An update on Parkinson’s disease

Parkinson’s disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms.¹ It is one of the commonest causes of disability in older people with at least 8,000 new cases diagnosed each year in the UK alone.²

PD is the second most common neurodegenerative disorder, and its global prevalence is projected to double by 2040, due partly to an ageing population.³ The rate of disease progression is variable, and the disease progression of PD from diagnosis has been conceptualised into four stages: Early stage (diagnosis phase), maintenance stage, advanced stage (complex phase) and palliative stage. The rate of PD progression is heterogeneous and is generally more rapid in those with older age and more severe motor impairment at onset.³

It is important to recognise a prodromal phase in which non-motor symptoms, such as anosmia, constipation, and rapid-eye-movement (REM) sleep behaviour disorder may predict the development of motor PD. There is no cure or disease-modifying treatment for PD, and the objective of patient-centred treatment is to decrease disability while maximising the patient’s quality of life and well-being.

Levodopa, a dopamine replacement treatment, is cornerstone of symptomatic therapies for PD and is especially useful in the early stages of the disease for alleviating motor symptoms. However, as the disease progresses and the dosage increases, levodopa has limitations in PD patients’ motor symptoms as it can lead to significant side effects. In addition, it is less effective in treating non-motor symptoms, which require further symptomatic medication.

Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off (off periods), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation.

Palliative care is part of Parkinson’s disease management. Physical exercise is effective in managing Parkinson’s disease, but the relative benefit of different exercise types remains unclear.

Neuropathology

Dopamine denervation due to Lewy body deposition and cell death in the substantia nigra is the primary neuropathology, but a large number of extra-nigral and non-dopaminergic brain regions are also affected.³ The α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system.¹

Diagnosis

The diagnosis of Parkinson’s disease is clinical and requires bradykinesia, defined as ‘slowness of movement and decrement in amplitude or speed’, usually assessed using finger tapping, foot tapping or pronation–supination hand movements.³ In addition, rest tremor or rigidity is required to confirm the clinical diagnosis of a parkinsonian syndrome.² At least two supportive criteria and no red flags, such as severe autonomic failure seen in multiple system atrophy (MSA), required for a diagnosis of ‘clinically established’ Parkinson’s disease.² However, tremor was absent at presentation in 30% in one series of pathologically proven PD.⁴ Clinically, the diagnosis of Parkinson disease is based on history and clinical examination.

1. History may include:
   • Prodromal features: Such as rapid eye movement sleep behaviour disorder, hyposmia, and/or constipation.
   • Characteristic movement difficulty: Such as tremor, stiffness, and slowness.
   • Psychological or cognitive problems: These may include cognitive decline, depression, or anxiety.
2. Clinical examination typically demonstrates bradykinesia with tremor, rigidity, or both.

Post-mortem studies of clinically diagnosed PD show an overall diagnostic accuracy of 81%, indicating the need to re-appraise the clinical diagnosis regularly.⁵ Attention should be paid to exclusion criteria indicating an alternative diagnosis and to ‘red flag’ features.⁴

The most common causes of PD misdiagnosis are atypical parkinsonian syndromes, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). These conditions generally have a more aggressive disease course and poorer response to dopaminergic treatment compared to PD but may present initially in a similar manner.³ Red flag features should be regularly reviewed during follow-up.³ These may include:

• Absent progression over 5 years may indicate non-degenerative such as essential tremor, or dystonic tremor, or even drug-induced parkinsonism.
• Early severe dysphonia, dysarthria, dysphagia could point at progressive supranuclear palsy (PSP) or multiple system atrophy (MSA) as an alternative diagnosis
• Disproportionate antecollis (excessive forward flexion and anterior shift of the neck) is a warning sign for MSA but could be seen in in the later stages of parkinsonian syndromes.
• Limb contractures within 10 years that could be associated with MSA
• Symmetrical parkinsonism throughout disease course could be due to DIP or atypical parkinsonism

Where postural tremor is the main feature, an important differential diagnosis is essential or dystonic tremor.³ Several ‘red flag’ features should also prompt re-appraisal of the diagnosis.³

Investigations

Brain imaging

Dopamine transporter single-photon emission computed tomography (SPECT scan) can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. SPECT scan can be useful to distinguish PD from such tremor syndromes but is not sufficiently accurate to differentiate other degenerative parkinsonian syndromes.⁵

Structural magnetic resonance imaging (MRI) of the brain is useful where MSA or PSP are considered, showing specific patterns of focal atrophy, and may also help interpretation of dopaminergic imaging where pre-existing lesions can cause difficulties in interpretation.⁶

Facial expression recognition (digital diagnosis)

Facial expression recognition via ‘artificial intelligence’ to diagnose a typical neurological system disease has been studied to assess if it can contribute to the ‘digital’ diagnosis of PD. Hypomimia (reduced facial expression) is one of the clinical features of PD and is considered an extremely sensitive biomarker for the disease, making it a promising tool for early diagnosis of PD.

This digital biomarker can be captured by wearable sensors which use relative coordinates and positional jitter to extract facial expression features (facial expression amplitude and shaking of small facial muscle groups). The experimental results of one of the studies showed that the models used can achieve significant facial expression recognition ability for PD diagnosis.⁷

Management

For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (e.g., tremor, rigidity, bradykinesia) and nonmotor (e.g., constipation, cognition, mood, sleep) signs and symptoms. There is currently no proven disease-modifying or neuroprotective therapy for PD.⁸ Current evidence-based treatment for PD is symptomatic and mainly based around dopaminergic replacement or modulation,³

Dopamine-based therapies typically help initial motor symptoms. The choice of initial dopaminergic treatments should be individually tailored but long-term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias.¹ The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remain a major therapeutic challenge. Most of the nonmotor symptoms require nondopaminergic approaches (e.g., selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition).

Pharmacologic therapy

Levodopa controls symptoms for most patients but long-term use is associated with motor complications. Several other drugs have been used, either alone or with reduced doses of Levodopa, to delay the onset of motor complications or to control complications in later stages of the disease once they have developed. These agents have primarily been from three classes of drug:

• Dopamine agonists (DA)
• Monoamine oxidase type B inhibitors (MAOB-I)
• Catechol-O-methyltransferase inhibitors (COMT-I).

Levodopa, dopamine agonists and monoamine oxidase B inhibitors are all licensed for use as initial therapy in PD. Anticholinergics are no longer routinely used due to the risk of cognitive decompensation.³

Guidelines recommend treating motor symptoms when they impact the functions of daily life or decrease quality of life. Treatment options for early Parkinson disease include carbidopa/levodopa, monoamine oxidase-B (MAOB) inhibitors, non-ergot dopamine agonists, or amantadine.⁹

L-Dopa

The most effective symptomatic treatment remains levodopa, which has superior benefits for quality of life in early PD compared to other therapies. The recent delayed-start LEAP study showed no disease-modifying effect of levodopa in patients diagnosed <2 years prior, but PDQ-39 score (a Parkinson’s Disease Questionnaire that assesses how often people with Parkinson’s experience difficulties across 8 dimensions of daily living) was improved in the blinded phase in those receiving early vs delayed treatment.¹⁰

Concerns about the development of motor complications with levodopa led to a ‘levodopa-sparing’ approach by many physicians treating PD³. The PD MED study was a large “real-life” trial that aimed to determine much more reliably which class of drugs provides the most effective control, with the fewest side-effects, for both early and later PD.¹¹

The study randomised 1,620 patients with early PD to either levodopa or ‘levodopa-sparing’ therapy (dopamine agonist or MAOB-I) with a median follow-up of 3 years. The main outcome measure was patient-rated quality of life, using the PDQ-39 scale, which assesses all aspects of the patient’s life, and is sensitive to changes considered important to patients but not identified by clinical ratings. The mobility score of the PDQ-39 and overall QoL was improved in those treated with levodopa vs levodopa-sparing therapy. While dyskinesia occurred earlier in those started on levodopa, there was no difference in motor fluctuations.¹¹

Dopamine agonists

Patients must be counselled about the potential risk of impulse control disorder (ICD) when taking dopaminergic therapy, especially dopamine agonists.³ The increasing recognition of ICD has altered perceptions of the risk profile of dopamine agonists. ICDs include pathological gambling, hypersexuality, and compulsive shopping and eating; occur in around 14% of patients with PD; with an increase of about 2–3 folds among those taking dopamine agonists.¹²

Furthermore, recent data suggest that ICD may occur in over 40% of people with PD after 5 years of dopamine agonist treatment, with a relationship to agonist dose and treatment duration.¹²

Monoamine oxidase type B inhibitors (MAOB-I)

Safinamide, a combined MAOB-I and glutamate release inhibitor, is one of the new adjunctive therapies that have recently been licensed. It improved on-time compared to placebo, although proposed anti-dyskinetic effects were only observed in a subgroup with more severe baseline dyskinesia.¹³

Catechol-O-methyltransferase inhibitors (COMT-I)

A newer adjunctive therapy has recently been licensed, Opicapone. The once-daily COMT inhibitor opicapone has shown significant reductions in off-time vs placebo, and non-inferiority to entacapone.¹⁴

Adjuvant therapies for motor complications

Observational studies showed that duration of disease rather than treatment is a key determinant of motor complications. Therefore, delaying dopaminergic therapy does not avoid the development of motor complications and may be associated with poorer QoL,³ Wearing-off, in which motor benefit decreases before the next levodopa dose is due, and delayed-on periods are the most common motor fluctuations, but sudden or unpredictable off-periods can also occur.¹⁵.

Motor fluctuations and dyskinesia later in the disease course can be improved with adjunctive treatments. The addition of dopamine agonists, MAOB-I or catechol-O-methyltransferase inhibitors (COMT-I) to a levodopa-based regimen have all been shown to reduce off-time and improve on-time, although all may result in more dyskinesia.³

Among the adjunctive therapies that have been recently licensed is opicapone and Safinamide. Opicapone, a once-daily COMT-I, has shown significant reductions in off-time vs placebo, and was not inferior to entacapone.¹³ Safinamide, a combined MAOB-I and glutamate release inhibitor, has shown to improve on-time compared to placebo¹⁴. Levodopa-induced dyskinesia, involuntary choreiform or dystonic movements, typically worst at peak motor benefit, may also cause significant disability. Amantadine is the main oral treatment for dyskinesia.³

Non-motor symptoms

Non-motor symptoms such as depression, constipation, and REM sleep behaviour disorder, are increasingly recognised and may precede the diagnosis of PD by many years. There is emerging evidence for the management of non-motor symptoms in PD, and the importance of multidisciplinary care.³ Non-motor fluctuations are well recognised, and some may improve with optimisation of dopaminergic therapies to improve wearing-off.¹⁵ However, many non-motor symptoms have a non-dopaminergic or extra-nigral origin.³

Invasive and advanced therapies

Around 10% of patients per year with refractory motor fluctuations may be eligible for advanced therapies, including deep-brain stimulation surgery.³ When significant off-time or dyskinesia persists despite optimised oral treatment, advanced therapies should be considered. Apomorphine, a potent dopamine agonist given by continuous subcutaneous infusion, is the least invasive and most straightforward of the advanced therapies.³ A recent double-blind TOLEDO study confirmed a significant reduction in off-time and improved on-time with apomorphine versus placebo.¹⁶

Deep-brain stimulation (DBS)

DBS involves surgical placement of electrodes into brain regions such as the subthalamic nucleus to improve motor fluctuations or refractory tremor. DBS is typically considered in patients without significant axial or neuropsychiatric problems. It improves motor function, off-time and QoL in patients with PD, and provides significant benefits over medical therapy even in patients with an average disease duration of 7 years.¹⁷ The benefits of DBS on motor function, fluctuations and activities of daily living have been demonstrated up to 10 years postoperatively, although axial features continue to progress.¹⁸

Levodopa–carbidopa intestinal gel

Infusion of levodopa–carbidopa intestinal gel via jejunostomy has also been shown to improve off-time compared to oral levodopa and is commissioned in specialist centres where other advanced therapies are ineffective or contraindicated.¹⁹

Stem cell transplantation

Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies.¹

New modes of treatment

New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise.¹ Electroacupuncture, which may be viewed as a modern extension of acupuncture by introducing electronics in it, has been shown some benefits in patient with constipation. In a twelve-week study, electroacupuncture (given as 3 sessions per week) has been compared with conventional pharmacological treatment, and electroacupuncture significantly enhanced bowel movements in patients with PD.²⁰

Non-pharmacological

Exercise is increasingly recognised as important in PD management. A recent randomised controlled trial in 130 patients with early PD showed a significant improvement in off-state motor severity following 6 months of home-based aerobic exercise, compared with controls.²¹ However, the long-term effects need to be further investigated.

In addition, a recent meta-analysis found evidence of beneficial effects on the severity of motor signs and QoL for most types of physical exercise for people with PD included in the review, but little evidence of differences between these interventions. Although the evidence is very uncertain about the effect of exercise on the risk of adverse events, the interventions included in the review were described as relatively safe.²² Many so-called ‘axial’ symptoms of later stage PD, such as dysphagia, gait disturbance and falls, do not respond to levodopa therapy, but may be helped by multidisciplinary team input.

Course and progress

Clinically, manifest Parkinson’s disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. However, there is no reason to postpone symptomatic treatment in people developing disability due to Parkinson’s disease.

There is no cure or disease-modifying treatment for PD, and the rate of progression is variable.³ However, PD progression is generally more rapid in those with older age and more severe motor impairment at onset.³ Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson’s disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential.²³ Furthermore, Parkinson’s disease has multiple disease variants with different prognoses:²⁴

• Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression.
• Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (e.g., carbidopa-levodopa, dopamine agonists), and slower disease progression.
• Other individuals have an intermediate subtype.

Prognosis

Parkinson disease progression is variable, and there is currently no available method to predict how it will progress. No therapies, including levodopa, have demonstrated the ability to slow progression.³  A 2012 study showed approximately 77% of patients had poor outcomes (i.e., death, postural instability, or dementia) 10 years after disease onset. The transition from disease impairment (i.e., difficulty with activities but maintaining independence) to disability (i.e., loss of independence) happens between three and seven years after the onset of Parkinson disease. A prominent tremor at presentation may predict slower disease progression rates. Risk factors for rapid motor function decline and the need for care home placement may include:

1. Advanced age
2. Bradykinesia or rigidity as presenting symptoms.
3. Swallowing issues with risk of aspiration pneumonia
4. Weight loss attributed to anorexia and difficulty feeding

Psychosis, most commonly auditory and visual hallucinations, and paranoid delusions occur in 20% to 40% of patients with Parkinson disease and are the most influential risk factors for a patient’s placement in a nursing home. The prevalence of dementia in Parkinson disease is 40% and increases with the duration of disease and age of onset.⁹ Dementia may occur in up to 80% of people with PD after 20 years’ disease duration.²⁵

Conclusion

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms The diagnosis of PD remains clinical, and close attention and review for features indicating an alternative diagnosis is key given the absence of a definitive diagnostic test. Brain imaging has been increasingly used to aid the clinical diagnosis, mainly by excluding other neurological syndromes. There is a growing interest in exploring the use of facial expression recognition via artificial intelligence as it can contribute to the ‘digital’ diagnosis of PD.

There is no cure or disease-modifying treatment for PD, and the rate of progression is variable.  Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. Levodopa remains the most effective as well as the first-line therapy for motor symptoms of PD, but individualised therapy is important given the heterogeneity of progression of motor and non-motor features. It is important to recognise and manage the non-motor symptoms of PD effectively, and to consider potential candidates for advanced therapies, including DBS. Lastly, targeted multidisciplinary care is crucial to effective management of this complex condition.

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Dr Nabil Aly, Consultant physician, Royal Liverpool University Hospital, Liverpool

[email protected]     [email protected]

Conflict of interest: none declared

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