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The paramedian tract (PMT) neurons, a group of neurons associated with eye movement that project into the cerebellar flocculus, are present in or near the medial longitudinal fasciculus (MLF) in the paramedian region of the lower brainstem. A 66-year-old man with multiple sclerosis in whom downbeat nystagmus appeared along with right MLF syndrome due to a unilateral pontomedullary lesion is described. In light of these findings, a possible schema for the vestibular balance control mechanism circuit of the PMT neurons via the flocculus is presented. Damage to the PMT neurons impaired the elective inhibitory control mechanism of the anterior semicircular canal neural pathway by the flocculus. This resulted in the appearance of anterior semicircular canal-dominant vestibular imbalance and the formation of downbeat nystagmus. From the pathogenesis of this vertical vestibular nystagmus, the action of the PMT neurons in the vestibular eye movement neuronal pathway to maintain vestibular balance was conjectured to be as follows. PMT neurons transmit vestibular information from the anterior semicircular canals to the cerebellum, forming a cerebellum/brainstem feedback loop. Vestibular information from that loop is integrated in the cerebellum, inhibiting only the anterior semicircular canal neuronal pathway via the flocculus and controlling vestibular balance., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Drinking well water contaminated with the organoarsenic compound diphenylarsinic acid (DPAA) causes central nervous system (CNS) disorders that improve within several years after last drinking such water. Subjective symptoms such as lightheadedness and dizziness appear to persist, however, suggesting CNS damage. We evaluated CNS damage due to DPAA by detecting abnormal eye movements., Methods: Subjects comprised 29 victims of exposure to DPAA in whom this substance had been detected in the nails. Investigations were performed more than 3years following cessation of DPAA exposure. Abnormal eye movements were monitored using electronystagmography. We analysed unpaired t-test between exposure subjects who exhibited upbeat nystagmus and those who did not. Upbeat nystagmus parameters were measured, and mean values were calculated. Associations between the properties of upbeat nystagmus and maximum concentrations of DPAA among DPAA exposure were also investigated., Results: Upbeat nystagmus was common among exposure victims, occurring in 23 of 29 subjects (79.0%). The subjects with upbeat nystagmus had significantly higher ratio than those without upbeat nystagmus in the points of subjective symptoms and DPAA concentration of drinking water (p<0.01). The slow-phase amplitude of upbeat nystagmus enlarged with increasing DPAA concentrations, showing a significant positive correlation (p<0.05). These findings suggest that the level of exposure to DPAA affects the properties of nystagmus. High-frequency pathological square-wave jerks (SWJ) were seen in 14 of 29 patients (48.0%), and mean SWJ frequency was 112.4±16.7/min., Conclusions: Detection of abnormal ocular movements may be useful in evaluating residual/persistent/chronic CNS damage due to organoarsenic poisoning., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To investigate the frequency and pattern of nystagmus associated with isolated cerebellar infarction in the territory of the superior cerebellar artery (SCA) and to discuss its possible mechanism., Methods: We identified 41 consecutive patients with isolated SCA territory cerebellar infarction diagnosed by MRI. Each patient completed a standardised dizziness questionnaire and underwent neurotological evaluations. Eye movements were recorded using 3-dimensional video-oculography during the acute period., Results: Approximately half (19/41) of the patients experienced true vertigo early in the course of the SCA distribution infarct. 11 (27%) of the 41 patients showed spontaneous nystagmus (SN) or direction changed bidirectional gaze-evoked nystagmus (GEN). SN was observed in 10 patients (24%) and the horizontal component of SN was predominant in most case (80%, 8/10) and always beat towards the lesion side. Direction changed bidirectional GEN was observed in five patients and was mostly (4/5) accompanied by SN. Lesion subtraction analyses revealed that damage to the rostral anterior cerebellum including the ala of the central lobule and part of the quadrangular lobule was more frequent in patients with nystagmus compared to patients without nystagmus (9/11, 82% vs 11/30, 37%) (p=0.015). In most (82%, 9/11) patients with SN or GEN, the nystagmus subsided within 1 week after hospitalisation., Discussion: Vertigo and nystagmus in SCA territory cerebellar infarction are more common than previously thought. Ipsilesional SN may result from damage to the anterior lobe of the cerebellum, which transmits the vestibular output to the fastigial nucleus.

Three months after brainstem hemorrhage, MRI revealed a hyperintense lesion of the left inferior olivary nucleus of a 45-year-old man (figure). The patient was completely asymptomatic, but exhibited oculopalatal tremor (OPT), rhythmic palatal oscillations, and small-amplitude vertical pendular nystagmus of the right eye, best visualized on fundus examination (see video).

Introduction: Foveation is the fundamental requirement for clear vision. Saccades rapidly shift the gaze to the interesting target while gaze holding ensures foveation of the desired object., Purpose: We will review the pertinent physiology of saccades and gaze holding and their pathophysiology leading to saccadic oscillations, slow saccades, saccadic dysmetria, and nystagmus., Summary: Motor commands for saccades are generated at multiple levels of the neuraxis. The frontal and parietal eye field send saccadic commands to the superior colliculus. Latter then projects to the brain-stem saccadic burst generator. The brain-stem burst generators guarantee optimum signal to ensure rapid saccadic velocity, while the neural integrator, by mathematically integrating the saccadic pulse, facilitates stable gaze holding. Reciprocal innervations that ensure rapid saccadic velocity are prone to inherent instability leading to saccadic oscillations. In contrast, suboptimal function of the burst generators causes slow saccades. Impaired error correction, either at the cerebellum or the inferior olive, leads to impaired saccade adaptation and ultimately saccadic dysmetria and oculopalatal tremor. Impairment in the function of neural integrator causes nystagmus., Conclusion: Neurophysiology of saccades, gaze holding, and their deficits are well recognized. These principles can be implemented to define novel therapeutic and rehabilitation approaches.

The Aryl hydrocarbon Receptor or AhR, a ligand-activated transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Recent studies in Caenorhabditis elegans and Drosophila melanogaster show that the orthologs of the AhR are expressed exclusively in certain types of neurons and are implicated in the development and the homeostasis of the central nervous system. While physiological roles of the AhR were demonstrated in the mammalian heart, liver and gametogenesis, its ontogenic expression and putative neural functions remain elusive. Here, we report that the constitutive absence of the AhR in adult mice (AhR-/-) leads to abnormal eye movements in the form of a spontaneous pendular horizontal nystagmus. To determine if the nystagmus is of vestibular, visual, or cerebellar origin, gaze stabilizing reflexes, namely vestibulo-ocular and optokinetic reflexes (VOR and OKR), were investigated. The OKR is less effective in the AhR-/- mice suggesting a deficit in the visuo-motor circuitry, while the VOR is mildly affected. Furthermore, the AhR is expressed in the retinal ganglion cells during the development, however electroretinograms revealed no impairment of retinal cell function. The structure of the cerebellum of the AhR-/- mice is normal which is compatible with the preserved VOR adaptation, a plastic process dependent on cerebellar integrity. Finally, intoxication with TCDD of control adults did not lead to any abnormality of the oculomotor control. These results demonstrate that the absence of the AhR leads to acquired central nervous system deficits in the adults. Given the many common features between both AhR mouse and human infantile nystagmus syndromes, the AhR-/- mice might give insights into the developmental mechanisms which lead to congenital eye disorders.

Objective: To evaluate geometrical and volume changes of membranous vestibular labyrinths in guinea pigs after endolymphatic hydrops (EH)., Methods: The membranous labyrinths of normal guinea pigs and of those with EH for 4 and 8 weeks were reconstructed after being scanned using micro-computed tomography subseqent to being stained in osmium tetroxide (OsO4). The diameters and volumes of the semicircular ducts, ampullae, utricles and saccules were measured based on the three-dimensional models., Results: The diameters of the ampullae and utricles of EH guinea pigs were greater than those of the normal guinea pigs, while there were no significant differences in the diameters of the semicircular ducts among all groups. The volumes of ampullae, utricles and saccules of the EH groups were greater than those of the control group, but there were no changes in volumes of semicircular ducts after EH., Conclusion: The dilations of the membranous vestibular labyrinth in guinea pigs with EH mainly occur at the ampullae, utricles and saccules., (© 2013 S. Karger AG, Basel.)

Impairment of gaze holding mechanism and gaze-evoked nystagmus (GEN) in the vertical plane due to a focal brain lesion is usually caused by a failure of the vertical neural integrator, which is known to be localized in the interstitial nucleus of the Cajal in the upper midbrain. We report a patient with hemorrhagic stroke involving the paramedian pontine tegmentum who presented with vertical GEN due to a failure of vertical gaze holding mechanism and unilateral internuclear ophthalmoplegia. The possible structure taking a role as a vertical neural integrator in this patient might be the paramedian tract (PMT) neuron., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Charged by the Pope Julius II for painting the Cappella Sistina in Rome (between 1508 and 1512), Michelangelo worked in an elevated scaffolding, in an anomalous position with dyes (including poisoning lead salts) and solvents (such as toxic turpentine) dripping on his face and continuously inhaling, in a dim environment illuminated only with oil lamps and candles, as he described himself and sketched in a sonet addressed to Giovanni da Pistoia. In 1510 he began suffering from eye disease: the main symptom was the necessity to elevate the document he was reading up to the level of his eyes. This defect disappeared few months after he finished painting his masterpiece. We hypothesize that the Michelangelo's eyes disease was a form of acquired and transitory nystagmus induced by the many hours he spent in up gaze, with a skew deviation, a form of ocular tilt reaction resulting from the impairment of spatial sensitivity (inversion illusion) due to the persistence of the artist's head in a horizontal position, looking upward., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Upbeat nystagmus (UBN) is typically increased with upward gaze and decreased with downward gaze. We describe a patient with acute multiple sclerosis who developed primary position UBN with a linear slow phase waveform, in which the velocity of nystagmus was intensified in downward gaze and decreased during upward gaze. Brain MRI showed high signal lesions in the paramedian dorsal area of the caudal medulla encompassing the most caudal part of the perihypoglossal nuclei. Clinicians should be aware of possibility of a caudal medullary lesion in a patient with UBN, especially when the velocity of the UBN is increased in downward gaze., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Hyperemesis gravidarum can impair correct absorption of an adequate amount of thiamine and can cause electrolyte imbalance. This study investigated the neurological complications in a pregnant woman with hyperemesis gravidarum. A 29-year-old pregnant woman was admitted for hyperemesis gravidarum. Besides undernutrition, a neurological examination disclosed weakness with hyporeflexia, ophthalmoparesis, multidirectional nystagmus and optic disks swelling; the patient became rapidly comatose. Brain MRI showed symmetric signal hyperintensity and swelling of periaqueductal area, hypothalamus and mammillary bodies, medial and posterior portions of the thalamus and columns of fornix, consistent with Wernicke encephalopathy (WE). Neurophysiological studies revealed an axonal sensory-motor polyneuropathy, likely due to thiamine deficiency or critical illness polyneuropathy. Sodium and potassium supplementation and parenteral thiamine were administered with improvement of consciousness state in a few days. WE evolved in Korsakoff syndrome. A repeat MRI showed a marked improvement of WE-related alterations and a new hyperintense lesion in the pons, suggestive of central pontine myelinolysis. No sign or symptom due to involvement of the pons was present.

Horizontal head-shaking may induce nystagmus in peripheral as well as central vestibular lesions. While the patterns and mechanism of head-shaking nystagmus are well established in peripheral vestibulopathy, they require further exploration in central vestibular disorders. To define the characteristics and mechanism of head-shaking nystagmus in central vestibulopathies, we investigated spontaneous nystagmus and head-shaking nystagmus in 72 patients with isolated cerebellar infarction. Spontaneous nystagmus was observed in 28 (39%) patients, and was mostly ipsilesional when observed in unilateral infarction (15/18, 83%). Head-shaking nystagmus developed in 37 (51%) patients, and the horizontal component of head-shaking nystagmus was uniformly ipsilesional when induced in patients with unilateral infarction. Perverted head-shaking nystagmus occurred in 23 (23/37, 62%) patients and was mostly downbeat (22/23, 96%). Lesion subtraction analyses revealed that damage to the uvula, nodulus and inferior tonsil was mostly responsible for generation of head-shaking nystagmus in patients with unilateral posterior inferior cerebellar artery infarction. Ipsilesional head-shaking nystagmus in patients with unilateral cerebellar infarction may be explained by unilateral disruption of uvulonodular inhibition over the velocity storage. Perverted (downbeat) head-shaking nystagmus may be ascribed to impaired control over the spatial orientation of the angular vestibulo-ocular reflex due to uvulonodular lesions or a build-up of vertical vestibular asymmetry favouring upward bias due to lesions involving the inferior tonsil.

A cavernoma is a vascular malformation in the central nervous system. Brainstem cavernoma are relatively common and induce variable neurological symptoms. A 19-year-old woman visited our hospital with complaints of continuous dizziness. On a neurological examination, continuous conjugated upbeat nystagmus was observed in the primary position of gaze. A brain CT scan and MRI showed focal hemorrhagic signals in the central caudal medulla caused by a cavernoma. The spontaneous upbeat nystagmus disappeared gradually. To our knowledge, this is the first report of a probable cavernoma in the medulla oblongata presenting with upbeat nystagmus only., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The fourth ventricle encompasses many vital structures including the brainstem as its floor and the cerebellum as its lateral wall and roof. Therefore, lesions affecting the fourth ventricle may present as cerebellar or brainstem manifestations. Herein, we presented our experience in the diagnosis of disorders affecting the fourth ventricle during the past 15 years., Study Design: Retrospective study., Setting: University hospital., Subjects: From September 1995 to August 2010, 24,838 patients with vertigo/dizziness visited the clinic. Of them, 13 patients (0.5%) had tumor/stroke affecting the fourth ventricle., Main Outcome Measures: All patients underwent a battery of audiovestibular function test., Results: All patients had vertigo (100%) and then ataxia (92%) and nausea/vomiting (85%). Eight patients (68%) displayed persistent nystagmus. Most (>75%) patients showed central signs in electronystagmographic recordings and abnormal caloric coupled with visual suppression test. Three patients underwent both ocular and cervical vestibular-evoked myogenic potential tests, and abnormal results were noted in all 3 patients indicating a brainstem involvement. However, magnetic resonance imaging failed to demonstrate brainstem lesion in these 3 patients. Final diagnoses consisted of the following: cavernoma, n = 3; metastatic cancer, n = 3; astrocytoma, n = 2; meningioma, n = 2; epidermoid cyst, n = 1; ependymoma, n = 1; and lymphoma, n = 1. The prognosis was poor as 10 patients (77%) died within 2 years., Conclusion: When a vertiginous patient displayed ataxia, persistent vomiting, and persistent nystagmus, lesion affecting the fourth ventricle should be kept in mind because its prognosis is poor. Abnormal results in electronystagmography and in ocular and cervical vestibular-evoked myogenic potentials may serve as a supplementary to magnetic resonance imaging to delineate the involvement of the lesion.

Objective: Several repositioning maneuvers have been proposed for the treatment of benign paroxysmal positional vertigo (BPPV) due to canalithiasis of the horizontal semicircular canal (HSC). However, comparisons between these canalith repositioning procedures as well as a generally accepted algorithm for the management of HSC canalithiasis are currently lacking. The aim of this study was to compare the efficacy of 3 different treatment proposals and review the relevant literature., Study Design: Prospective clinical study., Setting: Tertiary neurotology department., Patients: Sixty patients diagnosed with HSC canalithiasis., Interventions: A single application of Baloh's maneuver (n = 13), Vannucchi's forced prolonged position (n = 29), or Asprella-Gufoni maneuver (n = 18)., Main Outcome Measures: Bilateral geotropic nystagmus., Results: The first application of the Baloh's maneuver seemed to be significantly less effective than both Vannucchi's forced prolonged position (p = 0.035) and the Asprella-Gufoni maneuver (p = 0.006). No significant difference was detected in the efficiency of Vannucchi's forced prolonged position and the Asprella-Gufoni maneuver for this population (p = 0.4)., Conclusion: The Asprella-Gufoni maneuver and Vannucchi's forced prolonged position both seem to be significantly more effective than the Baloh's maneuver in the treatment of HSC canalithiasis. The important pros of the Asprella-Gufoni maneuver versus Vannucchi's forced prolonged position are patient's convenience and maximal use of gravitational and angular acceleration forces. Controlled clinical studies are needed to conclude to an evidence-based proposal for the therapeutical steps that should be followed after the diagnosis of HSC canalithiasis.

Four French West Indian women complained of oscillopsia and were found to have an acquired eye movement disorder. In 3 of them, different types of nystagmus were found, including upbeat, downbeat, and central form of vestibular nystagmus. One developed opsoclonus-myoclonus syndrome. Three patients had neuromyelitis optica antibodies, and 3 had brainstem abnormalities detected on MRI. Two patients had definite NMO, while the other 2 were considered to be at high risk for developing NMO. Treatment with high-dose systemic corticosteroids, with plasma exchanges, or in combination led to resolution of oscillopsia. We propose that eye movement disorders be added to the neurological manifestations of NMO.

Downbeat nystagmus (DBN) is a frequent sign in patients with cerebellar degeneration. It consists of an upward drift of the eye that does not depend on vertical head position (spontaneous drift, SD), a gravity-dependent component (GD), and a gaze-evoked drift reflecting gaze-holding impairment (deficient neural integrator function). The potassium-channel blocker 4-aminopyridine (4-AP) is reported to reduce DBN in patients with cerebellar atrophy but with little or no effect in patients with idiopathic DBN. We prospectively studied the effect of 4-AP on all three components in a large (n = 24) group of the clinically frequent idiopathic DBN. DBN was reduced by 22-31% when the head was off the head erect position. In contrast, there was no effect on vertical gaze-evoked drift. This indicates the therapeutic efficacy of 4-AP not only in patients with cerebellar atrophy but also in idiopathic DBN patients. This beneficial effect, which might be missed when gravity-dependent head positions are not tested, was not related to an improvement of gaze-holding deficit. We suggest it may be related to the restored inhibition of the overacting otolith-ocular reflex.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Objective: Ataxia is characterized clinically by four signs (gait and limb ataxia, dysarthria and nystagmus). Although ataxia has been described in posterior circulation (PC) stroke series, there are no prospective studies that have investigated a possible differential role of the cerebellum or its input/outputs in causing ataxia., Methods: Ataxia was semi-quantified according to the International Cooperative Ataxia Rating Scale (ICARS) in 92 consecutive patients with acute PC stroke. Four topographical patterns based on magnetic resonance imaging (MRI) findings were identified: picaCH pattern (posterior inferior cerebellar artery infarct); scaCH pattern (superior cerebellar artery infarct); CH/CP pattern (infarct involving both the cerebellum and the brainstem cerebellar pathways); and CP pattern (infarct involving the brainstem cerebellar pathways)., Results: Gait ataxia was present in 95.7%, limb ataxia in 76.1%, dysarthria in 56.5% and nystagmus in 65.2% of patients. Gait ataxia frequency did not differ between the patterns, but was significantly more severe in the CH/CP pattern than in either picaCH (P=0.0059) or CP (P=0.0065) pattern. Limb ataxia was significantly less frequent (P<0.001) and less severe (P<0.001) in picaCH pattern than other patterns. Dysarthria was less frequent in picaCH pattern than in other patterns (P=0.018) and less severe than in scaCH (P=0.0043) or CP (P=0.0047) pattern. No differences in nystagmus frequency or severity were observed across all four patterns., Conclusion: In PC stroke gait ataxia was almost always present, regardless of the lesion site. Limb ataxia and dysarthria were less frequent in the picaCH pattern, whereas nystagmus, when present, did not differ among the topographical patterns., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We report a case showing apogeotropic nystagmus with the lesion of the brain stem, and discuss a possible mechanism of central apogeotropic nystagmus. The case was a 73-year-old male. We analyzed his nystagmus three-dimensionally. He showed apogeotropic nystagmus. Axis angles of slow phase eye velocity of his apogeotropic nystagmus were not in line with the axes perpendicular to the plane of horizontal semicircular canals, but with the patient's vertical axis. We then found that his nystagmus including the apogeotropic nystagmus was positioning, but not positional and that the direction of his positioning nystagmus was the same direction of postrotatory nystagmus after his head movement. His MRI scans showed an infarction around the prepositus hypoglossi nucleus of the brain. His apogeotropic nystagmus seemed to consist of a combination of prolonged postrotatory nystagmus after his head rotation to the left and right lateral position because the axis of postrotatory nystamus was in line with the axis of the head rotation. Therefore, it is suggested that a possible mechanism of central apogeotropic nystagmus is a prolonged postrotatory nystagmus after his head movement in the supine position due to the brain lesion involving the velocity storage mechanisms., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Latent nystagmus (LN) is the by-product of fusion maldevelopment in infancy. Because fusion maldevelopment--in the form of strabismus and amblyopia--is common, LN is a prevalent form of pathologic nystagmus encountered in clinical practice. It originates as an afferent visual pathway disorder. To unravel the mechanism for LN, we studied patients and nonhuman primates with maldeveloped fusion. These experiments have revealed that loss of binocular connections within striate cortex (area V1) in the first months of life is the necessary and sufficient cause of LN. The severity of LN increases systematically with longer durations of binocular decorrelation and greater losses of V1 connections. Decorrelation durations that exceed the equivalent of 2-3 months in human development result in an LN prevalence of 100%. No manipulation of brain stem motor pathways is required. The binocular maldevelopment originating in area V1 is passed on to downstream extrastriate regions of cerebral cortex that drive conjugate gaze, notably MSTd. Conjugate gaze is stable when MSTd neurons of the right and left cerebral hemispheres have balanced binocular activity. Fusion maldevelopment in infancy causes unbalanced monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Acting through downstream projections to the ipsilateral nucleus of the optic tract, the eyes are driven conjugately to that side. The unbalanced MSTd drive is evident as the nasalward gaze-holding bias of LN when viewing with either eye.

Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10-25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.

Background: Recently we proposed the therapeutic potential of pyruvate therapy for mitochondrial diseases. Leigh syndrome is a progressive neurodegenerative disorder ascribed to either mitochondrial or nuclear DNA mutations., Methods: In an attempt to circumvent the mitochondrial dysfunction, we orally applied sodium pyruvate and analyzed its effect on an 11-year-old female with Leigh syndrome due to cytochrome c oxidase deficiency accompanied by cardiomyopathy. The patient was administered sodium pyruvate at a maintenance dose of 0.5 g/kg/day and followed up for 1 year., Results: The exercise intolerance was remarkably improved so that she became capable of running. Echocardiography indicated improvements both in the left ventricle ejection fraction and in the fractional shortening. Electrocardiography demonstrated amelioration of the inverted T waves. When the pyruvate administration was interrupted because of a gastrointestinal infection, the serum lactate level became elevated and the serum pyruvate level, decreased, suggesting that the pyruvate administration was effective in decreasing the lactate-to-pyruvate ratio., Conclusions: These data indicate that pyruvate therapy was effective in improving exercise intolerance at least in a patient with cytochrome c oxidase deficiency., General Significance: Administration of sodium pyruvate may prove effective for other patients with cytochrome c oxidase deficiency due to mitochondrial or nuclear DNA mutations., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Objective: To investigate the occurrence rate, prognosis, and inner ear abnormality in intractable benign paroxysmal positioning vertigo (BPPV)., Study Design: A prospective study., Setting: Tertiary referral university hospital., Patients: Intractable BPPV was defined in case of either a persistent nystagmus or a frequent relapse each lasting more than 1 year after the initial diagnosis., Intervention: T2-weighted 3-dimensional fast imaging employing steady-state acquisition sequences of magnetic resonance imaging (MRI) were reconstructed 3-dimensionally for 13 intractable BPPV patients and 14 control volunteers., Main Outcome Measure: Transition and relapse of nystagmus were monitored. Semicircular canals were evaluated for a stenosis or filling defect (obturation)., Results: Eighteen patients (4 with posterior canal type, 2 with horizontal canal type with geotropic nystagmus, and 12 with apogeotropic nystagmus) fulfilled the above criteria for intractability among 495 BPPV patients. The occurrence rate of intractable BPPV was 3.6%. Also, the rate of nystagmus transition was significantly higher in patients with geotropic nystagmus and the posterior canal type (100%) compared with those with apogeotropic nystagmus (33.3%). Of the 13 intractable BPPV patients who underwent MRI, 11 (84.6%) had a total of 23 canals with abnormal appearance (29.5%), showing a significantly higher incidence compared with controls. There was no correlation between the affected canal diagnosed by MRI and the type of nystagmus., Conclusion: The low incidence of nystagmus transition in patients with apogeotropic nystagmus suggests a difference in pathophysiology between apogeotropic nystagmus and other types of BPPV. Stenosis and filling defect (obturation) of canals on MRI, which would indicate an innate narrowing and/or an otoconial jam of the semicircular canal, may account for the intractability of BPPV.

Nystagmus is a spontaneous, repetitive movement of the eyes caused by slow eye drifts. Clinical evaluation of nystagmus requires familiarity with the functional classes of eye movements, the types of acquired nystagmus and a differential diagnosis for each type, and the ability to differentiate acquired nystagmus from infantile nystagmus and saccadic intrusions., ((c) Thieme Medical Publishers.)

The Vestibulo-Ocular Reflex (VOR) stabilizes the images of the world on the retinae when the head is in motion. Basic daily activities such as walking or driving depend on the proper functioning of this reflex. For several decades, scientists have developed methods to model and identify this system mathematically. However, traditional methods cannot analyze VOR data comprehensively because they disregard pieces of data (fast phases) which biases estimated reflex dynamics. Here we propose, for the first time, an automated tool to analyze entire VOR responses (slow and fast phases), without apriori classification of nystagmus segments.

The aim of this study was to report some clinical cases suggesting a possible correlation between benign paroxysmal positional vertigo (BPPV) and intense physical activity. Out of 430 BPPV cases referred to our out-patients clinic, 9 patients, showing symptoms of BPPV arising after an intense period of physical activity, were selected for this study. The posterior semicircular canal was affected in all the nine patients. The canalith repositioning procedure was successful and eliminated vertigo and nystagmus in all patients. During the follow-up period (12 months) all patients continued with the usual physical activity; four of the nine patients showed a recurrence of the BPPV symptoms after a new intense period of exercises: all were successfully treated by a new single Epley repositioning procedure. BPPV due to intense physical activity is a rare condition (9/430) and it may be caused by repeated vibratory vertical accelerations of a minor degree associated with metabolic variations during strenuous exercise.

A 74-year-old woman with sudden vertigo and dysarthria showed spontaneous nystagmus beating rightward, upward and clockwise. She also exhibited dysfunction of the left utricle and superior and horizontal canals, which was documented by head impulse and heave tests, measurements of ocular torsion and subjective visual vertical tilt, bithermal caloric tests, and rotation axis analysis of the spontaneous nystagmus. In contrast, functions of the left posterior canal, saccule, and cochlea were remained intact, as evidenced by normal head impulse test, audiometry and vestibular evoked myogenic potential. MRI revealed an acute infarction in the left lateral pons of anterior inferior cerebellar artery (AICA) territory. Our patient with AICA infarction showed isolated damage to the superior vestibular labyrinth or its afferents with preservation of the inferior vestibular labyrinth and auditory function. Our patient provides further evidence that isolated damage to the superior vestibular labyrinth or its afferents may be a mechanism of isolated vascular vertigo.

Even though pendular seesaw nystagmus (PSN) or periodic alternating nystagmus (PAN) has been reported in blind persons, the co-occurrence of PSN and PAN has not been described. A 69-year-old woman with progressive visual loss to only light perception in both eyes showed PSN with a conjugate torsional component and the vertical components in the opposite directions in both eyes. In complete darkness, she also exhibited PAN in addition to PSN. PSN remained unchanged in darkness. The rest of the neurological examination, testing for mitochondrial mutations of Leber's hereditary optic neuropathy, fluorescent angiography, electroretinogram, and brain MRI were normal except for bilateral optic atrophy. Deprivation of the visual inputs, which are required to calibrate normal eye motion, may produce various ocular motor abnormalities in blindness. Although the co-occurrence of PSN and PAN in our patient with visual loss indicates a common etiology, the different effects of darkness on nystagmus intensity suggest a distinct pathomechanism.

Objectives: To determine the prevalence of Bruns' nystagmus in patients undergoing surgical treatment for unilateral sporadic vestibular schwannomas (VSs), identify the clinical characteristics of patients with Bruns' nystagmus and compare these characteristics with those of VS patients with no nystagmus and other types of nystagmus, and determine the long-term impact of having preoperative Bruns' nystagmus., Study Design: A retrospective review using a prospectively updated database of patients who had undergone surgical removal of a VS. Patients were divided into 3 groups: Bruns' nystagmus, other types of nystagmus, or no nystagmus. Statistical comparison of each group was undertaken., Patients: Nine hundred eighty-four patients were included consisting of 492 men and 492 women with a mean age of 59 years (range, 11-86 yr)., Results: Bruns' nystagmus was present in 11% of patients. Bruns' nystagmus was associated with larger tumor size (p < 0.001). Beyond 3.5-cm maximum diameter, 92% of patients had nystagmus, 67% of which had Bruns' nystagmus. Preoperative balance impairment was present in 95% of patients with Bruns' nystagmus compared with 59% with no nystagmus. The balance status of all groups improved considerably postoperatively, but the patients with Bruns' nystagmus had a relatively greater improvement in balance status., Conclusion: Bruns' nystagmus occurs in patients with large VSs. These patients tend to have greater balance impairment pre\operatively, but after surgery, long-term balance outcomes are similar to those of patients with no nystagmus or other forms of nystagmus.

Purpose: To report the association of Duane syndrome with nystagmus and a patterned hyperpigmentation of the retinal pigment epithelium, developmental delay, micro- and pachygyria and craniopharyngioma., Case Report: We describe a 12-year old girl with developmental delay, hearing loss, cortical micro- and pachygyria, and a cystic craniopharyngioma; her ocular features include unilateral Duane syndrome, monocular nystagmus under binocular conditions, and a patterned hyperpigmentation of the retinal pigment epithelium. Her mother had similar retinal pigment epithelial abnormalities., Conclusions: The combination of two neuronal migrational disorders, the unusual retinal pigment epithelial abnormalities in the proband and her mother, and evidence that each feature may be genetic and are suggestive of a genetic basis for this constellation of features.

Background: To elucidate the mechanisms of paroxysmal ocular tilt reaction (OTR) from mesodiencephalic lesions by analyzing the associated ocular motor findings., Methods: Two patients with paroxysmal ipsiversive OTR due to mesodiencephalic lesions underwent evaluation of associated ocular motor abnormalities and one of them had three-dimensional recording of eye motion. We also reviewed previously reported six patients with paroxysmal OTR., Results: One patient showed contraversive torsional nystagmus during the paroxysms in association with vertical gaze limitation and vertical gaze-evoked nystagmus, which are consistent with baseline dysfunction and paroxysmal irritation of the interstitial nucleus of Cajal (INC) during the attacks. The other patient exhibited ipsiversive torsional nystagmus during the attacks, along with slowed vertical saccades and decreased amplitude of ipsitorsional nystagmus during the torsional vestibulo-ocular reflex between the attacks. These findings are best explained by underlying dysfunction and paroxysmal irritation of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF)., Conclusions: The associated ocular motor findings in our patients indicate that paroxysmal ipsiversive OTR in mesodiencephalic lesions is caused by intermittent hyperactivity of partially damaged ipsilesional riMLF or INC.

Background and Purpose: Isolated nodular infarction has rarely been described in human. The purpose of this study is to report clinical and laboratory findings of isolated nodular infarction., Methods: Eight patients with isolated nodular infarction were recruited from 6 hospitals in Korea. All patients underwent a complete and standardized neurotological evaluation including ocular torsion, bithermal caloric tests, and rotatory chair test in addition to MRI and MR angiography., Results: All patients presented with isolated vertigo and moderate to severe imbalance. The most common manifestation was unilateral nystagmus and falling in the opposite direction, which mimicked peripheral vestibulopathy. Six patients had unilateral lesion, and 2 showed bilateral lesions. The direction of the spontaneous nystagmus was all ipsilesional in the unilateral lesion. However, head impulse and bithermal caloric tests were normal. Other findings include periodic alternating nystagmus, perverted head shaking nystagmus, paroxysmal positional nystagmus, and impaired tilt suppression of the postrotatory nystagmus. Hypoplasia of the ipsilesional vertebral artery was the only abnormal finding on MR angiography in 3 patients. The prognosis was excellent., Conclusions: Isolated nodular infarction mostly presents with isolated vertigo mimicking acute peripheral vestibulopathy. However, severe imbalance and a negative head impulse test are important clinical discriminants between nodular infarcts and peripheral vestibular dysfunction. The findings of isolated nodular infarctions are consistent with impaired gravito-inertial processing of the vestibular signals and disrupted nodular inhibition on the vestibular secondary neurons and the velocity storage mechanism.

This case depicts an unusual presentation of septo-optic dysplasia. A four-year-old female presented with monocular nystagmus and temporal optic disc pallor in her left eye. Despite a normal sized optic nerve head, magnetic resonance imaging (MRI) showed a hypoplastic intraorbital and intracranial left optic nerve in the absence of a septum pellucidum. She was subsequently diagnosed with septo-optic dysplasia with sectoral optic nerve head hypoplasia.

Neurofibromatosis types 1 (NF1) and 2 (NF2) are genetically distinct conditions caused by mutations in tumour suppressor genes that share a number of phenotypic features. Childhood stroke and vasculopathy have been associated with NF1, but not with NF2. We describe a case of brainstem stroke in a child with NF2.

Objective: The aim of this study was to investigate the frequency of posterior semicircular canal benign paroxysmal positional vertigo in each ear, and to assess the association between the ear affected by benign paroxysmal positional vertigo and the head-lying side during sleep onset. Based on a previous study which used objective methods to prove the preference of the elderly for the right head-lying side during sleep, we hypothesised that a predominance of the same head-lying side in benign paroxysmal positional vertigo patients may affect the pathophysiology of otoconia displacement., Study Design: We conducted a prospective study of out-patients with posterior semicircular canal benign paroxysmal positional vertigo, confirmed by a positive Dix-Hallpike test., Methods: One hundred and forty-two patients with posterior semicircular canal benign paroxysmal positional vertigo were interviewed about their past medical history, focusing on factors predisposing to benign paroxysmal positional vertigo. All patients included in the study were able to define a predominant, favourite head-lying side, right or left, during sleep onset., Results: The Dix-Hallpike test was found to be positive on the right side in 82 patients and positive on the left side in 54; six patients were found to be positive bilaterally. During sleep onset, 97 patients habitually laid their head on the right side and the remaining 45 laid their head on the left. The association between the affected ear and the head-lying side during sleep onset was statistically significant (p < 0.001)., Conclusions: Our study found a predominance of right-sided benign paroxysmal positional vertigo, a subjective preference amongst patients for a right head-lying position during sleep onset, and an association between the ear affected by benign paroxysmal positional vertigo and the preferred head-lying side during sleep onset. The clinical and therapeutical implications of this observation are discussed.

A 51-year-old man developed positional vertigo, ataxia, dysgeusia, diplopia, and oscillopsia. Eye movement examination and video-oculographic recording disclosed primary position upbeat nystagmus (PPUN) and a right internuclear ophthalmoplegia. Brain MRI showed a small focal lesion in the right dorsal tegmentum of the caudal pons with signal characteristics consistent with a primary demyelinating central nervous system disease. PPUN has not been described previously with a lesion in such a location. Clinicoanatomic correlation in this patient suggests that a lesion of the superior vestibular nucleus and its efferent crossing ventral tegmental tract could be responsible for the PPUN. This case report contributes to a better understanding of the role of this pathway in humans.

Introduction: Primary exotropia is a divergent strabismus that appears from the first day of life to the second year. It can be isolated or associated with a pathological context requiring cerebral imaging to determine diagnosis and prognosis. The objective of this study was to report the sensorimotor state and the result of MRI in infantile exotropia., Patients and Method: Forty-seven children with primary exotropia had a complete ophthalmologic assessment (visual acuity, binocular vision, refraction with cycloplegia, eye fundus) and cerebral MRI (average age, 16 months). Deviation was classified into four categories<4 degrees, > or =4<10 degrees, > or =10<20 degrees, > or =20 degrees. MRI results were classified into seven categories: white matter abnormalities (gliosis, delay of maturation, periventricular leukomalacia, aspecific hyperintense signal, and necroses); Virchow-Robin enlargement space and enlarged subarachnoid space; gray matter abnormalities (necroses, cerebral atrophy, occipital cortex, basal ganglia); ventriculomegaly; thin corpus callosum; cerebellar injury; and tumor., Results: There was a statistically significant increase in the rate of pathological MRI as the angle deviation increased: 76.6% of patients had a pathological ophthalmologic exam (amblyopia, ptosis, head posture, Duane's syndrome, cataract, albinism, or pigmentary retinopathy). We found 38% nystagmus and 38% optic nerve hypoplasia. There was a real pathological context in 61.7% of the exotropia cases: 27.7% prematurity, 31.9% fetal distress, 21.3% facial dysmorphy (plagiocephaly), 12.8% psychomotor delay, and 14.9% epilepsy. Only three children had isolated exotropia. Thirty-four cerebral MRI (72.3%) were not normal. In pathological MRI, there was 61.8% white matter injury, 41.2% gray matter injury, and 17.6% thin corpus callosum., Conclusion: This study demonstrates the fundamental contribution of cerebral MRI in infantile exotropia. The greater the deviation, the more abnormal the MRI results are. The pathological context and ophthalmological abnormalities are important in infantile exotropia.

Septo-optic dysplasia (SOD) is an uncommon developmental disorder involving variable midline brain structures, characterized by optic nerve hypoplasia, dysgenesis of septum pellucidum, and pituitary-hypothalamic dysfunction such as growth hormone deficiency. The phenotype is highly variable and the clinical presentation may be mild or extremely severe. Other distinct features, which occur especially when cerebral cortical abnormalities are also present (SOD-plus), consist of significant generalized developmental delay and/or spastic motor deficits. We report a case of SOD-plus with mild cortical dysplasia which was revealed to be thickening of bilateral insular cortex without schizencephaly by MRI, and there was no sign or symptom of cortical dysfunction except for one episode of brief seizure.

We have described a neuromimetic model of the interaction between the inferior olive (IO) and the cerebellum that accounts for symptomatic oculopalatal tremor (OPT), a disorder characterized by oscillations of the eyes (nystagmus), palate and other branchial muscles. OPT develops months after some brainstem strokes, in association with hypertrophic degeneration of the inferior olivary nucleus (IO). We hypothesized that OPT requires both (1) a pulsatile oscillator created by tighter electrotonic coupling between cells in the IO, and (2) a learned response from the cerebellar cortex that combines with the IO pulses to generate the quasi-pendular oscillations. Since the vestibular nuclei project to both IO and vestibulocerebellum, one prediction of the model is that rapid head rotations could interrupt the oscillator, effectively resetting the timing of the ocular nystagmus. The ocular oscillations in OPT vary in amplitude and phase, making it difficult to determine by Fourier analysis whether head perturbations phase-shift the nystagmus. We applied complex wavelet analysis to data from four patients with OPT and checked whether vestibular stimuli induced a change in phase of the nystagmus. First we calculated a threshold for the spontaneous rate of change of phase of OPT by comparing many segments of nystagmus waveform with their time-shifted versions, bootstrapping these arrays, and computing 95% prediction intervals for each patient. Then we compared the rate of change of phase due to each head perturbation with the threshold for that patient. To minimize the effects of the head perturbation itself on the wavelet analysis, we measured effects in a plane orthogonal to the head rotation, e.g., effects of horizontal head rotations on the torsional component of OPT. In all four patients, the rate of change of phase shift increased sharply at the time of the head perturbation, and in three the change was judged to be statistically significant. Thus, the experimental tests supported the prediction of our model for OPT.

Cerebellar degeneration affects vestibular function. For instance, with lesions of the cerebellar flocculus, the ability to adaptively modify the VOR gain is markedly reduced, and cerebellar patients may even demonstrate severe vestibular deficits. We report five patients (m=3, f=2) with cerebellar disease, in whom search-coil head impulse testing revealed reduced gains of the angular VOR, while sacculus-mediated myogenic potentials were normal. Preserved static ocular counterroll in roll-tilt positions and prominent gravity-dependent modulation of downbeat nystagmus (DBN) along the pitch plane demonstrated the integrity of otolith (OL) function in these patients as well. Probably, at least in some cerebellar patients with marked floccular atrophy, the dissociation between impaired semicircular canal (SCC) function and preserved OL function may be explained by a predilection of the atrophic process for the flocculus and brainstem neurons involved in angular VOR gain control, while structures mediating OL function remain widely spared by the cerebellar degeneration. The exact pathomechanism leading to the vestibular impairment remains unclear: both a primary multi-system-type atrophy involving cerebellar and brainstem vestibular structures as well as a mechanism of secondary retrograde degeneration of floccular brainstem target neurons mediating SCC function seem plausible.