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NI FEATURE: PATHOLOGY PANORAMA - COMMENTARY
Year : 2018  |  Volume : 66  |  Issue : 2  |  Page : 434-438

Central nervous system lesions in scrub typhus rediscovered: An autopsy report


1 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication15-Mar-2018

Correspondence Address:
Dr. Kirti Gupta
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.227309

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 » Abstract 


While neurological manifestations in scrub typhus have been well described both in clinical and radiological reports in the literature, neuropathological features are rarely reported. They range from subtle “typhus nodules” to more widespread capillaritis. Familiarity with pathological features is essential for correct interpretation. We describe the clinical, imaging, and histological findings in an autopsy case of scrub typhus, which was pre-terminally superimposed by fungal meningoencephalitis. Interestingly, the autopsy revealed morphological evidence of both etiologies.


Keywords: Autopsy, central nervous system infections, pathology, scrub typhus
Key Message: A detailed morphological autopsy report of lesions in scrub typhus coexisting with fungal endocarditis with myocardial abscess is described. The case highlights the importance of suspecting scrub typhus in a patient presenting with fever, jaundice, reduced urinary output, and altered sensorium in endemic areas, as this disease can easily be treated with oral doxycycline if detected at an early stage.


How to cite this article:
Gupta K, Ahuja CK, Pandit AK, Biswal M, Shivaprakash M R. Central nervous system lesions in scrub typhus rediscovered: An autopsy report. Neurol India 2018;66:434-8

How to cite this URL:
Gupta K, Ahuja CK, Pandit AK, Biswal M, Shivaprakash M R. Central nervous system lesions in scrub typhus rediscovered: An autopsy report. Neurol India [serial online] 2018 [cited 2019 Aug 23];66:434-8. Available from: http://www.neurologyindia.com/text.asp?2018/66/2/434/227309




Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi, an obligate intracellular gram-negative bacterium. Infection in humans is accidental through contact with mite-infected scrub vegetation mostly during agricultural activities.[1] It is commonly reported from various parts of south India.[2] Scrub typhus has diverse clinical manifestations ranging from a nonspecific febrile illness to severe multi-organ dysfunction, primarily involving the liver, kidney, and heart. Involvement of the central nervous system (CNS) usually manifests as meningoencephalitis, encephalomyelitis, or with focal neurological deficits.[3],[4],[5] Comparative study of brain pathology associated with scrub typhus and other rickettsial disease from early literature showed that scrub typhus more commonly involves the meninges, and white matter lesions are extremely rare.[6] Histologically, it primarily causes systemic vasculitis due to destruction of endothelial cells resulting in a multi-organ failure.[7] Parenchymal changes in the brain in the form of “typhus nodules,” capillaritis, and collection of macrophages and giant cells have been described very early in the literature.[7],[8] A detailed morphological autopsy report of lesions in scrub typhus is lacking in the literature. Moreover, coexistent fungal endocarditis with myocardial abscess has not been documented earlier.


 » Patient Spectrum Top


A 48-year old farmer presented with fever of 10 days duration, yellowish discoloration of eyes, and altered sensorium for the past 1 day. Fever was of a high grade (103°F), intermittent and associated with chills, rigors, and bodyache. He also had dry cough and reduced urine output for the same duration. There was no history of headache, seizure, loss of consciousness, weakness of limbs, sensory or bladder disturbance. He also had scanty hemoptysis (three episodes over the last 5 days) and multiple episodes of vomiting and loose stools for 2 days without blood or mucous in the stool or associated pain abdomen. On examination, he was disoriented with tachycardia and tachypnoea. Blood pressure was normal (130/80 mmHg). He had pallor, icterus with bilateral pitting pedal edema without cyanosis, clubbing, or lymphadenopathy. Right subconjunctival hemorrhage was present. No focal neurological deficits were noted. Mild hepatomegaly with sluggish bowel sounds were noted with signs of free fluid. Cardiovascular and respiratory system examination was normal. Investigations revealed anemia (Hb 6.7 gm%) with neutrophilic leucocytosis (total leucocytic count [TLC]: 22 × 109/L; neutrophils 89%, lymphocytes 8%, monocytes 2%, eosinophils 1%). Biochemical parameters were deranged with hyponatremia (132 mEq/L), raised blood urea (253 mg/dL), and creatinine (8.2 mg/dL). Liver function tests showed conjugated hyperbilirubinemia (9.2 mg%) with raised liver enzymes (aspartate transaminase/alanine transaminase = 189/201 Units/L) and alkaline phosphatase (443 IU/L). The arterial blood gas analysis revealed respiratory acidosis. Cerebrospinal fluid (CSF) examination revealed neutrophilic pleocytosis (TLC = 510 cells; 90% neutrophils), raised proteins (109 mg/dL), and low glucose (23 mg/dL). India ink stain for Cryptococcus was negative. Polymerase chain reaction (PCR) for tuberculosis (TB) performed on the cerebrospinal fluid (CSF) was negative. Tests for malarial parasite and serology for dengue, Leptospira, and human immunodeficiency virus (HIV) were negative. Enzyme-linked immunosorbent assay (ELISA) for scrub typhus was conducted from serum using Scrub Typhus Detect IgM ELISA (InBios International, Inc., Seattle, WA, USA) following the manufacturer's instructions. An optical density (OD) of >0.5 was considered positive for the organism. IgM ELISA test for scrub typhus was positive (1.597). The coagulogram was deranged with positive D dimer. Blood culture pre-terminally was positive for Aspergillus. Serum galactomannan [GM] (Platelia Aspergillus EIA; Bio-Rad Laboratories) was tested according to the manufacturer's recommendations. The presence or absence of the GM antigen was determined by calculating the optical density index (ODI). The ODI is the optical density value of the patient's specimen divided by the mean optical density of the wells containing the cut-off control sample. An ODI of >0.5 was considered positive. Serum galactomannan ODI for Aspergillus antigen was 7.0 (normal: 0.5). All hepatitis viral markers were negative. Contrast-enhanced magnetic resonance imaging (CEMRI) of the brain [Figure 1] revealed multifocal nonenhancing areas of T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity scattered in the brain parenchyma with indistinct boundaries [[Figure 1]b, arrowheads]. In addition, there were lesions which had a distinct capsule around them [[Figure 1]a,[Figure 1]b,[Figure 1]c, arrows]; the larger ones were present in the left middle cerebellar peduncle and bilateral frontal lobes. These lesions showed a patchy and peripheral diffusion restriction and were hypo-to-isointense on T1-weighted images with a mild peripheral enhancement [Figure 1]c. Associated mild-to-moderate perilesional edema was noted. Few interspersed T2 hypointense foci were seen within the periphery of these lesions, which showed blooming on susceptibility-weighted images representing hemorrhages. A diagnosis of encephalitis versus multifocal cerebritis with some areas showing evolution into abscesses was entertained. No meningitis was identified. In view of the positive serology for scrub typhus, the multifocal white matter changes were ascribed to CNS infection by O. tsutsugamushi. However, other apparently capsulated lesions were unique in appearance and had peripheral micro-hemorrhages and diffusion restriction, which was characteristic of fungal infection. Thus, at this point, a suggestion of an alternate or superadded etiology of fungal infection was also considered. Repeat MRI done after 10 days revealed coalescence and marked increase in white matter signal changes. The focal lesions in the frontal lobes and middle cerebral peduncle (MCP) had become distinct with central necrosis, and the largest was present in the left frontal lobe measuring 2 × 1.5 cm in size [[Figure 1]d and [Figure 1]e, black arrows]. These lesions typified fungal granulomatous infection in view of central necrosis, complete peripheral encapsulation, and diffusion restriction. The foci of diffusion restriction [Figure 1]e and hemorrhages had increased in size and number within the nonenhancing confluent white matter lesions, indicative of an underlying vasculitis with secondary ischemia, which was now attributed to scrub typhus. Infarcts and hemorrhages are characteristic lesions of vasculitis, as was seen in the index case. A large left-sided gangliocapsular hematoma was also identified [[Figure 1]f, black arrow], measuring 4 × 3 × 8 cm in size, which precisely corresponded with the brain autopsy findings described later. Thus, a unique combination of fungal infection along with vasculitis secondary to scrub typhus was identified in a single patient.
Figure 1: Axial T2-weighted (a and b) and gadolinium-enhanced (c) MR images show presence of a few well-defined lesions in the left middle cerebellar peduncle, and bilateral frontal lobes, showing peripheral enhancement (white arrows) suggesting focal cerebritis/abscess formation. In addition, multifocal areas of T2 hyperintensity are noted in bilateral frontal white matter (white arrowheads) showing no enhancement. Follow-up MRI after 10 days demonstrates rapid progression of white matter lesions (d) with increase in ischemic areas (evident on diffusion weighted imaging); (e) vasculitis secondary to scrub typhus. The abscess in the left frontal lobe is now well-formed and shows diffusion restriction (black arrows); e) Scan representing fungal etiology. A large hematoma was noted in the left gangliocapsular location on susceptibility-weighted image (f) (black arrowhead)

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He was treated with antibiotics (ceftriaxone, doxycycline) and hemodialysis. His sensorium progressively worsened with the development of acute-onset right hemiparesis and respiratory distress on day 9 of the admission. Supportive measures were given with adequate intravenous antibiotics and antifungal medication; however, he developed acute kidney injury and succumbed to his illness.

Pathology findings

At autopsy, an eschar was noted in the right inguinal region. Brain weighed 1540 g; no meningeal exudates were identified on convexities or base of the brain. Coronal cuts revealed multiple abscesses present bilaterally (left, frontal lobe – 2.5 × 1.5 × 1cm, right, orbital cortex – 1 × 0.8 cm, and middle cerebellar peduncle – 0.8 cm). Further, a hemorrhagic lesion (4.5 × 3.5 × 8cm) was noted affecting the left putamen and globus pallidus, medially extending to the internal capsule. These were associated with edema and midline shift [Figure 2]a and [Figure 2]b. All these lesions demonstrated an excellent radiopathological correlation. Microscopically, abscesses comprised a neutrophil-rich centre and necrotic debris, bordered by giant cells which at many places were forming granulomas. Several giant cells contained negative shadows of fungal hyphae within them, which were highlighted by the periodic acid-Schiff (PAS) stain. Anterior cerebral artery showed fungal vasculitis with giant cells containing many Aspergillus hyphae [Figure 2]c,[Figure 2]d,[Figure 2]e,[Figure 2]f. A few of these were centred on capillaries with resulting fibrinoid necrosis of vessels termed as capillaritis, associated with collection of macrophages [Figure 2]g. Fibrin within the vessels was highlighted by Marshall scarlet blue stain [Figure 2]h. In addition, a second interesting pathology in the form of loose collections of giant cells, macrophages, and microglial nodules, described as “typhus nodules,” were noted diffusely scattered at many regions within the central white matter [Figure 2]i. These presumably corresponded to the multifocal T2/FLAIR white matter hyperintensity lesions seen on imaging.
Figure 2: (a) Coronal slice of the brain showing abscess in the left inferior frontal gyrus (arrow) and white matter edema; (b) coronal slice of the brain showing the hemorrhagic lesion affecting the left putamen and globus pallidus. Midline shift with cingulate gyrus herniation can also be appreciated; (c) abscess demonstrating neutrophil-rich infiltrate, necrotic debris in the centre bordered by scattered giant cells forming a granuloma identified in the left inferior frontal gyrus (Hematoxylin and Eosin [H and E] ×400); (d) Granuloma with giant cells containing fungal hyphae identified adjacent to the abscesses (Periodic acid Schiff [PAS] ×400); (e) Septate, slender Aspergillus hyphae highlighted by the PAS stain (PAS ×1000); (f) Anterior cerebral artery with destruction of the vessel wall (arrow) by inflammatory cells including giant cells (H and E, ×200); (g) Capillaritis with fibrinoid necrosis of vessel wall adjacent to typhus nodules (H and E, ×400); (h) Martius scarlet blue [MSB] stain highlights fibrin within the vessel wall (MSB ×400); (i) Loose collection of giant cells and macrophages defined as “typhus nodules” seen within the white matter (H and E, ×400)

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The heart weighed 300 g and revealed fungal vegetations on the right ventricular wall below the pulmonary valve and on the left interventricular wall. Multiple myocardial abscesses filled with pus were noted, which on microscopy comprised suppurative granulomas with giant cells containing Aspergillus hyphae [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d,[Figure 3]e. Molecular typing of fungus performed on deoxyribose nucleic acid (DNA) extracted from the valvular vegetation revealed Aspergillus terreus strain. Moreover, many septic emboli were noted within the myocardial vessels. Liver revealed expanded portal tracts with fibrosis, lymphocytic collection, macrophages, and fibrin deposition at places forming vague granulomas described as “fibrin-ring granulomas.” Kidneys on microscopy showed interstitial hemorrhages with vascular congestion and fibrin thrombi identified within glomerular capillaries. Both lungs revealed organizing pneumonia with formation of Masson's bodies, alveolar hemorrhage, and diffuse alveolar damage. None of these organs including the liver, lungs, and kidneys revealed any fungal granulomas, and special stains performed also did not reveal any evidence of fungal pathology. Rest of the organs were within normal limits. Thus, features of scrub typhus were identified in the brain (in the form of capillaritis, angiitis, and “typhus nodules”), liver (fibrin-rich granulomas), and kidney (interstitial inflammation and fibrin thrombi within glomeruli). Fungal vasculitis and fungal abscesses with intraparenchymal hemorrhage in the brain resulted due to dissemination of the fungus from valvular fungal endocarditis.
Figure 3: (a) Gross photograph of the heart demonstrating the vegetations (arrow) on the right ventricular wall below the pulmonary valve; (b) numerous myocardial abscesses (arrow) seen in the left ventricular wall; (c) direct mount of the left ventricular wall showing multiple myocardial abscesses, with basophilic areas representing the abscesses;(d) suppurative granulomas with giant cell destroying the cardiac myocytes (H and E ×400); (e) septate fungal hyphae are seen within the giant cell (PAS ×1000)

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 » Discussion Top


Clinical reports on scrub typhus have documented CNS involvement in a majority of affected patients, presenting as meningitis or meningoencephalitis.[3] Pathological lesions have been documented sparsely in early literature in the form of capillaritis, loose collections of giant cells, or as microglial nodules described as “typhus nodules.”[4],[5],[6] Most of the scanty neuropathological data relates to Rocky mountain spotted fever.[7] A detailed morphological evaluation of scrub typhus at autopsy is notably lacking in the literature. This case illustrates the clinical details, imaging, and autopsy findings, and is unique in several aspects.

  1. Clinically, there was absence of focal neurological deficits, which are commonly noted in acute encephalitic syndrome
  2. The classical imaging findings of scrub typhus in the CNS are secondary to inflammation of the brain parenchyma (encephalitis), while the hemorrhagic complications are secondary to disseminated intravascular coagulation and low platelet counts. The other forms of presentation are aseptic meningitis, encephalitis, meningoencephalitis, parenchymal infarction, cerebellitis, and demyelination.[8],[9] Noteworthy in our patient was the presence of cerebritis with subsequent abscess formation which is not commonly seen in scrub typhus. Moreover, the classical peripheral micro-hemorrhages in the abscesses made us consider fungal infection as an alternative/superadded diagnosis. However, rapid progression to extensive parenchymal ischemia was secondary to vasculitis attributed to scrub typhus which was correlated on histopathology
  3. From the pathologists' perspective, brain lesions can be distinctly grouped into two stages. An acute event which included neutrophil-rich abscesses bordered by histiocytes and giant cells containing phagocytosed Aspergillus hyphae. Secondary fungal vasculitis involving the anterior cerebral artery was also a part of the acute event. The chronic, smouldering event was the loose collection of mainly macrophages and occasional giant cells diffused within the central white matter along with microglial nodules. These clusters have been described as “typhus nodules” and finds mention very early in the literature.[4],[5],[6] Mostly described in an angiocentric location, these lesions produce microinfarcts due to thrombosis, as was observed in this case
  4. Associated fungal endocarditis (both mural and valvular) with myocardial abscesses are also rare and have not been described coexisting with scrub typhus. In scrub typhus, myocarditis with mononuclear infiltrate in the endocardium and myocardium have been observed at autopsy;[6] however, such lesions were not identified in the present case. Instead, the heart revealed mural endocarditis along with fungal vegetations which disseminated to the brain. Further, numerous myocardial abscesses with suppurative fungal granulomas were identified in the right and left ventricular walls. The development of superimposed fungal meningoencephalitis preterminally was incidental and led to the rapid downhill course, which contributed to the demise of the patient.


While the etiological agent for scrub typhus is well known, its target cell is poorly defined in humans. Immunohistochemical demonstration of the bacterium has been described with immunoreactivity noted in the macrophages in the liver, splenic parenchyma, and within endothelial cells in the brain, lung kidney, and cardiac myocytes. Moron et al., have demonstrated the bacterium within endothelial cells by electron microscopy.[10] In conclusion, the case, besides illustrating the detailed pathological lesions, also highlights the importance of considering scrub typhus in the differential diagnosis in a patient presenting with fever, jaundice, reduced urinary output, and altered sensorium in endemic areas. Diagnosing this entity accurately is especially important as this disease is easily treatable with oral doxycycline; however, it can be fatal without specific antibiotic therapy.[11],[12]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Saah AJ. Orientia tsutsugamushi (scrub typhus). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious disease. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000.pp. 2056-57.  Back to cited text no. 1
    
2.
Mathai E, Rolain JM, Verghese GM, Abraham OC, Mathai D, Mathai M,et al. Outbreak of scrub typhus in southern India during the cooler months. Ann N Y Acad Sci 2003;990:359-64.  Back to cited text no. 2
    
3.
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.  Back to cited text no. 3
    
4.
Abhilash KP, Gunasekaran K, Mitra S, Patole S, Sathyendra S, Jasmine S, Varghese GM. Scrub typhus meningitis: An under-recognized cause of aseptic meningitis in India. Neurol India 2015;63:209-14.  Back to cited text no. 4
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5.
Sawale VM, Upreti S, Singh TS, Singh NB, Singh TB. A rare case of Guillain-Barre syndrome following scrub typhus. Neurol India 2014;62:82-3.  Back to cited text no. 5
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6.
Allen AC, Spitz S. A comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial diseases. Am J Pathol 1945;21:603-81.  Back to cited text no. 6
    
7.
Settle EB, Pinkerton H, Corbett AJ. A pathologic study of tsutsugamushi disease (scrub typhus) with notes on clinicopathologic correlation. J Lab Clin Med 1945;30:639.  Back to cited text no. 7
    
8.
Levine HD. Pathologic study of thirty-one cases of scrub typhus fever with especial reference to the cardiovascular system. Am Heart J 1946;31:314-28.  Back to cited text no. 8
    
9.
Walker DH, Hawkins HK, Hudson P. Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency. Arch Pathol Lab Med 1983;107:121-5.  Back to cited text no. 9
    
10.
Yum KS, Na SJ, Lee KO, Ko JH. Scrub typhus meningo-encephalitis with focal neurologic signs and associated brain MRI abnormal findings: Literature review. Clin Neurol Neurosurg 2011;113:250-3.  Back to cited text no. 10
    
11.
Neyaz Z, Bhattacharya V, Muzaffar N, Gurjar M. Brain MRI findings in a patient with scrub typhus infection. Neurol India 2016;64:788-92.  Back to cited text no. 11
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12.
Moron CG, Popov VL, Feng HM, Wear D, Walker DH. Identification of the target cells of Orientia tsutsugamushi in human cases of scrub typhus. Mod Pathol 2001;14:752-9.  Back to cited text no. 12
    


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  [Figure 1], [Figure 2], [Figure 3]



 

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