Parkinson’s Disease is a slowly evolving neurodegenerative disorder that results in both motor and non-motor symptoms, writes Professor David Bradley

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Update on Parkinson’s Disease

By Prof David Bradley 9th April 2024

Parkinson’s Disease is a slowly evolving neurodegenerative disorder that results in both motor and non-motor symptoms, writes Professor David Bradley

Parkinson’s Disease (PD) remains one of the most common neurological disorders to present to Neurology services, with an (under)estimated prevalence in excess 15,000 cases based on UK data (Okunoye et al, 2022).

Prof David Bradley

Prof David Bradley

An estimated one in 37 individuals will be diagnosed with PD in their lifetime (Parkinson’s UK, 2024). It is a complex condition requiring individualised management and frequent follow up over the long-term. We will briefly review the diagnosis and clinical features of Parkinson’s Disease, and discuss current management.

Diagnosis of Parkinson’s Disease
Parkinson’s Disease is a slowly evolving neurodegenerative disorder that results in both motor and non-motor symptoms. Motor features manifest as parkinsonism, a clinical syndrome comprising four cardinal features (bradykinesia, rigidity, resting tremor and postural instability). The presence of bradykinesia and at least two of the other features allows a diagnosis of Parkinson’s Disease to be made without any ancillary testing (Bloem et al, 2021).

However, Parkinsonism has a broad differential and so PD should only be diagnosed where there are no atypical features or an alternative explanation for the presentation. General red flags that a patient is not presenting with typical PD include rapid evolution, lack of response to dopaminergic therapy, and bilateral onset.

Specific red flags may also be present to suggest a specific differential (e.g. cerebellar dysfunction in Multiple Systems Atrophy). Non-motor features in PD are diverse, including anosmia, autonomic features (constipation, bladder urgency, orthostatic hypotension, delayed gastric emptying) and neuropsychiatric features (sleep, mood, cognition, hallucinations, excessive daytime sleepiness) (Schapira et al, 2017).

Some features can predate the manifestation of motor dysfunction by many years (classically anosmia, constipation or REM sleep disorder) and it is estimated that 70 per cent of dopaminergic neuron function has been lost by the time of initial manifestation of motor symptoms (Costa et al, 2023).

In terms of differential diagnosis, other primary causes of Parkinsonism include the atypical parkinsonian syndromes; Multiple Systems Atrophy, Progressive Supranuclear Palsy, Corticobasal Syndrome, Dementia with Lewy Bodies (DLB). DLB is an interesting condition, in that it shares pathology with Parkinson’s Disease, but differs in the distribution and evolution of those pathological changes in the brain.

There is now considered to be a spectrum of Lewy Body Dementias, ranging from the specific diagnosis of DLB through to the development of a late dementia in some patients with Parkinson’s Disease (PDD, Parkinson’s Disease Dementia) (Hansen et al, 2019). Secondary parkinsonism is also relatively common.

We frequently encounter parkinsonism in the setting of dopamine-blocking drugs (e.g. neuroleptics, prochlorperazine).

However, parkinsonism has also been less frequently associated with a range of other drugs, such as valproate valproate, lithium, and amiodarone (Bondon-Guitton et al, 2016). Vascular parkinsonism and parkinsonism in the setting of other neurodegenerative disorders is also recognised.

Where there is uncertainty about the cause of parkinsonism, ancillary testing may be employed to clarify the situation. MRI may reveal structural changes supportive of specific differential diagnoses, DATscan can confirm the presence of a primary dopaminergic deficit (but note the scan is abnormal in both typical and atypical parkinsonism), and genetic testing may be appropriate as well as screens for specific diagnoses e.g. Wilson’s Disease may be necessary in younger patients (Tolosa et al, 2021).

Management of motor symptoms
The mainstay of motor symptom treatment is dopaminergic therapy, either in the form of levodopa combined with a dopa decarboxylase inhibitor (levodopa/carbidopa or levodopa/benserazide), or a dopamine agonist (pramipexole, ropinirole, rotigitine).

Other adjuncts commonly used include MAOI type B inhibitors (selegiline, rasagiline) or COMT inhibitors (entacapone, opicapone), which can prolong the effect of the core dopaminergic therapies. Occasionally, anticholinergics can be employed to help tremor (though tolerability is poor) and second line agents like amantadine are occasionally used, but again limited by adverse effect profile (Bloem et al, 2021). It is worth making special mention of the risk of impulse control disorders (ICDs) in patients with PD. These include compulsive gambling, shopping, eating, and hypersexuality.

While they can occur as part of the condition, they have been particularly been associated with use of dopamine agonists and should lead to alteration of therapy if they emerge (Marques et al, 2018).

Motor complications is the umbrella term for a range of issues that arise with dopaminergic therapies after the first few years. At initial diagnosis, levodopa/carbidopa three times per day can cover the day very well in most patients, but over time problems arise with ‘wearing off’ between doses, failed ‘on’ effect with some doses, dyskinesia, sudden ‘off’ fluctuations.

Initially, adjusting the number, dose and times of doses can be effective, but eventually these motor complications are an indication for a device-assisted therapy (Timpka et al, 2017). The three typical options currently available are deep brain stimulation, apomorphine (a dopamine agonist) in a subcutaneous infusion pump and levodopa/carbidopa intestinal gel delivered via pump through a jejunostomy.

The choice of approach is mostly determined by patient factors and suitability (for example, apomorphine may be a good choice where dyskinesia is a prominent issue, and a poor choice where hallucinations and sleep disturbance are established problems).

A new development this year is the availability of foslevodopa/foscarbidopa through a subcutanoues infusion pump, which provides the option for a levodopa-based device-assisted therapy without the need for a permanent jejunostomy (Soileau et al, 2022).

Management of non-motor features
Over time, many patients find that the non-motor features of their condition become the most intrusive aspect. Careful review is needed to correctly identify and quantify the issues affecting a particular patient, and an individualised approach is required to ensure optimal management (Schapira et al, 2017). Typically, these symptoms are exacerbated by motor treatments and can interact with each other.

For example, patients with bladder urgency may choose to limit their fluid intake, resulting in worsening of their orthostatic hypotension and constipation. Rivastigmine, a preferred agent for cognitive impairment, has a specific tendency to exacerbate orthostatic hypotension (Espay AJ et al, 2019).

Dopamine agonists, useful for their prolonged 24-hour effect, commonly exacerbate hallucinations and daytime somnolence. Specific agents have been licenced or are preferred for use in the setting of PD, for example the cholinesterase inhibitor rivastigmine for cognition (Sun C et al, 2021), the atypical neuroleptic pimavenserin for hallucinations (Rissardo et al, 2022), dual mechanism antidepressants such as the SNRI venlafaxine for mood (Prange et al, 2022).

Future developments
Many of the recent advances in PD management revolve around improved delivery systems for established therapeutic agents. A good example of this has been the development of levodopa/carbidopa intestinal gel and more recently subcutaneous prolevodopa/procarbidopa infusion therapy. Similarly, the electrodes deployed in DBS have become more advanced over time, allowing significant post-insertion modulation of stimulation effect to achieve best outcomes.

There are ongoing randomised trials of potential disease-modifying therapies and it is expected that, similar to Alzheimer’s Disease, we are not far from the point of seeing agents that can affect the pathology of the disease (as seen on functional imaging, CSF studies etc.), with demonstration of meaningful clinical effects hopefully to follow. Other areas of active research and development include improved accuracy of diagnosis, improved case ascertainment, improved patient self-management and self-monitoring of symptoms.

The importance of an MDT approach to PD management cannot be overstated. Patients require ongoing access to a range of overlapping specialist services with needs changing over time. Voluntary organisations such as Early Onset Parkinson’s Disease Ireland (EOPD.ie), Parkinson’s Ireland, and the Neurological Alliance of Ireland play an important role in supporting patients and kin, highlighting PD nationally, advocating for services with funders.

Priority areas for development nationally should include improved capacity to allow new assessment and return review at appropriate intervals across the country, universal access to specialist nursing services, access to therapy and rehabilitation services appropriate to life and disease stage, and systems to support self-management. imt_end6.jpg

Further reading
Please also read Dr Ray O’Connor’s article on Parkinson’s Disease from our April 9, 2024 newsletter on the topic.

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