2][3] The World Health Organization has estimated that 22% of the world's primary care patients have chronic pain making this condition a problem to be addressed by all physicians and health professionals. 4Peripheral neuropathy is a common, chronic pain problem encountered by neurologists and primary care physicians, and while there are many causes, no cause can be identified for a large percentage of patients. 5Many peripheral neuropathies are secondary to identifiable causes, such as diabetes, alcohol abuse and the use of certain medications.However, once known etiologies are excluded, at least 25% of neuropathies remain idiopathic.This is the case for 5 million people (of the estimated 20 million people with neuropathy) in the United States.][8][9][10][11][12][13][14][15][16] The research question is: What is the best available medication(s) to treat pain due to CSPN?There is only one comparative effectiveness study of medications most used to treat painful CSPN, conducted by the investigators involved in this application. 17This larger, open-label, pragmatic trial will paint a more complete picture of medication effectiveness, testing six new non-opiate medications and creatively blending the results from the prior four drug trial in an elegant statistical analysis.This study adds critical components that address barriers to diagnosis and barriers to implementation of study results in clinical practice.Description and diagnosis: Prior reports describing CSPN have used other terms such as idiopathic neuropathy or small fiber sensory peripheral neuropathy, but we prefer CSPN.The assigned ICD-10 code is G60.8.The diagnostic criteria for CSPN were established by Dr. Barohn and colleagues. 13Our retrospective review of databases from two North and one South American tertiary neuropathy clinics (NA-SA study) showed that CSPN represented at least one-quarter of all referred peripheral neuropathy patients and was the most common form of neuropathy evaluated at these sites (Table 1). 18The mean age of patients in prior publications ranges from 51 to 63 years. 8,9,13,18SPN is usually diagnosed based on pain (a presenting symptom in 70-80% of patients), numbness and/or tingling in the distal extremities.There are equal numbers of men and women with this condition, and it occurs in all races/ethnicities and all geographic regions.13][14][15][16][18][19][20][21][22] Lower extremity symptoms usually precede upper extremity symptoms. 13,14,18Approximately one-third to one-half of patients will have symptoms confined to their lower extremities.The average time for symptoms to spread to the upper extremities appears to be about five years.Worsening of sensory symptoms with contact, heat exposure, activity, or fatigue commonly is reported.Based on symptom presentation, our group and others have found that patients with CSPN constitute a homogeneous group of elderly women and men for whom a similar approach can be taken regarding diagnosis and treatment. 13,14,18

See article on pages 400‐404 in this issue

Objective. To introduce a modified transverse process-pedicle puncture technique applied to unilateral extrapedicular percutaneous vertebroplasty (PVP) for the treatment of osteoporotic lumbar vertebral compression fractures. Methods. A retrospective study was performed on 91 patients with osteoporotic vertebral compression fractures (OVCFs) who underwent unilateral extrapedicular PVP from June 2016 to September 2018. Lumbar and back pain was assessed through the visual analogue scale (VAS). Function recovery was assessed through the Oswestry disability index (ODI). Radiologic outcomes were assessed mainly on the basis of bone cement distribution and anterior vertebral height. Results. A total of 101 fractured vertebrae were successfully treated using the extrapedicular technique without any recognized clinical complications. The postoperative VAS and ODI values were significantly lower than the corresponding preoperative values (P < 0.01). Radiologic outcomes in all fractured vertebrae showed that the diffusion of bone cement could exceed the midline of the vertebral body. There was no significant difference between preoperative and postoperative anterior vertebral heights (P < 0.05). Conclusion. The modified transverse process-pedicle approach applied to unilateral extrapedicular percutaneous vertebroplasty is a simple, safe, and effective surgical method.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), is associated with Guillain-Barré syndrome (GBS).1-8 We describe a patient with quadriplegic GBS with dysautonomia preceded by mild COVID-19–induced diarrhea. A 72-year-old man with coronary artery disease, hypertension, and alcohol abuse presented to a tertiary hospital with symmetric paresthesias and ascending appendicular weakness. Seven days earlier he had mild diarrhea, anorexia, and chills, without fever or respiratory symptoms. This condition resolved in 5 days. Weakness began 6 days after diarrhea, and the patient presented 1 day after neurological symptom onset. On admission, he was afebrile with normal vital signs. Mental status and cranial nerves were normal. Strength was 4/5 for neck flexion, and 3/5 for proximal upper and lower extremities bilaterally. Tendon reflexes were absent. Sensation to light touch was diminished to wrists and knees bilaterally. Laboratory studies demonstrated a white blood cell (WBC) count of 12 000 cells/μL (granulocytes 84%), sodium 143 mmol/L, potassium 3.1 mmol/L, blood urea nitrogen (BUN) 16 mg/dL, creatinine 0.77 mg/dL, alanine transaminase 38 IU/L, aspartate transaminase 29 IU/L, alkaline phosphatase 76 IU/L, albumin 3.7 g/dL, and total bilirubin 0.8 mg/dL. Serum thiamine, vitamin B12, hemoglobin A1C, thyroid panel, creatine kinase, Lyme screen, and serum and urine protein electrophoreses were normal. Anti-ganglioside GM1, GD1b, and GQ1b and acetylcholine receptor binding, voltage-gated calcium channel, antinuclear, and antineutrophil cytoplasmic antibody titers were negative. Nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) was positive. Chest X-ray showed mild bibasilar atelectasis vs patchy consolidations. Computed tomography of the head was normal. Incompatible implant precluded magnetic resonance imaging. On day 3, the patient developed respiratory distress with a negative inspiratory force of −20 cmH2O and vital capacity of 1350 mL. He was transferred to the intensive care unit and intubated. He remained afebrile and followed commands. Oxygen saturation was normal on ventilator settings positive end-expiratory pressure 5 cm H2O and fraction of inspired oxygen 30%. Chest X-ray was stable. He was diagnosed with GBS and received intravenous immunoglobulin 2 g/kg between days 3 and 6. On day 4, he developed dysautonomia with hypotension alternating with hypertension and tachycardia. On day 6, his strength decreased to 1/5 for neck flexion, 1/5 for distal upper extremities bilaterally, and 0/5 for proximal upper extremities and throughout the lower extremities bilaterally. On day 8, he developed the syndrome of inappropriate antidiuretic hormone secretion (SIADH), with serum sodium 134 mmol/L and osmolality 271 mOsm/kg correlated with urine sodium 43 mmol/L and osmolality 731 mOsm/kg. He had no prior history of SIADH. Cerebrospinal fluid (CSF) collected on day 8 showed WBC 1 cell/μL and protein 313 mg/dL; CSF SARS-CoV-2 PCR, Gram stain and culture, herpes simplex, varicella zoster, and cytomegalovirus viral PCRs; immunoglubulin G index; oligoclonal bands; and cytology were negative. On day 10, his oropharyngeal secretions increased, and chest X-ray showed new right lower lobe consolidation. Sputum culture grew Stenotrophomonas maltophilia, an organism associated with ventilator-associated pneumonia in immunocompetent hosts. WBC increased to 20 400 cells/μL (granulocytes 88%), with improvement to 9400 cells/μL (granulocytes 69%) after 2 days on sulfamethoxazole-trimethoprim. On day 12, strength improved to 3/5 for neck flexion and 2/5 throughout all limbs bilaterally. Nerve conduction studies on day 13 showed diffusely decreased velocities, conduction block, and absent F waves, supporting demyelinating GBS (Table 1). Resting needle electromyography was normal, but there was poor effort. On day 19, tracheostomy and percutaneous endoscopic gastrostomy tubes were placed. He did not develop signs of active COVID-19 infection and repeat nasopharyngeal SARS-CoV-2 PCR was negative on day 28. He remains in the ICU with severe weakness. We have described a patient with SARS-CoV-2–associated quadriplegic GBS who had preceding diarrhea and was otherwise asymptomatic on presentation. Other patients with SARS-CoV-2–associated GBS presented with symptoms of upper respiratory infection, and some had a pre-existing diagnosis of COVID-19.2-8 Characterizing SARS-CoV-2 clinical phenotypes has been hindered by limited testing, and the prevalence of asymptomatic or mildly symptomatic carriers is likely underestimated. This case illustrates the importance of SARS-CoV-2 testing in patients with GBS. Dysautonomia and SIADH were prominent features in this patient. To date, these have been uncommon in other patients with SARS-CoV-2–associated GBS. An analysis of COVID-19 patients in Wuhan, China, showed that those with central nervous system symptoms had lower lymphocyte and platelet counts and higher BUN levels compared with those with peripheral nervous system or no neurological symptoms.9 Although these laboratory values in the patient we described are similar to those seen in the Wuhan cohort with peripheral nervous system or no neurologic complications, the underlying pathophysiology predisposing certain COVID-19 patients to neurological complications remains unclear. Continued investigation of neurological sequelae is needed. The authors thank the Critical Care Medicine team and ICU staff at the Veterans Affairs Pittsburgh Healthcare (VAPHS) Hospital for their assistance with diagnostic studies and clinical management. We also thank the inpatient clinical laboratory at the VAPHS Hospital for assistance with SARS-CoV-2 PCR testing. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclose.

Recent advances in the genetics of neurologic diseases coupled with improvements in sensitivity and specificity are making genetic testing an increasingly important part of diagnosis and management for neurologists. However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions. This review summarizes ethical issues related to genetic testing for neurologic diseases, with a focus on clinical practice. Informed consent for genetic testing of patients and asymptomatic at-risk family members is discussed. The roles and responsibilities of physicians as genetic counselors are reviewed, including the framing of incidental findings and variants of unknown significance that impact individuals' decisions about whether to pursue genetic testing and what results they wish to know. Disclosure and its consequences for the patient are placed within an ethical framework to permit a better understanding of why genetic testing is different from most other diagnostic testing ordered by physicians. The review ends with clinical vignettes that attempt to place ethical principles into familiar clinical settings involving physicians, patients and their families.

Genetic testing is rapidly becoming an increasingly significant part of the diagnostic armamentarium of neuromuscular clinicians. Although technically easy to order, the results of such testing, whether positive or negative, have potentially enormous consequences for the individual tested and for family members. As a result, ethical considerations must be in the forefront of the physician's agenda when obtaining genetic testing. Informed consent is an important starting point for discussions between physicians and patients, but the counseling embedded in the informed consent process must be an ongoing part of subsequent interactions, including return of results and follow-up. Patient autonomy, including the right to know and right not-to-know results, must be respected. Considerations of capacity, physician beneficence and nonmaleficence, and privacy all play roles in the process. Muscle Nerve 54: 997-1006, 2016.

HMG‐CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, dependent on HFE genotype. Methods: Mice harboring SOD1G93A heterozygous for H67D Hfe (homologous to human H63D HFE) were administered simvastatin and/or coenzyme Q10, and were allowed to reach end stage. Disease progression was measured by grip strength. A separate group of animals was administered simvastatin and euthanized at the symptomatic 120‐day time‐point. Mitochondria from gastrocnemius muscle and lumbar spine were analyzed. Results: Simvastatin and H67D Hfe accelerated disease progression. Simvastatin decreased survival. Coenzyme Q10 did not rescue statin‐induced effects. Statins did not alter mitochondrial protein levels. Conclusions: Statins and Hfe genotype alter disease course in the ALS mouse model. Because the H63D HFE polymorphism is present in 30% of patients with ALS, studying disease progression in patients who receive statins, stratified for HFE genotype, may guide therapy. Muscle Nerve, 2016 Muscle Nerve 54: 284–291, 2016

Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve49: 786-803, 2014

Our objective was to measure serum ferritin levels, which reflect iron metabolism, in ALS patients versus healthy and disease controls, and determine whether serum ferritin levels correlate with survival. We retrospectively analyzed data from 138 ALS patients, 152 healthy controls, and 82 disease controls. Gender, age, site of onset, and dates of symptom onset and death were recorded. Survival was defined as the time from symptom onset to death. Serum ferritin levels were measured using immunoassay. ANOVA and Pearson' s correlation were used to compare ferritin levels between groups and test the association between ferritin levels and age and survival. Ferritin levels were categorized into high and low groups, and Kaplan-Meier analysis performed. Results showed that gender proportions differed between ALS patients versus healthy and disease controls, and gender affected serum ferritin levels. Ferritin comparisons were stratified for gender. In both males and females, ferritin levels were higher in ALS patients versus healthy and disease controls. However, ferritin levels were unrelated to survival in either gender, by tests of association or survival analysis. In conclusion, ALS patients have altered iron metabolism that is not simply due to the presence of neurological disease. Serum ferritin levels alone are not sufficient to predict survival.

Introduction: H63D HFE polymorphisms increase the risk of neurodegenerative disorders and, specifically, may increase amyotrophic lateral sclerosis (ALS) risk. Investigating the physiological alterations induced by H63D polymorphisms in ALS patients may elucidate mechanisms by which this genotype alters disease. Methods: Clinical measures and muscle biopsies were available from patients previously diagnosed with ALS who underwent HFE genotyping. Clinical outcomes and SOD1 protein expression were analyzed using standard statistical analyses. Results: ALS patients harboring H63D HFE (n = 16) had 28.1 months longer average disease duration and 39.3% lower muscle SOD1 protein than ALS patients with wild-type HFE (n = 22). Conclusions: Combined with previous reports suggesting the H63D polymorphism is associated with ALS, these results support a model wherein the H63D polymorphism is involved in ALS by means of pathways involving SOD1 but may limit cellular damage in individuals who develop disease. The association between HFE genotype and disease duration has important implications for clinical care and treatment trials.

Degradation of the vascular basement membrane stimulates angiogenesis and is tightly controlled by balancing the actions of metalloproteases and their inhibitors. Previous work demonstrated that electroconvulsive seizure (ECS) elevates angiogenic factors and endothelial proliferation in the hippocampus. The robust induction of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) in the stratum lacunosum moleculare (SLM) corresponds to sites of increased vascular density. This led us to examine the spatial and cellular expression of TIMP-1 and its substrate, matrix metalloprotease 9 (MMP-9). Chronic ECS increased TIMP-1 by 12-fold and MMP-9 by 3-fold in discrete SLM cells. We then characterized the expression of TIMP-1 mRNA in relation to vasculature in the SLM and glial-limiting membrane (GLM). Employing laser microdissection we identified the cell types associated with SLM vasculature and also phenotyped the cells expressing TIMP-1 and MMP-9. We concluded that TIMP-1 is produced by perivascular cells positive for alpha smooth actin and that MMP-9 is expressed by GFAP-positive astrocytes. These studies suggest that ECS-induced remodelling occurs at the vascular basement membrane and facilitates neovascularization.

Brain monitoring techniques near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) ultrasound were used in pediatric patients undergoing cardiopulmonary bypass for congenital heart defect (CHD) repair to analyze the effect of pulsatile or nonpulsatile flow on brain protection. Regional cerebral oxygen saturation (rSO2) and cerebrovascular pulsatility index (PI) were measured by NIRS and TCD, respectively, in 111 pediatric patients undergoing bypass for CHD repair randomized to pulsatile (n = 77) or nonpulsatile (n = 34) perfusion. No significant differences in demographic and intraoperative data, including surgical risk stratification, existed between groups. Patients undergoing pulsatile perfusion had numerically lower decreases in rSO2 from baseline for all time points analyzed compared with the nonpulsatile group, with significant ∼12% lower decreases at 40 and 60 min after crossclamp. Patients undergoing pulsatile perfusion had numerically lower decreases in PI from baseline for the majority of time points compared with the nonpulsatile group, with significant ∼30% lower decreases between 5 and 40 min after crossclamp. Pulsatile flow has advantages over nonpulsatile flow as measured by NIRS and TCD, especially at advanced time points, which may improve postoperative neurodevelopmental outcomes.

手术技术和术后监护的进步已经大大降低了小儿先天性心脏病(先心病)手术的死亡率,并改善了患儿的长期预后.最近的研究显示[1],尽管病例的复杂性有所提高, 但术后的院内死亡率低于3%,而且一项大样本社会心理学研究显示,在儿童时期接受过先心病纠治手术的成年人能够较好的适应社会[2].

Improvements in peri- and postoperative surgical techniques have greatly improved outcomes for pediatric patients undergoing cardiopulmonary bypass (CPB) in the treatment of congenital heart defects (CHDs). With decreased mortality rates, the incidence of adverse neurological outcomes, comprising cognitive and speech impairments, motor deficits, and behavioral abnormalities, has increased in those patients surviving bypass. A number of mechanisms, including ischemia, reperfusion injury, hypothermia, inflammation, and hemodilution, contribute to brain insult, which is further confounded by unique challenges presented in the pediatric population. However, a number of brain monitoring and preventative techniques have been developed or are being currently evaluated in the practice of pediatric CPB. Monitoring techniques include electroencephalography, near-infrared as well as visible light spectroscopy, transcranial Doppler ultrasound, and emboli detection and classification quantitation. Preventative measures include hypothermic perfusion techniques such as deep hypothermic circulatory arrest, low-flow CPB, blood gas management, and pharmacologic prophylaxes, among others. The present review summarizes the principles of brain insult, neurodevelopmental abnormalities, monitoring techniques, methods of prevention, as well as preexisting morbidities and risk factors in pediatric CPB, with a focus on brain protection. Clinical and translational research is presented with the aim of determining methods that may optimize neurological outcomes post CPB and guiding further study.

Gaseous microemboli (GME) remain a challenge for cardiopulmonary bypass procedures in adult as well as pediatric cardiac surgery patients. The present study tested the effectiveness of a new adult membrane oxygenator in models both with and without an integrated arterial filter to evaluate GME trapping capability and determine membrane pressure drops at various flow rates and temperatures. The experimental circuit included a RotaFlow centrifugal blood pump, Quadrox-i® ( n = 8) or Quadrox® ( n = 8) adult microporous membrane oxygenator, and Sorin adult tubing package. A Sorin Cardiovascular® VVR® 4000i venous reservoir served as pseudo-patient. The circuit was primed with 900 mL heparinized human red blood cells and 300 mL Lactated Ringer’s solution. The final hematocrit was 36%. Tests were performed at different flow rates (4 L/min, 5 L/min, and 6 L/min) and temperatures (35° and 30°). Five mL of bolus air was injected into the venous line over 15 seconds using a syringe connected to a 3/8 × 1/2 luer connector. The Quadrox-i® adult microporous membrane oxygenator with integrated arterial filter had a similar pressure drop at 4 L/min and 35°C compared with Quadrox® membrane oxygenator whereas it had higher pressure drops at 5 L/min and 6 L/min ( p <.001). Quadrox-i® adult microporous membrane oxygenator reduced the total emboli count and total emboli volume delivered to the pseudo-patient at all flow rates ( p <.001). The emboli handling of Quadrox-i® adult microporous membrane oxygenator was not affected by flow rate and temperature. Compared with the traditional Quadrox® oxygenator, Quadrox-i® adult microporous membrane oxygenator with integrated arterial filter and Softline coating has improved GME handling capacity.