A Case Report of Siblings with Dystonia: A Potential Link Between DYT11 Mutation and Platelet Dysfunction.

Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon-sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.

Continual cerebrospinal fluid sampling in the neonatal domestic piglet for biomarker and discovery studies.

BACKGROUND: Longitudinal access to cerebrospinal fluid (CSF) is useful for biomarker discovery in neurological disorders or diseases affecting CSF composition. Here, we aim to test a new method for insertion of a permanent intrathecal catheter, facilitating longitudinal collection of CSF. NEW METHOD: We surgically placed a permanent intrathecal catheter into the cisterna magna of anesthetized neonatal piglets. The thecal sac was accessed at the L5-S1 spinal level and a radiopaque catheter was inserted under fluoroscopic x-ray guidance to position the tip at the cisterna magna. A titanium access port was connected to the catheter and anchored subcutaneously. Immediately after surgery, we confirmed CSF flow through the catheter and port via needle aspiration. Catheter patency over a two-month study period was determined through periodic CSF collection from the port. RESULTS: Frequent (up to 3 times weekly), longitudinal sampling of CSF was achievable in neonatal piglets up to 60 days after implantation. CSF was readily accessible through the port without major adverse events. Catheterized piglets demonstrated slower, but normal, weight gain compared to control piglets. Post-operative complications were managed with standard access precautions and medications. There were no complications involving the implanted hardware. COMPARISON WITH EXISTING METHOD(S): This method fills a critical gap in the existing methods for longitudinal CSF sampling through an implanted intrathecal catheter system in neonatal piglets. CONCLUSIONS: This novel method is both safe and effective for longitudinal CSF access in the domestic piglet. Catheter patency and access to CSF is maintained over multiple months without major adverse events.

VNS Stopping Anti-NMDA Receptor Encephalitis-Triggered Nonconvulsive Status Epilepticus.

BACKGROUND: Anti-NMDA receptor encephalitis (ANRE) is a rare autoimmune neurologic disorder characterized by encephalitis and a constellational of symptoms, including seizures, psychiatric disturbances, autonomic instability, and respiratory insufficiency. It is caused by the anti-NMDA receptor antibody. The most common etiologies for ANRE include malignancy and infection. Ovarian teratoma is the most commonly associated malignancy. CASE DESCRIPTION: We describe the first reported case to our knowledge of ovarian teratoma causing ANRE resulting in nonconvulsive status epilepticus (NCSE), which was terminated with vagus nerve stimulation (VNS). CONCLUSIONS: This case report provides a temporal correlation suggesting that VNS significantly altered the natural history of this patient's NCSE-ANRE. As more data are collected, and the VNS treatment modality more liberally used to treat NCSE, especially in the situation of ANRE, stronger layers of evidence will emerge to fill the gaps of understanding beyond this case report.

Retrospective analysis of pedicle screw accuracy for patients undergoing spinal surgery assisted by intraoperative computed tomography (CT) scanner AIRO® and BrainLab© navigation.

Minimally invasive spine surgery techniques for pedicle screw instrumentation are being more frequently used. They offer shorter operative times, shorter hospital stays for patients, faster recovery, less blood loss, and less damage to surrounding tissues. However, they may rely heavily on fluoroscopic imaging, and confer radiation exposure to the surgeon and team members. Use of the AIRO Mobile Intraoperative CT by Brainlab during surgery is a way to eliminate radiation exposure to staff and may improve accuracy rates for pedicle screw instrumentation. We designed a retrospective analysis of our first 12 patients who had a total of 59 pedicle screws inserted when we began to incorporate the AIRO iCT scanner to our surgical workflow. During pedicle screw insertion, projection images were saved, and compared to CT scans gone at the end of the case. We measured the distances between the projected and postprocedural screw locations, at both the screw tips and tulip heads. We observed a mean of 2.8 mm difference between the projection and postprocedural images. None of the screws inserted had any clinically significant complications, and no patient required revision surgery. Overall, iCT guided navigation with the AIRO system is a safe adjunct to spinal surgery. It decreased operator and staff radiation exposure, and helped facilitate successful MIS surgery without fluoroscopic imaging. Additional studies and research can be done to further improve accuracy and reliability.

Transpedicular Vertebrectomy With Circumferential Spinal Cord Decompression and Reconstruction for Thoracic Spine Metastasis: A Consecutive Case Series.

STUDY DESIGN: Retrospective case series. OBJECTIVE: To study the feasibility, outcomes, and complications of transpedicular vertebrectomy (TPV), and reconstruction for metastatic lesions to the thoracic spine. SUMMARY OF BACKGROUND DATA: Metastatic lesions to the thoracic spine may need surgical treatment requiring anterior-posterior decompression/stabilization. Anterior reconstruction may be performed using poly methyl meth acrylate (PMMA) cement or cages. Use of cement has been reported to be associated with complications. METHODS: From 2008 to 2016, consecutive cases (single surgeon) undergoing TPV for thoracic spine metastasis (T2-12) were included. Demographic, surgical, and clinical data were collected through chart review. MRI, CT, positron emission tomography images were used to identify extent of disease, epidural spinal cord compression (ESCC), and degree of vertebral body collapse. Hall-Wellner confidence band was used for the survival curve. RESULTS: Ninety six patients were studies with a median age 60 years. Most patients 56 (58%) presented with mechanical pain. 29% cases had lung metastasis. Single level TPV was performed in 73 patients (76%). Anterior reconstruction included PMMA in 78 patients (81.25%), and titanium cage in 18 patients (18.25%). Frankel grade improvement was seen in 16 cases (P = 0.013). ESCC improved by a median of 5.9 mm (P < 0.001). Kyphosis reduced by median of 7.5° (P < 0.001). VAS improved by median of seven (P < 0.001). Total 59 deaths were observed. The median survival time was estimated to be 6 months (95% CI: 5, 10). Surgical outcome and complication rates are similar between the two construct types. Correction of kyphosis was seen to be slightly better with the use of PMMA. Overall 29.16% cases developed complications (11.4% major). Two cases developed neurological deficit following epidural hematoma requiring surgery. One case had instrumentation failure from cement migration, needing revision. CONCLUSION: The result of our study shows significantly improved clinical and radiological outcomes for TPV for thoracic metastatic lesions. We also discuss some important steps for use of PMMA to avoid complications. LEVEL OF EVIDENCE: 4.

Biomechanical assessment of proximal junctional semi-rigid fixation in long-segment thoracolumbar constructs.

OBJECTIVEProximal junctional kyphosis (PJK) and failure (PJF) are potentially catastrophic complications that result from abrupt changes in stress across rigid instrumented and mobile non-fused segments of the spine (transition zone) after adult spinal deformity surgery. Recently, data have indicated that extension (widening) of the transitional zone via use of proximal junctional (PJ) semi-rigid fixation can mitigate this complication. To assess the biomechanical effectiveness of 3 semi-rigid fixation constructs (compared to pedicle screw fixation alone), the authors performed cadaveric studies that measured the extent of PJ motion and intradiscal pressure changes (ΔIDP).METHODSTo measure flexibility and ΔIDP at the PJ segments, moments in flexion, extension, lateral bending (LB), and torsion were conducted in 13 fresh-frozen human cadaveric specimens. Five testing cycles were conducted, including intact (INT), T10-L2 pedicle screw-rod fixation alone (PSF), supplemental hybrid T9 Mersilene tape insertion (MT), hybrid T9 sublaminar band insertion (SLB1), and hybrid T8/T9 sublaminar band insertion (SLB2).RESULTSCompared to PSF, SLB1 significantly reduced flexibility at the level rostral to the upper-instrumented vertebral level (UIV+1) under moments in 3 directions (flexion, LB, and torsion, p ≤ 0.01). SLB2 significantly reduced motion in all directions at UIV+1 (flexion, extension, LB, torsion, p < 0.05) and at UIV+2 (LB, torsion, p ≤ 0.03). MT only reduced flexibility in extension at UIV+1 (p = 0.02). All 3 constructs revealed significant reductions in ΔIDP at UIV+1 in flexion (MT, SLB1, SLB2, p ≤ 0.02) and torsion (MT, SLB1, SLB2, p ≤ 0.05), while SLB1 and SLB2 significantly reduced ΔIDP in extension (SLB1, SLB2, p ≤ 0.02) and SLB2 reduced ΔIDP in LB (p = 0.05). At UIV+2, SLB2 similarly significantly reduced ΔIDP in extension, LB, and torsion (p ≤ 0.05).CONCLUSIONSCompared to MT, the SLB1 and SLB2 constructs significantly reduced flexibility and ΔIDP in various directions through the application of robust anteroposterior force vectors at UIV+1 and UIV+2. These findings indicate that semi-rigid sublaminar banding can most effectively expand the transition zone and mitigate stresses at the PJ levels of long-segment thoracolumbar constructs.

MELK-a conserved kinase: functions, signaling, cancer, and controversy.

Maternal embryonic leucine zipper kinase (MELK) is a highly conserved serine/threonine kinase initially found to be expressed in a wide range of early embryonic cellular stages, and as a result has been implicated in embryogenesis and cell cycle control. Recent evidence has identified a broader spectrum of tissue expression pattern for this kinase than previously appreciated. MELK is expressed in several human cancers and stem cell populations. Unique spatial and temporal patterns of expression within these tissues suggest that MELK plays a prominent role in cell cycle control, cell proliferation, apoptosis, cell migration, cell renewal, embryogenesis, oncogenesis, and cancer treatment resistance and recurrence. These findings have important implications for our understanding of development, disease, and cancer therapeutics. Furthermore understanding MELK signaling may elucidate an added dimension of stem cell control.

Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers.

Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of protein serine/threonine kinases that has recently gained significant attention in the stem cell and cancer biology field. Recent studies suggest that activation of this kinase is tightly associated with extended survival and accelerated proliferation of cancer stem cells (CSC) in various organs. Overexpression of MELK has been noted in various cancers, including colon, breast, ovaries, pancreas, prostate, and brain, making the inhibition of MELK an attractive therapeutic strategy for a variety of cancers. In the experimental cancer models, depletion of MELK by RNA interference or small molecule inhibitors induces apoptotic cell death of CSCs derived from glioblastoma multiforme and breast cancer, both in vitro and in vivo. Mechanism of action of MELK includes, yet may not be restricted to, direct binding and activation of the oncogenic transcription factors c-JUN and FOXM1 in cancer cells but not in the normal counterparts. Following these preclinical studies, the phase I clinical trial for advanced cancers with OTSSP167 started in 2013, as the first-in-class MELK inhibitor. This review summarizes the current molecular understanding of MELK and the recent preclinical studies about MELK as a cancer therapeutic target.

Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice.

BACKGROUND: Nearly universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. Because DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with antifibrotic effect may be beneficial. METHODS AND RESULTS: Three groups of 10 utrn(+/-);mdx, or "het" mice, deficient for dystrophin and haploinsufficient for utrophin with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks of life (het-treated-8); a second received the same starting at 4 weeks of life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal ejection fractions though circumferential strain rate was abnormal (-0.21±0.08) in untreated hets. This improved to -0.40±0.07 in het-treated-8 mice (P=0.003) and further improved to -0.56±0.10 in het-treated-4 mice (P=0.014 for het-treated-4 versus het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intracardiomyocyte serum immunoglobulin G localization in het-treated-8 mice (P<0.0001) and a further 53% reduction in het-treated-4 mice (P=0.0003 versus het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb, and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment. CONCLUSIONS: These findings offer clinically available medications with proven antifibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory, and cardiac function for patients with DMD and related myopathies.