Coastal Neurological
Medical Group, Inc.

Understanding Parkinson’s Disease (IPD)

Parkinson’s disease is a disease that has the clinical triad of bradykinesia or akinesia (slowness), rigidity (stiffness), and resting tremor, which is a four to six cycles per second tremor. All of these three features, with the anchor being bradykinesia and resting tremor, have significant asymmetry. Later, the clinical picture is associated with postural instability and balance difficulty. If the patient has postural instability early in the first few years, then the patient either has an Atypical Parkinson’s disease (APD) or has comorbidities, such as vascular changes (stroke) or a structural lesion. The IPD has no biomarker that is 100 percent. A DAT Scan may be of some benefit at the present time, but following the patient’s journey and seeing how the clinical symptoms evolve in response to L-dopa is important in helping make the diagnosis more certain.

How can we be more certain that a patient has IPD? After the patient has had the disease for many years, the history will be that of a unilateral onset and asymmetry that persists for many years. There will be a resting tremor, but there may also be a postural tremor in 20% of the patients. 20% of patients will not have a resting tremor. The disease is progressive and L-Dopa will be a robust therapeutic agent. 70 – 90% of the IPD patients will have a robust response. Later in response to L-dopa, there will be evidence of motor complications, which are dyskinesia and wearing off or end-dose failure (EDF). The L-dopa response will be greater for more than five years. The patient who has the above criteria for greater than 10 years will be more likely to have a certain diagnosis of Parkinson’s disease. These above statements are supported by the London Brain Bank data and suggest if followed the diagnostic accuracy is 98.5%.

A patient may have a jaw tremor and postural tremor is present in 20% of the cases and it usually is asymmetrical. If, with the hands held out, a tremor reoccurs after a few seconds this is called a re-emerging tremor and this is very consistent and supportive of Parkinson’s disease. The patient often has the flexion of the upper extremities, the back and lower extremities and has a stooped posture. The mid fingers are often extended. Early in the diagnosis, before and after treatment, the patient may have morning dystonia in the feet and sometimes in the hands. The foot dystonia can make walking difficult. Dystonia, unless it is off dystonia with L-dopa, is usually seen in younger people, usually in the feet and usually with an inversion type of posture that is seen in the morning.

There is much consideration now about staging Parkinson’s disease. It is now proposed that there would be a preclinical stage, a pre-motor stage, which involves non-motor symptoms and then the motor phase or stage. There is a great deal of complexity in the preclinical phase, but this may later need to be divided up into genetic phase, environmental phase and other determined phases.

The differential diagnosis is significant in IPD. There is Atypical Parkinson’s disease (APD), which falls into essentially three groups. One is multi-system atrophy, which is an alpha synuclein disease like Parkinson’s. Also, PSP is an APD and has early eye signs with supranuclear palsy and can have dementia and is considered a tauopathy. It has the applause sign. Corticobasal ganglionic degeneration is another APD that can have cortical features, depression and is considered also a tauopathy. There are other less common Parkinson’s plus syndromes. A very important Parkinsonism to consider is always that of a drug-induced Parkinsonism. Most of these that we see today are related to dopamine antagonist such as prochlorperazine and metoclopramide (Reglan). Other atypical neuroleptics may give Parkinson’s features as can, infrequently, the SSRI’s. The older neuroleptics such as Haldol, Stelazine and Prolixin are not as commonly used, but certainly can give Parkinsonism as can Abilify.

Other diseases that are treatable need to be ruled out such as Wilson’s disease. There are a few cases with Parkinsonism that have a low ferritin level called a ferritinopathy. Atypical parkinsonism patients need to have a check for B12, Vit E, copper, acanthocytes plus other tests.

Genetic forms of Parkinson’s disease are now better understood and the common ones are Parkin 2, Parkin, Parkin 6 which is PINK 1, Parkinson 7 which is DJ-1, and Parkin 8 which is LRRK-2. Parkin 9 and 14 are less common and Parkin 1 and 4 have mutations for alpha-synuclein. Another interesting syndrome that usually presents as a dystonia in younger people but can be seen in adults is DRD syndrome or dopa-responsive dystonia. It is treatable with L-dopa and some of the patients will have Parkinson features, especially when older.

Non motor symptoms in IPD are very common; they are loss of smell or olfactory deficits, constipation, depression, REM behavior disorder (RBD), and sleep disturbances and may have some predictive ability. Other non-motor symptoms which can certainly precede the Parkinson’s motor symptoms are anxiety, panic attacks, sweating, pain, abdominal discomfort, hot and cold sensations, aching, mood changes and slow thinking; however, none considered to be predictive at the present time.

Treatment of IPD at the present time is symptomatic. We do not have any known drugs that give neuroprotection, delay of disability, delay of disease progression, or modification of the underlying disease. However, there are many drugs in the pipeline. The MAO type B inhibitors (MAOB-I), have been considered as possible disease-modifying agents, but at the present time, the evidence is not thought to be present to make that conclusion. When treating symptoms in the early diagnosed patient, many start with MAOB-I such as selegiline or rasagiline. Some will start with amantadine or Symmetrel or an anticholinergic such as Artane or Cogentin. These drugs have mild symptomatic benefit, but anticholinergic and sometimes Symmetrel can be definitely associated with cognitive side effects. Amantadine hydrochloride can cause myoclonus in the face or in extremities especially if renal failure is present. It is also associated with livedo reticularsis. These drugs show efficacy in benefit and are fairly robust in their improvement in the patient. Rasagiline, in clinical trials, has been shown to improve the UPDRS and when compared to the patients who had a delayed use of the Rasagiline at 18 months, the trial group was 1.7 points better on the UPDRS than the late treated patients. A trial in Sweden showed that patients who were given Selegiline were definitely better at five years than those who had not gotten Selegiline early.

After starting an MAOB-I, most neurologists would then start a dopamine agonist (DA) such as ropinirole, pramipexole, or rotigotine patch. Dopamine agonists have been shown to delay the need for L-dopa and also delay the onset of motor complications (MC), which are EDF and dyskinesia. Once the L-dopa is started, however, then the motor complications have a greater propensity of occurring. DA have significant adverse side effects. They are nausea, orthostatic hypotension, edema of the ankles and feet. This edema can occur early, but often takes months to develop and is often a difficult diagnostic dilemma. Excessive daytime sleepiness, hallucinations, sudden sleep events, and impulsive compulsive disorders (ICD) can certainly develop. Insomnia can also be seen with DA. The adverse side effect profile of DA is significant especially in patients who are older. In patients who had any type of addiction problems, DA should be very cautiously used. The ICD have a significant range, but may include gambling, hyper sexuality, pornography, shopping, computer use, and other impulsive behavior. The risk of ICD is greatest in the DA, probably next in L-Dopa and rarely in MAOB-I, however it has been reported. Patients are at greater risk if they are male, younger, and if they have an addictive history. In our practice, family history of addiction gives you a more likely chance of having ICD. Patients may also have an impulsive personality where they have irritability, anger and may certainly have bouts of rage. In patients with ICD, it is important to talk to family members. If they do have these symptoms, it is important to gradually taper off the DA. Therapeutic drugs have been tried such as quetiapine, amantadine and SSRI’s with little or no benefit. The treatment, obviously, is to get them off the drug; however, it must be determined how they are doing with their ADL and their QOL. When there is need for improved ADL or QOL and functional improvement, then L-dopa is the drug that has the most robust benefit. It does have, however, the side effects of MC. Analysis of L-Dopa studies show at 3 years, 30% will have dyskinesia and in eight years, 80% to 90% will have dyskinesia. They will also have EDF. Initiation of L-Dopa determines the time to onset of MC. The three in one pill, carbidopa, L-Dopa, and entacapone (Stalevo) has a theoretical benefit of increasing the amount of L-Dopa in the plasma, but the clinical trials have shown no evidence of delay of MC and in fact it may be associated with more dyskinesias, which would seem logical since there is more available L-Dopa.

L-dopa is the most robust therapeutic agent. The ELLDOPA trial is a 40-week trial that had various doses of L dopa; 150 mg, 300 mg and 600 mg, all compared to placebo. Then there was a two-week washout. This trial gave important information and documented efficacy of L-dopa. At the highest dose, 600 mg a day, it took 20 to 24 weeks to get maximum L-dopa improvement or benefit on the UPDRS scale. This important data tells us that we should definitely give L-dopa a significant amount of time to have its best clinical benefit. When the patients were washed out, the patients on L-dopa after two weeks did not have as severe impairment as did the placebo group. The 600-mg group had the best clinical state. Also 16% at 40 weeks had dyskinesias.

In treating advanced IPD, the most difficult clinical features to treat is the EDF or wearing off and the dyskinesia. If the patient has EDF, the best way to treat this is to give more frequent doses. It is important to monitor off time and dyskinesia, but also non-motor signs and symptoms. Shortening the interval between the doses will reduce the EDF and if there is no dyskinesia, then a higher dose may be used to avoid suboptimal treatment. To reduce EDF, a COMT inhibitor could be used (i.e.: Entocapone} or Stalevo, the three in one pill. If the patient is not on a DA, that could be added and Rasagiline has been shown in two trials to be definitely of benefit in reducing off time by about one hour. This was equivalent to a group of patients who were treated with entacapone. Amantadine hydrochloride and anticholinergic can be used but are of limited value and have side effects. MC are the most difficult side effect to treat when using L-dopa. EDF, wearing off or morning off is a significant problem. “Delayed on” is often a problem in L-dopa treated patients but it is often related to eating and taking protein too close to the administration of the medication. “Never on” can also occur. Importantly, if a patient is “off”, it is more difficult to get them to an “on” state and if deeper it is more difficult. Other treatments for EDF are the use of apomorphine, liquid Sinemet or a possible gel that is instilled via a duodenal tube.

Dyskinesias are either peak dyskinesias or at the time of peak plasma of L-dopa level which usually is about 90 minutes after the dose. Diphasic dyskinesias, occur as the drug is wearing off and before the next dose. The diphasic dyskinesias are what we call low-dose dyskinesias and are often associated with erratic leg movements. To help detect dyskinesia, it is important to have the patient do repetitive motor activity or repetitive verbal activity. This usually brings out the dyskinesias and can determine where the thresholds for dyskinesias are during the dosing. For treating dyskinesia, the dose can be reduced, the interval shortened or amantadine hydrochloride can be used, which will sometimes reduce the dyskinesia. If they are severe and the patient is responsive to L-Dopa and cognitively intact, then DBS should be considered. There can be off dystonia and on dystonia.

Other unusual symptoms are kyphosis, which is related to the flexion of the upper trunk, but often has a structural basis. Anteflexion or dropped head syndrome occurs and is usually associated with Parkinson’s disease but can be seen in MSA. Exercise may help. The dropped head syndrome usually improves when lying down, less so when sitting but definitely worse when standing.

Camptocormia is a flexion at the waist and it, again, like anteflexion is made worse by standing. It is probably a type of dystonia and Botox into the rectus abdominis muscles helps the flexion. There is also a consideration that it may be some type of myopathy and probably in many cases, it is in part related to degenerative diseases of the thoracic and lumbar regions. Both of these symptoms, anteflexion and Camptocormia are always better with lying down. Camptocormia was called Pisa syndrome. For the anteflexion, it is important to consider if the patient has MSA. Botulinum toxin may be of benefit in both of these syndromes.

Dopamine dysregulation syndrome (DDS) is a syndrome that has some connection to addictive behavior. In these cases, the patient is usually addicted to the DA, sometimes L-Dopa. The patient gradually increases the medication to very high levels and cannot do without it. They often develop repetitive behavior such as punding or other types of behavior where they have a fascination with an unusual type of repetitive non rewarding complex motor activity. The DDS has a very significant spectrum and can be either mild or at an extreme. Often, the patients will be taking so much dopaminergic medications that they will not get a very therapeutic symptomatic benefit.

Cognitive impairment in PDD is related to older age, longer disease duration and severity of Parkinson’s motor symptoms. Genetic indicators may help determine who is more likely to have neuropsychiatric features or dementia. Recently GBA mutations (glucocerobrosidase) show a relationship to more frequent Lewy Bodies, but also more cognitive and neuropsychiatric features. GBA mutations amount to 4-5% of sporadic cases of IPD. LRRK2 accounts for 5% of sporadic cases and 5-10% of familial cases.

Importantly in all IPD patients, it is important to have them understand the disease process and be involved in their therapy and understand their drug sequence and their drug dosage and the time it is taken. Education is an extremely important part of the patient’s therapeutic process and the patients who know more about their disease do better. Knowledge is power and it helps the patient be their own advocates. Individual responsibility is a major factor in the patient’s future. At every visit the patient and spouse should write down all the medications they are on with the exact times and dose. This helps the doctor and forces the patient to know the exact dose and times.

There is good evidence that exercise is of benefit and maximum exercise at 45 minutes to 60 minutes five to seven days a week is strongly emphasized and it has been shown to improve measured testing. It does appear that it does have the ability to delay the progression of the disease.

Dee E. Silver, M.D.5/30/12

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Coastal Neurological Medical Group
9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

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