Clin Neuroradiol DOI 10.1007/s00062-014-0348-9

Correspondence

Hemorrhagic Transformation of Scrub Typhus Encephalitis: A Rare Entity H.-C. Kim · K.-W. Yoon · D.-S. Yoo · C.-S. Cho

Received: 8 May 2014 / Accepted: 10 September 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Central nervous system (CNS) involvement of scrub typhus infection is well known. Most CNS involvement of scrub typhus infection present as meningitis or encephalitis. We report on a patient suffering from hemorrhagic transformation of intracranial lesions caused by Orientia tsutsugamushi. A 53-year-old female farmer who was infected by scrub typhus was treated with doxycycline and recovered from the systemic illness. However, headache persisted. Brain radiologic studies revealed acute intracranial hemorrhage and enhancing lesion, which implied a CNS involvement. Hemorrhagic transformation of encephalitis by scrub typhus is very rare complication and to our best knowledge, this is the first report of hemorrhagic transformation of scrub typhus encephalitis. Clinician should consider the possibility of hemorrhagic transformation of encephalitis in cases of scrub typhus infection.

Electronic supplementary material: The online version of this article (doi: 10.1007/s00062-014-0348-9) contains supplementary material, which is available to authorized users. C.-S. Cho, MD, PhD () · H.-C. Kim, MD · K.-W. Yoon, MD · D.-S. Yoo, MD, PhD Department of Neurosurgery, Dankook University College of Medicine, 201 Manghyang-ro Dongnam-gu, Cheonan, Chungnam 330–715, Republic of Korea e-mail: [email protected] D.-S. Yoo, MD, PhD Department of Radiology, Dankook University College of Medicine, Cheonan, Chungnam, Republic of Korea

Introduction Scrub typhus is a systemic infectious disease caused by Orientia tsutsugamushi. General clinical features of scrub typhus are headache, fever, rash, eschar, myalgia, pneumonia, and central nervous system (CNS) involvement [1]. Scrub typhus causes systemic vasculitis, which may produce multiorgan failure [2]. The vascular pathologic change due to O. tsutsugamushi infection is a destruction of endothelial cells lining of small blood vessels and the inflammatory lesions that result from infiltrating leukocytes [3]. CNS involvement of scrub typhus has been reported, and mainly comprises meningitis and encephalitis with or without neurologic deficits. Cerebrospinal fluid (CSF) profiles demonstrate mild-to-moderate pleocytosis, normal glucose levels, and mild increase in the protein levels [2]. Headache is a frequently observed symptom during the febrile stage after scrub typhus infection. Other neurologic deficits including tremor, confusion, and delirium are uncommon [2]. Hemorrhagic transformation of encephalitis is very rare disease entity among scrub typhus infections. To our knowledge, the present case is the first report of hemorrhagic transformation of scrub typhus encephalitis. Case Report A 53-year-old woman with a 3 weeks history of headache, fever, myalgia, and diagnosis of scrub typhus infection was referred to our department because of progressive neurological deficits. The patient was a farmer who resided a region in Korea endemic for O. tsutsugamushi. Eschar was found at right external auditory canal during a physical examination. Mentality was mild drowsiness and speech was slurred. Cranial nerve function test revealed left

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lateral gaze palsy, but there was no facial palsy. Neurologic examination revealed abnormal cerebellar dysfunctions with cerebellar function tests including Romberg, finger-nose-finger, and heel-shin. Motor power of extremities was normal but ataxic movement of legs was observed. Gait disturbance was not checkable because the patient could not stand. In laboratory findings, C-reactive protein was slightly elevated to 7.32 mg/dL. Serum chemical test and coagulation profiles were within normal ranges. Polymerase chain reaction (PCR) was positive for antibody to O. tsutsugamushi. CSF was elevated in protein (514.8 mg/dL) and normal for glucose (42 mg/dL) and its analysis revealed a white cell count of 80,000/mm3,red cell count of 520/mm3, and a lymphocyte rate of 92 %. CSF culture and Gram staining were negative.

H.-C. Kim et al.

Chest simple radiography showed no active lung lesions. Brain computed tomography (CT) and magnetic resonance images (MRI) revealed acute intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), and mass lesion (size: 1.7 * 1 cm) with subtle enhancement at the right cerebellum, pons, and left midbrain (Fig. 1). Three hours after admission, mentality decreased rapidly to a semi-comatose status. Emergent brain CT showed newly appeared SAH at interpeduncular cistern and intraventricular hemorrhage (IVH) at the left lateral ventricle (Fig. 2a, b). Conservative treatments including doxycycline and intracranial pressure control were continued. On the second day of admission, follow-up brain CT was performed, which revealed aggravation of ICH and IVH (Fig. 2c). The patient became comatose and died on seventh day of admission.

Fig. 1  Gadolinium enhanced T1-weighted magnetic resonance images show heterogenic enhancing lesion in brain stem (a: axial view, b: coronal view). Noncontrast axial computed tomography shows intracranial hemorrhage in right cerebellum (c)

Fig. 2  Noncontrast axial computed tomography (CT) presenting newly appeared subarachnoid hemorrhage and intraventricular hemorrhage. (a: initial axial CT, b: emergency brain CT after sudden mentality decrease after 3 hours from initial CT, c: brain CT on second day of admission)

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Hemorrhagic Transformation of Scrub Typhus Encephalitis: A Rare Entity

Discussion Scrub typhus commonly occurs in persons who reside in agricultural field throughout an endemic area, such as East Asia, Korea, and South Pacific. The risk factors of scrub typhus are mainly based on environmental situations. Those who farm in endemic areas are prone to scrub typhus infection [4]. Scrub typhus demonstrates fever, multiorgan dysfunction, pneumonia, acute renal failure, shock, myocarditis, gastrointestinal bleeding, and meningoencephalitis. Neurologic symptoms by CNS involvement of scrub typhus infection are often the main clinical features of scrub typhus [1]. Tremor, diplopia, nystagmus, dysarthria, and altered mentality can be present [5]. Encephalitis is the most fatal complication of scrub typhus with myocarditis [2]. Scrub typhus infection responds well to antibiotics, but some strains of O. tsutsugamushi were nonresponsive to tetracycline derivatives including doxycycline [6]. Treatment of scrub typhus should be started as soon as possible after diagnosis because the response to medical treatment is excellent [5]. However, our patient was treated with doxycycline therapy. One of possibilities of treatment failure is maintenance of lower serum doxycycline concentration at local hospital. Kim et al. [6] reported the clinical importance of a therapeutic range of serum doxycycline. Mortality rate of CNS involvement of scrub typhus infection is 25 %, which is higher than other CNS involvement of infection. Early diagnosis of CNS involvement of scrub typhus infection is likely important [7]. Diagnosis of scrub typhus can be achieved based on history, clinical characteristics, and PCR finding [6]. However, radiological differential diagnosis based on brain MRI is not quite simple. Cryptococcosis and Lyme disease present similar radiologic finding but there is no associated skin rash. Other vasculitis present multiple infarcts on diffusion-weighted image. Radiological chest abnormalities are detected in 70 % of patients [8]. In our case, there was no active lung lesion. Liver enzymes, especially ALT, are elevated in approximately 75 % of scrub typhus patients [7]. But, liver enzymes were in the normal range in this case, perhaps because they had been normalized during local treatment with doxycycline, although this was not confirmed. Disseminated vasculitis caused by destruction of endothelial cells is a main pathologic finding. Mainly, small vessels are affected throughout the body and typhus nodules are found in gray matter in case of CNS involvement. Abnormal CNS lesions were mainly found in gray matters of the spinal cord and brain according to literatures [9]. Scrub typhus commonly involves meningitis but no involvement of the white matter [2]. In this case, initial brain MRI showed enhanced mass lesion at the brain stem, indicat-

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ing involvement of the white matter. This enhancement of the white matter implies the possibility of vasculitis in the white matter. That is the reason that we could not conclude the absence of involvement of white matter in this case of CNS involvement of scrub typhus infection. Yum et al. [9] reported that white matter can be destroyed by breakdown in the blood–brain barrier, microinfarction, and edema. Hemorrhagic transformation of encephalitis in scrub typhus has not been reported. Therefore, general characteristics of hemorrhagic transformation are unknown in scrub typhus. Pathologic findings of scrub typhus are an acute inflammation of vascular structures including CNS. Inflammation of intracranial vascular weakens the vascular wall and contributes to arterial rupture in the brain. It may bring life-threatening complication such as intracranial hemorrhage. Acute transverse myelitis has been reported as a CNS complication of scrub typhus infection in the literature [10]. In general, transverse myelitis presents motor and sensory deficit of extremities, but our patient did not present these neurologic deficits. In case of scrub typhus, CNS involvement is not rare, so clinicians should be wary of a patient who complains of neurologic symptoms including headache, dizziness, and drowsiness, even with recovery of systemic fever and laboratory findings. The authors describe a case of hemorrhagic transformation of scrub typhus encephalitis. It is a very rare feature among CNS involvement of scrub typhus infection. Few reports have described CNS involvement of white matter. To our knowledge, this is first report of hemorrhagic transformation of encephalitis in scrub typhus. Hemorrhagic transformation of CNS involvement of scrub typhus infection may have poor prognosis, even there is not enough report about this disease entity. Acknowledgement   This work was supported by Dankook university research fund in 2014. Conflict of Interest  The authors declare that there are no conflicts of interest in relation to this article.

References   1. Kim DM, Kim SW, Choi SH, Yun NR. Clinical and laboratory findings associated with severe scrub typhus. BMC Infect Dis. 2010;10:108.   2. Pai H, Sohn S, Seong Y, Kee S, Chang WH, Choe KW. Central nervous system involvement in patients with scrub typhus. Clin Infect Dis. 1997;24:436–40.   3. Seong SY, Choi MS, Kim IS. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect. 2001;3:11–21.   4. Kim DM, Kim KY, Nam HS, Kweon SS, Park MY, Ryu SY. Riskfactors for human infection with Orientia tsutsugamushi: a casecontrol study in Korea. Clin Microbiol Infect. 2008;14:174–7.

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4   5. Kim DE, Lee SH, Park KI, Chang KH, Roh JK. Scrub typhus encephalomyelitis with prominent focal neurologic signs. Arch Neurol. 2000;57:1770–2.   6. Kim DM, Kim YS, Cho HY, Lee YB. Scrub typhus meningoencephalitis occurring during doxycycline therapy for Orientia tsutsugamushi. Diagn Microbiol Infect Dis. 2011;69:271–4.   7. Varghese GM, Mathew A, Kumar S, Abraham OC, Trowbridge P, Mathai E. Differential diagnosis of scrub typhus meningitis from bacterial meningitis using clinical and laboratory features. Neurol India. 2013;61:17–20.

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H.-C. Kim et al.   8. Choi YH, Kim SJ, Lee JY, Pai HJ, Lee KY, Lee YS. Scrub typhus: radiological and clinical findings. Clin Radiol. 2000;55:140–4.  9. Yum KS, Na S-J, Lee KO, Ko JH. Scrub typhus meningoencephalitis with focal neurologic signs and associated brain MRI abnormal findings: literature review. Clin Neurol Neurosurg. 2011;113:250–3. 10. Lee KL, Lee JK, Yim YM, Lim OK, Bae KH. Acute transverse myelitis associated with scrub typhus: case report and a review of literatures. Diagn Microbiol Infect Dis. 2008;60:237–9.

Hemorrhagic Transformation of Scrub Typhus Encephalitis: A Rare Entity.

Central nervous system (CNS) involvement of scrub typhus infection is well known. Most CNS involvement of scrub typhus infection present as meningitis...
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