THIRTEEN

Long-Term Clinical and Side Effects

In the last chapter, we talked about some of the risks of the DBS surgery itself, as well as some of the side effects that occur when the stimulator is first turned on. In this chapter, we will talk about some of the effects of DBS that have been reported long term.

LONG-TERM CLINICAL EFFECTS OF DBS

Parkinson’s Disease

The question that most people ask is how long the effects of DBS last. For Parkinson’s disease, we now have data that show that DBS can control the main motor symptoms of Parkinson’s disease, namely, tremor, slowness, and stiffness, for at least 10 years. However, because DBS was developed in the late 1980s, there are individuals who have had their DBS systems for even longer. Each DBS center probably has a handful of people who have had their DBS systems in for a long time and are still doing relatively well. This does not mean that DBS is a cure for Parkinson’s disease. In fact, many things tend to worsen over time in people with Parkinson’s who have undergone DBS. Speech and balance problems have been reported in most of the long-term studies of DBS for Parkinson’s disease. While speech problems certainly may be due to the stimulation and will be mentioned as a long-term side effect of DBS later in this chapter, part of the speech problems are due to progression of the disease. The balance problems that occur over time in people with Parkinson’s disease are also thought to be due to disease progression. Over time, individuals may develop what is called postural instability. This refers to a person’s inability to keep standing if something knocks them off balance. This is an unfortunate problem of advanced Parkinson’s disease that does not respond to stimulation or medication. Nevertheless, tremor, stiffness, and slowness are still improved 10 years after surgery in Parkinson’s disease, so the effects are pretty long lasting.

Essential Tremor

For essential tremor, the effect on tremor is also long term, with evidence that tremor can be improved by up to 90% and maintained for at least 7 years or more. However, some centers have reported that the effect of DBS does seem to decrease over time. There is also the issue of tolerance (discussed in Chapter 11), where the tremor control from stimulation is lost over time and seems to happen only in people with essential tremor. The reason for this is unknown.

Dystonia

There have been reports of individuals benefitting from DBS for generalized dystonia for up to 10 years. These are people with a genetic form of dystonia, called DYT1 dystonia. There are also people with other forms of dystonia, such as cervical dystonia, whose improvement has been maintained for up to 3 years.

LONG-TERM SIDE EFFECTS OF DBS

It should be mentioned that there seem to be relatively little long-term side effects in people with dystonia who undergo DBS. The main ones appear to be possible lead migration or wire fractures, which are mostly seen in children with dystonia who outgrow their leads. There also seem to be relatively little long-term side effects to thalamic stimulation for essential tremor. Most of the long-term side effects listed below are seen in people with Parkinson’s who undergo DBS, although when they occur in essential tremor or dystonia, they will be mentioned as well.

Speech

Speech can definitely be affected by DBS. Problems with speech are most commonly seen after DBS surgery for essential tremor, where leads are placed in the VIM nucleus of the thalamus, and Parkinson’s disease, where leads are placed in the subthalamic nucleus.

The nerve fibers that control the muscles responsible for speech are very close to the thalamus. As discussed in the last chapter, if the DBS lead is placed slightly lateral within the VIM nucleus, it is more likely to cause speech problems. Remember that if the stimulation is set at a monopolar setting, the stimulation spreads out from the lead in a radial fashion. The higher the voltage setting is, the more it is likely to spread. If someone needs a high setting to control his or her tremor, speech may be affected. Although this can occur when it is placed only on one side, the likelihood of problems increases when leads are placed on both sides. This is why most centers typically place a unilateral lead for essential tremor. When the stimulation spreads to the motor fibers controlling speech, the speech can sound strained, or it can sound slurred, as when people are drunk. Sometimes the DBS programmer can reduce the effect on speech by changing the stimulation to a bipolar setting, which concentrates the stimulation around the contact, but sometimes tremor cannot be completely controlled this way. It may be a choice between good tremor control with some speech problems or sub-optimal tremor control with less effect on speech in these particular cases.

For Parkinson’s individuals undergoing STN DBS surgery, the stimulation can certainly spread to speech fibers, although the problems are less prominent than with VIM stimulation in essential tremor. The problem with Parkinson’s disease is that speech normally worsens slowly as time goes on. Therefore, it can sometimes be unclear if speech issues are due to stimulation or to disease progression. Sometimes it is due to both. If it is due to stimulation, the speech can sound strained or strangled, or sometimes slurred. When the speech over time gets soft, raspy, or low, then it is usually attributed to disease progression. Either way, problems with speech can lead to communication issues and are very frustrating to both that person and their family.

Speech problems sometimes can be helped by speech therapy. Speech therapy teaches you techniques to help you speak louder and enunciate more clearly. There are different types of philosophies regarding speech therapy out there. One of the most popular regimens is the Lee Silverman Voice Therapy (LSVT), which focuses on thinking and speaking loudly.

Balance

Balance problems are typically seen in people with Parkinson’s disease after DBS, but may also be seen in people with essential tremor after DBS as well. Most of the time, balance problems are seen within the first 6 months after surgery in individuals with Parkinson’s, as the stimulation is being increased and the medications are being decreased. This happens because your body is trying to get used to all of the changes. The balance problems are typically gone once the stimulation and medications are optimized. A small proportion of people with Parkinson’s disease will continue to have balance problems, however. This may be due to a number of reasons. Some people continue to get dyskinesias despite the DBS (see next section for more details). These dyskinesias can throw you off balance. Sometimes the stimulation has spread to the nerve fibers controlling the muscles in your legs. When this happens, you may not have full control of your leg, and it may involuntarily turn in or move out. Sometimes it may be because the medications were reduced too quickly. In any of these cases, you should bring these problems up with your DBS neurologist and work with him or her to improve the problem. Sometimes physical therapy may also help you to regain your balance.

The balance problems seen in people with essential tremor are usually due to a lightheadedness that is experienced when the stimulators are turned up. This lightheadedness feeling seems to be more noticeable when DBS leads are placed on both sides of the brain. This is another reason why DBS centers may tend to recommend DBS leads on only one side for essential tremor. However, balance problems have also been reported in people with essential tremor who have not undergone DBS. In fact, there have been reports that the cerebellum is also affected in essential tremor. The cerebellum is the part of the brain that coordinates movement. When the cerebellum does not work correctly, people may walk or reach for things like they are drunk. In essential tremor, these balance problems are usually not quite that severe, but physical therapy seems to be helpful.

Dyskinesias

This is a problem seen only with Parkinson’s disease and can occur either with STN or GPi stimulation. Dyskinesias are a long-term side effect from chronic use of levodopa. They are involuntary movements of any part of the body that typically increase at the peak of the levodopa dose. Remember that stimulation is like an electrical form of levodopa. Thus, when stimulation is turned on, dyskinesias can be increased. Individuals generally notice a worsening of dyskinesias when the stimulation is turned on or when the stimulation settings are turned up. However, this usually lasts a couple of days at most and then wanes as the brain becomes used to the stimulation. Sometimes Parkinson’s disease medications are also reduced, which can also improve dyskinesias.

Although dyskinesias are typically reduced over the long term with DBS surgery, there are some people in whom we are unable to reduce dyskinesias. These individuals are very sensitive to the stimulation, and even small increases in stimulation result in dyskinesias that, unfortunately, do not diminish after a few days. With these people, trying to find the right combination of medication and stimulation can be very difficult. One approach is to try and increase the stimulation slowly, over a period of a year, rather than the usual 3–6 months. Another approach is to send the stimulation through one of the higher contacts, which may suppress dyskinesias.

Weight Gain

This problem seems to be a concern only for individuals with Parkinson’s disease, especially after STN DBS surgery. Weight gain does not seem to be a significant problem for people undergoing DBS surgery for essential tremor or dystonia.

Parkinson’s disease itself has been associated with weight loss. In fact, many people living with Parkinson’s disease tend to lose weight as the disease progresses. However, after DBS surgery, weight gains of 10%–25% have been reported. There are several theories out there as to why this happens. Many people living with Parkinson’s disease undergo DBS because of severe, disabling tremor or significant dyskinesias (abnormal involuntary movements). Because of these movements, such people are in constant motion and thus are burning calories. With DBS controlling the tremor and reducing dyskinesias, these people burn less calories and thus gain weight. Although this theory makes a lot of sense, individuals with Parkinson’s who do not have severe dyskinesias or tremor may also gain weight after DBS. We really do not know why this is. It is possible that we are changing some of the circuits in the brain that control our metabolism. Whatever the reason, weight gain is something that can be seen and should be monitored.

We typically encourage everyone undergoing DBS to exercise, which may keep weight gain to a minimum. Exercise is good for general health, an optimistic outlook, and increased energy. There is also evidence that exercise helps with thinking and memory. If you gain weight despite the exercise, we often refer people to a dietician or nutritionist for tips on healthy eating.

Apraxia of Eyelid Opening

Apraxia of eyelid opening is an inability to open the eyes voluntarily. In this condition, the eyes can close by themselves, but people then have difficulty opening them. Many have described having to use their fingers to pry their eyes open. This can be disabling. If you cannot open your eyes quickly, many activities, especially driving, are compromised. Apraxia of eyelid opening seems to occur only in people with Parkinson’s undergoing DBS and also seems to be associated with subthalamic nucleus (STN) DBS as opposed to GPi DBS. It can occur in between 2% and 30% of these individuals after STN DBS.

Treatment of apraxia of eyelid opening is with botulinum toxin, commonly known as Botox. Botulinum toxin is injected directly into the eyelids and the muscles around the eyes. It works by blocking the signal from the nerve to the muscle. If the muscle never gets the signal to contract, the muscle relaxes and the eyes open much more easily. In severe cases, when botulinum toxin does not work, individuals can undergo an operation called a frontalis suspension. In this operation, the eyebrow area is connected with the upper eyelid by sutures, located deeply under the skin and not visible to others. This allows a person to use the eyebrows to help open the eyes and can be helpful.

Depression

Depression is something that has been reported to occur after DBS surgery for Parkinson’s disease, especially with the STN target. Although rare, it is something that you and your DBS team should monitor. In some cases, the depression can be so severe that some individuals have tried to commit suicide. Virtually every DBS center, if it operates on enough people, will have one or two of these cases. Originally, it was thought to occur because the expectations of the individual were not met. However, there have been reports of people who have been satisfied with the results of their DBS but, despite that, tried to commit suicide. There was a report in the New England Journal of Medicine of a woman who started to become tearful when the DBS was turned on and did not feel that way when the DBS was turned off. The sadness that engulfed this person only happened when the lowest contacts of the DBS lead were stimulated. It turned out that the lowest contacts were probably outside and below the STN. Providing stimulation to this area was thought to stimulate fibers that were responsible for mood. This was evidence that depression could be “hard-wired” in the brain and that stimulation could activate these moods. Other studies have shown that people with a history of severe depression, especially those needing hospitalization for their depression, seem to be at highest risk for developing depression after DBS surgery. This is why DBS centers try to screen people for the presence of depression before operating. Although we still do not have a great handle on who will develop depression after surgery, it certainly makes sense not to operate on someone who is in the throes of depression.

Some people will experience worsening depression after DBS, and this may be related to the site of the electrodes. You should have any depressive or other psychiatric symptoms (anxiety, apathy, psychosis, or impulsivity) evaluated before surgery to be as safe as possible.

Cognition

Cognition, or your ability to think and remember things, is something that can definitely change after DBS surgery. Again, this does not seem to be much of a problem in people with essential tremor or dystonia, as long-term cognitive studies in these people do not show much change in formal neuropsychological testing.

In Parkinson’s disease, however, changes in cognition have been clearly reported. This seems to be reported more often in people with their leads placed in the STN than in those with their leads placed in the GPi. The most common change that we see after surgery is a decline in verbal fluency. Verbal fluency is a test where you are asked to name as many words beginning with the letter “F” as you can in 1 min. There are many variations on this task, with some asking you to name as many animals or vegetables in a minute and others using different letters. This task tests the organization of your brain and the ability of your brain to remember what you have said while trying to come up with new ones. After DBS surgery, the number of words that a person can produce in 1 min declines. This is the most consistent finding regarding cognition in the medical literature on DBS. However, it is still unclear what a decline in verbal fluency means, as many people have declines in this task after DBS but do not complain of problems in daily life. Others may complain of memory problems and may have changes in memory tasks on formal testing, but their performance on verbal fluency may not change. Overall, long-term studies in people living with Parkinson’s disease undergoing DBS have shown that mild cognitive decline is fairly common. However, all centers clearly have some people who have more than mild changes in thinking and memory after surgery.

A reason why cognition changes after DBS is that by placing hardware through the brain, you are disrupting the connections from one part of the brain to another. It is also possible that stimulation itself is affecting your thought processes, although it has been difficult to separate whether changes in cognition are due to the surgery itself or due to stimulation. One thing that is clear is that certain individuals worsen cognitively after surgery. People who already have significant problems with their thinking and memory are more likely to experience problems after surgery. This is why neuropsychological testing is done before the surgery. Those who are on the borderline of dementia or who have dementia could likely worsen after the surgery. With DBS surgery, we are trying to improve your quality of life. If we worsen your cognition to the point that dementia is an issue, then we are not improving quality of life.

Sometimes when cognition worsens after surgery, it can also be due to progression of Parkinson’s disease. It is estimated that up to half of the people living with Parkinson’s may develop dementia. There are medications that can be given to help such individuals. These medications are called cholinesterase inhibitors, and they increase the amount of acetylcholine, a chemical in the brain. The cholinesterase inhibitors were initially developed for the treatment of Alzheimer’s disease, although they have certainly proven to be helpful for cognitive problems in Parkinson’s as well. The common ones used are donepezil (Aricept) and rivastigmine (Exelon). Only rivastigmine is FDA approved for Parkinson’s dementia; however, there are data to suggest that donepezil could be helpful as well. Many clinicians may actually start with donepezil because it is available as a generic medication and is less expensive than rivastigmine. However, rivastigmine is available in a patch form, which may be easier to administer and is definitely better for people with swallowing difficulty.