April 2011 Archives

We all pretty much knew that armadillos are a source of leprosy

. (Right, we all pretty much knew that?) In fact, a 2005 review by Louisiana State's Richard W. Truman, PhD, reminds us that wild armadillos were recognized as early as 1975 to harbor Mycobacterium leprae, the causative agent,* and that the probable sources of the pathogen for armadillos were European and African immigrants to the New World some 400-500 years ago. But leprosy also appears to be a disease that has kept on giving, or more accurately circulating...between the 2 species.

This conclusion is supported by a recent genome-sequencing study, led by Truman and the results of which are published in this week's issue of the NEJM. The data show that infected humans and armadillos in disease-endemic areas of the Americas (like Louisiana and Venezuela), in fact, often harbor the same M. leprae strain—suggesting that leprosy is a bona-fide zoonosis.

But how North Americans have acquired and are acquiring the leprosy pathogen from armadillos has not been well-defined. Truman tells the NYT that the contact is probably not casual, given the persnickety nature of the bug.** He advises that "people should be discouraged from consuming armadillo flesh or handling it," a relatively common practice in areas of, for example, Brazil—a country that contributes one half of all leprosy cases in the Americas.

* The reason being that armadillos have a naturally low core body temperature, which fosters the growth of M. laprae.

** Because M. leprae cannot be cultivated in a Petri-dish-type culture, armadillos have historically been used to artificially propagate the pathogen.

iStockPhoto pic of armadillo. God, they're ugly.

A Montana woman is suing Abbott

, the maker of Humira, after she developed symptoms of peripheral neuropathy (PN) while taking the TNF inhibitor for Crohn's disease. Yesterday's news from Bloomberg prompts a bit of research here on a possible link between the use of TNF inhibitors and PN and the sticky task of dissecting out the underlying illness (eg, Crohn's disease, rheumatoid arthritis, psoriasis) as an alternative cause of neuropathy.

Cue a case report and literature review of probable TNF-inhibitor-associated PNs by Lozeron et al, which was published in a 2009 issue of the Archives of Neurology. The PN complication appears to be a bona fide, albeit very rare, drug-related event, with most neuropathies defined as sensory, motor, or mixed demyelinating PNs (vs axonal). And a sizable chunk of these PNs appear to be clinically indistinguishable from Guillain-Barre syndrome, aka acute demyelinating PN (which necessitated the standard treatments of plasma exchange and/or IV Ig).

The temporal sequence of events suggests a causal contribution of the drug,* although it should be noted that the underlying condition may well contribute to the development of a PN—which may, in turn, predispose a patient to superimposed drug-related damage. The long-term course for these TNF-inhibitor-treated patients—PN-wise—appears to be generally favorable, particularly if the drug is discontinued. Although Lozeron et al advise, on the basis of their long-term follow-up of 5 PN cases, that withdrawing TNF-inhibitor therapy is not always necessary.

As far as the personal-injury/legal angle is concerned, the overriding argument (at least by my understanding) will be to show that the drug maker failed to warn of the PN risk (provided that the drug maker was even aware of the adverse event). The latest, online version of the Humira package insert (March 2011) states,

Use of TNF blocking agents, including Humira, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS), and peripheral demyelinating disease, including Guillain-Barre syndrome. Prescribers should exercise caution in considering the use of Humira in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

A review of the text of historical labels for Humira (available at the FDA web site) shows a warning for CNS demyelination as early as 2002, when the drug was approved:

Use of TNF blocking agents, including Humira, has been associated with rare cases of exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Prescribers should exercise caution in considering the use of Humira in patients with preexisting or recent-onset central nervous system demyelinating disorders. 

However, warnings about potential PN damage were not included in the Humira label, until the FDA prompted their inclusion last year. In a letter dated July 29, 2010, the FDA advised Abbott's Associate Director of Global Pharmaceutical Regulatory Affairs,

Reference is also made to our letter dated April 20, 2010, notifying you, under Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA) of new safety information that we believe should be included in the labeling of TNF blockers. This information pertains to the risk of peripheral demyelinating disorders, including Guillain-Barre syndrome, demyelinating polyneuropathy, and multifocal motor neuropathy, associated with the use of the class of TNF blockers including Humira (adalimumab).

The label revision was apparently incorporated immediately by Abbott.

TNF = tumor necrosis factor.

* And it appears to be a drug class effect, with reports implicating infliximab (Remicade; Centocor Ortho Biotech), etanercept (Enbrel; Amgen/Pfizer), and adalimumab (Humira).

Antiinflammatory drugs, specifically aspirin and NSAIDs, may interfere with the antidepressant effect of SSRIs, according to a mouse study published online today in PNAS (subscription required). The speculative reason: These COX-2 inhibitors reduce the production of inflammatory cytokines, like TNF alpha and interferon gamma, which may otherwise figure importantly in the antidepressant effect of SSRIs.

In NSAID-treated mice, investigators at New York's Rockefeller University and Inter-Cellular Therapies found depressed brain* levels of TNF alpha and interferon gamma, which are otherwise increased with SSRI therapy. A human correlate is suggested by a post-hoc analysis of a subpopulation from the first round of the landmark STAR*D Study. Overall the SSRI citalopram (Celexa) was effective for about 55% of enrollees; among those taking NSAIDs, the efficacy rate was about 45%.

As expected, quoted scientific pundits say that more study, with confirmation of the results, is needed

COX = cyclooxygenase; NSAID = nonsteroidal antiinflammatory drug; PNAS = Proceedings of the National Academy of Sciences of the United States of America; SSRI = selective serotonin-reuptake inhibitor; STAR*D = Sequenced Treatment Alternative to Relieve Depression; TNF = tumor necrosis factor.

* Specifically in the murine frontal cortex.

Photo of generic ibuprofen tablets from Wikipedia.

Heartfelt blogger Melissa Walton-Shirley

, a cardiologist, offers important experiential praise and criticism of Pradaxa (in contradistinction to my paper-based and generally unwavering praise of the drug).

Turns out that one of the potential downsides of the pill is, in fact, one of its biggest assets: freedom from warfarin-like drug monitoring. It seems that the idea of periodically testing and monitoring an anticoagulant's effect has been so engrained in the practice of medicine (and specifically cardiology) that physicians actually miss the tangible feedback. Who knew? This issue becomes a particularly touchy one when providing anticoagulation to the potentially renally compromised elderly—at least according to Walton-Shirley and a few commenters.

Another area of practical hedging: when to discontinue Pradaxa before surgery. Apparently surgeons are tap dancing on a recommendation that spans 3-5 days pre-op. As Walton-Shirley asks about this "gray zone": "Well, is it three or is it five?"  

Le Doulos (1962): Another study of the criminal subculture provided by the brilliant Jean-Pierre Melville, French lover of American noir and the unrecognized pioneer of the contemporary movie thriller. Frankly (or Francophilically?) Melville is the rare director who makes cinema—yes, cinema—simultaneously entertaining and meaningful.

At its essence, Le Doulous, which refers either to a type of fedora or a "finger man," concerns the idea of loyalty and (perhaps, more important) the impression of it. There are enough brow-furrowing twists here to engage the most seasoned and sophisticated viewer, while averting sheer frustration. But perhaps the ultimate praise for Melville's take on allegiances is to write how the film motivates an immediate rewind.

Poster image of De Loulos, starring Jean Paul Belmondo and Serge Reggiani (who, weirdly, looks like Rowan Atkinson's hard-luck brother), from Wikipedia and reproduced under fair use law.

IMS Health released its report for 2010 prescription drug sales yesterday, and Forbes's Matthew Herper (among others) directs his commentary at the number-2 ranking of Nexium, AstraZeneca's me-too proton-pump inhibitor.

There are seemingly innumerable ways to slice, dice, and augment these data—all in the hopes of painting a clearer picture of what's exactly going on with prescription drug sales and costs. My take is to list the top 25 money makers (and who says the age of the blockbuster, let alone the uber-blockbuster, is over?) and compare these numbers with the latest monthly cost of each drug—courtesy of destinationrx.com (my latest, favorite go-to source for prescription drug prices). 

What becomes apparent when you divide the 2010 sales by the monthly cost* is that the makers of several drugs—Copaxone (Teva), Neulasta (Amgen), Rituxan (Genentech/ Roche), Epogen (Amgen)—are clearly capitalizing on the fewest prescriptions for the most desperate patients. Specifically those with multiple sclerosis or cancer. (Check out the last column of the table below.)

This is not to say that pharma should not be able to generate profits off its innovations (or "innovations," in some cases—like Nexium), but there is a point at which the cost of treatment cannot (or should not) be justified on the basis of, "We charge what we charge because we can."

	Drug Brand Name	2010 Sales, Billions $	Monthly Cost, $	2010 Sales/ Monthly Cost
1	Lipitor (Pfizer)	7.2	111 (10 mg)	64,865
2	Nexium (AstraZeneca)	6.3	186 (40 mg)	33,871
3	Plavix (sanofi-aventis/BMS)	6.1	197	30,964
4	Advair Diskus (GSK)	4.7	303	15,512
5	Abilify (BMS/Otsuka)	4.6	524 (10 mg)	8779
6	Seroquel (AstraZeneca)	4.4	199 (25 mg)	22,111
7	Singulair (Merck)	4.1	144 (10 mg)	28,472
8	Crestor (AstraZeneca)	3.8	141 (10 mg)	26,950
9	Actos (Takeda)	3.5	248 (30 mg)	14,113
10	Epogen (Amgen)	3.3	2814 (20 doses)	1173
11	Remicade (Centocor Ortho Biotech)	3.3	745 (1 dose)	4430
12	Enbrel (Amgen/Pfizer)	3.3	923 (4 doses)	3575
13	Cymbalta (Lilly)	3.2	146 (60 mg)	21,918
14	Avastin (Genentech/Roche)	3.1	630 (4 doses)	4921
15	OxyContin (Purdue Pharma)	3.1	235 (60 doses)	13,191
16	Neulasta (Amgen)	3	3689 (1 syringe)	813
17	Zyprexa (Lilly)	3	362 (5 mg)	8287
18	Humira (Abbott)	2.9	1811 (2 doses)	1601
19	Lexapro (Forest)	2.8	103 (10 mg)	27,184
20	Rituxan (Genentech/Roche)	2.8	3148 (500 mg)	889
21	Aricept (Eisai/Pfizer)	2.5	260 (10 mg)	9615
22	Lovenox (sanofi-aventis)	2.3	325 (4 doses)	7077
23	Atripla (BMS/Gilead)	2.2	1672	1316
24	Copaxone (Teva)	2.2	3754	586
25	Spiriva Handihaler (Pfizer/BI)	2	817 (90 doses)	2448

TNF = tumor necrosis factor.

* The big caveat to this informal analysis is that the overall sales for 2010 (numerator) are being divided by the latest (not necessarily 2010) monthly prescription drug prices (denominator).

Guidelines for the diagnosis of Alzheimer disease and its early companions MCI and preclinical dementia have been revamped for the first time in 27 years, reports the National Institute on Aging (NIA). And a quick scan of the online documents, offered freely at the site of the journal Alzheimer's & Dementia, reveals that a lot of thought and ink has been devoted to the burgeoning area of biomarkers—meaning the use of brain imaging, like MRI or PET, or assays of tell-tale molecules, like beta amyloid and tau, in spinal fluid (CSF).

The overriding admonishment, at least for now, is that these biomarkers aren't ready for routine practice—which is not necessarily something unexpected by practicing neurologists, but which may dampen the otherwise-unbridled enthusiasm of industry (eg, Lilly), venture capitalists, and some journalists. One big caveat offered by the members of the NIA- and Alzheimer's Association-sponsored panel, which revamped the moldy guidelines,* is that there is currently little standardization of these biomarkers to ensure their proper use and interpretation in routine practice. Consequently it is recommended that they be incorporated only into clinical trials and accompany other, conventional measures of the dementing process.

Another thought here is that CSF assays won't really take off in routine practice until somebody invents a quick-and-easy method for obtaining the fluid. As far as I can tell, the bedside/office procedure—which, although generally benign, is still a somewhat clunky process*—hasn't changed in more than 100 years. And much like the guy who (by legend) made money selling mining utensils during the various gold rushes, the guy or gal who revolutionizes our antiquated method for obtaining spinal fluid will profit the most when CSF biomarkers are (probably inevitably) incorporated into routine practice.

MCI = mild cognitive impairment.

* But the fact that the need to change these guidelines hasn't been acutely felt since 1984 shows just how little progress we've made in understanding this illness. Sigh.

** And without significant reimbursement.

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

Not to be confused with Troy McClure's Cry Yuma or even Cry Havoc (1943) and certainly not Cry Freedom (1987), Cry Danger (1951) is rock-solid film noir—thanks in large part to the rock-solid Dick Powell.

Powell, with his trademark half-jovial-half-fuck-you persona, is ex-con Rocky Mulloy, a guy who's been dubiously convicted of armed robbery, and who—in his clear opinion—has been wrongfully denied his share of the stolen loot by a cagey bar owner (played by the persistently underappreciated William Conrad). Added to the typically convoluted noir plot are a stalking detective who's intent on cracking the case (Regis Toomey); an opportunistic and seriously alcholic marine (Richard Erdman); and the wife (Rhonda Fleming) of Mulloy's best friend and partner, who's still in the pokey.

The big inner conflict for Mulloy, which Powell conveys with subtle perfection, is his allegience to his incarcerated friend and his undying torch for the guy's wife. But we should know by now: That ain't no thing in noir.

Poster for Cry Danger from Wikipedia and reproduced under fair use law.

Chronic cerebrospinal venous insufficiency (CCSVI)—a much-ballyhooed marker for multiple sclerosis and a possible target for treatment—appears to be neither a particularly sensitive nor specific indicator of the disease. This conclusion is based on a new study from the University of Buffalo, where hemodynamics of the transcranial and extracranial veins were assessed by echo-color Doppler ultrasound in 336 people with various neurologic conditions (including MS) and 163 healthy controls.

The essential take-away of this quasi-blinded study is this: That although the prevalence of CCSVI (established by meeting 2 of 5 criteria) was statistically significantly higher in individuals with MS than in healthy controls (62.5% vs 25.5%; P < .001), this difference was not significant between patients with MS and those with a wide variety of other neurologic diseases (62.5% vs 45.8%; P = .131). There was also a substantial percentage of so-called borderline CCSVI cases in each of the study subgroups (18 cases among healthy controls and 30 cases among patients with MS), making the condition a potentially difficult one to establish with comfortable certainty. (Read on for other technical caveats when attempting to measure CCSVI.)

Study Subgroup	CCSVI,* %	CCSVI,** %
Healthy controls	25.5	22.7
Clinically isolated syndrome	42.1	38.1
Other neurologic diseases	45.8	42.3
MS	62.5	56.1

In the Buffalo study, the highest calculated sensitivity for CCSVI as a potential marker for MS was 62.5%, and the highest calculated specificity was 77.3%. These values are considerably lower than the hard-to-believe calculations offered by Paolo Zamboni (100% and 100%), the Italian vascular surgeon who, in 2009, resurrected this mess—er, the idea that MS has a vascular cause. The Buffalo authors concluded,

Our findings are consistent with an increased prevalence of CCSVI in MS but with a modest sensitivity/specificity. Our findings point against CCSVI having a primary [emphasis added] causative role in the development of MS.

In an accompanying editorial, Fox and Rae-Grant of the Cleveland Clinic importantly note that the 5 ultrasound criteria for CCSVI proposed by Zamboni "have yet to be validated against a criterion standard." Moreover, they advise that the use of balloon venoplasty to treat presumed CCSVI in MS "should be restricted to a blinded, controlled clinical trial using carefully chosen clinical endpoints and appropriate patient safety oversight."

But the docs aren't entirely dismissive of the possibility that CCSVI could figure importantly in the pathogenesis of MS: "It behooves the clinical research community to carefully pursue CCSVI to its end," they advise. To that end, the US and Canadian MS Societies awarded a total of $2.4 million in grants to various groups last year to study CCSVI.

In a measured comment at MedPage Today (taped at the ongoing annual meeting at the AAN), Fox also advised that a number of factors (technician pressure on the blood vessel, patient hydration, machine knob settings) can dramatically affect whether CCSVI is detected or diagnosed. He charged that Zamboni did not provide sufficient information on these types of parameters to ensure that his impressive results can be reliably tested or replicated. When questioned about the possible alternative of MR venography to assess CCSVI, Fox warned that the technique is probably not sufficiently sensitive to detect the venous-flow changes that are assumed to be associated with the purported CCSVI. Consequently, he implied, we should stick with ultrasound for now and establish the methods and criteria for detecting CCSVI (if it even exists beyond that of an epiphenomenon).

* Borderline cases excluded from "no CCSVI" group.

** Borderline cases included in "no CCSVI" group.

Image of neck veins from Gray's Anatomy (1918).

Addendum: Also to further muddy the waters, the CCSVI rates in the Buffalo study between healthy controls and patients with other neurologic diseases were not significantly different (P = .39).

FDA officers clearly don't practice medicine.* And as a result, they can make some really boneheaded approval decisions. Case in point is the agency's October nod to the 150-mg pill of the anticoagulant dabigatran (Pradaxa), but not the 110-mg pill. (For background starters on this topic and my unalloyed opinions, go to last year's No. 4 "Top Ten" story.)

The government's tap-dancing rationale for such an otherwise-inexplicative move is now available in the NEJM. And it's not terribly convincing. The FDA's argument can be distilled to this:

• Because the 150-mg BID regimen was superior to the 110-mg BID regimen in the pivotal trial (RE-LY), we only approved the higher-dose pill.
• We couldn't find a subpopulation in the pivotal trial (like older patients) for whom the 110-mg BID dosage was clearly superior to the higher dosage.

So it appears that the FDA concentrated on the treatment benchmark of high-dose Pradaxa, when considering approval of the 110-mg pill, rather than the traditional standard of care: warfarin. This really doesn't make a whole lot of sense, especially when the 110-mg BID regimen—which unlike warfarin, doesn't require laboratory monitoring—was noninferior (ie, equivalent) to warfarin therapy. By its own logic, the FDA should then recall the use of warfarin to prevent stroke in patients with atrial fibrillation.

Nevertheless in the same breath, the FDA officers acknowledge that there "were certainly reasons why we might have approved both doses [of dabigatran]." Among these is the recognition that "patients and doctors value choices" and the fact that some patients refuse to take warfarin because of fear of bleeding. In the end, however, it appears that the agency was skittish about patients or doctors opting for the warfarin-comparable 110-mg BID regimen, instead of the warfarin-superior 150-mg BID regimen.

But that's really a clinical decision that should be left up to practicing clinicians—not government officers pouring over statistical trial data in a windowless room, and certainly not government officers for whom warfarin treatment, with all its headache-inducing monitoring and pesky dose fiddling, is a whitewashed abstraction. The FDA's restriction on treatment options for patients with atrial fibrillation simply means that fewer of these patients will receive effective and relatively convenient stroke prevention.

Aaagh. I can't shake my head enough.

At heartwire, RE-LY investigator Stuart J. Connolly, MD, FRCPC, essentially concurs and responds to the FDA editorial by calling it an "apology" for "a bad decision." He declares in no uncertain terms: 

I just think that they're wrong; they should have approved the lower dose. I don't think what they're saying is incorrect—they couldn't find a subgroup in the RE-LY study—but I do think that there are patients where the 110-mg dose makes perfect sense.

And adds:

What's needed is [a reduced dose for] those patients in whom the bleeding risk is considered to be sufficiently high that they wouldn't want to use the 150-mg dose. Without the 110-mg dose available, there are, I think, a lot of patients who now will not receive dabigatran at all—these are patients for whom warfarin was not being used because the bleeding risk was considered to be high, or patients who have some bleeding on the dabigatran 150-mg dose for whom there is no alternative available.

What's clear is that they don't trust physicians to make rational choices about the use of the two doses. The point that they're missing is that physicians have a lot more information at their disposal when they're encountering a patient than what is in the RE-LY database, including an appreciation of the patient's own values, a lot more information about the patient's bleeding risk, and other information about the patient's history that just isn't in the RE-LY database.

Heartwire also reports that Boehringer Ingelheim continues to "discuss" the approval of the 110-mg pill with the FDA.

It's clearly time (overtime) that the FDA admit its mistake and approve the 110-mg pill of dabigatran.

N.B. The 110-mg pill is approved in Canada (along with the 75- and 150-mg pills) for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation.

RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy.

* At least that's my only explanation for the boneheaded approval decision on Pradaxa. 

A securities firm* screwed the embargo pooch (or something like that), and so everybody can report on phase 3 data about Teva's investigational pill for multiple sclerosis. The data are to be presented this Friday at the annual meeting of the American Academy of Neurology (AAN) in Honolulu, but a teaser press release—for what it's worth (and that's not a whole lot)—provides these non-peer-reviewed data.

In an international placebo-controlled study of 1106 people with relapsing-remitting disease (ALLEGRO), laquinimod (Teva's pill) reduced the annual relapse rate by 23%. In addition, disability progression and brain atrophy (via MRI) were reduced by 36% and 33%, respectively. Safety issues associated with laquinimod were primarily related to temporary elevations of liver enzymes. The study duration was 2 years, and most enrollees stuck it out for the duration: 80% for laquinimod and 77% for placebo.

These "exciting results," to quote the quoted primary investigator, Giancarlo Comi, may be due to the drug's "novel mechanism of action...which effectively and safely addressed both the acute and inflammatory activity and the accumulation of irreversible tissue damage."

The only disease-modifying pill currently available in the United States for the treatment of MS is fingolimod, aka Gilenya—Novartis's recently approved and uber-expensive drug, which won the race to be the first FDA-approved disease-modifying oral treatment for the relapsing-remitting form of the disease.

In the placebo-controlled phase 3 study of fingolimod (FREEDOMS), the drug reduced the annual relapse rate by about 55%. And while it's not exactly kosher to compare outcomes from different studies, the cumulative data suggest (suggest) that laquinimod is safer, but less effective, than fingolimod.

And that's a marketing area that Teva is very comfortable with—having very successfully promoted Copaxone (glatiramer acetate), a-not-terribly-effective-but-reasonably-safe injectable MS drug,** to both patients and doctors for the last 14+ years.

* That's what MedPage Today reports from an Academy staff member.

** Essentially better than nothing, IMO.

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 frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

First: Thank you for stopping by.

Second: The comments and trackback functions have been completely disabled on this blog,* until I can export the contents of this site to a better (meaning not utterly shitty) blogging software—that is, NOT Movable Type. Once this transition has been made,

• visitors may actually be able to comment on posts without jumping through a number of sign-in hoops (and getting trapped in a TypeKey loop);
• spambots may actually be thwarted from dumping their truckloads of spam here;
• and I may be able to understand where essential functions can be found on the fucking dashboard. 

My ultimate comment on this subject, and this is possibly the only comment I'll ever make on this blog about blogging software, is that the recommendation 3+ years ago to use MT has to be one of the worst pieces of advice I have ever received, short of "Here, take this prednisone."

* Not that anyone but the most determined of human beings could comment anyway. 

No Man of Her Own (1950): Much like John Jon Hamm's character from "Mad Men," Barbara Stanwyck, as the unmarried and pregnant Helen Ferguson, gets a second chance at a decent life by adopting somebody else's identify through an accidental turn of events. (Although Stanwyck's character, unlike Don Draper, uses her opportunity for good, instead of for marketing cigarettes.) But a secretive life rarely plays out well in movieland (or TV land or real life, for that matter)—particularly when your Baby Daddy is played by the villainous Lyle Bettger.

High neurofilament levels (specifically those of heavy-chain subunits [NfH]) in CSF appear to be significant indicators of active neurodegeneration in the most common forms of established multiple sclerosis. This conclusion is based on newly published data from a medium-sized European study, in the latest issue of Neurology, which included 73 healthy controls, 63 patients with clinically isolated syndrome (CIS), and others with relapsing-remitting (n = 39), secondary-progressive (n = 25), or primary-progressive (n = 23) MS.

The data, which also demonstrate the importance of controlling for age-related changes in CSF Nf levels, appear to confirm the potential utility of this diagnostic and prognostic biomarker in MS and other neurodegenerative disorders (like Alzheimer disease and ALS). Nfs are structural proteins of axons and dendrites, and their release into the CSF is considered a sign of neuroaxonal damage.

However, the use of CSF Nf levels—for instance, to aid diagnosis or treatment decisions—is not ready for primetime practice. In an accompanying editorial, neuroscientists Giovanni and Nath recognize that "[t]he need to measure Nf in CSF [meaning the necessity of lumbar puncture] is a major hurdle to widespread application as an MS biomarker." They predict that the assay (which, given age-related increases in Nf levels, must be interpreted in the context of control values) will or should be adopted as surrogate endpoints in MS neuroprotective trials and "to enrich" these trials. So-called enrichment, in this case, would be realized by using CSF Nf levels to preferentially enroll patients with higher levels and who are, therefore, more likely to benefit from neuroprotective (eg, immunomodulatory) therapy.

CSF = cerebrospinal fluid.

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 frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

Add up to 5 new gene variants to the 5 that are already known to increase the risk of Alzheimer disease. Newly published data from huge (and I mean huge) genome-association studies in the United States and Europe provide a fresh parade of new high-risk loci*:

• CD2AP (detected by US group; confirmed by European group)
• EPHA1 (detected by US group; confirmed by European group)
• CD33 (detected by US group; confirmed by European group)
• ABCA7 (detected by US group)
• MS4A (detected by US group; confirmed by European group)

The US group also replicated previous AD associations at CR1, CLU, BIN1, and PICALM (but not EXOC3L2). And although the risk of AD appears to be increased by 10%-15% with the newly identified loci, this risk pales in comparison to that provided by the variants of the APOE allele—which can increase the risk of AD by 400%-1000%.

According to the above NCBI links, the function of the proteins of these newly recognized genes are unknown or poorly understood. Consequently their role in AD is even less apparent. EPH receptors (like that produced by EPHA1) "have been implicated in mediating developmental events, particularly in the nervous system," reveals the gene's dedicated web page.

The Nature Genetics authors, by way of coverage at GEN (Genetic Engineering and Biotechnology News), write that 5 of the new or previously detected genes (CR1, CLU, EPHA1, CD33, and ABCA7) "have putative functions in the immune system." Products of BIN1, PICALM, CD33, and CD2AP "are involved in processes at the cell membrane, including endocytosis." And APOE, CLU, and ABCA7 play some role in lipid processing.

According to Bloomberg, Harvard's Rudolph Tanzi, one of the 155 authors of the US article, is particularly jazzed about CD33. He muses that some AD-associated variant of the gene may reduce the brain's capacity to clear beta amyloid, the sheeted protein that accumulates in the illness. Conversely overactivity of the gene may trigger some pathogenic inflammation that causes or contributes to AD. The ultimate hope is that CD33 and the other high-risk loci may provide new targets for AD treatment and prevention. 

Among the lay press reports covering this story is a reasonable review from the NYT's Gina Kolata. A more scientifically detailed write-up by the good folks at Nature's The Great Beyond blog is awaited.

APOE = apolipoprotein E; NCBI = National Center for Biotechnology Information.

* See the advance online publications from Nature Genetics here and here (subscription required).

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

04/05/11 addendum: WTF TGB? No coverage?

A butt-saving KBF guest post by KTG, the greatest connoisseur of Nazi-zombie zombie-Nazi horror movies I know:

Call it unintended fallout. During the first few days of Japan's ongoing nuclear disaster, Wikipedia searches for "Godzilla" tripled, says NPR. (And yes, there's somebody tracking this. And yes, NPR's tracking that somebody.) In response, I say there's nothing like an impending nuclear catastrophe to pique a universal interest in cinema radioactiv—my made-up French term for those cheesy, don't-fuck-with-the-atom sci-fi movies (we can't call them "films," can we?) of the 1950s. Fans of the genre (there are dozen!*) agree: The tasty nougat center shared by every one of these movies is...preposterously bad special effects. And the cake taker in this category is The Crawling Eye (1958).

Adapted from a successful English TV miniseries (who knew?), this flick features probably hopelessly overtrained Brit thespians slumming it on the set of a faux Swiss mountain resort; but the starring role (requiring its fair share of chain smoking) goes to a pre-"F Troop" Forrest Tucker, ostensibly to improve the movie's US marketability.** The monsters, which are hidden behind clouds of radioactive gas*** until the very end (excellent decision, director Quentin Lawrence), are a screenwriter's hoot: Giant tentacled eyeballs that eat human heads. And those vulnerable heads might belong to any one of the resort's hapless villagers, prophetic psychics, visiting mountaineers, expository scientists, creepy zombies (yes, creepy zombies!), or nancy men who cover their faces with both hands at the sight of a headless corpse.

In short, The Crawling Eye is an ominously glowing B-grade (and I'm being gracious here) offering from the backyard bomb shelter.

* An ophthalmologist, I consider myself a pupil of the giant killer-eyeball sub-genre...I'll be here all week, folks.

** I missed the minute during the 1950s when Mr. Tucker was a bona-fide box-office draw.

*** Or only-slightly-less dangerous cigarette smoke.

Angioplasty of the cerebral veins may be generally (but certainly not absolutely) safe in patients with multiple sclerosis; however, it remains unknown whether the procedure has any benefit beyond a placebo effect in the disease—which is regarded by most neurologists as autoimmune, not vascular, in nature. The safety conclusion is based on data from 3 studies presented at the 36th annual meeting of the Society of Interventional Radiology in Chicago.

The radiology data are reported at face value by MedPage Today and without important input from MS neurologists. Another screaming caveat to the coverage is the following: The radiology abstracts implicity acknowledge the existence of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis—a completely unestablished concept that has been used to justify vacular intervention in the disease. It is the odd brainchild of Italy's Paolo Zamboni, and the idea has been embraced willy-nilly by some US physicians, including Stanford's Michael Dake. However, it is viewed with a very healthy skepticism by US neurologists who subspecialize in MS management. (For important background, go here, here, and here.)

According to MedPage, the rate of "major complications" in one retrospective series of 231 "CCSVI patients" with MS who underwent vascular intervention was 1.2% and consisted of venous thrombosis. So-called minor complications, however, weren't inconsequential and included "thrombosis or dissection after angioplasty requiring stent placement" at a rate of 10.5%. In a much smaller study of 24 patients, 1 case of inguinal bleeding, 2 cases of inguinal hematoma, and 1 case of retroperitoneal hematoma produced a complication rate of more than 16%—suggesting limited technical skills on the part of the interventionist(s). In a third series of 18 patients, 1 patient (>5%) experienced "rupture" of the internal jugular valve, which had to be treated with "balloon tamponade and stenting." (I don't imagine that calm reigned in the radiology suite that day.)

All of these non-controlled studies reported clinical improvement of MS symptoms in most patients. But, it should be noted, clinical improvement (however it was measured, if at all) didn't necessarily last, and "venous obstruction" recurred, in some cases. (And it's completely unclear whether clinical status deteriorated in concert with the return of the presumed venous obstraction.)

Another downfall of MedPage's coverage is the quoting of non-neurologist Michael Dake, who provided this useful [sarcasm alert] gem: "Currently there are many unknowns and lots of uncertainty." In addition, Dake called the field "a zone of chaos"—a situation that Dake arguably help to create. MedPage failed to note that Dake's own jugular-stent program at Stanford was shut down in December of 2009, after 1 of his MS patients died of cerebral hemorrhage and the stent of another became dislodged in his heart.  

SIR Abstracts Cited by MedPage

Mandato K et al. Safety of outpatient endovascular treatment of the internal jugular and azygos veins for chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis: a retrospective analysis. Abstract 3.

Haskal Z et al. Feasibility evaluation of catheter-directed interventions in multiple sclerosis CCSVI patients. Abstract 82.

Pisco JM et al. Percutaneous transluminal angioplasty and stenting in patients with multiple sclerosis and venous insufficiency--preliminary results. Abstract 33.

Image of neck veins from Gray's Anatomy (1918).