Influence of postural constraints on eye and head latency during voluntary rotations.

Redirecting gaze towards new targets often requires not only eye movements, but also synergistic rotations of the head, trunk and feet. This study investigates the influence of postural constraints on eye and head latency during voluntary refixations in the horizontal plane in 14 normal subjects. Three postural conditions were presented, (1) sitting in a chair using only eye and head movements, (2) standing without feet movements and (3) standing with feet movement. Head-eye reorientations towards eccentric un-predictable locations were performed towards ±45° and ±90° targets and back towards a central, spatially predictable target. Results showed that postural constraints affected eye latency but only when subjects knew the future location of the target (recentering "return" trials). Specifically, relatively longer eye latencies were observed when subjects had to turn their feet back towards the predictable central target. These findings suggest that the additional CNS processing required to reduce degrees of freedom during predictive motion introduces delays to the eye movement in order to efficiently assemble the components of a new motor synergy.

Tremor-related motor unit firing in Parkinson's disease: implications for tremor genesis.

Muscle tremors reflect rhythmical motor unit (MU) activities. Therefore, the MU firing patterns and synchrony determine the properties of the parkinsonian force tremor (FT) and the neurogenic components of associated limb tremors. They may also be indicative of the neural mechanisms of tremor genesis which to date remain uncertain. We examined these MU behaviours during isometric contractions of a finger muscle in 19 parkinsonian subjects. Our results reveal that the parkinsonian FT is abnormally large. Like the physiological FT, it is accompanied by in-phase rhythms in all MU activities. However, there exist two important differences. Firstly, the synchrony during the parkinsonian FT is stronger than the normal one and therefore contributes to the FT enhancement. Secondly, the synchronous MU components partly represent rhythmical sequences of spike doublets and triplets whose incidences directly reflect the differences of the MU firing rates to the FT frequency. According to our analyses, the latter frequency coincides with the MU recruitment rate. Consequently, the numerous medium- and small-sized active MUs contribute rhythmical twitch doublets and triplets, i.e. large force pulses, to the parkinsonian FT. The impact of this effect on the FT amplitude is found to predominate over the impact of the augmented synchrony. Importantly, apart from the rule governing the occurrence of doublets/triplets, the mean interspike intervals within such spike events are fairly fixed around 50 ms. Such regularities in MU activities may reflect properties of the neural input underlying the FT, and thus represent a basis for more focused studies of the generator(s) of parkinsonian tremors.

Foot rotation contribution to trunk and gaze stability during whole-body mediated gaze shifts: a principal component analysis study.

Large gaze displacements are mediated by combined motion of the eye, head, trunk, and foot. We applied principal component analysis (PCA) to examine the degree of variability and linearity in the angular velocity pattern of the various segments involved that participate in this task. Ten normal subjects stood up and had to visually fixate and realign their bodies with LED targets separated 45 degrees apart, ranging from +/-45 to 360 degrees. The outbound movement in this paradigm is unpredictable whereas the return (inbound) movement occurs under spatially predictable conditions. Under such predictable conditions, subjects generate in approximately 15% of the trials gaze shifts, with periods of fairly constant high gaze velocity (single-step gaze shifts). PCA showed that gaze velocity variability did not change if the feet were rotating or not. Foot velocity was variable and showed additional PCs suggestive of non-linear motion components. Trunk and head-in-space velocity showed intermediate levels of variability but its variability decreased during the foot stepping movements. The results suggest that the feet, trunk, and head are less tightly controlled by the central nervous system than gaze velocity. Movements of the feet seem to aid trunk stability and motion rather than gaze control.

A minute demyelinating lesion causing acute positional vertigo.

Clinico-anatomical correlations in multiple sclerosis patients presenting with central positional vertigo are lacking. We report on a patient with acute onset positional vertigo mimicking benign paroxysmal positional vertigo with a single enhancing lesion in the inner part of the superior cerebellar peduncle, disclosed only after thin slice MR-imaging. This location appears to be a common cause of central positional vertigo and should be regarded as characteristic for demyelinating rather than vascular pathology. In cases presenting with positional nystagmus and vertigo without other cerebellar deficits one should look explicitly for signal abnormalities in the inner part of the superior cerebellar peduncle. High spatial resolution-MRI seems to be mandatory for lesion detection.

[The concept of time and its relation to the psychoanalytic-psychotherapeutic setting].

Psychoanalysis is fundamentally related to time because it is an ef for t to understand how disturbances in the present are determined by events in the past. This paper represents an attempt to delineate the developmental line of time sense from birth to object constancy, concentrating on those maturational and environmental factors which determine psychotemporal adaptation in infancy and early childhood until the age of adolescence. Patients' distortions of time can frequently and readily be observed in clinical psychoanalysis reflecting both their psychopathology and their reactions to the temporal aspects of the psychoanalytic setting.

[Benign paroxysmal positional vertigo with and without manifest positional nystagmus: an 18-month follow-up study of 70 patients]. / Benigner paroxysmaler Lagerungsschwindel mit und ohne manifesten Lagerungsnystagmus: Achtzehnmonatige Verlaufsbeobachtung von 70 Patienten.

BACKGROUND: In this follow-up study of approximately 18 months we assessed parameters of medical management in a sample of 70 patients suffering from benign paroxysmal positional vertigo. METHODS: Apart from demographic data, we evaluated the time interval from the appearance of the first symptoms until a diagnostic positional manoeuvre was performed, the efficacy of liberatory manoeuvres, the prescription of medication, the use of technical diagnostic resources and the relapse rate. RESULTS: None of the patients had received a diagnostic positioning test until then. Moreover, in one out of three cases a further unnecessary technical diagnostic procedure was carried out. There was a tendency for the right labyrinth to be more frequently affected, a fact that was statistically independent from age and sex, as well as from overall prognosis, which was characterized by a 15.6% recurrence rate. All patients with manifest positional nystagmus were successfully treated: 87.2% immediately after the repositioning manoeuvre and the rest within 10 days by self-performing Brandt-Daroff exercises. Our retrospective analysis revealed that, given a normal neuro-otological examination, a typical medical history without manifest positioning nystagmus leads safely to the correct diagnosis. CONCLUSION: The delay between the onset of symptoms and the diagnosis of BPPV is very often unduly long. A focused medical history may be diagnostic even in the absence of nystagmus during the Dix-Hallpike manoeuvre.

Positional nystagmus and vertigo due to a solitary brachium conjunctivum plaque.

The authors describe two patients suffering from demyelinating central nervous system disease who developed intense vertigo and downbeat nystagmus upon tilting their heads relative to gravity. Brain MRI revealed in both cases a single, small active lesion in the right brachium conjunctivum. The disruption of otolithic signals carried in brachium conjunctivum fibres connecting the fastigial nucleus with the vestibular nuclei is thought to be causatively involved, in agreement with a recently formulated model simulating central positional nystagmus. Insufficient otolithic information results in erroneous adjustment of the Listing's plane in off-vertical head positions, thus producing nystagmic eye movements.

Smooth pursuit rather than visual signals mediate short-term adaptation of the cervico-ocular reflex in humans.

Cervical stimulation in the horizontal plane induces small and variable eye movements in normal human adults [cervico-ocular reflex (COR)]. In patients with bilateral vestibular loss, the slow COR component increases in amplitude and is thought to contribute to gaze stabilization during head movements, as it is directed opposite to head-on-trunk excursions. The procedures underlying COR slow phase gain enhancement in the compensatory direction remain unclear. We studied the horizontal COR during passive trunk oscillations of +/-16 degrees under the stationary head at 0.1 Hz in ten normal subjects, aged 24-30 years, before and immediately after the application of an adaptation procedure engaging various combinations of sinusoidal neck-proprioceptive, pursuit and retinal slip signals. The duration of this adaptation period was 40 min. A significant gain increase and phase modulation in the compensatory direction were observed in four out of eight subjects after exposing them to neck-proprioceptive stimulation, while pursuing a spot moving in-phase with their trunk. In contrast, staring at the rotating optokinetic pattern or fixating at a stationary spot, while being subjected to combined cervical and optokinetic stimulation, failed to result in any significant modification of the subjects' COR gain and phase. Conceivably, the contribution of the pursuit system was greatly reduced in the paradigm using optokinetic stimulation, while full engagement of retinal slip signals, in the absence of any pursuit contribution, was obtained in the latter adaptation paradigm. These results indicate that motor responses of target tracking rather than simply sensory signals of retinal slip may represent the 'error signal' modifying the COR in humans.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset inherited disease, characterised by recurrent strokes, migraine and cognitive impairment. We present the first Greek family with CADASIL, caused by the R153C mutation at exon 4 of the Notch3 gene. A member of this family carrying this mutation was also found to be heterozygotic for the MTHFR mutation, factor V Leiden mutation and had low serum levels of antithrombin III, thus resulting in the appearance of recurrent strokes and thrombotic episodes since his early adulthood. The co-existence of these thrombophilic disorders with CADASIL in a single person poses serious therapeutic dilemmas, as the administration of anticoagulant agents may correlate with increased risk of potentially fatal intracerebral haemorrhage.

Guillain-Barré syndrome in a patient with metastatic colon cancer receiving oxaliplatin-based chemotherapy.

We report Guillain-Barre syndrome (GBS), developed in a patient with metastatic colon cancer, receiving oxaliplatin-based chemotherapy. The 53-year-old patient was treated with first-line chemotherapy consisting of oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day in a weekly schedule. After 13 weeks of treatment and a cumulative oxaliplatin dose of 585 mg/m2, the patient developed unsteadiness of gait, dysphagia, and weakness of both the upper and lower limbs, as well as impairment of all sensory modalities. Clinical examination, computed tomography and magnetic resonance imaging scans of the brain, blood tests, nerve conduction studies, and cerebrospinal fluid analysis confirmed the diagnosis of GBS. Intravenous immunoglobulin G was administered for 5 days and the patient recovered fully. Oxaliplatin can cause acute and delayed neurotoxicity, but this is the first report of GBS in a patient receiving oxaliplatin-based chemotherapy. Elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin, may represent the relevant causal links involved in the cascade of events which have led to the immune-mediated demyelination in the peripheral nervous system in this patient.

Eye position signals modify vestibulo- and cervico-ocular fast phases during passive yaw rotations in humans.

We studied the amplitude, latency, and probability of occurrence of fast phases (FP) in darkness to unpredictable vestibular and/or cervical yaw stimulation in normal human subjects. The rotational stimuli were smoothed trapezoidal motion transients of 14 degrees amplitude and 1.25 s duration. Eye position before stimulus application (initial eye position, IEP) was introduced as a variable by asking the subjects to fixate a spot appearing either straight ahead or at 7 degrees eccentric positions. The recordings demonstrated that the generation of FP during vestibular stimulation was facilitated when the whole-body rotation was directed opposite the eccentric IEP. Conversely, FP were attenuated if the whole-body rotation was directed toward the eccentric IEP; i.e., the FP attenuated if they were made to further eccentric positions. Cervical stimulation-induced FP were small and variable in direction when IEP was directed straight ahead before stimulus onset. Eccentric IEPs resulted in large FP, the direction of which was essentially independent of the neck-proprioceptive stimulus. They tended to move the eye toward the primary position, both when the trunk motion under the stationary head was directed toward or away from the IEP. FP dependence on IEP was evident also during head-on-trunk rotations. No consistent interaction between vestibularly and cervically induced FP was found. We conclude that extraretinal eye position signals are able to modify vestibularly evoked reflexive FP in darkness, aiming at minimizing excursions of the eyes away from the primary position. However, neck-induced FP do not relate to specific tasks of stabilization or visual search. By keeping the eyes near the primary position, FP may permit flexibility of orienting responses to incoming stimuli. This recentering bias for both vestibularly and cervically generated FP may represent a visuomotor optimizing strategy.

Proprioceptive influence on the optokinetic nystagmus.

The influence of neck and leg proprioceptive inputs on optokinetic-induced quick phases was studied in humans. Ten subjects received unidirectional horizontal optokinetic stimulation (10-20%/s) during sinusoidal neck, leg and combined neck + leg proprioceptive stimulation. The optokinetic reflex was measured by electro-oculography. Neck stimulation induced a shift in the nystagmus beating field in the opposite direction to body movement (gain 0.3 0.4, phase 140-180 degrees). The beating field shift resulted totally from the amplitude and frequency modulation of optokinetic quick phases, as slow phases were not affected. Leg proprioceptive stimulation induced a similar effect, but the phase of the response lagged by approximately 90 degrees compared with that of neck response. With combined neck + leg stimulation, the amplitude of the effect was a sum of the separate effects, but the phase coincided with that of the leg response. This suggests that neck and leg proprioceptive signals do not add linearly and that the leg signal determines the time of the response.

A patient with essential thrombocytosis and multiple sclerosis.

We report on a patient with a 5-year history of essential thrombocytosis (ET) who developed multiple sclerosis (MS) during the last 5 months. The patient was treated for MS with interferon-beta (IFN-beta), which also had a beneficial effect on the ET. We describe the patient's history and the beneficial effect of IFN-beta administration in reducing the number of platelets. We also discuss the possible link between the pathogenesis of ET and MS.

Weekly docetaxel in minimally pretreated cancer patients: a dose-escalation study focused on feasibility and cumulative toxicity of long-term administration.

BACKGROUND: Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity. PATIENTS AND METHODS: Twenty-six patients (11 female/15 male, median age 56, range 23-73) were treated over the range of 25-50 mg/m2/week. Dose-limiting toxicity for this schedule was defined as any grade > 2 antiproliferative toxic effect resulting in a > 2-week delay for re-administration of the drug, or any grade > 2 organ-specific toxicity. Patients were monitored clinically and electrophysiologically for neurotoxicity. No prolonged corticosteroid co-medication or prophylactic haematopoietic growth factors were given. RESULTS: A median/mean number of 8.5/8.7 consecutive weekly courses were given per patient. The maximum tolerated dose that prevented on-schedule administration of the drug was 50 mg/m2. The main cumulative toxicities were a mild fluid retention and dacryorrhea which became evident as the number of treatment courses increased. Grade 2 alopecia and fatigue were observed only at 45 mg/m2 and higher. Activity was seen at all of the dose levels studied. CONCLUSIONS: Long-term weekly administration of docetaxel is feasible at doses up to 45 mg/m2/week with acceptable toxicity. Further clinical evaluation is justified at this schedule and 40 mg/m2/week of docetaxel is proposed for phase II studies as an active dose with minimal toxicity.

A case of thalamic syndrome: somatosensory influences on visual orientation.

The ability to set a straight line to the perceived gravitational vertical (subjective visual vertical, SVV) was investigated in a 21 year old woman with long standing left hemihypaesthesia due to a posterior thalamic infarct. The putative structures involved were the somatosensory and vestibular thalamus (VPL, VPM) and associative (pulvinar) thalamus. The SVV was normal when seated upright. When lying on her right side, line settings deviated about 17 degrees to the right, which is the normal A-effect. When lying on the hypaesthetic side the mean SVV remained close to true vertical-that is, the A-effect was absent, and there was a large increase in variability of the SVV settings. The findings support the view that the body tilt-induced bias of the SVV (A-effect) is largely mediated by somatosensory afferents. The finding that the A-effect was absent only when lying on the hypaesthetic side suggests that, during body tilt, the somatosensory system participates in visuogravitational orientation.

Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.

Smooth pursuit eye movements and otolith-ocular responses are differently impaired in cerebellar ataxia.

Horizontal and vertical smooth pursuit was compared with otolith-ocular responses in 11 patients with cerebellar ataxia and 21 normal subjects using three-dimensional magnetic search coil eye movement recordings. Otolith-ocular responses were investigated during off-vertical axis rotation. This stimulus induces nystagmus consisting of the exponentially decaying canalicular response, and an eye-velocity modulation and offset which arise from the excitation of the otoliths by the gravity vector, which lasts as long as the rotation continues. Otolith-ocular reflexes are intimately interrelated with visual tracking when real targets are viewed during linear motion. The responses of both the translational vestibulo-ocular reflex and the pursuit system have been shown to be linearly dependent on the inverse of the viewing distance, so that a common central pathway for the two systems has been suggested, probably travelling through the cerebellum. Thus, the aim of the study was to evaluate to what extent these reflexes are disturbed in cerebellar disease. The results confirm the earlier notion that in normal subjects pursuit performance is better for horizontal than for vertical tracking, and that it is better for upward than for downward tracking. This pattern is also found in patients. In addition, smooth pursuit performance is clearly degraded in patients, but the modulation of eye-velocity during off-vertical axis rotation is enhanced. Since the amount of this enhancement does not correlate with the amount of pursuit impairment, degradation of smooth pursuit and pathological enhancement of otolith-ocular responses seem to be independent effects of cerebellar degeneration. Thus, the increase in the otolith-ocular response in patients cannot be attributed to adaptational mechanisms trying to overcome the smooth pursuit deficiency; it is more likely to represent pathological disinhibition of otolith derived responses. The absence of compensatory eye-velocity offset during off-vertical axis rotation may reflect the fact that in patients the otolith signals are not utilized in computations thought to be important for spatial orientation mechanisms arising from the interaction of vestibular, visual and somatosensory signals.

Vestibular memory-contingent saccades involve somatosensory input from the body support.

Humans use vestibular head-in-space information when redirecting gaze towards remembered target location in space. This study shows that neck input is also involved. Normal subjects performed saccades towards remembered locations in space of a previously seen target following passive horizontal rotations of the head or trunk. Saccades based on vestibular input alone fell short at low stimulus frequencies. Addition of neck input modified the responses, making them more accurate when the head was rotated on the stationary trunk. The results support a concept according to which vestibular input is channeled via proprioceptive coordinate transformations through the haptically perceived body support before yielding a sense of head motion in space. The loop is also involved in the saccadic gaze mechanism.

Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra.

Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n = 12) or globus pallidus (GP, n = 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation.