Recently in Neurology Category

Hospitalizations are reduced by the upfront use of a genetic test for "warfarin sensitivity," according to new results from a comparative-effectiveness study. The Medco- and Mayo-sponsored trial of the anticoagulant (the dosing of which has caused more than one headache in physicians and patients during the last 70 years) compared hospitalization rates among warfarin-treated subjects who underwent genetic testing and those who didn't. The trial results were presented this morning at the ongoing meeting of the American College of Cardiology in Atlanta; data are also available at the company's web site.

In the study, the dose of newly initiated warfarin therapy in nearly 900 adult patients* was adjusted on the basis of Medco's genetic test (performed on blood or cheek swabs). During a 6-month period, the hospitalization rate in this group was 31% lower than that of a historical control group (N = 2688) who had not undergone genetic testing (ITT analysis: ~18% vs ~25%). The hospitalization rate for bleeding or thromboembolism was 28% lower in the genotyped group.

Results from the per-protocol analysis were even more impressive. The rate of all-cause hospitalization and the rate of hospitalization for bleeding or thromboembolism were 33% and 43% lower, respectively, in the genotyped group.

The genetic test, which is available from several companies,** assesses the function of 2 genes, CYP2DC and VKORC1. The former encodes a well-known P450 enzyme that metabolizes warfarin; the latter encodes an enzyme that activates vitamin K (which counteracts the anticoagulant properties of warfarin). The cost of a warfarin sensitivity test is quoted in the press at a range of $250-$400. The FDA first approved use of the genetic test (Verigene; Nanosphere) to inform warfarin dosing in 2007.

According to Medco, about 30 million warfarin prescriptions are written and 2 million patients start warfarin treatment each year. Warfarin is the leading cause of ED visits, hospitalizations, and drug-related deaths. One third of the variability in response to the drug is ascribed to the genetically determined function of CYP2C9 and VKORC1.

Last week, the FDA added a boxed warning to the PI for the antiplatelet drug clopidogrel (Plavix; BMS/sanofi), which may be less effective in patients with reduced function of the CYP2C19 enzyme. (To become active, clopidogrel, a prodrug, must be converted by CYP2C19.) The FDA advised that 2%-14% of Americans are "poor metabolizers" of clopidogrel. CYP2C19 testing is also commercially available through a number of companies.

ITT = intent to treat; PI = package insert.

* Patients were recruited through 29 Medco-managed prescription benefit plans.

** For example, Ambry Diagnostics and Arup Laboratories.

Image of warfarin (Coumadin) bottles from NIGMS/NIH.

Yesterday the FDA approved Botox (onabotulinumtoxin A; Allergan) to treat distal arm spasticity in adults.* The approval was based on results from at least 3 trials in a total of 305 people with arm spasticity after stroke. Two of the 3 studies have been published in peer-reviewed journals (see here and here).

While the FDA's new approval partially mitigates the legal issue that Allergan has had with the agency's mandate to disseminate off-label safety information about Botox (for necessary background, go here, here, here, and here), it does not resolve the problem with respect to the use of Botox for limb spasticity in children—a still unapproved indication.

The case of Allergan v the United States of America et al was scheduled for a motion hearing in the US District Court for the District of Columbia on March 2nd. However, the docket has evidently been altered. According to the current court calendar, a status conference is scheduled for March 25th in the chambers of Judge John D. Bates, and a motion hearing is scheduled for April 26th.

* Specifically the flexor muscles of the elbow (eg, biceps), wrist (eg, flexor carpi radialis), and fingers (eg, flexor digitorum profundus).

Image of deep muscles of the ventral forearm from Gray's Anatomy (1918).

The Alzheimer's Association has a new report on the large and growing effect of Alzheimer disease and other dementias on Americans. Here's the distillation:

• AD is the most common cause of dementia, affecting 5.3 million Americans (1.7% of the current US population). The vast majority (96%) of those affected are older than 64 years of age.
• Dementia affects women preferentially because they live longer, on average, than men. (Advancing age is the biggest risk factor for AD.)
• In 2006, AD was the 7th leading cause of death among all Americans. In those older than 64 years of age, AD was the 5th most likely cause of death.
• Next year, the first baby boomers will turn 65. In 30 years, all of the estimated 70 million baby boomers will be older than 65. The Association estimates that there will be 1 million new cases of AD by the year 2050.
• People with AD and other types of dementia need a lot of health care, including long-term and hospice care. In 2010, care costs for people with dementia will reach $172 billion. Medicare costs for people with dementia are nearly 3 times higher than those for the nondemented elderly. Medicaid costs are nearly 9 times higher. (Blogger's note: I suspect this is the result of Medicaid-funded nursing home care.)
• Older African Americans and Hispanics are about 2 and 1.5 times more likely, respectively, to have AD and other types of dementia than older whites.* Reasons for the higher risk of AD among these minorities include a greater prevalence of known risk factors for dementia, like hypertension, diabetes, and lower education and income levels. (Ethnically dependent genetic risks have not been identified.) Despite the higher risk of dementia among African Americans and Hispanics, the diagnosis is more likely to be delayed in affected minority patients. Delays in diagnosis mean missed opportunities for treatment, which is more likely to be effective in the early stages of AD.
• Last year, nearly 11 million family members or other uncompensated persons provided 12.5 billion hours of care for people with dementia. Unpaid care was assessed at $144 billion, which is more than the US government (ie, Medicare and Medicaid) spends on people with dementia. Costs of giving care are also measured in emotional and physical stress, declining caregiver health, and lost employment-related productivity. 

* This is the lead of today's press release from the Alzheimer's Association.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

The most common, identifiable form of pediatric epilepsy, absence seizures (formerly known as petit mal seizures) were first described in the early 18th century by (you guessed it) a French guy. Effective and relatively safe pharmacologic treatment for the condition has been available since 1960, when ethosuximide (Zarontin) was introduced by Parke-Davis (now a subsidiary of Pfizer, like just about every other drug company).

Absence seizures are also responsive to valproic acid (aka Depakene or Depakote; Abbott), which was FDA approved for treatment of the disorder in 1978, and lamotrigine (Lamictal; GSK), which has been studied for the treatment of absence seizures since at least the late 1990s.*

Despite our extensive clinical experience with these drugs, it was unknown which provided the best empirical therapy for absence epilepsy. In fact, Glauser and other neurologists at the University of Cincinnati concluded in 2006 that it was "impossible to develop an evidence-based guideline" for the initial, monotherapy treatment of generalized seizures and specifically those in children, because of the "alarming lack of well-designed, properly conducted" randomized, controlled trials. This finding evidently prompted Glauser and his colleagues to conduct a randomized, double-blind multicenter trial of the 3 drugs in children with newly diagnosed absence seizures—the results of which are available in today's issue of the NEJM.

Among 453 children with new-onset absence epilepsy, Glauser et al found that ethosuximide or valproic acid were significantly more likely to result in a primary composite outcome of seizure control and tolerability (~50%-60% of patients) than lamotrigine (~30% of patients) after 4 months. Attentional deficit, a secondary outcome measure, was significantly more likely with valproic acid than ethosuximide (49% vs 33%).

Commenting at MedPage Today, Glauser said, "[E]thosuximide gave the child the best chance to get the combination of seizure control without side effects or [adverse] effects on attention."

So ethosuximide, it is; then valproic acid; then lamotrigine.

* Although lamotrigine is not FDA approved for the treatment of absence seizures specifically.

The characteristic 3-per-second spike-and-wave EEG pattern of absence epilepsy from An Introduction to Epilepsy.

Someday I'm going to learn to capitalize on the overblown expectations and inevitable letdown of AD drug development.

Dimebon (latrepirdine), the nonselective antihistamine that Pfizer shelled out millions for, failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with mild-moderate Alzheimer disease. The disappointing results were distributed today by way of press release from the drug's codevelopers, Medivation and Pfizer.

In a double-blind study of 598 individuals with AD in North America, Europe, or South America, Dimebon 20 mg tid was no better than placebo for improving or delaying declines in cognition (as measured with the ADAS-cog) or global functioning (as measured with the CIBIC-plus) at 6 months. Measures of secondary endpoints (eg, activities of daily living) were, likewise, similar between Dimebon- and placebo-treated patients.

As expected, the most frequently reported adverse events with the antihistamine were somnolence and dry mouth. A 5-mg treatment arm and another, large phase 3 safety study revealed consistent drug tolerability. For what it's worth, the phase 3 safety study showed that the drug can be taken with common AD medications, like cholinesterase inhibitors (eg, Aricept; Pfizer) or memantine (Namenda; Forest).

Results from the phase 3 efficacy study were to be used in conjunction with positive results from a phase 2 Russian study to support FDA approval. But, evidently, no more. 

In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when the drug was approved. The agreement also conferred licensing rights to Pfizer for use of the drug in Huntington disease. Last month, results from a 90-day safety trial of Dimebon in HD showed that the drug may improve cognition.

The price of Medivation stock dropped nearly 30 points on release of the phase 3 trial results, from $40.12 to $12.88.

ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale; CIBIC-plus = Clinician's Interview-Based Impression of Change Plus Caregiver Input.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

Stenting of the carotid artery is a less invasive and potentially safer alternative to traditional endarterectomy (CEA) for the treatment of stenotic plaque. However, the relative efficacy of carotid stenting to prevent stroke has been unclear—a fact that has informed limited Medicare coverage for the procedure in the United States. Unfortunately the efficacy of carotid stenting remains unsettled after the recent release of conflicting results from 2 large, non-blinded studies.

Thursday the Lancet and Lancet Neurology published data from the International Carotid Stenting Study (ICSS), which showed a significantly higher incidence of ischemic stroke and related events after stenting. But results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), which were presented Friday at the International Stroke Conference, revealed comparable rates of stroke, MI, or death with the 2 procedures.

Salient differences between the 2 studies, which include different patient populations and primary endpoints, are tabulated here. The main difficulty when attempting to conclude anything practical from the studies' results is that there are no easy apples-to-apples comparisons.

Trial Feature	ICSS (MRI Substudy)	ICSS		CREST
Location	Europe, Canada, Australia, New Zealand			United States, Canada
No. centers	7	50		100
Sponsorship	UK Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union, Netherlands Heart Foundation, Mach-Gaensslen Foundation	Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union		NINDS, Abbott Vascular (maker of Acculink carotid stent)
Patient no.	231	1713		2502
Carotid stenosis	Recently symptomatic			Symptomatic or asymptomatic
Primary outcome	30-day rate of new ischemic lesion on MRI		120-day rate of stroke or death or periprocedural MI*	30-day rate of death, MI, or stroke plus ipsilateral stroke thereafter
Stenting, %	33**		8.5**	7.2
CEA, %	8**		5.2**	6.8

* For interim safety analysis. The primary outcome of the ICSS is fatal or disabling stroke at 3 years; results are expected in 2012.
** Statistically significant, stenting vs CEA.

Those physicians who favor the CREST results in news reports propose that the positive outcomes with stenting are dependent on a high surgical skill level. Those physicians who favor the ICSS results note that, in CREST, the risks of periprocedural stroke and the composite outcome of death, MI, or stroke at 30 days were significantly higher with stenting (4.3% vs 2.3% and 5.2% vs 4.5%, respectively). They also cite previous studies (ie, the EVA-3S and SPACE trials) that failed to show the short-term equivalence of stenting. 

Upcoming post-hoc analyses of CREST may aid the identification of subpopulations (eg, those younger than 70 years of age) who are likely to realize more positive outcomes with carotid stenting. These data may inform the preferential use of carotid stenting in practice—at least when the surgeon is skilled in the procedure.

N.B.--One notable and underreported finding from the ICSS MRI substudy is that, in patients who received stents, embolic protection devices (like the FiberNet EP System) were associated with significantly higher rates of stroke (73% vs 34%). In patients who underwent CEA, the stroke rates with and without embolic protection devices were 17% and 16%, respectively. 

EVA-3S = Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis; NINDS = National Institute of Neurological Disorders and Stroke; SPACE = Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy.

Anatomic diagram of the common, internal, and external carotid arteries from Gray's Anatomy (1918).

On the basis of improved survival in a small pilot study, selected patients with severe traumatic brain injury (TBI) will undergo treatment with natural progesterone in a soon-to-begin, multicenter, phase 3 study throughout the United States. The trial, led by Emory's David Wright, is unusual in that it will forgo the typical FDA requirement of informed consent to allow for the timely administration of therapy.

More than 1000 adults will receive randomized treatment, in a 4-to-1 ratio, of high-dose IV progesterone or placebo over the course of 4 days after emergency presentation. The primary outcome measure is the Extended Glasgow Outcome Scale score at 6 months. Secondary outcome measures, also at 6 months, include mortality, adverse events, and neurologic function. The trial is expected to be completed in 2015.

According to Dr. Wright, as quoted by BBC News, the progesterone dose in the trial will result in a blood level that is about 3 times higher than that found during the third trimester of pregnancy. Preclinical studies suggest that natural, but not synthetic, progesterone is neuroprotective—despite the chemical similarity of the molecules.

Sagittal view of shear stress in head model from sandia.gov.

People with migraine—especially people who experience aura before headache—are known be at increased risk of ischemic stroke and cardiovascular disease. What isn't well known, however, is 1) whether these increased risks apply to people who have migraines without aura; and 2) whether migraine is an independent risk factor for vascular disease or merely a marker for well-known risk factors, like diabetes.

A new survey study of more than 11,000 people, the results of which are published online in the journal Neurology, essentially answers "yes" to these issues.

1. People who experience migraine without aura have increased risks of heart attack and peripheral vascular disease—but, surprisingly, not stroke. These increased risks, however, are smaller than those for people who experience migraine with aura.
2. All people who experience migraine (with or without aura) are more likely to have been diagnosed with diabetes, hypertension, or high cholesterol levels—all well-known vascular risk factors.
3. But, on the basis of a multivariate analysis (including control for triptan use*), migraine also appears to be an independent risk factor for vascular disease.

The absolute rates of vascular events and vascular risk factors, discovered by the authors, are tabulated here:

Condition	Controls (Without Migraine)	All Migraineurs	Migraine With Aura	Migraine Without Aura
Heart attack, %	1.9	4.1	5.5	3.4
Stroke, %	1.3	2.0	3.8	1.1
Claudication, %	0.9	2.6	4.2	1.8
Diabetes diagnosis, %	9.4	12.6	13.8	12.0
Hypertension diagnosis, %	27.8	33.1	35.7	31.9
High cholesterol level, %	25.6	32.7	33.8	32.2
Smoking, %	14.2	15.8	16.3	15.5
Mean Framingham risk score	8.5	10.7	11.0	10.6

The mean Framingham risk scores for all 3 groups of migraineurs were significantly higher (P = .001) than the mean score for the surveyed control population.

The authors, who represent industry (Merck**) and academia (Albert Einstein, Brigham and Women's), stress that a history of migraine in patients should prompt a search for modifiable cardiovascular risk factors. They also postulate that migraine itself may predispose to vascular disease by compromising the function of vascular endothelium.

The question of whether triptan use or migraine prevention (eg, with beta blockers) alters the risk of vascular events is raised by Diener and Harrer in an accompanying editorial. They propose that the necessary length of a prospective study would be prohibitive (eg, >10 years). They also wonder whether the relatively low risks of vascular events in migraineurs would justify the effort and expense.

* Recently the same authors (Bigal et al) reported that tripan use is lower in migraineurs with cardiovascular risks, "suggesting that doctors and/or patients fear using tripans in individuals at risk."

** Merck makes Maxalt (rizatriptan).

Depiction of classic fortification spectra of migraine aura, as depicted by Dr. Gowers in 1907.

The defunct Russian antihistamine Dimebon may (may) improve cognition in Huntington disease, according to newly published results of a short-term, but well-controlled, trial in the Archives of Neurology. However, the efficacy outcome—which was just 1 of 3 efficacy measures made in the trial—was not the primary endpoint of this company-sponsored phase 2 study of the drug's tolerability.

Among 91 ambulatory enrollees with HD,* 90-day treatment with Dimebon, 20 mg tid, significantly improved the mean score on the 30-point MMSE by less than 1 point (0.97; P = .03, vs placebo). No significant differences between Dimebon and placebo treatment were noted, however, on the Unified Huntington's Disease Rating Scale (which assesses motor function, as well as cognition) or the 13-item ADAS-cog. Tolerability of Dimebon, the primary outcome measure, was comparable to that of placebo: 87% and 82% of patients, respectively, completed treatment. No significant treatment differences were noted with regard to the most commonly reported adverse events (eg, falls, headache, and dizziness).

The rationale for studying Dimebon in HD and other neurodegenerative disorders, like Alzheimer disease, is based on the drug's ability in the laboratory to stabilize mitochondrial membranes and possibly promote neuronal stability or even regeneration. According to the study authors, "Abnormal mitochondrial depolarization, which can lead to collapse of the mitochondrial membrane and ultimately neuronal apoptosis, has been implicated in the pathophysiologic progression of HD and other neurodegenerative diseases."

A placebo-controlled study of Dimebon in AD revealed significant improvement in cognition, behavior, and general function at 6 and 12 months. Results of this study evidently motivated Pfizer to give Medivation $725 million in 2008 for worldwide marketing rights to the drug. Corporate-funded phase 3 studies of Dimebon are currently recruiting patients with HD (here) or AD (for instance, here or here).

News of the phase 2 results was associated with a bump in Medivation's share price (but not Pfizer's).

N.B.--Dimebon is the trade name for dimebolin HCl or latrepirdine.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; MMSE = Mini-Mental State Examination.

* Study-eligible patients were allowed to take antipsychotic agents (at stable dosages), but they could not take cholinesterase inhibitors (eg, Aricept) or N-methyl-D-aspartate antagonists (eg, Namenda).

Image of Dimebon structure from Wikipedia.

Occupational exposure to the industrial solvent trichloroethylene increases the risk of Parkinson disease, according to researchers at the Parkinson's Institute and Clinical Center. The California-based, nonprofit organization released its study findings, which have not been presented at a scientific meeting or peer reviewed, on Sunday—apparently by way of press release. The data are scheduled to be presented at the annual meeting of the American Academy of Neurology in April.

According to sources picking up news of the study, data from 198 twin pairs in the World War II Veteran Twins Cohort Registry showed that the risk of PD in individuals with probable exposure to the solvent* was more than 5 times that of twins without probable exposure.** In a MedPage Today piece, an odds ratio (5.5) is reported, but no frequency rates of disease are provided. Also the 95% confidence interval for the odds ratio is very wide (1.02, 30)—indicating that the accuracy of the measured risk is uncertain.

Interest in trichloroethylene exposure as a risk factor in PD extends back to the early 90s, when it was reported by German investigators that a metabolite of the solvent is chemically similar to the neurotoxin MPTP. (The metabolite of MPTP, MPP+, has a predilection for the dopamine-producing neurons of the substantia nigra—the area of the brain that is primarily affected in PD. The MPTP story, itself, is fascinating and the subject of an excellent Nova episode, "The Case of the Frozen Addict," from 1986.)

In 2008, researchers at the University of Kentucky published their study of 30 industrial workers with PD or parkinsonism, who had long-term exposure to trichloroethylene. The study authors suggested that a worker's proximity to the solvent was related to his risk of the movement disorder. These findings were complemented by animal studies, which showed that oral intake of trichloroethylene for 6 weeks resulted in the degeneration of brain areas that are typically affected in PD.

* Presumed on the basis of occupation (eg, aircraft mechanic, electrician).

** The study of twins (and presumably, these are identical twins) largely eliminates any potentially confounding genetic risks of Parkinson disease.

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.