Upbeat Nystagmus Associated with the Heidenhain Variant of Creutzfeldt-Jakob Disease

Sir, A 49-year-old Chinese woman presented with blurred vision in both eyes 2 months before admission. She was unable to cut vegetables and cook food due to above clinical symptoms. She had no remarkable past medical history and family history. She visited Department of Ophthalmology in a local hospital, suggesting reduced visual acuity and no abnormalities in the fundus and intraocular pressure. She could only see objects in front of her eyes as the clinical symptom of blurred vision rapidly worsened. The patient experienced dizziness 1 month before admission, relieved by closing eyes and accompanied by unsteady walking. Vestibular function examination was performed, and bilateral upbeat nystagmus was observed by position tests (Dix-Hallpike and roll test). She received repositioning treatment, but it was ineffective. On neurological examinations, visual acuity was reduced in both eyes and visual field was totally blinded. Upbeat nystagmus was observed, especially when lying down. The Montreal Cognitive Assessment (MoCA) scored 12/30, suggesting cognitive dysfunction. Routine laboratory analysis including routine blood count, erythrocyte sedimentation rate, urine test, angiotensin converting enzyme, anti-neutrophil cytoplasmic antibody profile, anti-cardiolipin antibody profile, lupus anticoagulant substance test, and antinuclear antibody profile was negative. Blood/urine toxicology and metal tests were unremarkable. The patient underwent a diagnostic lumbar puncture, with the pressure being 90mmH2O. Infection and autoimmune diseases were carefully ruled out by extensive investigations. Brain DWI showed high signal intensities in bilateral frontal, parietal, temporal, and occipital cortices, particularly in parieto-occipital regions [Figure 1a-f].Figure 1: Neuroimaging of this patient. (a-f). Brain DWI images showed high signal intensities in bilateral frontal, parietal, temporal, and occipital cortexesThere was no abnormal enhancement. Video electroencephalography (EEG) showed bilateral periodic discharges in the posterior regions, slightly dominant in the left posterior temporal regions with sharp wave complexes [Figure 2].Figure 2: Video EEG 2 months after disease onset. The EEG revealed periodic sharp slow wave complexesA clinical diagnosis of ‘probable CJD’ was considered based on the Center for Disease Control and Prevention (CDC)’s Diagnostic Criteria for CJD.[1] RT-QuIC and 14-3-3 protein in the cerebrospinal fluid were positive, further supporting the diagnosis. Genetic analysis results revealed a missense mutation at the codon 188 of PRNP gene, resulting in the threonine (Thr) to lysine (Lys) substitution. The polymorphism of codon 129 was methionin homozygous, and codon 219 was glutamate homozygous. After another 1 month, the patient experienced rapid deterioration in cognitive function, frequent myoclonus, and muteness. She was transferred to a nursing home and still alive when we conducted telephone follow-up 6 months after disease onset. The Heidenhain variant of CJD (HvCJD) is typically characterized by isolated visual symptoms during early disease onset, considered as a relatively rare subgroup of sCJD. One recent study demonstrated that up to 20% HvCJD are hereditary.[2] We report a case of Heidenhain variant gCJD with visual impairment as the first symptom, followed by dizziness and upbeat nystagmus. In this case, a middle-aged woman presented with blurred vision during disease onset, rapidly progressing to cortical blindness and cognitive decline. The patient’s clinical features, neuroimaging findings (high signals in bilateral frontal-parietal-temporal-occipital regions), EEG (periodic sharp-slow complex waves), positive 14-3-3 protein in the cerebrospinal fluid, RT-QuIC analysis, and disease-specific gene mutation supported a diagnosis of ‘definite gCJD’ according to the CDC Diagnostic Criteria for CJD.[1] Specific upbeat nystagmus was noted in this patient, which was rarely reported in the literature. Pathophysiological mechanisms of upbeat nystagmus are thought to be caused by the disruption of maintaining vertical gaze stabilization: the connection of the vertical vestibulo-ocular reflex, the vertical neural integrator that conjugates eye movements, and the vertical smooth pursuit system.[3] In our case, the presence of upbeat nystagmus may be associated with extensive cortical impairment influencing the smooth pursuit system and neural integrator. Brain DWI scans showed high-intensity areas in bilateral frontal, parietal, temporal, and occipital cortexes in this patient. The high DWI signal observed in the brain gray matter suggested potential pathology of spongiform changes. Nystagmus was reported in frontal, parietal, temporal and occipital lobe seizures.[4] Eye position-sensitive neurons are located in the parieto-occipital and anterior-inferior temporal cortexes, which input eye position and participate in feedback from the neural integrator for binocular gaze maintenance. When the neural integrator is weakened, defective gaze maintenance and nystagmus can be observed. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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