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Progressive supranuclear palsy (PSP) is a parkinsonian disorder characterized by early, frequent falls, dysphagia, and vertical gaze disturbance.1,2 PSP has recently been split into 3 entities—Richardson syndrome (RS), progressive supranuclear palsy–parkinsonism (PSP-P), and pure akinesia—which correlate with the amount and distribution of tau-protein load in the brain at autopsy.3,4 We report an autopsy-proven case of RS who presented with atypical features; however, slow vertical saccades were evident at presentation.
A 49-year-old man presented complaining of binocular, horizontal diplopia for 1 year. He also reported difficulty “following a sentence” during reading. Because of memory problems, he had relinquished control of family finances to his wife. He denied falls but had stopped playing tennis because he “could not keep up.” He had a flat affect and Mini-Mental State Examination score of 29/30. Corrected visual acuity was 20/20 OD and 20/25 OS; eyelids and pupils were normal. Range of eye movements was full, but with concomitant 6-prism diopter esotropia during distance viewing (divergence insufficiency); convergence was also impaired. Voluntary saccades were slow, especially vertically, but full in range. Smooth pursuit and vestibular eye movements appeared normal. Tendon reflexes and jaw jerk were increased. He could not perform the Luria 3-step test; palmomental reflex was prominent. He could clap exactly 3 times. Neuropsychological testing suggested frontal lobe dysexecutive syndrome with a subcortical component. His mother had developed dementia at age 70, attributed to Alzheimer disease, and apparently showed similar clinical features.
Over the next 2 years, he developed greater hyperreflexia with ankle clonus, cervical dystonia, jaw-closing oromandibular dystonia, generalized akinesia, postural instability, visuospatial dysfunction, and inappropriate emotional expression. Repeat neuropsychological testing revealed a global decline, with predominant frontal lobe dysfunction. He failed trials of amantadine, baclofen, levodopa, and lithium. He died 4 years after onset from aspiration pneumonia.
Normal diagnostic testing included brain MRIs (1 and 3 years after onset), thyroid stimulating hormone, B12, folate, antinuclear antibodies, syphilis serology, HIV, antithyroglobulin antibodies, arylsulfatase A, ceruloplasmin, paraneoplastic antibodies, electroencephalography, testing for Gaucher and Tay-Sachs disease, serum heavy metals, and CSF protein, glucose, cell counts, VDRL, 14–3-3 prion protein, and Tropheryma whipplei PCR. CSF ABeta peptide and tau protein were nondiagnostic. PET FDG scan revealed decreased parietal-temporal lobe and thalamic metabolism. Tau and progranulin mutations were absent.
Eye movements were measured (search coil) 1 year and 3 years following disease onset. Square-wave jerks2 disrupted fixation at 21/minute during the first session, increasing to 34/minute during the second session, when they were clinically manifest. Vertical saccades were slower than in control subjects and became slower during the second session (figure, A and B); although they were initiated at longer reaction times, they were not decreased in amplitude (figure, D). Horizontal saccades were conjugate and similar to normal controls during the first session, but were abnormally slow 2 years later (figure, C). Smooth pursuit gain (first session) was 0.79 horizontally and 0.75 vertically, and (second session) was 0.47 horizontally and 0.50 vertically. Vestibulo-ocular reflex gain (first session) was 0.96 horizontally and 0.96 vertically, and (second session) was 0.88 horizontally and 0.93 vertically.
At autopsy (figures e-1–e-6 on the Neurology® Web site at www.neurology.org), gross atrophy was restricted to the superior colliculi. Rare neocortical and entorhinal neurofibrillary tangles were identified. Severe neurofibrillary degeneration was present within brainstem nuclei, thalamic and subthalamic nuclei, and pallidum. Subcortical tau burden3 was exceptionally high: 4 (nigra) + 3 (dentate) + 3 (caudate) = 10. Midbrain nuclei housing vertical burst neurons2 also showed tau accumulation. Immunohistochemical testing for progranulin and TDP-43 was negative. Lewy bodies (by hematoxylin-eosin and alpha-synuclein IHC) and senile plaques (by hematoxylin-eosin and B-amyloid IHC) were absent. Some neurons in the pontine nucleus raphe interpositus showed tau staining (figure e-6).
We report a patient with pathologically confirmed RS, who presented with atypical features: young age at onset, absence of falls, and the presenting complaint of horizontal diplopia (due to vergence abnormalities). His cognitive impairment was suggestive of frontotemporal dementia.5 However, vertical saccades were slow at presentation. Midbrain nuclei concerned with generating vertical saccades were severely affected (figures e-1–e-6),2 consistent with his short disease course.6 “Supranuclear vertical ophthalmoplegia” is a term often applied to patients with both RS and PSP-P,4 yet our patient's vertical saccades remained full in range throughout his illness. Restricted range of upward gaze in healthy elderly subjects probably reflects changes in orbital tissues7; however, their vertical saccadic velocity remains normal. We conclude that careful examination of the speed (more than amplitude) of vertical saccades in patients with undiagnosed parkinsonian disorders remains the cornerstone for recognition of PSP and differentiation from other parkinsonian disorders.
Supplemental data at www.neurology.org
Disclosure: Dr. Hardwick reports no disclosures. Dr. Rucker serves as neuro-ophthalmology Section Editor of the British Journal of Ophthalmology and has received honoraria for lectures or educational activities not funded by industry. Dr. Cohen serves on the editorial board of the Open Pathology Journal; receives royalties from publishing Practical Differential Diagnosis in Surgical Neuropathology (Humana Press, 2000); and receives research support from the Centers for Disease Control [RES502729 (Co-I)] and the Alzheimer's Association [ZEN-06-27485 (Co-PI)]. Dr. Friedland received speaker honoraria from Pfizer Inc.; served as a consultant for MIMVista Corp.; and receives research support from the NIH [R01-AG017173 (PI)], the Joseph and Florence Mandel Research Fund, and the Nickman Family. Dr. Gustaw-Rothenberg reports no disclosures. Dr. Riley serves on the Medical Advisory Board of CurePSP; serves on speakers' bureaus for and/or received speaker honoraria from Allergan, Inc., GlaxoSmithKline, and Lundbeck Inc.; and has received research support from Allergan, Inc., SCHWARZ PHARMA, Medtronic, Inc., the NIH [R01 AG024040-03 (Investigator)], the National Center for Research Resources, Cleveland Medical Devices, and the Gift of Nina and Sandy McAfee. Dr. Leigh serves as a member of the NIH /National Eye Institute Central Visual Processing study section; receives royalties from coauthoring The Neurology of Eye Movements (Oxford University Press, 2006); and receives research support from the NIH [NEI R01 EY06717 (PI)], the Department of Veterans Affairs, the Office of Research and Development, Medical Research Service (Investigation and Treatment of Vestibulo-Visual Disorders, PI), and the Evenor Armington Fund.
Received June 16, 2009. Accepted in final form September 9, 2009.
Address correspondence and reprint requests to Dr. R. John Leigh, Department of Neurology, 11100 Euclid Avenue, Cleveland, OH 44106-5040; ude.esac@4ljr