20th July 2023

Movement Disorders

Parkinson’s Disease (PD)

Pathophysiology

PD is a neurodegenerative disorder affecting the central nervous system. The onset is usually gradual, and as the disease progresses, both motor and non-motor symptoms occur. The area of the brain affected is the substantia nigra (midbrain,) where cell necrosis causes a reduction in dopamine levels. As dopamine plays a key role in regulating movement, this manifests as akinesia. It is thought that the degree of cell loss correlates clinically with the extent of akinesia. This leads to the accumulation of Lewy bodies (eosinophilic inclusion bodies) which contain ubiquitin and alpha-synuclein in the neurons.

PD has a variety of presentations which can be divided into motor (such as tremors and rigidity), and non-motor symptoms (cognitive, sleep disorder, and mood).

Signs and Symptoms

The symptoms usually noted initially are motor, although autonomic dysfunction, neuropsychiatric and sensory issues can present at any time in the disease (table 1). Symptoms known as prodromal features can be used to help diagnose PD; these include rapid eye movement, sleep disorders, hyposmia, typical motor symptoms and neuropsychiatric.

Table 1: Symptoms of Parkinson’s Disease

Diagnosis

PD tends to be a clinical diagnosis, made through an extensive history and examination, ensuring that all secondary causes of Parkinsonism have been excluded. This includes prodromal features such as rapid eye movement, sleep disorders, hyposmia, typical motor symptoms and neuropsychiatric symptoms. Neurological examination may show cardinal motor signs of bradykinesia with tremor, rigidity or both. Typically, the diagnosis should only be made by a specialist. NICE recommends neurologist referrals before medication is started. Diagnosis is not concrete; it should be reviewed throughout an individual’s illness, especially if it takes an atypical course.

Imaging: A DaT (Dopamine Transporter) scan can be useful if the diagnosis is unclear. This involves using small quantities of a radioactive drug to determine how much dopamine is available in the CNS.

Management

Medication

Before commencing treatment, the extent to which a patient’s symptoms are affecting their life should be ascertained. High risk of poly-pharmacy, goals of care and side effects of medications should be established. Dopamine receptor agonists, particularly in those with pre-existing impulse control disorders, history of alcohol or smoking should be used with caution, as this can cause these disorders to relapse.

Medication should not be withdrawn suddenly as this can cause acute akinesia or neuroleptic malignant syndrome. Timing of medication administration is integral to maintaining optimum control. It is important to ensure these medications remain on the same schedule whilst a patient is admitted. Common medications are shown in Table 2.

Table 2: Medications used in the management of Parkinson’s Disease

Other medications can be used to treat non-motor symptoms, such as modafinil for excessive daytime sleepiness and midodrine for postural hypotension.

Palliative Care

Important to involve palliative care and have early discussions of advanced care planning. Providing written and verbal information regarding progression and advanced care planning is also helpful to the patient, especially for decisions regarding artificial feeding. This helps patients make advanced directives.

Other

Other members of the MDT are important to involve, such as physiotherapists and occupational therapists, to ensure patients can safely mobilise and manage at home. Speech and language therapists can support with hypophonia and dysphagia.

Essential Tremor (ET)

Introduction

The most common movement disorder; is a slowly progressive symmetrical intention tremor of unknown aetiology. It typically affects the upper limbs, head and vocal cords and occurs in those over 40 years old. The tremor tends to improve with alcohol and rest, worsening with anxiety. It is described as an involuntary, rhythmic shaking 5-8Hz, mostly affecting the hands.

Causes

The familial type of this tremor is inherited as an autosomal dominant trait. However, there are also sporadic cases and environmental causes, including heavy metal exposure (usually mercury, manganese and lead), agriculture, pesticides, and glass work. Its pathophysiology involves patchy neuronal loss in the cerebellum.

Diagnosis

Clinical examination and history are common in those over 40 years.

Management

Beta blockers such as propranolol, anti-epileptics, benzodiazepines, botox injections, and primidone.

Parkinsonism

Parkinsonism is a term used to describe a group of disorders which cause symptoms similar to those in Parkinson’s disease, such as rigidity, bradykinesia and tremors. Typically, this group of disorders represents up to 15% of all diagnosed cases of Parkinson’s. The disease progression of these syndromes tends to be quicker than PD, and the response to levodopa therapy is either short lived or non-existent.

Multiple System Atrophy (MSA)

A rare neurodegenerative disorder caused by neuronal loss in multiple areas of the brain manifesting as ataxia and Parkinsonism. An important feature is autonomic dysfunction causing postural hypotension and autonomic symptoms.

There are 2 main types; MSA-P (Parkinson’s features) and MSA-C (Cerebellar features); the type depends on which symptoms are predominant at diagnosis. MSA-P is more common, and the symptoms include rigidity, bradykinesia, tremors, posture and balance difficulties. MSA-C includes ataxia, dysarthria, visual disturbances and dysphagia. Symptoms of autonomic dysfunction can overlap in both types and can manifest as postural hypotension, urinary retention/incontinence, sleep disorders, erectile dysfunction, and emotional dysregulation. Autonomic dysfunction tends to present earlier than in Parkinson’s disease. MSA is caused by inclusion bodies containing alpha-synuclein leading to cell loss and reactive changes to glial cells in the CNS. A pathological diagnosis can only be made at autopsy. Management is mainly through an MDT approach, e.g. physios to help with contractures. Postural hypotension can respond to synthetic mineralocorticosteroids such as fludrocortisone. In contrast to Parkinson’s, medications such as levodopa are not found to work as well, and it tends to have a more rapid disease progression, with life expectancy from symptom onset being 6-9 years.

Progressive Supranuclear Palsy (PSP)

PSP is a rare progressive degenerative syndrome characterised by ataxia, vertical gaze palsy and cognitive impairment. It tends to be slightly later onset (60-70 years) than other similar syndromes. Common symptoms include ataxia, frontotemporal dementia, gaze palsy and hypokinesia. Some patients are also noted to have disinhibition and dysphagia. Often a patient complains of difficulty looking down and describes diplopia when reading. PSP is thought to be caused by the accumulation of tau proteins within the brain (described as tufts seen in astrocytes), particularly in the basal ganglia and brainstem. An MRI can be used to diagnose PSP by showing a ‘hummingbird’ and ‘Mickey Mouse’ sign. Management requires an MDT approach, with physio and occupational therapist input. There is currently no thorough research to strongly back medication use.

Lewy body Dementia (LBD)

LBD is a progressive form of dementia caused by the neurodegeneration of the central nervous system manifesting as changes in cognition, motor function, sleep, behaviour and autonomic systems. It is caused by abnormal clumps of Lewy bodies (protein in neurons) being deposited through the brain. This causes neuronal dysfunction, leading to a dopamine dysfunction and a loss of acetylcholine producing neurons.

LBD manifests as motor dysfunction, and autonomic dysfunction, and patients often report visual hallucinations (usually animals and people, often children) and vivid dreams. Patients are often aware that their hallucinations are not real. Autonomic dysfunction typically manifests as postural hypotension. Psychiatric symptoms appear as altered behaviour, depression, apathy, attention deficits, and executive and visuospatial dysfunction.

For diagnosis, cognitive impairment should appear within one year of parkinsonism features. However, a definitive diagnosis is only possible by autopsy. It usually takes years to diagnose, and is commonly misdiagnosed as there is a lot of overlap with other conditions such as Parkinson’s disease and Alzheimers.

Cholinesterase inhibitors such as donepezil and rivastigmine are used to try and help with cognition and function. Melatonin is used for sleep to try to restore the day/night cycle.

Corticobasal Degeneration (CBD)

A rare neurodegenerative disease involving the cerebral cortex and basal ganglia, manifesting as a gradual onset movement and cognitive disorder. It typically occurs in those aged 50-70 years, and it tends to progress over 6-8 years.

Patients find difficulties in cortical processing and basal ganglia dysfunction. Symptoms include bradykinesia, apraxia, aphasia, limb dystonia, parkinsonism, and myoclonus. These can present unilaterally initially, which then become bilateral. Another important feature is alien-limb phenomena. The pathophysiology behind this is an accumulation of tau proteins and astrocyte inclusions, which cause astrocytic plaques which appear as blurry outgrowths from the astrocyte. Unfortunately, there are no known treatments which slow the course of the disease. Parkinson’s drugs don’t show sustained improvement though clonazepam can be used for myoclonus. Otherwise an MDT approach, including speech therapy, is used to try to manage the symptoms of the disease. Patients typically die from complications such as pneumonia.

Drug-Induced Parkinsonism

This is the second most common aetiology of Parkinsonism and is usually caused by medications which antagonise dopamine receptors in the basal ganglia. Culprit medications include antipsychotics, stimulants, GI prokinetics or calcium channel blockers. Usually, the symptoms should improve if the causative medication is stopped, although it can take up to 18 months to do so. If the medication cannot be stopped, it should be reduced where possible. Alternative treatment options are anticholinergics, such as procyclidine.

Clinical symptoms include bilateral and symmetrical Parkinsonism without a resting tremor; however, in practice, a significant portion of patients present with an asymmetrical and resting tremor.

Huntington’s Disease (HD)

HD is an inherited, progressive neurodegenerative disorder, which predominantly causes chorea, impaired cognition and psychiatric conditions.

Pathophysiology

HD is inherited in an autosomal dominant manner, although 10% of cases are due to a de novo mutation. A mutation in the HTT gene located on the short arm of chromosome 4 leads to the expansion of the CAG trinucleotide segment. This leads to patchy neuronal loss in the cerebellum, occurring predominantly in the basal ganglia. HD demonstrates a phenomenon known as genetic anticipation; this means that each subsequent generation tends to experience symptoms at an earlier age.

Signs and Symptoms

Onset is usually in the 30s-/40s, and initial symptoms tend to be mood change or cognitive impairment. As the disease progresses, ataxia and poor gait follow.

It is classed as juvenile if onset is in the 20s – the predominant symptoms initially tend to be hypokinesia, then behavioural changes, including poor attention span, contractures, tremors, frequent falls, and seizures.

Table 3: Symptoms of Huntington’s Disease

Complications

Complications include aspiration pneumonia, falls and dysphagia. Clinical depression isn’t uncommon and increases the risk of suicide, which is a cause of death in 9% of patients. The rate of disease progression varies, and the prognosis tends to be 10-30 years.

Diagnosis

Clinical examination and history, common in those over 40 years.

Genetic testing for the mutant HTT gene and CAG nucleotide repeats.

Imaging such as MRI head or CT head can show atrophy of the caudate nuclei. However, this is not singularly diagnostic for HD.

Management

Currently, management is for the best supportive care. Certain medications can be used to help manage symptoms, such as tetrabenazine for chorea, and antidepressants and antiepileptics to help stabilise mood. An MDT approach including speech and language therapists, physiotherapists and occupational therapists is required.

Other Movement Disorders

Restless Legs Syndrome (RLS)

RLS causes spontaneous, continuous, lower limb movements, which may be associated with paraesthesia. It generally comes on with rest and at night. Initially, patients tend to be symptomatic during the night, which can progress into daytime symptoms. 2-10% of the general population are affected, and 50% of cases have a positive family history.

Causes

Two distinct types; familial – early onset occurring before the age of 45, which worsens with age. Late onset begins after 45, tends to be sudden onset but does not progress.

Found to be common in those with iron deficiency states, including iron deficiency anaemia (IDA), CKD, diabetes, rheumatoid arthritis, pregnancy, coeliac, Parkinson’s disease, electrolyte deficiency, peripheral neuropathy and some autoimmune diseases. Medications have also been noted to precipitate the disorder, including antipsychotics, calcium channel blockers, and antidepressants.

Signs and Symptoms

Sensation of compulsion to move legs, paraesthesia, daytime somnolence, lethargy and low mood.

Mobilising eases the symptoms and brings temporary relief.

Diagnosis

Diagnosis of exclusion – must rule out all other potential causes of other pathology for symptoms.

Diagnostic criteria have 5 main symptoms – worsens with rest, improves with activity, worse in the evening/night, a strong urge to move limbs, not caused by a medical condition.

Management

Treat the underlying cause where possible, e.g. iron supplementation. Sleep hygiene, alcohol and smoking cessation. Some use of dopamine agonists or gabapentin. If treatment resistant, opioids may be used.

Wilson’s Disease

A genetic disorder in which there is a problem with copper metabolism, causing an accumulation of copper in the body. Copper deposition occurs in the basal ganglia, cornea and liver. Akinetic-rigid syndrome +/- dyskinesia. Neurological damage can be reversible with early treatment. Treatment is with a chelating agent such as penicillamine.

Causes

It is autosomal recessive in inheritance, caused by a mutation in the protein ATP7B gene on chromosome 13q14.3. The protein codes for the transportation of excess copper into bile for excretion. Gene codes for P-type ATPase that transports copper to bile and incorporates it into cerulosplasmin.

Signs and Symptoms

These arise from the accumulation of copper in the liver and brain, causing liver disease and neuropsychiatric symptoms. Generally, those with liver issues present in childhood or teenage years. Copper deposition in the liver can lead to increased coagulopathy, lethargy, hepatic encephalopathy or portal hypertension and, as a result, other sequelae of chronic liver disease. Copper deposition in the brain causes cognitive impairment and ataxia. They can also present as symptoms of Parkinsonism. Deposition is predominantly in the basal ganglia.

Other manifestations include Kayser-Fleischer rings in the eyes, hypoparathyroidism, renal tubular acidosis type 2 or cardiomyopathy.

Diagnosis

A combination of blood tests checking the level of ceruloplasmin and copper, genetic testing, urinary copper excretion tests and liver biopsy is used.

MRI shows copper deposition in the basal ganglia giving a ‘face of the giant panda’.

Management

Reduce dietary copper intake, such as by avoiding mushrooms, liver, nuts, chocolate and dried fruit. Lifelong penicillamine is used, which is a chelating agent which binds copper and excretes it in the urine. Note its side effect of drug-induced lupus. Liver transplant is curative, although there are strict criteria by which this can be used.