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Show ORIGINAL CONTRIBUTION Ocular Dipping in Creutzfeldt-Jakob Disease Seong-Hae Jeong, MD, SangYun Kim, MD, Seong-Ho Park, MD, and Ji Soo Kim, MD Abstract: Ocular dipping refers to a slow downward deviation of both eyes followed by a quick return to the midposition after a brief delay. Two patients with rapid neurologic deterioration in Creutzfeldt-Jakob disease (CJD) displayed ocular dipping, which quickly evolved into sustained downgaze deviation. Ocular dipping may thus be a transitional sign in a vertical gaze disturbance. (J Neuro-Ophthalmol 2008;28:293-295) Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia, myoclonus, and ataxia (1). Involuntary eye movements in CJD include periodic alternating, upbeat, centripetal, and rebound nystagmus (2-4). As the disease progresses, saccadic slowing, supra-nuclear vertical gaze palsy, and periodic alternating gaze deviation may develop (2,4). Eventually, all saccades, including quick phases of nystagmus, are lost. We report transient ocular dipping (inverse bobbing) that evolved into downgaze deviation in 2 patients with CJD. This is the first report of ocular dipping in CJD and its link to downgaze deviation. CASE REPORTS Case 1 A 47-year-old man reported that people appeared to him as aliens. His acquaintances had begun to notice that he did not recognize them as he did not greet them. Over the following weeks, he began to bump against his surround-ings as if he were blind. His wife noticed severe deficits of memory and executive function. His past medical history was unremarkable. He did not take any medication. On admission to our hospital, vital signs and general examination findings were normal. However, he showed Departments of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea. Address correspondence to Ji Soo Kim, MD, Department of Neurology, College of Medicine, Seoul National University, Department of Neurology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea; E mail: jisookim@snu.ac.kr psychomotor slowing, anomia with preserved fluency, ideomotor apraxia, right-left disorientation, finger agnosia, agraphia, and acalculia. He failed to copy simple figures such as interlocking pentagons. All three components of Balint syndrome-ocular apraxia, optic ataxia, and simultanagnosia-were present, as well as color agnosia. He could not follow a visual target, and vertical and horizontal saccadic eye movements appeared to be slow. A lumbar puncture showed clear cerebrospinal fluid (CSF) with an opening pressure of 100 mm H2O, 15 red blood cells, 0 polymorphonuclear cells, 142 mg/dL protein, and 91 mg/dL glucose (blood glucose, 87 mg/dL). CSF 14- 3-3 protein was positive. Routine chemistry values, syphilis serology, and thyroid function were unrevealing. Electro-encephalography (EEG) demonstrated continuous 4-6 Hz irregular mixed slowing in all leads. Diffusion MRI revealed high signal abnormalities in the caudate and putamen, left frontal cortex, and bilateral occipitotemporal and insular areas (Fig. 1). On the second hospital day, he began to deteriorate rapidly, showing confusion and intermittent violent behavior. He was akinetic between the violent episodes. He was unable to open his eyes voluntarily or follow simple commands and showed intermittent myoclonus in the fingers and hands. Doll's eye movements were full in all directions. The pupils were equal at 3 mm and normally reactive to light. When his eyelids were held open by the examiner, a slow downward deviation of both eyes was followed by a quick return to the mid position after a brief delay, a finding considered consistent with ocular dipping. The ocular dipping clustered for 6-10 seconds; two or three cycles would occur in succession at intervals of 3-10 seconds. Subtle upbeat nystagmus appeared to be inter-mixed. There was no phasic contraction of the orbicularis oculi muscle. The ocular dipping lasted a few days and changed to sustained downward gaze deviation. Genetic analyses of the prion protein gene using blood demonstrated a homozygosity for methionine at the codon 129 polymorphic site on the short arm of chromo-some 20. The family members declined brain biopsy. The patient was discharged and lost to follow-up. Case 2 A 67-year-old journalist had a 1-month history of facial paresthesias and slurred speech that had started after J Neuro-Ophthalmol, Vol. 28, No. 4, 2008 293 J Neuro-Ophthalmol, Vol. 28, No. 4, 2008 Jeong et al FIG. 1. Case 1. Diffusion MRI shows high signal in the caudate nuclei (curved arrows), putamen (arrows), and cerebral cortex (arrowheads). horizontal gaze-evoked nystagmus, and slow saccades. Upbeat nystagmus increased during upgaze, convergence, lying down, straight head hanging, and Hallpike maneu-vers. Volitional eye movements were full in all planes. Although results of diffusion MRI 20 days earlier had been normal, follow-up imaging showed subtle high signal intensities in the left caudate nucleus, anterior putamen, insular cortex, and precentral and postcentral gyri, and bilateral medial parietal cortex (Fig. 2). [18F]Fluorodeox-yglucose positron emission tomography (PET) of the brain showed hypometabolism in the areas corresponding to the MRI lesions. CSF 14-3-3 protein was positive. EEG showed diffuse slowing. Over the next 2 weeks, the patient deteriorated into a vegetative state with intermittent twitching of the extremities. Along with the spontaneous upbeat nystagmus, the patient showed ocular dipping, which was present only for a few days and evolved into downward gaze deviation and then horizontal periodic alternating gaze deviation. Genetic analyses of the prion protein gene using blood demonstrated homozygosity for methionine at the codon 129 polymorphic site on the short arm of chromo-some 20. The patient was discharged without further workup including brain biopsy and was lost to follow-up. a quarrel. Two weeks before admission, he experienced unsteadiness and became unable to walk without support. He also had swallowing difficulties. On admission, he was alert and fully oriented. However, he showed spontaneous upbeat nystagmus, DISCUSSION Although pathologic confirmation was unavailable in our patients, the clinical, laboratory, genetic, and imaging findings were consistent with CJD (5). Case #1 presented FIG. 2. Case 2. Diffusion MRI (upper panel) shows subtle high signal in the left caudate nucleus (arrow), anterior putamen (curved arrow), insula (filled arrow), and frontoparietal areas (arrowheads). [18F]Fluorodeoxyglucose positron emission tomog-raphy of the brain (lower panel) shows hypometabolism in the areas corresponding to the lesions detected in the diffusion MRI. 294 q 2008 Lippincott Williams & Wilkins Ocular Dipping in Creutzfeldt-Jakob Disease J Neuro-Ophthalmol, Vol. 28, No. 4, 2008 with isolated visual symptoms that are characteristic of the Heidenhain variant of CJD (6). In contrast, Case #2 initially developed severe ataxia and dysphagia. Examination revealed upbeat and gaze-evoked nystagmus, which are consistent with the ataxic form of CJD (7). Both patients rapidly lapsed into a bedridden or vegetative state over a few weeks. Our patients showed upbeat and gaze-evoked nystagmus, downward gaze deviation, slow saccades, and ocular dipping. Although other ocular motor findings developed early in the course of the disease, ocular dipping was observed after marked deterioration of the patients' conditions. Ocular dipping consists of an initial slow downward movement of the eyes and a following rapid return to the primary position (8). It occurs most often in hypoxic or metabolic encephalopathy (9-13). In contrast to ocular bobbing, which consists of a rapid downward movement of the eyes followed by slow return to the primary position and is generally regarded a sign of intrinsic pontine lesions (14,15), ocular dipping does not have localizing value and usually indicates diffuse brain dysfunction (8-10). Ocular dipping also should be differentiated from reverse and converse bobbing. Reverse bobbing consists of an initial jerk upward movement and a slow return to the mid position after a brief delay (16). Converse bobbing (also called ‘‘reverse dipping'') consists of an initial slow upward gaze deviation followed by a rapid return to the mid position (14). Diffuse hypometabolism on brain PET in one of our patients and the development of ocular dipping in the advanced phase of the disease also support the notion that diffuse cerebral dysfunction is required to develop ocular dipping. In patients with ocular dipping, previous studies have reported diffuse pathologic changes in the basal ganglia, cerebral cortex (including the hippocampus), and cerebellum (9,12). The neuropathologic changes of CJD have been observed in similar areas, including the neocortex, thalamus, basal ganglia, and cerebellar cortex (3,17). Previous reports on eye movements in CJD were mostly of patients with the ataxic (cerebellar) form of the disease. Periodic alternating nystagmus and slow vertical saccades appearing early in the course of CJD suggest involvement of the cerebellar nodulus and ventral uvula and the brainstem reticular formation (2,7). Case #2 presented with severe imbalance along with upbeat and gaze-evoked nystagmus, which suggests cerebellar dysfunction. The evolution of ocular dipping into sustained downgaze in our patients also indicates a complete loss of upward saccades (18,19). Ocular dipping may thus be a preliminary phase of downward gaze deviation. Development of periodic alternating gaze deviation in the later stage of the disease is explained by progressive loss of saccades and quick phases of nystagmus (20). In our two patients, ocular dipping developed after marked deterioration in neurologic function and lasted only a few days before evolving into downgaze deviation. Ocular dipping in CJD presumably indicates an advanced stage of this devastating disorder. REFERENCES 1. Brown P, Cathala F, Castaigne P, et al. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 1986;20:597-602. 2. Grant MP, Cohen M, Petersen RB, et al. 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