We are delighted to contribute an article on Parkinson’s disease to the April issue of the Hospital Professional News Ireland. This is especially as the month of April is dedicated to Parkinson’s disease awareness, and April 11 is designated as World Parkinson’s Day. In this article we highlight different aspects of Parkinson’s disease care. We begin with a historical note, to celebrate the memory of James Parkinson (born on this very day in 1755) and follow with some background information about the disease. We then focus on several special management considerations and conclude with an emphasis on the importance of patients’ education, research, and need for a disease-modifying treatment.
While the first descriptions indicative of Parkinson’s disease (PD) can be found both in historic Indian texts dating to 2500 BC and in ancient Chinese texts from 425-221 BC, PD seems to be also described in the non-medical literature: for example, in Shakespeare’s Henry VI: “why dost thou quiver man?” “the palsy and not the fear provokes me”, and other work for example by Leonardo da Vinci who described in his anatomical manuscripts “this appears clearly in paralytics… who move their trembling limbs such as the head or the hands without permission of the soul; which soul with all its power cannot prevent these limbs from trembling.”1-5
However, it was only 206 years ago, in 1817, when James Parkinson (1755-1824), a Londoner, and son of an apothecary and surgeon provided the first comprehensive medical description of the disease. In his Essay on Shaking Palsy comprising five chapters and 66 pages, James Parkinson described six patients (three of whom he observed from a distance) with the disease emphasizing its main characteristics such as insidious onset, slow progression, asymmetry, rest tremor, flexed posture, and festinating gait.
“Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward and to pass from a walking to a running pace: the senses and intellects being uninjured” (Parkinson, 1817) 6-7
Fifty years later Jean-Martin Charcot (1825-1893) from Hôpital de la Salpetriere in Paris distinguished an additional feature of bradykinesia in its characteristics: “their problem relates more to slowness in the execution of movement rather than to real weakness. In spite of tremor, a patient is able to do most things, but he performs them with remarkable slowness . . .” (Charcot, 1887) and renamed the disease as “maladie de Parkinson’s” (Parkinson’s disease).6,8
PD prevalence and diagnosis
PD is the most common cause of parkinsonism (a heterogeneous symptom complex characterized by tremor, bradykinesia, and rigidity), and the second most prevalent neurodegenerative disorder, following Alzheimer’s disease (AD).9
It is estimated that PD affects seven to ten million people worldwide, including 1.2 million of the European population alone. 9 One percent of people over the age of 65, rising to 4% above the age of 85, are affected.10
Approximately 15,000 people in the Republic of Ireland have the disease (Parkinson’s Association Ireland).11 With the aging population, the prevalence of PD is set to double by the year 2030.11 This poses a major socioeconomic burden, as not only direct costs are implicated, but also indirect costs, such as quality of patient’s life, family planning, and consequences of the loss of employment. The annual European cost of brain diseases is estimated at 798 billion euro, while PD alone costs 13.9 billion euro.11-12
PD remains an incurable, progressive condition with only symptomatic treatment available. It is postulated that multiple factors contribute to its pathogenesis. PD may be triggered by familial and environmental risk factors.11 Most cases are sporadic. Approximately 10% of patients have a family history of PD.12 PD is twice as prevalent in men as in women. It is important to distinguish PD from other forms of parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). However, this poses a significant challenge as the diagnosis of probable PD is clinical, based on the United Kingdom PD Society Brain Bank Clinical Diagnostic Criteria and/or International Movement Disorders Society Criteria, and symptoms between different types of parkinsonism frequently overlap, especially in the early stages when the misdiagnosis rate may be as high as 25% by non-expert secondary care physicians.13-14 While typical PD has an asymmetric, unilateral onset and is frequently accompanied by a typical hand tremor, in atypical parkinsonism the symptoms may be bilateral, and pill-rolling tremor is uncommon. PD is more benign and characterized by a good response to levodopa in comparison to the atypical parkinsonism group where the response to levodopa is poor and progression is much faster. Moreover, red flags for PD such as very early postural instability, or severe autonomic impairment should be considered as part of the atypical parkinsonism spectrum and are now incorporated into the diagnostic criteria.14 It is also important to differentiate neurodegenerative parkinsonism from drug-induced parkinsonism. While certain drugs such as neuroleptics may either cause drug-induced parkinsonism or unmask neurodegenerative parkinsonism, the former is typically associated with bilateral symptoms. A dopamine transporter (DaT) scan may aid in differentiation between the two, however, it does not help to differentiate between different types of neurodegenerative parkinsonism such as PD, MSA, and PSP.14
Currently, there is no diagnostic test for PD (a biomarker), and a definite diagnosis can only be achieved at a post-mortem examination showing degeneration of dopaminergic neurons in the brain area called substantia nigra pars compacta and build-up of proteinaceous inclusions called Lewy Bodies.15
Selected special considerations:
• Young onset PD
While PD prevalence increases with age, PD can also occur in younger individuals (young onset <50, juvenile onset <21).16 Younger age at onset is more commonly associated with genetic forms of PD. While it is worth considering genetic testing in any patient with a young onset PD and/or family history of PD, it is also worth noting that genetic test results may be negative. As more genes are being discovered, repeat testing should be considered, particularly as those with specific genetic forms of PD may be candidates for future disease-modifying therapeutic trials. Genetic counseling may be required as the risk of inheritance of several genetic forms of PD is 50%.16
Patients with certain genetic forms, for example, Parkin-PD, may have a more benign disease course than those with an idiopathic PD.16 Patients with Parkin-PD are usually more sensitive to small doses of levodopa/carbidopa and more prone to dyskinesia (involuntary, choreic/dance-like movements), therefore a slow medication titration is warranted (e.g. 50/12.5mg three times daily). While usually preferred to the “OFF” state, dyskinesia may cause embarrassment, and a detailed history should be elicited to assess the patient’s concerns.
Patients with young-onset PD may be at the peak of their professional careers. It is important to minimize the impact of the disease on work and activities of daily living (e.g., tremors on fine motor skills) through careful medication adjustments.
Pregnancy is another important consideration in this group, and while no dedicated clinical trials are addressing this topic, younger individuals may be relatively less affected at the onset of the disease (but not all) and those minimally symptomatic should be withdrawn from all PD medications if possible.
Unlike in other conditions, there is no diseasemodifying therapy, and treatment is only symptomatic, therefore, the withdrawal of treatment does not affect the disease course.
In a pregnant patient who is too disabled to be weaned off PD medications, levodopa/carbidopa at the smallest possible doses is considered to be the safest option, but expert opinion should be sought. In fact, the latest review on the topic recommends continuing levodopa/carbidopa throughout the pregnancy as the safest option with less clear data on other available treatment options.17
• An elderly patient with PD
The most important concern in this group surrounds the aspects of daily living and independence. Multidisciplinary approach is an even more vital component of PD management in the elderly than in any other patient group. An occupational therapist can aid in creating a safe home environment, a physiotherapist may aid in fall prevention and improvement of spatial awareness, and a speech and language therapist in speech exercises and swallowing assessment. Family support is invaluable.
Other special considerations in this group include frailty, polypharmacy, comorbidities, co-existent memory problems, hallucinations, and dementia. Medications should be rationalized as polypharmacy may contribute to falls and result in drug interactions. Importantly, MAOB inhibitors, amantadine, or dopamine agonists should not be used for treatment of PD in the elderly, especially in those with cognitive problems, or dementia (worsening).18 MAOB inhibitors such as rasagiline and selegiline are much less potent as a symptomatic therapy, can contribute to cognitive deterioration (selegiline is metabolized to methamphetamine), and may have serious interactions with other medications. Anticholinergics e.g., trihexyphenidyl should also be avoided in the elderly.18 In case of visual hallucinations, a careful medication history should be elicited (to look for an offending drug). A trial of a low dose of quetiapine can be given along with practical suggestions such as rearranging the home environment to remove visual cues causing confusion (e.g., removing coats on coat hangers which can look like people)
• Motor and Non-motor symptoms
While motor symptoms of PD such as tremors, slowness, and rigidity are the focus of each clinic visit, and the assessment begins while the patient makes their way into the clinic room, non-motor symptoms may not be as easily recognised. Non-motor symptoms not only contribute to the deterioration of the motor signs/symptoms but are frequently reported by the patients as the primary problem. James Parkinson noted in his “Essay” that the disturbances in sleep and bodily functions associated with bowels, saliva, speech, and swallowing occur in PD.7 The majority of patients with PD suffer from constipation. Daily bowel motion is vital for the appropriate absorption of oral symptomatic therapy. An increase in the dose of oral levodopa/carbidopa in a constipated patient will not provide symptomatic relief until bowel movement frequency improves. It is common for patients to fear the use of laxatives, and this topic has to be carefully explained.
Depression and anxiety are frequent comorbidities. Apathy is very prevalent and needs to be differentiated from the former two.19 While anxiety and depression may require treatment, it is important to note that apathy is part of the condition and has to be recognized in time to avoid overmedicating an apathetic patient with an antidepressant. Drooling of saliva is another nonmotor symptom that may cause major upset for the patient with PD. While oral atropine drops/ scopolamine patches may be useful in younger patients (<65 years old), these should be avoided in the elderly population due to the anticholinergic properties (worsening of cognition, and hallucinations). Three monthly botulinum toxin injections into salivary glands are a good alternative.
Non-motor manifestations of PD are presented in table 1. An adequate history must be taken in the clinic to address non-motor symptoms, as their presence may result in the deterioration of motor symptoms/signs of PD.
Hospitalization for another cause such as infection, fracture, or a procedure may contribute to a sudden deterioration in PD. Assessment of both motor and non-motor symptoms is equally important as discussed earlier. Hospitalizations are associated with two main risks:
1. Medications not being given on time or given with meals resulting in increased OFF time and erroneous assessments (a situation when the patient appears to be persistently OFF, the tablet was dispensed, but never actually taken).
2. Medications being abruptly stopped for surgery or when the patient is made nil per os.
Sudden withdrawal of all PD medications may result in a lifethreatening neuroleptic malignant syndrome characterized by fever, altered level of consciousness, severe bradykinesia, and rigidity. Levodopa/carbidopa should be immediately re-started. Morning doses of PD medications should be given pre-surgery and as soon as it is safe to do so after the surgery.
Neurology should be consulted for advice regarding the pre- and post-surgical management of complex patients. Patients being made nil per os should be considered on an individual basis. Younger patients without any history of impulsivecompulsive behaviors could be tried on a dopamine agonist patch (rotigotine), while elderly and those with cognitive impairment/ hallucinations should be considered for a nasogastric (NG) tube placement and switched to a levodopa/benserazide dispersible via NG (Madopar Dispersible) (better absorption than the crushed levodopa/carbidopa). The use of the dopamine patch in the elderly may result
As a result, antipsychotics, including those contraindicated in PD such as haloperidol, may then be given to counteract the psychosis leading to a chain of undesired events, which could be avoided by increasing awareness among prescribers. In certain cases, rotigotine patch can be used, but at the lowest possible dose and under close monitoring.
• First treatment conundrum
Levodopa has been the most effective symptomatic treatment for PD for over 60 years, however, its use has been associated with an increased risk of motor complications (MC) in the first five years of treatment (e.g., dyskinesia). 20,21 Dopamine agonists (DA) have a lower MC risk in the early years of therapy and have been considered a good alternative, especially in younger, more prone to MC, patients.22 It has been a frequent practice to use DA to delay levodopa use.
However, it is not known if this translates into any benefit later. Not only are DA less effective but they are also associated with significant side effects (sleep attacks, impulsive compulsive disorders, hallucinations, and confusion). In addition, the use of DA does not protect from dyskinesia once the levodopa is added and usually dyskinesia is preferable to patients than the OFF state. This conundrum has recently been investigated by the first author in the only study to date to evaluate the duration between levodopa-first and DA-first treatment and the development of MCs of sufficient severity to warrant consideration of deep brain stimulation (DBS) in 438 patients with PD.23 The duration between the first treatment to the assessment for DBS or DBS surgery itself did not differ between the groups. The results suggested that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment and delaying levodopa may not be indicated.23
It is important to mention that while some patients are sensitive to levodopa/carbidopa, others may need much higher doses and the dose should be gradually built up to a total of 1 gram (in divided doses) of levodopa to decide whether the patient is levodopa-responsive or not (a specialist may decide to build it to even higher doses).
• Advanced Therapies
Currently available advanced therapies include apomorphine subcutaneous infusion, levodopa/ carbidopa or levodopa/carbidopa/ entacapone intestinal gels and deep brain stimulation (electrodes are placed in either subthalamic nucleus or globus pallidus internus and are connected to an implantable pulse generator located below the clavicle).24-26 DBS parameters can be programmed using a wand to optimize the response. Patients still need to be on symptomatic therapy, but this can be significantly reduced.
Advanced therapies may help reduce unpredictable motor fluctuations by continuous delivery of medication, result in an improvement of OFF symptoms, and help to reduce significant side effect profiles. While DBS used to be considered in more advanced disease, more recently, there has been a shift toward its earlier use. 24-26 While Irish patients have been assessed pre- and post-DBS in Dublin, they still had to travel for surgery itself to the United Kingdom or Northern Ireland until recently when the National DBS Center was established at the Mater Misericoridae University Hospital, Dublin. Advanced therapies are very effective in managing symptoms but are not without possible complications. DBS is a neurosurgical procedure, intestinal gels are delivered through jejunostomy (and require a small procedure), and apomorphine is a dopamine agonist (although very effective as an advanced therapy).
In addition to the management of motor and non-motor symptoms, it is important to advise patients about the beneficial role of physical therapy and exercise. Regular exercise positively impacts coordination, spatial awareness, and rigidity in PD.
• Biomarkers and Diseasemodifying trials (research)
Although the research field has been very active, currently, there is no reliable diagnostic biomarker for PD available. As discussed earlier, the diagnosis of probable PD is clinical, heavily relying on the clinician’s skill set. Establishing the correct diagnosis would significantly improve the patient’s quality of life, delivery of prognosis, and recruitment into disease-modifying trials. To date, the development of diagnostic tests capable of differentiating PD from similar clinical parkinsonian syndromes has been challenging.
Therapy in PD is advancing slowly. So far, all disease-modifying trials to date have failed. This is partially due to the lack of diagnostic biomarkers and the high misdiagnosis rate (and enrollment of misdiagnosed patients into clinical trials). Change of perspective and intense research is vital in developing a diagnostic test for PD.
• Hospital staff and patient education
Education is a crucial step in achieving optimum care for patients.
This applies to nursing staff (medication on time in a busy hospital setting), physicians (assessment of both motor and non-motor symptoms), and patients (improved awareness) alike.
A survey assessing knowledge of PD among 100 PD patients/family members conducted by the first author in one of the Irish hospitals, demonstrated that 30% of patients believed a cure was available, 41% were convinced DBS was curative, and 50% did not know PD could be hereditary. Fifty-one percent of family members mistake apathy for depression (unpublished data). In another survey, PD patients were asked to identify factors worsening their disease. Those with constipation identified constipation as the most important factor (46%), followed by stress, irregular timing of medication, and sleep deprivation; while those without constipation identified stress as a predominant factor (74%), followed by the irregular timing of medication, lack of exercise, and sleep deprivation.28
PD is a complex neurodegenerative condition affecting all ages. The diagnosis remains largely clinical although much work is being done to identify suitable biomarkers. Management of PD requires specialist knowledge of medication and advanced / device-led therapies as well as input from a multidisciplinary team and community rehabilitation facilities. Education, comprehensive patient care, and patient participation in research will help move the field toward discovery of a diagnostic test and development of a successful disease-modifying therapy.
References available on request
Written by Diana Angelika Olszewska MD, PhD; Aisling M Ryan, MB, PhD Affiliations: National Neuroscience Centre, Cork University Hospital, Cork/ University College Cork, Ireland Corresponding author: email@example.com