Acute fluid ingestion in the treatment of orthostatic intolerance - important implications for daily practice.

BACKGROUND: Rapid water ingestion improves orthostatic intolerance (OI) in multiple system atrophy (MSA) and postural tachycardia syndrome (PoTS). We compared haemodynamic changes after water and clear soup intake, the latter being a common treatment strategy for OI in daily practice. METHODS: Seven MSA and seven PoTS patients underwent head-up tilt (HUT) without fluid intake and 30 min after drinking 450 ml of water and clear soup, respectively. All patients suffered from moderate to severe OI because of neurogenic orthostatic hypotension (OH) and excessive orthostatic heart rate (HR) increase, respectively. Beat-to-beat cardiovascular indices were measured non-invasively. RESULTS: In MSA, HUT had to be terminated prematurely in 2/7 patients after water, but in 6/7 after clear soup. At 3 min of HUT, there was an increase in blood pressure of 15.7(8.2)/8.3(2.3) mmHg after water, but a decrease of 11.6(18.9)/8.1(9.2) mmHg after clear soup (P < 0.05). In PoTS, HUT could always be completed for 10 min, but OI subjectively improved after both water and clear soup. The attenuation of excessive orthostatic HR increase did not differ significantly after water and clear soup drinking. CONCLUSIONS: In MSA, clear soup cannot substitute water for eliciting a pressor effect, but even worsens OI after rapid ingestion. In PoTS, acute water and clear soup intake both result in improvement of OI. These findings cannot solely be explained by difference in osmolarity but may reflect some degree of superimposed postprandial hypotension in widespread autonomic failure in MSA compared to the mild and limited autonomic dysfunction in PoTS.

Effects of ventral intermediate nucleus deep brain stimulation across multiple effectors in essential tremor.

OBJECTIVE: Essential tremor (ET) prominently affects the upper-limbs during voluntary movements, but can also affect the lower-limbs, head, and chin. Although deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of thalamus improves both clinical ratings and quantitative measures of tremor, no study has quantified effects of DBS on tremor across multiple body parts. Our objective was to quantify therapeutic effects of DBS across multiple body parts in ET. METHODS: We performed quantitative assessment of tremor in ET patients who had DBS for at least one year. We assessed tremor on and off VIM-stimulation using triaxial accelerometers on the upper-limbs, lower-limbs, head and chin during seated and standing tasks. RESULTS: VIM-DBS significantly reduced tremor, but there was no statistical difference in degree of tremor reduction across the measured effectors. Compared to healthy controls, ET patients treated with DBS showed significantly greater tremor power (4-8 Hz) across all effectors during seated and standing tasks. CONCLUSIONS: VIM-DBS reduced tremor in ET patients. There was no significant difference in the degree of tremor reduction across the measured effectors. SIGNIFICANCE: This study provides new quantitative evidence that VIM-DBS is effective at reducing tremor across multiple parts of the body.

Mapping of direction and muscle representation in the human primary motor cortex controlling thumb movements.

Larger body parts are somatotopically represented in the primary motor cortex (M1), while smaller body parts, such as the fingers, have partially overlapping representations. The principles that govern the overlapping organization of M1 remain unclear. We used transcranial magnetic stimulation (TMS) to examine the cortical encoding of thumb movements in M1 of healthy humans. We performed M1 mapping of the probability of inducing a thumb movement in a particular direction and used low intensity TMS to disturb a voluntary thumb movement in the same direction during a reaction time task. With both techniques we found spatially segregated representations of the direction of TMS-induced thumb movements, thumb flexion and extension being best separated. Furthermore, the cortical regions corresponding to activation of a thumb muscle differ, depending on whether the muscle functions as agonist or as antagonist for flexion or extension. In addition, we found in the reaction time experiment that the direction of a movement is processed in M1 before the muscles participating in it are activated. It thus appears that one of the organizing principles for the human corticospinal motor system is based on a spatially segregated representation of movement directions and that the representation of individual somatic structures, such as the hand muscles, overlap.

Sleepiness and vigilance tests.

Objective assessments of subjective complaints such as sleepiness, tiredness or fatigue using sleepiness and vigilance tests aim to identify its causes and to judge the fitness to drive or to work of the affected person. "Vigilance" comprises wakefulness, alertness and attention and is therefore not merely reciprocal to sleepiness. Since it is a complex phenomenon with several dimensions it is unlikely to be appropriately assessed by one single "vigilance test". One important dimension of vigilance discussed here is wakefulness with its counterpart of overt sleep and the whole spectrum of various levels in between. The transit zone between full wakefulness and overt sleep is mainly characterised by the subjective complaint of sleepiness, which cannot be measured directly. Only the consequences of reduced wakefulness such as a shortened sleep latency, slowed cognitive function and prolonged reaction time can be measured objectively. It is, therefore, more promising to combine a battery of subjective and objective tests to answer a specific question in order to achieve the most appropriate description for a given clinical or medicolegal situation. However even then we must keep in mind that many other important aspects of fitness to drive / fitness to work such as neurological, psychiatric and neuropsychological functions including risk taking behaviour are not covered by vigilance tests. A comprehensive, multidisciplinary approach is essential in such situations.

Time course of blood oxygenation level-dependent signal response after theta burst transcranial magnetic stimulation of the frontal eye field.

The aim of the current study was to examine the effect of theta burst repetitive transcranial magnetic stimulation (rTMS) on the blood oxygenation level-dependent (BOLD) activation during repeated functional magnetic resonance imaging (fMRI) measurements. Theta burst rTMS was applied over the right frontal eye field in seven healthy subjects. Subsequently, repeated fMRI measurements were performed during a saccade-fixation task (block design) 5, 20, 35, and 60 min after stimulation. We found that theta burst rTMS induced a strong and long-lasting decrease of the BOLD signal response of the stimulated frontal eye field at 20 and 35 min. Furthermore, less pronounced alterations of the BOLD signal response with different dynamics were found for remote oculomotor areas such as the left frontal eye field, the pre-supplementary eye field, the supplementary eye field, and both parietal eye fields. Recovery of the BOLD signal changes in the anterior remote areas started earlier than in the posterior remote areas. These results show that a) the major inhibitory impact of theta burst rTMS occurs directly in the stimulated area itself, and that b) a lower effect on remote, oculomotor areas can be induced.

Loss of exploratory vertical saccades after unilateral frontal eye field damage.

Despite their relevance for locomotion and social interaction in everyday situations, little is known about the cortical control of vertical saccades in humans. Results from microstimulation studies indicate that both frontal eye fields (FEFs) contribute to these eye movements. Here, we present a patient with a damaged right FEF, who hardly made vertical saccades during visual exploration. This finding suggests that, for the cortical control of exploratory vertical saccades, integrity of both FEFs is indeed important.

Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder.

Narcolepsy is usually an idiopathic disorder, often with a genetic predisposition. Symptomatic cases have been described repeatedly, often as a consequence of hypothalamic lesions. Conversely, REM (rapid eye movement) sleep behaviour disorder (RBD) is usually a secondary disorder, often due to degenerative brain stem disorders or narcolepsy. The case of a hitherto healthy man is presented, who simultaneously developed narcolepsy and RBD as the result of an acute focal inflammatory lesion in the dorsomedial pontine tegmentum in the presence of normal cerebrospinal fluid hypocretin-1 levels and in the absence of human lymphocyte antigen haplotypes typically associated with narcolepsy and RBD (DQB1*0602, DQB1*05). This first observation of symptomatic narcolepsy with RBD underlines the importance of the mediotegmental pontine area in the pathophysiology of both disorders, even in the absence of a detectable hypocretin deficiency and a genetic predisposition.

Grey matter volumetric changes related to recovery from hand paresis after cortical sensorimotor stroke.

Preclinical studies using animal models have shown that grey matter plasticity in both perilesional and distant neural networks contributes to behavioural recovery of sensorimotor functions after ischaemic cortical stroke. Whether such morphological changes can be detected after human cortical stroke is not yet known, but this would be essential to better understand post-stroke brain architecture and its impact on recovery. Using serial behavioural and high-resolution magnetic resonance imaging (MRI) measurements, we tracked recovery of dexterous hand function in 28 patients with ischaemic stroke involving the primary sensorimotor cortices. We were able to classify three recovery subgroups (fast, slow, and poor) using response feature analysis of individual recovery curves. To detect areas with significant longitudinal grey matter volume (GMV) change, we performed tensor-based morphometry of MRI data acquired in the subacute phase, i.e. after the stage compromised by acute oedema and inflammation. We found significant GMV expansion in the perilesional premotor cortex, ipsilesional mediodorsal thalamus, and caudate nucleus, and GMV contraction in the contralesional cerebellum. According to an interaction model, patients with fast recovery had more perilesional than subcortical expansion, whereas the contrary was true for patients with impaired recovery. Also, there were significant voxel-wise correlations between motor performance and ipsilesional GMV contraction in the posterior parietal lobes and expansion in dorsolateral prefrontal cortex. In sum, perilesional GMV expansion is associated with successful recovery after cortical stroke, possibly reflecting the restructuring of local cortical networks. Distant changes within the prefrontal-striato-thalamic network are related to impaired recovery, probably indicating higher demands on cognitive control of motor behaviour.

Visual evoked response abnormality in myoclonus epilepsy with large pupils. Occurrence in a family with acorpuscular myoclonus epilepsy.

Flash and pattern evoked responses were recorded from three siblings with myoclonus epilepsy who all had strikingly large pupils in daylight. Comparison with the visual evoked responses (VERs) of 15 normal and eight epileptic control subjects (including one with myoclonus epilepsy but normal pupils) disclosed a substantial reduction of the amplitude of the flash response as compared with the normal pattern response in these three patients. It is suggested that the VER constellation and the pupillary abnormality, together with the normal electroretinogram and diffusely distributed relative scotomas, were due to a ganglion cell loss in the retina.

Human cortical plasticity: functional recovery with mirror movements.

Cortical plasticity of the human brain permits functional recovery after brain injury even in the absence of neuronal recovery. We report the combined evaluation, including electrophysiology and functional magnetic resonance imaging, of the pattern of cortical and cerebellar reorganization, in a patient with mirror movements as a sequel of perinatal unilateral brain injury. Recovery resulted in motor control by the healthy hemisphere using direct ipsilateral corticospinal projections and the contralateral cerebellum.

Hemispheric asymmetry in cortical control of memory-guided saccades. A transcranial magnetic stimulation study.

To study the temporal organisation of memory-guided saccade control we used single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal (PPC) and prefrontal cortex (PFC) in eight healthy subjects. TMS was applied either following presentation of a visual target, i.e. 160, 260, and 360 ms after the flashed point, or during the period of memorisation, i.e. between 700 and 1500 ms, or finally 100 ms after extinguishing of the central fixation point (i.e. 2100 ms after the target presentation). Latency of memory-guided saccades and the percentage of error in amplitude (PEA) was measured and compared with results without stimulation.TMS over the left PPC 100 ms after the extinguishing of the central fixation point significantly increased memory-guided saccade latency bilaterally. Furthermore, stimulation over the left PFC had a significant effect on the PEA of contralateral memory-guided saccades when applied during the period of memorisation, i.e. between 700 and 1500 ms.In a previous study using identical methodology [13: Müri RM, Vermersch SI, Rivaud S, Gaymard B, Pierrot-Deseilligny C. Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans. Journal of Neurophysiology 1996;76:2102-2106], we found that TMS over the right PPC increased the contralateral PEA when applied 260 ms after the flash, the effects on saccade latency after right PPC stimulation or on the PEA after right PFC stimulation being similar to those observed here. Taken together, these results show that (1) a hemispheric asymmetry in the preparation of memory-guided saccade amplitude during the early phase of sensorimotor integration exists, (2) memory-guided saccade triggering is controlled by PPC on both sides, and (3) PFC on both sides are involved in spatial working memory performance.

Role of the prefrontal cortex in the control of express saccades. A transcranial magnetic stimulation study.

Single pulse transcranial magnet stimulation (TMS) was applied in five subjects during a saccadic gap task, i.e. with a temporal gap of 200 ms between the extinguishing of the central fixation point and the appearance of the lateral target. In all subjects, a significant increase of contralateral express saccades was found when TMS was applied over the dorsolateral prefrontal cortex (DPFC) at the end of the gap of 200 ms. Earlier stimulation over the DPFC during the gap had no significant effect. Furthermore, stimulation over the posterior parietal cortex with the same time intervals, and stimulation during a no gap task had no significant influence on express saccades. These results suggest that TMS is capable of interfering specifically with the functioning of the DPFC, probably by inhibition of this region. Possibly such stimulation of the DPFC reduces the inhibition by this region onto the superior colliculus, which results in a facilitation of express saccades.

Motor-evoked responses to transcranial brain stimulation persist during cataplexy: a case report.

Magnetic brain stimulation was performed in a patient with the narcolepsy-cataplexy syndrome during and after a cataplectic status. Amplitudes and thresholds of responses in six muscles (diaphragm, lumbar erector spinae, trapezius, biceps, tibialis anterior and abductor digiti V) remained unchanged during cataplexy as compared to the normal state. Our data suggest that, similar to rapid eye movement (REM) sleep, an enhanced cortical excitability to magnetic brain stimulation may compensate for the postsynaptic spinal inhibition of muscle tone during cataplexy, and that there is no difference in this respect between axial and distal muscles. Our data agree well with other evidence of increased cortex activity during cataplexy and REM sleep.

Sleepiness-related accidents in sleep apnea patients.

The frequency of motor vehicle and working accidents was analyzed by means of a strictly anonymous questionnaire in 156 patients with sleep apnea syndrome (SAS) and in 160 age-gender matched controls. In the SAS group 12.4% of all drivers had motor vehicle accidents as compared to 2.9% in the control group (p<0.005). The motor vehicle accident rate was 13.0 per million km in patients with more severe SAS (AHI > 34/h, n=78) as compared to 1.1 in patients with milder SAS (AHI 10-34/h, n=78) (p<0.05), and 0.78 in control group (p<0.005), respectively. The accident rates in both patients and the control group were also greater than the rate of 0.02 "accidents due to sleepiness" per one million km in the Swiss driving population as reported by official statistics. During treatment with nasal continuous airway pressure (nCPAP) in 85 SAS patients, the motor vehicle accident rate dropped from 10.6 to 2.7 per million km (p<0.05). We conclude that patients with moderate to severe SAS have an up to fifteen-fold risk increase of motor vehicle accidents that constitutes a serious and often underestimated hazard on the roads, which can be reduced by adequate treatment.

Rapid cortical motor output map changes assessed by the triple stimulation technique.

The amplitudes of motor evoked potentials (MEPs) were mapped by transcranial magnetic stimulation (TMS) using the triple stimulation technique (TST) in 11 normal individuals. Stimuli were given while the subjects were (a) distracted, (b) concentrating on their target (recorded) hand, and (c) concentrating on their contralateral hand. Within seconds, the proportion of excited motor units increased, similarly in all subjects, by an average of 70% from (a) to (b), and by 48% from (a) to (c). At the optimal stimulation site, results obtained with the TST were compared to those of conventional MEPs. The TST proved superior in detecting the rapid changes of the motor output caused by the non-specific mental tasks studied.

Auditory brain-stem potentials studied with paired stimuli in normals.

Brain-stem auditory evoked potentials (BAEPs) to paired stimuli of various intervals were recorded using a subtraction technique to cancel the first and facilitate recognition of the second response. In a pilot series of 12 experiments, no latency change was encountered with paired click intervals (PCI) of 8 and 6 ms. Thirty healthy subjects were then investigated by presenting single and paired stimuli with a PCI of 4, 3.1, 2.3 and 1.5 ms at a repetition rate of 10/s to each subject. With diminishing PCIs, identification and latency measurement of waves IV and V became increasingly difficult because of marked amplitude reduction. Component III remained identifiable in all but two recordings and showed a statistically significant latency increase and amplitude reduction only when the stimuli were presented 1.5 ms apart. Component I did not show a consistent latency change with any PCI but its amplitude was significantly reduced with 4 ms PCI. These findings differ from those reported when using PCIs of 5 ms or more and when using single stimuli at a high repetition rate, where component V was the most stable. The alterations of evoked potentials found only with a PCI of 1.5 ms are probably of central origin.

Visual evoked potentials in acute occipital blindness. Diagnostic and prognostic value.

Pattern-evoked and flash-evoked responses were recorded from four patients with acute blindness due to occipital ischaemia. No responses could be obtained with pattern stimulation. Flash stimulation, however, yielded well-reproducible potentials in all four cases in spite of practically complete visual loss. In one patient vision recovered completely while the three others showed poor or minimal recovery in restricted visual field areas only. It is concluded that the flash method is not appropriate for differentiation of occipital blindness from psychogenic visual disorders. Furthermore, preserved flash-evoked potentials in the acute stage of occipital blindness cannot be taken as a reliable prognostic sign for visual recovery, as has been postulated by others. A possible extrastriate origin of these flash responses is discussed in view of recent theories on a second visual system.

Thalidomide-induced peripheral neuropathy. A prospective clinical, neurophysiological and pharmacogenetic evaluation.

Prospective clinical and electrophysiological follow-up was performed on nine patients under thalidomide treatment in order to detect the very beginning of possible drug-induced peripheral neuropathy. For neurophysiological assessment, nerve conduction measurements of the median, peroneal and sural nerves (7 conduction parameters) and needle EMG examination of the anterior tibial muscle were performed. The results of a first control after about 3 months of treatment were compared with the starting point examination, and the patients were then classified as "affected" or "not affected" according to clinical and neurophysiological criteria. At this point, three patients showed clinical and electrophysiological, and another two only electrophysiological alterations suggesting early neuropathy. This classification did not change after further clinical and electrophysiological controls. Without starting-point values, the early detection of neuropathy would not have been possible in all patients. No single reliable neurophysiological parameter for detection of thalidomide-induced neuropathy could be found. Pharmacogenetic classification with regard to hydroxylation and acetylation phenotypes was then performed in some patients and interpreted with relation to thalidomide neurotoxicity. A possible relationship between slow acetylators and development of thalidomide-induced neuropathy was found.

Beneficial effect of inhaled CO2 in a patient with non-obstructive sleep apnoea.

A 63-year-old man with severe non-obstructive sleep apnoea (apnoea index 28; apnoea duration 45-60s; O2 saturation between 72% and 98%), who did not respond to common modes of treatment, was successfully treated with CO2. A tent was perfused with compressed air (6 1/min) and increasing amounts of CO2. A concentration of 3% CO2 (180 ml/min) was sufficient to raise the PaCO2 above apnoea threshold and to suppress apnoeas completely. As a result, O2 saturation remained normal throughout the whole night and the symptoms of sleep apnoea disappeared. We hypothesize that the PCO2 ventilatory drive was intact in our patient and that hypocapnia was the major factor causing the non-obstructive sleep apnoea syndrome. Administration of CO2 with a constant flow system could be a safe and easy alternative for patients with non-obstructive sleep apnoea syndrome who present with hypocapnia and an intact respiratory feedback control system.

Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment.

Six patients with Hashimoto thyroiditis (HT) and associated encephalopathy (HE) are described and compared with 14 well-documented cases retrieved from the literature. HE typically affects patients when they are euthyroid and, in an appropriate clinical situation, antithyroid autoantibodies are the main indicators of HE. Since clinical features of HE are unspecific, other aetiologies such as infectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic causes have to be excluded. Our own six cases and those from the literature show that two types of initial clinical presentation can be differentiated: a vasculitic type with stroke-like episodes and mild cognitive impairment in nine patients, and a diffuse progressive type with dementia, seizures, psychotic episodes or altered consciousness in 11 patients. These types may overlap, particularly in the long-term course without treatment. Response to steroids was usually excellent with complete remission in 80%. Eighteen of the 20 patients were women. Characteristic, though unspecific, findings were abnormal EEG (90%) and CSF (80%). Together with quantitative neuropsychological testing, these proved sensitive for monitoring the efficacy of therapy. Conversely, antithyroid autoantibody titres did not correlate with the severity or type of clinical presentation. The link between HE and HT is not clear. A pathogenetic role for antithyroid autoantibodies in the central nervous system seems unlikely.