Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy.

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).

Neurocognitive monitoring in patients undergoing opioid pain medication after spinal surgery: a feasibility study of a new monitoring method.

PURPOSE: Patients undergoing spinal surgery require postoperative pain management to alleviate wound pain. Pain medication includes WHO grade 1 analgesic as well as potent opioids, potentially leading to cognitive decline. Up until now, the cognitive impairment is only poorly studied and difficult to monitor. We hereby investigate the feasibility of a digital monitoring method for neurocognitive function under opioid medication after spinal instrumentation. METHODS: Prospective monocenter feasibility study enrolling patients before undergoing spinal surgery. We performed cognitive testing using a tablet-based application before (baseline), as well as on day 2 after surgery (intravenous opioids), before discharge (oral opioids), and at follow-up. We recorded the exact pain medication and its other side effects. Potential risk factors for the postoperative decline in cognition included age, high-dose opioid application, and length of surgery. RESULTS: We included 20 patients in our study. The baseline assessment revealed no cognitive impairment before surgery. All patients underwent dorsal instrumentation for degenerative (60%), osteoporotic fracture (15%), or spinal tumor (25%) indications. Cognitive testing after surgery showed a significant decline under intravenous opioid therapy including short time and delayed verbal recall (p < 0.001) as well as arithmetic fluency. Cognitive performance significantly improved with partial recovery until follow-up and opioid discontinuation. CONCLUSION: Cognition testing and monitoring of neurocognitive decline under high-dose opioid medication were feasible using the digital tablet-based application. The cognition app helps to identify difficulties in cognitive function as a side effect of overdosage in opioid medication, and care givers should evaluate the risk of non-comprehension and impaired informed consent appropriately.

Neuropathic pain after spinal intradural benign tumor surgery: an underestimated complication?

Neuropathic pain presents a burdening and impairing condition which may occasionally occur after spinal tumor surgery. While it has been described in peripheral nerve sheath tumors, data on other intradural tumor patients is sparse. We hereby present a large cohort population undergoing different intradural spinal tumor surgery with assessment of early postoperative and follow-up outcomes, focusing on the occurrence of neuropathic pain. We performed a retrospective monocentric study including all patients treated for intradural spinal tumors between 2009 and 2020. We extracted surgical aspects as well as pre- and postoperative clinical courses from the records. Statistical analysis of potential contributing prognostic factors was performed including matched pair analysis. In total, 360 patients were included for analysis. At a median follow-up of 2 years, 26/360 patients complained of a neuropathic pain syndrome (7.2%) requiring continuous medication. Of these patients only 50% complained preoperatively of pain. Tumor entity did not significantly influence the incidence of postoperative neuropathic pain (p = 0.91). Sacrifice of the tumor carrying nerve root and tumor recurrence also did not increase the risk for this condition. Persistent neuropathic pain requiring continuous treatment occurred in 7.2% of patients undergoing intradural spinal surgery in our cohort. This frequently underestimated postoperative adverse event represents a disabling condition leading to a substantial impairment in the quality of life among the affected patients.

Non-invasive mapping of cortical categorization function by repetitive navigated transcranial magnetic stimulation.

Over the past years navigated repetitive transcranial magnetic stimulation (nrTMS) had become increasingly important for the preoperative examination and mapping of eloquent brain areas. Among other applications it was demonstrated that the detection of neuropsychological function, such as arithmetic processing or face recognition, is feasible with nrTMS. In order to investigate the mapping of further brain functions, this study aims to investigate the cortical mapping of categorization function via nrTMS. 20 healthy volunteers purely right-handed, with German as mother tongue underwent nrTMS mapping using 5 Hz/10 pulses. 52 cortical spots spread over each hemisphere were stimulated. The task consisted of 80 pictures of living and non-living images, which the volunteers were instructed to categorize while the simulation pulses were applied. The highest error rates for all errors of all subjects were observed in the left hemisphere's posterior middle frontal gyrus (pMFG) with an error rate of 60%, as well as in the right pMFG and posterior supra marginal gyrus (pSMG) (45%). In total the task processing of non-living objects elicited more errors in total, than the recognition of living objects. nrTMS is able to detect cortical categorization function. Moreover, the observed bihemispheric representation, as well as the higher error incidence for the recognition of non-living objects is well in accordance with current literature. Clinical applicability for preoperative mapping in brain tumor patients but also in general neuroscience has to be evaluated as the next step.

A Case Series of Surgically Treated Spinal Dumbbell Tumors of Critical Parent Nerve Roots: To Cut or Not to Cut?

BACKGROUND: Dumbbell tumors present challenging cases, with either an incomplete tumor resection or a need to sacrifice nerve roots. Published literature suggests encouraging neurological outcomes after nerve root amputation. OBJECTIVE: To determine the incidence of postoperative neurological deficits after amputating the parent nerve root. METHODS: A retrospective consecutive analysis of all patients treated for dumbbell nerve sheet tumors with a reported amputation of the functional relevant parent nerve roots C5-Th1 and L3-S1. RESULTS: Among 21 evaluated patients, minor postoperative neurological motor function deterioration occurred in 4 patients (19%). Most patients recovered to the preoperative level at the follow-up examination, and only one patient retained a new Medical Research Council (MRC) scale of 4/5 for deltoid weakness. The majority of tumors were resected at the lumbar level (nerve root L3: 28.6%, L5: 19%). Gross total resection was achieved in 90.5% of patients. Neuropathic pain was reported in one third of the patients during the long-term follow-up. CONCLUSION: Amputating critical parent nerve roots during the dumbbell tumor resections seems to result in a low incidence of postoperative motor deficits and may offer an acceptable sacrifice in otherwise only incompletely resectable dumbbell tumors. The cross-innervation of neighboring nerve roots and its, probably, per-se-reduced functionality may be a possible mechanism for maintaining motor function.

Bilateral thoracic disc herniation with abdominal wall paresis: a case report.

We present a rare case of a patient initially presenting with unilateral abdominal wall bulging and radicular pain caused by a lateral disc herniation at Th11/12, later suffering from a hernia recurrence with bilateral disc prolapse and motor deficits. The patient underwent sequesterectomy via a right hemilaminectomy at Th11, and after 8 weeks, a bilateral sequesterectomy with semirigid fusion Th11/12 was performed. Unilateral motor deficits at the thoracic level have been discussed in case reports; a bilateral disc protrusion with abdominal wall bulging occurring as a recurrent disc herniation has never been described before.

Quality-adjusted life years in glioma patients: a systematic review on currently available data and the lack of evidence-based utilities.

BACKGROUND: Cost-effectiveness studies gain importance in the context of rising health care expenses and treatment options. Especially in the neuro-oncological context, surgical therapy may increase overall survival, but restrain the patient by postoperative disability. Quality-adjusted life years, express treatment effects and are based on health utilities. In our study, we analyze the current evidence on health economic evaluations in glioma patients. MATERIAL AND METHODS: We performed a systematic database search including Medline and Cochrane Library. Studies were critically appraised for statistical analyzes including glioma patients, health economic modeling and detailed health outcome. Study evidence was classified according to levels of evidence for therapeutic studies from the Centre for Evidence-Based Medicine (Oxford). RESULTS: 37 studies (1995-2018) were identified, 29 matched our inclusion criteria. Studies addressed surgical cost-efficiency and/or the standard treatment, postoperative chemotherapy (n = 6) and 5-ALA (n = 3). Only 16 studies used QALY as the outcome measure, most used overall survival or life years gained (LYG). Utilities were either based on one single study (Garside et al. in Health Technol Assess 11:iii-iv, ix-221) or derived from visual analogue scale (VAS). None assessed quality of life values for specific health statuses or utilities. Incremental cost-effectiveness ratios varied from 8325€ per QALY (5-ALA) to 518,342€ per LYG (tumor treating fields). CONCLUSIONS: Only one study generated utility values to conduct cost-effectiveness analysis (CEA); most studies used indirect outcomes such as LYG or based their model on previously published data. Health economic evaluations lack specific utilities, further investigations are necessary to conduct reliable CEA in the neurosurgical context.

Cost of dengue outbreaks: literature review and country case studies.

BACKGROUND: Dengue disease surveillance and vector surveillance are presumed to detect dengue outbreaks at an early stage and to save--through early response activities--resources, and reduce the social and economic impact of outbreaks on individuals, health systems and economies. The aim of this study is to unveil evidence on the cost of dengue outbreaks. METHODS: Economic evidence on dengue outbreaks was gathered by conducting a literature review and collecting information on the costs of recent dengue outbreaks in 4 countries: Peru, Dominican Republic, Vietnam, and Indonesia. The literature review distinguished between costs of dengue illness including cost of dengue outbreaks, cost of interventions and cost-effectiveness of interventions. RESULTS: Seventeen publications on cost of dengue showed a large range of costs from 0.2 Million US$ in Venezuela to 135.2 Million US$ in Brazil. However, these figures were not standardized to make them comparable. Furthermore, dengue outbreak costs are calculated differently across the publications, and cost of dengue illness is used interchangeably with cost of dengue outbreaks. Only one paper from Australia analysed the resources saved through active dengue surveillance. Costs of vector control interventions have been reported in 4 studies, indicating that the costs of such interventions are lower than those of actual outbreaks. Nine papers focussed on the cost-effectiveness of dengue vaccines or dengue vector control; they do not provide any direct information on cost of dengue outbreaks, but their modelling methodologies could guide future research on cost-effectiveness of national surveillance systems.The country case studies--conducted in very different geographic and health system settings - unveiled rough estimates for 2011 outbreak costs of: 12 million US$ in Vietnam, 6.75 million US$ in Indonesia, 4.5 million US$ in Peru and 2.8 million US$ in Dominican Republic (all in 2012 US$). The proportions of the different cost components (vector control; surveillance; information, education and communication; direct medical and indirect costs), as percentage of total costs, differed across the respective countries. Resources used for dengue disease control and treatment were country specific. CONCLUSIONS: The evidence so far collected further confirms the methodological challenges in this field: 1) to define technically dengue outbreaks (what do we measure?) and 2) to measure accurately the costs in prospective field studies (how do we measure?). Currently, consensus on the technical definition of an outbreak is sought through the International Research Consortium on Dengue Risk Assessment, Management and Surveillance (IDAMS). Best practice guidelines should be further developed, also to improve the quality and comparability of cost study findings. Modelling the costs of dengue outbreaks and validating these models through field studies should guide further research.