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Objective: This study aimed to evaluate the feasibility and measure the impact of an in situ interdisciplinary pediatric trauma quality improvement simulation program., Methods: Twenty-two monthly simulations were conducted in a tertiary care pediatric emergency department with the aim of improving the quality of pediatric trauma (February 2010 to November 2012). Each session included 20 minutes of simulated patient care, followed by 30 minutes of debriefing that focused on teamwork, communication, and the identification of gaps in care. A single rater scored the performance of the team in real time using a validated assessment instrument for 6 subcomponents of care (teamwork, airway, intubation, breathing, circulation, and disability). Participants completed a survey and written feedback forms., Results: A trend analysis of the 22 simulations found statistically significant positive trends for overall performance, teamwork, and intubation subcomponents; the strength of the upward trend was the strongest for the teamwork (τ = 0.512), followed by overall performance (τ = 0.488) and intubation (τ = 0.433). Two hundred fifty-one of 398 participants completed the participant feedback form (response rate, 63%), reporting that debriefing was the most valuable aspect of the simulation., Conclusions: An in situ interdisciplinary pediatric trauma simulation quality improvement program resulted in improved validated trauma simulation assessment scores for overall performance, teamwork, and intubation. Participants reported high levels of satisfaction with the program, and debriefing was reported as the most valuable component of the program.

Genetic testing is considered the only reliable diagnostic approach in myotonic dystrophy. However it has recently been reported that a considerable number of patients with genetically proven types of the disease have unusual phenotypic presentation. The aim of our study was to evaluate motor unit reorganization reflected by various electrophysiological abnormalities in myotonic dystrophies and to compare findings between type 1 (DM 1) and type 2 myotonic dystrophy (DM2). Quantitative electromyography (EMG) recordings in 63 patients (33 with DM1 and 30 with DM2) from the biceps brachii (BB), rectus femoris (RF), first dorsal interosseus (FDI), and tibialis anterior (TA) muscles were analyzed. Mean amplitude and size index (SI) of motor unit potentials recorded in TA and RF muscles, mean potential duration in TA, and mean SI and the number of outliers with amplitude above the normal range in BB were significantly increased in DM2 as compared to DM1. Myotonic discharges were recorded more frequently in DM1 than in DM2. EMG findings significantly differ between DM1 and DM2. The presence of high amplitude potentials in lower limb muscles in DM2 patients, atypical for myogenic muscle lesions, could be explained by muscle fiber hypertrophy observed in muscle biopsies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Awaji criteria, recently introduced to increase diagnosis sensitivity in amyotrophic lateral sclerosis (ALS), equate the diagnostic significance of neurogenic electrophysiological changes to clinical signs of lower motor neuron dysfunction. They also increase the electrophysiological significance of fasciculation potentials (FPs). The aim of our study was to analyse whether the new parameters improve diagnostic sensitivity in ALS patients primarily diagnosed with the El Escorial criteria. Medical and electrophysiological records of 135 consecutive patients with ALS and 25 patients with progressive muscular atrophy (PMA) who underwent electrophysiological examination of at least three anatomical regions were analysed retrospectively. Results showed that implementation of the Awaji criteria increased the level of ALS diagnosis sensitivity in 5.9% of cases - 1.5% due to the new role of FPs potentials and 4.4% because of equalization of clinical and EMG findings. In 4% of patients the ALS diagnosis was, however, changed from laboratory-supported probable ALS to possible ALS. In conclusion, our study confirms that Awaji modifications are able to improve the diagnostic certainty in a few ALS cases. Although the new approach to FPs markedly increases the number of involved muscles, it only slightly raises the number of involved regions.

Purpose: Motor unit number estimation (MUNE) is a tool for estimating the number of motor units. The aim was to evaluate the multipoint incremental MUNE method in a healthy population, to analyze whether aging, gender, and the dominant hand side influence the motor unit number, and to assess reproducibility of MUNE with the Shefner modification., Materials and Methods: We studied 60 volunteers (mean age, 47 ± 17.7 years) in four groups aged 18 to 30, 31 to 45, 46 to 60, and above 60 years. Motor unit number estimation was calculated in the abductor pollicis brevis (APB) and the abductor digiti minimi (ADM) by dividing the single motor unit action potential amplitude into the maximal compound motor action potential amplitude., Results: Test-retest variability was 7%. The mean value of MUNE for APB was 133.2 ± 43 and for ADM was 157.1 ± 39.4. Significant differences in MUNE results were found between groups aged 18 to 30 and 60 years or older and between groups aged 31 to 45 and 60 years or older. Motor unit number estimation results correlated negatively with the age of subjects for both APB and ADM. Single motor unit action potential, reflecting the size of motor unit, increased with the age of subjects only in APB. Compound motor action potential amplitude correlated negatively with the age of subjects in APB and ADM. Significant correlations were seen between MUNE in APB or ADM and compound motor action potential amplitude in these muscles and the age of female subjects. A similar relationship was not found in males., Conclusions: Multipoint incremental MUNE method with the Shefner modification is a noninvasive, easy to perform method with high reproducibility. The loss of motor neurons because of aging could be confirmed by our MUNE study and seems to be more pronounced in females.

Carpal tunnel syndrome rarely occurs in children. We retrospectively analyzed clinical data of 11 patients aged 5-17 diagnosed with carpal tunnel syndrome at a single pediatric neuromuscular center. Nerve conduction studies were performed according to the American Association of Electrodiagnostic Medicine recommendations. Additional imaging tests of the wrist were performed in 10 patients. In our group of 11 children, carpal tunnel syndrome was idiopathic in only 1 case. In the remaining subjects, it was secondary to congenital bone anomaly (6), hypothyroidism (2), or myopathic contractures (1). In 1 case, metabolic workup revealed an underlying mucopolysaccharidosis. Our results confirm that idiopathic carpal tunnel syndrome is rare in children. Hand clumsiness and thenar hypoplasia rather than sensory complaints are the presenting symptoms. Whenever carpal tunnel syndrome is diagnosed in a child, a thorough differential diagnosis should be made because of the secondary nature of this disease in most pediatric patients.

Introduction: Standard electromyography (EMG) is useful in the diagnosis of myotonic dystrophy type 1 (DM1) and type 2 (DM2), but it does not differentiate between them. The aim of this study was to estimate the utility of the short exercise test (SET) and short exercise test with cooling (SETC) in differentiating between DM1 and DM2., Methods: SET and SETC were performed in 32 patients with DM1 (mean age 35.8 ± 12.7 years) and 28 patients with DM2 (mean age 44.5 ± 12.5 years)., Results: We observed a significant decline in compound motor action potential (CMAP) amplitude in DM1 with both SET and SETC immediately after effort. In DM2, there was no marked change in CMAP amplitude with either SET or SETC., Conclusions: SET and SETC may serve as useful tools for clinical differentiation between DM1 and DM2, and they may be used as a guide for molecular testing., (Copyright © 2013 Wiley Periodicals, Inc.)

Dicentric chromosomes undergo breakage in mitosis, resulting in chromosome deletions, duplications, and translocations. In this study, we map chromosome break sites of dicentrics in Saccharomyces cerevisiae by a mitotic recombination assay. The assay uses a diploid strain in which one homolog has a conditional centromere in addition to a wild-type centromere, and the other homolog has only the wild-type centromere; the conditional centromere is inactive when cells are grown in galactose and is activated when the cells are switched to glucose. In addition, the two homologs are distinguishable by multiple single-nucleotide polymorphisms (SNPs). Under conditions in which the conditional centromere is activated, the functionally dicentric chromosome undergoes double-stranded DNA breaks (DSBs) that can be repaired by mitotic recombination with the homolog. Such recombination events often lead to loss of heterozygosity (LOH) of SNPs that are centromere distal to the crossover. Using a PCR-based assay, we determined the position of LOH in multiple independent recombination events to a resolution of ∼4 kb. This analysis shows that dicentric chromosomes have recombination breakpoints that are broadly distributed between the two centromeres, although there is a clustering of breakpoints within 10 kb of the conditional centromere.

Background: Abnormalities of the spinal cord were considered uncommon in progressive supranuclear palsy (PSP), and therefore spinal symptoms were not included among PSP characteristic features. However there have been some neuropathological reports of spinal cord lesions in patients with PSP. The aim of our study was to find out if the possible lower motor neuron involvement in PSP is reflected by electromyographic (EMG) and/or electroneurographic (ENG) abnormalities., Material: 24 patients with clinically probable PSP (mean age 67.5 yrs; 66% males) were included in the study. The control group for ENG studies consisted 25 age matched healthy volunteers., Methods: Nerve conduction studies in the ulnar, peroneal and sural nerves and EMG of the first interosseus dorsal and tibial anterior muscles were performed., Results: The only ENG abnormality observed was decreased compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes in the ulnar nerve. Such decrease was registered in 8.3% and 20% of PSP patients respectively. There was no significant difference between the values of ENG parameters between PSP patients and the control group. In EMG abnormalities suggesting chronic reinnervation were recorded in the first interosseous dorsal (FID) muscle in 45.8%, and in the tibialis anterior (TA) muscle in 37.5% of PSP patients. A significant correlation was found between the age of PSP patients and their mean motor unit potential (MUP) amplitude in TA muscle (p=0.04) and also between the age of onset and MUP amplitude in both, the TA and FID muscles (p=0.026 and p=0.03 respectively)., Conclusions: In PSP, neurogenic EMG abnormalities in skeletal muscles are present in nearly half the patients suggesting a loss of motor neurons in the anterior horns of the spinal cord which is in line with our histopathological findings. In contrast, electrophysiological signs of neuropathy in peripheral nerves in PSP are very rare. Concluding, although PSP is characterized by the pathological process in specific basal ganglia and brainstem areas, our electromyographic study suggests the need for broadening the spectrum of PSP for lower motor neurons degeneration., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Expansion of certain trinucleotide repeats causes several types of human diseases, and such tracts are associated with the formation of deletions and other types of genetic rearrangements in Escherichia coli, yeast, and mammalian cells. Below, we show that long (230 repeats) tracts of the trinucleotide associated with Friedreich's ataxia (GAA·TTC) stimulate both large (>50 bp) deletions and point mutations in a reporter gene located more than 1 kb from the repetitive tract. Sequence analysis of deletion breakpoints indicates that the deletions reflect non-homologous end joining of double-stranded DNA breaks (DSBs) initiated in the tract. The tract-induced point mutations appear to reflect a different mechanism involving single-strand annealing of DNA molecules generated by DSBs within the tract, followed by filling-in of single-stranded gaps by the error-prone DNA polymerase zeta., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aims were to assess dysautonomia in Alzheimer's Disease (AD), clinically and electrophysiologically, using sympathetic skin response (SSR) test and R-R interval variation (RRIV) test and to analyze the relationship between symptoms of dysautonomia and SSR/RRIV results. A tota of 54 patients with AD and 37 controls were evaluated using Autonomic Symptoms Questionnaire and SSR/RRIV test. Clinical dysautonomia was observed in 66% of patients (eg, orthostatic hypotension in 34.5%, constipation in 17.2%, urinary incontinence in 13.8%). The SSR test was abnormal in 26%, but the RRIV test was abnormal in 97.7% of cases; there was significant difference in RRIV test results between AD and controls (R mean 8.05% and 14.6%, respectively). In AD, clinical dysautonomia occurs at a various degree, and the abnormal SSR and RRIV test results were not always related to the presence of clinical dysautonomia; this observation points that the tests could be used as a useful tool in the assessment of subclinical dysautonomia.

Unlabelled: Lower motor neuron lesions are not among the characteristic features of multiple system atrophy (MSA), although electromyography (EMG) and autopsy studies revealed peripheral neuron abnormalities in some cases of MSA. The aim of the study was to evaluate subclinical involvement of the peripheral neuron in MSA using EMG and electroneurography (ENG)., Material: 48 patients with clinically probable MSA (mean age 60.6 years; 67% males) were included in the study and divided into subgroups, with predominant cerebellar (MSA-C) and parkinsonian signs (MSA-P)., Methods: ENG in ulnar, peroneal and sural nerves and EMG of the first interosseus dorsal and tibial anterior muscles were performed., Results: Abnormal ENG in one nerve was recorded in 20.8% of patients, and in two nerves in another 20.8% of patients. The most frequent and significant findings were decreased compound motor action potential amplitudes in the ulnar nerve in the overall MSA group as well as in the MSA-P type as compared to controls. Abnormalities suggesting reinnervation was observed in 43 of 96 examined muscles (44.7%). In individual cases, neurogenic features were recorded in one muscle in 31.2% of patients and in two muscles in 29.1% of patients., Conclusions: Subclinical axonopathy in MSA is not frequent and is more pronounced in MSA with predominant parkinsonian signs. In MSA, neurogenic EMG abnormalities in muscles are more frequent than peripheral nerve lesions and as evidenced by increased motor unit potential amplitudes, could be considered a sign of anterior horn cell involvement and a hallmark of the "continuum" of neurodegeneration in MSA., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: We compared motor unit potentials (MUPs) with satellite components recorded in two anterior horn disorders: amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA, types II and III)., Methods: We analyzed MUPs recorded from biceps brachii muscle, including 209 associated with ALS (12 patients) and 127 with SMA (5 patients). Simulations were applied to determine the origin of satellites in these processes., Results: MUP parameters differ in ALS and SMA. Simulations indicate that the satellite potential in ALS often originated from a single fiber, whereas in SMA it originated from a group of fibers of smaller diameters than the surrounding ones., Conclusions: These results suggest that, except for neurogenic factors, the variability of muscle fiber diameters also leads to the formation of MUPs with satellites. This variability seems to be responsible for the differences in the shape of the main and satellite MUP components in ALS and SMA., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Patients with chronic migraine and medication overuse are significant consumers of health care resources., Objective: To determine whether botulinum toxin type A prophylaxis reduces the cost of acute migraine medications in patients with chronic migraine and triptan overuse., Methods: In this multicenter, open-label study, patients with chronic migraine (≥ 15 headache days/month) who were triptan overusers (triptan intake ≥ 10 days/month for ≥ 3 months) received botulinum toxin type A (95-130 U) at baseline and month three. Headache (HA) frequency and medication use were assessed with patient diaries, and headache-related disability by means of the MIDAS and Headache Impact Test-6 questionnaires., Results: Of 53 patients enrolled (mean age ± standard deviation, 46.5 years ± 8.4; 47 [88.7%] females), 48 (90.6%) completed the study at month six. Based on headache diaries, significant (P ≤ 0.0002) decreases from baseline were observed for days per month with headache/migraine, days with any acute headache medication use, days with triptan use, and triptan doses taken per month. A significant (P < 0.0001) increase from baseline in headache-free days per month was also observed. Prescription medication costs for acute headache medications decreased significantly, including significant reductions in triptan costs (mean reduction of -C$106.32 ± 122.87/month during botulinum toxin type A prophylaxis; P < 0.0001). At baseline, 78% of patients had severe disability (MIDAS score) and 86.8% had severe impact due to headache (HIT-6 scores); at month six, this decreased to 60% and 68%, respectively., Conclusions: Botulinum toxin type A prophylactic therapy markedly decreased costs related to acute headache medication use in patients with chronic migraine and triptan overuse.

Homologous recombination is an important mechanism for the repair of DNA damage in mitotically dividing cells. Mitotic crossovers between homologues with heterozygous alleles can produce two homozygous daughter cells (loss of heterozygosity), whereas crossovers between repeated genes on non-homologous chromosomes can result in translocations. Using a genetic system that allows selection of daughter cells that contain the reciprocal products of mitotic crossing over, we mapped crossovers and gene conversion events at a resolution of about 4 kb in a 120-kb region of chromosome V of Saccharomyces cerevisiae. The gene conversion tracts associated with mitotic crossovers are much longer (averaging about 12 kb) than the conversion tracts associated with meiotic recombination and are non-randomly distributed along the chromosome. In addition, about 40% of the conversion events have patterns of marker segregation that are most simply explained as reflecting the repair of a chromosome that was broken in G1 of the cell cycle., Competing Interests: The authors have declared that no competing interests exist.

Ionizing radiation is an established source of chromosome aberrations (CAs). Although double-strand breaks (DSBs) are implicated in radiation-induced and other CAs, the underlying mechanisms are poorly understood. Here, we show that, although the vast majority of randomly induced DSBs in G(2) diploid yeast cells are repaired efficiently through homologous recombination (HR) between sister chromatids or homologous chromosomes, approximately 2% of all DSBs give rise to CAs. Complete molecular analysis of the genome revealed that nearly all of the CAs resulted from HR between nonallelic repetitive elements, primarily Ty retrotransposons. Nonhomologous end-joining (NHEJ) accounted for few, if any, of the CAs. We conclude that only those DSBs that fall at the 3-5% of the genome composed of repetitive DNA elements are efficient at generating rearrangements with dispersed small repeats across the genome, whereas DSBs in unique sequences are confined to recombinational repair between the large regions of homology contained in sister chromatids or homologous chromosomes. Because repeat-associated DSBs can efficiently lead to CAs and reshape the genome, they could be a rich source of evolutionary change.

Statin medications for elevated cholesterol are one of the most commonly prescribed medications worldwide. The aim of this study was to determine if statin medications affect the rate of disease progression, the severity and frequency of muscle cramping, and serum CK levels in patients with ALS. We conducted a prospective cohort study in patients diagnosed with ALS with statin medication as the predetermined exposure variable and the rate of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome. One hundred and sixty-four consecutive patients with laboratory supported probable, clinically probable, or clinically definite ALS were evaluated from January 2006 to September 2007. Thirty-two patients (20%) were taking statin medications and 132 were in the control group. After adjusting for covariates, we found a highly significant increase in the rate of decline in the ALSFRS-R for the statin group (1.71 units/month) compared to the control group (1.05 units/month, pB0.0001) representing a 63% increase in the rate of functional decline. Patients on statin therapy also reported a significant increase in muscle cramp frequency and severity (pB0.0001). This study has demonstrated a strong association between statin medications and an increased rate of functional decline and muscle cramping in patients with ALS. Although this association does not prove a causal relationship, it is prudent to exercise caution and discuss discontinuation or replacement of statin medications in patients with ALS.

The ribosomal DNA (rDNA) genes of Saccharomyces cerevisiae are located in a tandem array of about 150 repeats. Using a diploid with markers flanking and within the rDNA array, we showed that low levels of DNA polymerase alpha elevate recombination between both homologues and sister chromatids, about five-fold in mitotic cells and 30-fold in meiotic cells. This stimulation is independent of Fob1p, a protein required for the programmed replication fork block (RFB) in the rDNA. We observed that the fob1 mutation alone significantly increased meiotic, but not mitotic, rDNA recombination, suggesting a meiosis-specific role for this protein. We found that meiotic cells with low polymerase alpha had decreased Sir2p binding and increased Spo11p-catalyzed double-strand DNA breaks in the rDNA. Furthermore, meiotic crossover interference in the rDNA is absent. These results suggest that the hyper-Rec phenotypes resulting from low levels of DNA polymerase alpha in mitosis and meiosis reflect two fundamentally different mechanisms: the increased mitotic recombination is likely due to increased double-strand DNA breaks (DSBs) resulting from Fob1p-independent stalled replication forks, whereas the hyper-Rec meiotic phenotype results from increased levels of Spo11-catalyzed DSBs in the rDNA., Competing Interests: The authors have declared that no competing interests exist.

The goal of the Canadian Migraine Forum was to work towards improving the lives of Canadians with migraine by reducing their migraine-related disability. This paper focuses on migraine treatment in its many aspects, including symptomatic therapy of individual migraine headache attacks, prophylactic drug therapy, non-pharmacological interventions, and diagnosis and management of symptomatic medication overuse. Many patients with difficult migraine experience significant frustration in trying to obtain the help they need from our current medical system. Although many symptomatic medications are available for use in migraine, migraine specific medications are still underutilized. An ideal migraine preventative medication does not yet exist, but currently available preventatives do have utility, and are also thought to be underutilized. Behavioral approaches to migraine management as an adjunct to medication therapy show promise, but the availability of programs to bring these to patients is limited, and more research is needed on their efficacy. Symptomatic medication overuse in migraine sufferers remains a large problem in Canada, and better defined treatment paradigms and programs are needed both to prevent and to treat this problem. Such programs should include strong elements of public, patient, and health professional education. A potential solution to some of these problems may be to develop treatment approaches to migraine similar to those that are being developed for other chronic medical disorders. For patients with severe migraine, these would optimally include multidisciplinary teams so that the multiple facets of migraine management can be adequately addressed.

Background: The buildup time of migraine headaches has not been well delineated in publications to date and we are aware of patients whose migraines last well over 72 hours. More concentration on these factors in the assessment of patients might lead to more appropriate therapeutic choices., Method: Prospective ascertainment of such data through a questionnaire completed by 253 informed and willing patients with IHS migraine with or without aura consulting Canadian headache specialists. Data were electronically sent to a central computer from each center, tabulated and analyzed using standard statistical parameters., Results: In 253 patients with migraine ascertained using applied IHS criteria, nausea was a feature in over 90% of cases, especially in those with aura. This inhibited the ingestion of oral medications in about a quarter of all subjects. The time to build from no pain to moderate/severe pain was shorter in subjects with auras and was less than 2 hours in 97% of those with and 86% of those without auras. However, we also identified a group of subjects with migraine (over 10% of all) in whom the build time to maximum pain is delayed for over 2 hours. Nausea was experienced by 91.7% of subjects, slightly but significantly later in those without auras. While most headaches in each group lasted from 4 to 72 hours, 24.3% of those with and 20.6% of those without aura expected to experience pain for more than 72 hours, while in untreated cases disability due to pain, nausea, or malaise usually persisted for over 3 days in 24.3% and 16.7% of those with and without aura, respectively. One-fifth of migraineurs may be in pain and/or disabled by accompanying symptoms for over 3 days in a typical migraine attack. Over half of our subjects reported that their medications worked well or excellently., Conclusions: Attacks of migraine in real-life clinical situations vary somewhat from the IHS criteria in that they are more often associated with nausea that interferes with oral therapy; can persist for over 72 hours; may have slow (>2 hours) buildup to maximum pain in 10% of cases; and may cause disability for over 3 days. Nevertheless, current therapeutic regimens (including prescribed medications) work well for a substantial majority.

Intranasal zolmitriptan has recently been launched in the US and Canada and is a novel formulation of the antimigraine drug zolmitriptan. This drug has been used extensively in its oral formulation. The intranasal formulation offers a more rapid onset of action. Pharmacokinetic studies have demonstrated that it is absorbed rapidly into the systemic circulation and traces can be seen in the brain within 5 min. The onset of efficacy in the Real Life Intranasal Zolmitriptan Exposure (REALIZE) study was measurable at 10 min and at 15 min in the US 22 study, which demonstrates rapid absorption and effect at the 5-HT(1B/1D) receptors. This article reviews the initial studies of intranasal zolmitriptan; three of the most recent studies will be examined in detail.

Background: Previous studies have shown that zolmitriptan 5 mg nasal spray has a fast onset of action, high efficacy, and good tolerability in the acute treatment of migraine. Objective.-This open-label, noncomparative, multicenter, multinational phase III study was designed to further evaluate the long-term safety and tolerability of zolmitriptan 5 mg nasal spray in a population of migraineurs largely naive to triptan nasal sprays who treated multiple migraine attacks over a 1-year period., Methods: Patients were required to have an established diagnosis of migraine with or without aura (based on International Headache Society criteria), a high frequency of migraine attacks, and were allowed to treat migraine with any baseline headache intensity. A secondary objective of the study was to assess the long-term efficacy of zolmitriptan nasal spray. A subgroup analysis aimed to determine whether rhinitis had any influence on outcomes of treatment., Results: The safety population consisted of 538 patients who treated 20,717 migraine attacks with zolmitriptan 5 mg nasal spray. Overall, adverse events occurred in 32.8% of attacks, and led to treatment withdrawal in 4.5% of patients. The most common adverse events were unusual taste (19.0%) and paresthesia (6.8%). Adverse events were generally of mild intensity, transient, and well tolerated, showing a decline in incidence over time. Serious adverse events were rare. The presence of rhinitis and use of a second dose of trial medication had no effect on the incidence of adverse events. At 2 hours, 53.8% of attacks treated with zolmitriptan nasal spray 5 mg were rendered pain free. The highest 2-hour pain free rates were seen for headaches of mild baseline intensity (83.3%), followed by headaches of moderate (56.5%), and severe (32.2%) baseline intensity. The 2-hour pain-free rate remained consistent throughout the study period. The presence of rhinitis had no effect on efficacy., Conclusions: Zolmitriptan 5 mg nasal spray demonstrated a well-tolerated and efficacious profile in the acute treatment of multiple migraine attacks over a 1-year period.

Background: Migraine is a common, chronic, neurovascular disorder, generally characterised by attacks of severe headache and autonomic nervous system dysfunction. Triptans are selective serotonin 5-HT(1B/1D) receptor agonists that represent effective therapeutic options for moderate-to-severe migraine attacks but with higher acquisition costs relative to usual care therapies., Objective: The objective of this study was to examine the cost effectiveness of rizatriptan treatment compared with 'Usual Care' or other triptans available in Canada for patients with moderate-to-severe migraine for whom other therapies (e.g. NSAIDs, simple analgesics) are insufficient or contraindicated., Methods: A decision-analysis model was created to estimate migraine treatment costs over a 24-hour period in patients with a diagnosis of moderate-to-severe migraine as defined by the International Headache Society criteria. Costs and clinical outcomes were observed over a 24-hour period from therapy initiation. Efficacy measures consisted of 'pain-free response at 2 hours' and 'sustained pain free for 2-24 hours'. Oral rizatriptan 10 mg was compared with other oral triptans (i.e. sumatriptan 50 or 100 mg), naratriptan 2.5 mg and zolmitriptan 2.5 mg, based on a meta-analysis and compared with 'Usual Care' based on a naturalistic study of people who experience migraine and who were similar to the target population. 'Usual Care' was defined as an aggregate of medications prescribed for the Canadian population for the indication of migraine, weighted by the relative frequency of use of prescriptions over a 1-year period. Analyses were conducted from the Ontario (Canada) Ministry of Health and Long-Term Care (MOH

Migraine is a common, frequently incapacitating, headache disorder that imposes a substantial burden on both the individual patient and society. The last two decades have witnessed an explosion in our understanding of the pathophysiology of migraine, and in our development of an efficacious and diverse therapeutic armamentarium. There are several routes of drug administration available to patients with migraine. All the serotonin 5-HT(1B/1D) receptor agonists (triptans) are available as oral tablets (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan and eletriptan). Only sumatriptan is available as a subcutaneous injection. Some triptans are also available via newer routes of administration, including orally disintegrating tablets (rizatriptan and zolmitriptan), rectal suppositories (sumatriptan) and intranasal sprays (sumatriptan and zolmitriptan). Oral disintegrating tablets and other non-oral triptan routes (subcutaneous, intranasal, rectal) are a useful alternative to conventional oral tablets for patients who have difficulty swallowing pills or prefer not to do so, and for patients whose nausea and/or vomiting precludes swallowing tablets and/or makes the likelihood of complete absorption unpredictable. This is important because epidemiological studies in migraine reveal that the vast majority of patients (>90%) have experienced nausea during a migraine attack and more than 50% have nausea with the majority of attacks. Similarly, most (almost 70%) have vomited at some time during an attack and of these patients, almost one-third vomit in the majority of attacks. The newer formulations, rapidly dissolving tablets and intranasal sprays, afford patients the opportunity to use abortive therapy without the need for liquids, at anytime and anywhere, at the onset of a migraine attack. Furthermore, the intranasal sprays are absorbed rapidly and have a prompt onset of action allowing for significant pain free rates versus placebo as early as 15 minutes post administration. The ability to administer treatment early in a migraine attack and have a rapid onset of action is particularly important in acute migraine treatment in order to prevent the development of central sensitisation. While many patients and physicians choose conventional oral tablets because of familiarity and ease of administration, the newer formulations, oral disintegrating tablets and intranasal sprays, should be given consideration as first-line agents in selected patients.

Background: Despite the availability of objective criteria, the diagnosis of migraine is thought to be missed frequently in primary practice., Objective: To determine the most important questions assisting in the clinical diagnosis of migraine headache., Methods: A cohort of 461 patients referred to headache specialists in Canada was assessed using a pro-forma questionnaire that was completed by the patients alone or administered by the physicians themselves. A final clinical diagnosis was recorded after a complete clinical evaluation. In a subsequent validation study, three questions derived from the results of the first phase of the study were administered to a new cohort of 128 patients, and diagnoses of "migraine" or "not migraine" were recorded according to the decision generated in the first part of the study. The final clinical diagnosis was taken as the "gold standard" for diagnosis, and the results from the two independently derived diagnostic methods were compared., Results: Statistical analysis of the responses from part 1 of the study yielded three questions (related to daily occurrence, unilaterally, and functional impairment) that distinguished between pure migraine and other headache diagnoses with high reliability and validity. The sensitivity and selectivity of the three-question protocol exceeded 91%., Conclusions: The use of three questions related to headache frequency, laterality, and impact on functioning may represent an attractive screening instrument in primary care practice, alerting physicians to the diagnosis of migraine in patients or to the possibility of a second or alternative headache diagnosis in patients in whom their diagnosis of migraine previously has been made. The presence of multiple headache syndromes in individual patients, as is common in tertiary referral practice, may reduce the discriminating power of the three-question protocol.

The triptans have provided a major advance in the treatment of the pain and disability associated with migraine headache. With seven triptans in use or in clinical development, the clinician is faced with the decision of which triptan to prescribe to the patient with migraine. Although the triptans are pharmacologically similar, they each have unique attributes. This article focuses on the pharmacologic differences between triptans with regard to their pharmacokinetics and drug interactions, and provides some helpful tips on how to optimize migraine treatment with the triptans.

The aim of our study was to analyze EEG changes in patients with Alzheimer disease (AD) and to determine how closely EEG reflects the progression of mental impairment in people with AD. Ninety-five patients with probable AD according to National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria treated in our Clinic for Memory Disorders were selected for this study. Patients were divided into three subgroups with mild, marked, and severe dementia according to the results of psychometric scales. The EEG findings were classified using an eight-degree scale according to the background activity, presence and amount of theta and delta waves, focal changes, lateralization of focal changes, synchronization, and presence of sharp and spike waves. A significant correlation between the degree of EEG abnormalities and cognitive impairment was found. We did not observe any correlation between the presence of delta waves and the results of neuropsychological tests. Our study revealed an important diagnostic value of EEG in the estimation of the severity of dementia parallel to psychometric scales.

Eletriptan (Relpax, Pfizer) is one of a group of anti-migraine medications commonly referred to as 'triptans'. It is a potent serotonin agonist at the 5-HT(1B/1D) receptor and is indicated for the acute treatment of migraine headaches. Eletriptan is administered orally. It is rapidly absorbed and has a bioavailability of 50% compared to 14% for sumatriptan. The relatively high lipophilicity of eletriptan compared to sumatriptan may explain its faster oral absorption and shorter time to onset of action. Results from comparative studies between oral eletriptan and sumatriptan indicate that eletriptan 80 mg was superior to sumatriptan 100 mg in onset of action, headache response rate, pain free response rate and relief of associated migraine symptoms at the 1 or 2 h time intervals. Although there was a modest increase in adverse events with eletriptan 80 mg than with sumatriptan 100 mg, eletriptan received a high patient acceptability rating (84%).

Objective: A systematic review of the literature was undertaken, to consolidate evidence concerning the efficacy and safety of triptans currently available in Canada (sumatriptan, rizatriptan, naratriptan, zolmitriptan), and to provide guidelines for selection of a triptan., Methods: Data from published, randomized, placebo-controlled trials were pooled and a combined number needed to treat (NNT) and number needed to harm (NNH) was generated for each triptan. Direct comparative trials of triptans were also examined., Results: The lowest NNT for headache response/pain-free at one/two hours is observed with subcutaneous sumatriptan. Among the oral formulations, the lowest NNT is observed with rizatriptan and the highest NNT with naratriptan. The lowest NNH is observed with subcutaneous sumatriptan., Conclusions: Triptans are relatively safe and effective medications for acute migraine attacks. However, differences among them are relatively small. Considerations in selecting a triptan include individual patient response/tolerance, characteristics of the attacks, relief of associated symptoms, consistency of response, headache recurrence, delivery systems and patient preference.

In the past 10 years, new compounds have been developed for the acute treatment of migraine. Studies of a group of compounds called the triptans are summarized. The triptans are derived from the serotonin molecule and act on the 5-hydroxytryptamine 1B/1D receptors. The receptors are on the blood vessels, trigeminal neurons and trigeminal nucleus caudalis. Activation of these receptors causes constriction of extracerebral intracranial vessels, abolition of the dural extravasation and neurogenic inflammation, and inhibition of trigeminal neuronal discharge. The drugs are sumatriptan, zolmitriptan, naratriptan, rizatriptan and eletriptan. Their pharmacology and clinical properties are reviewed and compared.

Objective: To provide physicians and allied health care professionals with guidelines for the nonpharmacologic management of migraine in clinical practice., Options: The full range and quality of nonpharmacologic therapies available for the management of migraine., Outcomes: Improvement in the nonpharmacologic management of migraine. EVIDENCE AND VALUES: The creation of the guidelines followed a needs assessment by members of the Canadian Headache Society and included a statement of objectives; development of guidelines by multidisciplinary working groups using information from literature reviews and other resources; comparison of alternative clinical pathways and description of how published data were analysed; definition of the level of evidence for data in each case; evaluation and revision of the guidelines at a consensus conference held in Ottawa on Oct. 27-29, 1995; redrafting and insertion of tables showing key variables and data from various studies and tables of data with recommendations; and reassessment by all conference participants., Benefits, Harms and Costs: Augmentation of the use of nonpharmacologic therapies for the acute and prophylactic management of migraine is likely to lead to substantial benefits in both human and economic terms., Recommendations: Both the avoidance of migraine trigger factors and the use of nonpharmacologic therapies have a part to play in overall migraine management., Validation: The guidelines are based on consensus of Canadian experts in neurology, emergency medicine, psychiatry, psychology and family medicine, and consumers. Previous guidelines did not exist. Field testing of the guidelines is in progress.

Butorphanol tartrate is a synthetic mixed agonist-antagonist opioid analgesic. Its transnasal dosage form, which may be self-administered when the use of an opioid analgesic is appropriate, was previously shown to provide rapid relief of migraine pain. In this double-blind, parallel-group, outpatient study, we compared butorphanol nasal spray 1 mg followed in 1 hour by an optional second 1-mg dose with the orally administered analgesic, Fiorinal with Codeine (one capsule containing butalbital 50 mg, caffeine 40 mg, aspirin 325 mg, and codeine phosphate 30 mg). Patients (N=321) were assigned by randomization to one of two treatment groups (butorphanol or Fiorinal with Codeine) and instructed to self-administer medication when migraine pain reached an intensity of moderate or severe and to record study-related events in a diary for 24 hours posttreatment. Efficacy analyses were performed on data from 275 patients who took study medication and returned a patient diary; 136 in the butorphanol group and 139 in the Fiorinal with Codeine group. During the first 2 hours after treatment, butorphanol was more effective than Fiorinal with Codeine in treating migraine pain as measured by pain intensity difference scores, percentage of responders (pain decreased to mild or none), percentage of pain-free patients, and degree of pain relief, with a more rapid time to onset of 15 minutes. A similar percentage of patients in the two groups used rescue medication during the first 4 hours, after which more butorphanol-treated than Fiorinal with Codeine-treated patients used rescue medication. Butorphanol patients had more side effects, less improvement in digestive symptoms, and less improvement in functional ability than Fiorinal with Codeine patients.

Problem Addressed: Headache is a common clinical disorder. Nearly 50% of patients with headaches use prescription medications, and 90% regularly use nonprescription drugs. Medication-induced headaches (MIH) are chronic daily headaches caused by overuse of medicine., Objectives: To summarize the diagnostic criteria for MIH, to determine the investigations necessary to confirm the diagnosis and exclude other possible diagnoses, and to establish recommendations for managing MIH., Main Findings: Diagnosis of MIH is based on patient's history and the clinical characteristics of the headache. Treatment includes patient education and support, withdrawal of offending medications, relief of withdrawal symptoms, and specific treatment of residual headache. When migraine and other causes of headache are adequately addressed, patients will not seek additional pain relief., Conclusion: Medication-induced headache is preventable. The key to prevention is appropriate drug therapy to relieve the primary headache. All patients with MIH can be treated and most cured.

Objective: To provide physicians and allied health care professionals with guidelines for the diagnosis and management of migraine in clinical practice., Options: The full range and quality of diagnostic and therapeutic methods available for the management of migraine., Outcomes: Improvement in the diagnosis and treatment of migraine, which will lead to a reduction in suffering, increased productivity and decreased economic burden. EVIDENCE AND VALUES: The creation of the guidelines followed a needs assessment by members of the Canadian Headache Society and included a statement of objectives; development of guidelines by multidisciplinary working groups using information from literature reviews and other resources; comparison of alternative clinical pathways and description of how published data were analysed; definition of the level of evidence for data in each case; evaluation and revision of the guidelines at a consensus conference held in Ottawa on Oct. 27-29, 1995; redrafting and insertion of tables showing key variables and data from various studies and tables of data with recommendations; and reassessment by all conference participants., Benefits, Harms and Costs: Accuracy in diagnosis is a major factor in improving therapeutic effectiveness. Improvement in the precise diagnosis of migraine, coupled with a rational plan for the treatment of acute attacks and for prophylactic therapy, is likely to lead to substantial benefits in both human and economic terms., Recommendations: The diagnosis of migraine can be improved by using modified criteria of the International Headache Society as well as a semistructured patient interview technique. Appropriate treatment of symptoms should take into account the severity of the migraine attack, since most patients will have attacks of differing severity and can learn to use medication appropriate for each attack. When headaches are frequent or particularly severe, prophylactic therapy should be considered. Both the avoidance of migraine trigger factors and the application of nonpharmacological therapies play important roles in overall migraine management and will be addressed at a later date., Validation: The guidelines are based on consensus of Canadian experts in neurology, emergency medicine, psychiatry, psychology, family medicine and pharmacology, and consumers. Previous guidelines did not exist. Field testing of the guidelines is in progress.

Background: Neurological injury is an important cause of morbidity and mortality after cardiac surgery. With the advent of warm heart surgery, the neuroprotective role of hypothermic cardiopulmonary bypass (CPB) has come under increasing scrutiny. Preliminary work by us in the area found no increased risk of neurological morbidity with normothermic CPB in a small group of patients and suggested a possible benefit. The purpose of the present study is to compare the incidence of neurological and neuropsychological dysfunction in a larger number of patients randomized to warm or cold aortocoronary bypass surgery., Methods and Results: With the approval of the institutional research ethics committee, 201 aortocoronary bypass patients were randomized to normothermic or moderate hypothermic CPB and subjected to neurological and neuropsychological evaluation. These subjects were a subset of patients enrolled in a large multicenter trial comparing warm versus cold heart surgery. The examinations took place preoperatively, 5 days after operation, and a 3-month follow-up. The examination consisted of a clinical neurological examination and a brief neuropsychological test battery. The neuropsychological tests included the Buschke selective reminding procedure, the Wechsler memory scale-revised visual reproduction subtest, the trial making test (parts A and B), the Wechsler adult intelligence scale-revised digit symbol subtest, and the grooved pegboard test. The examiner and subjects were unaware of the CPB temperature allocation (warm, > 34 degrees C; cold, < or = 28 degrees C). Statistical analysis was performed using the SAS statistical software package. Two hundred one patients were enrolled in the study. Of these, 155 patients completed the entire protocol and were included in the final analysis (warm group, n = 78; cold group, n = 77). One patient in the warm group died perioperatively from a massive hemispheric stroke. Another warm group patient was unable to complete neuropsychological evaluation because of a perioperative stroke. Thus, 153 patients completed the entire series of neuropsychological tests. A total of 6 patients (warm group, n = 2; cold group, n = 4; P = NS) suffered from perioperative focal neurological deficits. There was a consistent deterioration in scores from tests of psychomotor speed/coordination (trial making, digit symbol, pegboard) in the early postoperative period, which resolved by the 3-month follow-up. Tests of memory (Buschke, Wechsler memory scale) showed no evidence of patient deterioration in the postoperative period. No difference was seen between the warm and cold groups., Conclusions: In this randomized trial of normothermic versus hypothermic CPB, we found deterioration in scores of tests of psychomotor speed but not of memory in the early postoperative period. We were unable to demonstrate any neuroprotective effect from moderate hypothermia in this patient population.

Seven patients with posttraumatic headaches refractory to other medical treatment were treated with sumatriptan, 6 mg subcutaneously, at the peak of a headache. In all, the throbbing temporal part of the headache disappeared leaving a persistent occipital pain. It is postulated that involvement of the trigeminovascular system is involved in part of the pain of posttraumatic headache, making it amenable to treatment with sumatriptan.

The Headache Classification Committee of the International Headache Society has developed a new classification system for headache, cranial neuralgia, and facial pain. The value of the classification for the practising clinician is that it forces him or her to take a more careful history in order to determine the nature of the headache. This article reviews the classification system and gives examples of case histories and subsequent diagnoses.

This study was designed to compare flunarizine, a cerebro-specific calcium channel antagonist, and propranolol in the prophylaxis of migraine with or without aura. Following a 1 month single-blind placebo baseline period, 94 patients were equitably randomised under double-blind conditions to take flunarizine 10 mg daily or propranolol 80 mg twice daily for 4 months. Both treatments led to a significant reduction in the frequency of migraines and use of rescue analgesics with a significantly greater decrease in number of attacks for flunarizine after 1 and 4 months. Neither treatment affected the severity nor duration of migraines. Overall, 67% of flunarizine patients and 51% of propranolol patients responded positively. Propranolol significantly reduced blood pressure and heart rate; flunarizine had no effect on cardiovascular function. Weight gain was noted with both treatments. Flunarizine is at least as effective as propranolol in the prophylactic treatment of migraine and may have a better safety profile.

The increasing popularity of warm heart surgery led us to assess the effect of temperature during cardiopulmonary bypass (CPB) on neuropsychological function after coronary surgery. 34 patients enrolled in a randomised trial of normothermic versus hypothermic CPB were subjected to a battery of psychomotor and memory tests before and after their operations. The mean nasopharyngeal temperature for warm CPB was 34.7 (SD 0.5) degrees C and that for hypothermic CPB was 27.8 (2.0) degrees C. In all seven neuropsychological tests the postoperative scores were better in the warm CPB than in the hypothermic group, although only one difference achieved significance (trial-making test A; p less than 0.023). Thus, neurological function after normothermic CPB seems to be no worse than that after hypothermic procedures.

The origins of chronic headache and the role of the greater occipital nerve in headache syndromes are reviewed. The anatomical pathways and physiological basis of these headaches are discussed with a view to synthesizing some current concepts of headache generation. Studies of occipital nerve blockade for treatment of headaches of various types are assessed and a retrospective analysis of our own experience is presented.

We present further evidence for a sympathetic defect of vasomotor control of the anterior cerebral artery (ACA) on the side of the headache during cluster periods. In 119 cluster headache patients, utilizing transcranial Doppler, we measured CO2 reactivity of the major intracranial vessels, in and out of cluster. Reactivity was significantly lower during the cluster period, but only in the ACA on the side of the headache. Nineteen patients followed sequentially for a full cycle (ie/both in and out of a cluster period) showed the same changes. In 3 out of 6 patients in an active cluster period, we describe a lesion on Gallium single-photon emission computerized tomography (SPECT) in the region of the cavernous sinus which fades as the patient moves out of cluster. It is felt that this lesion may represent the cavernous sinus plexus lesion postulated as the central lesion in cluster. Changes in the sympathetic outflow at this point could explain the changes we have described in ACA CO2 reactivity during cluster.

The efficacy of three preparations (placebo, analgesic agent, and analgesic plus antihistaminic agent) were compared in a double-blind crossover study in subjects with recurring headaches. It was confirmed that headache as a pain model does not show the usual return of pain with as the effects of a single analgesic dose wear off. Consequently, there is no "peak effect," and the rationale for comparing treatments by "area under the curve" calculations is weakened. Greater efficacy was demonstrated for the analgesic over the placebo and for the analgesic and antihistaminic combined over the analgesic alone in several parameters. Slopes of straight lines derived as a quadratic function of pain versus time data proved to be a more effective discriminator between treatments than area under the curve calculations from the same data.

During severe exercise or noradrenaline infusion in healthy male volunteers, the platelet count first rose and then fell. Platelet monoamine oxidase activity per unit protein rose and fell in parallel and the correlation with the platelet count was highly significant (P less than 0.001). The increase in observed specific monoamine oxidase activity might be due to the release of a population of platelets with higher specific activity, and the decrease to their selective removal.

Sixty-three patients with motor neuron disease and sixty-one controls matched for age and sex were interviewed concerning life events. An antecedent history of back injuries was found more often and there was an increased incidence of prior electric shock amongst the patients. No increase of head injuries, fractures, malignancy or previous poliomyelitis was detected.

Following cerebral angiography, the level of beta thromboglobulin rose in five of seven patients (P = less than 0.05). This would indicate that there had been generalised platelet activation. In view of the morbidity of cerebral angiography it is proposed that a trial of prophylactic anti-thrombotic therapy be instituted.

A Coulter Model "S Plus" counter has been used to study platelets from 39 migrainous patients between attacks, six during attacks, eight with active cluster headache and 26 controls. None of the patient groups showed any abnormality in platelet size profile. There was no correlation between platelet monoamine oxidase activity and mean platelet volume in any of the groups.