Visual Disturbances and Headache as Presenting Symptoms of Creutzfeldt-Jakob Disease

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Visual Disturbances and Headache as Presenting Symptoms of Creutzfeldt–Jakob Disease Natalia M. Binczyk, MD, Meghan J. Smith, MD, Nabeela Nathoo, MD, PhD, Valerie L. Sim, MD, FRCPC, Dean Jeffery, MD, FRCPC, Imran Jivraj, MD, FRCSC C reutzfeldt–Jakob disease (CJD) is a progressive neurodegenerative prion disease which presents clinically as a rapidly progressive dementia and is fatal within months. The Heidenhain variant of CJD (HvCJD) is rare and presents predominantly with visual symptoms such as decreased visual acuity, blurred vision, cortical visual field defects, dyschromatopsia, palinopsia, and other visual symptoms (1). In this article, we present a case of rapidly progressive HvCJD which presented with unusual visual distortions and headache. CASE DESCRIPTION A 77-year-old man was referred for evaluation of blurred vision in both eyes. His medical history was significant for malignant melanoma which was in remission and migraine headaches. He described distortion of shapes, unusual colors, and fatigue, myalgias for the preceding 3 weeks. An outside ophthalmic examination revealed dry eyes and mild cataracts. He was started on 20 mg of prednisone for presumed polymyalgia rheumatica although his inflammatory markers were normal. Initial neuroimaging with a computed tomography (CT) scan of the head and CT angiogram was normal. Because of his complaint of persistent blurred vision and ongoing visual distortion, he was referred for reevaluation. The best-corrected visual acuity was 20/30-2 in the right eye and 20/40 in the left eye; he read 1/21 Ishihara color plates bilaterally. Pupils were equal and briskly reactive without an afferent pupillary defect. Visual fields were full to confrontation, although automated visual field testing revealed generalized depression with a superimposed left homonymous hemianopsia. Fundus examination did not reveal any macular abnormalities. One week later, he presented with worsening confusion and constant visual distortions, which he described as Department of Ophthalmology and Visual Sciences (NMB, MJS, IJ), University of Alberta, Edmonton, Canada; Department of Medicine, Division of Neurology (NN, VLS), University of Alberta, Edmonton, Canada; and Department of Radiology and Diagnostic Imaging (DJ), University of Alberta, Edmonton, Canada. The authors report no conflicts of interest. Address correspondence to Imran Jivraj, MD, FRCSC, Eye Institute of Alberta, Royal Alexandra Hospital, 10240 Kingsway NW, Edmonton, AB T5H 3V9; E-mail: [e-mail] e488 seeing “elevated cracks in the ground.” At that time, he reported that he had a nearly constant, dull headache for the past 3 to 4 weeks which was graded as 5/10 in severity. His family reported worsening memory and an unsteady gait. He was observed to be performing unusual behaviors such as using the television remote control as a cell phone, trying to set the temperature on the security system at home, and sleeping sideways in bed. Neurological examination at the time was normal. He was treated for status migrainosus with intravenous fluids, metoclopramide, and dexamethasone which had decreased the headache severity to 2/10 and helped with the visual distortions. He was discharged with plan for outpatient follow-up. Over the subsequent week, he developed intrusive and disturbing visual hallucinations involving seeing other individuals in the room; he also began to suffer from frequent falls. Neurologic examination revealed impaired naming of familiar objects, confusion of color (e.g., mistaking yellow with dark green), bilateral intention tremor with finger-tonose testing, and gait ataxia. MRI of the brain was reported as normal. Given concerns about seizures, an electroencephalogram (EEG) was ordered but not performed at the time of presentation. For the headaches, treatment with amitriptyline was initiated. Two days later, he presented with worsening visual hallucinations, paranoid delusions, cognitive changes, and falls. He was getting lost in his own home and was no longer oriented to date or time and suffered paranoid ideation about being poisoned. His previous neuroimaging was reviewed, and subtle asymmetrical cortical T2 hyperintensity was seen on FLAIR with corresponding diffusion restriction in multiple cortical gyri bilaterally, typical of cortical ribboning (Fig. 1). On the day of representation, an EEG showed generalized periodic 1–2 Hz sharp waves (Fig. 2). Lumbar puncture was performed and cerebrospinal fluid (CSF) analysis revealed 1 white blood cell per cubic millimeter, normal protein, and glucose; however, 14-3-3 protein was identified, and the end point quaking-induced conversion (EP-QuIC) assay for Creutzfeldt–Jakob disease was positive. Genetic testing for mutations in the PRNP gene, coding for prion protein (PrP), was negative. He was diagnosed with HvCJD. He passed away one month later in palliative care. Postmortem brain-only autopsy confirmed sporadic CJD. Binczyk et al: J Neuro-Ophthalmol 2022; 42: e488-e490 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Diffusion-weighted MRI (DW-MRI) of the head showing cortical ribboning. Scans show diffusion restriction in multiple cortical gyri, including the left frontal region, right insular ribbon, left parietal lobe (A), right temporal lobes (B, D), and right occipital lobe (C). Arrows indicate locations of restricted diffusion. DISCUSSION HvCJD is rare; a retrospective review of 594 pathologically proven cases of spontaneous CJD showed that only 22 (3.7%) of these cases presented as the Heidenhain variant (1). Our patient’s initial presentation with visual distor- tions, impaired color perception, and potential homonymous visual field loss suggest involvement of the occipital cortex and the optic radiations. Rapid clinical deterioration and subtle neuroradiologic findings suggested HvCJD, which was confirmed with EEG and EP-QuIC testing. The presence of restricted diffusion in the cortex and/or deep gray matter on diffusion-weighted imaging (DWI) MRI has a 92.3% sensitivity and 93.8% specificity for the early diagnosis of CJD (2) but can be subtle and is believed to occur because of spongiform change. These spongiform changes have been previously shown to correlate with scrapie isoform of the prion protein (PrPSc) load in the cortical and deep gray brain regions (3). The presence of 14-33 protein in the cerebrospinal fluid is a nonspecific biomarker of prion disease but may also be found in other prionunrelated dementias, stroke, and encephalitis. Confirmation of CJD previously required brain biopsy which incurs significant patient morbidity and risk of instrument contamination. In 2010, Wilham et al (4) described a novel real-time quaking-induced conversion (RT-QuIC) test. In the RT-QuIC test, patient’s CSF is added to recombinant PrP (rPrP) and thioflavin T, a dye that fluoresces when it binds beta sheet fibrils. CJD patients have PrPSc in their CSF, which can bind to rPrP and induce it to form beat sheet fibrils that will then bind the dye and cause fluorescence. In RT-QuIC, this fluorescence is monitored in real time. EP-QuIC, an assay modified from the RT-QuIC, measures fluorescence at the beginning and end of the assay. The sensitivity and specificity of the EP-QuIC assay for CJD is 98% and 91%, respectively (5). To the best of our knowledge, this is the first case describing use of EP-QuIC in the diagnosis of HvCJD. Physicians should consider HvCJD in the differential diagnosis for patients presenting with headache and progressive visual disturbances. Cortical ribboning on MRI, generalized epileptiform discharges on EEG, and positive EP-QuIC test can be used to predict the diagnosis with high certainty. FIG. 2. Electroencephalogram (EEG). The EEG shows generalized periodic 1–2 Hz sharp waves throughout (black boxes). Binczyk et al: J Neuro-Ophthalmol 2022; 42: e488-e490 e489 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj; b. Acquisition of data: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj; c. Analysis and interpretation of data: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj. Category 2: a. Drafting the manuscript: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj; b. Revising it for intellectual content: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj. Category 3: a. Final approval of the completed manuscript: N. M. Binczyk, M. J. Smith, N. Nathoo, V. L. Sim, D. Jeffery, and I. Jivraj. REFERENCES 1. Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG. Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the “Heidenhain variant”. Br J Ophthalmol. 2005;89:1341–1342. e490 2. Shiga Y, Miyazawa K, Sato S, Fukushima R, Shibuya S, Sato Y, Konno H, Doh-ura K, Mugikura S, Tamura H, Higano S, Takahashi S, Itoyama Y. Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology. 2004;63:443– 449. 3. Manners DN, Parchi P, Tonon C, Capellari S, Strammiello R, Testa C, Tani G, Malucelli E, Spagnolo C, Cortelli P, Montagna P, Lodi R, Barbiroli B. Pathologic correlates of diffusion MRI changes in Creutzfeldt–Jakob disease. Neurology. 2009;72:1425–1431. 4. Wilham JM, Orrú CD, Bessen RA, Atarashi R, Sano K, Race B, Meade-White KD, Taubner LM, Timmes A, Caughey B. Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathog. 2010;6:e1001217. 5. Cheng K, Vendramelli R, Sloan A, Waitt B, Podhorodecki L, Godal D, Knox JD. Endpoint quaking-induced conversion: a sensitive, specific, and high-throughput method for antemortem diagnosis of Creutzfeldt-Jacob disease. J Clin Microbiol. 2016;54:1751–1754. Binczyk et al: J Neuro-Ophthalmol 2022; 42: e488-e490 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.