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Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.
HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease
Abstract Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Clinical data and reporting quality in NMDAR-antibody encephalitis and pregnancy: a systematic review
BackgroundN-methyl-D-aspartate receptor antibody encephalitis (NMDAR-Ab-E) can have an onset during, after or prior to a pregnancy. In animal models, transplacental NMDAR immunoglobulin G transfer can affect neurodevelopment. In contrast, clinical reports of mothers affected by NMDAR-Ab-E typically are reassuring. We systematically reviewed maternal, infant and childhood clinical data pertaining to NMDAR-Ab-E with an onset before, during or after pregnancy and compared this to our single autoimmune neurology centre experience.MethodsAfter pre-registration on PROSPERO (CRD42023408447), we searched PubMed and Scopus for NMDAR-Ab-E case reports/series with an onset before, during or after pregnancy (last search 19/10/2023). We extracted maternal, neonatal and childhood outcomes using an idealised checklist to derive summary statistics.ResultsAfter quality control, we identified 66 pregnancies in 61 women from 48 reports or series. 72% of women recovered with minimal or no neurological deficits, comparable to non-pregnancy-associated NMDAR-Ab-E. Likewise, 80% of pregnancies resulted in live births with a single neonatal death reported. Data on neonatal outcome measures were frequently unreported, and childhood follow-up was provided in only 60%. Our centre’s experience is consistent: 3/4 mothers recovered with no functional deficits and 7/8 children without evidence of compromise at a median follow-up of 2 years.ConclusionsCurrent evidence does not overall suggest unfavourable maternal, fetal or childhood outcomes after NMDAR-Ab-E. However, the available sample is small, predominantly single case reports with modest follow-up, lacks standardisation, and data are often incomplete. Future approaches should address these caveats: developing multi-centre collaboration towards an international registry.
Anatomy of the diaphragmatic crura and other paraspinal structures relevant to en-bloc spondylectomy for lumbar spine tumours
Abstract Introduction En-bloc spondylectomy in the lumbar spine is a challenging procedure mainly due to a complex prevertebral anatomy. The aim of our study is to describe the anatomy of the diaphragmatic crura and surrounding vascular and neural structures which may be iatrogenically injured during the surgical resection. Materials and methods Ten embalmed specimens were meticulously dissected. Widths of the diaphragmatic crura, abdominal aorta, cisterna chyli, thoracic duct, sympathetic trunks, and inferior vena cava as well as their distances from the midline were measured at nine levels (L1 to L4 vertebra and adjacent intervertebral discs). Results The right crus was attached to the L2–L4 vertebral bodies and L2/3 intervertebral disc, while the left crus inserted onto L1–L3 vertebrae. The thoracic duct arose commonly at the level of L2 vertebra and overlaid the right crus at the L3 vertebra and L2/3-disc levels. The cisterna chyli was present in 70% of specimens and overlapped with the left crus at the same levels. Both sympathetic trunks emerged underneath the crura at the L1/2 discs or L1 vertebra level. The aorta overlapped with the crura at all levels. Conclusion The L3 level appears to be the riskiest for spondylectomy due to the overlap of both diaphragmatic crura with the thoracic duct and cisterna chyli, respectively. Spondylectomy at the L2 level also brings the risk of lymphatic structures injury while injury to the left sympathetic trunk may be the main issue at the L1 level.
New options and techniques in reconstructing the sacrum
Abstract Purpose Sacral tumours, both benign and malignant, often necessitate surgical removal (sacrectomy) to achieve optimal outcomes. However, this procedure disrupts the pelvic ring’s stability, potentially leading to pain and limited mobility. Methods This article explores innovative approaches to reconstruct the sacrum and restore function in primary and secondary sacral tumours. Results Beyond traditional bone graft-based spino-pelvic fixation, the paper delves into minimally invasive alternatives like robotic-assisted surgery which may be used especially as a palliative procedure in destructive lumbosacral junction metastases. This technique offers enhanced precision for implant placement and often a reduced surgical exposure, potentially improving patient recovery. Additionally, the article discusses the application of 3D-printed custom implants, precisely matched the patient’s anatomy to provide immediate structural support. It also explores the use of vascularised long bone flaps for pelvic reconstruction to achieve both stability and ambulation after sacrectomy. Additionally, it is necessary to mention the crucial role of soft tissue reconstruction using local flaps or free flaps from other body regions. Conclusion By presenting these advancements in sacral reconstruction techniques, this article empowers surgeons to select an individualised approach for their patient. This personalised approach can optimise post-operative outcomes, allowing patients to regain function and improve their quality of life.
Diagnosis and management of de novo non-specific spinal infections: European Association of Neurosurgical Societies (EANS) Spine Section Delphi consensus recommendations.
INTRODUCTION: The management of de novo non-specific spinal infections (spondylodiscitis - SD) remains inconsistent due to varying clinical practices and a lack of high-level evidence, particularly regarding the indications for surgery. RESEARCH QUESTION: This study aims to develop consensus recommendations for the diagnosis and management of SD, addressing diagnostic modalities, surgical indications, and treatment strategies. MATERIAL AND METHODS: A Delphi process was conducted with 26 experts from the European Association of Neurosurgical Societies (EANS). Sixtytwo statements were developed on diagnostic workup, management decisions, surgical techniques, non-surgical treatment, and follow-up and submitted to the panel of experts. RESULTS: Consensus was reached on 38 of 62 statements. MRI was confirmed as the gold standard for diagnosis. Regarding surgical indications, the panel agreed that any new neurological deficit, even subtle, warrants surgical consideration. Motor deficits with a motor score (MRC) below 4 and bladder or bowel dysfunction were unanimously considered clear indications for surgery. For spinal deformity and instability, thresholds such as kyphosis >20°, scoliosis >10°, and vertebral body collapse >50% were established to guide surgical decision-making. Minimally invasive surgery (MIS) was endorsed whenever feasible, and a 12 week antibiotic treatment regimen was favored in cases of complicated infections. DISCUSSION AND CONCLUSION: This EANS consensus provides updated recommendations for SD management, incorporating recent evidence on improved outcomes with surgical therapy. While these guidelines offer a more structured approach to clinical decision-making, further research is required to optimize surgical timing and validate the long-term impact of these treatment strategies.
Partial sacrectomy with en bloc tumor resection without instrumentation. What level is safe?
INTRODUCTION: En bloc sacrectomy is an extensive surgical procedure which is often the only option which provides cure. Our experience shows that, in selected cases, instrumentation is not necessary even in case of a high en bloc sacrectomy retaining the cranial part of the sacrum in situ. This creates suitable conditions for subsequent proton therapy. RESEARCH QUESTION: What level of resection is safe without reconstruction? MATERIAL AND METHODS: Between 2014 and 2023 we performed a total of 29 sacral resections for various etiologies. Patients following reconstruction of the lumbosacral region by internal fixator (3) and patient after hemicorporectomy (1) were excluded from the study. The study group comprised 25 patients, 15 men and 10 women with a mean age of 45.1 years (range, 1.7-72.2 years). The most frequent indication for surgery was chordoma (8), followed by MPNST (4), yolk sac tumor (2) and undifferentiated sarcoma (2). RESULTS: Stress fractures of the sacral stump occur in elderly patients with lower bone mineral density, or in younger patients with a higher bone mineral density who are more active when resuming their daily routine after the operation. DISCUSSION AND CONCLUSION: Instrumentation is, in our view, primarily indicated in younger and more active patients, whereas in most cases, even with lower bone mineral density, non-instrumented procedure results in sufficient stability in all levels of partial resection.
Intra-septal sensory branch as an alternative to the sural nerve grafting in radial nerve reconstruction: Anatomical and histomorphological study.
INTRODUCTION: Nerve grafting with the sural nerve is a standard treatment method for radial nerve injury that requires another incision at the lateral ankle distal from the injured upper limb. The aim of this study was to investigate the common trunk (CTCB) of the inferior lateral brachial cutaneous nerve (ILBCN) and posterior antebrachial cutaneous nerve (PACN) as a possible donor inside the lateral intermuscular septum. MATERIALS AND METHODS: The arms and legs of 8 formalin-embalmed cadaver specimens were studied. The radial nerve, common trunk of the ILBCN and PACN, and the sural nerve were identified and measured in length and diameter. For histological examination, nerve samples from 6 fresh cadavers were harvested and processed for further axonal counting. RESULTS: The average length of the CTCB was 114.92 ± 18.9 mm. To match the diameter of the radial nerve at its proximal third, 3 cables of CTCB graft were necessary, which corresponds to a defect length of 3.8 cm. At the level of the distal third, the number of grafts was reduced to 2 with a corresponding defect length of 5.7 cm. The radial nerve contained 15162 ± 318 axons, and the CTCB comprised 3959 ± 176 axons. To match the axon count of the recipient nerve, 4 grafts of CTCB were necessary, which corresponded to a defect length of 2.8 cm. CONCLUSION: CTCB is a consistent and easily dissected cutaneous nerve branch of the radial nerve that can be used for bridging small gaps after neuroma-in-continuity in radial nerve palsy.
End-to-side neurorrhaphy of the sural nerve to the superficial fibular nerve: An anatomically feasible technique for restoring sensation following sural nerve harvest.
The sural nerve is commonly used as an autologous nerve graft. Its harvest results in a sensory deficit in the corresponding distribution area. End-to-side neurorrhaphy of the distal sural nerve stump to the superficial fibular nerve could address the problem of sensory loss in the dorsolateral foot without altering the donor nerve. The purpose of our study is to elaborate on a technique for sural nerve-to-superficial fibular nerve end-to-side neurorrhaphy. Fourteen legs from seven formaldehyde-preserved cadavers were dissected. The sural nerve was transected two centimeters above the distal tip of the lateral malleolus (LM) and mobilised to reach the intermediate dorsal cutaneous nerve (IDCN) and the medial dorsal cutaneous nerve (MDCN). The measurements were taken to localise the coaptation points with the nerves. The distal stump of the sural nerve had to be mobilised 18.0 (8.6-24.9) mm distally in relation to the distal tip of LM in order to reach the IDCN. The coaptation point with the IDCN was 18.9 (15.3-22.8) mm above the distal tip of the LM on the anterior margin of the LM. Mobilisation of 33.7 (25.5-38.8) mm was required for reaching the MDCN. The coaptation point with the MDCN was 19.9 (15.8-27.0) mm above the distal tip of the LM, overlaying the lateral margin of the extensor digitorum longus muscle. The end-to-side neurorrhaphy of the sural nerve to the superficial fibular nerve is anatomically feasible and can be performed on both IDCN and MDCN. We recommend using the MDCN due to its larger diameter.
Unusual innervation of the sartorius muscle by the ilioinguinal and femoral nerves with unique arrangement of the lumbar plexus: a case report and clinical implications.
The sartorius muscle is typically innervated by two branches of the femoral nerve arising from the lumbar plexus. We present an unreported variant where the sartorius muscle was innervated by an accessory branch arising from the ilioinguinal nerve in addition to the proper two branches from the femoral nerve. The iliohypogastric nerve was fused with the ilioinguinal nerve. More proximally, the lumbar plexus also showed unusual arrangement. The anterior branch of the lateral femoral cutaneous nerve arose from the femoral branch of the genitofemoral nerve while the posterior branch arose directly from the second lumbar nerve. The genital branch of the genitofemoral nerve pierced the psoas major muscle more distally than usual, and featured a close proximity with the femoral nerve. Possible variable appearance of these nerves should be kept in mind during several surgical and diagnostic procedures since their iatrogenic or traumatic damage, or their susceptibility to entrapment, pose unpredictable clinical consequences.
Isolated musculocutaneous nerve injury in a motorcyclist - a case report.
INTRODUCTION: Isolated musculocutaneous nerve injuries occur rarely due to their anatomical location. We present our patient with a musculocutaneous nerve injury in a motorcyclist. CASE: The patient was initially treated for a motorcycle accident. Further examination of the patient revealed impaired elbow flexion and numbness of the lateral forearm. Electromyography confirmed impaired function of the musculocutaneous nerve. After 3 months, the patient's condition did not show any improvement, neither electromyography confirmed recovery of the nerve activity, so surgical treatment was planned. In the surgical revision, neuroma-in-continuity was discovered and resected. The resulting nerve defect was 6 cm long. We provided nerve grafting using sural nerve from the right lower limb. After surgery, the patient began physical therapy and electrical stimulation. Two years later, the patient reached complete recovery of muscle strength. CONCLUSION: Due to the lack of improvement after a 3-month period, we proceeded with a surgical revision, which demonstrated a complete lesion of the nerve that could not heal spontaneously. Therefore, we opted for the nerve graft method and the patient regained full function of elbow flexors.
Correlation of MRI-Evaluated Degenerative Disc Disease with Positivity on Single-Photon Emission Computed Tomography Imaging in Patients with Chronic Low Back Pain.
OBJECTIVE: Chronic low back pain, affecting up to 58% of the population, often stems from intervertebral disc degeneration. Although magnetic resonance imaging (MRI) is commonly used for diagnostics, challenges arise in pinpointing pain sources due to frequent asymptomatic findings. Single-photon emission tomography (SPECT) integrated with computed tomography (CT) offers a promising approach, enhancing sensitivity and specificity. METHODS: In this retrospective study, spanning 2016 to 2022, SPECT/CT imaging was performed on 193 patients meeting specific criteria. We correlated SPECT/CT findings with lumbar MRI results, utilizing Pfirrmann and Rajasekaran classifications for disc degeneration and endplate damage assessment. Logistic regression analysis adjusted for age and sex evaluated associations. RESULTS: Of 965 spinal levels assessed, SPECT/CT positivity strongly correlated with higher Pfirrmann grades and Rajasekaran endplate classifications. Notably, Modic changes (MCs) on MRI displayed a nonsignificant relationship with SPECT/CT positivity. Significant associations were observed in older patients with positive MCs, Pfirrmann grades, and Rajasekaran classifications. CONCLUSIONS: This comprehensive study, the largest of its kind, establishes a significant link between SPECT/CT positivity and advanced lumbar degenerative changes. Higher Pfirrmann grades and increased Rajasekaran endplate damage demonstrated substantial correlations with SPECT/CT positivity. Notably, MCs did not exhibit such association. Our findings underscore the potential of SPECT/CT in identifying pain generators in degenerative spinal conditions, offering valuable insights for future interventions.
Variations of the extrapsoas course of the lumbar plexus with implications for the lateral transpsoas approach to the lumbar spine: a cadaveric study.
BACKGROUND: Together with an increased interest in minimally invasive lateral transpsoas approach to the lumbar spine goes a demand for detailed anatomical descriptions of the lumbar plexus. Although definitions of safe zones and essential descriptions of topographical anatomy have been presented in several studies, the existing literature expects standard appearance of the neural structures. Therefore, the aim of this study was to investigate the variability of the extrapsoas portion of the lumbar plexus in regard to the lateral transpsoas approach. METHODS: A total of 260 lumbar regions from embalmed cadavers were utilized in this study. The specimens were dissected as per protocol and all nerves from the lumbar plexus were morphologically evaluated. RESULTS: The most common variation of the iliohypogastric and ilioinguinal nerves was fusion of these two nerves (9.6%). Nearly in the half of the cases (48.1%) the genitofemoral nerve left the psoas major muscle already divided into the femoral and genital branches. The lateral femoral cutaneous nerve was the least variable one as it resembled its normal morphology in 95.0% of cases. Regarding the variant origins of the femoral nerve, there was a low formation outside the psoas major muscle in 3.8% of cases. The obturator nerve was not variable at its emergence point but frequently branched (40.4%) before entering the obturator canal. In addition to the proper femoral and obturator nerves, accessory nerves were present in 12.3% and 9.2% of cases, respectively. CONCLUSION: Nerves of the lumbar plexus frequently show atypical anatomy outside the psoas major muscle. The presented study provides a compendious information source of the possibly encountered neural variations during retroperitoneal access to different segments of the lumbar spine.
Superficial branch of the radial nerve passing through the supinator canal, emerging between the extensor digitorum and abductor pollicis longus muscles and consequently supplying the second finger and radial portion of the third finger: a case report and clinical implications.
Awareness of unique path of the superficial branch of the radial nerve and its unusual sensory distribution can help avoid potential diagnostic confusion. We present a unique case encountered during a routine dissection of a Central European male cadaver. An unusual course of the superficial branch of the radial nerve was found in the right forearm, where the superficial branch of the radial nerve originated from the radial nerve distally, within the supinator canal, emerged between the extensor digitorum and abductor pollicis longus muscles and supplied the second and a radial half of the third digit, featuring communications with the lateral antebrachial cutaneous nerve and the dorsal branch of the ulnar nerve. Due to dorsal emerging of the superficial branch of the radial nerve the dorsal aspect of the thumb was innervated by the lateral antebrachial cutaneous nerve. To our best knowledge such variation of the superficial branch of the radial nerve has never been reported before. This variation dramatically changes aetiology and manifestation of possible entrapment syndromes which clinicians should be aware of.
Superficial branch of the radial nerve regularly contains fibers from the lateral antebrachial cutaneous nerve: A role in neuroma treatment.
BACKGROUND: Many surgical strategies aim to treat the symptomatic neuroma of the superficial branch of the radial nerve (SBRN). It is still difficult to treat despite many attempts to reveal a reason for surgical treatment failure. The lateral antebrachial cutaneous nerve (LACN) is known to overlap and communicate with SBRN. Our study aims to determine the frequency of spreading of LACN fibers into SBRN branches through a microscopic dissection to predict where and how often LACN fibers may be involved in SBRN neuroma. METHODS: Eighty-seven cadaveric forearms were thoroughly dissected. The path of LACN fibers through the SBRN branching was ascertained using microscopic dissection. Distances between the interstyloid line and entry of LACN fibers into the SBRN and emerging and bifurcation points of the SBRN were measured. RESULTS: The LACN fibers joined the SBRN at a mean distance of 1.7 ± 2.5 cm proximal to the interstyloid line. The SBRN contained fibers from the LACN in 62% of cases. Most commonly, there were LACN fibers within the SBRN's third branch (59%), but they were also observed within the first branch, the second branch, and their common trunk (21%, 9.2%, and 22%, respectively). The lowest rate of the LACN fibers was found within the SBRN trunk (6.9%). CONCLUSION: The SBRN contains LACN fibers in almost 2/3 of the cases, therefore, the denervation of both nerves might be required to treat the neuroma. However, the method must be considered based on the particular clinical situation.