Physician compensation for industry-sponsored clinical trials in multiple sclerosis influences patient trust.

BACKGROUND: Perceived physician financial conflicts of interest of can affect patient trust. Payment to physicians for industry sponsored clinical trials in multiple sclerosis is a relatively new potential source of physician conflict of interest. There is limited available data on how physician payment for trial involvement in multiple sclerosis clinical trials may influence patient trust. OBJECTIVE: To understand how patient trust is influenced by information about physician payment for multiple sclerosis clinical trials. METHODS: An anonymous online instrument was developed. RESULTS: 597 people with multiple sclerosis participated in the study. The study found that 61% of patients who had not previously participated in a clinical trial estimated that they would have lower levels of trust in their physician if the physician was paid for involvement in their clinical trial. Among former clinical trial participants, 38% self-reported a lower level of trust. Other potential physician-industry relationships, such as industry consulting or giving industry-sponsored talks, also adversely affected trust, though to a lesser extent than physician payment for subject participation in clinical trials. CONCLUSIONS: Results of this study demonstrate that physician payment for study participation in multiple sclerosis clinical trials is a potential conflict that can adversely affect patient trust.

The association between multiple sclerosis-related fatigue and balance as a function of central sensory integration.

BACKGROUND: Fatigue and impaired upright postural control (balance) are the two most common complaints in persons with multiple sclerosis (MS), with limited evidence on how they are related. OBJECTIVE: To examine the relationship between symptomatic fatigue and balance as a function of central sensory integration in persons with multiple sclerosis. MATERIALS AND METHODS: Seventeen persons with relapsing-remitting MS were enrolled in this cross-sectional study. Primary measurements included fatigue (modified fatigue impact scale - MFIS); balance (dynamic posturography, sensory organization testing - SOT); and walking capacity (six-minute walk test - 6MWT). RESULTS: Fatigue scores were significantly associated with balance: MFIS total (r=-0.78; p<0.001), physical subscale (r=-0.77; p<0.001), cognitive subscale (r=-0.75; p=0.001) and psychosocial subscale (r=-0.53; p=0.030) scores. MFIS total score was a significant predictor of balance (p≤0.001), accounting for 62% of the variability in SOT composite scores. Significant differences in fatigue (d=1.75; p=0.005) and balance (d=1.74; p=0.005) were found for participants who had cerebellar and brainstem involvement compared to those without. CONCLUSIONS: Symptomatic fatigue is significantly related to balance and is a significant predictor of balance as a function of central sensory integration in persons with MS. Fatigue and balance are associated with cerebellar and brainstem involvement. This study provides early evidence supporting the theory that for those persons with MS who struggle to maintain steady balance during tasks that stimulate the central sensory integration process, complaints of significant levels of fatigue are probable.

Results of the American Academy of Neurology resident survey.

BACKGROUND: To assess the effect of neurology residency education as trainees advance into independent practice, the American Academy of Neurology (AAN) elected to survey all graduating neurology residents at time of graduation and in 3-year cycles thereafter. METHODS: A 22-question survey was sent to all neurology residents completing residency training in the United States in 2007. RESULTS: Of 523 eligible residents, 285 (54.5%) responded. Of these, 92% reported good to excellent quality teaching of basic neurology from their faculty; however, 47% noted less than ideal training in basic neuroscience. Two-thirds indicated that the Residency In-service Training Examination was used only as a self-assessment tool, but reports of misuse were made by some residents. After residency, 78% entered fellowships (with 61% choosing a fellowship based on interactions with a mentor at their institution), whereas 20% entered practice directly. After adjustment for the proportion of residents who worked before the duty hour rules were implemented and after their implementation, more than half reported improvement in quality of life (87%), education (60%), and patient care (62%). The majority of international medical graduates reported wanting to stay in the United States to practice rather than return to their country of residence. CONCLUSIONS: Neurology residents are generally satisfied with training, and most entered a fellowship. Duty hour implementation may have improved resident quality of life, but reciprocal concerns were raised about impact on patient care and education. Despite the majority of international trainees wishing to stay in the United States, stricter immigration laws may limit their entry into the future neurology workforce.

Education research: neurology residency training in the new millennium.

OBJECTIVE: To survey adult neurology program directors (ANPD) to identify their most pressing needs at a time of dramatic change in neurology resident education. METHODS: All US ANPD were surveyed in 2007 using an instrument adjusted from a 1999 survey instrument. The goal was to characterize current program content, the institution and evaluation of the core competencies, program director characteristics, program director support, the institution of work duty hour requirements, resident support, and the curriculum needs of program directors and programs. RESULTS: A response rate of 82.9% was obtained. There is a significant disconnect between administration time spent by ANPD and departmental/institutional support of this, with ANPD spending approximately 35% of a 50-hour week on administration with only 16.7% salary support. Rearrangement of rotations or services has been the most common mode for ANPD to deal with work duty hour requirements, with few programs employing mid level providers. Most ANPD do not feel work duty hour reform has improved resident education. More residents are entering fellowships following graduation than documented in the past. Curriculum deficiencies still exist for ANPD to meet all Neurology Program Requirements, especially for nontraditional neurology topics outside the conventional bounds of clinical neurology (e.g., practice management). Nearly one quarter of neurology residency programs do not have a meeting or book fund for every resident in the program. CONCLUSIONS: Adult neurology program directors (ANPDs) face multiple important financial and organizational hurdles. At a time of increasing complexity in medical education, ANPDs need more institutional support.

The differential diagnosis of Axis I psychopathology presenting to a university-based multiple sclerosis clinic.

Patients carrying a presumptive diagnosis of multiple sclerosis (MS) sometimes present with non-specific clinical signs and symptoms that may be, at least in part, somatic manifestations of psychiatric conditions. This retrospective study was undertaken to identify psychiatric diagnoses among 63 patients whose initial clinical evaluations suggested a primary psychiatric, rather than a primary neurological, etiology for their symptoms. Some 92% of patients met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR) criteria for one or more primary psychiatric disorders, most often including somatoform, mood, and anxiety disorders. Accurate identification and diagnosis of psychiatric conditions producing pseudoneurological or non-specific somatic symptoms is necessary for both treatment and medico-economic reasons.

Survey of training programs' means for promoting neurology and attracting trainees.

OBJECTIVE: To determine neurology training opportunities available to medical students and to define factors that influence program choice. METHODS: All neurology residency program directors and a random sample of residents were surveyed. Resident questions related to application, interview, and training experience. Directors' questions focused on ways their department generated interest in clinical neurosciences. RESULTS: Medical schools introduce students to clinical neurology primarily through required clerkships. Contact time averages less than 4 weeks and emphasizes inpatient encounters. Preceptorships with neurology faculty do not exist at almost 40% of schools and only 14% have neuroscience tracks. Nearly all residency applicants matched their first or second choice. The majority declined at least one interview and 39% failed to rank at least one site they visited. When choosing where to apply, the programs' reputation and geographic considerations were paramount. When making a rank list, interactions with faculty and residents at interview were most important. Residents generally reported satisfaction with their programs and attribute morale to supportive relationships with faculty and residents. CONCLUSIONS: Neurology programs may be able to enhance students' impression of neurology through changes in their clinical experience and development of venues for more meaningful relationships with faculty. Attention to the residents' personal needs may increase the likelihood of matching the best available candidates and ensuring their satisfaction.

Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions.

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Accuracy of clinical detection of INO in MS: corroboration with quantitative infrared oculography.

The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

HIV-1 LTR C/EBP binding site sequence configurations preferentially encountered in brain lead to enhanced C/EBP factor binding and increased LTR-specific activity.

Recent studies have shown that two CAAT/enhancer binding protein (C/EBP) sites are critically important for efficient human immunodeficiency virus (HIV) type 1 (HIV-1) replication within cells of the monocyte/macrophage lineage, a primary cell type infected by HIV-1 and a potentially important vehicle for transport of virus to the central nervous system (CNS). Given the relevance of HIV-1 LTR sequence variation with respect to HIV-1 replication within monocyte populations and the important role that monocyte tropism likely plays in HIV-1 infection of the brain, C/EBP site sequence variation was examined within peripheral blood- and brain-derived LTR populations. Brain-derived LTRs commonly possessed a C/EBP site I configuration (6G, comprised of a thymidine to guanosine substitution with respect to the clade B consensus sequence at position 6 of C/EBP site I) that leads to enhanced binding of C/EBP proteins over that observed with the HIV-1 clade B consensus sequence at this site. In contrast, the 6GC/EBP site I configuration appeared infrequently within sequenced peripheral blood-derived LTRs. In addition, C/EBP site II was even more highly conserved in brain-derived HIV-1 LTR populations than site I. This was not the case with peripheral blood-derived LTR C/EBP site II sequences. The high degree of C/EBP site II conservation in brain-derived LTRs was likely important in LTR regulation since the clade B consensus sequence conserved at C/EBP site II recruited high amounts of C/EBP family members. Transient transfection analyses indicated that conservation of the strong C/EBP site II in brain-derived LTRs was likely due to important interactions with Tat. Overall, brain-derived HIV-1 LTRs preferentially contained two highly reactive C/EBP binding sites, which may suggest that these sites play important roles in LTR-directed transcription during invasion and maintenance of HIV-1 in the central nervous system.

Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of unknown cause that afflicts the central nervous system. MS is typified by a highly clonally restricted antigen-driven antibody response that is confined largely to the central nervous system. The major antigenic targets of this response and the role of antibody in disease pathogenesis remain unclear. To help resolve these issues, we cloned the IgG repertoire directly from active plaque and periplaque regions in MS brain and from B cells recovered from the cerebrospinal fluid of a patient with MS with subacute disease. We found that high-affinity anti-DNA antibodies are a major component of the intrathecal IgG response in the patients with MS that we studied. Furthermore, we show DNA-specific monoclonal antibodies rescued from two subjects with MS as well as a DNA-specific antibody rescued from an individual suffering from systemic lupus erythematosus bound efficiently to the surface of neuronal cells and oligodendrocytes. For two of these antibodies, cell-surface recognition was DNA dependent. Our findings indicate that anti-DNA antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders, such as MS and systemic lupus erythematosus.

Curriculum renewal and a process of care curriculum for teaching clerkship students.

BACKGROUND AND OBJECTIVES: A school-wide curriculum renewal led to a new clerkship curriculum that teaches core family practice competencies by focusing on the process of care in generalist practice. The organizing framework consists of five prototypic visits and their encounter tasks: 1) new problem visit, 2) checkup visit, 3) chronic illness visit, 4) psychosocial problem visit, and 5) behavioral change visit. METHODS: The seminars occur at the beginning of the rotation and use active learning techniques. Evaluation includes student perceptions of the seminars and teachers and student performance on a clinical performance examination (CPX). RESULTS: Students rated the usefulness of the seminars and the seminar leaders' teaching behaviors favorably. The CPX checklist scores showed that students could perform most of the behaviors expected for each prototypic visit. The students listed the appropriate encounter tasks nearly half of the time when describing what tasks they tried to accomplish during the CPX cases. The students listed concrete behaviors just over 50% of the time. CONCLUSIONS: The students learned the material presented in the seminars and applied it during the CPX. Students can do most of the behaviors but do not seem to describe the tasks as abstractly as faculty. These results come from one class cohort in one medical school, so the generalizability is limited until further work, including other learners, confirms these findings.

Diffuse leptomeningeal gliomatosis associated with multifocal CNS infarcts.

BACKGROUND: Widespread dissemination of astrocytoma throughout the cerebrospinal fluid is unusual, especially as the initial presentation in a patient, and association with cerebral infarcts is rare. CASE DESCRIPTION A 47-year-old man subacutely developed progressive headache and backache, vomiting, altered consciousness, and numbness in both arms. Brain computerized axial tomography showed calcification in the fourth ventricle and magnetic resonance imaging demonstrated diffuse meningeal enhancement, a lesion in the canal of Magendie, and T2-weighted hyperintense lesions in several locations. Angiography showed vasospasm/vasculopathy involving multiple cerebral vessels. Biopsy of the fourth ventricular mass revealed a subependymoma with an overlying leptomeningeal anaplastic astrocytoma with numerous Rosenthal fibers. The patient was treated with three doses of intrathecal methotrexate via lumbar puncture but suddenly became unresponsive and died 6 days later, 8 weeks after initial symptoms. Autopsy demonstrated the subependymoma and a widespread leptomeningeal anaplastic astrocytoma, which showed no clear-cut origin from the subependymoma, but microscopically infiltrated the left medial temporal lobe. Multiple subacute and acute infarcts of the brain, brain stem, and upper spinal cord were seen only in areas with leptomeningeal tumor. CONCLUSION Glioma cells surrounding and focally permeating central nervous system vessels without lumenal occlusion can lead to vasospasm and widespread infarcts.

Human herpesvirus 8 DNA in CNS lymphomas from patients with and without AIDS.

BACKGROUND AND OBJECTIVE: Human herpesvirus 8 (HHV-8) has been found in association with Kaposi's sarcomas in human immunodeficiency virus (HIV)-positive and -negative patients, primary effusion lymphomas (PELs), multicentric Castleman's disease, and multiple myeloma. The PELs share several features with acquired immunodeficiency syndrome (AIDS)-associated primary central nervous system lymphomas (1 degree CNS-L), including B-cell phenotype, infection with Epstein-Barr virus, and lack of c-myc gene rearrangements. This prompted us to investigate the role of HHV-8 in 1 degree CNS-L and other brain lymphomas. METHODS: To identify HHV-8, we performed nested and single polymerase chain reaction using DNA extracted from autopsy and biopsy brain lymphoma specimens of 36 patients with and without AIDS. RESULTS: We detected HHV-8 DNA in 56% of all 1 degree CNS-L, with similar rates for patients with and without AIDS, but in just one of five metastatic B-cell lymphomas. Brain tissues histologically uninvolved by lymphoma were negative for HHV-8 in three patients in whom their 1 degree CNS-L was HHV-8 positive. In contrast, we easily demonstrated HHV-8 DNA in spleens and a KS lesion of patients with HHV-8-positive 1 degree CNS-L. All nonlymphoma brain controls were negative for HHV-8. CONCLUSIONS: HHV-8 DNA is found in a significant percentage of 1 degree CNS-L, including patients with and without AIDS. Identification of HHV-8 in splenic tissue and absence of HHV-8 in control brain tissues suggests the possibility of a peripheral lymphocyte reservoir for HHV-8. Systemically infected lymphocytes may play a direct or indirect role in the pathogenesis of 1 degree CNS-L.

Factors associated with unintended pregnancy.

This research was designed to identify determinants of unintended pregnancy among women attending family practice or family planning clinics. Survey data were collected from 95 women who were categorized according to whether or not they had experienced an unintended pregnancy. Women reporting unintended pregnancy were younger, reported earlier sexual debut and a greater number of sexual partners than those not having experienced an unintended pregnancy. Those who had avoided unintended pregnancy displayed higher levels of preventive sexual self-efficacy, had more confidence in their ability to use contraceptive methods, perceived more negative consequences associated with having children in the near future, and believed pregnancy among unmarried women to be less acceptable than did women who had had unintended pregnancies.

HIV-1 LTR DNA sequence variation in brain-derived isolates.

Isolates of human immunodeficiency virus (HIV-1) derived from the central nervous system (CNS) display properties distinctive from blood-derived isolates, including a high incidence of macrophage tropism in CNS isolates. Macrophage tropism is a result, in part, of DNA sequence variation in the HIV-1 envelope glycoprotein gene, but evidence also exists suggesting differences in the long terminal repeat (LTR) may contribute to differential gene expression. To investigate the nature of HIV-1 LTR sequence variation in the brain, we have sequenced bases -374 to +43 of the LTR from the brains of four HIV-1-infected patients. A total of 56 clones were derived from either both gray and white matter (three brains) or white matter alone (one brain), and these sequences were compared to 17 published sequences derived from multiple sources. A total of five LTR quasispecies were found. Overall, there was a significant amount of sequence variation both within and between brains, comparable to that seen in quasispecies of the envelope glycoprotein derived from blood or brain. The vast majority of the variation was seen in regions upstream from the two NF-kappa B sites. Compared to the blood-derived, T cell-tropic IIIB LTR, a majority of clones from two or more of the brains shared 11 unique substitutions in transcription factor binding sites, of which eight were shared with the CNS-derived clones JR-CSF and JR-FL and altered the NF-AT and LEF-1 transcription factor binding sites. These findings correlate with published functional studies showing CNS-derived HIV-1 LTRs are distinct from the blood-derived IIIB LTR, and represent a starting point for future studies designed to determine which LTR sequence variations are associated with cell-specific differences in gene expression in the CNS.

Postanesthetic hypotropia: a unique syndrome in left eyes.

PURPOSE: To investigate a recurring syndrome of postoperative hypotropia after cataract surgery performed under local anesthesia. SETTING: Hawaiian Eye Center, Wahiawa, Hawaii, USA. METHODS: Thirty-one left eyes in 2143 cataract surgeries developed postoperative hypotropia. Phacoemulsification and intraocular lens implantation were performed by one surgeon; the anesthetic (containing bupivacaine) was administered by one anesthesiologist who had treated 4200 patients without incident. We conducted epidemiologic, outcomes, and prevention studies to identify the etiology, evaluate hypotropia treatment, and test specific anesthetic techniques, respectively. RESULTS: Changes in preoperative and intraoperative management and surgical methods were unsuccessful in preventing the hypotropia. In 55% of the cases, strabismus surgery was required and in 13%, prism glasses. Early recession of the inferior rectus and conjunctiva was successful. After repeated observations of the anesthetic technique, it was noted that the right-handed anesthesiologist misdirected the retrobulbar needle into the left orbit. This resulted in a change in the anesthetic technique, and there has been no incidence of postoperative hypotropia in 3000 surgeries. CONCLUSION: We believe this syndrome resulted from mytoxicity or perimuscular inflammation, producing contracture hypotropia and restricted elevation of the globe. We propose the term postbupivacaine hypotropia for this chiefly left-sided syndrome.