Although most patients with Parkinson disease (PD) experience some nonmotor symptoms, there is little dedicated, evidenced-based medical research to guide treatment decisions.
To help clinicians better diagnose and treat patients with nonmotor symptoms, the AAN Quality Standards Subcommittee issued a new practice parameter covering a range of symptoms and treatment options in the March 15 issue of Neurology.
We asked subcommittee member William J. Weiner, MD, professor and chair of the department of neurology at the University of Maryland School of Medicine in Baltimore, to explain the findings. Dr. Weiner, director of the Maryland Parkinson's Disease and Movement Disorders Center, has published 20 neurology textbooks and more than 225 professional articles.
WHAT ARE THE MOST COMMON NONMOTOR PD SYMPTOMS?
Symptoms can vary widely and all of them have been known for some time, but only recently have they started attracting attention, largely because of the PD community. The most common are autonomic disorders such as incontinence and constipation, and mood disorders such as anxiety and depression. Sleep disorders are also common, as are fatigue and restless leg syndrome. Many individuals do not associate these symptoms with PD, so patients are often less inclined to report them to their neurologist.
IS IT POSSISBLE TO PREDICT WHICH PATIENTS WILL DEVELOP THE NONMOTOR SYMPTOMS
No, but most patients will experience some combination of these problems during the course of their disease. Many patients will experience some form of sleep dysfunction, urinary dysfunction and constipation. Depression and anxiety are often common. Some studies suggest that age at onset, duration of PD, and early psychosis may be risk factors for dementia, but other symptoms are more difficult to predict.
HOW SHOULD CLINICIANS EVALUATE PATIENTS FOR NONMOTOR SYMPTOMS?
There are several scales that can be used routinely to evaluate nonmotor symptoms, including two newer ones that can be useful in early detection. The NMS Quest questionnaire is a valid and reliable scale for identifying non-motor symptoms and a revised version of the Unified Parkinson's Disease Rating Scale (UPDRS) will include an expanded section to assess these symptoms.
WHICH SYMPTOMS DID THE PRACTICE PARAMETER ADDRESS?
We reviewed treatments for sexual dysfunction, constipation, sleep disorders, sensory symptoms, psychiatric problems, fatigue, and seborrhea. Previous AAN practice parameters have evaluated research articles on depression, cognitive and mood dysfunction in PD (2006), treatment of sialorrhea with botulinum toxin (2008), and falls in PD patients (2008).
PLEASE HIGHLIGHT THE COMMITTEE FINDINGS.
Erectile dysfunction: Sildenafil citrate (50 mg) may be considered, however, a complete medical evaluation should determine whether other treatable causes may be present, such as other medical conditions or side effects of medications.
Constipation: it is important to note that drugs used to treat many conditions, including PD, can cause constipation. Macrogol (polyethylene glycol) may be considered, based on some studies. Randomized controlled trials of treatments for constipation specifically in patients with PD are lacking, but the pharmacologic action and widespread clinical use among the general public are consistent with benefits. Nonpharmacologic treatments such as increased water and dietary fiber intake have shown some clinical benefit. Data are insufficient regarding the use of botulinum toxin for constipation in PD.
Restless leg syndrome: The use of levodopa/carbidopa probably decreases the frequency of these symptoms, and should be considered to treat periodic limb movements. Data regarding the use of non-ergot dopamine agonists specifically in patients with PD are insufficient to make any recommendations.
Excessive daytime somnolence (EDS): This is a common complaint in PD patients, and may be caused by the disease process, medications, or other sleep disorders. EDS may be related to dopaminergic medications and is more common with dopamine agonists than with levodopa. Three major studies assessed the therapeutic efficacy of modafinil, a medication that is approved for narcolepsy, and while modafinil can improve patients' perception of wakefulness, there is no objective evidence of this.
Insomnia: The etiology of insomnia in PD is multifactorial, including mood disturbances, persistent tremor, night-time re-emergence of PD symptoms, nocturia, and reversal of sleep patterns. Few controlled trials have evaluated conventional sleep aids, and research suggests levodopa/carbidopa may improve sleep-associated motor symptoms, but it can also contribute to insomnia. Objective data were insufficient for the panel to make any recommendations. Melatonin is established as effective in improving patients' perception of sleep quality but again, the data are conflicting regarding objective improvements.
Orthostatic hypotension (OH): Patients may experience syncope, and nonspecific complaints include fatigue, unsteadiness, headache, neck tightness, and cognitive slowing. There is also a rather unique symptom that we call “coat hanger syndrome” — where patients complain of discomfort across their shoulders in a coat hanger distribution. Generally, there have been few placebo-controlled trials of treatment for OH in PD. The only medications currently approved by the FDA are midodrine and L-threo-dihydroxyphenylserine (L-threo-DOPS; Droxidopa).
Urinary incontinence: We were unable to find sufficient evidence to support or refute any specific treatments for urinary incontinence, including the use of apomorphine or deep brain stimulation (DBS), but medications used by the general public may help.
Anxiety: There have not been any good investigations of anxiety treatments in PD patients, so we found insufficient evidence to support or refute any benefits. However, randomized controlled trials of anti-anxiety medications in the general public, their pharmacologic action, and widespread clinical use show they help many patients. One concern is that the medications are also associated with increased risk of falls in PD, something that has been addressed in an earlier AAN parameter (2008).
WHEN YOU SAY THERE IS INSUFFICIENT EVIDENCE, DOES THAT MEAN THAT NOTHING WILL WORK FOR THE SYMPTOMS?
This is the problem with evidence-based guidelines where research is lacking and there are still many important clinical questions. The AAN has very well respected and strict procedures for developing practice parameters, but sometimes you cannot get good evidence-based answers. When we say there is not enough evidence for or against a treatment that simply means it cannot be established — not that it does not work. This is why physician experience is important. For example, selective serotonin reuptake inhibitors, or SSRIs, can be very helpful in PD patients with depression, but there is little evidence in the published trials in PD patients. Just because there is no available high level randomized, placebo-controlled trial evidence does not mean a neurologist should not try to alleviate patient symptoms based on case reports, case series, observational trials, and experience.
WHAT FUTURE RESEARCH IS NEEDED?
If anything, this review has shown just how little evidence there is for treating nonmotor symptoms. Trials are urgently needed to examine options for urinary incontinence, orthostatic hypotension, excessive daytime sleepiness, and anxiety. Future research should also include concerted and interdisciplinary efforts toward finding treatments for these symptoms.
FOR CLINICIANS WITH PD PATIENTS, WHAT DO YOU RECOMMEND?
It is very important to ask patients specifically about nonmotor symptoms every 12 months. Patients tend to see us for their motor symptoms because those are their primary complaint — tremor, slowness, gait problems — but they go to their primary care physician for most of these other symptoms and may not even mention them to their neurologist. We need to take the initiative and ask. •