A Simple Procedure of Epidural Electrode Lead Replacement through a Tissue Sheath in Spinal Cord Stimulation.

Spinal cord stimulation (SCS) is widely performed to treat several types of intractable chronic pain. To maintain lasting SCS, epidural electrode leads must be replaced sometimes due to problems like lead breakage. However, in lead replacement, guiding the new lead to the original position may be difficult because granulation tissue sheath forms around the lead. We encountered a surgical case where we inserted new leads through tissue sheaths forming around the old leads from the epidural space to the thoracolumbar fascia; the lead was smoothly introduced to the original place. This procedure is simpler than previously reported techniques. Here, we report the detailed surgical procedure and review the relevant literature.

[A case of idiopathic spinal cord herniation with incomplete Brown-Séquard syndrome].

A 50-year-old man was referred to our hospital with myelitis associated with a 10-months history of progressive muscle weakness in the left leg. Neurological examinations demonstrated diffuse muscle weakness of the left leg, touch hypoesthesia of the right leg, reduced pain sensation below the right nipple, left pyramidal sign, and urinary incontinence. On the basis of thoracic spinal MRI and thoracic CT myelography, revealing anterior displacement of the spinal cord and enlargement of the posterior subarachnoid space at the Th4 vertebral level, we diagnosed the patient as having idiopathic spinal cord herniation with incomplete Brown-Séquard syndrome. After microsurgical release of the spinal cord and subsequent covering of the anterior dural defect with an artificial dura mater, the symptoms improved without progression. Clinicians should consider spinal cord herniation as a cause of slowly progressive thoracic myelopathy with Brown-Séquard syndrome.

Prevalence and Screening of Deep Vein Thrombosis in Patients with Osteoporotic Vertebral Fracture.

AIM: To determine the prevalence of a deep vein thrombosis (DVT) in osteoporotic vertebral fractures. MATERIAL AND METHODS: Data were retrospectively collected from the medical records of 50 patients who were admitted to the Kameda Medical Center for osteoporotic vertebral fracture from 2019 to 2020. Inpatients were screened for DVT using D-dimer, and those who were screened positive underwent lower extremity venous ultrasonography to confirm DVT. Associations between various clinical factors and DVT were analyzed. RESULTS: Six (12.0%) inpatients with osteoporotic vertebral fractures were found to have DVT. Two (33.3%) of the six had proximal DVT, although no pulmonary embolism was detected by chest computed tomography angiography. Univariate analysis showed that D-dimer values and duration from onset to hospitalization were predictive of DVT (p < 0.05). CONCLUSION: The prevalence of DVT among inpatients with osteoporotic vertebral fractures was 12.0%. This finding emphasizes the importance of DVT screening using D-dimer in those with osteoporotic vertebral fractures.

Two cases of normal pressure hydrocephalus caused by ependymoma of the cauda equina.

BACKGROUND: Normal pressure hydrocephalus (NPH) associated with tumors of the cauda equina is rare. Here, we report two cases of NPH attributed to cauda equina ependymomas. CASE DESCRIPTION: A 63-year-old male presented with progressive gait disturbance, dementia, and urinary incontinence. When the lumbar MR documented an intradural tumor involving the cauda equina at the L2-L3 level; the tumor was excised; pathologically, it proved to be a myxopapillary ependymoma. Postoperatively, however, the patient's continued gait disturbance led to a brain CT that documented ventricular dilation consistent with NPH; following ventriculoperitoneal (VP) shunt placement his symptoms improved. A 65-year-old female also presented with gait disturbance, dementia, and urinary retention. Here, procedures were performed in reverse. When a brain CT showed hydrocephalus, a VP shunt was placed. When symptoms persisted, a lumbar MR demonstrated a T12-L2 intradural tumor; following a lumbar laminectomy for tumor excision, symptoms stabilized. The pathological diagnosis was also consistent with a conus/cauda equina ependymoma. Over the next 10 years, the patient had residual bladder dysfunction (e.g., requiring straight catheterization), but had no shunt dysfunction. CONCLUSION: We observed two cases of ependymomas of the cauda equina and brain CTs documenting NPH that was successfully surgically managed with stabilization of neurological deficit. In the first case, L2-L3 laminectomy for tumor removal was succeeded by shunting for NPH, while in the second case, initial VP shunting for NPH was followed by a T12-L2 laminectomy for tumor excision.

Effect of asymptomatic postoperative epidural hematoma on recovery rate after surgery for myelopathy caused by thoracic ossified ligamentum flavum.

AIM: To analyze the clinical characteristics of thoracic ossified ligamentum flavum (OLF) and clarify prognostic factors. MATERIAL AND METHODS: We retrospectively collected clinical data from the medical records of 29 patients who underwent decompressive surgery for myelopathy caused by thoracic OLF from 2011 to 2019. Associations between various clinical and radiological factors and surgical outcomes were analyzed. RESULTS: The mean preoperative and final follow-up modified Japanese Orthopaedic Association scores were 6.7 and 7.9 points, respectively (mean follow-up period, 22.4 months; P 0.0001). Univariate analysis revealed that preoperative symptom duration and postoperative epidural hematoma on magnetic resonance imaging (MRI) were significant surgical outcome predictors. The recovery rate was higher in patients without postoperative epidural hematoma (n = 16) than in those with postoperative epidural hematoma (n = 13; 38.7% ± 28.1% vs. 12.9% ± 24.4% mm; P = 0.01). Multiple regression analysis showed that postoperative epidural hematoma on MRI was a significant surgical outcome predictor (P 0.05). CONCLUSION: Posterior decompressive laminectomy and resection of OLF can be considered effective. Postoperative epidural hematoma on MRI may be an important surgical outcome predictor.

Tumoral Calcinosis of Thoracic Spine Associated with Vertebral Fracture and Inflammatory Reactions.

Tumoral calcinosis involving the spine is rare. The involvement of the thoracic spine is rarer than that of the cervical or lumbar spine. We report a case of thoracic tumoral calcinosis accompanied by vertebral fracture with increased concentrations of inflammatory markers and no abnormalities in serum calcinosis and phosphorus concentration. A 60-year-old woman presented with complete paraplegia. Her white blood cell count and C-reactive protein (CRP) concentration were elevated. The thoracic magnetic resonance imaging revealed vertebral fracture and an epidural mass that demonstrated low intensity on both T2- and T1-weighted images at the T9/10 dorsal side of the central canal. This lesion is larger in size than that observed in the previous 2 months. Her laboratory data showed signs of infection, and only decompression surgery without fixation for treatment and diagnosis was performed. Histopathological examination was consistent with tumoral calcinosis. Postoperatively, the patient's white cell count and CRP concentration were normalized. We found that tumoral calcinosis can occur at the thoracic level on the basis of the spinal instability due to the vertebral compression fracture and the accompanying increase in inflammation indicated by increased white blood cell count and CRP concentration.

Posterior spinal fusion for severe kyphoscoliosis in a Loeys-Dietz syndrome patient with a large syringomyelia.

Spinal deformity is a characteristic feature of Loeys-Dietz syndrome (LDS). Surgical correction in LDS is indicated when the deformity is progressive to avoid neurological deficits, respiratory impairment, and back pain. However, few reports exist on the surgical treatment of spinal deformity in LDS, and no therapeutic standards have been established. We described the clinical and radiological outcomes of a patient with LDS receiving surgery for severe kyphoscoliosis. A 21-year-old male patient with LDS underwent posterior spinal fusion with an all-pedicle screw construct from T10 to L5 for a preoperative main curve Cobb angle of 70 degrees and kyphotic angle of 49 degrees. The postoperative Cobb angle of the main curve and kyphotic angle improved to 36 and 8 degrees, respectively. Correction surgery was performed with frequent motor evoked potential testing, taking care not to cause motor paralysis. Ameliorated low back pain and improvements in clinical questionnaire scores were noted at 21 months after surgery. No perioperative complications were reported. Based on the present case, posterior spinal fusion represents a good correction option for severe spinal deformity in LDS with syringomyelia. Careful preoperative examination and treatment for neurovascular and neurological lesions is advised to prevent severe complications.

Spinal Subdural Abscess following Transforaminal Lumbar Interbody Fusion.

Spinal subdural abscesses are rare lesions. We report the case of surgical site infection complicated with meningitis and rapidly progressive spinal subdural abscess caused by P. aeruginosa following transforaminal lumbar interbody fusion (TLIF). A 72-year-old woman was admitted to our hospital complaining of drop foot syndrome and sciatica caused by stenosis of the L5/6 intervertebral foramen accompanied by L5 lumbar vertebral fracture. Accordingly, TLIF of L5-L6 and balloon kyphoplasty of L5 were performed. On the 3rd postoperative day (POD), she was diagnosed with surgical site infection complicated with bacterial meningitis. Subcutaneous fluid, blood, and cerebrospinal fluid cultures indicated P. aeruginosa. On the 7th POD, a repeat MRI showed a large dorsal fluid collection consistent with a subdural infection and massive cauda equina compression. We performed debridement and instrument removal and found a dural laceration that was not observed during the first operation. An intraoperative insensible dural laceration may cause bacteria intrusion into the subdural space.

A Rapidly Growing Cervical Meningeal Melanocytoma with a Dumbbell-Shaped Extension.

BACKGROUND: Meningeal melanocytoma is a rare benign lesion found in the central nervous system. Preoperative diagnosis of meningeal melanocytoma is often a diagnostic challenge, as the clinical and neurologic features are often nonspecific. Various characteristics, including the natural course of this tumor, remain poorly understood. We report a case of a rapidly growing dumbbell-shaped melanocytoma compressing the spinal cord that manifested 2 years after a tumor was identified at the right C2-C3 foramen. CASE DESCRIPTION: A 40-year-old, right-handed man presented with a 2-month history of right palm and left leg numbness. Magnetic resonance imaging of the cervical spine showed a dumbbell-shaped tumor at the right C2-C3 foramen with extension into the central canal. The lesion was hyperintense on T1-weighted images and hypointense to isointense on T2-weighted images. Contrast enhancement was not visualized clearly. Fluorodeoxyglucose-positron emission tomography with computed tomography showed intense uptake in the lesion. The patient's history included a small lesion that had been localized at the right C2-C3 foramen 2 years before admission. The pathologic findings were consistent with melanocytoma. CONCLUSIONS: It is important to include meningeal melanocytoma in the differential diagnosis of dumbbell tumors, as meningeal melanocytomas may show rapid progression.

Lumbar Ganglioneuroma from the Paravertebral Body Presenting in Continuity Between Intradural and Extradural Spaces.

BACKGROUND: Ganglioneuroma is a well-differentiated benign tumor that develops from the ganglion cells of the posterior mediastinum, retroperitoneum, cervical spine, and adrenal glands. The paravertebral body, in which the sympathetic trunk exists, is a common tumor site, and tumor sometimes invades the spinal canal through the intervertebral foramen. There have been no reports regarding tumors with intradural and extradural continuity. We report a paravertebral ganglioneuroma extending between the intradural and extradural spaces and its surgical treatment. CASE DESCRIPTION: A 33-year-old man was admitted to the hospital with progressive left lower limb numbness. A dumbbell-type tumor progressing to the spinal canal via the left intervertebral foramen from the paravertebral body at L1-2 was detected, and intradural calcified lesions were found. Pathologic examination of a computed tomography-guided biopsy sample revealed a ganglioglioma. The extradural tumor was removed; however, the left lower limb pain gradually worsened. As complete block was observed on myelography, the intradural tumor was removed 8 months later. Intraoperative findings revealed that the intradural and extradural tumors were continuous through the L1 nerve root. CONCLUSIONS: This is the first known reported case of paravertebral ganglioneuroma presenting in continuity between the intradural and extradural spaces.

The Transspinal Canal Screwing Technique for Atlantoaxial Anomalies: A Technical Note and 2 Case Reports.

It is difficult to treat atlantoaxial instability in patients with a high-riding vertebral artery or anomalies of the craniocervical junction. We report 2 successful cases in which the transspinal canal screwing technique was used because of difficulties performing conventional fixation methods. Case 1: A 78-year-old woman suffered from progressive myelopathy due to severe spinal cord compression with a congenital anomaly of the craniovertebral junction. Bilateral transspinal canal screws from the axis body with spondylolisthesis to the dens were inserted by retracting the dural sac medially after foramen magnum decompression and cervical laminoplasty. Case 2: A 20-year-old man with a spinal deformity due to Loeys-Dietz syndrome presented to our hospital for treatment of syringomyelia. He had no obvious neurological deficits, but spinal cord compression due to right atlantoaxial rotating dislocation was observed. A screw was inserted from the vertebral body of the axis to the right lateral mass of the atlas via the spinal canal after laminectomy of the atlas. The transspinal canal screwing technique is useful for treating atlantoaxial instability in cases where other fixation methods are difficult.

[Availability of Early Balloon Kyphoplasty for the Treatment of Osteoporotic Compression Fractures].

INTRODUCTION: Japan has many patients with osteoporosis; however, only about one-fifth of these patients receive treatment. Although some treatment guidelines exist for osteoporosis, the number of newly diagnosed patients with osteoporotic compression fractures is increasing and protocols for treatment of osteoporotic compression fractures vary from one hospital to another. This study aims to investigate the availability of early balloon kyphoplasty(BKP)in relation to our treatment strategy for osteoporotic compression fractures. METHODS: In our hospital, patients diagnosed with osteoporotic compression fractures were treated conservatively with a corset and rehabilitation. In cases where pain was prolonged and computed tomography(CT)imaging revealed formation of a cavity, we performed BKP. We divided the patients admitted between April 2016 and December 2016 with osteoporotic compression fractures into 2 groups, based on whether they received conservative treatment or BKP. We assessed the patients' age, fracture site, CT and MRI findings, bone density, Numerical Rating Scale(NRS), duration of hospital stay, and outcomes. RESULTS: In the BKP group, the number of Th12 and L1 compression fractures was higher than fractures to other vertebral bodies. No difference was observed in bone density, improvement of NRS, and outcomes between groups. CT cavity signs were more frequently observed in the BKP group than in the conservative group. CONCLUSIONS: This study establishes a correlation between the appearance of CT cavity sign and prolonged pain, which increases the likelihood of a patient undergoing BKP. The CT cavity sign and prolonged pain could be indicators of pre-stage pseudoarthrosis. BKP performed in the early stages of a fracture is safe and does not result in complications. However, BKP should be performed according to appropriate indications, including delayed neurological deficit, pain, and reduced bone adhesion.

Identification of stroke-associated-antigens via screening of recombinant proteins from the human expression cDNA library (SEREX).

BACKGROUND: Because circulating antibodies against a variety of antigens have been detected in patients with coronary heart disease, carotid atherosclerosis and those who have suffered a stroke, it is suspected that immune response may be one of the mechanisms of atherogenesis The objective of this study is to identify novel antibodies in ischemic stroke patients by screening the expressed recombinant proteins using a human cDNA library (SEREX). METHODS: To identify the candidate antigens, cDNA library was screened by SEREX using plasma from ten patients with ischemic stroke. Subsequently, via ELISA using recombinant proteins and synthetic peptides, the serum antibody levels were measured in two independent patient/healthy donor (HD) cohorts (142 and 78 in the 2nd screening and a validation cohort, respectively). RESULTS: The initial screening resulted in the identification of six candidate antigens. Of these antigens, replication protein A2 (RPA2) was determined to be the antigen associated with stroke (P < 0.05) by ELISA with 2nd screening and validation cohort. Multifactorial logistic regression analysis showed that the increased levels of the RPA2 antibodies (RPA2-Abs) associated with stroke independent of other risk factors for stroke (P < 0.05). Receiver operating curve analysis demonstrated that the area under the curve from ELISA using GST fusion RPA2 and synthetic peptides (bRPA2-132) were 0.867 (95% CI: 0.798-0.936) and 0.971 (95% CI: 0.940-1.00), respectively. If the cut-off value of the bRPA2-132-Ab level was determined to be 0.334, the sensitivity and specificity of the antibody level as the diagnostic marker for stroke were 0.323 (95% CI: 0.209-0.453) and 1.00 (95% CI: 0.713-1.00), respectively. CONCLUSIONS: SEREX identified RPA2 as the antigen associated with ischemic stroke and serum auto-antibodies against RPA2 elevates in stroke patients. RPA2-Abs could become a biomarker for the evaluation of ischemic stroke at risk.

Neuroendocrine tumor arising from tailgut cyst with spinal cord tethering: case report and literature review.

BACKGROUND CONTEXT: Neuroendocrine tumors (NETs) from tailgut cysts are rare; only 15 cases have been reported until now. A tailgut cyst with spinal cord tethering has not been previously reported, although both diseases are congenital anomalies in the early stage of gestation. PURPOSE: To report a rare case of NET from tailgut cyst associated with spinal cord tethering and review the literature. STUDY DESIGN: Case report and literature review. METHODS: We describe the clinical course of a 53-year-old man, who presented with gluteal pain and bladder dysfunction. Magnetic resonance images showed that a tumor of the sacral spinal canal extended into the retrorectal space and connected to a thickened fatty filum terminale, which was tethering the spinal cord. RESULTS: Because of tumor malignancy on a computed tomography-guided biopsy and the imaging data of involvement of presacral lymph nodes, we performed total removal of the tumor. Pathologic examination revealed NET (Grade 2) arising from a tailgut cyst. The patient received somatostatin analog therapy after surgery, followed by local radiation because of the further enlargement of the lymph nodes. Later, we started everolimus therapy for the metastases to the retroperitoneal lymph nodes. He presented with no local recurrence or further disease progression at 28 months after surgery. The review indicated that tumors in Grade 2 or 3 showed progressive clinical course after surgery and three of seven patients with biopsy were misdiagnosed. CONCLUSIONS: The correct preoperative diagnosis of NETs from tailgut cysts is difficult, but extremely important because Grade 2 or 3 tumors show disease progression even after surgery. Presacral congenital tumors, such as tailgut cysts, have the potential of malignant transformation into neuroendcrine tumors or adenocarcinomas. Comorbidity of spinal cord tethering and tailgut cyst suggests some relationship to common developmental errors in embryogenesis.

The pitfalls in surgical management of lumbar canal stenosis associated with rheumatoid arthritis.

There have been few clinical studies in the area of cervical spine that focused on surgery for treating degenerative lumbar disease in patients with rheumatoid arthritis (RA). High rates of wound complications and instrumentation failure have been reported more for RA than for non-RA patients, although clinical outcomes are similar between the two groups. Lumbar canal stenosis in RA is caused not only by degeneration but also by RA-related spondylitis, which includes facet arthritis and inflammation around the vertebral endplate. The pitfalls in surgical management of lumbar canal stenosis in RA patients are highlighted in this study. The study reviewed 12 patients with RA, who were surgically treated for lumbar canal stenosis. Two out of five patients with pulmonary fibrosis died of worsened pulmonary condition, even though there were no perioperative pulmonary complications. Two patients with pedicle screw fixation showed no instrumentation failure, but two patients with spinous process fixation needed re-operation or vertebral fracture. Surgical treatment for lumbar canal stenosis in RA patients needs to be individually adjusted. Preoperative assessments and treatments of pulmonary fibrosis and osteopenia are essential. Surgery for lumbar canal stenosis with RA should be deferred for patients with advanced pulmonary fibrosis because of its potential life-threatening risk. Fusion surgery is indicated only in patients with kyphosis or severe symptoms caused by intervertebral instability. Pedicle screw fixation with hydroxyapatite granules or sublaminar tape is recommended. Closer follow-up after surgery is necessary because of possible delayed wound infection, instrumentation failure, pathological fracture, and respiratory deterioration.

Diagnosis and surgical strategy for sacral meningeal cysts with check-valve mechanism: technical note.

OBJECTIVE: There is agreement that symptomatic sacral meningeal cysts with a check-valve mechanism and/or large cysts representing space-occupying lesions should be treated surgically. This study investigated factors indicating a need for surgical intervention and surgical techniques for sacral meningeal cysts with a check-valve mechanism. METHODS: In ten patients presenting with sciatica and neurological deficits, myelography, computed tomography (CT) myelography, and magnetic resonance imaging (MR imaging) detected sacral meningeal cysts with a check-valve mechanism. One patient had two primary cysts. Ten cysts were type 2 and one cyst was type 1. Nine of the ten patients had not undergone previous surgery, while the remaining case involved recurrent cyst. For the seven patients with normal (i.e., not huge or recurrent) type 2 cysts and no previous surgery (eight cysts), suture after collapse of the cyst wall was performed. For the recurrent type 2 cyst, duraplasty and suture with collapse of the cyst wall were performed to eliminate the check-valve mechanism. For the remaining type 2 cyst, a primary root was sacrificed because of the huge size of the cyst. For the type 1 cyst, the neck of the cyst was ligated. RESULTS: In all cases, chief complaints disappeared immediately postoperatively and no deterioration of clinical symptoms has been seen after a mean follow-up of 27 months. CONCLUSIONS: The presence or absence of a check-valve mechanism is very important in determining the need for surgical intervention for sacral meningeal cysts.

A case of Proteus syndrome with severe spinal canal stenosis, scoliosis, and thoracic deformity associated with tethered cord.

Proteus syndrome is a rare, sporadic, hamartomatous disorder manifesting with multifocal overgrowth of tissue. The features seem to develop most often during childhood. Vertebral overgrowth with severe spinal canal stenosis is unusual, although scoliosis with abnormal vertebral bodies is one of the typical features of Proteus syndrome. We report a case of Proteus syndrome with severe spinal canal stenosis, scoliosis, cervical kyphosis, and thoracic deformity with airway obstruction because of asymmetrical overgrowth of vertebrae and ribs associated with a tethered cord, lipomas, strawberry hemangioma, flat nasal bridge, and bilateral hypoplasty of the first metatarsal bones with hyperplasty of soft tissue.

A huge presacral Tarlov cyst. Case report.

Perineural cysts have become a common incidental finding during lumbosacral magnetic resonance (MR) imaging. Only some of the symptomatic cysts warrant treatment. The authors describe the successful operative treatment of a patient with, to the best of their knowledge, the largest perineural cyst reported to date. A 29-year-old woman had been suffering from long-standing constipation and low-back pain. During an obstetric investigation for infertility, the clinician discovered a huge presacral cystic mass. Computed tomography myelography showed the lesion to be a huge Tarlov cyst arising from the left S-3 nerve root and compressing the ipsilateral S-2 nerve. The cyst was successfully treated by ligation of the cyst neck together with sectioning of the S-3 nerve root. Postoperative improvement in her symptoms and MR imaging findings were noted. Identification of the nerve root involved by the cyst wall, operative indication, operative procedure, and treatment of multiple cysts are important preoperative considerations.

Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms.

Four lysyl oxidase family genes (LOXL1, LOXL2, LOXL3, and LOXL4), which catalyze cross-linking of collagen and elastin, were considered to be functional candidates for intracranial aneurysms (IA) and were extensively screened for genetic susceptibility in Japanese IA patients. Total RNA was isolated from four paired ruptured IA and superficial temporal artery (STA) tissue and examined by real-time RT-PCR. The expression of LOXL2 in the paired IA and STA tissues was elevated in the IA tissue. A total of 55 single nucleotide polymorphisms (SNPs) of LOXL1-4 were genotyped for an allelic association study in 402 Japanese IA patients and 462 Japanese non-IA controls. Allelic associations were evaluated with the chi-square test and the permutation test especially designed for adjustment of multiple testing. SNPs of LOXL1 and LOXL4 were not significantly associated with IA, while several SNPs of LOXL2 and LOXL3 showed nominally significant associations in IA patients. We detected an empirically significant association with one SNP of LOXL2 in familial IA patients after adjustment for multiple testing [chi(2) = 10.23, empirical P = 0.023, OR (95% CI) = 1.49 (1.17, 1.90)]. Furthermore, multilocus interaction was evaluated by multifactor dimensionality reduction analysis. We found that the SNPs of LOXL2 have an interactive effect with elastin (ELN) and LIM kinase 1 (LIMK1) that have been previously found to be associated with IA. In conclusion, one SNP of LOXL2 showed a significant association with IA individually, and we also detected a gene-gene interaction of LOXL2 with ELN/LIMK1, which may play an important role in susceptibility to IA.

A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms.

The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3'-untranslated region (3'-UTR) of ELN and the entire region of LIMK1. An association study with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.