[COVID-19 and the central and peripheral nervous system]. / COVID-19: Auswirkungen auf das zentrale und periphere Nervensystem.

The health effects of coronavirus disease 2019 (COVID-19) caused by the infection of SARS-CoV­2 (severe acute respiratory syndrome coronavirus 2) are becoming increasingly clear as the pandemic spreads. In addition to the lungs, other organs are also affected, which can significantly influence morbidity and mortality. In particular, neurological symptoms involving the central nervous system can lead to acute or long-term consequences. The mechanisms of this neuropathogenesis of SARS-CoV­2 infection and its relation to acute and chronic neurological symptoms are the subject of current studies investigating a potential direct and indirect viral infection of the nervous system. The following review summarizes the current status of neuropathological manifestations, molecular pathogenesis, possible infection pathways in the nervous system, and systemic effects. In addition, an overview of the Germany-wide CNS-COVID19 registry and collaborations is presented, which should contribute to a better understanding of the neurological symptoms of COVID-19.

An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease.

AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

Demethylation of the hypoxia induction factor 1 binding site of GPX3 at excess blood ammonia in propionic acidemia.

OBJECTIVES: Elevated levels of metabolites such as ammonia and propionylcarnitine in propionic acidemia (PA) lead to an increased reactive oxygen species (ROS) production which could activate and stabilize the epigenetic regulated hypoxia-inducible factor-1α (HIF-1α). In order to evaluate the DNA methylation status of the HIF-1α binding site in PA, we investigated the antioxidant gluthatione peroxidase 3 gene (GPX3) promoter region. DESIGN AND METHODS: Using leukocyte DNA extracted from bloodspots collected 2-4 days after birth from diet free newborns, the cytosine phosphodiester bond guanine (CpG) dinucleotides of a HIF-1α binding site (CGTTTTTTACG) in the promoter region of GPX3 was retrospectively analysed. Patients included 7 PA. and 7 healthy controls (KO) respectively. RESULTS: A demethylated TGTTTTTTATG allele was detected in 3 PA patients with blood ammonia (NH3) concentrations of 500, 595, and 987 umol/L respectively; a demethylated/partial methylated TGTTTTTTAC/TG allele in 4 PA patients (2 PA with blood NH3 = 213, 271 umol/L respectively); a partial methylated C/TGTTTTTTAC/TG allele in 5 healthy controls respectively; a partial methylated/methylated C/TGTTTTTTACG allele in 2 healthy controls. CONCLUSION: Our results suggest that at excess NH3, the DNA methylation status of the HIF-1α binding site of GPX3 in newborns with PA is demethylated (TGTTTTTTATG allele). However, the demethylated allele has to be confirmed as a statistically significant change in more patients.

Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3.

Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies.

Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog.

Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenländische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known.

Duchenne muscular dystrophy in a 4-year-old girl due to heterozygous frame shift deletion of the dystrophin gene and skewed X-inactivation.

X-linked recessive diseases affect males, whereas female carriers are generally asymptomatic.We report on a 4-year-old girl who presented with a classical phenotype of Duchenne Muscular Dystrophy (DMD), a severe X-linked recessive type of muscular dystrophy affecting boys in early childhood.A thorough diagnostic work-up revealed that this resulted from a heterozygous out-of frame deletion in the DMD-gene in combination with an X-inactivation ratio of <10:90 in blood leukocytes and muscle.The case exemplifies that a skewed X-inactivation pattern has to be taken into account as mechanism causing clinical symptoms in female carriers of X-linked recessive disorders.

MERRF-like phenotype associated with a rare mitochondrial trnaile mutation (m.4284 G>A).

Nearly all patients affected by myoclonic epilepsy with ragged-red fibres (MERRF) harbour a mutation in the mitochondrial transfer RNALys gene. We report on an 8-year-old girl with clinical and diagnostic features of MERRF. After excluding one of the common mutations associated with MERRF, a complete sequence analysis of the mitochondrial genome revealed an m.4284 G>A mutation in the mitochondrial transfer RNAIle gene. This mutation has only once been described in a family with variable clinical symptoms, but has not yet been linked to MERRF. This case extends the mutational spectrum associated with the MERRF phenotype, and demonstrates the importance of performing a comprehensive mutational analysis in patients with suspected mitochondrial disease when common mutations have been ruled out.

New insights into the relationship of neurogenesis and affect: tickling induces hippocampal cell proliferation in rats emitting appetitive 50-kHz ultrasonic vocalizations.

Adult hippocampal cell proliferation (HCP) has been associated with psychopathology, especially depression. However, it is controversial whether a constitutively low rate of HCP is a trait predisposing an individual to psychopathology or whether HCP varies with the subject's affective state. We made use of a so-far neglected measure of affect, namely ultrasonic vocalizations, to gain new insights into the relationship of HCP and affect. Rats emit distinct types of ultrasonic vocalizations, which serve as situation-dependent affective signals. In appetitive situations, rats produce 50-kHz-calls, whereas 22-kHz-calls occur in aversive situations. We applied a standardized protocol of repeated tickling and assessed tickling-induced ultrasonic vocalizations as an index of the animals affect. Stereological quantifications of 5-bromo-2'-deoxyuridine (BrdU) and proliferating-cells-nuclear-antigen (PCNA) immunolabeled cells were used to estimate the rate of cell proliferation in the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. The rate of cell proliferation was compared between the groups of tickled vs. non-tickled rats and between subgroups of tickled rats defined by the effect of tickling on ultrasonic vocalizations. Tickling induced ultrasonic vocalizations in a subject-dependent manner. HCP correlated positively with appetitive 50-kHz-calls, but negatively with aversive 22-kHz-calls in individual animals, while cell proliferation in the subventricular zone was not associated with the emission of ultrasonic vocalizations. Repeated tickling did not change HCP in all rats, but increased HCP in the subgroup of rats, which experienced this procedure as appetitive, i.e. in rats emitting high numbers of 50-kHz-calls or low numbers of 22-kHz-calls. Together, these data indicate that the effect of tickling on HCP depends on an interaction between a predisposing trait and stimulation-dependent variations of the subject's affective state.

Serum GFAP is a diagnostic marker for glioblastoma multiforme.

A serum marker for malignant cerebral astrocytomas could improve both differential diagnosis and clinical management of brain tumour patients. To evaluate whether the serum concentration of glial fibrillary acidic protein (GFAP) may indicate glioblastoma multiforme (GBM) in patients with single supratentorial space-occupying lesions, we prospectively examined 50 consecutive patients with histologically proven GBM, World Health Organization (WHO) grade IV, 14 patients with anaplastic astrocytoma (WHO grade III), 4 patients with anaplastic oligodendroglioma, 13 patients with diffuse astrocytoma (WHO grade II), 17 patients with a single cerebral metastasis and 50 healthy controls. Serum was taken from the patients before tumour resection or stereotactic biopsy. Serum GFAP levels were determined using a commercially available ELISA test and were detectable in 40 out of the 50 GBM patients (median: 0.18 microg/l; range: 0-5.6 microg/l). The levels were significantly elevated compared with those of the non-GBM tumour patients and healthy controls (median: 0 mug/l; range: 0-0.024 microg/l; P < 0.0001, respectively). Non-GBM tumour patients and all healthy subjects showed zero serum GFAP levels. There was a significant correlation between tumour volume (Spearman Rho, CC = 0.47; 95% confidence interval, 0.2-0.67; P < 0.001), tumour necrosis volume (CC = 0.49; 95% confidence interval, 0.2-0.72; P = 0.004), the amount of necrotic GFAP positive cells (CC = 0.61; 95% confidence interval, 0.29-0.81; P = 0.007) and serum GFAP level among the GBM patients. A serum GFAP level of >0.05 microg/l was 76% sensitive and 100% specific for the diagnosis of GBM in patients with a single supratentorial mass lesion in this series. Therefore, it can be concluded that serum GFAP constitutes a diagnostic biomarker for GBM. Future studies should investigate whether serum GFAP could also be used to monitor therapeutic effects and whether it may have a prognostic value.

Xanthogranuloma of the sellar region.

The incidence of diagnosed xanthogranuloma of the sellar region is very low [1, 2, 5, 6]. We report about two cases 1) in a 57-year-old female and 2) in a 5-year-old boy. In both cases radiographic findings revealed an inhomogeneous, contrast enhancing sellar lesion. Histopathology showed the typical features of a xanthogranuloma of the sellar region with cholesterol clefts, lympho-plasmacellular infiltrates, marked hemosiderin deposits, multinucleated foreign body giant cells around cholesterol clefts, accumulation of macrophages and only small epithelial cell clusters [6]. As xanthogranuloma of the sellar region are rarely diagnosed we want to draw attention to this rather unusual diagnosis.

Profile of adult rat sensory neuron loss, apoptosis and replacement after sciatic nerve crush.

Following permanent transection of the adult rat sciatic nerve, sensory neuron apoptosis in the contributing L4 and L5 dorsal root ganglia can be observed for at least 6 months afterwards. To establish the profile of any sensory neuron apoptosis and loss over time when axonal regeneration is allowed, serial sections of L4 and L5 ganglia were examined and the neurons counted using a stereological technique 1, 2 and 3 months after crushing the right sciatic nerve at mid-thigh level. Our results show that an identical degree of sensory neuron loss and apoptosis occurs 1 month after crush as at 1 month after permanent transection. However, at 3 months no neurons undergoing apoptosis could be observed and no significant loss could be detected in the ipsilateral ganglia when compared to unoperated controls. One explanation was a neuronal replacement mechanism, which was investigated by administering bromodeoxyuridine to rats for 1 month after sciatic nerve transection or crush, prior to detection using immunohistochemistry on sections of their ganglia after 2 months. The presence of bromodeoxyuridine in the nuclei of occasional cells that would be counted as neurons on the basis of size and morphology indicates that a process of apparent neurogenesis may underlie the profile of sensory neuron loss after axotomy.

[Metastatic esthesioneuroblastoma. Challenge in interdisciplinary combined modality therapy]. / Metastasierendes Asthesioneuroblastom. Herausforderung an ein interdisziplinäres multimodales Therapiekonzept.

Esthesioneuroblastoma is a rare tumor, which in many cases is diagnosed at an advanced stage with an high recurrence rate and incidence of metastases. Regionary metastases predict a poor prognosis. There is no standard therapy approach for these tumors. The most widly accepted primary therapy is radical craniofacial enbloc resection followed by radiation therapy. Today chemotherapy is getting more important and is administered with curative intention. Multidisciplinary management results in significantly longer survival in advanced tumor stages and recurrence. A clinical staging system as well as histopathological grading according of Hyams could be from importance for selection and timing of the different therapeutic modalities. We present a case of a 34-year-old female patient who was diagnosed with an advanced olfactory neuroblastoma of the upper nasal cavity with bilateral cervical lymph node metastasis (modified Kadish-stage D). Craniofacial resection and bilateral neck dissection was performed, followed by postoperative radiotherapy. Reviewing the recent literature the different therapeutic approaches are compared and discussed.

Causes of perioperative stroke after carotid endarterectomy: special considerations in symptomatic patients.

In order to maximize the efficacy of carotid endarterectomy (CEA), the rate of perioperative stroke must be kept to a minimum. A recent analysis of carotid surgery at our institution found that most perioperative strokes were due to technical errors resulting in thrombosis or embolization. From 1992 through 1997 we have performed nearly 1200 additional CEAs; the purpose of this study was to examine recent trends in the causes of perioperative stroke, with specific attention to differences in symptomatic and asymptomatic patients. The records of 1041 patients undergoing 1165 CEAs were reviewed from a prospectively compiled database. Analysis of these data showed that a history of preoperative stroke appears to increase the risk of perioperative stroke after CEA. Surgical factors associated with perioperative stroke include an inability to tolerate clamping, use of an intraarterial shunt, and having surgery performed under general anesthesia; these factors are clearly interrelated and only the use of intraarterial shunting remains a risk factor by multivariate analysis. Over half of all perioperative strokes (54%) appear to be caused by intraoperative or postoperative thrombosis and embolization. The patient requiring use of intraarterial shunting and/or with a preoperative stroke most likely has a significant watershed area of brain at increased risk of infarction. However, technical errors are still the most common cause of perioperative stroke in these high-risk patients. Such high-risk patients may manifest clinical stroke from small emboli that may be tolerated by asymptomatic clamp-tolerant patients. Technical precision and appropriate cerebral protection are particularly critical for successful outcomes in high-risk patients.

Immediate reexploration for the perioperative neurologic event after carotid endarterectomy: is it worthwhile?

PURPOSE: When managing a new neurologic deficit after carotid endarterectomy (CEA), the surgeon is often preoccupied with determining the cause of the problem, requesting diagnostics tests, and deciding whether the patient should be surgically reexplored. The goal of this study was to analyze a series of perioperative neurologic events and to determine if careful analysis of their timing and mechanisms can predict which cases are likely to improve with reoperation. METHODS: A review of 2024 CEAs performed from 1985 to 1997 revealed 38 patients who manifested a neurologic deficit in the perioperative period (1.9%). These cases form the focus of this analysis. RESULTS: The causes of the events included intraoperative clamping ischemia in 5 patients (13.2%); thromboembolic events in 24 (63.2%); intracerebral hemorrhage in 5 (13.2%); and deficits unrelated to the operated artery in 4 (10.5%). Neurologic events manifesting in the first 24 hours after surgery were significantly more likely to be caused by thromboembolic events than by other causes of stroke (88.0% vs. 12.0%, P<.002); deficits manifesting after the first 24 hours were significantly more likely to be related to other causes. Of 25 deficits manifesting in the first 24 hours after surgery, 18 underwent immediate surgical reexploration. Intraluminal thrombus was noted in 15 of the 18 reexplorations (83. 3%); any technical defects were corrected. After the 18 reexplorations, in 12 cases there was either complete resolution of or significant improvement in the neurologic deficit that had been present (66.7%). CONCLUSIONS: Careful analysis of the timing and presentation of perioperative neurologic events after CEA can predict which cases are likely to improve with reoperation. Neurologic deficits that present during the first 24 hours after CEA are likely to be related to intraluminal thrombus formation and embolization. Unless another etiology for stroke has clearly been established, we think immediate reexploration of the artery without other confirmatory tests is mandatory to remove the embolic source and correct any technical problems. This will likely improve the neurologic outcome in these patients, because an uncorrected situation would lead to continued embolization and compromise.

Circadian rhythms in the renin-angiotensin system and adrenal steroids may contribute to the inverse blood pressure rhythm in hypertensive TGR(mREN-2)27 rats.

The transgenic TGR(mREN-2)27 rat is not only characterized by fulminant hypertension, but also by a disturbance in circadian blood pressure regulation, resulting in inverse circadian blood pressure profiles. The reasons for these alterations are not very well understood at present. We therefore investigated the circadian rhythms in several hormones participating in blood pressure regulation. From TGR and Sprague-Dawley (SPRD) control rats synchronized to 12h light and 12h dark (LD 12:12) blood was collected at different circadian times (07, 11, 15, 19, 23, 03, and 07 again, 5 rats per strain and time). The activities of plasma renin and converting enzyme, as well as plasma concentrations of corticosterone and aldosterone, were determined by radioimmunoassay (RIA). SPRD rats showed significant circadian rhythms in all variables except plasma renin activity, with maxima occurring during the day. TGR rats showed significant circadian rhythmicity in plasma renin activity and corticosterone and daily variation in aldosterone; angiotensin-converting enzyme (ACE) activity did not reach statistical significance. In TGR rats, 24h means in plasma renin activity and aldosterone were approximately sevenfold and fourfold higher, respectively, than in SPRD rats. Peak concentrations in corticosterone around 15h were more than two times higher in TGR rats than in SPRD rats, whereas no differences were observed during the night. It is concluded that, in TGR rats, the overall increase in plasma renin activity and aldosterone may contribute to the elevated blood pressure. The comparatively high levels in corticosterone and plasma renin activity during daytime may be involved in the inverse circadian blood pressure profiles in the transgenic animals.

Guidewire entrapment during deployment of the over-the-guidewire stainless steel Greenfield filter: a device design-related complication.

The Greenfield filter (Medi-tech/Boston Scientific, Watertown, Mass) is widely used for the prevention of pulmonary embolism. The latest version is a stainless steel over-the-wire filter. The purpose of the guidewire is to facilitate placement of the device down through the atrium or through tortuous vessels and to prevent tilting of the released filter. A case of entrapment of the guidewire in the filter after deployment through the right internal jugular approach and its recovery by reentering it into the sheath is presented. To prevent this complication, the guidewire should be removed completely before releasing this type of filter. The potential risk of tilting the filter does not outweigh the risk of guidewire entrapment.

Internal jugular vein thrombosis in association with the ovarian hyperstimulation syndrome.

Thrombosis of the internal jugular vein is a rare entity with the potential for serious consequences. Most of the reported cases of jugular venous thrombosis have occurred in the presence of an indwelling venous catheter, an established hypercoagulable state, or in association with head and neck sepsis. This report presents a case of a patient in whom jugular venous thrombosis developed during the first trimester of pregnancy after in vitro fertilization. Thromboembolism in these circumstances can be related to a condition known as the ovarian hyperstimulation syndrome. The presentation of severe neck pain in pregnant women, especially in those who have undergone assisted reproduction procedures, should prompt evaluation by duplex scan to evaluate the jugular veins for thrombosis. Anticoagulation is the treatment of choice.

A comparison of GABAC and rho subunit receptors from the white perch retina.

There is increasing evidence that GABAC receptors are composed of GABA rho subunits. In this study, we compared the properties of native GABAC receptors with those of receptors composed of a GABA rho subunit. A homologue of the GABA rho gene was cloned from a white perch (Roccus americana) retinal cDNA library. The clone (perch-s) has an open reading frame of 1422 nucleotide base pairs and encodes a predicted protein of 473 amino acids. It is highly homologous to GABA rho subunits cloned from human and rat retinas. The receptors (perch-s receptor) expressed by this gene in Xenopus oocytes show properties similar to those of the GABAC receptors present on white perch retinal neurons. GABA induced a sustained response that had a reversal potential of -27.1 +/- 3.6 mV. The EC50 for the response was 1.74 +/- 1.25 microM, a value similar to that reported for GABAC receptors. Pharmacologically, the responses were bicuculline insensitive and not modulated by either diazepam or pentobarbital as is the case for GABAC receptors. There were, however, some distinct differences between native GABAC and perch-s receptors. I4AA acts as a partial agonist on perch-s receptors whereas it is strictly an antagonist on native GABAC receptors. Picrotoxin inhibition is noncompetitive on perch-s receptors, but both competitive and noncompetitive on GABAC receptors. We conclude that GABAC receptors are formed by GABA rho subunits but that native GABAC receptors probably consist of a mixture of GABA rho subunits.