Glazed (Vision) and Confused

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<ul><li><p>EsMD</p><p>gylph</p><p>ofap</p><p>He had been well until 3 months earlier when he</p><p>months after the headaches started he becameconfused and forgetful. He forgot the code for hishouse alarm and how to use a cellular phone. Hehad an episode when he awoke confused and then</p><p>and trouble walking due to hip pain.He was evaluated by a neurologist, endocrinolo-</p><p>gist, otorhinolaryngologist, and psychologist prior</p><p>Laboratory testing during his illness included</p><p>lipid panel, and iron studies. Lead and arsenic wereundetectable. Thyroid studies were normal. Testos-</p><p>examination revealed 0 white blood cells(wbc)/mL,40 red blood cells(rbc)/mL, 76 mg/dL protein, 64mg/dL glucose, negative venereal disease researchlaboratory, no cryptococcal antigen, and no malig-</p><p>strated an opacified left frontal sinus and noparenchymal abnormalities. Repeat MRI of the</p><p>SURVEY OF OPHTHALMOLOGY VOLUME 55 NUMBER 2 MARCHAPRIL 2010had brief loss of consciousness with his eyes rolledback. He had no recollection of this event. Thevisual symptoms started 1 week later. Review ofsystems included a 45-pound weight loss attributedto medication, occasional dizziness, diffuse pain,</p><p>nant cells. Electroencephalogram (EEG) performedafter his transient loss of consciousness did notreveal epileptiform activity. Echocardiogram wasunremarkable.Magnetic resonance imaging (MRI) of the brain</p><p>two weeks after the onset of headaches demon-had flu-like symptoms of fever, fatigue, and malaisefor several days followed by the onset of severefrontal headaches without phonophobia or photo-phobia. One month after the headaches started hedeveloped depressed mood and anxiety. Three</p><p>terone was 132 (normal 241--827). Lyme and rapidplasma reagin (RPR) testing were negative. Lumbarpuncture 1 month after the start of headaches didnot provide any relief. Cerebrospinal fluid (CSF)fields. He denied double vision or positive visualphenomena. He had had a normal screeningophthalmologic examination 4 months before.</p><p>normal complete blood count, basic metabolicpanel, liver studies, B12, folate, urinalysis, fastingmic consultation for progressive blurred vision over2 weeks associated with black spots in all visual</p><p>headache and once after the episode of losingconsciousness.A 60-year-old man presented for neuro-ophthal- 201All rigCase Report to his neuro-ophthalmology referral. He was admit-ted to the hospital twice: once for evaluation ofCLINICAL CHALLENGPETER SAVINO AND HELEN DANESH-MEY</p><p>Glazed (Vision) and ConfuHeather E. Moss, MD, PhD,1 Grant T. Liu,</p><p>1Division of Neuro-Ophthalmology, Departments of Neurolothe University of Pennsylvania School of Medicine, Philade</p><p>(In keeping with the formatthe abstract and key words169</p><p>0 by Elsevier Inc.hts reserved.ESR, EDITORS</p><p>ed,1 and Josep Dalmau, MD, PhD2</p><p>and Ophthalmology; and 2Department of Neurology,ia, Pennsylvania, USA</p><p>a clinical pathologic conference,pear at the end of this article.)0039-6257/10/$--see front matterdoi:10.1016/j.survophthal.2009.03.008</p></li><li><p>decreased attention, poor effort, and labile affect. Hewas npresi5minconta</p><p>vi</p><p>170 Surv Ophthalmol 55 (2) March--April 2010 MOSS ET ALbrain three months into his symptoms was un-changed. Computed tomography (CT) angiogramof the head was unremarkable 3 months after theonset of headaches. Chest X-ray showed no acutedisease and was stable when compared with a studyfrom 6 years prior.He was started on testosterone gel for low</p><p>testosterone 2 months into his illness without anyimprovement. Therapeutic trials for his headachesand psychiatric symptoms included antibiotics, non-steroidal anti-inflammatory agents,metoclopromide,topiramate, valproic acid, methylprednisolone, oxy-codone, clonazepam, and escitalopram. None pro-vided significant symptom relief.He had no known drug allergies. Medications</p><p>included levothyroxine, testosterone gel, flutica-sone/salmeterol inhaler, fluticasone nasal spray,montelukast, clonazepam, escitalopram, multivita-mins, folic acid, B-vitamin complex, fish oil, and</p><p>Fig. 1. Bilateral optic disk swelling; theibuprofen as needed. Past medical history includeda benign spinal cord tumor that was removed inJune 2003, hypothyroidism, and sinus surgery.He was married. He was self-employed in sales</p><p>until 3 months into his illness when he becameunable to work due to his cognitive impairments. Hehad a 25-pack an year smoking history. He quitsmoking 14 years prior to presentation. He deniedillicit drug use. Family history was remarkable forcardiac disease in both parents who died at 78 and86 years of age and an aunt with epilepsy.On examination he was normotensive weighing</p><p>228 pounds. Visual acuity was 20/80 1 ODimproving to 20/60 1 with pinhole and 20/50 2OS improving to 20/302 with pinhole. He saw only2 of 8 Ishihara color plates with the right eye, and 6of 8 with the left. Visual fields to confrontation,pupils, eyelids, and eye movements were all normal.Slit-lamp examination showed no cells in the anteriorded commands. Naming and repetition were intact.He had normal strength, sensation, coordination,gait, and deep tendon reflexes.</p><p>What are the diagnostic possibilities?</p><p>How would you proceed?</p><p>Comments</p><p>COMMENTS BY JOSEP DALMAU, MD, PHDThsubacof coon tproceningeand pup alocalioutparenlogicMRIpreseVis</p><p>an opthe rinvolinflamot oriented to city or year, he did not know thedent, and he could not recall three objects afterutes. Spontaneous speechwas perseverative andined many curses. He could not follow embed-chamber. He had bilateral optic disk swelling andbilateral vitreous haze due to vitritis (Fig. 1).On neurological examination he was agitated, with</p><p>treous haze accounts for the poor view.is is the case of a middle-aged man withute cognitive decline, visual changes, and lossnciousness starting after a febrile illness. Basedhis history a central nervous system (CNS)ss with brain parenchymal and/or leptome-al involvement causing functional impairmentossibly seizures is suggested. A negative work-t this juncture should not distract from thiszation. A normal interictal EEG does not ruleseizures unless an event is captured andchymal inflammation causing clinical neuro-al compromise may be below the resolution ofand CSF sampling, particularly early in thentation of many leptomeningeal processes.ual acuity changes and color vision loss suggesttic nerve process with or without involvement ofetina; identification of disk swelling confirmedvement of the optic nerve. The vitritis implies anmatory, infectious, or neoplastic etiology. The</p></li><li><p>2mL, 55 mg/dL glucose, 110 mg/dL protein, nomalignant cells on cytology, and no monoclonal</p><p>What is your most likely diagnosis?</p><p>Comments (Continued)</p><p>COMMENTS BY DR. DALMAU</p><p>Although the identification of a mixed popula-tion of T- and B-cells with possible expression ofCD43 in the vitreous biopsy may have suggested anocular lymphoma with CNS involvement, none ofthe subsequent studies, including CSF analysis andflow cytometry, supported this diagnosis. Moreover,expression of CD43 has been reported in non-neoplastic inflammatory disorders. Detection ofthyroglobulin and TPO antibodies is often iden-tified in patients with Hashimoto thyroiditis(a frequent cause of hypothyroidism), other thyroidand autoimmune disorders, as well as in a smallnumber of normal individuals. Our patient did nothave thyroid dysfunction, and the ophthalmologicand MRI findings did not suggest Hashimotoencephalitis, an ill-defined steroid-responsive en-cephalitis that occurs in association with thyroglob-ulin and thyroperoxidase antibodies. In contrast,the asymmetric T2 hyperintensity involving themedial temporal lobes in association with lympho-cytic pleocytosis in the CSF and rapidly progressivebehavioral change and memory deficits are highly</p><p>6</p><p>GLAZED AND CONFUSED 171population on flow cytometry.EEG showed diffuse slowing without epileptiform</p><p>activity.BrainMRI showedbilateral (left greater than right)</p><p>hippocampal T2 hyperintensity with mild associatedrestricted diffusion and no enhancement (Fig. 2).These findings were not seen on direct comparisonwith the MRI performed 2 weeks earlier.Serological testing for paraneoplastic antibodies</p><p>revealed the presence of antibodies to collapsin-differential diagnosis of a combined CNS and opticnerve process with vitritis includes CNS lymphoma,herpes simplex virus, syphilis, vasculitis, sarcoidosis,and paraneoplastic syndromes.Considerations for further work-up include re-</p><p>peating the lumbar puncture and MRI brainimaging as well as serological testing for markersof inflammation and paraneoplastic antibodies.Vitritis offers the possibility of tissue diagnosis withminimal morbidity.</p><p>Case Report (Continued)</p><p>The patient was referred to a retinal specialist,who confirmed the fundus findings. Fluoresceinangiogram did not reveal vasculitis or retinitis. Diskstaining was consistent with edema. A vitreousbiopsy OD showed mixed T and B lymphocytes withpossible aberrant expression of CD 43, consistentwith a B-cell proliferative disorder.During the week following his initial evaluation</p><p>the patient clinically declined with worseningvision, more confusion, and severe nausea andvomiting. He started complaining of episodicstrange odors. He was admitted to the hospital forfurther work-up.Laboratory data included normal complete blood</p><p>count, metabolic profile, liver function tests, eryth-rocyte sedimentation rate, c-reactive protein, andB12. Thyroid stimulating hormone and free T4 werenormal, anti thyroglobulin antibodies were elevatedat 641 units/mL, and antithyroperoxidase antibodies(anti-TPO) were elevated atO3000 units/mL. Anti-nuclear antibodies were positive at 1:1280 ina pattern resembling perinuclear anti-neutrophilcytoplasmic antibody although lacked specificity formyeloperoxidase on further testing. Sjogren anti-bodies (a and b) were negative. Serum proteinelectropheresis showed no evidence of a paraprotein.Human immunodeficiency virus antibody testing wasnegative. Lumbar puncture had an opening pressureof 16.8 cm H O, and the CSF had 17 wbc/mL, 1 rbc/response mediator protein 5 (CRMP5). suggeWhat are the next therapeutic and diagnostic steps?Fig. 2. Axial FLAIR image from brain MRI showing T2hyperintensity in bilateral hippocampi (left greater thanright).stive of limbic encephalitis. This disorder is</p></li><li><p>frequently a paraneoplastic manifestation of an</p><p>neoplastic syndromes. The clinical features areheterogeneous, with optic neuritis,3 vitritis, chorea,7</p><p>and sensorimotor axonal neuropathy1 being themost helpful in distinguishing it from other para-</p><p>172 Surv Ophthalmol 55 (2) March--April 2010 MOSS ET ALoccult neoplasm, which, in a patient with historyof smoking, should raise the suspicion of lungcancer. The detection of antibodies to CRMP5 (alsocalled CV2) strongly supports the paraneoplasticetiology of this disorder and enhances the suspicionfor lung cancer.4,8 Therefore, the next step would beto perform a comprehensive tumor search using CTand positron emission tomography (PET) studies.Fig. 3. CT of the chest showing enlarged lymph nodes(closed arrows) and tumor (open arrow).Case Report (Continued)</p><p>CT of the chest revealed a 2-cm left upper lobelung mass and multiple enlarged (2--4 cm) lymphnodes in the hilar, mediastinal, and paratrachealregions (Fig. 3). CT of the abdomen and pelvis didnot show lymphadenopathy or other masses.Paratracheal needle biopsy revealed small-cell</p><p>lung cancer (SCLC). Bone scan and PET scan didnot reveal metastatic disease. He was diagnosed withparaneoplastic limbic encephalitis, optic neuritis,and vitritis.</p><p>Comments (Continued)</p><p>COMMENTS BY DR. DALMAU</p><p>Antibodies to CRMP5 have been identified inpatients with paraneoplastic neurological and visualsymptoms associated with SCLC, thymoma, uterinesarcoma, thyroid papillary carcinoma, and renal cellcarcinoma.1,5,8 The most common symptoms arecognitive dysfunction, memory loss, and cerebellarataxia; however, these symptoms do not help tonarrow the differential diagnosis as they areassociated with many other neurologic and para-</p><p>Fig. 4. Axial FLAIR image from brain MRI 5 monthsfollowing diagnosis showing persistent, though improved,hippocampal signal.neoplastic syndromes. In addition to CRMP5 anti-bodies in the serum and CSF, the most frequentlaboratory findings are CSF lymphocytic pleocytosisand elevated protein concentration. Less frequentfindings include an abnormal brain or spinal cordMRI and an abnormal EEG. The underlying tumoris frequently identified at the time of neurologicalsymptom presentation.5</p><p>CRMP5 immunoreactivity has been demonstratedin small-cell lung carcinoma lines as well as in thecytoplasm of neurons,1 including those in retina,optic nerve,3 and peripheral nerves,1 supporting thehypothesis of CRMP5 as the responsible pathogenicantigen. However, given the intracellular location ofthe antigen it is unlikely that the antibodies arepathogenic. Rather, the accompanying cytotoxicT-cell immune response is likely the effector of theneuronal damage. This is suggested by the frequentinfiltrates of T-cells in affected optic nerves, mesialtemporal lobes, cerebellum, brain stem, spinal cord,and peripheral nerves.3,8 It is important to note thatantibodies to CRMP5 may occur in 10% of patientswith SCLC without paraneoplastic syndromes, and</p></li><li><p>are also frequently detected in association withother paZic4.2 Nin our patient.The t</p><p>suppresof theplastic sgens (elimited</p><p>Case Report (Concluded)</p><p>Comments (Concluded)</p><p>agnosiscoupled with aggressive immunotherapy and onco-</p><p>araneo-poorly</p><p>Paraneo-plastic anti-CV2 antibodies react with peripheral nerve andare associated with a mixed axonal and demyelinatingperipheral neuropathy. Ann Neurol. 2001;49:214--21</p><p>Abstract. A 60-year-old man presented with vitritis aateed with small cell lung cancer with a paraneoplasticse of his symptoms. His visual symptoms improveds c, paph</p><p>op</p><p>GLAZED AND CONFUSED 173and behavioral changes. MRI brain revealed billimbic encephalitis. He was subsequently diagnossyndrome characterized by CRMP5 IgG as a caumarkedly after anti-inflammatory therapy and hisystemic chemotherapy. The clinical presentationparaneoplastic syndromes are discussed. (Surv OAll rights reserved.)</p><p>Key words. CRMP5 limbic encephalitis vitritisThe patient was treated with high-dose intrave-nous corticosteroids to reduce inflammation fromhis paraneoplastic syndrome. Seven days later hisvision was 20/25 OU, he identified 6 of 6 colorplates OU, and the vitreous haze and disk swellingwere resolving. However, his cognitive deficitspersisted. He was treated empirically for presumedtemporal lobe seizures with antiepileptic medica-tions. Although the initial EEG was not epilepti-form, future studies revealed electrographictemporal lobe seizures. Agitation and hypersexualbehaviors, likely due to bilateral temporal lobeinjury, were managed with benzodiazepines, seroto-nin reuptake inhibitors, and mood stabilizingagents. He received radiation and chemotherapywith cisplatin and etoposide for his lung cancer.Twelve months after evaluation (16 months after</p><p>symptom onset) his visual acuity was 20/40 pinholeOD and 20/3...</p></li></ul>