Then and Now: 20 Years of Monumental Strides in Movement… : Neurology Today – LWW Journals

Article In Brief

Experts in movement disorders highlighted advances in the field from 20 years ago to now, including improvements in deep brain stimulation, earlier treatment with levodopa, and a focus on nonmotor symptoms.

While neurologists still hope for elusive cures for movement disorders, they appreciate the major scientific advances that have led to a greater understanding and management of Parkinson's disease (PD), dystonia, and essential tremor.

Deep brain stimulation (DBS) is a major case in point. When DBS first received approval from the Food and Drug Administration in 1997, it was indicated for stimulating the ventral intermediate nucleus of the thalamus to treat tremor resulting from PD or essential tremor. In 2002, the FDA approved DBS of the subthalamic nucleus or internal portion of the globus pallidus internus to treat PD symptoms that were no longer adequately controlled with medications. The following year, DBS was approved for dystonia.

As a result, many clinicians and patients held it out as a last resort, said David Charles, MD, FAAN, a DBS researcher who is professor and vice chair of neurology at Vanderbilt University Medical Center in Nashville.

Then a European study became the catalyst for a paradigm shift in the United States when the FDA approved DBS in 2016 for mid-stage PD. The approval paved the way for the use of DBS as adjunct therapy when disease duration is at least four years and motor complications persist for four months or longer. Dr. Charles hailed that development as one of the biggest advances in DBS.

A number of studies have demonstrated that DBS often continues to be effective over the long haul. The data are very clear that DBS plus medicine is superior to medicine alone in controlling symptoms and improving quality of life in mid- and advanced-stage disease, he said. Furthermore, providing the therapy in mid-stage means that the person with Parkinson's gets many years of benefit.

DBS implantation techniques have become more targeted, greatly reducing the incidence of complications. It's actually safer to do the operation on people with mid-stage disease, because they are often younger and have fewer comorbidities, Dr. Charles said, explaining that the older the patient is, the higher the risk of an adverse event occurring.

The selection of DBS equipment also has expanded. Initially, only one manufacturer produced equipment approved for use in the United States, he said. Now, three companies are vying for market share.

The technology has also improved from the standpoint that electrodes, or leads, implanted in a patient's brain will now allow the physician to steer the current, Dr. Charles told Neurology Today. By directing the energy more precisely toward the optimal location in the brain, the physician can decrease the possibility of side effects. In addition, one of the devices can be programmed and adjusted remotely via telehealth.

While DBS remains an invasive procedure and the risks are never nil, it can be extremely effective, said Michele Tagliati, MD, FAAN, professor and vice chairman of neurology and director of the movement disorders division at Cedars-Sinai Medical Center in Los Angeles.

Dr. Tagliati noted that the last 20 years have seen the explosion, for lack of a better term, of deep brain stimulation for movement disorders. FDA approval for PD came again in 2002 and in 2003 for dystonia, following the approval for essential tremor in 1997.

With properly selected patients and in good handsin terms of surgery and programming the deviceDBS can be life-changing in advanced Parkinson's, untreatable dystonia, and medication-refractory essential tremor, he said, adding that the incidence of complications is much lower under a seasoned surgeon's wing.

Recent progress in human genetics also has led to significant strides in the understanding of PD and related disorders. For instance, in the last two decades, scientists have discovered many more contributing genes. Mutations in the glucocerebrosidase gene, which encodes the lysosomal enzyme that is impaired in Gaucher's disease, are relatively common risk factors for movement disorders.

Although genetic cause is thought to be a small proportion of Parkinson's, this is an important discovery for therapeutics, said Cheryl H. Waters, MD, FAAN, FRCPC, the Albert and Judith Glickman Professor of Neurology in the division of movement disorders at Columbia University Medical Center in New York. Identifying the genes helps establish new drug targets that may help some, if not, all patients.

During this time framein the early 2000sanother discovery led to an association between PD and mutations in the leucine-rich repeat kinase-2 gene.

One of the big changes in the last 20 years, from my perspective, is the recognition of genetic mutations that can increase risk of Parkinson's, said Andrew S. Feigin, MD, professor of neurology at NYU Langone Health and director of the Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders.

This holds a lot of promise, Dr. Feigin said. Future clinical trials will likely target therapies at mechanisms related to these genetic mutations.

More recently, deep phenotypingthe use of big data to arrive at full clinical and biomarker characterizationis a strategy that has the potential to change the prognostic landscape for movement disorders, said Christopher G. Goetz, MD, FAAN, professor of neurological sciences and pharmacology at Rush University Medical Center in Chicago.

To this end, neurologists are playing a pivotal role in the epidemiological research arena by collecting repositories on patients, documenting behaviors such as hallucinations and dyskinesias, duration of their PD since onset, and the presence or absence of a genetic link to their disorder. The repositories could be useful to compare patients with similar profiles miles apart, even in different countries, said Dr. Goetz, a senior neurologist in the movement disorders program at Rush.

In the past, when we were trying to understand how a patient would respond or have a prognosis, we looked at the meanthe averageresponse across the population, and now we are thinking that's not the strategy, he said. Instead, we should be phenotypingdeeply understanding each patient's profile.

The idea that we could learn from all the big data of an individual essentially represents a whole new way of thinking, Dr. Goetz added. In advancing this notion a step further, he suggested that theoretically, we could predict also who would respond better to a given medication. It's a new concept that we didn't have 20 years ago.

On the medication front, neurologists have come to a consensus that they should consider prescribing levodopa sooner rather than later. There has been a significant change in Parkinson's disease management, with the pendulum swinging towards more use of levodopa and less use of dopamine agonists, even early in the disease, said Melissa J. Nirenberg, MD, PhD, FAAN, professor of neurology at the Icahn School of Medicine at Mount Sinai in New York.

We have learned that dopamine agonists can cause impulse control disorders, Dr. Nirenberg added, noting that some patients may develop severe withdrawal symptoms. Known as dopamine agonist withdrawal syndrome, this complication can make it difficult to taper treatment.

Neurologists previously were reluctant to use levodopa early in PD due to unfounded fears that it might be toxic to the brain or worsen long-term outcomes. It is now clear that levodopa is not neurotoxic and does not worsen outcomes, said Dr. Nirenberg, a member of Neurology Today's editorial board. Levodopa is the most effective treatment for Parkinson's disease, and it should be used as needed to treat symptoms.

Dr. Waters agreed with that assessment, stating that whereas 20 years ago we might have used dopamine agonists, we now recognize a high risk of impulsive and compulsive behaviors with dopamine agonists, she said. So, we do not delay levodopa, as it was shown not to cause the disease to progress more rapidly or lose its efficacy over time.

Many adjunctive agents, such as infusion and rescue therapy, have been helpful as complements to levodopa therapy. Rescue therapies, which can reduce the burden of the off experience for patients, include injections of apomorphine, sublingual apomorphine, and inhaled levodopa, she added.

Dr. Waters pointed out, too, that there are now three vesicular monoamine transporter type 2 inhibitors for the treatment of tardive dyskinesia and possibly the tics associated with Tourette syndrome. Side effects include drug-induced or secondary parkinsonism and depression. Not all have been approved for these indications in the United States.

Another major change in our understanding and treatment of Parkinson's disease has been the increased recognition of nonmotor symptoms, Dr. Nirenberg said, citing the need to diagnose and treat these symptoms. This is a very active area of study and very important in the clinic, she said.

These concerning signs run the gamut from sleep disorders to cognitive decline, depression, urinary problems and constipation, as well as hallucinations, anxiety, depression, orthostatic hypotension, or a combination of such disturbances, neurologists noted.

Rapid eye movement sleep behavior disorder is one of the most indicative nonmotor manifestations of PD and can be particularly disruptive, Dr. Feigin said, because patients may end up punching their bed partner, falling on the floor, or even sleepwalking as they literally act out their dreams.

Neurologists interviewed for the article highlighted orthostatic hypotension as yet another nonmotor symptom of PD. However, they noted, more treatments are also more available for various nonmotor complications than there were 20 years ago, as is the case with the impact of depression on PD. This increasing awareness has led to better management of depression, including more frequent use of antidepressants, helping patients feel and function better, they said.

Neurologists also have become more adept at differentiating typical PD from atypical forms of the disorder, such as multiple system atrophy and progressive supranuclear palsy. Clinical characteristics complemented by magnetic resonance imaging can make a significant difference in these assessments, allowing clinicians to determine the treatment course, progression, and prognosis, Dr. Waters said.

Advancing technology has brought other benefits as well. Applications catering to remote office visits have been useful for monitoring patients and for engaging them in physical activities, particularly during the pandemic, she said, adding that the only thing that we've learned for certain to protect [against the progression of] Parkinson's is exercise.

Dr. Feigin concurred that there has been more widespread use of nonmedical interventions to improve the quality of life for patients with PD. Among the plethora of options are physical therapy, boxing programs, and dance and art initiatives. While they may not slow disease progression, these approaches have been helpful to people, he said. And there is some evidence that these types of therapies may improve long-term functioning and general well-being.

The importance of multifaceted care cannot be understated. In one day, Dr. Tagliati noted, patients with movement disorders can consult with several specialists under one rooffor instance, a neurologist, neurosurgeon, psychologist, and physical therapist. The convenience represents an evolution toward multidisciplinary care clinics in premier academic medical centers that serve as a one-stop shop for meeting patients' multiple needs.

Patients love this opportunity to share their different problems with different specialists in one single day, in one single morning, Dr. Tagliati said. That's one of the trends he has observed in his specialty when he compares it with two decades ago. The changes are particularly notable for PD, which he calls the bread and butter of movement disorders due to its frequency.

Training of neurology residents and fellowship trainees has adapted to these myriad changes. Residents are taught to identify various movement disorders, while fellows learn much more than previous cohorts of trainees, Dr. Waters said.

Fellows must recognize all the illnesses within the subspecialty, determine when to order genetic testing, and how to perform botulinum toxin injections and conduct DBS programming. They also need to be well-versed in all the different medications and know how to interpret imaging studies. In addition, she said, they may become involved in administering advanced treatments such as intestinal gel or subcutaneous infusions or rescue therapies.

Patients are also better educated and now seek input from neurologists at earlier stages of their disease trajectory than they did 20 years ago. This affords neurologists the opportunity to treat them with lower doses of medications, reducing the rate of side effects, said Dr. Goetz.

But at times, it is still disconcerting that curative treatments haven't emerged. Our disappointment is that we don't know precisely what causes Parkinson's, and multiple clinical trials for neuroprotection have failed, Dr. Waters said, adding that we have failed in finding treatments for freezing of gait, dementia, and fatigue.

Dr. Nirenberg remains enthusiastic about active clinical trials investigating drugs that specifically target genetic subtypes. She is also excited about the study of biomarkers, including blood, tissue, and spinal fluid markers and imaging studies that can facilitate early diagnosis and make a difference in bringing about breakthrough discoveries.

The holy grail is to find disease-modifying treatment for Parkinson's, she said. I hope that we will be able to offer patients such treatments way before the next anniversary issue [of Neurology Today]. That's what we're working on right now.

Dr. Goetz's contends that the inevitably progressive nature of neurodegenerative diseases doesn't mean the field of movement disorders isn't brimming with optimism. In addition to his interest in deep phenotyping, he said alpha-synuclein, which damages the dopamine cell, could be a target for antibody therapy in the future.

Especially in the context of the COVID era, we're excited about the prospects, he said. Could we develop a vaccine against the abnormal synuclein, just like the way we did with the vaccine against a virus?

Another scientific area of possibilities stems from research into gut bacteria and their impact on the brain, suggesting that dietary changes could have a positive effect on patients with movement disorders.

We all wish that we could have cracked the disease in these past 20 years and that we found the single chemical equation for the causation of the diseasethe very first chemical reaction that takes a normal dopamine cell and starts to make it into a pathologic cell, Dr. Goetz said. We have failed to crack that today, but that doesn't mean that we won't crack it tomorrow.

Until then, if you can change a patient's quality of life, you have changed him and his family, and that is an enormous scientific contribution.

Rush University Medical has received funding for research by Dr. Goetz from the NIH, Department of Defense, and Michael J. Fox Foundation. Dr. Goetz has received a faculty stipend from the International Parkinson and Movement Disorder Society; guest professorship honorarium provided by the University of Chicago and Illinois State Neurological Society, a volume editor stipend from Elsevier Publishers, and royalties from Elsevier and Wolters Kluwer. Dr. Waters received research support from Neuraly, Biogen, Roche, and Sanofi; consulting fees from Kyowa, Sunovion, and Acadia; and speakers' honoraria from Adamas, Amneal, Kyowa, Neurocrine, and Acorda. Dr. Feigin has received honorarium from Kyowa-Kirin. Dr. Charles has received education grants paid to Vanderbilt from Aeon, Abbott, AbbVie, Boston Scientific, Impax, Intec, Ipsen, Lundbeck, Medtronic, Merz, Novartis, Pharma Two B, Supernus. He has received consulting fees from Merz, Supernus, Alliance for Patient Access, Newronika, Revance, and is a nonpaid member of the data safety and monitoring board for the trial, STN DBS in PD Sleep Dysfunction.

Here is the original post:
Then and Now: 20 Years of Monumental Strides in Movement... : Neurology Today - LWW Journals