It is my privilege to welcome you to the 46th Annual Scientific Meeting of the American Academy of Neurological and Orthopaedic Surgeons. We are gathered here at the Hilton Palacio Del Rio for our annual educational program.

Our conference will provide information on a variety of Neurological, Orthopaedic and Spine related topics and I encourage you to review the information available on the meeting APP to learn all about the various speakers and their presentations. I am delighted that in this year’s program will include a number of speakers from San Antonio and the surrounding area. Joining us from UT San Antonio will be Prof. Cristian Gragnaniello, who will present Modern Management Strategies in Thoraco-Lumbar Trauma on Saturday morning. In addition, invited guest speakers, Drs. Jon-Cecil Walkes from Houston and Steven Cyr from San Antonio will contribute two fascinating lectures on Friday morning.

I am pleased that the International College of Surgeons, as our educational partner, has worked closely with our Scientific Organizing Committee to develop additional programming that is likely to be of interest to all surgical specialties. I encourage every member of the Academy to peruse the program and participate in as many sessions as possible to earn the maximum number of CME credits.

I hope you have a most enjoyable visit to the home of the Alamo during our annual meeting!

Lucia Zamorano, MD, FICS, FAANOS
Chair, American Academy of Neurological and Orthopaedic Surgeons

Welcome Letters

“Our findings contradict many but not all previous studies and is currently controversial” Nawab Qizilbash, MBChB, MRCP (UK), head of OXON Epidemiology Ltd, and honorary senior lecturer in epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, told Medscape Medical News.

The study was published online April 9 in The Lancet Diabetes & Endocrinology.

Using the UK Clinical Practice Research Datalink (CPRD), the researchers analyzed the medical records of nearly 2 million (1,958,191) people with an average age of 55 years at the outset and an average BMI of 26.5 kg/m². During an average follow-up of 9 years (range, 6.3 to 12.6 years), nearly 45,507 were diagnosed with dementia, at a rate of 2.4 cases per 1000 person-years.

Compared with middle-aged adults with a normal weight (BMI, 20 to 24.9 kg/m²), those who were underweight were roughly a third more likely to develop dementia during follow-up. And the incidence of dementia fell with increasing BMI.

Table. Risk for Dementia by BMI Category

The pattern persisted throughout follow-up, after adjustment for potential confounders and allowance for the J-shape association of BMI with mortality, the researchers say.

“The jury is out” on why higher BMI in mid-life might help protect against dementia, Dr Qizilbash told Medscape Medical News. Factors postulated to explain the previously observed protective effect of increased BMI on late-life dementia include low late-life blood pressure; high late-life cholesterol levels; higher leptin levels; age-related regulatory changes in carbohydrate, lipid, or protein metabolism; and increased intake of vitamin E antioxidant and vitamin D. “Clearly more investigation is required,” Dr Qizilbash said.

In a statement, study investigator Stuart Pocock, PhD, from the London School of Hygiene & Tropical Medicine, said the findings “open up an intriguing new avenue in the search for protective factors for dementia — if we can understand why people with a high BMI have a reduced risk of dementia, it’s possible that further down the line, researchers might be able to use these insights to develop new treatments for dementia.”

Not the Final Word

In a linked Comment, Deborah Gustafson, PhD, from SUNY Downstate Medical Center in New York, urges caution in interpreting the findings. “There are some key issues with the study design that influence the validity of the results presented. I hope the Commentary sheds light on this,” she told Medscape Medical News.

She notes that the published literature on BMI and dementia is “equivocal. Some studies report a positive association between high mid-life BMI and dementia, whereas others do not.”

“Many considerations are needed in the assessment of the epidemiology of the association between BMI and late-onset dementia, as is the case for many recorded associations involving late-life disorders,” Dr Gustafson writes. For example, BMI trajectory throughout life, baseline BMI, competing causes of death, and adiposity measurement (total vs central) are “important considerations.”

“To understand the association between BMI and late-onset dementia should sober us as to the complexity of identifying risk and protective factors for dementia. The report by Qizilbash and colleagues is not the final word on this controversial topic,” Dr Gustafson concludes.

A small phase 1 pilot study showed that some patients with AD who received constant stimulation to the fornix — the principle outflow tract from the hippocampus — had increased hippocampal volume after 1 year.

There was also some evidence that this increased hippocampal volume correlated with cognitive benefit.

These results, published online in Brain Stimulation, suggest that fornix stimulation affects the structure of the brain and, if replicated, would be promising for AD treatment.

“In Alzheimer’s disease, the brain, in particular the hippocampus, melts away; as you lose your hippocampus, you lose your memory, and so far, there is nothing that can stop or slow down this process,” said study author Andres Lozano, MD, a neurosurgeon at Toronto Western Hospital and professor and chair, neurosurgery, University of Toronto, Ontario, Canada.

“If we are able to apply electrical stimulation, and if indeed we’re able in some cases to slow down or even reverse the process, it would be a very exciting finding.”

A second, larger study, a double-blind, randomized trial in 42 patients, is about to wrap up and should soon shed more light on the effectiveness of DBS in AD, the researchers say.

Circuit of Papez

Characterized by atrophy in the hippocampus as well as other brain structures, AD involves amyloid and tau deposition, formation of neurofibrillary tangles, and cerebral hypometabolism, the authors note. These processes result in dysfunction in several neural circuits, including the memory circuit of Papez.

DBS has already been proven effective for movement disorders, such as Parkinson’s disease, tremor, and dystonia. It’s also being used experimentally to treat patients with intractable psychiatric conditions, including major depression, obsessive-compulsive disorder, and anorexia nervosa.

Although the mechanism of action is uncertain, experts believe it likely involves modulated activity within dysfunctional neural circuits. But the prevailing thought has been that DBS is unable to influence progressive neurodegenerative processes acting on these circuits.

The current study included six patients with AD who participated in a phase 1 clinical trial showing that the DBS procedure was safe and could alter brain metabolism. These patients with AD were the first in the world to receive DBS, according to Dr Lozano.

The patients — four men and two women — were relatively young (aged 51, 69, 58, 62, 60, and 64 years) and had received the diagnosis of probable AD within the previous 2 years. They had a spectrum of dementia from mild to moderate and severe.

After electrodes were implanted, these patients received constant mild stimulation of the fornix. From structural MRI scans, researchers measured the volume of the hippocampus, fornix, and mammillary bodies — critical components of the Papez circuit — at baseline and after 1 year of continuous stimulation. They also looked for evidence of brain-wide structural changes.

At the end of the study period, two of the six patients (patients 1 and 4) showed a striking increase in right and left hippocampal volume. The mean (average of right and left) hippocampal enlargement was 5.6% in patient 1 and 8.2% in patient 4.

Caught by Surprise

“Not only did the hippocampus not shrink in these patients but the thing that caught us completely by surprise was that it actually grew and it grew by a large amount,” said Dr Lozano.

He noted that the baseline Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score for these two patients (18.67 for patient 1 and 11.67 for patient 4) indicated relatively mild AD.

Hippocampal volume did not increase in the other four patients, but their baseline ADAS-Cog scores were higher. “They were too far along and the circuit too destroyed or damaged that there was no one home to stimulate,” commented Dr Lozano.

“We think there may be a point of no return where damage is so extensive that you can’t recuperate function. Our feeling is that the earlier you go in, the more likely there will be something to rescue and something to work with.”

The researchers compared these hippocampal volume changes to a control group of 25 persons matched for age, sex, and neurocognitive severity who did not receive DBS. MRI data at baseline and at 12 months for these controls were available from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

No hippocampal growth occurred in any of these 25 controls. “So we think this does not occur spontaneously in Alzheimer’s disease, that it has occurred as a consequence of the brain stimulation in this case,” commented Dr Lozano.

Circuit Training

He believes that the stimulation is reactivating the memory circuit that is atrophying in AD. “It’s almost like circuit training, putting the circuit on a treadmill and making it work, and in so doing so, we think that the circuit can be maintained.”

Studies show that rodents receiving DBS actually generate more neurons, he added. “If this were to occur in humans, maybe we would have a way of repairing these damaged circuits. That’s important because you would go from a purely symptomatic treatment to actually treating the root cause and modifying the course of the illness.”

The hippocampal volume increases in the two patients appeared to correspond to cognitive outcome. Patient 4’s ADAS-Cog score improved from 11.67 at baseline to 7.33 at 1 year. Patient 1 did not have an improved ADAS-Cog score but showed the least deterioration among the other patients.

“Those whose hippocampus grew either got better cognitive function or stabilized whereas in those where it shrunk, cognitive function continued to deteriorate as expected in a progressive disease like Alzheimer’s disease,” said Dr Lozano.

The study also found evidence that fornix stimulation was associated with clusters of local volume expansion in temporoparietal regions of the brain that, although far from the Papez circuit, are known to be atrophic in AD.

The study did not find enlargement of the fornix or mammillary bodies. However, patients 1 and 4 showed the slowest atrophy rate in both of these structures, possibly suggesting a circuit-wide structural effect of fornix DBS.

Patient 4, who opted to continue to receive DBS, was reimaged at 3 years. After the 4-point improvement at year 1, this male patient got worse again (ADAS-Cog score of 15.33). But Dr Lozano pointed out that the average per year drop in this score in patients with AD is 7 points.

“So we would expect him to go from 11 to 18 to 25. That’s not what happened; he went from 11 to 7 to 15. We think that is possibly significant; it’s different than the expected natural course.”

Glucose Metabolism

Researchers also measured hippocampal glucose metabolism using positron emission tomography (PET) with a radio tracer. They did this preoperatively and in the “on” stimulation condition following 12 months of continuous DBS.

They found increased glucose metabolism — indicating the brain is using fuel — but it’s not clear how this is connected to increased hippocampal volume, said Dr Lozano. “We think the two are linked, but we don’t know which one comes first or whether one leads to the other or they’re independent.”

According to Dr Lozano, noninvasive stimulation methods, such as transcranial magnetic stimulation, would not produce the same results. For one thing, DBS provides targeted and precise stimulation “24/7,” which wouldn’t be possible with other modalities. In addition, the fornix is located at the center of the brain, which would be difficult to reach externally.

Would a stronger stimulus produce even better results? Possibly, he said, but when researchers at one point turned up the stimulation to a very high level, it produced unwanted vivid memories in some patients. The current settings were arrived at through patient input.

Information on the two patients whose hippocampus got bigger and whose illness stabilized has informed the next year-long study. The multicenter, randomized, blinded study included only patients with milder AD. Half of the 42 enrolled patients received DBS and the other half a sham treatment (electrodes were implanted but not turned on).

Cutting Edge

Medscape Medical News invited Howard Chertkow, MD, professor, neurology, McGill University, and director, aging and Alzheimer’s research axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada, as well as scientific director, Canadian Consortium on Neurodegeneration in Aging, to comment on this new study.

Dr Chertkow applauded Dr Lozano, whom he called a “very respected” world expert in neuromodulation in DBS. The new research, he said, is “cutting edge” and the study findings “certainly novel.”

Because there are limited effective treatments for AD, which affects almost 36 million people worldwide, and its cause is not yet confirmed, “any new treatment, any new lead, certainly has to be pursued,” he said.

The suggestion that stimulating the memory network can improve memory and is accompanied by changes on MRI and PET “is very exciting” and indicates that the results “are not just serendipitous,” added Dr Chertkow.

Another encouraging aspect of the study for Dr Chertkow is that it provides “the first clear evidence in humans” that stimulation might produce neurogenesis. “If we can create new connections in the hippocampus, maybe we can do so in a whole range of other brain disease, even beyond Alzheimer’s disease.”

But Dr Chertkow pointed out what he sees as negative aspects of the DBS approach used in the study. For example, the stimulation targets memory and so the best result is improved memory, but AD also involves changes in personality, emotions, and other cognitive functions, such as planning and language.

“There are other brain networks involved and it doesn’t seem logical that if you impact on one network that you are going to necessarily improve things in other networks.”

AD is a degenerative disease characterized by deposition of toxic proteins, such as amyloid and tau. “It’s doubtful that this treatment is going to stall or attenuate or stop this process,” said Dr Chertkow. “While it might improve symptoms, it’s not really attacking the disease itself.”

Other disadvantages to DBS in AD are that it’s invasive and costly and so “will always have limited applicability,” said Dr Chertkow.

“This is not going to be the answer for Alzheimer’s disease and memory loss with aging around the world, but it may have a role.”

Dr Lozano received support from the Surgeon Scientist Program, Department of Surgery, University of Toronto, and Neurosurgical Research and Education Foundation of the American Association of Neurological Surgeons. He is a Canada Research Chair in Neuroscience and is supported by the R.R. Tasker Chair in Functional Neurosurgery. Additional support was provided by the Dana Foundation and Krembil Neuroscience Discovery Fund. Dr Lozano is a consultant to Medtronic, St. Jude, and Boston Scientific; serves on the scientific advisory board of Ceregene, Codman, Neurophage, Aleva, and Alcyone Life Sciences; is cofounder of Functional Neuromodulation Inc; and holds intellectual property in the field of deep brain stimulation. Dr Chertkow has disclosed no relevant financial relationships.

Brain Stim. Published online December 3, 2014.

The retrospective analysis examined a consecutive series of 1,358 patients who underwent cervical spine surgery performed by a single surgeon. The procedural breakdown included:

• 1,038 anterior approaches
• 29 posterior approaches
• 28 combined anterior and posterior approaches

There were 214 posterior decompression patients, 14 laminoplasty patients and 69 foraminotomy patients. There were 32 patients who had arthroplasty and 17 patients who underwent a combination of arthroplasty and anterior arthrodesis.

Here are the findings:

1. There was a relatively constant adjacent segment reoperation rate of 2.3 percent of patients per year.

2. A Kaplan-Meier analysis predicts 21.9 percent of the patients will need an adjacent segment surgery 10 years postoperatively.

3. Factors associated with increased reoperation risk at the adjacent segment include:

• Smoking
• Female sex
• Type of surgery

4. Posterior-only arthrodesis or combined anterior and posterior arthrodesis had a 7.5-times greater risk of the adjacent-segment disease requiring surgery than posterior decompression, and three-times greater risk than anterior arthrodesis, according to the report.

5. The arthroplasty group — including arthroplasty alone and hybrid arthroplasty, anterior cervical arthrodesis group and posterior decompression group showed no significant differences in reoperation risk.

6. The other factors that didn’t show risk were:

• Age
• Neurological diagnosis
• Diabetes
• Number of surgically treated segments

Source

The new study shows that the risk for glioma was tripled among those using a wireless phone for more than 25 years and that the risk was also greater for those who had started using mobile or cordless phones before age 20 years.

“Doctors should be very concerned by this and discuss precautions with their patients,” study author Lennart Hardell, MD, PhD, professor, Department of Oncology, University Hospital, Örebro, Sweden, told Medscape Medical News.

Such precautions, he said, include using hands-free phones with the “loud speaker” feature and text messaging instead of phoning.

The study was published online October 28 in Pathophysiology.

Pooled Data

The recent worldwide increase in use of wireless communications has resulted in greater exposure to radiofrequency electromagnetic fields (RF-EMF). The brain is the main target of RF-EMF when these phones are used, with the highest exposure being on the same side of the brain where the phone is placed.

The new study pooled data from two case-control studies on histopathologically confirmed malignant brain tumours. The first included patients aged 20 to 80 years diagnosed from 1997 to 2003, and the second included those aged 18 to 75 years diagnosed between 2007 and 2009. Cases came from six oncology centers in Sweden.

Cases were matched with controls of the same sex and approximate age who were randomly drawn from the Swedish Population Registry.

All participants filled out a questionnaire detailing exposure to mobile phones and cordless desktop phones.

The analysis included 1498 cases of malignant brain tumors; the mean age was 52 years. Most patients (92%) had a diagnosis of glioma, and just over half of the gliomas (50.3%) were the most malignant variety — astrocytoma grade IV (glioblastoma multiforme). Also included were 3530 controls, with a mean age of 54 years.

The analysis showed an increased risk for glioma associated with use for more than 1 year of both mobile and cordless phones after adjustment for age at diagnosis, sex, socioeconomic index, and year of diagnosis. The highest risk was for those with the longest latency for mobile phone use over 25 years.

Table. Glioma Risk With Mobile and Cordless Phone Use

The risk was increased the more that wireless phones were used. The odds ratios steadily rose with increasing hours of use.

The risk for glioma was greatest in the most exposed part of the brain. The odds ratios were higher for ipsilateral exposure and for glioma in the temporal and overlapping lobes.

Further, the risk was highest among participants who first used a mobile phone (odds ratio, 1.8) or cordless phone (odds ratio, 2.3) before age 20 years, although the number of cases and controls was relatively small.

Developing Brain

As Dr Hardell explained, children and adolescents are more exposed to RF-EMF than adults because of their thinner skull bone and smaller head and the higher conductivity in their brain tissue. The brain is still developing up to about the age of 20 and until that time it is relatively vulnerable, he said.

There was a higher risk for third-generation (3G) mobile phone use compared with other types, but this was based on short latency and rather low numbers of exposed participants, said the authors. 3G universal global telecommunications system mobile phones emit wide band microwave signals, which “hypothetically” may result in higher biological effects compared to other signals, they write.

Such biological effects, said Dr Hardell, could include an increase in reactive oxygen species, which several articles have linked to cancer. The p53 gene has also been implicated, he said.

The study’s very high participation rate (86% for cases and 87% for controls) makes it unlikely that selection bias influenced the results, said the authors.

Dr Hardell believes the new findings reinforce the message that EF-EMF emissions from wireless phones should be regarded as carcinogenic under International Agency on Research on Cancer (IARC) classifications and that current guidelines for exposure “should be urgently revised” to reflect that.

According to the IARC’s 2013 report, there is a “causal” relationship between use of both mobile and cordless phones and that the risk of glioma is “possible.”

Numerous studies have looked at the link between use of wireless phones and brain tumors. Studies by Dr Hardell and his colleagues dating back to the late 1990s have found a connection with mobile and cordless phones.

But the INTERPHONE study (Int J Epidemiol 2011;39:675-694; Cancer Epidemiol 2011;32:453-464) failed to find strong evidence that mobile phones increase the risk for brain tumors.

In addition, a large prospective study (Int J Epidemiol 2013;42:792-802) found that mobile phone use was not associated with increased incidence of glioma or of meningioma or non–central nervous system cancers in middle-aged British women.

According to Dr Hardell, this last study was limited because it used information at one point in time. “It is not a case-control study and has serious problems with the methods used,” he told Medscape Medical News.

Evidence “Unconvincing”

Reached for a comment, L. Dade Lunsford, MD, Lars Leksell Professor of Neurosurgery, and director, Center for Image Guided Neurosurgery, University of Pittsburgh, Pennsylvania, said the new study provides additional “but as yet unconvincing” evidence of a potential role of cell or cordless phone technologies in the pathogenesis of gliomas.

He noted that some features were not controlled, including ionizing radiation exposure and family history.

As well, he said, the study suffers from recall bias, with results possibly being affected by patients being anxious to solve the question of “why me?”

“It is of interest that the only study that used actual industry data of cell phone use (the Danish study [Lancet Oncol 2011;12:624-626; Rev Environment Health 2012;27:51-58]) was dismissed by the authors as ‘uninformative’,” he said. “Perhaps it was not supportive of the author’s premise.”

Although the study didn’t specify the side of the tumor, Dr Lunsford pointed out that about 90% of the world’s population is right-handed and that most hold their mobile phone to their left ear in order to write with their dominant hand. “One could theorize then that left-sided tumors would predominate with the temporal lobe being most adjacent to the cell phone output.”

Dr Lunsford also commented that both glial and Schwann cells are late-responding tissues and that the oncogenesis of such cells by mobile phone technologies remains unexplained. “If cell phones cause such tumors, why do patients not develop higher rates of ipsilateral basal or squamous cell cancers, or melanomas — these are frequently dividing cell lines that theoretically ought to be even more susceptible.”

While the potential role of cell phones as an additional factor in oncogenesis “can’t be dismissed out of hand,” the use of this technology does save lives, stressed Dr Lunsford.

“Cell phone has provided an amazing safety net for citizens of almost all cultures across the world. The lives saved by the proliferation of cell phone communication is phenomenal — emergency calls, quick first responders, warnings of severe weather are only a few examples.”

Researchers at the University of Calgary say a new treatment plan for an aggressive brain cancer called glioblastoma is showing promise.

A combination of two drugs increased the lifespan of animals in test trials by 30 per cent, according to researchers at the Hotchkiss Brain Institute.

“It seems when the tumour is growing in the brain there’s multiple processes going on. So just shutting off this specific one doesn’t seem to have as much of an effect as hitting the cancer from different sides,” said Artee Luchman, one of the researchers.

“We’re just very encouraged by this study, which started as a lab inquiry research question, being moved into a human study.”

One drug is Temozolomide — already taken by most glioblastoma patients — while the other is AZD8055. Together they inhibit a pathway in the cancer cells known as mTOR signaling, causing more cancer cells to die when combined with current standard therapy.

Results of the study was recently published in the scientific journal Clinical Cancer Research.

Researchers hope to start a clinical trial next spring on people with glioblastoma, an aggressive form of brain cancer and the most common and deadly form among adults.

The researchers analyzed data from the American College of Surgeons National Surgical Quality Improvement Project Database. There were 50,361 patients included in the study. Neurosurgeons performed surgery on 66 percent; the remaining were treated by an orthopedic surgeon.

Here are five key findings from the study:

1. The only differences between the surgical subspecialties were diagnosis and outcomes.

2. When orthopedic surgeons performed the elective spine surgeries, patients were twice as likely to have a prolonged hospital length of stay as when neurosurgeons were performing the procedure. Even after matching patients on propensity scores, patients treated by orthopedic surgeons had slightly higher odds of longer length of stay.

3. Patients who underwent treatment by orthopedic surgeons were also more likely to:

• Receive a perioperative transfusion
• Have complications
• Require discharge with continued care

After matching patients, those treated by orthopedic surgeons were at twice the odds for receiving perioperative transfusions when compared with the neurosurgeons’ patients.

4. The difference in length of stay remained even when taking perioperative transfusions into account.

5. However, differences in 30-day postoperative outcomes were minimal. “Analysis of a large, multi-institutional sample of prospectively collected clinical data suggests that surgeon specialty has limited influence on short-term outcomes after elective spine surgery,” concluded the study authors.

“I think sleep has always intrigued a lot of people because not everyone even today believes sleep contributes to useful active processing in the brain,” Karen Debas, PhD, neuropsychologist, University of Montreal, Quebec, Canada, told Medscape Medical News.

“So the fact that we found sleep contributes to the consolidation of memory is important and to prove that it is doing so is to understand the mechanisms that are taking place during sleep.”

The study is published in the October issue of NeuroImage.

Functional Connectivity

The aim of the study was to directly compare changes in functional connectivity related to the consolidation process of a motor memory in 2 groups of young adults. Some 24 participants between 19 and 30 years of age who had no experience playing a musical instrument executed a 5-element version of the finger sequence learning task. Essentially, participants were taught a new sequence of piano-type finger movements on a box.

However, one group performed the task in the evening and was retested the following morning (night/sleep group), while the other group performed the same task during the morning and repeated the task again that evening (day/awake group). All participants performed the test and repeated test while being observed using functional MRI.

Changes in connectivity within the cortico-striatal network were significantly different depending on whether participants had slept or not, investigators report. Specifically, results showed a 21% decrease in the level of integration in the cortico-striatal region in the day/awake group compared with a 7% increase in integration levels following a night of sleep (night/sleep group) (P = .03).

Investigators also noted that only the cortico-striatal system revealed a strong tendency toward an increase in integration following sleep and that none of the other networks demonstrated significant sleep-related changes in integration.

These findings suggest that there is greater synchrony of activity between regions forming the cortico-striatal network and that communication between the various regions of the network is optimized after a period of sleep. As Dr. Debas explained, the network the investigators evaluated consists of a lot of subcortical and cortical areas, including the putamen, that are important for motor skill consolidation.

“After a night of sleep, we found that this network was more integrated than the others, that is, interaction among these regions was greater when consolidation had occurred,” Dr. Debas said in a press release. “So a night of sleep seems to provide active protection of this network, which the passage of daytime does not provide.”

Dr. Debas emphasized that findings from this study are essentially a step forward toward a better understanding of the mechanisms involved in memory consolidation.

“Ultimately, however, we believe that we will be better able to explain and act on memory difficulties presented by certain clinical populations who have sleeping problems and help patients who are relearning motor sequences in rehabilitation centers,” she suggested.

Thought-Provoking

Stephan Swinnen, PhD, Francqui Research Professor, Motor Control Laboratory, Movement Control and Neuroplasticity Research Group, Leuven, Belgium, told Medscape Medical News the study’s results are very interesting and thought-provoking because the data show that when someone practices a motor task during the day, it does not mean that the task-related activity is abolished as soon as practice has stopped.

“There may be exciting brain activity going on during sleep that results from the activity in particular brain areas that were recruited while you were involved in practice,” he elaborated. “It is as if the brain replays this activity in one way or another and this may help in laying down this experience in your memory in a more durable or long-lasting manner.”

Dr. Swinnen added that as a result of sleep following practice, a “privileged interaction” is established between the brain areas that were strongly active during practice — that is, the cortico-striatal pathway — as part of a broader brain network.

“Again, it is as if these brain areas resonate better with each other as a consequence of sleep following practice of the motor task,” he explained. “It’s like improving traffic on the freeway between 2 important cities such that the 2 towns interact more intensively with each other and function better as a result.”

Mark Mahowald, MD, professor of neurology (retired) University of Minnesota, Minneapolis, and a member of the American Academy of Neurology, told Medscape Medical News that the study adds further evidence to the concept that at least one of the functions of sleep is memory consolidation.

“In our society today, we equate sleep and sleepiness with laziness and depression and other defects of character and where sleep deprivation is held out as a badge of honor,” Dr. Mahowald said. “When in fact, any degree of sleep deprivation will impair performance and will impair learning. This is good evidence that the brain is not resting during sleep — it’s consolidating memories and performing extremely important memory-related functions. Sleep is important.”

The study was funded by the Canadian Institutes of Health Research and the Fonds de recherché due Quebec en santé. The authors, Dr. Swinnen, and Dr. Mahowald have disclosed no relevant financial relationships.

NeuroImage. 2014:99:50-58. Abstract

The study, published online September 9 in the Journal of Neurology Neurosurgery & Psychiatry 9 and conducted by a team led by Christopher M. DeGiorgio, MD, Department of Neurology, UCLA School of Medicine, Los Angeles, California, showed a significant reduction in seizure frequency with the low-dose but not the high-dose treatment vs placebo.

Dr. DeGiorgio told Medscape Medical News that the results of this study may reinvigorate interest in fish oil research for epilepsy.

“Previous studies of fish oil in epilepsy have been negative, which has been very disappointing after promising animal data. The disappointing clinical results have caused interest to wane, but this is the first study to look at a low dose,” he said.

He explained that the previous studies tested a dose of fish oil containing 1700 to 2000 mg of omega-3 fatty acids per day. This is similar to the higher dose in the current study, which also showed no effect.

But the lower dose in this study — 1000 mg of omega-3 fatty acids per day — showed a reduction in seizure frequency of about one third. “This is quite remarkable given that the patients included all had intractable epilepsy,” he commented.

Noting that the 1000-mg dose may also have some benefit in cardiovascular disease and has shown some promise in depression and cognition, Dr. DeGiorgio said, “We seem to have hit the sweet spot in terms of dose.”

But he cautioned that the current study was small and the results need to be confirmed in larger studies before any clinical recommendations can be made.

“It’s too early to make any definitive statements, but I am excited about what we found and what the future may hold,” he added.

Seizures Reduced by One Third

The randomized, double-blind study included 24 patients with intractable epilepsy who averaged 18 seizures per month while receiving placebo. In a 3-period crossover design, each patient underwent 3 treatment periods of 10 weeks’ duration with low-dose fish oil (1080 mg of omega-3 fatty acids daily as 3 fish oil capsules per day); high-dose fish oil (2160 mg daily as 3 fish oil capsules twice a day), or placebo.

In between each treatment period there was a 6-week washout. Patients continued to receive their current antiepileptic medication throughout the study.

Results showed that the low dose was associated with a 33.6% reduction in seizure frequency compared with placebo (P = .02). High-dose fish oil was no different than placebo in reducing seizures.

Table. Average Seizure Frequency

In the low-dose group, 2 patients (10%) actually achieved seizure-free status, which Dr. DeGiorgio said was “quite an achievement.”

He said he was surprised at first to see an effect with the low dose but not the high dose, but there is a potential explanation for these observations. “When we got the results back, I was shocked and a little perplexed at first, but having thought about it some more I am now very encouraged,” he told Medscape Medical News.

He noted that some animal studies have also suggested that lower doses of omega-3 fatty acids have a better effect on reducing seizures than do higher doses, and a great antidepressant effect has also been reported with a lower dose in a clinical study.

He adds: “It is not unusual to see a very narrow therapeutic index with epilepsy drugs. Two of the most popular drugs used — phenytoin and carbamazepine — can both exacerbate seizures if too much is given.”

Mechanism?

Dr. DeGiorgio explained that omega-3 fatty acids are believed to work by regulating the passage of sodium and calcium ions into brain cells. These ions increase excitability of the cells and can trigger seizures.

“Omega-3 fatty acids cause these ion channels to close earlier than normal, so blocking sodium and calcium entry to the cell. Too high a dose could cause sodium and calcium levels inside the cell to fall so low that other excitatory mechanisms are triggered,” he suggests.

He also pointed out that omega-3 fatty acids are believed to have an antiarrhythmic effect — again thought to be mediated by reducing the excitability of cardiac cells, and 1000 mg is the dose shown to beneficial in this indication. “This fits in perfectly with our data.”

“The 1000 mg/day dose has shown benefits in heart disease, and epilepsy patients have a higher risk of cardiovascular disease,” he says. However, the most recent trials of fish oil have failed to show a benefit in cardiovascular disease.

Dr. DeGiorgio noted that the 1000-mg dose may also reduce blood pressure and has shown some preliminary positive results in depression and cognition. “Indeed in our study, we also measured cognition, and while we haven’t processed the exact data yet, we are pretty sure we’ve seen an improvement in memory and thinking with the 1000-mg dose,” he noted.

He adds: “I obviously cannot recommend anyone take omega-3 fatty acids based just on this 1 study but I do believe it has many health benefits and very little risk. It is widely available and it could be a reasonable option to consider for patients with intractable epilepsy. If they are interested in this approach they should talk to their doctor about it.”

Before any definitive claims in epilepsy can be made, a larger study is needed, he added. Dr. DeGiorgio is hoping to conduct such a study and is optimistic that these results will help him acquire funding.

Most recent trials of fish oil in cardiovascular disease have failed to show any benefit.

The study was funded by grants from the National Institute of Health, National Center for Complementary and Alternative Medicine; Clinical Research Center Grant, and by the generous support of: James and Beverly Peters, The Kwock Family, Marc and Teri Jacoby, the Salter Family Trust, Pepper and Joseph Edmiston, Mrs Elsie Bierner-Johnson, Richard and Linda Lester, Robert and Linda Brill and their families. Dr. DeGeorgio is a part-time employee of NeuroSigma, a device company, which develops devices for epilepsy and other disorders.

J Neurol Neurosurg Psychiatry. Published online September 9, 2014. Abstract

“We developed a strategy to successfully shield the marrow and blood cells and thus patients can now get this drug combination with benzylguanine and temozolomide while the marrow and blood cells are protected and shielded,” Dr. Hans-Peter Kiem from Fred Hutchinson Cancer Research Center in Seattle told Reuters Health by email.

“MGMT (methylguanine methyltransferase) in the tumor will inactivate the chemotherapy and thus make the tumor insensitive to chemotherapy,” Dr. Kiem explained. “We can reverse this by disabling MGMT and making the tumor again sensitive to temozolomide using a drug called benzylguanine. Unfortunately disabling MGMT in blood and marrow cells makes them also more sensitive to temozolomide causing low blood counts and preventing the use of this approach.”

In an effort to protect blood cells from the benzylguanine-temozolomide combination, Dr. Kiem and colleagues transplanted autologous gene-modified CD34+ cells into seven patients with newly diagnosed MGMT promoter unmethylated glioblastoma who had already received >50% surgical resection followed by radiation therapy.

Once they recovered from the stem cell transplant, patients received between two and nine cycles of adjuvant benzylguanine-temozolomide at or above the previously established maximum tolerated dose of temozolomide.

Five of the seven patients experienced myelosuppression following chemotherapy, the researcher report in the Journal of Clinical Investigation, online August 8.

But by 100 days after transplantation, only one patient had significant chemotherapy-associated myelosuppression, and this patient displayed little to no gene-modified cells in circulation at the time of chemotherapy.

In the four patients with durable gene marking throughout chemotherapy, there was a gradual decline in circulating gene-modified peripheral blood cell levels immediately following discontinuation of chemotherapy. The researchers say this suggests a potential disadvantage for gene-modified stem cells in the absence of chemoselective pressure.

One patient experienced a partial response, and six of seven patients experienced progressive disease while on chemotherapy, with a median progression-free survival of nine months. Five of these patients had demonstrated a best response of stable disease, according to the report.

Median overall survival was 20 months, with all seven patients living at one year from diagnosis. Three of seven patients were alive at two years, a significant improvement compared to similar historical patients receiving radiation therapy followed by adjuvant temozolomide. Moreover, all seven patients surpassed the median survival for patients in the same recursive partitioning analysis (RPA) class.

All patients also demonstrated greater average days gained and prevention of radial tumor growth per milligram of temozolomide administered compared with matched controls, and this was sustained for the duration of the treatment course.

As for the cost of treatment, Dr. Kiem said, “I don’t think the cost will be higher than other experimental drug therapies currently being pursued — the main cost is the genetic modification and protection of the blood cells and this is a one-time procedure.”

“This is indeed an interesting strategy especially for those patients who develop temozolomide resistance and are more likely to have severe myelosuppression as an off-target effect of (benzylguanine),” Dr. Rajiv Khanna from Royal Brisbane Hospital in Herston, Queensland, Australia, told Reuters Health by email. “Although the results are quite promising, the cohort size to too small to make any firm conclusion.”

Dr. Khanna, who has investigated other treatments for glioblastoma but was not involved in this study, added, “Immune-based therapies are emerging as powerful tool for the treatment of glioblastoma multiforme (GBM) patients. In particular, T cell therapies targeting GBM-associated antigens have provided promising results and should be considered in combination with gene therapy approach developed by these authors.”

“While lot more work will be required to provide a firm evidence for the benefit of genetically modified stem cell transplantation, this study provides an important platform for the application of this strategy for other cancers (including brain) where alkylating agent chemotherapy is a potential option,” Dr. Khanna concluded.

Source

Data Presented at IMAST shows over 99 percent accuracy when placing screws with Mazor Robotics Renaissance^® Guidance System

ORLANDO, Fla., July 17, 2014 – Mazor Robotics, Ltd. (TASE: MZOR; NASDAQ GM: MZOR), a developer of innovative guidance systems and complementary products, announced results of data being presented July 16-19 at the 21^st International Meeting on Advanced Spine Techniques (IMAST) meeting in Valencia, Spain.

An e-poster entitled, Retrospective, Five-Center Analysis of 3,270 Pedicle Screws Placed with Robotic Guidance in Adolescent Idiopathic Scoliosis (AIS), reports that 223 patients with AIS in five centers, had a total of 3,270 pedicle screws placed using the Renaissance system with over 99 percent accuracy.

A podium presentation, entitled: Retrospective Analysis of Feasibility and Performance of Robotic Guidance for Placement of Pedicle Screws in 223 Adolescents with Idiopathic Scoliosis (AIS), highlights that 3,270 screws were placed with the Renaissance system while fluoroscopy use was limited to 1.58 seconds per screw.

“Anatomic constraints in AIS frequently confound placement of pedicle screws, especially when instrumenting the most deformed regions of a curved spine,” said Dr. Dennis P. Devito of Children’s Healthcare of Atlanta, one of the lead investigators of the study. “The accuracy of screw placement and reduced exposure to radiation per case results in safer operations for both the patient and surgical staff.”

Other researchers involved in the study included:
Dr. Isador Lieberman, Texas Back Institute, Plano, TX
Dr. Samuel Bederman, UCI Irvine Medical Center, Irvine, CA
Dr. Raymond Woo, Florida Hospital for Children, Orlando, FL
Dr. Sajan Hegde, Apollo Hospitals Chennai, Chennai, India

About The Renaissance System
Mazor Robotics Renaissance system is the only mechanical guidance system cleared by the US Food and Drug Administration for use in both spine and brain surgery.
To date, thousands of spine procedures have been performed with the Renaissance system, ranging from minimally-invasive one-level fusions to complex deformity reconstructions.

About Mazor
Mazor Robotics is dedicated to the development and marketing of innovative surgical guidance systems and complementary products that provide a safer surgical environment for patients, surgeons, and operating room staff. Mazor Robotics’ flagship product, Renaissance^®, is a state-of-the-art surgical guidance system that enables surgeons to conduct spine and brain procedures in an accurate and secure manner. Mazor Robotics systems have been successfully used in the placement of over 45,000 implants worldwide. Numerous peer-reviewed publications and presentations at leading scientific conferences have validated the accuracy, usability, and clinical advantages of Mazor Robotics technology. For more information, the content of which is not part of this press release, please visit www.mazorrobotics.com.

Preliminary results from 2 studies presented here at the Alzheimer’s Association International Conference (AAIC) 2014 show that beta-amyloid detected in the eyes significantly correlated with the burden of beta-amyloid in the brain, allowing investigators to accurately identify individuals with AD.

In the first study, researchers at the Commonwealth Scientific and Industrial Research Organization (CSIRO), Australia’s national science agency, used curcumin fluorescence imaging to highlight beta-amyloid in the retina and correlated these results using Pittsburgh compound B (PiB) positron emission tomography (PET) imaging findings in the brain.

“Every single person who tested positive with high levels of plaque in the brain tested positive to the retinal test as well, so we had 100% sensitivity and no false negatives, which is a crucial component on a screen for Alzheimer’s disease because we don’t want to leave anyone behind when it comes to the early signs,” lead investigator Sean Frost said at a press briefing here.

The investigators note that although AD-related pathology in the brain is well documented, the disease has also been reported to affect the retina, a developmental outgrowth of the brain that is more accessible for imaging.

The primary substance in the Asian spice turmeric, curcumin has several properties that make it a good contrast medium ― it binds with high affinity to beta-amyloid, and it has fluorescent properties that enable amyloid plaques to be imaged in the retina. In addition, said Frost, it is safe.

Study participants included individuals with AD, individuals with mild cognitive impairment, and healthy control participants from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) study.

In addition to undergoing PiB PET imaging, participants made 2 visits for retinal fluorescence imaging. During the first visit, they drank a proprietary curcumin supplement. On the second visit, they underwent retinal amyloid imaging (RAI).

Preliminary data from the first 40 participants showed that amyloid levels detected in the retina were significantly correlated with brain amyloid levels, as shown by PiB PET imaging. In addition, RAI differentiated participants with AD from those without AD with 100% sensitivity and 80.6% specificity.

Furthermore, said Frost, longitudinal data showed an average increase of 3.5% in retinal amyloid during a 3.5-month period, suggesting that the technique may be used as a means of monitoring response to therapy.

If these early findings bear out, Frost said, this technology could be used as an initial screen for AD that could potentially be part of regular eye examinations.

“One day we hope there’s going to be better treatments available, and this will definitely provide a frontline screening tool to detect it in the early stages, before cognitive decline, and hopefully change the course of Alzheimer’s disease,” he said.

The full study is expected to be completed later this year.

On-the-Spot Results

In the second study, investigators from Cognoptix Inc, in Acton, Massachusetts, reported findings showing that a novel fluorescent ligand eye scanning (FLES) system that detects beta-amyloid in the lens of the eye also accurately detects amyloid burden and correlates with florbetapir PET brain imaging.

This phase 2 study included 20 individuals with probable mild to moderate AD and 20 healthy, age-matched control participants.

For the study, participants had a small molecule applied to the eye in the form of a sterile ophthalmic ointment. The compound is left to diffuse into the eye overnight; the next day, the eye is scanned with the laser and results are computed.

All 40 participants also underwent PET amyloid brain imaging.

According to Paul D. Hartung, president and CEO of Cognoptix Inc, who presented the findings, the study showed that the test was able to differentiate individuals with Alzheimer’s from healthy control participants with 85% sensitivity and 95% specificity (P < .001). In addition, amyloid levels in the lens significantly correlated with PET imaging results.

Hartung pointed out that at approximately $300, the test is about 10 times less expensive than PET imaging and much less invasive than cerebrospinal fluid testing.

In addition, he said, a single scan takes less than a second, and the instrument can compute a score, known as a fluorescence uptake value, in less than 5 minutes.

Furthermore, he said, the technology requires minimal training and has the potential to be used by general practitioners, nurses, and other healthcare practitioners in clinics and offices. It is also safe and could be administered on a regular basis to track disease progression and to monitor treatment.

“Early detection is critical. We are hoping the treatments that are being developed will be more effective if they are administered earlier, and we need something that can be made accessible to doctors everywhere,” he said.

With principal investigator Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, Arizona, Hartung said the investigators are currently conducting a pivotal phase 3, multicenter, US-based study to support US Food and Drug Administration approval of the FLES system as an aid in the diagnosis of probable AD.

Exciting Findings

Commenting on the studies for Medscape Medical News, David Knopman, MD, professor of neurology at the Mayo Clinic College of Medicine, consultant in neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the Alzheimer’s Association Medical and Scientific Advisory Council, who moderated a press conference on this topic, said he was “very impressed” by both papers and particularly the retina paper.

“I thought the data were very interesting, and if it is the case that the amyloid in the retina parallels the amyloid in the brain ― and that’s what they were showing ― that’s really an exciting finding.

“I think that brain amyloid imaging at this point has been of tremendous scientific value in allowing us to understand who is either at risk, or who actually has the pathology of Alzheimer’s disease in life, but it’s so expensive. At my institution, to do an Amyvid [Avid Radiopharmaceuticals, Inc] scan is somewhere between $5000 and $7000.

“The Center for Medicare and Medicaid Services doesn’t pay for amyloid imaging. We’re looking into that for research purposes, but if this actually could substitute for that, say, in clinical trials or under appropriate circumstances if there were therapies to identify people who would benefit from the therapies, that would be a tremendous advance.”

Unfortunately, said Dr. Knopman, at this point, the Alzheimer’s field lacks a powerful therapy to prevent the disease or stop it in its tracks.

“At this point, we understand that, but the kind of approaches described here are the kind of approaches we need to have in place when we have those effective therapies,” he said.