- Email: [email protected]
Holohemispheric Invasive Aspergillus Granulomatous Cerebritis of the Brain
Journal Pre-proof HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN Dr Karthik Kulanthaivelu, DM, Dr Chandrajit Prasad, DM, Dr Yerasi Varun Kumar Reddy, M. Ch, Dr Anita Mahadevan, MD PII:
S1878-8750(19)32531-8
DOI:
https://doi.org/10.1016/j.wneu.2019.09.100
Reference:
WNEU 13399
To appear in:
World Neurosurgery
Received Date: 21 August 2019 Revised Date:
17 September 2019
Accepted Date: 18 September 2019
Please cite this article as: Kulanthaivelu K, Prasad C, Kumar Reddy YV, Mahadevan A, HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.09.100. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Title page HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN
Authors Dr Karthik Kulanthaivelua, DM; Dr Chandrajit Prasada*, DM; Dr Yerasi Varun Kumar Reddyb, M. Ch, Dr Anita Mahadevanc ,MD
a
Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India b Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India c Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India
Corresponding author Dr Chandrajit Prasad*, Additional professor Mailing address: Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Tel.: +9108026005424, Mobile phone: +919480606741 E-mail: [email protected]
Authors and Affiliations: 1)Dr Karthik Kulanthaivelu, D.M., Assistant Professor, Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
2)Dr Chandrajit Prasad, D.M., Additional Professor, Department of Neuroimaging and Interventional Radiology,
National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
3) Dr Yerasi Varun Kumar Reddy, M.Ch., Senior Resident, Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
4)Dr Anita Mahadevan, MD, Professor, Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
Key words- Invasive, hematogenous, holohemispheric, fungal, granuloma, cerebritis Running title- Holohemispheric Invasive Fungal Granuloma
HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN ABSTRACT BACKGROUND Invasive aspergillosis of the central nervous system, a saprophytic infection with a unique vascular tropism, carries the burden of increased morbidity and mortality. Early clinical and imaging findings can masquerade as an innocuous condition before a secondary inexorable progression. We highlight the clinical and imaging phenotype of a patient with fatal invasive granulomatous aspergillosis. CASE DESCRIPTION A 39-year-old man presented with progressive weakness of the left upper and lower limb for 4 months. Imaging demonstrated right holohemispheric extensive, numerous, confluent, illdefined, T2 hypointense foci with moderate perilesional edema. Numerous foci of microhaemorrhages with cortical asymmetric mineralization were seen. Post-contrast heterogeneous, variegate, punctiform enhancement of the lesions was observed extending to the ventricular margins. Volume loss of the left cerebral peduncle and ipsilateral long white matter descending tracts was noted. Histopathologic examination of a stereotactic biopsy specimen from the frontal region lesion showed dense inflammatory infiltrate with granulomas, a few in a perivascular distribution and branching septate hyphae resembling Aspergillus. The patient was initiated on antifungal therapy and in the following week, he had progressive drowsiness. The patient succumbed the next day. CONCLUSION Diffuse holohemispheric, progressive presentation of a granulomatous form of invasive aspergillosis is a rare entity. The miliary pattern of heterogenous enhancement, holohemispheric conglomerate T2 hypointensities, interspersed hemorrhage, juxtacortical punctate T2 hyperintense foci, low perfusion, and the relative absence of diffusion abnormality are distinctive features. Early diagnosis of this atypical imaging phenotype of Aspergillus infection and appropriate treatment is critical for better prognosis.
INTRODUCTION Aspergillosis of the central nervous system has high mortality even in immunocompetent individuals(1–5). The spectrum of clinicopathological syndromes includes meningitis, meningoencephalitis, abscess, skull base syndromes, stroke/infarction, mycotic aneurysms disseminated granulomatous affliction of the cerebral parenchyma, orbital cellulitis, and spinal cord compression(6,7). The definitive diagnosis of invasive neuroaspergillosis requires histopathological identification in the tissue or its growth in culture. However, a high degree of suspicion may be raised in the presence of specific imaging findings. Here we present an atypical holohemispheric pattern of parenchymal invasive granulomatous aspergillosis.
CASE REPORT A 39-year-old man, symptomatic for one year, presented with progressive weakness of the left upper and lower limb and intermittent headaches for the 4 months. An episode of generalized tonic-clonic seizure was documented approximately one year earlier. He was a diagnosed case of diabetes and was compliant with medication. On examination, he had spastic left hemiparesis with brisk deep tendon reflexes on the affected side. His first clinical manifestation was approximately a year earlier when he had one episode of generalised tonic-clonic seizures. He presented to another peripheral centre nearby his village where he was investigated with CT which revealed a mass lesion in the right frontoparietal region. The focal lesion was opined as possibly neoplastic. He was started on anti-epileptic drugs and was asked to consult a higher centre for further management. The patient and family failed to seek medical consultation during the ensuing months. Review of the CT, (Fig. 1) acquired at that timepoint, revealed an ill-defined, infiltrative, heterogeneously hyperdense lesion in the right frontoparietal region, involving both gray and white matter extending into the periventricular region. Moderate perilesional oedema and homogenous post-contrast enhancement were present. The subsequent clinical picture was characterised by an insidious onset and indolent course of left sided weakness that worsened over many months. The patient was later brought to the author’s institution due to progressive nature of the weakness and headache. The prompt in-hospital investigation began with imaging, blood and CSF examination. MRI at admission (Fig. 2) demonstrated holohemipsheric extension of the abnormality. The cortex, juxtacortical white matter, deep white matter, and the deep grey nuclei showed numerous miliary, ill-defined, T2 hypointense foci, with the majority being confluent. The lesions incited moderate perilesional oedema. The lesions were isointense on T1 weighted
sequence. Numerous foci of microhaemorrhages with an associated diffuse asymmetric mineralization of the ipsilateral cortex and deep grey nuclei were evident on SWI. There was no evidence of diffusion abnormality in these lesions. Post-contrast enhancement of the lesions was heterogenous, variegate, punctiform in a few locations and patchy in others. The enhancement was reaching up to the ventricular margins. Corpus callosum involvement paralleled the hemispheric involvement and lesions were not crossing the midline. The lesions were hypoperfused. Besides, a few juxtacortical T2 hyperintense foci were seen throughout the hemisphere that did not show any enhancement on postcontrast T1 weighted images. Additionally, the left lateral ventricle demonstrated reduced dimensions of the frontal horn with dilatation of the body, temporal and occipital horns and contralateral midline shift. Also evident were the volume loss of the left cerebral peduncle, ipsilateral long white matter descending tracts, possibly due to Wallerian degeneration. This finding was reflective of the chronicity of the disease in this patient. Review of the paranasal sinuses and the skull base in the cross-sectional imaging revealed no significant abnormality. X-ray of the chest did not reveal parenchymal changes. No infected surface wound was seen on examination. The patient’s blood investigation was remarkable for a WBC count of 22500/microlitre with a predominance of neutrophils (85.6%). Serum glucose (random) was 132 mg/dL. HIV- ELISA test result was negative. CSF analysis was done. The gross appearance was slightly hazy. Cells were 24/cu.mm. Polymorphs were 12/cu.mm, degenerated cells were 12/cu.mm, occasional RBCs were seen. On biochemical analysis, CSF chloride was 119mmol/L; CSF glucose was 26 mg/dL; CSF lactate was 62.1mg/dL; CSF protein was 155 mg/dL. The CSF picture suggested meningitis. The patient underwent stereotactic biopsy from the right frontal region lesion. Histopathologic examination revealed dense inflammatory infiltrate with granulomas composed of lymphocytes, macrophages, plasma cells. Perifocal epithelioid cells, numerous Langhans giant cells and foreign body giant cells containing septate branching fungal hyphae were seen. Perivascular granulomas were also present. Periodic acid Schiff and GrocottGomori’s methenamine silver stain highlighted the branching septate hyphae morphologically resembling Aspergillus (Fig 3). The patient was immediately initiated on Inj. Voriconazole 6mg/kg/day on Day1 followed by 4mg/kg/day from day 2 with plan to be continued for 12 weeks. He sought discharge against medical advice and in the following week, he had progressive drowsiness. A repeat CT (Fig 4) at readmission revealed a further increase in the lesion dimensions and mass effect. Given the absence of papilledema, relative preservation of the CSF spaces of the basal cisterns surgical intervention with CSF drainage was not contemplated at that time point. The plan was to immediately place an EVD if any further deterioration or features of raised intracranial tension were noted. The patient got discharged against medical advice and succumbed to cardiorespiratory arrest the next day.
DISCUSSION – Aspergillus genus represents a ubiquitous, saprophytic, septate mold, the most common human pathogen being Aspergillus fumigatus(5). Invasive aspergillosis has mortality ranging from 40 – 90 % in immunocompromised hosts(5). The principal determinant of the disease course is the innate immunity of host (mediated by the monocyte-macrophage system and polymorphonuclear cells) which in turn may be negatively affected by disease states such as neutropenia, solid organ transplantation, chemotherapy, bronchiectasis, tuberculosis, antimicrobial agents and steroids(8–11). Primary infection occurs via the airways(12,13), the smaller conidial forms of the A. fumigatus(2-4 microns) gain access to alveoli, followed by evasion of innate host immune response and hematogenous dissemination(5). Angiocentric invasion of small and large vessels with resultant thrombosis, infarction, hemorrhage is the usual course of the disease evolution(4,12). Aspergillus is also the most common etiology of mycotic aneurysm of the central nervous system(4,8). Fungal exit across the blood-brain barrier happens possibly via transcellular/ paracellular migration or by a hypothetical Trojan Horse scheme(14). Following the egress from the vascular compartment, extravascular spread typically leads to the formation of necrotizing lesions, and abscess(1). Alternatively, locoregional contiguous spread from the paranasal sinuses may facilitate the formation of chronic granulomas. In line with the clinicopathological syndromes, the imaging phenotype is varied and includes meningoencephalitis, abscess, skull base syndromes, stroke/infarction, mycotic aneurysms, “tumoral aspergillomas” of the cerebral parenchyma, orbital cellulitis, and spinal cord compression(7,15). Aspergillus is the most common etiologic agent for fungal cerebral abscess among posttransplant patients(16). On MRI, the lesion demonstrates T2 hypointense rim, susceptibility effect, and diffusion restriction, probably mirroring the haemorrhagic residue and the dense hyphal elements(17). Central diffusion restriction, if present is attributed to tenacious, protein-rich fluid and cellular infiltration. The histologic hallmark, unlike bacterial abscess, is necrosis, rather than suppuration(12). The angioinvasive nature is partly conferred by the enzyme elastase(17). The vascular tropism manifests as vasculitis, thrombosis, haemorrhage, and mycotic aneurysms(18). Perforator territorial diffusion abnormality is the tell-tale sign of hematogenous dissemination. In the acute phase, contrast enhancement is absent in these medium-sized lesions (12). Parenchymal involvement is relatively common compared to meningeal affliction(19). Contiguous extensions with dural involvement, orbital cellulitis, optic neuritis, calvarial osteomyelitis are described in conjunction with a sinonasal source of infection(20). CSF culture for Aspergillus fungus has poor sensitivity (21) and the notion of proven infection by mold is strongly supported on histopathological basis(22).
Holohemispheric involvement has been described only once earlier from Southern India (23). A remarkable correspondence of clinical and imaging phenotype between these two cases in the background of immunocompetence, ethnic similarities is noteworthy. Earlier accounts of Aspergillus have reiterated signal characteristics of T1 hypo- to iso intensity and T2 hypointensity with bright homogenous enhancement on post gadolinium T1-weighted imaging, have been reported(24). High concentrations of iron in forms other than hemosiderin, is purported as the candidate species rendering these signal characteristics(24), although contrary evidence for the signal arising from blood breakdown products exists(25), including that from this index case. The protracted clinical course in the index case, in the context of no known primary source of infection is exceptional. Primary intracranial cerebral aspergillosis is a fulminant rapidly progressive disease with symptoms for lesser than three months(26,27). While slow progressive neuroaspergillosis has been described earlier, most reports are usually in the context of rhino-orbito-cerebral forms, rather than primary intracranial forms(26,28,29). One immunocompetent patient, in a series by Saini et al(23), presented with a similar gradual worsening of hemiparesis whose imaging showed a comparable holohemispheric involvement. While it has been claimed that an elongated duration of symptoms before presentation has been associated with lesser mortality(26), conflicting evidence too exists(28) as in our case. Although infrequent, primary CNS aspergillosis without proven extraneous source of infection has been reported(30). Treatment with Voriconazole has been reported to increase survival by 35-47 %(31,32). Surgical debridement with an appropriate margin is considered to be curative(33). Prognosis is generally poor despite aggressive management with antifungals (16,34). To conclude, we intend to draw attention to diffuse holohemispheric, indolent, progressive presentation of a granulomatous form of invasive aspergillosis. The miliary as well as a patchy pattern of heterogenous enhancement, holohemispheric punctate as well as conglomerate T2 hypointensities, interspersed haemorrhagic residue, juxtacortical multifocal punctate T2 hyperintense foci, low perfusion, the relative absence of diffusion abnormality are the standout features. We wish to emphasize that the testimony to the initial indolent nature and a secondarily accelerated course is in the appearance of mass effect later in the disease with co-existent stigmata of Wallerian changes in the right cerebral peduncle involving the descending tracts contiguous with the hemispheric lesions. It is important to recognize an atypical imaging phenotype of Aspergillus infection as early diagnosis and appropriate treatment is critical for better prognosis. The value of early diagnosis has been underscored by the index case in which the delay resulted in an inexorable downward course.
Figures and Legends
Fig 1. Imaging done 10 months earlier a) Non-contrast CT showed an ill-defined, infiltrative, heterogeneously hyperdense lesion in the right frontoparietal region extending to involve both gray and white matter and reaching the periventricular region with mild perilesional edema. b) Contrastenhanced CT revealed mild heterogeneous post-contrast enhancement.
Fig 2 Imaging at the presentation- Axial T2 at the level of the midbrain(a) reveals volume loss with diffuse T2 hyperintense signal changes in the right temporal lobe and cerebral peduncles.(b,c)show large areas of involvement including the juxtacortical and deep white matter, deep gray nuclei and numerous miliary, ill-defined, punctate foci of T2 hypointense signal that were patchily confluent in few other areas and a few subcortical areas of T2 hyperintense cystic changes. Axial T2 weighted FLAIR image(d) shows Moderate perilesional edema with mass effect extending up to the midline; SWI sequence (e)shows numerous foci of microhaemorrhages with a gyriform and variegate pattern a with an associated diffuse asymmetric mineralization of the ipsilateral cortex ad deep grey nuclei. Interhemispheric blooming due to hemorrhage is a post-biopsy change; Axial T1 weighted image (f) shows that the lesions are T1 isointense ; ADC (g) and trace (h) maps reveal no diffusion restriction ; Axial post-contrast T1 weighted image (i) demonstrate enhancement of the lesions in a heterogenous, variegated pattern, punctiform in a few locations and patchy in others. The enhancement was traceable up to the ventricular margins.
Fig 3- Histopathology- H and E stain (A) showing epithelioid granulomas with foreign body giant cells engulfing fungal hyphae which are slender, septate and branching and acute angles, suggestive of aspergillosis. The fungal hyphae are highlighted on PAS (B) and GMS stains (C). [Magnification A-C Obj. X200]
Fig 4 Axial NCCT (a) and CECT(b) following the clinical deterioration in consciousness the following week shows an interval increase in the dimensions and mass effect in the lesion.
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14. Koutsouras GW, Ramos RL, Martinez LR. Role of microglia in fungal infections of the central nervous system. Virulence. 2017 18;8(6):705–18. 15. Kastrup O, Wanke I, Maschke M. Neuroimaging of Infections. NeuroRx. 2005 Apr;2(2):324–32. 16. Nadkarni T, Goel A. Aspergilloma of the brain: an overview. J Postgrad Med. 2005 Oct 1;51(5):37. 17. Mathur M, Johnson CE, Sze G. Fungal Infections of the Central Nervous System. Neuroimaging Clin N Am. 2012 Nov 1;22(4):609–32. 18. Hurst RW, Judkins A, Bolger W, Chu A, Loevner LA. Mycotic Aneurysm and Cerebral Infarction Resulting from Fungal Sinusitis: Imaging and Pathologic Correlation. Am J Neuroradiol. 2001 May 1;22(5):858–63. 19. Ostrow TD, Hudgins PA. Magnetic resonance imaging of intracranial fungal infections. Top Magn Reson Imaging TMRI. 1994;6(1):22–31. 20. Ashdown BC, Tien RD, Felsberg GJ. Aspergillosis of the brain and paranasal sinuses in immunocompromised patients: CT and MR imaging findings. AJR Am J Roentgenol. 1994 Jan;162(1):155–9. 21. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, et al. Defining Opportunistic Invasive Fungal Infections in Immunocompromised Patients with Cancer and Hematopoietic Stem Cell Transplants: An International Consensus. Clin Infect Dis. 2002 Jan 1;34(1):7–14. 22. Kourkoumpetis T, Desalermos A, Muhammed M, Mylonakis E. Central Nervous System Aspergillosis: A Series of 14 Cases From a General Hospital and Review of 123 Cases From the Literature. Medicine (Baltimore). 2012 Nov;91(6):328–36. 23. Saini J, Gupta AK, Jolapara MB, Chatterjee S, Pendharkar HS, Kesavadas C, et al. Imaging findings in intracranial aspergillus infection in immunocompetent patients. World Neurosurg. 2010 Dec;74(6):661–70. 24. Yamada K, Zoarski GH, Rothman MI, Zagardo MT, Nishimura T, Sun CCJ. An intracranial aspergilloma with low signal on T2-weighted images corresponding to iron accumulation. Neuroradiology. 2001 Jul 1;43(7):559–61. 25. Jain KK, Mittal SK, Kumar S, Gupta RK. Imaging features of central nervous system fungal infections. Neurol India. 2007 Jul 1;55(3):241. 26. Sharma BS, Khosla VK, Kak VK, Banerjee AK, Vasishtha RK, Prasad KS, et al. Intracranial fungal granuloma. Surg Neurol. 1997 May;47(5):489–97. 27. Challa S, Uppin SG, Purohit AK. Isolated cerebral Aspergillus granuloma with no obvious source of infection. Neurol India. 2007 Jul 1;55(3):289. 28. de Martin Truzzi G, Furlan Pauna H, Moreira Hazboun I, Benedick Coimbra I, Sakuma ETI, Barreto IS, et al. Slowly progressive invasive rhino orbito cerebral aspergillosis: case report and literature review. Clin Case Rep. 2017 Jan 26;5(3):218–24.
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Abbreviation list: CT-Computed tomography MRI-Magnetic Resonance Imaging SWI- Susceptibility Weighted Imaging
S1878-8750(19)32531-8
DOI:
https://doi.org/10.1016/j.wneu.2019.09.100
Reference:
WNEU 13399
To appear in:
World Neurosurgery
Received Date: 21 August 2019 Revised Date:
17 September 2019
Accepted Date: 18 September 2019
Please cite this article as: Kulanthaivelu K, Prasad C, Kumar Reddy YV, Mahadevan A, HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.09.100. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Title page HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN
Authors Dr Karthik Kulanthaivelua, DM; Dr Chandrajit Prasada*, DM; Dr Yerasi Varun Kumar Reddyb, M. Ch, Dr Anita Mahadevanc ,MD
a
Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India b Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India c Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India
Corresponding author Dr Chandrajit Prasad*, Additional professor Mailing address: Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Tel.: +9108026005424, Mobile phone: +919480606741 E-mail: [email protected]
Authors and Affiliations: 1)Dr Karthik Kulanthaivelu, D.M., Assistant Professor, Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
2)Dr Chandrajit Prasad, D.M., Additional Professor, Department of Neuroimaging and Interventional Radiology,
National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
3) Dr Yerasi Varun Kumar Reddy, M.Ch., Senior Resident, Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
4)Dr Anita Mahadevan, MD, Professor, Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru-560029, Karnataka, India Email: [email protected]
Key words- Invasive, hematogenous, holohemispheric, fungal, granuloma, cerebritis Running title- Holohemispheric Invasive Fungal Granuloma
HOLOHEMISPHERIC INVASIVE ASPERGILLUS GRANULOMATOUS CEREBRITIS OF THE BRAIN ABSTRACT BACKGROUND Invasive aspergillosis of the central nervous system, a saprophytic infection with a unique vascular tropism, carries the burden of increased morbidity and mortality. Early clinical and imaging findings can masquerade as an innocuous condition before a secondary inexorable progression. We highlight the clinical and imaging phenotype of a patient with fatal invasive granulomatous aspergillosis. CASE DESCRIPTION A 39-year-old man presented with progressive weakness of the left upper and lower limb for 4 months. Imaging demonstrated right holohemispheric extensive, numerous, confluent, illdefined, T2 hypointense foci with moderate perilesional edema. Numerous foci of microhaemorrhages with cortical asymmetric mineralization were seen. Post-contrast heterogeneous, variegate, punctiform enhancement of the lesions was observed extending to the ventricular margins. Volume loss of the left cerebral peduncle and ipsilateral long white matter descending tracts was noted. Histopathologic examination of a stereotactic biopsy specimen from the frontal region lesion showed dense inflammatory infiltrate with granulomas, a few in a perivascular distribution and branching septate hyphae resembling Aspergillus. The patient was initiated on antifungal therapy and in the following week, he had progressive drowsiness. The patient succumbed the next day. CONCLUSION Diffuse holohemispheric, progressive presentation of a granulomatous form of invasive aspergillosis is a rare entity. The miliary pattern of heterogenous enhancement, holohemispheric conglomerate T2 hypointensities, interspersed hemorrhage, juxtacortical punctate T2 hyperintense foci, low perfusion, and the relative absence of diffusion abnormality are distinctive features. Early diagnosis of this atypical imaging phenotype of Aspergillus infection and appropriate treatment is critical for better prognosis.
INTRODUCTION Aspergillosis of the central nervous system has high mortality even in immunocompetent individuals(1–5). The spectrum of clinicopathological syndromes includes meningitis, meningoencephalitis, abscess, skull base syndromes, stroke/infarction, mycotic aneurysms disseminated granulomatous affliction of the cerebral parenchyma, orbital cellulitis, and spinal cord compression(6,7). The definitive diagnosis of invasive neuroaspergillosis requires histopathological identification in the tissue or its growth in culture. However, a high degree of suspicion may be raised in the presence of specific imaging findings. Here we present an atypical holohemispheric pattern of parenchymal invasive granulomatous aspergillosis.
CASE REPORT A 39-year-old man, symptomatic for one year, presented with progressive weakness of the left upper and lower limb and intermittent headaches for the 4 months. An episode of generalized tonic-clonic seizure was documented approximately one year earlier. He was a diagnosed case of diabetes and was compliant with medication. On examination, he had spastic left hemiparesis with brisk deep tendon reflexes on the affected side. His first clinical manifestation was approximately a year earlier when he had one episode of generalised tonic-clonic seizures. He presented to another peripheral centre nearby his village where he was investigated with CT which revealed a mass lesion in the right frontoparietal region. The focal lesion was opined as possibly neoplastic. He was started on anti-epileptic drugs and was asked to consult a higher centre for further management. The patient and family failed to seek medical consultation during the ensuing months. Review of the CT, (Fig. 1) acquired at that timepoint, revealed an ill-defined, infiltrative, heterogeneously hyperdense lesion in the right frontoparietal region, involving both gray and white matter extending into the periventricular region. Moderate perilesional oedema and homogenous post-contrast enhancement were present. The subsequent clinical picture was characterised by an insidious onset and indolent course of left sided weakness that worsened over many months. The patient was later brought to the author’s institution due to progressive nature of the weakness and headache. The prompt in-hospital investigation began with imaging, blood and CSF examination. MRI at admission (Fig. 2) demonstrated holohemipsheric extension of the abnormality. The cortex, juxtacortical white matter, deep white matter, and the deep grey nuclei showed numerous miliary, ill-defined, T2 hypointense foci, with the majority being confluent. The lesions incited moderate perilesional oedema. The lesions were isointense on T1 weighted
sequence. Numerous foci of microhaemorrhages with an associated diffuse asymmetric mineralization of the ipsilateral cortex and deep grey nuclei were evident on SWI. There was no evidence of diffusion abnormality in these lesions. Post-contrast enhancement of the lesions was heterogenous, variegate, punctiform in a few locations and patchy in others. The enhancement was reaching up to the ventricular margins. Corpus callosum involvement paralleled the hemispheric involvement and lesions were not crossing the midline. The lesions were hypoperfused. Besides, a few juxtacortical T2 hyperintense foci were seen throughout the hemisphere that did not show any enhancement on postcontrast T1 weighted images. Additionally, the left lateral ventricle demonstrated reduced dimensions of the frontal horn with dilatation of the body, temporal and occipital horns and contralateral midline shift. Also evident were the volume loss of the left cerebral peduncle, ipsilateral long white matter descending tracts, possibly due to Wallerian degeneration. This finding was reflective of the chronicity of the disease in this patient. Review of the paranasal sinuses and the skull base in the cross-sectional imaging revealed no significant abnormality. X-ray of the chest did not reveal parenchymal changes. No infected surface wound was seen on examination. The patient’s blood investigation was remarkable for a WBC count of 22500/microlitre with a predominance of neutrophils (85.6%). Serum glucose (random) was 132 mg/dL. HIV- ELISA test result was negative. CSF analysis was done. The gross appearance was slightly hazy. Cells were 24/cu.mm. Polymorphs were 12/cu.mm, degenerated cells were 12/cu.mm, occasional RBCs were seen. On biochemical analysis, CSF chloride was 119mmol/L; CSF glucose was 26 mg/dL; CSF lactate was 62.1mg/dL; CSF protein was 155 mg/dL. The CSF picture suggested meningitis. The patient underwent stereotactic biopsy from the right frontal region lesion. Histopathologic examination revealed dense inflammatory infiltrate with granulomas composed of lymphocytes, macrophages, plasma cells. Perifocal epithelioid cells, numerous Langhans giant cells and foreign body giant cells containing septate branching fungal hyphae were seen. Perivascular granulomas were also present. Periodic acid Schiff and GrocottGomori’s methenamine silver stain highlighted the branching septate hyphae morphologically resembling Aspergillus (Fig 3). The patient was immediately initiated on Inj. Voriconazole 6mg/kg/day on Day1 followed by 4mg/kg/day from day 2 with plan to be continued for 12 weeks. He sought discharge against medical advice and in the following week, he had progressive drowsiness. A repeat CT (Fig 4) at readmission revealed a further increase in the lesion dimensions and mass effect. Given the absence of papilledema, relative preservation of the CSF spaces of the basal cisterns surgical intervention with CSF drainage was not contemplated at that time point. The plan was to immediately place an EVD if any further deterioration or features of raised intracranial tension were noted. The patient got discharged against medical advice and succumbed to cardiorespiratory arrest the next day.
DISCUSSION – Aspergillus genus represents a ubiquitous, saprophytic, septate mold, the most common human pathogen being Aspergillus fumigatus(5). Invasive aspergillosis has mortality ranging from 40 – 90 % in immunocompromised hosts(5). The principal determinant of the disease course is the innate immunity of host (mediated by the monocyte-macrophage system and polymorphonuclear cells) which in turn may be negatively affected by disease states such as neutropenia, solid organ transplantation, chemotherapy, bronchiectasis, tuberculosis, antimicrobial agents and steroids(8–11). Primary infection occurs via the airways(12,13), the smaller conidial forms of the A. fumigatus(2-4 microns) gain access to alveoli, followed by evasion of innate host immune response and hematogenous dissemination(5). Angiocentric invasion of small and large vessels with resultant thrombosis, infarction, hemorrhage is the usual course of the disease evolution(4,12). Aspergillus is also the most common etiology of mycotic aneurysm of the central nervous system(4,8). Fungal exit across the blood-brain barrier happens possibly via transcellular/ paracellular migration or by a hypothetical Trojan Horse scheme(14). Following the egress from the vascular compartment, extravascular spread typically leads to the formation of necrotizing lesions, and abscess(1). Alternatively, locoregional contiguous spread from the paranasal sinuses may facilitate the formation of chronic granulomas. In line with the clinicopathological syndromes, the imaging phenotype is varied and includes meningoencephalitis, abscess, skull base syndromes, stroke/infarction, mycotic aneurysms, “tumoral aspergillomas” of the cerebral parenchyma, orbital cellulitis, and spinal cord compression(7,15). Aspergillus is the most common etiologic agent for fungal cerebral abscess among posttransplant patients(16). On MRI, the lesion demonstrates T2 hypointense rim, susceptibility effect, and diffusion restriction, probably mirroring the haemorrhagic residue and the dense hyphal elements(17). Central diffusion restriction, if present is attributed to tenacious, protein-rich fluid and cellular infiltration. The histologic hallmark, unlike bacterial abscess, is necrosis, rather than suppuration(12). The angioinvasive nature is partly conferred by the enzyme elastase(17). The vascular tropism manifests as vasculitis, thrombosis, haemorrhage, and mycotic aneurysms(18). Perforator territorial diffusion abnormality is the tell-tale sign of hematogenous dissemination. In the acute phase, contrast enhancement is absent in these medium-sized lesions (12). Parenchymal involvement is relatively common compared to meningeal affliction(19). Contiguous extensions with dural involvement, orbital cellulitis, optic neuritis, calvarial osteomyelitis are described in conjunction with a sinonasal source of infection(20). CSF culture for Aspergillus fungus has poor sensitivity (21) and the notion of proven infection by mold is strongly supported on histopathological basis(22).
Holohemispheric involvement has been described only once earlier from Southern India (23). A remarkable correspondence of clinical and imaging phenotype between these two cases in the background of immunocompetence, ethnic similarities is noteworthy. Earlier accounts of Aspergillus have reiterated signal characteristics of T1 hypo- to iso intensity and T2 hypointensity with bright homogenous enhancement on post gadolinium T1-weighted imaging, have been reported(24). High concentrations of iron in forms other than hemosiderin, is purported as the candidate species rendering these signal characteristics(24), although contrary evidence for the signal arising from blood breakdown products exists(25), including that from this index case. The protracted clinical course in the index case, in the context of no known primary source of infection is exceptional. Primary intracranial cerebral aspergillosis is a fulminant rapidly progressive disease with symptoms for lesser than three months(26,27). While slow progressive neuroaspergillosis has been described earlier, most reports are usually in the context of rhino-orbito-cerebral forms, rather than primary intracranial forms(26,28,29). One immunocompetent patient, in a series by Saini et al(23), presented with a similar gradual worsening of hemiparesis whose imaging showed a comparable holohemispheric involvement. While it has been claimed that an elongated duration of symptoms before presentation has been associated with lesser mortality(26), conflicting evidence too exists(28) as in our case. Although infrequent, primary CNS aspergillosis without proven extraneous source of infection has been reported(30). Treatment with Voriconazole has been reported to increase survival by 35-47 %(31,32). Surgical debridement with an appropriate margin is considered to be curative(33). Prognosis is generally poor despite aggressive management with antifungals (16,34). To conclude, we intend to draw attention to diffuse holohemispheric, indolent, progressive presentation of a granulomatous form of invasive aspergillosis. The miliary as well as a patchy pattern of heterogenous enhancement, holohemispheric punctate as well as conglomerate T2 hypointensities, interspersed haemorrhagic residue, juxtacortical multifocal punctate T2 hyperintense foci, low perfusion, the relative absence of diffusion abnormality are the standout features. We wish to emphasize that the testimony to the initial indolent nature and a secondarily accelerated course is in the appearance of mass effect later in the disease with co-existent stigmata of Wallerian changes in the right cerebral peduncle involving the descending tracts contiguous with the hemispheric lesions. It is important to recognize an atypical imaging phenotype of Aspergillus infection as early diagnosis and appropriate treatment is critical for better prognosis. The value of early diagnosis has been underscored by the index case in which the delay resulted in an inexorable downward course.
Figures and Legends
Fig 1. Imaging done 10 months earlier a) Non-contrast CT showed an ill-defined, infiltrative, heterogeneously hyperdense lesion in the right frontoparietal region extending to involve both gray and white matter and reaching the periventricular region with mild perilesional edema. b) Contrastenhanced CT revealed mild heterogeneous post-contrast enhancement.
Fig 2 Imaging at the presentation- Axial T2 at the level of the midbrain(a) reveals volume loss with diffuse T2 hyperintense signal changes in the right temporal lobe and cerebral peduncles.(b,c)show large areas of involvement including the juxtacortical and deep white matter, deep gray nuclei and numerous miliary, ill-defined, punctate foci of T2 hypointense signal that were patchily confluent in few other areas and a few subcortical areas of T2 hyperintense cystic changes. Axial T2 weighted FLAIR image(d) shows Moderate perilesional edema with mass effect extending up to the midline; SWI sequence (e)shows numerous foci of microhaemorrhages with a gyriform and variegate pattern a with an associated diffuse asymmetric mineralization of the ipsilateral cortex ad deep grey nuclei. Interhemispheric blooming due to hemorrhage is a post-biopsy change; Axial T1 weighted image (f) shows that the lesions are T1 isointense ; ADC (g) and trace (h) maps reveal no diffusion restriction ; Axial post-contrast T1 weighted image (i) demonstrate enhancement of the lesions in a heterogenous, variegated pattern, punctiform in a few locations and patchy in others. The enhancement was traceable up to the ventricular margins.
Fig 3- Histopathology- H and E stain (A) showing epithelioid granulomas with foreign body giant cells engulfing fungal hyphae which are slender, septate and branching and acute angles, suggestive of aspergillosis. The fungal hyphae are highlighted on PAS (B) and GMS stains (C). [Magnification A-C Obj. X200]
Fig 4 Axial NCCT (a) and CECT(b) following the clinical deterioration in consciousness the following week shows an interval increase in the dimensions and mass effect in the lesion.
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Abbreviation list: CT-Computed tomography MRI-Magnetic Resonance Imaging SWI- Susceptibility Weighted Imaging