RESIDENT & FELLOW SECTION Clinical Reasoning: Section Editor A 73-year-old man with diplopia and ataxia John J. Millichap, MD Harsh V. Gupta, MD SECTION 1 nonreactive to light, and there was mechanical ptosis Rohan Samant, MD A 73-year-old right-handed man with a history of on the left. He had left exotropia with full eye move- Murat Gokden, MD hypertension and hyperlipidemia presented with ments, bilateral horizontal gaze-evoked nystagmus, Ricky W. Lee, MD an 18-month history of diplopia and unsteady gait. and upbeat nystagmus on upgaze. Motor strength Kinshuk Sahaya, MD He also noted oscillating vision when turning his and tone were normal. He was diffusely hyperre- Tuhin Virmani, MD, head to the left. The diplopia was horizontal and flexic with bilateral extensor plantar responses. PhD was worse looking at objects on his right or at a dis- Detailed sensory examination was normal. Dysmet- tance. Over a year, his balance worsened to the point ria was present bilaterally, more prominent on the where he required a walker due to recurrent falls. Six left compared to right, with finger to nose testing Correspondence to months prior to presentation, he developed dyspha- and finger chase. His gait was ataxic with wide base Dr. Gupta: gia(liquidsmorethanthesolids).Hewasalsonoted [email protected] and a tendency to fall toward the left side. He was to have short-term memory problems in the last 3 unable to tandem walk (video on the Neurology® months.Onexamination,hehadmoderatecogni- Web site at Neurology.org). Systemic examination tive impairment with a Montreal Cognitive Assess- was unremarkable. ment (MoCA) score of 20/30 with predominant Questions for consideration: deficits in visuospatial functions and language. Glabellar, bilateral palmomental, and snout reflexes 1. Where would you localize his lesions? were present. The left pupil was surgical and 2. What is your initial differential diagnosis? GO TO SECTION 2 Supplemental data at Neurology.org From the Departments of Neurology (H.V.G., R.W.L., K.S., T.V.), Radiology (R.S.), and Pathology (M.G.), University of Arkansas for Medical Sciences, Little Rock. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. e96 © 2015 American Academy of Neurology ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 2 Based on the history and examination, the differ- There are clues in the history and examination that can ential diagnosis includes the following: help us localize his symptoms. Hyperreflexia and bilat- 1. Neurodegenerative conditions (multisystem atro- eral extensor plantar responses indicate upper motor phy or spinocerebellar ataxia) neuron involvement. Palmomental, snout, and glabel- 2. Inflammatory/autoimmune disorders (sarcoidosis, lar reflexes indicate disruption of the cortical inhibitory anti-GAD, Sjögren syndrome, demyelinating dis- pathways. Visuospatial deficits on cognitive testing ease, or steroid-responsive encephalopathy associ- indicate nondominant parietal lobe involvement, while ated with autoimmune thyroiditis) language impairments indicate dominant temporal 3. Vascular causes (arteriovenous malformation, lobe deficits. Impaired suppression of the vestibulo- vasculitis, or superficial siderosis) ocular reflex by cerebellar or brainstem lesions results 4. Paraneoplastic disorders (anti-Yo, anti-Ri, anti- in symmetric gaze-evoked nystagmus and oscillopsia. Hu, or anti-CV2) Upbeat nystagmus could be due to lesions in the dorsal 5. Neoplastic disorders (leptomeningeal carcinoma- central medulla or central mid pons. Dysmetria with tosis, metastatic cancer, or lymphoma) gait ataxia (in the absence of sensory findings) also 6. Infectious disorders (Creutzfeldt-Jakob disease, localizes to the cerebellum. Horizontal diplopia with Whipple disease, syphilis, tuberculosis, HIV, or distance vision that worsens on lateral gaze localizes fungal meningitis) to an ipsilateral lateral rectus palsy. 7. Nutritional deficiencies (vitamin E, vitamin B12, These findings suggest a progressive disorder or celiac disease) involving the posterior fossa along with a multifocal process in the cerebral cortex. MRI of the brain (figure 1) demonstrated numer- ous punctate randomly scattered foci of intraparen- chymal enhancement in the brainstem, basal ganglia, Figure 1 MRI brain and cerebral and cerebellar hemispheres (figure 1, C and D). They correspond to subtle fluid-attenuated inversion recovery (FLAIR) hyperintensities (figure 1, A and B) and the pattern suggested perivascular dis- tribution of lesions. CSF studies showed 7 leukocytes, 0 erythrocytes, protein 69 mg/dL (15–45 mg/dL), and glucose 61 mg/dL (40–70 mg/dL). Culture for bacterial, fungal, and acid-fast organisms did not demonstrate any growth. CSF immunoglobulin G (IgG) index, IgG synthesis, oligoclonal bands, and CSF myelin basic protein were within normal limits. CSF cytology was negative for malignant cells in 3 samples sent over a period of 2 weeks. Paraneoplastic panel results were normal. Testing for autoimmune etiologies in the serum (antinuclear antibodies, SSa, SSb, anti-GAD, gliadin antibodies, antiphospholipid antibodies, rheu- matoid factor, antineutrophil cytoplasmic antibody, and angiotensin-converting enzyme) had normal re- sults. Vitamin E and vitamin B12 levels were within normal range. CT scan of the chest, abdomen, and pelvis and a whole-body PET scan did not reveal evidence of malignancy. Questions for consideration: Axial fluid-attenuated inversion recovery images at the level of the pons (A) and basal ganglia 1. Based on these results, how would you narrow (B) show very small hyperintense foci. Postcontrast axial T1-weighted images at the level of the pons (C) and basal ganglia (D) show punctuate areas with morphology suggestive of your differential diagnosis? perivascular enhancement. 2. What further investigations would you consider? GO TO SECTION 3 Neurology 85 September 29, 2015 e97 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 3 occipital pole regions (figure 2). A biopsy from the The differential diagnosis with the inclusion of imag- right frontal gyrus was taken. The patient tolerated ing findings included neuro-Behçet disease, isolated the procedure well without complications. Histopa- CNS vasculitis, lymphomatoid granulomatosis, thology was remarkable for a vasculocentric popula- Erdheim-Chester disease, and chronic lymphocytic tion of small round lymphocytes and histiocytes. The inflammation with pontine perivascular enhancement lymphocytic infiltrate was composed primarily of T responsive to steroids (CLIPPERS). Further testing cells (CD3 positive) with a smaller subpopulation of for lactic dehydrogenase, b2 microglobulin, antineu- B cells without any evidence of vessel wall damage or trophil cytoplasmic antibody, and HIV was negative. thrombosis in the lumen to suggest vasculitis (figure 3). The level of serum immunoglobulin E (IgE) was No giant cells or well-defined granulomata were pre- found to be elevated at 346 kU/L (normal ,214 sent. The lymphocytic population was composed of kU/L); absolute CD4 and CD8 counts were low at small and round mature lymphocytes, which were 270/mL (normal range 720–1,348/mL) and 100/mL predominantly CD3-positive T cells with a small (normal range 318–710/mL), respectively, with a subpopulation of CD20-positive B cells, consistent CD4:CD8 ratio of 2.7 (high). with a reactive, rather than a neoplastic, lymphoid Due to worsening balance and more frequent falls, population. Special staining for viral (herpes simplex the patient became very limited in his ability to walk virus and cytomegalovirus), fungal (Gomori meth- and was readmitted to the inpatient neurology ser- enamine silver), and acid-fast microorganisms vice. A repeat MRI of the brain with a double dose (Ziehl-Neelsen) was negative. Luxol fast blue stain of gadolinium contrast was performed to evaluate demonstrated no myelin loss to suggest a demyelin- for additional regions that could be more amenable ating process. to biopsy. The repeat MRI brain demonstrated new Based on the clinical, radiologic, and pathologic lesions over the bilateral frontoparietal and right findings, the diagnosis of CLIPPERS was made. The patient received 1 g IV methylprednisolone for 5 days. He was discharged home on 60 mg of oral prednisone and has not yet been started on any steroid-sparing Figure 2 Double-dose contrast immunosuppressive agent. At a 1-month follow-up visit, the patient had improved gait ataxia and was able to walk slowly with wide base without the use of a walker and stand with feet together for 10 sec- onds with mild sway, but still had difficulty with tandem more than 2–3steps.Hereportedno improvement in his diplopia, but mild subjective improvement in dysphagia. A very slow wean in his steroid dose over months with repeat MRI was planned. DISCUSSION CLIPPERS was first described by Pittock et al.1 in 2010 as a distinct form of enceph- alitis responsive to immunosuppression with gluco- corticoid therapy. Patients with CLIPPERS present with brainstem and cerebellum predominant symp- toms, including ataxia, diplopia, dysarthria, vertigo, and long tract signs.1,2 MRI findings described in this condition include multiple punctate and curvilinear patterned gadolinium contrast-enhancing lesions with faint visualization on T2- and FLAIR-weighted images suggesting scarce edema. The contrast enhancement