Journal of Neuro-Ophthalmology, September 2015, Volume 35, Issue 3

Ataxia at the Masquerade Ball

Ataxia at the Masquerade Ball Krista Kinard, MD, Anne G. Osborn, MD, Cheryl A. Palmer, MD, Judith E. A. Warner, MD, Bradley J. Katz, MD, PhD, Alison V. Crum, MD, L. Dana DeWitt, MD, Joshua A. Sonnen, MD, Kathleen B. Digre, MD Dr. Kinard: Five years previously, a 52-year-old man developed dip-lopia requiring prism glasses. This was followed by imbalance resulting in frequent backward falls as well as oscillopsia and episodic vertigo. Subsequently, he developed fatigue, dysarthria, weight loss, numbness of his right foot, and easy bruising. He had complaints of cognitive decline but formal neuropsychological testing was normal. He had had 1 previous neurology consult and brain magnetic reso-nance imaging (MRI) without an explanation for his symp-toms. His medical history consisted of hypertension, viral pericarditis, mononucleosis, hepatitis, and treated prostate and squamous cell skin cancers. His only medications were over-the-counter supplements. His father had undiagnosed balance problems. At the time of initial evaluation, he reported progressive worsening of his balance. Visual acuity was normal as was examination of the anterior and posterior segment of each eye. His fixation was interrupted by intermittent square-wave jerks, and his eye movements were abnormal, with saccadic pursuit, slowed adducting saccades, gaze-evoked torsional-downbeat nystagmus, and minor bilateral abduc-tion deficits with an esodeviation in both right and left gazes. He was unable to suppress his vestibular-ocular reflex. His neurologic examination showed normal cranial nerves and normal strength, but he had mild dysarthria, a wide-based ataxic gait, unsteady tandem walk, appendicular dysmetria, absent ankle reflexes, and decreased peripheral sensation in his feet. His workup revealed normal nerve conduction studies, but brainstem auditory evoked responses showed delays in waves 3 and 5. Evaluation of his swallowing showed mild dysphagia with intermittent delay of pharyngeal response. MRI demonstrated only white matter disease consistent with microvascular ischemia, which was unchanged from previous studies. The following laboratory studies were normal or negative: complete blood count with differen-tial, erythrocyte sedimentation rate, comprehensive met-abolic panel, thyroid stimulating hormone, thyroxine, vitamins B1, B12, D, and E, serum protein electropho-resis/ immunoelectrophoresis, mercury, arsenic, and cad-mium levels, urine protein electrophoresis, antinuclear antibody (ANA) assay, Bartonella henselae, Bartonella quintana, Lyme disease, rapid plasma reagin, fluorescent treponemal antibody absorption, Mycoplasma pneumoniae, antineutrophil cytoplasmic antibodies (ANCA) titers, Toxoplasma, Anti-Ro(SSA) and Anti-La(SSB), Coxiella burnetii, acid-fast bacilli, Mycobacterium tuberculosis anti-body, quantiferon gold, Tropheryma whipplei, hepatitis C virus (HCV), herpes simplex virus (HSV), anti-JC virus (JCV) antibodies, Rocky Mountain spotted fever, varicella-zoster virus (VZV), HIV-1, HIV-2, and Epstein- Barr virus. He had a low absolute CD4 count with a low CD4:CD8 ratio, normal anticardiolipin IgG but high anti-cardiolipin IgM, high parvovirus B19 IgG but normal IgM, and normal cerebrospinal fluid (CSF) studies except for high HSV IgG. CSF cytology revealed no malignant cells. He had an unremarkable whole-body bone scan as well as negative findings on computed tomography of chest, abdomen, and pelvis. A subsequent sleep study confirmed sleep apnea for which he was placed on continuous positive airway pressure treatment. He was also evaluated at the cerebellar ataxia clinic and diagnosed with familial spinocerebellar ataxia as the most likely etiology of his symptoms. He was offered genetic testing but declined due to cost. He was placed on acetazolamide and then memantine without improvement. Over the next 6 years, his symptoms worsened despite phys-ical and occupational therapy. He became disabled and wheelchair bound. Due to progressive decline, he had repeat MRI of the brain. Dr. Osborn: MRI shows multiple enhancing hyperintense foci and areas of linear enhancement (Fig. 1). When the MRI obtained 6 years earlier was reviewed, it was clear that similar foci were present at that time (Fig. 2). Department of Ophthalmology and Visual Sciences (KK, JEAW, BJK, AC, KBD), John A. Moran Eye Center, University of Utah, Salt Lake City, Utah; Departments of Radiology (AJO), Pathology (CAP, JAS), and Neurology (JEAW, BJK, LDD, KBD), University of Utah, Salt Lake City, Utah. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. A. G. Osborn is a consultant for Elsevier. The remaining authors report no conflicts of interest. Address correspondence to Kathleen B. Digre, MD, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132; E-mail: [e-mail] Kinard et al: J Neuro-Ophthalmol 2015; 35: 315-318 315 Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Dr. Kinard: The differential with this new information included infiltrative processes such as sarcoidosis, lymphomatoid granulomatosis, intravascular lymphoma, metastases, and infection. Repeat laboratory studies and lumbar puncture were performed and were negative or normal except for elevated CSF protein on a repeat lumbar puncture. A biopsy of the right frontal leptomeninges and brain biopsy were performed. Dr. Palmer: The biopsy specimen shows fibrotic leptomeninges with hyperplastic meningothelial cells and psammoma body deposition. The right frontal neocortex demonstrates multifocal perivascular and intramural chronic inflam-matory cells, and diffuse astrogliosis (Fig. 3). Neither granulomas nor giant cells are seen. Trichrome staining confirmed vascular wall destruction and transmural inflammation. Immunohistochemistry is negative for cytomegalovirus and VZV. Immunohistochemical stain-ing also shows predominantly CD3-positive T lympho-cytes (Fig. 4A) with occasional CD20-positive B lymphocytes. A CD68 stain demonstrates activated micogliosis in the neocortex and transmural macrophages (Fig. 4B). These findings are diagnostic of central nervous system (CNS) vasculitis. Dr. Kinard: Because of the pathological diagnosis of probable CNS vasculitis, a catheter cerebral angiogram was performed to determine the extent of involvement. Dr. Osborn: The cerebral angiogram shows subtle irregularities of multiple distal internal carotid and vertebral artery branches consistent with vasculitis (Fig. 5). Angiography also showed normal renal and femoral arteries. Dr. Kinard: Laboratory studies were performed to determine if there was a specific cause for the vasculitis. These included c- and p- ANCA, ANA, and HCV, all of which were negative. Final Diagnosis Primary central nervous system vasculitis. FIG. 1. Brain magnetic resonance imaging. A. Postcontrast T1 axial images show multiple areas of punctate and linear enhancement. B. Diffusion-weighted imaging reveals patchy areas of restricted diffusion. FIG. 2. Brain magnetic resonance imaging 6 years earlier. Postcontrast T1 axial scans also show multiple foci of enhancement. 316 Kinard et al: J Neuro-Ophthalmol 2015; 35: 315-318 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Dr. Kinard: The patient was treated with oral prednisone (60 mg/d) with resolution of the enhancing lesions on repeat brain MRI 4 months later. Due to poor tolerance of steroids, he was started on azathioprine and tapered off of steroids. His clinical picture has improved slightly on chronic immuno-suppression. He was able to go from wheelchair bound to walking with assistive devices. Dr. Osborn: Repeat imaging 4 months after starting steroids shows remarkable improvement. The previously noted punctate enhancement in the cerebellum is no longer present, and there is no longer any patchy diffusion restriction (Fig. 6). Dr. Kinard: Primary CNS vasculitis (PCNSV) is rare, usually presenting with nonspecific signs and symptoms of CNS dysfunction. Headache is the most common symptom (60%) followed by altered cognition (50%) and hemiparesis (44%). Visual abnormalities are varied and can include visual field defects and persistent or intermittent diplopia (1). Other findings include vertigo, dysarthria, and fever. There is no sex pre-dilection. The incidence is 2.4/1,000,000 people. The eti-ology is unknown and without pathologic confirmation. Thus, PCNSV is a diagnosis of exclusion (1). The cause of PCNSV is unknown but theories implicate infectious diseases causing vasculitis, a specific immune response to an antigen (as yet unknown) and an association with amy-loid angiopathy (1). There are 3 histopathologic presentations of PCNSV: granulomatous, necrotizing, and lymphocytic (1). Gran-ulomatous is the most common, and 50% of patients with this pathology also have amyloid deposition in affected vessels. The necrotizing variant is the least com-mon. Necrotizing and granulomatous forms occasionally coexist. Our patient suffered from lymphocytic infiltra-tion, which occurs more frequently in children than in adults. There are no validated diagnostic criteria for PCNSV. Angiography may be helpful when abnormal, but it has limited sensitivity (2). Brain biopsy has strong negative and positive predictive values and is considered the gold standard (2). A negative biopsy does not exclude the diagnosis, so often a targeted biopsy is needed. This has a 78% diagnosis rate, as opposed to a 53%-55% diagnosis rate for a nontargeted biopsy (1). Treatment for PCNSV usually involves administration of steroids; but, despite treatment, PCNSV has a high mortality due to complications such as cerebral infarcts (2,3). There have been no prospective clinical treatment trials due to the rarity of the condition; however, a series from the Mayo Clinic described 101 patients with PCNSV who were followed for an average of 13 months and re-ported that 81% responded favorably to corticosteroids. However, the patients still had an increased mortality despite treatment and approximately one-quarter had a clinical relapse during the period of follow-up (3). FIG. 4. Immunohistochemistry of brain biopsy. A. CD3 immunostain shows scattered T lymphocytes as expected in a reactive process, not consistent with T-cell lymphoma (·100). B. CD68 stain reveals activated macrophages throughout the neocortex located in perivascular locations including blood vessel wall (·200). FIG. 3. Right frontal lobe biopsy demonstrates vasculitis and focal cerebritis. Lymphocytes are scattered throughout the gray matter, but most are localized to the vessel wall (hematoxylin & eosin, ·100). Inset, lymphocytes are pres-ent throughout the vessel wall, and the lumen is occluded due to chronic inflammation (hematoxylin & eosin, ·400). Kinard et al: J Neuro-Ophthalmol 2015; 35: 315-318 317 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Pizzanelli et al (4) reported a series of 8 patients with PCNSV that was classified as either moderate or severe. The patients classified as having moderate disease were treated with steroids, whereas patients with severe disease were treated with steroids plus additional forms of immu-nosuppression. The patients were followed for 7-62 months, during which 1 patient experienced a relapse. The authors concluded that brain biopsy and angiography are helpful for diagnosis and that treatment should be tailored to the patient's clinical picture until diagnostic and therapeutic guidelines are developed. PCNSV has long been thought to be an acute or rapidly progressive illness (2). However, Burrows et al (5) published a case report of a patient with headache and cognitive decline for 20 years, culminating with seizures. He underwent a brain biopsy that demonstrated PCNSV and was treated with steroids and lamotrigine. His seizures and apraxia resolved, and his cognitive def-icits and a left homonymous hemianopia stabilized. That report and our case suggest that PCNSV may be indolent or slowly progressive over many years. The diagnosis of vasculitis in our patient was obscured by the patient's predominant signs and symptoms that mimicked or masqueraded as a spinocerebellar ataxia (SCA) syndrome, including a vague family history of imbalance; however, the rate of decline in our patient was faster than is typically seen in SCA. Our report high-lights that PCNSV can be an insidious very slowly pro-gressive disease. MRI findings can be subtle and nonspecific, mimicking a variety of entities and cerebral angiography, at times in conjunction with brain biopsy, provide the best possible means of diagnosis. REFERENCES 1. Salvarani C, Brown RD Jr, Hunder GG. Adult primary central nervous system vasculitis. Lancet. 2012;380:767-777. 2. Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 2014;48- 49:149-152. 3. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJ, Weigand SD, Miller DV, Giannini C, Meshia JF, Huston J III, Hunder GG. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62:442-451. 4. Pizzanelli C, Catarsi E, Pelliccia V, Cosottini M, Pesaresi I, Puglioli M, Moretti P, Tavoni A. Primary angiitis of the central nervous system: report of eight cases from a single Italian center. J Neurol Sci. 2011;307:69-73. 5. Burrows AM, Maloney PR, Van Gompel JJ. Not so small vessel vasculitis. JAMA Neurol. 2013;70:1578-1579. FIG. 6. Brain magnetic resonance imaging after 4 months of systemic corticosteroids. Postcontrast T1 axial scan no longer shows areas of enhancement (A) and diffusion-weighted imaging is normal (B). FIG. 5. Cerebral catheter angiogram. Anterior-posterior (A and B) and lateral (C) projections show subtle irregularities of the lateral distal small vessels (arrows) of both the right and left carotid arterial systems. 318 Kinard et al: J Neuro-Ophthalmol 2015; 35: 315-318 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.