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A woman, age 44, with a positive anti-YO paraneoplastic cerebellar syndrome and normal imaging developed an ocular motor disorder including periodic alternating nystagmus (PAN), gaze-evoked nystagmus (GEN) and rebound nystagmus (RN). During fixation there was typical PAN but changes in gaze position evoked complex, time-varying oscillations of GEN and RN. To unravel the pathophysiology of this unusual pattern of nystagmus, we developed a mathematical model of normal function of the circuits mediating the vestibular-ocular reflex and gaze-holding including their adaptive mechanisms. Simulations showed that all the findings of our patient could be explained by two, small, isolated changes in cerebellar circuits: reducing the time constant of the gaze-holding integrator, producing GEN and RN, and increasing the gain of the vestibular velocity-storage positive feedback loop, producing PAN. We conclude that the gaze- and time-varying pattern of nystagmus in our patient can be accounted for by superposition of one model that produces typical PAN and another model that produces typical GEN and RN, without requiring a new oscillator in the gaze-holding system or a more complex, nonlinear interaction between the two models. This analysis suggest a strategy for uncovering gaze-evoked and rebound nystagmus in the setting of a time-varying nystagmus such as PAN. Our results are also consistent with current ideas of compartmentalization of cerebellar functions for the control of the vestibular velocity-storage mechanism (nodulus and ventral uvula) and for holding horizontal gaze steady (the flocculus and tonsil).

Idiopathic infantile nystagmus (IIN) is an inherited disease, which can occur through a number of different inheritance patterns (autosomal dominant, recessive, or X-linked). The most common of these is X-linked inheritance with incomplete penetrance and variable expressivity, and can also be dominant or recessive. To date, only two mutations have been described: the first, affecting the FPR143 gene, which is associated with ocular albinism type I, and located on chromosome Xp22, and the second, affecting the FRMD7 gene located on chromosome X26-q27. To date, a causative gene on locus Xp11.3p11.4 has not yet been identified. The most common cause of IIN is due to mutations in the FRMD7 gene, located on chromosome Xq26. We present a case of a new mutation found in three siblings from a family with FRMD7-related infantile nystagmus, whose parents are consanguineously related in the first degree. A complex mutation has occurred in this family, which, to date, has not been previously reported in the scientific literature. The complex mutation consists of the presence of three consecutive 1 bp deletions in exon 12 (c.1248delT; 1299del C; and 1312delT), causing a secondary deletion (c. 1340-2145 + 214del), and resulting in a truncated protein. We also present a 7-year-old patient from a different family, with periodic alternating nystagmus, having no mutation in the FRMD7 gene, which we assume may be an example of non-FRMD7-related IIN. This patient does not have a family history of nystagmus. [ABSTRACT FROM AUTHOR]

Acquired periodic alternating nystagmus (PAN) describes a horizontal jerk nystagmus that reverses its direction with a predictable cycle, and is thought to arise from lesions involving the brainstem and cerebellum. We report a 20-year-old patient with PAN who presented with an acute vertiginous episode and developed an involuntary head movement that initially masked the PAN. The involuntary head movements were abolished with a subtherapeutic dose of botulinum toxin to the neck muscles. We propose that the head movements initially developed as a compensatory movement to the nystagmus, to maintain visual fixation in the presence of the underlying nystagmus, and became an entrained involuntary behavior. This case highlights the importance of disambiguating psychogenic from organic pathology as this may have clinical therapeutic implications, in this case resolution of the most disabling symptom which was her head oscillations, leading to improved day-to-day function despite PAN.

Acquired periodic alternating nystagmus (PAN) describes a horizontal jerk nystagmus that reverses its direction with a predictable cycle, and is thought to arise from lesions involving the brainstem and cerebellum. We report a 20-year-old patient with PAN who presented with an acute vertiginous episode and developed an involuntary head movement that initially masked the PAN. The involuntary head movements were abolished with a subtherapeutic dose of botulinum toxin to the neck muscles. We propose that the head movements initially developed as a compensatory movement to the nystagmus, to maintain visual fixation in the presence of the underlying nystagmus, and became an entrained involuntary behavior. This case highlights the importance of disambiguating psychogenic from organic pathology as this may have clinical therapeutic implications, in this case resolution of the most disabling symptom which was her head oscillations, leading to improved day-to-day function despite PAN. [ABSTRACT FROM AUTHOR]

Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of 'eye movements of the blind.' It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration. [ABSTRACT FROM AUTHOR]

Periodic alternating nystagmus (PAN) is a rare oscillatory ocular motor disorder. The effects of gravity on the dynamic behavior of PAN can be studied by monitoring the nystagmus while changing head orientation. Previous studies of patients with PAN reached different conclusions about the effect of changing the orientation of the head relative to gravity on the ongoing PAN, either no effect or a damping of the nystagmus within several minutes. What neuronal circuits could account for the difference in the effects of gravity among PAN patients? We modeled how the brain resolves the tilt-translation ambiguity in normal individuals and added an unstable, oscillatory vestibular system generating PAN. PAN was suppressed in our patient in ear-down positions, in a similar pattern to that of a previously reported patient. This effect was simulated by reducing the gain of the projection of the "rotation feedback" loop to the velocity-storage integrator to approximately 5% of its normal value. With normal "rotation feedback" PAN is expected to dissipate quickly as soon as the head is rotated away from upright position. Moreover, by disconnecting the rotation feedback completely (gain = zero) the model simulated PAN that was reported to be unaffected by gravity. Thus, understanding the effect of this single parameter, the gain of the rotation feedback, can explain the observed variability among our own and previous studies. • Previous studies have shown contradicting effects of gravity on PAN. • Computational models of "rotation feedback", critical in tilt translation disambiguation, can explain the contradictions. • A very low gain of "rotation feedback" can suppress PAN in head down positions, but the effect takes a few minutes. • Understanding the role of "rotational feedback" in patients with PAN may enhance neurological localization. [ABSTRACT FROM AUTHOR]

Abstract: Periodic alternating nystagmus (PAN) is a form of horizontal jerk nystagmus characterized by periodic reversals in direction. We report a case who exhibited transient PAN induced by caloric stimulation. The patient was a 75-year-old male. He had experienced floating sensation in January 2010. Eight months later, he was referred to our university hospital. Gaze nystagmus and positional tests revealed no nystagmus. Only weak right-beating horizontal nystagmus was observed during left Dix–Hallpike maneuver. Electronystagmography showed normal saccadic and smooth pursuit eye movements. The optokinetic nystagmus pattern test was also bilaterally normal. However, during the caloric stimulation to the right ear, at 166s from the start of irrigation, the direction of nystagmus alternated from leftward to rightward, and thereafter this reversal of direction repeated 15 times. Magnetic resonance imaging showed no significant lesion except for chronic ischemia in the brain. The patient probably had some kind of latent lesion of impaired velocity storage and exhibited transient PAN induced by caloric stimulation. Caloric stimulation is useful and simple examination to disclose latent eye movement disorders of which velocity storage mechanism is impaired. [Copyright &y& Elsevier]

Objectives/Hypothesis Periodic alternating nystagmus (PAN) is most commonly found either in its congenital form or after cerebellar/pontomedullary lesions. However, we identified PAN in 10 patients with peripheral vestibular disorders and will try to describe their characteristics to aid in the differential diagnosis between peripheral and central etiologies. Study Design Observation of a case series. Method Peripheral vestibular lesions were confirmed by neurological examinations, vestibular function tests, and brain magnetic resonance imaging (MRIs). Eye movements of the patients were recorded using electronystagmography or video nystagmography for a minimum of 10 minutes to confirm the nystagmus change in direction. Results The final diagnoses of the patients included Meniere's disease (n = 3), acute labyrinthitis (n = 4), sudden sensorineural hearing loss with vertigo (n = 2), and vestibular schwannoma (n = 1). Direction-changing spontaneous horizontal nystagmus with quiescent intervals was observed in all patients under dark conditions. The nystagmus was suppressed by visual fixation; and the results of oculomotor tests were normal for saccadic and smooth pursuit eye movements and optokinetic nystagmus. All patients showed mild to complete canal paresis on a bithermal caloric test. PAN progressed into unidirectional nystagmus of the contra-lesion side in all patients within 48 hours. Conclusion PAN can be observed in patients with peripheral vestibular disorders, but detecting PAN in this subpopulation is difficult because of its transitory nature. The absence of central symptoms and signs, the visual suppression of PAN, normal oculomotor tests, and transient persistence are important diagnostic clues for differentiating peripheral from central PAN. Level of Evidence 4. Laryngoscope, 124:980-983, 2014 [ABSTRACT FROM AUTHOR]

We review current pharmacological treatments for peripheral and central vestibular disorders, and ocular motor disorders that impair vision, especially pathological nystagmus. The prerequisites for successful pharmacotherapy of vertigo, dizziness, and abnormal eye movements are the '4 D's': correct diagnosis, correct drug, appropriate dosage, and sufficient duration. There are seven groups of drugs (the '7 A's') that can be used: antiemetics; anti-inflammatory, anti-Ménière's, and anti-migrainous medications; anti-depressants, anti-convulsants, and aminopyridines. A recovery from acute vestibular neuritis can be promoted by treatment with oral corticosteroids. Betahistine may reduce the frequency of attacks of Ménière's disease. The aminopyridines constitute a novel treatment approach for downbeat and upbeat nystagmus, as well as episodic ataxia type 2 (EA 2); these drugs may restore normal 'pacemaker' activity to the Purkinje cells that govern vestibular and cerebellar nuclei. A limited number of trials indicate that baclofen improves periodic alternating nystagmus, and that gabapentin and memantine improve acquired pendular and infantile (congenital) nystagmus. Preliminary reports suggest suppression of square-wave saccadic intrusions by memantine, and ocular flutter by beta-blockers. Thus, although progress has been made in the treatment of vestibular neuritis, some forms of pathological nystagmus, and EA 2, controlled, masked trials are still needed to evaluate treatments for many vestibular and ocular motor disorders, including betahistine for Ménière's disease, oxcarbazepine for vestibular paroxysmia, or metoprolol for vestibular migraine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Periodic alternating nystagmus (PAN) is a spontaneous horizontal nystagmus that reverses direction periodically. PAN has been reported in acquired and congenital forms. The lesion site of the acquired form of PAN has been attributed to the caudal brainstem or cerebellum. We report an extremely rare case (a 59-year-old woman) with bilateral Meniere's disease, who presented PAN. PAN in this patient was suppressed in the light. This patient had smooth pursuit and normal optokinetic nystagmus, although patients with PAN usually show saccadic pursuit and impaired optokinetic nystagmus. These findings were different features from those of the central or congenital form of PAN. It should be kept in mind that peripheral vestibular disorders such as Meniere's disease could produce PAN. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical effect of baclofen on a group of patients with congenital periodic alternating nystagmus. Methods: A retrospective review of case notes was carried out of all patients with congenital periodic alternating nystagmus (PAN) treated with baclofen between 1999 and 2004. Eight patients were identified, 6 males and 2 females with a mean age of 21 years (range 9 to 34 years). Clinical data were recorded for all patients pre- and post-treatment with the GABA agonist baclofen. Adverse effects of the treatment were recorded and a questionnaire was constructed to evaluate patient satisfaction with the treatment. Results: All 8 patients had an abnormal head posture (AHP) before treatment which improved following treatment in 4 patients, one of whom had recurrence following treatment withdrawal. Binocular Snellen visual acuity (VA) improved by one line in 4 cases, while none of the other 4 patients suffered any loss of vision from the treatment. Three of the eight patients have continued on treatment long-term, in one case for 6 years. In the other five, treatment was withdrawn due to side effects in 4 cases, and in the fifth due to a lack of effect. The most commonly reported side effect was drowsiness, which occurred in 3 patients. Using a patient-centered survey, complete responses were obtained from 6 of the 8 patients treated. Five patients were either pleased or very pleased that they had tried the treatment. The reasons given were: improved vision or head posture, an appreciation of slowing of ocular movements, improved cosmesis and improved confidence. Conclusions: Baclofen may be effective in a select group of patients with congenital PAN and a trial of treatment may be worthwhile, prior to considering surgical intervention in this condition. [ABSTRACT FROM AUTHOR]

To evaluate the usefulness of the short-time Fourier transform (STFT) in the analysis of temporal congenital nystagmus characteristics. Methods: We carried out an observational case series in patients with congenital nystagmus. An electronystagmogram (ENG) recording was performed for 300s in 13 consecutive subjects with congenital nystagmus (age: 7-68 years). Digitized ENG signals (12 bits, 100Hz) were divided into 2-s segments with a Hanning window, and a Fourier transform was carried out for each segment. The power spectrum obtained for each segment was graphically reconstructed as a function of time. The results were compared among the patients. Results: Clear periodicity in the time-frequency distribution was observed in 3 of the 13 patients (23%). One of the three patients was diagnosed with periodic alternating nystagmus, but the other two patients showed periodicity without alternation of beat direction. No significant difference was observed in clinical characteristics, except for sex, between patients who showed periodicity and those who did not. Conclusions: Some patients with congenital nystagmus showed clear periodicity in the nystagmus waveform without alternation of beat direction. The STFT is a useful tool to evaluate the temporal characteristics of congenital nystagmus in clinics. [ABSTRACT FROM AUTHOR]

This chapter starts by comparing two different models to account for optokinetic-vestibular symbiosis. In the first, there are two separate velocity storage (integrator) elements for vestibular and optokinetic systems, and in the second model, velocity storage is shared between the two systems. Behavioral and electrophysiological evidence is presented to support the model with shared velocity storage and its ability to provide a linear addition of vestibular and optokinetic signals, account for different time constants of optokinetic and vestibular responses and separate adaptive properties of the two systems. This model is then extended to account for an unexplained clinical disorder-periodic alternating nystagmus-and provide insights into its pathogenesis and treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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Copyright of Canadian Journal of Ophthalmology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

When a new patient presents with a chief complaint of nystagmus, the clinician must know what further action is necessary in order to identify vision or life-threatening diseases. Some types of acquired nystagmus include upbeat nystagmus, downbeat nystagmus, see-saw nystagmus, and period alternating nystagmus. By identifying the characteristics and causes, acquired nystagmus can be recognized as a "red flag." In contrast, children diagnosed with infantile or physiological nystagmus generally will not need neurological testing. As crucial as it is to recognize acquired nystagmus, it is equally important to differentiate among the specific subtypes and to be familiar with the key features of infantile nystagmus.