Parkinson’s disease

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9 Parkinson’s disease

Introduction

Parkinson’s disease (PD) was first described by James Parkinson, the English physician after whom it was named, in his monograph on the ‘Shaking Palsy’ in 1817.1 While it occurs in 0.3% of the general population this climbs to 1% of those 60+ years old2 and up to 3% in patients aged at least 80 years.3

It is a progressive degenerative neurological disorder characterised by a tetralogy of symptoms, including tremor, rigidity, bradykinesia and postural instability.4 The pathological features are loss of dopamine-producing neurons from the substantia nigra in the brainstem and other brainstem nuclei,5 together with Lewy bodies (ubiquinated protein deposits in the cytoplasm of neurons) and Lewy neurites (thread-like proteinaceous inclusions in neurites).6,7

Most general practitioners are less concerned with pathophysiology of the illness and much more concerned with diagnosis and treatment. What follows is a coalface clinician’s approach to diagnosing and treating PD. While the above provides a scientific backdrop to PD, the purpose of this chapter is to alert the general practitioner to proper management.

PD is diagnosed on the basis of history and examination, rather than any specific blood test.8 The 2006 United Kingdom clinical guidelines suggest that PD requires specialist confirmation of diagnosis and subsequent follow-up.9 While there is good argument for the involvement of a neurologist, PD is a chronic illness with a predictably progressive decline so optimal care dictates a partnership between the specialist and general practitioner. As with all chronic illnesses, ideal care must accommodate lifestyle factors, careers and demonstrate an empathic approach, which is the forte of the general practitioner who is often more closely aligned with the patient and the home environment.

While the exact cause is unknown, a variety of genes have been identified from PARK1 at locus 4 q2110 through to PARK13 at locus 2 p1211 and the list is continuing to expand. This has special relevance when PD occurs in young patients, especially those younger than 50 years. It is hard to organise the tests in Australia but any condition with a potential genetic basis mandates discussion. The majority of cases of PD are sporadic and hence counselling will probably not alter the prevalence.

There was a major outbreak of Parkinsonism after the influenza epidemic (with encephalitis lethargica) in the early twentieth century, when lesions in the substantia nigra became apparent.12 Nevertheless the role of environmental factors was not fully appreciated until the 1980s when MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a by-product of synthetic opiate MPPP, a meperidine analogue designer drug, was reported to cause acute Parkinsonism in drug addicts in California.13 Since then it has been acknowledged that pesticides may cause Parkinsonism,14,15 thus various potential toxins can be avoided.

One may also consider lifestyle issues thought to protect against PD, such as smoking or taking of Chinese green tea,16,17 although smoking has sufficient other reasons to be avoided.

What follows is an idiosyncratic approach to the diagnosis and treatment of PD. It does not follow some of the rules endorsed by many ‘Parkinsonologists’ but after considerable clinical experience it has proven effective and is provided as one possible way to manage the disease.

Making the Diagnosis

As with all diagnoses in neurology, the diagnosis starts with a high index of suspicion and a detailed history. Often ‘the penny drops’ when calling the patient to come into the consultation. The patient is slow to respond to the call; has difficulty rising from the chair, especially if that chair is low; and will be slow to walk into the consultation room.

Critical observation will reveal that the patient has a paucity of movement, is somewhat bent forward rather than standing erect, and may take smaller steps than is usual for their age group. The face is often expressionless, looks younger than that of chronological peers, and there is reduced blinking. The patient often doesn’t swing both arms when walking (but may swing one arm) and appears to be shuffling along rather than taking discrete steps. The alternative may be the patient about to be called into the consultation room, seen sitting in the waiting room appearing to be somewhat bored, with a slow ‘pill rolling’ tremor of one hand. This seems to stop as soon as the patient realises it is their turn to see the doctor, and they may use that ‘shaking’ hand to push up from the chair to walk into the room and in so doing the ‘shaking’ stops.

It can be seen that in the classical case the diagnosis has been offered on a platter, even before the patient has entered the consultation room when the formal process is supposed to start. The corollary of this is that one has to be acutely aware of what is on the platter to realise that the diagnosis is being offered, otherwise it may be missed and rely on someone else to show superior clinical acumen.

Taking a History

Patients with PD will present with a number of initial complaints, which may be as vague as a feeling of ‘slowing down’ to a complaint of falling without cause, or of shaking. There are no prizes for diagnosing the classical case with the patient having the obvious Parkinsonian tremor and those features described above. Skill is required to tease out early cases, especially if one believes in early treatment, something that remains quite controversial but is a personal preference.

Once suspicion has been aroused, there is a series of mandatory questions to seek out the early symptoms that even the patient may not have identified without prompting. Patients with early PD may have trouble turning over in bed at night; they may have difficulty rising from a low sofa; or getting in or out of a car, especially a low-slung car such as a convertible. They may complain of difficulty initiating gait because they are afraid of falling over. Some may report falling when they turn quickly or losing their balance and being unable to regain stability, although they were able to do so previously. Symptoms of feeling stiff, which may translate as ‘feeling funny or heavy in the limbs’, may be confirmed if actively sought.

PD has been staged by Hoehn and Yahr4 (see Table 9.1) as starting with unilateral symptoms and signs through to serious disability. As the condition progresses a patient may report speech changes with softer, monotonous speech, possibly complicated by excessive dribbling or drooling. Patients may have problems initiating gait, having what is called ‘inertia’. These patients may report that they cannot get started when they want to walk but once they get going they seem to gain speed, even starting to run without wanting to, and may have difficulty stopping. They might develop techniques to stop, such as selecting a fixed object like a wall and walking into it to slow down their centre of gravity that they have been chasing.

TABLE 9.1 The Hoehn and Yahr staging of Parkinson’s disease

Stage 1 Unilateral symptoms and signs
Stage 2 Bilateral symptoms and signs
Stage 3 Bilateral features with impaired postural reflexes causing disability
Stage 4 Severe gait disturbance though still able to stand and walk without aids
Stage 5 Inability to stand or walk without aids, wheelchair or bed-bound

Posture, being bent in the middle and unable to stand up straight, may be a major symptom. Writing may be difficult, either due to the imposition of the tremor or patients may report their handwriting has become smaller, veering up and off the horizontal, hence becoming difficult to read even without tremor.

Often the patient will present with the complaint of tremor and will suspect the diagnosis of PD. Benign essential tremor is far more common than is PD, and the patient will be greatly relieved if given this diagnosis. It is therefore important to have simple tools with which to compare the two most common causes of tremor (see Table 9.2). A patient with PD may have both an essential and a PD tremor.

TABLE 9.2 Differentiating Parkinsonian tremor from essential tremor

Characteristic Parkinson’s disease Benign essential tremor
Tremor location Hands, legs, circumoral Hands, head (titubation), voice
Laterality Usually unilateral at onset Usually bilateral
Bradykinesia + –
Rigidity + –
Family history Usually – + in ≥ 50%
Effect of alcohol – + (reduces tremor)
Age of onset Usually > 60 years Younger, ~40 years
Timing of tremor At rest (when distracted) With activity (rarely at rest)

More recently there has been a realisation that PD may be associated with symptoms that transcend the motor features. These include neuropsychiatric symptoms, sleep disorders (such as REM sleep behaviour disorder), autonomic symptoms and sensory symptoms.18 Impulsivity, increased gambling and antisocial behaviour have been associated with PD and its treatment.19 The term ‘punding’ with associated compulsive sequenced behaviour is associated with PD. Impotence is reported by up to 60% of men with PD.20

It can be seen that there are many questions needing to be asked, both to assist with the diagnosis and with defining the extent of the illness and its impact on the patient’s life.

Examination

In the section above ‘Making the diagnosis’, many of the early features have already been described and should be apparent even before starting the formal consultation. From these findings and corroboration based on the history, the doctor can steer directly towards the signs to be displayed.

The tetralogy of principal features is well accepted (see Box 9.1) and available for examination. Working from the head downwards, the features include: positive glabellar tap (tapping the patient over the forehead above the bridge of the nose should only illicit three blinks—more than this is considered positive); paucity of blinking; difficulty with upward gaze; cog-wheeling of saccadic eye movements; decreased facial wrinkling with increased sebum in the skin, giving an oily appearance and looking younger than actual age; increased drooling; soft voice devoid of intonation; expressionless face; and possibly a posture with the head somewhat flexed forward. The patient may well have a positive palmar mental response (scratching the patient’s palm may elicit movement of the ipsilateral jaw, via the mentalis muscle) and is concurrent with other frontal lobe signs such as grasp reflexes.

Box 9.1 Tetralogy of principal features of Parkinson’s disease

1 Tremor
2 Rigidity
3 Bradykinesia
4 Postural instability

In the early stages of the disease tone may seem superficially normal. Once the patient is distracted, such as asking the patient to turn the head from side to side, it will exacerbate the increased tone, feeling like a lead pipe. With the superimposed tremor, this may feel like a cogwheel going over the cogs. To elicit this response the doctor flexes and extends the hand at the wrist while asking the patient to turn their head from side to side. This increases the tone as it allows the expression of resting tone. Without distraction the patient often tries to help, even without being aware of it (see Fig 9.1). In some cases there may be the need for further distraction, such as waving the contralateral arm.

image

FIGURE 9.1 Provoking leadpipe and cogwheel rigidity in a patient with Parkinson’s Disease.

The patient may adopt a stooped posture and have failure of righting reflexes in which they are incapable of correcting for propulsion or retropulsion. This is explained by an inability to spread the centre of gravity once balance has been disrupted, due to stiffness of the joints, especially the hips. Hence, following loss of balance, the patient will often fall down. The patient may have inertia of gait, again due to fear of falling once the centre of gravity has been disturbed. A ‘trick’ to initiate walking is to ask the patient to step over a dropped object, such as a pen or piece of paper. Performing the task of stepping over the pen automatically moves the patient forward and they can then continue in the same direction because the centre of gravity has likewise moved forward.

Festinating gait is a further expression of the fear of moving forward with the patient stepping on the spot, thereby retaining the position of the centre of gravity. Having moved forward, the patient may have a shuffling gait with small steps and have difficulty turning, such that the turn is made by small steps, called ‘turning by numbers’.

Differential Diagnosis

The differential diagnosis of PD includes a variety of other neurodegenerative diseases, such as atypical Parkinsonisms, including progressive supranuclear palsy; multiple system atrophy; autonomic type (Shy-Drager syndrome); olivopontocerebellar atrophy; and corticobasal degeneration. Other conditions to be considered include Alzheimer’s disease with extrapyramidal signs; Lewy body dementia (LBD); Huntington’s disease; Wilson’s disease; calcification of basal ganglia and Creutzfeldt-Jakob disease.

A number of acquired diseases also need to be considered, such as carbon monoxide poisoning, carbon disulfide poisoning and methanol intoxication. Other conditions, such as subcortical vascular disease, tumours, subdural haematomas and anoxic brain injury are included in the differential. Drug effects, as may accompany psychotropic antipsychotic neuroleptic medications, such as phenothiazine, can evoke the extrapyramidal features seen in PD.

Features that favour illnesses other than PD include: symmetric onset; early gait disturbance or falling; non-responsiveness to agents such as L-dopa; severe disability within five years; and stepwise progressive disorder or sustained remission. Some clinical signs, such as cerebellar signs, lower motor neurone features, and features typical of the above-cited differential diagnoses, also make PD less likely.

In his initial description of PD, Parkinson felt that cognition remained unimpaired but this is not accurate, although early onset dementia makes PD less likely and favours LBD.

One of the simplest diagnostic tools for PD, as compared with Parkinsonism, is a trial of therapy with L-dopa. The response with PD is excellent while that for ‘Parkinsonism’ is poor.

Treatment

The approach to treatment of PD that follows reflects an idiosyncratic approach, as explained earlier. It may be at odds with what many advocate but has proven efficacious, at least from the view of the author.

a Levodopa

Since the 1960s when levodopa (L-dopa) benefits were first recognised,21 L-dopa has become the gold standard of PD therapy.22 There is a dichotomy as to whether one starts this early or waits. Many experts prefer to wait until the condition is fully apparent, arguing that L-dopa may have a finite period of possible effect after which the potency is diminished. This is contrary to personal view and is not the course personally adopted. The patient is referred because symptoms are affecting quality of life, which should improve with treatment. This translates into a personal choice to start therapy early after diagnosis.

L-dopa is provided either in combination with carbidopa or benserazide (Sinemet® or Madopar® respectively). Both carbidopa and benserazide are peripheral dopa decarboxylase inhibitors (DDI). They act by reducing the peripheral metabolism of L-dopa, which translates into more L-dopa crossing the blood–brain barrier (BBB). This, in turn, means that less L-dopa need be administered. L-dopa is used because dopamine does not cross the BBB and L-dopa is metabolised to dopamine after crossing it, replacing failing dopamine stores.

Personal preference is to start low and go slow (SLGS), starting with a 100 : 25 combination of either Sinemet® or Madopar® with half b.d. as the initial dose. This often produces significant benefit and can be maintained at this low level for a period of years. Early in the disease process the response to L-dopa lasts longer than later in the disease, thereby allowing small doses to give prolonged benefit.

To properly use the carbidopa or benserazide there has to be enough of it to make a difference. Initially Sinemet® was produced in a 1 : 10 ratio of carbdopia:L-dopa (while Madopar® adopted 1 : 4 ratio (of benserazide:L-dopa). Subsequently it was realised that the 1 : 4 ratio was more effective and hence it was adopted for Sinemet®, while still offering the 1 : 10 ratio as an alternative. Unfortunately some still use the 250 : 25 formulation, often to the patient’s detriment.

The best tools to judge efficacy are the patients themselves. It is important to note their ability to get out of the chair in the waiting room, the gait while walking to the consultation room and their facial expression (namely, the ability to smile). The primary ‘quality of life’ question, ‘How are you?’, will clinch it, as patients become acutely aware when things start deteriorating.

Once symptoms progress, the dosage of Sinemet® or Madopar® can be increased to one b.d. but, if symptoms progress to the point of requiring more than one b.d., personal preference is to add a second agent rather than chase L-dopa dosages.

L-dopa is not without side-effects and is known to activate malignant melanoma. It can react with other agents, such as antihypertensives, causing postural hypotension but can also do this in its own right. One of the reasons to SLGS is the potential to cause dyskinetic movements, and one may be forced to reduce dosages of L-dopa because of this troublesome side-effect. This is less common when using the low doses as recommended above, until one is forced to chase symptoms as the condition deteriorates.

Other than involuntary movements, other adverse effects include nausea, vomiting, diarrhoea, constipation and rash, which attach to every medication. Mental changes may be experienced, including paranoia, psychotic hallucinations and delusions, and can be of sufficient intensity to preclude its use. Cardiac irregularities and orthostatic hypotension can also be quite intrusive, dictating cessation of use, especially if given in combination with selegiline (discussed below). Special precautions are also advised in patients known to have glaucoma.

b Selegiline

Selegiline has largely fallen out of favour. It is a selective monoamine oxidase-B inhibitor (MAOBI). Rasagiline is another within this family but it is not available in Australia. Examination of ‘MIMS Annual’ states that ‘… Monamine oxidase inhibitors (MAOIs) and Sinemet® should not be given concomitantly’. It is accepted that the combination of L-dopa and Eldepryl® ‘may be accompanied by orthostatic hypotension of a severity, which precludes their combined use…’. Again, adopting the SLGS approach minimises this potential but it still does occur and must be anticipated.

Personal preference is to introduce Eldepryl® 5 mg at half b.d. and review the patient in a month. Depending on efficacy, the dosage can then be increased to one b.d. The patient will be on combination therapy with both L-dopa and MAOBI at one b.d. and may remain on this for a period of years before requiring further adjustment.

The most supportive evidence favouring the use of Eldepryl® emerged from the DATATOP study23 that suggested Eldepryl® delayed disease progression, although it was less clear as to its direct symptomatic effects.

One of the reasons Eldepryl® fell out of favour was the 1995 United Kingdom report that identified increased mortality from the combination of Eldepryl® and Sinemet®.24 This has subsequently been criticised25,26 and ‘MIMS Annual’ states ‘No other clinical trial to date has shown an increase in mortality associated with the use of selegiline’.

MAOIs have been associated with hypertensive crises when administered with cheese and red wine, but this is not a problem with the selective MAOBI, such as Eldepryl®, especially at the low dosages recommended. Nevertheless the potential should not be ignored. Similarly the possibility of postural hypotension with L-dopa combination cannot be dismissed, but personal experience indicates that it is sufficiently rare not to obviate its use. It may exacerbate other L-dopa side effects set out earlier, including dyskinesia, hallucinations, agitation and confusion, and possibly the sleeping disorders already recognised as part of PD. Thankfully the SLGS policy minimises these troublesome issues that surface in a few patients.

c Dopamine agonists

The role of dopamine agonists is changing with the introduction of non-ergot derivative dopamine agonists. These should eliminate the current risks of fibrosis associated with ergot-based agents, which can cause cardiac valvular disease, pulmonary and retroperitoneal fibrosis. Some advocate repeated echocardiography and routine ESR monitoring of patients on the ergot-derived agonists, which may become superseded as non-ergot derivatives become more popular.

Once the patient has shown progression on the combination of low dose L-dopa and selegiline (Sinemet® or Madopar®) in 100 : 25 combination one b.d. (maximum one t.d.s.) plus Eldepryl® 5 mg one b.d., personal preference advocates addition of low dose dopamine agonist to the cocktail. Previous personal preference was for cabergoline (Cabaser®), a long-acting ergoline-8-carbamoxide dopamine agonist. Such is the changing face of therapeutics that a whole different genre of dopamine agonists is currently available.

The first of these is pramipexole (known as Mirapex® overseas and Sifrol® in Australia). It will probably be the first to achieve Pharmaceutical Benefits Scheme (PBS) listing for its 125 µg, 250 µg and 1 mg scored tablets. The company literature advocates slow introduction starting at 125 µg t.d.s. and titrating to need and efficacy or a rapid overnight conversion from the previously used dopamine agonist. Slow introduction and caution are advocated in patients with renal impairment. More recently, this has been superseded by the extended release formulation that allows a once-a-day dosing. Most patients can be transferred from standard Sifrol® to Sifrol ER® without skipping a beat. Again, the SLGS approach has seen personal preference start Sifrol ER® at 0.375 µg one mane. Many patients can be maintained at this very low dosage with them reporting very satisfactory efficacy. This has caused some difficulty because the dosage is so low that the PBS will only allow a single prescription without repeats. This translates into the patient being compelled to visit the doctor once a month to get a prescription. Personal preference is to maintain this low dosage while the patient reports adequate efficacy, even if the PBS insists the dosage is too low thereby necessitating monthly visits. As a consequence, personal approach is for the patient to attend the general practitioner once a month and to visit the consultant as needs be.

Pramipexole is not the only non-ergot dopamine agonist with other agents, such as rotigotine, to be offered as a transdermal patch. It may possibly have beneficial compliance considerations on the basis of an alternative mode of delivery but it is far too early, at least within the Australian context, to know what will be the place of these ‘newer’ agents. The use of patches as an alternative to oral administration may have particular relevance for patients with PD who undergo surgery and are on ‘nil orally’.

It is argued that dopamine agonists are particularly useful for PD patients experiencing the on–off fluctuations and dyskinesias associated with L-dopa. It seems reasonable to assume adopting the SLGS policy will dictate that by the time the patient is on a dopamine agonist, the partnership between consultant and general practitioner will have been well established. Thus the role of the general practitioner will be to monitor patient progression and help determine when it is time to add further anti-PD agents to improve quality of life, which remains the ultimate goal.

One must consider the role of dopamine agonists in the evolution of ‘punding’ and discontrol syndromes, such as compulsive gambling and impulsivity. Punding is a constellation of complex sterile and stereotyped behaviours, including absorption in use of technical equipment, almost obsessional behaviour (including handling, examining, sorting, grooming, hoarding, fidgeting while rearranging) and purposeless behaviour.19 While first noted in amphetamine and cocaine addicts in the 1970s, it was described with PD therapy in 1994.19 Excessive gambling and impulsivity are other considerations thought to be exacerbated by dopamine agonists, as is hypersexuality.

d COMT inhibitors

Stalevo®, essentially a combination of Sinemet® with entacapone (Comtan®) in a single tablet (100 mg L-dopa, 25 mg carbidopa, 200 mg Entacapone® with other combinations also available), allows the addition of a catechol-O-methyl transferase (COMT) inhibitor without increasing the number of pills required. When adding Stalevo® there is no need to also take Sinemet® or Madopar®.

Entacapone® is a reversible, specific and mainly peripherally acting COMT inhibitor, which slows the clearance of L-dopa from the blood, thereby enhancing and prolonging its efficacy. Thus, once the benefits of combination L-dopa (Sinemet® or Madopar®), Eldepryl® and dopamine agonist, such as Sifrol ER®, start to wear off, personal preference is to substitute Stalevo® for the L-dopa. Adverse effects of L-dopa may be enhanced and the amount of L-dopa may need to be reduced.

Other Medications

By the time the patient is on a combination of four anti-PD drugs the partnership between general practitioner and consultant has been fully developed. This translates into the consultant advising changes in medications and the general practitioner supervising ongoing care. The above four types of medications provide the framework for treatment of PD but do not exhaust it.

Should tremor be the major complaint then the above combination may seriously fail the patient. Personal preference is to rely on anticholinergic agents, such as benzhexol (Artane®), starting with a dosage of 2 mg half b.d. and titrating to need but rarely exceeding one t.d.s. Anticholinergic effects, such as dry mouth and constipation, may limit its use. Some doctors suggest these agents exacerbate psychotic behaviour or depression, but this is contrary to personal experience.

Tremor may not be restricted to PD ‘pill rolling’ tremor and may also include physiological, so-called benign essential type tremor, for which β-blockers, such as propranolol, provide additional benefit. Starting dosage is 40 mg half b.d. and titrating to need may relieve this additional tremor.

Should tremor persist despite Artane® then apomorphine, delivered by way of a pump, may help. This requires in-hospital titration to determine dosage plus domperidone (Motilium®) to counteract troublesome gastrointestinal side-effects. If this still doesn’t give adequate relief of intrusive tremors then deep brain stimulation and neurosurgery, directed at the subthalamic nucleus, may offer a viable alternative.

Should there be need for greater dopamine effect the use of amantadine (Symmetrel®), starting at a dosage of 100 mg per day and again titrating to efficacy, may offer additional gain. Psychiatric side-effects with Symmetrel® may limit its use.

Pain, depression, sleep disturbance and vague aches may be addressed with tricyclic antidepressants such as imipramine (Tofranil®) or amitriptyline (Endep®), starting at 25 mg nocte and titrating to need. They may also reduce the problem of enuresis that can accompany PD. The tricyclic antidepressants also produce anticholinergic effects leading to the same criticisms mentioned above with Artane®. Personal experience has not encountered significant problems in this area.

No antipsychotic agent is totally without Parkinsonian side-effects, but personal preference favours use of olanzepine (Zyprexa®). The SLGS rule applies if one wishes to achieve maximal benefit, namely improvement in control of schizophreniform features without exacerbation of PD. Some advocate quetiapine fumarate (Seroquel®) as superior to Zyprexa® but personal preference is for Zyprexa®, starting at 2.5 mg nocte and titrating to need.

Conclusion

PD is a complex and chronic illness that may evade early detection unless one maintains vigilance and closely observes patients as they come into the consultation. Personal preference is to start treatment early upon the diagnosis, but this is not universally accepted.

The SLGS policy underpins introduction of anti-PD agents with preferential choice favouring sequential and additive introduction of L-dopa, selegiline, dopamine agonist, COMT inhibitor and additional agents for specific symptomatic relief as the symptoms increase and the patient continues on the inevitable downward slide. The aim of treatment is to flatten the slope of the slide, as it is virtually impossible to totally arrest progression.

This chapter has not discussed physical intervention with mobilisation training and rehabilitation with physiotherapy. This does not diminish their role but the focus is on pharmacological treatment. Having said that, the general practitioner is ideally placed to observe the patient and recommend mobilisation training as the condition progresses. The use of a walking stick or later a walking frame may greatly reduce the propensity to falls, as a consequence of ‘failed’ ‘righting reflexes’. The use of these aids is somewhat different to their use in painful situations, as their purpose is to spread the centre of gravity (rather than function as a splint). The addition of a walking aid in PD is to widen the area of stance, thereby enhancing stability. This is often a foreign concept for patients and hence requires training. This may dictate referral to an experienced physiotherapist, possibly within a rehabilitation service. These concepts are definitely the role of the general practitioner, who is best equipped to approach each individual patient’s needs and expectations. This confirms the ongoing need for a strong, working partnership between the general practitioner and consultant.

References

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