Introduction: Scrub encephalitis (SE) is one of the known causes of acute encephalitis syndrome (AES). Although central nervous system involvement is known in scrub typhus, its association with AES is less understood and lesser diagnosed. In the absence of a point of care test for scrub typhus, cases of SE can be easily missed. A clinical approach using detailed history and clinical profiling of SE will help to diagnose SE in our region, using minimum resources, within a reasonable period. Aims: To analyze the clinical spectrum in patients of SE and to evaluate the investigations required to diagnose SE. Methodology: This is a retrospective study that analyzed Scrub typhus patients over 2 years from January 2018 to December 2019. A total of 370 patients were screened and 23 patients who satisfied the study criteria were included in the study and analyzed. Results: Among the cases of scrub typhus admitted in the hospital, the prevalence of SE was 6%. The most common presenting complaint was fever in 21 patients (91%) followed by altered sensorium in 16 (70%) and seizures in 9 patients (39%). An eschar was noted in 66% of the cases. The mean Glasgow Coma scale was 11 among the cases with almost 70% of cases showing signs of meningeal irritation. Organ involvement was noted as thrombocytopenia in 21 patients (91%), 16 patients (69%) with jaundice, and 1 (4%) with acute kidney injury. Conclusion: SE is an AES which, if detected early, is easily treatable with no residual neurological sequelae. Hence, identification of this condition and prompt diagnosis of SE becomes crucial to the management of this complication of scrub typhus.
Keywords: Acute encephalitis syndrome, scrub encephalitis, scrub typhus
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Sukumar CA, Bolanthakodi N, Lakhmani L, Singh A, Vidyasagar S. Unraveling scrub encephalitis: A study on the clinical profile and investigations of scrub encephalitis. Indian J Med Spec [Epub ahead of print] [cited 2022 May 28]. Available from: http://www.ijms.in/preprintarticle.asp?id=337425
| Introduction|| |
Scrub typhus caused by Orientia tsutsugamushi shi is a common, zoonotic disease in South East Asia. It is re-emerging infection and a growing public health problem in India recently due to the urbanization of rural regions.
Scrub typhus presents as fever, jaundice, myalgia, headache, with an inoculation eschar. In severe forms, pneumonia, myocarditis, azotemia, shock, gastrointestinal bleed, and meningoencephalitis can occur. Although central nervous system (CNS) involvement is known in scrub typhus, its association with acute encephalitis syndrome (AES) is less understood and lesser diagnosed.
We sought to describe the clinical presentation and laboratory investigations in SE with this study to understand the clinical presentation and specific investigations required to diagnose this condition.
| Methodology|| |
We conducted a retrospective study on all cases of scrub encephalitis (SE) for 2 years (January 2018 to December 2019). Patients admitted in ward or intensive care unit in Kasturba hospital meeting the inclusion–exclusion criteria were included.
Cases of SE were defined as patients who tested positive for Scrub typhus (Detect IgM ELISA by InBIOS International) and presented with altered mental status which could not be attributed to any other infection or any definite metabolic/structural cause.
Patients in the age group of 18–75 years of both sexes were included. Patients with AES proven to have scrub typhus with positive Scrub typhus Detect IgM ELISA (by InBIOS International).
Patient in whom there was a definite proven cause of altered sensorium such as pyogenic and tubercular meningitis, tumors, neurocysticercosis, epilepsy, or a definite metabolic/structural cause. All other causes of tropical illnesses causing encephalitis were excluded by appropriate investigations.
Scrub typhus Detect IgM ELISA (by InBIOS International) test was done to ascertain positive cases of Scrub typhus. A thorough history of their presenting complaints and associated co-morbidities were taken using a structured proforma. Details of patient examination, focusing on neurological evaluation (including assessment of Glasgow coma scale [GCS]), and other systems were also collected. Data regarding laboratory investigations done to ascertain the cause of febrile illness (malaria, dengue, etc.), complete blood count, renal and hepatic function tests, and cerebrospinal fluid (CSF) analysis (if available) were collected.
| Results|| |
A total of 370 cases who tested positive for Scrub typhus were screened and only 23 cases of SE were included in this study. There were no significant differences in the demographics of the screened population and the study population. The screened population included patients from both the rural and urban districts of Karnataka. [Table 1] shows the baseline characteristics of the study population.
|Table 1: Baseline characteristics of all patients in the study population|
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Among the demographic data, there was a definite male preponderance among the population with 65% males and 35% females. The mean age of patients was found to be middle age of around 43 years. None of the cases had any significant history of contact with animals or travel history. None of the cases were immunocompromised. There were only two patients having essential hypertension in comorbidities.
Among the 23 patients, a majority (15) were men and all the patients were from a poor socioeconomic background. The male patients were predominantly agricultural laborers and only one of them was a driver. All the female patients were home-makers. However, 91% (twenty-one of 23 patients) lived in and around farms and even the female patients were exposed to outdoor activities while tending to the farm. It was also noted that a majority of the male patients habitually defecated in open spaces near their houses which could have predisposed them to tick bites.
The most common clinical presentation among the cases of SE was fever which was seen in 91% of the patients. Almost 70% of the patients presented with altered mental status while 39% presented with seizures, 17% presented with nausea and vomiting, and 4% presented with a headache. Almost 50% of the patients showed involvement of the other organ systems clinically such as decreased urine output and jaundice.
On examination, an eschar was noted in 66% of the cases. Among the study population of SE and the mean value on the GCS was 11. Signs of meningeal irritation were noted in 30% of the patients. The spectrum of clinical presentation is shown in [Figure 1].
The average duration of illness before presentation to the hospital was 4 days in our study. The median duration of fever was 6 (3–7) days. There was an association between the duration of fever and the day of onset of altered sensorium in our encephalitis patients (r = 0.833, n = 16; P < 0.001).
The biochemical profile of the patients with SE is shown in [Table 2]. Among the laboratory investigations, thrombocytopenia was seen in most of the patients with the average platelet count being 1, 14, 000/μl. The average serum creatinine and the total bilirubin were 1.1 mg/dl and 1.98 mg/dl, respectively. There was transaminitis and increased alkaline phosphatase (ALP) noted among all the cases.
CSF analysis was done in 6 (26%) patients. The findings of the fluid analysis are summarized in [Table 3]. There was lymphocytic predominance noted with elevated protein. Adenosine deaminase (ADA) was done in all 6 patients and was <10 U/L in them.
| Discussion|| |
Scrub typhus was first identified in China in the 3rd century AD. The causative organism was Orientia tsutsugamushi which was named thus as “tsutsuga” means “small and dangerous” and “mushi” means “small creature.” Typhus is derived from typho which means fever with stupor in Greek.
Although this disease has been known for centuries, India encountered it for the first time during world war II among the soldiers posted in West Bengal and Assam. Scrub typhus has now monopolized a geographical area called the “tsutsugamushi triangle” with India stationed at the west end of this triangle. Over the past decades, Scrub typhus has re-emerged and is endemic to our country with an increase in cases noted during the summer months and the autumn-winter period.
Scrub typhus accounts for 30%–40% of hospitalizations for undifferentiated fever. Complications associated with scrub typhus include meningoencephalitis, acute respiratory distress syndrome, interstitial pneumonia, acute renal failure, gastrointestinal bleeding, and multiple organ failure.
In our study, we looked at the neurological involvement of scrub typhus. The causative organism, which is an obligatory intracellular bacterium enters the CSF engulfed in a monocyte or via the endothelium wherein it enters the perivascular space through the luminal cell membrane. The pathogen then invades and multiplies in the vascular endothelium and causes widespread vasculitis.
We noted a prevalence of 6% cases of SE among all the cases of Scrub typhus cases treated at our hospital during the study period. The mean age of the study population was 43 years with a male preponderance. This could be because males generally undertake work outdoor and hence are more susceptible to tick bites. A North-East Indian study that included 113 cases of scrub typhus also showed a male:female ratio of 2.5:1 which was similar to the findings in our study. However, some other studies reported the same age predominance but equal gender distribution. This may reflect the recent increase in the number of women working outdoors.
A majority of the patients presented with fever (91%). Those who did not present with fever presented with seizures (9%). The two patients who presented with seizures have generalized tonic-clonic seizures with no history of seizures before this episode. Altered sensorium was seen in 69% of our patients. This is higher than the findings from other studies of SE which noted around 56% of cases presenting with altered sensorium. This could be attributed to referral bias as our center is a tertiary hospital providing service to several adjacent districts as well.
Interestingly, headache which is usually a common feature in SE was noted only in one patient. In fact, headache in patients with Scrub typhus helps to diagnose suspect cases of SE. However, in our study altered sensorium and seizures have taken precedence in patients presenting with SE This could be because altered sensorium and seizures are more alarming symptoms compared to headache and prompt patients to seek immediate medical care. Also, many patients neglect vague symptoms like headache, unless it is very severe.
The average duration of illness before presentation to the hospital was 4 days in our study. There was an association between the duration of fever and altered sensorium. It means that the longer the duration of fever, more the occurrence of altered sensorium.
AES due to viral etiology is known to be a close provisional diagnosis for patients with SE. However, in viral AES, the fever and the altered sensorium occur together at presentation. In SE, the altered sensorium occurs after a period of febrile illness. This temporal association of fever and altered sensorium can give a clue to the diagnosis of SE in patients who present with fever and altered sensorium.
It has been found that Scrub typhus involves the meninges more commonly, compared to other rickettsial infections. The overall CNS presentation in scrub typhus is ideally described as meningoencephalitis. However, studies have noted that patients without obvious signs of CNS involvement had reactive spinal fluid with mononuclear pleocytosis and their CSF tested positive for polymerase chain reaction for scrub typhus as well. This suggests that CNS invasion in scrub typhus is actually more common than what is suggested by associated CNS symptoms alone. The CSF analysis was performed in 6 patients on presentation, as they had no eschar on presentation to indicate a scrub typhus etiology,
On clinical examination, we noted the presence of the pathognomic eschar in 66% of our cases of SE. This was similar to its incidence in other studies as well. The importance of this eschar is reiterated by the fact it aids in earlier diagnosis which otherwise would have been confirmed only after laboratory investigations. However, eschars are reported from 20% to 40% in different Indian studies due to the challenge of identifying it in our Indian population.
Although the identification of an eschar can be challenging, a meticulous clinical bedside examination, which includes checking in the arm-pits, groin, gluteal region, and breast folds cannot be emphasized enough in such cases. This not only confirms a diagnosis within minutes but also obviates the need for further investigations to confirm the diagnosis in these cases. An eschar also has immense prognostic significance in addition to its diagnostic benefit.
A significant number of our patients were found to be hypotensive (52%). This corroborates with evidence from other studies where severe scrub typhus commonly presents with low blood pressure. In a recent study from Himachal Pradesh, it was found that hypotension was one of the most common (in 88% of cases) cardio-vascular complications that occur in severe scrub typhus. This could be attributed to the associated shock, arrhythmias, or myocarditis that are encountered in cases with severe scrub typhus.
The altered sensorium in our patients persisted even after the correction of hypotension, pointing to another cause. However, the association of SE and hypotension points to the severity of the illness and should alert to the possibility of infection causing both.
On examination of the CNS, signs of meningeal irritation such as nuchal rigidity were found in 6 (26%) cases and Kernig's sign was positive in 4 (17%) of them. Cranial nerve involvement was noted in one patient (4%) in the form of right adductor palsy. This was noted in another study as well where abducent nerve palsy was noted 2 days after initiation of treatment for SE. Eighth cranial nerve involvement has also been reported in up to 19% of patients of SE which is caused by direct invasion of the cranial nerve or by immune-mediated effect. However, in our study, we did not note any cases with cochlear nerve involvement.
Other organ systems involved in SE were hepato-biliary, gastrointestinal, and renal. Although jaundice was noted in only one patient at presentation, eleven patients (47%) developed jaundice during their course in the hospital. Seven patients had severe jaundice (Total bilirubin >5 mg/dl). Although transaminitis was noted among these patients (in 60%), it was noted that there was a disproportionate increase in Serum glutamic oxaloacetic transaminase (SGOT) compared to Serum glutamic puruvic transmaminase (SGPT) in our study. This was also noted in the North-Eastern Indian study done on SE. Serum alkaline phosphatase (ALP) was elevated (>120 IU/L) in 78% of the patients with 35% of them having ALP >400 IU/L. This indicates a possible association between severe scrub typhus (such as SE) and serum ALP. In a comprehensive review article on tropical infections like scrub typhus, it was noted that hepatic involvement could present as transaminitis in 90%, and elevated alkaline phosphatase was noted in up to 50% of the patients diagnosed with scrub typhus. Our study concurred with these findings and showed elevated ALP in 18 patients (78%) and transaminitis in 14 patients (60%) of the SE patients.
Gastrointestinal involvement in SE was noted only in 3 patients. GI involvement is common in cases of moderate-to-severe scrub typhus and causes disseminated or focal gastrointestinal vasculitis. This leads to complications such as abdominal pain, loose stools, gastrointestinal bleed, pancreatitis, splenomegaly, etc.
Although acute kidney injury is common in cases of severe scrub typhus, we had only one patient with oliguria secondary to acute kidney injury. This is in contrast to data from other studies which show up to 38% renal involvement in SE.
CSF analysis in SE usually indicates, increased protein, low-to-normal glucose and lymphocytic pleocytosis. We performed CSF analysis in six of our patients. All of them showed lymphocytic predominance. While lymphocytic predominance aids in differentiating from bacterial meningitis, tubercular meningitis remains a close differential diagnosis. However, staining for acid-fast bacilli was not suggestive of tuberculosis in these patients. Markers like CSF ADA are useful here as it helps differentiate between scrub meningitis and tubercular meningitis. In our study, all values of ADA were <10U/L. As mentioned previously, our patients show 100% lymphocyte predominance which is also reflected in a study by Viswanathan et al.(98%). CSF protein was more than 100 mg% in only 8% of our cases and there was a wider range in protein levels (52%–432 mg%). This similar trend was also noted in one of the largest cohort studies on SE which showed a CSF protein range between 13% and 640 mg%. This is even wider than the CSF protein range described by Boorugu et al. which was only 13–360 mg%.
The treatment of a majority of cases of SE was done with intravenous doxycycline. Only a few patients received additional oral azithromycin. Despite reports of doxycycline being bacteriostatic and not crossing the blood-brain barrier in SE, we found good outcomes in all our patients. There was no mortality due to SE in our study population. Oral azithromycin was used in cases where doxycycline was contraindicated due to deranged liver function tests. One of the most common complications in our cohort was hypotension. All these patients responded well to fluid challenges and low-dose inotropes for a brief period. Patients with severe thrombocytopenia were given platelet transfusions in view of mild bleeding tendencies. Jaundice and transaminitis were symptomatically managed. Patients with acute kidney injury recovered spontaneously without the need for dialysis. Patients who presented with poor Glasgow Coma scale (GCS) were intubated on the presentation for airway protection and subsequently extubated on the improvement of sensorium in an average of 2–3 days.
Only 39% of the patients (nine) who were included in the study returned to the hospital for follow-up. Among these patients, there were no residual neurological sequelae and all of them had resumed their routine activities following discharge. Fourteen patients did not return for their follow-up and hence could not be evaluated for any neurological sequelae.
| Conclusion|| |
SE is an important diagnosis to be made in any patient with altered sensorium, as it is eminently treatable. Clinical clues such as eschar, and investigations showing altered liver function tests and thrombocytopenia, may point to this diagnosis as shown in our study. Prompt therapy can be lifesaving, and hence, this is an important diagnosis to be made in tropical countries.
Ethical approval was obtained from Institutional Ethics Committee (IEC), Kasturba Medical College Manipal, Karnataka.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]