NEW AVENUES IN MANAGEMENT OF NYSTAGMUS

FromDr.Shashank Ranade

DNB, DO, DOMS,FCPS,FICO(UK)Fellow, Pediatric Ophthalmology, Strabismus & Ocular motility disorders

[International Guest Speaker, UK]

RANADE SUPER-SPECIALITY EYE CENTREMumbai

Expert panelist talk given at ALL INDIA OPHTHALMOLOGICAL SOCIETY MEET held at KOCHI, February 2012

Financial Disclosure• I hereby declare that I don’t have any financial interests

in any of the products or procedures mentioned in the forthcoming presentation

Nystagmus Work-up• History taking- Onset, consanguinity and family history• Vision assessment- Dilated refraction• Slit lamp examination - iris transillumination defects ?• Fundus examination - Optic nerve or retinal pathologies ?• Eye Movement recordings / EOG / ENG• ERG & pVEP- CSNB, Cone dyst, Ocular albinism, ON

disorders• MRI/ CT Scan and Neurologist opinion -suspected

central/sub-cortical causes• Genetic analysis -FRMD7 in CIN

EYE MOVEMENT RECORDINGS• Electo-oculography (EOG)• Infrared reflectance (IR) • Scleral search coil• Video-electronystagmography ( VENG)- Latest &

most preferred choice amongst all. Good saccadic resolution and linearity for testing saccades and pursuit, less noisy

Various treatment modalities available

• PRISMS• OPTICAL METHODS• SOMATOSENSORY / AUDITORY FEEDBACK

• ELECTRONIC METHODS Fields in which newer • PHARMACOTHERAPY avenues have developed• SURGERY• GENE THERAPY

Clinical division of treatment optionsRx

OlderLess practicedSomatosensory Auditory

stimuli Optical methods , PrismsOld drugs, Botox Inj , Stereotactic NeuroSx and

Artf.diverg.SurgWidely practicedWide recessions , AHP SurgeriesNewer

Widely practicedDrugs- Gabapentin , Baclofen

Futuristic Surgery- Tenotomy , Aug. Tend. Suture

Electronic methodsMolecular genetics / Gene

therapyDrugs- Memantine, 4-Aminopyridines

OLDER- LESSER PRACTICED

TREATMENT OPTIONS

PRISMS Used in 3 scenario’s- • Pre-surgical evaluation purpose• Congenital Nystagmus which gets suppressed while

viewing near targets- we use 7 D BO prisms• Nystagmus with altered head postures- Amount

of prism required ( > 30 pd ), hence it obscures functional vision , are cumbersome and cause chromatic aberration.

Dell’Osso LF .Developments of new treatments for congenital nystagmus, Ann N Y Acad Sci

OPTICAL METHODS • More useful in Acquired Nystagmus of Neurological

type.• It Stabilises the image on the retina through high convex

specs coupled with high negative power CL ( RGP, PMMA).

• Limitations- • Disables all eye movements, works monocularly and in

stationary state only• Field of view -limited• Difficult to handle

Refinement of an optical device that stabilizes vision in patients with nystagmus, Yaniglos SS, Leigh RJ, Optom Vis Sci, 1992,June, 69 ;447-

50

AUDITORY/SOMATOSENSORY STIMULI & BIOFEEDBACK METHOD

• Suppression via trigeminal afferents by using a contact lens over cornea or auditory stimuli

over forehead or acupuncture over neck

muscles and has been primarily found with some effects in CIN.

• Biofeedback has not been reported to be useful.

Dell Osso,Tracis,Abel,Erzurum-Contact Lens in congenital nystagmus,Clin Vis Sci 1988 ; 3: 229-32

Sheth,Dell Osso,Leigh,Van Doren-The effects of afferent stimulation on congenital nystagmus foveation periods. Vision Res 1995 ; 35 : 2371-82

ARTIFICIAL DIVERGENCE SURGERY

• Aim - induce exophoria by bi- medial rectus recessions or recess-resect procedure which in turn the patient overcomes by exerting fusional convergence

• The former is useful in Congenital nystagmus which dampens on convergence while the later in AHP cases

Sedler S, Shallo-Hoffman J, Muhlendyck H. Die Artifizielle-Divergenz-Operation beim kongenitalen Nystagmus. Fortschritte Ophthalmol 1990; 87: 85-9.

Zubcov AA, Stark N, Weber A, Wizov SS, Reinecke RD. Improvement of visual acuity after surgery for nystagmus. Ophthalmology 1993;100: 1488-97

Kestenbaum and artificial divergence surgery for abnormal head turn secondary to nystagmus. Specific and nonspecific effects of artificial divergence, Graf. M, Strabismus, 2002 ; June; 10(2): 69-74.

BOTOX • 25 U of Botulinum Toxin A Injection is injected

directly into the retrobulbar space.• Used in : Acquired Nystagmus ( Post CVA )-

reduces oscillopsia and improve visual acuity• Effect is short lived (3 to 6 months approx),diplopia

and ptosis • Might need to cover the other eye to prevent

‘competition/ diplopia’

Helveston EM, Pogrebiank AE: Treatment of acquired nystagmus with botulinum A toxin. Am J Ophthalmol, 106:584, 1988.

Lennerstrand G, Nordbo OA, Tian S, et al: Treatment of strabismus and nystagmus with botulinum toxin A. Acta Ophthalmol Scand 76:27, 1998

Ruben ST, Lee JP, O’Neill D, et al: The use of botulinum toxin for treatment of acquired nystagmus and oscillopsia.Ophthalmology 101:783, 1994.

OLDER – WIDELY PRACTICED

TREATMENT OPTIONS

HORIZONTAL RECTUS MUSCLE RECESSIONS

• Maximal recession of all 4 horizontal muscles i.e, as high BMRc of 10 mm & BLRc of 12 mm

• First suggested by Briti-Bagolini (1960) but revived by Von-Noorden- Helveston (1991)

• Not only decreases nystagmus intensity and improve visual acuity but also addresses strabismus and head posture issue effectively after thorough surgical planning.

The effect of horizontal rectus muscle surgery on clinical and eye movement recording indices in infantile nystagmus syndrome, Bagheri et al, Strabismus, 2010,June, 18(2) ; 58-64

Vertical rectus muscle surgery for nystagmus patients with vertical abnormal head posture,Yang MB,Archer et al, J AAPOS, 2004,Aug ; 8 (4), 299-309

SOURCE- The effect of bilateral horizontal rectus recession on visual acuity, ocular deviation or head posture in patients with nystagmus, BagheriA, Farahi A, Yazdani,

J AAPOS, 2005, Oct, 9(5), 433-7

RECESS- RESECT PROCEDURES• 1953, Anderson and Kestenbaum independantly

suggested them. Anderson had mentioned about recession of horizontal rectii ,While Gotto had suggested resection, Kestenbaum came with idea of operating all the 4 muscles (5mm)

• Parks modified it (5,6,7,8) & Calhoun-Harley -Nelson ‘Augmented’ it.

• The surgery not only shifts the eye to null position to correct AHP but also improves nystagmus waveforms and broaden the null zone

Anderson JR. Causes and treatment of congenital eccentric nystagmus. Br J Ophthalmol 1953;37: 267-80.

Kestenbaum A. Nouvelle opération du nystagmus. Bull Soc Ophthamol Fr 1954

Parks MM. Congenital nystagmus surgery. Am Orthopt J 1973;23: 35-9

FIG 1. Comparison of preoperative (A) and 3 months postoperative (B) electronystagmogram showing shift of null position from 30° right gazepreoperatively to primary position after augmented Anderson procedure

FIG 1 -Prospective Clinical Evaluation of Augmented Anderson Procedure for Idiopathic Infantile Nystagmus ,Pradeep Sharma, Vimala Menon, JAAPOS,Aug 2006, 10 (4), 312-317

FIG 2- Improvement in Visual Acuity Following Surgery for Correction of Head Posture in Infantile Nystagmus SyndromeVijayalaxmi, A Kumar, J POS, Nov 2011,48 (6), 341-346

HEAD POSTURE CORRECTION SURGERIESSurgery Indication What is done ?

Kestenbaum Head turn Bilateral 5mm recess-resect of hor. recti

Augmented Anderson’s

Head Turn Yolk muscle recess ( MR-9, LR-12 )

Classic Parks Head turn upto 30 deg

5,6,7,8 Rule

Aug Kestenbaum / Classic Plus(Calhoun-Harley)

Head turn above 30 deg

Necessary augmentaions of 40 % and 60 % required ( for 40 and 45 deg resp)

Vert Kestenbaum /Parks

Chin elevation/depression

Bilateral recess-resect of SR & IR

Torsional Kesten

Nyst with Head tilt SO & IO surgeries

Decker’s Same as above Vertical transposition of horizontal recti

Spielmann’s Same as above Surgical slanting of insertion of all 4 recti

Von Noorden’s

Same as above Horizontal transposition of Vertical recti

PHARMACOTHERAPY

Pharmacology in NystagmusName of the drug Mode of action Preferred drug of

choiceGabapentin & Baclofen

GABA receptor agonists Acquired pendular nystagmus

Memantine NMDA receptor antagonist

Congenital Idiopathic Nystagmus

4-Aminopyridines K+ channel blocker Vertical upbeat- downbeat nystagmus

Clonazepam Benzodiazapine / GABA a receptor agonist

Carbamazepine Na+ channel blocker Sup Oblique MyokimiaSodium valproate Na+ channel blocker &

GABA agonistsPendular nystagmus

Acetozolamide & Brinzolamiode

Carbonic anhydrase inhibitor

Infantile Nystamus

Benztropine & Trihexphenydyl

Anti-Cholinergic Oculopalatal tremor

Propranolol B- Blocker Opsoclonus

NEWER- WIDELY PRACTICED

TREATMENT OPTIONS

BACLOFEN• Useful in- Acquired Pendular Nystagmus ( esp.

post fossa tumors and Post MS)• Recommended dosage schedule- 5 -10 mg TDS • Visible changes noted- reduced amplitude of

horizontal pendular nystagmus ( 70 % times ), subjective improvement of oscillopsia ( 45 % times ) and visual acuity improvement ( 35 % times )

• Side effects- Drowsiness(63%),dizziness (15%), Nausea (12%)

Effects of baclofen on upbeat and downbeat nystagmus,M Dietrich, A Straube et al, J of Neurology, neurosurgery and Psychiatry, 1991 ;54 :627-32

CASE REPORT• 26 yr old, male with h/o horizontal diplopia and dizziness since 2 weeks • Confirmed to have right INO with upbeat nystagmus • MRI - Hyperintense area in right midbrain tegmentum and anterior cerbellar vermis s/o of inflammatory plaque• EEG and evoked potentials were normal• Introduced on 5mg TDS dose of baclofen• Decrease in nystagmus intensity in primary , right , left , up and down gaze was noticed.

GABAPENTIN• Useful in- Acquired Pendular–Jerk Nystagmus (esp.

Post MS, Post ocular pathology) and CIN• Recommended dosage schedule- 300 – 800 mg

TDS• Visible changes noted- reduced amplitude of

horizontal pendular nystagmus ( 95 % times ), subjective improvement of oscillopsia ( 60 % times ) and visual acuity improvement ( 35 % times )

• Side effects- Fatigue, dizziness, emotional and behavioral problems in children

The effects of gabapentin and memantine in acquired and congenital nystagmus : a retrospective study, T Shery, I Gottlob, Br J O, 2006 ; 90: 839-843 Gabapentin but not vigabatrin is effective in acquired nystagmus in multiple sclerosis, F Bandini, E Castello et al, Journal of Neurology Neurosurgery Psychiatry, 2001; 71 : 107-11

CASE REPORT• 60 yr old, male , K/C/O Multiple sclerosis • Presented with elliptical pendular nystagmus• BCVA -OD 6/24, OS 6/60. • Patient put on oral gabapentin. Started on 300 mg TDS and since the patient was able to tolerate with inadequate response the dosage was further increased to 800 mg TDS. • BCVA improved in OD to 6/12 OS to 6/18.• Nystagmus amplitude also showed 50 % improvement.• Now almost 6 years he is still on gabapentin with good tolerance and consistent response.

After GabapentinBefore Gabapentin

RIGHT EYE

LEFT EYE

Source- The effects of gabapentin and memantine in acquired and congenital nystagmus : a retrospective study, T Shery, I Gottlob, Br J O, 2006 ; 90: 839-843

NEWER- FUTURE TRENDS

MEMANTINE• Useful in- Congenital idiopathic nystagmus, Acquired

pendular Nystagmus ( even those refractory to gabapentin )

• Recommended dosage schedule- 10 -20 mg BD • Visible changes noted- reduced amplitude of

horizontal pendular nystagmus ( 70 % times ), subjective improvement of oscillopsia ( 45 % times ) and visual acuity improvement ( 35 % times )

• Side effects- Dizziness(7%), headache (6%), confusion (6%), constipation(5%)

The effects of gabapentin and memantine in acquired and congenital nystagmus : a retrospective study, T Shery, I Gottlob, Br J O, 2006 ; 90: 839-843

Memantine dosage schedule (Source- Dept of Ophthalmology, Leicester Royal Infirmary

,England)New cases

10 mg BD for 56 daysIf responds adequatelyShift to

maintenance dosage

10 mg OD

If response is poor / inadequateIncrease the

dosage to 20 mg BD for 56

daysIf responds,

shift to maintenanc

e doseMaintain

on 10 mg BD dose

CASE REPORT• 65 yr old, male with c/o oscillopsia, ataxia, hyper-reflexia of right extremities• MRI showed plaques• CSF confirmed the same• Diagnosed with MS• Started on gabapentin 300 and then 800 TDS with poor response • Patient was shifted to memantine 10 mg TDS and showed a spontaneous improvement in nystagmus intensity.

RIGHT EYE

LEFT EYE

Gabapentin Memantine

AFTER TREATMENTBEFORE TREATMENT

Source- The effects of gabapentin and memantine in acquired and congenital nystagmus : a retrospective study, T Shery, I Gottlob, Br J O, 2006 ; 90: 839-843

4- AMINOPYRIDINES• A latest study by Strupp et al established the role of 4-

Aminopyridines and 3,4-diaminopyridines in Upbeat nystagmus secondary to any lesion between pathway from vestibular to oculomotor nuclei

• Reduction in oscillopsia and improvement in upward smooth pursuit movement during attempted fixation in daylight ( abolished in darkness !)

• Dosage used was- 10 mg OD with no documented side efffects

• Probable mode of action is via increased excitability of cerebellar purkinje cells from K+ channel blockade

4-aminopyridine restores visual ocular motor function in upbeat nystagmus ,S Glasauer, M Strupp et al, Jour. Neurol Neurosurg Psychiatry 2005;76:451–453.

Electronic methods • Device uses infrared sensor guided measurement of

eye movements and feeding the same to a phase locked loop / adaptive filters which generates an electric signal which in turn rotate the riley prisms synchronous with the nystagmus and through which the person views the world.

• In future we might have specs which uses this miniature principle to cancel out the visual effects of pathological nystagmus.

Application of adaptive filters to visual testing and treatment in acquired pendular nystagmus, Ryan M. Smith, John S. Stahl, Journal of Rehabilitation, Research & Development,Vol 41,June 2004, 313-324

Prospects for Treating Acquired Pendular Nystagmus with Servo-Controlled Optics, John Stahl et al, Invest Ophthal Vis Sci, 2000, Apr, 41(5), 1084-90

Prototype electronic device

Infrared device

Prism assembly

Acuity card

T & R (Tenotomy & Resuturing)• Principle- Operating on the tendon where the Proprioceptive

feedback loop for ocular-motor control is located.• Method- Surgically detach the muscles from the globe and suture

them back to their original insertions without resection or recession• Holds lots of promise for CIN where AHP is not an issue• There are group of people who don’t believe in and find it

contentious• Improves NAFX ( eXpanded Nystagmus Acuity Function) - an

indicator of target foveation, fastens target acquisition time and also reduce oscillopsia.

.

Dell'Osso LF, Hertle RW, Williams RW, Jacobs JB. A new surgery for congenital nystagmus: effects of tenotomy on an achiasmatic canine and the role of extraocular proprioception. J AAPOS 1999;3: 166-82

Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in patients with infantile nystagmus syndrome: a pilot study. J AAPOS. 2004;8:539-548

Source- Effects of tenotomy on patients with infantile nystagmus syndrome, Wang, Dell Osso et al, JAAPOS,2006,10: 552-560

Simple Augmented Tendon Suture ( ATS)

• No tenotomy is required. • 3 cross sword sutures with 6-0 vicryl are placed in the tendon towards the myotendinous junction,not suturing the globe• Probable mode of action- ischemia, irritation and scarring which would act through the proprioceptive loop. It causes relaxation of the resting muscle /steady state innervation and puts it on lower portion of length- tension curve.

Two hypothetical Nystagmus procedures : Augmented Tenotomy and Reattachment and Augmented tendon suture ( Sans Tenotomy ), Dell’ Osso, J Pediatr Ophthalmol Strabismus, 2009;46:337-344

Split Tendon, ATS methodAs the name suggests you need to do a tendon split along the length and then pass the sutures on either side taking care of the vascular arcades.

No concrete evidence has yet been established about this procedureIts efficacy needs to be established and is just a hypothesis in current scenarioTwo hypothetical Nystagmus procedures : Augmented Tenotomy and Reattachment and Augmented tendon suture ( Sans Tenotomy ), Dell’ Osso, J Pediatr Ophthalmol Strabismus, 2009;46:337-344

GENETICS IN NYSTAGMUS

GENE THERAPY• Applicable in SENSORY DEFICIT NYSTAGMUS

secondary to retinal pathologies• Applied to the retina to correct genetic deficits that

impair vision directly and may facilitate the development of nystagmus

• E.g- RPE65 gene deficiency in Leber’s Congenital Amaurosis

Achromatopsia• Moorefields hosp performed recombinant adenovirus vector guided delivery of missing gene in 3 patientsMaguire, A. M., Simonelli, F et al. (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis The New England

journal of medicine, 358(21), 2240–2248.

Bainbridge, J. W. B., Smith et al. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis The New England journal of medicine, 358(21), 2231–2239

GENETIC ANALYSIS & COUNSELLING• Individual cases- History taking and thorough documentation

of family tree will help us know the mode of transmission, associated conditions and penetrance.

• Helpful in CIN- FRMD7 gene mutation, if documented then its known to have better vision, lesser AHP issue and better prognosis

• Genetic analysis provides scope for research, which might turn a milestone for gene therapy in future

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7, Gottlob I, Shery et al, Brain (2008), 131, 1259-1267

SOCIAL ISSUES• Need extra help at school• Positioning : Front benches of classroom to match AHP which will

improve visual acuity, teachers need to adopt bold writing, high contrast boards

• Extra-curricular activities- Avoid sports requiring fine vision i.e., ball games. Instead swimming can be preferred

• Carrier guidance - Prefer visually less demanding professions • Personality development workshops

• Helpline / Networking -• In India we don’t have any helpline like NN (Nystagmus Network) in

Europe http://www.nystagmusnet.org/ • In US they have the ANN ( American Nystagmus Network)

http://nystagmus.org/ • The main intent of these sites/ networks is to improve the quality of

life for all persons and families affected by nystagmus, through organized community support, education and public awareness

Thank You