11th August 2024

Parkinson’s and other movement disorders

Overview of movement disorders

This section will explain what a movement disorder is, and the forms that it can take. Movement disorders affect the nervous system, classically the basal ganglia or cerebellum, resulting in abnormal voluntary movements or causing involuntary movements. It is important to note that not all disorders causing abnormalities of movement are part of a movement disorder syndrome; examples include hemiplegia in stroke, tonic-clonic seizures in epilepsy and neuromuscular disorders. There are a few treatable movement disorders – Parkinson’s disease, Wilson’s disease and dopa-responsive dystonia – and there should be a high index of suspicion for these.

Movement disorders have historically been, and still are, broadly divided into two categories: hypokinetic (reduced movement) or hyperkinetic (excess movement). Even though a degree of overlap is now recognised, with many disease processes not falling neatly into one category, they are still widely used today. This original classification was based on clinical syndromes with suspected underlying basal ganglia dysfunction. However with longer life spans allowing diseases to progress, the development of modern imaging techniques and new investigations we now have a much greater understanding of these conditions and the widespread effects they have on the CNS, outside of the classical movement disorder presentation from which they were originally described and categorised.

Tremor

Tremor is the rhythmic shaking of a part of the body due to involuntary muscle contractions. It can be divided into two main forms, resting or action, the latter occurring during voluntary movement. Action tremors can be divided into sub-categories including intention, postural, and isometric amongst others. Everyone has a physiological tremor, most commonly a fine shaking of the hands which is often not visible to the naked eye due to its low amplitude and frequency. In some individuals it is more prominent, including in those with hyperthyroidism, hypoglycaemia and alcohol withdrawal in which the normal physiological tremor is enhanced.

Essential tremor

This is the most common type of tremor and most common movement disorder worldwide. It can be a mix of a number of different tremor types, including kinetic, postural and sometimes rest. The tremor is mostly symmetrical and progresses over time. It commonly involves the hands and forearms and can also involve the voice, head and jaw. Incidence increases with age, although in those with a family history it can appear in adolescence. Stress and caffeine can make essential tremors more prominent while alcohol can lessen them. It is a clinical diagnosis although sometimes investigations are used to rule out other pathologies such as hyperthyroidism or Wilson’s disease.

For most the tremor does not cause any problems and no treatment is needed. As it progresses it may start to interfere with daily activities and cause social distress for which propranolol or primidone can be used. Second-line agents include gabapentin and topiramate. In very severe cases deep brain stimulation (DBS) or thalamotomy, either using MRI-guided focused ultrasound or gamma knife radiation, are possible.

Myoclonus

Sudden, brief, involuntary jerking or twitching movements, most commonly non-rhythmic. It can be described as positive or negative with the former being a sudden muscle contraction and the latter being a sudden loss of muscle tone. Myoclonic jerks occur physiologically including as hiccups or as limb twitches when a person drifts off to sleep. However, myoclonus can also be pathological and can occur in many different forms in isolation and as part of other neurological disorders, e.g. post-anoxic brain injury, genetic and neurodegenerative disease. Of note it can sometimes be the only manifestation of epilepsy and thus can indicate underlying seizure activity. Asterixis is a form of negative myoclonus which can occur due to metabolic disturbance such as hypercapnia (carbon dioxide retention flap), uraemia and liver failure (liver flap).

Parkinsonism

Parkinsonism is the triad of:

• Akinesia and bradykinesia
• Tremor: a resting tremor; described as ‘pill rolling’ when limited to the fingers
• Rigidity: lead-pipe (constant resistance to motion) and cogwheel (intermittent resistance to passive movement)

Although not part of the triad, the festinant, stooped, slow-turning gait of parkinsonism is also a cardinal sign.

Parkinsonism is due to impaired functioning of the basal ganglia. It most commonly presents due to idiopathic Parkinson’s disease (PD), but can be caused by a number of other conditions, including vascular disease (vascular parkinsonism), Parkinson’s plus syndromes, Wilson’s disease, post encephalitis, drug induced (antipsychotics most commonly) or toxins (carbon monoxide, MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]).

Idiopathic Parkinson’s disease

Overview of idiopathic Parkinson’s disease

Idiopathic Parkinson’s disease (PD) is characterised by the presence of Lewy bodies in the dopaminergic cells of the substantia nigra resulting in the death of those cells over time. It is more commonly seen in men, with an average age of onset of age of 65 years and a prevalence of 1% in the over 60s.

Symptoms frequently start unilaterally, and all three components of the triad may not be present. Over time, postural instability and gait disturbance develop along with speech and swallowing difficulties, hypomimia and micrographia, and non-motor symptoms such as depression, autonomic dysfunction, sleep disturbance and dementia. The rate at which the symptoms progress varies greatly, with most patients having a near-normal life expectancy. The biggest cause of death in the PD population is pneumonia, with dysphagia greatly contributing to this.

Idiopathic PD is normally a clinical diagnosis, but where there is uncertainty a dopamine transporter (DaT) scan can be performed. This has a good negative predictive value, with a negative result almost ruling out idiopathic PD or a Parkinson’s plus syndrome (unless too early in the disease course). However, a positive DaT scan does not necessarily indicate PD. In young patients, other movement disorders should be considered and investigated, including Wilson’s and Huntington’s diseases.

The next two sections will cover pharmacological management of the symptoms of idiopathic PD. It is important to note that non-pharmacological management is also incredibly important, including speech and language therapy, counselling, psychological support, physiotherapy and occupational therapy.

Pharmacological management of motor symptoms

Treatment is to manage symptoms; at present we do not have a way to slow disease progression. The aim is to minimise the frequency and severity of ‘off’ periods, when patients feel their movements slowing and becoming increasingly difficult to initiate.

Diagnosis and treatment initiation should only be done by those with expertise in movement disorders. The first-line therapy depends on whether motor symptoms are affecting the patient’s quality of life. NICE suggests the following:

Some further information about the above medications is as follows:

• Levodopa is nearly always combined with a decarboxylase inhibitor, either carbidopa or benserazide (as co-careldopa and co-beneldopa respectively), to prevent its conversion to dopamine in the peripheral circulation. This increases the amount of levodopa that reaches the CNS and reduces side effects.
• Dopamine agonists include ropinirole, rotigotine and pramipexole. Apomorphine is a liquid dopamine agonist preparation, which is fast acting and can help with the management of off periods.
• MAO B inhibitors reduce the breakdown of dopamine within the CNS and include selegiline, rasagiline and safinamide.
• COMT is an enzyme that breaks down levodopa, and its inhibitors prolong the activity of the levodopa. Examples include entacapone and tolcapone. They can only be used as an adjunct to levodopa.

Other treatment options include:

• Amantadine: considered if medication-induced dyskinesia is not managed by alternative agents. Side effects include ataxia, slurred speech, confusion, dizziness and livedo reticularis.
• Deep brain stimulation: can be considered when medical therapy alone is ineffective or insufficient.

A summary of the potential harms and benefits of the main drugs used in idiopathic PD is as follows:

* Excessive sleepiness, hallucinations and impulse control disorders

** Not included in NICE guideline tables but added here for completeness

The side effect profiles are similar across the four main treatments (levodopa, dopamine agonists, MAO B and COMT inhibitors) but vary in severity. Hallucinations, impulse control disorders, psychosis and dyskinesias are related to increased dopamine activity and are most severe with dopamine agonists. Side effects common to all drug classes mentioned in Table 2 and sometimes due to the Parkinson’s disease itself, include dry mouth, nausea and low blood pressure (most commonly orthostatic),

• MAO B inhibitors are mostly well tolerated, although they have been known to cause serotonin syndrome, especially if taken alongside SSRIs or other drugs that increase serotonin, and these should therefore be avoided.
• COMT inhibitors can cause gastrointestinal upset; tolcapone therapy requires careful monitoring due to the risk of hepatotoxicity.
• Psychotic symptoms (hallucinations or delusions) can occur with all treatments and can also occur later on due to the disease itself. Hallucinations are most commonly visual, like in Lewy body dementia. They do not always need treatment if well tolerated. If needed, the offending medication can be reduced, and if there is no cognitive impairment, quetiapine can be considered. Clozapine is an alternative if standard treatment is ineffective. NICE recommends that olanzapine should NOT be offered due to its possible worsening of motor symptoms.
• Impulse control disorders may manifest as gambling, hypersexuality, binge eating or obsessive shopping, and can develop at any time in the disease course. Risk factors include high alcohol consumption, smoking and history of impulsive behaviours. If these develop, the NICE recommendation is to reduce the dose of the dopamine agonist or, if this is not sufficient, the medication may need to be discontinued.
• Excessive sleepiness can be related to the disease itself or dopamine agonists. If this develops the patient must not drive and needs to inform DVLA. It is also important to consider any hazards at work. If reducing the medication is not possible then modafinil can be considered.

The pharmacological response threshold increases as the disease progresses and thus patients require increasing doses of levodopa and additional agents for symptom control. This reduces the therapeutic window between a sufficient motor response and dyskinesia, resulting in increasing difficulty managing ‘off’ periods and dyskinesias later in the disease course. Gait freezing can also develop, even when other motor symptoms are well controlled.

Another important side effect is neuroleptic malignant syndrome. This can occur on abrupt withdrawal of medication or in patients initiated on antipsychotic treatment. This is important to consider when patients develop poor absorption, for example secondary to diarrhoea or vomiting, or if they become unable to take their medication orally due to confusion or an unsafe swallow. Levodopa is a medication that is particularly at risk of poor absorption. In such cases either an NG tube can be considered or the oral medication can be converted into the equivalent dose as a dopamine agonist patch. If anti-emetics are required, domperidone is the medication of choice in idiopathic PD, as it does not cross the blood-brain barrier and therefore does not cause extrapyramidal side effects.

Management of other symptoms

Along with the traditional motor symptoms managed with the dopamine treatments above, there are other motor and non-motor symptoms of PD which require different treatment.

Other motor symptoms include:

• REM sleep disorders: loss of the normal paralysis during this sleep phase, which may result in violent, powerful movements, which may cause harm to the patient or those with whom they share a bed. It can be due to the disease process itself or secondary to medication. If it is due to the latter, the offending medication should ideally be discontinued; if this is not an option or does not work, clonazepam or melatonin can be trialled. Note that REM sleep disorders are not the same disease process as sleepwalking or night terrors common in childhood, which occur in the non-REM sleep phase.
• Restless leg syndrome.
• Nocturnal akinesia: reduced or absent movement overnight, hindering re-positioning and ultimately causing pain and sleep impairment. Thus, it is important to use long-acting forms of dopamine overnight.
• Dysphagia: impaired swallowing in PD is multifactorial. It causes two major complications: an inability to meet nutritional requirements and a risk of aspiration. Patients may eventually need a gastrostomy, although this does not eliminate the risk of salivary aspiration and some patients may decide to risk feed for pleasure alongside the gastrostomy.
• Sialorrhea (drooling): thought to be due to increased saliva secretion, an inability to maintain saliva in the mouth due to head drooping and hypomimia, and impaired saliva clearance. Treatment involves behaviour modification (such as frequent conscious swallowing), dopamine treatment, glycopyrronium bromide and botox injections.

Psychiatric symptoms include:

• Depression: the aetiology of depression in PD is not well understood but it occurs in around 35% of patients and is likely often multifactorial. NICE recommends psychosocial interventions first, such as a physical activity programme, a peer support group, a guided self-help programme or CBT (cognitive behavioural therapy). If these do not help then antidepressant medication such as an SSRI can be trialled.
• Dementia: there are two dementias associated with lewy body deposition – PD dementia and Lewy body dementia. In PD dementia, cognitive impairment is a late sign usually occurring many years after the motor symptoms have developed. In Lewy body dementia, cognitive impairment is an early symptom with motor symptoms developing after or at the same time, and progressing together. Management of these conditions is similar to other dementias such as Alzheimer’s and involves cognitive therapies along with medications.

Autonomic symptoms:

• Constipation: often occurs early and is likely multifactorial, partly due to autonomic dysfunction.
• Gastroparesis: affects >70% of individuals with PD. Although often asymptomatic, it is of particular importance in regards to levodopa treatment as delayed absorption causes delayed onset of action.
• Bladder dysfunction: can present as either an overactive bladder/urge incontinence, nocturia or less commonly urinary retention. Retention increases the risk of a urinary tract infection, which is an important cause of acute neurological deterioration. Overactive bladder can be treated with anticholinergic agents.
• Orthostatic hypotension: more commonly seen in later stages of the disease. Unfortunately, PD medication can precipitate or worsen hypotension. The advice is to stop possible contributing medications such as antihypertensives and diuretics, avoid dehydration and optimise cardiac function. If lifestyle measures are not sufficient then midodrine is first line and fludrocortisone is second line.
• Sexual dysfunction: erectile dysfunction or ejaculation difficulties in men and loss of lubrication and involuntary urination in women. Sexual counselling is important. Sildenafil and apomorphine can be used in erectile dysfunction. Other important factors that contribute to sexual dysfunction include hypersexuality from dopaminergic treatment and the effect low mood has on sexual drive and arousal.

A key miscellaneous symptom is that of:

• Olfactory dysfunction: impaired smell often precedes motor symptoms.

Parkinson’s plus syndromes

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) often present in a similar way to idiopathic PD but have a different pathogenesis. Unfortunately, they are usually unresponsive to dopamine therapy, or at best respond transiently. A trial of levodopa can therefore help to distinguish them from PD.

Multiple system atrophy

MSA is classified according to the predominant motor symptoms: parkinsonian MSA (MSA-P) or cerebellar MSA (MSA-C). The cerebellar subtype may present with cerebellar ataxia rather than parkinsonism. MSA is characterised by prominent early onset autonomic involvement resulting in bladder problems (most commonly retention, also urgency and incontinence), erectile dysfunction, constipation and significant orthostatic hypotension. MRI showing pontine and cerebellar atrophy can support the diagnosis but is not diagnostic.

Progressive supranuclear palsy

Loss of truncal control and vertical gaze are key features of PSP and result in frequent falls and impaired sight. As the disease progresses the patient can also lose eye movements in the horizontal plane. There are a few different subtypes of PSP, which unfortunately progress more rapidly than idiopathic Parkinson’s disease. Midbrain atrophy can support the clinical diagnosis but is not diagnostic.

Corticobasal degeneration

CBD is a type of frontotemporal dementia. The cortex and basal ganglia are affected resulting in personality changes, memory impairment and difficulties with language or maths along with parkinsonian symptoms. It is a clinical diagnosis with apraxia being a common finding. ‘Alien limb’ is a diagnostic feature of CBD and describes the feeling of disassociation the patient has from the involuntary movements in the affected limb.

Other causes of parkinsonism

Drug-induced parkinsonism

Drug-induced parkinsonism is the second most common cause of parkinsonism after idiopathic Parkinson’s disease. There are a range of different medications that have been identified as triggers including calcium channel blockers, tetrabenazine and metoclopramide, but most commonly it is due to antipsychotic medications resulting in iatrogenic inhibition of dopamine. It is normally more rapid in onset and symmetrical given the drug will affect both sides of the brain equally, with tremor a less prominent feature compared to idiopathic Parkinson’s disease. DaT imaging can help differentiate drug-induced parkinsonism from idiopathic PD or Parkinson’s plus syndromes, as it will normally be negative in drug-induced parkinsonism. Treatment involves stopping the offending drug if possible and/or using antimuscarinics such as procyclidine, benztropine or trihexyphenidyl (benzhexol).

Vascular parkinsonism

Vascular parkinsonism is a clinical syndrome secondary to vascular insults to the basal ganglia. The predominant feature is gait disturbance known as lower body parkinsonism, along with dementia, pyramidal signs and incontinence. Symptoms are normally symmetrical and progress in a stepwise manner. MRI imaging in these patients will typically show significant small vessel disease or basal ganglia lacunar infarcts. This group of patients have minimal response to dopamine therapy if at all. Treatment involves managing vascular risk factors to reduce the risk of disease progression.

Huntington’s disease

Huntington’s is a neurodegenerative condition resulting in a choreiform movement disorder, impaired cognition and emotional/behavioural disturbance. It has autosomal dominant inheritance due to an abnormally long triplet ‘CAG’ repeat in the huntingtin gene on chromosome 4. Disease usually occurs in middle age, age 40-60 years, but onset can be much earlier or later than this. With successive generations there is a risk of elongation of the CAG repeat length, resulting in earlier symptom onset (anticipation). This is much more common when the gene is transmitted through the paternal line.

Clinical onset is insidious, and subtle cognitive and behavioural changes often predate the onset of motor symptoms by a decade or more, but may not be recognised. The defining movement abnormality is chorea, Latin for ‘dance’, characterised by sudden, uncontrollable and involuntary jerking movements of the limbs or face, which may make the patient appear to be dancing or fidgeting.  The more severe form is ballism, in which the movements are quite violent and can be distressing for the patient, sometimes resulting in injuries to the patient or others in the vicinity.

Huntingdon’s is a clinical diagnosis although genetic testing can be useful if there is uncertainty such as in de novo cases with no family history. Brain atrophy is prominent and occurs earliest in the caudate nucleus and putamen, with cortical involvement as the condition advances.

Unfortunately, there is currently no way to prevent disease progression, so treatment aims to manage symptoms. Anti-dopaminergic drugs such as tetrabenazine or antipsychotics can be used for movement disorders including chorea. A variety of standard psychiatric drugs are used to treat the behavioural impairments including antidepressants, in particular SSRIs and other mood-stabilising drugs such as valproate or carbamazepine for the irritability. There are no pharmacological options for the cognitive impairment. As the disease progresses, physiotherapy, occupational therapy and speech therapy input are very helpful, and affected individuals may eventually need a wheelchair or be bed bound and need full-time care due to the combination of motor and cognitive impairment.

Wilson’s disease

Wilson’s disease is characterised by liver failure, neuropsychiatric symptoms and movement disorders. It is an autosomal recessive disorder that results in abnormal copper metabolism leading to excessive copper deposition in tissues, most notably the liver, eyes and brain. The defective gene responsible is ATP7B located on chromosome 13. It usually presents between 10-25 years of age. If it presents earlier in life it is normally through liver failure, while those with later presentation predominantly display neurological signs.

The copper in the liver results in hepatitis, which leads over time to cirrhosis. In the brain, copper accumulation, particularly in the basal ganglia, can result in chorea, parkinsonism, dementia, speech disturbance, behavioural and psychiatric symptoms. Corneal deposition leads to green-brown rings around the edge of the iris known as Kayser-Fleischer rings, which can be seen on slit-lamp testing. These deposits do not affect vision and are more commonly seen in those who have neurological involvement compared to those with isolated liver disease. The excess copper can also result in renal tubular acidosis (Fanconi syndrome), haemolysis and blue nails.

Test results include reduced serum caeruloplasmin, reduced total serum copper (due to 95% copper being carried by caeruloplasmin), increased free serum copper and increased 24-hour urinary copper. MRI brain is non specific but may show basal ganglia abnormalities. There is a clinical criteria, ‘a Leipzig score,’ that helps to guide clinicians as to the likelihood of Wilson’s disease.

Treatment is with penicillamine, which chelates copper, enabling its excretion in the urine. Trientine hydrochloride is an alternative chelating treatment. The prognosis is very good with patients leading normal lives with normal life expectancy if the disease is detected early and there is good treatment adherence.

Restless legs syndrome

Restless legs syndrome is a condition that results in a strong and often overwhelming urge to move one’s legs, often accompanied by an unpleasant sensation if the legs are kept still. Its mechanism is unknown. Although similar to akathisia (generalised restlessness), restless legs syndrome is considered a distinct clinical syndrome. It usually occurs during inactivity or at rest in the late afternoon, evening and prior to sleep.

It is more commonly seen in those with PD and often predates the onset of parkinsonism. It can also be related to iron deficiency, and thus all patients should have iron studies performed (in particular ferritin – although remember this is an acute phase reactant so may be raised in infection and inflammation). If ferritin is low, then iron supplements should be prescribed as this may reduce or eliminate the condition. The cause of the iron deficiency, if unknown, may also require investigation using quantitative faecal immunochemical testing (FIT) in line with the two-week-wait colorectal cancer NICE guidelines. Less commonly, restless leg syndrome can be related to renal disease, neuropathy, pregnancy and other sleep disorders.

Management involves walking or stretching exercises and avoiding alcohol, nicotine and caffeine. Medications can also be used, the first line being dopamine agonists and alternatives/additional treatments including gabapentin and benzodiazepines.

Stiff person syndrome

This is a rare condition that is more common in females. It presents mostly between the ages of 30-50 with stiffness and muscle spasms, most commonly of the truncal muscles, which can be painful and over time impair gait, resulting in frequent falls. The spasms can be triggered by emotional stress or environmental stimuli such as an unexpected loud noise, physical touch or cold temperatures.

It is associated with anti-GAD (glutamic acid decarboxylase) antibodies, like in type 1 diabetes but in much higher concentrations, and thus can be associated with T1DM and other related autoimmune conditions, including pernicious anaemia, thyroid disease and vitiligo. The anti-GAD antibodies can be found in either the serum or CSF.

The mainstay of treatment is symptom control with botox, benzodiazepines and neuropathic agents such as gabapentin. There are some immune therapies now to help to slow disease progression including plasma exchange, IVIg and immunosuppressants.

Acute drug reactions to medications affecting dopaminergic transmission

Acute dystonia

Dystonia describes an involuntary muscle contraction, which can be primary or secondary. Cervical dystonia, also known as torticollis, is the most common focal dystonia.

Acute dystonia is rare and usually secondary to anti-dopaminergic agents, including metoclopramide. It is often painful and can be life threatening due to occlusion of the airway depending on the muscle groups affected. Examples include oculogyric crisis causing intermittent deviation of the eyes, often upwards, or laryngeal dystonia, which causes intermittent contractions of the muscles in the larynx and therefore difficulty speaking or changes/hoarseness to the voice.

If the patient has been exposed to an anti-dopaminergic treatment then benztropine or diphenhydramine should be given intravenously and the offending agent should be discontinued or weaned. It is important to assess for concurrent pathology such as neuroleptic malignant syndrome or metabolic, infectious or toxin causes.

Of note, dopa-responsive dystonia, which presents in childhood, is a rare disorder but one which is treatable, responding to L-dopa or dopamine agonists and is therefore important not to miss.

Tardive dyskinesia

Hyperkinetic movement disorders (including tardive dystonia, myoclonus and tremor) that develop due to prolonged anti-dopaminergic treatment, usually antipsychotic medication but also metoclopramide. Tardive, derived from the Latin for ‘slow’, describes the slow, writhing (choreiform or athetoid) movements often seen in the face, commonly lip smacking, lip puckering and intermittent blinking. The diagnosis is clinical and requires the movements to have been present for at least 4 weeks.

The offending drug should be withdrawn, however that may involve a weaning regime while an alternative medication is uptitrated. Symptoms can last up to 6 months after the offending medication is discontinued, and in unfortunate cases may be irreversible. First-line treatment is tetrabenazine (also used in the management of chorea in Huntington’s disease).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome, also known as parkinsonism hyperpyrexia syndrome, is a drug reaction that presents similarly to severe parkinsonism with rigidity along with a high fever, confusion or altered behaviour and autonomic dysfunction resulting in labile blood pressures, dilated pupils, tachycardia and sweating. In severe cases the airway may be compromised due to loss of consciousness, or severe rigidity may prevent adequate ventilation. It most commonly occurs in patients recently started on antipsychotic treatment, but can also develop in those whose dopaminergic treatment is abruptly withdrawn. Clinically it can look quite similar to serotonin syndrome and thus it is important to take a thorough drug history.

Treatment involves addressing the precipitant, i.e. stopping the offending antipsychotic medication or restarting the necessary dopamine agonist, alongside managing the fever and any kidney injury or rhabdomyolysis. In severe cases dantrolene, a muscle relaxant, and bromocriptine, a dopamine agonist, can be used.

Ataxia

Ataxia is the loss of coordination, which can cause gait, speech, swallow and balance problems. It is not a specific diagnosis, but a neurological sign which can develop due to damage to a number of different areas within both the peripheral and the central nervous systems. Ataxia due to dysfunction of the cerebellum or its tracts is considered a movement disorder, whereas sensory (peripheral or dorsal column lesions) and vestibular ataxias result in disorders of movement but would not be cared for by a movement disorders specialist.

Sensory ataxia

Sensory ataxia will only briefly be covered here as it is not a movement disorder. It develops due to damage to the somatosensory nerves, inhibiting sensory feedback and therefore proprioception.

Sensory ataxia can be due to peripheral sensory neuropathies or spinal lesions. Peripheral neuropathies are commonly due to diabetes or alcohol excess, but can also be due to nutritional deficiencies, or metabolic, genetic, toxin, vascular and autoimmune causes. Spinal causes are due to damage to the dorsal column of the spinal cord, including tabes dorsalis secondary to syphilis, subacute combined degeneration of the spinal cord due to B12 deficiency (or functional B12 deficiency, as in nitric oxide poisoning), and vascular causes. Gluten ataxia describes ataxia in the presence of the antibodies of gluten sensitivity or coeliac disease, and may occur without gastrointestinal symptoms. Coeliac testing is therefore recommended in those who have unexplained peripheral neuropathies or ataxia.

Cerebellar disease

Cerebellar disease gives a specific set of findings remembered by the acronym ‘DANISH’: dysdiadochokinesia, ataxia, nystagmus, intention tremor, slurred speech and hypotonia. The ataxia can manifest as a wide-based gait, difficulty with the heel-to-shin test, past-pointing and slow hyper and hypometric saccades.

The causes of cerebellar disease can be split into genetic and non-genetic. Non genetic causes include:

• Vascular: stroke
• Autoimmune: MS, immune-mediated (Miller Fisher syndrome), paraneoplastic
• Metabolic: thiamine deficiency, hepatic encephalopathy
• Toxin: alcohol, gluten in coeliac disease
• Infectious: syphilis
• Degenerative: MSA-C

We will focus on a few genetic conditions in more detail.

Spinocerebellar ataxia

Spinocerebellar ataxias (SCA) are a large, complex group of over 20 inherited degenerative conditions presenting with progressive cerebellar ataxia, and named numerically in order of discovery (SCA1, SCA2 etc.). Alongside cerebellar syndromes, the various SCAs can also present with movement disorders, peripheral neuropathies, cognitive impairment, oculomotor/retinal/bulbar symptoms and pyramidal signs. Like Huntington’s disease they are mostly caused by triplet repeats with autosomal dominant inheritance. Most SCAs present in adulthood, however some can present in childhood. Treatment aims to reduce symptoms and maximise function as there are no cures.

Friedreich’s ataxia

Friedreich’s ataxia is an autosomal recessive progressive ataxia due to mutations in the frataxin gene. It is the most common hereditary ataxia and has a mean age of onset of 14 years. It is due to abnormal iron metabolism in the mitochondria leading to increasing cell death over time. It particularly affects the heart, pancreas, and nervous system (specifically the cerebellum, spinal cord and peripheral nerves), and leads to hypertrophic obstructive cardiomyopathy (90%), diabetes and ataxia/loss of proprioception/weakness. The cardiac complications are the leading cause of death.

The first and classical feature is ataxia with gait disturbance. Other symptoms include ataxia of the trunk and limbs, which may be described by the patient as ‘general clumsiness’, cerebellar dysarthria, loss of tendon reflexes with upgoing plantars, and a sensory neuropathy with distal loss of proprioception and vibration sensation, but typically preservation of pain and temperature sensation. Later features include motor weakness, more prominently of the lower limbs, and optic and vestibular atrophy. Other findings include scoliosis. There is generally no cognitive impairment.

There is currently no cure or effective treatment for the disease, so focus is on managing complications, in particular  cardiac involvement given the high associated mortality, and helping individuals maintain a normal level of function for as long as possible.

Ataxia telangiectasia

Ataxia telangiectasia is another autosomal recessive ataxia, similar to Fredrich’s ataxia. It is one of the inherited combined immunodeficiency disorders that begins early in childhood. As the name suggests, it causes a progressive cerebellar ataxia resulting in most affected individuals requiring a wheelchair by adolescence, and telangiectasias, spider-like clusters of dilated capillaries most commonly seen around the eyes and cheeks. In addition, it results in  recurrent infections (IgA deficiency) and an increased risk of cancer (10-30% lifetime risk), in particular lymphoma and leukaemia.

Functional neurology

Functional neurology can present in many different ways, including with movement disorders. Functional neurological disorder should ideally be a positive diagnosis based on clinical findings rather than a diagnosis of exclusion, although initial tests may be necessary to rule out some disorders with similar presentations. A full discussion is beyond the scope of this chapter.

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