Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Closing the gap: unmet needs of individuals with impulsive aggressive behavior observed in children and adolescents.

Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.

Repeat Cooled Radiofrequency Ablation Is Beneficial for Chronic Posterior Sacroiliac Joint Pain.

OBJECTIVE: This study aimed to investigate the effectiveness of repeat cooled radiofrequency ablation (CRFA) in chronic posterior sacroiliac joint (SIJ) pain. DESIGN: The electronic records of 41 adult patients who had successful CRFA were reviewed for duration of pain relief and utilization of medical care for six months before and after each CRFA procedure. SETTING: Academic, tertiary medical center. PATIENTS: Forty-one adult patients who had CRFA for chronic posterior SIJ pain. RESULTS: A repeat ipsilateral CRFA ablation procedure provided 9.0 months of pain relief compared with 5.5 months after the first CRFA procedure (P = 0.0378). The total number of medical treatments decreased after the first CRFA procedure (from 343 to 201). The medical cost decreased by 51.0% after the first CRFA and by 70.4% after the repeated CRFA procedure. CONCLUSIONS: Using repeated nonsurgical, minimally invasive approach, CRFA relieves chronic posterior SIJ pain and reduces patients' utilization of medical services.

A Novel Assessment Tool for Impulsive Aggression in Children with Attention-Deficit/Hyperactivity Disorder.

Objective: To establish the validity and reliability of a provisional 30-item impulsive aggression (IA) diary in children (ages 6-12 years, inclusive) with attention-deficit/hyperactivity disorder (ADHD). Methods: The provisional 30-item IA diary was administered for 14 days to parents of children with ADHD and IA symptoms (n = 103). Key inclusion criteria: confirmed ADHD diagnosis; signs of IA as measured by a Retrospective-Modified Overt Aggression Scale (R-MOAS) score ≥20 and an Aggression Questionnaire score of -2 to -5. Analyses included inter-item correlations, exploratory factor analysis (EFA), item response theory (IRT) modeling, internal consistency, test-retest reliability (TRT), concurrent validity (estimated by correlation between the IA diary and the R-MOAS/Nisonger Child Behavior Rating Form), and known-groups methods. Results: The prevalence rates of 15 (50.0%) items were found to be too low (<1%) for analysis; three items with prevalence rates ≤1% were retained, as content validity was deemed high by clinical experts. The remaining 12 behavior items had prevalence rates of 2.7%-73.6%. EFA and IRT models confirmed two subdomains in the IA diary included within a general domain of IA behavior frequency, yielding a single total behavioral frequency score (TBFS). Internal consistency was high for this TBFS (marginal reliability = 0.86 and α = 0.73). TRT for the TBFS, based on the intraclass correlation coefficient, was 0.8. Concurrent validity of TBFS with R-MOAS ranged from r = 0.49 to r = 0.62. Conclusion: The final 15-item IA diary is a reliable, psychometrically validated IA measurement tool that will allow clinicians and researchers to assess the frequency of IA behavior.

Application of the Impulsive Aggression Diary in Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objective: Impulsive aggression (IA) is a maladaptive form of aggressive behavior that is an associated feature of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). As one of the most common forms of aggressive behavior, IA is a serious clinical concern. Recognition, monitoring, and management of IA symptoms are complicated by the lack of IA-specific psychometric instruments and evidence-based treatments. A recently developed electronic observer-reported outcome instrument has been validated in children for monitoring the frequency of 15 IA-related behaviors in the context of ADHD. This study seeks to first determine if the behaviors included in the pediatric IA diary are applicable to adolescents with ADHD, and second, compare the reliability of adolescent versus parent reporters. Methods: We evaluated the utility of the pediatric IA diary through concept elicitation and cognitive interviews with 17 pairs of parents and adolescents (aged 13-17 years) with IA and ADHD, supplemented with 15 new behaviors potentially applicable to adolescents. Results: The behaviors most frequently reported by adolescents included arguing (93.8%), raising their voice/shouting/yelling (93.8%), hitting others (87.5%), slamming (87.5%), pushing/shoving (81.3%), breaking (75.0%), fighting (75.0%), throwing (75.0%), and cursing (68.8%). The behaviors most commonly reported by parents included raising their voice/shouting/yelling (94.1%), arguing (88.2%), being disrespectful/mean/rude (88.2%), slamming (88.2%), throwing (88.2%), cursing (82.4%), hitting others (82.4%), pushing/shoving (82.4%), breaking (76.5%), name-calling (76.5%), and threatening (70.6%). Of all commonly reported behaviors, only being "disrespectful/mean/rude" and "breaking" are not part of the pediatric IA diary, likely due to the imprecision of these terms. No significant usability issues were found for the IA diary device. Conclusions: These findings suggest that the 15-item pediatric IA diary should be applicable to adolescent populations to appropriately characterize IA behaviors in individuals with ADHD. Furthermore, this study indicated that parents may be more reliable reporters of IA behavior than adolescents.

A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression.

Proper drug categorization enables clinicians to readily identify the agents most appropriate for patients in need. Currently, patients with maladaptive aggression do not all always fall into a single existing diagnostic or treatment category. Such is the case for those with impulsive aggression (IA). IA is an associated feature of numerous neuropsychiatric disorders, and can be described as eruptive, aggressive behavior or a 'short fuse'. Although agents from a broad spectrum of drug classes have been used to treat maladaptive aggression, few have been tested distinctly in patients with IA, and there is no drug specifically indicated by the US Food and Drug Administration (US FDA) for IA. Further, current treatments often fail to sufficiently treat IA symptomatology. These issues create an unclear and inadequate treatment path for patients. Here we will propose the establishment of a class of anti-maladaptive aggression agents to begin addressing this clinical issue. The development of such a class would unify the various drugs currently used to treat maladaptive aggression and streamline the treatment approach towards IA. As an important case example of the range of candidate drugs that could fit into a new anti-maladaptive aggression agent category, we will review an investigational IA pharmacotherapy. SPN-810 (extended-release molindone) is currently being investigated as a novel treatment for children with IA and ADHD. Based on these studies we will review how SPN-810 may be well suited for a new, anti-maladaptive aggression drug class and more precisely, a proposed subgroup of IA modulators. The goal of this review is to begin improving the identification of and therapeutic approach for maladaptive aggression as well as IA through more precise anti-maladaptive aggression agent categorization.

Needle placement for piriformis injection using 3-D imaging.

Piriformis syndrome is a pain syndrome originating in the buttock and is attributed to 6% - 8% of patients referred for the treatment of back and leg pain. The treatment for piriformis syndrome using fluoroscopy, computed tomography (CT), electromyography (EMG), and ultrasound (US) has become standard practice. The treatment of Piriformis Syndrome has evolved to include fluoroscopy and EMG with CT guidance. We present a case study of 5 successful piriformis injections using 3-D computer-assisted electromagnet needle tracking coupled with ultrasound. A 6-degree of freedom electromagnetic position tracker was attached to the ultrasound probe that allowed the system to detect the position and orientation of the probe in the magnetic field. The tracked ultrasound probe was used to find the posterior superior iliac spine. Subsequently, 3 points were captured to register the ultrasound image with the CT or magnetic resonance image scan. Moreover, after the registration was obtained, the navigation system visualized the tracked needle relative to the CT scan in real-time using 2 orthogonal multi-planar reconstructions centered at the tracked needle tip. Conversely, a recent study revealed that fluoroscopically guided injections had 30% accuracy compared to ultrasound guided injections, which tripled the accuracy percentage. This novel technique exhibited an accurate needle guidance injection precision of 98% while advancing to the piriformis muscle and avoiding the sciatic nerve. The mean (± SD) procedure time was 19.08 (± 4.9) minutes. This technique allows for electromagnetic instrument tip tracking with real-time 3-D guidance to the selected target. As with any new technique, a learning curve is expected; however, this technique could offer an alternative, minimizing radiation exposure.

Placement of an intrathecal catheter through a bony fusion mass using 3D image guidance: a case report.

OBJECTIVE: We describe the 3-dimensional (3D) image-guided placement technique for a lumbar intrathecal catheter through a dorsal fusion mass. This is the first time this technique has been reported. A patient with 6 prior spine surgeries and chronic pain syndrome presented with a challenging large dorsal fusion mass. The use of 3D cone beam computed tomography-based image guidance proved advantageous for the placement of an intrathecal drug delivery system (IDDS). METHOD: Under general anesthesia, image guidance was accomplished with the Medtronic Stealth S7 image guidance system, used in conjunction with the O-ARM (Medtronic Inc.). Using an image-guided probe over the skin surface, we navigated the dorsal fusion mass to identify a thin area at the L4-L5 level. A small incision was made and the image-guided probe was used to target the selected thin area and drill an adequate opening in the fusion mass. We inserted a Tuohy needle through the bony defect for passage of the intrathecal catheter. We confirmed adequate catheter placement using free flowing cerebrospinal fluid and fluoroscopy. The remainder of the IDDS implant proceeded per routine. RESULTS: The patient tolerated the procedure well and had no complications. The morphine IDDS improved his overall pain and function with minimal side effects. CONCLUSIONS: This is the first case report using 3D cone beam computed tomography-based image guidance for the placement of an intrathecal catheter through a bony fusion mass. This technique appears to be a viable option for IDDS implantation in patients with difficult anatomy.