Doppler and Duplex Sonography for the Diagnosis of the Irreversible Cessation of Brain Function ("Brain Death"): Current Guidelines in Germany and Neighboring Countries.

Extra- and transcranial sonography of brain-supplying arteries is accepted worldwide in brain death protocols as a valid "ancillary" method of proving brain circulatory arrest. Color-coded duplex sonography and CT angiography have been newly incorporated in the fourth update of the German Medical Association's guidelines for the determination of the irreversible cessation of brain function ("brain death"), effective July 2015. The updated guidelines address in more detail the diagnostic procedures and the required qualifications of the examiners. The present article summarizes the guidelines and the recommendations regarding the application and documentation of ultrasound findings for the diagnosis of brain circulatory arrest in children and adults, as valid in Germany. The method, limitations, and procedure in the case of inconclusive findings are described. Age-related minimum values of mean arterial pressure for the diagnosis of cerebral circulatory arrest in children are presented. A concise overview of the respective regulations for the use of sonography for diagnosing brain death in other countries, especially in the countries neighboring Germany, is given.

7 Tesla MRI demonstrates vascular pathology in Balo's concentric sclerosis.

Baló's concentric sclerosis (BCS) is an inflammatory demyelinating disease related to multiple sclerosis; its underlying pathology remains unclear. At 7 T MRI in a 19-year-old female BCS patient, microhaemorrhages and ectatic veins were found in T2 hyperintense regions, features which have not been previously reported in conjunction with BCS, and these findings may support the view that vascular pathology plays a role in BCS. MRS data suggest that neuron loss and lipid turnover still took place months after a remission. Plasma exchange was effective in treating a relapse with severe motor deficits, and the off-label use of natalizumab was successful in maintaining remission in this patient.

Altrenogest treatment reduces the stress response of three-year-old warmblood mares during their initial equestrian training.

Horse mares are frequently treated with the progestin altrenogest with the aim to suppress estrous behavior and its negative impact on equestrian performance. Progestogens, however, also have sedative effects in males, and females of different species. The aim of our study was therefore to investigate altrenogest-induced changes in the stress response of female horses during initial equestrian training. Three-yr-old Warmblood mares were randomly assigned to treatment with altrenogest (ALT; 0.044 mg/kg once daily; n = 6) or sunflower oil (CON; n = 5) for 12 wk during training. At predefined steps of the training program (free movement, lunging without and with side reins, lunging with saddle, mounting of a rider, free riding, riding by an unfamiliar rider) salivary cortisol concentration, and heart rate were determined from 60 min before to 120 min after training. The same procedures were performed during repeated gynecologic examinations and 2 novel object tests. Bodyweight and body condition scores (BCS) were assessed at 4-wk intervals. During all training units, salivary cortisol concentration and heart rate increased (P < 0.001), but the increase was smaller in group ALT mares (time x treatment P < 0.001). Gynecologic examinations and novel object tests induced a much smaller increase in cortisol and heart rate (P < 0.001) than equestrian training with no difference between groups ALT and CON. Initially, bodyweight, and BCS decreased during training. The subsequent increase was larger in group ALT vs CON (time x treatment P < 0.05). In conclusion, altrenogest reduced the stress response of 3-yr-old mares to equestrian training. The use of altrenogest during equestrian competitions should therefore be reconsidered.

Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study.

BACKGROUND: Early occurrence of small-fibre neuropathy (SFN) is a common feature of Fabry disease (FD) - an X-linked storage disorder caused by reduced activity of the α-galactosidase A (α-GAL). Although SFN may result from different disorders, the cause is often unclear. Therefore, we investigated the frequency of FD in patients with SFN of unknown aetiology. METHODS: Patients with idiopathic SFN, established by sensory quantitative testing and/or skin biopsy, were examined for mutations in the α-GAL gene. Where mutations in the α-GAL gene were identified, levels of globotriaosylceramide (Gb(3)) were measured in urine and blood and the α-GAL activity was evaluated. When new mutations were detected, a diagnostic work-up was performed as well as a Gb(3) accumulation in the skin, lyso-Gb(3) in blood and Gb(3)_24 in urine were proved. RESULTS: Twenty-four of 29 eligible patients were enrolled in the study. Mutations in the α-GAL gene were observed in five patients. A typical mutation for FD (c.424T>C, [C142R]) was detected in one patient. In four patients, a complex intronic haplotype within the α-GAL gene (IVS0-10C>T [rs2071225], IVS4-16A>G [rs2071397], IVS6-22C>T [rs2071228]) was identified. The relevance of this haplotype in the pathogenesis of FD remains unclear until now. However, these patients showed increased concentrations of Gb(3) and/or lyso-Gb(3), while no further manifestations for FD could be proved. CONCLUSIONS: Fabry disease should be considered in patients with SFN of unknown aetiology, and screening for FD should be included in the diagnostic guidelines for SFN. The significance of the intronic haplotype regarding SFN needs further evaluation.

[Cognitive deterioration after cardiosurgery]. / Kognitive Störungen nach kardiochirurgischen Eingriffen.

Over 100,000 heart surgeries are performed in Germany annually. Although severe neurological complications like ischaemic strokes have meanwhile become rare occurrences, subtle neuropsychological changes are still frequently recognized after major heart surgeries. The hitherto unsolved problem of postoperative cognitive decline (POCD) is portrayed in this article. Multifactorial aetiologies including microembolism and preoperative risk factors are supposed to play a significant role in POCD. A variety of neuroprotective strategies such as intraoperative microemboli filtration have been suggested to minimize cerebral risks. The utility of neuroprotective methods has recently been verified in randomized studies.

Transient suppression of ovulatory ovarian function in pony mares after treatment with slow-release deslorelin implants.

Behavior during the estrous cycle of mares can affect their performance and therefore inhibition of cyclical ovarian activity is indicated. We hypothesized that implants containing the GnRH analog deslorelin downregulate GnRH receptors and inhibit ovulation in mares. The estrous cycles of Shetland mares were synchronized with 2 injections of a PGF2α analog. One day after the second injection (day 0), mares received 9.4 (group D1, n = 6) and 4.7 mg deslorelin (D2, n = 5) as slow-release implants or 1.25 mg short-acting deslorelin as a control (C, n = 5). Ultrasonography of the reproductive tract and ovaries and observation of estrous behavior and collection of blood samples for analysis of progesterone and LH concentrations were performed every second day until day 10 and thereafter at 5-d intervals. Stimulation tests with the GnRH-agonist buserelin were performed on days 10 and 45. Until day 50, there were less spontaneous ovulations in group D1 (P < 0.01) and estrous behavior was reduced in groups D1 and D2 compared with group C (P < 0.05). The time until first ovulation (D1 62.0 ± 8.6, D2 44.2 ± 14.1, C 22.2 ± 3.1 d, P < 0.05) and the number of days with estrous behavior (P < 0.05) differed among groups. On day 10 after treatment, a GnRH stimulation test revealed interactions between group and time (P < 0.001) in plasma LH concentration that were no longer detectable on day 45 after treatment. In conclusion, long-acting deslorelin implants result in a transient downregulation of pituitary GnRH receptors that is associated with inhibition of ovulation and estrous behavior in Shetland mares.

A simultaneous EEG and transcranial Doppler technique to investigate the neurovascular coupling in the human visual cortex.

Due to lacking energy stores, high energy consumption and dependency on a strict aerobic glycolysis, the brain is very dependent on an adequate blood supply of active neurons. Adequate regulation of the functionally induced local cerebral blood flow is assured by neurovascular coupling. Our understanding of its role in different disease processes has improved considerably in the last few years. Consequently, a diagnostic tool is needed which allows an easy and cost-effective investigation of the coupling in clinical conditions. A combined EEG and Doppler technique might be suitable in this regard. This review gives a short overview of the neurophysiological background and the techniques, before validation studies and first clinical applications are addressed.

Severity of coronary artery disease but not degree of coronary stenosis is correlated to cerebrovascular reactivity.

BACKGROUND: A decade difference in peak incidences of coronary and cerebral ischemia assumes a protection of the brain vasculature. Therefore, we hypothesize that early indicators of cerebrovascular disease such as parameters of the neurovascular coupling show a higher correlation to coronary artery disease than morphologic parameters. METHODS: Stenotic degree (%) of coronary arteries (RCA, LCA, LAD, RCX) was determined together with the Gensini score by angiography in 96 patients (80 men; 62 +/- 10 years), which were grouped according to disease severity (sclerosis, 1-vessel disease (VD), 2-VD, 3-VD). Presence of internal carotid artery stenosis and left ventricular ejection fraction (LVEF) were established with duplex sonography. Resting and visually evoked hemodynamic responses were measured with transcranial Doppler ultrasound in both posterior cerebral arteries and expressed in terms of control system parameters. These were gain, natural frequency, attenuation, and rate time. Group differences and correlations between stenosis and parameters of vasoreactivity were tested. RESULTS: Groups differed in stenotic degree of coronary arteries, Gensini score, LVEF, carotid artery stenosis, resting flow velocity, and evoked responses (gain, p < 0.005; attenuation, p < 0.05). Stenosis of each coronary artery and LVEF were correlated to carotid artery stenosis but no association was found to cerebrovascular parameters. Only severity of coronary artery disease and the Gensini score were associated with disturbed cerebrovascular reactivity. Carotid artery stenosis was associated with decreased cerebrovascular parameters (attenuation, p < 0.05; rate time, p < 0.01). CONCLUSIONS: Although atherosclerosis is a systemic disease our data support concepts of a heterogeneous distribution of the disease indicating protection of brain vessels.

Synaptophysin is an autoantigen in paraneoplastic neuropathy.

Paraneoplastic neurological syndromes (PNS) are often associated with antineuronal autoantibodies and many of them could be identified in the recent years. However, there are still new antineuronal binding patterns with yet unidentified autoantigens. We here describe a new autoantibody associated with paraneoplastic sensorimotor and autonomic neuropathy in a patient with small cell lung cancer. In indirect immunofluorescence test, the patient's serum colocalised with the synaptic protein synaptophysin in the cerebellum and myenteric plexus of the gut. Immunoblotting showed a 38 kDa reactivity, which is also the molecular weight of synaptophysin. Therefore a Western Blot with recombinant synaptophysin has been used and revealed reactivity of the serum against synaptophysin. In patients with non-paraneoplastic neuropathies or healthy controls, anti-synaptophysin autoantibodies were not detectable. In 20 SCLC patients without neurological syndromes, two patients had low-titer anti-synaptophysin autoantibodies. The patient's serum and IgG fraction showed cytotoxicity to primary cultured myenteric plexus neurons. We conclude that synaptophysin is an autoantigen in paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes in patients with carcinoid.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are mainly associated with small-cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin-related myopathy. We report four patients with a PNS associated with carcinoid. PATIENTS AND RESULTS: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti-Hu, one anti-Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated. CONCLUSION: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody-associated PNS.

IgG subclass distribution of autoantibodies in pediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) in children is a rare disorder including a severe eye movement disturbance, myoclonia, ataxia and often developmental retardation. Both OMS forms, idiopathic or neuroblastoma-associated (paraneoplastic), have been suspected to be autoimmune. Recently, autoantibodies have been found in OMS sera. We here show that autoantibodies in OMS, both intracellular and surface binding, belong mainly to the IgG3 subclass, although the total serum IgG3 level is normal. These results support the autoimmune hypothesis and point to a protein autoantigen as antigenic target.

Autoantibodies against glial antigens in paraneoplastic neurological diseases.

Paraneoplastic neurological syndromes are clinically heterogeneous manifestations of cancer, but are not caused by the tumor or its metastases. Because autoantibodies reacting with tumor and nervous system tissue have been described, an autoimmune pathogenesis is suspected. Most autoantibodies are directed against neuronal proteins. Here, we describe the impact of antiglial autoantibodies in paraneoplastic neurological syndromes. Anti-CRMP5 and antiglial nuclear antibody both can be associated with different paraneoplastic neurological syndromes and tumors.

Autoimmunity in complex-regional pain syndrome.

Complex regional pain syndrome (CRPS) is an etiologically unclear syndrome with the main symptoms being pain, trophic and autonomic disturbances, and functional impairment that develops after limb trauma or operation and is located at the distal site of the affected limb. Because autoantibodies against nervous system structures have been described in these patients, an autoimmune etiology of CRPS is discussed. These autoantibodies bind to the surface of peripheral autonomic neurons. Using a competitive binding assay, it can be shown that at least some of the CRPS sera bind to the same neuronal epitope. Autoimmune etiology of CRPS is a new pathophysiological concept and may have severe impact on the treatment of this often chronic disease.

New autoantibodies in pediatric opsoclonus myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is a rare neurologic disorder comprising the main symptoms of eye-movement disturbances, muscle jerks, and severe ataxia. In children and adults, some cases are associated with a tumor as a paraneoplastic syndrome, whereas in children the paraneoplastic form is almost exclusively associated with neuroblastoma. The detection of autoantibodies in some OMS sera led to the hypothesis that the syndrome is of autoimmune origin. Beside autoantibodies against intracellular proteins, such as anti-Hu, alpha-enolase, and KHSRP, specific binding of autoantibodies to the surface of neuroblastoma cells and cerebellar granular neurons have been found. Antiproliferative and proapoptotic effects of these autoantibodies on neuroblastoma cell lines were noted as well. These results support the concept of a humoral autoimmune process in the pathogenesis of OMS.

Experimental stroke: ischaemic lesion volume and oedema formation differ among rat strains (a comparison between Wistar and Sprague-Dawley rats using MRI).

Investigating focal cerebral ischaemia requires animal models that are relevant to human stroke. This study was designed to evaluate the influence of early reperfusion and choice of rat strains on infarct volume and oedema formation. Thirty-six Wistar and Sprague-Dawley rats were subjected to temporary middle cerebral artery occlusion (MCAO) for 90 min (groups I and II) or to permanent MCAO (groups III and IV) using the suture technique. Ischaemic lesion volume and oedema formation were quantified 24 h after MCAO using 7T-magnetic resonance imaging (MRI). Impact of rat strains: Reperfusion led to significant larger ischaemic lesion volumes in Wistar rats as compared to Sprague-Dawley rats (P<0.0005). Oedema formation was similar in both rat strains. Permanent MCAO led to significantly larger ischaemic lesion volumes in Sprague-Dawley rats (P<0.05). Oedema formation, however, was significantly more accentuated in Wistar rats (P<0.005). Impact of reperfusion: Reperfusion did not cause any changes in ischaemic lesion volume in Wistar rats. Oedema formation, however, was significantly reduced (P<0.0005). In Sprague-Dawley rats, reperfusion caused a significant reduction of ischaemic lesion volume (P<0.00005), but did not modify oedema formation. These findings emphasize the critical importance of rat strain differences in experimental stroke research.

Upper cranial nerve palsy resulting from spontaneous carotid dissection.

INTRODUCTION: Upper cranial nerve palsy has a variety of causes such as cerebral and nerve ischemia, diabetes, infectious and non-infectious meningitis, subarachnoid hemorrhage and intracranial aneurysm. CASE 1 : A 45-year-old man suffered from holocephalic headaches and a right-sided neck pain for two weeks. He presented to our emergency department because of a sudden ptosis of the right eye. On admission neurological examination revealed a right sided Horner's syndrome and hypesthesia of the right side of the face. Magnetic resonance angiography identified a circumscribed dissection of the right extracranial internal carotid artery originating from the carotid bifurcation. Conventional angiography 2 weeks later showed a nearly recanalized artery. CASE 2 : A 55-year-old previously healthy man without cardiovascular risk factors developed right sided neck pain when loading a seeder with several sacks of crop. A few hours later he noticed a left-sided weakness. On admission a severe left sided hemiparesis and a mild neglect were present. Duplex sonography revealed a right-sided distal internal carotid artery (ICA) occlusion. The next morning the patient complained of double vision; he had a right-sided pupil-sparing oculomotor palsy. The diagnosis of ICA dissection was confirmed by conventional angiography, at that time showing a partially recanalized ICA without involvement of the cavernous region by the dissection. CONCLUSION: ICA dissection must be included in the differential diagnosis of upper cranial nerve palsy and should be assessed by duplex ultrasound and magnetic resonance imaging. A possible explanation is nerve ischemia due to a transient or permanent interruption of the blood supply by compression of the vasa nervorum originating from the intracranial carotid artery.

Horticultural Performance of Eight American Elderberry Genotypes at Three Missouri Locations.

American elderberry (Sambucus nigra subsp. canadensis) is being increasingly cultivated in North America for its edible and medicinal fruit and flowers, yet remains largely undeveloped as a horticultural crop. Productive genotypes with desirable horticultural attributes, including disease and insect resistance, precocity, uniform fruit ripening, and large berry size are needed in order to advance the commercial production of elderberries. A four-year study of eight elderberry genotypes was established in 2008 at three diverse Missouri (USA) locations. Phenology, plant morphology, pest susceptibility, productivity, and fruit characteristics data were collected over three growing seasons, 2009-2011. Significant differences for most phenological, horticultural, and fruit juice characteristics were observed among the three sites, three years, and eight genotypes. The genotype 'Ozark' was the earliest to break bud, produced fruit with high levels of soluble solids, and out-yielded most other genotypes at the three sites over the three-year study. None of the new genotypes produced berries as large as or larger than the standard 'York' which is known for its large fruit. Some of the genotypes tested, especially 'Ozark' show promise as potential cultivars and as breeding stock for further development of elderberry as a commercially-viable horticultural crop.

Occurrence of Polyphenols, Organic Acids, and Sugars among Diverse Elderberry Genotypes Grown in Three Missouri (USA) Locations.

Elderberry (Sambucus spp.) is an emerging horticultural crop used in a variety of foods, wines, and dietary supplements. A better understanding of the elderberry juice complex including its putative health-promoting compounds in relation to genetic and environmental parameters is needed. A multi-location planting of nine elderberry genotypes was established in 2008 at three geographically-diverse sites in Missouri, USA. Fruits were harvested from replicated plots 2009-2011, frozen, and later prepared for laboratory analysis. Polyphenols, organic acids, and sugars were quantified by HPLC and the results evaluated for response to genotype, site, and year. The American genotypes 'Ocoee' and 'Ozark' were consistently higher in chlorogenic acids compared to other genotypes, whereas 'Ocoee' was significantly higher in rutin than 'Ozark'. The European 'Marge' was significantly higher in isoquercitrin and other flavonoids compared to most North American genotypes. Significant differences in polyphenols were also detected among sites and production years. Malic, citric, and tartaric acids varied significantly among genotypes, sites, and years, whereas succinic, shikimic, and fumaric acids generally did not. Levels of lactic, acetic, and propionic acids were negligible in most samples. The American genotype 'Ocoee' was higher in citric and tartaric acids, while lower in malic acid. The sugars glucose and fructose also responded significantly to genotype, site, and year. 'Ocoee', 'Ozark', and 'Marge' perform very well in Missouri horticulturally and appear to have additional potential as cultivars based on their unique juice characteristics.

'Marge': a European Elderberry for North American Producers.

Elderberries are being increasingly produced and consumed in North America for their edible and medicinal flowers and fruits. The American elderberry (Sambucus nigra subsp. canadensis) is native to, and most often cultivated in North America. The European elderberry (S. nigra subsp. nigra) has been developed into an economically-important horticultural crop in Europe, but most European cultivars do not perform well in the midwestern USA. The genotype S. nigra subsp. nigra 'Marge' is an open-pollinated seedling of S. nigra subsp. nigra 'Haschberg', which is one of the most popular elderberry cultivars grown in Europe. In a four-year study (one establishment year followed by 3 production years; 2008-2011) at three Missouri (USA) locations, 'Marge' significantly out-performed and out-yielded eight American elderberry genotypes within the same replicated field plots. Across 3 production years at all three sites, 'Marge' achieved budbreak later, flowered earlier, suffered less Eriophyid mite damage, was taller, produced larger berries, and yielded significantly greater amounts of fruit compared with all eight American elderberry genotypes in the study. At one site, 'Marge' produced three times the yield (1.89 kg/plant) compared with the next highest-producing American elderberry genotype (0.65 kg/plant). It is an exceptionally robust and drought-resistant elderberry. The phenotypic attributes of 'Marge' are similar to that of European elderberry except that it performs exceptionally well in the midwestern USA. DNA marker results, along with phenological and morphological characteristics, indicate that 'Marge' is a European elderberry (S. nigra subsp. nigra). As with most European genotypes, 'Marge' does not fruit on first-year wood, and will therefore require a different pruning regimen compared with American elderberry for success in North American production. We do not yet know how 'Marge' will perform outside the midwestern USA, but it is so productive, unique, and mite resistant, that it merits introduction as a cultivar.

Improvement of complex regional pain syndrome after plasmapheresis.

Complex regional pain syndrome is a severe complication following trauma that is associated with vasomotor, sudomotor and sensory disturbances in an affected limb or region of the body. The exact physiopathology is not fully understood yet. Recently, autoantibody findings suggested an immune-mediated physiopathology of the disease. We here describe two otherwise treatment-resistant patients with complex regional pain syndrome and high-titre beta2 adrenergic receptor autoantibodies, who did respond to plasmapheresis. Both patients showed strong improvement of pain and autonomic symptoms measured by impairment level sum score.