Journal of the Neurological Sciences 352 (2015) 125–126
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Acute ischemic strokes from small vessel vasculitis due to disseminated histoplasmosis infection Keywords: Small vessel vasculitis Disseminated histoplasmosis Ischemic infarcts
1. Case presentation A 61 year old previously healthy male with recent diagnosis of disseminated histoplasmosis presented due to transient right hand numbness and word finding difficulties. Neurologic exam was normal on our evaluation. The patient had presented 6 weeks prior with night sweats, weight loss, and fever and was eventually diagnosed with disseminated histoplasmosis. Work-up that led to the diagnosis included CT chest showing pulmonary nodules and lymphadenopathy, as well as blood cultures and bone marrow biopsy both positive for Histoplasma capsulatum. The patient was also found to have thrombocytopenia, leukopenia, and signs of adrenal insufficiency. He was initially treated with amphotericin b and then transitioned to oral itraconazole. He had no history of AIDS or immunodeficiency but did have exposure to black mold in his home prior to onset of constitutional symptoms. Work-up for the patient's neurologic symptoms included an MRI of the brain that revealed multiple punctate areas of acute and sub-acute ischemia in the bilateral cerebral and cerebellar hemispheres mostly cortical in location (Fig. 1 A). Further work-up included a TTE that showed a normal ejection fraction with no right-to-left shunt, carotid ultrasounds that showed no significant stenotic flow, and laboratory evaluation showing LDL of 28 and HgbA1c of 5.0. Given the appearance of infarcts on MRI, a central embolic source was considered, but telemetry revealed no atrial fibrillation after 72 h of monitoring and TEE revealed no left atrial thrombus or valvular abnormalities. A catheter angiogram was performed for further work-up and results showed small vessel vasculitis in the distal left anterior cerebral and middle cerebral arteries (Fig. 1 B). Very mild vasculitic changes were seen in the other vascular distributions. Given the patient's symptoms (right hand numbness and presumed expressive aphasia), MRI findings (multiple areas of punctate infarcts), and angiographic evidence of left anterior circulation vasculitis, his presentation was thought to be due to small vessel CNS vasculitis from disseminated histoplasmosis. 2. Discussion Histoplasma capsulatum is a dimorphic fungus that causes a range of clinical manifestations based on degree of exposure, immunologic status of host, and the virulence of infecting strain [1]. H. capsulatum can in-
http://dx.doi.org/10.1016/j.jns.2015.03.037 0022-510X/© 2015 Elsevier B.V. All rights reserved.
fect the CNS by hematogenous route as an isolated event or as part of disseminated infection [2]. Symptoms of disseminated infection include fever and weight loss as well as hepatomegaly and/or splenomegaly. Severe cases can be complicated by shock, respiratory distress, and hepatic or renal failure [1,3]. Histoplasmosis of the CNS occurs in 10–20% of cases of disseminated infection and may be difficult to diagnose as no typical clinical picture exists [1]. Chronic meningitis involving the basilar meninges is the most common manifestation, with other presentations including acute meningitis, encephalitis, small ringenhancing lesions, large brain abscesses, and stroke due to infected emboli [1,4]. While septic emboli have been described as an etiology of stroke in patients with disseminated histoplasmosis, review articles on CNS histoplasmosis do not mention vasculitis as a potential cause of acute ischemic infarct. In fact, our literature search at the time of this case revealed only four case reports, describing three unique patients, which suggested vasculitis as the cause of ischemic stroke in the setting of histoplasmosis [2,4–6]. The first case involved a patient presenting with meningitis and cranial nerve palsies who was found to have white matter and basal ganglia hypodensities on CT scan as well as enhancement of the basal meninges on MRI [2]. The hypodensities were presumed to be infarcts in the setting of small vessel occlusion from a basilar inflammatory process. The patient underwent temporal lobe biopsy that revealed H. capsulatum. Treatment with amphotericin B was started, but the patient decompensated. Post-mortem, an autopsy revealed an inflammatory infiltrate around the large blood vessels of the pons, indicative of vasculitis. The second case involved a patient presenting with worsening dysarthria and confusion after initial presentation with dysarthria, ataxia, and upper extremity weakness [4,5]. MRI revealed bilateral pontine infarcts, thought to be due to small vessel vasculitis (though angiographic imaging was not performed). The patient initially had no systemic symptoms, but later developed fevers and signs of meningitis. Lumbar puncture was performed and CSF returned positive for H. capsulatum. The patient was started on amphotericin b and then transitioned to oral voriconizole. The third case identified a patient initially treated for tuberculosis due to noncaseating granulomas found on biopsy of the GI tract after presentation with fevers and gastrointestinal symptoms [6]. Ten months after his original presentation he was readmitted for fevers and altered mental status. He was found to have areas of infarct in the bilateral basal ganglia and left white matter on imaging scans. He underwent cerebral angiogram that showed multiple areas of vessel narrowing including A1 segment of ACA and M1 segment of the MCA. He was given the diagnosis of CNS vasculitis, but again had decline after treatment. At that time, lumbar puncture was done and ELISA for Histoplasma polysaccharide antigen was positive, resulting in a diagnosis of disseminated histoplasmosis. He was treated with amphotericin b followed by oral fluconazole. Our case is unique to the cases described above due to the vasculitis involving the small vessels and the lack of clinical meningitis. Our
126
Letter to the Editor
A
B
Fig. 1. A.) Diffusion weighted axial MRI images showing punctate areas of restricted diffusion. B.) Digital subtraction angiogram of the left anterior circulation showing small vessel vasculitic changes (caliber changes and irregularity) of the distal left anterior and middle cerebral arteries.
patient's infarcts were due to vasculitis of the very distal cerebral arteries supported by the cortical location of infarcts as well as the appearance of distal small vessel vasculitic changes on angiogram. In contrast, the previous patients described all suffered infarcts in the basal ganglia, brainstem, and subcortical white matter. In addition, our patient did not have clinical signs of meningitis or decrease in mental status which was present in all the previous cases. It could be considered that the previous patients suffered infarcts due to local basilar meningitis causing inflammation of the medium sized arteries near the circle of Willis, whereas our patient suffered infarcts due to diffuse infection resulting in small vessel vasculitis. References [1] Trofa D, Nosanchuk J. Histoplasmosis of the central nervous system. J Neuroparasitol Aug 2012;3:1–7. [2] Zalduondo FM, Provenzale JM, Hulette C, Gorecki JP. Meningitis, vasculitis, and cerebritis caused by CNS histoplasmosis: radiologic–pathologic correlation. AJR 1996;166:194–6. [3] Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30: 688–95.
[4] Ramireddy S, Wanger A, Ostrosky L. An instructive case of CNS histoplasmosis in an immunocompetent host. Med Mycol Case Rep 2012;1:69–71. [5] Nguyen FN, Kar JK, Zakaria A, Schiess M. Isolated central nervous system histoplasmosis presenting with ischemic pontine stroke and meningitis in an immune-competent patient. JAMA Neurol 2013;70(5):638–41. [6] Stone JH, Pomper MG, Hellman DB. Histoplasmosis mimicking vasculitis of the central nervous system. J Rheumatol 1998;25:1644–8.
Robert D. Bolen⁎ Cheryl D. Bushnell Patrick S. Reynolds Department of Neurology Wake Forest Baptist Hospital, Winston-Salem NC 27157, United States ⁎Corresponding author at: Wake Forest Baptist Hospital, Medical Center Boulevard, Winston Salem, NC 27157, United States. Tel.: +1 336 716 4101; fax: +1 336 716 2810. E-mail address: [email protected] (R.D. Bolen). 18 February 2015
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Acute ischemic strokes from small vessel vasculitis due to disseminated histoplasmosis infection Keywords: Small vessel vasculitis Disseminated histoplasmosis Ischemic infarcts
1. Case presentation A 61 year old previously healthy male with recent diagnosis of disseminated histoplasmosis presented due to transient right hand numbness and word finding difficulties. Neurologic exam was normal on our evaluation. The patient had presented 6 weeks prior with night sweats, weight loss, and fever and was eventually diagnosed with disseminated histoplasmosis. Work-up that led to the diagnosis included CT chest showing pulmonary nodules and lymphadenopathy, as well as blood cultures and bone marrow biopsy both positive for Histoplasma capsulatum. The patient was also found to have thrombocytopenia, leukopenia, and signs of adrenal insufficiency. He was initially treated with amphotericin b and then transitioned to oral itraconazole. He had no history of AIDS or immunodeficiency but did have exposure to black mold in his home prior to onset of constitutional symptoms. Work-up for the patient's neurologic symptoms included an MRI of the brain that revealed multiple punctate areas of acute and sub-acute ischemia in the bilateral cerebral and cerebellar hemispheres mostly cortical in location (Fig. 1 A). Further work-up included a TTE that showed a normal ejection fraction with no right-to-left shunt, carotid ultrasounds that showed no significant stenotic flow, and laboratory evaluation showing LDL of 28 and HgbA1c of 5.0. Given the appearance of infarcts on MRI, a central embolic source was considered, but telemetry revealed no atrial fibrillation after 72 h of monitoring and TEE revealed no left atrial thrombus or valvular abnormalities. A catheter angiogram was performed for further work-up and results showed small vessel vasculitis in the distal left anterior cerebral and middle cerebral arteries (Fig. 1 B). Very mild vasculitic changes were seen in the other vascular distributions. Given the patient's symptoms (right hand numbness and presumed expressive aphasia), MRI findings (multiple areas of punctate infarcts), and angiographic evidence of left anterior circulation vasculitis, his presentation was thought to be due to small vessel CNS vasculitis from disseminated histoplasmosis. 2. Discussion Histoplasma capsulatum is a dimorphic fungus that causes a range of clinical manifestations based on degree of exposure, immunologic status of host, and the virulence of infecting strain [1]. H. capsulatum can in-
http://dx.doi.org/10.1016/j.jns.2015.03.037 0022-510X/© 2015 Elsevier B.V. All rights reserved.
fect the CNS by hematogenous route as an isolated event or as part of disseminated infection [2]. Symptoms of disseminated infection include fever and weight loss as well as hepatomegaly and/or splenomegaly. Severe cases can be complicated by shock, respiratory distress, and hepatic or renal failure [1,3]. Histoplasmosis of the CNS occurs in 10–20% of cases of disseminated infection and may be difficult to diagnose as no typical clinical picture exists [1]. Chronic meningitis involving the basilar meninges is the most common manifestation, with other presentations including acute meningitis, encephalitis, small ringenhancing lesions, large brain abscesses, and stroke due to infected emboli [1,4]. While septic emboli have been described as an etiology of stroke in patients with disseminated histoplasmosis, review articles on CNS histoplasmosis do not mention vasculitis as a potential cause of acute ischemic infarct. In fact, our literature search at the time of this case revealed only four case reports, describing three unique patients, which suggested vasculitis as the cause of ischemic stroke in the setting of histoplasmosis [2,4–6]. The first case involved a patient presenting with meningitis and cranial nerve palsies who was found to have white matter and basal ganglia hypodensities on CT scan as well as enhancement of the basal meninges on MRI [2]. The hypodensities were presumed to be infarcts in the setting of small vessel occlusion from a basilar inflammatory process. The patient underwent temporal lobe biopsy that revealed H. capsulatum. Treatment with amphotericin B was started, but the patient decompensated. Post-mortem, an autopsy revealed an inflammatory infiltrate around the large blood vessels of the pons, indicative of vasculitis. The second case involved a patient presenting with worsening dysarthria and confusion after initial presentation with dysarthria, ataxia, and upper extremity weakness [4,5]. MRI revealed bilateral pontine infarcts, thought to be due to small vessel vasculitis (though angiographic imaging was not performed). The patient initially had no systemic symptoms, but later developed fevers and signs of meningitis. Lumbar puncture was performed and CSF returned positive for H. capsulatum. The patient was started on amphotericin b and then transitioned to oral voriconizole. The third case identified a patient initially treated for tuberculosis due to noncaseating granulomas found on biopsy of the GI tract after presentation with fevers and gastrointestinal symptoms [6]. Ten months after his original presentation he was readmitted for fevers and altered mental status. He was found to have areas of infarct in the bilateral basal ganglia and left white matter on imaging scans. He underwent cerebral angiogram that showed multiple areas of vessel narrowing including A1 segment of ACA and M1 segment of the MCA. He was given the diagnosis of CNS vasculitis, but again had decline after treatment. At that time, lumbar puncture was done and ELISA for Histoplasma polysaccharide antigen was positive, resulting in a diagnosis of disseminated histoplasmosis. He was treated with amphotericin b followed by oral fluconazole. Our case is unique to the cases described above due to the vasculitis involving the small vessels and the lack of clinical meningitis. Our
126
Letter to the Editor
A
B
Fig. 1. A.) Diffusion weighted axial MRI images showing punctate areas of restricted diffusion. B.) Digital subtraction angiogram of the left anterior circulation showing small vessel vasculitic changes (caliber changes and irregularity) of the distal left anterior and middle cerebral arteries.
patient's infarcts were due to vasculitis of the very distal cerebral arteries supported by the cortical location of infarcts as well as the appearance of distal small vessel vasculitic changes on angiogram. In contrast, the previous patients described all suffered infarcts in the basal ganglia, brainstem, and subcortical white matter. In addition, our patient did not have clinical signs of meningitis or decrease in mental status which was present in all the previous cases. It could be considered that the previous patients suffered infarcts due to local basilar meningitis causing inflammation of the medium sized arteries near the circle of Willis, whereas our patient suffered infarcts due to diffuse infection resulting in small vessel vasculitis. References [1] Trofa D, Nosanchuk J. Histoplasmosis of the central nervous system. J Neuroparasitol Aug 2012;3:1–7. [2] Zalduondo FM, Provenzale JM, Hulette C, Gorecki JP. Meningitis, vasculitis, and cerebritis caused by CNS histoplasmosis: radiologic–pathologic correlation. AJR 1996;166:194–6. [3] Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30: 688–95.
[4] Ramireddy S, Wanger A, Ostrosky L. An instructive case of CNS histoplasmosis in an immunocompetent host. Med Mycol Case Rep 2012;1:69–71. [5] Nguyen FN, Kar JK, Zakaria A, Schiess M. Isolated central nervous system histoplasmosis presenting with ischemic pontine stroke and meningitis in an immune-competent patient. JAMA Neurol 2013;70(5):638–41. [6] Stone JH, Pomper MG, Hellman DB. Histoplasmosis mimicking vasculitis of the central nervous system. J Rheumatol 1998;25:1644–8.
Robert D. Bolen⁎ Cheryl D. Bushnell Patrick S. Reynolds Department of Neurology Wake Forest Baptist Hospital, Winston-Salem NC 27157, United States ⁎Corresponding author at: Wake Forest Baptist Hospital, Medical Center Boulevard, Winston Salem, NC 27157, United States. Tel.: +1 336 716 4101; fax: +1 336 716 2810. E-mail address: [email protected] (R.D. Bolen). 18 February 2015
