


Over the course of 2 years (December 2017–August 2019), a total of 81 cases were diagnosed with Scrub typhus, after excluding all other causes of acute febrile illness. Of these, we report the cases of five patients who were confirmed to have scrub typhus (Weil felix OXK titers >1:320, Scrub typhus immunoglobulin M [IgM] ELISA positive) and had neurological manifestations. Wherever applicable descriptive statistics has been used.

[Table 1] elucidates the symptomatology of the patients. The mean duration of fever was 6 days (range 4–10 days). It was high grade fever, associated with malaise. All patients had headache which was holocranial, nonpulsatile, constant, with retro-orbital pain. Patients experiencing seizure had generalized tonic–clonic seizure (GTCS) lasting mean of 1.5 min (1 patient experienced status epilepticus). Three patients experienced 1 episode each of vomiting, which was projectile, nonblood stained, nonbilious.
Table 1: Clinical profile of the patients

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[Table 2] shows the salient clinical findings in the patients. Tachycardia and fever were seen in all patients. Icterus was present in 40%, macular rash in 40%, eschar in 60%, and splenomegaly in 20% cases. Glasgow Coma Scale (GCS) was decreased in all patients. It was <10 in 60% cases. Neck rigidity and signs of meningeal irritation were present in 80% cases. No sign of papilloedema, cranial nerve involvement, and focal neurological deficits was noted. Two of the patients had additionally respiratory signs in the form of bilateral coarse crepitations all over the lung fields.
Table 2: Examination findings

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[Table 3] outlines the important laboratory and radiological features. Thrombocytopenia was the most common hematological manifestation (100%), followed by leukocytosis (60%), leukopenia (40%), and anemia (40%). A bilirubin level =1.3 mg/dL (range 1.2–4.3 mg/dl) was observed in 80% of scrub typhus patients. Alanine aminotransaminase (ALT): lactate dehydrogenase ratio was =5 in all of the patients. Sixty percent of the cases had hypoalbuminemia (range 1.8–4 g/dl).
Table 3: Important laboratory and radiological features

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Sixty percent of the patients had increased creatinine levels (range 0.9–2.1 mg/dl) and increased serum urea levels (range 25–99 mg/dl). None of the patients showed any derangement in serum electrolytes over the course of their stay.

The CSF showed a reactive picture in all the patients. CSF adenosine deaminase was not done as the diagnosis was confirmed by serology, and the patients showed appropriate response after initiating antibiotic therapy.

Noncontrast computed tomography (NCCT) of the brain was normal in all patients. Magnetic resonance imaging (MRI) of the brain showed consistent meningeal enhancement in 60% patients, while others had variable small lesions/areas showing hyperintense T2 signal. Two of the patients had abnormal chest X-rays showing bilateral infiltrates.

[Table 4] shows the course in the hospital for each of these patients. All patients with meningitis had received ceftriaxone 2 g Q12 hourly until serum IgM ELISA reports (or Weil-Felix test [WFT]) were available. Mannitol and dexamethasone were additionally given in all of the patients. Once the patients were diagnosed as scrub typhus, the patients were treated with doxycycline cover along with other supportive measures as appropriate. The average duration of stay was 8.8 days (range 5–11 days). All the patients required intensive care stay (average duration 4.8 days: range 4–6 days). Two patients required mechanical ventilation. All but one patient recovered after completing course of the treatment. The other patients were discharged without any neurological sequelae.
Table 4: Course in the hospital

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  Discussion Top


In our study, out of 81 patients who were diagnosed with scrub typhus, only five patients had neurological manifestations. CNS is the most crucial target in other rickettsial diseases.[3] In comparison, the burden of neurological complications in scrub typhus was perceived to be low. However, there have been several reports of encephalitis or meningitis without direct evidence of rickettsial invasion of the CNS in recent studies.[3] Growing evidence in literature suggest that O. tsutsugamushi does invade the CSF and CNS invasion may be seen in 2%–5% cases of tsutsugamushi disease.[3],[11],[12] In our study of the 81 patients studied, 5 of them had neurological involvement (6.17%). Therefore, in newer emerging areas, ST should be considered as one of the causes of aseptic meningitis during the seasonal outbreaks of ST.

Fever and headache in the setting of eschar or maculo-papular rash should alert the physician regarding this diagnosis.[4],[13] Common CNS presentations are nuchal rigidity, seizures, delirium, and meningitis.[4],[13],[14] In our study, all patients presented with altered sensorium. GCS was decreased in all patients. It was <10 in 60% cases. Neck rigidity and signs of meningeal irritation were present in 80% cases. There was no sign of papilledema, cranial nerve involvement, and focal neurological deficits. Two of the patients had seizure which was GTCS in semiology.

The meninges are more commonly involved by O. tsutsugamushi than by other rickettsial infections.[15] The overall histological picture of CNS is that of ME.[15] Rickettsia invades and multiplies in the vascular endothelium and results in widespread vasculitis involving capillaries, arterioles and small arteries.[16] Histiocytes, lymphocytes, and plasma cell infiltration of the meninges and perivascular spaces have also been described. Scrub typhus causes profound disturbances in T-cell homeostasis.[16] Therefore, it suggests the possibility that mechanisms other than antibiotic resistance/failure are the causes of CNS presentations.

CSF analysis was done within 24 h of admission in all five patients. In all cases which showed lymphocytic predominance (between 150 and 400 cells/mm[3]) with high protein and low to normal CSF sugar levels. This compares to Sood et al., which showed 83.3% had abnormal CSF when presenting with neurological complication in scrub typhus?.[3]

The neurological manifestations of scrub typhus mimics any other viral or bacterial ME. The CSF picture closely resembles bacterial meningitis. Therefore, if the clinical picture/tempo of progression is that resembling viral ME but CSF picture issuggestive of bacterial ME then a rickettsial including scrub typhus must be suspected.

There is no specific neuroradiological features pathognomic of ST have been described. In a study from Uttar Pradesh, Neyaz et al. have compiled the isolated findings from the observations in other studies.[17] In addition to meningeal enhancement, the other documented neuroradiological abnormalities on MRI are mainly localised in periventricle and deep white matter in a patient of ST ME?.[17] Kar et al. reported abnormalities like diffuse cerebral edema along with T2-weighted and fluid-attenuated inversion recovery hyper intensities in the putamen and thalamus, indicating primary involvement of the brain parenchyma on MR imaging in a case with ST ME, whereas the index patients had only findings suggestive of diffuse brain edema on computed tomography (CT) scan.[18] In our study, NCCT brain was normal. MRI of the brain showed meningeal enhancement in 60% cases. In addition, hyperintense signal on T2 was observed in 60% cases.

In this case series, 5 (6.17%) had neurological involvement manifesting as ME.

Systemic manifestations were more frequent in these patients with CNS involvement probably due to the relatively unique propensity of O. tsutsugamushi to cause multiple organ dysfunction by infecting vascular endothelial cells.[19],[20]

It is thought that O. tsutsugamushi infection causes direct cytopathic injury to Kuppfer cells and hepatocytes and sinusoidal endothelial cell vasculitis, resulting in increases in serum levels of aspartate transaminase, ALT, and γ-glutamyl transferase?.[21] A bilirubin level =1.3 mg/dL was observed in 80% of scrub typhus patients. Although necrosis and apoptosis of hepatocytes are significantly more severe in patients with viral hepatitis than in those with scrub typhus, the possible reason for the increased extent of direct hyperbilirubinemia can be because the cases in our study also met the criteria for nonhepatobiliary sepsis. The ALT: lactate dehydrogenase ratio was =5 in all of the patients with scrub typhus. Sixty percent of the cases had hypoalbuminaemia. Low levels of serum protein and albumin in our scrub typhus patients may be due to underlying liver disease, suppression of liver function due to a septic process, or the loss of albumin in the urine due to scrub typhus infection. A study by Kamath et al. has shown that hypoalbuminemia is a predictor of worse outcome.[20] The same is evidenced in our study.

Rickettsial fever is known to respond dramatically to antimicrobial therapy within 48 h, and in the absence of such a response, the diagnosis of rickettsial fever needs to be reconsidered.

All patients with meningitis had received ceftriaxone 2 g Q12 hourly until serum IgM ELISA reports (or WFT) were available. None of our patients had had a repeat CSF study due to serological diagnosis and clinical recovery within 48 h. In our study, all five patients responded to doxycycline. All but one patient made a complete recovery. Although neurological sequelae have been reported with scrub typhus,?[6],[16] none of the patients had any neurological deficit at the time of discharge.

It should be noted in resource-poor settings many a times during the treatment of ME infections, doxycycline is added to the antibiotic regimen if the serological investigations are not available. However, this is based on the gestalt of the attending physician, and therefore, this practice is on a case by case basis.

This study is limited by its size; hence, it is difficult to say that the CSF abnormalities and imaging findings mentioned above are pathognomonic of scrub typhus as these are also observed in aseptic meningitis or encephalitis too. Larger multicentric studies on CSF characteristics and neuroradiology in ST infections with the involvement of CNS are warranted. In addition, we did not do a CSF analysis or neuro-imaging in patients who did not show any neurological symptoms or signs. This may have reduced the potential number of cases who had CNS invasion by the organism but did not show any clinical disease.


  Conclusion Top


In an endemic area during specific seasons when such infections are more prevalent, especially if there is a presence of a rash/skin lesion then the differential diagnosis must necessarily include scrub typhus infection. Scrub typhus has protean manifestations. CNS involvement is rare but it should be considered as an important differential in the setting of known areas of scrub typhus outbreak. ME with or without focal neurological deficits is the most common clinical picture. However, the neurological manifestations can be highly variable. Confirmation of the case requires serological evidence. CSF and neuroimaging picture are not pathognomonic. In the setting of acute fever, headache along with eschar or macular rash, scrub typhus must be ruled as a cause of neurological manifestations, such as altered sensorium and seizure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Wiwanitkit V. Epidemiological and clinical features of scrub typhus. Med J Dr DY Patil Vidyapeeth 2019;12:424. Available from: http://www.mjdrdypv.org/text.asp?2019/12/5/424/267090. [Last accessed on 2020 Mar 12].  Back to cited text no. 1
    
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Lin WR, Chen TC, Lin CY, Lu PL, Chen YH. Bilateral simultaneous facial palsy following scrub typhus meningitis: A case report and literature review. Kaohsiung J Med Sci 2011;27:573-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22208541. [Last acessed on 2020 Mar 14].  Back to cited text no. 8
    
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Aung-Thu T, Supanaranond W, Phumiratanaprapin W, Phonrat B, Chinprasatsak S, Ratanajaratroj N. Gastrointestinal manifestations of septic patients with scrub typhus in Maharat Nakhon Ratchasima Hospital. Southeast Asian J Trop Med Public Health 2004; 35:845-51.  Back to cited text no. 21
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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