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.
Vertigo; Dizziness; Vestibular neuritis; Ménière’s disease; Vestibular paroxysmia; Vestibular migraine; Episodic ataxia type 2; Downbeat nystagmus; Upbeat nystagmus; Pendular nystagmus; Periodic alternating nystagmus; Infantile nystagmus; Square-wave saccadic intrusion; Ocular flutter; Opsoclonus
Acquired nystagmus occurs frequently in patients with multiple
sclerosis and is often the cause of illusory motion of the environment
(oscillopsia), and blurring of vision. Based primarily on the
beneficial effect of gabapentin on acquired pendular nystagmus (APN), a
GABAergic mechanism in controlling nystagmus has been hypothesised. If
increasing GABA concentrations in the CNS are critical for the
treatment of nystagmus, then a selective GABAergic drug should be
highly successful. However, as gabapentin is not a selective GABAergic
agent, vigabatrin, a "pure" GABAergic medication, and gabapentin,
were compared in a single blind cross over trial in eight patients with
definite multiple sclerosis.
Patients were randomly assigned to begin with
gabapentin (1200 mg daily) or vigabatrin (2000 mg daily).
Neuro-ophthalmological and electro-oculographic (EOG) evaluations were
performed four and three times, respectively. Treatment efficacy was
based on improving visual acuity and EOG indices (amplitude or
frequency of nystagmus, or both) by at least 50% of pretreatment
values. Three out of eight patients dropped out due to adverse effects.
In the remaining five patients gabapentin improved symptomatic
pendular or gaze evoked jerk nystagmus in four. Three patients decided
to continue gabapentin therapy. Importantly, vigabatrin proved useful
in only one out of five patients, suggesting that gabapentin
effectiveness may be related to additional non-GABAergic mechanisms of
action. Interaction with cerebral glutamate transmission by inhibition
of NMDA receptor might be an alternative hypothesis for the therapeutic
action of gabapentin.
We conducted a masked, cross-over, therapeutic trial of gabapentin (1200mg/day) versus memantine (40mg/day) for acquired nystagmus in 10 patients (28–61 years; 7 female; MS: 3, post-stroke: 6, post-traumatic: 1). Nystagmus was pendular in 6 patients (oculopalatal tremor: 4, MS: 2) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. Both drugs reduced median eye speed (p<0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p<0.05). Each patient improved with one or both drugs. Side-effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus.
nystagmus; oscillopsia; multiple sclerosis; oculopalatal tremor
Pharmacological treatment has been successful in some forms of acquired neurological nystagmus. However, drugs are not known to be effective in idiopathic infantile nystagmus or nystagmus associated with ocular diseases.
The authors retrospectively analysed Snellen visual acuity (VA), subjective visual function, and eye movement recordings of 23 patients with nystagmus (13 secondary to multiple sclerosis, three associated with other neurological diseases, two idiopathic infantile, and five with associated ocular diseases) treated with gabapentin or memantine.
With gabapentin, 10 of 13 patients with nystagmus secondary to multiple sclerosis (MS) showed some improvement. Memantine improved the VA in all three patients with MS who did not improve on gabapentin. There was no change of nystagmus in other neurological disorders. Patients with congenital nystagmus showed reduction of nystagmus and their VA changes depended on the ocular pathology.
Gabapentin and memantine may be effective in acquired nystagmus secondary to MS. To the authors' knowledge this is the first series of patients showing that gabapentin is effective in improving nystagmus in congenital nystagmus/nystagmus associated with ocular pathology. Memantine may be useful as an alternative drug in treating patients with nystagmus.
acquired nystagmus; congenital nystagmus; gabapentin; memantine; pharmacological treatment
Vertigo and dizziness are among the most common complaints with a lifetime
prevalence of about 30%. The various forms of vestibular disorders can be
treated with pharmacological therapy, physical therapy, psychotherapeutic
measures or, rarely, surgery. In this review, the current pharmacological
treatment options for peripheral and central vestibular, cerebellar and ocular
motor disorders will be described. They are as follows for peripheral vestibular
disorders. In vestibular neuritis recovery of the peripheral vestibular function
can be improved by treatment with oral corticosteroids. In
Menière's disease a recent study showed long-term
high-dose treatment with betahistine has a significant effect on the frequency
of the attacks. The use of aminopyridines introduced a new therapeutic principle
in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA
2). These potassium channel blockers presumably increase the activity and
excitability of cerebellar Purkinje cells, thereby augmenting the inhibitory
influence of these cells on vestibular and cerebellar nuclei. A few studies
showed that baclofen improves periodic alternating nystagmus, and gabapentin and
memantine, pendular nystagmus. However, many other eye movement disorders such
as ocular flutter opsoclonus, central positioning, or see-saw nystagmus are
still difficult to treat. Although progress has been made in the treatment of
vestibular neuritis, downbeat and upbeat nystagmus, as well as EA 2,
state-of-the-art trials must still be performed on many vestibular and ocular
motor disorders, namely Menière's disease, bilateral
vestibular failure, vestibular paroxysmia, vestibular migraine, and many forms
of central eye movement disorders.
vertigo; dizziness; benign paroxysmal positioning vertigo; vestibular neuritis; Menière's disease; vestibular paroxysmia; vestibular migraine; episodic ataxia type 2; downbeat nystagmus; upbeat nystagmus
Investigations were made of 16 patients with acquired pendular nystagmus and a further 32 cases reported in the literature were reviewed. Amongst our own patients two thirds had multiple sclerosis, almost one third a cerebrovascular accident or angioma and two had optic atrophy with squint. The nystagmus took forms which could be monocular or binocular, conjugate or disconjugate and could involve movements about single or multiple axes. Spectral analysis was used to characterise the amplitude and frequency of the movements and to estimate the degree of relationship (coherence) between movements of the two eyes or between movements of one eye about several axes. The oscillations ranged in frequency from 2·5 Hz to 6 Hz, with typical amplitudes between 3° and 5°. In a given patient all oscillations, regardless of plane, were highly synchronised. Somatic tremors of the upper limb, face and palate associated with the nystagmus were often at similar frequencies to the eye movement. The other ocular signs common to all our patients were the presence of squint with failure of convergence. Most patients also had skew deviation or internuclear ophthalmoplegia or both. The major oculomotor systems, that is, saccades, pursuit, optokinetic and vestibulo-ocular reflexes could be intact. It is inferred that the mechanism responsible for the pendular nystagmus lies at a level which is close to the oculomotor nuclei so that it can have monocular effects but is not part of the primary motor pathways. It is possible that this mechanism normally subserves maintenance of conjugate movement and posture of the eyes. The periodicity of the nystagmus is likely to arise from instability in a certain type(s) of neurone, for the associated somatic tremors have similar characteristics and yet involve very different neuronal muscular circuitry. Prognosis for cessation of the nystagmus is poor. In five patients with multiple sclerosis it was suppressed by intravenous hyoscine with, however, unacceptable subsequent side effects.
The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.
vestibular; gap junction; connexin; motor disorders; eye movement
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.
periodic alternating nystagmus; FRMD7; optokinetic reflex; vestibulo-ocular reflex; in situ hybridization
Ocular motor disorders are a well recognized feature of multiple sclerosis (MS). Clinical abnormalities of eye movements, early in the disease course, are associated with generalized disability, probably because the burden of disease in affected patients falls on the brainstem and cerebellar pathways, which are important for gait and balance. Measurement of eye movements, especially when used to detect internuclear ophthalmoplegia (INO), may aid diagnosis of MS. Measurement of the ocular following response to moving sinusoidal gratings of specified spatial frequency and contrast can be used as an experimental tool to better understand persistent visual complaints in patients who have suffered optic neuritis. Patients with MS who develop acquired pendular nystagmus often benefit from treatment with gabapentin or memantine.
multiple sclerosis; eye movements; ocular motor disorders
In an unselected series of 644 cases of multiple sclerosis, 25 cases with acquired pendular nystagmus were found. Ten additional cases of pendular nystagmus in multiple sclerosis were investigated, and four cases from the literature are analysed. Acquired pendular nystagmus is purely sinusoidal in form, ceases with eye closure, is accompanied by oscillopsia, often monocular and vertical in direction, and never accompanied by optokinetic inversion. This is different from congenital nystagmus. Acquired pendular nystagmus in multiple sclerosis shows a high correlation with holding tremor of head and arm and with trunk ataxia, and must therefore be viewed as a result of lesions of cerebellar nuclei or their fibre connections with the brain-stem. Supporting evidence is discussed. The results fit into a theory of cerebellar function according to which the cerebellar nuclei are involved in the maintenance of positions.
A survey of a college age population revealed that 8% could produce voluntary nystagmus. Seventy-nine per cent of this sample had relatives who could also produce it. A systematic investigation of the characteristics of voluntary nystagmus under a number of stimulus conditions showed that it resembles pendular nystagmus in waveform, and certain ocular oscillations, such as ocular flutter and opsoclonus, in frequency. The results indicate that voluntary nystagmus can be differentiated from other forms of nystagmus by its frequency, duration, and occurrence in individuals whose neuro-ophthalmological examination is normal. Voluntary nystagmus probably involves the "hold" mechanism of the cerebellar nuclei because of its frequency correspondence to ocular oscillations which result from a dysfunction in this anatomical area.
To use ocular motility recordings to determine the changes over time of infantile nystagmus syndrome (INS) in RPE65-deficient canines with Leber Congenital Amaurosis (LCA) and assess the time course of the recalibration of the ocular motor system (OMS).
Nine dogs were treated bilaterally with AAV-RPE65. A second cohort of four dogs was treated with AAV2.RPE65, an optimized vector. Their fixation eye movements were recorded before treatment and at 4-week intervals for 3 months, by using high-speed (500 Hz) digital videography. The dogs were suspended in a sling and encouraged to fixate on distant (57 inches) targets at gaze angles varying between ±15° horizontally and ±10° vertically. The records for each eye were examined for qualitative changes in waveform and for quantitative changes in centralisation with the expanded nystagmus acuity function (NAFX) and compared with ERG results for restoration of receptor function.
First group: Before treatment, five of the dogs had clinically apparent INS with jerk, pendular, or both waveforms and with peak-to-peak amplitudes as great as 15°. One dog had intermittent nystagmus. At the 1- and 2-month examinations, no change in nystagmus waveform or NAFX was observed in any of the initial dogs, while at 10 weeks, one dog treated bilaterally with the standard dosage showed reduced nystagmus in only one eye. The other eye did not respond to treatment, as confirmed by ERG. This result was unexpected since it was previously documented that unilateral treatment leads to bilateral reduction of INS. The other dog treated with the standard dosage showed no reduction of its small-amplitude, high-frequency pendular nystagmus despite positive ERG responses. Second group: Only one dog of the four had clinically detectable INS, similar in characteristics to that seen in the affected dogs of the first group. Unlike any previous dog studied, this one showed a damping of the nystagmus within the first 4 weeks after treatment.
In all but one of the cases in which OMS recalibration occurred, as measured by the clinical appearance of nystagmus and by quantitative measurement using the NAFX, the improvement was apparent no sooner than 10 weeks after treatment. Longer term, dose-related studies are needed to determine the minimum necessary degree of restored receptor functionality, the duration after rescue for recalibration of the OMS, and the conditions under which recalibration information can successfully affect the contralateral eye.
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 expressedin 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.
Background/aims: Past studies have explored some of the associations between particular motor and sensory characteristics and specific categories of non-neurological infantile nystagmus. The purpose of this case study is to extend this body of work significantly by describing the trends and associations found in a database of 224 subjects who have undergone extensive clinical and psychophysical evaluations.
Methods: The records of 224 subjects with infantile nystagmus were examined, where 62% were idiopaths, 28% albinos, and 10% exhibited ocular anomalies. Recorded variables included age, mode of inheritance, birth history, nystagmus presentation, direction of the nystagmus, waveform types, spatial and temporal null zones, head postures and nodding, convergence, foveation, ocular alignment, refractive error, visual acuity, stereoacuity, and oscillopsia.
Results: The age distribution of the 224 patients was between 1 month and 71 years, with the mean age and mode being 23 (SD 16) years and 16–20 years respectively. By far the most common pattern of inheritance was found to be autosomal dominant (n = 40), with the nystagmus being observed by the age of 6 months in 87% of the sample (n = 128). 139 (62%) of the 224 subjects were classified as idiopaths, 63 (28%) as albinos, and 22 (10%) exhibited ocular anomalies. Conjugate uniplanar horizontal oscillations were found in 174 (77.7%) of the sample. 32 (14.3%) had a torsional component to their nystagmus. 182 (81.2%) were classed as congenital nystagmus (CN), 32 (14.3%) as manifest latent nystagmus (MLN), and 10 (4.5%) as a CN/MLN hybrid. Neither CN nor MLN waveforms were related to any of the three subject groups (idiopaths, albinos, and ocular anomalies) MLN was found in idiopaths and albinos, but most frequently in the ocular anomaly group. The most common oscillation was a horizontal jerk with extended foveation (n = 49; 27%). The amplitudes and frequencies of the nystagmus ranged between 0.3–15.7° and 0.5–8 Hz, respectively. Periodic alternating nystagmus is commonly found in albinos. Albino subjects did not show a statistically significantly higher nystagmus intensity when compared with the idiopaths (p>0.01). 105 of 143 subjects (73%) had spatial nulls within plus or minus 10° of the primary position although 98 subjects (69%) employed a compensatory head posture. Subjects with spatial null zones at or beyond plus or minus 20° always adopted constant head postures. Head nodding was found in 38 subjects (27% of the sample). Horizontal tropias were very common (133 out of 213; 62.4%) and all but one of the 32 subjects with MLN exhibited a squint. Adult visual acuity is strongly related to the duration and accuracy of the foveation period. Visual acuity and stereoacuity were significantly better (p<0.01) in the idiopaths compared to the albino and ocular anomaly groups. 66 subjects out of a sample of 168 (39%) indicated that they had experienced oscillopsia at some time.
Conclusions: There are strong ocular motor and sensory patterns and associations that can help define an infantile nystagmus. These include the nystagmus being bilateral, conjugate, horizontal uniplanar, and having an accelerating slow phase (that is, CN). Decelerating slow phases (that is, MLN) are frequently associated with strabismus and early form deprivation. Waveform shape (CN or MLN) is not pathognomonic of any of the three subject groups (idiopaths, albinos, or ocular anomalies). There is no one single stand alone ocular motor characteristic that can differentiate a benign form of infantile nystagmus (CN, MLN) from a neurological one. Rather, the clinician must consider a host of clinical features.
infantile nystagmus; congenital nystagmus; manifest latent nystagmus; albino; visual acuity
To report the occurrence of nystagmus in children exposed to opiates and/or benzodiazepines during pregnancy, and to describe the associated ocular and systemic findings.
Clinical examination and casenote review of 14 children with nystagmus whose mothers had misused opiates and/or benzodiazepines during pregnancy.
Twelve children were exposed to opiates during pregnancy, of whom nine had also been exposed to benzodiazepines. Two children were exposed to benzodiazepines alone. In the primary position, the nystagmus was a fine horizontal pendular type in 10 (71.4%) children and was a fine horizontal jerk nystagmus in the other 4 (28.6%) children. The onset of the nystagmus probably occurred in the first 6 months of life in all cases. The mean binocular best‐corrected logarithm of the minimum angle of resolution visual acuity was 0.59 (20/80). Electroretinogram and visual evoked potential examinations were found to be normal in the three children tested. Nine (64.3%) children had developmental delay and at least 7 (50%) had delayed visual maturation. Six children had microcephaly and two had bilateral optic nerve hypoplasia. None of the children had a specific neurological diagnosis or seizure disorder.
This study strongly supports a teratogenic association between exposure to controlled drugs in utero and infantile nystagmus. Furthermore, the nystagmus and associated clinical features seem to be particularly associated with combined use of opiates and benzodiazepines. Exposure to opiates and/or benzodiazepines during pregnancy should be considered in the differential diagnosis of infantile nystagmus.
Thirty seven patients with pendular nystagmus due to multiple sclerosis were reviewed. Most developed nystagmus later in a progressive phase of the disease. All had cerebellar signs on examination and evidence of optic neuropathy. MRI in eight patients showed cerebellar or brainstem lesions in seven; the most consistent finding was a lesion in the dorsal pontine tegmentum. Dissociated nystagmus was seen in 18 patients: in these the signs of optic neuropathy were often asymmetric and the severity correlated closely with the side with larger oscillations. This suggests that dissociations in acquired pendular nystagmus may be due to asymmetries in optic neuropathy rather than asymmetries in cerebellar or brainstem disease.
An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.
Ocular motor; Examination; Neurodegenerative disorder; Diagnosis; Treatment
The Hyperventilation Test is widely used in the "bed-side examination" of vestibular patients. It can either activate a latent nystagmus in central or peripheral vestibular diseases or it can interact with a spontaneous nystagmus, by reducing it or increasing it. Aims of this study were to determine the incidence, patterns and temporal characteristics of Hyperventilation-induced nystagmus in patients suffering from vestibular diseases, as well as its contribution to the differential diagnosis between vestibular neuritis and neuroma of the 8th cranial nerve, and its behaviour in some central vestibular diseases. The present study includes 1202 patients featuring, at vestibular examination, at least one sign of vestibular system disorders or patients diagnosed with a "Migraine-related vertigo" or "Chronic subjective dizziness". The overall incidence of Hyperventilation-induced nystagmus was 21.9%. It was detected more frequently in retrocochlear vestibular diseases rather than in end-organ vestibular diseases: 5.3% in Paroxysmal Positional Vertigo, 37.1% in Menière's disease, 37.6% in compensated vestibular neuritis, 77.2% in acute vestibular neuritis and 91.7% in neuroma of the 8th cranial nerve. In acute vestibular neuritis, three HVIN patterns were observed: Paretic pattern: temporary enhancement of the spontaneous nystagmus; Excitatory pattern: temporary inhibition of the spontaneous nystagmus; Strong excitatory pattern: temporary inversion of the spontaneous nystagmus. Excitatory patterns proved to be time-dependent in that they disappeared and were replaced by the paretic pattern over a period of maximum 18 days since the beginning of the disorder. In acoustic neuroma, Hyperventilation-induced nystagmus was frequently observed (91.7%), either in the form of an excitatory pattern (fast phases towards the affected site) or in the form of a paretic pattern (fast phases towards the healthy side). The direction of the nystagmus is only partially related to tumour size, whereas other mechanisms, such as demyelination or a break in nerve fibres, might have an important role in triggering the situation. Hyperventilation-induced nystagmus has frequently been detected in cases of demyelinating diseases and in cerebellar diseases: in multiple sclerosis, hyperventilation inhibits a central type of spontaneous nystagmus or evokes nystagmus in 75% of patients; in cerebellar diseases, hyperventilation evokes or enhances a central spontaneous nystagmus in 72.7% of patients. In conclusion the Hyperventilation Test can provide patterns of oculomotor responses that indicate a diagnostic investigation through cerebral magnetic resonance imaging enhanced by gadolinium, upon suspicion of neuroma of the 8th cranial nerve or of a central disease. In our opinion, however, Hyperventilation-induced nystagmus always needs to be viewed within the more general context of a complete examination of the vestibular and acoustic system.
Vestibular neuritis; Acoustic neuroma; Multiple sclerosis; Cerebellar diseases; Hyperventilation; Hyperventilationinduced nystagmus
Background and Purpose
The mechanism of upbeat nystagmus is unknown and clinicoanatomical correlative studies in series of patients with upbeat nystagmus are limited.
Fifteen patients with upbeat nystagmus received full neuro-ophthalmological evaluation by the senior author. Nystagmus was observed using video Frenzel goggles and recorded with video-oculography. Brain lesions were documented with MRI.
Lesions responsible for nystagmus were found throughout the brainstem, mainly in the paramedian area: in the medulla (n=8), pons (n=3), pons and midbrain with or without cerebellar lesions (n=3), and midbrain and thalamus (n=1). Underlying diseases comprised cerebral infarction (n=10), multiple sclerosis (n=2), cerebral hemorrhage (n=1), Wernicke encephalopathy (n=1), and hydrocephalus (n=1). Upbeat nystagmus was mostly transient and showed occasional evolution during the acute phase. In one patient with a bilateral medial medullary infarction, the upbeat nystagmus changed into a hemiseesaw pattern with near complete resolution of the unilateral lesion. Gaze and positional changes usually affected both the intensity and direction of the nystagmus. A patient with a cervicomedullary lesion showed a reversal of upbeat into downbeat nystagmus by straight-head hanging and leftward head turning while in the supine position. Gaze-evoked nystagmus (n=7), ocular tilt reaction (n=7), and internuclear ophthalmoplegia (n=4) were also commonly associated with upbeat nystagmus.
In view of the responsible lesions and associated neuro-ophthalmological findings, upbeat nystagmus may be ascribed to damage to the pathways mediating the upward vestibulo-ocular reflex or the neural integrators involved in vertical gaze holding.
Upbeat nystagmus; Vestibulo-ocular reflex; Neural integrator
Infantile nystagmus is an involuntary, bilateral, conjugate, and rhythmic oscillation of the eyes which is present at birth or develops within the first 6 months of life. It may be pendular or jerk-like and, its intensity usually increases in lateral gaze, decreasing with convergence. Up to 64% of all patients with nystagmus also present strabismus, and even more patients have an abnormal head position. The abnormal head positions are more often horizontal, but they may also be vertical or take the form of a tilt, even though the nystagmus itself is horizontal. The aim of this article is to review available information about the origin and treatment of the abnormal head position associated to nystagmus, and to describe our treatment strategies.
The GABAergic drug baclofen and the cholinergic drug physostigmine were administered to patients with upbeat and downbeat nystagmus. Baclofen (orally, 5 mg three times daily) reduced nystagmus slow phase velocity and distressing oscillopsia by 25-75% in four out of five patients (two upbeat nystagmus; two downbeat nystagmus). Physostigmine (1 mg single intravenous injection) increased nystagmus in five additional patients with downbeat (1) or positional downbeat nystagmus (4) for a duration of 15-20 minutes. The different interactions of baclofen and physostigmine on neurotransmission subserving vertical vestibulo-ocular reflex could account for these effects. The response to baclofen appears to be a GABA-B-ergic effect with augmentation of the physiological inhibitory influence of the vestibulo-cerebellum on the vestibular nuclei. Similarly baclofen has an inhibitory effect on the velocity storage mechanism. Cholinergic action may cause the increment of nystagmus by physostigmine.
Interruption of the dentato-olivary projections, interconnecting the dentate nucleus (DN) and the contralateral inferior olivary nucleus (ION), is predicted to interfere with the DN’ role in estimating direction of gravity. In a patient with pendular nystagmus due to hypertrophy of the ION secondary to predominantly right-sided ponto-mesencephalic hemorrhage, perceived vertical shifted from clockwise to counter-clockwise deviations within 4 months. We hypothesize that synchronized oscillations of ION neurons induce a loss of inhibitory control, leading to hyperactivity of the contralateral DN and, as a result, to perceived vertical roll–tilt to the side of the over-active DN.
vestibular; Guillain–Mollaret triangle; subjective visual vertical; brainstem
Clinical examinations and eye movement recordings of 91 consecutive patients with DBN were analyzed to describe the characteristics of DBN and to localize the lesions producing this abnormality. Horizontal and vertical eye movement recordings were made with EOG and/or magnetic search coil. The most frequent causes were infarction, cerebellar and spinocerebellar degeneration syndromes, MS and developmental anomalies affecting the pons and cerebellum. Toxicity from anticonvulsant drugs probably caused nystagmus in a few patients. Clinical examinations, excluding electronic eye movement recordings, were used to localize lesions. Localizations included the cerebellum in 88% of the patients. However, localizations to structures outside of the cerebellum were made in several patients. The effects of DBN of gaze position, convergence, blockage of fixation, and positioning of the head and body were observed. Almost all patients had DBN in some position of gaze while sitting and fixating a distant target. A few patients demonstrated DBN only with convergence, in the dark, or with positioning of the head and body. Horizontal gaze increased DBN in most patients. The nystagmus slow components usually had constant-velocity or increasing-velocity waveforms. The effects of vertical gaze on DBN were variable. In general, statistically significant differences in the frequencies of these effects among the various causes and localizations of lesions were not found. Horizontal eye movements were electronically recorded in DBN patients, in a group of normal subjects, and in a group of patients with isolated cerebellar atrophy who did not have DBN. The pattern of abnormal horizontal eye movements characteristic of damage to the midline structures of the cerebellum (impaired pursuit, impaired OKN, and inability to suppress VOR) was found in almost all DBN patients (99%), including patients with lesions localized to structures outside the cerebellum by clinical examination. DBN is usually produced by lesions in the cerebellum that also damage pathways that control horizontal tracking and visual-vestibulo-ocular interactions.
Early diagnosis of the affected side in Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo is important in effectively applying treatment manoeuvres. This study was performed to examine the frequency of a new clinical sign, pseudo-spontaneous nystagmus, in a large cohort of patients with Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo, comparing its efficacy in the identification of the involved side with that of other diagnostic signs, seated supine positioning nystagmus, and the intensity of the nystagmus evoked by the head yaw test in the supine position. Overall, 293 patients affected by Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo (197 geotropic and 96 apogeotropic forms) were examined. Pseudo-spontaneous nystagmus was observed in 222 patients (76%). After a very slow, repeated horizontal rotation of the head, in the seated position, this percentage increased to 96% (281 patients). The pseudo-spontaneous nystagmus and the seated supine positioning nystagmus always beat in the same direction and both were in accordance in identifying the affected side with the nystagmus evoked by the head yaw test. The differential diagnosis between spontaneous nystagmus and pseudo-spontaneous nystagmus is easily achieved with the head pitch test in the sitting position: the pseudo-spontaneous nystagmus disappears with the head bent forward 30° (neutral position), it reverses its direction with the head bent 60° forward, it returns visible bringing the head in axis with the body and increases its intensity extending the head about 30° backwards. Pseudo-spontaneous nystagmus is an important sign for determining the affected ear in Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo. Early identification of the affected side improves efficacy of treatment and compliance of patients.
Vertigo; Otoliths; Benign Paroxysmal Positional Vertigo; Lateral Semicircular Canal; Liberatory Manoeuvre
In recent decades there has been marked progress in the imaging and laboratory evaluation of dizzy patients. However, detailed history taking and comprehensive bedside neurotological evaluation remain crucial for a diagnosis of dizziness. Bedside neurotological evaluation should include examinations for ocular alignment, spontaneous and gaze-evoked nystagmus, the vestibulo-ocular reflex, saccades, smooth pursuit, and balance. In patients with acute spontaneous vertigo, negative head impulse test, direction-changing nystagmus, and skew deviation mostly indicate central vestibular disorders. In contrast, patients with unilateral peripheral deafferentation invariably have a positive head impulse test and mixed horizontal-torsional nystagmus beating away from the lesion side. Since suppression by visual fixation is the rule in peripheral nystagmus and is frequent even in central nystagmus, removal of visual fixation using Frenzel glasses is required for the proper evaluation of central as well as peripheral nystagmus. Head-shaking, cranial vibration, hyperventilation, pressure to the external auditory canal, and loud sounds may disclose underlying vestibular dysfunction by inducing nystagmus or modulating the spontaneous nystagmus. In patients with positional vertigo, the diagnosis can be made by determining patterns of the nystagmus induced during various positional maneuvers that include straight head hanging, the Dix-Hallpike maneuver, supine head roll, and head turning and bending while sitting. Abnormal smooth pursuit and saccades, and severe imbalance also indicate central pathologies. Physicians should be familiar with bedside neurotological examinations and be aware of the clinical implications of the findings when evaluating dizzy patients.
dizziness; bedside examination; nystagmus; head impulse test