Richard Robinson

In the Pipeline-Lambert-Eaton Myasthenic Syndrome: Will a Tried-and-True Treatment for LEMS Be Approved and Then Priced Out of Reach?

Two new trials sponsored by two different pharmaceutical companies show that 3,4diaminopyridine (3,4-DAP) provide dramatic benefit to patients with LambertEaton myasthenic syndrome (LEMS), a rare autoimmune disorder characterized by muscle weakness of the limbs. But the trials only confirm what clinicians have known for a long time — 3,4-DAP has been recognized as the gold standard of LEMS therapy for several decades. LEMS is caused by autoantibodies that reduce entry of calcium through the presynaptic voltage-gated calcium channel at the neuromuscular junction, leading to reduction in acetylcholine release. 3,4-DAP blocks presynaptic potassium channels, prolonging depolarization and allowing calcium channels to remain open longer. While both trials provide rigorous support for the benefits of the drug, the major goal of at least one trial is to secure US Food and Drug Administration (FDA) approval of the drug under the Orphan Drug Act, and with it seven years of market exclusivity. If that happens, most observers believe that the drug, which patients have been receiving virtually for free for more than two decades, will almost certainly be priced out of reach for a significant number of patients. “I think this is an unforeseen consequence of the regulations that permit and foster the acquisition of orphan drugs by commercial entities,” said Donald Sanders, MD, lead investigator on the trial published December 27, 2017 in Muscle and Nerve. Dr. Sanders is a professor of neurology at Duke University School of Medicine in Durham, NC.

Pre-Concussion Somatization Predicts Longer Recovery, New Study Finds

The first prospective study of pre-injury contributors to concussion recovery indicates that athletes with higher preinjury somatization symptoms who become concussed report more severe post-concussive symptoms, and take longer to experience symptom recovery. The study was published in the April 20 online edition of Neurology. “Because of the prospective nature of our study, we were able to verify what clinicians have long thought to be the case about the role of pre-injury somatization tendencies for recovery,” said the lead investigator Lindsay D. Nelson, PhD, an assistant professor of neurosurgery and neurology at the Medical College of Wisconsin in Milwaukee. “The results suggest that in dealing with the injured athlete, we need to focus not only on injury factors, but also on individual factors” in order to aid recovery. In response to growing concern over sports-related concussions, baseline testing has become common in contact sports at every level. Dr. Nelson worked with nine high schools and four colleges in southeastern Wisconsin, administering pre-season baseline assessments to over 2,000 athletes. Tests included the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scale, a reading test, and the Brief Symptom Inventory-18 (BSI-18), a self-reported neuropsychiatric scale comprising three domains: somatization, depression, and anxiety. “Pre-injury psychiatric symptoms have long been thought to increase the risk of post-concussive symptoms, at least in military samples,” Dr. Nelson said, “but previous studies have relied on estimating preinjury psychiatric status retrospectively, or through medical records,” which may introduce significant recall errors. The BSI-18 is a standard tool for measuring somatization, the tendency to be excessively distressed by physical symptoms. Subjects report on a Likert scale the extent to which they are troubled by autonomic, gastrointestinal, and related symptoms. “About half our athletes report not even minimal distress on any of the items,” Dr. Nelson said. “It is not too unusual to endorse maybe one item to a mild degree, but it is quite rare to endorse two or more, or to be highly bothered by them.”

MONTHLY DACLIZUMAB FOUND SUPERIOR TO INTERFERON BETA-1A FOR RELAPSING-REMITTING MS

opposed to costly in-hospital interventions. This includes palliative and hospice care, which is not well understood by patients, or even by certain healthcare providers, the report noted. The report sketches out a detailed picture of end-of-life care in the United States as it exists today, and advocates for more comprehensive standards governing discussions of end-of-life care in medical education, physician-patient interactions, and public awareness campaigns. It also emphasizes the need for Medicare and private insurers to fund end-of-life care in a way that incentivizes palliative and hospice care as opposed to acute in-hospital interventions. INSIDE 10/16/14

Multiple Rare Variants Contribute to Earlier ALS Onset, New Study Finds

Carrying multiple rare variants in known amyotrophic lateral sclerosis (ALS) genes lowers the age of onset of the disease in both familial and sporadic cases, according to a new study. The results strengthen the case that a portion of ALS is oligogenic in nature, and that an increase in the mutation burden can have clinical consequences. The study, which was published in the Nov. 7 online edition of Annals of Neurology, highlights the potential for “nextgeneration” sequencing to uncover novel gene interactions, and provides a preview of the discoveries likely to be made as even more powerful gene-hunting techniques are brought to bear on even larger samples of neurologic patients.

Success for Pimavanserin in Parkinsonʼs Disease May Provide ‘Breakthrough’ for PD Psychosis

The recent discovery of 11 new gene locations involved with the development of Alzheimer’s disease (AD) made international news. But researchers said knowing the exact cause — and what to target for a cure — is not close at hand. There is no denying that the study is cause for celebration, they said. The study confirmed the role of genes discovered earlier and emphasized the role of particular regions associated with the immune system and inflammation. The study also identified new pathways underlying Alzheimer’s disease, including those that involve hippocampal synaptic function, cytoskeletal function and axonal transport, regulation of gene expression and post-translational modification of proteins, and microglial and myeloid cell function. Scientists from more than a dozen countries and more than 40 institutions collaborated on the analysis, the largest international

New Master Switch for Muscle Function Discovered, But Is It A Target for Therapy?

A new study shows that a “master molecule” can make a muscle burn fat instead of sugar, and that doing so has real benefi ts: its mitochondria proliferate and become more active, the muscle increases in bulk, and the organism can run further and longer. Proponents think that exploiting this switch may lead not only to new treatments of muscle disease, but also help reverse the inevitable frailty associated with aging. But, says one expert who was not involved with the study, while the fi nding is an important advance in the basic biology of muscle, the therapeutic applications are far less certain. The switch from sugar to fat occurs through the action of a complex set of signaling pathways under the control of transcription factors, proteins that sit on DNA and promote gene expression. But INSIDE 1/5/12

Experimental Therapy is Effective in an FSHD Mouse Model, but is it the Right Target?

RNA interference may be an effective treatment strategy for facioscapulohumeral muscular dystrophy (FSHD), according to two new mouse studies in online editions of Molecular Therapy. But researchers aren’t breaking out the champagne quite yet, since new gene discoveries have called the relevance of the mouse model into question. ARTICLE IN BRIEF Two diff erent research teams eff ectively used RNA interference to reduce overexpression of a candidate gene in facioscapulohumeral dystrophy, providing proof of principle that the mutant is worth targeting for future therapies.

Drug to Combat Muscle Fatigue Looks Promising in ALS

ORLANDO, FL—An experimental drug that increases the force of contraction of skeletal muscle may improve endurance in amyotrophic lateral sclerosis patients (ALS), according to a study presented here at the annual meeting of the ALS-MND Society in December. The drug does not have any effect on disease progression, but may allow patients, especially early in the disease, to better perform their activities of daily living. “While it isn’t a cure, it may be able to help with fatigue,” said Terry Heiman-Patterson, MD, professor of neurology at Drexel University College of Medicine in Philadelphia, who was not involved in the study. “Fatigue is a major concern for patients. If we can help with that, it means patients may get more done in a day.” The drug, known as CK-2017357, increases the sensitivity to calcium of the troponin complex in fast skeletal muscle fi bers. Binding of calcium to the troponin complex triggers muscle contraction. CK-2017357 is manufactured by Cytokinetics, a biotechnology fi rm located in South San Francisco, CA. Lead investigator Jeremy Shefner, MD, PhD, said that previous studies have shown that, when delivered orally, the drug reaches a maximum serum concentration after three to fi ve hours. It has no effect at maximal contraction force, when all available troponin complexes are already engaged. Instead, “it improves the force of muscle contraction at submaximal contraction forces, delaying the onset and magnitude of fatigue in animals and healthy humans,” said Dr. Shefner, professor and chair of neurology at Upstate

New Algorithm Using Scalp Electrodes Predicts Seizures

by using scalp electrodes to monitor brain activity has met with little success. Now, results from a test in over fifty patients suggest that a new computer algorithm that monitors scalp electrode output can predict 95 percent of seizures in selected patients, with relatively few false positives, a record one expert called “amazing.” The research was described in a poster here at the annual meeting of the American Neurological Association. The study enrolled 51 patients with medically intractable partial seizures who had been admitted to an epilepsy monitoring unit for presurgical evaluation. Scalp electrodes were attached in standardized positions, and EEG data were analyzed by software developed by a team of investigators at Optima Neurosciences

Evidence Points to Amyloid Beta as the Key to Alzheimer Disease

TORONTO—The amyloid beta (Abeta) peptide lies at the heart of amyloid plaques in Alzheimer disease (AD) and is central to disease pathogenesis, according to Dennis Selkoe, MD, professor of neurological sciences at Harvard Medical School in Boston. In the George C. Cotzias Lecture here at the AAN annual meeting, Dr. Selkoe, one of the original architects of the Abeta hypothesis of AD, offered an update about what is known about the molecular mechanisms through which Abeta impairs memory. “The hypothesis is that Alzheimer disease is a syndrome caused by imbalance of production and clearance of the Abeta protein, which leads to its gradual accumulation in brain circuits involved in memory,” Dr. Selkoe said. By the end of the decade, he said, Alzheimer disease research will be focused sharply on Abeta, assessing the risk for its accumulation, measuring its levels in the blood and CNS, and beginning early treatment to prevent its build-up and enhance its clearance. Such strategies will become central to the prevention and treatment of AD, he predicted. The Abeta peptide is formed by cleavage off of amyloid precursor protein (APP), catalyzed by a protease, presenilin, he explained. “The strongest evidence for the hypothesis comes from genetics. All of the mutations currently known that cause autosomal dominant Alzheimer disease occur either in the substrate APP, or the protease, presenilin, that produces Abeta,” he said. Presenilin actually has a much more important substrate than APP, Dr. Selkoe noted, since it also cleaves the protein notch, central to a developmental signaling pathway. While animals can live without APP, they can’t live without notch. The long-term accumulation of Abeta, he suggested, may simply be the byproduct of a secondary function of an enzyme whose central importance lies elsewhere. “This may help explain how Alzheimer disease arose,” he said. The three dominant mutations — one in APP, two in different forms of presenilin — all increase the production of Abeta. But the most common risk factor for the disease, the e4 allele of the apolipoprotein (APOE) gene, does not, at least not directly. Instead, it increases the density of Abeta plaques and vascular deposits. “We know there is an increased level of Abeta as a result of inheritance of APOE4, but we don’t know the precise mechanism. This is one of the most important unsolved issues in the fi eld,” Dr. Selkoe said, “in terms of exactly how APOE4 inheritance changes the molecular milieu in the brain, and leads to Alzheimer disease.” And many patients don’t possess even this risk factor. “We don’t know why most of our patients have elevated Abeta,” he added. How does an increase in Abeta cause disease? Abeta monomers can link to form soluble dimers or trimers (collectively called oligomers), which may coalesce to form plaques, the pathological hallmark of the disease. While plaques were originally thought to be the problem, they are increasingly seen as a partial and ultimately unsuccessful mitigation strategy by the neuron attempting to cope with toxic oligomers. “Soluble Abeta is detected selectively in the cortices of patients with clinically and pathologically typical Alzheimer disease,” he said. When Abeta isolated from brains of patients with Alzheimer disease or other forms of dementia is inoculated into animal brain, it is the more soluble oligomers that appear to cause the most Alzheimer-like degeneration. “Soluble Abeta seems to correlate better with the disease we call Alzheimer’s.” The same conclusion can be drawn from experiments in mouse brain, which have begun to reveal the direct effects of Abeta on memory. Applying Abeta to hippocampal slices from healthy mice leads to impairment of long-term potentiation (LTP), the molecular mechanism underlying synaptic plasticity and, ultimately, learning and memory. The same soluble Abeta oligomers facilitate longterm depression, reducing basal synaptic transmission. In live rats, injection of soluble oligomers through a cannula into the brain impairs their ability to learn in a standard avoidance task. “It’s the soluble species we believe are generally causing functional problems.” Exactly how they do so is still unclear. At the membrane, they bind to a still unidentifi ed “molecule X,” and secondarily perturb a variety of receptors, including those for AMPA (alpha-amino3-hydroxyl-5-methyl-4-isoxazole-propionate), NMDA (N-methyl-D-aspartic acid), and insulin.