[COVID-19 in old age-The geriatric perspective]. / COVID-19 im Alter ­ Die geriatrische Perspektive.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.

[Paraneoplastic subacute degeneration of the cerebellum in non-small cell lung cancer and positive anti-Tr3 antibodies]. / Paraneoplastische subakute Degeneration des Kleinhirns bei nichtkleinzelligem Bronchialkarzinom und positiven Anti-Tr3-Antikörpern.

Neurological disorders can occur before the diagnosis of a malignoma is set. These disorders are induced by a misguided immune response with antibodies against intracellular or cell surface antigens. One of the most common paraneoplastic diseases is the subacute degeneration of the cerebellum. In most of the cases antibodies against Anti Hu, CRMP5/CV2, Amphiphysin and Ma/Ta are found and small cell bronchial carcinoma, breast cancer and lymphoma are diagnosed. We report about a 67 years old man with cerebellar symptoms and a weight loss of 10 kg who was treated in our clinic. After our diagnostic work up we found a non small cell cancer and diagnosed a subacute degeneration of the cerebellum as a paraneoplastic disorder. We found a high positive titer for Anti-Tr3 antibodies while the rest of the paraneoplastic antibodies described as typically associated with the subacute degeneration of the cerebellum were negative. The Anti-Tr3 antibodies are usually found in patients with Hodgkin and less often Non-Hodgkin disease. After initiation of a tumor specific therapy and intravenous immunoglobulin therapy the cerebellar symptoms decreased. In future follow up examinations we will see if the anti-Tr3 antibodies were associated with the non small cell bronchial carcinoma or if a lymphoma will occur in our patient.

[Altered orientation and aggressiveness in an 89-year-old woman]. / Wechselnde Vigilanz und Fremdaggressivität bei einer 89­jährigen Patientin.

An 89-year-old woman with Alzheimer's dementia was admitted because of altered orientation, aggressiveness and inability to take care of herself at home. Her patient history indicated that 14 days ago the battery of the pacemaker had be renewed. During that time the patient suffered from psychomotor alterations. Therefore, melperone had been initiated. Inspection of the urine and laboratory findings pointed towards an acute exacerbation of acute intermittent porphyria as a possible cause of the delirium. After discontinuation of melperone with additional parenteral therapy with physiological fluids, the signs of delirium significantly improved.

PEGylated human serum albumin (HSA) nanoparticles: preparation, characterization and quantification of the PEGylation extent.

Modification with poly(ethylene glycol) (PEG) is a widely used method for the prolongation of plasma half-life of colloidal carrier systems such as nanoparticles prepared from human serum albumin (HSA). However, the quantification of the PEGylation extent is still challenging. Moreover, the influence of different PEG derivatives, which are commonly used for nanoparticle conjugation, has not been investigated so far. The objective of the present study is to develop a method for the quantification of PEG and to monitor the influence of diverse PEG reagents on the amount of PEG linked to the surface of HSA nanoparticles. A size exclusion chromatography method with refractive index detection was established which enabled the quantification of unreacted PEG in the supernatant. The achieved results were confirmed using a fluorescent PEG derivative, which was detected by photometry and fluorimetry. Additionally, PEGylated HSA nanoparticles were enzymatically digested and the linked amount of fluorescently active PEG was directly determined. All the analytical methods confirmed that under optimized PEGylation conditions a PEGylation efficiency of up to 0.5 mg PEG per mg nanoparticle could be achieved. Model calculations made a 'brush' conformation of the PEG chains on the particle surface very likely. By incubating the nanoparticles with fetal bovine serum the reduced adsorption of serum proteins on PEGylated HSA nanoparticles compared to non-PEGylated HSA nanoparticles was demonstrated using sodium dodecylsulfate polyacrylamide gel electrophoresis. Finally, the positive effect of PEGylation on plasma half-life was demonstrated in an in vivo study in mice. Compared to unmodified nanoparticles the PEGylation led to a four times larger plasma half-life.

[Sarcopenia and frailty in neurology]. / Sarkopenie und Frailty in der Neurologie.

Sarcopenia and frailty are common geriatric syndromes and are associated with adverse health outcome and impaired health-related quality of life. Co-occurrences of these two syndromes with age-related neurological diseases are potentially high but not well investigated. Moreover, it is not well understood how these syndromes interact with neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke. This article introduces the currently most accepted concepts of sarcopenia and frailty, discusses the potential relevance of the syndromes for geriatric patients and presents examples of studies that investigated potential interactions between these geriatric and neurological syndromes and conditions. First results indicate that (i) the co-occurrence of these geriatric syndromes and age-related neurological diseases is high, (ii) sarcopenia and frailty can influence the clinical state of neurological diseases to a relevant extent and (iii) at least some common causes and pathophysiological processes confer the geriatric and neurological conditions. In conclusion, profound knowledge about the interaction of sarcopenia, frailty and age-associated neurological conditions is currently not available. Such knowledge would have an enormous potential for improved therapy of these neurological conditions.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

[Primary brain tumors and brain metastases. Symptomatic epilepsy and driving ability - systematic review and expert opinion]. / Primäre Hirntumoren und Hirnmetastasen. Symptomatische Epilepsie und Fahreignung - Expertenumfrage und systematisches Review.

PURPOSE: Primary brain tumors and metastases are common causes of symptomatic epilepsy. Seizures, neurological and neuropsychological deficits can interfere with driving ability. The present paper aims to systematically review the incidence of epileptic seizures in brain tumor patients and to discuss driving ability in the context of the current German guidelines and expert opinions. METHODS: To evaluate the incidence of epileptic seizures which occur at the beginning and in the course of the disease, we performed a systematic literature research in PubMed from 1960 to 2007. Additionally on the basis of this data we performed a survey collecting expert opinions regarding the driving ability of brain tumor patients from members of the German working groups "Arbeitsgemeinschaft für prächirurgische Epilepsiediagnostik und operative Epilepsietherapie" (Working Group for Presurgical Epilepsy Diagnostics and Operative Epileptic Therapy) and "Neuroonkologische Arbeitsgemeinschaft" (Neuro-oncological Working Group). RESULTS: The incidence of epileptic seizures depends on the entity, dignity and localization of the tumor. The driving ability of brain tumor patients is not explicitly regulated in Germany. Of the interviewed experts 72% judged the guidelines to be precise enough and 44% did not want to deprive the patients of their driving ability without a first seizure, independent of the individual risk. DISCUSSION: The available studies are methodologically insufficient and show that a further evaluation is necessary to assess the driving ability. Possible restrictions of the driving ability in patients with a high risk of seizures in the course of the disease have to take into account the balance between individual rights and the interests of the general public.

In vivo evaluation of the uptake of [(123)I]FIAU, [(123)I]IVFRU and [(123)I]IVFAU by normal mouse brain: potential for noninvasive assessment of HSV-1 thymidine kinase gene expression in gliomas.

Radioiodinated 5-iodo-1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)uracil (F *IAU) is most commonly used for noninvasive assessment of herpes simplex virus type 1 thymidine kinase (HSV-1-tk) gene expression. However, it does not permeate the intact blood-brain barrier (BBB) because of its moderate lipophilicity. In this work, three iodo-nucleosides, FIAU, IVFRU, and IVFAU, were radiolabeled with iodine-123 and tested for permeation of the BBB in mice and for potential measurement of HSV-1-tk gene expression in gliomas. The results demonstrate that brain uptake and retention of these nucleosides is not directly related to their lipophilicity. The low brain uptake of IVFAU, in conjunction with its higher and constant brain/blood ratio, may reflect greater stability against hydrolysis of the N-glycosidic bond. In vivo PET evaluations of [(124)I]IVFRU and [(124)I]IVFAU in tumor-bearing mice are warranted.

Immediate CEA for symptomatic carotid disease preferably performed under local anaesthesia is safe.

BACKGROUND: Previous general reservations against carotid endarterectomy (CEA) early after stroke, which were primarily based on concerns of postoperative intracerebral hemorrhage, are resolved. Moreover, a delay of surgery is proofed to be associated with a risk of recurrent cerebral ischemia. However, the complication rate of CEA seems to increase with less time interval to the onset of symptoms. The main purpose of this study was to assess the safety of very early CEA. PATIENTS AND METHODS: Patients having a symptomatic high-grade (> 70%) internal carotid artery (ICA) stenosis were referred by neurologists for CEA within different timeframes, so that they were later differentiated depending on whether surgery was performed within 2 days (immediate CEA = iCEA) or 2 weeks (urgent CEA = uCEA) after neurological deficits have occurred primarily. The perioperative complication rate in these groups was than evaluated and compared. RESULTS: From January 2000 until August 2006 130 consecutive patients (median age 68 years, range: 42-90; 66% male, 34%female)presenting with an ipsilateral TIA (n = 80), stroke (n = 50) underwent iCEA (n = 40) or uCEA (n = 90). Demographic and clinical characteristics were equally distributed between treatment groups. Mostly (121/130), CEA was performed under local anaesthesia with selective shunt use which became necessary in 26%. Besides postoperative hemorrhage (n = 4), cardiac complications (n = 2) and temporary cranial nerve lesions (n = 2), new perioperative neurological deficits occurred in total in 8 patients of which 6 were temporary. The other 2 patients developed strokes of which one patient died. Therefore, the combined stroke- and mortality rate was 1.5% (2/130) for the whole study population. With regard to the timing of surgery, a single incident was observed after iCEA (1/40) which also was the only intracerebral hemorrhage. CONCLUSIONS: It seems that patients with a symptomatic high-grade ICA stenosis can undergo CEA particularly under local anaesthesia as soon as possible without anticipating an increased complication rate.

Long-term remission in progressive multifocal leukoencephalopathy caused by idiopathic CD4+ T lymphocytopenia: a case report.

Progressive multifocal leukoencephalopathy is caused by JC virus, an opportunistic infection of the central nervous system. Antiretroviral treatment for progressive multifocal leukoencephalopathy in human immunodeficiency virus-infected patients is beneficial, but few data exist for patients who are not infected with human immunodeficiency virus. Idiopathic CD4+ T lymphocytopenia excludes human immunodeficiency virus infection. We describe a patient with progressive multifocal leukoencephalopathy with underlying idiopathic CD4+ T lymphocytopenia in whom functional recovery occurred without antiviral therapy.

Recurring digital fibrous tumors of childhood: a review.

Two new cases that conform to the clinical and histopathological features of recurring digital fibrous tumor of childhood, described by Reye in 1965, are reported. This tumor, which is considered a distinct entity among the juvenile fibromatoses, characteristically presents in infancy and early childhood, involves only the digits, recurs frequently following surgical excision without metastatic spread, and demonstrates the distinct histopathological finding of intracytoplasmic inclusion bodies within proliferated fibroblasts. This tumor is reviewed with reference to clinical features, histopathology, etiological considerations, and management.

The incidence of birthmarks in the neonate.

The presence of various types of birthmarks was determined in 1,058 newborn infants under 72 hours of age. Of these, 79.5% were white, 6.2% were black, 11.2% were ladinos, and 2.6% were Asiatic. Mongol spots were present in 9.6% of the white babies, 95.5% of the black babies, 81% of the Asiatic babies, and 70.1% of ladino infants. Pigmented lesions were present in 42 (4%) of the infants. Biopsies obtained in 34 (3.2%) revealed that only one-third (11) of these were melanocytic nevi. Salmon patches were present in 40.3% of the infants, recognizable early strawberry marks in 2.6%, and port-wine strains in 0.3%. In addition to birthmarks, it was determined that 30.3% of the 508 babies examined at one of the two hospitals had toxic erythema of the newborn.

Jessner's lymphocytic infiltrate in two girls.

Two girls demonstrated waxing and waning predominantly facial eruptions. Clinically as well as histologically, the lesions are consistent with lymphocytic infiltrate to Jessner and Kanof and constitute the first reported childhood cases. Although primarily a disease of male adults, this entity should be included in the differential diagnosis of facial plaques in children.

Congenital smooth muscle hamartoma. A report of six cases and a review of the literature.

Congenital smooth muscle hamartoma (CSMH) represents a proliferation of randomly oriented dermal smooth-muscle bundles. Six patients with CSMH were observed, the largest series to date, and the literature was reviewed. Congenital smooth muscle hamartoma has presented as congenital patches or slightly indurated plaques with prominent overlying hair (88% of cases), or rarely as patches with perifollicular papules without prominent hair (12% of cases). Most lesions (61% of cases) have been somewhat hyperpigmented, but 39% of cases have been flesh colored. Congenital smooth muscle hamartoma has occurred on the torso and proximal extremities, except for one case on the eyebrow and eyelid (present study). A positive pseudo-Darier's sign (temporary induration or piloerection after rubbing) helped to differentiate CSMH from congenital hairy nevo-cellular nevus. Congenital smooth muscle hamartoma is a distinct entity that is at one end of a spectrum that includes Becker's nevus, and should be considered in the differential diagnosis of any congenital hairy lesion.

Immunohistologic patterns of congenital nevocellular nevi.

To establish sensitive histologic criteria for small congenital nevi (SCN), we examined 29 biopsy specimens of SCN from patients younger than age 1 year by serial sectioning and S100 immunoperoxidase staining. The depth of papillary and reticular dermal infiltration was variable; only the results of six biopsy specimens contained nevomelanocytes in the lower third of reticular dermis. However, all cases had focal nevomelanocytic involvement of adnexa at the midreticular dermis or below (26 of 29 cases in eccrine and 15 of 29 in pilosebaceous structures). Follow-up specimens in ten patients were obtained (mean interval, 10.25 years), and no difference in histologic pattern or cytology was observed. There were variable size increases in the surface area of SCN, ranging from no increase to a maximal ninefold increase.

Molecular and functional imaging technology for the development of efficient treatment strategies for gliomas.

Gliomas are the most common types of brain tumors, which invariably lead to death over months or years. Before new and potentially more effective treatment strategies, such as gene therapy, can be effectively introduced into clinical application the following goals must be reached: (1) the determination of localization, extent and metabolic activity of the glioma; (2) the assessment of functional changes within the surrounding brain tissue; (3) the identification of genetic changes on the molecular level leading to disease; and in addition (4) a detailed non-invasive analysis of both endogenous and exogenous gene expression in animal models and in the clinical setting. Non-invasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging techniques may reveal the assessment of the location, magnitude and duration of therapeutic gene expression and its relation to the therapeutic effect. Here, we review the main principles of PET imaging and its key roles in neurooncology research.

Novel neuroimaging findings in a patient with cerebral Whipple's disease: a magnetic resonance imaging and positron emission tomography study.

The authors report a 43-year-old patient with histopathologically proven cerebral Whipple's disease. Magnetic resonance imaging (MRI) revealed a multilayered left frontal lesion without mass effect, no perifocal brain edema, no contrast enhancement, and a thin shell of fluid signal that presented as an incomplete, open ring. An [11C]methionine positron emission tomography (PET) study showed low uptake below the threshold that is characteristic for brain tumors. In precise co-registration to the MR images, the PET data showed that increased uptake was mainly located in the direct adjacent part of the MRI lesion. The fluid signal on MRI corresponded to the extensive outflow of fluid from the lesion, which was observed during neurosurgical resection, and also to the neuropathological findings. The authors conclude that this cerebral manifestation of Whipple's disease made a unique and hitherto undescribed appearance on MRI; uptake pattern of PET amino acid tracer may help in the preoperative distinction of inflammatory from neoplastic lesions.

Speech therapy after total laryngectomy and esophageal replacement in a preschool patient: a case study.

This case study reports the development of a speech and language therapy program for a preschool boy laryngectomized at age two and three-quarters. Etiology was attributed to the accidental ingestion of lye, which caused severe burns and subsequent damage to both the larynx and esophagus. During the 20-month hospital stay, colon transplantation to the pharynx and laryngectomy were performed and a speech therapy program was initiated. The speech pathologist worked closely with the patient by stimulating his speech and language, developing his articulation skills, and finally providing him with a means of using expressive speech via an electrolarynx designed for him. In addition to the case study, this report reviews the different methods of alaryngeal speech, and suggests the need for further research in developing these methods as viable alternatives for the young laryngectomized child.

[Sensory aphasia during therapy with metronidazole--an important differential diagnosis of acute cerebral ischemia]. / Sensorische Aphasie unter Therapie mit Metronidazol--eine wichtige Differenzialdiagnose der akuten zerebralen Ischämie.

HISTORY AND ADMISSION FINDINGS: A 74-year old man was admitted after neurosurgical treatment of a lumbar vertebral fracture. He had a slight paresis of the right leg in combination with bladder dysfunction. INVESTIGATIONS: There were signs of a postoperative anemia (hemoglobin 10.4 mg/dl) and mildly elevated infection parameters (CRP 2 mg/dl). Routine ECG and chest X-ray were normal. TREATMENT AND COURSE: Physical training was initiated, but diarrhea occurred 2 days after admission. As the patient had received antibiotics after the operation, a treatment with metronidazole was initiated under the suspicion of diarrhoea induced by clostridium difficile. At day 6 of treatment a hypertensive crisis (blood pressure 230/120 mmHg) developed, followed by sensory aphasia. Despite treatment at the stroke unit and blood pressure regulation, the clinical signs of aphasia persisted. MRI could not detect an acute cerebral infarction. After discontinuation of metronidazole complete reconstitution occurred within 72 h. CONCLUSION: Metronidazole should be taken into account as cause of severe neurological side effects including ischemia-like syndromes like aphasia.

Appropriate end-points for right results in the age of antiangiogenic agents: future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6 months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.