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1.  Cross-Over Trial of Gabapentin and Memantine as Treatment for Acquired Nystagmus 
Annals of neurology  2010;67(5):676-680.
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.
doi:10.1002/ana.21991
PMCID: PMC3064518  PMID: 20437565
nystagmus; oscillopsia; multiple sclerosis; oculopalatal tremor
2.  Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: how valid is the GABAergic hypothesis? 
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.


doi:10.1136/jnnp.71.1.107
PMCID: PMC1737451  PMID: 11413274
3.  The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1136/bjo.2005.086322
PMCID: PMC1857134  PMID: 16556621
acquired nystagmus; congenital nystagmus; gabapentin; memantine; pharmacological treatment
4.  Acquired pendular nystagmus with oscillopsia in multiple sclerosis: a sign of cerebellar nuclei disease 
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.
PMCID: PMC494702  PMID: 4836752
5.  Neuro-ophthalmologic aspects of multiple sclerosis: Using eye movements as a clinical and experimental tool 
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.
PMCID: PMC2701138  PMID: 19668480
multiple sclerosis; eye movements; ocular motor disorders
6.  Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity 
Brain  2010;133(3):923-940.
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.
doi:10.1093/brain/awp323
PMCID: PMC2842510  PMID: 20080879
vestibular; gap junction; connexin; motor disorders; eye movement
7.  Incidence and characteristics of voluntary nystagmus. 
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.
PMCID: PMC493105  PMID: 690639
8.  Acquired pendular nystagmus: its characteristics, localising value and pathophysiology 
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.
PMCID: PMC1083123  PMID: 7086456
9.  Hypertrophy of the Inferior Olivary Nucleus Impacts Perception of Gravity 
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.
doi:10.3389/fneur.2012.00079
PMCID: PMC3350027  PMID: 22593754
vestibular; Guillain–Mollaret triangle; subjective visual vertical; brainstem
10.  Acquired pendular nystagmus in multiple sclerosis: clinical observations and the role of optic neuropathy. 
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.
Images
PMCID: PMC1014858  PMID: 8459242
11.  Abnormal Head Position in Infantile Nystagmus Syndrome 
ISRN Ophthalmology  2012;2011:594848.
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.
doi:10.5402/2011/594848
PMCID: PMC3912622  PMID: 24533187
12.  Oculomotor Deficits in Aryl Hydrocarbon Receptor Null Mouse 
PLoS ONE  2013;8(1):e53520.
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.
doi:10.1371/journal.pone.0053520
PMCID: PMC3536739  PMID: 23301081
13.  Is acquired pendular nystagmus always phase locked? 
A patient with multiple sclerosis presented with oscillopsia due to an acquired pendular nystagmus that was dissociated in amplitude, being larger in the eye with a relative afferent pupil defect. Eye movement recordings showed an unusual dissociation in nystagmus frequency as well. Although the frequencies differed, the eyes remained phase locked as the right eye was oscillating exactly twice as fast as the left eye.
Images
PMCID: PMC485501  PMID: 7931394
14.  The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. 
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.
PMCID: PMC1014435  PMID: 1654396
15.  A case of "voluntary nystagmus" and head tremor. 
A 24-year-old woman presented with nystagmus and head tremor. Both were transient and could be executed simultaneously at different frequencies of oscillation. It is unusual for these two movements, which can be voluntary, to occur together. Suspicions of an acquired disease were not confirmed on further investigation using DC-coupled electro-oculography and angular accelerometry, and on an admission by the patient that the nystagmus could be voluntary. Voluntary nystagmus can become semi-automatic and a patient may be able to simulate more than one "involuntary movement" simultaneously yet at different frequencies.
PMCID: PMC1015383  PMID: 8270936
16.  Pseudo-Spontaneous Nystagmus: a new sign to diagnose the affected side in Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo 
Summary
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.
PMCID: PMC2644980  PMID: 18669071
Vertigo; Otoliths; Benign Paroxysmal Positional Vertigo; Lateral Semicircular Canal; Liberatory Manoeuvre
17.  Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial 
Translational Psychiatry  2012;2(7):e141-.
Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer's disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted.
doi:10.1038/tp.2012.66
PMCID: PMC3410988  PMID: 22806212
Alzheimer disease; Down syndrome; intellectual disability; memantine; trisomy 21; Ts65Dn
18.  Study of congenital nystagmus: optokinetic nystagmus. 
A severe defect of optokinetic nystagmus (OKN) was found in 46 patients with congenital nystagmus. Abnormal patterns of OKN, such as superimposition of pendular oscillations on the optokinetic slow component and inversion of OKN, were observed. Optokinetic gain (eye movement velocity/drum velocity) was decreased compared to that in normal subjects, and optokinetic after-nystagmus, or transient persistence of OKN after cessation of visual stimulation, was absent. These findings suggest that there is a defect in the subcortical optokinetic system in congenital nystagmus. Optokinetic responses did not clearly differentiate patients who had ocular lesions that impair vision, such as ocular albinism and opacities of the ocular media, from patients who did not have such lesions. Similar abnormal patterns of OKN were found in both groups of patients, although optokinetic gain tended to be lower in patients with ocular lesions than in those without lesions.
PMCID: PMC1042576  PMID: 7448147
19.  Leber's Hereditary Optic Neuropathy with Olivocerebellar Degeneration due to G11778A and T3394C Mutations in the Mitochondrial DNA 
Background
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported.
Case Report
The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations.
Conclusions
These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.
doi:10.3988/jcn.2012.8.3.230
PMCID: PMC3469805  PMID: 23091534
Leber's hereditary optic neuropathy; Leber's hereditary optic neuropathy plus; mitochondria; inferior olivary nucleus; G11778A; T3394C
20.  A Case of Linear Scleroderma Involving Cerebellum with Vertigo 
Korean Journal of Audiology  2012;16(2):87-90.
Linear scleroderma is a kind of disease that can cause complication of the central nervous system. Sometimes, ipsilateral intracerebral or white matter lesions in the brain magnetic resonance imaging are noted. Nystagmus is important for the differential diagnosis of dizziness. Positional nystagmus was classified into regular direction nystagmus, direction changing positional nystagmus (DCPN) and irregular nystagmus by their character. DCPN is defined as a nystagmus that changes its direction with different head and body positions, and it can be the sign of lesion in the central vestibular system. Recently, we experienced a 17-year-old woman who had a scalp linear scleroderma, treated for about 10 years and showed DCPN induced by positional nystagmus test. We report a case of linear scleroderma accompanied by cerebellar lesion with a brief review of literature.
doi:10.7874/kja.2012.16.2.87
PMCID: PMC3936567  PMID: 24653878
Dizziness; Positional nystagmus; Linear scleroderma
21.  Paroxysmal alternating skew deviation and nystagmus after partial destruction of the uvula 
A patient with suspected brain stem glioma involving the area of the left vestibular nuclei and cerebellar peduncle, developed paroxysmal alternating skew deviation and direction changing nystagmus after biopsy of the inferior cerebellar vermis resulting in destruction of the uvula. Between attacks she had right over left skew deviation with asymptomatic right beating horizontal nystagmus. Slow phases of the resting nystagmus showed increasing velocity, similar to congenital nystagmus. At intervals of 40-50 seconds, paroxysmal reversal of her skew deviation occurred, accompanied by violent left beating horizontal torsional nystagmus lasting 10-12 seconds and causing severe oscillopsia. It is proposed that this complex paroxysmal eye movement disorder results from (1) a lesion in the left vestibular nuclei causing right over left skew and right beating resting nystagmus and (2) a disruption of cerebellar inhibition of vestibular nuclei, causing alternating activity in the vestibular system with intermittent reversal of the skew deviation and paroxysmal nystagmus towards the side of the lesion.


doi:10.1136/jnnp.70.6.790
PMCID: PMC1737375  PMID: 11385016
22.  Joubert Syndrome Presenting with Motor Delay and Oculomotor Apraxia 
Case Reports in Pediatrics  2012;2011:262641.
We describe two sisters who presented in early childhood with motor delay and unusual eye movements. Both demonstrated hypotonia and poor visual attention. The older girl at 14 weeks of age showed fine pendular horizontal nystagmus more pronounced on lateral gaze, but despite investigation with cranial MRI no diagnosis was reached. The birth of her younger sister four years later with a similar presentation triggered review of the sisters' visual behaviour. Each had developed an unusual but similar form of oculomotor apraxia (OMA) with head thrusts to maintain fixation rather than to change fixation. MRI of the older sibling demonstrated the characteristic “molar tooth sign” (MTS) of Joubert syndrome which was subsequently confirmed on MRI in the younger sibling. We discuss the genetically heterogeneous ciliopathies now grouped as Joubert syndrome and Related Disorders. Clinicians need to consider this group of disorders when faced with unusual eye movements in the developmentally delayed child.
doi:10.1155/2011/262641
PMCID: PMC3350021  PMID: 22606509
23.  Adiponectin Decreases Pulmonary Arterial Remodeling in Murine Models of Pulmonary Hypertension 
Remodeling of the pulmonary arteries is a common feature among the heterogeneous disorders that cause pulmonary hypertension. In these disorders, the remodeled pulmonary arteries often demonstrate inflammation and an accumulation of pulmonary artery smooth muscle cells (PASMCs) within the vessels. Adipose tissue secretes multiple bioactive mediators (adipokines) that can influence both inflammation and remodeling, suggesting that adipokines may contribute to the development of pulmonary hypertension. We recently reported on a model of pulmonary hypertension induced by vascular inflammation, in which a deficiency of the adipokine adiponectin (APN) was associated with the extensive proliferation of PASMCs and increased pulmonary artery pressures. Based on these data, we hypothesize that APN can suppress pulmonary hypertension by directly inhibiting the proliferation of PASMCs. Here, we tested the effects of APN overexpression on pulmonary arterial remodeling by using APN-overexpressing mice in a model of pulmonary hypertension induced by inflammation. Consistent with our hypothesis, mice that overexpressed APN manfiested reduced pulmonary hypertension and remodeling compared with wild-type mice, despite developing similar levels of pulmonary vascular inflammation in the model. The overexpression of APN was also protective in a hypoxic model of pulmonary hypertension. Furthermore, APN suppressed the proliferation of PASMCs, and reduced the activity of the serum response factor–serum response element pathway, which is a critical signaling pathway for smooth muscle cell proliferation. Overall, these data suggest that APN can regulate pulmonary hypertension and pulmonary arterial remodeling through its direct effects on PASMCs. Hence, the activation of APN-like activity in the pulmonary vasculature may be beneficial in pulmonary hypertension.
doi:10.1165/rcmb.2010-0316OC
PMCID: PMC3175561  PMID: 21075862
pulmonary hypertension; pulmonary artery smooth muscle cells; metabolism; adiponectin
24.  Bedside Evaluation of Dizzy Patients 
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.
doi:10.3988/jcn.2013.9.4.203
PMCID: PMC3840130  PMID: 24285961
dizziness; bedside examination; nystagmus; head impulse test
25.  Genetic essential tremor in γ-aminobutyric acidA receptor α1 subunit knockout mice 
Journal of Clinical Investigation  2005;115(3):774-779.
Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acidA (GABAA) receptor α1–/– mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethanol; the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801; the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the GABAA receptor modulators diazepam, allopregnanolone, and Ro15-4513; and the L-type Ca2+ channel antagonist nitrendipine. Primidone, propranolol, and gabapentin reduced the amplitude (power) of the pathologic tremor. Nonsedative doses of ethanol eliminated tremor in mice. Diazepam, allopregnanolone, Ro15-4513, and nitrendipine had no effect or enhanced tremor, whereas MK-801 and CCPA reduced tremor. To understand the etiology of tremor in these mice, we studied the electrophysiological properties of cerebellar Purkinje cells. Cerebellar Purkinje cells in GABAA receptor α1–/– mice exhibited a profound loss of all responses to synaptic or exogenous GABA, but no differences in abundance, gross morphology, or spontaneous synaptic activity were observed. This genetic animal model elucidates a mechanism of GABAergic dysfunction in the major motor pathway and potential targets for pharmacotherapy of essential tremor.
doi:10.1172/JCI200523625
PMCID: PMC1052003  PMID: 15765150

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