Acute large-vessel occlusion due to an infected thrombus formation induced by invasive sphenoid sinus aspergillosis: illustrative case

Yoshiyasu Matsumoto Departments of Neurosurgery and

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Yosuke Akamatsu Department of Neurosurgery, Iwate Medical University, Yahaba-cho, Iwate, Japan

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Koji Yoshida Departments of Neurosurgery and

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Yasushi Ogasawara Department of Neurosurgery, Iwate Medical University, Yahaba-cho, Iwate, Japan

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Toshinari Misaki Departments of Neurosurgery and

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Shunichi Sasou Pathology, Hachinohe Red-Cross Hospital, Hachinohe, Aomori, Japan; and

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Hiromu Konno Departments of Neurosurgery and

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Kuniaki Ogasawara Department of Neurosurgery, Iwate Medical University, Yahaba-cho, Iwate, Japan

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BACKGROUND

The authors describe a rare case of acute large-vessel occlusion due to an infected thrombus formation that was induced by invasive sphenoid sinus aspergillosis.

OBSERVATIONS

An 82-year-old man with a history of immunoglobulin G4–related disease and long-term use of steroids and immunosuppressants was admitted to the authors’ hospital with severe right hemiparesis. Cerebral angiography revealed occlusion of the left internal carotid artery (ICA). He underwent thrombectomy, resulting in successful recanalization. However, severe stenosis was evident in the left ICA cavernous segment. Pathological analysis of the retrieved thrombus identified Aspergillus. Postoperative magnetic resonance imaging revealed sinusitis in the left sphenoid sinus as a possible source of the infection. The patient’s general condition deteriorated during the course of hospitalization due to refractory aspiration pneumonia, and he died 46 days after thrombectomy. Pathological autopsy and histopathological investigation of the left ICA and the left sphenoid sinus showed that Aspergillus had invaded the wall of the left ICA from the adjacent sphenoid sinus. These findings indicate a diagnosis of acute large-vessel occlusion due to infected thrombus formation induced by invasive sphenoid sinus aspergillosis.

LESSONS

Pathological analysis of a retrieved thrombus appears useful for identifying rare stroke etiologies such as fungal infection.

ABBREVIATIONS

CT = computed tomography; H&E = hematoxylin and eosin; ICA = internal carotid artery; IgG = immunoglobulin G; NIHSS = National Institutes of Health Stroke Scale

BACKGROUND

The authors describe a rare case of acute large-vessel occlusion due to an infected thrombus formation that was induced by invasive sphenoid sinus aspergillosis.

OBSERVATIONS

An 82-year-old man with a history of immunoglobulin G4–related disease and long-term use of steroids and immunosuppressants was admitted to the authors’ hospital with severe right hemiparesis. Cerebral angiography revealed occlusion of the left internal carotid artery (ICA). He underwent thrombectomy, resulting in successful recanalization. However, severe stenosis was evident in the left ICA cavernous segment. Pathological analysis of the retrieved thrombus identified Aspergillus. Postoperative magnetic resonance imaging revealed sinusitis in the left sphenoid sinus as a possible source of the infection. The patient’s general condition deteriorated during the course of hospitalization due to refractory aspiration pneumonia, and he died 46 days after thrombectomy. Pathological autopsy and histopathological investigation of the left ICA and the left sphenoid sinus showed that Aspergillus had invaded the wall of the left ICA from the adjacent sphenoid sinus. These findings indicate a diagnosis of acute large-vessel occlusion due to infected thrombus formation induced by invasive sphenoid sinus aspergillosis.

LESSONS

Pathological analysis of a retrieved thrombus appears useful for identifying rare stroke etiologies such as fungal infection.

ABBREVIATIONS

CT = computed tomography; H&E = hematoxylin and eosin; ICA = internal carotid artery; IgG = immunoglobulin G; NIHSS = National Institutes of Health Stroke Scale

Cardioembolic and atherosclerotic occlusions are two leading causes of acute ischemic stroke with large artery occlusion.1 However, the etiology can be unclear in many cases. Although fungal infection is a rare cause of ischemic stroke, the incidence of fungal infection of the central nervous system has increased due to growth in the number of transplant procedures performed and the proliferation of steroid use and immunosuppressive medications.2,3 In this study, we report a case of acute ischemic stroke due to Aspergillus infection that was diagnosed pathologically following thrombectomy.

Illustrative Case

The patient was an 82-year-old man with a history of immunoglobulin G4 (IgG4)–related disease who had been treated at our hospital for 7 years and was receiving oral steroids and immunosuppressants. He was brought to our hospital’s emergency department at 3 hours 10 minutes after sudden onset of disturbed consciousness. On examination, he had severe right hemiparesis, left conjugate deviation, and total aphasia. His National Institutes of Health Stroke Scale (NIHSS) score was 20/42. Computed tomography (CT) at admission showed no intracerebral hemorrhage (Alberta Stroke Program Early CT Score of 10), and large-vessel occlusion was suspected. Emergency cerebral angiography performed 3 hours 28 minutes after the onset of symptoms demonstrated occlusion of the left internal carotid artery (ICA) (Fig. 1A). Mechanical thrombectomy was performed using a combined technique with an aspiration catheter and stent retriever. As shown in Fig. 1B and C, complete recanalization (Thrombolysis in Cerebral Infarction 3, onset to recanalization 4 hours 2 minutes) of the ICA was achieved after a single procedure, with residual stenosis of 77% in the left ICA cavernous segment (measured using the method of the Warfarin–Aspirin Symptomatic Intracranial Disease trial).4

FIG. 1
FIG. 1

Left internal carotid angiograms. A: Lateral view shows occlusion of the left proximal ICA. Anteroposterior (B) and lateral (C) views after thrombectomy show complete recanalization of the ICA with residual stenosis in the cavernous segment of the left ICA.

Because atherosclerotic stenosis was suspected, 200 mg aspirin and 20 mg prasugrel were administered through a nasogastric tube immediately after recanalization. The symptoms improved immediately (from NIHSS score 20 to 3) after the procedure without reocclusion of the ICA, and the procedure was therefore terminated without angioplasty. According to our protocol for histological assessment of a retrieved thrombus, the retrieved red thrombus underwent pathological analysis. Fungal hyphae were identified within the thrombus by hematoxylin and eosin (H&E) and Grocott methenamine silver staining on the 4th postoperative day (Fig. 2A and B). Postoperative magnetic resonance imaging revealed left sphenoid sinusitis as a possible source of the thrombus infection (Fig. 2C). Antifungal medications were then administered. However, despite the neurological improvement, the patient’s general condition gradually deteriorated due to refractory aspiration pneumonia, and he died 46 days after the thrombectomy.

FIG. 2
FIG. 2

Histological slides. H&E staining (A) and Grocott methenamine silver staining (B) of the retrieved thrombus reveal hyphae with parallel and acute angle branching that is morphologically consistent with Aspergillus. Scale bar = 20 µm. T2-weighted magnetic resonance imaging (C) shows a hyperintense lesion (arrowhead) along the wall of the left sphenoid sinus.

Pathological autopsy performed with the consent of the patient’s family detected a whitish fungal mass macroscopically within the left sphenoid sinus (Fig. 3A). Detailed pathological examination of the structures around the left sphenoid sinus and the left ICA revealed invasion of Aspergillus into the wall of the ICA by direct continuous spread from the left sphenoid sinus (Fig. 3B and C). Examination of the rest of the patient’s body revealed no other infection.

FIG. 3
FIG. 3

Autopsy photographs. A: A whitish fungal mass is seen within the left sphenoidal sinus (arrowhead). B: The black bar placed on the skull base indicates the position of the cavernous segment of the left ICA, adjacent to the left sphenoidal sinus, where the stenotic left ICA was observed. C: Magnified view of H&E staining of the wall of the left carotid artery harvested from the cavernous segment. Hyphae with parallel and acute angle branching suggest invasion of Aspergillus. Scale bar = 200 µm.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

Mechanical thrombectomy is now widely performed, and several recent studies have reported the results of pathological analysis of the retrieved thrombus.5–7 In some of these studies, the embolic source could be identified by pathological examination,8,9 which is invaluable in terms of obtaining a diagnosis. To the best of our knowledge, there is only one reported finding of a fungal mass in a thrombus that had been retrieved by thrombectomy.10 Among several reports of cerebrovascular diseases caused by fungal infections, most of the patients had been administered steroids or immunosuppressive drugs.11–14 The present patient was also receiving long-term steroid and immunosuppressive drugs for management of IgG4-related diseases, and we assumed that the patient was immunocompromised. Fungal infections are highly invasive and are known to have a high fatality rate and poor prognosis.15,16 Even if administered systemically, antifungal drugs alone are considered ineffective due to the physical barrier of fibrosis, which prevents their penetration into the lesion. Previous studies have investigated combining systemic antifungal therapy with intralesional applications17 and radical removal of the affected lesion.18

Anatomically, the bones of the skull base are located near the sinuses, and adjacent intracranial blood vessels are easily susceptible to infiltrative destruction caused by fungal infection within the sinuses.15,16 Furthermore, because Aspergillus has a form that can easily invade blood vessels and produces degrading enzymes such as elastase, it is highly invasive to blood vessels.19 Its routes of infection are presumed to be spread to the cerebral blood vessel walls from sinusitis/skull base dura mater13,15,16 and by hematogenous dissemination.20 In the present case, autopsy determined that the route of infection was the left sphenoid sinus with spread into the left ICA and subsequent formation of an infected thrombus. These findings suggest that pathological analysis of a retrieved thrombus might be useful for the diagnosis of this rare stroke etiology.

Lessons

To the best of our knowledge, this is the first reported patient to demonstrate acute large vessel occlusion due to an infected thrombus formation that was induced by invasive sphenoid sinus aspergillosis and confirmed thorough pathological autopsy. The pathological diagnosis of a retrieved thrombus might be useful for detection of rare stroke etiologies.

Author Contributions

Conception and design: Matsumoto, Akamatsu, Misaki. Acquisition of data: Matsumoto, Yoshida. Analysis and interpretation of data: Matsumoto, Sasou. Drafting the article: Matsumoto. Critically revising the article: Matsumoto, Akamatsu, K Ogasawara. Reviewed submitted version of manuscript: Matsumoto, Akamatsu, K Ogasawara. Approved the final version of the manuscript on behalf of all authors: Matsumoto. Statistical analysis: Matsumoto. Administrative/technical/material support: Matsumoto, Akamatsu, Y Ogasawara, Konno. Study supervision: Matsumoto, Akamatsu, K Ogasawara.

References

  • 1

    Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):3541.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    George P, Ramiro JI, Gomes JA, Newey CR, Bhimraj A Central nervous system fungal infection-related stroke: a descriptive study of mold and yeast-associated ischemic stroke. J Stroke Cerebrovasc Dis. 2020;29(6):104759.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Raman Sharma R Fungal infections of the nervous system: current perspective and controversies in management. Int J Surg. 2010;8(8):591601.

  • 4

    Samuels OB, Joseph GJ, Lynn MJ, Smith HA, Chimowitz MI A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol. 2000;21(4):643646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sporns PB, Hanning U, Schwindt W, et al. Ischemic stroke what does the histological composition tell us about the origin of the thrombus? Stroke. 2017;48(8):22062210.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Duffy S, McCarthy R, Farrell M, et al. Per-pass analysis of thrombus composition in patients with acute ischemic stroke undergoing mechanical thrombectomy. Stroke. 2019;50(5):11561163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Katano T, Usui G, Hashimoto H, et al. Histological examination of thrombi in patients with cerebral infarction in embolic stroke of undetermined source. J Neuroendovasc Ther. 2019;13:359366.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Usui G, Takayama Y, Hashimoto H, et al. Cerebral embolism caused by thrombus in the pulmonary vein stump after left lower lobectomy. Intern Med. 2019;58(9):13491354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sugiyama N, Hasegawa H, Kudo K, et al. Cholesterol crystals in the retrieved thrombus by mechanical thrombectomy for cerebral embolism: a case report and literature review. NMC Case Rep J. 2022;9:225230.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Katano T, Sakamoto Y, Kunugi S, Nishiyama Y, Shimizu A, Kimura K A fungus in a thrombus by mechanical thrombectomy in acute cerebral infarction: a case report. Article in Japanese. Rinsho Shinkeigaku. 2020;60(5):340345.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Masago A, Fukuoka H, Yoshida T, Majima K, Tada T, Nagai H Intracranial mycotic aneurysm caused by Aspergillus – case report. Neurol Med Chir (Tokyo). 1992;32(12):904907.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Kim YC, Lee H, Ryu HH, et al. Aspergillus-associated cerebral aneurysm successfully treated by endovascular and surgical intervention with voriconazole in lupus nephritis patient. J Korean Med Sci. 2012;27(3):317320.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Shinya Y, Miyawaki S, Nakatomi H, et al. Recurrent cerebral aneurysm formation and rupture within a short period due to invasive aspergillosis of the nasal sinus; pathological analysis of the catastrophic clinical course. Int J Clin Exp Pathol. 2015;8(10):1351013522.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Iihara K, Makita Y, Nabeshima S, Tei T, Keyaki A, Nioka H Aspergillosis of the central nervous system causing subarachnoid hemorrhage from mycotic aneurysm of the basilar artery – case report. Neurol Med Chir (Tokyo). 1990;30(8):618623.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Lin SJ, Schranz J, Teutsch SM Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358366.

  • 16

    Ho CL, Deruytter MJ CNS aspergillosis with mycotic aneurysm, cerebral granuloma and infarction. Acta Neurochir (Wien). 2004;146(8):851856.

  • 17

    Murthy JM, Sundaram C, Prasad VS, Purohit AK, Rammurti S, Laxmi V Sinocranial aspergillosis: a form of central nervous system aspergillosis in south India. Mycoses. 2001;44(5):141145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Sundaram C, Murthy JM Intracranial Aspergillus granuloma. Pathol Res Int. 2011;2011:157320.

  • 19

    Hurst RW, Judkins A, Bolger W, Chu A, Loevner LA Mycotic aneurysm and cerebral infarction resulting from fungal sinusitis: imaging and pathologic correlation. AJNR Am J Neuroradiol. 2001;22(5):858863.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Endo T, Tominaga T, Konno H, Yoshimoto T Fatal subarachnoid hemorrhage, with brainstem and cerebellar infarction, caused by Aspergillus infection after cerebral aneurysm surgery: case report. Neurosurgery. 2002;50(5):11471151.

    • PubMed
    • Search Google Scholar
    • Export Citation
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  • Expand
  • FIG. 1

    Left internal carotid angiograms. A: Lateral view shows occlusion of the left proximal ICA. Anteroposterior (B) and lateral (C) views after thrombectomy show complete recanalization of the ICA with residual stenosis in the cavernous segment of the left ICA.

  • FIG. 2

    Histological slides. H&E staining (A) and Grocott methenamine silver staining (B) of the retrieved thrombus reveal hyphae with parallel and acute angle branching that is morphologically consistent with Aspergillus. Scale bar = 20 µm. T2-weighted magnetic resonance imaging (C) shows a hyperintense lesion (arrowhead) along the wall of the left sphenoid sinus.

  • FIG. 3

    Autopsy photographs. A: A whitish fungal mass is seen within the left sphenoidal sinus (arrowhead). B: The black bar placed on the skull base indicates the position of the cavernous segment of the left ICA, adjacent to the left sphenoidal sinus, where the stenotic left ICA was observed. C: Magnified view of H&E staining of the wall of the left carotid artery harvested from the cavernous segment. Hyphae with parallel and acute angle branching suggest invasion of Aspergillus. Scale bar = 200 µm.

  • 1

    Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):3541.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    George P, Ramiro JI, Gomes JA, Newey CR, Bhimraj A Central nervous system fungal infection-related stroke: a descriptive study of mold and yeast-associated ischemic stroke. J Stroke Cerebrovasc Dis. 2020;29(6):104759.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Raman Sharma R Fungal infections of the nervous system: current perspective and controversies in management. Int J Surg. 2010;8(8):591601.

  • 4

    Samuels OB, Joseph GJ, Lynn MJ, Smith HA, Chimowitz MI A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol. 2000;21(4):643646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sporns PB, Hanning U, Schwindt W, et al. Ischemic stroke what does the histological composition tell us about the origin of the thrombus? Stroke. 2017;48(8):22062210.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Duffy S, McCarthy R, Farrell M, et al. Per-pass analysis of thrombus composition in patients with acute ischemic stroke undergoing mechanical thrombectomy. Stroke. 2019;50(5):11561163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Katano T, Usui G, Hashimoto H, et al. Histological examination of thrombi in patients with cerebral infarction in embolic stroke of undetermined source. J Neuroendovasc Ther. 2019;13:359366.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Usui G, Takayama Y, Hashimoto H, et al. Cerebral embolism caused by thrombus in the pulmonary vein stump after left lower lobectomy. Intern Med. 2019;58(9):13491354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sugiyama N, Hasegawa H, Kudo K, et al. Cholesterol crystals in the retrieved thrombus by mechanical thrombectomy for cerebral embolism: a case report and literature review. NMC Case Rep J. 2022;9:225230.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Katano T, Sakamoto Y, Kunugi S, Nishiyama Y, Shimizu A, Kimura K A fungus in a thrombus by mechanical thrombectomy in acute cerebral infarction: a case report. Article in Japanese. Rinsho Shinkeigaku. 2020;60(5):340345.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Masago A, Fukuoka H, Yoshida T, Majima K, Tada T, Nagai H Intracranial mycotic aneurysm caused by Aspergillus – case report. Neurol Med Chir (Tokyo). 1992;32(12):904907.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Kim YC, Lee H, Ryu HH, et al. Aspergillus-associated cerebral aneurysm successfully treated by endovascular and surgical intervention with voriconazole in lupus nephritis patient. J Korean Med Sci. 2012;27(3):317320.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Shinya Y, Miyawaki S, Nakatomi H, et al. Recurrent cerebral aneurysm formation and rupture within a short period due to invasive aspergillosis of the nasal sinus; pathological analysis of the catastrophic clinical course. Int J Clin Exp Pathol. 2015;8(10):1351013522.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Iihara K, Makita Y, Nabeshima S, Tei T, Keyaki A, Nioka H Aspergillosis of the central nervous system causing subarachnoid hemorrhage from mycotic aneurysm of the basilar artery – case report. Neurol Med Chir (Tokyo). 1990;30(8):618623.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Lin SJ, Schranz J, Teutsch SM Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358366.

  • 16

    Ho CL, Deruytter MJ CNS aspergillosis with mycotic aneurysm, cerebral granuloma and infarction. Acta Neurochir (Wien). 2004;146(8):851856.

  • 17

    Murthy JM, Sundaram C, Prasad VS, Purohit AK, Rammurti S, Laxmi V Sinocranial aspergillosis: a form of central nervous system aspergillosis in south India. Mycoses. 2001;44(5):141145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Sundaram C, Murthy JM Intracranial Aspergillus granuloma. Pathol Res Int. 2011;2011:157320.

  • 19

    Hurst RW, Judkins A, Bolger W, Chu A, Loevner LA Mycotic aneurysm and cerebral infarction resulting from fungal sinusitis: imaging and pathologic correlation. AJNR Am J Neuroradiol. 2001;22(5):858863.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Endo T, Tominaga T, Konno H, Yoshimoto T Fatal subarachnoid hemorrhage, with brainstem and cerebellar infarction, caused by Aspergillus infection after cerebral aneurysm surgery: case report. Neurosurgery. 2002;50(5):11471151.

    • PubMed
    • Search Google Scholar
    • Export Citation

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