A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson's disease.

AIM: To evaluate relationship between odour identification, taste threshold, dopamine transporter scan (DaTSCAN) and motor function in early Parkinson's disease (PD) and their diagnostic accuracy. METHODS: Seventy-three patients with early parkinsonism were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS), DaTSCAN, electrogustometry (EGM) threshold and University of Pennsylvania Smell Identification Test (UPSIT). Olfactory Event-Related potentials (OERP) were performed on 49 patients. At follow-up (mean 15.3 months), patients were diagnosed as 'PD' or 'non-PD'. DaTSCAN images were assessed visually and semi-quantitatively by QuantiSPECT. RESULTS: The sensitivity of UPSIT (86%) was not significantly different from that of the DaTSCAN (92%). UPSIT correlated moderately with DaTSCAN uptake (r = 0.44; P < 0.005) and UPDRS score (r = 0.43; P < 0.05) and weakly with symptom duration (r = 0.25; P < 0.05). In the PD group, OERP showed increased latency but no change in amplitude and no correlation with DaTSCAN. EGM thresholds were impaired in 22% of the PD group but they did not correlate with any other test parameters. DaTSCAN-UPSIT discordance was found in nine patients with PD, but neither was diagnostically superior. CONCLUSION: Our patients with early PD have a frequent and severe olfactory deficit that correlates with disease severity, symptom duration and DaTSCAN but not EGM. The sensitivities of UPSIT and DaTSCAN are high at 86% and 92%, respectively. Although DaTSCAN is superior for 'localization', UPSIT is considerably 'cheaper', and neither is disease specific. EGM threshold impairment in PD is independent of the smell deficit, and probably signifies advanced disease.

A randomly assigned double-blind cross-over study examining the relative anti-parkinsonian tremor effects of pramipexole and pergolide.

This study examined the relative anti-Parkinson's disease (PD) tremor potencies of pergolide and pramipexole in people with PD, using a 3-month double-blind cross-over design. Patients were randomly assigned to receive either pergolide and then pramipexole (n=9) or vice versa (n=8). The dose of the respective dopamine agonist was increased according to a titration schedule up to a maximum 1.5 mg t.d.s., with cross-over at 10 weeks. Assessments were performed at baseline, 4, 8 and 12 weeks. The primary outcome measures were the differences in the clinical (rest and postural) tremor scores on pergolide versus pramipexole. Seventeen PD patients (11 females and six males) with a mean age 68.4 years (range: 55-84 years) and a mean disease duration of 3.9 years (range: 2 months to 13 years) participated in the study. Twelve of the patients were taking other anti-parkinsonian medications. Two patients dropped out of the study whilst on pergolide. Fifteen of 16 patients were able to cross-over from one dopamine agonist to the other, without major retitration. There were no significant differences between the effects of the two drugs on the primary outcome measures, suggesting that the anti-PD tremor efficacies of dopaminergic medications are not dependent on differential affinities for dopamine receptor types.

[Sleepy drivers have a high frequency of traffic accidents related to respiratory effort-related arousals]. / Los conductores somnolientos tienen alta frecuencia de accidentes de tráfico asociados a exceso de RERA.

INTRODUCTION: Respiratory effort-related arousals (RERA) are secondary to subtle obstructions of the upper airway during sleep and can appear in the absence of a predominance of apneas and hypopneas, causing excessive daytime sleepiness. Analyzing the possible consequences of these new respiratory events is of increasing interest. Habitually sleepy drivers are at high risk of having traffic accidents related to sleep disorders (apneas, hypopneas and RERA). OBJECTIVE: The aim of this study was to determine whether excess RERA alone is an independent risk factor among sleepy drivers. METHOD: We studied 40 habitually sleepy drivers and 23 age- and sex-matched controls selected from a sample of 4,002 automobile drivers. We surveyed sleep habits, daytime sleepiness and traffic accidents. Sleep studies of esophageal pressure were performed. RESULTS: The sleepy drivers with apneas (apnea/hypopnea index > 10) had a higher 5-year accident rate (0.33 0.50) than did control drivers (0.004 0.21; p < 0.05). However, a high RERA index, but not sleep apnea, was an independent risk factor among the habitually sleepy drivers. The adjusted odds ratio (OR) for a RERA index > or = 10 was 7.6 (confidence interval [CI], 1.2 to 48); for a RERA index > or = 15, the OR was 17 (CI 1.5 to 91). CONCLUSIONS: The high risk of traffic accidents among sleepy drivers is mainly determined by the presence of RERA rather than the presence of apneas and hypopneas. These findings verify the importance of identifying RERA in routine sleep laboratory studies.

Los conductores somnolientos tienen alta frecuenciade accidentes de tráfico asociados a exceso de RERA / Sleepy drivers have a high frequency of traffic accidents related to respiratory effort-related arousals

INTRODUCCIÓN: Los RERA (respiratory effort-related arousal) son secundarios a sutiles obstrucciones de la vía aérea superior durante el sueño, pueden aparecer sin predominio de apneas e hipopneas y causan somnolencia diurna excesiva. El análisis de las potenciales consecuencias de estos nuevos acontecimientos respiratorios tiene hoy un interés creciente. Los conductores habitualmente somnolientos tienen un riesgo alto de sufrir accidentes de tráfico asociados a trastornos respiratorios durante el sueño (apneas más hipopneas más RERA). OBJETIVO: El objetivo de este trabajo es determinar si exclusivamente el exceso de RERA es un factor independiente de riesgo de accidentes en los conductores somnolientos. MÉTODO: Estudiamos a 40 conductores habitualmente somnolientos y 23 controles (conductores no somnolientos) pareados por edad y sexo, y ambos extraídos de una muestra de 4.002 conductores de vehículos. Se estudiaron datos sobre hábitos de sueño, somnolencia diurna, accidentes de tráfico y se realizaron estudios de sueño con medida de presión esofágica. RESULTADOS: Los conductores somnolientos con apneas de sueño tienen una tasa de accidentes en 5 años mayor que los controles (índice de apneas-hipoapneas [IAH] > 10; 0,33 ñ 0,50 frente a 0,004 ñ 0,21 en los controles; p < 0,05), pero sólo el exceso de RERA y no el de apneas de sueño fue un factor independiente de riesgo de accidentes en conductores somnolientos. La odds ratio (OR) ajustada para un índice de RERA 10 fue de 7,6 (intervalo de confianza [IC] del 95 por ciento, 1,2-48) y para un índice de RERA 15 fue de 17 (IC, 1,5-91).CONCLUSIONES: El alto riesgo de accidentes de tráfico de los conductores somnolientos viene principalmente determinado por la presencia de RERA más que por la presencia de apneas e hipopneas de sueño. Estos datos ratifican la importancia y la necesidad de identificar RERA en la práctica habitual de los laboratorios de sueño (AU)

Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep.

Sleepiness is a common cause of traffic crashes with a cost of billions of dollars per year. A recent study has found that 2 to 3% of drivers are habitually sleepy while driving. However, there has not been a controlled study to define the characteristics, driving performance, or automobile crash rate of habitually sleepy drivers. The prevalence of respiratory disorders during sleep, and whether these respiratory disorders contribute to the increased automobile crash frequency, is unknown in habitually sleepy drivers. We interviewed 4,002 randomly selected drivers to define the prevalence of drivers who are habitually sleepy while driving. We studied the habitually sleepy drivers and an age- and sex-matched control group of drivers. These studies included reporting of daytime sleepiness, automobile crashes, driving performance and sleep studies. Of the 4, 002 drivers interviewed, 145 (3.6%, confidence interval [CI] = 3.1 to 4.3) were habitually sleepy while driving. The habitually sleepy drivers reported a significantly higher frequency of auto crashes than control subjects (the adjusted odds ratio [OR] was 13.3, CI = 4. 1 to 43). The habitually sleepy drivers had a significantly higher prevalence of respiratory sleep disorders than control subjects. For a total respiratory events index (apneas, hypopneas, and other respiratory effort-related arousals) >/= 15 the adjusted OR was 6.0, CI = 1.1 to 32. In the habitually sleepy drivers group, the frequency of sleep apnea (apnea-hypopnea index) between subjects with or without auto crashes was not statistically different. However, if we consider total respiratory events index, this frequency of respiratory sleep disorders was significantly higher in subjects with automobile crashes (the adjusted OR for a total respiratory event index >/= 15 was 8.5, CI = 1.2 to 59). Habitually sleepy drivers are a large group of drivers (1 of 30 drivers) who are involved in several fold more automobile crashes than control subjects. As these excess auto crashes can be explained in part by the presence of respiratory disorders during sleep, which are treatable, many automobile crashes in these sleepy drivers may be preventable. Our findings suggest that asking about excessive sleepiness while driving may better predict which subjects with breathing disorders during sleep have crashes than asking about overall sleepiness.

Epidemiology and genetics of essential tremor.

Essential tremor (ET) is probably the most common movement disorder and is a common cause of social, physical, and psychological handicaps. Its etiology and pathogenesis are unknown. Phenomenologically, ET overlaps and is associated with other disorders of movement, such as parkinsonism and dystonia. There is large variation in the stated prevalence of ET as well as limited availability of epidemiologic studies. Prevalence variations reflect differences in the definition of ET and the methodologies of investigation. The familial and sporadic forms of ET are generally assumed to be similar. The familial form appears to have a narrow phenotype. Wide variation in the reported percentage of patients with positive family history reflects ascertainment and classification differences. Linkage of ET to two different chromosome locations has been reported.

Evaluation of three different ways of assessing tremor in multiple sclerosis.

OBJECTIVES: To examine the comparative reliability and validity of three simple ways of rating upper limb tremor in patients with multiple sclerosis. METHODS: Three examiners independently rated severity of upper limb tremor in patients with multiple sclerosis on a 0-10 scale by studying videotape recordings of patients' examinations, spiral drawings, and handwriting samples. The correlations of the tremor severity scores with scores from arm dexterity tests and a tremor related disability scale were also assessed. RESULTS: Rating tremor on posture had a good intrarater and interrater reliability. However, these reliabilities decreased when kinetic tremor was assessed, in part because dysmetria was a confounding factor. The intrarater reliabilities of rating tremor from spirals and handwriting were also good but the interrater reliabilities were only fair to moderate. Tremor severity scored by all three methods correlated highly with scores obtained from the nine hole peg test, finger tapping test, and a tremor related activities of daily living (ADL) questionnaire, indicating that all three methods were valid ways of assessing tremor in multiple sclerosis. CONCLUSION: Multiple sclerosis tremors in posture can be scored using a clinical rating scale in a valid and reliable way, and from spirals and handwriting samples if the ratings are carried out by the same examiner. However, scoring kinetic tremor was less reliable. In addition, the nine hole peg and finger tapping tests provide useful objective assessments of upper limb function in tremulous patients with multiple sclerosis.

The timing of primary orthostatic tremor bursts has a task-specific plasticity.

Primary orthostatic tremor is characterized by unsteadiness and shakiness of the legs while standing. It is due to a remarkably strong and regular EMG modulation at approximately 16 Hz that is thought to be of CNS origin. Previous studies have shown that the tremor frequency is the same in all involved muscles and that the time relation between bursts of activity in different muscles may be fixed (e.g. always co-contracting or always contracting in an alternating pattern). Here we have used frequency domain analysis of postural muscle EMG signals in five primary orthostatic tremor patients and in two normal controls to explore the nature of such fixed timing patterns. The timing is found not to relate simply to the relative conduction times for passage of rhythmic bursts from a central oscillation to different muscles. Indeed, although the timing pattern (expressed as phase) of the 16-Hz EMG bursts in different postural muscles remains constant while the subject adopts a certain steady posture, it is different for different subjects and also changes when the same subject adopts a different posture. It seems unlikely that such complex task-dependent timing relations of rhythmic postural muscle activity are due to the primary pathology of primary orthostatic tremor. Instead, we suggest that the abnormally strong peripheral manifestation of a 16-Hz CNS oscillation merely unmasks normal central processes so that the timing patterns may provide a clue to the nature of postural motor control.

Time-on-task decrements in "steer clear" performance of patients with sleep apnea and narcolepsy.

Loss of attention with time-on-task reflects the increasing instability of the waking state during performance in experimentally induced sleepiness. To determine whether patients with disorders of excessive sleepiness also displayed time-on-task decrements indicative of wake state instability, visual sustained attention performance on "Steer Clear," a computerized simple RT driving simulation task, was compared among 31 patients with untreated sleep apnea, 16 patients with narcolepsy, and 14 healthy control subjects. Vigilance decrement functions were generated by analyzing the number of collisions in each of six four-minute periods of Steer Clear task performance in a mixed-model analysis of variance and linear regression equations. As expected, patients had more Steer Clear collisions than control subjects (p=0.006). However, the inter-subject variability in errors among the narcoleptic patients was four-fold that of the apnea patients, and 100-fold that of the controls volunteers; the variance in errors among untreated apnea patients was 27-times that of controls. The results of transformed collision data revealed main effects for group (p=0.006), time-on-task (p=0.001), and a significant interaction (p=0.022). Control subjects showed no clear evidence of increasing collision errors with time-on-task (adjusted R2=0.22), while apnea patients showed a trend toward vigilance decrement (adjusted R2=0.42, p=0.097), and narcolepsy patients evidenced a robust linear vigilance decrement (adjusted R2=0.87, p=0.004). The association of disorders of excessive somnolence with escalating time-on-task decrements makes it imperative that when assessment of neurobehavioral performance is conducted in patients, it involves task durations and analyses that will evaluate the underlying vulnerability of potentially sleepy patients to decrements over time in tasks that require sustained attention and timely responses, both of which are key components in safe driving performance.

Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.

PURPOSE: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. METHODS: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for < or =48 weeks. RESULTS: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. CONCLUSIONS: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.

S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study.

S-fluoxetine is the long-acting enantiomer of the racemic antidepressant serotonin reuptake inhibitor. Sixty-five patients needing migraine prophylaxis were recruited into a phase II, double-blind, placebo-controlled trial. After a 1-month placebo run-in, 53 patients met entry criteria with regard to attack frequency and were randomized, 27 to S-fluoxetine and 26 to matching placebo. Three failed to start treatment and there were 17 early discontinuations, 9 from S-fluoxetine, 8 from placebo, at similar times and for similar reasons. The primary efficacy variable was attack frequency and analysis compared decline-from-baseline in the two groups. This was earlier and greater (1.7 attacks/28 days, or 52%) on active therapy than on placebo (1.1 attacks/28 days, or 27%), and statistically significant in month 2 (F = 4.93; p = 0.033) and month 4 (F = 4.55; p = 0.041). As secondary measures of efficacy, migraine-days per month and Patient's Global Impression of Disease Severity coherently reflected the changes in attack frequency. Mean attack severity and acute medication use (doses per attack) were unaltered by either treatment. There were no serious adverse events. Withdrawals for adverse events were four from each group but none was considered causally related. The finding of greater efficacy of S-fluoxetine than of placebo should be interpreted conservatively, since the analysis in the final month was made on only half of the entered patients. It supports progression to phase III evaluation, which was the purpose of the study.

Electrophysiological aids in distinguishing organic from psychogenic tremor.

The clinical differentiation of tremors of organic and psychogenic origin can be difficult. We describe a patient with unilateral upper limb tremor that was initially considered to have a psychogenic cause, but subsequent frequency analysis of EMG signals and accelerometer recordings indicated that the tremor was organic in nature. An ischemic lesion in the contralateral lentiform nucleus found on MRI supported this conclusion. Quantitative electrophysiologic studies may thus be useful in distinguishing organic from psychogenic tremor.

Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II).

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.

Electrophysiological observations on an unusual, task specific jaw tremor.

A patient with no other neurological signs or symptoms presented with a prominent tremor restricted to the mandible. This 5-6 Hz tremor was interesting in that it was normally confined to the digastric muscles and was highly task specific. In the course of her normal daily activities, it began only when the patient drank from a cup or glass. The localisation of this tremor to a muscle that has no muscle spindles and no reciprocal inhibitory reflexes suggests that such tremors must be capable of being generated centrally.

Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.

Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition of neuronal release of glutamate. Release of glutamate may be essential in the propagation of spreading cortical depression, which some believe is central to the genesis of migraine attacks. This study compared safety and efficacy of lamotrigine and placebo in migraine prophylaxis in a double-blind randomized parallel-groups trial. A total of 110 patients entered; after a 1-month placebo run-in period, placebo-responders and non-compliers were excluded, leaving 77 to be treated with lamotrigine (n = 37) or placebo (n = 40) for up to 3 months. Initially, lamotrigine therapy was commenced at the full dose of 200 mg/day, but, following a high incidence of skin rashes, a slow dose-escalation was introduced: 25 mg/day for 2 weeks, 50 mg/day for 2 weeks, then 200 mg/day. Attack rates were reduced from baseline means of 3.6 per month on lamotrigine and 4.4 on placebo to 3.2 and 3.0 respectively during the last month of treatment. Improvements were greater on placebo and these changes, not statistically significant, indicate that lamotrigine is ineffective for migraine prophylaxis. There were more adverse events on lamotrigine than on placebo, most commonly rash. With slow dose-escalation their frequency was reduced and the rate of withdrawal for adverse events was similar in both treatment groups.