Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.

OBJECTIVE: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). METHODS: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score ≥13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). RESULTS: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. INTERPRETATION: DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA.

The prevalence of multiple sclerosis in 3 US communities.

INTRODUCTION: We estimated the prevalence of multiple sclerosis (MS) in 3 large geographic areas in the southern, middle, and northern United States. METHODS: The primary data source was medical records from office visits to private neurologists' practices or to neurology departments in tertiary care facilities during a 3-year period. Additional data sources included patient advocacy groups, nursing homes, and general practitioners. RESULTS: Three-year US age-adjusted prevalence estimates for the study areas varied substantially. The prevalence was lowest (47.2 per 100,000 population) in the Texas study area (33 degrees 30' north latitude), intermediate (86.3 per 100,000 population) in the Missouri study area (39 degrees 07' north latitude), and highest (109.5 per 100,000 population) in the Ohio study area (41 degrees 24' north latitude). The geographic differences remained strong after age-adjustment to the world standard population. The inverse association between UV light exposure and MS prevalence estimates was consistent with this observed latitude gradient. In all 3 areas, MS prevalence was highest among women, people aged 40 to 59 years, and non-Hispanics. CONCLUSION: These results provide necessary prevalence estimates for community cluster investigations and establish baseline estimates for future studies to evaluate temporal trends in disease prevalence.

Depression in neurological practice: diagnosis, treatment, implications.

Ambulatory prevalence rates for significant depressive syndromes in general neurology clinics are quite high, in the range of 15 to 20% of clinic attendees. These depressive syndromes are a source of considerable morbidity and even mortality for the patients who suffer from them. Depression is a treatable syndrome, but there are not enough psychiatrists to administer all the treatments. Inevitably, many neurologists will become involved with some antidepressant therapies. In this article, I review a series of steps that can be used by neurologists to diagnose and treat the depressive disorders that occur in their practices. The Goldman algorithm for the treatment of depression is also presented as a therapeutic tool for practicing neurologists.

Inhibition of thromboxane a synthase activity enhances steroidogenesis and steroidogenic acute regulatory gene expression in MA-10 mouse Leydig cells.

The cyclooxygenase-2 (COX2)-dependent inhibition of Leydig cell steroidogenesis has been demonstrated. To understand the mechanism for this effect of COX2, the present study examined the role of an enzyme downstream of COX2, namely thromboxane A synthase (TBXAS), in steroidogenesis. Inhibition of TBXAS activity with the inhibitor furegrelate induced a concentration-dependent increase in cAMP-induced steroidogenic acute regulatory (StAR) protein in MA-10 mouse Leydig cells. The increase in StAR protein occurred concomitantly with a significant increase in steroid hormone production. Similar results were obtained in StAR promoter activity assays and RT-PCR analyses of StAR mRNA levels, suggesting that inhibition of TBXAS activity enhanced StAR gene transcription. These observations were corroborated when TBXAS expression was specifically inhibited by RNA interference. Although the RNA interference reduced mRNA levels of TBXAS, it increased StAR mRNA levels, StAR protein, and steroidogenesis. Additional studies indicated that inhibition of TBXAS activity reduced DAX-1 protein, a repressor in StAR gene transcription. In the absence of cAMP, inhibition of TBXAS activity did not induce a significant increase in steroid hormone and StAR protein. However, addition of a low level of cAMP analogs dramatically increased steroidogenesis. Lastly, inhibition of protein kinase A activity essentially abolished the steroidogenic effect of the TBXAS inhibitor. Thus, the results from the present study suggest that a minimal level of protein kinase A activity is required for the steroidogenic effect of the TBXAS inhibitor and that inhibition of TBXAS activity or its expression increase the steroidogenic sensitivity of MA-10 mouse Leydig cells to cAMP stimulation.

Unilateral or "side-locked" migrainous headache with autonomic symptoms linked to night guard use.

Night guards are commonly prescribed as a palliative measure for bruxism, temporomandibular joint symptoms, and associated disorders. We describe a patient with a 10- to 12-year history of night guard use with concurrent unilateral side-locked migrainous headaches with autonomic symptoms characteristic of trigeminal autonomic cephalgia. These headaches were refractory to numerous pharmacological interventions. Upon self-initiated cessation of night guard use, there was complete remission of headaches. We believe the headaches were initiated by night guard-initiated irritation of the trigeminal nerve and a trigeminal autonomic reflex resulting in unilateral migrainous headache with autonomic signs.

Case-finding for MS prevalence studies in small communities requires a community-based approach.

In response to citizen concerns in 5 small Illinois towns, community-based case-finding determined the prevalence of multiple sclerosis (MS). Potential cases were identified through town meetings, publicity, advocacy groups and local volunteer outreach coordinators. Estimated prevalence based on available medical records for self-identifying individuals for 3 of the 5 communities was high (218-231 per 100,000 population) compared to other studies. Scanning databases in medical offices used in many other studies may miss MS cases; yet tracking medical records is labor-intensive and sometimes restricted by privacy guidelines. MS registries could improve case-finding accuracy and efficiency.

Prevalence of multiple sclerosis in 19 Texas counties, 1998-2000.

The study reported here determined the prevalence of multiple sclerosis (MS) between January 1, 1998, and December 31, 2000, for a 19-county study area surrounding Lubbock, Texas. The primary data source for case ascertainment was medical records from the offices of neurologists practicing in the study area. The study found that the overall prevalence for the 19-county study area was 42.8 per 100,000 population (95 percent CI = 36.8-49.5). The prevalence estimate for females was 68.6 per 100,000 (95 percent CI = 58.0-80.6), and for males it was 16.6 per 100,000 (95 percent CI = 11.6-23.1). The prevalence estimate for non-Hispanic whites was 56.0 per 100,000 (95 percent CI = 47.1-66.1); the next highest prevalence was among non-Hispanic blacks at 22.1 per 100,000 (95 percent Cl = 8.1-48.1), and Hispanics at 11.2 per 100,000 (95 percent CI = 6.4-18.2). This project generated the first Texas-specific population-based MS prevalence estimates, including prevalence estimates specific to Hispanics and blacks in Texas. The results underscore the need for additional epidemiologic information on the distribution of MS in other areas of Texas and the United States, as well as information on the underlying etiology of the disease.

Investigation of a cluster of multiple sclerosis in two elementary school cohorts.

The authors investigated a cluster of multiple sclerosis (MS) among people who had attended two elementary schools in El Paso, Texas, from 1948 through 1970. The community was concerned about the possibility of childhood exposure to heavy metals from a large nearby smelter because historical environmental and biological sampling data demonstrated the potential for study cohort members to have been exposed to heavy metals during their pre-adolescent years. One cohort had no reported cases of MS. In the second cohort, 22 members self-reported a diagnosis of MS, and 16 of these cases were confirmed as MS by an independent board-certified neurologist. The crude MS prevalence estimate was 411 per 100,000 (95 percent confidence interval [CI] = 197-603), Prevalence estimates from four different populations were used for calculation of standardized morbidity ratios (SMRs). At the extremes, the study cohort represents a deficit of cases (SMR= 0.9; 95 percent CI = 0.51-1.44) or a four-fold excess (SMR = 4.0; 95 percent Cl = 2.29-6.5).

The involvement of epoxygenase metabolites of arachidonic acid in cAMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression.

The essential role of arachidonic acid (AA) in steroidogenesis has been previously demonstrated. The present study continues the investigation into how AA regulates steroidogenesis by examining the effects of epoxygenase-derived AA metabolites on cAMP-stimulated steroidogenic acute regulatory (StAR) gene expression and steroid hormone production in MA-10 mouse Leydig cells. The HPLC analysis of cell extracts from MA-10 cells treated with the cAMP analog dibutyryl cAMP (dbcAMP) demonstrated an increase in three epoxygenase-generated AA metabolites: 5,6-epoxyeicosatrienoic acid (EET), 8,9-EET, and 11,12-EET. Incubating MA-10 cells with each of the EETs induced a dose-dependent increase in StAR protein expression and steroid hormone production in the presence of dbcAMP. These metabolites also significantly enhanced StAR gene transcription as determined by luciferase assays of StAR promoter activity and reverse transcriptase-PCR analysis of StAR mRNA levels. While the EETs enhanced steroidogenesis, inhibiting the activity of protein kinase A (PKA) abolished the stimulatory effects of these AA metabolites on StAR expression and steroid hormone production. This study suggests that cAMP stimulation of MA-10 cells increases epoxygenase-generated AA metabolites and the co-action of these metabolites with PKA significantly increases StAR gene expression and steroid hormone production.

Defining and diagnosing involuntary emotional expression disorder.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

Satisfaction with mental health care among people with multiple sclerosis in urban and rural areas.

OBJECTIVES: This study explored urban and rural differences in mental health needs and treatments among people with multiple sclerosis, as well as their satisfaction with access to and quality of mental health care. METHODS: Data were collected in a nationwide survey of 1,518 people with multiple sclerosis. RESULTS: More than 40 percent of people with multiple sclerosis in each urban or rural area had received a diagnosis of depression, and more than 90 percent of them received mental health services, regardless of location of residence. However, rural residents were significantly less likely than their urban counterparts to receive the recommended combined medication and psychotherapy for treatment of depression. CONCLUSIONS: Current mental health care systems, even in rural areas, are capable of reaching out to patients with neuromedical illnesses, such as multiple sclerosis. Patients perceive some limitations in quality and accessibility, and recommended treatment differs between urban and rural areas.

The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting.

This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content ad incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.

Retrospective review of modafinil use for cerebral palsy.

A retrospective review was undertaken at Texas Tech University Health Sciences Center regarding the use of modafinil for the treatment of spasticity associated with cerebral palsy. Neurology clinic records were reviewed from January 1, 2000, until October 1, 2001. Thirty pediatric patients with cerebral palsy were identified who were treated empirically with modafinil during this time period. Twenty-three (76%) patients reported diminished spasticity with treatment, which was confirmed by physical examination; these patients had improved joint mobility. Seventeen (56%) patients continued treatment with modafinil by the end of the formal review period (September 30, 2001). Twenty-three percent (seven) of the patients stopped taking modafinil during the study owing to one of the following: decreased sleep time (four), decreased appetite (one), hyperactivity, and irritability (two). Thus, this retrospective review shows a reduction in spasticity from cerebral palsy, with only minor and reversible side effects noted from modafinil. A blinded, crossover study using modafinil for spastic cerebral palsy is planned.

Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS: report of the Guideline Development Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based recommendations for screening, diagnosing, and treating psychiatric disorders in individuals with multiple sclerosis (MS). METHODS: We reviewed the literature (1950 to August 2011) and evaluated the available evidence. RESULTS AND RECOMMENDATIONS: Clinicians may consider using the Center for Neurologic Study Emotional Lability Scale to screen for pseudobulbar affect (Level C). Clinicians may consider the Beck Depression Inventory and a 2-question tool to screen for depressive disorders and the General Health Questionnaire to screen for broadly defined emotional disturbances (Level C). Evidence is insufficient to support/refute the use of other screening tools, the possibility that somatic/neurovegetative symptoms affect these tools' accuracy, or the use of diagnostic instruments or clinical evaluation procedures for identifying psychiatric disorders in MS (Level U). Clinicians may consider a telephone-administered cognitive behavioral therapy program for treating depressive symptoms (Level C). Although pharmacologic and nonpharmacologic therapies are widely used to treat depressive and anxiety disorders in individuals with MS, evidence is insufficient to support/refute the use of the antidepressants and individual and group therapies reviewed herein (Level U). For pseudobulbar affect, a combination of dextromethorphan and quinidine may be considered (Level C). Evidence is insufficient to determine the psychiatric effects in individuals with MS of disease-modifying and symptomatic therapies and corticosteroids; risk factors for suicide; and treatment of psychotic disorders (Level U). Research is needed on the effectiveness in individuals with MS of pharmacologic and nonpharmacologic treatments frequently used in the non-MS population.

Prevalence of amyotrophic lateral sclerosis in Texas, 1998-2003.

A prevalence study of amyotrophic lateral sclerosis (ALS) was conducted in 3 areas in Texas to enable the state health department to better respond to community concerns regarding the occurrence of ALS and to contribute to national prevalence estimates. The overall ALS point prevalence was lower than previously published US estimates. This study provides ALS prevalence estimates for Texas, including Hispanic populations.

Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments.

Pseudobulbar affect (PBA) consists of uncontrollable outbursts of laughter or crying inappropriate to the patient's external circumstances and incongruent with the patient's internal emotional state. Recent data suggest disruption of cortico-pontine-cerebellar circuits, reducing the threshold for motor expression of emotion. Disruption of the microcircuitry of the cerebellum itself may likewise impair its ability to act as a gate-control for emotional expression. Current evidence also suggests that serotonergic and glutamatergic neurotransmission play key roles. Although antidepressants have shown benefit, the supportive clinical data have often derived from small numbers of patients and unvalidated measures of PBA severity. Dextromethorphan/quinidine, the first FDA-approved PBA medication, is a novel therapy with antiglutamatergic actions. As life expectancy lengthens and the neurologic settings of PBA become more common, the need for treatment can be expected to increase.

Involvement of the thromboxane A2 receptor in the regulation of steroidogenic acute regulatory gene expression in murine Leydig cells.

Recent studies suggested an involvement of thromboxane A2 in cyclooxygenase-2-dependent inhibition of steroidogenic acute regulatory (StAR) gene expression. The present study further investigated the role of thromboxane A2 receptor in StAR gene expression and steroidogenesis in testicular Leydig cells. The thromboxane A2 receptor was detected in several Leydig cell lines. Blocking thromboxane A2 binding to the receptor using specific antagonist SQ29548 or BM567 resulted in dose-dependent increases in StAR protein and steroid production in MA-10 mouse Leydig cells. The results were confirmed with Leydig cells isolated from rats. StAR promoter activity and StAR mRNA level in the cells were also increased after the treatments, suggesting an involvement of the thromboxane A2 receptor in StAR gene transcription. Furthermore study indicated that blocking the thromboxane A2 receptor reduced dosage sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 protein, a transcriptional repressor of StAR gene expression. Specific binding of the antagonists to the receptors on cellular membrane was demonstrated by binding assays using (3)H-SQ29548 and binding competition between (3)H-SQ29548 and BM567. Whereas SQ29548 enhanced cAMP-induced StAR gene expression, in the absence of cAMP, it was unable to increase StAR protein and steroidogenesis. However, when the receptor was blocked by the antagonist, subthreshold levels of cAMP were able to induce maximal levels of StAR protein expression, suggesting that blocking the thromboxane A2 receptor increase sensitivity of MA-10 cells to cAMP stimulation. Taken together, the results from the present and previous studies suggest an autocrine loop, involving cyclooxygenase-2, thromboxane A synthase, and thromboxane A2 and its receptor, in cyclooxygenase-2-dependent inhibition of StAR gene expression.

Updated prevalence estimates of multiple sclerosis in Texas, 1998 to 2003.

The Texas Department of State Health Services extended a prevalence study of multiple sclerosis (MS) in a 19-county area in North Texas to include 3 additional years of data and included a new geographic area with a predominantly Hispanic population (El Paso County). Patients in whom MS was diagnosed by a neurologist, who resided in the study areas, and who had an office visit between 1998 and 2003 were included in the study. The 6-year MS prevalence estimate for the North Texas counties was 71.5 per 100,000, and for El Paso County it was 49.4 per 100,000. In both areas, prevalence estimates were higher for females, age groups 40 to 49 and 50 to 59, and for non-Hispanic whites. These estimates provide valuable information about the epidemiology of MS in Texas and allow for a comparison with national estimates. The results also provide much needed prevalence data for the Hispanic population.

What makes a good clinical teacher in medicine? A review of the literature.

PURPOSE: The authors perform a review of the literature pertinent to the question, "What makes a good clinical teacher in medicine?" METHOD: After framing the question, based on discussions of their own experiences with clinical teachers, the authors performed a search of the literature pertinent to the question, "What are the qualities of a good clinical teacher in medicine?" Between July and December, 2006, they reviewed titles from Index Medicus (1909-1966), PubMed (1966 to the present), PubMed Related Articles, and referenced articles. The initial selections were chosen by scanning pre-1966 Index Medicus title lists and post-1966 abstracts. Chosen articles were then read in their entirety, and those which described specific characteristics of clinical teachers were selected for inclusion. Qualitative analysis was used to identify themes. RESULTS: From 4,914 titles, 68 articles were selected for analysis-26 published before 1966, and 42 published after 1966. Four hundred eighty descriptors were identified and grouped into 49 themes, which were clustered into three main categories: physician, teacher, and human characteristics. Echoing the authors' intuitive descriptions, noncognitive characteristics dominated the descriptions and themes. CONCLUSIONS: Excellent clinical teaching, although multifactorial, transcends ordinary teaching and is characterized by inspiring, supporting, actively involving, and communicating with students. Faculty development programs and future research should focus on development of the noncognitive attributes of clinical teachers, as well as the knowledge and skills associated with effective teaching.