Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew Deviation & the OTR Extra ‘steps’ and the old ‘new’ language of vertical and cyclovertical strabismus David E. Newman-Toker, M.D. The Johns Hopkins Hospital Bloomberg School of Public Health 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Objectives Understand the current use of the terms “ocular tilt reaction” and “skew deviation” Be familiar with the anatomic & physiologic substrate of ocular tilt & skew Know how to distinguish between skew and isolated oblique palsies at the bedside, recognizing limitations in our understanding of cyclovertical ‘palsies’ 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Why Care About Skew? A 51-year-old woman complains of vertical diplopia for a day. Her exam reveals subtle vertical strabismus. A CT scan of the brain is normal. Is it just a 4th? Can she go home? She then develops symptoms of nausea, hearing loss, ventilation problems (dyspnea) and somnolence. 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

MRI & Angio - Basilar Occlusion Ophthalmology Grand Rounds, Moran Eye 11/16/05 MRI & Angio - Basilar Occlusion Pre-lysis Post-lysis Mennel, Clin Exp Ophth 2005 Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Overview Definition & Brief History of “Skew” Vertical & Torsional VOR Normal & Pathologic OTR Skew vs. Superior Oblique Palsy Implications & Future Directions 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Modern Definition of Skew & OTR Ophthalmology Grand Rounds, Moran Eye 11/16/05 Modern Definition of Skew & OTR Newman-Toker, Skew Deviation & OTR

Modern Definition of Skew & OTR Ophthalmology Grand Rounds, Moran Eye 11/16/05 Modern Definition of Skew & OTR Skew Deviation An acquired vertical* strabismus resulting from imbalance in vestibular (balance system) inputs to the oculomotor system Pathologic OTR – Ocular Tilt Reaction The triad of skew deviation, binocular torsion (ocular counterroll), and head tilt 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 A Brief History of Skew & Cyclovertical Strabismus A Tale of Two Disciplines Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 A Brief History of Skew 1850+ – Latin terminology is purely descriptive (e.g. “strabiusmus sursoadductorius” to describe overaction in adduction); no implication of oblique dsyfunction 1871 – Nagel first to figure out cycloduction; forgotten 1900 – Hoffman & Bielschowsky ‘discover’ and popularize head tilt to diagnose “cyclovertical palsy” 1913 – ocular tilt discovered in animals; forgotten 1926 – Brain describes head tilt & skew from ear disease (otitis interna) 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 A Brief History of Skew 1958 – Parks labels & delineates elements of the “three-step test” for cyclovertical muscle ‘palsy’ 1960s – ‘skew’ is vertical strabismus that ‘doesn’t fit’ three-step test, and implies central cause 1975 – Keane publishes 100 cases, mostly posterior fossa disease, unclear localizing value; Westheimer & Blair (re)‘discover’ & characterize OTR in monkeys 1977 – Rabinovitch et al. report 1st human OTR in MS 1979 – Halmagyi et al. report 1st human OTR from peripheral vestibular lesion 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 A Brief History of Skew 1980s – skew & OTR linked, but not linked to generic cyclovertical muscle ‘palsies’ 1991 – Brandt & Dieterich describe 3 ‘types’ of skew; later show localizing value with brainstem lesions 1999 – Donahue et al. 5 cases of skew mimicking SO palsy, then 6 cases of skew mimicking IO palsy 2001 – Demer points out tautologic thinking in strabismology of cyclovertical terminology 2003 – Brodsky considers possible ‘horizontal skew’ 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR Ophthalmology Grand Rounds, Moran Eye 11/16/05 Vertical & Torsional VOR Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR What is the V.O.R.? Ophthalmology Grand Rounds, Moran Eye 11/16/05 Vertical & Torsional VOR What is the V.O.R.? The vestibulo-ocular reflex… Is the circuit (reflex arc) connecting balance organs and eye movement structures Keeps our vision steady when we move, by instantaneously moving our eyes in the direction opposite any head movement The (angular) vestibulo-ocular reflex [VOR] is the disynaptic neural reflex that connects the semicircular canals to the eye muscle cranial nerve nuclei 3, 4, 6. The semicircular canals respond to head rotations (specifically to angular acceleration – e.g. turning your head to the right). In addition to the ‘angular’ VOR, there is a ‘linear’ VOR. The otolith organs (utricle and saccule) respond to head translations (e.g. driving in a car; riding in an elevator) and tilts (maintaining the head tilted with respect to gravity, after the head movement has stopped). 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Vestibulo-Ocular Reflex Ophthalmology Grand Rounds, Moran Eye 11/16/05 Vestibulo-Ocular Reflex Here we are examining the VOR by asking the patient to look at the camera as her head is turned from side to side. Because we are asking the patient to do it herself, we call it an “active” head rotation. If we did it manually for her, we would call it a “passive” head rotation. Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR The Ear Ophthalmology Grand Rounds, Moran Eye Vertical & Torsional VOR The Ear 11/16/05 Middle Ear Inner Ear Outer Ear – hearing Middle Ear – hearing Inner Ear – hearing & balance Balance Organ = labyrinth Outer Ear Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR Inner Ear Ophthalmology Grand Rounds, Moran Eye Vertical & Torsional VOR Inner Ear 11/16/05 Labyrinth Semicircular Canals x 3 (A-VOR) Each labyrinth (one in each inner ear) is made up of 3 semicircular canals and 2 otolith organs. The semicircular canals are the horizontal (a.k.a. lateral), anterior (a.k.a. superior), and posterior (a.k.a. inferior) SCC. The otolith organs are the utricle (which senses tilting or linear acceleration to the side, forwards, or backwards) and the saccule (which senses gravity and linear acceleration forwards, backwards, up, or down). The precise differences in function between utricle and saccule remain incompletely understood. Otolith Organs (L-VOR, OTR) 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR Inner Ear to Brainstem Ophthalmology Grand Rounds, Moran Eye Vertical & Torsional VOR Inner Ear to Brainstem 11/16/05 Labyrinth Vestibular Nuclei Cochlea The “vestibular nuclei” are a cluster of four brainstem nuclei that receive input from the labyrinth via the 8th cranial nerve. For most clinical purposes, there is no need to differentiate among the subnuclei. Note that although the 8th nerves enter the brainstem in the low pons (close to the ponto-medullary junction), the vestibular nuclei are ‘long’ enough that they dip down into the upper medulla, and can be damaged in acute strokes of the lateral medulla. 8th Nerve 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 extensive connections with oculomotor nuclei Angular VOR Substrate 3 Vestibular nuclei (8th) are connected to the oculomotor nuclei 3rd & 4th – to move the eyes vertically and torsionally 6th & 3rd – to move the eyes horizontally 4 The 3rd & 4th nuclei are in the midbrain, while the 6th is in the pons (Cranial Nerve 2-2-4-4 rule). 6 Keep vision stable Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Vestibulocerebellum (the green colored stuff) 8th Nerve Vestibular Nuclei The ‘vestibular system’ includes the inferior part of the cerebellum, the so-called ‘vestibulocerebellum’ (flocculus, paraflocculus, & nodulus). Just to make matters confusing, the vestibulocerebellum is also known as the ‘flocculonodular lobe’ (for obvious reasons) and the ‘archicerebellum’ (because it’s phylogenetically the oldest). There are extensive bi-directional connections between the cerebellum and the vestibular nuclei. There are also direct connections from the labyrinth to the cerebellum that bypass the vestibular nuclear complex. Gaze-holding structures Newman-Toker, Skew Deviation & OTR

Vertical & Torsional VOR How does the VOR work? Ophthalmology Grand Rounds, Moran Eye Vertical & Torsional VOR How does the VOR work? 11/16/05 Towards the canal(s) is ‘ON’ Tonic firing at rest; rate changes with head motion; reciprocal innervation Stimulates eyes to move in plane of canal, opposite head rotation 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Normal & Pathologic OTR Ophthalmology Grand Rounds, Moran Eye 11/16/05 Normal & Pathologic OTR Newman-Toker, Skew Deviation & OTR

Ocular Tilt Response: Normal Anatomy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Ocular Tilt Response: Normal Anatomy Newman-Toker, Skew Deviation & OTR

Maintain a Stable Horizon Ophthalmology Grand Rounds, Moran Eye 11/16/05 Maintain a Stable Horizon At least if you’re a horse!!! Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Dynamic Roll VOR R L Which muscles are these? Where are these? R-IR R-IO L-SR L-SO 3 - SR, IR, IO 4 - SO The seemingly confusing organization of ‘crossed’ oculomotor nuclei (from 4th to superior oblique and 3rd medial subnucleus to superior rectus) makes perfect sense from a teleologic standpoint, when you consider the phylogenetically older vestibular system. This allows one ear to drive the bilateral eye response to tilt simply by stimulating one side of the brainstem, rather than both sides. Ant/Post SCC MVN Left Tilt Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Static Normal OTR R L R-IR R-IO L-SR L-SO 3 - SR, IR, IO INC 4 - SO The cerebellum keeps most of these movements in check in normals (as a vestigial reflex) such that counterroll is only about 10% of head roll, and the vertical displacements are minimal. Utricle cerebellum partly suppresses these movements in normals LVN Left Tilt Newman-Toker, Skew Deviation & OTR

Ocular Tilt Response: Patho-anatomy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Ocular Tilt Response: Patho-anatomy Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic OTR Dynamic roll-plane VOR (i.e. damage to semicircular canal afferents) Torsional nystagmus with slow phase rolling towards the shoulder opposite the hypertropia (i.e. in the direction of the head tilt) plus skew Static roll-plane OTR (i.e. damage to utricular afferents or integrating centers) Static ocular counterroll & skew 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic Dynamic Roll VOR R L 3 - SR, IR, IO 4 - SO Patient will have an associated LEFT internuclear ophthalmoplegia X Ant/Post SCC The fast phase of nystagmus beats towards the hyper eye damage dynamic pathway from RIGHT ear in LEFT MLF MVN Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Static Pathologic OTR R L 3 - SR, IR, IO INC 4 - SO compensatory ipsilesional ‘wrong way’ head tilt damage RIGHT ear pathway equivalent of LEFT head tilt X Utricle LVN Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic OTR (Ocular Tilt Reaction) Triad Head tilt Vertical (skew) deviation Ocular torsion Note that eyes are opposite that expected for head tilt!!! Modified from original in Rabinovitch, Archives of Ophthalmology, 1977 Image has been flipped (actual original had left head tilt, rather than right tilt Modified from Rabinovitch,Arch Ophth 1977 Newman-Toker, Skew Deviation & OTR

Skew vs. SO Palsy Ophthalmoscopy & Photography Ophthalmology Grand Rounds, Moran Eye Skew vs. SO Palsy Ophthalmoscopy & Photography 11/16/05 normal fovea sits 2-7º below center of disc… Intorsion is easier than extorsion to measure because normal position is 2-7 degrees extorted. …so intorsion is easier to ‘see’ than extorsion Newman-Toker, Skew Deviation & OTR

Pathologic OTR – Ocular Torsion Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic OTR – Ocular Torsion RIGHT head tilt, LEFT hyperdeviation, fundus torsion towards RIGHT shoulder Mossman, Neurol 1997 Mossman & Halmagyi, Neurology 1997 (not same case as presented with head tilt, but similar torsion) EXcyclotorsion OD INcyclotorsion OS Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic OTR Profound, lasting head tilts/OTR Midbrain – Interstitial nucleus of Cajal [INC] (contralesional head tilts) Lateral medulla (ipsilesional head tilts) Transient head tilts/OTR Pons – medial longitudinal fasciculus [MLF] (usually contralesional head tilts) Labyrinth/8th Nerve – ipsilesional head tilts 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew vs. SO Palsy Newman-Toker, Skew Deviation & OTR

Skew Deviation vs. SO Palsy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew Deviation vs. SO Palsy Parks 3-Step test with Bielschowsky Tilt Test Which eye is higher? Is it worst looking away from the side of the hyper? Is it worst with head tilted toward the hyper? 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 1. Which Eye Is Higher? Pathologic OTR with LEFT hyperdeviation LEFT 4th Nerve Palsy Left Left Newman-Toker, Skew Deviation & OTR

2. Worse Looking Right or Left? Ophthalmology Grand Rounds, Moran Eye 11/16/05 2. Worse Looking Right or Left? Pathologic OTR with LEFT hyperdeviation LEFT 4th Nerve Palsy Variable, Could be Right Should be Right Newman-Toker, Skew Deviation & OTR

Bielschowsky Head Tilt Test 3. Worse with Tilt Right or Left? Ophthalmology Grand Rounds, Moran Eye 11/16/05 Pathologic OTR with LEFT hyperdeviation LEFT 4th Nerve Palsy Remember, what you’re doing here is using the NORMAL OTR to induce torsional eye movements. Should be Left Should be Left Newman-Toker, Skew Deviation & OTR

Skew Deviation vs. SO Palsy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew Deviation vs. SO Palsy Parks 3-Step test with Bielschowsky Tilt Test Which eye is higher? Is it worst looking away from the side of the hyper? Is it worst with head tilted toward the hyper? 4th Step Is it worst looking down? 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

4. Worse Looking Up or Down? Ophthalmology Grand Rounds, Moran Eye 11/16/05 4. Worse Looking Up or Down? Pathologic OTR with LEFT hyperdeviation LEFT 4th Nerve Palsy Variable, Could be either Down early, Up late Newman-Toker, Skew Deviation & OTR

Skew Deviation vs. SO Palsy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew Deviation vs. SO Palsy Parks 3-Step test with Bielschowsky Tilt Test Which eye is higher? Is it worst looking away from the side of the hyper? Is it worst with head tilted toward the hyper? 4th Step Is it worst looking down? 5th Step Is the fundus of the hyper eye excyclorotated? 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

5. Is Hyper Eye Excyclorotated? Ophthalmology Grand Rounds, Moran Eye 11/16/05 5. Is Hyper Eye Excyclorotated? Pathologic OTR with LEFT hyperdeviation LEFT 4th Nerve Palsy Should be Incyclo (?) Should be Excyclo Newman-Toker, Skew Deviation & OTR

Skew Deviation vs. SO Palsy Ophthalmology Grand Rounds, Moran Eye 11/16/05 Skew Deviation vs. SO Palsy Parks 3-Step test with Bielschowsky Tilt Test Which eye is higher? Is it worst looking away from the side of the hyper? Is it worst with head tilted toward the hyper? 4th Step Is it worst looking down? 5th Step Is the fundus of the hyper eye excyclorotated? More Steps? MRI ocular muscles & pulleys? 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Skew vs. SO Palsy Other Features Suggesting Skew Ophthalmology Grand Rounds, Moran Eye Skew vs. SO Palsy Other Features Suggesting Skew 11/16/05 Symptoms Dizziness or vertigo Oscillopsia Nausea/vomiting Dysarthria/dysphagia Clumsiness or poor coordination Balance or gait problems (except due to loss of stereopsis) Signs Impaired dynamic visual acuity Head thrust sign Breakdown of smooth pursuit tracking or VOR suppression Saccadic dysmetria Nystagmus Limb or gait ataxia 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Implication & Future Directions Ophthalmology Grand Rounds, Moran Eye 11/16/05 Implication & Future Directions Newman-Toker, Skew Deviation & OTR

Implications & Future Directions Ophthalmology Grand Rounds, Moran Eye 11/16/05 Implications & Future Directions Revisiting the ‘old’ language of cyclovertical strabismus (Demer, 2001) ‘Secondary’ skews? Horizontal skews? (Brodsky, 2003); Pulley problems? (Demer) Implications for strabismus surgery… Do the ‘opposite’ procedure? (Donahue) Will it work? (9/10 Siatkowski, beware cerebellar/ongoing) Educational tools – NOVEL animations 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Demer, AJO 2001 Newman-Toker, Skew Deviation & OTR

NOVEL Animations – Utah/NLM Ophthalmology Grand Rounds, Moran Eye 11/16/05 NOVEL Animations – Utah/NLM N.B. – These animations are ‘works in progress’ and are not yet accurately rendered. In particular the ocular torsion seen with head tilt in this ‘normal’ is exaggerated, and lacking corrective quick phase torsional movements. Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 Take Home Messages “Skew” is more than strabismus that doesn’t fit SO palsy by 3-step test Eye movement pattern in skew/OTR - towards ear is ‘on’; keeps horizon stable; ‘derivable’ Some skews look like oblique palsy except fundus torted the ‘wrong’ way Ask about balance symptoms and look for signs in patients with vertical strabismus Keep an open mind… this story is not over yet 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR

Ophthalmology Grand Rounds, Moran Eye 11/16/05 ERRATUM 11/17/05 For those attending Moran Eye Institute Grand Rounds on 11/16/05, I answered a question after the lecture incorrectly. The correct answer is that direction of head tilt CANNOT distinguish between a superior oblique palsy and a pathologic OTR, since both will generally be ‘away’ from the hyperdeviated eye. Head tilt can, of course, distinguish between ‘normal’ OTR (towards the hyperdeviated eye) and ‘pathologic’ OTR (away from the hyperdeviated eye), though the hyperdeviation with ‘normal’ OTR is quite small, and would not generally be confused for a pathologic state. 11/16/05 Newman-Toker Newman-Toker, Skew Deviation & OTR