In one breath
Take out one arrow of the basal ganglia circuit and you can predict the disease. Lose the dopaminergic nigrostriatal arrow and you get Parkinson’s disease: akinesia, bradykinesia and loss of associated movements (too little movement) together with lead-pipe rigidity, a resting tremor of about 8 per second and a festinant gait (too much), treated by replacing dopamine with L-dopa and by restoring the acetylcholine : dopamine ratio. Lose the GABAergic striatonigral arrow, through a dominant gene on chromosome 4, and you get Huntington’s disease: chorea, dementia and slurred speech, with no treatment. Lose the subthalamic nucleus and you get ballism.
Builds on: Basal ganglia: circuits and functions · Neurotransmitters · Leads to: Upper vs lower motor neuron lesions · Cerebellar functions, lesions and tests
Why basal ganglia disease gives both too little and too much movement
The direct and indirect pathways normally balance each other. Disease shifts one of them, so a single patient shows hypokinetic features (movement that will not start) and hyperkinetic features (movement that will not stop) at the same time. Keep that in mind and the feature lists below stop looking contradictory.
Parkinson’s disease
First described by James Parkinson (1755–1824), an English surgeon, in his 1817 essay on the shaking palsy, where he called it paralysis agitans.
The lesion: degeneration of the nigrostriatal dopaminergic neurons. With age, both the transmitter itself and its receptors are slowly lost from these nuclei; when that loss becomes exaggerated, Parkinsonism appears.
Causes
| Cause | Mechanism |
|---|---|
| Idiopathic | Why the dopamine cells die is not known — the commonest situation |
| Drugs | Long-term phenothiazines, D₂ receptor blockers and similar agents |
| MPP | A toxin that accumulates in and kills basal ganglia neurons |
The MPP route is worth the detail, because examiners like it:
- MPTP (methyl-phenyl-tetrahydropyridinium) is converted to MPP (methyl-phenyl-pyridinium) by monoamine oxidase B (MAO-B).
- MPP piles up quickly inside basal ganglia neurons and destroys them.
- MPP levels are found to be high in the Parkinsonian brain.
- This is the reason a MAO-B inhibitor is used in treatment (see deprenyl, below).
Features: hypokinetic
- Akinesia — movement is hard to initiate, and spontaneous movement is reduced.
- Bradykinesia — whatever movement happens is slow.
- Loss of associated movements — the arm swing of walking and the play of expression during speech are greatly reduced. The face becomes an expressionless face or mask face, and the patient speaks without emotional colouring.
Features: hyperkinetic
Rigidity
- Motor neuron discharge rises in agonists and antagonists together, so the limb resists passive bending through the whole range — lead-pipe rigidity.
- Sometimes the resistance comes in a series of catches during passive movement: cogwheel rigidity.
- The clasp-knife give-way of upper motor neuron spasticity is never found.
Tremor
- Antagonist muscles contract alternately and regularly, at about 8 per second.
- It is present at rest and disappears as soon as the patient starts to move — hence resting tremor.
Festinant gait
- The trunk is bent forwards, as though the patient were chasing his own centre of gravity, which is now in front of him.
- He does not fall; instead he takes short, shuffling steps that hurry along.
Rigidity is not spasticity
- Rigidity (Parkinsonism): agonists and antagonists both overactive, resistance right through the range, called lead-pipe or cogwheel.
- Spasticity (UMN lesion): antigravity groups mainly, resistance that gives way suddenly — the clasp-knife response, which is never seen in Parkinsonism.
And the tremor: at rest, disappearing on movement is Parkinsonian. Worth knowing, though not in your pages: a tremor that appears during a movement and worsens as the finger approaches the target is intention tremor, a cerebellar sign (Cerebellar functions, lesions and tests) — the classic 2-mark comparison.
Treatment
| Approach | What is done and why |
|---|---|
| L-dopa | Drug of choice |
| Dopamine agonists | Bromocriptine and similar |
| Anticholinergics | Restore the transmitter ratio |
| Deprenyl | Blocks MAO-B |
| Adrenal medullary graft | Regenerate dopamine neurons |
| Fetal basal ganglia implant | Replace lost tissue |
| Glomus cell transplant | A local dopamine source |
Now the reasoning behind each:
- Replacing dopamine. Dopamine itself will not cross the blood–brain barrier, so its precursor L-dopa, which crosses easily, is given instead; it is the drug of choice and also helps make good the dopamine deficit. Dopamine agonists such as bromocriptine are used as well.
- Anticholinergics. The deficiency is of dopamine, but what matters is the dopamine : acetylcholine ratio in the striatum. Lowering striatal acetylcholine brings the ratio back towards normal and improves the symptoms.
- Deprenyl inhibits MAO-B, so MPP can no longer be made from MPTP.
- Adrenal medullary transplantation. One of the patient’s own adrenal medullae is grafted into his basal ganglia, where it assists regeneration of the dopaminergic neurons.
- Implantation of fetal basal ganglia tissue into the patient’s basal ganglia improves the condition.
- Glomus cell transplantation. Glomus cells taken from the carotid body release dopamine where they are placed; this newer approach has given encouraging results, and your book flags it as the promising one.
Worth knowing, though not in your pages: the surgical treatment used today is deep brain stimulation, a chronic stimulating electrode placed in the subthalamic nucleus or the globus pallidus internus — exactly the two nodes whose overactivity the circuit predicts. Write the book’s list for the marks, and add this one line if you want to show you know current practice.
Applied: why L-dopa and not dopamine
This single point is asked again and again. Dopamine is a catecholamine that the blood–brain barrier will not admit, so injecting it treats the body and not the brain. L-dopa is an amino acid precursor, is carried across the barrier, and is decarboxylated to dopamine inside the central nervous system. The same logic explains why the anticholinergic works: with the dopamine side of the striatal balance unfixable, the cholinergic side is pulled down to match.
Huntington’s disease
Inheritance: a genetic defect of autosomal dominant type, from a faulty gene on chromosome 4. The gene encodes huntingtin, the abnormal protein responsible.
Cause
- Degeneration of the GABAergic striatonigral pathway.
- Both GABAergic and cholinergic neurons are lost from the striatum.
Features
- Age: it usually begins between 30 and 40 years, advances steadily, and death follows in 10–15 years.
- Three cardinal features: chorea, dementia and slurred speech.
| Feature | Basis |
|---|---|
| Chorea | Loss of striatal GABA neurons |
| Dementia | Progressive loss of cortical cholinergic neurons |
| Slurred speech | Appears gradually as the disease advances |
How the chorea arises — the mechanism to write out, not just name:
- The GABAergic striatal neurons are lost.
- Their inhibitory hold on the globus pallidus is removed.
- Activity in the thalamic nuclei falls.
- The result is chorea — here called Huntington’s chorea.
Treatment
There is no definite treatment. The disease advances until it kills.
Applied: two diseases, one diagram, opposite directions
Parkinson’s disease takes away a dopaminergic arrow into the striatum, so the brake (indirect pathway) is released and the patient moves too little. Huntington’s disease takes away the striatum’s own GABAergic output, so pallidal inhibition of the thalamus is deranged and the patient moves too much. Loss of dopamine → hypokinesia; loss of striatal GABA → hyperkinesia. That one sentence answers most viva questions on this chapter.
Other dysfunctions
Ballism
- Definition: involuntary movements that are violent and intense, and flail the limb about; the onset is sudden.
- Lesion: damage to the subthalamic nucleus.
- Hemiballism is the commoner form and follows haemorrhage into the subthalamic nucleus on the side opposite the affected limbs.
Athetosis
- Definition: continuous but slow writhing movements.
- Lesion: damage to the striatum.
Chorea
- Definition: rapid, involuntary, dancing movements.
- Lesion: damage to the caudate nucleus.
The three definitions, in one line each
- Chorea — rapid, dancing movements — caudate nucleus.
- Athetosis — slow, writhing movements — striatum.
- Ballism — violent, flailing movements — subthalamic nucleus.
The examiner almost always asks for these three together, and marks are lost by giving the movement without the site. Note that hemiballism, not ballism, is the usual clinical picture.
Draw it: the failing arrow in each disease
Start from the standard motor-loop diagram on Basal ganglia: circuits and functions — cortex, striatum, GPe, subthalamic nucleus, GPi, thalamus, substantia nigra — then mark the lesion on it. Draw the same skeleton three times, small, side by side.
- Parkinson’s disease. Put a cross on the dopamine arrow from pars compacta to striatum. Beside it write “direct pathway loses its + ; indirect pathway loses its −”, and below, “indirect pathway overactive → GPi overactive → thalamus suppressed → hypokinesia”. Add the clinical trio in the margin: akinesia and bradykinesia, lead-pipe rigidity, resting tremor at 8/second.
- Huntington’s disease. Put a cross on the GABA output of the striatum (the striatonigral arrow, and the striatal projection to the pallidum). Write “pallidum no longer inhibited → thalamic activity falls → chorea”, and add dementia and slurred speech.
- Hemiballism. Put a cross on the subthalamic nucleus itself, so the excitatory arrow into GPi is gone. Write “GPi underdriven → thalamus released → violent flailing movements on the opposite side”.
- Under all three write the rule: less dopamine = too little movement; less striatal or subthalamic output = too much movement.
- If gait is asked for, add a small stick figure: trunk flexed forwards, arms held still at the sides with no swing, short shuffling steps — festinant gait, with “rigidity + resting tremor” written next to it.
Exam-answer skeleton: "Parkinsonism: cause, features and treatment" (long essay)
- Define and place it: a hypokinetic disorder of the basal ganglia from degeneration of the nigrostriatal dopaminergic neurons, first described by James Parkinson as paralysis agitans.
- Circuit basis: dopamine excites the direct and inhibits the indirect pathway; losing it leaves the indirect pathway dominant, so GPi output rises, the thalamus is suppressed and the cortex is underdriven. Draw the diagram with the crossed-out dopamine arrow.
- Causes: idiopathic; drugs (phenothiazines, D₂ blockers); MPTP → MPP via MAO-B, with the toxin accumulating in basal ganglia neurons.
- Hypokinetic features: akinesia, bradykinesia, loss of associated movements, mask face.
- Hyperkinetic features: lead-pipe and cogwheel rigidity (with the contrast against clasp-knife spasticity), resting tremor at about 8 per second, festinant gait.
- Treatment: L-dopa and why not dopamine; dopamine agonists; anticholinergics and the acetylcholine : dopamine ratio; deprenyl and MAO-B; adrenal medullary, fetal tissue and glomus cell transplantation.
- Contrast in two lines: Huntington’s disease — autosomal dominant, chromosome 4, huntingtin, striatonigral GABA loss, chorea with dementia and slurred speech, no treatment.
- Finish with the definitions of chorea, athetosis and ballism, each with its lesion site.
Asked in exams
- Parkinsonism and the other basal ganglia disorders: Jan 2010, 4 marks · Jul 2012, 4 marks · Nov 2013, 4 marks · Jul 2018, 4 marks · Apr 2021, 4 marks · Jan/Feb 2022, 5 marks · Jan/Feb 2022, MCQ · Apr 2023, MCQ · Dec 2023, MCQ · Mar 2024, 15 marks
- Tremor: at rest and on movement: Jan 2010, 2 marks