New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis. Although rigorous magnetic resonance imaging requirements were provided, the "new criteria paper" fell short in terms of guidelines as to how the CSF analysis should be performed and simply equated the IgG index with isoelectric focusing, without any justification. The spectrum of parameters analyzed and methods for CSF analysis differ worldwide and often yield variable results in terms of sensitivity, specificity, accuracy, and reliability, with no decided "optimal" CSF test for the diagnosis of MS. To address this question specifically, an international panel of experts in MS and CSF diagnostic techniques was convened and the result was this article, representing a consensus of all the participants. These recommendations for establishing a standard for the evaluation of CSF in patients suspected of having MS should greatly complement the new criteria in ensuring that a correct diagnosis of MS is being made.

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Frank Phillips, MD Midwest OrthopedIcs at Rush Chic-ago, FL

De novo sources of SI joint dysfunction include inflammation, postpartum pain, or a new onset of chronic low back pain with or without trauma. In this edition of the Sentinel Newsletter Mark Reiley shares an interesting article on sacral dysplasia as a de novo source of low back pain. He recommends including oblique plain X-rays of the pelvis and axial CT scans of the pelvis as part of the process of diagnosing SI joint disease. In my practice, I order a low back MRI that extends through the sacrum, I take close notes ofpatient complaints and history, perform provocative testing using 5 or 6 provocative tests with the highest sensitivities and specificities, and I have a minimum of 2 diagnostic SI joint blocks performed to rule out false positives. When reviewing surgical options, the iFuse is an ideal minimally invasive option for fusing the SI joint due to its unique design and ability to stabilize the joint.

Bengt Sturesson shares a very interesting case study on a patient who suffered for years after a traumatic injury before he was diagnosed with SI joint dysfunction. His diagnostic work-up is exhaustive and his method detailed in order to get to the point of MIS surgery as an option. This iFuse patient had considerable success and at six months this patient was off medication and was able to return to work.

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Which Foods Are Best for the Brain?

Diet is inextricably linked to conditions such as heart disease, obesity, and diabetes. However, what we consume also seems to have significant implications for the brain: Unhealthy diets may increase risk for psychiatric and neurologic conditions, such as depression and dementia, whereas healthy diets may be protective. Based primarily on recent Medscape News coverage, the following slideshow collects some of the more prominent investigations on nutrition and the brain into a single resource to aid in counseling your patients.

Make for Malta in Depression, Stroke, and Dementia

A 2009 study published in Archives of General Psychiatry found that people who follow Mediterranean dietary patterns -- that is, a diet high in fruits, vegetables, nuts, whole grains, fish, and unsaturated fat (common in olive and other plant oils) -- are up to 30% less likely to develop depression than those who typically consume meatier, dairy-heavy fare.^[1] The olive oil-inclined also show a lower risk for ischemic stroke^[2,3] and are less likely to develop mild cognitive impairment and Alzheimer disease, particularly when they engage in higher levels of physical activity.

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Results of a randomized trial confirm that treatment with amantadine can accelerate functional recovery among patients in vegetative or minimally conscious states after a traumatic brain injury (TBI).

Compared with placebo, amantadine effectively accelerated the pace of recovery of cognitively mediated behaviors, such as recognition of objects or verbalization, activities that form the foundation for functional independence, the researchers report. At week 4, more patients in the amantadine than the placebo group had recovery of all 6 behaviors.

"I do think this is going to influence practice," lead author Joseph T. Giacino, PhD, from the Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News. "This is first time we have convincing evidence in a Class I study, for any treatment — at all — for brain injury."

The study will have to be replicated before amantadine could be viewed as a standard of care, he added, "but it's certainly a big step toward having a standard of care for treatment of this population."

Disorders of Consciousness

Between 10% and 15% of patients with severe TBI are discharged from acute care in a vegetative state, the authors write. The prevalence of minimally conscious states is estimated to be 8 times that of vegetative states. Vegetative state is defined as wakefulness without behavioral evidence of conscious awareness, whereas in a minimally conscious state, there is at least 1 clearly discernible sign of consciousness, they note.

Although outcomes for patients in minimally conscious states are generally more favorable than those in vegetative states, about half of these patients remain severely disabled at 1 year after the injury, the authors note. To date, no treatment has been shown to change the pace of recovery or improve functional outcome in these patients, although several therapies are used off label, they note, with amantadine being one of the most commonly prescribed.

Amantadine has been used since the 1980s to address parkinsonian symptoms in patients with brain injury, a natural follow-on to its use in Parkinson's disease, Dr. Giacino said. The mechanism is unclear, but amantadine appears to act as an N-methyl-D-aspartate antagonist and indirect dopamine agonist, the researchers note.

Two small previous trials in patients with disorders of consciousness after a TBI suggested it can be effective, but small, unbalanced sample sizes prevented definitive conclusions, they note. "Our intent was to do a definitive trial," Dr. Giacino noted.

The current trial, a prospective, double-blind, randomized, placebo-controlled study of patients in post-traumatic vegetative or minimally conscious states, involved 9 centers in the United States and 3 in Europe.

"We needed that many centers because it's very difficult to enroll these patients, because many of them never make into rehabilitation settings," he said. "Often insurance companies will not authorize rehabilitation because they view these individuals as beyond repair. In fact all of the centers, over the 6 and a half years that it took to complete the trial, we saw slowing in our enrollment because it was getting more and more difficult just to get access to these patients in inpatient rehab settings."

They also limited treatment in the trial to 4 weeks because the average length of stay in an inpatient brain injury program for someone with a severe brain injury is about 4.5 weeks in the United States, he added.

The researchers' hypothesis for this trial, then, was that 4 weeks of treatment with amantadine, given 4 to 16 weeks after injury in patients in vegetative and minimally conscious states after TBI, would improve functional recovery and that the improvement would be maintained 2 weeks after drug washout.

During the 4-week treatment period, recovery was significantly faster in the amantadine group, measured by using the Disability Rating Scale (DRS), a global functional outcome measure. The difference in the slope for this measure was 0.24 point per week (P = .007) indicating a benefit, the researchers note.

Subgroup analysis showed that the treatment effect was similar whether patients were in vegetative or minimally conscious states.

However, Dr. Giacino said, "we were surprised to find, when we stopped the drug, an almost immediate leveling off of the pace of recovery in the amantadine group, so much so that the placebo group caught up to the amantadine group in 2 weeks. So at week 6, they were no longer significantly different."

The difference in the slope on the DRS was 0.30 point per week at this point (P = .02).

Dr. Giacino points out, though, that this provides compelling evidence that the drug worked. "To see such a sharp change in that trajectory when the drug was stopped makes a compelling case that it was influencing neural function when it was on board."

There were no significant differences in the incidence of serious adverse events between groups, the researchers note.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown," the researchers conclude. "In view of health care cost restraints and declining lengths of stay for inpatient rehabilitation, amantadine-induced acceleration of recovery may represent an important advance."

Future research should look at trying to identify characteristics of the patients who have a response to amantadine, the most effective dosage, the optimal duration of treatment, and timing of initiation of treatment. The efficacy of amantadine in patients with nontraumatic brain injuries will also be of interest.

"After having completed this trial, I think for the first time there is cause for optimism in patient population that has been viewed as largely beyond repair and hopeless," Dr. Giacino concluded.

"Elegant" Design

Asked for comment on these findings, Jose A. Cardenas, MD, a neurologist in North Platte, Nebraska, and a member of the American Academy of Neurology, said the study is "elegantly designed, and although it contains some variables that could not be controlled due to the clinical settings of the patient population, it does provide good evidence to favor the use of amantadine in the treatment of patients with post-traumatic disorders of consciousness."

He agreed with the researchers that one of the greatest challenges for clinical studies in these conditions is enrollment and sample size. "This study certainly excels in this area with a very significant sample size," he told Medscape Medical News. "The observed clinical effect of amantadine has long been hypothesized, and is widely used in clinical practice."

Despite a number of limitations that were pointed out in the discussion section of the publication, Dr. Cardenas concludes, "I believe its greatest strength is that we now have clinical evidence via a randomized, placebo-controlled trial that amantadine is safe and effective to be used in patients with post-traumatic disorders of consciousness and we can expect to see a faster recovery in some of these patients."

The study was supported by a grant from the National Institute on Disability and Rehabilitation Research. Disclosures for the researchers are available at www.nejm.org.

N Engl J Med. 2012;366:819-826.

For patients with drug-resistant temporal lobe epilepsy, surgery soon after failure of 2 antiepileptic drug (AED) trials is more effective than continued medical management in controlling seizures and improving quality of life, according to results of the Early Randomized Surgical Epilepsy Trial (ERSET).

"Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort," the study team notes in a new report published March 7 in the Journal of the American Medical Association. "Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death."

First author Jerome Engel Jr., MD, PhD, from the David Geffen School of Medicine, University of California, Los Angeles, told Medscape Medical News that surgery "should be considered early to avoid irreversible disabling social and psychological consequences of recurrent seizures. All patients with refractory epilepsy should be referred to an epilepsy center to determine if they might be surgical candidates, and for additional advanced diagnostic and therapeutic support if they are not," he added.

The results of this study "support the conclusions of the American Academy of Neurology practice parameter, namely that all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 AEDs fail, and surgery should be performed if patients meet criteria for an AMTR [anteromesial temporal resection]," the authors note in their paper.

Most Seizure-Free After Surgery

ERSET was a controlled, parallel-group clinical trial performed at 16 epilepsy surgery centers in the United States. It included 18 males and 20 females aged 12 years and older with mesial temporal lobe epilepsy (MTLE) and disabling seizures for no more than 2 consecutive years after adequate trials of 2 AEDs. Planned enrollment was 200, but the trial was halted prematurely because of slow accrual.

Patients were randomly allocated to continued AED treatment (n = 23) or to standard AMTR plus AED treatment (n = 15) and observed for 2 years. In the medical group, 7 patients underwent AMTR before the end of follow-up and 1 patient in the surgical group never had surgery.

In the primary analysis, which included patients who did not have complete follow-up data during year 2, freedom from disabling seizures during the second year of follow-up was achieved in 11 of 15 patients who had surgery (73%) and none of the 23 patients who continued on medical therapy (P < .001).

An analysis of only patients who provided complete data in year 2 (or reported seizures in year 2) found that 11 of 13 in the surgical group (85%) were seizure free compared with 0 of 19 in the medical group. Nine of the 11 participants in the surgical group who became seizure free never experienced a seizure after surgery.

Surgery also improved quality of life (QOL) as well as ability and access to driving and socialization, "despite the small number of participants," the researchers report. They say the effect on surgery on overall QOL was reflected in the Mental Health, Epilepsy-Targeted, and Cognitive Subscales of the Quality of Life in Epilepsy-89 (QOLIE-89).

"We were pleased to see such robustly positive results with respect to quality of life, as well as seizures, with such a small sample," Dr. Engel told Medscape Medical News.

Yet, freedom from seizures and improved QOL did not predict return to work, Donald L. Schomer, MD, from the Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, and Roger J. Lewis, MD, PhD, from Harbor-UCLA Medical Center, Torrance, California, and David Geffen School of Medicine at University of California, Los Angeles, point out in a commentary published with the study.

"Employment activities did not seem to show a group difference even though measures of social engagement did show a positive effect," they write.

"This matter is especially troublesome in terms of the ultimate effect of either treatment approach on the total medical and social burden and costs of MTLE," they note. "Patients with MTLE need ongoing counseling and access to work-related training whether they receive surgery or not."

Memory May Decline

In terms of cognitive function, there were no significant treatment group differences with respect to the primary memory and nonmemory measures, although participants in the medical group tended to perform better on memory tests, particularly at 24 months (P = .08).

When individual tests were examined, the surgical group performed worse than the medical group on immediate (P = .01) and delayed (P = .02) recall tests at 24 months. Also, a higher percentage of patients in the surgery group than the medical group showed a decline at 12 months in delayed verbal recall (36% [4 patients] vs 0%; P = .03) and naming (55% vs 7%; P = .02), "consistent with postsurgical rates reported in a recent meta-analysis," the investigators write.

"Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe," the investigators say. They also point out that continued epileptic seizures can also have a negative effect on cognitive function. The current sample was too small to permit definitive conclusions on the effects of surgery on cognitive function.

"What is not known from this study is whether the surgically induced memory decline is equal to, greater than, or less than memory decline that might occur during the long-term medical management," Dr. Schomer and Dr. Lewis write in their commentary.

Thirteen serious adverse events (7 in the medical group and 6 in the surgical group) occurred in 9 study patients (4 in the medical group, 5 in the surgical group) during the study. Of the 7 serious adverse events in the medical group, 2 were unrelated to the study or to seizures and 5 were related to seizures, including 3 cases of status epilepticus in the medical group.

Of the 6 serious adverse events in the surgery group, 3 were findings on postoperative magnetic resonance imaging suggestive of ischemic changes, but only 1 was a cerebral infarction with clinical manifestations (transient mild impairment in naming and receptive language).

Two others were postoperative complications; 1 was vomiting due to worsening of a preexisting esophageal dysmotility that required gastrostomy and the other was a communicating hydrocephalus attributed to resection-related bleeding into the subarachnoid space that resulted in placement of a ventriculoperitoneal shunt. The other serious adverse event in the surgery group was a shoulder dislocation and fracture due to a seizure during video-electroencephalography monitoring.

Confirmatory Data

John Duncan, MA, DM, FRCP, FMedSci, professor of neurology, University College London, United Kingdom, who was not involved in the study, agrees with the conclusions put forward by the researchers. "This paper confirms the utility of anterior temporal lobe resection early in the course of temporal lobe epilepsy that is not controlled with AEDs."

"All too often," he told Medscape Medical News, "individuals are only referred for epilepsy surgery when they have endured epilepsy for 2 decades. This study had the opportunity to make definitive statements and it is very regrettable that it was closed prematurely by the funding agency."

The study was supported by the National Institutes of Health. Dr. Engel has disclosed receiving consultancy fees from Medtronic, Valeant, Acorda, the US Food and Drug Administration, and Best Doctors; fees to his institution for expert testimony; lecture/speakers bureau fees from Esai, Johnson & Johnson, Novartis, and Lippincott; royalties from Wolters Kluwer, Wiley Blackwell, Elsevier, and MedLink; and fees for travel accommodations/meeting expenses from UCB Pharma. A complete list of disclosures for study and commentary authors are listed with the original article. Dr. Duncan has been consulted by and received fees to his institution for lectures from Eisai, GE Healthcare, Pfizer, GlaxoSmithKline, sanofi-aventis, and UCB, as well as departmental and grant support from Medtronic, Cyberonics, and VSM MedTech.

JAMA. 2012;307:922-930, 966-968. By Megan Brooks