Parkinson's Disease and Myasthenia Gravis

1. Introduction
2. Parkinson's Disease
   • Pathology
   • Clinical Features
   • Levodopa
   • Dopamine Receptor Agonists
   • MAO-B Inhibitors
   • COMT Inhibitors
   • Anticholinergics
   • Amantadine
   • Motor Fluctuations
   • Surgical Treatment
3. Myasthenia Gravis
   • Pathology
   • Clinical Features
   • Pyridostigmine
   • Immunosuppression and Other Treatments
   • Myasthenic and Cholinergic Crisis
   • Drugs to Avoid in Myasthenia
4. Summary
5. Drug Summary Table
6. Quiz

• Parkinson's disease is caused by loss of dopaminergic neurons (nerve cells that make dopamine) in the substantia nigra pars compacta, a dopamine-producing area of the midbrain. Pharmacological treatment aims to restore dopamine signalling in the basal ganglia (deep brain structures that control movement).
• Levodopa remains the most effective drug, given with a peripheral DOPA decarboxylase inhibitor (a drug that blocks the enzyme DOPA decarboxylase outside the brain). The two combinations are co-careldopa (levodopa with carbidopa) and co-beneldopa (levodopa with benserazide). This maximises central availability, meaning that more levodopa reaches the brain. Dopamine agonists (drugs that stimulate dopamine receptors), MAO-B inhibitors (monoamine oxidase B inhibitors) and COMT inhibitors (catechol-O-methyltransferase inhibitors) are the other principal classes.
• Myasthenia gravis is an autoimmune disease caused by antibodies to the nicotinic acetylcholine receptor (the receptor on the muscle that acetylcholine switches on). These receptors are at the neuromuscular junction (where a nerve meets a muscle). The main symptom is fatiguable skeletal muscle weakness, which worsens with repeated use and improves with rest.
• First-line treatment is the acetylcholinesterase inhibitor pyridostigmine (a drug that stops the breakdown of acetylcholine). Immunosuppression (drugs that dampen the immune system, such as steroids and azathioprine) is added for sustained control. Myasthenic crisis is a respiratory emergency treated with intravenous immunoglobulin (IVIG, pooled antibodies given into a vein) or plasmapheresis (filtering antibodies out of the blood).

Introduction

This lesson covers two illustrative neurological disorders. In Parkinson's disease, the central problem is loss of a single neurotransmitter (dopamine). In myasthenia gravis, the central problem is failure of neurotransmission at the muscle end-plate (the part of the muscle fibre that receives the signal from its nerve). Both are good examples of how rational pharmacology can improve symptoms. In Parkinson's disease, current drugs relieve symptoms but are not established to slow the loss of nerve cells.

Parkinson's Disease

Pathology

Parkinson's disease is a progressive neurodegenerative disease (a disease in which nerve cells gradually die) characterised by:

• Loss of dopaminergic neurons in the substantia nigra pars compacta. Symptoms are not clinically apparent until at least 50% of dopaminergic cell activity has been lost.
• Lewy bodies in surviving neurons: intracellular aggregates (clumps inside the cell) of misfolded α-synuclein (a protein that has folded the wrong way and sticks together).
• Loss of dopamine input to the striatum (the part of the basal ganglia that receives signals from the substantia nigra) alters basal ganglia signalling. Dopamine normally excites the D₁ direct pathway (which promotes movement) and inhibits the D₂ indirect pathway (which suppresses movement); losing these effects impairs movement. For a fuller account of these pathways, see Neuroscience Online.

Parkinsonism is the clinical syndrome of bradykinesia (slowness of movement) plus at least one of tremor, rigidity or postural instability (poor balance, with a tendency to fall). Idiopathic Parkinson's disease (Parkinson's disease with no identified cause) is the commonest form, but several other conditions can mimic it. Other causes of parkinsonism include drug-induced parkinsonism and vascular parkinsonism (due to cerebrovascular disease). Dementia with Lewy bodies is another mimic. Progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration are neurodegenerative parkinsonian syndromes that involve a wider area of the nervous system. They are often called "Parkinson-plus syndromes" or atypical parkinsonism.

Parkinson's disease is diagnosed clinically, using the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. Atypical syndromes such as progressive supranuclear palsy and multiple system atrophy tend to respond less well to dopaminergic drugs, and an insufficient response should prompt a review of the diagnosis. Separately, NICE advises against acute levodopa and apomorphine challenge tests (a single test dose, given to see whether symptoms improve) to tell parkinsonian syndromes apart.

Clinical Features

The main motor features:

• Bradykinesia: slowness of movement, "masked face" (reduced facial expression), micrographia (progressively smaller handwriting), reduced arm swing on walking. Required for diagnosis.
• Resting tremor: classic 4-6 Hz "pill-rolling" of the thumb and fingers; disappears with movement and during sleep.
• Rigidity: "lead pipe" or "cogwheel" rigidity (the cogwheeling reflects superimposed tremor).
• Postural instability: later feature.

Non-motor features (often pre-dating motor symptoms by years):

• REM sleep behaviour disorder (acting out dreams during rapid eye movement sleep), anosmia (loss of the sense of smell), constipation.
• Depression and anxiety.
• Cognitive decline and dementia in late disease (Parkinson's disease dementia).
• Autonomic features: postural hypotension, urinary urgency, drooling.

Levodopa

Dopamine itself does not cross the blood-brain barrier (the tightly sealed lining of the brain's blood vessels, which keeps most substances out of the brain). Levodopa (L-DOPA) is the immediate biosynthetic precursor of dopamine (the compound the body converts into dopamine in a single step). Unlike dopamine, it does cross the blood-brain barrier. In the brain, surviving dopaminergic neurons convert it to dopamine using the enzyme aromatic L-amino acid decarboxylase (AADC, also known as DOPA decarboxylase). The remaining nigrostriatal neurons (those running from the substantia nigra to the striatum) take up levodopa, convert it, and release dopamine.

Levodopa is the most effective single agent for Parkinson's symptoms and remains the cornerstone of treatment. Two important pharmacological problems need managing. The first is managed by combination therapy and the second by timing doses around meals:

• Peripheral conversion of levodopa to dopamine by AADC produces side effects (nausea, hypotension) and reduces central availability. To prevent this, levodopa is always co-administered with a peripheral AADC inhibitor:
  • Co-careldopa (Sinemet) = levodopa + carbidopa (a peripheral AADC inhibitor).
  • Co-beneldopa (Madopar) = levodopa + benserazide (also a peripheral AADC inhibitor).
  The decarboxylase inhibitors do not cross the blood-brain barrier, so peripheral conversion is blocked but central conversion is unaffected. Using an inhibitor in this way reduces the levodopa dose required by around 75% and improves tolerability.
• Active intestinal absorption of levodopa competes with dietary amino acids; large protein meals reduce its uptake. For co-beneldopa, the British National Formulary (BNF) advises taking doses 30 minutes before or 1 hour after meals. If gastrointestinal side effects occur, doses can be taken with a low-protein snack or liquid. For people with motor fluctuations, NICE advises discussing a protein redistribution diet, in which most of the day's protein is eaten at the final main meal. Total daily protein should not be reduced.

Side effects:

• Nausea, usually transient. Taking levodopa with food can help. If nausea persists, NICE Clinical Knowledge Summaries (CKS) advise low-dose domperidone (a peripheral D₂ antagonist, meaning it blocks dopamine D₂ receptors outside the brain), reduced or stopped once the nausea settles. Domperidone has been associated with an increased risk of ventricular arrhythmias (abnormal heart rhythms starting in the lower chambers of the heart) and sudden cardiac death. The BNF lists patients over 60 years as at increased risk. The Medicines and Healthcare products Regulatory Agency (MHRA) advises the lowest effective dose for the shortest possible time. Avoid metoclopramide and prochlorperazine, which can cause or worsen parkinsonism.
• Postural hypotension.
• Cardiovascular effects (arrhythmia, meaning an abnormal heart rhythm; rare).
• Visual hallucinations (seeing things that are not there) and confusion, particularly in the elderly and in dementia with Lewy bodies.
• Motor fluctuations with prolonged use: "on-off" phenomena, end-of-dose wearing off, and dyskinesias (involuntary, often writhing or jerking movements; see below).

Important interactions and precautions:

• Abrupt withdrawal: do not stop antiparkinsonian medicines suddenly, and do not let doses fail through poor absorption (for example with gastroenteritis or after abdominal surgery). This can cause acute akinesia (sudden severe immobility) or neuroleptic malignant syndrome (a dangerous reaction with fever and muscle rigidity).
• Pyridoxine (vitamin B₆): cofactor for peripheral AADC, increases peripheral metabolism of levodopa. Less of an issue with modern AADC-inhibitor combinations.
• Non-selective MAOIs (monoamine oxidase inhibitors, a type of antidepressant): risk of hypertensive crisis (a sudden dangerous rise in blood pressure). Avoid them. A washout period (a drug-free gap after stopping one drug before starting the other) is required.
• Antipsychotics (drugs for psychosis, such as hallucinations and delusions): D₂ blockade antagonises levodopa effect and can precipitate or worsen parkinsonism. For hallucinations and delusions in people with no cognitive impairment, NICE advises considering quetiapine. If standard treatment is not effective, NICE advises offering clozapine, which needs registration with a patient monitoring service. Olanzapine should not be offered. Other antipsychotics, such as phenothiazines (for example chlorpromazine) and butyrophenones (for example haloperidol), can worsen the motor features.

Dopamine Receptor Agonists

These directly stimulate dopamine receptors, bypassing the need for a functioning nigrostriatal terminal (the dopamine-releasing nerve ending in the striatum). NICE NG71 recommends offering levodopa to people in the early stages of Parkinson's disease whose motor symptoms affect their quality of life. If motor symptoms do not affect quality of life, levodopa, a dopamine agonist or an MAO-B inhibitor can all be considered. The choice is made with the person, after discussing the trade-offs. These include the risk of impulse control disorders (compulsive behaviours such as gambling) with agonists and motor fluctuations with long-term levodopa.

Dopamine agonists are also useful as add-on therapy to levodopa:

• Non-ergot dopamine agonists: ropinirole, pramipexole, rotigotine (transdermal patch). These are now the usual choice when an agonist is used.
• Ergot-derived agonists (chemically related to ergot, a fungus that grows on rye and other grains): bromocriptine, pergolide, cabergoline. These are not offered first-line because of fibrotic complications (scarring of the heart valves, the lungs and the tissue behind the abdominal organs, called retroperitoneal fibrosis), which need monitoring. NICE advises considering one only as an add-on to levodopa, in people with dyskinesia or motor fluctuations despite optimal levodopa whose symptoms are not adequately controlled with a non-ergot agonist.
• Apomorphine: subcutaneous (injection or pump); used for severe motor fluctuations; can produce dramatic "rescue" of off-periods (times when a dose has worn off and symptoms return).

Side effects are similar to levodopa, plus a distinctive class effect:

• Impulse control disorders (ICDs): pathological gambling, hypersexuality, compulsive shopping, binge eating, "punding" (repetitive purposeless activity). CKS gives a range of 1 to 14% of people with Parkinson's disease, with a higher risk in those taking dopamine agonists. Impulse control disorders can develop on any dopaminergic therapy, and the person may conceal them, so warn patients and their families explicitly. If an impulse control disorder develops, the dopamine agonist is reduced gradually first.
• Sedation and sudden onset of sleep ("sleep attacks"): impacts driving safety.
• Hallucinations and psychosis (losing touch with reality, for example through delusions).
• Postural hypotension, peripheral oedema.

MAO-B Inhibitors

Monoamine oxidase B (MAO-B) is the enzyme that metabolises dopamine in the brain. Selegiline and rasagiline selectively inhibit MAO-B, prolonging the action of endogenous (the body's own) and levodopa-derived dopamine.

MAO-B inhibitors are used as monotherapy (on their own) in early disease, with a modest symptom benefit. They are also used as add-on therapy to smooth out motor fluctuations in established disease. They are generally well tolerated. At therapeutic doses they are selective for MAO-B over MAO-A. This avoids the "cheese reaction" seen with non-selective MAOIs. This reaction is a hypertensive crisis (a sudden dangerous rise in blood pressure) after eating foods containing tyramine (an amine found in foods such as mature cheese). However, selectivity can be lost at higher doses.

COMT Inhibitors

Catechol-O-methyltransferase (COMT) is the second major enzyme that metabolises levodopa peripherally. Entacapone and tolcapone inhibit COMT and prolong the half-life of levodopa (the time its blood level takes to halve), reducing end-of-dose wearing off (the return of symptoms before the next dose is due). Opicapone is another COMT inhibitor. It is taken once daily at bedtime, at least one hour before or after levodopa, as an add-on for end-of-dose fluctuations under expert supervision.

Entacapone is given with each levodopa dose; the combination tablet co-careldopa + entacapone is marketed as Stalevo. COMT inhibitors have no effect alone (they slow levodopa metabolism but do not increase dopamine synthesis themselves).

Tolcapone can cause potentially life-threatening hepatotoxicity (liver damage), although this is reported rarely. It is therefore used only under expert supervision, and only when another COMT inhibitor is inappropriate.

Anticholinergics

Loss of dopamine in the striatum allows the cholinergic interneurons (local nerve cells that release acetylcholine) to dominate. Procyclidine, orphenadrine and trihexyphenidyl are anticholinergics that partially restore the balance, helping particularly with tremor.

Their side-effect profile (confusion, dry mouth, urinary retention, constipation, and glaucoma, which is raised pressure inside the eye) limits use, particularly in older patients. The BNF says that trihexyphenidyl is not recommended in Parkinson's disease because of toxicity in the elderly and the risk of aggravating dementia. NICE advises against offering anticholinergics to people with Parkinson's disease who have developed dyskinesia or motor fluctuations. Otherwise, they retain a role in younger patients with tremor-predominant disease, and in drug-induced parkinsonism (where the antipsychotic cannot be reduced).

Amantadine

Amantadine has a complex mechanism (NMDA antagonism, meaning it blocks N-methyl-D-aspartate glutamate receptors; dopamine release; anticholinergic effect). Used mainly to manage levodopa-induced dyskinesias.

Motor Fluctuations

The principal pharmacological problem of long-term Parkinson's treatment is the development of motor fluctuations:

• End-of-dose "wearing off": reduced response as plasma levodopa falls. Manage by adding COMT inhibitor, MAO-B inhibitor, or dopamine agonist; or switch to slow-release / dispersible levodopa formulations; or shorten the dose interval.
• "On-off" phenomena: unpredictable transitions between mobility ("on") and immobility ("off"). Apomorphine rescue (an injection given during an "off" period) is an option for severe cases. Two infusion treatments may be used for advanced disease with severe motor fluctuations. One is intestinal gel containing co-careldopa (Duodopa, a continuous levodopa infusion into the intestine). The other is a continuous subcutaneous infusion of foslevodopa with foscarbidopa. NICE recommends foslevodopa with foscarbidopa only when available medicines are not working well enough, and either the person cannot have apomorphine or deep brain stimulation, or these treatments no longer control their symptoms.
• Dyskinesias: involuntary chorea-like movements (irregular, flowing, dance-like jerks) at peak levodopa concentration. Reduce levodopa dose, add amantadine.

Surgical Treatment

For selected patients with motor fluctuations refractory to medical therapy (not adequately controlled by drugs):

• Deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus (two deep structures in the basal ganglia circuit). Now the surgical mainstay.
• Lesional surgery makes a small, deliberate area of damage in the brain (thalamotomy for tremor, pallidotomy for dyskinesia). It was used extensively before DBS and is now much less common. MRI-guided focused ultrasound (a way of making a small lesion in the brain using focused sound waves, guided by MRI scanning) is not yet a routine NHS treatment for Parkinson's tremor. NICE guidance from December 2024 (HTG733 and HTG734) says that more research is needed first, and that it should only be done as part of a formal research study.

Myasthenia Gravis

Pathology

Myasthenia gravis (MG) is an autoimmune disease in which immunoglobulin G (IgG) antibodies are directed against the nicotinic acetylcholine receptor (AChR) at the post-synaptic membrane of the neuromuscular junction. In roughly 5 to 10% of patients, antibodies target instead the muscle-specific tyrosine kinase (MuSK), a protein on the muscle membrane that helps cluster the receptors. This produces a related but distinct phenotype.

The antibodies block acetylcholine binding, increase receptor turnover (the muscle takes in and breaks down the receptors faster), and activate complement-mediated post-synaptic membrane damage (damage caused by complement, a group of immune system proteins that attack cells). Acetylcholine is then broken down by acetylcholinesterase before sufficient receptors are activated. The result is failure of neuromuscular transmission.

The thymus is abnormal in around 75% of patients. Thymic hyperplasia (enlargement of the thymus) is seen mainly in early-onset disease, which means onset before the age of 50. About 1 in 10 patients have a thymoma (a tumour of the thymus). Thymectomy (surgical removal of the thymus) is indicated in all patients with a thymoma. It is also offered to selected patients with generalised disease (see Immunosuppression and Other Treatments).

Clinical Features

The main feature is "fatiguable" weakness: muscle strength declines with repeated or sustained use and recovers with rest. Patterns of involvement:

• Ocular: ptosis (drooping eyelid) and diplopia (double vision). These are the most common presenting symptoms. Up to 80% of people with ocular onset go on to develop generalised symptoms, usually within two years. People whose disease stays confined to the eyes have ocular myasthenia.
• Bulbar (the brainstem-innervated muscles of speech and swallowing): dysarthria (slurred speech), dysphagia (difficulty swallowing), weakness of mastication (weak chewing). Patients may "fade" through a meal.
• Limb weakness: proximal, symmetrical.
• Respiratory weakness: weakness of the breathing muscles can become severe enough to need breathing support (intubation and ventilation). This is called myasthenic crisis, a medical emergency.

Diagnosis is supported by anti-AChR (or anti-MuSK) antibodies. It is also supported by characteristic findings on repetitive nerve stimulation (repeated electrical stimulation of a nerve while the muscle response is recorded) or single-fibre electromyography (EMG, which records the electrical activity of single muscle fibres). The response to anticholinesterase challenge (giving a short-acting anticholinesterase drug to see whether strength improves; now rarely used) can also help. All patients should have CT or MRI of the chest to look for thymoma.

Pyridostigmine

Pyridostigmine is the first-line symptomatic treatment. It is a reversible acetylcholinesterase inhibitor that increases the concentration of acetylcholine at the neuromuscular junction. This improves the chance of receptor activation, despite the antibody-mediated reduction in functional receptor numbers.

Pharmacokinetics (how the body handles the drug): oral, onset ~30 minutes, duration 3-6 hours, so given several times daily. Does not cross the blood-brain barrier (it is a quaternary amine, a permanently charged molecule).

Side effects arise from off-target muscarinic stimulation (unwanted stimulation of muscarinic acetylcholine receptors, which belong to the parasympathetic nervous system), summarised by a commonly taught mnemonic for cholinergic effects:

Cholinergic effects: SLUDGE
S: Salivation
L: Lacrimation (tear production)
U: Urination
D: Defecation (diarrhoea, abdominal cramps)
G: Gastric upset
E: Emesis (vomiting)

Plus miosis (small pupils), bradycardia (slow heart rate), and bronchospasm and bronchorrhoea (airway narrowing and excess airway secretions). The longer mnemonic DUMBELS covers diaphoresis (sweating) or defecation (the first letter can stand for either), urination, miosis, bronchospasm or bronchorrhoea, emesis, lacrimation and salivation.

Pyridostigmine treats symptoms but does not modify the autoimmune process, so most patients also receive immunosuppression.

Immunosuppression and Other Treatments

• Corticosteroids: prednisolone, started gradually (rapid initiation can transiently worsen weakness). Often used long-term at the lowest effective dose.
• Steroid-sparing immunosuppression (immunosuppressants that let the steroid dose be kept lower): azathioprine first-line, with mycophenolate mofetil, ciclosporin, methotrexate or rituximab as alternatives.
• Thymectomy: indicated in any patient with a thymoma. It is also offered to selected AChR-antibody-positive patients with generalised disease and no thymoma. The MGTX trial (a randomised trial of thymectomy in myasthenia gravis) enrolled people aged 18 to 65, and in it thymectomy lowered the average prednisone requirement (44 mg versus 60 mg on alternate days). International consensus guidance suggests considering thymectomy early in the disease for people aged 18 to 50 with generalised, AChR-antibody-positive disease and no thymoma. Thymectomy is not routine in ocular-only myasthenia, MuSK-antibody disease, or in older patients without thymoma.
• Intravenous immunoglobulin (IVIG) or plasmapheresis (plasma exchange): rapid, short-acting treatments for myasthenic crisis or pre-operative optimisation (getting the patient as strong as possible before surgery).
• Newer biologics (protein-based medicines, such as antibodies, that target a specific part of the immune system): eculizumab (blocks C5, a protein of the complement system; used for refractory AChR-positive disease), efgartigimod and rozanolixizumab (FcRn antagonists: they block the neonatal Fc receptor, which recycles IgG, so IgG levels fall). NICE does not recommend efgartigimod, recommends rozanolixizumab only for defined groups, and could not make a recommendation on eculizumab because the company did not submit evidence.

Myasthenic and Cholinergic Crisis

Two opposing emergencies, with similar symptoms but opposite causes:

• Myasthenic crisis: severe muscle weakness and respiratory failure. Triggered by infection, surgery or other stress, certain drugs (see below), pregnancy, or abrupt stopping of immunotherapy (treatment that suppresses the immune system). Treatment: ICU support (intubation if needed), IVIG or plasmapheresis, increase immunosuppression.
• Cholinergic crisis: muscle weakness caused by over-treatment with pyridostigmine, with prominent muscarinic features (SLUDGE). The excess acetylcholine produces a depolarising blockade (persistent depolarisation of the muscle end-plate, so the muscle stops responding) similar to that of suxamethonium (a depolarising muscle relaxant used in anaesthesia). Treatment: stop pyridostigmine, supportive care; atropine to reduce muscarinic effects.

The clinical distinction can be difficult. Small pupils (miosis), fasciculations (visible muscle twitches) and SLUDGE features favour cholinergic crisis. Historically, the edrophonium (Tensilon) test was used to differentiate the two (transient improvement with edrophonium suggests myasthenic crisis). It is now rarely used. The drug has restricted availability in many countries. Rare side effects of edrophonium include bradycardia and respiratory failure, so patients must be closely monitored and atropine kept readily available.

Drugs to Avoid in Myasthenia

Several common drugs can worsen myasthenia by interfering with neuromuscular transmission. This is an essential prescribing point. The list is long but the most commonly tested:

• Aminoglycosides (antibiotics, such as gentamicin and streptomycin): pre-synaptic neuromuscular blockade, meaning they impair neuromuscular transmission from the nerve side.
• Macrolides (antibiotics, especially erythromycin, clarithromycin, azithromycin and telithromycin): the BNF cautions that macrolides may aggravate myasthenia gravis.
• Fluoroquinolones (antibiotics, such as ciprofloxacin and levofloxacin): the BNF lists myasthenia gravis as a caution because of a risk of exacerbation. The Medicines and Healthcare products Regulatory Agency (MHRA) advises that systemic fluoroquinolones must only be prescribed when other commonly recommended antibiotics are inappropriate.
• β-blockers.
• Quinine.
• Magnesium at high doses (for example, IV magnesium for eclampsia, which means seizures in pregnancy linked to pre-eclampsia). It can worsen weakness in myasthenia, so it needs great caution.
• Lithium, phenytoin.
• Botulinum toxin.
• Neuromuscular blocking drugs (muscle relaxants used in anaesthesia): myasthenic patients are resistant to depolarising agents, which act by first depolarising the muscle (suxamethonium often needs higher doses). Myasthenic patients are markedly more sensitive to non-depolarising agents (rocuronium and atracurium need much lower doses, with careful monitoring). Concurrent pyridostigmine can also prolong suxamethonium effect.

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