Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
forum distance learning programme in association with the ICGP study lea v e ved pro ap hours study le a e ap v Neurology 2 Management of Parkinson’s disease Module 177: May 2012 pro ved Management has improved considerably over the past two decades with the introduction of new therapies and better utilisation of older ones offering more options for dealing with symptoms (This module was facilitated by Drs Sarah Moran and Christina Donnellan) Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disorder of unknown cause. It is characterised by a resting tremor, rigidity, bradykinesia (slowness of movement), and postural instability. The mean age of onset of PD is 57 years1� and it affects 1-2% of the population over 60 years of age. Quality of life is most affected by mental problems, gait disorders and complications of dopaminergic medications.2 Dementia is diagnosed in 69.6% of patients3� and develops after years of disease.4,5 The pathogenesis of Parkinson’s disease is likely to be multifactorial. Some 10-15% of patients have a family history, which suggests that PD may be inherited. Eleven genetic forms of the disease have been described to date. The motor impairments of Parkinson’s disease result from selective loss of pigmented mid-brain neurons in the substantia nigra pars compacta. Diagnosis The most important investigation is clinical examination. Patients must have bradykinesia in addition to one of two other cardinal signs – tremor or rigidity. A response to acute challenge testing with dopamine therapy is also supportive. Routine bloods and imaging, ie. CT brain, are not routinely required for diagnosis. However, it can be used if there are atypical features to exclude a structural abnormality, ie. normal pressure hydrocephalus. Striatal dopamine transporter imaging using SPECT (DAT scan) can help distinguish patients with PD and other Parkinson plus syndromes from patients with parkinsonism (ie drug induced) or essential tremor.6,7 Clinical features that suggest a diagnosis other than PD include a history of encephalitis, head injury, recurrent strokes, stepwise progression, rapid progression, use of antipsychotic medication, abnormal CNS imaging, cerebellar signs, supranuclear gaze palsy, dementia preceding or occurring concurrently with parkinsonism, apraxia, or strictly unilateral signs after three years. Features suggestive of an alternative cause for parkinsonism8 (ie. multisystem atrophy, progressive supranuclear DL May/Parkinsons-NH 1 palsy, corticobasilar degeneration and dementia with Lewy bodies) rather than PD include falls at presentation, a poor response to dopamine, symmetrical motor signs, rapid progression, a lack of tremor and early dysautonomia. There is increasing evidence that non-motor symptoms such as loss of the sense of smell, sleep problems, sweating, fatigue, constipation, mood change and muscular symptoms may be early signs and an index of suspicion is required. Pharmacological treatments The main medications available for symptomatic therapy include levodopa, MAO-B inhibitors, dopamine agonists and COMT inhibitors (see Table 1). Levodopa, MAO-B inhibitors or dopamine agonists (DA) can be used as first-line treatment for PD in patients who require symptomatic therapy. The choice depends on the degree of functional impairment and comorbidities. In younger patients a levodopa-sparing strategy can be a reasonable approach depending on circumstances. Practitioners should always try to find the lowest effective dose of dopaminergic medication, either singly or in combination, for patients with PD. It is essential that each PD patient be evaluated and managed in a highly individualised manner. Levodopa Levodopa is established as the most effective drug for the treatment of PD. Tremor and rigidity may also respond to levodopa therapy, but postural instability is less likely to do so. Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. When commencing levodopa, it is important to begin with small doses, titrating slowly upwards (over weeks) to allow for tolerance and to minimise side-effects with an aim to use the lowest dose levodopa that produces symptomatic 27/04/2012 15:04:09 DISTANCE LEARNING Parkinson’s disease Table 1 Common pharmacotherapy for Parkinson’s disease Generic name Trade name Starting dose Maximum dose Carbidopa/levodopa Sinemet 12.5/50mg 25/250mg 8/day Levodopa/carbidopa/ entacapone Stalevo 50/12.5/200mg 200/50/200mg 7/day Levodopa/benserazide Madopar 62.5mg 250mg Mechanism of action Dopamine precursor/dopa decarboxylase inhibitor Dopamine precursor/ dopa decarboxylase inhibitor/COMT inhibitor Dopamine precursor/ dopa decarboxylase inhibitor Rasagiline Azilect 1mg OD 1mg OD Selegiline Eldepryl 5mg 10mg OD MAO-B inhibitor Entacapone Comtess 200mg Max 10/day with levodopa COMT inhibitor Pramipexole Mirapexin 0.088mg 3.3mg Rotigotine Neupro 1mg patch 8mg patch/day Dopamine agonist Ropinirole Requip 0.25mg 24mg/day Dopamine agonist relief. Absence of a response to escalating doses of levodopa is suggestive of an alternative diagnosis to PD. An adequate trial of dopamine therapy is defined as 1,000mg/day for at least one month.9 Controlled or sustained-release levodopa preparations are less completely absorbed and require a dose up to 30% higher to achieve an equivalent clinical effect. The peak clinical effect of each tablet is typically less than for immediate-release preparations, since controlled-release formulations reach the brain more slowly over time. Therapy should be started with an immediate-release preparation with a subsequent switch to controlled-release if desired. Controlled-release medications are usually used in circumstances such as an overnight medication. Nausea can be treated with domperidone. Metoclopramide and prochlorperazine should be avoided as they are dopamine receptor blockers and can therefore aggravate parkinsonism. MAO-B inhibitors Rasagiline and selegiline are selective monoamine oxidase (MAO) type B inhibitors. They are effective as first-line and adjunctive treatments for PD for both motor complications and motor fluctuations,10,11� and may have neuroprotective properties. Evidence suggests that early use can delay need for levodopa therapy and disability progression. The adverse effects include nausea, headache, insomnia and confusion in the elderly. MAO-B inhibitors are contraindicated with concomitant use of MAOIs. Dopamine agonists The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. They include bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine. DAs can be used as either first-line or adjunctive treatments for PD. As an adjunctive treatment they are useful for treatment of: Irreversible MAO-B inhibitor Selective dopamine agonist • Reduced levodopa response • Motor fluctuations • Dyskinesia • Other adverse effects of levodopa. The choice of DA depends on comorbidities and preferred route of administration (ie. oral or topical). Adverse effects include nausea, vomiting, somnolence, orthostatic hypotension, confusion, hallucinations, peripheral oedema and constipation. Somnolence can occur abruptly and without premonition, particularly at a dose above 1.5mg/day. Patients with PD who drive are at particular risk of developing these ‘sleep attacks’.12 Patients should be warned of this potential sideeffect and asked about factors that may increase the risk of drowsiness, such as concomitant sedating medications and sleep disorders. DAs may be associated with an increased risk of impulse control disorders including pathological gambling, compulsive sexual behaviour or compulsive buying.13,14� Patients with a history of cognitive impairment or psychiatric illness may experience a deterioration in these comorbidities with DA therapy, and they are therefore usually not used as firstline treatments in this setting. Adverse effects of DAs can usually be avoided by initiating treatment with very small doses and titrating to therapeutic levels slowly over several weeks. In order to reduce sideeffects, patients can be prescribed domperidone to reduce nausea at treatment commencement. Patients intolerant to one DA may tolerate a different DA. Some patients can experience a ‘dopamine agonist withdrawal syndrome’ if they abruptly stop taking a DA.15 Symptoms of withdrawal include anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving, and these symptoms are refractory to other antiparkinsonian medications, including levodopa, only responding to a resumption of the DA. Apomorphine is used in specialist centres as a treatment for disabling motor fluctuations that persist despite adequate levodopa and dopamine agonist treatment. It FORUM May 2012 DL May/Parkinsons-NH 2 27/04/2012 10:45:42 DISTANCE LEARNING Parkinson’s disease Figure 1 Management of Parkinson’s disease: pharmacological approach DIAGNOSIS Provide education upon diagnosis and monitor for functional impairment or failure to cope. Consider referral to consultant neurologist or geriatrician with an interest in PD on suspicion of diagnosis Consider: Dopamine agonist (non-ergot/ergot*) Consider: MAOB-I (rasagiline/selegiline) Monitor for two or more cardinal signs affecting daily function or psychological impact: rest tremor, rigidity, bradykinesia, poor balance, freezing of gait, stooped posture and gait disturbance. When commencing medication, consideration of patient’s age, lifestyle, personal preference and circumstances are essential Consider: Amantadine# Consider: **Levodopa +/- entacapone (QDS recommended) Monitor for symptom relief in both motor and non-motor symptoms using UPDRS~, ‘wearing off’ questionnaire and non-motor questionnaire. Observe for motor fluctuations, wearing-off and dyskinesia Consider: **Levodopa +/- entacapone (QDS recommended) Medications may be adjusted, added or removed from an individual’s regime throughout the course of the disease Tolcapone protocol must be followed. Prescription indicated if patient is unresponsive to entacapone. Liver function tests every two weeks Consider: Surgical option (deep brain stimulation) Consider (if not already prescribed): MAO-B inhibitors (rasagiline/selegiline) Consider (if not already prescribed): Dopamine agonist (non-ergot/ergot*) Consider: Tolcapone (COMT inhibitor) Consider: Apomorphine (subcutaneous pen injection or pump infusion) The following options can be added in during treatment: • Amantadine (dyskinesia, tremor, rigidity) • Diazepam (anxiety, aggravated tremor) • Akineton/kemadrin*** (predominant tremor) • Laxatives/high-fibre diet (constipation) • Modafinil (daytime sleepiness) • Antidepressants SSRIs/SNRIs (depression) • Quetiapine/clozapine (hallucinations) • Acetylcholinesterase inhibitor/memantine (cognitive impairment/dementia) • Clonazepam (REM sleep behaviour disorder) Consider: Levodopa/carbidopa gel (via PEG infusion pump) *Caution: monitor for cardiac valve fibrosis (cabergolide and pergolide) ** Take half an hour before food if tolerated *** Caution in elderly or cognitively impaired # Watch for ankle and leg swelling, leg rash, hallucinations and postural hypotension ~Unified Parkinson’s Disease Rating Scale Adapted from the Management in Parkinson’s disease: Pharmacological approach 2nd edition 2010 by Prof Timothy Lynch and Mr Brian Magennis is usually commenced under nursing supervision with a challenge test and blood pressure monitoring. It must be commenced under antiemetic cover with domperidone. Concomitant use of ondansetron is contraindicated as it may lead to hypotension. COMT inhibitors The catechol-O-methyl transferase (COMT) inhibitor entacapone (Comtess) is useful as a levodopa adjunct therapy. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose ‘wearing off’ periods. They should be given at the same time as levodopa therapy and in order to facilitate compliance and reduce pill burden they are usually prescribed as a combination medication (levodopa/carbidopa/entacapone, Stalevo). Inhibition of catechol-O-methyl transferase reduces the peripheral methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. Use of COMT inhibitors may allow a reduction in the total daily levodopa dose by as much as 30%. The net result is an increased levodopa effect. Adverse effects include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension and diarrhoea. Amantadine Amantadine is an antiviral agent that has mild antiparkinsonian activity.16 Its mechanism of action is uncertain. It is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects. The dose of amantadine is 200-300mg daily. The main advantage of this agent is a low incidence of side-effects. It is excreted unchanged in the urine. Peripheral side-effects include livedo reticularis and ankle oedema, which are rarely severe enough to limit treatment. FORUM May 2012 DL May/Parkinsons-NH 3 27/04/2012 10:45:50 DISTANCE LEARNING Parkinson’s disease Pharmacological summary Initial treatment of early PD and motor symptoms includes some therapies first line. Levodopa may be prescribed in combination with a dopa decarboxylase inhibitor, monoamine oxidase inhibitors or topical levodopa.17 Suggested treatment regimens include those as outlined in Figure 1, while typical starting doses of medications are outlined in Table 1. An individualised approach should be taken, particularly in relation to the introduction of levodopa. Some agents have shown promise as neuroprotective treatment strategies but more research is needed. Non-pharmacological treatments These include regular exercise, physiotherapy, dietetics, patient education and support. There are also surgical options including deep brain stimulation. Non-motor features of Parkinson’s disease Hallucinations and psychosis Parkinson’s disease psychosis (PDP) is a common complication of PD. It is usually manifest by visual hallucination and delusions. Sixty per cent of PD patients develop hallucinations or delusions, with an incidence rate of 79.7 per 1,000 person years.18 Risk factors for PDP include older age at onset, higher baseline levodopa requirements and REM sleep disorder at baseline (abnormal behaviour during REM sleep, including physically acting out vivid dreams). In the setting of new onset of hallucinations or psychosis in a patient with PD, an assessment for delirium should be made and underlying cause addressed. Hallucinations may also be a feature of PD dementia. All medications should be reviewed and stopped as appropriate (ie. anticholinergics, opioids). Cessation of PD medications is usually not a viable option, but dose reductions can help.19 Atypical neuroleptics such as quetiapine and clozapine are useful if dose reductions provide insufficient benefit, or symptoms are debilitating.20,21 Quetiapine and clozapine cause less deterioration in parkinsonism than risperidone, olanzapine and typical neuroleptics (ie. haloperidol). Clozapine use in practice is limited by the need for frequent haematological monitoring (risk of agranulocytosis). A recent study showed that 50% of patients diagnosed with PD were prescribed an antipsychotic, with quetiapine the most frequently prescribed (66%) and clozapine the least frequently prescribed (2%).22 Depression Depression is the most common psychiatric disturbance seen in PD.23 It is generally mild to moderate in severity. Major depression occurs in less than 10% of patients with PD.24 However, despite its high prevalence, depression in PD remains undertreated.25 It can be difficult to recognise depressive features in PD as blunted affect and psychomotor slowing can mimic the bradykinesia and mask like facies of PD. Somatic features of depression, including reduced appetite and concentration, can occur in PD patients without depression.26 Clinical features that can be helpful are low mood and anhedonia. Guilt and feeling of worthlessness occur with less frequency in the PD population. Suicide occurs at the same rate as the general population.27 To date, there appears to be no clear consensus with regard to the antidepressant of choice in the treatment of PD-associated depression. Amitriptyline was recommended by the American Academy of Neurology in their 2006 report based on evidence available at that time. Caution was recommended when prescribing due to a possible increase in postural instability. Other reviews suggest commencing SSRIs as first-line therapy. The first randomised trial of antidepressants in PD was published in April 2012. It found that both paroxetine and venlafaxine significantly improved depression, were safe, well tolerated and did not worsen motor function.28 There are, however, theoretical concerns with the prescription of SSRIs in the setting of PD. The manufacturers of selegiline have issued warnings about the possibility of developing a serotonin syndrome in event of co-prescription of selegiline and SSRIs. Daytime somnolence Excessive daytime sleepiness is common, affecting 74-98% of patients.29 Pharmacological treatments have not been shown to be effective to date. Measures used include nocturnal sleep hygiene. Autonomic dysfunction Autonomic dysfunction occurs with less frequency in PD than it does in multisystem atrophy. Features include orthostatic hypotension, urinary frequency and urgency, dysphagia, diaphoresis and sexual dysfunction. Constipation Constipation is a common clinical problem which is managed with laxatives. It can cause deterioration in motor symptoms from reduced levodopa absorption. Conclusion PD is a progressive neurodegenerative condition resulting from the death of the dopamine-containing cells of the substantia nigra. The diagnosis is primarily clinical, based on a history and examination. Management is individualised. Sarah Moran is a specialist registrar in general internal medicine/nephrology and Christina Donnellan is a consultant geriatrician at South Tipperary General Hospital, Clonmel Co Tipperary Acknowledgements: The authors would like to thank Prof Timothy Lynch and Mr Brian Magennis for allowing us to reproduce their diagram The management of Parkinsons Disease, Pharmacological approach. References on request FORUM May 2012 DL May/Parkinsons-NH 4 27/04/2012 10:45:58