Trace eyeblink conditioning in human subjects with cerebellar lesions.

Trace eyeblink conditioning was investigated in 31 patients with focal cerebellar lesions and 19 age-matched controls. Twelve patients presented with lesions including the territory of the superior cerebellar artery (SCA). In 19 patients lesions were restricted to the territory of the posterior inferior cerebellar artery (PICA). A 3D magnetic resonance imaging was used to determine the extent of the cortical lesion and possible involvement of cerebellar nuclei. Eyeblink conditioning was performed using a 40 ms tone as conditioned stimulus (CS) followed by a stimulus free trace-interval of 400 ms and a 100 ms air-puff as unconditioned stimulus (US). In SCA patients with lesions including parts of the cerebellar interposed nucleus trace eyeblink conditioning was significantly impaired. Pure cortical lesions of the superior cerebellum were not sufficient to reduce acquisition of trace conditioned eyeblink responses. PICA patients were not impaired in trace eyeblink conditioning. Consistent with animal studies the findings of the present human lesion study suggest that, in addition to forebrain areas, the interposed nucleus is of importance in trace eyeblink conditioning. Although cortical cerebellar areas appear less important in trace compared with delay eyeblink conditioning, the present data strengthen the view that cerebellar structures contribute to different forms of eyeblink conditioning paradigms.

Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions.

The aim of the present study was to compare eyeblink conditioning in cerebellar patients with lesions including the territory of the superior cerebellar artery (SCA) and in patients with lesions restricted to the territory of the posterior inferior cerebellar artery (PICA). The cerebellar areas known to be most critical in eyeblink conditioning based on animal data (i.e. Larsell lobule H VI and interposed nucleus) are commonly supplied by the SCA. Eyeblink conditioning was expected to be impaired in SCA, but not in PICA patients. A total of 27 cerebellar patients and 25 age-matched controls were tested. Cerebellar lesions were primarily unilateral (n = 20). Most patients suffered from ischaemic infarctions of the SCA (n = 11) or the PICA (n = 13). The other patients presented with cerebellar tumours (n = 2) and cerebellar agenesis (n = 1). The extent of the cortical lesion (i.e. which lobuli were affected) and possible involvement of the cerebellar nuclei was determined by 3D-MRI. As expected, the ability to acquire classically conditioned eyeblink responses was significantly reduced in the group of all cerebellar patients compared with the controls. In the patients with unilateral cerebellar lesions, conditioning deficits were present ipsilaterally. In SCA patients with lesions including hemispheral lobules VI and Crus I, eyeblink conditioning was significantly reduced on the affected side compared with the unaffected side. No significant difference between the affected and unaffected sides was present in patients with lesions restricted to the common PICA territory (i.e. Crus II and below). Conditioning deficits were neither significantly different in SCA patients with pure cortical lesions compared with SCA patients with additional nuclear impairment nor in SCA patients with unilateral lesions compared with SCA patients with bilateral lesions. To summarize, unilateral cortical lesions of the superior cerebellum appear to be sufficient to reduce eyeblink conditioning in humans significantly.

[Pulse oximetry screening for sleep-disordered breathing in stroke]. / Pulsoximetrie als Schlafapnoescreening bei Schlaganfallpatienten.

BACKGROUND: The prevalence of sleep-disordered breathing, particularly obstructive sleep apnea, among stroke patients is high. Routine screening with the current diagnostic gold standard of polysomnography is not feasible. Pulse oximetry could be a simple screening test. METHODS: The signal of pulse oximetry, recorded during full polysomnography in 184 stroke patients during neurological rehabilitation, was analyzed automatically by software for desaturations >/= 4 %. The polysomnographic apnoea-hypopnoea-index (AHI) was used as the diagnostic gold standard and compared with the oxygen desaturation index (ODI). RESULTS: Correlation between AHI of PSG and ODI of oximetry was r = 0.84 (p < 0.001). Dependent on the definition of SDB (AHI 10, 15, 20 or 30/h) and the cut-off-point for the ODI (e. g. 15/h) sensitivity was 32 - 83 % and specificity 99 - 96 %. The diagnostic accuracy as determined by the area under the ROC-curve was 96 %. CONCLUSION: Automated analysis of pulse oximetry gives reasonable results for screening for SDB in stroke patients and could be used in populations with high pre-test probability.

Motor deficits cannot explain impaired cognitive associative learning in cerebellar patients.

There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.

Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke.

The prevalence of obstructive sleep apnoea (OSA) following stroke is high and OSA is associated with increased morbidity, mortality and poor functional outcome. Nasal continuous positive airway pressure (nCPAP) is the treatment of choice for OSA, but its effects in stroke patients are unknown. The effectiveness and acceptance of treatment with nCPAP in 105 stroke patients with OSA, admitted to rehabilitation was prospectively investigated. Subjective wellbeing was measured with a visual analogue scale in 41 patients and 24-h blood pressure was determined in 16 patients before and after 10 days of treatment. Differences were compared between patients who did and did not accept treatment. There was an 80% reduction of respiratory events with concomitant increase in oxygen saturation and improvement in sleep architecture. No serious side-effects were noticed. Seventy-four patients (70.5%) continued treatment at home. Nonacceptance was associated with a lower functional status, as measured by the Barthel Index, and the presence of aphasia. Ten days after initiation of nCPAP, compliant users showed a clear improvement in wellbeing (differences in visual analogue scale (deltaVAS) mean+/-SD 26+/-26 mm) versus noncompliant patients (deltaVAS 2+/-25 mm, p=0.021). Only the compliant group had a reduction in mean nocturnal blood pressure (deltaBP; -8+/-7.3 mmHg versus 0.8+/-8.4 mmHg, p=0.037). Stroke patients with obstructive sleep apnoea can be treated effectively with nasal continuous positive airway pressure and show a similar improvement and primary acceptance to obstructive sleep apnoea patients without stroke. Continuous positive airway pressure acceptance is associated with improved wellbeing and decreased nocturnal blood pressure.

Fibrinogen levels and obstructive sleep apnea in ischemic stroke.

The plasma level of fibrinogen is felt to be an independent risk factor for vascular events. Obstructive sleep apnea (OSA) has a high prevalence in patients with stroke and may also be an independent risk factor. The aim of our study was to determine the association between OSA and plasma levels of fibrinogen in patients with stroke. Polysomnography was performed during neurological rehabilitation in 113 patients (82 men, 31 women, age 58 +/- 11.1 yr, mean +/- SD) with ischemic stroke. OSA was absent (RDI < 5) in 44 patients, 42 had mild OSA (5 < or = RDI < 20), and 27 had moderate to severe OSA (RDI > or = 20). Parameters of OSA (respiratory disturbance index [RDI], oxygen indices) were correlated to plasma levels of fibrinogen, measured in the morning after admission to rehabilitation. Fibrinogen was positively correlated with RDI (r = 0.24, p = 0.007), duration of the longest apnea (r = 0.18, p = 0.049), and negatively correlated with several oxygen indices including average minimal oxygen saturation (r = -0.41, p < 0.001). Correlation coefficients were slightly higher when excluding patients with stroke of presumed cardiac origin. Multiple linear regression identified minimal mean oxygen saturation and sex as independent predictors of fibrinogen level. The correlation between severity of coexisting OSA and fibrinogen level in patients with stroke suggests a possible pathophysiological mechanism for an increased risk of stroke in patients with OSA.

A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke.

BACKGROUND AND PURPOSE: We sought to define an effective and safe dose of botulinum toxin type A (Dysport) for the treatment of upper limb muscle spasticity due to stroke. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, dose-ranging study. Patients received either a placebo or 1 of 3 doses of Dysport (500, 1000, 1500 U) into 5 muscles of the affected arm. Efficacy was assessed periodically by the Modified Ashworth Scale and a battery of functional outcome measures. RESULTS: Eighty-three patients were recruited, and 82 completed the study. The 4 study groups were comparable at baseline with respect to their demographic characteristics and severity of spasticity. All doses of Dysport studied showed a significant reduction from baseline of muscle tone compared with placebo. However, the effect on functional disability was not statistically significant and was best at a dose of 1000 U. There were no statistically significant differences between the groups in the incidence of adverse events. CONCLUSIONS: The present study suggests that treatment with Dysport reduces muscle tone in patients with poststroke upper limb spasticity. Treatment was effective at doses of Dysport of 500, 1000, and 1500 U. The optimal dose for treatment of patients with residual voluntary movements in the upper limb appears to be 1000 U. Dysport is safe in the doses used in this study.

Sleep-disordered breathing among patients with first-ever stroke.

Sleep-disordered breathing (SDB) in the form of obstructive sleep apnea is a possible risk factor for stroke. We carried out a cross-sectional survey out in a rehabilitation center among patients with first-ever stroke to further determine the incidence and types of SDB and its relationship to known risk factors for stroke. Full polysomnography was performed in 147 consecutive patients (95 men, 52 women, age 61+/-10 years) admitted to our neurological Rehabilitation Department 46+/-20 days after first-ever stroke. Subjective sleepiness (Epworth Sleepiness Scale), vascular risk factors, anthropometric data, and polysomnographic findings were compared between stroke patients with varying degrees of SDB. With a cutoff point for the respiratory disturbance index (RDI) of 5, 10, 15, or 20 the respective prevalence of SDB was 61%, 44%, 32%, and 22%. The type of SDB was generally obstructive, with dominant central apneas in only 6% of patients. Patients with an RDI of 20 or higher had less REM sleep, thicker necks, and a more central type of obesity. Even in patients with an RDI of 20 or higher subjective sleepiness, although higher than in those without SDB, was not a predominant symptom. Snoring and anthropometric data suggest that obstructive SDB may have existed prior to stroke. The prevalence of hypertension and coronary heart disease were higher among stroke patients with an RDI of 20 or higher than in those without SDB. We conclude that the prevalence of SDB among patients with stroke is high. Examination of stroke should include screening for SDB.

[Obstructive sleep apnea syndrome. A probably cause of therapy refractory hypertension in intracerebral hemorrhage]. / Obstruktives Schlafapnoesyndrom. Wahrscheinliche Ursache einer therapieresistenten Hypertonie bei intrazerebraler Blutung.

There is clear evidence for obstructive sleep apnea as an independent cause of arterial hypertension. We report a case of intracranial hemorrhage with systemic hypertension resistant to antihypertensive medication, which could only be adjusted after effective treatment of coexisting sleep-disordered breathing. The 36 year old male (body mass index 31 kg/m2) was admitted to hospital three weeks before for intracranial bleeding at the left external capsule. Diagnosis of primary hypertension was made after extensive work-up in the acute hospital. Blood pressure was adjusted with five-fold antihypertensive medication at the time of admission to neurological rehabilitation, but was still elevated with "non-dipping" as determined by long-term measurement despite medications above the recommended dosages. Polysomnography confirmed the diagnosis of obstructive sleep apnea. 10 days after initiation of treatment with nasal CPAP blood pressure control was easier with normal dipping at night. Medication could be reduced during rehabilitation with further reduction after discharge. Moderate obstructive sleep apnea appears to be the cause of severe hypertension resistant to pharmacological therapy in this patient. The case underlines the impact of diagnosis and treatment of sleep-disordered breathing for the secondary prevention of stroke.

Postural responses to changing task conditions in patients with cerebellar lesions.

OBJECTIVE: To investigate the role of the cerebellum in postural adaptation for changes to the stimulus type of support surface displacements (backward translations v "toes up" rotations). METHODS: A group of 13 patients with chronic, isolated lesions of the cerebellum and 15 control subjects were tested. Automatic postural responses of the medial gastrocnemius and anterior tibial muscles were recorded. The first paradigm consisted of 10 rotational perturbations followed by 10 backward translations of the platform, and 10 backward translations followed by 10 rotations. The second paradigm consisted of 18 rotations and two randomly interposed translational perturbations, and 18 translations with two rotations randomly interposed. RESULTS: When the type of perturbation changed from an expected translation to an unexpected rotation and vice versa both control subjects and cerebellar patients showed an immediate and significant change in the response amplitude of the medial gastrocnemius and at the same time an immediate and significant change in the response amplitude of the anterior tibial muscles. Neither controls nor cerebellar patients showed effects of prediction in surface displacements of unexpected types of perturbation. Both controls and cerebellar patients showed no gradual increase in the gastrocnemius response in subsequent trials of surface translations following a block of 10 surface rotations and no gradual increase in the response amplitude of the anterior tibial muscle in subsequent trials of surface rotations following a block of 10 surface translations. CONCLUSIONS: Despite postural hypermetria, the integrity of the cerebellum does not seem critical for adaptation of postural synergies to changing stimulus types of surface displacements. The present results support previous findings suggesting that the main role of the cerebellum in automatic postural responses may be gain control.

The relevance of sensory input for the cerebellar control of movements.

The performance of a motor task not only requires subjects to plan, prepare, and initiate but also to monitor how a movement is performed. We used positron emission tomography to examine to what extent the human cerebellum is involved in controlling motor output or sensory input from movements in normal subjects. In the first study, we compared the active performance of a motor task (flexion and extension of the right elbow) to the passive execution of the same movements. Passive movements were driven by a motor with the arm fixed in a guide hinge. Active movements (compared to rest) elicited increases of rCBF mainly in the ipsilateral neocerebellar hemisphere and vermis of the posterior lobe. During passive movements, almost identical parts of the cerebellar hemispheres and vermis were activated (compared to the rest condition). The direct comparison of active and passive movement conditions revealed a small activation of the neocerebellar hemisphere of the posterior lobe and cerebellar nuclei ipsilateral to the movement. Approximately 90% of cerebellar neuronal activity was related to sensory input. In the second study, we compared the execution of a free selection joystick movement task to a condition in which subjects simply imagined the movements. The execution of movements (compared to rest) was associated with increases of rCBF in the ipsilateral neocerebellar hemisphere and vermis of the posterior lobe. During movement imagination, a small part of the ipsilateral cerebellar hemisphere and vermis of the posterior lobe was activated (compared to rest). The increase of rCBF during movement imagination accounted for only 20% of the signal seen during movement execution. Our results indicate that the neocerebellum may be much more concerned with sensory information processing than has been considered previously.

Brain representation of active and passive movements.

During active and passive (driven by a torque motor) flexion and extension of the right elbow, regional cerebral blood flow (rCBF) was measured in six healthy, male volunteers using positron emission tomography and the standard H2(15)O injection technique. During active as well as during passive movements of the right elbow there were strong increases in rCBF, identical in location, amount, and extent in the contralateral sensorimotor cortex. There were activations during both conditions in the supplementary motor area (stronger and more inferior in the active condition) and inferior parietal cortex (on the convexity during active movements and in the depth of the central sulcus during passive movements). During active movements only, activations of the basal ganglia and the cingulate gyrus were found. Brain activations during motor tasks are largely related to the processing of afferent information.

Stretch reflexes of the proximal arm in a patient with mirror movements: absence of bilateral long-latency components.

The stretch reflex responses evoked by unilateral limb displacement in distal (first dorsal interosseus (FDI)) and in proximal (biceps brachii (Bb)) arm muscles were studied during matched bilateral contractions in a patient with congenital mirror movements. In this patient unilateral transcortical magnetic stimulation (TMS) elicited not only the normal contralateral EMG response but also a clear ipsilateral component in the EMG of both proximal and distal arm muscles. As expected from previous studies, the ipsilateral FDI muscle responded to stretch of the index finger with short- (M1) and long-latency (M2) reflex components. In addition, the FDI contralateral to displacement exhibited an abnormal mirrored response corresponding to the M2 interval. In contrast, whereas the ipsilateral Bb responded to imposed elbow extension with a marked M1/M2 reflex response, no mirroring of either reflex component was apparent in the contralateral Bb EMG. If the mirroring of the M2 in the FDI is accepted as evidence for the transcortical nature of the M2 reflex response, then it follows that the absence of such mirroring in the Bb indicates that a transcortical mechanism cannot play a major role in the generation of long-latency stretch reflex responses in proximal arm muscles.

Voluntary movement at the elbow in spastic hemiparesis.

The relative importance of hyperreflexia and paresis in disturbances of voluntary arm movement was studied in a group of patients (n = 25) with spasticity arising from a unilateral ischemic cerebral lesion. Patient performance was evaluated against data obtained from normal subjects (n = 15). Spastic patients achieved lower maximum movement velocities during flexion or extension than did normal subjects. The more marked the paresis of the elbow flexor and extensor muscles of the patients, relative to the strength of the normal subjects, the greater was this reduction in maximum velocity. For a given velocity, however, the time taken to complete a movement and the time to reach the peak velocity were normal. No relationship was found between the degree of impairment of voluntary movement and the level of passive muscle hypertonia in the antagonist. Although overactivity of the antagonist muscle may play some role in disturbance of movements made at low velocities without an opposing load, antagonist activity during movements made against a load (i.e., under more natural conditions) was at or below normal levels, even in those patients with the most marked passive muscle hypertonia. It is concluded that agonist muscle paresis, rather than antagonist muscle hypertonia, plays the dominant role in the disturbance of voluntary elbow movement following stroke.

Agonist and antagonist EMG activation during isometric torque development at the elbow in spastic hemiparesis.

Voluntary isometric step contractions of the elbow flexor and extensor muscles were studied in a group of patients with paresis arising as the result of unilateral cerebral lesion and in a control group of normal subjects. For each subject the maximum isometric torque in flexion and extension was obtained, along with a series of graduated torque steps up to this maximum, in order to perform a regression analysis between torque developed and the associated agonist and antagonist EMG. This relationship proved to be linear in all normal subjects and in all but the most paretic spastic patients. If the patients were grouped according to their ability to make discrete large angle flexion and extension movements at the elbow, a clear correspondence was seen between increasing movement disability and the degree of paresis. No significant differences were found in the torque/EMG relationship of spastic patients when either elbow extensors or flexors were acting as the agonist in a contraction. Similarly, no evidence of exaggerated antagonist co-activation was found. It is concluded that, in the upper arm muscles, hemiparesis following stroke cannot, under isometric conditions, be attributed to hyperactivity of antagonist muscles.

Changes in the short- and long-latency stretch reflex components of the triceps surae muscle during ischaemia in man.

1. In order to establish the afferent source responsible for the M1 and M2 stretch reflex components of the voluntarily activated human triceps surae muscle, mechanical reflex testing was applied before and during ischaemic blockade of the lower limb. This procedure is known to affect large, fast conducting afferent fibres earliest, specifically Ia afferents arising from muscle spindle afferents. 2. It was found that both the M1 and M2 components were eliminated at the same time, at a point when the P40 peak in the somatosensory evoked potential, produced from stimulation of fast conducting peripheral afferents, was also abolished. This evidence indicates that both reflex components are mediated by information carried by muscle spindle Ia afferents. 3. The M1 component was selectively increased in the early stages of ischaemia. The M2 response did not increase during this period, but showed a tendency to reduce in amplitude. This effect may arise as the result of increased recruitment of motor units in the M1 component reducing the number of units available for activation in the M2 response. 4. These results do not support the view that the M2 reflex component of the triceps surae muscle is mediated by secondary afferent information, but indicate, rather, that both the M1 and M2 components are mediated by Ia afferent information acting on spinal pathways.

The limitations of the tendon jerk as a marker of pathological stretch reflex activity in human spasticity.

The motor disorders associated with human spasticity arise, partly from a pathological increase in the excitability of muscle stretch reflexes. In clinical practice, reflex excitability is commonly assessed by grading the reflex response to a blow delivered to the tendon of a muscle. This is a much simpler response than the complex patterns of activity which may be elicited following muscle stretch caused by active or passive movement. Changes in the biceps brachii tendon jerk response have been followed over the first year after stroke in a group of hemiparetic patients and compared with changes in short and medium latency reflex responses elicited by imposed elbow flexion of initially relaxed spastic muscle and with the development of the late reflex responses which contribute to spastic hypertonia. A progressive increase in tendon jerk responses occurred over the first year following stroke, whereas reflex responses to imposed displacement, in particular the late reflex responses contributing to muscle hypertonia, reached their peak excitability one to three months after stroke, with a subsequent reduction in activity. The tendon jerk reflex therefore provides an incomplete picture of the pathological changes in the reflex responses in spasticity.

[Intraventricular antibiotic therapy]. / Intraventrikuläre Antibiotikatherapie.

While shunt infections are regularly treated with intraventricular antibiotics, the validity of such an application in bacterial meningitis of other origin is controversial. We report two cases of partly successful treatment with intraventricular Ceftazidime (10-20 mg twice per week). One patient with pseudomonas aeruginosa meningitis who was treated as an out-patient for nearly two years died after an attempted withdrawal of the intraventricular treatment. In our experience, intraventricular application of antibiotics can be a part of the therapeutic regimen in all cases of chronic meningitis with problematic bacteria. Depending on the bacillus, Ceftazidime, Vancomycin or Netilmicin can be recommended for intrathecal application.

[Recurrent aseptic meningitis (Mollaret meningitis)--spontaneous and drug-induced origin]. / Rezidivierende aseptische Meningitis (Mollaret-Meningitis)--spontanes und medikamentös induziertes Auftreten.

Since its initial description by Mollaret in 1944, the etiology of the chronic aseptic meningitis has remained unknown. This rare disease may cause diagnostic problems if bacterial or viral causes are suspected. A different form of aseptic meningitis may be seen following a variety of drug treatments, especially with non-steroidal anti-rheumatic drugs: In many reports since 1978, meningitic attacks following administration of ibuprofen have been reported. We describe two cases of Mollaret-Meningitis with certain specialities: one case shows clear encephalitic involvement with aphasia in all six attacks. In the other case, five meningitic attacks appeared spontaneously, while two were drug-induced: the first attack was seen after a lumbar myelography with lopamidol and one attack appeared two hours after oral administration of 400 mg ibuprofen. It is suggested that Mollaret-Meningitis is a special form of a drug-induced allergic reaction, the provoking agent of which remains unknown.

Different mechanisms underlie the long-latency stretch reflex response of active human muscle at different joints.

1. Stretch of voluntarily activated human muscle results in a reflex response consisting of short-latency (M1) and delayed long-latency (M2) components. The mechanism of the M2 response remains the subject of controversy. The present study tested the universality of the hypothesis that the M2 response results from the transmission of low-threshold muscle afferent input travelling over a long-loop supraspinal pathway. Muscle reflex responses resulting from imposed stretch were obtained from the first dorsal interosseus (FDI), biceps brachii (BB), triceps brachii (TB) and triceps surae (TS) muscles. 2. Patients suffering from Huntington's disease (HD) show a selective loss of FDI-M2 responses, with sparing of the M1. This has been attributed to disruption of supraspinal pathways as a part of the disease pathology. Accordingly, HD has been used in the present study as a model to test the universality of the long-loop hypothesis: if this is so, then HD patients with an absent FDI M2 should also fail to show an M2 response in other muscles. 3. It is shown that a group of HD patients in whom the FDI-M2 response was absent or residual developed clear M2 responses in the TB, BB and TS muscles following stretch sufficient to invariably evoke this component in normal subjects. 4. It is thus concluded that longer-latency stretch reflex components are not invariably mediated over long-loop supraspinal pathways, but that this mode of control is dominant only in muscles, such as those of the hand, whose function depends largely on direct cortical control.