Haemorrhagic encephalitis in the garb of scrub typhus

Abstract

A 19-year-old girl presented with fever, headache, vomiting and drowsiness. She had grade 1 papilloedema and neck rigidity but no focal deficits or seizures. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, slightly elevated protein and normal glucose. MRI of the brain showed a hyperintense lesion in left ganglio-capsular region on the fluid attenuation inversion recovery sequence with perilesional oedema and mild midline shift. Haemorrhage was seen in the region on susceptibility weighted imaging. The patient was thoroughly investigated for known causes of meningoencephalitis, but the diagnosis of scrub typhus was delayed till the 10th day of illness. She was treated with doxycycline for 2 weeks and had marked improvement, both clinically and radiologically. Literature review has revealed that although meningoencephalitis in scrub typhus is not uncommon, such atypical lesions on brain MRI are a rarity. Serial imaging was performed to document the disease progression and resolution on treatment.

Background

Haemorrhagic encephalitis is a potentially lethal entity presenting with fever and altered neurological features. The brain lesions may be accompanied by raised intracranial tension and mass effect. Diagnosis is made primarily on MRI of the brain. The pattern of brain involvement observed on imaging and serological tests carried out on serum and cerebrospinal fluid (CSF) contribute to ascertaining the pathological agent. Demyelinating disorders such as acute disseminated encephalomyelitis (ADEM) can result in similar clinical picture. Establishing an early diagnosis is critical since it would determine which antimicrobial is to be used, if at all indicated. Inappropriate use of immunosuppressive drugs can be catastrophic and should be given only when the diagnosis of an autoimmune process has been proven beyond doubt. Herein, an unusual case of haemorrhagic encephalitis occurring due to scrub typhus has been presented.

Case presentation

A 19-year-old girl living at a village was taken to a peripheral health centre with history of fever up to 102°F with chills and rigours for 4 days. During the admission, she developed severe headache and vomiting, followed by drowsiness accompanied with faecal and urinary incontinence. She had no history of photophobia, ear discharge or convulsions. Until this time she was managed with intravenous ceftriaxone. An MRI of the brain (figure 1) was done and she was referred to our hospital. She was brought in by her parents to the casualty on the 7th day of illness in an obtunded state. She had a Ryle’s tube, Foley’s catheter and a venous cannula in situ. Spontaneous movements were scarce and her words were incomprehensible. On painful stimuli, she had no purposeful movement of the right upper limb and the tone was decreased. Plantar reflexes were bilaterally extensor. The axillary temperature was 101°F, pulse was 105/min and blood pressure was 110/70 mm Hg. The respirations were regular with a rate of 15 per minute and oxygen saturation was 98%. She had no eschar, rash or lymphadenopathy, pupils were normally reactive and nuchal rigidity was present. Fundus examination revealed grade 1 papilloedema (figure 2). Respiratory examination revealed vesicular sounds over both lungs without any added sounds. Cardiovascular examination was unremarkable.

Figure 1.

MRI on 6th day of illness (before doxycycline)—axial sections of T1 weighted image (A), gradient echo sequence (GRE) (B) and T2 weighted image (C). Large ill-defined area of altered signal intensity diffusely involving the left basal ganglia, thalamus and internal capsule. It is isointense to hypointense on T1 and hyperintense on T2 weighted images. There is mild perilesional oedema and mass effect is seen in the form of partial effacement of left lateral and third ventricles. There is mild dilatation of right lateral ventricle and mild midline shift to right side. The GRE sequence shows punctate foci with minimal blooming in left ganglio-capsular region, suggestive of nominal haemorrhage.

Figure 2.

Fundus showing grade 1 papilloedema. The nasal margin (arrow) of the optic discs is blurred and the temporal margin is well defined.

Investigations

The complete blood count revealed total leucocyte count (TLC) of 10.3×10⁹/L with 79% neutrophils, 16% lymphocytes, 3% monocytes and 2% eosinophils. The haemoglobin was 10.5 g/L with mean corpuscular volume of 79 fL and platelet count was 150×10⁹/L. There was mild hepatic dysfunction with aspartate transaminase of 55 IU/L and alanine transaminase of 73 IU/L. Total serum bilirubin was 0.5 mg/dL and albumin was 4 g/dL. Serum sodium, potassium, calcium and phosphorus were within normal range. The renal functions were normal with urea of 20 mg/dL and creatinine of 0.7 mg/dL. Elevation of acute phase reactants was noticed with erythrocyte sedimentation rate of 54 mm in 1st hour and C reactive protein of 61 mg/L. Coagulogram and urinalysis revealed no abnormality. Procalcitonin was elevated to 0.5 µg/L. The thyroid function tests and random serum cortisol were within normal range.

Blood and urine cultures were sterile. Serology for dengue IgM antibody and NS1 antigen, herpes simplex and Japanese B encephalitis IgM antibody was negative. Simultaneous search for other tropical infections like malaria, leptospirosis and chikungunya was negative. A guarded lumbar puncture was performed in view of her mild papilloedema. CSF analysis yielded a cell count of 16 cells μ/L with 80% lymphocytes and 20% neutrophils. Total protein was slightly elevated to 51 g/dL, glucose was 73 mg/dL (blood capillary glucose was 83 mg/dL) and adenosine deaminase was 2.5 IU/L. No organism was seen on Gram stain, Ziehl-Neelsen stain and India ink stain. The CSF culture was sterile and PCR for herpes simplex virus (HSV) and Mycobacterium tuberculosis was negative.

Plain chest radiograph was normal and ultrasound of the abdomen revealed mild hepatomegaly. The liver had a span of 15.3 cm with normal outline, shape and echotexture. The spleen measured 11.7 cm and both kidneys had a span of 9 cm. The biliary tract and pancreas were normal, and there was no ascites. The MRI brain was repeated twice during the admission. The findings are depicted in figures 3 and 4.

Figure 3.

MRI on 9th day of illness (before doxycycline)—axial sections of fluid attenuation inversion recovery (FLAIR) sequence in upper row and coronal sections in the middle row (A), and axial sections of susceptibility weighted imaging (SWI) (B). Altered signal intensity appearing heterogeneously hyperintense on FLAIR sequence is seen in left ganglio-capsular region and thalamus. The lesion has irregular peripheral enhancement and enhancement is also seen in ependymal surface of left lateral ventricle. The lesion has moderate surrounding oedema which also involves genu and body of corpus callosum on left side, left cerebral peduncle and right thalamus. Mass effect is seen in the form of effacement of body and frontal region of left lateral ventricle and third ventricle. There is mild midline shift. SWI sequence shows extensive area of blooming in the left basal ganglia region, suggestive of significant haemorrhage.

Figure 4.

MRI on 17th day of illness (7th day of treatment with doxycycline)—axial sections of susceptibility weighted imaging sequence showing markedly reduced blooming and oedema in the left ganglio-capsular region. There is no midline shift.

Although the patient did not have any seizure, generalised cerebral dysfunction was seen on electroencephalogram. There was a background activity of theta waves with intermittent delta waves and occasional spike-and-wave discharges seen in left fronto-parietal leads.

Further serologies for HIV, varicella zoster and Epstein-Barr virus were also negative. However, diagnosis was achieved when IgM ELISA for scrub typhus was reported as positive on the 10th day of illness (3 days following admission) and subsequently confirmed on nested real time PCR assay 2 days later.

Differential diagnosis

The clinical syndrome of fever followed by depressed sensorium and neck rigidity was consistent with meningoencephalitis. Partially treated pyogenic meningitis was the foremost plausible diagnosis. The absence of prior meningitis vaccination (Neisseria meningitidis) and the acute phase response along with elevated procalcitonin also provided credibility, though they are not specific. The major impediment was the imaging finding. In pyogenic meningitis, the classic MRI finding is that of leptomeningeal enhancement. Parenchymal lesions are seen only in complicated illness and consist of abscess, which is visible as a focal lesion and infarction due to secondary vasculitis.¹

Viral meningoencephalitis is usually mild and self-limiting, but severe illness can also occur. Although the CSF biochemical profile seen in the patient was consistent, the other CSF and blood investigations ruled out infection by viruses prevalent in the region. In herpes simplex encephalitis, the MRI findings are characteristic; In HSV-1, T2 hyperintensities are seen in frontal and temporal lobes, while in HSV-2, diffuse brain involvement can be seen.² It confers a very high mortality rate, hence, acyclovir should be started even when the suspicion is slight, as was done in the present case. In Japanese encephalitis, T2 hyperintensities are commonly seen in thalamus, though they may occur in basal ganglia and brainstem as well, and sometimes haemorrhagic foci are seen.² Extrapyramidal symptoms are not infrequent. The probability of Japanese encephalitis was considered low since there was currently no outbreak reported from the region. The mortality is high, especially in children, and treatment is supportive. Dengue encephalitis is rare and reported to cause T2 hyperintensities in thalamus, pons and medulla.² The suspicion was again low as the sensitive features, such as arthralgia, rash, thrombocytopenia and liver dysfunction were absent. Nevertheless, it was ruled out by appropriate investigations. There is no specific treatment. Varicella encephalitis is characterised by T2 hyperintensities in cerebellum, cortex, basal ganglia and thalamus, and haemorrhage and necrosis can occur.² Cerebellar dysfunction is common and only expectant management is required.

The patient tested negative for HIV and there were no comorbidities, so the possibility of opportunistic infections like cryptococcal and cytomegalovirus (CMV) meningitis were rejected. In CMV, MRI can be normal, or it can show white matter hyperintensities due to demyelination and ependymal enhancement due to ventricullitis.³ Cryptococcal meningitis can lead to varied lesions on MRI such as leptomeningeal enhancement, hydrocephalus and space occupying lesions with mass effect. It can be diagnosed easily by cryptococcal antigen detection in the CSF, or by India ink which stains the capsule.⁴

ADEM is autoimmune demyelination in the central nervous system (CNS) after certain infections or immunisations. The onset is acute, and seizures and focal deficits such as motor and sensory disturbances, diplopia, aphasia and cerebellar dysfunction are common. The illness is monophasic and can mimic meningoencephalitis.⁵ Asymmetrical contrast enhancing white matter lesions can be seen on brain MRI bilaterally, which can vary from patchy and punctate to large confluent lesions that can cause mass effect. Spinal cord involvement can be seen in up to one-third of the cases.⁶ The treatment modalities are high dose corticosteroids, intravenous immunoglobulin and plasmapheresis.⁷ Weston-Hurst syndrome, a rare variant of ADEM, presents with relentless neurological deterioration and carries very high risk of mortality. The demyelinating lesions on MRI consist of areas of haemorrhage and necrosis.⁸

Treatment

Ceftriaxone, which was already started at the centre where she was referred from, was continued and the dose was doubled to 2 g two times per day. Intravenous acyclovir was added in a dose of 500 mg three times per day and it was discontinued after herpes simplex encephalitis was ruled out. Dexamethasone and mannitol were started to ease cerebral oedema. Ceftriaxone was substituted with doxycycline 100 mg two times per day intravenously on the 10th day of illness after scrub typhus was diagnosed. Fever subsided 2 days later and she was gradually able to communicate verbally and eat food by herself. She continued to have weakness of the right upper limb; the muscle power being 3/5 on day 7. Objective improvement was documented on MRI and papilloedema resolved. Doxycycline was administered for a total of 2 weeks.

Outcome and follow-up

The patient was discharged after 16 days of hospital stay. The right arm had regained power to 4/5. Although she was fatigued and lethargic, she walked out of the hospital unaided. She had no headache and nausea. Follow-up was done after a fortnight. She had resumed helping her family in the household and farm work, had poor memory of events during her admission and, as reported by her parents, she was more irritable than her previous self.

Discussion

Scrub typhus is a rickettsial infection caused by Orientia tsutsugamushi which is mostly prevalent in South Asia. The incidence of scrub typhus has been steadily increasing in India since past few years and many outbreaks continue to be reported.⁹ Transmission to humans occurs by bite of the chigger larva of Leptotrombidium mite. From the site of bite, the bacterium is distributed throughout the body via blood and lymphatics. It induces a vasculitic type of reaction with endothelial injury, perivascular infiltration of leucocytes, increased vascular permeability and microvascular thrombosis which can be severe enough to lead to organ damage. The treatment of choice is doxycycline, while azithromycin is the drug of choice in children and in pregnant women.¹⁰

The exact mechanism of entry into the CNS is unknown, however, there is evidence to suggest that there may be direct entry by breakdown of blood brain barrier due to microvascular endothelial damage, or there may be transcellular migration of the bacterium, which can occur independently or by way of macrophages that have engulfed the bacterium. After entry into the CNS, it activates certain transcription factors such as nuclear factor- kappa B that induces inflammation.¹¹ This inflammation is demonstrable even in the absence of overt neurological manifestations. Pai et al¹² studied the CSF profile of 25 patients with scrub typhus with no apparent neurological signs and symptoms. Forty-eight per cent had mild pleocytosis and 28% had elevated protein.

Several neurological syndromes have been reported in the setting of scrub typhus. A literature search has revealed case reports of acute transverse myelitis, myoclonus, parkinsonism and acute disseminated encephalomyelitis.^13–15 Cranial nerve affliction has been seen in the form of facial nerve palsy, sensorineural hearing loss, trigeminal neuralgia and diplopia due to abducens nerve palsy.^16–19 Brachial plexopathy and Guillain-Barré syndrome have also been documented.^{20 21}

Seizures have been reported more commonly. Kalita et al²² have studied the profile of 10 patients who developed status epilepticus. All of them had normal MRI of the brain. Only two patients required three or more antiepileptics and the drugs were successfully withdrawn in less than a year in all of the patients.

Ralph et al retrospectively analysed 1650 patients with scrub typhus and found that 18 of them had opsoclonus.²³ Most of them had other concomitant neurological phenomena in the form of meningoencephalitis, myoclonus, cerebellar dysfunction or extrapyramidal syndrome. Three patients had MRI finding of cerebellitis. Those having meningoencephalitis had a mean CSF TLC of 55±12.2 μ/L, protein of 69.3±12.2 mg/dL and glucose of 50±8 mg/dL.

Few authors have suggested that scrub typhus should be considered as a differential diagnosis in all patients with aseptic meningitis accompanied by renal or hepatic dysfunction, if they reside in the endemic areas.²⁴ They found that the CSF profile mimicked tubercular or viral meningitis. The CSF had predominantly lymphocytic pleocytosis, elevated protein with low or normal glucose.

In another study on patients with scrub typhus meningoencephalitis, 53.7% had altered sensorium and 22.1% had seizures.²⁵ The mean CSF TLC was 80 cells/µL with lymphocytic pleocytosis in majority, and the mean CSF protein was 105 mg/dL with 640 mg/dL being the highest value recorded. The mean CSF glucose was 63.9 mg/dL with a range of 25–350 mg/dL.

Misra et al²⁶ studied 37 scrub typhus patients with neurological involvement. Eighty-four per cent had altered sensorium, 16% were comatose and 20% had status epilepticus. All the patients had excellent response to doxycycline with no long term damage. Only one patient had an abnormal MRI which revealed meningeal enhancement.

Some of the atypical MRI findings reported in scrub typhus have been summarised in table 1.

Table 1.

Atypical MRI findings reported in scrub typhus

Author	Patient’s age/sex	MRI finding (T2/fluid attenuation inversion recovery sequence)
Chua et al27	40/M	Bilateral periventricular hyperintensities
Kim et al28	64/M	Hyperintensity in right parieto-occipital cortex and corona radiata
Yum et al29	30/M	Hyperintensity in brainstem, cerebellar peduncle and basal ganglia
Jena et al30	48/M	Infarct with haemorrhagic transformation in left frontal region
Neyaz et al31	55/M	Hyperintensities in bilateral subcortical white matter

Learning points.

• Scrub typhus is a common cause of aseptic meningitis/meningoencephalitis in endemic regions. The clinical features and cerebrospinal fluid profile can sometimes mimic viral or tubercular meningitis.

• Atypical manifestations like cranial nerve palsies, peripheral neuropathy, extrapyramidal and cerebellar syndromes, and haemorrhagic encephalitis can be rarely seen.

• MRI is usually normal but rarely it may show meningeal enhancement and altered signals in cortex, basal ganglia, periventricular region, brainstem and cerebellum.

• The response to early and empirical treatment is good with little residual neurological dysfunction.