Recommendations for the management of gastrointestinal comorbidities with or without trofinetide use in rett syndrome.

INTRODUCTION: Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations in the MECP2 gene, many neurologists and pediatricians do not rank the management of these comorbidities among the most important treatment goals for RTT. Trofinetide, the first approved pharmacologic treatment for RTT, confers improvements in RTT symptoms but is associated with adverse GI events, primarily diarrhea and vomiting. Treatment strategies for GI comorbidities and drug-associated symptoms in RTT represent an unmet clinical need. AREAS COVERED: This perspective covers GI comorbidities experienced by those with RTT, either with or without trofinetide treatment. PubMed literature searches were undertaken on treatment recommendations for the following conditions: constipation, diarrhea, vomiting, aspiration, dysphagia, gastroesophageal reflux, nausea, gastroparesis, gastritis, and abdominal bloating. EXPERT OPINION: The authors recommend a proactive approach to management of symptomatic GI comorbidities and drug-associated symptoms in RTT to enhance drug tolerance and improve the quality of life of affected individuals. Management strategies for common GI comorbidities associated with RTT are reviewed based on authors' clinical experience and augmented by recommendations from the literature.

Distribution of hand function by age in individuals with Rett syndrome.

Objective: To determine the longitudinal distribution of hand function skills in individuals with classic Rett Syndrome (RTT), an X-linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus in this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C-terminal truncations) compared to groups composed of individuals with more severe variants. Conclusions: These temporal variations in hand use represent specific considerations which could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.

Healthcare access, satisfaction, and health-related quality of life among children and adults with rare diseases.

BACKGROUND: Research in a variety of countries indicates that healthcare access and health-related quality of life are challenged among people with a variety of rare diseases (RDs). However, there has been little systematic research on the experiences of children and adults with RDs in the American healthcare system that identifies commonalities across RDs. This research aimed to: (1) Describe demographics, disease characteristics, diagnostic experiences, access to healthcare, knowledge about RDs, support from healthcare professionals, and patient satisfaction among people with RDs and their caregivers; (2) examine predictors of patient satisfaction among adults with RDs; (3) compare health-related quality of life and stigma to US population norms; 4) examine predictors of anxiety and depression among adults and children with RDs. RESULTS: This large-scale survey included (n = 1128) adults with RD or parents or caregivers of children with RDs representing 344 different RDs. About one third of participants waited four or more years for a diagnosis and misdiagnosis was common. A subset of participants reported experiencing insurance-related delays or denials for tests, treatments, specialists, or services. Approximately half of participants felt their medical and social support was sufficient, yet less than a third had sufficient dental and psychological support. Patients were generally neither satisfied or dissatisfied with their healthcare providers. Major predictors of satisfaction were lower stigma, lower anxiety, shorter diagnostic odyssey, greater physical function, and less pain interference. Adults and children with RDs had significantly poorer health-related quality of life and stigma in all domains compared to US norms. Predictors of both anxiety and depression were greater stigma/poor peer relationships, fatigue, sleep disturbance, limited ability to participate in social roles, and unstable disease course. CONCLUSIONS: People in the U.S. with RDs have poor health-related quality of life and high stigma. These factors are related to patient satisfaction and healthcare access, including diagnostic delays and misdiagnosis. Advocacy work is needed in order to improve healthcare access and ultimately health-related quality of life for children and adults with RDs.

Analysis of X-inactivation status in a Rett syndrome natural history study cohort.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder associated with pathogenic MECP2 variants. Because the MECP2 gene is subject to X-chromosome inactivation (XCI), factors including MECP2 genotypic variation, tissue differences in XCI, and skewing of XCI all likely contribute to the clinical severity of individuals with RTT. METHODS: We analyzed the XCI patterns from blood samples of 320 individuals and their mothers. It includes individuals with RTT (n = 287) and other syndromes sharing overlapping phenotypes with RTT (such as CDKL5 Deficiency Disorder [CDD, n = 16]). XCI status in each proband/mother duo and the parental origin of the preferentially inactivated X chromosome were analyzed. RESULTS: The average XCI ratio in probands was slightly increased compared to their unaffected mothers (73% vs. 69%, p = .0006). Among the duos with informative XCI data, the majority of individuals with classic RTT had their paternal allele preferentially inactivated (n = 180/220, 82%). In sharp contrast, individuals with CDD had their maternal allele preferentially inactivated (n = 10/12, 83%). Our data indicate a weak positive correlation between XCI skewing ratio and clinical severity scale (CSS) scores in classic RTT patients with maternal allele preferentially inactivated XCI (rs  = 0.35, n = 40), but not in those with paternal allele preferentially inactivated XCI (rs  = -0.06, n = 180). The most frequent MECP2 pathogenic variants were enriched in individuals with highly/moderately skewed XCI patterns, suggesting an association with higher levels of XCI skewing. CONCLUSION: These results extend our understanding of the pathogenesis of RTT and other syndromes with overlapping clinical features by providing insight into the both XCI and the preferential XCI of parental alleles.

Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome.

OBJECTIVE: To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. STUDY DESIGN: We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. RESULTS: Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. CONCLUSIONS: The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Phenotypic features in MECP2 duplication syndrome: Effects of age.

BACKGROUND: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. METHODS: The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden. RESULTS: The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. CONCLUSIONS: The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

Special Education Supports and Services for Rett Syndrome: Parent Perceptions and Satisfaction.

There are no published studies describing educational experiences for girls with Rett syndrome. Given the extensive educational needs associated with Rett syndrome, it is important to understand how families perceive their daughters' educational experiences to inform education service provision. The purpose of this study was to survey parents of school-aged children with Rett syndrome to describe the educational services that they receive and understand parents' perceptions of and satisfaction with the special educational and related services. The majority of parents were satisfied with their daughters' educational services. Communication was the most frequently endorsed priority skill area, and many parents expressed frustration with limited access to augmentative and alternative communication (AAC) devices and staff training in their use. These results suggest there is a need for high-quality speech therapy and an emphasis on AAC support.

Preliminary Evidence That Resting State Heart Rate Variability Predicts Reactivity to Tactile Stimuli in Rett Syndrome.

Patients with Rett syndrome may manifest altered pain perception/experience and are vulnerable to conditions associated with chronic pain. Pain response is difficult to measure, however, because of severe communicative impairment. There is also documented autonomic dysfunction, including decreased heart rate variability. Given the relation between pain and the autonomic nervous system, we tested the feasibility of using resting heart rate variability to predict nonverbal pain/discomfort behavior during a standardized modified quantitative sensory test in Rett syndrome. All stimulus applications resulted in increased behavioral reactivity compared to baseline, with repeated von Frey significantly greater than all other stimuli. Resting heart rate variability predicted behavioral reactivity to repeated von Frey. These preliminary findings provide feasibility evidence for an integrated autonomic-sensory measurement approach and are consistent at a construct level with preclinical evidence in Rett syndrome. Further work is needed to determine how heart rate variability changes during stimulus application.

Evidence of altered salivary cytokine concentrations in Rett syndrome and associations with clinical severity.

Background: Immune dysregulation may play a role in the development of Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations of the MECP2 gene. Abnormal cytokine concentrations have been documented in the serum of individuals with RTT. Measurement of salivary cytokines has been investigated as a potential alternative approach to measurement in blood and serum, but it is unclear whether salivary cytokine concentrations can provide valid information about systemic immune function in neurodevelopmental disorders. The goal of this study was to evaluate the potential validity of salivary cytokines as biomarkers of immune dysregulation in RTT. Methods: Saliva samples from 16 individuals with RTT (all female; age range 2-40 years) and 16 healthy control females (age range 2-40 years) were analyzed for concentrations of 12 cytokines. Between-group differences in concentrations, and correlations with clinical severity in the RTT group were evaluated. Results: Concentrations of several salivary cytokines (IL-1ß, IL-6, IL-8, IL-10, GM-CSF, TNF-α, and VEGF) were increased in RTT compared to controls. The same cytokines showed significant positive correlations with clinical severity scores. There were no differences in concentrations of IL-2, IL-4, IL-5, IL-12p70, and IFN-γ. Conclusion: The results suggest that salivary cytokines may be a possible indicator of immune dysregulation in RTT. Future research should investigate whether these results can be applied to other neurodevelopmental disorders.

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome.

BACKGROUND: This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features. METHODS: This was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, dose-escalation study of the safety and tolerability of trofinetide in 56 adolescent and adult females with Rett syndrome. Subjects were randomly assigned in a 2:1 ratio to 35 mg/kg twice daily of trofinetide or placebo for 14 days; 35 mg/kg twice daily or placebo for 28 days; or 70 mg/kg twice daily or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant, phenotypic dimensions of impairment associated with Rett syndrome. RESULTS: Both 35 mg/kg and 70 mg/kg dose levels of trofinetide were well tolerated and generally safe. Trofinetide at 70 mg/kg demonstrated efficacy compared with placebo based on prespecified criteria. CONCLUSION: Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.

A case-controlled comparison of postoperative analgesic dosing between girls with Rett syndrome and girls with and without developmental disability undergoing spinal fusion surgery.

BACKGROUND: Rett syndrome is associated with severe motor and communicative impairment making optimal postoperative pain management a challenge. There are case reports documenting reduced postoperative analgesic requirement in Rett syndrome. AIM: The goal of this preliminary investigation was to compare postoperative analgesic management among a sample of girls with Rett syndrome compared to girls with and without developmental disability undergoing spinal fusion surgery. METHOD: The medical records of eight girls with Rett syndrome (mean age = 13.2 years, sd = 1.9), eight girls with developmental disability (cerebral palsy; mean age = 13.1 years, sd = 2.0), and eight girls without developmental disability (adolescent idiopathic scoliosis; mean age = 13.4, sd = 1.8) were reviewed. Data related to demographics, medications, and route of drug administration were recorded. RESULTS: Girls with Rett syndrome received significantly fewer morphine equivalent opioids postoperatively (M = 0.26 mg·kg-1 ·day-1 , sd = 0.10) compared to girls with adolescent idiopathic scoliosis (M = 0.47mg·kg-1 ·day-1 , sd = 0.13; 95% CI -0.34 to -0.08; P = 0.001) and girls with CP (M = 0.40 mg·kg-1 per day, sd = 0.14; 95% CI -0.27 to -0.02; P = 0.01). Girls with Rett syndrome received significantly fewer opioid patient-controlled analgesic (PCA) bolus doses (given by proxy; M = 42.63, sd = 17.84) compared to girls with adolescent idiopathic scoliosis (M = 98.25, sd = 52.77; 95% CI -96.42 to -14.83; P = 0.01). There was also some evidence indicating girls with Rett syndrome received fewer bolus doses compared to girls with CP (M = 80.88, sd = 38.93; 95% CI -79.05 to 2.55; P = 0.06). On average, girls with Rett syndrome also received smaller total doses of acetaminophen, diazepam, and hydroxyzine. CONCLUSION: This study highlights possible discrepancies in postoperative pain management specific to girls with Rett syndrome and suggests further investigation is warranted to determine best practice for postoperative analgesic management for this vulnerable patient population.

Pain experience and expression in Rett syndrome: Subjective and objective measurement approaches.

Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain 'looks like' in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age= 12.8 years, SD= 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children's Pain Checklist - Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89%) were reported to experience pain in the previous week which presented as gastrointestinal (n=8), musculoskeletal (n=5), and seizure related pain (n=5) that was intense (scored 0-10; M= 5.67, SD= 3.09) and long in duration (M= 25.22 hours, SD= 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child's typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact.

Infrared Thermal Analysis and Individual Differences in Skin Temperature Asymmetry in Rett Syndrome.

PURPOSE: We evaluated the feasibility of using a portable infrared thermal camera to quantify the degree of thermal dysregulation (cold hands/feet) and test for naturally occurring within-patient skin temperature asymmetry in Rett syndrome. PROCEDURES: Infrared thermal images were acquired passively from 15 patients (mean age = 13.7 years, range 4-47) with clinical diagnoses of Rett. Images were acquired using a FLIR T400 infrared thermal camera (still images recorded at 5 Hz, resolution of 320 × 240 pixels, thermal sensitivity = 0.05 °C; capture session lasted approximately 3 minutes). The infrared thermal camera was orthogonal to the body part (hands, feet) and positioned approximately 1 meter from the skin's surface. RESULTS: There were large intraindividual left/right differences in temperature. Seven (47%) and eight (53%) patients had statistically significant (P <0.05) left/right asymmetries between hands (mean difference = 0.87 °C, standard deviation = 1.21) and feet (mean difference = 1.73 °C, standard deviation = 3.03), respectively. Coders were reliable (intraclass correlations 0.97-0.99) on temperatures and selection of anatomical regions of interest. CONCLUSIONS: The degree of thermal asymmetry may reflect prolonged activity of the sympathetic nervous system and individual differences in sympathetic regulation. As clinical trials emerge and endpoints are considered, portable infrared thermal camera may provide one noninvasive means of evaluating changes in sympathetic regulation.

Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale.

Rett syndrome is a genetically based neurodevelopmental disorder. Although the clinical consequences of Rett syndrome are profound and lifelong, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component of well-designed clinical trials for individuals with neurodevelopmental disorders. The Clinical Global Impression Scale is a measure of global clinical change with strong face validity that has been widely used as an outcome measure in clinical trials of central nervous system disorders. Despite its favorable assay sensitivity in clinical trials, as a global measure, the Clinical Global Impression Scale is not specific to the signs and symptoms of the disorder under study. Development of key anchors for the scale, specific to the disorder being assessed, holds promise for enhancing the validity and reliability of the measure for disorders such as Rett syndrome.

Parent-reported pain in Rett syndrome.

OBJECTIVES: Clinical reports suggest that patients with Rett syndrome (RTT) live with significant chronic health issues as well as severe motor and communication impairments. Consequently, patients with RTT may be at risk for living with pain but not having it recognized. The purpose of this preliminary study was to document parent reported estimates of pain frequency, pain communication, and pain source. METHODS: Caregivers of 44 patients with clinically diagnosed RTT (mean RTT age = 21.5, SD = 13.5) completed a health survey about their daughter that contained a number of items specific to pain from the Non-Communicating Children's Pain Checklist - Revised SURVEY RESULTS: Among survey responders, 24% reported that their child had experienced pain on 8 or more days (> 1 week) in the previous 30 days. The most frequent form of pain communication was facial expression (85%) and vocalization (82%, eg, moan, cry). The most commonly reported pain source was gastro-intestinal (66%). Pain frequency was significantly (P<0.05) correlated with age (0.41), number of pain sources (0.72), and number of health problems (0.45); and the number pain sources was significantly (P<0.05) correlated with number of health problems (0.67). DISCUSSION: These preliminary results suggest that pain is a problem for a significant subgroup of patients with RTT. Almost one quarter of respondents indicated their daughters experience over a week of pain per month. The frequent health and communication issues associated with RTT suggest an increased risk that pain may be overlooked or discounted in this vulnerable population.

Passive prophylaxis with permethrin-treated tents reduces mosquito bites among North American summer campers.

OBJECTIVE: Over 2 million adolescents participate in summer-camp experiences, placing themselves at risk for mosquito-borne illness. Insect repellent is recommended but often not used. It is unknown whether permethrin treatment of a location, such as a campsite, provides passive prophylaxis reducing mosquito bites among all persons in the immediate vicinity. METHODS: This randomized, double-blind controlled trial used 0.4% permethrin (2.5% permethrin diluted by 7 parts water) sprayed once onto the external surface of canvas tents at a Boy Scout summer camp. During a 9-week period, subjects (n = 545) completed nightly mosquito-bite and -landing counts for 5 minutes at dusk and recorded insect-repellent use within 2 hours of counting. Weekly mosquito sampling with CO2-baited Centers for Disease Control and Prevention traps occurred at study campsites. The primary outcome measure was the number of mosquito bites per 5 minutes. RESULTS: A total of 1614 person nights averaged 5.1 +/- 7.2 (+/- SD) mosquito bites per 5 minutes. The permethrin-treated campsites had decreased mosquito landings and bites (relative risk reduction [RRR] 44%; 95% CI 34% to 55%; P < .001) compared with controls. Insect repellent was used only 32% of nights, decreasing bites by 36% (RRR 36%; 95% CI 25% to 47%; P < .001). Permethrin was superior to insect repellent alone (RRR 20%; 95% CI 4% to 37%; P = .01). CONCLUSIONS: Permethrin treatment of tents is an effective, inexpensive public health measure to reduce mosquito bites. Permethrin is effective among all individuals in a camping setting and was more effective than topical insect repellent alone, which, although recommended, was inconsistently used.