Neurology: July 2009 Archives

Visualization of the central nervous system—namely the brain and spinal cord—with MR imaging has been routinely available for about 2 decades. But assessment of the peripheral nerves is largely confined to biopsy data or physiologic measurements (eg, nerve conduction studies and electromyography).* Historically the problem of using common MR methods to inspect long stretches of peripheral nerve has been confounded by similarities in signal intensities between the nerve and its surrounding tissues.

Now investigators in Japan and The Netherlands report their technique of "whole-body MR neurography" to support the diagnosis of chronic inflammatory demyelinating polyneuropathy, or CIDP, an acquired, autoimmune disorder of the peripheral nerves. Their MR method is provided in correspondence within the latest issue of the NEJM.

In short, the technique suppresses background signals from surrounding body tissues to enable detailed views of diseased, thickened nerves. Abnormalities are readily apparent in comparison views of the brachial plexus in a healthy 23-year-old man (A) and that in a 73-year-old man with CIDP (B).

The practical utility of MR neurography is questionable, however, given that the diagnosis of many peripheral-nerve disorders—and specifically those in which the nerves are not subtly diseased—can be made by using currently available methods. Also the technique would seem to have its limitations in cases of atretic nerve disorders, like advanced axonal neuropathies. But the pictures are way cool.

MR = magnetic resonance.

* Although the condition of very proximal nerve roots is typically assessed with spinal MR imaging.

Detail from Figure 1 in Yamashita T, Kwee TC, Takahara T. Whole-body magnetic resonance neurography. N Engl J Med. 2009;361:538-539.

When attempting to discriminate among Alzheimer disease (AD), mild cognitive impairment (aMCI),* and normal cognition, structural abnormalities on MR images are more useful than known CSF biomarkers; but the use of both together is more diagnostically helpful than each individually. This conclusion is based on data from the Alzheimer Disease Neuroimaging Initiative, now available in the latest issue of Neurology.

In a statistical analysis of data from 399 subjects, the degree and location of AD-related brain atrophy on 3D MR images (condensed into the so-called Structural Abnormality Index, or STAND, score) correlated with clinical measures of cognition (eg, the MMSE score). However, known CSF biomarkers for AD—total tau, amyloid beta(1-42), and phosphorylated tau(181P)—did not. Nevertheless, the diagnostic accuracy for AD was best with the combined use of the STAND score, CSF total tau, and CSF amyloid beta. (Measures of total tau are expected to directly reflect neurofibrillary tangle pathology in AD.) In a related study, the STAND score was also a better predictor of clinical cognitive decline—namely the progression of aMCI to AD—than CSF biomarkers.

The Alzheimer Disease Neuroimaging Initiative is a longitudinal, multisite, observational study of elderly individuals with normal cognition, aMCI, or AD at 56 US or Canadian institutes. Funding for the study originates from the National Institute of Aging, the National Institute of Bioimaging and Bioengineering, pharma, and "several foundations."

CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; MR = magnetic resonance.

* Amnestic mild cognitive impairment.

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

People with amnestic mild cognitive impairment* (MCI) develop Alzheimer disease (AD) at an annual rate of 10%-15%, and about half show AD-type brain pathology—neurofibrillary tangles and beta-amyloid plaques—at autopsy. However, clinical conversion is not a given. Consequently a number of investigators have attempted to identify biomarkers that predict the conversion of MCI to AD, such as hippocampal volume on MR images.

Now researchers show that MCI patients with a relatively increased brain load of beta-amyloid, measured by using positron emission tomography** (PET), are much more likely to develop AD than MCI patients with control levels of beta-amyloid. Results of the small UK and Finnish study (N = 31) are available in an advanced e-printing of Neurology.

During a 1-3-year follow-up, 14 of 17 (82%) MCI patients with increased beta-amyloid on PET images and 1 of 14 (7%) MCI patients with nonincreased beta-amyloid converted to AD. The speed of clinical conversion was positively associated with the beta-amyloid load and the APOE ε4 carrier status in MCI patients.

APOE = apolipoprotein E.

* Defined as subjective and objective memory impairment for age but largely preserved general cognition and normal activities of daily living (Petersen, 2004).

** By using the thioflavin-based radiotracer Pittsburgh compound B (PIB).

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

This week, 2 articles examine the possible benefit of closing a patent foramen ovale (PFO), the vestige congenital hole between the left and right atria. Individuals with isolated PFO are typically asymptomatic, but longstanding reason has dictated that PFO, as a conduit for cardiac emboli, increases the risk of stroke and is a prominent cause of brain infarction in young adults. At least 2 studies indicated that the prevalence of PFO is increased (up to 45%) in patients with cryptogenic stroke.

However, a meta-analysis of 4 trials (N = 1081), published in this week's Neurology, indicates that the pooled relative risk (RR) of recurrent ischemic stroke or TIA in patients with PFO (vs those without) is only 1.1 (P = .149). The pooled RR for ischemic stroke alone in patients with PFO is 0.8 (P = .666).* Post-event treatments in these studies included antiplatelet therapy, warfarin, and/or surgical closure (the latter in 28% of patients with PFO), but the authors advise against using their meta-analysis data—which cannot be adjusted for important study differences—to assess therapeutic efficacies.

In this week's JAMA, a second study, performed at the Cleveland Clinic, assessed the effects of closing an incidental PFO—which was seen in 2277 of 13,092 (17%) surgical patients. Surgical closure was performed in 639 patients (28%) with PFO. The investigators calculated similar rates of in-hospital death (3.4% vs 2.6%) and stroke (2.3% vs 2.3%) in matched PFO groups. But patients with a repaired PFO were significantly more likely to experience a longer-term postoperative stroke than patients whose PFO was not repaired (2.8% vs 1.2%; P = .04). Surgical closure was statistically more likely in younger patients, in patients undergoing atrial valve surgery, or in those with a history of stroke or TIA. Long-term survival was not affected by PFO closure.

Currently there are no completed randomized trials comparing medical therapy with surgery in patients with cryptogenic stroke and PFO. The NIH database indicates that at least 1 US-based controlled trial is active but not recruiting.

In 2004, the American Academy of Neurology concluded that PFO does not increase the risk of subsequent stroke or death in medically treated patients. However, the combination of PFO and an atrial septal aneurysm possibly increases the risk of recurrent stroke (but not death) in medically treated patients who are younger than 55 years of age.

TIA = transient ischemic attack.

* In patients with PFO, the pooled absolute rate of recurrent stroke or TIA is 4 events per 100 person-years; the pooled absolute rate of recurrent stroke is 1.6 events per 100 person-years. The authors write that this rate is similar to the annual rate of major bleeding with warfarin therapy for cryptogenic stroke.

Mini-graphic of atrial septal defect (ASD) attributed to the NIH.

And another thing that Avastin (bevacizumab; Genentech) may be good for:

The anti-VEGF monoclonal antibody improved hearing loss and reduced tumor volume in patients with growing vestibular schwannomas. The conclusions are based on data from a small, first-of-its-kind study of patients with neurofibromatosis (NF) type 2—data which are available in an early release article from The NEJM.

Ten consecutive patients with NF type 2 and progressive vestibular schwannomas (who were not candidates for or declined the standard treatment of surgery and radiation therapy*) received at least one dose of bevacizumab (5 mg/kg every 2 weeks). The median annual growth rate of schwannomas before treatment was 62%, and the median duration of treatment was 12 months. (The rationale for assessing bevacizumab in NF-associated schwannomas is based on the expression of VEGF in tumor cells. However, the expression of the VEGF receptor, VEGFR-2, on tumor vessels is not particularly high—which suggests that an anti-VEGF-receptor drug is less likely to be of benefit than bevacizumab.)

In a retrospective analysis, 9/10 tumors shrank (best median response, 26% reduction) after bevacizumab treatment, and 6 demonstrated an imaging response. Only 1 patient experienced an increase in tumor volume (of 32%). Tumor reduction strongly correlated with baseline vasogenic edema on MR images (ie, the mean apparent diffusion coefficent). Improvements in hearing (at <12 weeks) were observed in 5 of 7 eligible patients and were progressive and durable (up to 16 months) in most.

This pilot study was not funded by Genentech; although 1 author (Gregory Sorensen, MD) reported receiving grant support from the company.

NF2 is a dominantly inherited disorder with a prevalence of 1 in 25,000. The most common tumor type associated with the condition is vestibular (or acoustic) schwannomas, benign tumors of the 8th cranial nerve. Growth of tumors causes progressive hearing loss, as does surgical and radiation therapy. Progressive vestibular schwannomas can also produce brainstem compression.

In May, the FDA approved Avastin for the treatment of the uniformly fatal brain tumor, glioblastoma multiforme, after standard therapy.

VEGF = vascular endothelial-cell growth factor.

* Eight patients were at high risk for complete hearing loss with standard therapy.