Pathophilia

The Hospital (1971): Paddy Chayefsky's biting satire of the bureaucracy and incompetence of inpatient care, some of which rings true 40 years later...sadly. George C. Scott plays a suicidal Chief of Medicine, who simultaneous confronts serial murders in his big-city medical center. A zone of confusion, the hospital is also beset by some serious 60s-type social anarchy from community activists. Chayefsky's story goes off the rails during a prolonged encounter between Scott's character and the daughter of a comatose inpatient (played by Diana Rigg and Barnard Hughes, respectively). But the film still amuses owing to the fact that several actors—including Nancy Marchand, Frances Sternhagen, and an uncredited Stockard Channing—were cast in bit roles.

A buried joke:
Patient: At 9:15 this morning I rang for my nurse.
Doctor: You rang for your nurse?
Patient: To ensure one full hour of uninterrupted privacy.

A remarkable, unprecedented development. Roche's anti-amyloid MAb, crenezumab (for which there are no entries at PubMed—!), will be given in an attempt to stave off familial Alzheimer disease. According to Reuters and the NYT, the experimental drug will be studied in members of an extended Colombian family who harbor mutations in a deterministic gene (presenilin 1*) for AD. The US DHHS and Banner Health are providing $16 million and $15 million, respectively, to fund the study. The US government's support is part of the new National Alzheimer's Project (announced yesterday), which has an advertised goal of finding an effective treatment for AD by 2025.

Also according to news coverage, crenezumab was chosen as a potential preemptive treatment for AD among "25 rivals," primarily because it does not cause vasogenic edema—for instance, like Pfizer/Janssen's bapineuzumab. This information is sourced in news write-ups to a Colombian neurologist. Although I have to say Roche's MAb has really come out of left field. As someone who has followed the investigational development of anti-amyloid drugs fairly closely, this molecule has flown way under my radar—partly because it has been registered heretofore under the unfriendly research name of MABT5102A. (Nevertheless, the oversight says something about my limitations.)

According to the NIH database, crenezumab/MABT5102A is currently being investigated in two phase 2 studies in the United States, Canada, and/or the United Kingdom (see here and here). Respective study completion dates are currently designated as June and August of 2014. Presumably the data regarding vasogenic edema (or lack thereof) were determined during phase 1 study and/or confirmed during the ongoing phase 2 trials.

Roche also has the investigational anti-amyloid MAb gantenerumab, which is also in phase 2 development.

As previously written, phase 3 data for the anti-amyloid MAbs bapineuzumab and solanezumab (in existing AD) are expected sometime this summer—which is drawing nigh.

DHHS = Department of Health and Human Services; MAb = monoclonal antibody.
* Presenilin 1 is a component of a metabolic enzyme that cleaves amyloid precursor protein to ultimately create beta amyloid--the stuff the aggregates and forms plaques in the brains of patients with AD.

Update: AC Immune, from which crenezumab was licensed by Roche/Genentech, reported last year that the "drug showed no signs of cerebral vasogenic edema in any of the [phase 1 trial] patients at any dose."

Another update: You have to wonder, though. If crenezumab doesn't cause (or isn't associated with) vascular edema, how effective is it at removing amyloid? If the cause of vasogenic edema with these anti-amyloid compounds is due to the immune-mediated vascular removal of amyloid and/or a direct attack on vascular amyloid (see, for instance, Figure 5 in Sperling et al. Lancet Neurol. 2012:11:241-249), then you would expect some kind of class effect given the putative mechanism of action. Consequently I wonder at the efficacy of an anti-amyloid MAb that doesn't cause some vasogenic edema in a percentage of patients. Certainly amyloid PET imaging in this Colombian study will allow researchers to visualize the removal or prevention of amyloid buildup with crenezumab. So...wait to see. Of course, the bigger question is whether the targeting of amyloid is associated with clinical improvement or, as in this study, the prevention of AD dementia.

The FDA has revised its recommendations for cardiovascular monitoring after the initiation of Gilenya (fingolimod), Novartis's oral drug for relapsing-remitting MS. The new recommendations, which extend the post-dosage monitoring for bradycardia from 6 to 24 hours, are based on the report of a woman who died within a day after starting the drug.

Although the cause of the woman's death was not determined, the agency reported that she was taking two antihypertensive medications, including the beta-blocker metoprolol. In addition, she had "extensive" MS lesions in her brainstem, which have been associated with sudden death.

On the basis of a post-hoc analysis of clinical-trial data, the FDA also concluded that the possible depressant effect of Gilenya on the heart rate is biphasic: There is an initial risk during the first 6 hours after the first dose and a second risk during hours 12-20. Therefore the agency believes that cardiac monitoring beyond 6 hours is warranted in patients whose heart rate falls below 45 bpm during the first 6 hours after the first dose.

Other reports of cardiovascular death in Gilenya-treated patients are being examined. However, the FDA cautions, "For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya."

Regardless it seems prudent to consider the drug very carefully in MS patients with concomitant cardiovascular disease (especially arrhythmia) and particularly those patients taking beta-blockers or antiarrhythmics.

This morning, the FDA has finally stepped in and is warning healthcare professionals and MS patients alike about death and other injuries associated with the so-called "liberation procedure" (ugh), which amounts to either angioplasty or stenting of (typically) jugular veins. The procedure, which is ostensibly designed to promote the egress of blood flow from the brain, has no basis for use, because there is no confirmed link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. For background on this ever-vexing issue, start here.

The FDA has received reports of associated adverse events, which include "death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding." In February, the agency sent a letter to a NY vascular surgeon, warning of "objectionable conditions" and the lack of regulatory protocol and oversight for what amounts to an investigational (ie, non-FDA-approved) procedure.

For the Internet's edification, the phase 3 trials of MAbs in AD are tabulated by drug (bapineuzumab, solanezumab) and expected completion date.

Although the phase 3 trial of bapineuzumab in APOE ε4 carriers (NCT00575055 or ELN115727-302) reached its estimated completion date last month, the online buzz indicates that Pfizer/Janssen won't publicly release these data until the phase 3 study in noncarriers is completed in August of this year. As readers may recall, the phase 2 data of bapineuzumab suggested that APOE ε4 noncarriers with AD (meaning generally those patients with a lower beta-amyloid burden) fared somewhat clinically better than APOE ε4 carriers and were specifically less likely to develop vasogenic brain edema.

The public release of phase 3 solanezumab data is also expected imminently or at least (I would think) this summer.

Bapineuzumab (Pfizer/Janssen) Phase 3 Trials*

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1121 APOE ε4 carriers	NCT00575055 (aka ELN115727-302)	1.5 years	April 2012
1300 APOE ε4 noncarriers	NCT00574132 (aka ELN115727-301)	1.5 years	August 2012
Subjects who participated in above studies	NCT00937352	2.5 years or marketing application	June 2012
1100 APOE ε4 carriers	NCT00676143 (aka 3133K1-3001)	1.5 years	June 2013
Subjects who participated in above study	NCT00998764	4 years (extension)	June 2017
1000 APOE ε4 noncarriers	NCT00667810 (aka 3133K1-3000)	1.5 years	June 2014
Subjects who participated in above study	NCT00996918	4 years (extension)	June 2018

Solanezumab (Eli Lilly) Phase 3 Trials**

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1000 AD patients	NCT00905372	~1.5 years	April 2012
1000 AD patients	NCT00904683	~1.5 years	June 2012
1250 AD patients	NCT01127633 (extension)	2 years	July 2014

In addition, there are several phase 3 studies evaluating IV Ig (eg, Baxter's Gammagard) in patients with AD. Clinical data from these trials aren't expected until 2013 and later.

MAb = monoclonal antibody.

* Owing to a dose-dependent effect on the risk of amyloid-related imaging abnormalities (aka vasogenic edema and microhemorrhages), particularly in APOE ε4 carriers, the dosage of bapineuzumab received by APOE ε4 carriers is now the lowest, tested dosage: 0.5 mg/kg. APOE ε4 noncarriers are receiving 2 dosages of bapineuzumab (0.5 or 1.0 mg/kg) in phase 3 clinical trials.

** Treated patients are receiving one, standard dosage of the MAb.

Chronic cerebrospinal venous insufficiency (CCSVI) is neither common, nor more common, in patients with multiple sclerosis, say investigators at the University of Texas Health Sciences Center in Houston. According to 2 preliminary reports presented at the recent annual meeting of the American Academy of Neurology, CCSVI—determined by blinded readers using "strict" ultrasound criteria*—was detected in only 8 of 206 (~4%) patients with MS** and 5 of 59 (~8%) patients with other neurologic disorders (eg, stroke).

In a companion MR venography study, only 9 of 63 (14%) patients with MS showed evidence of CCSVI. None of these patients met ultrasound criteria for CCSVI, but 2 patients with normal MR venography showed ultrasound evidence of CCSVI. Although MR venography appeared, therefore, to be more sensitive for detecting venous insufficiency than ultrasound, the investigators found that there was reasonable correlation between the 2 imaging techniques.

In 2009, Italian physician Paolo Zamboni proposed that the cause of MS was related to obstructed venous outflow from the brain and documented CCSVI by ultrasonography in an inordinately high number of MS subjects. His published findings led to unjustified zeal for venous stenting and other procedures that were intended to increase venous outflow from the brain. However, Zamboni's data have not been reliably replicated; more damning, in fact, is that his data have been refuted in numerous studies.

General consensus among MS specialists is that the condition is an autoimmune (not vascular) disorder, and the most effective, known treatments for delaying the progression of MS are immunomodulatory drugs.

MR = magnetic resonance.
* Consistent with those criteria outlined by Zamboni.
** Approximately two thirds of patients with MS had relapsing-remitting disease.

HT: MedPage Today.

Small Town Murder Songs (2010): A heavy and heavily mustachioed Peter Stormare (the kidnapping guy from Fargo) plays Walter, a born-again cop who investigates the local murder of a stripper in his rural Canadian town. However, director Ed Gass-Donnelly places less emphasis on the murder than on the ideas of salvation, redemption, and forgiveness, particularly as they are informed by the local Mennonite community. Most notably Gass-Donnelly cuts up his too-short film with jarring sectional edits that feature bold, all-caps biblical admonitions and disturbing, percussion-heavy, group chants by the strangely named Canadian band Bruce Peninsula. With a plump Martha Plimpton and a trailer-trashy Jill Hennessey as Walter's current and former girlfriends, respectively.

According to Medscape's newly published (2012) report on physician income, almost half (46%) of the surveyed physicians (N > 25,000) would not choose medicine as a career, and nearly 80% would not choose the same practice setting, if they had to do it over again. Nearly 60% regret their specialty choice. Perhaps income, especially for radiologists and orthopedic surgeons, lightens the emotional load. But money can soothe only so much unhappiness.

The distressing thought for the day: The general dissatisfaction among currently practicing physicians bodes ill for encouraging bright young adults to pursue medical careers.

Law professor Mark Hall (Wake Forest) makes predictions in the latest NEJM about the Supreme Court's decision on the recently argued Affordable Care Act (ACA)—specifically with respect to the constitutionality of the individual insurance mandate. (Although frankly, anyone who's been watching this story could make the same predictions.)

• The 4 Democratic appointees (Ginsberg, Breyer, Sotomayor, Kagan) will vote to uphold the ACA (and thereby the individual mandate).
• Consequently only 1 Republican appointee is needed to side with the Democratic appointees to uphold the ACA. However, there is "no clear support" from the 5 Republican appointees (Roberts, Scalia, Kennedy, Thomas, Alito). Nevertheless, Kennedy is historically a critical swing vote in close decisions, and his statements during the recent argument indicate that he is able to consider both sides of the issues.
  
• It is "very unclear" if the Supremes will toss the ACA, if the individual mandate is declared unconstitutional.
• While some justices appear to be against the Medicaid expansion (which was originally thought to be a non-starter), it is unlikely that there will be enough votes to 86 the provision.

A decision is expected by the end of June.

The use of Avid/Lilly's newly approved amyloid tracer, Amyvid, hinges on the accuracy (or inaccuracy) of a clinical diagnosis of Alzheimer disease (AD) during life. If the historic accuracy of a clinical diagnosis of AD is generally high—meaning the correlation between a clinical diagnosis of AD during life and postmortem evidence of the disease is good—then use of the very expensive radiolabeled tracer (and the consequent ordering of associated PET scanning) is less well justified, if at all.

In Avid/Lilly's press release for the approval of Amyvid, Avid's President and CEO, radiologist Daniel Skovronsky, implicitly promotes the use of amyloid imaging by claiming, "It's estimated that one in five patients clinically diagnosed with probable Alzheimer's Disease during life do not end up having Alzheimer's Disease pathology upon autopsy." The references cited to support his statement are the following:

• Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of Alzheimer's disease in a community-based case series. J Am Geriatr Soc. 1999;47(5):564-569.
• Petrovitch H, White LR, Ross GW, et al. Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study. Neurology. 2001;57(2):226-234.

Let's examine these references to determine if they really do support Skovronsky's claim of diagnostic accuracy and, moreover, if they're representative of the literature at large.

The article by Lim et al, from 1999, is not available online. Therefore I'm currently limited to examining the PubMed abstract, which describes a "community-based case series" of 134 patients with "memory complaints" (who were presumably seen at the VA Puget Sound Health Care System in Seattle, Washington). The rationale for the study was to make a clinico-pathologic correlation for AD in non-research subjects. These community-based subjects, who were enrolled in the University of Washington/Group Health Cooperative Alzheimer's Disease Patient Registry, met a diagnosis of "probable AD" on the basis of NINCDS-ADRDA criteria (1984 guidelines). Among the 134 individuals, postmortem criteria for AD (CERAD criteria) were met in 95 patients (71%). The authors calculated the sensitivity of a clinical diagnosis of AD ("probable AD" during life) at 83% and an overall diagnostic accuracy of 75%. Of the 94 cases with postmortem evidence of AD, most of these patients demonstrated coexisting pathology—like vascular lesions and evidence of Parkinson disease. Neuropathologic diagnoses in the patients without postmortem evidence of AD are, unfortunately, not provided in the abstract. In other words, the Lim abstract doesn't reveal what was misdiagnosed as AD during life in this study.

The other cited article, by Petrovitch et al, describes a kind of a holy-smokes study, in which the clinico-pathologic correlation for a diagnosis of AD in Japanese-American men (who participated in the Honolulu-Asia Aging Study in the early-mid 90s) was a paltry 65%. (Again, the rationale for this study was to assess the diagnostic accuracy in a community-based sample [ie, outside of a referral center], as well as to examine a non-Caucasian population.) A closer look at the article reveals that, among the 20 men (ie, a small study) diagnosed with "pure AD" (as opposed to pure vascular dementia or AD plus something else) who came to autopsy, only 13 (65%) met CERAD criteria for "definite" or "probable" AD (which was partly based on the density of neuritic, amyloid-containing plaques*). Many of these patients also showed evidence of amyloid angiopathy and/or cerebrovascular disease. Among the patients with "possible" or no postmortem evidence of AD (ie, with minimal evidence of neuritic plaques), diagnoses for the most part were confined to vascular disease (which CT or MRI somehow missed). In one case, there was evidence of midbrain Lewy bodies (eg, Parkinson disease); in another, there was evidence of chronic subdural hematoma.

Petrovitch et al also cite several previous clinico-path studies (performed at referral centers in Western countries), in which the correlation of a diagnosis of "pure" AD during life and postmortem evidence varied between 80% and 90%. In cases of "probable" AD, the correlation rates were even higher: between 80% and 100%. The accuracy of the clinical diagnosis of "possible" AD, logically, has been historically lower: 60%-90%.

In a very recently published study, which draws on more recent NIA registry data (2005-2010), the sensitivity of a clinical diagnosis of "probable" or "possible" AD (when measured against neuropathologic data—which were based on amyloid-plaque density* and neurofibrillary tangles) was about 80%70%-90%. Meaning: Physicians correctly identified clinical AD as being neuropathologic AD about 85% 80% of the time (438/526 subjects). These data are consistent with the median values provided by the bulk of clinico-path studies in the literature. Conversely the specificity of clinical diagnosis was lower, from about 40%-70%. Meaning: Clinicians were not as good at correctly recognizing non-AD causes of dementia and often ascribed other causes of dementia to neuropathologic AD.

Among the most common primary neuropathologic diagnoses that were misidentified as AD during life were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration (aka Pick's disease), cerebrovascular disease, Lewy body disease, and hippocampal sclerosis. (Addendum: It's also curious to note that among the 88 patients who were diagnosed with probable AD but who didn't meet the minimum pathologic standards for AD at autopsy, 17 were still considered to have a "primary neuropathologic diagnosis of AD despite [the] low level of AD histopathology." So the rate of diagnostic accuracy for clinical AD was a slightly higher, at ~85%. But the authors note that the criteria for the histopathologic diagnosis of AD has been a bit of a moving target over the last few decades.)

So circling back to Dr. Skovronsky's quote, a 25% 20% rate of a misapplied diagnosis of AD during life is a bit of an overstatement reasonable—especially if the reference standard for clinical diagnosis is some type of AD referral center. (And I bet any primary care physician who might ever entertain an amyloid-imaging study would first refer his suspect patient to an AD referral center, or at least a neurologist.) A more accurate percentage of a misapplied diagnosis, on the basis of a totality of the literature, is closer to 15%. But despite the reasonable agreement with the literature at large, Skovronsky should have cited some other reference than the Honolulu-Asia Aging Study, which indicates a relatively high rate of misdiagnosis, at 35%.

Regardless, the crucial follow-up question is What are we missing when we mistakenly diagnose dementia as AD during life? And the answer is a number of related neurodegenerative, dementing illnesses and cerebrovascular disease—features of which may coexist. Moreover, evidence of some of these non-AD conditions (hippocampal sclerosis, vascular disease) should be detectable on standard MR imaging.

* What Amyvid is designed to detect.

NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; CERAD = Consortium to Establish a Registry for Alzheimer's Disease.