Published Ahead of Print on August 4, 2020 as 10.1212/WNL.0000000000010475 Bose 1 TE D Neurology Publish Ahead of Print DOI: 10.1212/WNL.0000000000010475 Clinical Reasoning: A 73-year-old man with recurrent aphasia, headaches and confusion Authors: Gauruv Bose, MD1, Tess Fitzpatrick, MD1, Vignan Yogendrakumar, MD1, C EP Jocelyn Christine Zwicker, MD1, Gerard Jansen, MD 2 1. Division of Neurology, The Ottawa Hospital, University of Ottawa, Ottawa, Canada 2. Division of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Canada A C Corresponding author: Gauruv Bose MD (gbose@toh.ca) Neurology® Published Ahead of Print articles have been peer reviewed and accepted for publication. This manuscript will be published in its final form after copyediting, page composition, and review of proofs. Errors that could affect the content may be corrected during these processes. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 2 Word count: 1486 Title Character Count: 85 Reference Count: 9 TE D Figures: 2 Search Terms: Stroke, All Clinical Neurology, All Headache, Vasculitis, Fungal Infections Study funding: Disclosures: C EP No targeted funding reported. A C The authors report no disclosures relevant to the manuscript Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 3 Section 1. A 73-year-old man presented with sudden right-sided weakness, aphasia, and low-grade headache. Medical history was pertinent for obstructive sleep apnea, hypertension, diabetes, and dyslipidemia, for which he was appropriately treated, in addition to taking D aspirin for primary prevention. Initial blood work, head CT, and vessel imaging were normal. Magnetic resonance imaging (MRI) showed a non-enhancing, non-restricting, T2 TE hyperintensity in the left temporal lobe, in addition to multiple microhemorrhages (Fig.1a-b). Symptoms resolved within 24 hours and he was discharged on a second antiplatelet agent, clopidogrel. Three weeks later, a second episode of aphasia and rightsided weakness occurred, resolving within hours. He returned to hospital the following C EP day as symptoms recurred again. He had had been continually complaining of headaches, and his family had noted a gradual cognitive decline over the past month. Repeat blood work and ESR was normal. MRI demonstrated persistent microhemorrhages and superficial siderosis, worsening of the left temporal lobe subcortical changes, as well as C diffuse leptomeningeal enhancement. Questions for consideration: A 1. What is the differential diagnosis for recurrent neurologic symptoms? 2. What investigations ought to be considered given this differential and MRI findings? Section 2. The differential included transient ischemic attack, although lack of diffusion restriction on MRI and stereotyped events despite normal vessel imaging made this less likely. An Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 4 echocardiogram and 72-hour Holter monitor were done and also normal. Recurrent events are typical of focal seizures, and given the increasing temporal lobe hyperintensity, a low-grade glioma was a potential cause and levetiracetam was initiated. A routine 1-hour electroencephalogram (EEG) was performed and did not capture any D clinical events or epileptic abnormalities; however, the medication was continued. The patient’s age, headaches, and focal neurologic symptoms prompted investigation for TE giant-cell arteritis, though erythrocyte sedimentation rate were normal. The leptomeningeal enhancement was investigated with cerebrospinal fluid (CSF) analysis, which showed marked elevation in protein at 1.87g/L; however, there were zero C EP total nucleated or red blood cells/microlitre, the gram stain was negative, normal CSF glucose, no detected oligoclonal bands were detected, and flow cytometry and cytology testing were negative for malignancy. No opening pressure was obtained. Given the absence of total nucleated cells, and lack of fever, herpes simplex virus was not sent despite the temporal lobe abnormality on MRI. The elevated protein was suggestive of an C inflammatory etiology, yet vessel imaging did no show changes suspected for primary angiitis of the CNS (PACNS), and a CT chest was performed that did not show hilar A lymphadenopathy that can be seen in sarcoidosis. Despite a negative CSF cytology and flow cytometry, lymphoma was still a potential differential and a CT abdomen and pelvis was performed without abnormality. The clinical course of recurrent neurologic symptoms, headache, and cognitive decline, presence of multiple microhemorrhages with superficial siderosis and leptomeningeal Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 5 enhancement, and inflammatory CSF analysis was suggestive of amyloid-beta related angiitis (ABRA). Questions for consideration: TE 2. What is the definition and treatment of ABRA? D 1. What further investigations would assist in the diagnostic clarification for this patient? Section 3. Treatment for the presumed diagnosis of ABRA was initiated with a 5-day course of intravenous methylprednisolone 1000mg daily followed by oral prednisone 50mg per C EP day, and clopidogrel was discontinued. Brain biopsy and cyclophosphamide were recommended, however the headaches, neurologic examination and leptomeningeal enhancement improved. Consequently, the patient and his family deferred brain biopsy with sampling of parenchyma and meninges, the gold standard test for ABRA. The patient’s cognitive testing initially improved from a Montreal Cognitive Assessment C (MoCA) of 20/30 to 24/30 after one month of therapy, however he remained fatigued, attributed to steroid use and weaned to 40mg daily one month post-discharge. Two A months post-discharge, methotrexate was added to prednisone to reduce risk of ABRA recurrence. Despite these adjustments, the patient’s fatigue worsened and his cognition progressively declined. Six months post-discharge, the confusion had progressed, headaches worsened, and the patient developed gait difficulty prompting return to hospital. Blood work including Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 6 absolute neutrophil count, thyroid, liver and renal function, serum inflammatory markers including ESR, antinuclear antibody (ANA), and antineutrophil cytoplasmic antibody (ANCA) were normal. An infectious work-up for HIV, syphilis, and Lyme borreliosis was negative. Repeat CSF analysis yielded protein elevation at D 1.06g/L, slightly less than previous, and again zero total nucleated cells or red blood cells were detected, cytology was negative, CSF glucose was normal, and gram stain, fungal TE culture, and mycobacterium culture were negative, and again opening CSF pressure was not obtained. Creutzfeldt-Jakob disease testing with CSF 14-3-3, tau, and Endpoint Quaking-induced Conversion (EP-QuiC) assay were negative. Both serum and CSF paraneoplastic and autoimmune antibody panels were negative. Repeat CT chest, C EP abdomen, and pelvis were negative. MRI showed resolution of the previously observed left temporal hyperintensity, but development of a new left parietal infarct with petechial hemorrhages, as well as worsening leptomeningeal enhancement (Fig.1c). Questions for consideration: C 1. What could be the reason for the patient’s worsening? A 2. Are there any further tests that would be helpful in this patient’s case? Section 4. Due to concern for ABRA recurrence, a course of intravenous immunoglobulin G (IVIG) 2g/kg over 5 days followed by intravenous methylprednisolone 1000mg daily for 5 days was delivered. Brain biopsy and cyclophosphamide were again recommended; however, as the patient’s cognitive status and expected quality of life were guarded, after Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 7 discussion with the family no further diagnostic investigations or treatments were pursued. The patient passed away and subsequent autopsy was performed. Neuropathological examination revealed significantly thickened arachnoid and a D 4x2.5x3.5cm subacute left parietal infarct. At microscopy throughout the cerebral hemispheres amyloid beta accumulation was found within intracortical and arachnoidal TE artery and arteriole walls, at times fragmented (Fig.2a), and focally surrounded by mononuclear inflammatory cells. Focal hemosiderin was noted in the arachnoid. In addition to this first process the arachnoid was filled with granulomas (Fig.2b) with halosurrounded budding organisms in keeping with Cryptococcus sp. yeast (Fig.2c). The EP arachnoid near to the infarct was especially involved, and the arteries showed obliterating endarteritis, likely causing the infarct. C C Questions for consideration: 1. What are the risk factors for developing cryptococcal meningoencephalitis? 2. What is the diagnostic yield of CSF culture for Cryptococcus sp. yeast and what is the most specific and sensitive test? A 3. What is the treatment for cryptococcal meningoencephalitis? What is the prognosis? Discussion Cryptococcus neoformans is a yeast responsible for 30–66 infections in the United States annually and is the most common fungal infection of the CNS world-wide (CNS).(1) In HIV patients with CD4 count less than 100 cells/microlitre in the United States, incidence Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 8 of cryptococcal meningoencephalitis may be as high as 3%.(2) In HIV-negative patients who are immunocompromised, as in our patient, there may not be signs of raised intracranial pressure (ICP) or disseminated fungicemia. CSF analysis may show increased opening pressure, elevated total nucleated cell counts of 20 to 200 ED cells/microlitre of predominantly monocytes, and hypoglycorrhachia, which was not the case in our patient, although elevated CSF protein is also reported.(3) Gram stain is typically normal with Cryptococcus neoformans due to resemblance to host lymphocytes, and fungal culture is often normal. However, cryptococcal antigen in CSF can be EP T detected quickly with either latex agglutination test assays or enzyme-linked immunoassays that both yield sensitivities and specificities over 90%, and has been reported to be present 3 weeks prior to neurologic symptoms.(4) Treatment of cryptococcal meningoencephalitis requires antifungals, control of raised ICP, and reducing immune suppression. Induction with intravenous amphotericin B plus oral C flucytosine for at least six weeks in patients with neurologic involvement, followed by oral fluconazole for an additional eight weeks is recommended.(5) The prognosis is C dependent on underlying comorbidity and cryptococcal antigen titres, but even with A prompt adequate treatment, mortality may be 10-30%.(6) Patients may have non-specific symptoms, such as headaches, cognitive changes, and ataxia, with either cryptococcal meningoencephalitis or ABRA. Furthermore, CSF analysis in ABRA can also show increased opening pressure, elevated protein and total nucleated cells. MRI may not differentiate ABRA from cryptococcal meningoencephalitis, as both may show leptomeningeal enhancement, cerebral atrophy Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 9 or hydrocephalus, and occasionally cerebral infarcts, as in our patient.(7) Clinical and radiographic findings can have high likelihood of detecting ABRA, however require absence of neoplastic, infectious or other cause.(8) Thus, biopsy of brain parenchyma or meninges with examination of vasculature is needed for definitive diagnosis. Tissue TE D biopsy in ABRA will show amyloid beta accumulation within the regions of vasculitic vessel wall destruction, as was seen in our patient on autopsy, and differentiates from PACNS, sarcoidosis, or intravascular lymphoma. Initiation of immune suppressive medication improves outcomes in ABRA, as seen initially for our patient’s clinical symptoms, cognitive testing, reduced CSF protein, and resolution of the left temporal lobe lesion.(9) Although, the subsequent immunocompromised state can leave a patient C EP susceptible to opportunistic infections, which may have been the sequence of events resulting in cryptococcal meningoencephalitis in our patient. A high index of suspicion for cryptococcal meningoencephalitis in patients on immune suppression with nonspecific symptoms, and testing CSF cryptococcal antigen, is A C important as this is a potentially treatable entity with high mortality. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 10 Appendix 1: Authors Location Contribution Gauruv Bose, The Ottawa Hospital, Collected and synthesized the data; MD University of Ottawa drafted the manuscript for intellectual TE D Name content. Tess Fitzpatrick, The Ottawa Hospital, Collected and synthesized the data; MD University of Ottawa drafted the manuscript for intellectual content. The Ottawa Hospital, Yogendrakumar, University of Ottawa content. The Ottawa Hospital, Revised the manuscript for intellectual MD A C C Jocelyn C. Revised the manuscript for intellectual EP Vignan Zwicker, MD University of Ottawa content. Gerard H. The Ottawa Hospital, Collected and synthesized the data; Jansen, MD University of Ottawa drafted the manuscript for intellectual content. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 11 References: 1. Góralska K, Blaszkowska J, Dzikowiec M. Neuroinfections caused by fungi. Infection. 2018;46:443–459. 2. McKenney J, Bauman S, Neary B, et al. Prevalence, Correlates, and Outcomes of 2012. Clin Infect Dis. 2015;60:959–965. 3. Pappas PG. Cryptococcal infections in non-HIV-infected patients. Trans Am Clin Climatol Assoc. 2013;124:61–79. 4. TE D Cryptococcal Antigen Positivity Among Patients With AIDS, United States, 1986– Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin 5. C EP Microbiol. 1994;32:1680–1684. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of Cryptococcal Meningitis with Combination Amphotericin B and Flucytosine for Four as Compared with Six Weeks. N Engl J Med. 1987;317:334–341. 6. Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in Human C Immunodeficiency Virus–Negative Patients in the Era of Effective Azole Therapy. Clin Infect Dis. 2001;33:690–699. Salvarani C, Morris JM, Giannini C, Brown RD, Christianson T, Hunder GG. A 7. Imaging Findings of Cerebral Amyloid Angiopathy, Aβ-Related Angiitis (ABRA), and Cerebral Amyloid Angiopathy–Related Inflammation. Medicine. 2016;95:e3613. 8. Auriel E, Charidimou A, Gurol ME, et al. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 12 JAMA Neurol. 2016;73:197. 9. Corovic A, Kelly S, Markus HS. Cerebral amyloid angiopathy associated with inflammation: A systematic review of clinical and imaging features and outcome. A C C EP TE D Int J Stroke. 2018;13:257–267. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 13 Figure Legends Figure 1. Magnetic resonance imaging characteristic of amyloid beta-related angiitis (A) T2 fluid attenuated inversion recovery image showing left temporal lobe TE D hyperintensity (arrow). (B) Susceptibility weighted images showing microhemorrhages and superficial siderosis (arrows). (C) Six-month gadolinium-enhanced T2 fluid A C C EP attenuated inversion recovery showing leptomeningeal enhancement (arrows). Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Bose 14 Figure 2. Microscopical examination post-mortem demonstrating findings of amyloid beta-related angiitis and cryptococcal meningoencephalitis (A) Amyloid beta antibody staining showing amyloid beta accumulation within cortical TE D arterioles, occasionally with irregular interruptions due to previous amyloid phagocytosis. (B) Granulomatous inflammation of arachnoid (hematoxylin and eosin). (C) Arachnoid with mucin carmine showing Cryptococcus species organisms. Size bar indicates 100 A C C EP µm. Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Clinical Reasoning: A 73-year-old man with recurrent aphasia, headaches and confusion Gauruv Bose, Tess Fitzpatrick, Vignan Yogendrakumar, et al. Neurology published online August 4, 2020 DOI 10.1212/WNL.0000000000010475 This information is current as of August 4, 2020 Updated Information & Services including high resolution figures, can be found at: http://n.neurology.org/content/early/2020/08/04/WNL.0000000000010 475.citation.full Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Cerebrovascular disease/Stroke http://n.neurology.org/cgi/collection/all_cerebrovascular_disease_strok e All Clinical Neurology http://n.neurology.org/cgi/collection/all_clinical_neurology All Headache http://n.neurology.org/cgi/collection/all_headache Fungal infections http://n.neurology.org/cgi/collection/fungal_infections Vasculitis http://n.neurology.org/cgi/collection/vasculitis Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/about/about_the_journal#permissions Reprints Information about ordering reprints can be found online: http://n.neurology.org/subscribers/advertise Neurology ® is the official journal of the American Academy of Neurology. 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