Gabapentin and Memantine for Treatment of Acquired Pendular Nystagmus: Effects on Visual Outcomes.

BACKGROUND: The most common causes of acquired pendular nystagmus (APN) are multiple sclerosis (MS) and oculopalatal tremor (OPT), both of which result in poor visual quality of life. The objective of our study was to evaluate the effects of memantine and gabapentin treatments on visual function. We also sought to correlate visual outcomes with ocular motor measures and to describe the side effects of our treatments. METHODS: This study was single-center cross-over trial. A total of 16 patients with chronic pendular nystagmus, 10 with MS and 6 with OPT were enrolled. Visual acuity (in logarithm of the minimum angle of resolution [LogMAR]), oscillopsia amplitude and direction, eye movement recordings, and visual function questionnaires (25-Item National Eye Institute Visual Functioning Questionnaire [NEI-VFQ-25]) were performed before and during the treatments (gabapentin: 300 mg 4 times a day and memantine: 10 mg 4 times a day). RESULTS: A total of 29 eyes with nystagmus were evaluated. Median near monocular visual acuity improved in both treatment arms, by 0.18 LogMAR on memantine and 0.12 LogMAR on gabapentin. Distance oscillopsia improved on memantine and on gabapentin. Median near oscillopsia did not significantly change on memantine or gabapentin. Significant improvement in ocular motor parameters was observed on both treatments. Because of side effects, 18.8% of patients discontinued memantine treatment-one of them for a serious adverse event. Only 6.7% of patients discontinued gabapentin. Baseline near oscillopsia was greater among those with higher nystagmus amplitude and velocity. CONCLUSIONS: This study demonstrated that both memantine and gabapentin reduce APN, improving functional visual outcomes. Gabapentin showed a better tolerability, suggesting that this agent should be used as a first-line agent for APN. Data from our investigation emphasize the importance of visual functional outcome evaluations in clinical trials for APN.

Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion.

OBJECTIVE: Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. METHODS: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. RESULTS: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. CONCLUSIONS: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.

A New Symptom, 'Palinendophonia', Associated with Pure Verbal Palinacousis Induced by a Right Inferior Temporal Lesion.

We describe the case of a patient with pure verbal palinacousis and perseveration of inner speech after a right inferior temporal lesion. The superior temporal lobe, including the superior temporal sulcus and the interhemispheric connection between the 2 superior temporal lobes, explored by tractography, were preserved. These regions are involved in voice processing, verbal short-term memory and inner speech. It can then be hypothesised that abnormal activity in this network has occurred. Palinacousis and 'palinendophonia', a term proposed for this symptom not previously reported, may be due to common cognitive processes disorders involved in both voice hearing and inner speech.

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

INTRODUCTION: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). METHODS: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. RESULTS: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. DISCUSSION: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Relapsing optic neuritis: a multicentre study of 62 patients.

BACKGROUND: Optic neuritis (ON) may be the first symptom of a central nervous system demyelinating, systemic or infectious disease but few patients experience recurrent episodes and have a negative workup. OBJECTIVE: This disorder, named relapsing optic neuritis (RON), is poorly described in the literature and still presents a particular challenge in diagnosis and management. METHODS: We describe the clinical, laboratory, magnetic resonance imaging (MRI) and disability course of RON in a French cohort of 62 patients, based on a multicentre, retrospective, observational study. RESULTS: In our cohort, we identified two distinct groups of RON patients. The first is characterised by relapsing inflammatory optic neuritis (RION, 68%), which is non-progressive, whereas the second presented as a chronic relapsing inflammatory optic neuritis (CRION, 32%), which is progressive. We have noted more cases with steroid dependence in the CRION group than the RION group (42% vs 10%). The long-term visual prognosis was more severe in CRION patients and neuromyelitis optica-immunoglobulin G (NMO-IgG)-positive patients. CONCLUSION: RON is likely a separate entity corresponding to an autoimmune disease that differs from multiple sclerosis (MS), NMO and vasculitis. We provide a new classification system based on a better understanding of RON which could allow an improved management by early treatment of poor prognosis forms.

Endoscopic endonasal optic nerve and orbital apex decompression for nontraumatic optic neuropathy: surgical nuances and review of the literature.

OBJECT: While several approaches have been described for optic nerve decompression, the endoscopic endonasal route is gaining favor because it provides excellent exposure of the optic canal and the orbital apex in a minimally invasive manner. Very few studies have detailed the experience with nontraumatic optic nerve decompressions, whereas traumatic cases have been widely documented. Herein, the authors describe their preliminary experience with endoscopic endonasal decompression for nontraumatic optic neuropathies (NONs) to determine the procedure's efficacy and delineate its potential indications and limits. METHODS: The medical reports of patients who had undergone endoscopic endonasal optic nerve and orbital apex decompression for NONs at the Lyon University Neurosurgical Hospital in the period from January 2012 to March 2014 were reviewed. For all cases, clinical and imaging data on the underlying pathology and the patient, including demographics, preoperative and 6-month postoperative ophthalmological assessment results, symptom duration, operative details with video debriefing, as well as the immediate and delayed postoperative course, were collected from the medical records. RESULTS: Eleven patients underwent endoscopic endonasal decompression for NON in the multidisciplinary skull base surgery unit of the Lyon University Neurosurgical Hospital during the 27-month study period. The mean patient age was 53.4 years, and there was a clear female predominance (8 females and 3 males). Among the underlying pathologies were 4 sphenoorbital meningiomas (36%), 3 optic nerve meningiomas (27%), and 1 each of trigeminal neuroma (9%), orbital apex meningioma (9%), ossifying fibroma (9%), and inflammatory pseudotumor of the orbit (9%). Fifty-four percent of the patients had improved visual acuity at the 6-month follow-up. Only 1 patient whose sphenoorbital meningioma had been treated at the optic nerve atrophy stage continued to worsen despite surgical decompression. The 2 patients presenting with preoperative papilledema totally recovered. One case of postoperative epistaxis was successfully treated using balloon inflation, and 1 case of air swelling of the orbit spontaneously resolved. CONCLUSIONS: Endoscopic endonasal optic nerve decompression is a safe, effective, and minimally invasive technique affording the restoration of visual function in patients with nontraumatic compressive processes of the orbital apex and optic nerve. The timing of decompression remains crucial, and patients should undergo such a procedure early in the disease course before optic atrophy.

Saccades and eye-head coordination in ataxia with oculomotor apraxia type 2.

Ataxia with oculomotor apraxia type 2 (AOA2) is one of the most frequent autosomal recessive cerebellar ataxias. Oculomotor apraxia refers to horizontal gaze failure due to deficits in voluntary/reactive eye movements. These deficits can manifest as increased latency and/or hypometria of saccades with a staircase pattern and are frequently associated with compensatory head thrust movements. Oculomotor disturbances associated with AOA2 have been poorly studied mainly because the diagnosis of oculomotor apraxia was based on the presence of compensatory head thrusts. The aim of this study was to characterise the nature of horizontal gaze failure in patients with AOA2 and to demonstrate oculomotor apraxia even in the absence of head thrusts. Five patients with AOA2, without head thrusts, were tested in saccadic tasks with the head restrained or free to move and their performance was compared to a group of six healthy participants. The most salient deficit of the patients was saccadic hypometria with a typical staircase pattern. Saccade latency in the patients was longer than controls only for memory-guided saccades. In the head-free condition, head movements were delayed relative to the eye and their amplitude and velocity were strongly reduced compared to controls. Our study emphasises that in AOA2, hypometric saccades with a staircase pattern are a more reliable sign of oculomotor apraxia than head thrust movements. In addition, the variety of eye and head movements' deficits suggests that, although the main neural degeneration in AOA2 affects the cerebellum, this disease affects other structures.

Persistent visual impairment in multiple sclerosis: prevalence, mechanisms and resulting disability.

OBJECTIVE: The objective of this article is to evaluate in multiple sclerosis (MS) patients the prevalence of persistent complaints of visual disturbances and the mechanisms and resulting functional disability of persistent visual complaints (PVCs). METHODS: Firstly, the prevalence of PVCs was calculated in 303 MS patients. MS-related data of patients with or without PVCs were compared. Secondly, 70 patients with PVCs performed an extensive neuro-ophthalmologic assessment and a vision-related quality of life questionnaire, the National Eye Institute Visual Functionary Questionnaire (NEI-VFQ-25). RESULTS: PVCs were reported in 105 MS patients (34.6%). Patients with PVCs had more frequently primary progressive MS (30.5% vs 13.6%) and more neuro-ophthalmologic relapses (1.97 vs 1.36) than patients without PVCs. In the mechanisms/disability study, an afferent visual and an ocular-motor pathways dysfunction were respectively diagnosed in 41 and 59 patients, mostly related to bilateral optic neuropathy and bilateral internuclear ophthalmoplegia. The NEI-VFQ 25 score was poor and significantly correlated with the number of impaired neuro-ophthalmologic tests. CONCLUSION: Our study emphasizes the high prevalence of PVC in MS patients. Regarding the nature of neuro-ophthalmologic deficit, our results suggest that persistent optic neuropathy, as part of the progressive evolution of the disease, is not rare. We also demonstrate that isolated ocular motor dysfunctions induce visual disability in daily life.

Oscillopsia: causes and management.

PURPOSE OF REVIEW: Oscillopsia is an illusion of an unstable visual world. It is associated with poor visual acuity and is a disabling and distressing condition reported by numerous patients with neurological disorders. The goal of this study is to review the recent findings in the various pathophysiological mechanisms of oscillopsia and the potential treatments available. RECENT FINDINGS: Oscillopsia most often results from abnormal eye movements or from impaired vestibulo-ocular reflex. A special emphasis is provided on new hypotheses concerning the mechanisms of pendular nystagmus associated with oculopalatal tremor; on the clinical relevance of fixation instability in the diagnosis of degenerative disease; and on the causes of vestibular areflexia. Oscillopsia could also theoretically result from a deficit in mechanisms underpinning perceptual stability maintenance despite constant gaze displacement in the environment. The recent findings concerning the mechanisms and underlying neural network subserving this phenomenon of 'spatial constancy' are developed. SUMMARY: Oscillopsia may result either from impaired ocular stability or impaired compensation or suppression of afferent visual information resulting from normal eye movements. Understanding the exact mechanisms of oscillopsia may lead to novel treatment.

Unusual monocular pendular nystagmus in multiple sclerosis.

Two unusual cases of monocular pendular nystagmus in patients with multiple sclerosis are reported. One patient showed regular horizontal oscillations of the right eye in abduction, associated with right abduction paresis. The second patient had a similar abnormal eye movement of the left eye in adduction, with partial left internuclear ophthalmoplegia. Such eye position-dependent monocular pendular nystagmus provides new insights into pathogenic mechanism for acquired pendular nystagmus. Different mechanisms are discussed such as the combination of paresis and commonly accepted hypothesis of dysfunction of visual and/or motor feedback loops in the ocular motor neural network.

Acute ophthalmoparesis associated with human parvovirus B19 infection.

PURPOSE: Parvovirus B19 infection (PVB19) has been linked with a broad spectrum of clinical syndromes. In addition to erythema infectiosum and asymptomatic infection, other less common manifestations include transient aplastic crisis in patients with hemoglobinopathies, pure red cell aplasia and pancytopenia in immunocompromised persons, nonimmune hydrops fetalis, chronic arthritis, myocarditis, and hepatitis. METHODS: Only 19% of patients had peripheral nervous system damage, mainly including brachial plexitis and carpal tunnel syndrome. Two cases of cranial nerves palsies have been described in children in the literature, including one case of peripheral facial nerve palsy and one case of velopalatine hemiparalysis. We report the first case of acute ophthalmoparesis associated with PVB19 infection. RESULTS: We present a 40-year-old man with PVB19 with acute sixth cranial nerve palsy, diagnosed on the basis of serology and polymerase chain reaction carried out both on serum and cerebrospinal fluid. CONCLUSIONS: Clinicians should be aware of this possible clinical presentation.

Secondary deterioration of visual field during cabergoline treatment for macroprolactinoma.

OBJECTIVE: During dopaminergic agonist treatment for macroprolactinoma, tumour shrinkage can be accompanied by secondary deterioration of the visual field in rare instances. The aim of the present study was to evaluate the incidence of symptomatic or asymptomatic delayed visual loss associated with chiasmal herniation during long-term cabergoline treatment of macroprolactinomas and to report our experience of its management. PATIENTS: The study included 28 patients (11 women and 17 men) aged 14-85 years treated for macroprolactinoma with cabergoline at our centre from 1997 to 2006. RESULTS: Chiasmal herniation was observed at MRI in five out of the 28 cases. A systematic visual field evaluation revealed visual field worsening, during cabergoline treatment, in three out of these five patients. In two asymptomatic patients, secondary deterioration of visual field occurred 2.5 years and 4 years, respectively, after cabergoline treatment initiation. In the third case, cabergoline treatment resulted in a paradoxical worsening of an initial visual defect. In all three cases, visual fields improved after cabergoline withdrawal although chiasmal herniation persisted. Visual field remained normal in the two other patients. CONCLUSIONS: Our results suggested that chiasmal herniation associated with delayed visual field defect is not a rare feature during cabergoline treatment of macroprolactinomas. It should be assessed by systematic visual field evaluation and treated by adaptation of medical treatment.

Impaired social cognition in mild Alzheimer disease.

Abnormal decoding of social information has been associated with the conversion from prodromal Alzheimer's disease (AD) to dementia. Since the distributed neural networks involved in face processing are differentially affected in prodromal and dementia states of AD and in Fronto-Temporal Dementia (FTD), we hypothesized a differential impairment in face processing in these populations. Facial expression, gender and gaze direction decoding abilities were examined in patients with probable amnesic Mild Cognitive Impairment (aMCI, N=10) fulfilling criteria for prodromal AD, in patients with mild and moderate AD (N=10) as well as in FTD patients (N=10) and in a group of age- and sex-matched healthy comparison subjects (N=10). Gender recognition was preserved in all groups. Compared to controls, patients with mild or moderate AD were impaired in expression recognition and FTD patients were impaired in expression and gaze direction determination, whereas MCI patients were not impaired at all.

A new MRI marker of ataxia with oculomotor apraxia.

PURPOSE: Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA). METHOD: In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied. RESULTS: Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02). CONCLUSION: This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.

A Spatial Decision Eye-Tracking Task in Patients with Prodromal and Mild Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Performances on spatial decision eye-tracking tasks are known to be impaired in patients with moderate Alzheimer's disease (AD), but the clinical relevance of this deficit during earlier stages of AD remains unclear. METHODS: This study recruited patients with amnestic mild cognitive impairment (aMCI, prodromal AD), patients with mild AD, and age-matched controls from three French memory clinics. Participants' ability to make spatial judgments and decisions was assessed with an eye-tracking system, and cognitive performance on conventional neuropsychological tests was evaluated. RESULTS: We enrolled 26 controls, 25 aMCI patients (median Mini-Mental State Exam [MMSE] 26), and 23 mild-AD patients (median MMSE 23). Patients with mild AD had higher error rates on the spatial decision task than aMCI patients and controls (32.4% versus 23.5%; p < 0.01 and 32.4% versus 22.2%; p < 0.05, respectively), but there were no differences among the groups in anticipation rate or the percentage of express saccades. Additionally, error rates on the spatial decision task were inversely correlated with performance on visual memory tests (immediate and delayed recall on the DMS- 48: r =-0.44, p = 0.0019 and r =-0.43, p = 0.0020, respectively), semantic fluency (r =-0.44, p = 0.0016), and global cognition (MMSE: r =-0.44, p = 0.0019). Performance on the spatial decision task was not correlated with anti-saccades, processing speed, or attentional performance. CONCLUSIONS: Patients with mild AD made more errors on a spatial decision task than aMCI patients and controls. We hypothesize that impaired visuospatial judgment may explain these results and distinguish aMCI patients from mild AD patients.

Pheochromocytoma, paragangliomas, and pituitary adenoma: An unusual association in a patient with an SDHD mutation. Case report.

RATIONALE: Pituitary adenomas and paragangliomas are both rare endocrine diseases. Paragangliomas (PGL)/pheochromocytomas (PHEO) are part of an inherited syndrome in about 30% to 40% of cases. Among familial cases, mutations of the succinate dehydrogenase (SDH) subunit genes (succinate dehydrogenase subunit [SDH]B, SDHC, SDHD, succinate dehydrogenase subunit AF2 [SDHAF2] , and SDHA) are the most common cause. PATIENT CONCERNS: We here report a 31-year-old patient with a known SDHD mutation whose disease has been revealed by a left PHEO during childhood and who presented at age 29 years a large paraganglioma of the right jugular foramen, a concomitant PHEO of the left adrenal and 2 retroperitoneal paragangliomas. A pituitary incidentaloma was found during investigations on a fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET). DIAGNOSIS: A pituitary magnetic resonance imaging (MRI) confirmed the presence of a 14 mm pituitary macroadenoma. The pituitary function was normal except for hypogonadotropic hypogonadism. On examination of the fundus, a diagnosis of Pseudo Foster-Kennedy syndrome was made due to a venous compression of the right jugular vein caused by the paraganglioma (PGL). The pituitary adenoma was not compressive to the optic chiasm. INTERVENTIONS: A treatment with acetazolamide was started in order to improve intracranial hypertension. The patient couldn't benefit of a surgical approach for the paraganglioma of the right jugular foramen; the patient has been treated with stereotactic radiosurgery (Gamma Knife). OUTCOMES: The most recent MRI revealed that the right jugular foramen PGL is stable and the latest visual assessment demonstrated stability despite a recent reduction in acetazolamide dosage. A surveillance by MRI of the pituitary adenoma has been planned. LESSONS: The association of a pituitary adenoma to paragangliomas within a same patient is very uncommon and raises the question of related physiopathological mechanisms.

Early amygdala reaction to fear spreading in occipital, temporal, and frontal cortex: a depth electrode ERP study in human.

The amygdala involvement in fear processing has been reported in behavioral, electrophysiological, and functional imaging studies. However, the literature does not provide precise data on the temporal course of facial emotional processing. Intracranial event-related potentials to facial expressions were recorded in epileptic patients implanted with depth electrodes during a presurgical evaluation. Specific potentials to fear beginning 200 ms poststimulus were observed in amygdala, both individually in two patients and in a ten patient population study. These potentials occurred 100 ms earlier than potentials to disgust recorded in insula in a previous study. Potentials to fear were confined in amygdala during a first transient period and then, during a second period of sustained activity, spread to occipito-temporal, anterior temporal, and orbitofrontal cortex in two patients. This study clarifies the temporal course of the involvement of these structures known to be part of a neural network recruited to process emotional information.

Saccade control and eye-hand coordination in optic ataxia.

The aim of this work was to investigate ocular control in patients with optic ataxia (OA). Following a lesion in the posterior parietal cortex (PPC), these patients exhibit a deficit for fast visuo-motor control of reach-to-grasp movements. Here, we assessed the fast visuo-motor control of saccades as well as spontaneous eye-hand coordination in two bilateral OA patients and five neurologically intact controls in an ecological "look and point" paradigm. To test fast saccadic control, trials with unexpected target-jumps synchronised with saccade onset were randomly intermixed with stationary target trials. Results confirmed that control subjects achieved visual capture (foveation) of the displaced targets with the same timing as stationary targets (fast saccadic control) and began their hand movement systematically at the end of the primary saccade. In contrast, the two bilateral OA patients exhibited a delayed visual capture, especially of displaced targets, resulting from an impairment of fast saccadic control. They also exhibited a peculiar eye-hand coordination pattern, spontaneously delaying their hand movement onset until the execution of a final corrective saccade, which allowed target foveation. To test whether this pathological behaviour results from a delay in updating visual target location, we had subjects perform a second experiment in the same control subjects in which the target-jump was synchronised with saccade offset. With less time for target location updating, the control subjects exhibited the same lack of fast saccadic control as the OA patients. We propose that OA corresponds to an impairment of fast updating of target location, therefore affecting both eye and hand movements.