Human Induced Pluripotent Stem Cells: Clinical Significance and Applications in Neurologic Diseases

The generation of human induced pluripotent stem cells (iPSCs) from somatic cells using gene transfer opens new areas for precision medicine with personalized cell therapy and encourages the discovery of essential platforms for targeted drug development. iPSCs retain the genome of the donor, may regenerate indefinitely, and undergo differentiation into virtually any cell type of interest using a range of published protocols. There has been enormous interest among researchers regarding the application of iPSC technology to regenerative medicine and human disease modeling, in particular, modeling of neurologic diseases using patient-specific iPSCs. For instance, Parkinson’s disease, Alzheimer’s disease, and spinal cord injuries may be treated with iPSC therapy or replacement tissues obtained from iPSCs. In this review, we discuss the work so far on generation and characterization of iPSCs and focus on recent advances in the use of human iPSCs in clinical setting.

Human Induced Pluripotent Stem Cells: Clinical Significance and Applications in Neurologic Diseases

The generation of human induced pluripotent stem cells (iPSCs) from somatic cells using gene transfer opens new areas for precision medicine with personalized cell therapy and encourages the discovery of essential platforms for targeted drug development. iPSCs retain the genome of the donor, may regenerate indefinitely, and undergo differentiation into virtually any cell type of interest using a range of published protocols. There has been enormous interest among researchers regarding the application of iPSC technology to regenerative medicine and human disease modeling, in particular, modeling of neurologic diseases using patient-specific iPSCs. For instance, Parkinson’s disease, Alzheimer’s disease, and spinal cord injuries may be treated with iPSC therapy or replacement tissues obtained from iPSCs. In this review, we discuss the work so far on generation and characterization of iPSCs and focus on recent advances in the use of human iPSCs in clinical setting.

Comparative Analysis of Spontaneous Infectious Spondylitis : Pyogenic versus Tuberculous

OBJECTIVE: Spondylitis is often chemotherapy resistant and requires long-term treatment. Without adequate chemotherapy, the outcome can be fatal or result in severe neurologic damage. Therefore, differentiating the etiology of spondylitis is very important, particularly in spontaneous cases. As the prevalence of tuberculosis in Korea has decreased in recent years, updated clinical research about spondylitis is warranted. METHODS: From April 2010 to March 2016, data from spondylitis patients were collected retrospectively. In total, 69 patients (51 with pyogenic spondylitis and 18 with tuberculous spondylitis) were included. Clinical data, laboratory findings including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, measurements of Cobb angles at the initial and final follow-up, and radiologic features on magnetic resonance imaging (MRI) scans were evaluated. To test differences between the pyogenic and tuberculous groups, numerical data were compared using the student’s t-test and Mann-Whitney U test, and categorical data were compared using the chi-square test and Fisher’s exact test. RESULTS: The patients’ mean age was 60.0 years. Male sex was slightly predominant (56.5%). There was no difference in mean age and sex between the two groups. The pyogenic group had a relatively higher proportion of immunocompromised patients. The peak CRP value was higher in the pyogenic group than in the tuberculous group (14.08 mg/dL and 8.50 mg/dL, respectively, p=0.009), whereas the ESR was not significantly different between the groups (81.5 mm/h and 75.6 mm/h, respectively, p=0.442). Radiologically, the presence of disc space sparing and vertebral body collapse differed between the groups. In the tuberculous group, the disc was more commonly preserved on contrast-enhanced MRI (50% and 23.5%, respectively, p=0.044), and vertebral body collapse was more common (66.6% and 15.7%, respectively, p < 0.001). The mean length of hospitalization was longer in the pyogenic group (56.5 days and 41.2 days, respectively, p=0.001). Four mortality cases were observed only in the pyogenic group. The most commonly isolated microorganism in the pyogenic group was Staphylococcus aureus (S. aureus) (methicillin susceptible S. aureus and methicillin resistant S. aureus [MRSA] in 8 and 4 cases, respectively). CONCLUSION: The clinical and radiological manifestations of spontaneous spondylitis differ based on the causative organism. Pyogenic spondylitis patients tend to have a higher CRP level and a more severe clinical course, whereas tuberculous spondylitis patients present with destruction of the vertebral body with disc sparing more frequently. The presence of MRSA is increasing in community-acquired spondylitis cases.

Comparative Analysis of Spontaneous Infectious Spondylitis : Pyogenic versus Tuberculous

OBJECTIVE: Spondylitis is often chemotherapy resistant and requires long-term treatment. Without adequate chemotherapy, the outcome can be fatal or result in severe neurologic damage. Therefore, differentiating the etiology of spondylitis is very important, particularly in spontaneous cases. As the prevalence of tuberculosis in Korea has decreased in recent years, updated clinical research about spondylitis is warranted.METHODS: From April 2010 to March 2016, data from spondylitis patients were collected retrospectively. In total, 69 patients (51 with pyogenic spondylitis and 18 with tuberculous spondylitis) were included. Clinical data, laboratory findings including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, measurements of Cobb angles at the initial and final follow-up, and radiologic features on magnetic resonance imaging (MRI) scans were evaluated. To test differences between the pyogenic and tuberculous groups, numerical data were compared using the student’s t-test and Mann-Whitney U test, and categorical data were compared using the chi-square test and Fisher’s exact test.RESULTS: The patients’ mean age was 60.0 years. Male sex was slightly predominant (56.5%). There was no difference in mean age and sex between the two groups. The pyogenic group had a relatively higher proportion of immunocompromised patients. The peak CRP value was higher in the pyogenic group than in the tuberculous group (14.08 mg/dL and 8.50 mg/dL, respectively, p=0.009), whereas the ESR was not significantly different between the groups (81.5 mm/h and 75.6 mm/h, respectively, p=0.442). Radiologically, the presence of disc space sparing and vertebral body collapse differed between the groups. In the tuberculous group, the disc was more commonly preserved on contrast-enhanced MRI (50% and 23.5%, respectively, p=0.044), and vertebral body collapse was more common (66.6% and 15.7%, respectively, p < 0.001). The mean length of hospitalization was longer in the pyogenic group (56.5 days and 41.2 days, respectively, p=0.001). Four mortality cases were observed only in the pyogenic group. The most commonly isolated microorganism in the pyogenic group was Staphylococcus aureus (S. aureus) (methicillin susceptible S. aureus and methicillin resistant S. aureus [MRSA] in 8 and 4 cases, respectively).CONCLUSION: The clinical and radiological manifestations of spontaneous spondylitis differ based on the causative organism. Pyogenic spondylitis patients tend to have a higher CRP level and a more severe clinical course, whereas tuberculous spondylitis patients present with destruction of the vertebral body with disc sparing more frequently. The presence of MRSA is increasing in community-acquired spondylitis cases.

Clinical Results of Odontoid Fractures according to a Modified, Treatment-Oriented Classification

OBJECTIVE: Odontoid fracture is common in cervical injury, representing about 20% of total cervical fractures. Classic odontoid fracture classification focused on anatomy of fracture site has no treatment recommendation and a modified treatment-oriented classification of odontoid fracture was suggested in 2005. We reviewed our odontoid fracture patients to assess the feasibility and efficacy of Grauer's classification. METHODS: Between October 2000 and September 2015, we collected data from patients who came to our institute for odontoid fracture. Demographic data of patients was reviewed, and neck visual analog scale (VAS) score and fusion rate were assessed by reviewing electronic medical records retrospectively. RESULTS: Sixty-nine patients out of a total of eighty two odontoid fracture patients were reviewed according to Grauer's classification. Neck VAS of all subtypes in odontoid fracture classification were decreased at last follow-up (p=0.001). Overall fusion rate was 88.4% at last follow-up. Concordance rate between Grauer's recommendation and our treatment was 69.9%, especially in type II with the concordance higher than 80%. Complication was minimal representing 7.2%, only in types I and III. CONCLUSION: In this study, there were statistically significant improvement in all subtypes in terms of neck VAS at the last follow up, especially in types II and III. Grauer's classification appears to be meaningful to decide treatment plan for odontoid fractures, especially type II odontoid fracture.

Demineralized Bone Matrix (DBM) as a Bone Void Filler in Lumbar Interbody Fusion: A Prospective Pilot Study of Simultaneous DBM and Autologous Bone Grafts

OBJECTIVE: Solid bone fusion is an essential process in spinal stabilization surgery. Recently, as several minimally invasive spinal surgeries have developed, a need of artificial bone substitutes such as demineralized bone matrix (DBM), has arisen. We investigated the in vivo bone growth rate of DBM as a bone void filler compared to a local autologous bone grafts. METHODS: From April 2014 to August 2015, 20 patients with a one or two-level spinal stenosis were included. A posterior lumbar interbody fusion using two cages and pedicle screw fixation was performed for every patient, and each cage was packed with autologous local bone and DBM. Clinical outcomes were assessed using the Numeric Rating Scale (NRS) of leg pain and back pain and the Korean Oswestry Disability Index (K-ODI). Clinical outcome parameters and range of motion (ROM) of the operated level were collected preoperatively and at 3 months, 6 months, and 1 year postoperatively. Computed tomography was performed 1 year after fusion surgery and bone growth of the autologous bone grafts and DBM were analyzed by ImageJ software. RESULTS: Eighteen patients completed 1 year of follow-up, including 10 men and 8 women, and the mean age was 56.4 (32–71). The operated level ranged from L3/4 to L5/S1. Eleven patients had single level and 7 patients had two-level repairs. The mean back pain NRS improved from 4.61 to 2.78 (p=0.003) and the leg pain NRS improved from 6.89 to 2.39 (p<0.001). The mean K-ODI score also improved from 27.33 to 13.83 (p<0.001). The ROM decreased below 2.0 degrees at the 3-month assessment, and remained less than 2 degrees through the 1 year postoperative assessment. Every local autologous bone graft and DBM packed cage showed bone bridge formation. On the quantitative analysis of bone growth, the autologous bone grafts showed significantly higher bone growth compared to DBM on both coronal and sagittal images (p<0.001 and p=0.028, respectively). Osteoporotic patients showed less bone growth on sagittal images. CONCLUSION: Though DBM alone can induce favorable bone bridging in lumbar interbody fusion, it is still inferior to autologous bone grafts. Therefore, DBM is recommended as a bone graft extender rather than bone void filler, particularly in patients with osteoporosis.

Development and Growth of the Normal Cranial Vault : An Embryologic Review

Understanding the development of a skull deformity requires an understanding of the normal morphogenesis of the cranium. Craniosynostosis is the premature, pathologic ossification of one or more cranial sutures leading to skull deformities. A review of the English medical literature using textbooks and standard search engines was performed to gather information about the prenatal development and growth of the cranial vault of the neurocranium. A process of morphogenic sequencing begins during prenatal development and growth, continues postnatally, and contributes to the basis for the differential manner of growth of cranial vault bones. This improved knowledge might facilitate comprehension of the pathophysiology of craniosynostosis.

The Use of Gentamicin-Impregnated Collagen Sponge for Reducing Surgical Site Infection after Spine Surgery

OBJECTIVE: Surgical site infection (SSI) is the one of the most frequent complications in hospitalized patients, and it extends hospital stays and causes extra morbidities. To reduce SSI after spine surgery, we applied the gentamicin-impregnated collagen sponge (Collatamp G) during the operation and analyzed the results retrospectively. METHODS: Between October 2012 and December 2015, we collected data who applied the Collatamp G in spine surgery at a single institution. Demographic data of patients and another possible risk factors of SSI were also included, and we assessed the correlation between the risk factors and the developing of SSI by reviewing electronic medical records retrospectively. RESULTS: Three percent of all patients (10 of 280) developed the SSI and only 0.8% of patients who applied Collatamp G developed SSI (1 of 119). Otherwise, 5% of patients who did not apply Collatamp G developed SSI (9 of 161) (p=0.034). We also analyzed the correlation between SSI and other potential risk factors but nothings showed statistical correlation with SSI. CONCLUSION: In this study, there were statistically significant results that SSI rate was decreased in the group of patients using Collatamp G in spine surgery generally. However, further studies are required to resolve some limitations in the future.

Endovascular Treatment of Symptomatic Vertebral Artery Dissecting Aneurysms

OBJECTIVE: Vertebral artery dissecting aneurysms (VADAs) are rare and many debates are present about treatment options. We review types and efficacy of our endovascular treatments and establish a safe endovascular therapeutic strategy regard to the angio-architecture of VADAs. MATERIALS AND METHODS: Between July 2008 and October 2015, we treated 22 patients with symptomatic VADAs. Fifteen patients presented with subarachnoid hemorrhage from the ruptured VADAs, digital subtraction angiography and magnetic resonance image confirmed the diagnosis and endovascular treatments were followed as their angio-architecture. RESULTS: Clinical results were good in 13 patients (86.7%), and there were no technical problems during endovascular procedures. The other 2 patients with poor prognosis showed severe neurological deficits at the initial evaluation. Among the three different endovascular treatments, there were no radiologic cure in one patient with stent insertion alone, but the patient had no significant clinical symptoms either. CONCLUSION: Endovascular treatments are safe and effective treatment option for managing VADAs and can be the first treatment of choice for most patients. To select proper endovascular treatment according to the angio-architecture of VADAs can reduce the risk of the treatment.

A Rare Case of Malignant Lymphoma Occurred at Spinal Epidural Space: A Case Report

The sacral spinal epidural space is an uncommon site for primary malignant lymphomas, presenting with symptoms associated with cauda equina compression. Especially, lumbo-sacral epidural lymphoma has been reported to be very rare. We present a rare case of 29-year-old male with sacral spinal epidural malignant lymphoma. The patient complained of tingling sensation in his buttocks that was radiating to his calf. The neurological examination was normal. Magnetic resonance imaging (MRI) with contrast showed a well-defined extradural mass lesion at the mid L5 to mid S2 level. The lesion was iso- to hypointense on T1 and T2 weighted images and showed homogenous enhancement and a focal enhancement in the L5 vertebral body on post-contrast images. The patient underwent a L5-S2 laminectomy and subtotal excision of the lesion. Intra-operatively, the lesion was extradural and not densely adherent to the dura; the lesion was friable, not firm, fleshy, brownish and hypervascular. The histologic diagnosis was grade 2 non-Hodgkin's follicular lymphoma. Even though the primary spinal epidural non-Hodgkin's lymphoma is a very rare disease, clinicians should take it into consideration in the differential diagnosis of patients with spinal epidural tumor.

Predictors of Outcome in Patients with Cervical Spondylotic Myelopathy Undergoing Unilateral Open-Door Laminoplasty

OBJECTIVE: This study aimed to analyze prognostic factors affecting surgical outcomes of expansive laminoplasty for cervical spondylotic myelopathy (CSM). METHODS: Using the Frankel scale and Japanese Orthopaedic Association (JOA) scale, we retrospectively reviewed the outcomes of 45 consecutive patients who underwent modified unilateral open-door laminoplasty using hydroxyapatite spacers and malleable titanium miniplates between June 2008 and May 2014. The patients were assigned to the good and poor clinical outcome groups, with good outcome defined as a JOA recovery rate >75%. RESULTS: The mean preoperative JOA scale was significantly higher in the good outcome group (14.95+/-3.21 vs. 10.78+/-6.07, p<0.001), whereas the preoperative cervical range of motion (ROM) in this group was significantly lower (29.89degrees+/-10.11 vs. 44.35degrees+/- 8.88, p<0.001). In univariate analysis, a high preoperative JOA scale (odds ratio (OR) 1.271, 95% confidence interval (CI) 1.005-1.607) and low preoperative cervical ROM(OR 0.858, 95% CI 0.786-0.936) were statistically correlated with good outcomes. Furthermore, these factors demonstrated an independent association with clinical outcomes (preoperative JOA scale: OR 1.344, 95% CI 1.019-1.774, p=0.036; preoperative cervical ROM: OR 0.860, 95% CI 0.788-0.940, p=0.001). CONCLUSION: In this study, a high preoperative JOA scale was associated with good clinical outcome after laminoplasty, whereas a higher preoperative cervical spine ROM was associated with poor clinical outcome. This may suggests that cervical mobility and preoperative neurological status affect clinical outcomes of laminoplasty.

Modified Open-door Laminoplasty Using Hydroxyapatite Spacers and Miniplates

OBJECTIVE: Cervical laminoplasty has been widely accepted as one of the major treatments for cervical myelopathy and various modifications and supplementary procedures have been devised to achieve both proper decompression and stability of the cervical spine. We present the retrospectively analyzed results of a modified unilateral open-door laminoplasty using hydroxyapatite (HA) spacers and malleable titanium miniplates. METHODS: From June 2008 to May 2012, among patients diagnosed with cervical spondylotic myelopathy and ossification of posterior longitudinal ligament, the patients who received laminoplasty were reviewed. Clinical outcome was assessed using Frankel grade and Japanese Orthopaedic Association score. The radiologic parameters were obtained from plain films, 3-dimensional computed tomography and magnetic resonance images. RESULTS: A total of 125 cervical laminae were operated in 38 patients. 11 patients received 4-level laminoplasty and 27 patients received 3-level laminoplasty. Postoperatively, the mean Frankel grade and JOA score were significantly improved from 3.97 to 4.55 and from 12.76 to 14.63, respectively (p<0.001). Radiologically, cervical curvature was worsened from 19.09 to 15.60 (p=0.025). The percentage of range of motion preservation was 73.32+/-22.39%. The axial dimension of the operated spinal canal was increased from 1.75 to 2.70 cm2 (p<0.001). CONCLUSION: In the presenting study, unilateral open-door laminoplasty using HA spacers and miniplates appears to be a safe, rapid and easy procedure to obtain an immediate and rigid stabilization of the posterior elements of the cervical spine. This modified laminoplasty method showed effective expansion of the spinal canal and favorable clinical outcomes.

Late Infection from Anterior Cervical Discectomy and Fusion after Twenty Years

Anterior cervical discectomy and fusion (ACDF) has been performed for degenerative and traumatic cervical diseases to improve pain and neurologic symptoms including sensory change and motor weakness. Infection, however, is a rare complication of ACDF, and late infection is even much rarer. We present a case of late Infection from ACDF C4-5 using Biocompatible Osteoconductive Polymer (BOP) after twenty years in the absence of an esophageal perforation, Zenker's diverticulum, or recent surgery or bacteremia. Late infection from ACDF after 20 years is extremely rare in the literature. However, possibility of such a late complication should be appreciated during the follow-up period and surgical resection will be required for proper treatment.

Intracisternal Cranial Root Accessory Nerve Schwannoma Associated with Recurrent Laryngeal Neuropathy

Intracisternal accessory nerve schwannomas are very rare; only 18 cases have been reported in the literature. In the majority of cases, the tumor origin was the spinal root of the accessory nerve and the tumors usually presented with symptoms and signs of intracranial hypertension, cerebellar ataxia, and myelopathy. Here, we report a unique case of an intracisternal schwannoma arising from the cranial root of the accessory nerve in a 58-year-old woman. The patient presented with the atypical symptom of hoarseness associated with recurrent laryngeal neuropathy which is noted by needle electromyography, and mild hypesthesia on the left side of her body. The tumor was completely removed with sacrifice of the originating nerve rootlet, but no additional neurological deficits. In this report, we describe the anatomical basis for the patient's unusual clinical symptoms and discuss the feasibility and safety of sacrificing the cranial rootlet of the accessory nerve in an effort to achieve total tumor resection. To our knowledge, this is the first case of schwannoma originating from the cranial root of the accessory nerve that has been associated with the symptoms of recurrent laryngeal neuropathy.

Egg-laying capacity of Clonorchis sinensis in guinea pig and rabbit

Thirteen guinea pigs and 23 rabbits were challenged with 300 metacercariae of Clonorchis sinensis each and the recovery of adult worms and egg counts in feces were compared at 11-13 weeks post-infection in guinea pigs and at 7-9 weeks post-infection in rabbits. The recovery rate of adult worm was 23.5 percent in guinea pigs and 20.l-30.5 percent in rabbits. The mean E.P.G. of these animals in above period of infection was 106 in guinea pigs and 121 in rabbits. When one hundredth of E.P.G. was expressed as X and the number of adult worms as Y, the relationships between X and Y were as follows; Y=0.8X+10.8 in guinea pigs and Y=0.7X+6 in rabbits.