Journal of Neuro-Ophthalmology, September 2000, Volume 20, Issue 3

Ocular Motility Review for 1997-1998

Each year brings new scientific knowledge that builds on itself in a geometric fashion. Ocular motility basic and clinical neurosciences continue to advance with this accelerating pace. The years 1997 and 1998 brought new knowledge to the motility world. This review focuses on the clinical advances within this realm. Part I of this review appeared in the June 2000 (20:2) issue.

Journal of Neuro- Ophthalmology 20( 3): 192- 206, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphi; Ocular Motility Review for 1997- 1998: Part II Eric R. Eggenberger, DO, and David I. Kaufman, DO Each year brings new scientific knowledge that builds on itself in a geometric fashion. Ocular motility basic and clinical neu-rosciences continue to advance with this accelerating pace. The years 1997 and 1998 brought new knowledge to the motility world. This review focuses on the clinical advances within this realm. Part I of this review appeared in the June 2000 ( 20: 2) issue. Key Words: Nystagmus- Ocular motor palsy- Thyroid eye disease. EXTRAOCULAR MUSCLES High- resolution magnetic resonance imaging ( MRI) has demonstrated the existence of a series of connective tissue sleeves or pulleys constraining the recti muscles. These pulleys were the subject of further research by Clark et al. ( 64). Imaging ten normal orbits, these inves­tigators demonstrated highly uniform muscle paths in primary position. Twelve orbits with strabismus demon­strated no significant difference from normal orbits in recti paths in primary or secondary gaze. However, two subjects with incomitant strabismus ( one with superior oblique palsy) demonstrated grossly abnormal recti muscle paths in primary position, which was suggestive of heterotopic pulleys. The authors concluded that het­erotopic pulleys were a potential contributor to incomi­tant strabismus. Further advances in functional orbital imaging may enhance our understanding of this delicate anatomy. Magnetic resonance imaging has excellent extraocular muscle ( EOM) resolution characteristics. With more re­cent imaging techniques that shorten imaging times, MRI has been investigated as a functional tool for eye move­ment assessment. Scheiber et al. ( 65) reported findings of an MRI technique composed of 20- second images that produce a video loop. In 20 volunteers, the techniques provided a means of assessment of muscle contraction and eye movement with an acceptable level of artifact. Jager et al. ( 66) reported an MRI technique for eye movement assessment in six volunteers that produced Manuscript received December 24, 1999; accepted February 1, 2000. From the Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan. Address correspondence and reprint requests to Eric R. Eggenberger, DO, Michigan State University, A- 217 Clinical Center, 138 Service Road, East Lansing, MI 48824. temporal resolution of five images/ s. These investigators also concluded that MRI techniques provided useful views of the dynamics of eye movement. Magnetic resonance imaging was also used to inves­tigate muscle dynamics in restrictive EOM disease asso­ciated with high myopia. This enigmatic syndrome pro­duces esotropia and hypotropia and has been referred to as the heavy eye syndrome. Krzizok et al. ( 67) reported MRI findings in 37 patients with high myopia (> 15 di­opters). The path of the lateral rectus was displaced downward in the medial and anterior orbit, which pro­duced esotropia and downward displacement. Muscle at­tachments appeared to be normal, and no evidence of pathophysiology referable to a enlarged globe was ob­served. The authors concluded that the eye movement abnormality of high myopia was another strabismus syn­drome, and MRI may provided useful information before strabismus surgery is performed. Congenital fibrosis of the EOM ( CFEOM) is typically an autosomal dominant disorder that produces bilateral ptosis, restrictive ophthalmoplegia, and a fixed infraduc-tion position. Brown coined the category " fibrosis syn­dromes" for CFEOM, Duane syndrome, Brown syn­drome, and vertical retraction syndrome. Since this time, it has become apparent that some of these syndromes may have a neuropathic origin. Engle et al. ( 68) reported findings in three patients with chromosome 12- linked CFEOM; one finding was from a postmortem examina­tion and two findings were from strabismus surgical specimens. Results of pathology from one of these pa­tients showed marked abnormalities of the caudal central alpha motor neurons of the oculomotor nerve ( destined to send axons to the superior division of cranial nerve [ CN] III), loss of large motor axons in the proximal oculomotor nerve, absence of the superior division of the oculomotor nerve, and a diminutive inferior division. However, the EOM also had marked abnormalities, in­cluding a single structure for the superior rectus and levator palpebrae composed of fat, connective tissue, and a few myofibers. Muscle specimens demonstrated in­creased numbers of internal nuclei and central mitochon­drial clumping. These findings were consistent with pre­viously reported postmortem findings by Heuck et al. ( 68A). The authors suggested that CFEOM resulted from an abnormality of the extraocular lower motor unit de­velopment; however, the exact pathophysiology of this syndrome ( nerve, muscle, or the entire unit simulta­neously) remains unknown. 192 OCULAR MOTILITY REVIEW 1997- 1998 193 Further insight into congenital fibrosis of the extraocu­lar muscles ( CFEOM) was published by Brodsky ( 69). Synergistic extraocular movements previously have been noted in this disorder by Brodsky et al. ( 69A). This ad­ditional report regarded three patients with a variant of synergistic divergence superimposed on diffuse bilateral ophthalmoplegia. The patients exhibited synergistic di­vergence, a variant of the Marcus Gunn jaw- winking phenomena, and oculocutaneous hypopigmentation. The authors suggested that the displayed neuronal misdirec­tion implied a regional innervational disturbance that in­volved cranial nerves III through VI, which lent credence to a neurogenic pathophysiology in at least some patients with CFEOM. Myotonic dystrophy ( MD), with autosomal dominant inheritance linked to chromosome 19, is the most com­mon muscular dystrophy. Although ptosis is common in this multisystem disease, other extraocular involvement may include ophthalmoparesis, hypometric and slowed saccades, and saccadic pursuit. The origin of these ab­normalities- muscle or central- remains enigmatic. Di- Costanzo et al. ( 70) explored this issue in a cohort of 40 patients with MD studied with electroculographics. Slowed saccades were present in 70%; saccadic latency and accuracy were normal. Saccadic speed did not cor­relate with disease duration or muscular disability. Fast eye movements generated by the vestibular ocular reflex were normal. The authors suggested that EOMs were at least partially spared and that pathologic abnormalities of supranuclear structures, such as burst cells, may con­tribute to the eye movement abnormalities associated with MD. Orbital masses with EOM involvement may present diagnostic challenges. Stockl et al. ( 71) provided the first report of a case of thymic carcinoma metastatic to the orbit. A 37- year- old patient was diagnosed and treated for small cell carcinoma of the thymus approximately 20 months before the patient's presentation with proptosis and diplopia. Results of fine- needle biopsy of a com­puted tomography ( CT)- demonstrable, left superior, or­bital mass disclosed malignant cells consistent with me­tastasis. The case of a 43- year- old man with vertical diplopia was presented by Hashimoto et al. ( 72). Mag­netic resonance imaging revealed a spindle- shaped mass that involved the inferior oblique muscle. Results of bi­opsy demonstrated a granular cell tumor. The authors speculated that the tumor arose form neural crest cells within the EOM. Chronic progressive external ophthalmoplegia ( CPEO) is a mitochondrial oculomyopathy that produces ptosis and ophthalmoparesis. Chronic progressive exter­nal ophthalmoplegia is related to mitochondrial dele­tions; the pattern and location of these deletions vary from patient to patient, and this pattern dictates the phe-notype. Heteroplasmy is a common phenomena in mito­chondrial deletions, which appear to arise de novo. Mar-zuki et al. ( 73) explored this issue histologically in the autopsy findings of a patient with CPEO. The level of mitochondrial DNA deletion ranged from 1 % to 20% in involved tissues. Deletions were present in mesodermal and ectodermal- derived tissues; however, tissues primar­ily derived from entodermal origin did not contain Southern analysis- detectable DNA deletions. The au­thors suggested that these findings infer that the deletions occurred early in embryonic development. • Persistent diplopia is a relatively infrequent complica­tion of CPEO. Wallace et al. ( 74) presented the findings and courses of four patients with CPEO, three of whom had diplopia. Although exotropia is the most common pattern of misalignment in CPEO, hypertropia was present in two of their patients, while one patient had exotropia and one patient had esotropia. Three of the patients required a single surgery, while one patient re­quired multiple surgeries. The authors stressed the po­tential benefits of strabismus surgery in carefully se­lected patients with CPEO in whom a stable pattern of misalignment exists, with the understanding that mis­alignment may continue to slowly progress. Orbital cysticercosis is a rare condition in the United States. Sekhar et al. ( 75) reported the findings of 20 cases from an urban practice in southern India. Among this cohort, 9 patients had subconjunctival cysts, and 11 pa­tients had single EOM cysts. Patients with EOM cysts presented with proptosis, restricted motility, ptosis, and recurrent inflammation and pain. Computed tomography was helpful in the diagnosis when a scolex was demon­strable; enzyme- linked immunosorbent assay testing was also useful diagnostically. Although the cases were treated differently, the authors felt that surgical excision was the treatment of choice for subconjunctival cysts, while oral albendazole and corticosteroids can arrest the recurrent inflammatory process and improve motility in cases with EOM cysts. Orbital myositis, a subset of idiopathic orbital inflam­mation ( orbital pseudotumor), is characterized by pain, restrictive motility, diplopia, and enlargement of the EOM as seen with neuroimaging. Mombaerts and Koornneef ( 76) reported their experience with 16 pa­tients with orbital myositis. Recurrence after initially successful treatment with steroids ( 14 patients) or non­steroidal antiinflammatory drugs ( NSAIDs) ( two pa­tients) was noted in 56%. Recurrences were managed with corticosteroids, NSAIDs, or orbital radiation ( 20 gray). Of six patients with recurrent disease treated with radiation, all experienced improvement of symptoms during the first 3 months, but they continued to have recurrences. Although radiation as been reported to be effective treatment of orbital myositis, the authors felt that this treatment was ineffective based on follow- up in these six patients. Oculopharyngeal muscular dystrophy ( OPMD) is an autosomal dominant disorder that produces dysphagia and progressive ptosis. The largest kindred is of French Canadian ancestry, and the gene has been mapped to chromosome 14. An Australian kindred of German de­scent was reported by Teh et al. ( 77) Linkage analysis supported localization on chromosome 14; however, no trinucleotide repeats segregating with the disease were J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 194 E. R. EGGENBERGER AND D. I. KAUFMAN noted. The authors concluded that there was no evidence of genetic heterogeneity or repeat expansion in OPMD. A rapidly progressive adolescent- onset oculopharyn­geal syndrome similar to OPMD was reported by Rose et al. ( 78). Their report regarded two Greek siblings, ages 11 and 14 years, in whom nasal speech, bilateral ptosis, ophthalmoplegia, and dysphagia developed over weeks to months, with subsequent development of extremity weakness and wasting. Results of muscle biopsy dem­onstrated rimmed vacuoles ( also noted in OPMD) in both cases and cytoplasmic and intranuclear tubulofilamen-tous inclusions in one case. The authors felt that the age of onset and the inclusions in one case separated this syndrome from OPMD. The indications for plain radiographs in the manage­ment of orbital fractures in 100 consecutive patients with blunt trauma was reported by Bhattacharya et al. ( 79). The authors noted that managing ophthalmologists who viewed the films were guided by physical signs, and no patient in whom a fracture was overlooked by the oph­thalmologist was referred for surgery. All patients un­dergoing surgery for blow- out fractures underwent pre­operative orbital CT. Because the decision to operate was driven exclusively by clinical rather than radiographic findings, the authors suggested that radiographic evalu­ation should be reserved for patients with greater than 2- mm enophthalmos or diplopia in primary or reading position that persisted for more than 2 weeks. Magnetic resonance imaging provides excellent reso­lution of the EOM and is often used in the diagnosis of myopathic processes, such as hyperthyroidism, sarcoid, and orbital pseudotumor. Fat- suppressed gadolinium-enhanced images often provide the best assessment of the EOM. Amano et al. ( 80) analyzed the enhancing characteristics of the EOM in normal control patients compared with the temporalis muscles. The EOM was markedly enhanced in all cases, whereas the temporalis muscle exhibited no or little enhancement. The cause of this vigorous enhancement may be related to the abun­dant blood supply to these muscles as demonstrated by Woodlief ( 81). This enhancement characteristics of the EOM must be kept in mind when viewing such images, or it may lead to overestimation of EOM size by the unwary viewer. The mechanism of strabismus after cataract surgery has been the subject of several reports, including that of Capo and Guy ton ( 82) reviewed in the 1996 Motility Review. Rosenbaum ( 83) reviewed this issue in an edi­torial and noted the multiple causes for this syndrome, including monocular pathophysiology related to corneal irregularity or lens decentralization ( uncommon), ani­sometropia, or preexisting misalignment manifest by sur­gery. One of the prime causes in recently described cases appears to relate to the anesthetic technique. One pos­sible mechanism is local anesthesia- induced muscle paresis or subsequent scarring with restriction, and the transformation from an initial hypertropia to subsequent hypotropia has been documented. The syndrome has not been reported after either tropica or blunt cannula infu­sion of anesthetic. Patients should be informed about the possibility of postoperative diplopia and the potential of strabismus surgery. Restrictive strabismus after ocular surgery for retinitis pigmentosa ( RP) in Cuba was reported by Bacal et al. ( 84). Although the benefits of the Cuban procedure for RP have been questioned, reports of side effects have been sparse. Their patient reported diplopia postopera­tively after the Cuban procedure for RP. Examination demonstrated 6- to 8- prism diopter ( A) exotropia and left hypertropia ( LHT) with 10- 8 LHT in downgaze and positive forced ductions for elevation and adduction re­striction OD. Strabismus surgery corrected the misalign­ment; however, the authors stressed the potential for dip­lopia after this unproved procedure. The case of a 15- year- old boy with heart failure, a thick tongue, and diplopia was presented by Karsten et al. ( 85). Diplopia was episodic with binocular oblique character. With active tongue movements, the tongue appeared to swell, broaden, and turn blue transiently. Results of lab data revealed low parathyroid levels with severe hypocalcemia that was consistent with hypopar­athyroidism. Treatment with intravenous calcium glu­conate, oral calcitriol, and calcium supplements resolved the symptoms. The authors postulated that the tongue symptoms were related to local tetany and diplopia was related to superior oblique dysfunction. According to this report, tetany is known to affect all muscles except the EOM ( see Orwitz et al. [ 85A], mentioned in part I [ ref. 32] of this review, Clostridium tetani). Lid retraction is one of the most characteristic signs of thyroid eye disease ( TED). The Dalrymple sign refers to lid retraction in primary position, and retraction in down-gaze is referred to as the von Graefe sign ( or lid lag). The pathophysiology of this sign is unclear, and hypotheses include synkinetic levator activation related to superior rectus tone needed to overcome inferior rectus restric­tion, hypertrophy of levator muscles, connective tissue adhesions between the levator and other orbital tissue, or sympathetic stimulation of levator or the Miiller muscle. Guimaraes and Cruz ( 86) investigated this issue in 25 control subjects, 34 patients with Graves disease, and 16 patients with congenital ptosis. These investigators rea­soned that because downward lid position in downgaze results primarily from relaxation of the levator muscle, insight into the pathophysiology of lid retraction in TED could be obtained by analysis of the lid positioning downgaze. The relation between vertical eyelid fissure height and downgaze was linear, and it was nearly iden­tical for control and Graves patients. In contrast, the slope of vertical eyelid fissure height and degree of downgaze was almost zero for patients with congenital ptosis. When eyelid fissure height was corrected for arc values of downgaze, the slope of fissure height to down­gaze arc was significantly greater in TED patients than in control subjects. The amount of vertical phoria did not relate to the amount of lid retraction in the patients with Graves disease. The authors concluded that hyperactivity of the levator muscle accounted for the retraction ob­served in patients with Graves disease. Separate lines of J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 195 evidence have suggested that this may be related to in­creased ^- adrenergic receptors induced by thyroid hor­mone. Although thyroid eye disease is presumably immuno-genetic and has a close association with Grave disease, the exact relationship and target antigens remains un­known. Pappa et al. ( 87) studied the lymphocytes from biopsied EOM in TED compared with peripheral lym­phocytes. Most EOM and circulating T- cell lines were CD4+, CD45RO+, and TCR a/( 3+. A wide variety of cytokines were present, and no specific pattern was iden­tified. Further work is needed to increase our understand­ing of the immune system's role in TED. Additional investigation into the nature of the immunologic re­sponse in TED was provided by Papa et al. ( 88). These investigators assesses the presence of adhesion molecule expression in biopsy specimens from 19 patients with TED. In muscle specimens from patients with early un­treated TED, strong intercellular adhesion molecule- 1 ( ICAM- 1) was noted in interstitial and perimysial con­nective tissue, and in mononuclear cells. The vascular endothelial cells stained strongly for endothelial-leukocyte adhesion molecule- 1 ( ELAM- 1), vascular cell adhesion molecule- 1 ( VCAM- 1), and ICAM- 1. A similar pattern was observed in specimens from patients with late TED, but with significantly lower staining. The au­thors concluded that the presence of adhesion molecules correlated with early TED. It is hoped that further re­search into these molecules will produce a directed therapy for patients with early TED. Thyroid eye disease involves lymphocytic infiltration, but also accumulation of glycosaminoglycan ( GAG), ap­parently in response to lymphocyte cytokine secretion. Pentoxifylline ( Trental; Hoechst Marion Roussel, Kansas City, MO) has been shown to decrease glycosaminogly­can synthesis in vitro. Accordingly, Balazs et al. ( 89) performed a pilot study that examined the effect of this medication on moderately severe TED in ten patients. Pentoxifylline was administered intravenously ( 200 mg/ d) for 10 days, followed by 1,800 mg/ d by mouth for 4 weeks, and 1,200 mg/ d by mouth thereafter. At 12 weeks, 80% of patients had improvement of soft tissue involvement, but not of proptosis or EOM involvement. Levels of serum GAG, tumor necrosis factor- a, and an-tieye antibodies decreased in the eight responders. The authors concluded that pentoxifylline may have a role in the treatment of TED, and it has the advantages of tol-erability and low cost. Dabbs and Kline ( 90) presented the unusual associa­tion of TED and bilateral optic nerve sheath meningio­mas. The patient presented with a steroid- responsive op­tic neuropathy and EOM enlargement that occurred over an 11- year period. The differential diagnosis of the case was provided by Abdul- Rahim ( 90) that expounded upon the cause of optic nerve or sheath enlargement, including neoplasm, infection, and inflammation. Although sar­coidosis and idiopathic orbital inflammation were dis­cussed as entities that potentially accounted for EOM and optic nerve enlargement, the clinical features were more in keeping with two distinct pathophysiologies. The patient was treated with radiation therapy, which provided stability at the 12- month follow- up examina­tion. Therapy for TED may be quite challenging, and op­tions include radiation, immunosuppression, and surgery. The most common indication for orbital decompression in TED is compressive optic neuropathy; however, sur­gery is also advocated for cosmetic indications. A 2- walled decompression via the transantral approach is often used; however, postoperative EOM misalignment ranges from 25% to 64%. Kalmann et al. ( 91) reported their experience with a 3- wall decompression via the coronal approach in 125 patients. Mean proptosis reduc­tion was 4.34 mm, and the greatest reductions occurred in the group with the greatest preoperative Hertel read­ings. Maximal proptosis reduction was achieved within 9 months in 88% of patients, and the authors emphasized the importance of this time frame for planning any sub­sequent lid surgery. Postoperatively, 3.2% of patients reported new diplopia in reading or primary position, and among patients with normal preoperative motility, 4% demonstrated diplopia in lateral gaze. The surgical co­hort was 94% female, and the authors noted that the coronal approach might not be desirable for patients with male pattern baldness because of the incisional scar. The authors concluded that the coronal 3- wall approach was a safe and effective means to reduce proptosis in TED. Tremolada and Tremolada ( 92) advocated a different approach for mild to moderate TED. These investigators reported their experience with 32 eyes ( 16 patients) using the " triple technique": conservative orbital lipectomy, marginal myotomy lengthening of the levator- Muller complex, and limited lateral tarsal apposition. The pa­tients had been stable for at least 9 months preopera-tively. This procedure was performed OU at the same sitting with local anesthesia and sedation, which allowed hospital discharge within hours. All patients experienced marked cosmetic and functional improvement with mini­mal reduction in proptosis ( mean, 2.23 mm). Proptosis continued to reduce for up to 6 months. Only five pa­tients had ocular dysmotility preoperatively, and this im­proved in three of these patients postoperatively. The authors believed this approach was ideal for patients with mild to moderate TED- related impairment. Commentary by Kazim ( 92A) noted his preference for general anes­thesia and hospitalization and concern for combined or­bital and lid procedures, given the tendency for lid re­duction after initial orbital decompression. Additionally, he emphasized the need to take into account the range of orbital TED involvement, including EOM enlargement, and orbital fat expansion in varying combinations. Over­all, this approach appears well suited for a subgroup of patients with TED. The EOM appear to follow stable paths within the orbit, despite changes in gaze. This finding led to the discovery of a pulley system within the EOM, composed of a ring of collagen encircling the EOM near the globe's equator. These pulleys are joined to the orbital wall and J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 196 E. R. EGGENBERGER AND D. I. KAUFMAN surrounding tissue by bands containing collagen, elastin, and smooth muscle. The innervation of this smooth muscle was explored in cadaveric human and monkey orbits by Demer et al. ( 93). The muscle was richly in­nervated with unmyelinated autonomic nerves, including both sympathetic ( from the superior cervical ganglia) and parasympathetic ( probably from the pterygopalatine and ciliary ganglia) branches. These nerves used norepi­nephrine, acetylcholine, and nitric oxide neurotransmit­ters. The authors speculated that this autonomic innerva­tion influenced the pulley stiffness, which refines bin­ocular control or vergence eye movements. NYSTAGMUS While lateral medullary infarcts are the most common in the brainstem, medial medullary infarcts are relatively rare. Like in the pons, the medulla is supplied by four separate arteries, including the anteromedial medullary artery ( medial pyramidal tract, medial lemniscus, and medial longitudinal fasciculus [ MLF]), the anterolateral medullary artery ( lateral pyramidal tract and medial in­ferior olive), the lateral medullary artery ( lateral olivary nucleus, spinal trigeminal tract and nucleus, spinotha­lamic tract, spinocerebellar tract, lateral reticular forma­tion, and cranial nerves IX and X), and the posterior medullary artery ( vestibular nucleus, inferior cerebellar peduncle, nucleus gracilis, and cuneatus). Bassetti et al. ( 94) reported the cases of seven patients with medial medullary infarcts. Contralateral hemiparesis and sen­sory loss was present in all cases. Vertigo and nausea were present in five patients, and ptosis and nystagmus were present in four patients ( horizontal in three patients and upbeat in one patient). The authors felt that vertebral dissection accounted for four of the cases, and they con­cluded that medial medullary infarct was more heterog­enous than previously reported. Spasmus nutans is characterized by asymmetric, fine nystagmus, head tilt, and head nodding. Spasmus nutans typically begins in the first year of life and quiets within years. Young et al. ( 95) reported the cases of 18 patients with spasmus nutans with attention to associated eye findings. Strabismus was noted in 10 out of 18 cases, and amblyopia was present in 8 out of 18 cases. Amblyopia, when present, was always associated with the eye that exhibited greater amplitude nystagmus. Spectacle correc­tion was required in 12 out of 18 patients. The authors emphasized the importance of early detection and treat­ment of visual abnormalities associated with spasmus nutans. Although familial ataxias are uncommon, they are an important group of clinical disorders because of potential treatment issues and the increased understanding of ge­netic pathophysiology. Baloh ( 96) reported the clinical and oculographic findings in four families with familial episodic ataxia linked to chromosome 19p. Episodes of neurologic dysfunction were variable and ranged from pure ataxia to combinations of symptoms suggestive of brainstem or cortical dysfunction. Migraine headache or basilar migraine was present in approximately 50% of patients. Rebound nystagmus was present in 10 out of 13 patients. Response to acetazolamide treatment was noted in 11 out of 12 patients. Marked clinical heterogenicity was noted in this cohort, and the authors speculated that additional genetic and environmental factors likely ac­count for diverse clinical syndromes. A review of the episodic ataxias types 1 and 2 was presented by Brandt and Strupp ( 97). These authors em­phasized the separation of this group of disorders into type 1 ( EA- 1), characterized by interictal myokymia and lack of vertigo, and type 2, which manifests as vertigo with interictal nystagmus. Both of these groups appear to result from channelopathies that affect the potassium channel via chromosome 12pl3 in EA- 1 and the calcium channel via chromosome 19p in EA- 2. The duration of attacks in EA- 1 was in the seconds to minutes range, compared with EA- 2 episodes that last hours to days. EA- 1 has been reported in seven families and is associ­ated with attacks of incoordination, in addition to trem­bling of the face, head, and limbs, often elicited by startle or exercise. Myokymia, which particularly affects the face, may be present. Recall that facial myokymia is also associated with brainstem glioma or multiple sclerosis ( MS), and EA- 1 should be added to this differential di­agnostic list. Approximately 20 families have been de­scribed with EA- 2. EA- 2 typically manifests as recurrent attacks of instability or vertigo with nystagmus and may be associate with dysarthria, tinnitus, or diplopia. Down­beat nystagmus is particularly prevalent during an attack. The differentia diagnosis includes migraine, MS, epi­lepsy, and Meniere disease. This group of disorders is important because of their amenability to therapy. Acet­azolamide is the treatment of choice, and it may exert its effect via decreased pH. Gottlob ( 98) presented a case of infantile nystagmus and documented the oculographic development of signs over time. No nystagmus was present at 5 weeks of age; however, square- wave jerks were noted at 7 weeks of age and pendular nystagmus recorder at 8 weeks of age. Con­jugate pendular nystagmus typical of infantile nystagmus with exponentially increased slow- phase velocities was present between 7 and 12 months of age. The authors emphasized the normality of early ocular findings and subsequent saccadic abnormalities before typical nystag­mus appearance. Nystagmus is a common and distressing problem in patients with MS. Common subtypes of nystagmus in this population include downbeat, dissociated abducting, and pendular waveforms. Pendular nystagmus typically produces distressing oscillopsia in this population, and treatment with agents, including gabapentin or clonaze­pam, have produced variable results. Starck et al. ( 99) reported the effects of memantine, a glutamate antago­nist, in 14 patients with MS- related pendular nystagmus. Memantine has been in clinical use in Europe for several years, and contains N- methyl- D- aspartate ( NMDA) blocking, alpha- amino- 3- hydroxy- 5- methyl- 4- isoxazole-propionic acid ( AMPA) modulating, and dopaminergic actions. Memantine was used in dosages of 5 to 20 mg by J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 197 mouth three times a day and produced tolerable side effects, such as dizziness in one patient, fatigue in two patients, and muscle weakness in two patients. Meman-tine was effective in all 11 patients, while scopolamine produced no ( for six out of eight patients) or minor ( for two out of eight patients) reduction in nystagmus. A dose- dependent effect of memantine was noted with nys­tagmus cessation in all 11 patients treated for 1 to 3 years. Memantine will necessitate larger scale confirma­tion over extended periods of treatment to confirm safety; however, it appears to be quite promising. A double- masked trial of gabapentin and baclofen as treatment for acquired nystagmus was reported by Averbuch- Heller et al. ( 100). The study was composed of 21 patients: 15 patients with acquired pendular nys­tagmus ( nine cases related to MS) and six patients with downbeat or torsional downbeat nystagmus. Visual acu­ity significantly improved in the acquired pendular nys­tagmus group while administered gabapentin, but not when administered baclofen. Substantial reduction in nystagmus was noted in ten patients, and eight patients chose to remain on treatment. Among the jerk nystagmus cohort, slow phase velocity was less consistently changed, and only one patient demonstrated consistent reduction ( achievable with either drug). The authors sug­gested that gabapentin may be an effective treatment for acquired pendular nystagmus, and patients with down­beat nystagmus occasionally respond to baclofen or gabapentin. The progressive ataxias are a heterogeneous group of disorders that include Friedreich ataxia, spinocerebellar or cerebellar degeneration, multisystem atrophy, and oth­ers. Ophthalmic findings are not infrequently associated with this group of disorders. Rabiah et al. ( 101) reviewed their experience with 184 patients undergoing complete ophthalmologic examinations. Diplopia was the most frequent finding in this group, noted in 28% of the pa­tients; however, this finding was constant in only 6% of the patients. Diplopia was related to esotropia ( 33%), esotropia ( 19%), combined horizontal and vertical ( 8%), variable esotropia and exotropia ( 4%), and skew ( 2%). No identifiable misalignment was found in 35% of the patients. Reduced best- corrected acuity was noted in 16% of the patients, related to optic atrophy ( most fre­quent with spastic ataxia or myoclonic ataxia) in 9% of the patients, and to retinopathy ( most frequent in olivop­ontocerebellar or mitochondrial myopathy) in 7% of the patients. The authors emphasized the association of fixa­tion instability with Friedreich ataxia, and they associ­ated the normal saccadic speed with pure cerebellar de­generations. Osteogenesis imperfecta ( 01) is a group of heritable bone disorders that result in defective collagen synthesis with pathologic bone fragility and tendency toward frac­ture. Several types of 01 are associated with a blue sclera. The presence of basilar invagination with 01 of­fers a treatment challenge. Sawin et al. ( 102) reviewed the management of 01 with basilar invagination in 25 patients. The mean age at presentation was 11.9 years ( range, 13 months- 20 years). Nystagmus was present in 28% of patients. The most common symptom was head­ache ( 76%), followed by lower cranial neuropathy ( 68%), dysphagia ( 60%), hyperreflexia ( 56%), and quad-riparesis ( 48%). Hydrocephalus was treated with ven­tricular shunting. The authors suggested that ventral brainstem compression necessitated ventral decompres­sion followed by occipitocervical fusion with contoured loop instrumentation to prevent further squamooccipital infolding. Basilar infolding tended to progress despite this intervention, and prolonged immobilization, particu­larly in adolescence, may be needed to stabilize symp­toms. Although uncommon, 01 and basilar invagination are important to neuro- ophthalmologists because of the ocular symptoms and lower cranial neuropathies. Lateral medullary ( Wallenberg) syndrome is the most common brainstem stroke syndrome encountered in clinical practice. Findings include ipsilateral facial numbness, ataxia, and Horner syndrome with contralat­eral body hypesthesia. Lateralopulsion toward the lesion side is observed with eye closure, and skew deviation and nystagmus are frequent neuro- ophthalmologic signs. Nickerson et al. ( 103) reported the case of a 69- year- old man with lateral medullary infarct and persistent hiccups ( singultus) that occurred at a frequency of 25/ min. Hic­cups were refractory to prochlorperazine, promethazine, and chlorpromazine. Baclofen 5 mg three times a day produced resolution within 48 hours, and after discon­tinuation 1 week later, no return of hiccups was noted. Baclofen has appeared in the European literature as a useful drug for refractory hiccups, and it should be con­sidered in such cases. Peripheral vestibular dysfunction produces a charac­teristic syndrome of vertigo and nystagmus, in addition to gait instability, nausea, vomiting, and malaise. Typi­cally, compensation occurs that leads to symptom reso­lution over a variable period of weeks. The exact mecha­nism of compensation is unknown, but it is thought to involve the cerebellum. Furman et al. ( 104) reported the case of an illustrative patient who experienced a trau­matic, unilateral, peripheral, vestibular injury 2 years af­ter an unrelated cerebellar infarction. The patient did not compensate for the peripheral vestibular loss and exhib­ited spontaneous nystagmus and directional preponder­ance 4 months after the injury. An MRI demonstrated infarction of the left cerebellar hemisphere that involved the pyramis and uvula; however, the flocculo- nodular lobe ( vestibulo- cerebellum) was spared. The authors concluded that cerebellar lesions that spare the vestibulo-cerebellum may hinder peripheral vestibular compensa­tion. Familial period ataxias are a group of inherited disor­ders with variable characteristics that include vestibular ocular reflex dysfunction. Furman ( 105) reported the otolith- ocular responses in a family of episodic ataxia linked to chromosome 19p. Clinical characteristics within this pedigree include rebound nystagmus, sac­cadic overshoot, abnormal pursuit, and optokinetic nys­tagmus ( OKN) with normal semicircular canal function. J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 198 E. R. EGGENBERGER AND D. I. KAUFMAN This genetic marker and the clinical features place this syndrome into the episodic ataxia type 2 category. Off-vertical axis rotation ( OVAR) was used to investigate these patients. This devise consists of a rotary chair at­tached to a tilt stand that allows a 30° tilt of the rotating chair. Oculomotor, semicircular canal- ocular, and semi­circular canal- otolith interactions suggested flocculo-nodular lobe impairment with relative sparing of the brainstem. Off- vertical axis rotation is considered a pure otolith stimulus; the OVAR modulation component was normal, and the bias component was reduced or absent. The author concluded that the bias component of OVAR depends on the caudal midline cerebellum, whereas the cerebellum does not appear to be responsible for the modulation component of OVAR. A summary of a symposium on therapy of ocular mo­tility disturbances was reported by Kaminski and Leigh ( 106). The symposium included aspects of basic mecha­nisms for gaze control and holding, pathophysiology, and treatment of different forms of nystagmus, peripheral ocular motor characteristics, and the use of botulinum toxin in ocular therapy. Biittner- Ennever, one of the sym­posium speakers, discussed the cell groups of the para­median tracts, located in the midline pontine and med­ullary levels, close to the medial longitudinal fasciculus. These cells receive input from all structures that project to the ocular motor nuclei and send efferent fibers to the cerebellar flocculus and paraflocculus. Accordingly, they are in a suitable position to monitor premotor eye signals and to participate in compensatory mechanisms. Biittner- Ennever reported on the pharmacology of the vestibular and ocular motor system, including the - y- aminobutyric acid [ GAB A]- system of the nucleus prepositus hypoglo-ssi and medial vestibular nucleus ( the neural integrator), which is important in eccentric gaze holding. Leigh, an­other symposium speaker, reported on gaze- holding physiology, with emphasis on the role of visual fixation, vestibular ocular reflex, and neural integrator function. In addition to derangements of these systems, delayed feedback from afferent cell groups may be responsible for other types of nystagmus. A delay from the parame­dian cell groups to the cerebellum caused by demyelina-tion appears to explain the clinical phenomena of pen-dular nystagmus. The role of vestibular ocular reflex dys­function in visual dysfunction and oscillopsia was discussed by symposium speaker Tusa. Vestibular reha­bilitation produced significant improvement in vestibul­opathy related signs. Congenital and latent nystagmus were discussed in several papers. Tusa presented a mon­key model of latent nystagmus produced by deprivation of binocular vision early in life. Optical, surgical, and pharmacologic methods of nystagmus were discussed. A review of EOM anatomy and physiology was presented, which emphasized the distinct features of the EOM. Symposium speaker Kaminski discussed preferential af­fection and sparing of the EOM in myasthenia gravis and Duchenne muscular dystrophy ( MD). He noted that the EOMs superior calcium sequestration and free radical scavenger abilities may account for the EOM sparing in Duchenne MD, and immunologic differences may ex­plain EOM common involvement in myasthenia. Over­all, the conference showcased a new subdiscipline of neuro- ophthalmology and the fruits of novel investiga­tion techniques regarding ocular motility. The varied manifestations of Creutzfeldt- Jacob ( CJD) disease have been highlighted by the emergence of new variant CJD, thought to be related to bovine spongiform encephalopathy. A case reported by Vingerhoets et al. ( 107) furthered this spectrum. The patient developed in­somnia at 58 years of age, followed by Parkinsonian symptoms. Evaluation included a normal neuropsychiat-ric examination and mild blepharospasm with occasional oculogyric crisis. Dopamine agonists for bradykinesia and rigidity without tremor produced hallucinations and dyskinesias. Falling began within 1 year, and an exami­nation revealed moderate supraduction limitation, sac­cadic pursuit, and bilateral, horizontal, gaze- evoked nys­tagmus with moderate truncal and appendicular ataxia. Results of EEGs demonstrated no periodic activity, and MRI revealed mild atrophy only. The patient committed suicide, and an autopsy demonstrated loss of Perkinje cells with positive prion protein ( PrP) staining. No Lewy bodies, plaques, or spongiform change was noted. The case was quite atypical in that no dementia was present 12 months into the disease, and EEG changes were not apparent. The authors suggested that the early occurrence of insomnia and the ocular motor signs may be helpful in the diagnosis of other atypical cases. Primary- position vertical nystagmus indicates a cen­tral vestibular pathophysiology. Downbeat nystagmus is the most common form of central vestibular nystagmus, while upbeat variation is relatively rare. Generally, cen­tral vestibular nystagmus obeys die Alexander law, in­creasing in intensity with gaze toward the fast phase. Ohkinoshi et al. ( 108) reported a case of primary-position upbeat nystagmus that increased in downgaze related to MS with clinicopathologic study. The patient had vertical diplopia and primary- position upbeat nys­tagmus that increased on downgaze. Results of a CT of the brain were unremarkable; however, after the patient died of pneumonia, autopsy confirmed the diagnosis of MS. Multiple demyelinating foci within the medulla ( particularly in the lower medulla) were noted, but pons, mesencephalon, and cerebellar peduncles were spared. The medullary lesions included midline demyelination around the intercalatus nuclei, which is known to have cerebellar, vestibular nuclear, ocular motor, and nucleus prepositus hypoglossi connections. This case provided additional support for the suggestion of Daroff and Troost ( 109) that small- amplitude upbeat nystagmus that increases in downgaze reflects a medullary lesion; large amplitude upbeat that increases in upgaze ( obeying the Alexander law) typically results from a lesion of the cerebellar anterior vermis. Nystagmus is most often related to vestibular asym­metries. The acute vestibular syndrome includes not only nystagmus, but also vertigo, nausea, and postural insta­bility. This syndrome was reviewed by Hotson and Baloh ( 110). The authors emphasized the anatomy, potential J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 199 pathophysiologies, evaluation, and management of the acute vestibular syndrome. They noted the potential for inferior cerebellar dysfunction to simulate vestibular neuritis. Key anatomic and physiologic points included the findings that semicircular canals were sensitive to angular acceleration, that bilateral vestibulopathy does not typically result in vertigo because of the balanced loss of function, and that slowly progressive lesions, such as acoustic neuroma, rarely produce vertigo because of ongoing central compensation. The causes of vertigo were divided based upon time course, with episodes last­ing a day or longer potentially related to vestibular neu­ritis, vertebro- basilar infarcts, or MS. Vertigo in the hours to minutes range may result form Meniere disease, transient ischemic attack ( TIA), or perilymph fistula. Vertigo of seconds duration may be produced by benign paroxysmal positional vertigo, which is an important cause of symptoms because of common occurrence and excellent repositioning treatment response. The impor­tance of the type of nystagmus and the severity of pos­tural instability were highlighted as the keys to differen­tiate peripheral vestibular dysfunction from inferior cer­ebellar stroke. Central forms of nystagmus are often vertical and exhibit little change in response to visual fixation, while peripheral vestibular nystagmus dampens with fixation and has a constant direction, which is typi­cally horizontal with a torsional component. Although peripheral vestibular disorders produce discomfort and a reluctance to walk, most patients are able to ambulate, albeit with a tendency to veer toward one side. Cerebellar infarcts often produce greater instability or ataxia of gait and stance. The authors suggest neuroimaging if a central process is likely, if atypical features inconsistent with a peripheral process are noted, if new and severe headache accompany vertigo onset, or if prominent vascular risk factors exist. In the case of isolated vertigo with periph­eral vestibular findings, neuroimaging may be delayed 48 hours and avoided if substantial improvement of the symptoms begins during this time. The mucopolysaccharidoses ( MPS) are a group of dis­orders related to abnormal protein- polysaccharide me­tabolism that result in multisystem dysfunction inclusive of retinopathy and blindness. Bone marrow transplant has been shown to improve systemic health, but it may not produce visual improvement. Gullingsrud et al. ( I l l) reported the ocular findings from 23 patients with MPS undergoing bone marrow transplant at 3 years of age or younger. This cohort demonstrated a relatively high rate of ocular abnormalities on examination, in addition to retinopathy inclusive of optic atrophy ( 7 out of 23 pa­tients), disc edema ( 6 out of 23 patients), strabismus ( 6 out of 23 patients) and nystagmus ( 6 out of 23 patients). Although electroretinogram recordings improved over the first year after the transplant, slow progressive de­cline was subsequently noted in all patients. Perilymph fistulas are often challenging to diagnose and treat. These abnormal communications between the inner ear and middle ear produce hearing loss and ver­tigo, and they may result from barotrauma. The fistula test is often used as a clinical means of diagnosis; how­ever, the sensitivity and specificity of the test are un­known. This test has been applied in several forms de­signed to produce increased inner- ear pressure. The Hen-nebert sign is the slow conjugate horizontal deviation of the eyes with positive pressure within the external audi­tory canal and the reversal of eye movements with ap­plication of negative pressure. Hain and Ostrowski ( 112) reported the results of pneumatic- otoscopic, bulb-pressure application on 13 normal subjects and on 7 pa­tients with a history of pressure- sensitive nystagmus who subsequently underwent exploratory tympanotomy. Nor­mal subjects demonstrated a change in nystagmus ( spon­taneous nystagmus with mean slow- phase velocity of - 0.0027s was noted; range, 1.3- 0.97s). The authors found the fistula test, as conventionally performed, to be insensitive for the diagnosis of perilymph fistula. A method of analysis that uses interear disparity of re­sponse to pressure application was predictive of response to surgical exploration in the four patients with positive surgical results. The authors emphasized the need for detection methods with greater sensitivity. Nystagmus remains important to distinguish central from peripheral causes of vertigo. A three- dimensional analysis of nystagmus in peripheral vertigo was under­taken by Toshiaki et al. ( 113) to assist with anatomic localization. These investigators studied four patients with Meniere disease and six patients with vestibular neuritis, using a high- speed infrared video camera. The patients with Meniere disease demonstrated horizontal and torsional plane eye movements, while the patients with vestibular neuritis exhibited horizontal, vertical, and torsional movements. Similar findings were observed by Ohyama et al. ( 114), using two- dimensional analysis during peripheral vestibular attacks. The authors postu­lated that Meniere disease involved all three semicircular canals ( therefore the vertical components of the anterior and posterior semicircular canals cancel out), while ves­tibular neuritis involved the superior vestibular nerve. This segment of the nerve supplies the lateral and ante­rior canals, and hypofunction of these segments would account for the observed nystagmus. Down syndrome, or trisomy 21, is the most common identifiable genetic disorder that produces mental retar­dation. A review of the ocular abnormalities of Down syndrome was reported by Wong et al. ( 115) that em­phasized the frequency of ocular abnormalities. Among a cohort of 140 Chinese patients with Down syndrome, 69% had evidence of ophthalmic abnormalities on ex­amination. Refractive error was the most common ( 58%), followed by strabismus ( 20%) and nystagmus ( 11%). The presence of nystagmus ranged from 15% to 29% in previous studies, which was slightly higher than in the present study; this increase is thought to reflect the unselected nature of the reported cohort. No Brushfield spots were detected; the authors felt this may reflect the darker iris in Chinese patients, which renders detection more difficult. Latent nystagmus ( LN) is a distinct pattern of nystag­mus with decreasing velocity slow phases directed to- J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 200 E. R. EGGENBERGER AND D. I. KAUFMAN ward the nose with respect to the fixing eye. While latent nystagmus is present with occlusion of one eye, manifest latent nystagmus ( ML) is present under binocular condi­tions. Among patients with LN and good acuity, unusual fast- phase eye movements were noted by Dell'Osso et al. ( 116). In a follow- up report, Erchul et al. ( 117) reported the characteristics of defoveating fast- phase eye move­ments in LN. These investigators studied four patients with LN and defoveating fast phases. The defoveating fast phases occurred in the presence of higher slow- phase velocities, and larger saccade sizes corresponded with larger slow- phase velocities. These investigators postu­lated that defoveating fast phases in LN may be the sum­mation of saccadic pulses to linear slow phases. See- saw nystagmus is a rare condition that is tradi­tionally linked to perichiasmal lesions. In a report of achiasmatic mutant Belgian sheepdogs, Dell'Osso et al. ( 118) recorded not only a horizontal component ( similar to human congenital nystagmus), but also a see- saw component. This see- saw component appears to be a rec­ognized sign of achiasma in canines, and it was present in one person with achiasma. The authors suggest that the presence of achiasma may be suspected in congenital see- saw nystagmus in human infants. The exact relation of chiasmal abnormalities and the generation of see- saw nystagmus need further work. Benign paroxysmal positional vertigo ( BPPV) is the most common peripheral vestibular cause of vertigo in most vestibular clinics. Patients with BPPV typically re­port short- lived isolated episodes of vertigo precipitated by head movements. The diagnostic hallmark is charac­teristic nystagmus that reflects activation of the posterior semicircular canal ( ipsilateral superior oblique and con­tralateral inferior rectus). Benign paroxysmal positional vertigo appears to result from debris within the posterior semicircular canal ( the canalolithiasis hypothesis)- probably otoconia from the utricle. Benign paroxysmal positional vertigo typically responds to repositioning procedures, such as the Epley or Semont maneuvers, which are designed to clear the posterior canal of debris. Lempert et al. ( 119) reported the results of 360° back­ward rotation in a three- dimensional rotational devise. Forward rotation did not relieve symptoms in any of 15 patients; backward rotation produced immediate relief in 10 out of 14 patients. Backward rotation would be ex­pected to directionally clear the posterior canal of debris, and findings in this study help support the canalolithiasis hypothesis of BPPV. Although an association between BPPV and trauma is well known, the disease is otherwise often presumed to be idiopathic in origin. The epidemiology of BPPV in a large vestibular clinic was reported by Hughes and Proc­tor ( 120), inclusive of BPPV associations. These authors reviewed 151 cases of BPPV, comprising approximately 19% of patients considered for this review. Among the BPPV cohort, 34% presented with no preceding disorder and were considered to have primary BPPV. The remain­ing 66% presented with coexisting or preceding disor­ders, including Meniere disease ( 30%), head trauma ( 15%), previous ear surgery ( 4%), vestibular neuritis ( 3%), and migraine ( 3%). The authors emphasized the occurrence of Meniere disease as a common coexistent or preceding disorder associated with BPPV. This report stresses the importance of considering other vestibular diseases when the BPPV syndrome is encountered. Typical BPPV responds favorably to" repositioning maneuvers ( cure rates range from 57% to 90% in the literature). The mechanism of therapy is presumed to be gravity- aided movements in direction suitable to remove free- floating debris from the posterior semicircular canal. In order to investigate the time frame of improvement after repositioning maneuvers, Smouha ( 121) studied 27 consecutive cases of BPPV. Absence of provokable nys­tagmus was taken as cure after therapy. Repositioning, as described by Epley ( 121 A), was used, and treatment was repeated during clinical visits until nystagmus was ab­sent upon Hallpike testing. Among this cohort, 93% of patients improved after treatment, although seven pa­tients required two cycles of repositioning, six patients required three cycles of treatment, and four patients re­quired more than three repositioning treatments. Resolu­tion of nystagmus with subsequent follow- up was ob­served in 63% of patients in relation to repositioning treatments, which lead the authors to speculate that re­positioning may act via adaptive conditioning in some patients. Given the duration of repositioning therapy, it appears unlikely this is the predominant mechanism of improvement in these patients. While BPPV is quite common among vestibular clin­ics, the syndrome almost always reflects involvement of the posterior semicircular canal consistent with canalolithiasis, or free- floating debris amenable to repo­sitioning maneuvers. Involvement of the anterior or hori­zontal canals is relatively rare in BPPV. Casani et al. ( 122) reported nine patients with ageotropic bidirectional nystagmus that was postulated to result from horizontal canal involvement. The patients reported positional ver­tigo that was provoked by lateral turning of the head while in the supine position. Strong paroxysmal nystag­mus was present in all patients that was evoked with lateral positioning of the head. Nystagmus was ageotro­pic with lateral positioning to either side and tended to persist for longer than 1 minute ( only 4 patients ceased nystagmus within 160 seconds). The prognosis was gen­erally good, and all patients were asymptomatic within 15 days to 4 months after diagnosis postpharmacologic treatment ( 7 patients), repositioning maneuvers ( 6 pa­tients), or after no therapy. The authors speculated that this clinical syndrome was from cupulolithiasis (" heavy cupula") that resulted in cupula density greater than otolith density. The (^- hexosaminidase ( Hex) enzyme is involved in the degradation of complex glycolipids, glycoproteins, and glycosaminoglycans. Deficiencies within the Hex A enzyme system result in the GM2 gangliosidoses, the best known of which is Tay- Sachs disease. Although classic Tay- Sachs disease presents in infancy, less severe variants have presented in patients up until the second decade of life. These later- onset variants commonly have J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 201 been, associated with ocular motor dysfunction, including supranuclear ophthalmoparesis, internuclear ophthal­moplegia ( INO), slowed saccades, or ocular apraxia- like head thrusts. Hund et al. ( 123) reported the cases of four non- Ashkenazi siblings with hexosaminidase A and later ( teenage) clinical onset. These patients presented with a homogeneous syndrome of cerebellar ataxia, motor neu­ron disease, and ocular motor abnormalities. All patients had marked eye movement disturbance, including ves­tibular ocular reflex ( VOR) suppression abnormalities, saccadic smooth pursuit, and abnormal OKN. Only one patient had supranuclear paresis of upward gaze. This report emphasizes the varied clinical spectrum of these disorders. Dejerine- Sottas disease is typified by severe infantile demyelinating motor and sensory neuropathy. Nystag­mus has not been reported previously in this condition. Coarse gaze- evoked nystagmus was reported as a com­ponent of Dejerine- Sottas disease in a 32- year- old woman with a de novo point mutation at gene 22. The patient also had bifacial paresis, deafness, and congenital wheelchair- requiring quadriparesis. Gaze- evoked nys­tagmus was present in the horizontal and vertical planes. This report emphasizes a degree of heterogeneity to this inherited polyneuropathy inclusive of cranial nerve in­volvement. ( 124). Periodic alternating nystagmus ( PAN) is a distinct eye movement abnormality that occurs in acquired and con­genital settings. The acquired form of PAN may be re­lated to vestibulocerebellar disease and responds to bac­lofen or phenytoin, while congenital PAN is much less amenable to pharmacologic therapy. Gradstein et al. ( 125) reported the findings of 18 patients with congenital PAN. Among this cohort, 16 patients had abnormal head posture, and 5 patients had ocular or oculocutaneous al­binism. The nystagmus cycles were of variable duration, often with asymmetric right/ left components. Baclofen was ineffective for management of nystagmus. Kesten-baum procedures were performed on three patients and failed to change nystagmus or acuity; however, large, horizontal, four- muscle recti recessions provided favor­able change in nystagmus in all five patients so treated. The authors emphasized the value of attentive nystagmus observation in the diagnosis, and suggested that Kesten-baum procedures seem inappropriate, while recti reces­sion may improve clinical status. Head- shaking nystagmus ( HSN) is a unique form of nystagmus that is indicative of asymmetry of velocity storage. Head- shaking nystagmus may result from pe­ripheral or central pathophysiologies. Peripheral vestib­ular disorders are often associated with horizontal nys­tagmus inclusive of slow phases toward the paretic ear and may require stronger stimuli (> 15 seconds of head shaking). Head- shaking nystagmus with central vestibu­lar disorders may be observed with weaker or shorter stimulation, and slow- phase direction is inconsistently related to lesion side. The secondary phase of HSN is generally much weaker if present in peripheral disorders, while the secondary phase of central disorders may be larger than the primary phase. Cross- coupling, or nys­tagmus about one axis after head shaking in another axis, is associated with central disorders. Asawavichianginda et al. ( 126) reported on the pathophysiologies that pro­duced HSN in 300 clinical patients. These authors found HSN significantly associated with peripheral disorders; of 196 patients with identifiable origin for vestibulopa­thy, 190 ( 96%) resulted from peripheral disorders. The authors noted an association with the degree of vestibular dysfunction- greater end- organ or nerve involvement was more likely to produce HSN. Although HSN is nei­ther sensitive nor specific, it remains a simple clinical test to include in the assessment of vestibular patients. Pelizaeus- Merzbacher disease ( PMD) is a rare, X-linked, dysmyelinating disorder of the central nervous system. The disorder typically presents within months of birth and is associated with characteristic pendular nys­tagmus. A novel variant of PMD with a distinct genotype was reported by Hodes et al. ( 127). The clinical picture shared features in common with X- linked spastic paraplegia, which also appears to be linked to proteolipid protein ( the major protein of central nervous system my­elin). The reported clinical syndrome was notable for relatively mild clinical form, onset after 2 years of age, tremors, and the absence of nystagmus. The discovery of intermediate or atypical cases of recognized genetic dis­orders is becoming increasingly common with advanced genetic testing. The VOR serves to foveate objects during head move­ments. The gain of the VOR is a well- quantified entity in adults as measured by rotary chair testing; however, this testing is more difficult in children. Sakaguchi et al. ( 128) investigated the gain of the VOR under conditions of dark and light ( visual VOR) in 20 children 3 to 6 years of age and compared this group with 24 healthy adults 21 to 29 years of age. Although the phase of the VOR did not significantly differ between the two groups under either lighting condition, a larger VOR gain was noted in children in darkness. The authors speculated that this finding was related to immaturity of vestibular inhibition in the children. The possibility that the children were tested with a higher level of alertness could also contrib­ute to the findings. Acute vestibular dysfunction produces not only ver­tigo and nausea, but also changes in gait and stance. The effect of vestibular dysfunction on gait was analyzed by Kubo et al. ( 129) using infrared video cameras. The co­hort was composed of eighit healthy volunteers who un­derwent instillation of 5 mL ice water into the left ear. After the ice water, stride length and step cycle became smaller when walking on a treadmill. The primary effect on gait was a large lateral sway away from the side of the caloric stimulation. Medial- lateral sway amplitude was increased at the hips, but not significantly at the head and neck, which suggested that the vestibulospinal reflex contributed insignificantly to upper- body dynamic bal­ance. The authors stressed the importance of the hip strategy for compensation for an acute vestibular lesion. Video analysis of locomotion has more promise as a functional tool for patient evaluation than posturography J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 202 E. R. EGGENBERGER AND D. I. KAUFMAN has; however, further studies are needed to confirm the characteristics of gait dysfunction produced by the vari­ous pathophysiologies before more widespread use is anticipated. SACCADES The exact anatomy of saccadic generation has been explored with functional imaging techniques. Bodis- Wollner et al. ( 130) reported the results of occipital and frontal cortex activity during voluntary and imagined saccades with functional MRI ( fMRI). This group pre­viously demonstrated voluntary saccadic activation of the precentral and posterior medial frontal gyrus ( supple­mental eye fields), medial superior frontal gyrus ( supple­mentary eye fields), and occipital lobes. In the follow- up fMRI study, imagined eye movements were similar to voluntary saccade- demonstrated activation, except there was no occipital lobe activation. The authors reiterated that the fMRI- documented activation of the motor and primary visual areas was produced by voluntary saccades and that imaginary saccades do not activate the primary visual cortex. The exact significance of this anatomic distinction remains unknown. At least three different types of saccades exist, includ­ing express saccades ( latency 100 ms), fast- regular sac­cades ( latency 150 ms), and regular saccades ( latency 200 ms). The antisaccade task requires a subject to gaze opposite a presented target, therefore inhibiting reflex saccades and evoking voluntary gaze. The anatomy of fast- regular saccades, antisaccades, and fixation was as­sessed in ten normal subjects using positron emission tomography ( PET) scan by Doricchi et al. ( 131). Imaging illustrated an occipitotemporal network that involved the fast- regular saccades and a frontoparietal network that was associated with the antisaccade task. Fixation acti­vated overlapping regions between these two networks. The authors concluded that these results suggested pre­dominantly subcortical ( collicular) regulation of fast-regular saccades, and parietal and prefrontal regions were involved in antisaccade performance. Gilles de la Tourette syndrome ( GTS) is an inherited disorder characterized by childhood- onset motor and vo­cal tics. The pathophysiology of GTS is presumed to be related to the basal ganglia. Huntington disease, also af­fecting the basal ganglia, has been shown to produce difficulty with the antisaccade task and to suppress re­flexive saccades, and Parkinson disease is associated with slowed memory- guided saccades. Straube et al. ( 132) studied the effects of GTS on saccades in ten pa­tients. Patients with GTS demonstrated a significant in­crease in antisaccade latency with peak antisaccade ve­locity reduction and impaired sequencing of memory-guided saccades. The authors speculated that the demonstrated defects resulted from deranged cortico-basal ganglia loops, aspects of which are involved in specific saccadic tasks. A study that examined the ocular motor abnormalities in Meniere disease was reported by Isotalo and Pyykko ( 133). These investigators found pseudo- random saccade latency correctly discriminated a group of 62 patients compared with 38 controls ( 75%). Although the authors concluded that peripheral vestibular lesions influence voluntary eye movements, other necessary control fea­tures, such as the medications, need to be taken into account. A review of cerebral ocular motor control with an emphasis on saccades was reported by Pierrot- Deseilligny et al. ( 134). Among the four major classes of eye movements- saccades, convergence, pursuit, and VOR- only VOR and nystagmus quick phases are con­trolled by the brainstem. The frontal eye fields ( FEF) appear to be involved in intentional saccades used for visual exploration, while the parietal eye fields primarily deal with reflex saccades, and the supplementary eye fields participate in the preparation of motor programs. Clinically, only bilateral lesions of these regions produce enduring ocular motor defects. Balint syndrome results from bilateral parietal lesions, and ocular motor apraxia results from bilateral fronto- parietal lesions. Frontal eye fields and the medial superior temporal areas control smooth pursuit. This article serves as a good overview of the contribution of the hemisphere to eye movements. Spinocerebellar degenerations are genetic disorders that produce varied constellations of symptoms. The eye signs of three patients with spinocerebellar atrophy ( SCA) type 1 ( SCA I) were presented by Klostermann et al. ( 135). All patients had cytosine- adenosine- guanine ( CAG) repeat in the SCA gene on chromosome 6p. A progressive saccadic disorder was present in all patients that was characterized by slowing of saccades with loss of nystagmus. Upgaze palsy was an early feature that progressed to downgaze and horizontal ophthalmopare-sis. In addition, severe loss of visual acuity because of optic atrophy was observed. The present cases widen the spectrum of SCA I phenotype while blurring the margins with SCA II. The authors emphasized that the findings indicate brainstem dysfunction rather than cerebellar dis­ease, and they emphasize the variable phenotype of the SCAs. Machado- Joseph disease ( MJD) is a spinocerebellar ataxia characterized by pyramidal tract signs, progressive external ophthalmoplegia and ataxia, and variable de­grees of proptosis, peripheral amyotrophy, and dystonia. The disease appears more commonly in patients of Por­tuguese descent. The characteristics of MJD in 21 Chi­nese kindreds was presented by Soong et al. ( 136). Machado- Joseph disease accounted for 52% of the fami­lies with spinocerebellar ataxia in this series. The fea­tures of progressive ataxia, dysarthria, and optokinetic nystagmus loss were present in 100% of the cohort, and ocular dysmetria and nystagmus, corticospinal dysfunc­tion ( 75%- 90%), proprioceptive loss, and progressive external ophthalmoparesis ( 50%- 65%), and proptosis and facial fasciculations ( less than 50%) were less fre­quent. A strong inverse relation existed between the number of CAG repeats and the age of onset, with an­ticipation in succeeding generations. PET studies dem­onstrated progressive occipital cortex, cerebellar hemi­spheres, vermis, and brainstem hypometabolism. The au- J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 203 thors stressed the common occurrence of MJD among Chinese spinocerebellar patients, which de- emphasized the Portuguese lineage. Opsoclonus is one of the saccadic intrusions charac­terized by multidirectional saccades without an intersac-cadic latency. Opsoclonus may be part of several disor­ders, including toxic or metabolic encephalopathies, en­cephalitis, hydrocephalus, thalamic hemorrhage, or paraneoplastic disorders. As a paraneoplastic disorder, opsoclonus is usually associated with anti- Ri antibodies and lung or breast carcinoma. The syndrome appears to result from disruption of omnipause cells in the pons that otherwise exert inhibitory control over saccadic genera­tion. Honnorat et al. ( 137) reported the case of a 60- year-old woman with pancreatic carcinoma presenting with opsoclonus, ataxia, dysarthria, and episodic confusion. The patient had a novel cerebrospinal fluid ( CSF) and serum anti- Purkinje cell antibody, distinct from anti- Yo, - Ri, and - Hu antibodies. Ultimately, a pancreatic carci­noma was diagnosed, and the patient died with progres­sive neoplastic disease. This case is noteworthy as an­other non- Anti- Yo, anti- Purkinje cell antibody and for the association with pancreatic carcinoma. Opsoclonus- myoclonus ( OM) is a rare disorder typi­cally related to postinfectious, paraneoplastic, toxic, metabolic, or vascular pathophysiologies. The paraneo­plastic variety is most often associated with neuroblas­toma. The syndrome is presumably immune mediated because of the presence of autoantibodies and the re­sponse to immune suppressants. The neural targets of these autoantibodies were studied by Connolly et al. ( 138) with use of serum from six children with postviral OM and three children with paraneoplastic OM. Sera from all patients contained immunoglobulin G and im­munoglobulin M that bound to cytoplasmic Purkinje cells and nuclei, and to some white matter axons. The immunoglobulin M antibodies appeared to be distinct from immunoglobulin G anti- Ri antibodies that occur in adults. In addition, sera from all patients bound to both larger and smaller peripheral axons. The authors con­cluded that childhood OM is associated with a distinct set of immunoglobulin G and immunoglobulin M anti­bodies. The exact role of these antibodies in the patho­physiology of paraneoplastic syndromes remains an enigma. Posner ( 138), in an editorial comment related to the report, discussed paraneoplastic syndromes in gen­eral, and OM in specific. The general paraneoplastic pathophysiologic theory of " onconeural" antigen expres­sion on tumor cells with cross reactivity to central ner­vous system cells was discussed and accounted for the better neoplasm- related prognosis for those patients with paraneoplastic syndromes. This model fits some para­neoplastic syndromes quite well, such as Lambert- Eaton myasthenic syndrome, while other paraneoplastic syn­drome present challenges to this model. Posner pointed out that no central nervous system disease is found in many patients with OM through imaging or autopsy, al­though the disease is presumed to be related to om­nipause cell dysfunction. Posner concluded that Con­nolly et al. provided the first steps toward identification of a specific antigen target; however, further work re­mains if a full understanding of OM is to be achieved. A rare case of paraneoplastic opsoclonus associated with adenocarcinoma of pancreaticobiliary origin was presented by Coria et al. ( 139). The patient was a 72- year- old woman who presented with sudden onset ver­tigo and impaired consciousness. Examination revealed opsoclonus and cerebellar dysfunction; MRI and two lumbar punctures ( LPs) were normal. Results of liver biopsy demonstrated carcinoma suggestive of pancreati­cobiliary origin. Anti- Hu, anti- Ri, and anti- Yo antibodies were negative, and Solu- Medrol therapy was ineffective. The patient died 5 weeks later. This cases reemphasizes the limitations of current diagnostic assays and points out the potential association of biliary system carcinoma with paraneoplastic opsoclonus. Ocular flutter is distinguished from opsoclonus by the exclusive horizontal plane of the saccadic intrusions. Cogan ( 140) reported ocular flutter as a postinfectious complication. Wiest et al. ( 141) reported three cases of ocular flutter and truncal ataxia. All patients displayed CSF lymphocytosis ranging from 10 to 74 cells/ mm3 and recovered over 3 to 8 weeks. A single patient demon­strated seroconversion of enterovirus serology. The au­thors suggested that enterovirus may serve as the trigger for postinfectious ocular flutter. Saccades and blinks have several things in common, such as visual interference and time- locked character, and appear to be neurophysiologically linked. Eye move­ments occur with blinks even in the absence of voluntary gaze shifting, usually with a nasal and downward direc­tion ( 142). These movements in rabbits and guinea pigs are because of co- contracture of all EOMs, except the superior oblique ( 143). Rottach et al. ( 144) studied the properties of horizontal saccades accompanied by blinks in five normal subjects. Their goal was to discern if blink- associated saccades displayed characteristics ex­plained by the superimposition of blink- induced EOM movements and the saccade itself. These investigators also found the nasal and downward blink- induced eye movements. Blink- associated 20° saccades were associ­ated with a - 20% decrease in peak velocity and accel­eration with only a small effect on gain. A significantly increased incidence of dynamic overshoot was observed in three of the five subjects. The authors concluded that blink- induced saccades could not be accounted for by simple summation, but rather the blink influenced the central programming of the saccade. This study is con­sistent with the theory that saccadic omnipause cells are inhibited by blinks. Internuclear ophthalmoparesis ( INO) is extremely common in clinically definite MS. A complete INO dem­onstrates impaired adduction, while incomplete forms may only be apparent in saccadic testing as slowed ad­duction. The presence of an INO may be quite helpful in the diagnosis of MS, and scleral search coils recordings were investigated by Flipse et al. ( 145). They studied 10 control subjects and 26 patients with definite or probable MS, 7 of whom had clinically apparent INO. Slower J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 204 E. R. EGGENBERGER AND D. I. KAUFMAN peak velocity adduction was noted in the clinically in­volved INO patients; however, the values overlapped controls, and, accordingly, were not of discriminatory value. The ratio of peak acceleration or velocity ( abduct-ing/ adducting eye) produced a much sharper cut- off, without overlap between controls and clinical INO. The controls demonstrated an average velocity ratio of 1.07 ± 0.05, compared with clinical INO of 2.17 ± 1.08. The peak acceleration ratio for controls was 1.14 ± 0.09, compared with clinically apparent INO values of 3.31 ± 1.42. Applying these findings, 5 of the 19 patients with­out clinically apparent INO demonstrated velocity and acceleration ratio abnormalities consistent with subclini­cal INO. This study reemphasizes the value of eye move­ment recording in the detection of subtle abnormalities and has specific relevance in the diagnosis of INO in patients evaluated for MS. In a general sense, saccadic eye movements follow the Listing law that states that any eye position can be reached from the primary position by rotation of the eyes about a single axis ( equatorial plane). With more accu­rate recordings, " blips" ( transient torsional movements) have been demonstrated in normal subjects up to 2° in amplitude. Building on this knowledge, Helmchen et al. ( 146) reported a patient with clinically apparent torsional eye movements during voluntary saccades, which repre­sented a gross violation of the Listing law. A 44- year- old man presented with vertigo, vomiting, left hemi- ataxia, and left facial numbness related to medial branch occlu­sion of the left posterior inferior cerebellar artery. All symptoms remitted within months, except vertigo with head movements. Examination 1 year after the infarct demonstrated some quick torsional eye movements with large horizontal saccades and vertical plus horizontal pursuit movements ( saccadic at higher frequencies). These torsional movements ranged up to 10.5° in ampli­tude ( with < 6° variation) and were of greater magnitude toward the left ( ipsi- lesional) side. Leftward saccades tended to demonstrate counterclockwise torsional blips, and rightward saccades demonstrated clockwise tor­sional blips. Blips represent another type of saccadic dis­order. The authors emphasized that the magnitude of the blips in their patient was pathologic compared with nor­mal subjects, and that blips were direction- specific with an amplitude that correlated with the amount of saccadic dysmetria, perhaps suggesting " torsional saccadic dys-metria." Risperidone is a novel antipsychotic medication with potent 5- HA2A antagonist properties at low dose and po­tent D2 antagonist properties at higher dose. Risperidone has 2 to 3 times less D2 receptor affinity than haloperi-dol. The effect of these medications on eye movements was investigated by Sweeney et al. ( 147). These inves­tigators studied 20 antipsychotic- naive schizophrenic pa­tients treated with either low- dose haloperidol or low-dose risperidone. Risperidone was associated with pro­longed latency and decreased accuracy and peak velocity of saccades; these effects were not observed in the cohort treated with haloperidol. The authors speculated that these effects may be related to risperidone's powerful serotonergic antagonism, and they stressed the impor­tance of these results during evaluation of eye move­ments in schizophrenic patients. Ataxia is the prototypical stigmata of cerebellar dis­ease. In order to standardize findings related to cerebellar dysfunction, an ad hoc committee of the World Federa­tion of Neurology proposed a 100- point semi­quantitative rating scale, the International Cooperative Ataxia Rating Scale ( ICARS). The scale quantifies pos­tural and stance instability, limb ataxia, dysarthria, and oculomotor disorders. Gaze- evoked nystagmus, pursuit abnormalities, and saccadic dysmetria were included in the scale, although these eye signs contribute only six total points to the resultant score ( 148). PURSUIT Smooth pursuit ( SP) was the focus of a few interesting studies during 1997 and 1998. Hutton and Kennard ( 149) reviewed the status of SP research as a biological marker in schizophrenia. They concluded that despite the large volume of data published, important questions remain unanswered. They state that many of the studies use un­reliable methods, few attempts have been made to inter­pret the dysfunction in terms of current understanding of eye movement physiology, and the effects of medication have been poorly addressed. However, they agree that more recent SP research that correlates ocular motility with neuropsychological deficits and MRI- determined abnormality may yield useful data and provide a more relevant use for these types of eye movements in schizo­phrenia. Domino et al. ( 150) examined 20 nonsmokers and 14 smokers ( all approximately 31 years old) to determine the effect of tobacco on SP. A common opinion is that nicotine- induced nystagmus results in reduced ocular smooth muscle performance. Tobacco smokers had a small but statistically significant increase in SP OU to a moving target after only one cigarette. This was because of left, but not right, SP. Placebo had no such effect. There was no change in pupil diameter. Sparks ( 151) looked at gaze shifts and found that co­ordinated eye- head movements are characterized by a set of lawful relations. The initial position of the eyes in the orbits and the direction of the gaze shift are two factors that influence these relations. For shifts < 20°, head movements did not contribute to the change in gaze po­sition. Timing was influenced by initial eye position, and the direction also influenced the relative amplitudes. This implies that signals related to the initial position of the eyes and the direction of the gaze shift influence separate eye and head movement commands. This probably oc­curs downstream from the superior colliculus. Shi et al. ( 152) caused deficits in SP after microinjections of a reversible GAB A agonist, muscimol, in the frontal eye field ( FEF) smooth eye movement region ( FEF- sem). Smooth pursuit was severely impaired for hours and im­proved by the following day. Saccades were largely un­affected. This indicates that inclusion of FEF- sem is the J Neuro- Ophthalmol, Vol. 20, No. 3, 2000 OCULAR MOTILITY REVIEW 1997- 1998 205 critical factor that determines whether FEF lesions im­pair SP and how critical FEF- sem is for normal high- gain SP. Squatrito and Maioli ( 153) recorded from the dorsal bank of the superior temporal sulcus ( medial superior temporal area- dorsal [ area MSTd]) in alert Macaques. Tuning features of these neurons demonstrated an aver­age bandwidth of 130° that continuously overlapped, which suggested a type of vector coding for SP direction. Their results also showed that eye position and pursuit direction are signaled mainly by separate neuronal ele­ments in area MSTd. Some cells can integrate both sig­nals. This suggested that MSTd could be the site of in­teraction between visuo- oculomotor signals related to vi­sual motion detection, slow eye movement direction, and eye position. 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