Journal of the Neurological Sciences 315 (2012) 153–155

Contents lists available at SciVerse ScienceDirect

Journal of the Neurological Sciences

j ourna l homepage: www.e lsev ie r .com/ locate / jns

Short communication

WEBINO and the Return of the King's Speech

Shin C. Beh a,⁎, Elliot M. Frohman a,b

a Department of Neurology, University of Texas Southwestern Medical Center at Dallas, United Statesb Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, United States

⁎ Corresponding author at: Department of Neurology, UMedical Center, 5323 Harry Hines Blvd, Dallas, TX 75390,0555; fax: +1 214 645 0556.

E-mail address: scjbeh@gmail.com (S.C. Beh).

0022-510X/$ – see front matter © 2011 Elsevier B.V. Aldoi:10.1016/j.jns.2011.11.035

a b s t r a c t

a r t i c l e i n f o

Article history:Received 3 October 2011Accepted 28 November 2011Available online 15 December 2011

Keywords:Neurogenic stutteringWEBINO syndromePeriaqueductal grayMidbrainStutteringBilateral internuclear ophthalmoplegiaNeuro-ophthalmology

We present a 69 year-old man with hypertension who developed the sudden onset of horizontal binoculardiplopia and stuttering of speech. On examination, bilateral exotropia (i.e. ‘wall-eyed’) was observed in theprimary position. Attempted horizontal saccades revealed bilateral internuclear ophthalmoplegia; all consis-tent with the wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome. Convergence, verticalsaccades and vestibular ocular reflexes were likewise impaired. Pupillary and levator palpebrae superiorisfunctions were intact. Mild left-sided dysmetria, intention tremor and dysdiadochokinesia were elicited. Con-spicuously, further characterization of the patient's history revealed that he had stuttered as a child, but ithad resolved in adolescence. Brain MRI revealed an acute infarction of the mesencephalic and upper pontinetegmentum involving the periaqueductal gray region and the medial longitudinal fasciculus bilaterally withgreater involvement of the left. Like the WEBINO syndrome, re-emergent developmental stuttering is a rareneurologic phenomenon. To our knowledge, this is the first case report of a mesencephalic and upper pontineinfarction causing both syndromes. We discuss the pathobiological underpinnings of the WEBINO syndromeand neurogenic stuttering and in relationship to this unusual case.

© 2011 Elsevier B.V. All rights reserved.

1. Introduction

1.1. Case report

A 69 year-old man with hypertension presented to the emergencydepartment with acute horizontal diplopia and dysfluency. Bilateralexotropia (i.e. ‘wall-eyed’) was observed in the primary position.Attempted horizontal saccades revealed bilateral internuclearophthalmoplegia (INO). Convergence, vertical saccades and vestibu-lar ocular reflexes were likewise impaired. This picture was charac-teristic of the wall-eyed bilateral internuclear ophthalmoplegia(WEBINO) syndrome. Alternately, pupillary and levator palpebraesuperioris functions were intact. Subtle left-sided dysmetria, inten-tion tremor and dysdiadochokinesia were elicited. Spontaneousspeech, reading and repetition was slow and halting albeit grammat-ically intact with frequent repetitions, hesitations and blocks of initialsyllables. This persisted during recitation of familiar nursery rhymesand singing well-known songs (e.g. Happy Birthday). There was noimprovement with repeated reading of the same text. No facialgrimacing, fist clenching, head jerks, or other accessory behaviorswere observed. Although annoyed by his dysfluency, he was not over-ly anxious. Comprehension, naming, writing and calculation were

niversity of Texas SouthwesternUnited States. Tel.: +1 214 645

l rights reserved.

intact. Conspicuously, the patient stuttered as a child, but it had re-solved in adolescence.

Brain MRI revealed an acute midbrain infarction, extending fromthe periaqueductal gray (PAG) region to the interpeduncular fossa.Also involved in the midbrain was the area where the fibers of the su-perior cerebellar peduncle decussate and ascend to the contralateralred nucleus. The infarct also affected the upper pontine tegmentum,immediately ventral to the fourth ventricle, involving the medial lon-gitudinal fasciculus (MLF) bilaterally with greater involvement of theleft (Fig. 1).

2. Discussion

WEBINO is a rare disorder characterized by bilateral exotropia onprimary gaze, bilateral INO and impaired convergence. It may be asso-ciated with other features e.g. vertical gaze palsy, up-beat nystagmusand skew deviation [1,2]. The most common reported etiology is in-farction followed by multiple sclerosis and then trauma [2–4]. Otherreported etiologies are listed in the Supplementary online table.

While the pathobiological underpinnings of the WEBINO syn-drome remain a matter of some controversy, the clinical constellationof findings are thought to be derivative of bilateral MLF damage pro-ducing bilateral INO, likely in conjunction with abnormalities of themedial rectus subnuclei (MRSN) of the ventral oculomotor nuclearcomplex culminating in bilateral exotropia and signifying bilateralconvergence failure. Since MRSN neurons are scattered within theMLF at the level of the ponto-mesencephalic junction, a lesion at

Fig. 1. Brain MRI showing an acute midbrain infarction, extending from the periaqueductal gray region to the interpeduncular fossa. Also involved in the midbrain was the areawhere the fibers of the superior cerebellar peduncle decussate and ascend to the contralateral red nucleus. The infarct also affected the upper pontine tegmentum, immediatelyventral to the fourth ventricle, involving the medial longitudinal fasciculus bilaterally with greater involvement of the left.

154 S.C. Beh, E.M. Frohman / Journal of the Neurological Sciences 315 (2012) 153–155

this level could affect both structures, resulting in the WEBINO syn-drome [1,2]. Notwithstanding the WEBINO syndrome has been mostcommonly reported to be a consequence of mesencephalic lesions,there are reports of isolated pontine lesions causing the syndrome[1–4].

Experimentally, INO and impaired vergence have been induced byinjecting lidocaine directly into the MLF despite MRSN preservation[5]. This observation and reports of alternating exotropia indicatethat MRSN involvement should not be assumed as the exclusivecause of bilateral exotropia. In particular, this conspicuous feature ofthe syndrome may also result from paramedian pontine reticular for-mation overactivity during attempted fixation of the adducted pareticeye [1–3]. Thus, bilateral exotropia in WEBINO may also be a conse-quence of bilateral paralytic pontine exotropia (PPE).

While neurogenic stuttering (NS) has been associated with PPE [6]and a left INO [7], there has never been any association with theWEBINO syndrome, even within the largest series of WEBINO pa-tients reported to date [1]. Aside from strokes, to date, only progres-sive supranuclear palsy has been reported to cause either syndrome[3,8] but not both.

The critically-acclaimed movie The King's Speech portrayed KingGeorge VI's struggle with and triumph over stuttering and drewmuch attention to this disorder. Stuttering may be developmental oracquired (neurogenic). Developmental stuttering (DS) is a transientdysfluency, occurring in about 5% of children 4 to 5 years of age,marked by initial sound prolongations, word or part-word repetitions,hesitations and silent blocks with or without secondary anxiety-induced behaviors. Ultimately, about 85% of preschoolers developthe neuro-motor skills to overcome it. It is exacerbated by anxietyand is diminished by familiar or automatized formulae. Dysfluency isreduced with repetition, a phenomenon termed the adaptation effect[9].

NS is a rare neurologic disorder reported in the literature for over100 years and received scarce attention until the 1970s [9,10]. Basedon several notable publications [10–12], we propose to define NS asan adult-onset, acquired or re-acquired dysfluency secondary to abrain lesion characterized by involuntary repetitions, prolongationsand blocks that is not the result of a disorder of language formulation(i.e. aphasia) or a psychiatric condition.

Unlike DS, the dysfluency is not restricted to initial phonemes, oc-curs in monosyllabic and polysyllabic words, does not adapt, persistsduring singing but lacks secondary behaviors and anxiety [9,12,13].Despite proposed criteria for NS, it remains very challenging to

differentiate it from DS based on symptomatology alone [10,12,14].As such, the most important distinction between the two conditionsis phenomologic: NS occurs with a clear precipitating event [13]. Insubjects with NS, a history of DS was present in 12% [12] to 14%[14] indicating that adults who had recovered from DS were at great-er risk of NS following a brain insult.

Clinically, stuttering should be distinguished from other motordisorders of speech. Logoclonia is characterized by repetition of thelast syllable of words; echolalia by automatic repetition of wordsspoken to the patient [15], and palilalia by compulsive repetition ofa word or phrase with ‘palilalia aphone’ (i.e. increasing rate withdiminishing loudness) [16].

Lesions causing NS have been reported in all cortical lobes, cere-bellum, subcortical white matter, basal ganglia (BG), corpus callosum,thalamus and brainstem. Pontine lesions are uncommon and mesen-cephalic lesions are even more exceptional causes of NS [6,7,9–14].

The most commonly reported etiology for NS is strokes followedby traumatic brain injury [10,12,13]. Epilepsy, pathologic thalamicdischarges, Parkinsonian syndromes, dopaminergic medications anda wide variety of other drugs have also been etiologically-implicated[9,10].

The exact neural circuits involved in NS remain unknown. Humanspeech production requires an intact and constantly integrating neu-ronal circuitry of cortico-BG-thalamo-cortico-reticular projections in-cluding cerebellothalamic and PAG projections, to control andcoordinate the highly precise, dynamic, rapidly fine-tuned, sequentialmotor movements of the oral articulators (lips, jaw and tongue), re-spiratory musculature (adjusting inspiration, expiration and subglot-tic air pressure) and laryngeal activity (modulating vocal fold lengthand tension) [9,17–19].

A phylogenetically ancient midline neural network centered with-in the PAG controls visceromotor mechanisms producing involuntaryvocalizations. A neocortical system maintains hierarchical controlover this visceromotor system to produce volitional speech [17]. Cor-tical areas important for speech production include the motor cortex,supplementary motor area (SMA), pre-SMA, anterior cingulate cortex(ACC), medial prefrontal cortex (MPFC) and the auditory cortices[9,17,19,20]. While the SMA is important in organizing self-initiatedmovements [17], the pre-SMA is involved in syllable representationand spatial and temporal serial coordination of the motor apparatus[20].

Cortical efferents converge on the BG; in turn, BG efferents, refinedby projections from the brainstem reticular system (BRS) and the

155S.C. Beh, E.M. Frohman / Journal of the Neurological Sciences 315 (2012) 153–155

cerebellar cortex, project to the thalamocortical network [9]. The BGmodulates speech production by inhibiting any extraneous move-ments and provides species-specific learned motor control andbuilt-in reflex control patterns, indispensible to the production ofhighly skilled movement sequences required for speech [9].

The thalamic centromedian (CM) nucleus is essential in humanspeech production and has been described as an interface betweenthe visceromotor and neocortical systems [17]. Ascending BRS projec-tions to the CM nucleus ensure an optimized state of physiologicreadiness for the dynamic and synchronized interactions of neuralnetworks involved in speech production [9]. The many metabolic dis-orders and potentially-sedating medications etiologically-implicatedin NS may be secondary to a state of sub-optimal preparedness ofthis reticulo-thalamo-cortical network.

The PAG, which lies close to the ponto-mesencephalic junction, iscritical in vocalization [17,18]. PAG lesions may render both humansand animals mute. Correspondingly, PAG stimulation elicits species-specific vocalizations. The PAG may be an “anatomic Segway” ofthe descending vocalization-controlling pathway and a relay stationfor vocal information processing [19] that couples sensory andmotivation-processing structures to the vocal motor-coordinatingmechanisms [18]. It appears to be responsible for the initiation andintensity of vocalization, not its patterning [19]. As stutterers oftenexperience blocks with initial phonemes, and more so at the begin-ning of a sentence, this may implicate dysfunction of the PAG. Indeed,midbrain lesions affecting the PAG have been reported to cause a‘stuttering-like repetitive speech disorder’ [16], palilalia [15] and NS[6].

In summary, the dynamic interaction between the cortico-BG-thalamo-cortical andmidline PAG neural networks modulated by cer-ebellar and BRS projections, is important in the preparation and rapidmotor sequencing of volitional speech. Interruptions at any point inthis intricate circuit may compromise the precise synchrony ofmotor movements essential for speech, and cause stuttering.

3. Conclusion

The WEBINO syndrome in our patient was due a midbrain infarc-tion affecting the MRSN and bilateral MLF. The same infarct resultedin NS by affecting several neural circuits. Involvement of the PAG like-ly disrupted both its role in the initiation of vocalization and its abilityto couple sensory and motivation-processing mechanisms with thevocal motor-coordinating circuit. Interruption of the ascending BRSprojections resulted in suboptimal performance of the reticulo-thalamo-cortical circuit, compromising the state of physiologic readi-ness needed to ensure precise, synchronized motor speech move-ments. Furthermore, another contributing factor may have beendisrupted cerebellar automaticity, evidenced by the presence of left-sided ataxia.

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jns.2011.11.035.

Conflict of interest

Dr. Beh reports no disclosures. Dr. Frohman reports no disclosures.The drafting of this manuscript received no financial support from

industry or the NIH.

Contributions

Study concept and design (Drs. Beh and Frohman); acquisition ofdata (Dr. Beh); analysis and interpretation of data (Drs. Beh and Froh-man); drafting of the manuscript (Dr. Beh); and critical revision of themanuscript for important intellectual content (Drs. Beh and Frohman).

References

[1] Chen C-M, Lin S-H. Wall-eyed bilateral internuclear ophthalmoplegia from lesionsat different levels in the brainstem. J Neuroophthalmol 2007;27:9–15.

[2] Sierra-Hidalgo F, Moreno-Ramos T, Villarejo A, Martín-Gil L, de Pablo-FernándezE, Correas-Callero E, et al. A variant of WEBINO syndrome after top of the basilarartery stroke. Clin Neurol Neurosurg 2010;112(9):801–4.

[3] Matsumoto H, Ohminami S, Goto J, Tsuji S. Progressive supranuclear palsy withwall-eyed bilateral internuclear ophthalmoplegia syndrome. Arch Neurol2008;65:827–9.

[4] Sakamoto Y, Kimura K, Iguchi Y, Shibazaki K, Miki A. A small pontine infarct onDWI as a lesion responsible for wall-eyed bilateral internuclear ophthalmoplegiasyndrome. Neurol Sci June 8 2011, doi:10.1007/s10072-011-0647-8 (Publishedonline first).

[5] Gamlin PD, Gnadt JW, Mays LE. Lidocaine-induced unilateral internuclearophthalmoplegia: effects on convergence and conjugate eye movements. J Neuro-physiol 1989;65:82–95.

[6] Doi M, Nakayasu H, Soda T, Shimoda K, Ito A, Nakashima K. Brainstem infarctionpresenting with neurogenic stuttering. Intern Med 2003;42(9):884–7.

[7] Ciabarra AM, Elkind MS, Roberts JK, Marshall RS. Subcortical infarction resulting inacquired stuttering. J Neurol Neurosurg Psychiatry 2000;69(4):546–9.

[8] Kluin KJ, Foster NL, Berent S, Gilman S. Perceptual analysis of speech disorders inprogressive supranuclear palsy. Neurology 1993;43(3 Pt. 1):563–6.

[9] Bhatnagar S, Buckingham H. Neurogenic stuttering: its reticular modulation. CurrNeurol Neurosci Rep 2010;10(6):491–8.

[10] Lundgren K, Helm-Estabrooks N, Klein R. Stuttering following acquired braindamage: a review of the literature. J Neuroling 2010;23:447–54.

[11] Tani T, Sakai S. Analysis of five cases with neurogenic stuttering following braininjury in the basal ganglia. J Fluency Disord 2011;36:1–16.

[12] Theys C, Van Wieringen A, De Nil LF. A clinician survey of speech and non-speechcharacteristics of neurogenic stuttering. J Fluency Disord 2008;33:1–23.

[13] Grant AC, Biousse V, Cook AA, Newman NJ. Stroke-associated stuttering. ArchNeurol 1999;56:624–7.

[14] Ludlow CL, Loucks T. Stuttering: a dynamic motor control disorder. J Fluency Dis-ord 2003;28:273–95.

[15] Yasuda Y, Akiguchi I, Ino M, Nabatabe H, Kameyama M. Paramedian thalamic andmidbrain infarcts associated with palilalia. J Neurol Neurosurg Psychiatry1990;53(9):797–9.

[16] Abe K, Yokoyama R, Yorifuji S. Repetitive speech disorder resulting from infarctsin the paramedian thalami and midbrain. J Neurol Neurosurg Psychiatry1993;56(9):1024–6.

[17] Schulz GM, Varga M, Jeffries K, Ludlow CL, Braun AR. Functional neuroanatomy ofhuman vocalization: an H-2(15)-O PET study. Cereb Cortex 2005;15:1835–47.

[18] Jurgens U. A study of the central control of vocalization using the squirrel monkey.Med Eng Phys 2002;24:473–7.

[19] Jurgens U. The neural control of vocalization in mammals: a review. J Voice2007;23(1):1–10.

[20] Lu C, Peng D, Chen C, Ning N, Ding G, Li K, et al. Altered effective connectivity andanomalous anatomy in the basal ganglia-thalamocortical circuit of stutteringspeakers. Cortex 2010;46:49–67.