11/11/2015 Nonmotor Symptoms of Parkinson's Disease: Recognition, Diagnosis, and Treatment

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Faculty and Disclosures

Excessive daytime sleepiness is, again, a very frequent complaint for

patients with Parkinson's disease and is probably more common than in

the general population. The estimated prevalence is between 15% and

50% of Parkinson's disease patients. The reasons for excessive daytime

sleepiness are, again, likely multifactorial. These may include insomnia;

mood or anxiety disorders; dementia; as well as dopaminergic

medications in terms of a class effect, as opposed to any 1 specific

medication. Risk factors for excessive daytime sleepiness include

increased disease duration and severity, male gender, and dopaminergic

load.(Enlarge Slide)

One thing that is important to discuss in terms of excessive daytime

sleepiness is what has been termed "sleep attacks," that being the

sudden onset of sleep. This can include naps occurring at inappropriate

times, such as while driving, and these may be sudden and without

warning. There is some controversy whether or not sleep attacks are

true entities in and of themselves or whether they are extensions of

excessive daytime drowsiness. Most studies that have specifically looked

at sleep attacks, especially with respect to driving, have correlated high

Epworth Sleep Scale scores with sleep episodes while driving,

suggesting that the issue really is excessive drowsiness prior to falling

asleep, as opposed to a true sleep attack. True sleep attacks likely are

very rare, estimated in approximately 1% of Parkinson's disease patients.

Regardless, it is very important to discuss the issue of excessive daytime

drowsiness and falling asleep at the wheel with all patients with

Parkinson's disease.

(Enlarge Slide)

The treatment for excessive daytime sleepiness begins with good sleep

hygiene. This includes regular bedtime and waking times and an

appropriate amount of time in bed, which is over 7 hours. During the day,

patients should be exposed to bright light and daytime activities should

be maximized. Likewise, nap frequency and duration should be reduced

during the day, and people should avoid caffeinated and alcoholic

products in the evening. If good sleep hygiene is not enough to improve

symptoms of excessive daytime sleepiness, the reduction of some of the

dopaminergic medications should be considered. Finally, it may be

necessary to add alerting medications, such as modafinil,

methylphenidate, or possibly bupropion.

(Enlarge Slide)

Insomnia, again, is fairly common in patients with Parkinson's disease

and is estimated to occur in 30% of patients. It is most commonly due to

sleep fragmentation and early awakening, as opposed to difficulty falling

asleep. Treatment for insomnia also relates to good sleep hygiene.

Sometimes hypnotic medications may be used, such as zolpidem.

Benzodiazepines have some benefit and sedating antidepressants, such

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11/11/2015 Nonmotor Symptoms of Parkinson's Disease: Recognition, Diagnosis, and Treatment

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as trazodone or amitriptyline, are often used.

(Enlarge Slide)

Nightmares are not an unusual occurrence in Parkinson's disease and

are thought to occur in 30% of patients. Nightmares are correlated with

disease severity and levodopa dose. Treatment includes reduction in

dosage of the medications that may be partially causing the nightmares.

(Enlarge Slide)

One promising treatment that may alleviate some aspects of sleep

dysfunction that occur in Parkinson's disease is deep brain stimulation.

Though there has not been much work done on the impact of deep brain

stimulation on sleep, 1 prospective study was recently published. In this

study, the authors examined and performed polysomnographic testing on

5 patients before and 3 months following subthalamic nucleus deep brain

stimulation for Parkinson's disease. This study found that following deep

brain stimulation, there was an increase in total sleep time, with the

lengthening of the longest period of uninterrupted sleep. In addition,

there was a reduction in wakefulness after sleep onset. However, there

was no impact on REM behavior disorder or periodic leg movements of

sleep.

Sensory Nonmotor Symptoms

(Enlarge Slide)

We are now going to shift gears and talk about sensory nonmotor

symptoms, again a very prevalent problem in patients with Parkinson's

disease. These can be thought of as complaints of pain or as other

sensory symptoms, such as burning, tingling, numbness, stabbing,

aching, or itching. These are very difficult symptoms to study, as they are

subjective. The literature is relatively limited with respect to sensory

problems in Parkinson's disease. However, anecdotally it appears that

many patients complain of sensory symptoms prior to the onset of motor

features of Parkinson's.(Enlarge Slide)

Despite the limited data, there has been a recent study that tried to

quantitatively assess pain perception in Parkinson's disease patients. In

this study, 51 patients with Parkinson's disease were evaluated for

endogenous pain using a visual analog scale, as well as objective

measures, such as heat and pain thresholds (HPTs) and mechanical and

warmth sensory thresholds.

(Enlarge Slide)

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The results of the study showed that patients with Parkinson's disease

have significantly lower HPTs than control subjects. The results also

showed that patients with painful Parkinson's disease had significantly

lower HPTs compared with patients with pain-free Parkinson's disease.

Heat and pain thresholds were significantly lower in the more affected

limb, regardless of the presence or absence of pain, and no difference

was found in HPTs between the on- or the off-medication state.

(Enlarge Slide)

Some theories regarding the mechanism of altered pain perception in

Parkinson's disease include that the basal ganglia neurons have

somatic-sensory function. In addition, basal ganglia neurons may

modulate pain.

Sensory Symptom Fluctuation and Summary

(Enlarge Slide)

In contrast to the findings from the previous study, another study

documented that some sensory symptoms may indeed fluctuate during

the day, depending on plasma dopaminergic level. The majority of

complaints occurred in the "off" state.

(Enlarge Slide)

The same study that surveyed these Parkinson's patients for fluctuating

nonmotor symptoms also found that there was a correlation between the

number of sensory fluctuations, the severity of disease, and the level of

disability. Some of the patients also reported that the sensory

fluctuations were the most incapacitating of all nonmotor fluctuating

symptoms.

(Enlarge Slide)

In further support for the impact of sensory symptoms on quality of life,

our group at the University of Pennsylvania has been working to develop

a valid and reliable rating scale to measure the presence, severity, and

impact of nonmotor fluctuations in patients with Parkinson's disease. In

our study, the patients unanimously voted for pain as being the most

bothersome symptom that they encounter.

(Enlarge Slide)

In summary, nonmotor symptoms need to become recognized as part of

the symptom complex of Parkinson's disease by patients and their

healthcare providers. We will need to develop valid and reliable methods

of measuring and evaluating nonmotor symptoms in Parkinson's disease

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in order to design clinical trials that can establish the efficacy and safety

of interventions to facilitate clinical decision-making.

Discussion

(Enlarge Slide)

Speaker: Is there some association between sleep disorders prior to the

actual onset of the motor symptoms in Parkinson's disease?

(Enlarge Slide)

Galit Kleiner-Fisman, MD: Given the fact that there are problems with

sleep in the general population, it is very difficult, without motor

symptoms, to necessarily predict the onset of Parkinson's disease just by

virtue of sleep complaints. However, if primary care physicians and other

healthcare providers are cognizant of the fact that there may be a

relationship, they may be able to note the sleep disturbance and then

monitor patients carefully over time for onset of motor symptoms of

Parkinson's disease. Although currently we do not yet have any

treatments that may modify the course or the natural history of the

disease, in the future, if we do have some way to modify the disease,

then early diagnosis will be crucial and sleep disturbances may help alert

us to when we need to intervene. In addition, as I mentioned, there are

some conditions that are more correlated with Parkinson's disease than

others, such as REM-behavior disorder. Certainly if a patient has

complaints of REM-behavior disorder, it is important to keep in mind that

Parkinson's disease may occur in the future.

(Enlarge Slide)

Speaker: It may be that several of these phenomena actually are

preclinical markers of Parkinson's disease.

(Enlarge Slide)

Dr. Kleiner-Fisman: Until recently, when patients came to physicians

and mentioned these nonspecific complaints of pain or sleep

disturbances, patients were often perceived to be malingering or to have

symptoms of depression. It is only now becoming clear that, in fact, these

are part of the Parkinson's disease symptom complex, and we really

need to listen carefully to patients when they tell us these complaints. A

lot of pain complaints may also be mistaken for arthritis problems or

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pains that the elderly population commonly have. Many patients tell us

that they have knee, hip, or back problems and subsequently, especially

in our nonmotor fluctuation survey of patients, we found that even these

joint complaints could fluctuate between "on" and "off" states. As such,

these can be attributed to their Parkinson's disease, not just to

degenerative arthritic problems.

(Enlarge Slide)

Speaker: Sometimes the terminology can get a little confusing for the

symptomatology.

(Enlarge Slide)

Dr. Kleiner-Fisman: I think that is, again, a very good point, and one of

the reasons why in our study we pursued focus groups with patients

specifically, because the terminology may vary amongst them and may

not necessarily reflect the symptoms that we, as healthcare providers,

are trying to pursue. It is a question of what words mean to different

people. It is very difficult to use just 1 word to describe a phenomenon,

and often times I ask patients to describe to me specifically what they are

feeling. One of the things I ask them is whether or not their symptoms

change during the course of the day or if symptoms respond to

medications and so forth. Oftentimes we know that dystonia is

"medication responsive," and it is an "off" feature. So, that helps

sometimes to get at the underlying symptom.

Discussion (cont'd)

(Enlarge Slide)

Speaker: For sleep disorders, how do you decide when to just go with a

clinical evaluation vs referring for one of the sleep studies you

mentioned?

(Enlarge Slide)

Dr. Kleiner-Fisman: Some symptoms, especially in a cognitively intact

and articulate patient, can easily be distinguished. Patients may tell you

that they have violent thrashings at night and their partner, for example,

may have some injury as a result of the thrashing suggesting REM-

behavior disorder. However, in some cases patients just do not know why

it is that they are not sleeping well. In that case, it may be useful to have

a sleep assessment. This is an all-night videotape monitoring and

electrical recordings of brain and respiratory activity, so that features or

sleep may be further elucidated.(Enlarge Slide)

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Speaker: I think, if there was a definition of "off" states and fluctuations it

might be helpful for a 10-second description of what those are.

(Enlarge Slide)

Dr. Kleiner-Fisman: Symptoms may vary, depending on the "on" or "off"

state. When patients take their medications and they alleviate symptoms,

we refer to this as the "on" state. Their function may return to normal.

They may be mobile. They generally feel good during this period of time.

However, as dopaminergic levels may fall prior to taking their next dose

of dopaminergic medication, their symptoms of Parkinson's disease may

return; we refer to this as the "off" state.

Summary

(Enlarge Slide)

(Enlarge Slide)

In summary, nonmotor symptoms are common and menacing problems

for patients with Parkinson's disease. These are now becoming more

recognized as part of the Parkinson's disease symptom complex by

healthcare providers. Sleep disturbances in Parkinson's disease are

widespread and occur in at least half of all patients and appear to be

correlated to disease severity. Both Parkinson's disease-related and

non-Parkinson's disease-related medications may interfere with sleep. All

patients with Parkinson's disease should be screened for a sleep

disorder, given its high prevalence.

In many cases, treatment begins with adequate sleep hygiene. Then

various medications can be manipulated, depending on the specific

etiology of the sleep disorder. Another common nonmotor symptom

complex affecting Parkinson's patients is sensory symptoms that include

pain, which in some cases may be one of the most bothersome

symptoms that patients complain of. Further work needs to be done,

elucidating the mechanism of pain and sensory processing in

Parkinson's disease. In the future, as nonmotor symptoms become more

widely recognized and accepted as part of the Parkinson's disease

symptom complex, new tools that are valid and reliable will need to be

developed to evaluate nonmotor symptoms in order to design clinical

trials establishing the efficacy and safety of new interventions.

(Enlarge Slide)

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