Prevalence of Suicidality in Adolescents With Newly Diagnosed Focal Epilepsy at Diagnosis and Over the Following 36 Months.

BACKGROUND AND OBJECTIVES: Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months. METHODS: This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records. RESULTS: A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10). DISCUSSION: The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.

Unrecognized Focal Nonmotor Seizures in Adolescents Presenting to Emergency Departments.

BACKGROUND AND OBJECTIVES: Many adolescents with undiagnosed focal epilepsy seek evaluation in emergency departments (EDs). Accurate history-taking is essential to prompt diagnosis and treatment. In this study, we investigated ED recognition of motor vs nonmotor seizures and its effect on management and treatment of focal epilepsy in adolescents. METHODS: This was a retrospective analysis of enrollment data from the Human Epilepsy Project (HEP), an international multi-institutional study that collected data from 34 sites between 2012 and 2017. Participants were 12 years or older, neurotypical, and within 4 months of treatment initiation for focal epilepsy. We used HEP enrollment medical records to review participants' initial diagnosis and management. RESULTS: A total of 83 adolescents were enrolled between 12 and 18 years. Fifty-eight (70%) presented to an ED before diagnosis of epilepsy. Although most ED presentations were for motor seizures (n = 52; 90%), many patients had a history of nonmotor seizures (20/52 or 38%). Adolescents with initial nonmotor seizures were less likely to present to EDs (26/44 or 59% vs 32/39 or 82%, p = 0.02), and nonmotor seizures were less likely to be correctly identified (2/6 or 33% vs 42/52 or 81%, p = 0.008). A history of initial nonmotor seizures was not recognized in any adolescent who presented for a first-lifetime motor seizure. As a result, initiation of treatment and admission from the ED was not more likely for these adolescents who met the definition of epilepsy compared with those with no seizure history. This lack of nonmotor seizure history recognition in the ED was greater than that observed in the adult group (0% vs 23%, p = 0.03) and occurred in both pediatric and nonpediatric ED settings. DISCUSSION: Our study supports growing evidence that nonmotor seizures are often undiagnosed, with many individuals coming to attention only after conversion to motor seizures. We found this treatment gap is exacerbated in the adolescent population. Our study highlights a critical need for physicians to inquire about the symptoms of nonmotor seizures, even when the presenting seizure is motor. Future interventions should focus on improving nonmotor seizure recognition for this population in EDs.

Blood-Brain Barrier Dysfunction in Hypertensive Disorders of Pregnancy.

PURPOSE OF REVIEW: The incidence of hypertensive disorders of pregnancy (HDP), especially preeclampsia has increased significantly over the last two decades. Patients with these disorders often report cerebral and visual symptoms, which are listed as potential diagnosis criteria for preeclampsia, if accompanied by new-onset hypertension. Recent studies indicate that cerebral complications in HDP patients are associated with a compromised blood-brain barrier (BBB). The purpose of this review is to highlight the recent literature focused on the BBB in HDP, identify gaps in knowledge, and discuss future directions in this research area. RECENT FINDINGS: Majority of the studies addressing BBB changes in HDP are focused on preeclampsia. Recent studies show that hypertension induces increased association of perivascular macrophages/microglia to the cerebral vessels, increased circulating extracellular vesicles, and decreased autoregulation of cerebral blood flow. There is a critical need for more animal studies targeted to protecting the BBB and preventing cerebrovascular complications in the context of HDP. More clinical studies are needed that investigate both the short- and long-term interplay between each HDP subtype and BBB and cognitive function.

A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia.

In this study, we examined whether fetal hypoxia and other obstetric complications (OCs) are related to risk for adult schizophrenia; whether such effects are specific to cases with an early age at onset; and whether the obstetric influences depend on, covary with, or are independent of familial risk. Subjects were 72 patients with schizophrenia or schizoaffective disorder; 63 of their siblings not diagnosed with schizophrenia; and 7,941 nonpsychiatric controls, whose gestations and births were monitored prospectively with standard research protocols as part of the National Collaborative Perinatal Project. Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. We found that the odds of schizophrenia increased linearly with increasing number of hypoxia-associated OCs and that this effect was specific to cases with an early age at onset/first treatment contact. There were no relationships between schizophrenia and birth weight or other (prenatal/nonhypoxic) OCs. Siblings of patients with schizophrenia were no more likely to have suffered hypoxia-associated OCs than were nonpsychiatric cohort controls. Because the majority of individuals exposed to fetal hypoxia did not develop schizophrenia, such factors likely are incapable of causing schizophrenia on their own. Together, these findings suggest that hypoxia acts additively or interactively with genetic factors in influencing liability to schizophrenia. We propose a model in which the neurotoxic effects of fetal hypoxia may lead to an earlier onset of psychosis because of premature pruning of cortical synapses.

Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study.

Neuromotor dysfunction is a consistent finding in high-risk and archival studies of schizophrenia, but the sources of this dysfunction and its role in the developmental course of the disorder remain poorly understood. This study examined childhood motor predictors of adult psychiatric outcome in a birth cohort sample (72 patients with schizophrenia or schizoaffective disorder, 63 unaffected siblings, and 7,941 nonpsychiatric controls), evaluated prospectively with neurologic examinations at 8 months, 4 years, and 7 years of age. Deviance on motor coordination measures at 7 years was associated with both adult schizophrenia and unaffected sibling status, suggesting that a cofamilial (and perhaps genetic) factor underlies motor coordination deficits in schizophrenia. Unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sibling status, indicating that these deficits may be specific to those who will develop the clinical phenotype. None of the motor precursors were confined to patients with an early age at first treatment contact. Fetal hypoxia predicted unusual movements at 4 but not 7 years among the preschizophrenia subjects, suggesting neurodevelopmental dependence of its functional effects. Neither prenatal complications nor birth weight were associated with motor dysfunction in preschizophrenia subjects or their unaffected siblings at any age. Finally, preschizophrenia children did not show the expected developmental decline in unusual movements, perhaps reflecting aberrant functional maturation of cortical-subcortical pathways.

Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study.

While it is known that children of schizophrenia parents perform more poorly on tests of cognitive functioning than children of normal parents, less certain is the degree to which such deficits predict schizophrenia outcome, whether cognitive functioning deteriorates during childhood in preschizophrenia individuals, and whether nongenetic etiologic factors (such as obstetric complications) contribute to these deficits. In the present study, 72 patients with schizophrenia or schizoaffective disorder, 63 of their siblings not diagnosed with schizophrenia, and 7,941 controls with no diagnosis were ascertained from a birth cohort whose members had been evaluated with standardized tests of cognitive functioning at 4 and 7 years of age. Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. Both the patients with schizophrenia and their unaffected siblings performed significantly worse than the nonpsychiatric controls (but did not differ from each other) on verbal and nonverbal cognitive tests at 4 and 7 years of age. Preschizophrenia cases and their siblings were increasingly overrepresented across decreasing quartiles of the performance distributions. There was not significant intra-individual decline, and there were no significant relationships between obstetric complications and test performance among the preschizophrenia subjects. These results suggest that during the period from age 4 to age 7 years, premorbid cognitive dysfunction in schizophrenia represents a relatively stable indicator of vulnerability deriving from primarily genetic (and/or shared environmental) etiologic influences.

A prospective cohort study of childhood behavioral deviance and language abnormalities as predictors of adult schizophrenia.

Language and behavioral deviance in early childhood in preschizophrenia individuals suggests that the pathologic processes predisposing to schizophrenia are present from early in life. However, the etiologic antecedents of such impairments, and the degree to which they predict adult schizophrenia, have not been conclusively demonstrated. To address this, we examined language and behavioral predictors of adult psychiatric outcome in a population cohort (72 individuals with schizophrenia or schizoaffective disorder, 63 of their unaffected siblings, and 7,941 with no diagnosis) evaluated prospectively with behavioral examinations and a speech and language evaluation at 8 months, 4 years, and 7 years of age. Psychiatric outcome was ascertained via adult treatment contacts, and diagnoses were made by chart review according to DSM-IV criteria. Social maladjustment at age 7 was found to predict adult schizophrenia, and focal deviant behaviors (e.g., echolalia, meaningless laughter) at ages 4 and 7 were significantly associated with both schizophrenia and sibling status. Unintelligible speech at age 7 was a highly significant predictor of adult schizophrenia (odds ratio = 12.7), and poor expressive language ability predicted both schizophrenia and unaffected sibling outcome. Early behavioral and language dysfunction did not differentially characterize preschizophrenia subjects with a history of fetal hypoxia or an early age of first treatment contact. Given that unaffected siblings show similar signs of deviance, such problems may indicate genotypic susceptibility to the disorder, or shared environmental influences, or both.

A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia.

A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional-developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems.

The impact of closing a state psychiatric hospital on the county mental health system and its clients.

OBJECTIVE: This three-year study examined the impact of closing a state psychiatric hospital in 1991 on service utilization patterns and related costs for clients with and without serious mental illness. METHODS: The cohort consisted of all individuals discharged from state hospitals and those diverted from inpatient to community services and enrolled in the unified systems project, a state-county initiative to build up the service capacity of the community system. The size of the cohort grew from 1,533 enrollees to 2,240 over the three years. Information on the types, amounts, and cost of all services received by each enrollee was compiled from multiple administrative databases, beginning two years before enrollment and for up to three years after. The data were analyzed to reveal patterns of and changes in service utilization and related costs. RESULTS: Replacement of most inpatient services with residential and ambulatory services resulted in significant cost reduction. For project enrollees, a 94 percent reduction in state hospital services resulted in cost savings of more than $45 million during the three-year evaluation period. These savings more than offset the funds used to expand community services. Overall, the net savings to the system for mental health services for this group was $3.4 million over three years. CONCLUSIONS: The hospital closure and infusion of funds into community services produced desired growth of those services. The project reduced reliance on state psychiatric hospitalization and demonstrated that persons with serious mental illness can be effectively treated and maintained in the community.

Inpatient alcohol treatment in a private healthcare setting: which patients benefit and at what cost?

This study investigated whether selected patients have better outcomes with inpatient than outpatient treatment. There were 93 inpatients and 80 outpatients with alcohol dependence who were evaluated at treatment entry to a private healthcare setting. Patients with multiple drinking-related consequences were less likely to return to significant drinking in the first 3 months after treatment ended if they had attended inpatient compared to outpatient treatment. Thus, inpatient appeared to have some advantage over outpatient treatment in the early recovery period for patients with multiple drinking-related consequences. The gap between inpatient and outpatient costs was also reduced when computed as a cost-effectiveness ratio, although treatment costs continued to remain proportionally higher with inpatient than outpatient treatment.

Service utilization and cost of community care for discharged state hospital patients: a 3-year follow-up study.

OBJECTIVE: This study examined the mental health service utilization and costs of 321 discharged state hospital patients during a 3-year follow-up period compared with costs if the patients had remained in the hospital. METHOD: The study subjects were long-stay patients discharged from Philadelphia State Hospital after 1988. A longitudinal integrated database on all mental health and medical services reimbursed by Medicaid and Medicare as well as state- and county-funded services was used to construct service utilization and unit cost measures. RESULTS: During the 3-year period after discharge, 20%-30% of the patients required rehospitalization an average of 76-91 days per year. The percentage of rehospitalized patients decreased over time, but the number of hospital days increased. All of the discharged patients received case management services, and a majority also received outpatient mental health care (66%-70%) and residential services (75%) throughout the follow-up period. The total treatment cost per person was approximately $60,000 a year after controlling for inflation, with costs rising slightly over the 3-year period. The estimated cost of state hospitalization, with the use of 1992 estimates, would have been $130,000 per year if the patients had remained institutionalized. CONCLUSIONS: This analysis suggests that most former long-stay patients are able to live in residential settings while receiving community outpatient treatment and intensive case management services at a reduced cost. There is no indication of cost shifting from the psychiatric to the health care sector; however, some cost shifting from the state mental health agency to the Medicaid program has occurred, since most psychiatric hospital care now takes place in community hospitals.

The quality of medical evidence in hematology-oncology.

PURPOSE: The purpose of this study was to evaluate the quality of the medical evidence available to the clinician in the practice of hematology/oncology. METHODS: We selected 14 neoplastic hematologic disorders and identified 154 clinically important patient management decision/interventions, ranging from initial treatment decisions to those made for the treatment of recurrent or refractory disease. We also performed a search of the scientific literature for the years 1966 through 1996 to identify all randomized controlled trials in hematology/oncology. RESULTS: We identified 783 randomized controlled trials (level 1 evidence) pertaining to 37 (24%) of the decision/interventions. An additional 32 (21%) of the decision/interventions were supported by evidence from single arm prospective studies (level 2 evidence). However, only retrospective or anecdotal evidence (level 3 evidence) was available to support 55% of the identified decision/interventions. In a retrospective review of the decision/interventions made in the management of 255 consecutive patients, 78% of the initial decision/interventions in the management of newly diagnosed hematologic/oncologic disorders could have been based on level 1 evidence. However, more than half (52%) of all the decision/interventions made in the management of these 255 patients were supported only by level 2 or 3 evidence. CONCLUSIONS: We conclude that level 1 evidence to support the development of practice guidelines is available primarily for initial decision/interventions of newly diagnosed diseases. Level 1 evidence to develop guidelines for the management of relapsed or refractory malignant diseases is currently lacking.

Up-regulation of Duffy antigen receptor expression in children with renal disease.

BACKGROUND: The Duffy antigen chemokine receptor (DARC) is a promiscuous chemokine receptor that binds chemokines from the C-X-C and C-C families. DARC was initially described on red blood cells, but subsequent studies have demonstrated DARC protein expression on renal endothelial and epithelial cells, even in Duffy-negative individuals whose red cells lack DARC. Because approximately 68% of African Americans lack the Duffy/DARC on their red cells, we carried out experiments to identify the specific renal cells expressing DARC protein and mRNA in African American children and to define whether DARC expression was altered in renal inflammatory processes. METHODS: Immunohistochemistry and in situ hybridization studies were done in 28 renal sections from children with each of the following diagnoses: HIV nephropathy (HIVAN), HIV-associated hemolytic uremic syndrome (HIV-HUS), HIV infection without renal disease, HIV-negative children without renal disease, and Argentinean children with classic HUS. RESULTS: The predominant localization of DARC mRNA and protein was found in endothelial cells underlying postcapillary renal venules in all patients studied. However, DARC mRNA and protein were significantly up-regulated in peritubular and glomerular capillaries, collecting duct epithelial cells, and interstitial inflammatory cells in children with HIVAN, HIV-HUS, and classic HUS. CONCLUSION: These findings support the notion that the renal DARC is linked to the inflammatory cascade and that African American children may be at risk of accumulating chemokines in renal tissues.

Cost comparison of state hospital and community-based care for seriously mentally ill adults.

OBJECTIVE: In 1989, Philadelphia began a bold experiment involving the total shutdown of a 500-bed state hospital. This study examines the service utilization and cost of treating individuals with serious mental illness in a community-based care system in which the state hospital was replaced with 60 extended acute care beds in general hospitals and 583 residential beds. METHOD: A pre-post study design was used to determine the utilization and cost differences before and after the state hospital closed for individuals with a diagnosis of schizophrenia who required extended psychiatric hospitalization following an acute care crisis episode in a general hospital. The number and cost of days spent in general and in extended hospital and residential treatment were compared on an episode and an annual basis. RESULTS: The results of this analysis showed that after the state hospital closed, the direct treatment cost of an episode of care increased from $68,446 to $78,929, and the average annual cost of care per patient increased from $48,631 to $66,794 because of an increase in acute care hospitalization. CONCLUSIONS: This study suggests that an "admission" cohort of seriously mentally ill patients requires an optimal mix of acute care, extended care, and residential beds, as well as ambulatory services, in order for cost-efficient care to be delivered during a crisis period. Determining the appropriate allocation and supply of beds in different settings is essential if community mental health systems are to manage the care of individuals with serious mental illness outside of institutional settings.

Prevalence of treated behavioral disorders among adult shelter users: a longitudinal study.

Of 27,638 homeless adults admitted to Philadelphia public shelters in the years 1990 through 1992, 20.1% received treatment for a mental health disorder, and 25.3% for a substance use disorder in the years 1985 through 1993. An additional 20.7% were identified as having untreated substance use problems. Overall, a total of 65.5% of adult shelter users were identified as ever having had a mental health or substance use problem, treated or untreated.

Evaluating the quality of clinical guidelines. Linking decisions to medical evidence.

The validity and applicability of recommendations in clinical medicine are dependent on the design of studies upon which recommendations are based. Large prospective randomized controlled trials (RCT) generally provide the most reliable data to help guide our treatment decisions. However, analysis of decision-making in the field of hematologic malignancies indicates that only 24% of decisions can be based on randomized controlled trials. This lack of high-quality data to support many decisions in the treatment of malignant disorders underscores the need to evaluate the evidence that forms the backbone of guidelines themselves. As physicians are encouraged to conform to clinical guidelines, it is important that information be made available regarding the quality of data upon which these guidelines are based. We propose the development and use of a guideline quality score based on the quality of evidence supporting each decision in a guideline. By linking the quality of evidence with specific recommendations, physicians will be in a better position to understand the strengths and weaknesses of practice guidelines. This linkage will also help physicians to streamline their efforts to obtain a new line of evidence when an existing one is not satisfactory.

Are supplementary services provided during methadone maintenance really cost-effective?

OBJECTIVE: Previous research has suggested that support services supplementing methadone maintenance programs vary in their cost-effectiveness. This study examined the cost-effectiveness of varying levels of supplementary support services to determine whether the relative cost-effectiveness of alternative levels of support is sustained over time. METHOD: A group of 100 methadone-maintained opiate users were randomly assigned to three treatment groups receiving different levels of support services during a 24-week clinical trial. One group received methadone treatment with a minimum of counseling, the second received methadone plus more intensive counseling, and the third received methadone plus enhanced counseling, medical, and psychosocial services. The results at the end of the trial period have been published elsewhere. This article reports the results of an analysis at a 6-month follow-up. RESULTS: The follow-up analysis reaffirmed the preliminary findings that the methadone plus counseling level provided the most cost-effective implementation of the treatment program. At 12 months, the annual cost per abstinent client was $16,485, $9,804, and $11,818 for the low, intermediate, and high levels of support, respectively. Abstinence rates were highest, but modestly so, for the group receiving the high-intensity, high-cost methadone with enhanced services intervention. CONCLUSIONS: This study suggests that large amounts of support to methadone-maintained clients are not cost-effective, but it also demonstrates that moderate amounts of support are better than minimal amounts. As funding for these programs is reduced, these findings suggest a floor below which supplementary support should not fall.