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Monday, April 8, 2019

Study of multiple sclerosis patients shows 18 percent misdiagnosed

A recent study found that nearly 18 percent of patients diagnosed with multiple sclerosis before being referred to two major Los Angeles medical centers for treatment actually had been misdiagnosed with the autoimmune disease.
The , led by investigator Marwa Kaisey, MD, along with Nancy Sicotte, MD, interim chair of Neurology and director of the Cedars-Sinai Multiple Sclerosis and Neuroimmunology Center, and researchers from UCLA and the University of Vermont, analyzed the cases of 241 patients who had been diagnosed by other physicians and then referred to the Cedars-Sinai or UCLA MS clinics over the course of a year.
Investigators sought to determine how many patients were misdiagnosed with MS, and identify common characteristics among those who had been misdiagnosed.
“The  of MS is tricky. Both the symptoms and MRI testing results can look like other conditions, such as stroke, migraines and vitamin B12 deficiency,” Kaisey said. “You have to rule out any other diagnoses, and it’s not a perfect science.”
The investigators found that many patients who came to the medical centers with a previous diagnosis of MS did not fulfill the criteria for that diagnosis. The patients spent an average of four years being treated for MS before receiving a correct diagnosis.
“When we see a patient like that, even though they come to us with an established diagnosis, we just start from the beginning,” Sicotte said.
The most common  was migrane (16 percent), followed by radiologically isolated syndrome, a condition in which patients do not experience symptoms of MS even though their imaging tests look similar to those of MS patients. Other correct diagnoses included spondylopathy (a disorder of the vertebrae) and neuropathy (nerve damage).
Among those misdiagnosed, 72 percent had been prescribed MS treatments. Forty-eight percent of these patients received therapies that carry a known risk of developing , a serious disease in the white matter of the brain, caused by viral infection.
“I’ve seen patients suffering side effects from the medication they were taking for a disease they didn’t have,” Kaisey said. “Meanwhile, they weren’t getting treatment for what they did have. The cost to the patient is huge—medically, psychologically, financially.”
Investigators estimated that the unnecessary treatments identified in this study alone cost almost $10 million.
The investigators hope that the results of this study, which will be published in May’s issue of the peer-reviewed journal Multiple Sclerosis and Related Disorders, along with recently funded research into new biomarkers and improved imaging techniques, will help improve diagnostic procedures and help prevent future MS misdiagnoses.
Funding for the new research includes $60,000 from Cedars-Sinai Precision Health, a partnership among scientists, clinicians and industry designed to advance personalized medicine. Kaisey said that she hopes these studies will also lead to better availability of treatment for  who do have the disease.
“The first step, which is what we’ve done here, is to identify the problem, so now we’re working on potential solutions,” she said.
The study is available online and will be published in May’s print edition of the peer-reviewed journal Multiple Sclerosis and Related Disorders.
Explore further
More information: Marwa Kaisey et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers, Multiple Sclerosis and Related Disorders (2019). DOI: 10.1016/j.msard.2019.01.048
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Telemedicine tied to more antibiotics for kids

Telemedicine may be leading to the overprescribing of antibiotics to sniffling children, a new study suggests.
Kids with cold symptoms seen via telemedicine visits were far more likely to be prescribed antibiotics than those who went to a doctor’s office or clinic, researchers found. And a higher proportion of those prescriptions disregarded medical guidelines, raising the risk they could cause side effects or contribute to the rise of antibiotic-resistant germs.
“I understand the desire for care that’s more convenient and timely,” said the study’s lead author, Dr. Kristin Ray of the University of Pittsburgh. “But we want to make sure that we don’t sacrifice quality or safety or effectiveness in the process.”
The study was published Monday in the journal Pediatrics.
Ray and her colleagues looked at more than 340,000 insured children who had acute respiratory illness medical visits in 2015 and 2016.
Children received prescriptions for antibiotics more than half the time during telemedicine visits, compared with 42% at urgent care clinics and 31% at doctors’ offices.
While overprescribing can help germs build resistance to antibiotics and mutate into untreatable superbugs, they also can add a needless cost to medical bills and even cause serious side effects, said Tim Landers, an Ohio State University expert on antibiotic-resistant infections.
“These are not harmless drugs,” Landers said, who was not involved in the study.
The researchers also found that in looking at telemedicine doctors’ decisions about whether to prescribe or not prescribe antibiotics, 4 out of 10 failed to meet medical guidelines on matching treatment to diagnosis. That mainly had to do with doctors prescribing bacteria-fighting drugs to treat viral illnesses, such as colds and flus, that are unaffected by antibiotics.
In comparison, 3 out of 10 urgent care clinic decisions were inappropriate, and about 2 out of 10 doctors’ office decisions were.
The researchers also found telemedicine physicians appeared to be ignoring other guidelines. For example, doctors are supposed to take a throat swab and run a lab test before diagnosing strep throat. But that rarely happened in telemedicine visits, Ray said.
A large recent study on antibiotic prescribing patterns for adults found little difference between telemedicine and office visits. But there has been little study of the issue in children.
During telemedicine visits, patients interact with doctors and nurses through video or audio calls. They can be less expensive and easier than trying to get in at a pediatrician’s office or hauling kids to an urgent care center.
Some doctors and hospital systems use the technology for consultations, but the study focused on direct-to-consumer telemedicine programs that someone can call up without talking to their regular doctor. Only about 1 percent of the sick kids in the study were seen through such visits.
The American Academy of Pediatrics, which publishes the journal, encourages parents not to use such direct-to-consumer programs. Academy officials say limited physical examinations and lack of access to patient records can harm care.
But telemedicine seems to be catching on, especially among employers who believe it can save money, said Jason Doctor, a University of Southern California health policy and economics researcher.
Doctor is examining ways to improve antibiotic prescribing at telehealth firms. It’s an important issue, he said, because “telemedicine is going to grow. It’s going to become a more routine part of people’s medical care.”
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Working Memory Revived in Older Adults

Age-related declines in working memory were reversed temporarily with non-invasive transcranial alternating current stimulation (tACS), a small study of older adults demonstrated.
Stimulating temporal and prefrontal brain areas simultaneously at a specific rhythm improved older adults’ working memory and the effect outlasted a 50-minute period after stimulation stopped, according to Robert Reinhart, PhD, and John Nguyen, BS, both of Boston University.
Working memory deficits in older adults appear to emerge from weak cross-frequency coupling between gamma and theta rhythms and compromised theta phase synchronization between prefrontal and temporal areas, they reported in Nature Neuroscience.
This research supports theories of neurocognitive aging that suggest cortical disconnection underlies age-related cognitive decline and shows negative, age-related changes are not unchangeable, Reinhart said in a press briefing: “We can bring back the more superior working memory function that you had when you were much younger.”
“Working memory is a fundamental building block of human cognition,” Reinhart noted. “It allows us to hold information in our minds over a period of seconds … [it’s] where we think, where we problem-solve, where we reason, plan, perform mathematical calculations, and make decisions.”
Throughout the adult lifespan, working memory exhibits a strong linear decline, and the mechanism behind this decline is unknown.
Working memory is linked to specific neural interactions within and between brain regions and is thought to involve two patterns of neural oscillation — gamma and theta rhythms. A specific form of cross-frequency coupling known as theta-gamma phase-amplitude coupling — in which the amplitude of gamma rhythms is coupled to the phase of theta rhythms — has been observed in the temporal cortex and is thought to reflect the local processing and storage of memory contents.
In their study, the researchers used high-definition tACS (HD-tACS, a form of stimulation that offers more precise targeting of cortical structures) to modulate wave interactions associated with working memory and electroencephalography to monitor how these interactions changed.
They evaluated 42 younger adults (ages 20 to 29) and 42 older adults (ages 60 to 76) in a working memory task, with and without HD-tACS. When performing the task, younger adults displayed increased interactions between theta and gamma rhythms in the left temporal cortex and increased synchronization of theta rhythms in the frontotemporal regions.
Without brain stimulation, older adults were slower and less accurate at the task than younger adults: “They struggled to maintain robust representations of task-relevant information,” Reinhart observed. When they received stimulation, however, older adults exhibited a mean accuracy level statistically indistinguishable from that of younger adults at baseline.
The effect occurred relatively quickly — within about 12 minutes of HD-tACS delivery — and continued past a 50-minute follow-up period. Improvements in task accuracy correlated with increased theta-gamma coupling in the temporal cortex and enhanced theta phase synchronization across the frontotemporal cortex.
Working memory deficits and functional connectivity problems are central to many brain disorders, including schizophrenia, autism, and Alzheimer’s disease, Reinhart noted. “Our hope is that this work will help lay the basic science groundwork for an entirely new avenue of research where we develop non-invasive new neuroscience tools to help treat people who are suffering from brain disorders,” he said.
The authors declared no conflicts of interest.
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Bone Marrow Transplant for Autoimmune Disease: Is It Time?

Rheumatologists need to take another look at bone marrow transplant as a treatment for refractory autoimmune diseases, a Johns Hopkins University hematologist told a gathering here.
Most of the received wisdom on bone marrow transplant — that autologous procedures are better tolerated than allogeneic transplants, for example, and that only HLA-matched donations really work for the latter — is wrong and should be “unlearned,” said Richard J. Jones, MD, of Hopkins’ Sidney Kimmel Comprehensive Cancer Center in Baltimore.
Those beliefs may have been accurate 20 or 30 years ago, he told attendees at the American College of Rheumatology’s State of the Art Symposium, but research and experience gathered in the cancer setting have since upended them. (Though even in oncology not everyone has gotten the message, Jones lamented, noting that a National Cancer Institute website still promotes HLA matching as the gold standard.)
In rheumatologic disease, he said, it’s now clear that allogeneic transplant is both safer and more effective than autologous procedures, and that the key is threefold: haploidentical donor selection in place of HLA matching, recognition that graft-versus-host disease (GVHD) is not to be feared, and use of cyclophosphamide post-transplant.
Unpublished early data from his center indicates that in 16 patients with different autoimmune conditions treated under the new paradigm, everyone has so far remained in remission. Hopkins is now about to start a formal trial in scleroderma and multiple sclerosis, Jones said.
Old Ideas
The belief that autologous transplant is safer and more effective stemmed from worries over GVHD resulting from the introduction of “foreign” hematopoietic stem cells with allogeneic procedures. But, Jones pointed out, when the goal of transplant is to provide the patient with an entirely new and healthy immune system, that simply can’t work when the patient’s own, original stem cells are used. Although removal of autoreactive T cells from the patient’s autograft may be attempted, it’s never entirely successful. He estimated that in an average infusion, something like 20 million autoreactive T cells are likely to be included.
And the fear of GVHD turns out to be unwarranted for a reason many rheumatologists may find counterintuitive — it’s actually desirable. That’s because the graft-versus-host reaction “is the only truly ablative modality,” Jones said, explaining that it purges the memory lymph cells that perpetuate autoimmunity.
As for HLA matching, that went out the window in oncology years ago, he said. It’s simply not necessary — haploid matching works just as well, and doesn’t even need to be perfect, with excellent results seen with up to four mismatched antigens. The one limitation is that donors should not be older than 50 — but because matches don’t have to be perfect, when the most closely matched potential donor is too old, his or her child or even grandchild may be suitable, Jones said.
Another factor contributing to effective immune reset is a nonmyeloablative conditioning regimen pre-transplant followed by cyclophosphamide after transplant. The most desirable cells in an allogeneic transplant, notably the donor’s memory lymph cells, resist cyclophosphamide. That’s why the drug is not effective by itself long-term in autoimmune disease. But in the post-transplant setting it targets so-called cycling alloreactive T cells that would otherwise interfere with engraftment and promote undesirably widespread GVHD, Jones explained. (Success may be bolstered even further with antithymocyte globulin given prior to transplant and including thiotepa [Tepadina], another myeloablative drug, in the post-transplant regimen along with cyclophosphamide, he said.)
In 2017, his group published results with this approach in 21 patients with relapsed, severe aplastic anemia — all of whom remain alive and disease-free, Jones said. Two patients experienced mild GVHD that resolved within 18 months. He added that sickle cell anemia also appears amenable to marrow transplant, citing data expected to be published soon.
Outside of formal trials, Hopkins has used haploid-matched donor transplant with cyclophosphamide in six patients with lupus, six with inflammatory bowel disease, three with psoriasis, and one with multiple sclerosis, all apparently successful, although with limited follow-up.
Another advantage of the new approach, Jones said, is that the drugs involved are cheap and easily available — meaning that it’s accessible outside North America and Europe.
Jones said he had no relevant financial interests.
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Eye Test May Offer Early Diagnosis for Alzheimer’s

A new report published by researchers at Northwestern University offers the possibility of an early diagnostic test for Alzheimer’s disease—via an eye test. Using an infrared camera, the researchers were able to detect reduced blood capillaries in the back of the eye that appear linked to early Alzheimer’s. They published their research in the journal PLOS ONE.
“Once our results are validated, this approach could potentially provide an additional type of biomarker to identify individuals at high risk of progressing to Alzheimer’s,” stated Amani Fawzi, professor of ophthalmology at Northwestern University Feinberg School of Medicine and a physician at Northwestern Medicine. “These individuals can then be followed more closely and could be prime candidates for new therapies aimed at slowing down the progression of the disease or preventing the onset of the dementia associated with Alzheimer’s.”
Patients with Alzheimer’s have decreased blood flow to the retina as well as lower blood vessel density in the eye. It wasn’t known if those changes were also present in people with early Alzheimer’s or mild cognitive impairment.
Fawzi and colleague Sandra Weintraub recruited 32 patients whose cognitive testing was consistent with the forgetful type of cognitive impairment and matched them by way of age, gender and race to individuals who tested cognitively normal for their age. They all received eye imaging with OCT angiography, looking for changes in the vascular capillaries in the back of the eye.
The people who were cognitively impaired showed a statistically significant decrease in some measurements and not in others. The authors stated, “we found a significant positive correlation between MoCA scores for the entire study cohort and both the parafoveal SCP VD and peripapillary RPC VLD.” MoCA is the Montreal Cognitive Assessment Test for Dementia. VD stands for vessel density. SCP is parafoveal superficial plexus and RCP is radial peripapillary capillary. These refer to specific areas of the eye.
The test results are indicative, but aren’t rock solid and, as they note, the results need to be validated further. They plan to work further to correlate the results with other more standard, but also more invasive, types of Alzheimer’s biomarkers as well as look at the longitudinal changes in the eye parameters.
“Ideally the retinal findings would correlate well with other brain biomarkers,” stated Fawzi. “Long-term studies are also important to see if the retinal capillaries will change more dramatically in those who progressively decline and develop Alzheimer’s dementia.”
Early diagnosis of Alzheimer’s has gained a great of attention lately. Last week, Bill Gate’s The Bill & Melinda Gates Foundation and Amazon’s Jeff Bezos’ Day One Fund teamed to donate $15 million to the Diagnostics Accelerator, a project that is part of the Alzheimer’s Drug Discovery Foundation (ADDF). The Diagnostics Accelerator’s mission is fairly straightforward, although quite difficult—develop an easy and affordable test for Alzheimer’s disease.
On his blog, GatesNotes, Bill Gates outlined current advances in diagnosis Alzheimer’s, which is essentially via a spinal tap or a brain scan—invasive and expensive, respectively. And generally, people don’t look for diagnoses until they start showing symptoms. He wrote, “It’s hard to overstate how important finding a reliable, affordable, and easy-to-use diagnostic is for stopping Alzheimer’s.”
Part of Gates’s blog was related to the ADDF’s Diagnostic Accelerator’s announcement that it plans to fast-track digital tools for Alzheimer’s and related dementias. The Diagnostics Accelerator program itself was created in July 2018 with funding from co-founder Leonard Lauder, Gates, the Dolby family, and the Charles and Helen Schwab Foundation. Additional funds came from The Association for Frontotemporal Degeneration. Gates’ and Bezos’ funds bring the total program funding to almost $50 million.
The ADDF announced that funding for its Diagnostics Accelerator Digital Biomarker Initiative is now open to scientists and clinicians worldwide working in academic institutions, nonprofits, industry partnerships, and biotechnology companies, as well as new start-ups.
Funding priorities include portables, sensors, software, mobile and tablet apps, smart home systems, and virtual and augmented reality platforms.
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Translate Bio Presents Preclinical Data at Society for Inherited Metabolic Disorders

— MRT5201 was efficiently delivered to the liver of a mouse model of OTC deficiency —
— Preclinical data demonstrated a single IV dose of MRT5201 was sufficient to protect against hyperammonemia for up to 4 weeks —
 Translate Bio, Inc. (Nasdaq: TBIO), a clinical-stage messenger RNA (mRNA) therapeutics company developing a new class of potentially transformative medicines to treat diseases caused by protein or gene dysfunction, today announced the presentation of preclinical data for MRT5201, an mRNA therapeutic designed to treat patients with ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder. The poster presentation, entitled “Treatment of Ornithine Transcarbamylase Deficiency with a Targeted mRNA Therapeutic (MRT),” includes data demonstrating that a functional OTC mRNA encapsulated in a lipid nanoparticle (LNP) was successfully delivered to the liver in a preclinical mouse model of OTC deficiency via intravenous (IV) administration. These data were featured in a poster presentation at the Society for Inherited Metabolic Disorders (SIMD) Annual Meeting on April 7, 2019 in Bellevue, Washington.
“MRT5201 is designed to treat patients with OTC deficiency by intravenous delivery of mRNA encoding fully functional OTC enzyme to the liver to enable hepatocytes to produce the normal OTC enzyme,” said Dr. Ann Barbier, chief medical officer of Translate Bio. “These data demonstrate MRT5201’s ability to prevent hyperammonemia in a relevant disease model and support further study of MRT5201 as a possible treatment for OTC deficiency.”
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Revance to Present Trial Results at Aesthetics & Anti-Aging Conference

– Unprecedented clinical results for DaxibotulinumtoxinA for Injection (DAXI), Revance’s long-acting neuromodulator, were highlighted at the 17th Aesthetics & Anti-Aging Medical World Congress in Monte-Carlo –
Revance Therapeutics, Inc. (Nasdaq: RVNC), a biotechnology company developing next-generation neuromodulators for use in treating aesthetic and therapeutic conditions, today announced podium and poster presentations of its SAKURA 3 Phase 3 open-label, long-term safety study of DaxibotulinumtoxinA for Injection (DAXI) for the treatment of glabellar (frown) lines at the 17th Aesthetics & Anti-Aging Medical World Congress (AMWC). The leading international conference was held April 4 – 6 in Monte-Carlo, Monaco. SAKURA 3 was the culmination of the largest aesthetic clinical program of an aesthetic neuromodulator, which consistently demonstrated unprecedented efficacy, safety and duration across 65 sites and 3,800 treatments. The SAKURA 3 trial was specifically designed to evaluate the long-term safety of DAXI following both single and repeat treatment administration in adults 18 years of age and over.
“I was excited to present the SAKURA 3 study data on DAXI at the largest aesthetics meeting in the world, with more than 2,000 people in attendance,” said cosmetic dermatologic surgeon Sabrina Guillen-Fabi, MD, of Cosmetic Laser Dermatology in San Diego, Calif. “Colleagues were impressed with the consistent and predictable response rates, the safety profile and, most importantly, the duration of effect.”
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