[Cerebral amyloid angiopathy associated with inflammation]. / Zerebrale Amyloidangiopathie assoziiert mit Inflammation.

Cerebral amyloid angiopathy (CAA) associated with inflammation is a rare form of a potentially reversible encephalopathy in a subgroup of patients with CAA. The cerebral amyloid deposition can in isolated cases induce an inflammation predominantly of the cerebral blood vessels and a multifocal edema of the cerebral white matter. The courses can occur as monophasic, relapsing remitting and primarily progressive forms. We present seven cases with different courses of the disease and give an overview of the pathophysiology, clinical aspects and treatment of the disease with reference to the current literature. The cases presented show a very different and often difficult differential diagnostic clinical picture and all showed a significant improvement under steroid medication without signs of recurrence of the disease during the course. The recognition and early consistent treatment of inflammatory forms of CAA with and without direct inflammatory involvement of vessels can be decisive for successful treatment.

[Non-heart-beating donors are ineligible]. / "Non-heart-beating donors" sind nicht geeignet.

The death of the donor is a mandatory prerequisite for organ transplantation (dead donor rule) worldwide. It is a medical, legal and ethical consensus to accept the concept of brain death, as first proposed in 1968 by the ad hoc committee of the Harvard Medical School, as a certain criterion of death. In isolated cases where the diagnosis of brain death was claimed to be wrong, it could be demonstrated that the diagnostic procedure for brain death had not been correctly performed. In March 2014 a joint statement by the German neuromedical societies emphasized that 1) the diagnosis of brain death is one of the safest diagnoses in medicine if performed according to accepted medical standards and criteria and 2) the concept of non-heart-beating donors (NHBD, i. e. organ donation after an arbitrarily defined duration of circulatory and cardiac arrest) practiced in some European countries must be absolutely rejected because it implicates a high risk of diagnostic error. According to the current literature it is unclear at what time cardiac and circulatory arrest is irreversible and leads to irreversible cessation of all functions of the entire brain including the brainstem, even though clinical signs of cessation of brain functions are always found after 10 min. Furthermore, is it often an arbitrary decision to exactly define the duration of cardiac arrest if continuous echocardiographic monitoring has not been carried out from the very beginning. Last but not least there are ethical concerns against the concept of NHBD because it might influence therapeutic efforts to resuscitate a patient with cardiac arrest. Therefore, the German Medical Council (BÄK) has repeatedly rejected the concept of NHBD for organ transplantation since 1995.

Diagnostic accuracy and cost-effectiveness of dermoscopy in primary care: a cluster randomized clinical trial.

OBJECTIVES: To determine the DA and cost-effectiveness of the dermoscope in primary care for skin lesions suspected of malignancy. METHODS: In a cluster randomized clinical trial, 48 Dutch general practices were randomized to either intervention group using a dermoscope or control group using only naked-eye examination. A total of 194 lesions from 170 patients in the intervention group and 222 lesions from 211 patients in the control group were analysed for DA and cost-effectiveness. RESULTS: The percentage of correctly diagnosed lesions in intervention group and control group was 50.5% and 40.5% respectively. This was 61.5% and 22.2% for melanomas. In the intervention group, three malignancies were treated with the expectative treatment option compared to none in the control group. The odds ratio (OR) of a correct diagnosis in the intervention group, compared to control group, was 1.51 (95% CI: 0.96­2.37) P = 0.07. Consequently, the relative risk was 1.25. The incremental cost-effectiveness ratio was €89 (95% CI −€60 to €598), indicating that using a dermoscope costs an additional €89 for one additional correctly diagnosed patient. Additional analyses showed better effects of dermoscopy compared to the control group for 98% of the bootstrap resamples. CONCLUSIONS: The probability of a correct diagnosis was 1.25 times higher using a dermoscope than without a dermoscope. Although this difference is marginally not statistically significant, dermoscopy in general practice appears to be cost effective. We therefore think that GPs should be trained to use a dermoscope, although they should realize that even with the use of a dermoscope not all lesions will be diagnosed correctly.

Shifting networks and mixing metals: Changing metal trade routes to Scandinavia correlate with Neolithic and Bronze Age transformations.

Based on 550 metal analyses, this study sheds decisive light on how the Nordic Bronze Age was founded on metal imports from shifting ore sources associated with altered trade routes. On-and-off presence of copper characterised the Neolithic. At 2100-2000 BC, a continuous rise in the flow of metals to southern Scandinavia begins. First to arrive via the central German Únetician hubs was high-impurity metal from the Austrian Inn Valley and Slovakia; this was complemented by high-tin British metal, enabling early local production of tin bronzes. Increased metal use locally fuelled the leadership competitions visible in the metal-led material culture. The Únetice downfall c.1600 BC resulted for a short period in a raw materials shortage, visible in the reuse of existing stocks, but stimulated direct Nordic access to the Carpathian basin. This new access expedited innovations in metalwork with reliance on chalcopyrite from Slovakia, as well as opening new sources in the eastern Alps, along an eastern route that also conveyed Baltic amber as far as the Aegean. British metal plays a central role during this period. Finally, from c.1500 BC, when British copper imports ceased, the predominance of novel northern Italian copper coincides with the full establishment of the NBA and highlights a western route, connecting the NBA with the southern German Tumulus culture and the first transalpine amber traffic.

Correction: On the trail of Scandinavia's early metallurgy: Provenance, transfer and mixing.

[This corrects the article DOI: 10.1371/journal.pone.0219574.].

On the trail of Scandinavia's early metallurgy: Provenance, transfer and mixing.

The rich and long-lasting Nordic Bronze Age was dependent throughout on incoming flows of copper and tin. The crucial turning point for the development of the NBA can be pinpointed as the second phase of the Late Neolithic (LN II, c. 2000-1700 BC) precisely because the availability and use of metal increased markedly at this time. But the precise provenance of copper reaching Scandinavia in the early second millennium is still unclear and our knowledge about the driving force leading to the establishment of the Bronze Age in southern Scandinavia is fragmentary and incomplete. This study, drawing on a large data set of 210 samples representing almost 50% of all existing metal objects known from this period in Denmark, uses trace element (EDXRF) and isotope analyses (MC-ICP-MS) of copper-based artifacts in combination with substantial typological knowledge to profoundly illuminate the contact directions, networks and routes of the earliest metal supplies. It also presents the first investigation of local recycling or mixing of metals originating from different ore regions. Both continuity and change emerge clearly in the metal-trading networks of the Late Neolithic to the first Bronze Age period. Artifacts in LN II consist mainly of high-impurity copper (so-called fahlore type copper), with the clear exception of British imports. Targeted reuse of foreign artifacts in local production is demonstrated by the presence of British metal in local-style axes. The much smaller range of lead isotope ratios among locally crafted compared to imported artifacts is also likely due to mixing. In the latter half of Nordic LN II (1800-1700 BC), the first signs emerge of a new and distinct type of copper with low impurity levels, which gains enormously in importance later in NBA IA.

Distributed representations of the "preparatory set" in the frontal oculomotor system: a TMS study.

BACKGROUND: The generation of saccades is influenced by the level of "preparatory set activity" in cortical oculomotor areas. This preparatory activity can be examined using the gap-paradigm in which a temporal gap is introduced between the disappearance of a central fixation target and the appearance of an eccentric target. METHODS: Ten healthy subjects made horizontal pro- or antisaccades in response to lateralized cues after a gap period of 200 ms. Single-pulse transcranial magnetic stimulation (TMS) was applied to the dorsolateral prefrontal cortex (DLPFC), frontal eye field (FEF), or supplementary eye field (SEF) of the right hemisphere 100 or 200 ms after the disappearance of the fixation point. Saccade latencies were measured to probe the disruptive effect of TMS on saccade preparation. In six individuals, we gave realistic sham TMS during the gap period to mimic auditory and somatosensory stimulation without stimulating the cortex. RESULTS: TMS to DLPFC, FEF, or SEF increased the latencies of contraversive pro- and antisaccades. This TMS-induced delay of saccade initiation was particularly evident in conditions with a relatively high level of preparatory set activity: The increase in saccade latency was more pronounced at the end of the gap period and when participants prepared for prosaccades rather than antisaccades. Although the "lesion effect" of TMS was stronger with prefrontal TMS, TMS to FEF or SEF also interfered with the initiation of saccades. The delay in saccade onset induced by real TMS was not caused by non-specific effects because sham stimulation shortened the latencies of contra- and ipsiversive anti-saccades, presumably due to intersensory facilitation. CONCLUSION: Our results are compatible with the view that the "preparatory set" for contraversive saccades is represented in a distributed cortical network, including the contralateral DLPFC, FEF and SEF.

The cerebellum in the cerebro-cerebellar network for the control of eye and hand movements--an fMRI study.

The coordination of optical information and manipulation of objects in space by eye and hand movements is controlled by a cerebro-cerebellar network. The differential influence of prefrontal, motor, or parietal areas in combination with cerebellar areas, especially within the posterior hemispheres, on the control of eye and hand movements is not very well defined. Using fMRI we investigated the functional representation of isolated or combined eye and hand movements within the cerebellum and the impact of differential cognitive preload on the activation patterns. Each task consisted of the performance of saccades or hand movements triggered by a cue presented on a screen in front of the scanner. Saccades were tested for visually guided saccades, triple step saccades, and for visuospatial memory. Sequential finger opposition movements were tested for predictive and nonpredictive movements. Combined and isolated eye-hand reaching movements were tested toward a target presented in 5 different horizontal positions. Visually guided saccades activated the cerebellar vermis lobuli VI-VII, triple step saccades, including visuospatial memorization, in addition the cerebellar hemispheres lobuli VII-VIII. Sequential finger movements and reaching movements activated a cerebellar network consisting of the lobuli IV-VI, the vermis, and the lobuli VII-VIII with broader areas and additional regions especially within the lobus VII for more complex movements. The combined in contrast to the isolated performance of eye and hand movements demonstrated specialized activation foci within the cerebellar vermis and posterior hemispheres. We could demonstrate a differential representation of eye and hand movements within the cerebellum. Additional "cognitive" preload within a given task leads to additional activation of the posterior cerebellar hemispheres, with a subspecialization corresponding to premotor and parietal area connections.

Three-dimensional cytoarchitectonic analysis of the posterior bank of the human precentral sulcus.

Studies employing functional magnetic resonance imaging have identified the human frontal eye field as being in the anterior and partly in the posterior wall, as well as at the base of the precentral sulcus. Moreover, it is known that the frontal eye field extends rostrally to the superior frontal sulcus. According to Brodmann's cytoarchitectonic map, this region belongs to the dysgranular Brodmann area 6 of the premotor cortex. However, the frontal eye field in non-human primates has been located within the arcuate sulcus in Brodmann area 8, generating considerable debate about where to locate exactly the frontal eye field in humans. Functional studies of the primate frontal eye field have revealed a principal homology of voluntary saccadic control systems in human and old-world monkeys, especially the macaque. But these homologies seem to be contradicted by the reported topographic localization at the cytoarchitectonic level. Therefore, we studied the cytoarchitectonic structure of the posterior bank of the precentral sulcus of a human brain, employing newly developed spatial mapping techniques to provide data about whether or not this region should be considered cytoarchitecturally homogeneous or heterogeneous. We used functional magnetic resonance imaging results, as an initial guide in localizing a region which is activated by saccadic tasks. A maximum of activation was detected around the junction of the superior frontal sulcus and the precentral sulcus extending 1.5 cm along the precentral sulcus in direction of the lateral sulcus. Here, one human brain has been analyzed to obtain preliminary data about the cytoarchitectonical changes of a part of area 6. Statistical analysis of the three-dimensional architectonic data from this region allowed us to identify a zone at the posterior bank, which in other studies has been associated with a functional region that controls pursuit eye movements and performs sensory-to-motor transformations. We found two significant sectors along the ventral part of the posterior bank of the precentral sulcus. The caudal transition region coincides partly with a region that integrates retinal and eye position signals for target location, arm, and axial movements. The second more ventrally located region is attributed to process oral-facial movements. The caudal transition region coincides with our functional magnetic resonance imaging investigation. It was revealed that this region lies at the inferior frontal eye field, where a pronounced activation over a larger region can be stimulated. Currently, more studies are needed to combine functional magnetic resonance imaging data of maximal activation with data from whole histologic brain sections of more individuals and to quantify the variability of this region and its sub-regions by means of a standardized brain atlas.

Distinguishing schizophrenic patients from healthy controls by quantitative measurement of eye movement parameters.

BACKGROUND: Eye tracking dysfunction is a putative trait marker for susceptibility to schizophrenia; however, it cannot be recommended as an additional tool for the diagnosis of schizophrenia, due to low sensitivity and specificity. METHODS: To assess the diagnostic potentials of combinations of eye movement paradigms, four smooth pursuit experiments (1: constant velocity of 15 degrees/sec; 2 and 3: combination with either visual or auditory distractors; 4: constant velocity of 30 degrees/sec) and two saccadic eye movement experiments (1: reflexive saccades; 2: voluntary saccades) were conducted. Fourteen patients with residual schizophrenia and 17 healthy controls were studied. Two sets of discriminant analyses (each with the resubstitution and with the "leaving one out" method) were calculated. RESULTS: In the first set, all 10 characteristic variables were included, whereas for the second set, the three most powerful parameters were selected (two from smooth pursuit tasks and one from a voluntary saccade experiment). This procedure provided the best classification results, regarding concordance between clinical diagnoses and eye movement dysfunction (kappa = .67-.80). CONCLUSIONS: Schizophrenic patients of the residual subtype can be differentiated from healthy individuals with considerable criterion validity on the basis of paradigms from two different ocular motor systems.

Oculomotor testing in the differential diagnosis of degenerative ataxic disorders.

BACKGROUND: Oculomotor abnormalities have been reported in patients with degenerative ataxic disorders. OBJECTIVE: To assess the diagnostic sensitivity and specificity of oculomotor deficits in patients with Friedreich ataxia (FA), cerebellar atrophy (CA), and olivopontocerebellar atrophy (OPCA). SETTING: Neurology clinic at a university hospital in Lübeck, Germany. PATIENTS: Seven patients with FA, 9 with CA, and 10 with OPCA were studied. These patients were selected from an ongoing follow-up study. MAIN OUTCOME MEASURES: Eye movements were recorded by electro-oculography; an extensive battery of quantitative tests was used. RESULTS: A proven CAG repeat expansion on chromosome 6 or 14 was significantly associated with reduced saccadic eye velocity and vertical gaze palsy (P<.001, Mann-Whitney U test). All 6 patients with OPCA and slow saccades had an autosomal-dominant inheritance; 4 of them were proved to have spinocerebellar atrophy type 1. In 9 of these patients (4 with FA, 1 with CA, and 4 with OPCA), the genetic defect could not be identified. Saccadic dysmetria, impairment of smooth pursuit and optokinetic nystagmus, deficient suppression of the vestibulo-ocular reflex by either visual or otolith input, and pathological nystagmus were attributed to degenerative lesions in different parts of the cerebellum. However, these symptoms failed to clearly distinguish between the different groups of patients, whereas decreased vestibulo-ocular reflex gain, slow saccades, and vertical gaze palsy pointed to an extracerebellar manifestation of the degenerative disease, occurring only in patients with OPCA and FA. CONCLUSIONS: In this prospective study, oculomotor disturbances were mainly related to cerebellar dysfunction. Only a few of them were caused by extracerebellar manifestations of the disease, such as slowing of saccades, which was characteristic for patients with OPCA of autosomal-dominant inheritance.

Perilymph fistula associated with pulse-synchronous eye oscillations.

Three-dimensional eye movements (scleral search coil system) were recorded in a patient with a surgically acquired perilymph fistula of the left horizontal semicircular canal. Spontaneous horizontal pendular nystagmus was found to be related to the heart rate and may be caused by pressure transfer of blood pulses to the labyrinth. In addition, a contralesional horizontal jerk nystagmus was elicited by Valsalva maneuver, indicating that Ewald's first law may not only be valid for excitation but also for inhibition.

The role of GABAergic inhibition in the response properties of neurones in cat visual area 18.

Bicuculline methiodide was iontophoretically applied to single neurones in cat area 18 to investigate how removal of gamma-aminobutyrate mediated inhibition affects the visual response properties. Moving sinusoidal gratings were used to study spatial and temporal response characteristics. Orientation sensitivity and spatial and temporal frequency tuning curves were determined with and without iontophoretically applied bicuculline. In most neurones, orientation sensitivity and spatial frequency tuning remained largely unaffected, whereas temporal frequency tuning was very much broadened. It is suggested that the dominant excitatory input to area 18 cells is a spatially organized input from area 17 and local inhibition in area 18 sharpens primarily temporal selectivity. An alternative explanation of our results would be that the distribution of synapses mediating temporal tuning in area 18 is fundamentally different from that mediating spatial frequency and orientation tuning, which may be located at sites distant from the cell body and relatively inaccessible to the drug application.

Visual search in patients with left visual hemineglect.

In patients with hemi-spatial neglect eye movement patterns during visual search reflect not only inattention for the contralesional hemi-field, but interacting deficits of multiple visuo-spatial and cognitive functions, even in the ipsilesional hemi-field. Evidence for these deficits is presented from the literature and from saccadic scan-path analysis during feature and conjunction search in 10 healthy subjects and in 10 patients with manifest or recovered left visual neglect due to right-hemispheric stroke. Deficits include (1) a rightward shift of spatial representation, (2) deficient spatial working memory and failure of systematic search strategies, leading to multiple re-fixations, more after frontal lesions, and (3) a reduced spotlight of attention and a deficient pop-out effect of color, more after temporo-parietal lesions.

Reduction of P3b in patients with temporo-parietal lesions.

By recording event-related EEG potentials from patients with frontal, parietal, or temporo-parietal lesions, we wanted to determine the cortical area that is relevant to the P3b component, replicating the approach used by Knight and associates who found reduced P3bs in patients with temporo-parietal lesions. They used auditory and somatosensory stimuli. We wanted to replicate their findings in auditory and visual oddball tasks and analysed potentials evoked by targets and by standard stimuli. Temporo-parietal patients' P3bs were reduced with auditory targets and lacked a distinct Pz maximum with visual targets. Further, auditory N1 was reduced both with targets and standards, P3 to visual standards and P2 to auditory standards were reduced. Parietal patients' P3bs differed only slightly from the control group, being somewhat reduced over the lesioned hemisphere with visual stimuli. Their P3 to visual standards was, however, reduced to the same extent as was the temporo-parietal patients'. Frontal patients did not differ from the control group both in their P3b and in their P3 to standards but had a number of conspicuous features in modality-specific components. In sum, our results on P3b (as well as on N1) replicate Knight's findings, confirming his conclusion that integrity of the temporo-parietal junction is critical for P3b. Implications for hypotheses on P3 are discussed.

The effect of oral ethanol consumption on eye movements in healthy volunteers.

Horizontal and vertical eye movements were recorded and analysed with an infrared photoelectric technique in 12 healthy volunteers under various blood alcohol concentrations (0.0, 0.5, 1.0 g/kg body weight, [% per thousand]). The predictive smooth-pursuit tracking and saccadic eye movements were studied in response to unpredictable target jumps and during scanning of a classical kitchen scene and a traffic scene. Smooth-pursuit eye movement gain value decreased dose-dependently and was compensated by an increased number of catch-up saccades. With increasing blood alcohol concentrations peak velocities of horizontal and vertical visually guided reflexive saccades decreased while their latencies to the target increased. At blood alcohol concentrations of 0.5% per thousand and 1.0% per thousand healthy volunteers showed significantly longer mean fixation durations and a lower total number of exploratory saccades when scanning both the classical kitchen scene and the traffic scene. Surprisingly, in both of these scanning tasks the total fixation duration or the relative number of exploratory saccades increased in those scene sectors in which exciting situations were presented. Additionally, the time interval needed to foveate these exciting areas for the first time increased, probably due to an attention deficit. In conclusion, these findings indicate that alcohol consumption impairs the velocity and initiation of saccadic and smooth-pursuit eye movements, but that subjects can nevertheless still recognize exciting and relevant areas of visual scenes. The significant increase in fixation time, however, does not allow scanning of the entire visual scene during an adequate period of time. Therefore the reduced visual exploration caused by alcohol reflects an impaired sensorimotor processing of active visual perception.

Impairment of vertical motion detection and downgaze palsy due to rostral midbrain infarction.

We present two cases with acute onset of vertical gaze palsy, mainly consisting of impaired downgaze and apraxia of downward head movements, together with neuropsychological deficits (hypersomnia, impaired attention and disorders of memory and affective control). CT and MRI revealed bilateral post-ischaemic lesions in the dorsomedial thalamus and the mesodiencephalic junction, dorsomedial to the red nucleus, thus being restricted to the territory of the posterior thalamosubthalamic paramedian artery, which includes the region of the rostral interstitial nucleus of the medial longitudinal fascicle as the main premotor nucleus for the generation of vertical saccades. In our patients, oculographic examination with electro-oculography and magnetic search coil recording showed severe impairment of downward more than upward saccades and only minor deficits of vertical pursuit and the vestibulo-ocular reflex. Visual functions were normal, with one exception: a psychophysical test of motion perception revealed a significant deficit in the detection of vertical movements. This could be due to a central adaptive mechanism which, in order to minimize oscillopsia, might elevate thresholds for vertical motion perception in cases of vertical gaze palsy. As an alternative explanation, lesions within the midbrain tegmentum could have damaged subcortical visual pathways involved in motion perception.

Slow saccades and other eye movement disorders in spinocerebellar atrophy type 1.

In order to study the relation between genotype and phenotype, a detailed study of the course of oculomotor deficits was performed in three patients with autosomal-dominant cerebellar ataxia, subtype spinocerebellar atrophy type 1 (SCA 1) using clinical testing and electrooculography. DNA analysis revealed a CAG repeat expansion of 65 in the SCA 1 gene on chromosome 6p in all patients. A progressive disorder of the saccadic system became obvious, leading to a marked slowing of saccadic eye movements and loss of pathological and physiological nystagmus. An upward gaze palsy developed early, followed by horizontal and downward gaze palsy at a later state of the disease. Smooth pursuit eye movements were disturbed to a lesser extent; the vestibulo-ocular reflex was reduced. As an additional feature, severe loss of visual acuity developed due to progressive optic nerve atrophy. The oculomotor deficits can be explained by progressive damage to the brain stem rather than to the cerebellum. Each combination of oculomotor deficits with or without optic atrophy may occur irrespective of the gene locus of the disease, making a correlation between clinical signs and genetic findings difficult.

Representation of edges of variable blur by neuronal responses in the lateral geniculate body and the visual cortex of cats: limits of linear prediction.

We have measured the responses of cells in the cats lateral geniculate body and the visual cortex to edges which were blurred to various degrees (cosinusoidal blur). For the same cells also the responses were determined to sinusoidal gratings of various fundamental frequency and to slits of various blur and width. All stimuli were moved across the receptive fields at various speeds. The responses of most cells increased with increasing edge sharpness, but usually reached a maximum at a blur corresponding to a high frequency cutoff at 0.6-1.2 c/deg. The responses to the sharpest edges were usually smaller than those to a blurred edge (up to -50% in individual cells and -15% in the average). After normalization, the responses predicted from the spatial frequency tuning curves and the Fourier transform of the edge stimuli corresponded well to the measured blur functions up to the maximum of the edge response which varied considerably between cells, however. At edge sharpness beyond that maximum, the predicted curves rose up to edge sharpness with high frequency cutoff 1.6-1.8 times above that which produced the experimental neuronal response maximum. On the other hand, responses could increase with edge sharpening in spatial frequency regions, in which no or only small responses were seen with sinusoidal gratings (e.g. at lower spatial frequencies in "band pass neurons"). Geniculate X- and cortical simple cells as well as those geniculate Y-cells which showed phase locked grating responses behaved similarly in all respects. We concluded that edge sharpness is not represented by response amplitude of individual neurons but by the spatial distribution of excitatory peaks across the representation of the retinotopic cortical map. Our findings further indicate that spatial models of receptive fields assuming linear signal summation have only a limited value for predicting edge sharpness.