More Than Meets the Eye: 'In Vivo' Diagnosis of Heidenhain Variant of Sporadic Creutzfeldt-Jakob Disease

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD More Than Meets the Eye: “In Vivo” Diagnosis of Heidenhain Variant of Sporadic Creutzfeldt–Jakob Disease Eleonora Potente, MD, Paolo Pelliccioni, MD, Tommaso Rossi, MD, Manuela Sallei, MD, Roberto Rossi, MD, Piero Parchi, MD, PhD, Giuseppe Pelliccioni, MD A peculiar clinical presentation of sporadic Creutzfeldt– Jakob disease (sCJD) is the Heidenhain variant, characterized by isolated visual disturbances at disease onset reflecting early targeting of prion protein (PrP) to the occipital cortex (1). We describe 2 patients with Heidenhain variant of sCJD, who presented with decreased visual acuity and metamorphopsias, without cognitive decline, at onset. This report emphasizes the importance of neurological evaluation and neuropsychological assessment in patients with isolated visual disturbances of unclear etiology and probable “central” origin, without clinical and instrumental evidence of ocular disease. Various investigations, including diffusionweighted MRI (DWI), real-time quaking-induced conversion (RT-QuIC) assay (2,3), cerebrospinal fluid (CSF) 143-3 and tau protein, and electroencephalogram (EEG), can identify this particular variant of CJD with high accuracy. A 74-year-old man reported that he was not able to read newspapers because “the lines overlapped each other”; his visual symptoms had begun 4 months before. His medical history was remarkable for hypertension, hypercholesterolemia, and stenosis of the right internal carotid artery; familial history was negative for neurodegenerative diseases. Ophthalmological evaluation, including optical coherence tomography (OCT), was unremarkable (best-corrected visual acuity was 20/20 in the right eye and Neurology Department (EP, TR, GP), IRCCS INRCA, Ancona, Italy; Eye Clinic (Paolo Pelliccioni), Polytechnic University of Marche, University Hospital “Ospedali Riuniti,” Ancona, Italy; Radiology Unit (MS, RR), IRCCS INRCA, Ancona, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna (Piero Parchi), Bologna, Italy; and Department of Experimental, Diagnostic and Specialty Medicine (DIMES) (Piero Parchi), University of Bologna, Bologna, Italy. The authors report no conflicts of interest. All procedures performed in this study involving human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patients included in the article and from legal next of kin. Address correspondence to Giuseppe Pelliccioni, MD, Neurology Department, Ospedale Sestilli, IRCCS INRCA, Via della Montagnola 81, Ancona 60100, Italy; E-mail: [e-mail] Potente et al: J Neuro-Ophthalmol 2022; 42: e423-e426 20/25 in the left eye, a corticonuclear cataract was observed in both eyes, and intraocular pressure was 14 mm Hg in both eyes), excluding macular or vitreoretinal interface abnormalities. Gait instability and difficulties with fine movements of the right hand were noted; a neurological evaluation was requested, showing an ataxic syndrome with wide-based gait and a tendency to fall back without support. Strength, sensitivity, cranial nerve examination, and reflexes were normal. The right finger–nose test showed features of dysmetria and apraxia, resembling those of the “alien limb phenomenon.” Therefore, the patient was admitted to the neurology department. Sporadic myoclonic movements of the right hand and arm were observed during hospital stay. Brain MRI showed hyperintense signal in the left occipital and parietal cortex on DWI sequences, without basal ganglia lesions (Fig. 1 left). EEG revealed sharp waves, with a triphasic pattern and a periodic behavior, more prominent on the occipital regions (Fig. 1 right). Neuropsychological assessment (Table 1) showed impairment in attention-executive tests, in memory domain especially in relation to poor coding strategies (free and cued selective reminding test: immediate recall), in semantic fluency (animal naming), and severe constructive apraxia (figure copy). The other case was an 85-year-old man with gait impairment and postural instability who reported “intermittent distortion of images” for 1 month. Ophthalmological evaluation, including OCT, was unremarkable (best-corrected visual acuity was 20/25 both eyes, a corticonuclear cataract was observed in both eyes, and intraocular pressure was 12 mm Hg in the right eye and 13 mm Hg in the left eye); convergence insufficiency was seen (near point of convergence at about 20 cm and fusional amplitude of 14 prism diopters), whereas the other ocular movements were normal. Neurological examination revealed wide-based deambulation, dysmetria on the right finger–nose test, and a fine postural tremor of the right hand when arms and hands were extended. Flexor digitorum superficialis muscle activity was identified by the isolated flexion movements of the right middle finger, with no focal sensitive or motor deficits. e423 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Diffusion-weighted MRI (DWI) and electroencephalogram (EEG) of the first patient. DWI (left) showing ribbon-shaped bilateral hyperintensity in the occipital cortex with partial involvement of left parietal lobe and EEG recording (right) showing runs of bihemispheric periodic sharp–wave complexes (PSWCs), more prominent on the posterior regions. Brain MRI showed hyperintense lesions of the right occipital and parietal cortex, right insula, and left occipital cortex (Fig. 2 left). EEG showed a generally slowed pattern, with periodic and triphasic spike and sharp waves, more prominent in the parietal, temporal, and occipital right regions (Fig. 2 right). The neuropsychological assessment (Table 2) showed deficits in attention-executive tests and weak verbal memory performance, especially in relation to poor coding strategies (Rey auditory verbal learning test: immediate recall). He performed very poorly on the Rey figure (copy and memory) and failed all of the subtests from the Visual Object and Space Perception Battery except for the initial screening test (figure ground discrimination) and the dot counting. After 2 weeks neuropsychometric testing showed deficits involving all cognitive domains, the patient showed buccal apraxia, dysmetria became bilateral, and sporadic myoclonic movement of the left arm and leg was appreciated. Standard CSF analysis and viral titles of both patients showed normal values. CSF levels of proteins 14-3-3 and total Tau were markedly abnormal (34,500 AU/mL and 2,618 pg/mL, respectively, in the first patient, and 40,600 AU/mL and 4,956 pg/mL in the second patient). Prion RTQuIC, performed as described (3), gave a positive result. Genotypic analysis revealed homozygosity for methionine at the polymorphic codon 129 of PrP gene in both patients. Three weeks after discharge, the first patient rapidly developed a severe form of dementia with multifocal myoclonic jerks and monotonous speech that progressed to akinetic mutism and dysphagia until death, due to aspiration pneumonia. The second patient was discharged to a long-term care facility; before death, he was severely disabled and bedridden, being mute, akinetic, and cortically blind. This rare group of patients may cause diagnostic difficulties, and because ocular intervention carries with it the risk of onward transmission (4), awareness of this condition among ophthalmologists is mandatory. e424 Heidenhain variant represents about 4.9% of sCJD cases (1); most of them belong to the most common MM1 disease subtype, typically characterized by short disease duration, periodic sharp–wave complexes (PSWCs) in the EEG, parietal– occipital hyperintensity on DWI sequences, and markedly increased total Tau and 14-3-3 protein levels in CSF. Heidenhain variant usually presents a “classic CJD” pathology distribution with prominent involvement of the occipital cortex. TABLE 1. Case 1–Neuropsychological battery Raw Adjusted Normal Score Score Value Global cognition Mini mental state examination Memory Digit span Free and cued selective reminding test Immediate free recall Immediate total recall Delayed free recall Delayed total recall Attention/executive functions Attentional matrices Not applicable Frontal Assessment Battery (FAB) Raven progressive matrices (1947) Stroop test Time Errors Language Animal naming Phonemic fluency F-A-S Test Visuospatial ability Copy figure 25 22.7* .24 5 5.13 .4.26 12 11.5* 32* 8 8.18 11 .19.6 .35 .6.32 $11 — — 11 10.9* — .13.4 10 10.1* .18.96 99 11 91.25* ,36.91 10.25* ,4.23 7 19 8.1* 19.34 .9.62 .17.77 3 2.9* .7.18 *Pathological score. Potente et al: J Neuro-Ophthalmol 2022; 42: e423-e426 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Diffusion-weighted MRI (DWI) and electroencephalogram (EEG) of the second patient. DWI (left) showing hyperintense lesions, more evident in the right occipital and parietal cortex, and EEG recording (right) showing a generally slowed pattern, with periodic and triphasic spike and sharp–waves complexes, more prominent in the parietal, temporal, and occipital right regions. Visual symptoms include blurred vision, decreased visual acuity, visual field deficit, disturbed perception of colors and objects (dyschromatopsia, metamorphopsia), and “cortical symptoms” such as optical anosognosia and cortical blindness (4). PSWCs in the EEG and DWI-MRI increased signal intensity in the brain posterior regions (particularly in the parietal–occipital cortex) are useful for the diagnosis (5), and RT-QuIC assay demonstrated high specificity and sensitivity compared with other CSF biomarkers, making it the most accurate method for “in vivo” clinical diagnosis of sCJD (3). TABLE 2. Case 2–Neuropsychological battery Raw Score Global cognition Mini mental state examination Memory Digit span Rey auditory verbal learning test Immediate recall Delayed recall Rey figure complex B Immediate recall Delayed recall Attention/executive functions Frontal Assessment Battery (FAB) Trail making part A Language Animal naming Phonemic fluency F-A-S Test Noun naming (SAND) Visuospatial ability Rey figure B (copy) Visual object and space perception battery Screening test Incomplete letters Silhouettes Progressive silhouettes Object decision Dot counting Position discrimination Number location Cube analysis Adjusted Score Normal Value .24 23 23.4* 4 4.82 .4.25 12 1 24.2* 4.8 .28.53 .4.69 8 6 11.7* 9.9* .16.8 .16.03 9 101* 11.3* .13.4 ,95 8 9 11 12 18.25 11.675 .9.62 .17.77 .9.969 14 15.35* .26.91 16 5* 7* 16* 10* 9 15* 3* 3* .15 .16 .15 ,15 .14 .8 .18 .7 .6 *Pathological score. Potente et al: J Neuro-Ophthalmol 2022; 42: e423-e426 e425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Potente, P. Pelliccioni, and G. Pelliccioni; b. Acquisition of data: E. Potente, P. Pelliccioni, M. Sallei, R. Rossi, P. Parchi, and G. Pelliccioni; c. Analysis and interpretation of data: T. Rossi and G. Pelliccioni. Category 2: a. Drafting the manuscript: E. Potente, P. Pelliccioni, Piero Parchi, and G. Pelliccioni; b. Revising it for intellectual content: E. Potente, P. Pelliccioni, T. Rossi, M. Sallei, R. Rossi, P. Parchi, and G. Pelliccioni. Category 3: a. Final approval of the completed manuscript: E. Potente, P. Pelliccioni, T. Rossi, M. Sallei, R. Rossi, P. Parchi, and G. Pelliccioni. 2. 3. 4. 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