Long-term neurocognitive function after whole-brain radiotherapy in patients with melanoma brain metastases in the era of immunotherapy.

BACKGROUND: Whole-brain radiotherapy (WBRT) used to be standard of care for patients suffering from melanoma brain metastases (MBM) and may still be applicable in selected cases. Deterioration of neurocognitive function (NCF) is commonly seen during and after WBRT. Knowledge on long-term effects in melanoma patients is limited due to short survival rates. With the introduction of immune checkpoint inhibitors, patients may experience ongoing disease control, emphasizing the need for paying more attention to potential long-term adverse effects. METHODS: In this single-center study, we identified in a period of 11 years all long-term survivors of MBM who received WBRT at least 1 year prior to inclusion. NCF was assessed by Neuropsychological Assessment Battery (NAB) screening and detailed neurological exam; confounders were documented. RESULTS: Eight patients (median age 55 years) could be identified with a median follow-up of 5.4 years after WBRT. Six patients reported no subjective neurological impairment. NAB screening revealed an average-range score in 5/8 patients. In 3/8 patients a NAB score below average was obtained, correlating with subjective memory deficits in 2 patients. In these patients, limited performance shown in modalities like memory function, attention, and spatial abilities may be considerably attributed to metastasis localization itself. Six out of 8 patients were able to return to their previous work. CONCLUSION: Five of 8 long-term survivors with MBM after WBRT experienced little to no restriction in everyday activities. In 3 out of 8 patients, cognitive decline was primarily explained by localization of the metastases in functionally relevant areas of the brain. The results of our small patient cohort do not support general avoidance of WBRT for treatment of brain metastases. However, long-term studies including pretreatment NCF tests are needed to fully analyze the long-term neurocognitive effects of WBRT.

A search for cortical correlates of trait impulsivity in Parkinson´s disease.

BACKGROUND: Impulsivity is an enduring personality trait that is highly relevant for the development of neuropsychiatric disorders. Although impulse control disorders (ICD) are well-characterized non-motor features in Parkinson's disease (PD), mainly related to medication, little is known about neural correlates reflecting trait aspects of impulsivity in PD patients. Here, we address the question whether motor, attentional and non-planning components, measured by the Barratt Impulsiveness Scale (BIS-11), are distinctly related to cortical thickness and cortical folding abnormalities in PD when compared to age-matched healthy controls (HC). METHOD: We investigated cortical thickness (CT) and complexity of cortical folding (CCF) in 22 PD patients with moderately advanced disease stages without ICD and 18 HC using high-resolution structural magnetic resonance imaging (MRI) data. Surface-based data analysis was driven by CAT12 toolbox. RESULTS: PD patients showed widespread CT loss in frontal, cingulate, temporo-parietal and occipital regions (FDR corrected at p < 0.05 using threshold-free cluster enhancement). Significant differences in CCF between groups were not found. Using a multiple regression model, CT in inferior and superior frontal, anterior cingulate and precentral regions significantly predicted BIS attentional subscores (p = 0.041). CONCLUSION: These data suggest a specific cortical trajectory associated with impulsivity in moderately advanced staged PD patients. The attentional dimension of trait impulsivity appears to be specifically related to CT, in contrast to alterations of early neurodevelopmental markers, i. e. CCF. Our results shed light on structural correlates of trait impulsivity in PD patients and establish a baseline for future research into neural risk factors potentially predisposing to ICD development.

Reduced white matter integrity in amateur boxers.

INTRODUCTION: Professional boxing can lead to chronic traumatic encephalopathy, a variant of traumatic brain injury (TBI). Its occurrence in amateur boxers is a matter of debate since amateur boxing is considered to be less harmful due to more strict regulations. However, several studies using different methodological approaches have revealed subtle signs of TBI even in amateurs. Diffusion tensor imaging (DTI) is sensitive to microscopic white matter changes and has been proven useful in TBI when routine MR imaging often is unrevealing. METHODS: DTI, with tract-based spatial statistics (TBSS) together with neuropsychological examination of executive functions and memory, was used to investigate a collective of 31 male amateur boxers and 31 age-matched controls as well as a subgroup of 19 individuals, respectively, who were additionally matched for intellectual performance (IQ). RESULTS: All participants had normal findings in neurological examination and conventional MR. Amateur boxers did not show deficits in neuropsychological tests when their IQ was taken into account. Fractional anisotropy was significantly reduced, while diffusivity measures were increased along central white matter tracts in the boxers group. These changes were in part associated with the number of fights. CONCLUSIONS: TBSS revealed widespread white matter disturbance partially related to the individual fighting history in amateur boxers. These findings closely resemble those in patients with accidental TBI and indicate similar histological changes in amateur boxers.

A case-control study of sporadic Creutzfeldt-Jakob disease in Switzerland: analysis of potential risk factors with regard to an increased CJD incidence in the years 2001-2004.

BACKGROUND: In 2001, the observed annual mortality from Creutzfeldt-Jakob disease (CJD) in Switzerland increased from less than 1.5 to 2.6 per million inhabitants. An underlying cause could not be identified. METHODS: To analyse potential risk factors for sCJD in Switzerland, close relatives of 69 sCJD-patients and 224 frequency age-matched controls were interviewed in a case-control study using a standardised questionnaire. 135 potential risk factors including socio-demographics, medical history, occupation and diet were analysed by logistic regression adjusting for age, sex and education. RESULTS: sCJD patients were more likely to have travelled abroad, worked at an animal laboratory, undergone invasive dental treatment, orthopaedic surgery, ophthalmologic surgery after 1980, regular GP visits, taken medication regularly, and consumed kidney. No differences between patients and controls were found for residency, family history, and exposure to environmental and other dietary factors. CONCLUSION: Although some factors were significantly more frequent among sCJD-cases, this study did not reveal specific explanations for the increased incidence of deaths due to sporadic CJD observed in Switzerland since 2001. Results have to be interpreted with caution due to multiple testing and possible recall bias in association with a long incubation period. The most plausible reason for the increase in Swiss sCJD cases after 2000 is an improved case ascertainment. Therefore, underreporting of cases might well have occurred before the year 2001, and the "real" yearly incidence of sCJD might not be lower than, but rather above 2 per million inhabitants.

Heightened incidence of sporadic Creutzfeldt-Jakob disease is associated with a shift in clinicopathological profiles.

Incidences of human transmissible spongiform encephalopathies are monitored by national registries in the majority of countries in Western Europe. During the past 13 years incidences for Creutzfeldt-Jakob disease (CJD) in Switzerland fluctuated between 0.4 and 2.63 cases/10(6) inhabitants. We have compared clinicpathological patient profiles including geographic and gender distribution, age at disease onset, duration of disease, clinical symptoms, and recognized or hypothetical risk factors for CJD, genetic risk factors, biochemical and histopathological data for two cohorts of Swiss sporadic CJD patients from years of regular sporadic CJD incidence (1996-2000, mean incidence 1.3 cases/10(6) inhabitants, n = 47) to Swiss sporadic CJD patients from years of elevated sporadic CJD incidence (2001-2004, mean incidence 2.3 cases/10(6) inhabitants, n = 73). Sporadic CJD patients from the cohort with elevated sporadic CJD incidence presented with a higher frequency of rare sporadic CJD subtypes. Patients of these subtypes were significantly older and showed a skewed male/female ratio when compared to published patients of identical sporadic CJD-types or to patients from the 1996-2000 cohort and indicates that improved detection of rare sporadic CJD subtypes may have contributed to increased incidence.

Successful treatment of cold-induced neck pain and jaw claudication with revascularization of severe atherosclerotic external carotid artery stenoses.

PURPOSE: To present a patient whose cold-triggered neck pain and jaw claudication remitted after revascularization of severe atherosclerotic stenoses of both external carotid arteries (ECA). CASE REPORT: A 60-year-old vintner presented with jaw claudication and neck pain that increased in severity while he worked in cold temperatures. Angiography showed severe atherosclerotic narrowing of both ECAs. The symptoms disappeared after staged, bilateral percutaneous transluminal angioplasty procedures. However, the pain recurred together with severe bilateral ECA restenoses 6 months later; once again, the pain remitted after redilation. Right-sided neck pain and severe ECA narrowing recurred 5 months later and resolved after carotid endarterectomy. The patient remained asymptomatic and showed no ECA stenosis during a 3-year follow-up. CONCLUSION: Cold-triggered neck pain may be a symptom of atherosclerotic ECA stenoses, and carotid revascularization may be an efficient and safe treatment.

Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis.

BACKGROUND: The analysis of markers in the cerebrospinal fluid (CSF) is useful in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, the time at which the study of these markers is most sensitive remains controversal. OBJECTIVE: To assess the influence of time of sampling on the value of CSF tests in the diagnosis of sCJD. METHOD: In the framework of a multinational European study, we studied the results of 14-3-3, S100b, neurone specific enolase (NSE) and tau protein in 833 CSF samples from sCJD patients at different stages of disease and in 66 sequentially repeated lumbar punctures (LP). RESULTS: 14-3-3 and tau protein tended to increase in sensitivity from onset (88%, 81%) to the advanced stage (91%, 90%). This was significant only in the methionine-valine (MV) heterozygous group of patients at codon 129. The absolute levels of S100b (p < 0.05), NSE and tau protein increased in the last stage of disease. High levels of tau protein, NSE and S100b were associated with shorter survival times (p < 0.01). Sixty-six sCJD patients underwent repeated LP. These sCJD patients were younger, had longer disease durations and were more frequently MV at codon 129 (p < 0.001) than the whole group. 14-3-3 sensitivity increased from 64% to 82% in the second LP (p = 0.025) and 88% sCJD patients had at least one positive result. CONCLUSIONS: Sensitivity and absolute levels of CJD markers increased with disease progression and were modulated by the codon 129 genotype. Early negative results should be inter-preted with caution, especially in young patients or those who are MV at codon 129.

Whiplash and concussion: similar acute changes in middle-latency SEPs.

OBJECTIVE: Middle-latency somatosensory evoked potentials (SEPs) following median nerve stimulation can provide a sensitive measure of cortical function. We sought to determine whether the mechanical forces of whiplash injury or concussion alter normal processing of middle-latency SEPs. METHODS: In a cross-sectional pilot study 20 subjects with whiplash were investigated (50% between 0.5-2 months and 50% between 6-41 months post injury) and compared to 83 healthy subjects using a standard middle-latency SEP procedure. In a subsequent prospective study subjects with either acute whiplash (n=13) or Grade 3 concussion (n=16) were investigated within 48 hours and again three months post injury. RESULTS: In the pilot study the middle-latency SEP component N60 was significantly increased in the ten subjects investigated within two months after whiplash. In contrast, the ten subjects examined more than six months after injury showed normal latencies. In the prospective study N60 latencies were increased after whiplash and concussion when tested within 48 hours of injury. At three months, latencies were improved though still significantly different from controls post whiplash and concussion. CONCLUSIONS: Both whiplash injury and concussion alter processing of the middle-latency SEP component N60 in the acute post traumatic period. The acute changes appear to normalize between three-six months post injury. The SEP similarities suggest that the overlapping clinical symptomatology post whiplash and concussion may reflect a similar underlying mechanism of rotational mild traumatic brain injury.

Effect of high-dose cortisol on memory functions.

Although research indicates that hightened glucocorticoid levels impair long-term memory functions and may inhibit traumatic memory retrieval in humans, the impact of acutely elevated glucocorticoid levels on learning and attentional functions is still unclear. Furthermore, the effect of glucocorticoids on executive functions as well as the recovery from long-term memory deficits is insufficiently studied. The present study examined memory functions in patients with acute exacerbation of neurological diseases (multiple sclerosis, acute optic neuritis), who were treated with a high dose of glucocorticoids. All patients demonstrated a reversible impairment of long-term memory functions, whereas measures of short-term memory, attentional functions, and alertness remained unaffected. These findings indicate a selective cognitive disturbance, providing further evidence that the memory deficits reflect a receptor-mediated effect of glucocorticoids on hippocampal function thereby supporting a potential association of stress-induced elevated cortisol levels and memory disturbances in trauma-related psychiatric disorders (psychogenic amnesia, PTSD).

Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache.

The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P<0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO*) and alkyl (LC*) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0+/-4.8 mL or 0.6%+/-0.4%, P<0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.

Pilomotor seizures and status in non-paraneoplastic limbic encephalitis.

BACKGROUND AND AIMS: To describe an unusual clinical presentation of a patient with voltage-gated potassium channel Ab- positive, non-paraneoplastic limbic encephalitis. METHODS: We performed video-EEG monitoring, structural MRI, (18)F-FDG-PET, (1)H-MRS, neuropsychological testing and antibody serology. RESULTS: A 42-year-old male patient presented in an acute phase of non-paraneoplastic limbic encephalitis confirmed by MRI, with antibodies to voltage-gated potassium channels. His pilomotor status was pharmacoresistant to antiepileptic drugs, but responded to corticosteroid and azathioprine treatment. The MRI findings improved. The pilomotor seizures recurred when the immunosuppressive therapy was discontinued after 18 months. MRI at that time was consistent with hippocampal sclerosis. Complete seizure control was achieved after reintroduction of steroids. CONCLUSION: Pilomotor seizures were the predominant seizure type in this case of non-paraneoplastic limbic encephalitis. Immunosuppressive therapy may provide recovery including seizure control. However, long-term immunosuppression may be necessary to prevent relapse. Hippocampal sclerosis and chronic epilepsy might evolve as sequelae of limbic encephalitis.

Enhanced smooth pursuit eye movements in patients with bilateral vestibular deficits.

Patients with bilateral vestibular deficits experience unsteady gait and oscillopsia that can reduce the quality of life, though many patients adapt remarkably well and lead mostly normal lives. One source of adaptation could be the ability of sensory-motor systems to compensate for the vestibular loss by adaptive enhancement of their performance. We studied smooth-pursuit eye movements in five patients and six healthy control subjects using a step-ramp paradigm. Eye movements were measured with scleral search coils. Patients showed open- and closed-loop pursuit gains that were about 9% higher than controls. We suggest that the challenge of living with a deficient vestibular system caused an enhancement in the pursuit system, which contributes to the patient's overall compensation.