Untersuchungen der Blicksteuerung bei Patienten mit peripheren und zentralen okulomotorischen und vestibulären Störungen

Ein Ziel der dieser Habilitationsschrift zugrunde liegenden Versuche war es, durch ein tieferes Verständnis der Mechanismen, die der Blicksteuerung zugrunde liegen, die klinische Diagnostik peripherer und zentraler okulomotorischer und vestibulärer Störungen zu verbessern. Der Fokus lag auf den folgenden fünf unterschiedlichen Projekten mit verschiede-nen methodischen Zugängen, die von Untersuchungen bei Patienten mit strukturellen Läsionen im Mittelhirn bis hin zu methodischen Analysen zur Messung der Funk-tion des VOR reichten und damit ein weites Spektrum erfassten: 1) Systematische Untersuchung dreidimensionaler, kombinierter Augen- und Kopf-bewegungen (Blickbewegungen) bei Normalpersonen und bei Patienten mit Mittel-hirnläsionen 2) Analyse des VOR und Korrelation mit bildmorphologischen Veränderungen bei Patienten mit bilateralen vestibulären Defiziten und zusätzlichen zerebellären Störungen 3) Untersuchung der räumlichen Orientierung in Korrelation mit Veränderungen der Anatomie des limbischen Systems und der weißen Substanz bei Patienten mit bilateraler Vestibulopathie 4) Visuelle Fixation bei Patienten mit zerebellären Störungen, insbesondere mit Downbeat-Nystagmus 5) Ein direkter methodischer Vergleich von zwei Video-Kopfimpuls- (vHIT) Syste-men zur Quantifizierung des angulären VOR Dazu wurde ein breites Spektrum an Messmethoden eingesetzt: Zum Beispiel wur-den Kopf- und Augenbewegungen von Probanden und Patienten mittels der Search Coil-Methode (Robinson 1963) und der Videookulografie analysiert (Übersicht in (Bedell und Stevenson 2013; Eggert 2007)). Zusätzlich wurde sehr eng mit Ingeni-euren, Physikern und Mathematikern zusammengearbeitet, um Methodik und Ana-lyse der experimentellen Ergebnisse zu optimieren. Veränderungen in der kraniellen Bildgebung wurden mittels Verfahren wie der voxelbasierten Morphometrie in der Magnetresonanztomographie erfasst. Verhaltensaufgabenbezogene Veränderungen wurden unter anderem mit dem virtuellen Morris-Wasserlabyrinth analysiert. So konnten anatomische und verhaltensbezogene Veränderungen mit der Blicksteue-rung korreliert werden. Die in dieser Habilitationsschrift zusammengefassten Arbeiten befassen sich mit verschiedenen Aspekten der Blicksteuerung bei Gesunden und Patienten mit unter-schiedlichen peripheren vestibulären und zentralen Erkrankungen; dabei wurde ein breites Spektrum unterschiedlicher Messmethoden eingesetzt – von der Search-Coil Methode über die voxelbasierte Morphometrie im MRT bis hin zum virtuellen Morris-Wasserlabyrinth -, um projektbezogen die einzelnen Fragestellungen spezifisch zu untersuchen. Die wesentlichen Ergebnisse lassen sich wie folgt zusammenfassen: 1) A. Bei freien Blickbewegungen setzt der Kopf eine sog. Torque-basierte Strate-gie (optimale Kontrolle) ein, wogegen das Auge einen Mittelweg zwischen opti-maler und potenzieller Strategie zur Minimierung der angewendeten Kraft ver-wendet. B. Mittelhirnläsionen führen zur kontralateralen Verkippung des Kopfs bei und nach einer Blickbewegung. C. Isolierte, einseitige riMLF-Läsionen bei Menschen führen bei vertikalen Sak-kaden zu einer kontralateralen torsionellen Abweichung des Auges. 2) Zerebelläre Ataxien können auch ohne peripheres vestibuläres Funktionsdefizit klinisch mit einem (falsch-)pathologischen Kopfimpulstest einhergehen. Dies ist am ehesten auf eine Flokkulusdysfunktion zurückzuführen. In diesem Fall ist die niedrigfrequente VOR-Testung mittels kalorischer Testung zuverlässiger zur Detektion einer konkomitanten peripheren vestibulären Störung als die hochfrequente VOR-Testung mittels des Kopfimpulstests. 3) Die bilaterale Vestibulopathie verursacht Defizite in der räumlichen Orientierung und strukturelle Veränderungen im limbischen System und in der weißen Substanz. 4) Die schnellen Phasen des Downbeat-Nystagmus sind nicht immer rein kompensatorisch und verändern sich unter visueller Fixation, unabhängig von der lang-samen Phase. 5) A. Die beiden am häufigsten eingesetzten kommerziellen Video-HIT-Systeme liefern identische Ergebnisse. B. Bei der Auswertung und Beurteilung des Video-HIT muss beachtet werden, dass der VOR-Gain in die Richtung des registrierten Auges um 5 % höher ist als in die entgegengesetzte Richtung. Diese Arbeiten tragen zum besseren Verständnis der Physiologie und Pathophysio-logie sowie zur korrekten topografisch-anatomischen Diagnose innerhalb der komplexen peripheren und zentralen okulomotorischen Systeme bei

Acute binocular diplopia: peripheral or central?

OBJECTIVES Acute diplopia is a diagnostic challenge for clinicians, in particular in the emergency department. The most common cause of acute diplopia are ocular motor nerve palsies (OMP). In this prospective study, we focused on identifying the most crucial signs and symptoms for differentiating between peripheral and central OMP. METHODS We prospectively evaluated 56 non-consecutive patients who presented at our emergency department with acute binocular diplopia (≤ 10~days). The patient history was taken using a standardized questionnaire and patients underwent a neurological, neuro-ophthalmological and neuro-otological examination, including measurement of the subjective visual vertical (SVV), Harms tangent screen test, and cranial MRI. ESULTS Forty-six out of 56 patients were diagnosed with an ocular motor cranial nerve palsy (OMP), 21 of peripheral and 23 of central origin; in two patients, the etiology remained unknown. The following features were different in peripheral and central OMP: (1) the presence of vertigo/dizziness was more frequent in central (43.5%) than in peripheral (9.5%) OMP. (2) Central ocular motor signs, such as saccadic smooth pursuit, additional internuclear ophthalmoplegia, skew deviation, and saccade palsies, were also found more frequently in the central than in the peripheral group (86.7% vs. 33.3%). (3) Further, a pathological SVV deviation by monocular testing of the non-affected eye was also more common in central (77.3%) than in peripheral OMP (38.9%). The presence of all three factors has a positive predictive value of 100% (CI 50-100%) for the presence of a central lesion. CONCLUSIONS In acute diplopia due to central OMP, the most important accompanying symptom is vertigo/dizziness, and the most important clinical signs are central ocular motor disorders (which require examination of the non-paretic eye) and an SVV deviation in the non-paretic eye

An algorithm as a diagnostic tool for central ocular motor disorders, also to diagnose rare disorders

Background Recently an increasing number of digital tools to aid clinical work have been published. This study’s aim was to create an algorithm which can assist physicians as a “digital expert” with the differential diagnosis of central ocular motor disorders, in particular in rare diseases. Results The algorithm’s input consists of a maximum of 60 neurological and oculomotor signs and symptoms. The output is a list of the most probable diagnoses out of 14 alternatives and the most likely topographical anatomical localizations out of eight alternatives. Positive points are given for disease-associated symptoms, negative points for symptoms unlikely to occur with a disease. The accuracy of the algorithm was evaluated using the two diagnoses and two brain zones with the highest scores. In a first step, a dataset of 102 patients (56 males, 48.0 ± 22 yrs) with various central ocular motor disorders and underlying diseases, with a particular focus on rare diseases, was used as the basis for developing the algorithm iteratively. In a second step, the algorithm was validated with a dataset of 104 patients (59 males, 46.0 ± 23 yrs). For 12/14 diseases, the algorithm showed a sensitivity of between 80 and 100% and the specificity of 9/14 diseases was between 82 and 95% (e.g., 100% sensitivity and 75.5% specificity for Niemann Pick type C, and 80% specificity and 91.5% sensitivity for Gaucher’s disease). In terms of a topographic anatomical diagnosis, the sensitivity was between 77 and 100% for 4/8 brain zones, and the specificity of 5/8 zones ranged between 79 and 99%. Conclusion This algorithm using our knowledge of the functional anatomy of the ocular motor system and possible underlying diseases is a useful tool, in particular for the diagnosis of rare diseases associated with typical central ocular motor disorders, which are often overlooked

Experimental study on the effects of stress on spatial learning and memory

The hypothalamic-pituitary-adrenal (HPA) axis is known to control the central response to stressful events, by exerting a negative feedback on the hippocampus, hypothalamus and pituitary activity, helping thus the organism to regain its homeostasis. These actions are mediated through the glucocorticoid receptors type I (MRs) and II (GRs), which are vastly abundant in the limbic system. In the last years, an increasing literature has indicated that the levels of these receptors change after stress, in a way that depends on the type of stress, the sex of the animal and the brain area. In this study, we investigated the effects of a chronic and acute restraint stress on spatial learning and memory of adult male and female rats and evaluated the plasma corticosterone and glucocorticoid receptor levels in the hippocampus. For the chronic stress protocol, we used a 21-day, 6 hours a day, restraint stress paradigm. Afterwards, we tested the stressed animals and their age-matched controls on the Morris water maze task. Stressed females performed better than the controls, whereas stressed males performed worse, although stressed females had a higher and longer lasting increase in their plasma corticosterone levels. The performance of ovariectomized animals was not affected by chronic stress. The levels of the hippocampal GRs and MRs were also changed, before and after the water maze task, in a gender-dependent manner; higher levels of GRs in the CA1 hippocampal region before the learning task were associated with better performance in the female rats, whereas lower GR levels in the same region with worse performance in the males. MR levels increased only in the female CA3 after chronic stress. For the acute stress protocol, 6 hours of restraint were applied between the learning and memory session of the water maze task. Again, stressed females performed better and stressed males worse. Although, corticosterone levels were higher in the female animals, only the male hippocampus showed increased GR levels and Heat Shock Protein-70 activation. In conclusion, this study has shown that circulating glucocorticoids and their receptors in the rat hippocampus are affected in a gender-dependent manner after acute and chronic stress and that these changes are probably linked with the changes in spatial learning and memory performance of these animals. In view of the role of the HPA axis in depression and post-traumatic stress disorder, the therapeutic approach should also probably take in account the gender of the patient.Η απάντηση του οργανισμού στο στρες ρυθμίζεται κεντρικά μέσω της ενεργοποίησης του άξονα Υποθαλάμου –Υπόφυσης- Επινεφριδίων. Η αρνητική παλίνδρομη ρύθμιση που εξασκεί ο άξονας στη δραστηριότητα της υπόφυσης, του υποθαλάμου και του ιπποκάμπου οδηγεί στον ολοκλήρωση της απάντησης στο στρες και στη συνακόλουθη επαναφορά της ομοιόστασης. Η δράση αυτή εξασκείται κυρίως μέσω των υποδοχέων των γλυκοκορτικοειδών, που διακρίνονται σε τύπου Ι (MR) και τύπου ΙΙ (GR). Τα τελευταία χρόνια υπάρχουν ενδείξεις ότι η έκφραση και η λειτουργικότητα των γλυκοκορτικοειδών στον εγκέφαλο και των υποδοχέων τους αλλάζει μετά από έκθεση σε στρεσογόνα ερεθίσματα, με τρόπο που εξαρτάται από το είδος του στρες, την εγκεφαλική περιοχή και το φύλο του πειραματόζωου. Στην παρούσα διατριβή, μελετήσαμε την επίδραση του στρες περιορισμού, στην χωρική μάθηση και μνήμη, σε αρσενικούς, θηλυκούς και ωοθηκεκτομημένους ενήλικους επίμυες, και τις αντίστοιχες αλλαγές στα γλυκοκορτικοειδή του πλάσματος και στους υποδοχείς τους στον ιππόκαμπο. Για τη μελέτη των επιπτώσεων του χρόνιου στρες, τα πειραματόζωα υποβλήθησαν σε 21 ημέρες στρες περιορισμού, 6 ώρες την ημέρα και μετά υποβλήθησαν σε μια δοκιμασία χωρικής μνήμης και μάθησης, τον υδάτινο λαβύρινθο Morris. Τα θηλυκά της ομάδας του χρόνιου στρες βελτίωσαν την επίδοσή τους στη δοκιμασία αυτή, ενώ τα αρσενικά την χειροτέρευσαν. Τα ωοθηκεκτομημένα θηλυκά δεν είχαν αλλαγές στην απόδοσή τους. Η άνοδος της κορτικοστερόνης μετά από το στρες ήταν επίσης εντονότερη στα θηλυκά από ό,τι στα αρσενικά. Τα επίπεδα των υποδοχέων των γλυκοκορτικοειδών επηρεάστηκαν με διαφυλικό τρόπο, πριν και μετά την δοκιμασία του υδάτινου λαβύρινθου: Τα υψηλά επίπεδα GR στην CA1 ιπποκάμπεια περιοχή πριν τη δοκιμασία μάθησης συσχετίστηκαν με τη βελτιωμένη επίδοση στα θηλυκά ενώ τα χαμηλά επίπεδα GR στην ίδια περιοχή με τη χεριοτέρευση της επίδοσης των αρσενικών. Τα επίπεδα των MR στην CA3 περιοχή αυξήθηκαν σημαντικά μόνο στα θηλυκά πειραματόζωα μετά το χρόνιο στρες. Για τη μελέτη των επιπτώσεων του εφάπαξ στρες στη μνημονική ανάκληση, εφαρμόστηκαν 6 ώρες στρες περιορισμού μεταξύ των δοκιμασιών μάθησης και μνήμης. Και σε αυτήν την περίπτωση τα θηλυκά βελτίωσαν την απόδοσή τους, ενώ τα αρσενικά είχαν μειωμένη μνήμη για τη θέση της κρυμμένης πλατφόρμας. Τα θηλυκά πειραματόζωα, μία ημέρα μετά το στρες είχαν ακόμη υψηλά επίπεδα κορτικοστερόνης, ενώ στους νευρώνες του ιπποκάμπου των αρσενικών παρατηρήθηκε πυρηνική μετατόπιση των GR και αύξηση της πρωτε8νης θερμικού σοκ 70. Συμπερασματικά, η παρούσα διατριβή δείχνει ότι τα επίπεδα των κυκλοφορούντων γλυκοκορτικοειδών και των υποδοχεών τους στον ιππόκαμπο μετά από σύντομες και χρόνιες στρεσογόνες καταστάσεις συσχετίζονται πιθανώς με την μάθηση και τη μνήμη του χώρου, με διαφυλικό τρόπο. Λαμβάνοντας υπόψη το ρόλο του ΥΥΕ άξονα στην παθολογία της κατάθλιψης και της μετατραυματικής αγχώδους διαταραχής, ίσως είναι απαραίτητο οι θεραπευτικές προσεγγίσεις να λαμβάνουν υπόψη και το φύλο τους ασθενούς

Torsional deviations with voluntary saccades caused by a unilateral midbrain lesion

Three dimensional eye rotations were measured using the magnetic search coil technique in a patient with a lesion of the right rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) and in four control subjects. Up to 10° contralesional torsional deviations with each voluntary saccade were revealed, which also could be seen during bedside examination. There was no spontaneous nystagmus. Based on MRI criteria, the lesion involved the RIMLF but spared the interstitial nucleus of Cajal. To date, this deficit has not been described in patients. Our results support the hypothesis that the vertical–torsional saccade generator in humans is organised similarly as in monkeys: each RIMLF encodes torsional saccades in one direction, while both participate in vertical saccades

Vestibular Loss and Balance Training Cause Similar Changes in Human Cerebral White Matter Fractional Anisotropy

Patients with bilateral vestibular loss suffer from severe balance deficits during normal everyday movements. Ballet dancers, figure skaters, or slackliners, in contrast, are extraordinarily well trained in maintaining balance for the extreme balance situations that they are exposed to. Both training and disease can lead to changes in the diffusion properties of white matter that are related to skill level or disease progression respectively. In this study, we used diffusion tensor imaging (DTI) to compare white matter diffusivity between these two study groups and their age-and sex-matched controls. We found that vestibular patients and balance-trained subjects show a reduction of fractional anisotropy in similar white matter tracts, due to a relative increase in radial diffusivity (perpendicular to the main diffusion direction). Reduced fractional anisotropy was not only found in sensory and motor areas, but in a widespread network including long-range connections, limbic and association pathways. The reduced fractional anisotropy did not correlate with any cognitive, disease-related or skill-related factors. The similarity in FA between the two study groups, together with the absence of a relationship between skill or disease factors and white matter changes, suggests a common mechanism for these white matter differences. We propose that both study groups must exert increased effort to meet their respective usual balance requirements. Since balance training has been shown to effectively reduce the symptoms of vestibular failure, the changes in white matter shown here may represent a neuronal mechanism for rehabilitation

Torsional deviations with voluntary saccades caused by a unilateral midbrain lesion

Three dimensional eye rotations were measured using the magnetic search coil technique in a patient with a lesion of the right rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) and in four control subjects. Up to 10° contralesional torsional deviations with each voluntary saccade were revealed, which also could be seen during bedside examination. There was no spontaneous nystagmus. Based on MRI criteria, the lesion involved the RIMLF but spared the interstitial nucleus of Cajal. To date, this deficit has not been described in patients. Our results support the hypothesis that the vertical-torsional saccade generator in humans is organised similarly as in monkeys: each RIMLF encodes torsional saccades in one direction, while both participate in vertical saccades

Beyond Dizziness: Virtual Navigation, Spatial Anxiety and Hippocampal Volume in Bilateral Vestibulopathy

Bilateral vestibulopathy (BVP) is defined as the impairment or loss of function of either the labyrinths or the eighth nerves. Patients with total BVP due to bilateral vestibular nerve section exhibit difficulties in spatial memory and navigation and show a loss of hippocampal volume. In clinical practice, most patients do not have a complete loss of function but rather an asymmetrical residual functioning of the vestibular system. The purpose of the current study was to investigate navigational ability and hippocampal atrophy in BVP patients with residual vestibular function. Fifteen patients with BVP and a group of age- and gender- matched healthy controls were examined. Self -reported questionnaires on spatial anxiety and wayfinding were used to assess the applied strategy of wayfinding and quality of life. Spatial memory and navigation were tested directly using a virtual Morris Water Maze Task. The hippocampal volume of these two groups was evaluated by voxel-based morphometry. In the patients, the questionnaire showed a higher spatial anxiety and the Morris Water Maze Task a delayed spatial learning performance. MRI revealed a significant decrease in the gray matter mid-hippocampal volume (Left: p = 0.006, Z = 4.58, Right: p < 0.001, Z = 3.63) and posterior parahippocampal volume (Right p = 0.005, Z = 4.65, Left: p < 0.001, Z = 3.87) compared to those of healthy controls. In addition, a decrease in hippocampal formation volume correlated with a more dominant route-finding strategy. Our current findings demonstrate that even partial bilateral vestibular loss leads to anatomical and functional changes in the hippocampal formation and objective and subjective behavioral deficits

Fractional anisotropy correlates with age.

<p>FA values decrease with increasing age in widespread areas of white matter tracts. WM tracts showing significant correlation between FA and age of all 61 subjects are shown in blue. Altogether, 12,868 voxels were significant; atr = anterior thalamic radiation, cc = corpus callosum, ec = external capsule, fm = forceps minor, fM = forceps major, fx = fornix, ifof = inferior fronto-occipital fasciculus, uf = uncinate fasciculus, st = stria terminalis. Significant voxels are overlaid on seven axial slices of the MNI152_T1_1mm_brain standard image included in FSL and the mean FA skeleton mask (white).</p