Parkinsons, Schitzophrenia and Epilepsy Flashcards
Cause of Parkinson’s disease
Degeneration of dopaminergic neurones in the substantia nigra. Formation of Lewy bodies due to deposition of parkin and alpha-synuclein
Describe the pathophysiology of Parkinsons disease
Degeneration of neurones in the substantia nigra results in a loss of dopamine in the nigrostriatal tract of the basal ganglia.
DA transmission influences the output of the striatum and therefore thalamic input to the cortex. The striatum projects to the globus pallidus by direct and indirect pathways.
The Direct pathway projects directly to the GPi and inhibits it. GPi normally inhibits the thalamus so the striatum causes increased activity of the thalamus by blocking GPi. DA released from the substantia nigra to D1R excite this pathway.
In indirect pathway projects to the GPe which reduces inhibition of the subthalamic nucleus. The STN excites the GPi and causes inhibition of thalamic activity. Dopamine binds to D2R in the striatum to inhibit this pathway.
In Parkinsons, lack of DA means there is less excitation of the direct pathway, and less inhibiton of the indirect pathway. Activity of the GPi is increased and the thalamus is inhibited. This leads to akinesa and other Parkinsonian symptoms.
Signs of Parkinson’s disease
Tremor at rest (pill-rolling)
Bradykinesia (affects fine movements e.g. buttons)
Cog-wheel rigidity
Shuffling gait
Stooped posture
What are the four Dopamine pathways
Nigrostriatal - basal ganglia, fine movements
Mesolimbic - VTA to limbic system, reward and desire
Mesocortical - VTA to frontal lobes, motivation and emotional response
Tuberohypophyseal - regulates secretion of prolactin
Chemicals which can induce Parkinsons
Neuroleptics
Anti-emetics
Vestibular sedatives
carbon monoxide,
Wilson’s disease
Autosomal recessive disease that results in defective absorption and excreton of dietary copper. Copper becomes deposited in the body
Causes liver cirrhosis
Kayser-Fleischer rings in the eyes
Young onset Parkinsonian symptoms
Symptoms of Parkisons
Tremor at rest
Postural changes
Dysphagia/dysarthria
Micrographia
Clumpsiness
Symptoms do not appear until 80” of DA neurones have already been lost.
What tests can be used to confirm the diagnosis of Parkinsons?
Challenge with levodopa
MRI/CT scan - rule out space occupying lesion, vascular disease or hydrocephalus
PET scan - localise DA deficiency
Treatment options for Parkinsons
Pharmacological: dopamine replacement. Treats symptoms only.
Deep brain stimulation
Radiosurgery
Surgical intervention
Use of L-Dopa in Parkinson’s
Should be started at the minimal effective dose in combination with a decaarboxylase inhibitor to prevent L-dopa metabolism in the periphery
Can give dopamine antagonist to reduce side effects.
When are DA agonists used in Parkinsons?
Synthetic agonists replace DA loss by acting on receptors.
Given as initial therapy to younger patients and in late stages of disease to reduce ‘off’ effects.
e.g. ropinirole, pramipexole, rotigotine
Mechanism of action of L-dopa
Levodopa is the immediate precursor of dopamine and is able to penetrate the brain where it is converted.
What are anticholinergics given in Parkinson’s
As the nigrotriatal neurones decline in Parkinson’s, the releaase of DA neurones (inhibitory) declines and cholinergic neurones (excitatory) become overactive.
Can be used to reduce tremor.
Useful for drug-induced Parkinsonism
Complication of long term L-dopa treatment
Gradual recurrence of akinesia.
Over time the duration of action of L-dopa shortens, and leads to dyskinesia.
Patients experience on-off effect which corresponds to the peaks and troughs of l-dopa plasma levels.
Define schitzophrenia
Fundamental and characteristic distortions of thinking and perception. Affects (emotional responses) that are innapropriate or blunted.
Enzymes that break down DA in the brain
What drugs inhibit them?
MAO-B and COMT
DA metabolism prevented by giving inhibitors
COMT inhibitors: entacapone
MAOI-B: selegiline, rasagiline
Symptoms of schitzophrenia
Thought echo
Thought insertion or withdrawal
Though broadcasting
Delusional perceptions
Hallucinatory voices commenting or discussing the patient
Negative symptoms: Affective blunting, apathy, ahedonia (loss of intrest in activities), alogia (poverty of speech)
Treatment of schitzophrenia
Antipsychotics (neuroleptics) which are dopamine receptor antagonists. Drugs mostly act at D1 and D2.
Affinity for the DA receptor is related to antipsycotic potency. Classical neuropleptics block the D2R which is the most abundant subtype in the brain. However also causes extrapyramidal symptoms
Atypical drugs have wider effects and reduced extrapyramidal effects. Compliance with treatment is important. Need 60% occupancy at D2 for an effective response.
Mechanism of action of anti-psychotic drugs
Antipsychotics are dopamine D2 antagonists. .
- Block the mesolimbic/mesocortical pathway to remove positive symptoms. (also results in apathy and sedation)
- Blocks nigrostriatal pathway, causes extrapyramidal symptoms
- Blocks tuberinfindibular pathway, increases prolactin, results in galactorrhoea, gynaecomastia and amenorrhoea.
Also affect a1-adrenoreceptors, H1 and 5HT receptors.
Pyramidal motor symptoms
Muscle weakness in arm flexors and leg extensors
Decrased tone
Spactic paralysis
Clasp-knife rigidity
Babinki sign
Loss of cremasteric and abdominal reflex
Side effects of neuroleptic drugs
Movement disorders:
- Dystonias (spasm of face and muscles),
- Parkinsonian symptoms
- Sedation
- Tardive dyskinesia (repetitive tic movements)
Endocrine effects: Gynaecomastia, Galactorrhoea, Impotence, Weight gain
Extrapyramidal upper motor neurone signs
Hyperreflexia
Spastic paralysis
Little/no muscle atrophy
Clonus
Hypertonia
Clasp-knife rigidity.
Features of cerebellar lesions
Dysdiadochokinesia/dysmetria
Ataxia
Nystagmus
Intention tremor
Slurred speech/scanning dysarthria
Hypotonia
Simple partial epileptic seizure
No loss of consciousness or post-ictal confusion.
Symptoms depend on the focal site:
- Temporal: olfactory hallucinations, emotional changes, deja vu
- Frontal: Motor symptoms e.g. kicking, cycling
- Parietal: nausea, choking, illusions of body distortion
- Occipital: visual hallucinations, blackouts
Partial epileptic seizures
Originate in a focal region of the cortex and can be subdivided into simple (do not affect consciousness) and those that do (complex)
Complex partial seizures
Most common type of seizure seen in adults.
May experience aura/deja vu before onset.
Mostly in the temporal lobe. Symptoms: staring motionless, or engage in repetitive semi-purposeful behaviour e.g. facial grimacing, lip smacking, chewing
Altered consciousness. Patient may seem fully awake but do not respond to environment.
If restrained patients become hostile/aggressive. Often sleepy and confused after seizure.
Can progress to generalised due to proximity to the thalamus
Jacksonian seizure
Seizures originating in the motor cortex. Produce focal motor jerking.
Epileptic fit begins at one site and then spreads so other sites producing jerking of the limbs.
Generalised tonic-clonic seizure
Widespread involvement of the bilateral cortical regions and impaired consciousness.
No warning or aura before seizure
Tonic phase - whole body stiffness, breathing may stop, loss of bladder control.
Clonic phase - muscle jerks
Slow regain of consciousness, patient has no recall of the episode.
Absence seizure
Normally affects children.
Last 5-10 seconds and occur in clusters. Sudden onset of staing and impaired consciousness
Name 4 types of generalised seizures
- Tonic-clonic seizures - convulsive movements with impaired consciousness
- Myoclonic – sudden jerks (like when falling asleep), possibly familial
- Clonic – repeated twitches and jerks no stiffness
- Tonic – all muscle contract, whole body stiffness
- Atonic – ‘drop attacks,’ muscle tone lost
DDx in a patient with seizures
TIA
Migrane
Narcolepsy
Hypoglycaemia
Hpokalemia
Epilepsy
Molecular changes which lead to epilepsy
Changes cause increased neuronal excitability
Reduction in GABA
Reduction in Ach transmission
Increase in Na+ transmission
Decrease in K+
Mutations in channel structure linked to epilepsy.
Treatment methods for epilepsy
Pharmacological - anticonvulsants
Surgical - removal of abnormal areas seen on MRI/CT
Implants - vagal nerve stimulation
Status epilepticus
Continuous seizures lasting over 30mins, or fits that follow each other without consciousness being fully regained.
Requires urgent treatment with IV anticonvulsants.
Give Lorazepam, after 25mins phenytoin, anaesthetize after 45mins. If fits are not controlled, patient is anaesthetised.
Treatment of absence seizures
Ethosuxamide
Sodium valproate
Define epilepsy
Repeated disturbance in brain function that develops suddenly, ceases spontanously and can by induced by triggers.
Mechanism of action of anti-convulsants
Inhibit Na+ channels: Carbimazepine, valproate, phenytoin. Bind to inactivated Na+ channels to prevent high frequency repetitive activtity. Side effects - peripheral neuropathy, osteomalacia, visual impairment
Enhance GABA action: benzodiazepines, vigabatrin, tiagabine. Increase brain levels of GABA by inhibiting uptake and breakdown
Inhibit Ca2+ channels: Reduces oscillatory activity between the thalamus and the cortex produced in absence seizures. ethoxusamide and lamotrigine.
Benzdiazepines and Barbiturates
Benzodiazepines act on the gamma subunit of the GABAaR to increase activity.
barbiturates act on the beta subunit.
Both reduce neural transmission.
Should be used short term as tolerance and dependence can develop. Causes impaired motor coordination and cognitive performance, sedation, withdrawal.
Tiagabine and Vigabatrin
Both affect recycling of GABA
Vigabatrin is an irreversible inhibitor of GABA-ransaminase, which increases GABA brain levels
Tiagabine inhibits reuptake of GABA. Increasing the amount of GABA in the synaptic cleft increases central inhibition.
Side effects: confusion, sedation, dizziness, weight gain
Classes of drugs used in treatment for Parkinsons
Levodopa + decarboxylase inhibitor (carbodipa)
Dopamine receptor agonists: bromocriptine, apomorphine
MAOI-B: segiline
COMT inhibitors: entacapone
Anticholinergics: procyclidine hydrochloride
Glutamate antagonists: amantadine
