Victor G. Dostrow

As is the case with a number of chronic, progressive neurologic disorders, there is a long running debate about whether pharmacotherapy modifies the course of Parkinson's Disease (PD). The original selegiline (a monoamine oxidase inhibitor; MAOI) trials, done with the p.o. formulation, almost thirty years ago sought to address this, with limited success. In the same vein, there is also a division of opinion about whether the use of levodopa worsens PD over time. The idea of disease modification is important, since we have a number of therapies to address symptoms of PD, but none that are proven to actually affect the course of the disease. 

 One way to address this question is the "delayed start" trial. A 

 uses this approach with another MAOI, rasagiline (Azilect). This was a randomized, double blind, placebo controlled trial, sponsored by the drug manufacturer. The authors recruited patients with early PD, and divided them into immediate start (IS) and delayed start (DS) groups. Each group was further divided into cohorts treated with 1 mg. or 2 mg. of rasagiline per day. Patients receiving any recent PD treatment were excluded. 

 The trial was divided into 2 phases. In the first phase (36 weeks), patients in the IS group were started on rasagiline, while the DS patients received placebo. In phase 2 (also 36 weeks), all patients were treated with rasagiline. The primary measure was the Unified Parkinson's Disease Rating Scale (UPDRS), which is a 176 point, well validated instrument in which higher scores indicate worse disease.

 The analysis is complex. Three endpoints were used: The UPDRS curve slope change between 12 and 36 weeks, the UPDRS numerical change between the beginning and end of the trial, and a non-inferiority test between groups of the change between weeks 48 and 72. All these metrics had to reach statistical significance for the study to be considered positive. These complex measures were necessary to determine whether changes were due to disease modification or simply drug efficacy. 1,176 patients in 14 countries were recruited. 1,164 patients reached the first endpoint analysis, and 996 were included in the second and third endpoint analyses. 

 And the results were mixed. The 1 mg. IS group showed less progression by slope of curve analysis (0.09±0.02 points per week v. placebo (0.14±0.01 points per week); p=0.01. The other 2 measures were statistically significantly different between the IS and DS groups as well. The results were, however, different for the 2 mg. groups. The first endpoint and the non-inferiority measures were statistically significant. But the total UPDRS change over 72 weeks was not. So, a post-hoc analysis, stratified into quartiles by initial UPDRS scores, was done. The highest initial score quartile met the study criteria for significance.

 Adverse effects were not limiting. No tyramine reactions, a potentially serious reaction in persons taking MAOIs, were noted. One subject in the high dose group was found to have a melanoma at week 72. This is a concern with such therapy, but is also a common problem in older patients, and thus may have been an anomaly.

 The authors note that both doses of rasagiline had beneficial effects on PD symptoms, of a magnitude comparable to previous trials. They are hard pressed, however, to explain the difference in study outcome between the two different doses. They ultimately posit that the efficacy on symptoms masks the disease modifying effects in less affected patients, but they do not consider this to be conclusive. I note that an 

 on statistics addresses shortcomings of the delayed start trial design in great detail.

 Thus, 1 mg. rasagiline may delay the progression of PD. Unfortunately, however, this trial was not definitive. The authors recommend that the results be confirmed and longer term data be obtained before this becomes a clinical treatment standard to modify the course of PD.

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As is the case with a number of chronic, progressive neurologic disorders, there is a long running debate about whether pharmacotherapy modifies the course of Parkinson's Disease.

Can the Course of Parkinson's Disease be Modified?

While I have not tended to use this space to indicate my opinions about the opinions of others, this will be an exception. Prasugrel (trade name Effient) was recently 

 by the FDA for a very narrow indication:  Percutaneous coronary intervention patients with unstable angina, or MI with or without ST segment elevation. In such patients, the risk of subsequent non-fatal MI was reduced from 9.1% to 7.0%. This is a clinically significant reduction.

 This agent is another platelet ADP receptor inhibitor, in the same class as clopidogrel (Plavix). The manufacturer posits that prasugrel is a significant advance as it mitigates the variability in response seen in some patients taking clopidogrel. Prasugrel metabolism is reportedly more efficient, and possibly more consistent, leading to a higher degree of platelet aggregation inhibition. This results in a higher degree of efficacy in PCI patients, but also a higher hemorrhage risk.

 of prasugrel v. clopidogrel, added to aspirin. The author discusses a number of important concerns. One is the required duration of antiplatelet therapy, as a comparison trial between prasugrel and clopidogrel was of 15 months' duration. However, it is not clear that increasing the duration increases efficacy. Also well covered are issues of differences in response in low weight and older patients, and availability of various doses to address this.

 However, In my opinion, the biggest concern is hemorrhage. An excess fatal hemorrhage rate of 3/1000 was seen in the prasugrel group. And, the major hemorrhage rate in patients who progress from PCI to CABG was over four times higher in the prasugrel group: 13.4% v. 3.2%. Of particular neurologic interest: Patients with a history of symptomatic cerebrovascular disease (including stroke) and older patients had a significantly higher intracranial hemorrhage risk compared to the entire cohort. The author recommends avoiding adjunctive prasugrel use in patients with a history of cerebrovascular disease. 

 Another concern: Prasugrel requires the Cytochrome P450 3A4 enzyme for activation. Whether there will be problematic drug-drug interactions with many calcium channel agents, azole antifungal agents, and other commonly used 3A4 inhibitors remains to be seen. It often takes time for problems related to drug to drug interactions to become evident with new drugs. 

 The FDA was careful to approve this drug for only a well circumscribed set of indications. Despite this, there is already a material "buzz" in neurologic circles about this agent and its possible application for stroke prevention and other such uses. Some such discussions do not seem to properly account for the hemorrhage risk, the lack of data in stroke, or the excess hemorrhage rates in stroke patients in the comparative trial. I do hope that neurologists and primary care providers who elect to prescribe prasugrel off-label for neurologic indications avail themselves of the important data about these concerns.

Prasugrel was recently approved by the FDA for a very narrow indication:  Percutaneous coronary intervention patients with unstable angina, or MI with or without ST segment elevation.

A Cogent Discussion of Prasugrel and Neurologic Concerns

Long work hours and sleep interruptions are expected occupational hazards in medicine. And, it's clear that 

 impairs performance. However, data on persistent impairment from long working hours have been scarce, as most studies are cross-sectional. Also, most existing data pertain to long shifts, rather than total weekly work hours. 

 study [Note: Free full access to this manuscript is available at the publisher's website] fills in some of the gaps. The authors studied 2,214 British civil servants (average age at enrollment: 52.1 years old). Five different cognitive measures were obtained at baseline and 5 year follow up evaluations. This study was rather unusual in the breadth of additional factors evaluated as covariates. In addition to the typical age, gender, marital status, highest level of education, etc, the authors also determined job rank, a wide variety of physical and psychological health factors, and potentially adverse lifestyle choices.  The statistical analysis was detailed and rigorous. 

 The authors broke work hours into three groups: 35-40 hours per week: 853 (39% of total participants); 41-55 hours: 1,180 (53%); Over 55 hours: 181 (8%). The primary outcomes of interest were found in comparing the "over 55 hours per week" group to the "40 hours or less" group. Participants in the longest work hours group had lower vocabulary scores at both baseline and follow-up, and lower reasoning scores at the follow up assessments. These findings persisted when work hours were analyzed as a continuous variable, and when all demographic factors were taken into account.

 Of most concern to readers is the reasoning task deterioration. The authors note that this test is associated with executive functions, a cognitive domain especially vital to effective medical practice. The authors also note that the established adverse effects of long work hours on sleep, cardiac status and other physical health indicators, as well as possible increases in adverse behaviors, are probably not the mechanism mediating the cognitive declines. The magnitude of the declines is of much concern:  "...the 0.6- to 1.4-unit difference in aspects of cognitive functioning [...] is similar in magnitude to that of smoking, a risk factor for dementia." Thus, these impairments are of clinical, in addition to statistical, significance. Adding to the concern: The authors wonder if larger declines, and worsening in other areas, might be seen with a longer follow up interval.

 This study has clear, and not pleasant, implications for people working in healthcare. Those of us in medicine work long hours. Those long hours may take a toll on the cognitive function we need to adequately perform our jobs.

It's clear that sleep deprivation impairs performance. However, data on persistent impairment from long working hours have been scarce, as most studies are cross-sectional.

Warning: Working Long Hours May Rot Your Brain

Epilepsy is often a difficult disorder with which to live, as seizures are unpredictable and the consequences are potentially severe. The pharmacotherapy of epilepsy frequently entails a careful balance of drug dosing and timing, and anything upsetting this can lead to seizures or toxicity. Superimposed on this fragile substrate is the frequent use of 

 medicine (CAM), which includes herbal remedies, dietary supplements, and such. 

 used such remedies in 2007, an increase from 36% in 2002. Presumably use is even more widespread now. In persons with epilepsy, CAM use may prove problematic if the agents used are epileptogenic or interfere with the metabolism of existing antiepileptic drug (AED) therapy. However, data on prevalence of CAM use in the setting of epilepsy, or types of agents employed, have not been widely available in the past.

, Kaiboriboon et al. asked patients in a tertiary care epilepsy center about the use of such remedies. Over a one year recruitment period, all patients at the UCSF epilepsy clinic were asked to complete the survey. The survey asked about epilepsy types, various demographic characteristics, and supplement use, adverse effects, and cost. 187 patients completed the survey, of which 104 (56%) reported use of CAM. Of those, 34% used one such product, 32% two, and 34% took 3 or more CAM agents. 49% reported taking CAM products for five or more years. 71% disclosed use to their physicians. Multivitamins and minerals were the most commonly used preparations by a wide margin, taken by 83 of the respondents. 13 reported taking folic acid: I note that I often recommend supplemental folate use to my patients, as this vitamin may offset a number of AED related adverse effects. 

 Most CAM use was said to be for general health promotion, rather than directed at epilepsy per se. The most significant independent predictors of CAM use were partial epilepsy and Caucasian race. Of note, epilepsy severity and dissatisfaction with conventional treatment did not correlate with supplement use. Despite that lack of correlation, the authors note that some of the stated reasons for CAM use might be related to epilepsy or AED adverse effects: 13 patients reported CAM use to improve bone health and seven patients used CAM for memory improvement. Information sources were also surveyed. Most reported obtaining CAM information from a variety of sources. Fifty patients indicated that their primary physician was the main source of information. 

 Adverse effects were not especially common. Nine patients reported adverse effects, but no patient attributed seizures to the use of concomitant CAM products. That said, potential problems were more frequent, based on the specifics of the CAM products used: Twenty patients (19%) were taking a product which could affect metabolism throught changes in the hepatic cytochrome P450 systems. And 17 patients (16%) were taking potentially epileptogenic agents. 

 So, a majority of epilepsy patients in this study used CAM. This was higher than what had been previously reported in the literature. In this population, use of such remedies was prevalent. Half had been using CAM for five years or more, so use was often longstanding. Most disclosed use to their physicians. Adverse effects of CAM were not commonly reported.  It is important to note that a tertiary care epilepsy center is likely to have a cohort of more refractory patients, and such patients are probably going to be more sensitive to the interactions discussed above between AEDs and CAM. So, in a wider population, adverse effects may be even less likely. And, this San Francisco population may be more likely to use alternative therapies than persons with epilepsy in other areas. 

 CAM use in epilepsy is more common than previously thought but is probably rarely problematic.

Epilepsy is often a difficult disorder with which to live, as seizures are unpredictable and the consequences are potentially severe. The pharmacotherapy of epilepsy frequently entails a careful balance of drug dosing and timing, and anything upsetting this can lead to seizures or toxicity.

Victor G. Dostrow

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