Author Archives: Ana Pena PhD

#ECTRIMS2019 — Promises and Warnings About Stem Cell Therapy

Stem cell therapy, or stem cell transplant, is an emerging yet controversial treatment approach for multiple sclerosis (MS). While some data uphold it as one of the most efficacious MS treatments, to date there have been no controlled studies comparing it to conventional medicines and providing more robust…

Rituximab Leads to ‘Dramatic’ Recovery in Boy with Aggressive RRMS, Case Study Reports

Treatment with rituximab — sold as Rituxan in the U.S. by Roche and Biogen, and as MabThera by Roche in Europe — reversed disease course in a "dramatic fashion," leading to complete remission in a 12-year-old boy with aggressive relapse-remitting multiple sclerosis (RRMS), a case report states. The report, "Rituximab as Rescue Therapy for Aggressive Pediatric Multiple Sclerosis," was published in the journal Case Reports in Pediatrics. Almost 1 in 10 MS patients has a history of disease onset as a child. But while numerous therapy options exist for adults with MS, treatments available to children are limited. One emerging potential therapy is rituximab, approved to treat various types of blood cancer and used off-label in some people with MS. It is a monoclonal antibody that targets CD20, a protein found on immune B-cells, triggering their death. Because B-cells can contribute to inflammation and myelin damage in MS, rituximab may be helpful in treating the disease. A number of studies examining rituximab's use in adults with RRMS have reported promising results. Researchers in Greece described the case of a 12-year-old boy with particularly aggressive RRMS, who was unable to attain remission before being treated with rituximab. The child, previously healthy, was admitted to P & A Kyriakous Children's Hospital in Athens with complaints of headache, ataxia (lack of voluntary movement coordination), and paresthesias (burning or prickling sensations). Magnetic resonance imaging (MRI) scans depicted numerous active lesions in the brain and one in the spinal cord. Based on these finding, a provisory diagnosis of clinically isolated syndrome (CIS) — a first MS manifestation — was made. He was prescribed gamma globulin and pulses of corticosteroids, which were subsequently tapered. Although his condition quickly improved and MRI lesions partially resolved, the boy relapsed two months later and symptoms returned. Scans showed a worsening in brain damage and new lesions. Treatment with corticosteroids and cyclophosphamide were of little help, and he kept having relapses (every four to six weeks) with evidence of clinical and radiological deterioration. "On every occasion, his condition would partially improve after corticosteroid pulse therapy, only for a following relapse to occur while tapering the oral steroids," the scientists reported. Eight months after the start of therapy, his condition had declined significantly. He was unable to walk alone for more than 50 meters (about 164 feet), and had vision problems (double vision and repetitive, uncontrolled eye movements), slurred speech, and difficulties with movement affecting his left side. His disability degree, as measured by an EDSS score, was 6.5 — more than midway along this scale. Numerous old and new lesions across the brain and cervical spinal cord were evident. Doctors were particularly concerned with a lesion in the brainstem (the posterior part of the brain that connects it with the spinal cord) that was pressing against the pyramidal tracts. These are bunches of nerve fibers responsible for transmitting information from the cerebral cortex to the spinal cord and brainstem, and are fundamental to controlling movement. As the boy's life was at risk, doctors decided on a "rescue therapy" with rituximab, given as weekly infusions into the vein for one month. Soon after the second infusion, the boy's symptoms started improving. By the end of the treatment (a total of four doses) "his condition had improved dramatically," the researchers wrote; he was "troubled only by a mild tremor and nystagmus [repetitive eye movement." No new lesions were found on MRI scans, and the existing ones were either fewer in number or significantly smaller. None of the evident lesions had MRI contrast enhancement, indicating repair of the myelin coating around nerve fibers. Given the lack of published information about rituximab's use in children with MS, treatment continued with conventional immunomodulating agents, with a cyclophosphamide course followed by mycophenolate mofetil (sold as CellCept by Genentech). Three years after his diagnosis and two years after being treated with rituximab, the teenager remains free of symptoms, with an EDSS score of zero. "He did not experience any further relapses, and subsequent brain and spine MRIs showed further improvement," the team reported. Researchers believe that B-cell-related inflammation, which was uncontrolled in this child since disease onset, "is probably the reason why rituximab had such an impressive effect in our patient's condition," they wrote. B-cell-depleting therapies like rituximab or Ocrevus (ocrelizumab; by Genentech), for this reason, could be "a promising therapeutic approach for pediatric MS, especially at the early stages of the disease, when B-cell-related phenomena are pronounced," they concluded, and warrant clinical trials to further examine their effectiveness in young patients. "Newer anti-CD20 [B-cell] monoclonal antibodies, such as ocrelizumab, feature an enhanced antibody-dependent cellular toxicity when compared to rituximab, with a proven efficacy in adult MS patients," the researchers added.

Neuronal Circuit Likely Behind Chronic Itch in MS and Other Diseases Identified

The nerve cell circuit, stretching from the skin to the spinal cord, that is likely responsible for the persistent itching sensation  that can afflict people with multiple sclerosis (MS) and other conditions was identified in a study. The discovery was made in mice and as such is still preliminary, but researchers say this work may lead to specific treatments for chronic itch. The study "Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch" was published in the journal Neuron. People with MS can experience a range of altered and unpleasant sensations — frequently described as a tingling, itching, burning or aching feeling, or a “girdling” sensation across the body (popularly called the “MS hug”). These sensations are collectively known as dysesthesia. They are caused by damage to nerves that perturbs the normal transmission of messages to and from the brain. Chronic itch, that which lasts for six or more weeks, also troubles people with conditions such as eczema, nerve damage caused by diabetes (diabetic neuropathy), and cancer. Patients can show extra sensitivity to what's called mechanical itch — which normally comes from a light brushing or poking against the skin — as well as to persistent spontaneous itch. (Chemical itch, in contrast, is a response to things like an insect bite and linked to activation of the histamine system.) The underlying neural circuits are not well-defined, and no effective treatments exist. Researchers at the University of Michigan investigated in detail the mechanisms behind chronic mechanical itch, looking for possible treatment approaches. To narrow down which nerve cells (neurons) account for mechanical itch, they individually removed nine distinct groups of spinal neurons from mice. One, called excitatory interneurons, had high levels of a protein called Urocortin 3 (Ucn3); these neurons were central for the transmission of both acute and persistent mechanical itch. "Behavioral analysis after the ablations of these neuronal subsets revealed that Ucn3 neurons are the mechanical itch transmission neurons," Mahar Fatima, PhD, a study co-author, said in a university news release. Removing the other spinal neuronal groups did not "affect the transmission of mechanical itch," Fatima added. According to the team, a mechanical itch starts upon activation of specialized sensory cells found in skin, called Toll-like receptor 5-positive low-threshold mechanoreceptors. These cells react to a light touch, passing the message along to Ucn3 interneurons in the spinal cord. Researchers also found a third important player, called inhibitory interneurons expressing neuropeptide Y (NPY). These nerve cells control Ucn3 neuronal activity; that is, they control how much skin "tickling" is needed to cause itching. In other words, the researchers said, these inhibitory interneurons are "the gatekeepers" of sensitivity to itch. If they are defective, a person could experience chronic itch. To confirm that this neuronal circuit was indeed responsible for mechanical itch, the team manipulated mice to either lack Ucn3 neurons or to shut down their activity. Mice so altered stopped responding to a light tickle behind the ear, even though they still reacted to a chemical that triggers itching. This indicated that the chemical and mechanical itch pathways are separate, and that Ucn3 neurons are solely contributing in the latter pathway, the researchers said. In each of various experiments, the mice’s ability to sense touch, pain, or thermal sensation were not affected, demonstrating the specific role of these neurons in itching. Further mice experiments suggested that under chronic itch conditions, NYP interneurons do not work properly, preventing Ucn3 neurons from stopping as they should, and making them more prone to being overactive. This, the research team said, may explain why patients with chronic itch have heightened sensitivity and a tendency for persistent spontaneous itch. Consistent with this hypothesis, removing Ucn3 neurons from mice prevented mechanical itch sensitization and persistency in the animals. "Itching is one of the major symptoms in most skin disorders and other neurologic disorders," Bo Duan, the study's senior leader, said. "This is one mechanism we needed to understand to develop a new treatment for patients with chronic itch."

UK Researchers Pursuing Breath Test to Diagnose MS

Scientists at the University of Huddersfield, U.K., are trying to develop a breath test to detect volatile molecules exhaled only by people with multiple sclerosis (MS). Doing so might offer a non-invasive and simple way to diagnose the disease. The research team now plans to undertake…

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