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Case Report/Case Series |

Vascular Complications of Fungal Meningitis Attributed to Injections of Contaminated Methylprednisolone Acetate FREE

Kirk Kleinfeld, MD1; Pearl Jones, MD1; Derek Riebau, MD1; Ariana Beck, MD1; Paisit Paueksakon, MD1; Ty Abel, MD, PhD1; Daniel O. Claassen, MD, MS1
[+] Author Affiliations
1Departments of Neurology, Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
JAMA Neurol. 2013;70(9):1173-1176. doi:10.1001/jamaneurol.2013.3586.
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Published online

Importance  Fungal meningitis due to injections of contaminated methylprednisolone acetate can present with vascular sequelae in immunocompetent individuals. This is particularly germane to neurologists because better recognition of the clinical characteristics of patients with fungal meningitis and ischemic stroke will provide more timely and efficient care.

Observations  In a case series, 3 patients presented to Vanderbilt University Medical Center in Nashville, Tennessee, with acute ischemic stroke and later received a diagnosis of fungal meningitis attributed to epidural injections of contaminated methylprednisolone. Of these 3 patients, 2 were women, and the mean age for all 3 was 75.3 years. Their medical records and imaging scans were reviewed. All 3 patients presented with acute ischemic strokes and had a history of epidural spinal injections of methylprednisolone for low back pain. All 3 patients had 1 or more traditional risk factors for stroke. There were differing vascular patterns of presentation: 2 patients presented with small-vessel (lacunar) infarctions, whereas 1 patient presented with a large-vessel infarct. Of these 3 patients, 2 died and underwent an autopsy, which revealed Exserohilum rostratum as the presumed cause of death. For 2 cases, fever and meningeal signs were absent at presentation.

Conclusions and Relevance  Patients with fungal meningitis may present with ischemic stroke detected on initial imaging scans. A definitive diagnosis should not delay early antifungal treatment.

Figures in this Article

The recent identification of injections of contaminated methylprednisolone acetate has highlighted the diverse clinical presentations of fungal meningitis. When an injection of contaminated methylprednisolone is the cause of fungal meningitis, there is often a prolonged incubation period lasting 1 to 4 weeks between the last spinal injection and the clinical presentation; however, even longer incubation times have been reported.13 A recent series of the Tennessee cases revealed that approximately one-eighth of patients have presented with strokes.3 These cases show that the organism was primarily Exserohilum rostratum; in 1 case, it was Aspergillus fumigatus. Increased risk of infection is due to specific contaminated lots, older vials, higher corticosteroid doses, multiple procedures, and a translaminar approach.3 The objective of this series is to describe a cohort of patients who present with ischemic infarction in differing vascular distributions. These cases emphasize an unusual diagnostic dilemma, in which an ischemic infarct is initially attributable to a known stroke risk factor, such as atrial fibrillation or the presence of antiphospholipid protein antibodies, yet the patients were later found to have a fungal infection accounting for the presentation.

Case 1

A 78-year-old man presented with acute-onset left-sided weakness and dysarthria. His medical history included low back pain, hyperlipidemia, hypertension, and atrial fibrillation. At presentation, he was afebrile and complained of a mild persistent headache. A neurologic examination revealed dysarthria, lower facial weakness on the left side, and upper and lower extremity weakness on the left side in an upper motor neuron distribution. No meningeal signs were noted. Initial workup was notable for mild leukocytosis. A magnetic resonance imaging (MRI) scan of the brain showed a small-vessel (lacunar) ischemic infarct of the right anterior superior pons/lower midbrain (Figure 1). Magnetic resonance angiographic scans of the head and neck and a transthoracic echocardiogram were unremarkable. On hospital day 3, the patient had an exacerbation of left-sided weakness. Another MRI scan showed an extension of the infarct in the right midbrain and a new small lacunar infarct in the right thalamus (Figure 1B). On hospital day 4, the patient became unresponsive with a right dilated pupil. Repeated imaging showed enlargement and evolution of prior infarcts, along with a new right superior cerebellar artery occlusion. The patient died on hospital day 6. An autopsy was performed because he was noted to have received an epidural steroid injection approximately 2 weeks prior to presentation. An autopsy revealed small areas of focal cortical and pontine subarachnoid hemorrhage, as well as fungal cerebral vasculitis with aneurysm formation. Exserohilum species were found microscopically.

Place holder to copy figure label and caption
Figure 1.
Magnetic Resonance Imaging (MRI) Findings for 3 Cases

For case 1, on hospital day 1, a diffusion-weighted imaging (DWI) scan reveals an acute upper pontine/lower midbrain ischemic stroke suggestive of a small-vessel etiology (A); on hospital day 3, another MRI scan reveals the direct extension of stroke into the right thalamus, suggestive of a large-vessel etiology (B); and on hospital day 4, a computed tomographic angiography scan reveals an occlusion of the right superior cerebellar artery (C). For case 2, on hospital day 1, a DWI scan reveals acute left pontine and cerebellar ischemic strokes suggestive of a large-vessel etiology (D); on hospital day 15, a T1-weighted sequence with contrast reveals an abscess adjacent to the left cerebellopontine angle (E); and on hospital day 15, a lumbar MRI T1-weighted sequence with contrast reveals extradural enhancement and clumping of nerve roots suggesting arachnoiditis (F). For case 3, on hospital day 1, a DWI scan reveals a right small-vessel internal capsule stroke (G); on hospital day 7, a DWI scan reveals a right internal capsule and a left internal capsule genu stroke (H); and on hospital day 7, a T1-weighted sequence with contrast also reveals a left-sided cerebellopontine abscess (I).

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Case 2

A 78-year-old woman presented with subacute complaints of vertigo, nausea, and headache. Her medical history included low back pain, hypertension, hyperlipidemia, and coronary artery disease. An examination was notable for left-handed dysmetria and mild ataxia. An MRI scan revealed ischemic infarcts of the left lateral pons, superior cerebellar peduncle, and superior cerebellum suggestive of a large-vessel (superior cerebellar artery) etiology (Figure 1). Computed tomographic angiography did not reveal any significant posterior circulation stenosis, and a transthoracic echocardiogram was unremarkable. Screening laboratories revealed a new diagnosis of type 2 diabetes mellitus. Because the patient had a history of several prior miscarriages and an infarct pattern, a hypercoaguable panel was ordered and was positive for lupus anticoagulant and elevated antiphospholipid protein antibodies. The patient was anticoagulated. On hospital day 4, a low-grade fever and mild encephalopathy were noted. Another MRI scan showed a new ischemic pontine stroke on the left side of the brain. On hospital day 6, the patient developed acute urinary retention. Since she had received an epidural injection 2 weeks prior to admission, an MRI scan of the lumbar spine with and without contrast was obtained, and abnormal periarticular enhancement with central canal enhancement (but no drainable fluid) at L4-5 was noted. Initial blood cultures revealed methicillin-sensitive Staphylococcus aureus. Later, owing to her continued altered mental status and a recent report of fungal meningitis,4 a lumbar puncture was performed (Table). Intravenous antibiotics and intravenous voriconazole at 6 mg/kg twice daily for 2 doses, followed by 4 mg/kg twice daily, were initiated 15 days after initial presentation. Despite therapy, the patient died 50 days after presentation. An autopsy revealed a left superior cerebellar artery mycotic aneurysm with vascular infiltration of the arterial wall by hyphal fungal forms (Figure 2). Based on positive premortem Centers for Disease Control and Prevention polymerase chain reaction studies, these forms are thought to represent Exserohilum species.

Table Graphic Jump LocationTable.  Case Presentation and Laboratory and Imaging Summaries
Place holder to copy figure label and caption
Figure 2.
Pathology Findings

Hematoxylin-eosin stain of mycotic aneurysm of the left superior cerebellar artery (A [original magnification ×4]), higher-power view of Gomori methenamine silver stain of hyphal elements within the mycotic aneurysm of the superior cerebellar artery (B [original magnification ×40]), and gross photograph of mycotic aneurysm of the left superior cerebellar artery (C).

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Case 3

A 70-year-old woman presented with headaches, balance difficulty, nuchal rigidity, and fever. Her medical history was notable for hyperlipidemia and chronic back pain with the most recent epidural spinal injection 1 month prior. An examination revealed mild dysarthria and bilateral dysmetria. An MRI scan of the brain revealed acute small-vessel right thalamic and internal capsule ischemic strokes. Magnetic resonance angiographic scans of the head and neck showed no significant stenoses. Owing to concern for meningitis, a lumbar puncture was performed (Table). Based on initial cerebrospinal fluid results, intravenous antibiotics, voriconazole in a similar regimen to case 2, and liposomal amphotercin B (stopped after 4 days) were initiated. A MRI scan of the thoracic and lumbar spine revealed evidence of lumbosacral arachnoiditis with abnormal enhancement within the posterior epidural space at L4-5 and L5-S1, but again with no drainable fluid. On hospital day 7, the patient became encephalopathic, and another MRI scan revealed a new acute small-vessel left internal capsule. Her mental status and cerebrospinal fluid cell counts slowly improved with voriconazole monotherapy. The patient was discharged from the hospital 37 days later.

We describe 3 cases presenting with acute ischemic strokes that, after further workup, revealed fungal infections attributable to contaminated lots of methylprednisolone associated with epidural injections reportedly received at identified health care facilities.5 The presenting symptoms in all 3 patients were, at least in part, related to neurologic sequelae of ischemic stroke. Early MRI findings showed evidence of restricted diffusion. Initial imaging did not show evidence of hemorrhage or mycotic aneurysm. Interestingly, all patients were in their eighth decade, and all had 1 or more traditional risk factors for stroke. The pattern of infarcts differed, with 2 patients initially presenting with small-vessel infarcts and 1 patient initially presenting with a large-vessel pattern. In case 2, progressive vascular occlusion of the superior cerebellar artery was attributed to fungal infiltration at autopsy. Importantly, in case 3, the patient received earlier antifungal treatment, and we suspect that this halted the further vascular progression of her infection.

Regarding the territory of strokes, all 3 patients presented with posterior circulation infarcts (supplied by the basilar, superior cerebellar, and posterior cerebral artery branches/perforators). It is now apparent that a high index of suspicion should be raised for possible fungal meningitis in patients who present with posterior circulation ischemic strokes after receiving a recent epidural spinal injection.3 However, it remains unknown why there appears to be a predilection for the posterior circulation in epidural injections associated fungal meningitis. We hypothesize that the proximity of the epidural space may account for fungal infiltration to the posterior vasculature. A definitive diagnosis could not be made during hospitalization and was made at autopsy or by polymerase chain reaction testing for Exserohilum species. Owing to clinical suspicion, the patient without a known causative agent was treated early with both antibiotics and antifungals. This patient survived after hospitalization.

Although much larger in scale, this is not the first fungal meningitis outbreak due to epidural spinal injections of contaminated corticosteroids.68 These cases highlight a diagnostic dilemma of neurologists. Patients with fungal meningitis who present with ischemic strokes may be afebrile, lack signs of meningeal irritation, and have traditional stroke risk factors. In cases in which small-vessel infarctions expand locally or develop new infarctions in the same vascular territory, an atypical pathogenesis should be considered. We highlight that the angioinvasive nature of some fungal species,4 including Exserohilum, can lead to progressive vascular occlusion. An awareness of the presentation and vascular sequelae of fungal meningitis in immunocompetent patients should lead to earlier treatment and improved outcomes prior to a definitive diagnosis.

Corresponding Author: Daniel O. Claassen, MD, MS, Department of Neurology, Vanderbilt University, 1161 21st Ave S, A-0118, Nashville, TN 37232-2551 (daniel.claassen@vanderbilt.edu).

Accepted for Publication: May 17, 2013.

Published Online: July 22, 2013. doi:10.1001/jamaneurol.2013.3586.

Author Contributions:Study concept and design: Kleinfeld, Jones, Riebau, Claassen.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Kleinfeld, Jones, Claassen.

Critical revision of the manuscript for important intellectual content: All authors.

Conflict of Interest Disclosures: None reported.

Centers for Disease Control and Prevention (CDC). Multistate fungal meningitis outbreak investigation: current situation. CDC website. www.cdc.gov/hai/outbreaks/currentsituation. Accessed December 7, 2012.
Slama  T, Kauffman  CA, Patterson  TF, Neill  MA.  Fungal outbreak update from IDWeek. Clin Infect Dis. 2013;56(5):621-624.
PubMed   |  Link to Article
Kainer  MA, Reagan  DR, Nguyen  DB,  et al; Tennessee Fungal Meningitis Investigation Team.  Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med. 2012;367(23):2194-2203.
PubMed   |  Link to Article
Pettit  AC, Kropski  JA, Castilho  JL,  et al.  The index case for the fungal meningitis outbreak in the United States. N Engl J Med. 2012;367(22):2119-2125.
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC). Multistate fungal meningitis outbreak: healthcare facilities. CDC website. www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html. Accessed April 24, 2013.
Lyons  JL, Gireesh  ED, Trivedi  JB,  et al.  Fatal Exserohilum meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection. Ann Intern Med. 2012;157(11):835-836.
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy—United States, July-November 2002. MMWR Morb Mortal Wkly Rep. 2002;51(49):1109-1112.
PubMed
Centers for Disease Control and Prevention.  From the Centers for Disease Control and Prevention. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy—United States, July-November 2002. JAMA. 2003;289(3):291-293.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Magnetic Resonance Imaging (MRI) Findings for 3 Cases

For case 1, on hospital day 1, a diffusion-weighted imaging (DWI) scan reveals an acute upper pontine/lower midbrain ischemic stroke suggestive of a small-vessel etiology (A); on hospital day 3, another MRI scan reveals the direct extension of stroke into the right thalamus, suggestive of a large-vessel etiology (B); and on hospital day 4, a computed tomographic angiography scan reveals an occlusion of the right superior cerebellar artery (C). For case 2, on hospital day 1, a DWI scan reveals acute left pontine and cerebellar ischemic strokes suggestive of a large-vessel etiology (D); on hospital day 15, a T1-weighted sequence with contrast reveals an abscess adjacent to the left cerebellopontine angle (E); and on hospital day 15, a lumbar MRI T1-weighted sequence with contrast reveals extradural enhancement and clumping of nerve roots suggesting arachnoiditis (F). For case 3, on hospital day 1, a DWI scan reveals a right small-vessel internal capsule stroke (G); on hospital day 7, a DWI scan reveals a right internal capsule and a left internal capsule genu stroke (H); and on hospital day 7, a T1-weighted sequence with contrast also reveals a left-sided cerebellopontine abscess (I).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Pathology Findings

Hematoxylin-eosin stain of mycotic aneurysm of the left superior cerebellar artery (A [original magnification ×4]), higher-power view of Gomori methenamine silver stain of hyphal elements within the mycotic aneurysm of the superior cerebellar artery (B [original magnification ×40]), and gross photograph of mycotic aneurysm of the left superior cerebellar artery (C).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Case Presentation and Laboratory and Imaging Summaries

References

Centers for Disease Control and Prevention (CDC). Multistate fungal meningitis outbreak investigation: current situation. CDC website. www.cdc.gov/hai/outbreaks/currentsituation. Accessed December 7, 2012.
Slama  T, Kauffman  CA, Patterson  TF, Neill  MA.  Fungal outbreak update from IDWeek. Clin Infect Dis. 2013;56(5):621-624.
PubMed   |  Link to Article
Kainer  MA, Reagan  DR, Nguyen  DB,  et al; Tennessee Fungal Meningitis Investigation Team.  Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med. 2012;367(23):2194-2203.
PubMed   |  Link to Article
Pettit  AC, Kropski  JA, Castilho  JL,  et al.  The index case for the fungal meningitis outbreak in the United States. N Engl J Med. 2012;367(22):2119-2125.
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC). Multistate fungal meningitis outbreak: healthcare facilities. CDC website. www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html. Accessed April 24, 2013.
Lyons  JL, Gireesh  ED, Trivedi  JB,  et al.  Fatal Exserohilum meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection. Ann Intern Med. 2012;157(11):835-836.
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy—United States, July-November 2002. MMWR Morb Mortal Wkly Rep. 2002;51(49):1109-1112.
PubMed
Centers for Disease Control and Prevention.  From the Centers for Disease Control and Prevention. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy—United States, July-November 2002. JAMA. 2003;289(3):291-293.
PubMed   |  Link to Article

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