Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

The Effectiveness of Cervical Medial Branch Thermal Radiofrequency Neurotomy Stratified by Selection Criteria: A Systematic Review of the Literature.

OBJECTIVE: To determine the effectiveness of cervical medial branch thermal radiofrequency neurotomy in the treatment of neck pain or cervicogenic headache based on different selection criteria. DESIGN: Comprehensive systematic review. METHODS: A comprehensive literature search was conducted, and the authors screened and evaluated the studies. The Grades of Recommendation, Assessment, Development, and Evaluation system was used to assess all eligible studies. OUTCOME MEASURES: The primary outcome measure assessed was the success rate of the procedure, defined by varying degrees of pain relief following neurotomy. Data are stratified by number of diagnostic blocks and degree of pain relief. RESULTS: Results varied by selection criteria, which included triple placebo-controlled medial branch blocks, dual comparative medial branch blocks, single medial branch blocks, intra-articular blocks, physical examination findings, and symptoms alone. Outcome data showed a greater degree of pain relief more often when patients were selected by triple placebo-controlled medial branch blocks or dual comparative medial branch blocks, producing 100% relief of the index pain. The degree of pain relief was similar when triple or dual comparative blocks were used. CONCLUSIONS: Higher degrees of relief from cervical medial branch thermal radiofrequency neurotomy are more often achieved, to a statistically significant extent, if patients are selected on the basis of complete relief of index pain following comparative diagnostic blocks. If selected based on lesser degrees of relief, patients are less likely to obtain complete relief.

Congenital Myasthenic Syndromes in 2018.

PURPOSE OF REVIEW: Summarize features of the currently recognized congenital myasthenic syndromes (CMS) with emphasis on novel findings identified in the past 6 years. RECENT FINDINGS: Since the last review of the CMS in this journal in 2012, several novel CMS were identified. The identified disease proteins are SNAP25B, synaptotagmin 2, Munc13-1, synaptobrevin-1, GFPT1, DPAGT1, ALG2, ALG14, Agrin, GMPPB, LRP4, myosin 9A, collagen 13A1, the mitochondrial citrate carrier, PREPL, LAMA5, the vesicular ACh transporter, and the high-affinity presynaptic choline transporter. Exome sequencing has provided a powerful tool for identifying novel CMS. Identifying the disease genes is essential for determining optimal therapy. The landscape of the CMS is still unfolding.

Risks and Benefits of Ceasing or Continuing Anticoagulant Medication for Image-Guided Procedures for Spine Pain: A Systematic Review.

Objective: To determine the risks of continuing or ceasing anticoagulant or antiplatelet medications prior to image-guided procedures for spine pain. Design: Systematic review of the literature with comprehensive analysis of the published data. Interventions: Following a search of the literature for studies pertaining to spine pain interventions in patients on anticoagulant medication, seven reviewers appraised the studies identified and assessed the quality of evidence presented. Outcome Measures: Evidence was sought regarding risks associated with either continuing or ceasing anticoagulant and antiplatelet medication in patients having image-guided interventional spine procedures. The evidence was evaluated in accordance with the Grades of Recommendation, Assessment, Development, and Evaluation system. Results: From a source of 120 potentially relevant articles, 14 provided applicable evidence. Procedures involving interlaminar access carry a nonzero risk of hemorrhagic complications, regardless of whether anticoagulants are ceased or continued. For other procedures, hemorrhagic complications have not been reported, and case series indicate that they are safe when performed in patients who continue anticoagulants. Three articles reported the adverse effects of ceasing anticoagulants, with serious consequences, including death. Conclusions: Other than for interlaminar procedures, the evidence does not support the view that anticoagulant and antiplatelet medication must be ceased before image-guided spine pain procedures. Meanwhile, the evidence shows that ceasing anticoagulants carries a risk of serious consequences, including death. Guidelines on the use of anticoagulants should reflect these opposing bodies of evidence.

Investigation of Congenital Myasthenia Reveals Functional Asymmetry of Invariant Acetylcholine Receptor (AChR) Cys-loop Aspartates.

We identify two heteroallelic mutations in the acetylcholine receptor δ-subunit from a patient with severe myasthenic symptoms since birth: a novel δD140N mutation in the signature Cys-loop and a mutation in intron 7 of the δ-subunit gene that disrupts splicing of exon 8. The mutated Asp residue, which determines the disease phenotype, is conserved in all eukaryotic members of the Cys-loop receptor superfamily. Studies of the mutant acetylcholine receptor expressed in HEK 293 cells reveal that δD140N attenuates cell surface expression and apparent channel gating, predicting a reduced magnitude and an accelerated decay of the synaptic response, thus reducing the safety margin for neuromuscular transmission. Substituting Asn for Asp at equivalent positions in the α-, ß-, and ϵ-subunits also suppresses apparent channel gating, but the suppression is much greater in the α-subunit. Mutant cycle analysis applied to single and pairwise mutations reveals that αAsp-138 is energetically coupled to αArg-209 in the neighboring pre-M1 domain. Our findings suggest that the conserved αAsp-138 and αArg-209 contribute to a principal pathway that functionally links the ligand binding and pore domains.

Microvascular alterations and the role of complement in dermatomyositis.

Different mechanisms have been proposed to explain the pathological basis of perifascicular muscle fibre atrophy in dermatomyositis. These include ischaemia due to immune-mediated microvascular injury, enhanced expression of type 1 interferon-induced gene transcripts in perifascicular capillaries and muscle fibres, and occlusion of larger perimysial blood vessels. Microvascular complement deposition is a feature of dermatomyositis pathology but the trigger for complement activation, the predominant complement pathway involved, or its role in the pathogenesis of the disease, has not been clearly defined. In the first step of this study we examined the density of capillaries and transverse vessels and searched for occlusion or depletion of larger perimysial blood vessels in 10 patients with dermatomyositis. This revealed an invariable association of perifascicular atrophy with capillary and transverse vessel depletion. The capillary and transverse vessel densities in non-atrophic fibre regions were not significantly different from those in muscle specimens of 10 age-matched controls. Next, in the same 10, as well as in 40 additional dermatomyositis patients, we searched for vascular deposits of IgG, IgM, and the C5b-9 complement membrane attack complex. Thirty-one of 50 dermatomyositis specimens contained C5b-9 reactive endomysial microvessels but none of these or other vessels reacted for IgG. Ten of 50 specimens harboured IgM-positive capillaries but only a few of these reacted for C5b-9. Finally, we analysed and compared different pathways of complement activation in dermatomyositis, lupus nephritis, and necrotic muscle fibres in Duchenne dystrophy. In lupus nephritis, C5-b9 deposits co-localized with IgG, IgM, C1q, and C4d, consistent with immune complex dependent activation of the classical complement pathway. In both dermatomyositis and Duchenne dystrophy, C5-b9 deposits co-localized with C1q and C4d and rarely with IgM indicating activation of the classical complement pathway. We conclude that: perifascicular atrophy in dermatomyositis is consistently associated with focal microvascular depletion, and that microvascular membrane attack complex deposits in dermatomyositis result from activation of the classical complement pathway triggered by direct binding of C1q to injured endothelial cells.

Guidelines for Composing and Assessing a Paper on Treatment of Pain.

Authors, readers, and editors share a common focus. Authors want to publish their work. Readers want to see high-quality, new information. Referees and editors serve to ensure that authors provide valid conclusions based on the quality of information that readers want.Common to each of these roles are instructions to authors. However, these are typically written in an uninspiring, legalistic style, as if they are a set of rules that authors must obey if they expect to get published. This renders the instructions boring and oppressive, if not forbidding. Yet they need not be so, if they are set in context.Instructions to authors can be cast in a way as to reflect common purpose. They can remind authors what perceptive readers want to see in a paper and, thereby, prompt authors to include all necessary information. If cast in this way, instructions to authors are not a set of rules by which to satisfy publishers; they become guidelines for the etiquette of communication between authors and their readers.Against this background, the present article has been composed to serve several purposes. Foremost, it amplifies instructions to authors beyond the conventional technicalities such as headings, layout, font size, and line spacing. It prescribes the type of information that should be communicated and explains the reasons for those recommendations. Doing so not only informs authors about what to write, but also informs readers and referees about what to look for in a good paper. Secondarily, the article publicizes examples of errors and deficiencies of manuscripts submitted to the Journal in the past that have delayed their acceptance and publication, which could have been avoided had the forthcoming recommendations been followed. The recommendations also reprise the elements taught in courses conducted by the Spine Intervention Society in their extended program on evidence-based medicine. Doing so underscores that instructions for authors are not a procedural technicality but a way to ensure that what authors write, what readers read, and what the Journal publishes comply with contemporary precepts of good evidence.Some 20 years ago, the Journal of the American Medical Association published a comprehensive series of articles with a common title: "Users' Guides to the Medical Literature" [1,2]. These articles focused on the science of statistical tests and critical appraisal, and their importance for properly understanding the literature. The present article differs in that it does not presume to teach technicalities. Instead, it describes and explains, step by step, the critical components of an article, what authors should include, and what readers should look for, so that the Journal can ensure that consistent, high-quality information is shared between its authors and readers.The present article focuses on articles concerning treatment of pain, largely because this type of article is more commonly submitted than articles on reliability or validity of diagnostic procedures. Although the present article principally focuses on papers for the Spine Section of the Journal, the same principles, appropriately adapted, serve for other sections.

Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.

We identify two novel mutations in acetylcholine receptor (AChR) causing a slow-channel congenital myasthenia syndrome (CMS) in three unrelated patients (Pts). Pt 1 harbors a heterozygous ßV266A mutation (p.Val289Ala) in the second transmembrane domain (M2) of the AChR ß subunit (CHRNB1). Pts 2 and 3 carry the same mutation at an equivalent site in the ε subunit (CHRNE), εV265A (p.Val285Ala). The mutant residues are conserved across all AChR subunits of all species and are components of a valine ring in the channel pore, which is positioned four residues above the leucine ring. Both ßV266A and εV265A reduce the amino acid size and lengthen the channel opening bursts by fourfold by enhancing gating efficiency by approximately 30-fold. Substitution of alanine for valine at the corresponding position in the δ and α subunit prolongs the burst duration four- and eightfold, respectively. Replacing valine at ε codon 265 either by a still smaller glycine or by a larger leucine also lengthens the burst duration. Our analysis reveals that each valine in the valine ring contributes to channel kinetics equally, and the valine ring has been optimized in the course of evolution to govern channel gating.

LRP4 third ß-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner.

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.

IntSplice: prediction of the splicing consequences of intronic single-nucleotide variations in the human genome.

Precise spatiotemporal regulation of splicing is mediated by splicing cis-elements on pre-mRNA. Single-nucleotide variations (SNVs) affecting intronic cis-elements possibly compromise splicing, but no efficient tool has been available to identify them. Following an effect-size analysis of each intronic nucleotide on annotated alternative splicing, we extracted 105 parameters that could affect the strength of the splicing signals. However, we could not generate reliable support vector regression models to predict the percent-splice-in (PSI) scores for normal human tissues. Next, we generated support vector machine (SVM) models using 110 parameters to directly differentiate pathogenic SNVs in the Human Gene Mutation Database and normal SNVs in the dbSNP database, and we obtained models with a sensitivity of 0.800±0.041 (mean and s.d.) and a specificity of 0.849±0.021. Our IntSplice models were more discriminating than SVM models that we generated with Shapiro-Senapathy score and MaxEntScan::score3ss. We applied IntSplice to a naturally occurring and nine artificial intronic mutations in RAPSN causing congenital myasthenic syndrome. IntSplice correctly predicted the splicing consequences for nine of the ten mutants. We created a web service program, IntSplice (http://www.med.nagoya-u.ac.jp/neurogenetics/IntSplice) to predict splicing-affecting SNVs at intronic positions from -50 to -3.

Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel Megf10 mutations.

INTRODUCTION: Multiminicore disease is a congenital myopathy characterized pathologically by the presence of multiple minicore structures in the sarcoplasm. Mutations in the selenoprotein N1-encoding gene (SEPN1) and ryanodine receptor 1-encoding gene (RYR1) are responsible for half of the reported cases. Mutations in multiple epidermal growth factor-like domains 10-encoding gene (MEGF10) have been identified only recently in a few patients with antenatal to infantile-onset myopathy, with and without minicore pathology. METHODS: We report 2 sisters with adult-onset respiratory insufficiency followed by development of limb weakness. Both had scoliosis, distal joint hyperlaxity, and high-arched feet. RESULTS: A biopsy of the right triceps muscle in 1 sister showed multiple minicore structures. She had electromyographic changes of myopathy with fibrillation potentials and myotonic discharges. Next generation sequencing identified novel compound heterozygous missense variants in MEGF10 c.230G>A (p.Arg77Gln) and c.1833T>G (p.Cys611Trp) in both sisters. CONCLUSIONS: MEGF10 mutations can cause myopathy with adult-onset respiratory insufficiency. Muscle Nerve, 2016 Muscle Nerve 53: 984-988, 2016.

Mathematical Validation and Credibility of Diagnostic Blocks for Spinal Pain.

BACKGROUND: Diagnostic blocks are used in different ways for the diagnosis of spinal pain, but their validity has not been fully evaluated. METHODS: Four clinical protocols were analyzed mathematically to determine the probability of correct responses arising by chance. The complement of this probability was adopted as a measure of the credibility of correct responses. RESULTS: The credibility of responses varied from 50% to 95%, and was determined less by the agents used but more by what information was given to patients and if the agents were fully randomized for each block. CONCLUSIONS: Randomized, comparative local anesthetic blocks offer a credibility of 75%, but randomized, placebo-controlled blocks provide a credibility of 95%, and are thereby suitable as a criterion standard for diagnostic blocks.

The Effectiveness and Risks of Fluoroscopically-Guided Cervical Medial Branch Thermal Radiofrequency Neurotomy: A Systematic Review with Comprehensive Analysis of the Published Data.

OBJECTIVE: To determine the effectiveness and risks of fluoroscopically-guided cervical medial branch thermal radiofrequency neurotomy (CMBTRFN) for treating chronic neck pain of zygapophysial joint origin. DESIGN: Systematic review of the literature with comprehensive analysis of the published data. INTERVENTIONS: Four reviewers formally trained in evidence-based medicine searched the literature on CMBTRFN. Each assessed the methodologies of studies found and appraised the quality of evidence presented. OUTCOME MEASURES: The primary outcomes assessed were 100% relief of pain 6 and 12 months after treatment. Other outcomes were noted if reported. The evidence was evaluated in accordance with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. RESULTS: The searches yielded eight primary publications on the effectiveness of the procedure. The evidence shows a majority of patients were pain free at 6 months and over a third were pain free at 1 year. The number needed to treat for complete pain relief at 6 months is 2. The evidence of effectiveness is of high quality according to the GRADE system. Twelve papers were found reporting unwanted effects, most of which are minor and temporary. No serious complications have ever been reported from procedures performed according to the published guidelines. The evidence of risks is of low quality according to the GRADE system. CONCLUSIONS: If performed as described in the International Spine Intervention Society Guidelines, fluoroscopically-guided CMBTRFN is effective for abolishing zygapophysial joint pain and carries only minor risks.

A new muscle glycogen storage disease associated with glycogenin-1 deficiency.

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.

Electromyographic findings in 37 patients with adult-onset acid maltase deficiency.

INTRODUCTION: In acid maltase deficiency (AMD), electrical myotonia (EM) may be restricted to paraspinal muscles. A comprehensive description of the electromyographic (EMG) findings in AMD is lacking. The purpose of this study is to describe the EMG features in adult-onset AMD, focusing on the distribution of EM. METHODS: A retrospective chart review of AMD patients diagnosed at Mayo Clinic over age 18 years. RESULTS: Thirty-seven patients were included. Twenty-eight (76%) had EM in at least 1 muscle, and EM was more common in paraspinal and proximal limb muscles. The tensor fasciae latae (TFL) was equally sensitive to the paraspinals for EM. Three of 4 patients had EM identified in the diaphragm. CONCLUSIONS: Approximately three-quarters of adult-onset AMD patients display EM on EMG. The paraspinal muscles and TFL are the most likely to demonstrate EM, and EM can be detected in the diaphragm of adult onset AMD patients.

An Expedited Diagnostic Algorithm for Lumbosacral Pain: "The Best Likelihood Scenario Approach".

INTRODUCTION: The logic behind diagnostic blocks is very straightforward. What has not been determined is the way diagnostic blocks can be best used. STUDY DESIGN: Philosophical essay. DISCUSSION: The interventional pain management physician would serve as the diagnostic expert by efficiently determining the source of the patient's pain. CONCLUSION: "The Best Likelihood Scenario" might improve diagnostic accuracy while decreasing societal costs.

Fluoroscopically Guided Diagnostic and Therapeutic Intra-Articular Sacroiliac Joint Injections: A Systematic Review.

OBJECTIVE: To assess the validity of fluoroscopically guided diagnostic intra-articular injections of local anesthetic and effectiveness of intra-articular steroid injections in treating sacroiliac joint (SIJ) pain. DESIGN: Systematic review. INTERVENTIONS: Ten reviewers independently assessed 45 publications on diagnostic validity or effectiveness of fluoroscopically guided intra-articular SIJ injections. OUTCOME MEASURES: For diagnostic injections, the primary outcome was validity; for therapeutic injections, analgesia. Secondary outcomes were also described. RESULTS: Of 45 articles reviewed, 39 yielded diagnostic data on physical exam findings, provocation tests, and SIJ injections for diagnosing SIJ pain, and 15 addressed therapeutic effectiveness. When confirmed by comparative local anesthetic blocks with a high degree of pain relief, no single physical exam maneuver predicts response to diagnostic injections. When at least three physical exam findings are present, sensitivity, and specificity increases significantly. The prevalence of SIJ pain is likely 20-30% among patients that have suspected SIJ pain based on history and physical examination. This estimate may be higher in certain subgroups such as the elderly and fusion patients. Two randomized controlled trials and multiple observational studies supported the effectiveness of therapeutic sacroiliac joint injections. CONCLUSIONS: Based on this literature, it is unclear whether image-guided intra-articular diagnostic injections of local anesthetic predict positive responses to therapeutic agents. The overall quality of evidence is moderate for the effectiveness of therapeutic SIJ injections.

Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1.

Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy.

Inclusion-body myositis presenting with facial diplegia.

INTRODUCTION: The hallmark clinical presentation of inclusion-body myositis (IBM) is slowly progressive weakness that characteristically affects the quadriceps and finger and wrist finger flexor muscles. Facial weakness can also occur, but it is typically mild and not a prominent finding. METHODS: We describe the clinical features, laboratory investigations, and muscle biopsy findings in a 58-year old man who presented with a 6-year history of marked progressive symmetrical facial weakness. Examination also showed shoulder abduction and hip extensor weakness. RESULTS: The patient's serum creatine kinase level was 655 U/L, and electromyography showed fibrillation potentials and myopathic motor unit potentials. A biopsy specimen of the left biceps muscle was pathognomonic for IBM. CONCLUSIONS: This patient did not have a typical presentation for IBM but rather fulfilled the pathological criteria for IBM. To our knowledge, facial diplegia has not been reported previously as a presenting manifestation of IBM.

The effectiveness and risks of fluoroscopically guided cervical transforaminal injections of steroids: a systematic review with comprehensive analysis of the published data.

OBJECTIVE: To determine the effectiveness and risks of fluoroscopically guided cervical transforaminal injection of corticosteroids in the treatment of radicular pain. DESIGN: Systematic review of the literature with comprehensive analysis of the published data. INTERVENTIONS: Three reviewers with formal training in evidence-based medicine searched the literature on fluoroscopically guided cervical transforaminal injection of steroids (CTFIS). Each reviewer independently assessed the methodology of studies found and appraised the quality of the evidence presented. OUTCOME MEASURES: The primary outcome assessed was relief of radicular pain. Other outcomes such as reduction in surgery rate and complications were noted if reported. The evidence on each outcome was appraised in accordance with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system of evaluating evidence. RESULTS: The searches yielded 16 primary publications on effectiveness. Available evidence, derived mainly from observational studies, suggests that approximately 50% of patients experience 50% relief of radicular pain for at least 4 weeks after CTFIS, and the intervention may have surgery-sparing effects. The literature also contains 21 articles with primary reports of serious complications, including 13 deaths and many catastrophic neurological injuries. The evidence of pain-relieving effects, of surgery-sparing effects, and of risks of CTFIS were all rated as of very low quality according to the GRADE system. CONCLUSIONS: In patients with cervical radicular pain, fluoroscopically guided CTFIS may be effective in easing pain and reducing need for surgery. However, the evidence of effectiveness is of very low quality, and the benefits of the procedure are compromised by the risks of serious complications.