News Bulletin Revised Therapy Recommendations for Parkinson's Disease No. 2 / 2009-10-19
Interessegruppen for Parkinsons sykdom i Norge The Norwegian Centre for Movement Disorders www.sus.no/nkb
Therapy recommendations (Edition V – Autumn 2009) From "Interessegruppen for Parkinsons sykdom i Norge": • Professor Jan Petter Larsen, The Norwegian Centre for Movement Disorders, Stavanger University Hospital • Professor Espen Dietrichs, The National Hospital, Oslo • Consultant Dr. Steinar T. Vilming, Head of Department, Ullevål University Hospital • Consultant Dr. Antonie Giæver Beiske, Head of Department, Akershus University Hospital • Professor Ole-Bjørn Tysnes, Haukeland University Hospital • Professor Jan Olav Aasly, St. Olavs Hospital • Professor Svein Ivar Bekkelund, University Hospital in Northern Norway
Introduction This edition of the News Bulletin contains the fourth revision of "Therapy Recommendations for Parkinson's Disease". The recommendations have been formulated according to Norwegian conditions by the "Interessegruppen for Parkinsons sykdom i Norge". Much of what I wrote in the introduction to the previous versions of "Therapy Recommendations for Parkinson's Disease" still applies. There is still disagreement about the use of so-called disease modulating treatment and the debate continues on whether early symptomatic treatment should start with a dopamine agonist or levodopa as the first drug of choice. Different expert groups will often give different answers to these questions. Indications and contraindications for surgery seem to have become more defined. In several meetings the "Interessegruppen for Parkinsons sykdom i Norge" has discussed what the best treatment would be, and has made recommendations based on the results of clinical studies, indirect evidence, clinical experience and belief. We still believe that our conclusions form a sound basis for satisfactory treatment of patients with Parkinson's disease (PD). However, the recommendations should not be perceived as instructions and there must be room for individual variations in the treatment of individual patients. The "Interessegruppen" would like to emphasise the importance of non-drug treatment and that an optimal diagnosis is essential before starting treatment. It is also important to be aware that the psychiatric complications can significantly influence quality of life and function for both patient and family. The treatment of neuropsychiatric symptoms has been somewhat changed in this edition. The therapy recommendations have two parts. In the first part, suggestions are made for treatment of different phases of the disease. These recommendations are presented in figure 1. In the succeeding text, the recommendations are described in more detail. Part 2 contains an overview of a number of problems experienced by patients with more complicated PD (figure 2), and their treatment. The fact that the "Interessegruppen for Parkinsons sykdom i Norge" has formulated these therapy recommendations jointly does not mean that all members of the group necessarily agree to all the recommendations. The members of the group are Espen Dietrichs, Steinar T. Vilming, Antonie GiĂŚver Beiske, Ole-BjĂ¸rn Tysnes, Jan Olav Aasly, Svein Ivar Bekkelund and myself. We hope that the revised recommendations will be useful in day-to day work with patients with PD. Director of Research Jan Petter Larsen The Norwegian Centre for Movement Disorders Stavanger University Hospital Editor
News Bulletin Revised Therapy Recommendations For Parkinson's Disease No. 2 / 2009 Volume 14
Contents Introduction I. COMMON PROBLEMS OF PARKINSON'S DISEASE General Diagnosis Supplementary investigations Non-pharmacological measures When should symptomatic treatment start and with what? What should be done when the effect of treatment is unsatisfactory? Neurosurgical treatment II. SPECIAL PROBLEMS OF PARKINSON'S DISEASE General Predictable motor complications Treatment of predictable motor complications Unpredictable motor complications Autonomic disorders Tendency to fall Sleep disturbances Neuropsychiatric problems
I. Common problems of Parkinson's disease (PD) General Figure 1 (p. 7) illustrates the "Interessegruppen's" therapy recommendations for patients with PD. The figure starts by emphasising the need for the best possible diagnosis. If the most likely diagnosis is PD, the responsible doctor must consider both pharmacological and non-pharmacological measures. If pharmacological treatment is chosen, we recommend starting with possible disease modulating treatment. If the patient has no loss of function, it is usually possible to postpone symptomatic treatment. Within shorter or longer periods after starting symptomatic treatment, the need for adjustments and alterations may arise. The figure gives some of the choices which may be appropriate. More detailed recommendations are given in the following text and in part 2, which deals with complicated PD.
Diagnosis The diagnosis of PD is based on an evaluation of differential diagnoses in patients with demonstrable parkinsonism (i.e. patients with at least 2 of the following 4 cardinal signs: Resting tremor, akinesia, rigidity and postural instability / altered posture). The most important causes of parkinsonism are: 1. Idiopathic PD 2. Symptomatic parkinsonism (drugs and toxic substances) 3. Other neurodegenerative conditions (multisystem atrophy (MSA)), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and others) 4. Vascular parkinsonism ("lower body parkinsonism") When evaluating the cause of parkinsonism, it is important to consider the following factors in addition to the patient's age: The occurrence of resting tremor, drug effects, evidence of dementia or autonomic disorders at the time of diagnosis, evaluation of symptom asymmetry and possible demonstration of atypical neurological findings and symptoms. In PD, resting tremor and asymmetric symptoms are most commonly seen from the start, autonomic symptoms are not pronounced, dementia or severe postural instability are rare early on, and pyramidal or cerebellar symptoms are not present.
Supplementary investigations In patients with parkinsonism, supplementary investigations may be considered if they are likely to improve diagnostic certainty, help exclude other causes of the patient's symptoms and exclude illnesses / conditions necessitating caution when starting drug treatment. Imaging Imaging studies can be useful in the differential diagnosis of parkinsonism. CT scan / MRI may show changes indicating the presence of symptomatic parkinsonism or parkinsonism as part of a different neurodegenerative condition such as PSP or MSA. A cerebral CT scan is generally recommended to exclude large structural lesions in the brain. If the clinical examination or history reveals findings suggesting PSP or MSA, an MRI should be performed. A high Tesla MRI will demonstrate black areas (lack of signal) in the putamen suggesting iron deposits, this increases suspicion of MSA. Linear high-signal areas along the putamenal edge using T2 weighted MRI are also suggestive of MSA. Flattening of the pons increases suspicion of PSP. If the diagnosis of parkinsonism is uncertain, a cerebral isotope examination (SPECT) may be carried out, with a tracer which binds to the dopamine transporter protein (DAT scan). This investigation demonstrates loss of dopamine nerve terminals in the striatum, making parkinsonism more likely. It does not, however, differentiate between the various causes of parkinsonism.
Other investigations To determine whether there are contraindications or a need for caution relating to the start of medication, blood screening tests should be taken by the patients' GP to monitor liver and kidney function. In special cases, an ECG should be done.
Recommendations Imaging • • •
A cerebral CT scan should be taken whenever PD is suspected This can be replaced by an MRI scan if there are special circumstances DAT scan can be used to help determine whether parkinsonism is present or not. This test does not differentiate between PD, MSA or PSP
Other supplementary investigations •
Before starting drug treatment, screening tests of liver and kidney function should be carried out, and in some cases an ECG
Figure 1 Treatment strategies for motor symptoms of PD Diagnosis of parkinsonism Parkinson's disease
Disease modulation MAO-B inhibitors
Support Functional problems? Training Diet
Dopamine agonist (younger patients)
Levodopa standard (older patients)
Combinations of levodopa + MAO-B inhibitors + COMT inhibitors + dopamine agonist
Development of motor complications
Insufficient control with drug treatment
Different drug strategies
Unacceptable control with drug treatment
Non-pharmacological measures Patients with PD must be given information about the disease and offered support, training programmes and nutritional advice. The aim is to help the patient and the family to understand the nature of the disease, thereby giving the patient a feeling of mastery over it. This can reduce the risk of irrational anxiety associated with living with a chronic illness and its prognosis. Support includes assessment and measures related to emotional needs, information on support groups such as the local Parkinson association, and legal or financial advice related to the rights the patient has as a result of the disease. Physical training, alone and in groups or with a physiotherapist, can be beneficial for patients who have had the illness for a while. Some PD patients lose weight. Correct diet is important for general well-being. Some patients, with motor fluctuations, may also need to redistribute their protein intake (less protein during the day, more in the evening) to obtain the best possible effect of medication. Levodopa is an amino acid and high protein intake increases the serum concentration of other amino acids, which inhibit the transport of levodopa through the blood-brain barrier.
Disease modulation PD is caused by a combination of genetic and environmental factors. The pathological process, which leads to cell death in the substantia nigra, among other places, probably occurs through apoptosis. It is thought that several possible processes can lead to loss of dopamine neurones. These include oxidative stress, mitochondrial dysfunction, exitotoxicity with increased formation of nitrogen monoxide, glial proliferation and inflammatory processes. Various approaches have been tried in attempting to slow down the progressive development of the condition. The term 'disease modulation' is used to describe a potential slowing down of the development of the disease, as we know little about whether a more favourable disease progression is due to neuronal sparing effects or simply to other plastic changes in the brain. No drugs so far have been shown with certainty to have such an effect, but the chemically closely related MAO-B inhibitors selegiline (Eldepryl, Selegilin) and rasagiline (Azilect) have demonstrated a neuroprotective effect in vitro. Preclinical studies have shown that these substances reduce apoptosis. Placebo controlled long term studies with various designs show that selegiline 10 mg daily and rasagiline 1 mg daily in early treatment of PD appear to slow disease progression, i.e. a disease modulating effect. The patients also seem to have a reduced risk of developing motor fluctuations. Selegiline and rasagiline mainly differ in that selegiline forms amphetamine metabolites, which can potentially lead to a stimulating effect during the daytime, but also insomnia at night. Early treatment with dopamine agonists also appear to have a disease modulating effects in clinical studies as evaluated with PET and SPECT.
Patients with PD can be treated with selegiline 10 mg daily or rasagiline 1 mg daily from the time of diagnosis. Dopamine agonists can be considered from the start of treatment. Treatment aimed at disease modulation is less suitable for older patients (e.g. those over 75 years) due to shorter life expectancy and risk of side effects.
When should symptomatic treatment start and with what? There is no agreement either in Norway or internationally on when symptomatic treatment should be started and which drugs should be used initially. The majority believe, however, that start of symptomatic drug treatment can be postponed as long as the condition does not cause significant loss of social function. The degree of functional loss which can be tolerated before drug treatment starts depends on the patient's circumstances. Treatment should be started earlier in an employed patient threatened with disablement than in a pensioner, but this must be judged individually. Of the antiparkinsonism medicines, levodopa with a decarboxylase inhibitor is the most effective with the least side effects, and should be chosen for the majority of patients with pronounced symptoms of parkinsonism. However, many physicians delay treatment with levodopa because they believe there is a risk that the treatment itself may be harmful, even in therapeutic doses. There are no clear data on this, but several studies indicate that motor complications are caused by pulsed levodopa stimulation. Dopamine agonists are therefore usually recommended as the first choice in younger patients. Levodopa is often preferred in older patients, in whom motor complications occur more seldom, and because of the risk of hallucinations and other side effects of dopamine agonists. There are five dopamine agonists on the market in Norway. In some patients dopamine agonists have severe side effects and only a moderate effect, and the stipulations for continuing with a dopamine agonist are that the drug is effective in reducing the patient's functional loss to a socially significant degree, and that the side effects are acceptable. If this is not so, levodopa or a combination in lower doses should be used. Ergot-derived dopamine agonists may cause fibrosis in the retroperitoneum, the pleura and the cardiac valves, and drugs without ergot side effects are preferable: ropinirole (Requip, Requip Depot), pramipexole (Sifrol) and rotigotine transdermal patch (Neupro), Dopamine agonists should not be chosen in patients with dementia due to the risk of psychosis.Levodopa with decarboxylase inhibitor (Madopar, Sinemet) is available in both standard and prolonged release preparations. Standard preparations give somewhat higher pulsed levodopa concentrations in the brain than the prolonged release preparations, which could be unfortunate in regard to reducing the risk of motor complications, but this has not been demonstrated in clinical studies. A standard preparation is usually chosen, due to better absorption, especially in elderly patients with irregular gastric emptying. The dosage of dopamine agonists and levodopa preparations must be titrated individually. The daily dose of levodopa, as initial monotherapy, should not be higher than 600 mg for standard preparations and 800 mg for prolonged released preparations. If a higher dose is necessary, the addition or dose increase of a dopamine agonist should be considered.
If levodopa with decarboxylase inhibitor is chosen initially in antiparkinson treatment, adjuvant treatment with a COMT inhibitor has been recommended in some international circles to achieve a more continuous supply of levodopa to the brain. However, it is not certain that this is effective and in Norway COMT inhibitors are not reimbursable for this indication. COMT inhibitor (Comtess), which is also available combined with levodopa in one tablet (Stavelo), is reimbursable for fluctuations. The choice of MAO-B inhibitors initially is mainly because of an apparent disease modifying effect, but also due to a mild symptomatic effect.
Start treatment with a dopamine agonist in patients under 70 years. Levodopa with decarboxylase inhibitor should be chosen in elderly patients, patients with dementia or if dopamine agonists are insufficient or / and have unacceptable side effects. Primary initiation with levodopa should also be considered in all patients with pronounced symptoms of parkinsonism.
What should be done when the effect of treatment is unsatisfactory? 1. If a dopamine agonist has been used as monotherapy Recommendation: Increase the dose of the agonist to the highest recommended level as long as it is beneficial and the side effects are not severe. On signs of "wearing off" consider an agonist prescribed either once daily: Rotigotine, Neupro-plaster or ropinirole (Requip depot) or several times daily: ropinirole (Requip) or pramipexole (Sifrol). If this is not sufficient, adjuvant therapy with levodopa should be given, and the dose should be increased gradually to the optimal level. As adjuvant to an agonist, the dose of levodopa should be kept lower than in monotherapy. 2. If levodopa (Madopar or Sinemet) has been used as monotherapy in previous treatment Recommendation: Increase the daily dose of levodopa at first to 500-600 mg. If levodopa is effective but tends to wear off, supplement with a COMT inhibitor (entakapone, Comtess or a combination tablet of entakapone and levodopa, Stalevo) or rasagiline (Azilect). If there is further need for optimisation: Give an agonist as adjuvant. It may then be necessary to reduce the dose of levodopa due to dyskinesias. The newest dopamine agonists with once daily dosage, rotigotine transdermal patch (Neupro) and ropinirole prolonged release (Requip depot) maintain more continuous serum levels than ropinirole (Requip) and pramipexole (Sifrol). This treatment may be especially beneficial in patients who feel under medicated during the night and in the morning, with stiffness, poor sleep or "early morning dystonia". For dosage of the agonists see the recommendations in Felleskatalogen (the Norwegian Pharmaceutical Product Compendium), but in general, dosage of these drugs still seems to be too low in Norway. Adding an agonist instead of further increasing levodopa would tend to lead to less pronounced motor complications associated with long term levodopa treatment. If discontinuation of levodopa is necessary, reduce it gradually over 3 days before withdrawing, to reduce the risk of developing malignant neuroleptic-like syndrome. 3. If levodopa (Madopar or Sinemet) has been used from the start of treatment, with an agonist adjuvant. Recommendation: Increase the dose of the agonist optimally (perhaps change to a once-daily agonist) before further increasing levodopa, and give adjuvant therapy with a COMT inhibitor or MAO-B inhibitor for wearing-off or on-off. See above. Dopamine agonists are less potent than levodopa, but cause less risk of motor swings. When symptomatic treatment starts with a dopamine agonist and levodopa is added later, the risk of motor swings has been shown to be a little less than when treatment starts with levodopa. The dopamine agonists, however, also have side effects. None of the drugs help "freezing", most forms of unsteadiness, autonomic disorders or dementia. Agonists also increase psychotic symptoms more than levodopa.
Treatment of motor complications See part 2 on complicated PD.
Neurosurgical treatment If drug treatment does not have sufficient effect on the motor symptoms, neurosurgery may be necessary. The risk of complications means that surgical treatment is only an alternative for patients with difficult symptoms which cannot be controlled satisfactorily with drugs. Deep brain stimulation (DBS) is currently the only appropriate neurosurgical treatment for parkinsonism. Thin stimulating electrodes are placed in the brain and connected to a pacemaker which lies subcutaneously on the chest. The underlying mechanism of deep brain stimulation is not entirely clear, but it is usually thought that high frequency electrical stimulation inhibits normal impulse activity in the target area, thereby creating a "functional lesion" as long as the current is on. It was previously common practice to make permanent lesions in the thalamus (thalamotomy) or in the inner segment of the globus pallidus (pallidotomy), but these operations are no longer used in Western countries as the risk of intracerebral bleeding and permanent complications are far greater than with deep brain stimulation. Deep brain stimulation in PD patients is mainly appropriate for two indications: disabling tremor and severe motor fluctuations. In both cases, the subthalamic nucleus (STN) is normally the preferred target area for stimulation. STN stimulation is effective for tremor, rigidity and akinesia as well as for motor fluctuations. Although the symptoms are mainly dominant on one side of the body, experience has shown that it is best to implant electrodes bilaterally during the same procedure, to avoid worsening of the symptoms on the least affected side, and to reduce the risk of surgical complications. Deep brain stimulation of the STN is most effective in PD patients who respond well to levodopa. In patients with fluctuating symptoms, surgery can considerably reduce the motor swings, but a patient will rarely experience a level of motor function higher than that of his/her best preoperative levodopa response. Furthermore, it must be noted that deep brain stimulation does not improve the non-motor symptoms of parkinsonism, and will therefore not be very effective when autonomic disorders, depression, asthenia and fatigue are just as bothersome as the motor disorder. In fact, a number of such patients find that these symptoms worsen in the months after surgery, as the level of dopamine medication is reduced after the operation, which also reduces dopamine psychostimulation. Many patients also eventually experience speech difficulties after DBS. This may be partly a side effect of brain stimulation, partly a result of progressing disease. In the majority of cases there are few complications associated with the operation, but there is a slight risk of bleeding into the brain tissue, and there is always a small risk of infection from the insertion of the electrodes into the brain. The risk of complications increases considerably with age, while the benefit of surgery is thought to be smaller. Therefore, patients being evaluated for STN stimulator implantation should not be much over 70 years old. Reduced cognitive function or severe psychiatric problems also increase the risk of complications and are largely considered to be a contraindication to deep brain stimulation. It is possible that deep brain stimulation of the inner segment of the globus pallidus is gentler in these cases, but this has not yet been decided. Patients whose need for assistance increases in off periods, but are independent in on periods, often benefit from surgery as long as the other criteria for operation are fulfilled. In patients in whom tremor is the dominating symptom, deep brain stimulation of the thalamus is an alternative. The advantage of this procedure is that it is shorter, simpler and less stressful for the patient, and it can therefore be suitable for older patients. However, thalamic deep brain stimulation only has a moderate effect on the other Parkinson symptoms, and STN stimulation is therefore usually preferred, even if the main symptom is tremor. Current strength, frequency and pulse width can be regulated in a brain stimulator. The patient continues to use ordinary Parkinson medication, but at a lower dose. The pacemaker with its battery should normally be changed every four to five years, but rechargeable pacemakers are also available which can last for ten years with weekly recharging.
Transplantation of foetal brain cells into the basal ganglia was tried in several countries at one time, but two controlled scientific studies have shown that this procedure is of little value and is associated with complications. The method has therefore been abandoned. Extensive experimental research is being carried out with the aim of transplantation of stem cells or gene modified cells from various sources, but these animal experiments have so far not produced satisfactory results, and it will therefore be many years before such treatment can become an alternative. Private companies in various countries have already established "stem cell clinics", but there is no documentation, nor is there any indication that the methods used in these clinics have any benefits beyond the placebo effect.
Patients with uncontrollable fluctuations, as well as patients with disabling tremor in whom drug treatment is unsatisfactory, should be evaluated for deep brain stimulation. Thorough evaluation of possible contraindications is vital. Bilateral STN stimulation is preferable in most cases.
II. SPECIAL PROBLEMS OF PARKINSON'S DISEASE General Part 2 of these therapy recommendations describes the problems which may arise in patients with more complicated PD (see figure 2). Although motor complications attract the most attention, it is important to be aware that PD is a neurodegenerative disease which also affects non-motor systems in the brain. This may lead to a number of problems which must be considered in the overall treatment and care of patients with PD. Of these, sleep disorders and depression are the two factors most responsible for reducing quality of life in Parkinson patients. Motor complications are defined as motor fluctuations and/or involuntary movements (dyskinesias). When the level of motor function changes during the course of the day the term motor fluctuation is used. When the total level of dopaminergic stimulation (the sum of dopamine plus any dopaminecontaining drugs) lies within or above the therapeutic window, the patient is mobile (on). When stimulation is insufficient and below the therapeutic window, Parkinson symptoms dominate (off). In the same way, dyskinesias may occur when dopaminergic stimulation is higher or lower than the therapeutic window. Many patients, after a while, develop motor fluctuations and dyskinesias, and levodopa treatment, in particular, seems to be the cause. However, some types of motor fluctuation may also occur in patients who have not taken levodopa.
Figure 2 Complicated PD
Increased tendency to fall
Sleep disorders Insomnia Hypersomnia
Dose dependent fluctuations
Depression Psychotic symptoms
Levodopa is dependent on intact nigrostriatal nerve terminals for conversion to dopamine and storage. The storage capacity becomes reduced as the number of nigrostriatal nerve terminals decreases, but the ability to convert levodopa to dopamine remains intact. Therefore, the amount of dopamine released becomes steadily more dependent on the concentration of levodopa in the brain. As a result, the therapeutic window becomes narrower, and the duration of effect shortens. It is likely that these
changes significantly influence most types of motor complications, although several other mechanisms may also be involved. Motor complications may be predictable (i.e. related to doses of medication), or unpredictable.
Predictable motor complications Definition of predictable (dose dependent) motor complications: Dose dependent deterioration (end-of-dose deterioration or wearing off): Increasing Parkinson symptoms occur when the effect of a levodopa dose disappears. Overdose dyskinesias (peak-dose dyskinesia): Hyperkinesias when the serum concentration is above the therapeutic range. Early-morning dystonia: Painful, dystonic cramps early in the morning, most often in the feet. Occurs when levodopa concentration is at its lowest. Similar dystonias can also be seen in untreated patients. Diphasic dystonias or dyskinesias: Dystonias or dyskinesias which occur twice per dosing interval, during increasing and falling serum concentrations.
Treatment of predictable motor complications There is no simple and very effective treatment of motor complications (motor fluctuations and hyperkinesias). When related to medication intake, doses can be adjusted to achieve the most stable possible dopaminergic stimulation throughout the day. Many patients will already be using drugs with this aim in view, and new measures will usually have to be individually suited to each patient, depending on the treatment already in use. If the patient is not already using a dopamine agonist, it is reasonable to add one. Dopamine agonists work independently of the number of nigrostriatal terminals and have a longer duration than levodopa, so an agonist will provide more continuous stimulation of the dopamine receptors and thereby counter fluctuations. Another possibility is to improve the peripheral pharmacokinetics by trying to maintain a steadier serum concentration of levodopa, and consequently a more continuous dopamine release in the striatum. This can be done by administering levodopa more frequently and in smaller doses, or by giving a COMT inhibitor or MAO-B inhibitor with levodopa (see above for names of preparations). These metabolic inhibitors increase the bioavailability of levodopa and prolong the duration of each dose, without noticeably increasing the maximum concentration of levodopa in plasma. The dose of levodopa must nevertheless be reduced to some extent (up to 30%) due to the increased bioavailability of levodopa. Many patients will have already started using MAO-B inhibitors early on, as these drugs may have a modifying effect on progression on Parkinson-related symptoms. In such cases, a COMT inhibitor should be added. Theoretically, a slow-release formulation of levodopa should also give a more continuous release of the drug over time, but in practice, these preparations have proved relatively unhelpful in stabilising the serum concentration, and they are therefore used less frequently. Slow-release preparations have a lower bioavailability than standard formulations of levodopa, and a somewhat higher daily dose is therefore necessary. Neurosurgical treatment (see different chapter), apomorphine given as a subcutaneous infusion, and duodenal infusions of levodopa may be effective for these types of predictable fluctuations. However, oral treatment is usually sufficient, and apomorphine pumps or duodenal infusions are normally more valuable in the treatment of unpredictable motor fluctuations (see below).
Each type of motor complication must be evaluated individually in order for drug treatment to be adjusted optimally. Overdose must be avoided. To find effective treatment, knowledge of the patient's condition throughout the day is important. It is helpful if the patient fills out a mobility form for at least 3 - 4 days, providing as much information as possible about the problems that arise. We suggest the following strategy, in order of importance, for treating patients with predictable motor complications.
a. b. c.
COMT inhibitor or MAO-B inhibitor Dopamine agonist Deep brain stimulation, apomorphine pump or duodenal levodopa infusion.
In some patients, in whom the use of many different drugs is not suitable due to age and/or state of health, it may be best to increase the number of levodopa doses, but without increasing the total daily dose to any great extent. Further increases in size of individual doses is seldom effective, but it is important to ensure that each dose is large enough for the patient to achieve a proper on-period.
In some predictable motor complications the recommendations will be slightly different:
Diphasic dystonias and dyskinesias This is a combination of dystonias and dyskinesias in patients with advanced disease. See above under definitions.
Use single doses high enough for the patient to achieve a definite on-period. Try a COMT inhibitor, then an agonist. Deep brain stimulation or duodenal levodopa infusion is recommended if the fluctuations do not improve with other measures
Dystonias in off-periods Recommendation:
• • • •
Early morning dystonias: Start with a soluble levodopa preparation as soon as possible in the morning For repeated dystonias at other times, use the same guidelines as for fluctuations For especially prolonged and painful dystonias, apomorphine injection or soluble levodopa may help For continuously recurring, painful and therapy resistant focal dystonia, injections with botulinum toxin should be considered
Unpredictable motor complications Definition Unpredictable motor complications are changes in motor activity, often sudden, occurring unpredictably in relation to drug intake. The most common are sudden-off or yo-yo phenomena with rapid swings between on and off periods. Pronounced freezing occurs most often in the off-period, but may in rare cases occur in the on-period (unknown mechanism). This motor complication is the most difficult to treat. Treatment In general, this type of patient needs a balanced combination of an agonist, levodopa and a levodopa metabolism inhibitor. Patients will often take relatively frequent doses (at least 5 times daily). Absorption of drugs is influenced by gastrostasis after meals and patients must therefore adjust their mealtimes and type of food to their drug intake. Most often, protein rich meals will result in relatively long gastrostasis, but some patients report that it is easier to get the drugs to work if they take them with their meals. If, nevertheless, a patient still experiences rapid, unpredictable off-periods, soluble levodopa can be tried. Effect can be expected after 15-20 minutes, but may be delayed if the patient has eaten close to the off-period, especially if the food was protein-rich. If the patient still experiences pronounced swings with uncontrollable off-periods, apomorphine by injection or pump can be tried, or levodopa in a duodenal infusion. Deep brain stimulation may also be considered. When using apomorphine (injection pen) 1-6 mg per dose subcutaneously, the patient must be given domperidone (Motilium) 20 mg x 3 for 2 days before the first apomorphine dose. This prevents the peripheral side effects of apomorphine. Domperidone can often be discontinued gradually after a few weeks/months. It may be physically difficult for the patient to inject the dose in off-
periods. Family members should therefore receive instructions. An alternative to apomorphine is a duodenal infusion of levodopa. On admission to the neurological ward, an evaluation of the indication will be carried out. Levodopa is administered through a nasoduodenal tube, the effect of the infusion should be evaluated by close observation. An infusion pump provides a steady levodopa infusion in addition to the possibility of administering an extra dose of levodopa if the patient should suddenly experience an off-period. If this treatment is indicated, it is administered through percutaneous endoscopic gastrotomy (PEG). As this is a complicated treatment for the patients, it is often necessary that family members or district nurses can assist with adjustment of the infusion speed of the pump.
Recommendation: 1. 2.
Try soluble levodopa, 50-100 mg as needed Consider the possibility of duodopa or apomorphine injections
Autonomic disorders In advanced PD, there are often disorders of the autonomic nervous system, especially problems with the gastrointestinal tract or the bladder, or with orthostatism.
I. Gastrointestinal problems Dysphagia, dribbling and speech difficulties may occur. Reduced ability to swallow disposes the patient to retention and aspiration, and may lead to pneumonia. Degenerative changes in the dorsal vagal nucleus and in the oesophageal plexus may be causes of dysphagia. Hypersalivation is not caused by increased production, but by reduced spontaneous swallowing. Anticholinergics and transdermal scopolamine reduce the production of saliva, but the spit may become thick and sticky, and patients rarely find these drugs helpful. In some patients, a botulinum toxin injection, either in the salivary glands or subcutaneously over them, may be effective in reducing the secretion of saliva. Reduced emptying of the oesophagus/stomach: Some patients become too quickly satisfied, feel their stomachs are too full and complain of nausea. Reduced gastric emptying may affect uptake of medicines and cause a variation in their effect. Nausea should not be treated with metoclopramide, a D2 blocker which crosses the blood-brain barrier and aggravates the symptoms of PD. If the discomfort continues, domperidone may be tried. Constipation: This is common. The causes are complex, but a reduction in motility and degeneration of the neurones in the parasympathetic nervous system are the most important. The most pronounced cases may result in megacolon. Dystonia in the puborectal muscles may reduce the ability to defecate.
Recommendations for problems in the gastrointestinal tract: 1. Follow general principles as far as possible with plenty of fluids, exercise and fibre. 2. Optimal treatment of the underlying disease. Treatment with soluble Madopar can be tried in dysphagia. 3. Apomorphine injection may improve swallowing in off-periods. Apomorphine injection before defecation may also be tried for constipation caused by pelvic floor dystonia. 4. A PEG tube should be considered if nutrition is poor.
II. Bladder problems More than half of PD patients have bladder problems. There are several causes of this, but the most important are bladder hyperreflexia, pelvic floor muscle dystonia and detrusor-sphincter dyssynergia.
Pelvic floor problems can be reduced by optimising the antiparkinson therapy. In detrusor hyperactivity, evening fluid intake should be reduced, or a urinary antispasmodic should be given, or imipramine (Tofranil) can be tried. Incontinence is uncommon and suggests a different etiology. Prostate problems do occur and should not be confused with the above.
III. Orthostatism Orthostatic hypotension is defined as a reduction in blood pressure of at least 30 mmHg systolic or 15 mmHg diastolic after 3 minutes in the standing position. This occurs commonly in patients with advanced PD. When it occurs early, other diagnoses should be considered, particularly MSA. It should also be remembered that both levodopa and agonists can reduce blood pressure. Drug treatment is rarely effective.
1. 2. 3. 4. 5.
Rise slowly from sitting to standing position Raise the head end of the bed at night Elastic stockings may be tried Increase salt content in food Mineralocorticoid given as Florinef (fludrocortisone) 0.1 mg 1 x 2-3 daily
Falling tendency Frequent falls early in the course of PD are commonest in atypical parkinsonism, especially progressive supranuclear paresis (PSP), but they also occur in Parkinson's disease itself. Patients experience a tendency to fall most often in their best periods (on-periods), frequently developing in parallel to motor fluctuations or non-motor symptoms, such as cognitive weakness, which occurs later in the course of the disease. Many falls occur indoors, and injuries to the lower extremities are the most common, as patients are less able to check a fall due in part to reduced function in the arms. Injuries may be greater than normal as patients often fall full length. They are unaware of their stooped posture and will often lose their balance if they meet physical obstacles or become distracted in some way. Emotional influences will also worsen gait. It is characteristic in PD that balance suffers with changes in movements, such as starting, stopping, standing up, sitting down or turning round. Difficulty in starting a movement (freezing) most often suggests akinesia, and is seen in both PD and PSP. The reason for the variation in movement patterns is that changes due to the disease are localised to areas in the brain associated with higher motor control where cognitive functions also play a part in the ability to move. An important characteristic of this type of balance disorder is a reduced ability to adjust the movement to the circumstances or emotional changes. These problems may go unnoticed when examining a PD patient if the examination is limited to observation of the patient's natural gait as part of a traditional neurological examination. Examples of supplementary tests which may reveal postural instability are to ask the patient to stand up without the support of the arms (cross the arms over the chest), start and stop movements, and turn round. A Parkinson patient will often turn "en
bloc" which increases the risk of falling. It is also usual to test the patient's ability to check the tendency to fall by provoking retropulsion (pull test). In an abnormal test the patient will either fall or take several rapid steps backwards to avoid overbalancing.
Orthostatic hypotension: See section on orthostatism.
Postural instability: Balance is seldom improved by medication. Physiotherapy and instruction are useful. A walking aid or a wheelchair may be necessary.
Other medical causes: These are often found in older patients with multihandicaps. Early dementia, muscular weakness and sensory defects are common.
Environmental factors which can be remedied: Poor footwear, loose floor mats, doorsteps, poor lighting, etc.
Recommendation: • • • • • •
In cases of early falling tendency, consider causes other than parkinsonism. Examine the patient's ability to alter movement patterns and reaction to distractions in addition to the general neurological examination. Antiparkinson medication should be optimalised, but is seldom effective in treating gait problems. In some cases, medication can worsen gait, especially with drug induced dyskinesias, orthostatism or use of benzodiazepines. For freezing in off-periods, dopamine dose should be increased, and for freezing in on-periods (rare) it should be decreased. Daily physical activity such as going for walks etc. should be recommended to everyone. Many patients benefit from regular individual physiotherapy.
Sleep disorders Approximately 60% of all PD patients have problems sleeping at night and up to 40% may experience daytime hypersomnia. The commonest night time disturbance is insomnia with frequently interrupted sleep (sleep fragmentation), early waking or trouble initially falling asleep. Insomnia is most frequent in long term patients and is often associated with underlying depression. Recent studies show that depression and sleep disorders have a particularly negative effect on the quality of life of PD patients. Other sleep disorders: REM sleep behaviour disorder (RBD) (15 â€“ 30% of patients) in which patients can experience vivid dreams which they may act out during sleep, in some cases violently. The condition, which can be difficult to diagnose by history alone, usually responds well to clonazepam in small doses taken at bedtime. Hypersomnia (up to 40% of patients) which causes extra sleepiness during the day without improvement after sleep. Periodic limb movements during sleep (PLMS) (no definite percentage is available) which is often already present at the time of diagnosis. Sleep apnoea which is more frequent with increasing age. All sleep disorders can occur independently of the duration of the PD.
Recommendation: The causes of insomnia can be multiple and must be treated accordingly. A careful history (also from relatives) should be taken (sleep hygiene, nocturia, pain, off-phenomena, hallucinations, myoclonic jerks, etc.). Prescribing and dosage of sleeping pills should be somewhat restricted in these patients. Approx. 40% of PD patients also have depression and treatment of this can have a beneficial effect on insomnia (see section on depression). Sleep onset insomnia: Zoplicone (2.5-7.5 mg); Melatonin, 3 mg 2 hours before bedtime (special prescription). Sleep fragmentation and early waking: Mianserine (Tolvon) 10 mg (increased dose gives no increased effect). RBD: Consider withdrawing tricyclic antidepressant. Clonazepam (Rivotril), 0.25 â€“ 1.5 mg at bedtime; Melatonin, 3 mg 2 hours before bedtime (special prescription). Hypersomnia: Consider adjustment of dopaminergic treatment (reduction of dopamine agonists), Modafinil (Modiodal), 200-400 mg in 1-2 divided doses. PLMS: Symptoms usually disappear on starting dopamine treatment; 100-200 mg levodopa prolonged release at night as needed. Night time hallucinations: See section on neuropsychiatric problems. Night time myoclonic jerks: Reduction of dopaminergic treatment can be tried. Sleep apnoea: refer for sleep investigation.
Neuropsychiatric problems Many PD patients develop mental problems. At some point in the course of the disease, approximately 40% suffer depression, including both severe and mild conditions. Depression can be a psychological reaction to having a chronic illness, but there is much evidence that this is not the only explanation. Behavioural changes and anxiety are not rarely seen. Almost 20% of patients have psychotic symptoms, which is an important reason for nursing home admissions. In some cases, disturbances in impulse control, pathological gambling or altered sexual behaviour have been observed. The psychotic symptoms limit the possibility of optimal antiparkinson treatment. It is important for doctors treating PD patients to be aware that psychiatric complications which may arise during treatment. Most PD patients develop cognitive failure, including fluctuating attention, and over 50% develop dementia. The incidence of dementia increases with disease duration and higher age at onset of symptoms. In patients with cognitive failure, supplementary examinations such as cerebral CT or MRI scans should be performed to determine whether the dementia could be caused by anything other than PD. Dementia with Lewy bodies is a possible diagnosis in patients with parkinsonism and early onset of dementia. Non-pharmacological supportive measures are important for both the patient and family. However, drug treatment is often necessary for neuropsychiatric complications. Treatment of dementia in PD One should, in general, limit medication in PD patients with dementia, as these patients often develop side effects at relatively low doses. The non-pharmacological measures are the most important. Treatment with the cholinesterase inhibitor rivastigmine (Exelon) is relatively well documented and should be tried. Side effects such as gastrointestinal symptoms are common and parkinsonism may worsen in some patients. The effect may be difficult to evaluate, but the whole spectrum of neuropsychiatric symptoms associated with dementia in addition to memory, should be examined. If the condition can be stabilised, the treatment must be considered effective.
Recommendation: Rivastigmine: Starting dose 1.5 mg twice daily with gradual increase every four weeks to a maximum dose of 6 mg x 2. Therapeutic dose from 3 mg x 2. If side effects occur, rivastigmine patches or donepezil (Aricept) can be tried.
Treatment of depression in Parkinson's disease In addition to supportive treatment, depression in PD should often be treated with drugs. These should have the least possible side effects or danger of aggravating parkinsonism and the best possible effect on the depression. Documentation that such drugs exist is limited. After recent studies, the efficacy of nortriptyline (Noritren) is best documented. For many doctors, however, serotonin re-uptake inhibitors are still the first drug of choice in depression in PD. Of these, citalopram (Cipramil) is the best studied regarding interactions with, for instance, selegiline (Eldepryl). However, studies have shown that this treatment does not always succeed and combination treatment with noradrenergic drugs such as mianserine (Tolvon) may be tried.
Recommendation: Citalopram 10 mg (start with 5 mg for a few days). After 4 weeks, this can, if needed, be increased up to 20 mg daily. If the response is unsatisfactory after 1 month, citalopram should be combined with mianserine 10 mg in the evening, which can be gradually increased to 60 mg if necessary. Alternatively nortriptyline 25-30 mg initially, up to 150 mg.
Treatment of psychotic symptoms in Parkinson's disease Traditional neuroleptics with dopamine antagonistic effect are contraindicated in PD. New, atypical neuroleptics with a more powerful effect on serotonin receptors than on dopamine receptors seem to be the first choice in normal treatment of psychosis and have become the only alternative in management of psychotic symptoms in PD. Clozapine (Leponex) has long been used. Due to the risk of fatal leukopenia, a relatively demanding monitoring schedule with blood tests is necessary. This has limited the use of clozapine, although according to documentation and clinical use, it is the best treatment for patients with dementia associated with PD. Several other atypical neuroleptics have similar receptor profiles to clozapine. Of those registered in Norway today, quetiapine (Seroquel) seems to have the best receptor profile. Many doctors in Norway also have experience with olanzapine (Zyprexa). However, controlled studies now show that olanzapine may cause definite worsening of parkinsonism and also induce daytime somnolence. Similarly, risperidone (Risperdal) has been shown to aggravate parkinsonism. Quetiapine (Seroquel) has shown good tolerability in open studies, but placebo-controlled studies have not shown any significant effect.
Recommendation: Seroquel 12.5 or 25 mg in the evening. Can be increased if necessary to 50 mg or more. The maintenance dose will often be about 100 mg/day, sometimes higher. Alternatively, Leponex at the same dosage can be tried. If Zyprexa is to be used, start at 1.25 mg (half a 2.5 mg tablet) in the evening. If the effect is unsatisfactory, increase to 2.5 or 5 mg in the evening. To avoid sedation, doses should be kept low with all these preparations.
Nasjonalt Kompetansesenter for Bevegelsesforstyrrelser (NKB) The Norwegian Centre for Movement Disorders Stavanger University Hospital PO Box 8100 4068 Stavanger
Nyhetsbulletin 2 - 2009 - Revised Therapy recommendations for Parkinson's Disease