29th April 2024

Movement Disorders

Parkinson’s Disease

Background

Idiopathic Parkinson’s disease (PD) is characterised primarily by bradykinesia, the presence of which is key for a confident diagnosis. Bradykinesia is often seen with rigidity, resting tremor, postural instability and gait impairment. PD occurs as a result of degeneration of the dopaminergic neurons in the ventral pars compacta of the substantia nigra. α-synuclein, a protein bound to ubiquitin, aggregates in damaged cells, forming cellular inclusions called Lewy bodies.

Clinical manifestations

Anxiety can precede motor symptoms by decades, whilst anosmia can be an early, though non-specific sign. Early manifestations may also include rapid eye movement (REM) behavioural disorder, which is strongly predictive of future neurodegenerative pathology.

Motor symptoms in PD often develop asymmetrically. This asymmetry often persists as the disease progresses. The resting tremor has a slow frequency (4 – 6 cycles per second), typically with a pill rolling character. It is often a re-emergent tremor, it will subside when the limb is moved to take up a new position but will re-emerge a short time after maintaining the new position. Stress and emotion can also exacerbate the tremor, whilst distraction can reveal the tremor. For instance, asking the patient to perform simple cognitive tasks such as counting backwards may reveal the tremor. Tremors can also affect the legs, chin, lips and trunk.

Increased muscle tone, described as rigidity, is best seen on slow passive movements. This can be described as “lead pipe” unless there is a superimposed tremor as well, in which case it may be described as cogwheeling. Rigidity can be accentuated by asking the patient to move the contralateral limb.

Bradykinesia tends to interfere with voluntary movements. It encompasses a range of movement disturbances, including a breakdown of fine movements, fatiguing and difficulty in gait initiation. Bradykinesia or akinesia accounts for the lack of facial expression (hypomimia), soft, monotonous speech (hypophonia), impaired swallowing, which may result in drooling (sialorrhea), small handwriting (micrographia), reduced arm swing, short strides and shuffling gait.

Postural instability is another feature of PD. Patients are often stooped, with instability resulting in falls. Patients may also report an inability to stop themselves going forward (propulsion) and may have a hurried (festinant) gait.

As the disease progresses, or in late presentations, motor symptoms tend to be more severe and can affect contralateral limbs. In addition, systemic features are common. These include constipation, dysphagia, autonomic problems (orthostatic hypotension, thermodysregulation, constipation) and cognitive disturbances including dementia.

Diagnosis

Diagnosis is primarily clinical, with investigations primarily focused on excluding other causes of parkinsonism. Single-photon emission computed tomography (DaTSCAN) can be used. This involves the injection of a radioisotope with a high affinity for dopamine transporter, particularly in the striatum. SPECT images are then produced with a gamma camera. In PD, patients may demonstrate reduced uptake.

Management

Dopamine replacement using levodopa and a peripheral dopa-decarboxylase inhibitor is the most effective treatment for PD. Levodopa can, however, be associated with the development of dyskinesia, motor fluctuations and hallucinations.

Dopamine agonists can also be used but are associated with impulse control disorders. These, along with Monoamine oxidase-B inhibitors (MAO-B) and Catechol-O-methyltransferase (COMT) inhibitors can be used as an adjunct to levodopa in those who develop dyskinesia or motor fluctuations.

References

• National Institute for Health and Care Excellence (UK). Parkinson’s disease in adults: diagnosis and management. London: National Institute for Health and Care Excellence (UK); 2017 Jul. (NICE Guideline, No. 71.) Appendix B, National Institute for Health and Care Excellence. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535852/
• Talati R, Reinhart K, Baker W, et al. Pharmacologic treatment of advanced Parkinson’s disease: a meta-analysis of COMT inhibitors and MAO-B inhibitors. Parkinsonism Relat Disord. 2009 Aug;15(7):500-5

Parkinson’s-Plus conditions

Background

This refers to other causes of parkinsonism which is not caused by PD itself. Patients often have additional clinical features which suggest a more widespread pathology. Such conditions tend to generally be associated with postsynaptic changes, therefore response to levodopa can be poor or unsustained. The importance of these conditions lies in diagnosis and differentiation from PD.

Differentiating Parkinson’s-Plus conditions

Multiple system atrophy

Multiple system atrophy (MSA) is characterised by parkinsonism in association with autonomic failure. There is no clear etiological factor, and it is generally considered a sporadic disease. Most patients will have a history of prior or concurrent REM behaviour disorder. Patients tend to have a jerky tremor and rigidity is usually symmetrical, though not always. Postural instability is seen early, often within 3 years of onset and is rapidly progressive, and falls are common.   Orthostatic hypertension, erectile dysfunction, urinary incontinence/retention, as well as other autonomic complications are a hallmark.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is caused by abnormal tau protein accumulation, leading to degeneration of neurons in the nuclei in the brainstem and basal ganglia. Clinically, it is characterised by parkinsonism and supranuclear gaze impairment, as well as postural instability and cognitive decline. As well as a resting tremor, patients may present with frequent falls, axial rigidity, dysarthria, dysphagia and cognitive decline. Rigidity and resting tremor tend to be symmetrical. It is distinguished from MSA by the extent of dysautonomia and cerebellar ataxia, which is seen in MSA but less so in PSP.

Dementia with Lewy Bodies

Dementia with Lewy Bodies (DLB) is dementia which occurs concurrently with, or within 1 year, of parkinsonian symptoms. Core features include visual hallucinations, REM sleep behaviour disorder, and parkinsonism in the form of bradykinesia, resting tremor or rigidity. These features often occur early. Lewy bodies, round intracytoplasmic inclusions, aggregate in the nuclei of neurons in the substantia nigra, as well as in the brainstem amongst other places. The importance of recognising the diagnosis of DLB guides management, as it responds to cholinesterase inhibitors, whilst patients with DLB are very sensitive to neuroleptic agents.

Corticobasal degeneration

Corticobasal degeneration is a neurodegenerative condition which leads to asymmetrical neuronal loss and atrophy of the frontoparietal cortex. Clinical features include significantly asymmetrical rigidity and bradykinesia. This typically occurs first in an upper limb and can progress to limb dystonia, with patients exhibiting dystonic limb posturing or alien limb phenomenon. Parkinsonian features include rigidity and bradykinesia, as well as a resting tremor. It is not normally responsive to levodopa administration.

Clinical features are the mainstay of diagnosing Parkinson’s-plus conditions, as well as differentiating between them.

References

• Bhatia KP, Bain P, Bajaj N, et al. Consensus Statement on the classification of tremor. From the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018 Jan;33(1):75-87
• Okun MS, Lang AE. Parkinsonism. In: Goldman L, Schafer AI, editors. Goldman-Cecil Medicine. 26th ed. Philadelphia (US): Elsevier; 2020. p 2416-2423.e3
• Chou KL, Dayalu P. Assessment of tremor. BMJ Best Practice. Sep 2021 https://bestpractice.bmj.com/topics/en-gb/974