UC San Diego UC San Diego Previously Published Works Title Central Nervous System Systemic Lupus Erythematosus (CNS-SLE) Vasculitis Mimicking Lewy Body Dementia: A Case Report Emphasizing the Role of Imaging With an Analysis of 33 Comparable Cases From the Scientific Literature Permalink https://escholarship.org/uc/item/0940x42t Journal Journal of Geriatric Psychiatry and Neurology, 34(2) ISSN 0891-9887 Authors Abraham, Peter Neel, Ian Bishay, Steven et al. Publication Date 2021-03-01 DOI 10.1177/0891988720901788 Peer reviewed eScholarship.org Powered by the California Digital Library University of California For submission to the Journal of Geriatric Psychiatry and Neurology Word count: 7.987 CNS SLE Vasculitis Mimicking Lewy Body Dementia: A Case Report Emphasizing the Role of Imaging with an Analysis of 33 Comparable Cases from the Scientific Literature Peter Abraham, MAS University of California, San Diego San Diego, CA Ian Neel, MD University of California, San Diego San Diego, CA Steven Bishay, BS University of California, Riverside Riverside, CA Daniel D. Sewell, MD (corresponding author) University of California, San Diego 200 West Arbor Drive San Diego, CA 92103-8631 Phone: 619-543-2827 Fax: 619-543-3738 Email: dsewell@ucsd.edu CNS SLE Vasculitis, page 2 This work was completed at the University of California, San Diego in San Diego, CA. No research funding was received for the research reported in this article. The authors have no disclosures to report. A version of this care report was presented at the 2016 Annual Meeting of the American Geriatrics Society. ABSTRACT Introduction: Neuropsychiatric symptoms occur in 30 to 40% of patients living with systemic lupus erythematosus (SLE). Brain imaging may play a pivotal role in determining the etiology as it did for the case presented here. Methods: A new case of central nervous system SLE is presented along with an analysis of 33 comparable cases from the scientific literature. Results: A 70-year-old female with subacute cutaneous lupus presented to a university-based geropsychiatry program after one year of benign visual hallucinations and several months of shuffling gait, recurrent falls, and forgetfulness. These symptoms were highly suggestive of Lewy Body Dementia, however, the patient’s history of basal ganglia infarct, cognitive testing demonstrating inattention and executive dysfunction, and follow-up brain imaging, which did not reveal acute findings, aligned with cerebral pathology previously attributed to vasculitis and supported the diagnosis of subcortical dementia due to SLE CNS vasculitis. Oral prednisone 20 mg daily resolved her symptoms. Over the next 19 month her prednisone was tapered completely and her symptoms did not return. A systematic literature search identified 33 comparable cases. Conclusion: An analysis of previously published cases suggests that extending the duration of the prednisone taper beyond one year may decrease the risk of later occurring neuropsychiatric symptoms in this patient population. CNS SLE Vasculitis, page 3 Key Words: Case report; Lewy body dementia; lymphocytic angiitis; psychosis; systemic lupus erythematosus, vasculitis CNS SLE Vasculitis, page 4 Introduction Neuropsychiatric symptoms (NPS) occur in 30-40% of patients with systemic lupus erythematosus (SLE) with the majority of these symptoms (40-50%) occurring within the first two years following diagnosis. 1 NPS may be due to primary neurological or psychiatric diseases, systemic disease, secondary complications and/or adverse effects of treatment. 2 It is unclear to what degree NPS are directly attributable to SLE, with estimates ranging from 13-38%. 3 Neuropsychiatric SLE (NPSLE) presents overtly with events such as seizure, psychosis, polyneuropathy, and cerebrovascular disease. Symptoms of milder forms of NPS characterized by symptoms such as headache, anxiety or depressive symptoms, and minor cognitive dysfunction often remain unrecognized4 and usually cannot be attributed specifically to SLE, though they occur commonly in SLE patients. 1 Despite this, and as further discussed below, moderate to severe cognitive impairment in patients living with SLE is associated with antiphospholipid antibodies and is potentially due to multi-infarct dementia.5 Up to 3.5% of SLE patients will have psychosis due to recognized medical or physical disease and characterized by disordered/bizarre thinking, including delusions and hallucinations. 1, 2 While auditory hallucinations are often attributed to steroid therapy, visual and tactile hallucinations are thought to be due to SLE and are associated with antibodies to neuronal cells. 6 Cerebrovascular disease in SLE patients can contribute to NPS, including psychosis and cognitive dysfunction. Up to 10% of SLE patients will experience cerebrovascular disease. Though SLE patients can present with thromboembolic or CNS SLE Vasculitis, page 5 hemorrhagic symptoms, 80% of patients present with ischemic stroke/TIA.1 Antiphospholipid antibodies are associated with highly thrombotic states and can lead to multiple cerebral infarcts, causing recurrent stroke and multi-infarct dementia.7, 8 Cerebrovascular events have high morbidity and mortality, particularly when associated with ill-defined cerebrovascular events and rare nervous system disease, such as cerebral vasculitis, which is demonstrated in less than 10% of postmortem studies.9-11 One recent single-center study estimated that, compared to SLE patients without NPS, those with NPSLE had a three-times greater mortality and patients with CNS NPSLE, such as CNS vasculitis, had an almost eight-times greater mortality.12 Brain biopsy remains the gold standard in the diagnosis of CNS vasculitis, but neuroimaging in conjunction with appropriate clinical examination and laboratory testing to exclude other potential causes can spare patients the risks associated with biopsy. Magnetic resonance imaging (MRI) and angiography (MRA) are highly sensitive for changes to the cerebral vasculature. Findings such as thickened or enhancing endothelium in cerebral vascular walls, vascular stenosis, multiple ischemic infarctions distributed across different vascular territories are the most pathognomonic MRI findings of vasculitis. High-intensity white matter lesions that appear bright on T2 and fluid-attenuated inversion recovery (FLAIR) imaging, though extremely nonspecific, are also suggestive of vasculitis. 13 In the proper clinical context, these findings can be deemed sufficient to initiate treatment for vasculitis, without need for biopsy. 13 Psychosis and cognitive decline in SLE patients present diagnostic dilemmas. Differentiating psychosis due to steroid treatment from other medical or physical causes of psychosis requires a particularly thorough timeline of symptoms, CNS SLE Vasculitis, page 6 treatment doses, emergence of medication side effects, and changes on MRI. 14, 15 Similarly, understanding changes in cognitive function in SLE patients, especially in older adults, is challenging, as the frequency of cognitive dysfunction and cerebrovascular disease both increase with age, and subcortical vascular dementia can present with psychotic features.16-19 A thorough review of neurocognitive testing, especially when coupled with cerebrovascular MR imaging, can help identify medical causes of psychiatric symptoms in these patients. Methods We present here a case of new-onset psychosis and cognitive impairment, mimicking Lewy Body Dementia, in a 70-year-old female with CNS vasculitis coupled with an analysis of all similar cases identified through a systematic literature search. All the case reports in the English literature of human patients with CNS vasculitis mimicking psychiatric conditions obtained by search of the PubMed and MEDLINE databases were reviewed. Specifically, reports were searched using the MeSH terms: ("case reports"[Publication Type] OR "case report"[All Fields]) AND ("vasculitis, central nervous system"[MeSH Terms] OR ("vasculitis"[All Fields] AND "central"[All Fields] AND "nervous"[All Fields] AND "system"[All Fields]) OR "central nervous system vasculitis"[All Fields] OR ("central"[All Fields] AND "nervous"[All Fields] AND "system"[All Fields] AND "vasculitis"[All Fields])) AND ("psychiatry"[MeSH Terms] OR "psychiatry"[All Fields]) Articles previously acquired by the authors not identified from this search were also reviewed. Only case reports which met the following criteria were included: CNS SLE Vasculitis, page 7 (1) adult patient (>18 years) (2) patient experienced new-onset NPS, defined as chronic headache, cognitive impairment, neuropathic pain, changes in behavior or vision, or impairments in language production or construction (with or without impairments in gait, balance, or strength) (3) biopsy of a nerve or artery was consistent with vasculitis or, in cases where biopsy was not completed, imaging demonstrating thickened or enhancing endothelium in cerebral vascular walls, vascular stenosis, multiple ischemic infarctions distributed across different vascular territories, or high-intensity white matter lesions that appear bright on T2 and fluid-attenuated inversion recovery (FLAIR) imaging (4) Report that the patient improved with steroid treatment and/or other immunosuppressants Cases of transverse myelitis were excluded, as isolated spinal cord involvement is not expected to cause psychiatric symptoms. Further, this spinal cord disorder is estimated to affect 1-2% of lupus patients 20 and primary CNS angiitis is isolated to spinal cord in <1% of cases.21 Results Case Vignette A 70-year-old female with history of subacute cutaneous lupus (SCLE), hypertension, hyperlipidemia, and recurrent deep vein thromboses (DVTs) on warfarin who was brought to a university-based hospital emergency department by police officers for evaluation of dangerousness to herself and grave disability after she called the police to investigate intruders in her home. She was first diagnosed CNS SLE Vasculitis, page 8 with subacute cutaneous lupus (SCLE) in 2013, after development of an erythematous rash on her back, arms and face in 2012. The rash did not abate despite trial of trials of drug cessations and, hence, she was referred to dermatology for further evaluation. A biopsy in 2013 confirmed her diagnosis of SCLE. Her rash resolved with oral prednisone and topical clobetasol. Her rheumatologic laboratory findings at the time of her diagnosis are listed in Table 1. The police officers reported that when they arrived at the patient’s home, the patient was found alone, though she adamantly pointed towards a location in the room where she believed two intruders stood. Rotten food, massive piles of trash, and insects were found throughout her home and she while with the police she denied all forms of psychosis including visual hallucinations. During a review of symptoms conducted in the ED, she reported a one-year history of visual hallucinations and a few-month history of shuffling gait, recurrent falls, and forgetfulness. CT of the head on admission demonstrated no acute intracranial processes, though stable chronic sequelae of a previous right thalamic infarct were present. Her neurological examination revealed deficits in short-term memory, though her long-term memory was intact. Her motor exam was without significant tremor, rigidity, postural instability, masked face or bradykinesia. Her Montreal Cognitive Assessment (MoCA)22 score of 19/30 prompted neuropsychological testing, which yielded a Mattis Dementia Rating Scale-2 Score 23 of 133/144 (lowaverage range), with pronounced deficits in construction and low-average performance with executive function, though recall was intact with prompts. Apathy and left visual field inattention affected her score on several tasks. She had no CNS SLE Vasculitis, page 9 evidence of cutaneous involvement of lupus at her time of presentation nor other signs of active lupus. Medical History: Previous Imaging and Biopsy Suggesting CNS Vasculitis A review of the patient’s medical history demonstrated a previous diagnosis of CNS vasculitis (lymphocytic angiitis). During an admission one year previously, the patient experienced left-sided neglect, which led to motor vehicle accidents. This prompted a brain MRI, demonstrating irregularity/beading of her right Middle Cerebral Artery (Figure 1, left panel, white arrow). MR angiography at that time revealed that the distal branches of her right Middle Cerebral Artery appeared smaller in number and caliber compared to the contralateral side (Figure 1, right panel, red arrow). One month after the MRI and angiography, the patient developed left facial droop, left tongue deviation, and left hemiparesis. An MRI at this time demonstrated a right thalamic infarct and a brain biopsy demonstrated angiocentric and angioinfiltrative lymphocytes with macrophages and reactive gliosis. She was treated with rituximab and prednisone (20 mg daily) and demonstrated improvement in her neurologic deficits. She had not received treatment with anti-malarial agents as she declined an offer of hydroxychloroquine by rheumatology. Prednisone was tapered from 20 mg to 10 mg daily at her follow-up appointment three weeks later. The patient experienced worsening left-sided weakness over two weeks at 10 mg daily, so her dose was returned to 20 mg daily, and her deficits once again resolved. Subsequently, a slow prednisone taper, from 20 mg to 10 mg over three months, demonstrated no worsening of symptoms. CNS SLE Vasculitis, page 10 Follow-up Imaging During the evaluation of her visual hallucinations, shuffling gait, recurrent falls, and forgetfulness, another brain MRI was obtained in order to explore whether an acute vasculitic flare had caused the patient’s hallucinations, motor abnormalities and cognitive deficits. Although the contrast agent gadolinium improves the detection of inflammatory white matter lesions,24 for unknown reasons it was not used for the patient’s follow-up brain MRI. Nonetheless, this scan showed no evidence of vessel cutoff, focal vessel narrowing, beading, or aneurysms, though the right MCA changes were still present (Figure 2, blue arrow). Thus, no evidence for active or progressive vasculitis was seen on MRI. Management The patient’s lack of acute findings on her follow-up MRI, history of basal ganglia infarct, and neuropsychological testing demonstrating inattention and frontal (executive) dysfunction made subcortical dementia due to SLE CNS vasculitis a possible explanation for her symptoms. Rheumatology was consulted at the time of admission, reviewed her neuroimaging described above, and expressed concern that an alternate explanation to her SLE may be contributing based on lack of evidence of active or progressive vasculitis on imaging as well as her lack of signs of active disease on exam. They recommended a neurology consultation, which also was obtained. Neurology felt that her previously documented cerebral pathology and lack of Parkinsonism on neurological examination made Lewy Body dementia less likely, and felt that her cognitive changes most likely reflected her CNS vasculitis, based on her history of response to prednisone and rituximab in the past. Despite her history of recurrent deep vein thrombosis, she did not have CNS SLE Vasculitis, page 11 evidence of multiple infarcts on neuroimaging to raise concern for a vascular dementia. Due to the only symptom or sign of disease being neuropsychiatric symptoms, with no evidence of imaging or exam findings to correspond with a more active flare of SLE, rheumatology recommended against re-trial of rituximab, and instead recommended an increase in prednisone from 10 mg daily to the previously effective dose of 20 mg daily. Additionally, she was maintained on risperidone 0.5 mg PO BID PRN for agitation which she required only infrequently, escitalopram 20 mg PO daily for depression and trazadone 50 mg PO nightly for insomnia. Her neuropsychiatric symptoms resolved with these medication adjustments. After discharge from the geropsychiatry unit, she returned to her outpatient rheumatology clinic for ongoing oversight of her prednisone taper. Understanding that the 20-mg dose proved effective prior to and during her recent previous admission, the rheumatology consultant recommended a slow taper of 2.5 mg every 4 weeks, with careful attention to hallucinations. Six months post-discharge, the patient was tapered to a dose of 10 mg daily. Symptoms of adrenal insufficiency, in conjunction with a lack of hallucinations, led to continued tapering, until she was no longer taking prednisone about 19 months after her discharge from the geropsychiatry unit and her symptoms of hallucinations never returned. A repeat MRI and angiography demonstrated the expected interval evolution of her prior imaging findings without worsening. Summary of Previously Published Case Reports of CNS Vasculitis Findings CNS SLE Vasculitis, page 12 Table 2 lists all of the cases which met the study criteria. In addition to age, whenever reported, gender, past medical and psychiatric history, presenting symptoms, and medications at presentation, are detailed. Duration of vasculitis, treatment of vasculitis, laboratory and imaging findings, biopsy findings, and recurrence of vasculitis are also summarized. Table 3 provides a summary of the available data including age at presentation, gender, and duration of symptoms. The frequency of the most common psychotic features is also provided. Patients from the 33 case reports reviewed demonstrated a mean age of 52.85 years (range 18 – 90 years). Seventeen of the patients were male (51.51%), while 16 were female (48.48%). Symptoms lasted an average of 5.39 months (range 0.2524 months). The most common presenting symptoms included speech impairment (aphasia, paraphasia, dysarthria, apraxia, or incoherent or abnormal speech, in 12 cases) and chronic headaches (eight cases). No patients demonstrated concomitant headaches and speech impediments. Vision deficits (simultanagnosia, loss of vision, or blurred vision) were reported in seven cases. Coordination difficulties (disorientation, clumsiness, dizziness, vertigo, and ataxia) were reported in 13 cases, though separating these symptoms from concomitantly reported symptoms such as hemiparesis, hemiplegia, paralysis, arm weakness proved difficult. Only five cases reported psychotic symptoms: auditory and visual hallucinations were present in one case each, erratic thinking was present in one case, and delusions were present in two cases. Six cases reported cognitive deficits, with two patients demonstrating symptoms of dementia. Cognitive testing was not commonly performed, though Mini Mental State CNS SLE Vasculitis, page 13 Examination was performed in two reports: one patient demonstrated a score of 3/30, which improved to 14/30 after oral prednisolone for 12 days, while another scored 24/30. Pre-existing medical or neurological conditions were included in 25 reports. Perhaps unsurprisingly, in seven patients, a history of hypertension was reported (four of these patients had giant cell arteritis (GCA) ischemic events). A history of SLE was present in six patients. Only five cases provided previous psychiatric history, with four patients suffering from depression. Eleven cases included information about antibody test results and ten of these cases specifically reported on antiphospholipid antibody (APLS ab) test results. In these ten cases, the APLS ab was reported as normal (4) and negative (6). In the remaining case the report stated “antibodies were absent.” Imaging commonly demonstrated findings consistent with ischemia: CT and/or MR imaging demonstrated ischemic lesions in 30 of 33 patients, and subsequent angiography demonstrated an area of focal narrowing in nine cases. Most patients (31 of 33) received therapy targeted towards their underlying vasculitis. All therapies administered consisted of high dose steroids. Though the steroid agent was not always explicitly stated, reported treatments typically included methylprednisolone. Initial treatment doses varied by report, with the highest initial dose of 1 g per day over 5 days. Discharge dosing varied from 2.5 mg to 1 g per day, with subsequent taper. Cyclophosphamide was given alongside steroid treatment in 12 cases and given as monotherapy in two cases, with IV doses CNS SLE Vasculitis, page 14 ranging from a single pulse of 500 mg/m2 to pulses of 2 g per month for six months and oral doses ranging from 100-150 mg per day. Despite therapeutic steroid ranges, six patients either succumbed to their symptoms or experienced a recurrence of symptoms. Discussion Concomitantly occurring new cognitive impairment and psychotic features in SLE patients present a diagnostic dilemma, particularly in aging patients with vascular risk factors who are on maintenance steroid therapy. In this patient’s case, the differential diagnosis included an acute vasculitic episode, subcortical dementia due to chronic vascular inflammation, steroid psychosis due to supra-therapeutic dosing, and underlying primary psychosis as potential causes for her neurocognitive changes. Understanding the temporal relationship between symptoms, treatment doses, side effects, and changes in her findings on serially obtained MRI helped elucidate the underlying cause. Our review of literature of patients with CNS vasculitis mimicking psychiatric conditions demonstrated several important considerations for clinicians treating such patients. First, the most common psychotic symptoms found in our review of CNS vasculitis patients were delusions, followed by auditory/visual hallucinations and erratic thinking, though these were uncommon (3-6%). The low rate of hallucinations and delusions in these patients emphasizes the need for careful mental status examination during neuropsychiatric assessment to sense minor changes in mentation over time, as hallucinations and delusions are typically not present to help with diagnosis. A recent case series by Rodrigues et al. emphasized CNS SLE Vasculitis, page 15 the variety of presentations of CNS vasculitis in SLE patients. Their case series presented four patients with hypertension and/or dyslipidemia who went on to develop CNS vasculitis. Only one patient demonstrated cognitive deficits, including a language deficit (an inability to combine verbs). The other three patients presented with monoparesis, seizure, and demyelinating syndrome. 13 Second, our review of the CNS vasculitis literature yielded only four cases reporting pre-existing depression at the time of presentation. Crucially, depression is underrecognized in patients with CNS vasculitis and could represent an early symptom. 52 Providers should thus screen SLE patients for depression as new depressive symptoms might suggest an opportunity to intervene prior to the development of further neuropsychiatric disease. Several models have been proposed to describe dementia in CNS vasculitis patients, including a multiple-infarct model for vascular dementia. Vascular dementia can lead to severe cognitive dysfunction, impaired memory, impaired abstract thinking, and a decreased ability to perform simple manual tasks. Difficulty making decisions and controlling impulses are also common. 8 This patient’s memory deficits were thought to be related to inattention related to frontal executive dysfunction, since she had difficulty with immediate recall but fared better with recognition and cued recall. Her executive dysfunction contributed to her grave disability, as the inability to carry out complex tasks clearly impaired her ability to perform activities of daily living.16 CNS SLE Vasculitis, page 16 An older paradigm recognizes two patterns of cognitive impairment in SLE: impaired delayed recognition is associated with past or current nervous system involvement, and suggests residual neurological defect, whereas impaired immediate memory and concentration likely represent transient and diffuse CNS effects. 25 Though this patient appropriately fits the latter description, the pathophysiology of cognitive impairment is likely much more complex, as auto-antibodies, inflammatory mediators, endocrine factors, and vascular abnormalities have all been implicated in cognitive impairment in these patients.26 Hallucinations in this patient might have been affected by her previous thalamic injury, though her medications complicated the presentation. Whereas hallucinations in basal ganglia lesions are thought to occur due to frontal lobe dysfunction, causing an inability to utilize reality-checking pathways in the brain, 18 steroids typically cause dose-dependent psychosis within the first six weeks of treatment, with increased risk with prednisone-equivalent dose ≥ 40 mg/day. Crucially, discontinuation of the drug typically resolves NPS. 27 This patient’s taper of her prednisone regimen from 20 mg to 10 mg daily was felt to be the precipitating factor in the flare of her vasculitis, that would go on to damage her cerebral vasculature, predisposing her to subcortical dementia. Improvement on 20 mg daily dose of prednisone further supported damaged vasculature as the cause of her dementia. Imaging played a central role in understanding the pathophysiology of this patient’s presentation. MRI and angiography in patients with cerebrovascular disease, represent important tools in the diagnosis of CNS vasculitis. Several characteristic CNS SLE Vasculitis, page 17 MRI findings have been identified in such cases. These include white and grey matter hyper-intensities, parenchymal defects, and abnormal DWI, as discussed previously. The latter three findings are especially common in patients with cerebrovascular disease or seizures.28 Recent studies have shown SLE patients demonstrate a greater volume of white matter lesions compared to healthy controls, with corresponding cognitive dysfunction, particularly decreased verbal memory. Interestingly, bilateral hippocampal atrophy was also seen more commonly in patients with NPSLE than those with SLE without NPS. 29 Although imaging played a central role in the diagnosis of the vast majority of the cases included in this study, the allowance of three cases to be considered examples of CNS vasculitis in the absence of biopsy confirmation and with imaging revealing only white matter hyperintensities (Hirachi et al. 2015 and Rodrigues et al. cases 2 and 3) is a limitation of our study, given the well-known lack of specificity of white matter hyperintensities which has been acknowledged above. The role of histopathology in the diagnosis of CNS vasculitis should not be dismissed, even as highly-sensitive imaging modalities continue to be developed, as imaging in CNS vasculitis is often non-specific, and some patients with NPSLE demonstrate normal MRIs. Though suggestive of NPSLE in the proper clinical context, diffuse vasculopathy, macro- and micro-infarction, and vasculitis are not specific to NPSLE. Despite this, sections of cerebral vessels demonstrating microthrombi with C4d and C5b-9 deposits have recently been identified as histopathologically unique to NPSLE. In one study, these small vessel injuries were not detectable, even with 7T MRI, but were highly-specific to NPSLE. 30 Positron emission tomography (PET) scanning using 18F-FDG radiotracer has demonstrated CNS SLE Vasculitis, page 18 the ability to identify minor neuroinflammation, such as microthrombi, but research into this technology is in the early stages of evaluation. 31 Conclusion The presentation of the patient we have described demonstrates the difficulty in differentiating the many causes of neurocognitive changes and psychiatric symptoms in patients with SLE. 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Unihemispheric cerebral vasculitis: Case report and review of literature. J Neurol Sci. 2016;368:32-34. doi:10.1016 47. Kumar A, Goel A, Lapsiwala M, Singhal S. Refractory rheumatoid vasculitis. Oxf Med Case Reports. 2016; 2016(11). doi:10.1093. 48. Xiao Y-D, Paudel RC, Zhou S-K, et al. Imaging findings of primary angitis of central nervous system: case report and literature review. Int J Clin Exp Med. 2016;9(6):12341-12344. 49. Hasan TF, Maraka S, Leeds NE, Loghin ME. A Rare Case of Primary Angiitis of the Central Nervous System (PACNS) Associated with Metastatic Prostate Cancer. Neurology. 2017; 88 (16 Supplement):155. 50. Kumar PP, Rajesh A, Kandadai RM, et al. Primary CNS vasculitis masquerading as glioblastoma: A case report and review. Asian J Neurosurg. 2017;12(1):6971. CNS SLE Vasculitis, page 25 51. Lee JS, Jung TY, Lee KH, Kim SK. Primary Central Nervous System Vasculitis Mimicking a Cortical Brain Tumor: A Case Report. Brain Tumor Res Treat. 2017;5(1):30-33. 52. Chu L, Eustace M, Pittman N. Primary Angiitis of the Central Nervous System Presenting With Headache and Ataxia. Can J Neurol Sci. Aug 6 2018:1-2. CNS SLE Vasculitis, page 26 Figure 1:MRI/MRA prompted by Left-Sided Neglect One Year Prior to Admission: MRI demonstrates an irregularity/beading of the right Middle Cerebral Artery (left panel, white arrow). MR angiography demonstrates smaller/missing M2 segment and distal branches of the Middle Cerebral Artery on the right side (right panel, red arrow), compared to the left. CNS SLE Vasculitis, page 27 Figure 2: 3-D reconstruction of MRI at the Time of Presentation: Repeat MRI at the time of presentation to geropsychiatry demonstrated no focal narrowing or cutoff of cerebral vessels, to suggest an acute vasculitic episode. Distal right Middle Cerebral Artery branches remained reduced/absent, consistent with MRI one year prior. CNS SLE Vasculitis, page 28 Table 1: Laboratory Findings at the Time of SCLE Diagnosis Time of Diagnosis of ANA Anti-DSDNA ANCA C3 C4 Cardiolipin Ab SCLE Positive >1:640, speckled 3 Time of Diagnosis of CNS vasculitis Positive >1:640, speckled 2 Negative 109 16 3 IgM Cardiolipin Ab <10 IgG Cardiolipin Ab 1 IgA CCP Ab IgG Cryoglobulin RF RNP Serine Protease <8 No precipitate <10 Negative 0 IgG Smith Ab SSA Ab SSB Ab DRVVT Ratio DRVVT 1:1 Mix Ratio Positive, 1:4 Negative Negative Negative Negative 1.25 1.09 Table 2: Summary of 33 Published Cases of CNS Vasculitis Mimicking Psychiatric Conditions Report Age , Sex Preexisting Medical/ Neurologic al Conditions Seizures for 7 months, 12 months progressiv e dementia Preexisting Psychiat ric Conditio ns Not reported Primary treatme nt of Vasculiti s Other Treatments (length of time) 14 months None None Antibodies were absent Not reported 11 months Cycloph osphami de (IV 2 g per month for 6 months) Loxapine (400 mg per day for psychiatric symptoms), fluoxetine (40 mg daily for depression) None Labs: LP revealed blood cells CT: subarachnoid hemorrhage Medications at time of Symptoms Duration of Vasculitis Progressive dementia, disoriented, cognitive deficits, delusions, rigidity and myoclonus in arms and legs Sjögren's syndrome: auditory hallucinations, delusions of persecution, depression Not reported Presenting Symptoms Börnke et al (1999)32 50F Ampélas et al (2001)33 38M 3 months of systemic lupus erythemat osus Depressi on, with suicide attempts Jacobs et al (2004)34 81F Lyme Disease, breast cancer No Simultanagnos ia, optic ataxia, and ocular apraxia Doxycycline (for erythema chronica migrans) 1 month IV corticost eroids, tapered graduall y Lukas et al (2005)35 28M Headaches for 3 weeks Not reported Acute hoarseness and tingling in left extremities; dysarthria, clumsiness, dysmetric finger-to-nose testing Acidovir (suspected acute viral meningoence phalitis) 0.75 months Steroids (2 x 1000 mg per day) None SolansLaque´ et 63M Mild hypertensi Not reported Daily Occipital headache, Not reported 4 months IV pulses of Not reported Labs/ Imaging MRI: bilateral parieto-occipital region signal abnormalities, with DWI abnormality in the right parietooccipital region, and diffuse nodular leptomeningeal enhancement MR scans: hyperintensities of supratentorial grey and white matter; CCT: generalized brain edema Labs: Anemia, elevated erythrocyte Biopsy and Autopsy Findings Recurrenc e Necropsy: central nervous system angiitis with irregular distribution in both hemispheres No biopsy Died Brain biopsy: granulomato us angiitis Not reported Postmortem examination: granulomato us inflammation with occlusion of leptomeninge al and cerebral arteries with infarction of cerebrum Temporal artery biopsy Died No Not reported CNS SLE Vasculitis, page 30 al (2008)36 Case 1 on paroxystic vertigo methylpr ednisolo ne (1 g) and IV heparin Case 2 67F Hypertensi on Not reported Loss of vision in right eye, 3 months of headaches Not reported 3.25 months Methylpr ednisolo ne (1 g per day) Prednisone (2.5 mg per day), aspirin (150 mg per day), and acenocoum arol daily (stopped after 5 years) Case 3 74M Transient right hemiparesi s and aphasia Not reported Transient ischemic attacks, progressive cognitive impa irment, memory loss, confusion, disorientation Not reported 2 months Predniso ne (1 mg/kg per day) Clopidogrel after discharge Case 4 80M No Not reported Temporal headache, Not reported 2 months Predniso ne (80 None sedimentation rate, lupus anticoagulant, anticardiolipin antibody IgG and IgM, protein S, and prothrombin were normal. CT and MRI: lesions of acute ischemic infarction of both hemispheres. MRA: bilateral stenosis at vertebral arteries. Labs: Anticardiolipin was negative. MRI: Ischemic lesions of cerebral arteries. MRA: bilateral clinoidal stenosis of internal carotid arteries, anterior cerebral arteries, occlusion of posterior cerebral arteries. Labs: Normochromic normocytic anemia, elevated ESR. Clear CSF Ultrasonography at presentation: supraaortic arteries showed occlusion of left ICA. CT: frontal and temporal cerebral atrophy with hydrocephalus MRI: multiple infarcts in basal ganglia and internal capsule. Color ultrasonography 2 months after presentation: stenosis and dark halo in left temporal artery Labs: Normochromic normocytic anemia, consistent with GCA Necropsy revealed infarction of cerebellar hemispheres. Acute thrombosis of right vertebral artery. Temporal artery biopsy consistent with GCA Not reported No biopsy could be completed due to patient’s disorientation and agitation No Temporal artery Died CNS SLE Vasculitis, page 31 episodes of bilateral visual loss, diplopia, disorientation mg per day) Case 5 70F Hypertensi on, TIA with right hemiparesi s and blurred vision Not reported Loss of Vision in both eyes; headaches Enalapril (5 mg per day) 3 months 3 pulses of IV methylpr ednisolo ne (1 g) Discharged with prednisone and clopidogrel (75 mg per day) Case 6 90M 2 months of fever, facial pain, vertigo, nystagmus , dysarthria Not reported Ataxia, dysmetria, dysdiadokinesi s of left arm Not reported 2 months Predniso ne (1 mg/kg per day) Discharged with prednisone, clopidogrel, aspirin (300 mg per day) Case 7 85F Hypertensi on Not reported Enalapril 6 months 3 pulses of IV methylpr ednisolo ne (1 g per day) Discharged on prednisone and aspirin (300 mg per day) Qu et al (2009)37 50F Headaches No Antituberculosis therapy and daily dexameson 6 months Methylpr ednisolo ne, cyclopho sphamid e, and methotr exate None Pires et al (2011)38 70M No Depressi on Acute stroke with right hemiparesis, right upper limb paresis and blurred vision Sudden loss of vision; left side paralysis and quadriparesis; initial diagnosis of viral meningoencep halitis; frequent incoherent speech Cognitive impairment, N/A 0.5 months Oral predniso None elevated C-reactive protein MRI: multiple lacunar infarcts present in occipital lobes and cerebrum. MRA: stenosis of cerebral arteries. Labs: Normochromic normocytic anemia, elevated ESR, fibrinogen, Creactive protein, and alpha-2 globulin CT: no ischemic lesions; MRI: ischemic lesions in internal capsules Labs: Normochromic normocytic anemia, elevated ESR, fibrinogen, Creactive protein, and alpha-2 globulin CT: no signs of ischemia; Ultrasonography: occlusion of left ICA MRA: extracranial occlusion of left ICA Labs: Normochromic normocytic anemia, elevated ESR, fibrinogen, and Creactive protein CT: frontal cerebral atrophy Labs: Elevated lymphocyte count, antipospholipin antibodies within normal range. CT: Multifocal infarcts MRI: mass within right parietal lobe DSA: diffuse intracranial cerebral artery narrowing biopsy: inflammation of elastic lamina, consistent with GCA Labs Elevated ESR MRI: confluent Temporal artery biopsy consistent with GCA No Temporal artery biopsy consistent with GCA No Temporal artery biopsy consistent with GCA No Brain biopsy: extensive vessel inflammation (PCNSV) No Stereotactic brain biopsy: No CNS SLE Vasculitis, page 32 disorientation, memory deficits lone (1 mg/kg) hyperintense T2/FLAIR in periventricular and subcortical white matter Montefort et al (2012)39 57M Headaches Not reported Right arm weakness, decreased sensation, dyspraxia, left visual field impairment Not reported 11 months Dexame thasone; IV methylpr ednisolo ne (1 g for 3 days then 60 mg orally) with proton pump inhibitor. None CoronelRestrepo et al (2013)40 Case 1 54M No No Progressive headache and memory deficit; abnormal speech, disorientation, right hemiparesis and unstable gait Not reported 1 month IV methylpr ednisolo ne (1 g per day for 3 days), oral cyclopho sphamid e (100 mg per day), Aspirin (100 mg per day), and phenytoi n (300 mg per day) Physical therapy for a month Labs: Anticardiolipin antibody was negative. CT: blood in occipital horns of lateral ventricles, hypodensity in parietal, temporal, and occipital horns MRI: cortical infarction, blood present in ventricles, left capsule, and sulci MRA: irregularity in cerebral vessels (particular vessels not specified) Labs: Anticardiolipin antibody was negative. MRA: thinning at middle cerebral artery and anterior cerebral artery perivascular/ transmural small vessel inflammatory infiltrate, microglia activation, gliosis, sparse lymphocytes and neutrophils in brain parenchyma Biopsy within 4 weeks of presentation confirmed vasculitic changes Brain biopsy consistent with PACNS No No CNS SLE Vasculitis, page 33 Case 2 55F No No Severe headache with syncope, left hemiparesis, aphasia, stupor Not reported 0.25 months IV methylpr ednisolo ne (1 g per day for 3 days), IV cyclopho sphamid e (1 g per month for 6 months) Discharged with prednisolon e (1 mg/kg per day) and oral phenytoin (300 mg per day) Case 3 35M Arterial hypertensi on, left hip replaceme nt due to avascular necrosis, chronic convulsive syndrome No Progressive memory impairment, left hemiparesis, language disorder Enalapril, tegretol, phenobarbita l 24 months IV cyclopho sphamid e (1 g single dose), methylpr ednisolo ne (1 g per day for 3 days) Kalra et al (2013)41 24F Syncope Mild depressi on Collapsed at home; bilateral internuclear ophthalmopleg ia, left hemiparesis, dysarthria, left ataxia Not reported 3 months Oral aspirin and IV methylpr ednisolo ne after oral predniso lone (steroids tapered graduall y) prednisone (50 mg per day) with gradual decrease at month 6 (12.5 mg per day); after 2 years, methylpred nisolone (2 g/kg per day for 3 days), rituximab (2 doses of 1 g 2 weeks apart) Therapeutic anticoagulat ion with warfarin due to progression of vasculitis after a month of prednisolon e; Azathioprine daily; replaced steroids with aspirin (75 mg per day) CT: right frontal hematoma and vasogenic edema; cerebral angiography: cerebral vasculitis of posterior right carotid system and infundibular dilatation of left posterior communicating artery; MRI: intracerebral hematoma with right frontal edema Labs: Anticardioplipin antibody was negative. MRI: lesions in left frontal lobe and periventricular region; After 2 years MRI showed lesions in fronto-parietal and left cerebellum Brain biopsy: perivascular lymphocytic infiltrate with meninges No Brain biopsy: necrotizing granulomato us vasculitis 2 years after initial presentati on Labs: C-reactive protein and erythrocyte sedimentation normal, antiphospholipid screen within normal range. CT: multiple infarcts in left cerebellum, right thalamus, and left temporal lobe MRI: multiple infarcts in posterior and anterior circulation MRA: irregular narrowing of basilar artery and post No biopsy completed. Clinical picture and work-up were deemed sufficient to diagnose isolated CNS vasculitis No CNS SLE Vasculitis, page 34 Shiner et al (2014)42 62M Type 2 diabetes; persistent headache for 2 weeks Not reported Dysphasia due to stroke Metformin (for diabetes) 3 months 3 days IV methylpr ednisolo ne (1 g per day) then oral predniso ne (70 mg per day); weaned by 10 mg weekly IV Methylpr ednisolo ne (1 g x 3 days) with Tab omnacor t (1mg/kg OD) Oral Cyclophosp hamide (150 mg per day) Holay et al (2015)43 35M No Not reported Ischemic stroke and Left Hemiplegia Not reported 3 months Hirachi et al (2015)44 35F 4 years of systemic lupus erythemat osus No Prednisolone (20 mg per day discontinued a year before psychiatric symptoms manifested) Bönstrup et al (2016)45 47M No Not reported Arthralgia, manic symptoms: hallucinations, radical mood swings, and affective incontinence (Young’s mania rating scale: 29/60), depression Frontal lobe dementia syndrome: symmetric hyperreflexia, paraphasia, cerebellar dysarthria, 2.4 months Methylpr ednisolo ne (pulse: 1000 mg for 3 days), predniso lone (50 mg per day) Aripiprazole (6 mg per day increased to 24 mg per day), lithium (400 mg per day increased to 800 mg per day) Not reported 24 months IV methylpr ednisolo ne for 3 days (1g per day) 6 monthly doses of cyclophosph amide (750 mg/m2) with weekly methotrexat e (20 mg) Discharged on tapering doses of steroids stenotic dilatation. Labs: Anticardiolipin antibody was negative. MRI: regions of diffusion of restriction in left parietal and temporal lobes, areas of cortical fluid-attenuated inversion recovery Meningeal and brain biopsy: patchy infarcts of vasculitic changes in vessels of left inferior temporal lobe No Labs: Anticardiolipin antibody was negative. CT: acute infarct in right MCA MRI: lesion in right gangliocapsular, bilateral parietooccipital and midbrain right cerebral peduncle region signal abnormalities. MRA: Right MCA along M1 and bilateral PCA irregularity with significant narrowing Labs: Anticardiolipin antibodies were within normal range; ESR was high. MRI: multiple white matter hyperintensities I-IMP SPECT: hypoperfusion in occipital area No biopsy done: no provider capable of completing biopsy was available No No biopsy No Labs: elevated Creactive protein LP: Increased cell count and protein in CSF, MRI (6-9 months after initial symptoms): No Brain biopsy: hemosiderin deposits around small blood vessels. Also, perivascular accumulation Not reported CNS SLE Vasculitis, page 35 weight loss. Social deficits: erratic thought, memory loss, disinhibited behavior. Johnson et al (2016)46 30M No No Aphasia, homonymous hemianopia, right hemiparesis, and retinal peri-phlebitis of left eye; developed seizures Anti-epileptic medications for seizures 24 months IV methylpr ednisolo ne (1000 mg per day for 5 days) followed by high dose predniso ne taper Kumar et al (2016)47 48M Rheumatoi d arthritis Depressi on Became refractory to DMARDs; developed neuropathic pain in limbs Disease modifying antirheumatic drugs (DMARDS): methotrexate (15mg weekly), hydroxychlor oquine (200mg daily), sulphasalazin e (2000mg daily), leflunomide (20mg daily) 11 months IV predniso lone (3 x 1000 mg per day, 3 x 500 mg per day, 3 x 250 mg per day, 3 x 125 mg per day) followed by oral predniso lone (60 mg per day) Cyclophosp hamide (0.5 g/m2) after reexacerbatio n, re-dosed with solumedrol (5 days of high dose) and rituximab (2 cycles of 375 mg/m2); mycophenol ate (1000 mg twice a day) Psychothera py (functional component suspected) and antidepress ants; infusion of rituximab after appearance of gangrene in hands. abnormalities Repeat MRI (12-15 months after symptoms): Widespread, generalized cortical atrophy, especially in insular cortex and opercula, with ventricular widening, but also detectable in frontal and parietal lobes Contrast-enhanced MRA: No vascular irregularities CT: lesions in left parieto-occipital lobes; MRI: left medial frontal and parietal lesions; MRA: ipsilateral attenuation of left anterior, middle, and posterior cerebral arteries; EEG: left temporal seizures of inflammatory T-cells. Brain biopsy: cerebral gray and white matter changes within left ACA, MCA, and PCA unihemispher ic CNS vasculitis Symptom s never remitted despite steroid treatment . Exacerbat ion occurred 1 year after initiation of treatment . CT: right thalamic hemorrhage with cerebral infarcts due to cerebral vasculitis Sural nerve biopsy showed vasculitic neuropathy. Died CNS SLE Vasculitis, page 36 Xiao et al (2016)48 40F One episode of syncope; nephritis (treated and cured) Not reported Headache and dizziness Not reported 6 months Not reported Not reported MRI: lesion in fronto parietal region of left cerebrum; MRA: sudden termination of one branch of cerebral artery Hasan et al (2017)49 66M Metastatic prostate cancer Not reported Lower facial spasms and hand paresthesias; dizziness, dysarthria Not reported Not reported Cytoxan MRI: Ischemia in vascular territories Kumar et al (2017)50 56M Hypertensi on and diabetes No Behavioral changes, urinary incontinence, difficulty walking; glioblastoma later excised and revealed CNS vasculitis Not reported 2 months IV immuno globulin; IV and oral methylpr ednisolo ne IV cyclopho sphamid e (1000 mg per month for 6 months) IV immunoglob ulin (in full dose) after progression of mononeuriti s multiplex MRI: lesion in left frontal lobe; MRA: focal narrowing of vessels in left frontal region suggested vasculitis Lee et al (2017)51 25F No No Cortical brain tumor; headache and right hemiparesis Not reported 0.5 months Steroid administ ration None Labs: Leukocytosis with neutrophil dominance, elevated C-reactive protein CT: low-density lesion in left frontal lobe 67F 5 years of systemic lupus erythemat osus Psychom otor retardati on Subacute cognitive dysfunction, language deficit Hydroxychlor oquine (400 mg) 1 month Methylpr ednisolo ne (IV pulse 1g per day Speech and language therapy MRI: subacute infarcts in the left frontal parietal region. MRA: Focal stenosis Rodrigues Rodrigues et al (2017)13 Case 1 Microscopy of lump in fronto parietal region: blood vessels containing numerous inflammatory cells (consistent with CNS vasculitis) Brain biopsy: granulomato us angiitis Not reported Left frontal craniotomy and total excision of lesion. Biopsy: infiltrate of lymphonucle ar cells, perivascular granulomas, hemorrhages in adjacent brain parenchyma, gliosis Biopsy: dominant lymphocytic infiltration in small vessels, arachnoid membrane showed fibrotic changes No biopsy No Not reported No No CNS SLE Vasculitis, page 37 Case 2 Case 2 38F 12 years of systemic lupus erythemat osus Not reported Left lower limb monoparesis Hydroxychlor oquine (400 mg) 0.75 months Case 3C Case 3 18F 5 years of systemic lupus erythemat osus Not reported Tonic-clonic seizures Hydroxychlor oquine (300 mg), mycophenola te mofetil (2 g), prednisone (20 mg) 2 months Case 4 43F 16 years of systemic lupus erythemat osus No Diplopia, lower limb dysesthesia Prednisone (20 mg) 3 months for 3 days), Cycloph osphami de (IV 500/m2/ month for 6 months) Predniso ne (1 mg/kg per day), cyclopho sphamid e (IV 750/m2 per month for 6 months) Methylpr ednisolo ne (IV pulse .5 g per day for 3 days), predniso ne (1 mg/kg per day), IV human immuno globulin ( 2 g/kg per day) Predniso ne (0.5 mg/kg per day), cyclopho sphamid e (1 pulse of 500/m2), IV human immuno globulin (2 g/kg per 5 in M2 branch of MCA. None MRI: T2 hyperintense white matter lesions No biopsy No Anticonvuls ants MRI: fronto-parietal T2 hyperintense lesions No biopsy No None MRI: subacute infarct in head of right caudate nucleus, lenticulostriate arteries No biopsy (MRI supported vasculitis diagnosis) No CNS SLE Vasculitis, page 38 Chu et al (2018)52 63F 3 years of headaches, osteopenia , reflux, thyroid nodule, femur and skull lesions No Gait disturbance, incoordination, vertigo, nausea, vomiting; bilateral appendicular ataxia Rabeprazole and acetaminoph en 0.5 months days for 6 months) Dexame thasone (4 mg per os/ IV every 8 hours) Discharged with oral prednisone (60 mg per day), oral methotrexat e (15 mg per week), prednisone tapered down CT: right cerebellar edema; MRI: cerebellar leptomeningeal enhancement Cerebellar biopsy: vasculitis and lymphocyte infiltration of meninges No Table 3: Summary of Demographic and Clinical Data from 33 Published Cases of CNS Vasculitis Mimicking Psychiatric Conditions Age Mean (Range) Gender: M:F Count ( %) 52.85 years (18 – 90 years) 17/33 (51.51%): 16/33 (48.48%) Duration of Symptoms: Mean (MinimumMaximum) 5.39 months (0.25 months-24 months) Most Common Psychotic Features Erratic thoughts 1/33 (3.03%), auditory hallucinations 1/33 (3.03%), visual hallucinations 1/33 (3.03%), delusions 2/33 (6.06%)