Neurology: April 2010 Archives
An ungrounded tenet in the practice of neurology is to avoid, if possible, the use of generic antiepileptic drugs (AEDs) in patients with epilepsy.
The fear: Even small changes in the drug's makeup, from branded pill to unbranded pill and from generic company to generic company, can lead to inconsistent bioavailability, variable drug levels, and, consequently, breakthrough seizures.
A new study published in an advanced online issue of Neurology appears to substantiate the fear; however, caveats are necessary.
Investigators at the University of Arizona examined insurance claims of more than 33,000 continuously treated adults with epilepsy during 6-year period and found that the use of generic AEDs was associated with
- an increased use of all prescription drugs;
- higher epilepsy-related medical utilization (ie, hospitalizations, outpatient visits, length of hospital stays); and
- an increased risk of injury.
Their findings applied to both clinically stable and unstable patients.
However, in an accompanying editorial, UK neuropsychiatrist Frank Besag warns that an observed association does not indicate causation. Moreover the Arizona study was open and unblinded—an important point, because many physicians and patients have a negative view of generic AEDs. Last epilepsy is known to be a variable and fickle condition; often the cause of seizure breakthrough cannot be identified.
To better answer the question of whether generic AEDs alter the cost of epilepsy care, Besag advocates a study that uses a randomized, double-blind, and double-dummy design (meaning, in both treatment arms, patients take 2 pills, one placebo and one active or 2 placebo pills). He suggests that pharma companies would be motivated to fund such studies, if they believed that their branded AEDs were superior to generic versions.
In the meantime, Besage chastises the Neurology editors for printing the uncontrolled analysis. "It is time for journals to stop publishing open studies and to insist on rigorous scientific studies," he concludes.
First: Donald Trump is "dealing with" Bret Michaels's absence from "The Apprentice" reality show.
[Pause for universal brow mop.]
Second: The latest on the Poison singer is that he's suffered a "minor setback" while hospitalized with a subarachnoid hemorrhage (SAH). The 47-year-old Michaels reportedly has a "lack of sodium," or hyponatremia, reports the BBC News. The cause of Michaels's SAH, which occurred almost 1 week ago, is evidently still unknown.*
Hyponatremia occurs in 10%-30% of patients with SAH, according to the latest AHA guidelines on the management of the condition, and is more common in patients with a poor clinical status or hydrocephalus. The condition appears to be related to the inappropriate urinary excretion of sodium. The major concern with hyponatremia in SAH is that it is associated with reduced intravascular volume, which is linked to cerebral vasospasm (see below).
To reduce the risk of hyponatremia in SAH, the guidelines recommend that large volumes of hypotonic fluids and volume contraction should be avoided. Intensive-care monitoring of the circulatory volume is also advised. When hyponatremia occurs, the administration of hypertonic saline and fludrocortisone (Florinef) is "reasonable" to achieve euvolemia.
Other issues to concern Michaels's treating doctors are cerebral vasospasm and rebleeding—both major contributors to SAH-associated death.
Cerebral vasospasm, seen in 30%-70% of patients with SAH, typically occurs 3-5 days after the initial bleed and gradually resolves during the next 2-4 weeks. The calcium-channel blocker nimodipine (Nimotop; Bayer) has been shown to reduce the risk of poor outcomes associated with post-SAH vasospasm.
Efforts to reduce the risk of rebleeding in SAH include bed rest and the control of circulatory volume and blood pressure to some sort of equilibrium that avoids both hypertension and volume contraction. There are data suggesting that the risk of rebleeding is reduced with an early, short course of antifibrinolytic therapy (Amicar).
Among survivors of SAH, persistent deficits—including cognitive impairment—are common. The 3 strongest predictors of death or disability are impaired consciousness on admission, advancing age, and a large bleed.
AHA = American Heart Association.
* In about 75% of cases, subarachnoid bleeding is caused by a ruptured (eg, berry) cerebral aneurysm; and in about 20% of cases, there is not an identifiable cause. According to a 2006 review, a substantial percentage of the cases with an unidentified bleeding source are defined as idiopathic in nature. The remainder, 5%, are caused by vascular malformations, arterial dissection, sympathomimetic drugs (eg, cocaine, phenylpropanolamine), tumors, or vasculitis. Notably diabetes, which Michaels reportedly has, does not increase the risk of SAH.
From Wikipedia: Horizontal cut of CT image showing hyperdense subarachnoid blood in the basal cistern. To my knowledge, this is not Bret Michaels's scan.
05/06/10 addendum: Although today's FOXNews story of Bret Michaels's release from the hospital makes it sound like the rocker was discharged to home, Michaels was actually released to a physical rehab facility, according to USA Today. The latter story makes a whole lot more sense.
Michaels SAH occurred almost 2 weeks ago, and other than the report of hyponatremia, he did not suffer any of the usual SAH-related complications—like cerebral vasospasm or rebleeding. The cause of Michaels's SAH was evidently never identified, and he apparently has not experienced any significant neurologic deficits. In the setting of being really unlucky, Michaels is a very, very lucky guy. So is Donald Trump, who must be peeing himself, given the possibility that Michaels may rejoin "The Apprentice."
Although the primary endpoint was not achieved in a recent phase 2 study, high-dose atorvastatin (Lipitor; Pfizer), like the interferon betas, may reduce the likelihood of full-blown multiple sclerosis after a first attack.*
The results of the placebo-controlled trial (N = 81), which were reported last week at the annual meeting of the American Academy of Neurology in Toronto, showed that atorvastatin 80 mg/d significantly reduced the odds of new T2 lesions on brain MR images at 12 months. However, the percentages of patients developing 3 or more new T2 lesions or 1 or more clinical relapses (the combined primary endpoint) were not significantly different between atorvastatin and placebo treatment (49% vs 56%; P = .65).** And while the odds of remaining free of active (ie, gadolinium-enhancing) MR lesions were higher with atorvastatin, this finding also did not reach statistical significance.
The study was originally designed to enroll 150 patients; however, because of slow recruitment, it was stopped after treatments were randomized to 81 patients. The study was sponsored by the NIAID and managed by the Immune Tolerance Network, which receives support from Pfizer and Biogen Idec.
The rationale for assessing atorvastatin in MS relates to its ability to modulate immune reactions and reverse disease in rodent models (ie, experimental autoimmune encephalomyelitis). Open-label studies also suggested clinical benefit with atorvastatin in relapsing-remitting MS.
* AKA clinically isolated syndrome (CIS) manifesting, for example, as optic neuritis, spinal cord syndrome, or brainstem dysfunction.
** Those patients who experienced the primary endpoint were offered weekly IM interferon beta (Avonex; Biogen Idec).
T2-weighted supraventricular horizontal MR image from Harvard's Whole Brain Atlas. Multiple subcortical MS lesions are evident, including a very prominent lesion in the patient's right (left to the viewer) frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.
Wow. A drug company actually downplaying its phase 2 data?
Last month, PTC Therapeutics and its collaborator Genzyme announced that a treatment-related change in the primary endpoint, the 6-minute walk test, of a phase 2b trial of ataluren in Duchenne or Becker muscular dystrophy* (nmDBMD) did not reach statistical significance at 48 weeks. However, Wong, speaking at the just-completed annual meeting of the American Academy of Neurology in Toronto, said that patients treated with ataluren in the phase 2 trial experienced a mean improvement of 29 meters in the 6-minute walk test—which was just shy of the trial's prespecified target of 30 meters. This detail and others were not provided by PTC in its official communication.
Wong also said that the endpoint difference between ataluren- and placebo-treated patients was significant, when a different statistical test (a ranked analysis of covariance) was used, instead of what was prespecified (a simple analysis). Another important outcome: low-dose ataluren was more effective at delaying a deterioration in mobility than high-dose ataluren—which was no better than placebo. Wong proposed that low-dose ataluren may be more effective, because it has a relatively moderate effect on ribosomal activity. (Ataluren is designed to cause ribosomes to ignore a premature stop codon during protein translation.)
It's speculation here, but PTC may be reticent to broadcast details of its trial results, owing to the legal troubles it encountered in Gunvalson v. PTC Therapeutics in 2008 and the resultant threat to its clinical-trial program. In this legal case, which was correctly reversed on appeal (in favor of the company), a boy with nmDBMD demanded compassionate access to the drug outside of an ongoing clinical trial.
According to the NIH database, ataluren is currently being studied at the phase 2/3 level in cystic fibrosis and hemophilia A and B (in cases on nonsense mutations). Phase 3 trials in muscular dystrophy are not listed.
* Due to a nonsense (or premature stop codon) mutation, not a more common deletion mutation.
Worries about a rise in Guillain-Barre syndrome during the 2009 H1N1 vaccination campaign were unfounded. Only 35 cases of the acute autoimmune neuropathy were reported to the CDC or the FDA's voluntary reporting system, VAERS, at the end of last year, say researchers at the ongoing annual meeting of the American Academy of Neurology in Toronto.
The 2009 H1N1 (or swine flu) vaccination campaign began in earnest in mid-October of last year, and approximately 100 million vaccinations were administered in the United States. Consequently the rate of GBS associated with vaccination was 3.5 per 10 million. All but 1 case occurred within 6 months of vaccination; 23 cases occurred within 2 weeks of inoculation. The annual background rate of GBS is about 1-4 cases per 100,000. (The 2009 H1N1 vaccine protects against GBS, anyone?)
Original worries about a vaccine-associated increase in GBS stemmed from the observed rise in the condition during the 1976 swine-flu vaccination program.
VAERS = Vaccine Adverse Event Reporting System.
Yesterday's favorable news of Baxter's Gammagard (IV Ig) in Alzheimer disease (and the obligatory buzz) should be approached cautiously. Here's why.
First: The results are from a phase 2 study, not an all-important phase 3 study (two of which are typically required for FDA approval). As is common in a phase 2 study, different doses of the study drug were assessed.
Second: The study was small, enrolling only 21 subjects (14 with AD).
Third: The study was placebo controlled for a relatively limited time—6 months. Afterward all patients received IV Ig at various doses for 12 months.
Fourth: The difference in the ADCS-CGIC score change between treatment groups, while statistically significant, was not huge—1.36 points (-0.64 vs -2.0).
Fourth: The significant difference between the mean ADAS-cog scores at endpoint may be due to the substantial change in the mean score of control patients—15 points. It'd be nice to know when the bulk of this 15-point change in the control patients occurred: during placebo treatment or during IV Ig treatment?
Fifth: The results have not been peer reviewed.*
Perhaps the most intriguing result of Baxter's phase 2 AD study is the statistically significant associations among IV Ig treatment, brain atrophy on MR images, and clinical scores. Again, however, the study was small, and the outcome warrants confirmation in phase 3 investigations, which are ongoing or planned.
The rationale for administering IV Ig in AD is to provide nonspecific anti-amyloid antibodies.
ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; ADCS-CGIC = Alzheimer's Disease Cooperative Study, Clinical Global Impression of Change.
* While the Baxter press release indicates that these data were presented yesterday at the ongoing annual meeting of the American Academy of Neurology, I--for the life of me--cannot find the related abstract. The closest presentation from the same investigators is "Neuropsychological outcomes following 18-months of uninterrupted intravenous immunoglubulin (IVIg) treatment in patients with Alzheimer's disease (AD)." The data from this related trial are to be presented this evening.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
Addendum: D'oh! Here's the AAN abstract (found in late-breaking science, which—Hmm—is to be presented as a poster this evening. It is Wednesday, isn't it?). Relkin N et al. Intravenous immunoglobulin treatment decreases rates of ventricular enlargement and cognitive decline in Alzheimer's disease. P03.294.
The 6-month data were presented at the 2008 annual meeting of the AAN. Among 23 completers, 19 had "fully evaluable data." The difference between the change in the ADCS-CGIC score of IV Ig-treated patients and that of placebo-treated patients was statistically significant (IV Ig, +0.25; placebo, -1.25; absolute difference, 1.50); however, the mean change in the ADAS-cog score was not (IV Ig, -0.38; placebo, +2.61).
So most of the change in the ADAS-cog score of control patients at 18 months occurred while they were receiving IV Ig. It seems flukish that 6 months of upfront IV Ig therapy would provide that much neuroprotection in the treated group, whose ADAS-cog score changed by only 5 points at 18 months.
The small drop in pressure, 2-3 mm Hg, occurring after jugular-vein angioplasty in patients with multiple sclerosis is unlikely to be pathologically significant. The implication was made in Sunday's review of the procedure by US neurologist John Corboy at the ongoing annual meeting of the American Academy of Neurology in Toronto, Canada.
Corboy assessed the clinical data of Italian vascular surgeon Paolo Zamboni, who first proposed that MS is caused by an insufficiency of the cerebral veins. Consequently Zamboni performed angioplasty in 65 patients with MS (including his wife) and claimed clinical and radiographic improvement in an uncontrolled trial.
Among Zamboni's rationales for addressing venous insuffiency in MS is to reduce perivenular iron deposits, a known pathologic feature of MS. (Although no causative link has been established between these deposits and MS, to my knowledge.) Pathologists consulted by Corboy implied that the small drop in pressure due to jugular-vein angioplasty or stenting is unlikely to purge these deposits—or anything else, for that matter.
A much larger follow-up blinded study at the University of Buffalo reaffirmed reduced blood flow in the extracranial veins of patients with MS and correlated these data with iron deposits on MR images. These data are scheduled to be presented tomorrow in a poster session at the AAN meeting (P03.126).
Last December, Stanford correctly shut down the jugular-vein stent program of surgeon Michael Dake, who had performed the procedure in 40 patients with MS. One died of cerebral hemorrhage, and the stent of another became dislodged and found its way to the patient's heart. Dake's interest in the procedure was indirectly sparked by chat-room enthusiasm for Zamboni's work.
Corboy concluded his review by advising that he would not recommend jugular-vein angioplasty or stenting in patients with MS "until we had a much better idea whether this approach has any merit whatsoever."
News source: MedPage Today.
Image of neck veins from Gray's Anatomy (1918).
While reviewing trials of novel agents for Alzheimer disease at the NIH database, one thing is readily apparent: There are few candidates in the late-stage pipeline.
With 2 drugs in phase 3 development, Lilly is the clear frontrunner. Its sole competition appears to be a green tea extract, sunphenon EGCg, which is being assessed in 1 actively recruiting, phase 2/3 AD trial in Germany.*
Lilly's drugs of promise are semagacestat (LY450139), a gamma-secretase inhibitor, and solanezumab (LY2062430), a monoclonal antibody. For what it's worth (and that may not be much), both are intended to disrupt or break up the amyloid plaques of AD (like the woebegone bapineuzumab).
Two phase 3 company-sponsored trials of semagacestat are listed in the NIH database (here and here). The first trial, called IDENTITY, will be completed in June of next year. And two phase 3 trials of solanezumab, EXPEDITION and EXPEDITION 2, are recruiting patients with mild-to-moderate AD (here and here). These trials will not be completed until 2012.
A phase 2 safety trial of semgacestat in 51 patients with mild-to-moderate AD revealed possible "concerns" about skin and hair reactions. Although plasma levels of amyloid beta dropped significantly with semagacestat, there were no treatment-related changes in CSF levels and no between-group differences in cognitive measures; however, the trial was too short (14 weeks) to adequately assess any cognitive benefits. A more recently published study showed that single doses of semgacestat reduce amyloid beta production, but not clearance, in a dose-dependent fashion.
* The trial is expected to be completed in April of 2011.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
In ALS, lithium carbonate is no better than placebo when added to riluzole (Rilutek; sanofi aventis) therapy. The conclusion is based on the fully reported results of a 6-month, multicenter North American study, the details of which are now available in an advanced online issue of the Lancet Neurology. The disappointing findings were originally reported in September of last year, after a planned interim analysis showed no added benefit with the compound.
On the basis of favorable results from a highly publicized Italian pilot study by Fornai et al, Canadian and US researchers randomized lithium and placebo treatment in double-blind fashion to 84 patients with ALS. By using a distinctive time-to-event trial design, researchers would continue the study only if the statistical significance (P value) between treatment-related events equaled .68 or less at an interim analysis.
At a mean treatment duration of 5.4 months,* 22 of 40 (55%) patients receiving lithium and 20 of 44 (45%) patients receiving placebo either died or demonstrated a 6-point score drop on the revised ALS Functional Rating Scale. The statistical significance between the treatment groups was .78—which, according to plan, necessitated discontinuation of the study.
Despite the inefficacy of lithium, which was dosed to achieve blood levels of 0.4-0.8 mEq/L, the drug was reasonably well tolerated. The most common treatment-related adverse events were falls and back pain.
According to the NIH database, there are 5 phase 3 survival trials currently recruiting patients with ALS. Investigated drugs include IM mecobalamin (ie, vitamin B12), the novel agents olesoxime and arimoclomol, and the antibiotic ceftriaxone. Information about active trials can also be found at the ALS Association web site.
ALS = amyotrophic lateral sclerosis.
* The first interim analysis occurred when 84 patients were allocated to treatment, at 6 months or after 55 events, and after 100 events.
Image of lithium carbonate powder from Wikipedia.
I don't get it. How does an employee with, by all appearances, an inherited illness prevail in litigation against a company for personal injury? At least the federal judge in the case of McClain v Pfizer threw out the issue of whether a Pfizer-bioengineered virus caused the plaintiff's recurrent paralytic illness.
Nevertheless, a jury awarded nearly $1.4 million to ex-Pfizer scientist Becky McClain, by ruling that the company had violated free-speech and whistle-blower laws. (The judge left the personal-injury issue to workers' compensation litigation.)
Coverage of the jury's decision is provided by the NYT, which also reveals that McClain, 52, suffers from "a potassium deficiency that causes sporadic and temporary paralysis"—in other words, hypokalemic periodic paralysis, a rare, genetically determined* disorder of ion channels in muscle (ie, a channelopathy). Unfortunately news coverage of the trial fails to stress the crucial genetic feature of McClain's reported illness. (They also fail to note that her OSHA complaint was evidently dismissed.)
Approximately 60% of cases of Hypo PP are due to a mutation in CACNA1S (calcium channel) gene; 20% are caused by a mutation in the SCN4A (sodium channel) gene. The remainder are probably due to new dominant mutations, according to information cited in a review by Venance et al. These ion-channel mutations cause the aberrant depolarization of muscle fibers, which renders them inexcitable; the clinical result is periodic paralysis. It's not clear what kind of Hypo PP-related mutation, if known, is harbored by McClain.
The essential features of Hypo PP, beyond its genetically determined nature, are listed:
- Age at onset: 1st or 2nd decade
- Duration of paralytic attacks: hours to days (may be diffuse or focal)
- Usual triggers: rest after exercise, carb loading
- Ictal potassium level: low
- Cardiac arrhythmias or skeletal developmental abnormalities: no (unlike Anderson-Tawil syndrome**)
- Response to potassium: improvement of weakness
Hypo PP is diagnosed on the basis of episodic paralysis, low serum potassium levels during the paralysis, and EMG features (post-exercise features may be particularly helpful). For anybody presenting with Hypo PP-consistent symptoms after the age of 20 years or whose family history is nonexistent, thyroid function should be assessed to exclude thyrotoxic PP.
According to news reports, McClain—who has an MS degree—claims that her paralytic illness was triggered by infection with a genetically engineered lentivirus at Pfizer's Groton, CT, campus. The Connecticut Law Tribune reports that McClain left work in early 2004 after developing her alleged symptoms.
Though her doctor cleared her to resume working a few months later, her attorney instead negotiated with Pfizer over her work conditions. Unable to reach an agreement, McClain was terminated in May 2005; Pfizer said it was because she had abandoned her job.
By then, McClain had filed a complaint with OSHA. It was dismissed when investigators ruled that her complaints were without merit; the OSHA report cited Pfizer for making "substantial efforts" to address McClain's concerns.
Probably smelling the high possibility of litigation from McClain on whatever grounds, it seems reasonable to conclude that Pfizer would have bent over backwards to accommodate McClain and her safety concerns—at least on some kind of sensible level.
According to the Center for Public Awareness in Bioethics web site, McClain has a bachelor's degree from Indiana University and a Master of Science in Public Health from the University of Texas School of Public Health in Houston. She worked for Pfizer as an unspecified scientist from 1996 to 2005 and filed her suit against the company in 2006.
EMG = electromyography; OSHA = Occupational Safety and Health Administration.
* Prevalence is reported at 1 in 100,000. The disorder is inherited in autosomal dominant fashion, with reduced penetrance in women. Also sporadic mutations are reportedly common in Hypo PP.
** The triad of PP, ventricular ectopy, and skeletal anomalies.