Björn Machner

Vergence deficits in patients with cerebellar lesions.

The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence (to ramp and sinusoidal targets). The aim of this study was to investigate whether circumscribed cerebellar lesions affect these dynamic vergence eye movements. Disconjugate fast and slow vergence, conjugate smooth pursuit and saccades were binocularly recorded by a scleral search coil system in 20 patients with acute cerebellar lesions (all ischemic strokes except for one) and 20 age-matched healthy controls. Patients showed impairment of slow vergence while fast vergence was unaffected. Slow vergence gain to sinusoidal targets was significantly reduced, both in convergence and divergence direction. Divergence but not convergence velocity to ramp targets was reduced. Conjugate smooth pursuit eye movements to sinusoidal and to step-ramp targets were impaired. Patients had saccadic hypometria. All defects were particularly expressed in patients with vermis lesions. In contrast to recent animal data fast vergence was not impaired in any of our patient subgroups. We conclude that (i) the human cerebellum, in particular the vermis, is involved in the processing of dynamic vergence eye movements and (ii) cerebellar lesions elicit dissociable effects on fast and slow vergence.

Structural Changes in the Human Brain following Vestibular Neuritis Indicate Central Vestibular Compensation

Vestibular neuritis (VN) is a sudden unilateral vestibular failure (UVF) with a variable course. Caloric hyporesponsiveness often persists, and it is largely unknown why patients with the same degree of hyporesponsiveness show different functional recovery. As the peripheral vestibular deficit alone does not seem to determine functional recovery, it was the aim of this study to elucidate whether structural (morphological) brain changes (1) contribute to central vestibular compensation, and (2) account for the variability of clinical recovery in VN. Structural global gray‐matter volume (GMV) changes in 15 VN patients were compared with age‐matched controls. Morphometric changes in multisensory vestibular cortices, which may be related to functional disability scores, were hypothesized. Patients were examined with neuro‐otological tests and clinical scores to assess vestibular disability. Using voxel‐based morphometry (VBM, SPM2), categorical comparison revealed GMV increase in patients’ multisensory vestibular cortices [insula, inferior parietal lobe (IPL), superior temporal gyrus (STG)], cerebellum, and motion‐sensitive areas in the middle temporal area (MT). GMV decrease was found in the midline pontomedullary junction. Simple regression analysis revealed (1) GMV increase in insula and retroinsular vestibular cortex and STG with improving clinically assessed vestibular deficits, and (2) GMV increase in insula vestibular cortex and STG with improving self‐assessed vestibular impairment. For the first time, these data suggest structural cortical plasticity in multisensory vestibular‐cortex areas in VN that are related to clinical vestibular function and vertigo. As increase of GMV was related to an improvement of vestibular function, structural alterations may be related to central vestibular compensation.

Central representation of cold-evoked pain relief in capsaicin induced pain: an event-related fMRI study.

Abstract The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin‐elicited heat‐hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. We compared intraindividual neural responses of 15 healthy male volunteers to cold (20, 0 °C), intermediate (30 °C) and heat stimuli (43 °C) on untreated vs. capsaicin‐treated skin using event‐related fMRI in a 2 × 4 factorial design. Thermal stimuli were applied at the right hand in two separate imaging sessions using a Peltier‐element. Psychophysical ratings of the perceived valence and intensity (VAS: 1–100) were obtained after each stimulus. The 43 °C‐stimulus was perceived as excessively painful on capsaicin‐treated skin as opposed to an unpleasant sensation on normal skin. In contrast, the 0 °C‐stimulus was perceived unpleasant when applied on untreated skin while subjects rated the same stimulus pleasant in the capsaicin‐treated condition. When neural responses to the 0 °C‐stimulus were compared between the untreated and capsaicin‐treated skin condition there were stronger BOLD‐responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold‐dependent contributions of PFC activity with PAG in heat‐hyperalgesia we propose that cold‐induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive‐appetitive motivational states.

Visual Search Disorders in Acute and Chronic Homonymous Hemianopia: Lesion Effects and Adaptive Strategies

Patients with homonymous hemianopia due to occipital brain lesions show disorders of visual search. In everyday life this leads to difficulties in reading and spatial orientation. It is a matter of debate whether these disorders are due to the brain lesion or rather reflect compensatory eye movement strategies developing over time. For the first time, eye movements of acute hemianopic patients (n= 9) were recorded during the first days following stroke while they performed an exploratory visual‐search task. Compared to age‐matched control subjects their search duration was prolonged due to increased fixations and refixations, that is, repeated scanning of previously searched locations. Saccadic amplitudes were smaller in patients. Right hemianopic patients were more impaired than left hemianopic patients. The number of fixations and refixations did not differ significantly between both hemifields in the patients. Follow‐up of one patient revealed changes of visual search over 18 months. By using more structured scanpaths with fewer saccades his search duration decreased. Furthermore, he developed a more efficient eye‐movement strategy by making larger but less frequent saccades toward his blind side. In summary, visual‐search behavior of acute hemianopic patients differs from healthy control subjects and from chronic hemianopic patients. We conclude that abnormal visual search in acute hemianopic patients is related to the brain lesion. We provide some evidence for adaptive eye‐movement strategies developed over time. These adaptive strategies make the visual search more efficient and may help to compensate for the persisting visual‐field loss.

How reliable is repeated testing for hemispatial neglect? Implications for clinical follow-up and treatment trials

Patients with hemispatial neglect following right hemisphere brain damage fail to spontaneously orient towards or respond to contralesional stimuli.1 The diagnosis and longitudinal assessment of the syndrome is not always straightforward. This is mainly due to two reasons: the heterogeneity of the syndrome and inter-individual differences in the time course of recovery from the disorder. The neglect syndrome affects various cognitive components across patients, and one patient may show neglect on certain tasks but not on others.1 ,2 Because there is no single test able to detect neglect in all patients, a battery of several paper-and-pencil tests is usually required.1 ,3 However, little is known about their use as a tool for longitudinal assessments. This is of high clinical importance as repeat assessments are necessary to monitor changes in neglect severity related to spontaneous remission or a specific treatment. If a test per se is not ‘stable’, the variation in test results over repeated sessions may simply reflect low test–retest reliability and not the actual change of the underlying disorder. We therefore investigated the test–retest reliability of three …

Acute hemianopic patients do not show a contralesional deviation in the line bisection task.

JO N 3148 control subjects. Our objectives were twofold: (i) if adaptive attentional mechanisms are responsible for the LBE in hemianopic patients it may be absent in their acute stage, and if so (ii) is the line bisection task a reliable bedside tool to distinguish hemianopia from hemineglect in the acute stage of stroke? All participants (n = 21) gave their informed written consent according to the Declaration of Helsinki. Mean age (years/±SD) did not differ significantly between healthy control subjects (controls, n = 8, 56.6 ± 18.9), left hemianopic patients (LH, n = 5, 61.0 ± 10.4), right hemianopic patients (RH, n = 4, 58.0 ± 20.1) and patients with left spatial neglect (n = 4, 60.5 ± 11.3). Acute (< 1 month) unilateral stroke was confirmed by MRI. The hemianopic visual field defects, complete and incomplete, respectively, were assessed using the manual Goldmann perimeter (Table 1). Ophthalmological examination revealed corrected visual Bjorn Machner Andreas Sprenger Urban Hansen Wolfgang Heide Christoph Helmchen

Intralabyrinthine schwannoma affecting the low but not high frequency function of the vestibulo-ocular reflex: implications for the clinical diagnosis of chronic peripheral vestibular deficits.

Peripheral vestibular hypofunction can be identified by asymmetric vestibular responses to caloric irrigation of the horizontal semicircular canal or by the head impulse test.1 Whereas the first test investigates the low frequency function of the vestibulo-ocular reflex (VOR) the latter assesses the high frequency function. The high frequency VOR function is usually more persistently impaired in unilateral vestibular lesions (eg, vestibular neuritis) than the low frequency function and thus the more sensitive parameter to detect chronic peripheral vestibular deficits.2 Contrary to this current vestibular knowledge, we present a patient with a chronic peripheral vestibular deficit showing normal high frequency but impaired low frequency VOR function. This unusual lesion pattern was caused by an intralabyrinthine schwannoma. A 47-year-old patient presented with a 3 month history of repetitive episodes of vertigo, nausea and lateropulsion to his right side. The first episode lasted 1.5 h followed by short lasting (seconds to 15 min) episodes once a day. The patient reported a similar episode of vertigo 1 year previously, at that time associated with an acute hearing loss on the right side and persisting tinnitus ever since. Apart from moderate right sided hypacusis, neurological examination was normal in the asymptomatic stages during follow-up examinations over the next 2 years. Particularly, there was no spontaneous or head shaking nystagmus and no gaze evoked nystagmus. After written …

Randomized Controlled Trial on Hemifield Eye Patching and Optokinetic Stimulation in Acute Spatial Neglect

Background and Purpose— Right hemisphere stroke patients frequently experience spatial neglect, a severe lack of awareness for contralesional hemispace. Although neglect counts among the strongest predictors for poor functional outcome after stroke, there is no established therapy, particularly not for the acute stage. Methods— In a randomized controlled trial, we compared the combined treatment of hemifield eye patching and repetitive optokinetic stimulation in acute stroke patients with neglect to the spontaneous course. Outcome measures were a neuropsychological test battery for neglect as well as scales of functional independence and clinical impairment. Outcomes were assessed at baseline (day 1), post treatment (day 8), and at 1-month follow-up (day 30). Results— Final analysis included 21 acute right hemisphere stroke patients with neglect (23 enrolled, 2 lost to follow-up) allocated either to the treatment (1 week hemifield eye patching and daily sessions of optokinetic stimulation, n=11) or the control group (no neglect-specific treatment, n=10). At baseline, both groups did not differ in neuropsychological test performance, clinical impairment, or functional disability. At the post treatment session, both groups had improved in all these measures, and results were stable or further improved at follow-up. However, there was no significant difference in this change between the treatment and the control group. Conclusions— An early intervention of combined hemifield eye patching and optokinetic stimulation in acute stroke patients with spatial neglect has no additive effect to the spontaneous remitting course of the disorder. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01617343.

Pseudotumor cerebri as a reversible side effect of all-trans retinoic acid treatment in acute promyelocytic leukaemia.

Headache and bilateral papilloedema in overweight young woman may be indicative of pseudotumor cerebri syndrome (PTC). Idiopathic intracranial hypertension (IIH) refers to the PTC, provided that there are no symptomatic causes for elevated intracranial pressure. Such causes may be tumours, meningeal infiltration and cerebral venous sinus thrombosis as well as the use of certain medications including tetracycline, growth hormone or lithium [1]. Other drugs which have been linked to PTC are vitamin A derivatives such as isotretinoin for acne treatment and all-trans-retinoic acid (ATRA) which is successfully administered to treat acute promyelocytic leukaemia (APL) [1,2]. ATRA-induced PTC has been described by oncologists in several patients with APL, predominantly children and adolescents [3,4] as well as some adults [5]. In contrast to previous reports, in which treatment was discontinued once PTC had been diagnosed, we describe the clinical course with continuous medication using neurological and ophthalmological monitoring in a patient with APL who developed PTC during treatment with ATRA. Finally, we will discuss a pathophysiological link between vitamin A and PTC. A 20-year-old woman (J.E.) was admitted because of multiple spontaneous bruises. On examination, there were extensive subcutaneoushaematomasandobesity (112 kg body weight). Blood tests, bone marrow biopsy, karyotypic analysis and molecular biology were compatible with APL. Treatment was started with ATRA (45 mg/m once a day) and idarubicin [2]. After 2 weeks the patient developed holocephalic headaches, which neither responded to change of body position nor to analgetics. Three days later, she noticed progressive blurring of vision on the right eye. Ophthalmologic examination revealed bilateral papilloedema and preand intraretinal haemorrhages adjacent to the optic disc (Fig. 1a, right eye). Visual acuity was normal. Perimetry revealed an enlarged blind spot bilaterally corresponding to the pathology of the disc margins. Neurological examination was normal. Brain magnetic resonance imaging including venous angiography was normal. Cerebrospinal fluid (CSF)-opening pressure was 500 mm H2O in lateral decubitus position and 40 ml of CSF were removed. CSF analysis showed no abnormalities. Drug-induced pseudotumor cerebri was diagnosed, as signs and symptoms of increased intracranial pressure met the diagnostic criteria including no evidence of hydrocephalus, mass, structural or vascular lesion on our patient s MRI brain scan [1]. Immediately after lumbar puncture, headaches improved but persisted on a low level. Symptomatic therapy with acetazolamide (1000 mg/day) was started while ATRA therapy was interrupted, thereupon headaches improved again. As the patient had not yet reached complete remission, ATRA therapy was decided to be resumed after 2 days. Headaches remained stable on a low level and visual acuity was always full. Hence, lumbar puncture was not repeated. Following another 2 weeks under regular monitoring of visual acuity and fundoscopy (Fig. 1b), complete remission was achieved as assessed by blood tests and bone marrow investigations. Finally, headaches disappeared rapidly within 1 day after ATRA therapy had been

Eye movement disorders are different in Parkin-linked and idiopathic early-onset PD.

Objectives: Parkin gene mutations are the most common cause of early-onset parkinsonism. Patients with Parkin mutations may be clinically indistinguishable from patients with idiopathic early-onset Parkinson disease (EOPD) without Parkin mutations. Eye movement disorders have been shown to differentiate parkinsonian syndromes, but have never been systematically studied in Parkin mutation carriers. Methods: Eye movements were recorded in symptomatic (n = 9) and asymptomatic Parkin mutation carriers (n = 13), patients with idiopathic EOPD (n = 14), and age-matched control subjects (n = 27) during established oculomotor tasks. Results: Both patients with EOPD and symptomatic Parkin mutation carriers showed hypometric prosaccades toward visual stimuli, as well as deficits in suppressing reflexive saccades toward unintended targets (antisaccade task). When directing gaze toward memorized target positions, patients with EOPD exhibited hypometric saccades, whereas symptomatic Parkin mutation carriers showed normal saccades. In contrast to patients with EOPD, the symptomatic Parkin mutation carriers showed impaired tracking of a moving target (reduced smooth pursuit gain). The asymptomatic Parkin mutation carriers did not differ from healthy control subjects in any of the tasks. Conclusions: Although clinically similarly affected, symptomatic Parkin mutation carriers and patients with idiopathic EOPD differed in several oculomotor tasks. This finding may point to distinct anatomic structures underlying either condition: dysfunctions of cortical areas involved in smooth pursuit (V5, frontal eye field) in Parkin-linked parkinsonism vs greater impairment of basal ganglia circuits in idiopathic Parkinson disease.