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EPILEPSY- Neurostimulation

Neurostimulator devices have gained traction in 2017, evidenced by regulatory developments and compelling new data highlighting their utility in the management of epilepsy.

In June, the FDA approved LivaNova’s Vagus Nerve Stimulation (VNS) Therapy Programming System, a minimally invasive treatment designed to prevent seizures before they start, in patients as young as four years of age with partial-onset refractory seizures. Several months later, the company received approval for its next-generation VNS device for drug-resistant epilepsy and its SenTiva implantable device, allowing for guided and scheduled programming.

Brain-responsive neurostimulation has also earned wider recognition for the reduction of seizures. Studies presented at the American Academy of Neurology (AAN) Annual Meeting in April offered long-term perspective on the efficacy and safety of brain-responsive neuromodulation in patients with medically intractable mesial temporal lobe epilepsy1 and in patients with medically intractable seizures arising from eloquent and other neocortical areas.2

In the October edition of Practical Neurology® magazine, Barbara C. Jobst, MD, Professor of Neurology at Darmouth-Hitchcock Medical Center in Lebanon, NH, noted that these recent advances are making surgery less daunting from the standpoint of invasiveness. She emphasized that the onus is on physicians to ensure that patients receive optimal treatment. “Given the high proportion of patients with refractory epilepsy for whom adequate care is too often delayed, it is our duty to direct patients to the appropriate providers if we cannot offer the level of care required,” Dr. Jobst wrote.

Expanded Indications for Numerous Anti-Epileptic Drugs

The therapeutic armamentarium for epilepsy was given a boost with new approvals and indications for several drugs.

Briviact (briveracetam, UCB) was approved as a monotherapy in patient’s ages 16 years and older. It is the newest antiepileptic drug in the racetam class of medicines and demonstrates a high and selective affinity for synaptic vesicle protein 2A in the brain.

Qudexy XR (topiramate, Upsher-Smith) Extended-Release Capsules received two new supplemental indications, for use as prophylaxis of migraine headache in adults and adolescents 12 years of age and older.

Aptiom (eslicarbazepine acetate, Sunovion) was approved in patients between the ages of four and 17 based on FDA guidance that permits the extrapolation of adult data to support pediatric use.

SUDEP in Focus

The AAN and the American Epilepsy Society have released a new joint guideline for sudden unexpected death in epilepsy (SUDEP), recommending that health professionals tell people with epilepsy that controlling epileptic seizures and seizures in general may reduce the risk of SUDEP.3 Also endorsed by the International Child Neurology Association, the guidelines were the result of a review of all available evidence showing that general tonic-clonic seizures represent a major risk factor for SUDEP.

According to Michelle Dougherty, MD, Assistant Professor of Neurology and Director of the neurology residency program at the Drexel Neuroscience Institute in Philadelphia, significant knowledge gaps remain when it comes to SUDEP and physicians should take the opportunity to educate patients and families. “Ideally, a discussion of SUDEP risk and factors that influence risk could help patients and families take appropriate steps to lower that risk wherever possible, such as adherence to prescribed anti-epileptic drugs, continuing to pursue further treatments, and avoiding known seizure triggers,” she wrote in the July/August edition of Practical Neurology® magazine.


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Continuous subcutaneous apomorphine infusion for advanced Parkinson disease

Continuous subcutaneous infusion of apomorphine, a dopamine agonist, is an effective treatment option for motor fluctuations in Parkinson disease (PD). In a trial of 106 patients with PD and refractory motor fluctuations, apomorphine infusion both reduced “off” time and improved “on” time without dyskinesias by approximately two hours compared with placebo (saline) infusion [8]. The most common side effects were skin site reactions and nausea. Continuous subcutaneous apomorphine infusion is under review by the US Food and Drug Administration and is already available in Europe. (See “Device-assisted and surgical treatments for Parkinson disease”, section on ‘Efficacy of CSAI’.

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Continuous subcutaneous infusion of apomorphine, a dopamine agonist, is an effective treatment option for motor fluctuations in Parkinson disease (PD). In a trial of 106 patients with PD and refractory motor fluctuations, apomorphine infusion both reduced “off” time and improved “on” time without dyskinesias by approximately two hours compared with placebo (saline) infusion. The most common side effects were skin site reactions and nausea. Continuous subcutaneous apomorphine infusion is under review by the US Food and Drug Administration and is already available in Europe.

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Drug repositioning strategy identifies potential new treatments for epilepsy

Drug repositioning– taking known drugs and identifying new applications for them–is an attractive concept for speeding up the process of bringing drugs to human testing for unmet medical needs.

In a new study, published online Dec. 11 in the Annals of Clinical and Translational Neurology, University of Iowa researchers led by Alexander Bassuk, MD, PhD, professor of pediatrics and neurology with UI Health Care, use a multidisciplinary strategy that combines gene expression profiling and bioinformatics to identify a list of around 90 drugs, all of which already are approved by the Food and Drug Administration (FDA) for use in people or animals, that may also have potential as anti-seizure treatments.

“Taking a new look at medicines that are already approved for clinical use may help identify treatments that could reduce seizures and improve the quality of life for people with epilepsy who have been unable to find effective therapies,” said Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the study.

The UI team tested candidate drugs from the list in a zebrafish model of seizures and found that three–a diabetes drug, a hypertension medication, and an antiparasitic therapy– significantly reduced seizure-like movement in the fish.

“The long timeline and high cost of drug development is a particularly acute issue for a life-altering disease like epilepsy where up to one-third of patients are not completely helped by the medications we currently have,” says Bassuk, who also is division director of pediatric neurology and a member of the Iowa Neuroscience Institute (INI). “The question here was could we use novel techniques to identify potential new treatments more quickly than via traditional drug discovery and development routes.”

A unique starting point

A unique feature of the UI study, according to Bassuk, was the ability to use live human brain tissue from patients with epilepsy as a starting point.

The tissue was collected by UI neurosurgeons (led by Matthew Howard, MD, UI professor and DEO of neurosurgery) from six patients undergoing specialized surgery to remove brain areas causing seizures. This type of surgery is a treatment option for people with epilepsy whose seizures can’t be controlled by medications. The patients agreed to allow use of the tissue in the study. During the surgery, the neurosurgeons placed electrodes on the patient’s brain to determine which areas to remove. These electrodes also allowed the surgeons to distinguish which parts of the removed tissue were seizing and which areas, also contained within the removed tissue, were behaving normally.

Computational psychiatry researchers Jacob Michaelson, PhD, and Leo Brueggeman analyzed gene expression for more than 25,000 genes the brain tissue, and discovered strikingly different expression patterns in the diseased (seizing) tissue compared to non-seizing tissue. They then compared these expression signatures to a large database known as a connectivity map, which contains gene expression patterns produced by the action of drugs on cells. The comparison identified 184 compounds that were deemed potentially therapeutic because they produced patterns that were essentially the reverse of the seizure expression pattern.

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The “Big Bang” of Alzheimer’s: Breakthrough study uncovers genesis of the disease

Until now it was not known how, or when, these tau proteins began to accumulate into tangles in the brain. It was previously believed that isolated tau proteins didn’t have a distinctly harmful shape until they began to aggregate with other tau proteins. But the new research has revealed that a toxic tau protein actually presents itself as misfolded, exposing parts that are usually folded inside, before it begins to aggregate. It is these exposed parts of the protein that enable aggregation, forming the larger toxic tangles.

“We think of this as the ‘Big Bang’ of tau pathology,” says Diamond. “This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer’s.”

From here the research is set to take two different prospective pathways. One will first look at developing a simple diagnostic test to detect signs of this abnormal tau protein, either through a blood test, or less ideally a spinal fluid test. If these toxic tau proteins can be easily detected then clinicians may be able to diagnose Alzheimer’s before major degenerative cognitive symptoms take hold.

Tafamidis was designed to delay impairment to nerve function caused by the toxic aggregation of a normally harmless protein called transthyretin and is currently approved for use in both Europe and Japan. However, the FDA has called for further clinical proof before approving the drug for use in the United States.

Now that this early alteration in the shape of tau molecules has been identified, researchers can more effectively focus on potential drug targets to inhibit the toxic aggregations at this stage.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” says Diamond. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”

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