Parkinson’s disease

Published on 02/04/2015 by admin

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45 Parkinson’s disease

Instruction

Examine this patient.

Salient features

History

• Tremor: usually unilateral at onset; usually starts in upper limbs. Also seen in the legs and jaws

• Rigidity: ask about history of falls, poor balance, pain and muscle stiffness

• Poverty of movement: ask about drooling of saliva, difficulty in writing (micrographia), difficulty in turning in bed and change in voice (softness of voice)

• Family history of disease (susceptibility genes include α-synuclein, leucine rich repeat kinase 2 and glucocerebrosidase)

• History of encephalitis

• History of smoking (never smokers are twice as likely to develop disease) and caffeine intake (those who take no or very low quantities of daily caffeine, are at increased risk, ~25%) (Lancet 2009;373;2055–66)

• History of exposure to managanese dust, carbon disulfide or carbon monoxide

• Use of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for recreational purposes

• Elicit a drug history, particularly regarding neuroleptics (reserpine, metoclopramide)

• History of herbal medications, particularly Pacific sedative kava kava and Indian snake root Rauwolfia serpentina

• History of severe head injury, encephalitis, hypertension or cerebrovascular disease.

Examination

• Usually florid cases are seen in the examination and the striking abnormalities (Fig. 45.1) are:

• an expressionless or ‘mask-like’ face (fixed stare, infrequent blinking and ironed-out wrinkles)

• drooling of saliva

• resting or pill-rolling movement (most common in the distal extremities).

Fig. 45.1 Parkinson’s disease. (A) The slightly anxious frozen face and characteristic flexed posture. (B) Development of anterocollis. (C) Typical facial expression of a patient with progressive supranuclear palsy, illustrating worried or surprised appearance, with furrowed brow and fixed expression of lower face.

Proceed as follows:

• Comment on the expressionless face, pill-rolling movement and drooling of saliva so that the examiner knows that you have observed these abnormalities. Elicit bradykinesia by asking the patient to touch her thumb with each finger in turn.

• Examine the tone, in particular at the wrist for cog-wheel rigidity.

• Proceed to do the glabellar tap (tap the forehead just above the bridge of the nose repeatedly (about twice per second): in normal subjects, the blinking will stop whereas the patient with Parkinson’s disease continues to blink: referred to as Myerson’s sign. (It must be remembered that this sign is unreliable.)

• Ask the patient to walk and comment on the paucity of movement including the absence of arm swing and festinating gait (the patient walks with a stooped posture as if trying to catch up with her centre of gravity). The feet may scrape the floor in taking steps so the patient trips easily (be prepared to prevent the patient from falling when examining the gait).

• Tell the examiner that you would like to:

• ask the patient a few questions with a view to assessing her speech

• assess handwriting (tremulous and small, micrographia).

• Tell the examiner that you would like to look for:

• postural hypotension (Shy–Drager syndrome, levodopa treatment)

• impaired vertical gaze (Steele–Richardson–Olzewski syndrome)

• check for anosmia (an early sign)

• seborrhoea.

Note: The diagnosis of Parkinson’s disease is entirely clinical but the results of certain investigations may help in recognizing alternative causes for parkinsonism.

Diagnosis

This patient has features of Parkinson’s disease (lesion) that are caused by long-standing use of phenothiazines (aetiology). The patient is severely disabled by the bradykinesia (functional status).

Questions

What comprises Parkinson’s disease?

• Upper body dyskinesia must be present; it is a symptom complex containing many of the following features:

• Slowness of movement (bradykinesia)

• Poverty of movement (mask-like facies, diminished arm swing)

• Difficulty in initiating movement

• Diminished amplitude of repetitive alternative movement

• Inordinate difficulty in accomplishing some simultaneous or sequential motor acts.

• Rigidity is usually but not always present:

• Lead-pipe rigidity is where the increase in tone is equal in flexors and extensors of all four limbs but slightly more in flexors, resulting in a part flexed ‘simian’ posture

• Cog-wheel rigidity is caused by superimposed or underlying tremor.

• Postural instability is usually a late feature

• Absent in about one-third of patients with Parkinson’s disease at presentation and throughout its course in some

• Resting, 3–5 Hz pill, pronation and supination rolling tremor of the upper limb

• Intermittent (can usually be brought about by getting the subject to count backwards with the eyes closed and hands dangling over the armrests of the seat)

• Intensified by emotion or stress and disappearing during sleep

• May affect legs, head and jaw as well; jaw tremor is rare but is most distressing as the teeth may pound together until they become unbearably painful.

Advanced-level questions

What are the pathological changes in Parkinson’s disease?

The most typical pathological hallmarks of Parkinson’s disease are:

• neuronal loss with depigmentation of the substantia nigra

• Lewy bodies, which are eosinophilic cytoplasmic inclusions in neurons consisting of α-synuclein.

The following associations have been made with clinical features and pathological changes:

Clinical deficit	Pathology
Motor symptoms	Degeneration of dopaminergic nigrostriatal pathway
Cognitive defects	Degeneration of dopaminergic mesocortical and mesolimbic pathways
Autonomic dysfunction	Dopamine depletion in the hypothalamus
‘Freezing phenomenon’	Degeneration of the noradrenergic locus ceruleus
Dementia	Degeneration of the cholinergic nucleus

What is the mental status of patients with Parkinson’s disease?

• In the initial stages, intellect and senses are usually preserved. Many patients have some intellectual deterioration—a slowness of thought and of memory retrieval (bradyphrenia), and subtle personality changes.

• Global dementia may develop in one-fifth of patients.

• Depression occurs in one-third of patients.

• Acute confusion can be precipitated by drug therapy.

Note: Parkinson’s disease must be kept in mind in elderly patients presenting with a history of frequent falls.

What are the causes of Parkinson’s disease?

Pseudoparkinsonism

• Essential tremor

• Atherosclerotic (vascular) pseudoparkinsonism (mention that in the past atherosclerosis was thought to be a cause of Parkinson’s disease but this is no longer accepted as a cause)

• Hemiparkinsonism (presenting feature of a progressive space-occupying lesion)

What differences are seen in rigidity, spasticity and gegenhalten?

• Rigidity indicates increased tone affecting opposing muscle groups equally and is present throughout the range of passive movement. When smooth it is called lead-pipe rigidity and when intermittent is termed cog-wheel rigidity. It is common in extrapyramidal syndromes: Wilson’s disease and Creutzfeldt–Jakob disease.

• Spasticity of the clasp-knife type is characterized by increased tone, which is maximal at the beginning of movement and suddenly decreases as passive movement is continued. It occurs chiefly in the flexors of the upper limb and extensors of the lower limb (antigravity muscles).

• Gegenhalten, or paratonia, is where the increased muscle tone varies, and becomes worse the more the patient tries to relax.

What do you understand by the ‘wheelchair sign’ in Parkinson’s disease?

Patients with advanced disease and ‘on–off’ motor fluctuations require a wheelchair when ‘off’ and when ‘on’ are seen to walk about (sometimes pushing the chair!). These patients are rarely permanently wheelchair bound; in contrast, those who never leave their wheelchair usually do not have Parkinson’s disease.

What is the role of protein diets in patients who have episodes of sudden and substantial loss of mobility?

High-protein diets should be avoided in these patients because a large influx of dietary amino acids can interfere with the transport of levodopa into the brain (N Engl J Med 1967;276:374–9).

What do you understand by the term lower half parkinsonism?

It refers to vascular parkinsonism, which usually presents with severe failure to initiate gait, broad-based shuffling gait, mild bradykinesia, rigidity of the arms and subtle hypomimia. Risk factors include hypertension and history of ministrokes. There is no rest tremor; olfaction is normal and response to levodopa is usually poor (Lancet 2009;373;2055–66).

How is the severity of Parkinson’s disease graded?

Hoehn–Yahr staging grades Parkinson’s disease into five stages:

I: newly diagnosed disease

II and III: moderately severe disease

IV and V: advanced disease.

How would you manage a patient with Parkinson’s disease?

Step I: replacing dopamine neurotransmitter that is lost as the dopamine neurons degenerate is the mainstay treatment. All drugs are started at low doses and doses are increased slowly to reduce adverse effects (start low, go slow). Withdrawal of therapy also should be done slowly to avoid worsening of parkinsonism or precipitating neuroleptic malignant syndrome:

• First-line dopaminergic agents: carbidopa plus levodopa (immediate release and controlled release), carbidopa plus levodopa plus entacoapone, dopamine agonists including non-ergot (pramipexole, ropinirole) and ergot (pergolide)

• Second-line alternatives: anticholinergic agents (trihexyphenidyl, benztropine), selective monoamine oxidase B inhibitors (selegiline) and N-methyl-d-aspartate (NMDA) antagonist (amantidine); anticholinergic drugs are more effective in alleviating tremor and rigidity rather than bradykinesia.

Step II: transplanting fetal nerve tissue to replace dopamine neurons that have been lost.

Step III: halting neuronal loss altogether with trophic factors; this is in the early stages of clinical testing. At present, there are no neuroprotective therapies, although clinical trials with monoamine oxidase B inhibitors, dopamine agoists and coenzyme Q₀ may slow progression. Glial cell line-derived neurotrophic factor (GDNF) is under investigation. Data are still needed to clarify neuroprotective therapies.

In which condition is levodopa absolutely contraindicated?

What do you know about ‘drug holidays’ in levodopa therapy?

Drug holidays (i.e. discontinuation of therapy) was previously claimed to enhance the efficacy of treatment when it was resumed; it is now known to be dangerous (deaths have occurred) and of doubtful value.

What do you know about dopamine receptors?

At least four types of receptor have been reported: D₁ and D₂ are the two major families of dopamine receptors. For neurotransmission to occur, a complex consisting of a dopamine receptor and a G protein (guanine nucleotide-binding protein) must be formed. This complex then usually couples with the enzyme adenylate cyclase, which controls the formation of the second messenger cyclic AMP. Alteration of the second messenger leads to a cascade of events that ultimately determines the transfer of information between nerve cells. The D_2A receptor is involved in the therapeutic response elicited by dopaminergic agonists in parkinsonism, although the mechanism is not clear at a physiological level. The role of the D₁ family is unclear—whether the activation of these receptors leads to useful effects (i.e. reduction of parkinsonian deficits), undesireable effects (e.g. dyskinesia), or both. Bromocriptine, pergolide and lisuride all stimulate D₂ receptors, whereas bromocriptine and lisuride are D₁ receptor antagonists and pergolide is a D₁ receptor agonist.

What is the role of fetal tissue in potential treatment of Parkinson’s disease?

Parkinson’s disease is characterized by loss of the midbrain dopamine neurons that innervate the caudate and putamen. Patients tend to have a reduced response to levodopa after 5–20 years of therapy, with ‘on–off’ fluctuations consisting of dyskinesia alternating with immobility. Animal experiments have suggested that fetal dopaminergic neurons can survive transplantation and restore neurological function. Trials are underway to determine whether fetal grafts can improve motor function in patients with Parkinson’s disease. Fetal ventral mesencephalic tissue is implanted in the patient’s postcommissural putamen (N Engl J Med 1995;332:1118–24).

What is the role of thalamotomy in treatment of Parkinson’s disease?

Thalamotomy used to be the main treatment until 1950, but with the introduction of levodopa it became less popular. However, there has been a revival of stereotactic surgery prompted by the failure of levodopa in four main aspects: in severe tremor, levodopa-induced dyskinesia, advanced Parkinson’s disease and akinetic–rigid syndromes (BMJ 1998;316:1259–60). Four types of stereotactic surgery are practised:

• Thalamotomy is used for intractable tremor and radiofrequency ablation of an area of the venterointermediate nucleus of the thalamus. It is unsuitable for bilateral tremor as bilateral thalamotomy tends to cause impairment of speech.

• Thalamic stimulation is achieved with placement of a fine electrode in the venterointermediate nucleus and insertion of a pacemaker under the skin on the chest. This relieves tremor and can be performed bilaterally. Neither procedure improves akinesia, the most disabling aspect of Parkinson’s disease.

• Deep-brain stimulation of the globus pallidus and subthalamic nucleus may result in striking improvements in parkinsonism and dyskinesia, resulting in large reductions of levodopa dose and thus improvements in levodopa-induced dyskinesias (Lancet 1995;345:91–5).

• Unilateral posteroventral medial pallidotomy ameliorates contralateral parkinsonian symptoms and medication-related dyskinesia and the effect is sustained for up to 5.5 years. Improvements in ipsilateral and axial symptoms are not sustained and many patients undergo, a second contralateral procedure (N Engl J Med 2000;342:1708–14).

Note: Patients with dementia and hallucinations tolerate all surgical procedures poorly and any benefit in patients with rapidly progressive parkinsonism is likely to be short lived.

What are Parkinson plus syndromes?

Some patients have other neurological deficits in addition to Parkinson’s disease. Examples of these so-called Parkinson plus syndromes are:

• Steele–Richardson–Olszewski disease (akinesia, axial rigidity of the neck, bradyphrenia, supranuclear palsy)

• multiple system atrophy

• olivopontocerebellar degeneration

• strionigral degeneration.

• progressive autonomic failure (Shy–Drager syndrome)

• Basal ganglia calcification.

What is tardive dyskinesia?

Tardive dyskinesia is seen in patients taking neuroleptics. Its manifestations are orofacial dyskinesia such as smacking, chewing lip movements, discrete dystonia or choreiform movements and—rarely—rocking movements. Withdrawal of the offending drug will improve these symptoms over a period of 3–4 years, except in a small minority of patients. Drug-induced parkinsonism is usually bilateral with evident bradykinesia, rigidity and tremor. Tremor in drug-induced parkinsonism is often postural.

Mention some heredo-degenerative parkinsonian disorders

• Hallervorden–Spatz disease: autosomal recessive; patients also have dementia, dystonia, choreoathetosis, retinitis pigmentosa. There is increased iron deposition and increased cysteine in the globus pallidus.

• Fahr’s disease or familial basal ganglia calcification: patients also have chorea, dementia and palilalia.

• Olivopontocerebellar and spinocerebellar degenerations: autosomal dominant; associated cerebellar ataxia and retinitis pigmentosa.

How would you manage autonomic and psychological symptoms?

• Insomnia: adjust Parkinson’s disease drugs; use sleep hygiene techniques or clonazepam

• Depression: serotonin and noradrenergic reuptake inhibitors or amitryptiline

• Rapid eye movement behaviour disorders: adjust Parkinson’s disease drugs or give clonazepam

• Fatigue: amantidine or selegiline

• Day time sleepiness: modafinil

• Psychosis and hallucinations: adjust Parkinson’s disease drugs or use an antipsychotic (clozapine, quetiapine or aripiprazole). Quetapine typically does not worsen motor function and is often used as first-line therapy

• Constipation: osmotic laxatives (macrogol)

• Urinary urgency: check drugs; use anticholinergic bladder stabilizers, and desmopressin for nocturia

• Impotence: sildenafil, tadalafil and vardenafil

• Pain: adjust Parkinson’s disease drugs and give muscle relaxants

• Restless legs: dopamine agonists

• Orthostatic hypotension: adjust Parkinson’s disease drugs; increase water and salt intake; give fludrocortisone, ephedrine or midodrine

• Drooling: 0.5% atropine eye drops sublingually, scopoderm patch or botulinum toxin injections into salivary glands

• Excessive sweating: adjust Parkinson’s disease drugs; give propantheline, propranolol or topical aluminium creams.

James Parkinson (1755–1824) first reported six cases of this syndrome in 1817 (at the age of 62 years).

Jean Martin Charcot (the father of neurology) proposed that this syndrome be called ‘maladie de Parkinson’.

JC Steele, JC Richardson and J Olszewski were all US neurologists.

K von Economo (1876–1931), an Australian neurologist, also wrote on Wilson’s disease.

Muhammed Ali (or Cassius Clay) the world heavy-weight boxing champion is reported to have premature of Parkinsons disease, the ‘punch drunk’ syndrome.

Professor K Ray Chaudhuri MD FRCP DSc is Consultant Neurologist and Professor in Neurology/Movement Disorders at Kings College Hospital NHS foundation Trust, University Hospital Lewisham, Kings College London and the Institute of Psychiatry. He is a recognized teacher and active researcher within the Guy’s, King’s and St Thomas’ School of Medicine, London, UK and is the medical director of the National Parkinson Foundation International Centre of Excellence at Kings College, London.

Professor Christopher Mathias is Professor of Neurovascular Medicine in the University of London, with an appointment held jointly between Imperial College London and the Institute of Neurology, University College London. He has been a Consultant Physician at St Mary’s Hospital since 1982 and at the National Hospital for Neurology and Neurosurgery, Queen Square, since 1985. His main interest is autonomic failure.

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