Hyperkinetic movements

Tremors

A tremor is an involuntary, rhythmic muscular contraction causing shaking.

Essential Tremors

Essential tremors (ETs) are highly familial. Most patients present with hand and arm tremors and head tremors. ETs are at 4-10Hz. It occurs in certain postures or during movement. It is exacerbated by heightened emotion, stress, fever, and hypoglycaemia. Most essential tremors improve with alcohol or β-blockers.

The treatments for ETs are:

• β-blockers
• Antidepressants
• Anti-epileptic drugs (AEDs)
• Benzodiazepines
• Botulinum toxin

Resting Tremors

Resting tremors (RT) occur when the muscles are relaxed. It is classically a 3-5Hz pill-rolling of the hands or fingers. RT is seen in Parkinson’s Disease (PD) and parkinsonism. The features and treatment of PD and Parkinsonism are discussed in greater detail later.

Intention Tremors

Intention tremors occur when doing a purposeful movement or task. They get worse as they get closer to their target. It usually affects the upper limbs. The tremors are slow and high amplitude. It is caused by pathology affecting the cerebellum, such as stroke, multiple sclerosis, or neurodevelopmental disorders. Treatment depends on the cause.

Myoclonus

Myoclonus is the involuntary muscular jerking caused by a cluster of muscle or muscle group contractions lasting milliseconds. Myoclonus is typically positive, causing jerking, but it can also be negative, causing muscle tone loss.

The causes of myoclonus are:

• Cortical – intracranial causes such as epilepsy, multiple sclerosis, Parkinson’s disease, stroke, traumatic brain injury, or CNS tumours – EMG – <50ms burst potentials. EEG-EMG polygraphy – EEG discharges are low amplitude and precede myoclonic EMG activity. This confirms cortical myoclonus.
• Subcortical – brainstem myoclonus and propriospinal myoclonus. EMG – bursts of 25-300ms
• Segmental – spinal tumour or spinal cord injury. EMG – discharges of 50-1,000ms.
• Peripheral – A peripheral neuropathy with a motor component. EMG – discharges of 50-200ms in the affected muscles.
• Secondary – e.g. drug toxicity, metabolic disturbances, and liver or renal failure.

Myoclonus is diagnosed with the following tests:

• Examination – its distribution, whether or not it happens at rest, when the arms were outstretched, or during actions.
• Blood tests to rule out metabolic disorders – glucose, electrolytes, thyroid function tests, and drug and toxin testing
• MRI head or spine
• EEG
• EMG
• Somatosensory evoked potentials
• EEG-EMG polygraphy on pairs of agonist-antagonist muscles
• CSF analysis

Treatment of myoclonus depends on the cause:

• If secondary, treating the underlying cause by treating the drug toxicity or correcting the metabolic disturbance
• AEDs, e.g. levetiracetam or valproate– used for cortical myoclonus
• Clonazepam – first line for symptomatic relief
• Botulinum toxin A

Chorea

Chorea is the jerky contractions of muscles causing dance-like movements. The muscle groups commonly involved are the head, arms, trunk, and legs. It is the result of overactivity of dopamine and the basal ganglia, which at times is due to a lack of inhibition by the thalamocortical neurons.

The causes of chorea are:

• Huntington’s disease
• Hyperthyroidism
• Hypoparathyroidism
• Hyperglycaemia
• Autoimmune disorders
• Sydenham chorea
• Stroke
• Drug-induced, e.g. levodopa, phenytoin, and tricyclic antidepressants
• Tardive dyskinesia – occurs secondary to antipsychotic use

The treatments for chorea include:

• Tetrabenazine – depletes striatal dopamine
• Antipsychotics, e.g. haloperidol, olanzapine, or quetiapine

Dystonia

Dystonia is a neurological movement disorder caused by the sudden, uncontrollable contraction of agonists and antagonists of movement, which leads to an abnormal, fixed posture. The causes of dystonia are idiopathic, genetic, or secondary to hypoxic brain injury, stroke, CNS infections, traumatic brain injury, and heavy metal or carbon monoxide poisoning.

Dystonia can affect any muscle in the body but often affects the limbs first and then progresses to other muscle groups. The late stages often affect the neck and facial muscles. Overall, it can involve the face, eyes, neck, vocal cords, torso, limbs and feet. It can eventually cause fixed postures and contractures. It can be associated with pain and fatigue.

There are several types of dystonia:

• Generalised dystonia
• Focal dystonia – affects specific muscles:
  • Blepharospasm
  • Cervical dystonia – also known as torticollis
  • Tardive dystonia – causes slower, twisting movements compared to the fast, chorea-like movements of tardive dyskinesia.
• Multifocal dystonia – affects two or more muscle groups in the body
• Segmental dystonia – affects two or more related muscle groups in the body
• Hemidystonia – affects the same side of the body

The treatments for dystonia are:

• Trihexyphenidyl and benztropine (anticholinergics)
• Benzodiazepines
• Baclofen
• Tetrabenazine (dopamine antagonist)
• Botulinum toxin A – for focal dystonia
• PT and orthotics

Parkinsonism

Parkinson’s Disease

Aetiology

Parkinson’s Disease (PD) is a neurodegenerative disease characterised by two features:

1. Lewy bodies (LBs) – intracellular eosinophilic inclusions of α-synuclein.
2. Subsequent loss of dopaminergic neurons in the substantia nigra of the midbrain in the basal ganglia.

Diagnosis

PD is difficult to distinguish from other causes of parkinsonism. PD is a clinical diagnosis. It is important to distinguish between PD and parkinsonism, as PD responds well to antiparkinsonian drugs, but parkinsonism does not.

There are some prodromal non-motor symptoms:

• Anosmia
• Rapid eye movement (REM) sleep disorder – unwanted, violent motor behaviour during dreaming due to lack of normal muscle atonia during REM sleep.
• Constipation

The classic triad is:

1. Resting tremor – 3-5Hz, pill rolling action of thumb over fingers
2. Bradykinesia – slow to initiate movements
3. Rigidity – lead pipe rigidity refers to a hypertonic state throughout the movement of a joint; cogwheel rigidity refers to lead-pipe rigidity with superimposed tremor.

Other features of PD are:

• Slow, shuffling gait
• Hypophonic speech
• Micrographia
• Expressionless facies
• Urinary frequency
• Depression
• Autonomic dysfunction
• Immobility
• Falls

The only diagnostic test, according to NICE, is a DaTscan. A DaTScan is a scan using 23I-FP-CIT single photon emission tomography (SPECT) imaging to look for the presence of dopamine transporters. It distinguishes PD from essential tremor or drug-induced parkinsonism that cannot be determined clinically.

In the end stages of PD, 20% develop Lewy Body dementia, characterised by fluctuating cognitive impairment, hallucinations and parkinsonism.

Treatment

Levodopa

Levodopa is the first-line treatment for early PD with motor features that are impacting their quality of life.

The first line treatment when motor symptoms do not impact their quality of life is either non-ergot-derived dopamine agonists, levodopa, or monoamine oxidase B (MAO-B) inhibitors.

Several motor fluctuations can occur after being on levodopa for <10 years:

• Dyskinesia
• “On” time – PD symptoms well controlled
• Wearing-off symptoms – parkinsonian symptoms reoccur
• Freezing

Sudden dose reduction or withdrawal of levodopa can cause neuroleptic malignant syndrome (NMS).

Dopa-decarboxylase inhibitors

Levodopa is commonly prescribed in combination with peripheral dopa-decarboxylase inhibitors such as carbidopa and benserazide to prevent conversion to dopamine peripherally and therefore decrease the side effects of peripheral dopaminergic action. It causes a 4-5-fold reduction in levodopa dose due to increased levels crossing the blood brain barrier.

Dopamine-receptor agonists

Dopamine-receptor agonists (DAs) stimulate D2 and D3 receptors. DAs are split into older ergot-derived DAs and newer non-ergot-derived DAs. Safety advice has been released by the Medicines and Healthcare product Regulatory Agency on ergot-derived DAs:

• Echo on initiation – cardiac valvopathy and fibrosis
• Examine for pulmonary fibrosis and pleural effusion

Ergot-derived DAs	Non-ergot-derived DAs
Bromocriptine	Ropinirole
Cabergoline	Pramipexol
Pergolide	Rotigotine
	Apomorphine

Rotigotine and apomorphine are the only PD drugs that aren’t given orally. This is particularly important when a patient is nil-by-mouth. It is key to ensure that no doses of PD medications are missed. Rotigotine can be used in this case and is a transdermal patch. Apomorphine is given by subcutaneous injection and can be used in the end stages of PD.

In chronic use, DAs can cause:

• Choreiform and dystonic movements
• Psychosis
• Impulse control disorders, e.g. hypersexuality, excessive gambling, and obsessive hobbying

Dopamine toxicity:

• Dyskinesia
• Dystonia
• Hypotension
• Dysrhythmias

Monoamine oxidase-B (MAO-B) inhibitors

MAO-B inhibitors, such as rasagiline and selegiline, inhibit the breakdown of monoamines, such as dopamine.

One of the classic interactions of MAO-B inhibitors is with tyramine-rich foods, including cheese, cured meats, yeast extract, and pickled fish, which can lead to a hypertensive crisis, sometimes referred to as “the cheese effect”. Tyramine is a monoamine, and therefore the MAO-B inhibitors prevent its breakdown.

Catechol-O-methyl transferase inhibitors

Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone and tolcapone, prevent the breakdown of levodopa in the periphery, which increases its effects in the brain. COMT inhibitors are particularly used to increase the “on” time and decrease the “off” time of levodopa.

One severe side effect of COMT inhibitors is hepatic dysfunction and liver toxicity. COMT inhibitors should not be given to patients with liver impairment. LFTs should be monitored closely, as tolcapone can increase AST and ALT by 2-3 times.

Amantadine

The mechanism of action of amantadine is not fully understood, but it is an NMDA receptor antagonist, which increases dopamine release. NICE recommends amantadine in dyskinesia.

Serious adverse effects:

• Neuromalignant syndrome
• CNS depression
• Suicidal ideation
• Psychosis

Treatment of non-motor features

Levodopa and DAs can increase the risk of daytime sleepiness or sudden onset of sleep. The Driver and Vehicle Licensing Agency (DVLA) recommends that the patient cannot drive and to consider occupational hazards. This can be managed with modafinil.

Drooling:

• Glycopyrronium bromide
• Refractory – botulinum toxin A into parotids and submandibular glands

Orthostatic hypertension:

• Midodrine or fludrocortisone

Lewy Body Dementia:

• Rivastigmine – cholinesterase inhibitor

Parkinson’s Plus Syndromes

Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is caused by two pathological processes:

1. Neuronal loss in:
   • Midbrain – supranuclear gaze palsies
   • Basal ganglia – parkinsonism
   • Cortex – cognitive deficits
2. Tau inclusions

The cardinal features of PSP are:

• Supranuclear ophthalmoplegia
• Neck dystonia – backward tilt of the head
• Parkinsonism
• Pseudobulbar palsy
• Cognitive impairment
• Imbalance – axial rigidity, erect posture
• Fast walking
• Frequent falls backwards

Supranuclear ophthalmoplegia classically causes a downgaze palsy as well as square wave jerks when moving their eyes. The supranuclear ophthalmoplegia is due to an upper motor neuron problem of the extraocular muscles and is distinguished from a lower motor neuron problem with a negative doll’s eyes reflex. Patients struggle with the H test and have square wave jerks when moving their eyes.

MRI head – classic “hummingbird sign” – atrophy of midbrain, preservation of pons.

Later symptoms of PSP are:

• Spastic-ataxic dysarthria
• Dysphagia
• Falls
• Dementia

Treatment for PSP includes:

• Levodopa – will have only a brief beneficial effect
• Amantadine can help motor features
• Botulinum toxin A – neck dystonia and blepharospasm
• Often given a forward weighted walker, as they have a tendency to fall backwards.

Multi-system Atrophy

Multi-system atrophy (MSA) is caused by progressive neuronal loss in the substantia nigra, striatum, cerebellum, and autonomic nervous system.

The histopathologic hallmark of MSA is Papp-Lantos bodies of α-synuclein and ubiquitin.

The most common first sign of MSA is an “akinetic-rigid syndrome”.

MSA commonly presents as a triad of:

1. Parkinsonism
2. Ataxia
3. Autonomic dysfunction

There are two types of MSA:

1. MSA-P – predominantly parkinsonism. MRI head – hypodense putamen.
2. MSA-C – predominantly cerebellar – ataxia, dysphagia, and dysarthria. MRI head – “hot cross bun sign” – atrophy of the cerebellum, pons and pontocerebellar fibres.

Similarly to PSP, patients with MSA can sometimes briefly benefit from levodopa.

The postural hypotension can be treated with the following:

• Conservative management, such as compression stockings or additional salt
• Fludrocortisone or midodrine

Bladder issues can be managed with oxybutynin or tolterodine. Dystonia and contractures can be managed with physiotherapy or, in refractory cases, with botulinum toxin A.

Corticobasal Degeneration

Corticobasal degeneration (CBD) causes neurodegeneration in:

• Premotor cortex
• Parietal association areas
• White matter tracts
• Thalamus
• Basal ganglia

This is caused by astroglial tau inclusions in the anterior frontal lobe and the premotor area.

CBD presents with the following:

• Progressive asymmetric axial rigidity
• Abnormal hand or foot postures
• Parkinsonism

It commonly causes a clumsy hand due to apraxia, bradykinesia, akinetic rigidity and dystonia. A specific presentation of CBD is alien hand syndrome, a phenomenon presenting as a hand that moves on its own, in reaction to external stimuli, without control, and the hand feels foreign to the patient.

Patients with CBD also have the following:

• Ideomotor apraxia – unable to repeat or mimic particular movements. This makes the initiation of walking difficult, as their foot appears fixed to the floor.
• Non-fluent dysphasia/aphasia – disconnected speech and omission of words, which progresses to aphasia.

As CBD progresses, the symptoms become bilateral, and patients can develop frontotemporal dementia.

The diagnosis of CBD is usually a clinical one. However, the imaging modalities that can aid diagnosis include:

• MRI head – posterior parietal and frontal atrophy with atrophy of the corpus callosum.
• SPECT imaging – hypoperfusion in the posterior regions of the frontal and parietal lobes.

Levodopa has a limited effect in CBD. For painful stiffness, myoclonus, contractures, or dystonia, the treatments are:

• Regular splinting
• Clonazepam
• Baclofen
• Botulinum toxin A injections
• Intensive PT

Other causes of Parkinsonism

Drug-induced Parkinsonism

Drugs that block dopamine receptors and dopamine transmission can cause secondary drug-induced parkinsonism (DIP). The decrease in dopamine causes a denervation of the D1 and D2 receptors in the nigrostriatal pathway.

The dopamine antagonists that can cause DIP are:

• Antipsychotics such as fluphenazine, haloperidol, paliperidone, and risperidone
• Dopaminergic anti-emetics – such as metoclopramide, domperidone, and prochlorperazine
• Sodium valproate

The main difference in the presentation of DIP vs PD is the symmetrical and generalised tremor, rigidity and bradykinesia seen in DIP.

The most ideal treatment is to stop the causative drug. For psychiatric conditions, this might not be possible. In this case, the treatment for DIP is as follows:

• First line – anticholinergics – benztropine and trihexyphenidyl.
• Second line – amantadine.

Vascular Parkinsonism

Vascular parkinsonism (VP) is due to microangiopathy and lacunar infarcts affecting the basal ganglia, thalamus or the putaminal-pallido outflow.

Patients with VP present with:

• Parkinsonian-ataxic wide-based gait
• Dysphagia
• Dysarthria
• Hypertonia, brisk reflexes, and extensor plantar reflexes

MRI head can show white matter and periventricular hyperdensities.

The treatment for VP is levodopa for parkinsonism and antiplatelets for secondary prevention.

Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) occurs as a result of repetitive head trauma, usually from repetitive subconcussive blows and repetitive concussions. It commonly affects professional athletes in contact sports but also ex-soldiers and domestic violence victims. This trauma causes accumulation of tau and periventricular astrocytic tangles.
Much later in life, those affected develop CTE, which presents as a mixture of parkinsonism and dementia. Unfortunately, CTE can only be definitively diagnosed at post-mortem. There is currently no specific treatment for CTE. However, preventing head trauma with protective equipment and treating traumatic brain injury well might help prevent CTE.

Toxin-induced Parkinsonism

Toxin-induced parkinsonism (TIP) is caused by prolonged exposure to certain toxins that damage dopaminergic neurons. This presents as cogwheel rigidity, bradykinesia and falling when walking backwards.

Causative toxins are:

• Manganese
• Copper
• Mercury
• MPTP – by-product of incorrectly made synthetic heroin

Wilson’s Disease

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism from a lack of caeruloplasmin. Caeruloplasmin is the transporter protein of copper and removes excess copper. WD causes an accumulation of copper, especially in the liver and CNS.

The symptoms of WD are:

• Kayser–Fleischer rings
• Liver failure and coagulopathy
• Haemolytic anaemia – result of copper accumulation
• Parkinsonism

The following tests can aid diagnosis of WD:

• Deranged liver function tests
• Low caeruloplasmin levels
• Liver biopsy – raised copper concentration
• Genetic testing

The treatment of WD, including copper chelating medicines, is:

• D-penicillamine –– prevents and repairs the effects of copper overload.
• Trientine
• Zinc acetate – stops copper gut absorption.
• Low copper diet

These treatments can reverse the toxin-induced Parkinsonism seen in WD.

Huntington’s Disease

Pathophysiology

Huntington’s disease (HD) is an autosomal dominant neurodegenerative condition. It is caused by a CAG trinucleotide repeat mutation of the HTT gene, which encodes the protein huntingtin. Huntingtin is important in neuronal function. The CAG segment repeats an abnormal number of times – 36-120 times. It takes 40 CAG repeats for HD symptoms to develop. CAG repeats accumulate, causing symptoms to present earlier and more severely in subsequent generations, a phenomenon known as anticipation.

Presentation and diagnosis

Patients with HD usually start to have symptoms at 35-44 years old. The majority of patients have a family history.

HD presents in stages, which are:

• Early stage:
  • Irritability
  • Apathy
  • Depression
  • Hallucinations
  • Abnormal eye movements
  • Anosmia
• Middle stage:
  • Dystonia
  • Chorea
  • Unsteady gait
  • Frailty
• Late stage:
  • Rigidity
  • Bradykinesia
  • Immobility
  • Aphasia
  • Dysphagia

MRI head shows atrophy of the caudate and later cerebellar and cortical atrophy. The definitive, gold standard way diagnostic test is genetic testing looking for CAG repeats.

Treatment

The treatment of HD is currently symptomatic.

For the chorea, the treatment can include:

• Tetrabenazine
• Amantadine
• Riluzole
• Benzodiazepines

For parkinsonism, the treatment is:

• Levodopa
• Amantadine

Physiotherapy and Botulinum toxin A injections can be useful for dystonia. For mood issues, consider starting SSRIs or TCAs.

There are currently further studies of promising treatments, such as gene silencing therapies.