Supranuclear Paralysis of Upgaze

Lid Retraction; Positive Glabella Tap; Supranuclear Paralysis of Saccadic Upgaze; Pursuit Upgaze Intact; Slow Horizontal Hypometric SaccadesPowerPoint Presentations: Tauopathies: A contemporary way to consider a set of neurodegenerative diseases based on their molecular signature: http://library.med.utah.edu/NOVEL/Wray/PPT/Tauopathies_guest_lecture.ppt John Growdon, M.D. Massachusetts General Hospital Progressive Supranuclear Palsy: http://library.med.utah.edu/NOVEL/Wray/PPT/Progressive_Supranuclear_Palsy.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolMemory lossThis 84 year old woman carried the following diagnoses: 1. Extrapyramidal movement disorder; Parkinson's disease vs. Progressive supranuclear palsy 2. Hypertension 3. Recurrent left Bell's palsy In 1992, the patient and her family noted that she was drifting to the right when driving. She progressively became more unsteady on her feet and had multiple falls when turning or falling backwards. Her most severe fall caused a lumbar compression fracture. She was evaluated by her PCP. Brain MRI: showed white matter hyperintensities most compatible with small vessel disease and some atrophy. A diagnosis of Parkinson's disease was made and she was started on Sinemet 25/100, 1 tablet three times a day. Over the course of two years her family noted progressive garbled speech, increased bradykinesia, slight difficulty swallowing, decreased concentration and a wide-eyed staring quality to her face. Her son felt that her personality had changed and she had become more irritable. The patient was referred to the Movement Disorder Clinic for a second opinion. The neurological examination showed: Wide-eyed glassy stare Mild left lower motor neuron facial weakness Mild dysarthric speech Brisk jaw jerk Significant bradykinesia but no tremor Cog wheel-type rigidity Gait narrow based, small-stepped with 3+ on block turning Neuro-ophthalmological examination showed significant ocular motor signs. Eyelids: 1. Infrequent blinking 2. Positive glabella tap 3. Blepharoclonus 4. Slow eyelid opening- mild apraxia Extraocular movements 1. Supanuclear paralysis of upward gaze with intact Bell's and doll's eye movements 2. Slow saccades horizontally and on downgaze 3. Saccadic breakdown of smooth pursuit 4. Poor convergence 5. No nystagmus This constellation of signs is consistent with the diagnosis. Diagnosis: Progressive supranuclear palsy.This patient with Progressive Supranuclear Palsy (PSP) has: • Supranulcear saccadic paralysis of upgaze with intact upgaze pursuit eye movements tracking a target. • Slow downgaze saccades • Slow hypometric horizontal saccades • Slow eyelid opening - mild apraxia Dr. Zee commented on reviewing all the PSP cases with me that many of them have a look of astonishment as present in this case. Comment: The inability to initiate eyelid opening is a dysfunction of voluntary lid control due, in this patient, to disease of the extrapyramidal system. The patient can close her eyes readily on command and reopen them normally after blinking. The term "eyelid apraxia" is a misnomer and should not be used to describe the eyelid dysfunction in this case of PSP because the motor system is affected. Confirmation that the vertical gaze disorder is supranuclear and localized to the rostral interstitial nucleus of the MLF (riMLF) in the midbrain is the presence of : 1. upward deviation of the eyes on forced eye closure (intact Bell's) and 2. full upward eye movements when the head is bent forward, the oculocephalic or doll's eye reflex. At the onset of PSP: • Vertical saccades are slow • Vertical saccadic range is progressively reduced • Impaired initiation of vertical saccades • Vertical smooth pursuit impaired (reduced range) • Vertical optokinetic stimulation can cause gaze to tonically deviate in the direction of the stripe movement (Personal communication Zee DS 2005) Additional PSP signs are: 1. Positive glabella tap, (inability to inhibit a blink when the forehead is tapped) 2. Myerson's Sign (inability to inhibit a blink to a bright pen light shown in the eyes) 3. Blepharoclonus (tremor of the lids on gentle eye closure) 4. Square wave jerks 5. Bilateral ophthalmoparesis in the late stages of the disease Box 12-14 Clinical features of PSP. Pg 639 (5).PSP has characteristic changes on neuroimaging. In another case a sagittal T2-weighted MR scan shows the tectal plate is markedly thinned and atrophic. (Figure 1) Functional MRI reveals global metabolic reduction most pronounced in the frontal lobes, anterior cingulate gyrus, the basal ganglia, the ventrolateral and dorsomedial nuclei of thalamus and the upper brainstem. PET scans using fluorodopa demonstrate diminished striatal dopamine formation and storage. In addition to hypometabolism in the putamen, severe caudate involvement on PET scanning distinguishes PSP from Parkinson's disease. (Figures 2 and 3)Supranuclear paralysis of vertical gaze localizes to the midbrain and to the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). The riMLF is a wing-shaped structure that lies dorsomedial to the red nucleus and rostral to the interstitial nucleus of Cajal. The riMLF contains burst neurons for vertical and torsional saccades. The riMLF projects predominantly to the ipsilateral oculomotor (third nerve) and trochlear (fourth nerve) nuclei.In an autopsy case of PSP, a pale locus ceruleus and substantia nigra are two typical gross features on inspection of the brainstem. (Figure 4) Neuronal loss, granulovacuolar degeneration and fibrillary gliosis are present in areas of neuronal change. There is widespread neuronal and glial tau accumulation in the cortex, basal ganglia, in periaqueductal gray matter, subthalamic nucleus, red nucleus, substantia nigra, pedunculopontine nucleus, superior colliculus, and in the dentate nucleus of the cerebellum. Microscopically, globose neurofibrillary tangles are observed on LHE stain. (Figure 5) The neuronal cytoplasmic inclusions are strongly immunoreactive for tau. (Figure 6A) Tufted astrocytes are a specific finding in PSP. They are often binucleate and have long tau reactive processes. (Figure 6B) The intracellular aggregation of tau in PSP may be sufficient to cause nerve cell degeneration.PSP is a "tauopathy". Studies suggest that it is a recessive disorder in linkage disequilibrium with the tau gene. Rare familial forms of PSP exist including an autosomal dominant transmission with incomplete penetrance. The relationship to the tau gene further suggests a relationship to frontotemporal dementia/Pick's Disease (FTDP) and some families carrying the FTDP-17 mutation (chromosome 17) have affected members with PSP-type phenotypes.There is no cure for PSP and once the disease has begun, its course is relentlessly progressive.1. Buttner-Ennever JA, Horn AK. Pathways from cell groups of the paramedian tracts to the floccular region. Ann N Y Acad Sci. 1996 Jun 19;781:532-540. http://www.ncbi.nlm.nih.gov/pubmed/8694442 2. 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Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. a clinical report on eight cases of heterogenous system degeneration. Trans Am Neurol Assoc. 1963;88:25-29. http://www.ncbi.nlm.nih.gov/pubmed/14272249 8. Stanford PM, Halliday GM, Brooks WS, Kwok JBJ, Storey CE, Creasey H, Morris JGL, Fulham MJ, Schofield PR. Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain 2000;123(Pt 5):880-893. http://www.ncbi.nlm.nih.gov/pubmed/10775534 9. Sir Charles Bell (http://www.whonamedit.com/doctor.cfm/2103.html)SPprogressivesupranuclearpals