The Influence of a Genetic Variant in CCDC78 on LMNA-Associated Skeletal Muscle Disease.

Mutations in the LMNA gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in coiled-coil domain containing protein 78 (CCDC78). This variant was given priority because another mutation in CCDC78 causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the LMNA mutation and the CCDC78 variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the LMNA mutation. Taken together, our findings suggest that a relatively common variant in CCDC78 can impart profound muscle pathology in combination with a LMNA mutation and accounts for variability in skeletal muscle disease phenotypes.

Posterior fusion for fragility type 2 odontoid fractures.

OBJECTIVE: The purpose of this study was to evaluate the outcomes of elderly patients with type 2 odontoid fractures treated with an instrumented posterior fusion. METHODS: Ninety-three consecutive patients older than 65 years of age in whom a type 2 odontoid fracture had been treated with a variety of C1-2 posterior screw fixation techniques were retrospectively reviewed. RESULTS: The average age was 78 years (range 65-95 years). Thirty-seven patients had an additional fracture, 30 of which involved C1. Three patients had cervical spinal cord dysfunction due to their injury. All patients had comorbidities. The average total hospitalization was 9.6 days (range 2-37 days). There were 3 deaths and 19 major complications, the most common of which was pneumonia. No patient suffered a vertebral artery injury. Imaging studies were obtained in 64 patients at least 12 months postsurgery (mean 19 months). Fusion was assessed by dynamic radiographs in all cases and with a CT scan in 80% of the cases. Four of the 64 patients did not achieve fusion (6.25% overall). All patients in whom fusion failed had undergone C1 lateral mass fixation and C2 pars (1/29, 3.4%) or laminar (3/9, 33.3%) fixation. CONCLUSIONS: Instrumented posterior cervical fusions may be performed in elderly patients with acceptable morbidity and mortality. The fusion rate is excellent except when bilateral C2 translaminar screws are used for axis fixation.

Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors' institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.

Pathology of cavernous malformations.

Cavernous malformations (CMs) are low-pressure angiographically occult lesions, composed of blood-filled sinusoidal locules known as "caverns." Although these lesions were once believed to be congenital in nature, there is compelling evidence to support de novo formation of CMs as well. They can occur as sporadic lesions or be inherited in an autosomal-dominant phenotype in familial forms of the disease. The pathophysiology of CMs is commonly believed to be due to abnormal vascular pathology. Three genes, CCM1, CCM2, and CCM3, have been extensively studied for their role in vascular pathology, resulting in abnormal angiogenesis and compromising the structural integrity of vessel endothelial cell. The expression of growth factors has been researched to gain insight into the dynamic behavior of CM lesions. Gross and microscopic images are utilized in this chapter to illustrate the pathologic findings of these lesions. Ultrastructural analysis demonstrates the aberrations in CM endothelial cells and structural integrity that may provide better understanding into how and why these lesions have a propensity to hemorrhage.

Extracranial ligation of ethmoidal arteries before resection of giant olfactory groove or planum sphenoidale meningiomas: 3 illustrative cases with a review of the literature on surgical techniques.

OBJECT: There are several surgical techniques for reducing blood loss-open surgical and endoscopic-prior to resection of giant anterior skull base meningiomas, especially when preoperative embolization is risky or not technically feasible. The authors present examples of an institutional experience using surgical ligation of the anterior and posterior ethmoidal arteries producing persistent tumor blush in partially embolized tumors. METHODS: The authors identified 12 patients who underwent extracranial surgical ligation of ethmoidal arteries through either a transcaruncular or a Lynch approach. Of these, 3 patients had giant olfactory groove or planum sphenoidale meningiomas. After approval from the institution privacy officer, the authors studied the medical records and imaging data of these 3 patients, with special attention to surgical technique and outcome. The variations of ethmoidal artery foramina pertaining to this surgical approach were studied using preserved human skulls from the Hamann-Todd Osteological Collection at the Museum of Natural History, Cleveland, Ohio. RESULTS: The extracranial ligation was performed successfully for control of the ethmoidal arteries prior to resection of hypervascular giant anterior skull base meningiomas. The surgical anatomy and landmarks for ethmoidal arteries were reviewed in anthropology specimens and available literature with reference to described surgical techniques. CONCLUSIONS: Extracranial surgical ligation of anterior, and often posterior, ethmoidal arteries prior to resection of large olfactory groove or planum sphenoidale meningiomas provides a safe and feasible option for control of these vessels prior to either open or endoscopic resection of nonembolized or partially embolized tumors.

Unusual presentation of congenital dermal sinus: tethered spinal cord with intradural epidermoid and dual paramedian cutaneous ostia.

The authors present the first report of spinal congenital dermal sinus with paramedian dual ostia leading to 2 intradural epidermoid cysts. This 7-year-old girl had a history of recurrent left paramedian lumbosacral subcutaneous abscesses, with no chemical or pyogenic meningitis. Admission MRI studies demonstrated bilateral lumbar dermal sinus tracts and a tethered spinal cord. At surgery to release the tethered spinal cord the authors encountered paramedian dermal sinus tracts with dual ostia, as well as 2 intradural epidermoid cysts that were not readily apparent on MRI studies. Congenital dermal sinus should be considered in the differential diagnosis of lumbar subcutaneous abscesses, even if the neurocutaneous signatures are located off the midline.

Intraoperative femoral nerve stimulation in evaluation of patellar tracking: tourniquet effects and catheter placement.

BACKGROUND: Dynamic intraoperative assessment of patella tracking utilizes femoral nerve stimulation to contract the quadriceps muscles in assessing the proper distance to transfer the tibial tubercle during distal realignment procedures for patellofemoral instability. PURPOSE: We describe the effects of tourniquet inflation and catheter placement on intraoperative femoral nerve stimulation for assessment of patellar tracking. METHODS: Percutaneous electromyographic (EMG) needles were placed into the quadriceps and sartorius muscles to monitor muscle activity and changes in amplitude threshold (mA) required for femoral nerve stimulation with increasing tourniquet inflation times. Eleven patients used ultrasound for catheter placement and ten were manually placed based upon body landmarks. RESULTS: Tourniquet application time correlated positively with the change in amplitude threshold required to generate muscle contraction. Patients had an average four-fold increase in required stimulus amplitude from the baseline thresholds (pre-tourniquet inflation) to final thresholds (tourniquet inflated) with a two-hour tourniquet inflation time. The use of ultrasound for catheter placement significantly decreased the baseline amplitude required in comparison with catheters placed without ultrasound, (p = 0.0330). CONCLUSIONS: Increased tourniquet inflation times require greater stimulus amplitude to generate quadriceps muscle contraction. Ultrasound guidance for catheter placement can provide femoral nerve stimulation at low amplitudes.