1. Clinical Presentation 49 year-old man presented to Dr. Janet Rucker on November 8, 2004 Complained of double vision for about one year Diplopia was binocular, horizontal, worse when looking to the left or at distance Also difficulty reading – following a sentence Lightheadedness when rising from sitting or lying, worsened by moving around Had stopped playing tennis because “he could not keep up” His wife had taken over the finances

2. Other History Medicines: Ambien, Lexapro,Trazodone Mother –Italian origin –Diagnosed with Alzheimer’s in mid-70’s –Died at age 75 –She had a tendency to fall backward –Difficulty with her eye movements in her 60’s –May have had similar facial appearance and gait to the patient Patient’s brother was color blind

3. Examination – 1 Appearance: masked face, staring without blinks Blood Pressure: 126/80, not orthostatic Flat affect; Minimental score = 29/30; hypophonic speech Visual acuity with correction: 20/20 +3 OD, 20/25 -1 OS Congenital color blindness Normal ophthalmoscopic exam Pupils equal and fully reactive Ocular alignment: Concomitant 6-prism-diopter esotropia Unable to converge Slow saccades vertically and horizontally Other eye movements normal

4. Examination – 2 Motor Exam: –Involuntary intermittent shivering (tremor) of legs –Bradykinesia –Axial rigidity –Tendon reflexes increased and jaw jerk was clonic –Chin tremor –Frontal release signs –He could clap exactly three times Sensory Exam: normal GAIT: decreased right arm swing with walking

5. Laboratory Investigations Negative Studies: –CBC –SMAC20 –Urinalysis –TSH, free thyroxin, free T4 index, antithyroglobin, ANA –B12, folate –Tests for syphilis, HIV –Ceruloplasmin –Anti-HU and -MA –CSF protein and cell count, VDRL, prion 14-3-3 protein, Tropheryma whipplei –Tests for Gaucher and Tay-Sachs, Mucolipidoses 2 and 3, MLD CSF levels of A Beta peptide and TAU protein were inconclusive EEG: negative Urine arsenic was elevated at 2102ug/l (attributed to recent ingestion of seafood) Genetic testing for frontotemporal dementia with Parkinsonism or Pick’s disease was negative Neuropsychological testing: High premorbid intelligence, borderline executive functions

6. MRI: Normal on three occasions PET Scan: hypometabolism in the left parietal and posterior parietal regions bilaterally, left basal ganglia and thalamus MRI 2006: Non-specific white matter changes

7. Other eye movement findings Saccades were conjugate Fixation was disrupted by small saccadic intrusions (square-wave jerks) Smooth pursuit deteriorated, both horizontally and vertically (gain < 0.5) Vergence was progressive impaired Angular vestibulo-ocular reflex was normal Minor gaze-evoked nystagmus

8. Clinical Course – 1 Prisms eliminated diplopia Patient stopped driving Decreased endurance for housework Developed neck stiffness and pain, difficulty with arm movement Hand writing slower and smaller Problems with buttoning clothes with right hand

9. Clinical Course – 2 Lost expression of speech; labile emotions Neuropsychological testing 9/2006: Global decline, with impaired executive function and speed of processing Failed trials of amantidine, baclofen, L-dopa, lithium (for Tau effect) December 2006: Could not lift his neck, and feed himself. Some trouble breathing. Episodes of shaking, which he attributed to cold Developed episodes of choking on food During 2007, became progressively disabled, with difficulty feeding Died 4/11/2008

10. Consults Dr. Conomy noted postive glabellar tap and clonus, limitation of conjugate upgaze Dr Zinn-tested for frontotemporal dementia with Parkinsonism, Pick’s disease both were negative Dr Cappaert enrolled him in trial drug for pseudobulbar palsy, but no benefit Dr Ogrocki documented that he had high normal intelligence, but after resting after about 1 year he had significant global decline and depression Dr Bass evaluated him for lipid storage diseases, which were normal

11. Summary of differential diagnoses considered Progressive supranuclear palsy Other tauopathy Kuf’s disease Whipple’s Tay-Sachs Alzheimer’s Frontal temporal dementia with parksonism Pick’s disease NPH

12. The tau of PSP Neurofibrillary tangles Tufted astrocytes (Oligodendroglial) Coiled bodies

13. Basal ganglia

14. Subthalamic nucleus

15. Globus pallidus

16. Atrophy of superior colliculus

17. Superior colliculus

18. Substantia nigra

19. Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain. 2007 Jun;130(Pt 6):1566-76.

21. Grade 3

23. Dentate nucleus: Grumose degeneration

24. PSP-tau scores Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain. 2007 Jun;130(Pt 6):1566-76.

25. Distribution of tau pathology in PSP-tau score >7 Pink = Grade 1 Purple = Grade 2 Red = Grade 3 Brown = Grade 4 Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain. 2007 Jun;130(Pt 6):1566-76.

26. Mid-Frontal Hippocampus

27. Litvan, I. et al. Neurology 1996;47:1-9 PSP: Diagnostic Criteria

28. Features of PSP – 1 Slow vertical saccades, especially down, with a preserved range of movement, may be the first sign of the disorder; later, loss of vertical saccades and quick phases Horizontal saccades become slow and hypometric Disruption of steady gaze by horizontal saccadic intrusions (square-wave jerks) Impaired smooth pursuit, vertically (reduced range) and horizontally (with catch-up saccades) Preservation of angular vestibulo-ocular reflex Rare horizontal disconjugacy suggesting INO Disturbance/loss of vergence Ultimately, all eye movements may be lost, but vestibular movements are the last to go

29. Features of PSP – 2 Eyelid disorders: apraxia of lid opening, lid lag, repetitive blinking in response to flashlight stimulus (failure to habituate), blepharospasm Tonic head deviation opposite to direction of body rotation (vestibulocollic reflex) Inability to clap just three times (applause sign)

30. The syndrome of PSP Richardson’s syndrome: Within the first two years falls, cognitive dysfunction, supranuclear gaze palsy,abnormal saccades, postural instability PSP-PD : Asymmetric bradykinesia, Initial positive levodopa reponse, tremor, limb dystonia Pure akinesia with freezing attacks (list features): gradual onset of freezing of gait or speech, absent limb rigidity and tremor, no opthalmoplegia in the first 5 years Which parkinsonian disorders cause slow saccades?

31. ETIOLOGY OF SLOW SACCADES Spinocerebellar ataxias (SCA), especially SCA2 (olivopontocerebellar atrophy) Huntington's disease Progressive supranuclear palsy Parkinson's (advanced cases) Whipple's disease Lipid storage diseases Wilson's disease Drug intoxications: anticonvulsants, benzodiazepines Tetanus In dementia: Alzheimer's disease (stimulus-dependent), and in association with AIDS Lesions of the paramedian pontine reticular formation Internuclear ophthalmoplegia Paraneoplastic syndromes Amyotrophic lateral sclerosis (some cases) Peripheral nerve palsy, diseases affecting the neuromuscular junction and extraocular muscle, restrictive ophthalmopathy

32. Epidemiology and Genetics 6 to 7 per 100,000 Tropical fruit and tea with tetrahydroisoquinolones Few familial cases with AD inheritance Case reports with repeated head injury Chromosome 17 codes for tau protein

33. Oba, H. et al. Neurology 2005;64:2050-2055 Figure 5. New radiographic sign for the diagnosis of progressive supranuclear palsy (PSP)

34. Clinical Managment Motor symptoms: dopaminometics Visual symptoms: Prisms and botox for bleopharospasm Cognitive/Behavior: Methylpheniate for apathy