Purpose

To identify cases of synergistic divergence whose characteristics suggest that this entity is a form of Duane syndrome.

Methods

The records of all patients with a Duane syndrome diagnosis, including standardized eye position photographs, from the E-Consultation program of Cybersight, Orbis International were analyzed.

Results

A total of 350 Duane syndrome cases were identified. Of these, 19 (5%) had features consistent with synergistic divergence, or type 4 Duane syndrome. Of the 19, 16 (84%) were male, 15 (79%) had palpebral fissure narrowing, all had anomalous head posture, and 18 (95%) were exotropic. Only 9 (47%) patients were reported to have undergone surgery.

Conclusions

Synergistic divergence is a rare entity with features similar to those of Duane syndrome. We suggest that this entity be classified as type 4 Duane syndrome, because it has unique findings and an innervation pattern that differs from the other 3 recognized types

Helveston, Eugene M.

Schliesser, Joshua A.

Sprunger, Derek T.

Journal of American Association for Pediatric Ophthalmology and Strabismus

IUPUIScholarWorks

Type	IV	Duane	Syndrome	 1Type	IV	Duane	Syndrome	Joshua	A.	Schliesser,	MD1;	Derek	T.	Sprunger,	MD2;	Eugene	M.	Helveston,	MD2	1. Dixie	Ophthalmic	Specialists	at	the	Zion	Eye	Institute,	St.	George,	UT,	USA2. Indiana	University	School	of	Medicine,	Indianapolis,	IN,	USACorresponding	Author:	Joshua	Schliesser,	MD,	1791	East		280	North	St.	George,	UT	84790	(email:	josh.schliesser@gmail.com)	This	study	was	conducted	at	Riley	Hospital	for	Children	Indiana	University	School	of	Medicine,	Indianapolis,	Indiana.	Word	Count	1863	Word	Count	Abstract	163	_________________________________________________________________________________ This is the author's manuscript of the article published in final edited form as:Schliesser, J. A., Sprunger, D. T., & Helveston, E. M. (2016). Type 4 Duane syndrome. Journal of American Association for Pediatric Ophthalmology and Strabismus, 20(4), 301–304. https://doi.org/10.1016/j.jaapos.2016.05.012Type	IV	Duane	Syndrome		2ABSTRACT:		Purpose:		To	identify	cases	of	synergistic	divergence	and	suggest	that	this	entity	is	a	form	of	Duane	syndrome,	with	additional	features	that	would	characterize	this	entity	as	a	separate	type.			Methods:		The	records	of	all	patients	with	a	Duane	syndrome	diagnosis,	including	standardized	eye	position	photographs,	from	the	E‐Consultation	program	of	Cybersight,	Orbis	International	were	analyzed.		Results:		350	Duane	syndrome	cases	were	identified.	19	(5%)	of	these	cases	had	features	consistent	with	Type	IV	Duane	syndrome	or	synergistic	divergence.	There	was	a	male	predilection	as	16	(84%)	were	male.	15	(79%)	had	palpebral	fissure	narrowing.	19	(100%)	patients	had	anomalous	head	posture.		18	(95%)	patients	were	exotropic.	Only	9	(47%)	patients	with	Type	IV	were	reported	to	have	undergone	surgery.		Conclusions:		Synergistic	divergence	is	a	rare	entity	with	features	similar	to	those	of	Duane	syndrome.		We	suggest	that	this	entity	be	classified	as	Type	IV	Duane	syndrome	as	it	has	unique	findings	and	an	innervation	pattern	different	from	the	other	three	types.																										Type	IV	Duane	Syndrome		3INTRODUCTION	Duane	syndrome	encompasses	a	spectrum	of	strabismus	entities	that	have	as	common	features:	mis‐innervation	and	co‐contraction	of	extraocular	muscles	in	addition	to	enophthalmos	with	palpebral	fissure	narrowing.1‐3	Other	findings	often	include	an	abnormal	compensatory	head	posture	and	vertical	upshoots	or	downshoots.		Historically,	Duane	syndrome	has	been	classified	into	three	types.		Type	I	includes	patients	with	poor	eye	abduction	and	esotropia.		Type	II	includes	patients	with	poor	eye	adduction	and	exotropia.		Type	III	includes	patients	with	both	poor	eye	adduction	and	abduction.		Duane	syndrome	has	been	considered	a	continuum	of	diseases	with	variability	in	mis‐innervation	and	resultant	clinical	features.1	Initially	described	in	the	1800’s	by	multiple	authors,	Duane	was	the	first	to	obtain	a	relatively	large	case	series	of	patients	and	described	abnormal	motility,	head	position,	globe	retraction,	and	pseudoptosis.4	With	electrophysiology	testing,	Huber	demonstrated	paradoxical	mis‐innervation	of	rectus	muscles	and	further	classified	Duane	syndrome	into	the	three	subtypes	classically	observed.5		Simultaneous	abduction	or	synergistic	divergence	has	previously	been	reported	in	the	literature.1‐3,6,7	These	case	reports	demonstrate	typical	findings	of	a	Duane	syndrome	variant	as	well	as	an	extreme	form	of	mis‐innervation.	Patients	typically	have	exotropia	in	primary	gaze	with	synergistic	divergence	of	the	affected	eye	despite	expected	adduction	(Figure	1).		Type	IV	Duane	Syndrome		4Due	to	advancements	in	technology	and	communication	our	ability	to	understand	diseases	is	growing.	The	Internet	allows	physicians	from	all	over	the	world	to	communicate	and	consult	on	challenging	cases	while	still	maintaining	patient	confidentiality.	Cybersight®	is	a	telehealth	and	education	program	of	Orbis	International.	Through	Cybersight	physicians	are	able	to	consult	expert	eye	care	professionals	for	help	regarding	challenging	cases.	This	collaboration	helps	provide	education	and	care	to	patients	all	over	the	world.				METHODS	Utilizing	the	Cybersight	database,	350	cases	of	Duane	syndrome	were	presented	between	the	years	of	2003‐2012	for	electronic	consultation.	A	retrospective	review	of	patient	demographics	including	age	and	gender,	ophthalmologic	history,	medical	history,	patient/family	description	of	eye	problem	was	obtained	from	the	database.	Exam	results	including	visual	acuity,	head	position,	refraction,	description	of	ductions	and	versions	and	laterality	of	abnormality	were	also	noted.			The	cybersight	website	has	an	extensive	template	for	entering	and	uploading	patient	information.	This	standardization	simplifies	the	consultation	process.	Cybersight	receives	cases	from	all	over	the	world.	Lastly,	an	assigned	mentor	via	the	Cybersight	consultation	service	analyzed	patient	photographs	of	eye	alignment	of	Type	IV	Duane	Syndrome		5the	9	diagnostic	positions	of	gaze	including	right	and	left	head	tilt.		Multiple	mentors	volunteer	as	consultants	and	were	involved	in	these	electronic	consultations.				This	study	and	all	of	the	data	collection	performed	conform	to	all	local	laws	and	were	compliant	with	the	principles	of	the	Declaration	of	Helsinki.	Indiana	University	School	of	Medicine	ethics	committee	approved	this	study.			RESULTS	350	cases	of	Duane	syndrome	were	identified.	179	(51.1%)	patients	with	Type	I	Duane	syndrome	were	identified.	81	(23.1%)	patients	with	Type	II	Duane	syndrome	were	identified.	71	(20.3%)	patients	with	Type	III	Duane	syndrome	were	identified.	Patients	with	features	of	synergistic	divergence	were	observed	in	19	(5%)	of	patients	with	Duane	syndrome.	13	out	of	19	of	these	cases	were	initially	labeled	as	type	II	Duane	syndrome	or	Duane	variant.	However,	upon	careful	review	of	images,	the	telemedicine	consultant	identified	synergistic	divergence.			More	males	(16)	than	females	(3)	were	identified	with	synergistic	divergence.	Laterality	was	equal.	This	entity	was	observed	early	in	life,	with	parents	reporting	an	average	onset	of	0.5	(0‐4)	years	(AE‐1	comm.).	The	average	age	of	presentation	for	evaluation	was	11.5	(1‐26)	years.	Most	patients	were	exotropic	and	showed	palpebral	fissure	narrowing	on	attempted	adduction	of	the	involved	eye	(AE02	comm.).	An	anomalous	head	posture	was	identified	in	all	patients	with	synergistic	Type	IV	Duane	Syndrome		6divergence	(Table	1).	Infraduction	deficit	was	observed	in	6	patients.	One	patient	had	a	supraduction	deficit.	Dramatic	upshoots	were	only	observed	in	two	patients.			Neuroimaging	had	been	performed	on	4	of	the	19	patients,	and	only	one	of	these	patients	had	an	abnormality	picked	up	by	the	radiologist.	The	abnormality	was	described	as	“an	asymmetry	of	the	right	half	of	the	midbrain”.	One	patient	with	Goldenhar	syndrome	and	one	patient	with	cerebral	palsy	also	had	synergistic	divergence.	Nystagmus	was	observed	in	one	patient.	Anisometropia	was	observed	in	three	patients	(Table	2).		Eye	muscle	surgery	was	performed	on	nine	patients.	On	forced	duction	testing,	patients	were	reported	to	have	a	tight	lateral	rectus	(AE‐4	comm.),	Bilateral	lateral	rectus	recession	was	performed	on	three	patients.	A	single	lateral	rectus	recession	was	performed	on	five	patients.	One	patient	underwent	vertical	muscle	transposition	with	single	lateral	rectus	recession	(Table	3).	Post‐surgical	data	was	only	available	for	7	patients.	Of	these	7	patients,	6	had	good	alignment	in	primary	position	with	decreased	face	turn	after	one	surgery.	The	one	patient	who	had	a	significant	amount	of	residual	exotropia	and	face	turn	had	undergone	ipsilateral	lateral	rectus	recession(AE‐3	comm.).	All	patients	had	persisting	synergistic	divergence	after	surgery.				DISCUSSION	Type	IV	Duane	Syndrome		7Type	IV	Duane	syndrome	has	been	called	simultaneous	abduction,	synergistic	divergence,	the	“splits”,	and	perversion	of	the	extraocular	muscles.1,3,6,7	Type	IV	Duane	syndrome	has	previously	been	described	in	the	literature,	but	only	case	reports	have	been	reported.		We	characterize	Type	IV	Duane	syndrome	as	exotropia	in	primary	gaze,	face	turn	opposite	the	involved	eye,	essentially	full	abduction	of	the	involved	eye,	absent	adduction	of	involved	eye	with	simultaneous	abduction	in	gaze	opposite	the	involved	eye	and	narrowing	of	the	palpebral	fissure.	Figure	2	shows	the	potential	innervation	differences	to	the	medial	and	lateral	rectus	that	can	result	in	the	pathology	seen	with	Duane	syndrome.3	Wilcox	et	al	performed	electromyographical	testing	on	a	single	patient	with	synergistic	divergence.	His	results	showed	evidence	of	anomalous	innervation	that	was	on	the	continuum	of	Duane	syndrome.3	Similar	findings	have	been	reported	in	over	corrected	patients	who	have	undergone	ipsilateral	medial	rectus	recession	for	Type	I	Duane	syndrome.8	None	of	our	patients	had	a	history	of	previous	medial	rectus	surgery.			In	the	case	of	simultaneous	abduction	the	oculomotor	nerve	sends	nerve	fibers	to	the	lateral	rectus	and	the	signal	causes	the	eye	to	abduct	and	co‐contract	when	it	should	simply	adduct.	Several	questions	remain	unanswered	including:	1)	Does	the	oculomotor	“dividing”	weaken	the	medial	rectus?	2)	Does	this	contribute	to	the	wide	range	of	expressions?	3)	Does	the	relative	amount	of	abducens	innervation	from	none	to	robust	influence	the	tendency	toward	XT	(resistance	to	adduction)?		Type	IV	Duane	Syndrome		8	The	surgical	technique	most	suggested	for	this	condition	was	weakening	of	the	ipsilateral	lateral	rectus	muscle.	In	our	case	series	multiple	patients	underwent	bilateral	lateral	rectus	recession.	One	might	argue	that	weakening	the	contralateral	lateral	rectus	muscle	could	worsen	the	simultaneous	abduction	due	to	Hering’s	law.	However,	none	of	our	patients,	for	whom	we	had	postoperative	data,	had	worse	synergistic	divergence	following	surgery.	All	had	improved	alignment	and	face	turn	despite	persisting	synergistic	divergence.	This	is	likely	because	patients	had	a	large	recession	of	the	lateral	rectus	of	the	involved	eye,	which	would	cripple	the	muscle’s	action.			Some	have	suggested	transposition	procedures	for	these	patients.	Many	of	the	patients	were	found	to	have	a	tight	lateral	rectus	and	weak	medial	rectus,	so	transposition	of	vertical	recti	to	the	medial	rectus	would	not	likely	help	against	a	restricted	or	tight	lateral	rectus.	Weakening	or	crippling	the	tight	lateral	rectus	is	key	in	these	patients.		Review	of	electronic	or	e‐consultation	cases	provides	a	unique	method	to	evaluate	a	strabismus	population.	E‐consultation	provides	the	advantage	of	collecting	a	large	number	of	patients	to	retrospectively	assess	cases	provided	by	expert	consultants.	Cybersight	allows	for	collaboration	between	a	mentor	ophthalmologist	and	a	partner	ophthalmologist	from	around	the	world.	This	helps	ophthalmologists	in	underserved	areas	of	the	world	to	gain	the	confidence	they	need	to	provide	expert	Type	IV	Duane	Syndrome		9care	to	patients.		This	collaboration	leads	to	gained	knowledge	for	both	the	requesting	ophthalmologist	and	the	mentor.			Our	understanding	of	the	pathophysiology	of	Duane	retraction	syndrome	comes	much	from	the	electromyographical	studies	of	the	last	century.	Huber	classified	Duane	retraction	syndrome	into	different	types	as	they	corresponded	to	different	innervation	patterns	seen	on	electromyography.5	Many	clinicians	have	moved	away	from	Huber’s	classification	and	have	simplified	Duane	syndrome	patients	to	either	esotropic	or	exotropic	Duane	syndrome.	We	would	argue,	that	although	this	simplified	approach	to	Duane	syndrome	might	seem	appealing;	it	does	not	help	us	better	understand	the	pathophysiology	of	this	complex	disease.	Understanding	that	each	Duane	syndrome	type	has	unique	innervation	anomalies	aids	in	the	management	of	each	patient.			Multiple	studies	have	looked	at	the	epidemiology	of	Duane	retraction	syndrome.	The	typical	incidence	of	Type	I	reported	among	these	papers	is	73	to	92%.	Type	II	and	Type	III	have	similar	incidences	and	range	from	4	to	13%	of	cases	of	Duane	retraction	syndrome.9‐12	Our	study	population	had	less	type	I	and	more	type	II	and	type	III	patients.	This	is	likely	a	selection	bias.	Because	our	patient	database	was	composed	of	patients	needing	expert	consultation,	we	were	more	likely	to	see	less	routine	Duane	syndrome	patients.	Although	bilateral	synergistic	divergence	has	been	reported	in	the	literature,	only	unilateral	synergistic	divergence	was	observed	in	our	patients.13	Type	IV	Duane	Syndrome		10	There	are	other	limitations	to	our	study.	Although	our	collection	of	patients	with	synergistic	divergence	is	the	largest	to	date,	an	even	larger	collection	of	patients	would	be	useful	to	study.	Additional	information	including	forced	duction	results	and	electromyography	would	be	useful	in	further	studying	and	characterizing	this	entity.	Although	a	few	patients	had	imaging,	more	imaging	data	would	be	useful	to	characterize	the	extraocular	muscles.	Post‐operative	data	was	available	for	some	of	the	patients;	however,	more	post‐operative	information	would	have	been	useful.	Genetic	testing	for	Duane	syndrome	has	been	performed	and	genetic	mutations	have	included	Duane	syndrome	into	the	classification	of	Congential	cranial	dysinnervation	disorder	(CCDD).		CCDD	also	includes	congenital	fibrosis	of	the	extraocular	muscles,	congenital	ptosis,	and	Möbius	syndrome.14	Further	work	on	the	genetics	of	Duane	syndrome	and	its	individual	types	may	help	us	understand	the	complexity	of	this	condition.			While	many	questions	remain,	there	should	be	better	recognition	of	this	fourth	class	of	Duane	syndrome	that	has	been	noted	for	more	than	50	years.	Using	Cybersight	we	were	able	to	collect	the	largest	case	series	of	patients	with	synergistic	divergence	to	date.	We	show	that	these	patients	have	features	consistent	with	a	Duane	type	syndrome.	However,	these	patients	also	demonstrate	findings	that	would	indicate	a	unique	innervation	pattern.	We	characterize	these	patients	as	Type	IV	Duane	syndrome.		Type	IV	Duane	Syndrome		11REFERENCES		1. Wagner	 RS,	 Caputo	 AR,	 Frohman	 LP.	 Congenital	 unilateral	 adduction	 deficit	with	 simultaneous	 abduction.	 A	 variant	 of	 Duane’s	 retraction	 syndrome.	Ophthalmology	1987;	94(8):	1049‐1053.		2. VonNoorden	GK.	Binocular	vision	and	ocular	motility‐	Theory	and	management	of	strabismus	VI	edition.	Elsevier‐Mosby	2001.		3. Wilcox	 L,	 Gittinger	 J,	 Breinin	 G,	 Congenital	 adduction	 palsy	 and	 synergistic	divergence.	Am	J	Ophthlmol	1981;	91:1‐7.		4. Duane	 A.	 Congential	 deficiency	 of	 abduction,	 associated	 with	 impairment	 of	adduction,	 retraction	 movements,	 contraction	 of	 the	 palpebral	 fissure	 and	oblique	 movements	 of	 the	 eye.	 1905.	 Arch	 Ophthalmol.	 1996	 Oct;	114(10):1255‐66;	discussion	1257.		5. Huber	A.	Electrophysiology	of	the	retraction	syndromes.	Br	J	Ophthalmol.	1974	Mar;	58(3):293‐300.		6. Hamed	 L,	 Lingua	 R,	 Fanous	M,	 Saunders	 T,	 Lusby	 F,	 Synergystic	 Divergence:	Saccadic	 Velocity	 Analysis	 and	 Surgical	 Results.	 J	 Pediatric	 Ophthalmol	Strabismus	1992;	29:30‐37.	Type	IV	Duane	Syndrome		12	7. Bodh	 S,	 Kamal	 S,	 Kumar	 V,	 Bansal	 S,	Madhu.	 Duane’s	 retraction	 syndrome:	 a	review.	Del	J	Ophthalmol	2012;	22(3):169‐175.		8. Clinical	 Strabismus	 Management:	 Principles	 and	 Surgical	 Techniques.	 Eds	 AL	Rosenbaum,	AP	Santiago.	Pp	592;	135.	Philadelphia:	WB	Saunders,	1999.	ISBN	0‐7216‐7673‐1.		9. Zhang	 F.	 Clinical	 features	 of	 201	 cases	 with	 Duane’s	 retraction	 syndrome.	Zhonghua	Yan	Ke	Za	Zhi.	1999	Jul;35(4):280‐2.		10. Anvari	F,	Hatef	E,	Mohammadi	SF,	Eskandari	A.	Duane’s	retraction	syndrome,	a	case	series	from	Iran.	Int	Ophthalmol.	2008	Aug;28(4):275‐80.		11. Shrestha	GS,	Sharma	AK.	Duane’s	retraction	syndrome:	a	retrospective	review	from	Kathmandu,	Nepal.	Clin	Exp	Optom.	2012	Jan;95(1):19‐27.		12. Mohan	 K,	 Sharma	 A,	 Pandav	 SS.	 Differences	 in	 epidemiological	 and	 clinical	characteristics	 between	 various	 types	 	 of	 Duane	 retraction	 syndrome	 in	 331	patients.	J	AAPOS.	2008	Dec;12(6):576‐80.		Type	IV	Duane	Syndrome		1313. Khawam	E,	 Terro	A,	Hamadeh	 I.	 Surgical	 correction	 of	 synergistic	 divergence	strabismus.	A	report	of	three	cases.	Binocul	Vis	Strabismus	Q.	2007;22(4):227‐34.		14. Gutowski	NJ,	Chilton	JK.	The	congenital	cranial	dysinnervation	disorders.	Arch	Dis	Child.	2015	Jul;	100(7):678‐81.																		Type	IV	Duane	Syndrome		14Table	Legends	Table	1	–	Characteristics	of	Type	IV	Duane	syndrome	patients.		Table	2	–	Associated	neurologic,	systemic,	or	other	ocular	findings	observed	in	patients	with	Type	IV	Duane	syndrome.		Table	3	–	Surgical	interventions	performed	on	patients	with	Type	IV	Duane	syndrome.								Figure	Legends	Figure	1	–	External	photograph	of	patient	with	type	IV	Duane	syndrome		Figure	2	–	Right	eye	illustration	of	potential	innervation	patterns	in	different	types	of	Duane	syndrome.	VI	indicates	fibers	of	the	sixth	cranial	nerve.	III	indicates	fibers	of	the	third	cranial	nerve.	Dashed	lines	indicate	hypoplastic	or	absent	nerve	fibers.	Thin	lines	indicate	relative	decreased	innervation.		

Type IV Duane Syndrome

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