Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases.

Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.

Transcallosal, transchoroidal clipping of a hypothalamic collateral vessel aneurysm in Moyamoya disease.

Peripheral collateral vessel aneurysms in Moyamoya disease (MMD) remain difficult to treat due to their deep location, small size, and vascular fragility. We report the case of an aneurysm localized in the hypothalamus, which was rapidly increasing in size with repeated hemorrhage despite revascularization surgery. Aneurysm clipping was performed to prevent further progress and rerupture with favorable outcome. To our best knowledge, this is the first description of a hypothalamic aneurysm in MMD being clipped via a transcallosal, transchoroidal approach through the third ventricle.

Results of Phosphorus Magnetic Resonance Spectroscopy for Brain Metastases Correlate with Histopathologic Results.

BACKGROUND: Brain metastases (BMs) are classically well-circumscribed lesions. Still, the amount of edema in these neoplasms suggests either mechanisms of infiltration or defense. A better understanding of the mechanisms within the edema of BMs seems reasonable to preoperatively identify areas of potential infiltration and resect them. BMs represent tumors with high energy demand and cell turnover; therefore, they qualify for preoperative investigation with phosphorus-31 magnetic resonance spectroscopy (31PMRS), which reveals information about those characteristics. METHODS: Ten patients with BMs were included in this trial. All underwent preoperative standard magnetic resonance imaging with additional 31PMRS. In all patients, 1 voxel within the contrast-enhancing tumor (CE+), 1 voxel at the border (including CE+ areas and surrounding T2-hyperintensive [T2+] areas), and 1 distant voxel purely including T2+ areas were determined by a neuroradiologist and a neurosurgeon. A frameless stereotactic biopsy was performed after craniotomy. Subsequently, the metabolites of the 31PMRS were analyzed and compared with the histopathologic results. RESULTS: Ratios, reflecting resynthesis (CE+/border/T2+: 1.109 ± 0.192/1.112 ± 0.158/1.083 ± 0.097), hydrolysis (0.303 ± 0.089/0.360 ± 0.122/0.321 ± 0.089), energy demand (4.227 ± 2.35/3.453 ± 1.284/3.599 ± 0.833), and membrane turnover (1.239 ± 0.2611/3.453 ± 1.284/3.599 ± 0.283) were calculated and compared intraindividually with a voxel from the contralateral side (resynthesis/hydrolysis/energy demand/membrane turnover: 1.063 ± 0.085/0.335 ± 0.073/3.317 ± 0.7573/0.784 ± 0.186), respectively. Resynthesis showed a trend toward higher ratios in CE+ and border biopsies without reaching statistical significances. This trend was also seen concerning energy demand. Membrane turnover was significantly higher in CE+, border zone, and also in the T2+ areas compared with controls (P > 0.001). CONCLUSIONS: 31PMRS in BMs provides information on metabolic changes in tumor and surrounding edema. There is proof of enhanced metabolism in tissue without histologic tumor manifestation.

The influence of surface EMG-triggered multichannel electrical stimulation on sensomotoric recovery in patients with lumbar disc herniation: study protocol for a randomized controlled trial (RECO).

BACKGROUND: Intervertebral disc degeneration is one of the most common reasons for chronic low back pain and sensomotoric deficits, often treated by lumbar sequestrectomy. Nevertheless, the prognostic factors relevant for time and quality of recovery, of the surgical procedure, relative to conservative treatment, remain controversial and require further investigation. Surface electrical stimulation (SES) may be an influential intervention, already showing positive impact on motor and sensory recovery in different patient groups. Since mechanisms of SES still remain unclear, further inquiry is needed. METHODS/DESIGN: This is a prospective, monocentric, randomized, controlled clinical trial. A total of 80 adult patients suffering from a lumbar disc herniation (LDH; 40 treated surgically, 40 conservatively) are allocated in a ratio of 1:1. Patients in the treatment group will receive surface electromyography (EMG)-triggered electrical stimulation for eight weeks, whereas patients in the control group will not obtain any additional treatment. The primary outcome parameter is defined as the cold detection threshold (CDT), determined by quantitative sensory testing (QST), 24 months after intervention. Secondary outcome parameters include the inquiry of sensory nerve function by two-point discrimination and QST, the assessment of motor nerve function by manual muscle testing, and validated scales and scores. These include: the Oswestry Disability Index (ODI) and the Core Outcome Measures Index (COMI) assessing the domains pain, back-specific function, work disability, and patient satisfaction; the EQ-5D investigating the patient's generic health status; the painDETECT questionnaire (PD-Q) to identify neuropathic pain components; and the Beck Depression Inventory (BDI) to assess severity of depression. Moreover, neurological status, pain medication usage, and blood samples (CRP, TNFα, IL-1ß, IL-6) will be evaluated. Study data generation (study site) and data storage, processing, and statistical analysis are clearly separated. DISCUSSION: The results of the RECO study will detect the effect of EMG-triggered multichannel SES on the improvement of mechanical and thermal sensitivity and the effect on motor recovery and pain, associated with clinical and laboratory parameters. Furthermore, data comparing surgical and conservative treatment can be collected. This will hopefully allow treatment recommendations for patients with LDH accompanied by a sensomotoric deficit. TRIAL REGISTRATION: ISRCTN, ISRCTN12741173 . Registered on 15 January 2017.

Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. METHODS: We analyzed cerebral taurine levels using high-performance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. RESULTS: CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 µM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. CONCLUSIONS: Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a potential biomarker deserves further investigation.

Hypoperfusion in the acute phase of subarachnoid hemorrhage.

PURPOSE: Acute disruption of cerebral perfusion and metabolism is a well-established hallmark of the immediate phase after subarachnoid hemorrhage (SAH). It is thought to contribute significantly to acute brain injury, but despite its prognostic importance, the exact mechanism and time course is largely unknown and remains to be characterized. METHODS: We investigated changes in cerebral perfusion after SAH in both an experimental and clinical setting. Using an animal model of massive, experimental SAH (n=91), we employed Laser-Doppler flowmetry (LDF), parenchymal microdialysis (MD; n=61), Diffusion-weighted imaging (DWI) and MR spectroscopy (MRS; n=30) to characterize the first hours after SAH in greater detail. The effect of prophylactic treatment with hypothermia (HT; 32°C) and an endothelin-A (ET-A) receptor antagonist (Clazosentan) was also studied. In a group of patients presenting with acute SAH (n=17) we were able to determine cerebral blood flow (CBF) via Xenon-enhanced computed tomography (XeCT) within 12 h after the ictus. RESULTS: The acute phase after SAH is characterized both experimentally and clinically by profound and prolonged hypoperfusion independent from current intracranial pressure (ICP), indicating acute vasospasm. Experimentally, when treated with hypothermia or a ET-A receptor antagonist prophylactically, acute hypoperfusion improved rapidly. DWI showed a generalized, significant decline of the apparent diffusion coefficient (ADC) after SAH, indicating cytotoxic edema which was not present under hypothermia. SAH causes a highly significant reduction in glucose, as well as accumulation of lactate, glutmate and aspartate (MD and MRS). HT significantly ameliorated these metabolic disturbances. CONCLUSION: Acute vasospasm, cytotoxic edema and a general metabolic stress response occur immediately after experimental SAH. Prophylactic treatment with hypothermia or ET-A antagonists can correct these disturbances in the experimental setting. Clinically, prolonged and ICP-independent hypoperfusion was also confirmed. As the initial phase is of particular importance regarding the neurological outcome and is amenable to beneficial intervention, the acute stage after SAH demands further investigation and warrants the exploration of measures to improve the immediate management of SAH patients.

Two-year outcome after lumbar microdiscectomy versus microscopic sequestrectomy: part 1: evaluation of clinical outcome.

STUDY DESIGN: Single-center randomized prospective study at a university hospital. OBJECTIVE: The aim of the present study was to provide a 2-year outcome comparison of microdiscectomy (D) versus microscopic sequestrectomy (S) in terms of reherniation rates, clinical investigation, and self-rated parameters using a comprehensive questionnaire. SUMMARY OF BACKGROUND DATA: Simple fragment excision in cases of herniated lumbar discs has been repeatedly reported as an alternative to standard microdiscectomy, but prospective data with sufficient follow-up is lacking to date. Preliminary results of a prospective randomized study in patients with lumbar disc herniations indicated equal reherniation rates and a trend toward superior clinical results in patients undergoing only sequestrectomy after 4 to 6 months. MATERIAL AND METHODS: Eighty-four patients with lumbar disc herniations were treated with microdiscectomy or microscopic sequestrectomy in equal parts. Patients were re-evaluated thoroughly clinically after 2 years. Results of this investigation (low back pain, sciatica, motor-, sensory-, reflex-, straight leg raising test-indexes) and self-rated parameters including SF-36 were analyzed for differences between groups and between time points. RESULTS: Thirty-eight (D) and 40 (S) patients were attainable for follow-up. Reherniation rates did not differ significantly (10.5%, group D; 12.5%, group S; P = 1.0). Following dramatic improvement after surgery in both groups, results of the clinical investigation remained stable over time without significant differences between groups. In contrast, self-rated assessment demonstrated clinical deterioration of the surgical results within the first 2 years after microdiscectomy, while they rather improved after sequestrectomy. Because of this development, the outcome measures at 2 years pointed in favor of sequestrectomy with results being significant for important parameters such as use of analgesics, performance, and overall outcome. CONCLUSION: Reherniation rates within 2 years after sequestrectomy and microdiscectomy are comparable. However, outcome after microdiscectomy seems to worsen over time, whereas it remains stable after sequestrectomy. Thus, 2-year follow-up revealed clinical results favoring sequestrectomy. Performing sequestrectomy alone may therefore represent an advantageous alternative to standard microdiscectomy.