Long-term Natural History Studies Research Articles

A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study

BackgroundSELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).MethodsThe Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient’s age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.DiscussionThis study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.Trial registrationThis study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee (‘METC Oost-Nederland’; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland, file number: 2023–16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study.

Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10-26) years. The median yearly VA loss was 0.009 (range 0.002-0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002-4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.

Early surgery compared to nonoperative management for mild degenerative cervical myelopathy: a cost-utility analysis

BACKGROUND CONTEXTDegenerative cervical myelopathy (DCM) is a form of acquired spinal cord compression and contributes to reduced quality of life secondary to neurological dysfunction and pain. There remains uncertainty regarding optimal management for individuals with mild myelopathy. Specifically, owing to lacking long-term natural history studies in this population, we do not know whether these individuals should be treated with initial surgery or observation. PURPOSEWe sought to perform a cost-utility analysis to examine early surgery for mild degenerative cervical myelopathy from the healthcare payer perspective. STUDY DESIGN/SETTINGWe utilized data from the prospective observational cohorts included in the Cervical Spondylotic Myelopathy AO Spine International and North America studies to determine health related quality of life estimates and clinical myelopathy outcomes. PATIENT SAMPLEWe recruited all patients that underwent surgery for DCM enrolled in the Cervical Spondylotic Myelopathy AO Spine International and North America studies between December 2005 and January 2011. OUTCOME MEASURESClinical assessment measures were obtained using the Modified Japanese Orthopedic Association scale and health-related quality of life measures were obtained using the Short Form-6D utility score at baseline (preoperative), 6 months, 12 months and 24 months postsurgery. Cost measures inflated to January 2015 values were obtained using pooled estimates from the hospital payer perspective for surgical patients. METHODSWe employed a Markov state transition model with Monte Carlo microsimulation using a lifetime horizon to obtain an incremental cost utility ratio associated with early surgery for mild myelopathy. Parameter uncertainty was assessed through deterministic means using one-way and two-way sensitivity analyses and probabilistically using parameter estimate distributions with microsimulation (10,000 trials). Costs and utilities were discounted at 3% per annum. RESULTSInitial surgery for mild degenerative cervical myelopathy was associated with an incremental lifetime increase of 1.26 quality-adjusted life years (QALY) compared to observation. The associated cost incurred to the healthcare payer over a lifetime horizon was $12,894.56, resulting in a lifetime incremental cost-utility ratio of $10,250.71/QALY. Utilizing a willingness to pay threshold in keeping with the World Health Organization definition of "very cost-effective" ($54,000 CDN), the probabilistic sensitivity analysis demonstrated that 100% of cases were cost-effective. CONCLUSIONSSurgery compared to initial observation for mild degenerative cervical myelopathy was cost-effective from the Canadian healthcare payer perspective and was associated with lifetime gains in health-related quality of life.

Relationship between hemoglobin, hemolysis, and transcranial Doppler velocities in children with sickle cell disease: Results from a long-term natural history study in Italy in the era of multimodal therapy.

Stroke and cerebral vasculopathy are leading causes of morbidity and mortality in patients with sickle cell disease (SCD). Transcranial Doppler (TCD) is a reliable and validated predictor of stroke risk. Children with conditional or abnormal TCD are at an increased risk for stroke, which can be mitigated by red blood cell transfusion or hydroxyurea. Elucidating the relationship between cerebral hemodynamics and hemolytic anemia can help identify novel therapeutic approaches to reduce stroke risk and transfusion dependence. This long-term, real-world study was designed to evaluate the prevalence of TCD imaging (TCDi)-assessed flow velocities in children and to interrogate their relationship with markers of anemia and hemolysis. In total, 155 children (median follow-up 79.8 months, 1358.44 patient-years) had 583 evaluable TCDi results. Only patients with HbSS or HbSβ0 had abnormal (1.6%) or conditional (10.9%) TCDi. Children with abnormal or conditional TCDi had lower hemoglobin (Hb) and higher hemolysis markers. A linear correlation was detected between TCD velocity and Hb: an Hb increase of 1 g/dL corresponded to decreases in velocity in the internal carotid and middle cerebral arteries (6.137 cm/s and 7.243 cm/s). Moreover, patients with Hb >9 g/dL presented a lower risk of TCDi-associated events. These results support the need to optimize disease-modifying treatments that increase Hb and reduce hemolysis for stroke prevention in young children with SCD.

TENDOACHILLES LENGTHENING IMPROVES BAROPODOMETRIC PRESSURES ONE YEAR AFTER SURGERY FOR IDIOPATHIC TOE WALKERS

Idiopathic Toe-walking (ITW) is a condition where children persistently walk on their toes in the absence of neurological or orthopaedic structural abnormalities. ITW affects 2% of children at the age of 5.5yr. This may eventually result in fixed ankle equinus. There is a paucity of long-term natural history studies in untreated ITW however persisting equinus contractures are implicated in common adult foot conditions.The Aim of this study is to show if the percentage of contact pressure through the hindfoot during standing and walking improve following surgical tendoachilles lengthening one year after surgery in children with ITW when compared to a normative cohort23 patients (46 feet) diagnosed with ITW between 2017-2022; were treated with open zone III Achilles lengthening. We reported patient demographics, clinical resolution, or revision. Passive dorsiflexion range and hindfoot pressure percentage when standing and walking were measured on a baropodometric walkway and compared pre-operatively and at 12-18months postoperatively. We compared this to data from a previously studied normative cohort87% of children had compete resolution of toe-walking. 3 had recurrence with 1 patient having a revision surgery. Mean pre-operative static heel pressure percentage was 15.7%, this improved to 54.7% (p<0.001). This neared normative average of 70.6%. Mean pre-operative dynamic heel pressure percentage was 5.5%, this improved to 44.6% (p<0.001). This neared the normative mean of 52.0%. Mean Passive dorsiflexion in extension and 90˚ knee flexion was −5.8˚ and 0.5˚ respectively. This improved on average by 17.4˚ and 14.5˚ to a new mean of 11.6˚ and 15.0˚ (p<0.001).Open Zone III Achilles lengthening for ITW has high resolution rates. Hindfoot contact pressures and passive ankle dorsiflexion show improvement at 1 year post operatively.

A diagnostic confidence scheme for CLN3 disease.

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis

As trials and treatments for spinal muscular atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n = 56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.

Recent advances in understanding and managing pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disease that can range from isolated macrovesicular hepatocellular steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis to cirrhosis. The prevalence of NAFLD has increased over several decades, mirroring the global obesity pandemic. NAFLD currently represents the most common etiology of chronic liver disease in children and adolescents worldwide. Disease presentation in childhood strongly suggests that these children may have unique susceptibilities and more severe long-term consequences. Emerging data demonstrate that the pathogenesis of early-onset NAFLD is secondary to a complex interplay involving genetic, metabolic, environmental, and microbiological factors. Such influences may begin in utero. Dietary and lifestyle modifications remain the primary effective therapeutic interventions, although long-term efficacy is limited by poor adoption or adherence. Advances in the development and validation of non-invasive biomarkers and imaging modalities will facilitate diagnosis for affected children and adolescents and facilitate long-term natural history studies and the development of therapeutic interventions.

Natural history of X-linked hypohidrotic ectodermal dysplasia: a 5-year follow-up study

BackgroundX-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Cardinal symptoms are hypotrichosis, lack of teeth, and hypo- or anhidrosis, but the disease may also evoke other clinical problems. This study aimed at investigating the clinical course of XLHED in early childhood as the basis for an evaluation of the efficacy of potential treatments.Methods25 children (19 boys and 6 girls between 11 and 35 months of age) with genetically confirmed XLHED were enrolled in a long-term natural history study. Clinical data were collected both retrospectively using parent questionnaires and medical records (pregnancy, birth, infancy) and prospectively until the age of 60 months. General development, dentition, sweating ability, ocular, respiratory, and skin involvement were assessed by standardized clinical examination and yearly quantitative surveys.ResultsAll male subjects suffered from persistent anhidrosis and heat intolerance, although a few sweat ducts were detected in some patients. Sweating ability of girls with XLHED ranged from strongly reduced to almost normal. In the male subjects, 1–12 deciduous teeth erupted and 0–8 tooth germs of the permanent dentition became detectable. Tooth numbers were higher but variable in the female group. Most affected boys had no more than three if any Meibomian glands per eyelid, most girls had fewer than 10. Many male subjects developed additional, sometimes severe health issues, such as obstructive airway conditions, chronic eczema, or dry eye disease. Adverse events included various XLHED-related infections, unexplained fever, allergic reactions, and retardation of psychomotor development.ConclusionsThis first comprehensive study of the course of XLHED confirmed the early involvement of multiple organs, pointing to the need of early therapeutic intervention.

Age, race and viral genotype are associated with the prevalence of hepatitis B e antigen in children and adults with chronic hepatitis B.

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among thoseup to 10years of age to only 12% among those older than 50years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians>10-30years old vs Whites or Blacks who were >10 to 30years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy.

Strabismus in Cerebral Palsy: When and why to Operate

Cerebral palsy (CP) is the most common physical disability in children. Orthoptists and ophthalmologists who care for children with CP know that strabismus is a common feature. This paper reviews the literature on strabismus in patients with CP, and then provides summary data and recommendations for management of these patients. The incidence of strabismus in patients with CP, especially in patients with spastic diplegia, is much higher than in neurologically normal children. Esotropia is the most common ocular misalignment. CP patients with strabismus benefit from nonsurgical treatment and should be treated promptly. Strabismus surgery should be considered in CP patients for psychosocial reasons as well as for potential successful ocular realignment and restoration of binocular vision. The literature is lacking in a long-term natural history study, prospective strabismus surgery studies, and long-term outcome studies of strabismus management in patients with CP.

Is There a Role for Acetabular Dysplasia Correction in an Asymptomatic Patient?

Childhood hip dysplasia is best treated in infancy or early childhood with hopes that the acetabulum will be completely normalized by nonoperative treatment methods, which may include Pavlik and brace treatment as well as formal closed reduction and hip spica casting. In many cases, this ideal result cannot be achieved and the child is left with residual dysplasia, which is often not symptomatic. Other patients may present late with hip dysplasia that is not identified in early childhood. Some develop hip pain with no prior known hip problem. Other children have asymptomatic dysplasia that is picked up on an incidental radiograph. The orthopaedic literature is clear regarding the need for corrective hip osteotomies in symptomatic children. Surgery to correct asymptomatic hip dysplasia remains controversial. Children who have no symptoms yet have abnormal radiographs present a puzzling circumstance. In these cases, surgeons need to use quoted radiographic normal values for acetabular coverage of the femoral head as well as long-term natural history studies to decide whether to proceed with a corrective acetabular osteotomy. Long-term follow-up studies confirm that even patients with borderline dysplasia are likely to have significant hip symptoms and arthritis by middle age. Many children and adolescents with asymptomatic residual hip dysplasia should have corrective acetabular procedures performed. Surgery is more easily performed with more predictable results when the child is younger than 8 years. It is impossible to state with certainty which children with residual radiographic hip dysplasia, but without symptoms, should have a corrective acetabular osteotomy. Review of the literature confirms that many patients have been undertreated in the past, with a high percentage of children with borderline hip dysplasia developing premature arthritis in early to mid-adult life. Current data suggest that surgery should be performed in borderline cases. Skill of the surgeon in performing acetabular osteotomies and/or ease of referral to a treatment center may temper the timing of such decisions.

HIV DYNAMICS AND NATURAL HISTORY STUDIES: JOINT MODELING WITH DOUBLY INTERVAL-CENSORED EVENT TIME AND INFREQUENT LONGITUDINAL DATA.

Hepatitis C virus (HCV) coinfection has become one of the most challenging clinical situations to manage in HIV-infected patients. Recently the effect of HCV coinfection on HIV dynamics following initiation of highly active antiretroviral therapy (HAART) has drawn considerable attention. Post-HAART HIV dynamics are commonly studied in short-term clinical trials with frequent data collection design. For example, the elimination process of plasma virus during treatment is closely monitored with daily assessments in viral dynamics studies of AIDS clinical trials. In this article instead we use infrequent cohort data from long-term natural history studies and develop a model for characterizing post-HAART HIV dynamics and their associations with HCV coinfection. Specifically, we propose a joint model for doubly interval-censored data for the time between HAART initiation and viral suppression, and the longitudinal CD4 count measurements relative to the viral suppression. Inference is accomplished using a fully Bayesian approach. Doubly interval-censored data are modeled semiparametrically by Dirichlet process priors and Bayesian penalized splines are used for modeling population-level and individual-level mean CD4 count profiles. We use the proposed methods and data from the HIV Epidemiology Research Study (HERS) to investigate the effect of HCV coinfection on the response to HAART.

The history of the “natural history” of hepatitis C (1968–2009)

In the late 1960's, only types A and B hepatitis were believed to exist, distinguished by circumstances of exposure and incubation periods. In the early 1970's, studies of transfusion recipients were begun with the belief that hepatitis B would be responsible should transfusion-associated hepatitis develop. After discovery of the viruses of hepatitis A and B, neither agent was found responsible, hence non-A, non-B (NANB) hepatitis. Initial follow-up of these cases showed that approximately 50% developed chronic hepatitis based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after the hepatitis C virus had been identified as the cause for NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in over 80% of infected adults but in only about 50% of infected children or young women. Follow-up over 2 to 4 decades indicated that many infected persons developed progressive hepatic fibrosis, sometimes culminating in cirrhosis and/or liver cancer. Long-term natural history studies have proved to be challenging because disease onset is often silent and progression extremely slow. Differing strategies have been used to determine the natural history, the descriptions and results of which are presented in this review.

Hepatitis C in childhood

The approach of a pediatric hepatologist in managing children with hepatitis C virus (HCV) differs from adult practice, because the pediatric hepatologist is dealing with the beginning of a chronic illness in which long-term outcomes will not occur for 20 or 40 years, and it is not possible to predict in the early stages of the infection which patients have a more sinister prognosis. The prevalence of chronic HCV in children is low, but varies between different countries in the Asia-Pacific region. In most countries, screening of blood products for HCV has virtually eliminated the risk of post-transfusion HCV, so that in Australia children aged less than 11 years will not have acquired HCV from blood transfusion or extracorporeal membrane oxygenation. The risk of perinatal transmission of this virus is only about 6%, but this remains virtually the only source of HCV transmission for children in most countries. While available data are limited, mild histological changes are present in the majority of children with hepatitis C, and cirrhosis is rare. Unfortunately, long-term natural history studies of the course of HCV infection in children have not been reported. Individual decisions on antiviral treatment are more difficult in childhood, not because the treatment is any less effective or because of the severity of side-effects (which tend to be less severe than for adults), but because the long-term outcome of infection is unclear. At present, treatment should be confined to those with significant hepatic fibrosis and continued moderate to severe necroinflammatory change. Measures to prevent HCV infection in childhood center on whether, as recently suggested, elective cesarean section may reduce the risk of transmission. Despite the presence of HCV-RNA in some breast milk samples, there is no evidence that breast-feeding confers any risk of HCV infection.

Diagnosing human papillomaviruses: recent advances.

The biological importance of a group of human papillomaviruses, known as high-risk human papillomaviruses, as the key causal agent for almost all cervical cancer has now been established. Many aspects of the natural history of high-risk human papillomaviruses as sexually transmitted infections and as oncogenic agents have been researched. Although human papillomavirus diagnosis is largely confined to DNA detection techniques in cervical smears, there is accumulating evidence that the best polymerase chain reaction and hybrid capture techniques are more sensitive and probably of similar specificity compared with cervical cytology as a triage test for women with borderline smear abnormalities and for screening older women. This is strong presumptive evidence that high-risk human papillomavirus testing could be useful in cervical screening. Current research is aimed at establishing a place for high-risk human papillomavirus testing in routine screening practice. Randomised clinical trials, long-term natural history studies, mathematical modelling, and economic and psychosocial studies are being used to demonstrate whether this testing can improve both the effectiveness and efficiency of cervical screening in a range of situations.

Reduced stroke risk in patients with compromised cerebral blood flow reactivity treated with superficial temporal artery to distal middle cerebral artery bypass surgery

Extracranial-to-intracranial (EC-IC) bypass surgery for the prevention of stroke in patients with symptomatic carotid artery occlusion has nearly ended after a randomized trial showed no benefit of the procedure. Although an EC-IC bypass might benefit patients with compromised cerebrovascular hemodynamics, the randomized trial did not differentiate patients with hemodynamic from embolic etiologies. However, subsequent investigators have identified a subgroup of patients at increased stroke risk from hemodynamic compromise. We examined the subsequent stroke rate of 42 patients with symptomatic carotid occlusion at high risk for stroke identified as having a baseline cerebral blood flow (CBF)<45 mL/100 g/min and a >5% CBF reduction in one vascular territory after a vasodilatory challenge from 1 g of intravenous acetazolamide on stable xenon-computed tomography (CT) CBF imaging. Thirty patients (group 1) treated medically were a subgroup with carotid occlusion from our long-term natural history study. During a median follow-up of 12 months, 9 patients (30%) had a new stroke within a median of 5 months. Twelve patients (group 2) had recurrent, disabling cerebral ischemic symptoms, with 8 progressing to mild fixed neurological deficits from deep white matter infarction identified on CT. All were treated with superficial temporal artery to distal middle cerebral artery (STA-MCA) bypass with restoration of cerebrovascular reserve postoperatively; none had a stroke during the 18-month minimum follow-up (P=.041). Perioperative morbidity included subendocardial infarction in one and a small, asymptomatic left frontal hemorrhage in another patient. Early postoperative and delayed xenon/CT CBF studies obtained a median of 5 months postoperatively showed maintenance of cerebrovascular reserve. STA-MCA bypass surgery can restore cerebrovascular reserve in high-risk patients with symptomatic internal carotid artery occlusion. This was achieved with minimal perioperative complications, resulting in a subsequent reduction of stroke frequency. We suggest that the efficacy of STA-MCA bypass surgery for symptomatic carotid occlusion be re-examined prospectively using hemodynamic selection criteria.

Aseptic Meningitis in Infants Younger Than 2 Years of Age: Acute Illness and Neurologic Complications

We report the clinical features and cerebrospinal fluid (CSF) laboratory values for 277 children younger than 24 months of age with aseptic meningitis who were prospectively evaluated at three Baltimore hospitals between July 1986 and December 1990. A major objective was to define the incidence, etiology, and outcome of neurologic complications occurring during the acute illness. Cases were identified by surveillance in the ambulatory care departments of each of the three hospitals, pertinent historical and clinical data were obtained by interview of the parents and by review of the medical records, initial CSF laboratory values were recorded, and appropriate specimens were submitted to determine the viral etiology. A subset of 216 children who participated in a long-term natural history study were followed periodically with neurologic examinations and formal neurodevelopmental testing. Most cases occurred in very young infants; 63.5% of patients were 8 weeks of age or younger, and 84.1% were younger than 16 weeks of age. In this very young cohort, the dominant symptoms were fever and irritability; only 8.7% had evidence of meningeal irritation at the initial examination. The acute illness was complicated by either complex seizures, physical evidence of increased intracranial pressure, or coma in 25 (9.0%) cases. Within the age group under study, these complications were each significantly more likely to occur in patients older than 12 weeks of age than in younger infants. The risk of neurologic complications was similar among infants infected with group B coxsackieviruses and echoviruses, the two major enterovirus classes observed to cause disease. Acute central nervous system (CNS) complications could not be correlated with extremely abnormal CSF laboratory indices. Importantly, there was no risk of long-term neurologic sequelae attributable to acute CNS complications. While approximately 9% of infants and children younger than 2 years of age with aseptic meningitis experience acute CNS complications in the form of complex seizures, increased intracranial pressure, or coma, the prognosis for long-term cognitive development appears to be as favorable as the prognosis for children with aseptic meningitis who do not experience these complications.

Long-Term Natural History Study of Senile Retinoschisis with Implications for Management

This is a long-term natural history study of 123 consecutive, nonselected patients (218 eyes) with senile retinoschisis examined periodically, while deliberately withholding all forms of treatment, for from 1 to 21 years (average, 9.1 years) so that the natural behavior and prognosis of this disease could be learned and reasonable recommendations for management could be formulated. The quadrant of maximal involvement was the inferior temporal and 74% of the lesions had posterior borders which were postequatorial. Senile retinoschisis was found to be primarily asymptomatic and nonprogressive. Current indications for treatment, treatment modalities, and complication rates published in recent literature are analysed. No case of symptomatic progressive retinal detachment occurred, but there were 14 cases of localized, nonprogressive and asymptomatic “schisis-detachment”. Current indications for treatment of senile retinoschisis should be seriously reevaluated and reduced to one primary indication for treatment, namely symptomatic progressive retinal detachment.

A biomechanical analog of curve progression and orthotic stabilization in idiopathic scoliosis

A biomechanical analog of curve progression and orthotic stabilization in idiopathic scoliosis has been developed using the classical theory of curved beam-columns. The interaction of the spinal musculature and other supporting structures is incorporated in the model using an equivalent flexural rigidity. The stability of a given scoliotic curve relative to a normal spine is described in terms of the so-called critical load ratio ( P c P e ). This dimensionless quantity appears in the exact solution of the governing differential equation and boundary conditions. It is defined as the ratio of the load bearing capacity of a scoliotic spine ( P c ) to that of a normal spine where the load bearing capacity of a normal spine is defined as Euler's buckling load ( P e ). The computation of P c P e is based upon a maximum allowable moment criterion. This model is used to study the effect of the degree of initial curvature and curve pattern in the frontal plane on the stability of untreated idiopathic scoliosis. Although restricted to two-dimensions, the model appears to demonstrate the synergistic effects of end support, transverse loading, and curve correction on improvement in relative stability of an orthotically supported scoliotic curve. The results of this study are in qualitative agreement with clinical findings that are based on long-term studies of natural history of idiopathic scoliosis and of patients undergoing orthotic management for scoliosis.