T2 L7. Parkinson’s disease and drug therapy of basal ganglia disorders (JG).pptx

202 – Neuroscience and Behaviour Parkinson’s disease and drug therapy of basal ganglia disorders Dr Jeban Ganesalingam Consultant Neurologist Most slides courtesy of Dr Romi Saha, Consultant Neurologist, BSMS. Disorders of movement Hyperkinetic movements Hyperkinesis Jerky movements Ballismus Tic...

202 – Neuroscience and Behaviour Parkinson’s disease and drug therapy of basal ganglia disorders Dr Jeban Ganesalingam Consultant Neurologist Most slides courtesy of Dr Romi Saha, Consultant Neurologist, BSMS. Disorders of movement Hyperkinetic movements Hyperkinesis Jerky movements Ballismus Tics Chorea Myoclonus Non-jerky movements Dystonia Tremor Hypokinetic movements Hypokinesis Parkinsonian conditions Disturbance of co-ordinationAtaxia Disturbance of planning Apraxia Learning outcomes  To describe the clinical features and pathophysiology of PD  The role of Dopamine as a treatment for Parkinson’s disease and the side effects of treatment.  To outline alternative treatment options to optimise control of Parkinson’s disease.  To describe other diseases related to basal ganglia dysfunction (Chorea, Tourette’s syndrome). For each movement disorder • Description • Pathophysiology • Video • Causes Ballismus - description A high amplitude flailing of the limbs on one side of the body Hemiballismus - pathophysiology excitatory cortex hyperdire ct pathway indirect pathwa y inhibitory striatum thalamus GPe GPe Globus pallidus external STN GPi Globus pallidus internal GPi direct pathwa y STN Subthalamic nucleus Hemiballismus Video Commonest cause is stroke STN stroke Hemiballismus - cause Tic disorders - description  Brief repetitive stereotypes movements with a premonitory urge. – Simple: like blinking, coughing – Complex: jumping or twirling – Plus: motor disorder – Coprolalia: swearing - rare  Reduced by distraction and concentration  Worse with anxiety or fatigue.  Tourette syndrome is the more severe expression of a spectrum of tic disorders, Basal ganglia loops Basal Ganglia loops striatum caudate putamen Tic disorder  Video Tic disorder causes  Often associated with other co-morbid conditions. – 50% have ADHD – 33.3% have OCD – Up to 50% have anxiety  Complex genetic inheritance  Post infectious immune Chorea Jerky, brief, irregular contractions that are not repetitive rhythmic, but appear to flow from one muscle to the nex Patient appears fidgety, restless Chorea - pathophysiology excitatory cortex hyperdire ct pathway indirect pathwa y inhibitory striatum thalamus GPe GPe Globus pallidus external STN GPi Globus pallidus internal GPi direct pathwa y STN Subthalamic nucleus Chorea - video Chorea - causes Common causes include: Degenerative - Huntington’s disease Drugs - Neuroleptics Huntington’s chorea genetics Trinucleotide repeat on chromosome 4 Autosomal dominant with complete penetrance The longer the repeat sequence the earlier the disease presents Repeat sequence unstable and tends to enlarge ‘anticipate’ with each generation Huntington’s clinical presentation  Cognitive – Inability to make decisions, multitasking. Slowness of thought.  Behavioural – Irritability, depression, apathy, anxiety, delusions.  Physical – Chorea, motor persistence, dystonia, eye movements. Myoclonus - description  Brief movement  Rapid onset and offset  Positive (muscular contractions) or negative (muscular inhibitions) Myoclonus - pathophysiology  Unknown  Possibly an imbalance between excitatory and inhibitory neurotransmitters. – Explain why it is treatable with antiepileptic drugs.  Perturbations of the motor control system leading to a brief disequilibrium – Explain why present at multiple levels e.g cortical, subcortical , spinal etc. Myoclonus causes  Common causes include – Juvenile Myoclonic Epilepsy – Brain hypoxia – Prion disease Dystonia - description  Abnormal twisting posture – often axial/ facial/ truncal, may be associated with jerky tremor Dystonia - video Dystonia – pathophysiology  Not fully understood  Functional PET studies suggest abnormal activity in the motor cortex, supplementary motor areas, cerebellum and basal ganglia.  Abnormal dopaminergic activity in basal ganglia suggested by: – dystonia being caused by blocking dopamine receptors – Some dystonias being Levodopa responsive. Dystonia causes  Stroke  Brain injury  Encephalitis  Parkinsons disease  Huntingtdon’s disease Tremor  Involuntary, rhythmic, sinusoidal alternating movements of part of the body.  Affect different parts of the body – Limbs, head, chin, soft palate  Moment of occurence – Rest, Postural, Kinetic, – Most common is Essential tremor (predominantly postural) Tremor - pathophysiology  Postulated theory: Increased activity in the cerebellothalamocortical circuit.  PD: Dopamine dysfunction in the pallidum results in this.  ET: GABAergic dysfunction in the cerebellum causes this. MRI focussed ultrasound therapy https://www.youtube.com/watch?v=XyVdc6OeShY&feature=youtu.be Drug treatment of hyperkinetic movement disorders Tics/Chorea/Ballismus Dopamine receptor blocking agents (eg haloperidol, chlorpromazine, pimozide, risperidone) Dopamine depleting agents (eg Tetrabenazine, Reserpine) Atypical anti-psychotics (eg Clozapine, Olanzapine, Aripiprazole) Response of basal ganglia to dopamine blocking agents Neuroleptics and other D2 blockers (certain anti-emetics, vestibular sedatives) can cause acute problems (over days/weeks) Oculogyric crisis Neuroleptic malignant syndrome Subacute problems (over weeks/months) Drug induced Parkinsonism Or long term (tardive) dyskinesias (over months/years) Oculogyric crisis Very characteristic acute response to certain drugs Fixed stare, upward deviation of eyes Neck extension Trunk extension Jaw spasms +/- tongue protrusion ‘Acute dystonic’ reaction Neuroleptic malignant syndrome (NMS)      Acute medical emergency developing over hours/ days in response to Dopamine blocking drugs Rigidity/ muscle breakdown – raised CPK. Fever Autonomic instability (volatile BP/PR) Confusion Tardive dyskinesia    Choreic oral-facial movements (video), dystonic trunk posturing Exact mechanism unclear – likely dopamine supersensitvity of basal ganglia –ie secondary receptor/ plastic changes Treatment -gradual withdrawal of offending agent, substitution with an atypical anti-psychotic ; use of a dopamine depleting agent (tetrabenazine); use of a benzodiazepine (clonazepam) if distressing Tardive dyskinesia  Video Hypokinetic movement disorders Parkinsonism Parkinsonism=Akinetic-Rigid Syndrome symptoms are: • Slowness of movement (also thought/ psychomotor retardation) • Stiffness • Shaking. physical signs include: • Slowness and poverty of movement (bradykinesia) e.g. loss of facial expression and arm swing, difficulty with fine movements • Voluntary movements harder to initiate (akinesia) • Rigidity • Rest tremor. Non-motor symptoms  Mood: Depression, anxiety  Dementia: slowed thought, mental inflexibiity,  Autonomic involvement – Postural hypotension, Hypersalivation  Sleep disturbance – Restless legs, REM parasomnia  Reduced sense of smell PD -pathophysiology SN cortex excitatory D2 D1 ACh striatum indirect pathway thalamus inhibitory GPe GPe Globus pallidus external STN direct pathway GPi Decreased dopamine input leads to reduced activation of direct pathway and reduced inhibition (higher activity) of indirect pathway. This leads to reduced movements. GPi Globus pallidus internal STN Subthalamic nucleus SN Substantia nigra What is Parkinson’s disease? A neurodegenerative condition, primarily affecting dopaminergic cells of the substantia nigra Parkinson’s disease Normal Retrospective studies estimate 70% cell loss at disease onset. • Histopathological hallmark: Lewy bodies • Intraneuronal protein inclusion) Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15:27-44. Causes of Parkinsonism Neurodegenerative (Idiopathic) Parkinson’s disease >80% Diffuse Lewy body disease Atypical Parkinsonism (MSA, PSP, CBD) Multiple system atrophy, Progressive supranuclear palsy, Corticobasal degeneration Secondary Drugs (eg haloperidol, MPTP) Cerebrovascular disease Hydrocephalus Toxicity/ metal deposition disoders Genetic Metabolic - Wilson’s disease (copper deposition) Rare familial (dominant/ recessive) causes Levodopa breakdown Parkinson’s disease Early Drug therapies Amantadine – Initially anti-flu agent Glutamate agonist Anti-cholinergics – Procyclidine, Benzhexol May help with tremor Limited by side effects (confusion, urinary retention, dry mouth…) Mono-amine oxidase inhibitors Acetyl choline/ dopamine balance in basal ganglia Dopamine Acetylcholine Striatum is rich in acetyl choline as well as dopamine Reduction of dopamine within basal ganglia in Parkinson’s disease leads to a functional excess of acetylcholine Compensation can be achieved by reducing acetylcholine effect (by using anti-muscuranic agents) Monoamine oxidase inhibitors (MAO-I)      Prevent breakdown of monoamine chemical neurotransmitters; 2 isoforms: MAO- type A : serotonin, adrenaline, noradrenaline, dopamine MAO- type B : dopamine Non selective MAO-I – for depression (Moclobemide); rarely used now due to problems with metabolising dietary amines/ tryptophans – risk of hypertensive crisis – cheese, red wine, marmite More selective MAO- IB- for Parkinson’s disease (Selegiline, Rasagiline) – no dietary restrictions L-dopa The old and gold standard Available in several formulations. Always combined with Dopa decarboxylase inhibitor (to prevent peripheral conversion to dopamine). Commercial preparations: Madopar, Sinemet Immediate and controlled release L-dopa videos  Response to L-dopa  Dyskinesias Off of Long duration Time (hours) 2 4 6 clinical benefit Levodopa Low incidence of dyskinesias Advanced disease Clinical effect On Mid-stage disease Clinical effect Clinical effect Early disease Clinical response duration of Diminished Time (hours) Time (hours) mirrors levodopa 2 4 6 4 6 clinical benefit plasma 2 Levodopa Increased incidence of pharmacokinetic profile dyskinesias ‘On’ time is associated with dyskinesias Dyskinesia threshold Response threshold Figure adapted from Obeso et al. Neurology 2000; 55(4 Suppl): S13 Optimising L-dopa Peripheral Circulation Brain COMT – Catechol-o-methyl transferase Entacapone/Tolcapone Reduces peripheral (to a lesser extent central) metabolism of L-dopa. Pros: Increases duration of action of L-dopa, increases efficacy of Ldopa, good for ‘wearing off’ with L-dopa between doses Cons: Makes dyskinesia worse, Diarrhoea (both) Liver disease (tolcapone) Clinical effect Entacapone may also slightly increase peak dyskinesia worse COMT-I given with L-dopa (Entacapone) Extends effect of L-dopa by 30mins Time (hours) 2 4 Levodopa 6 Clinical effect Duodopa for advanced PD (duodenal L-dopa infusion) Dyskinesia ON without dyskinesia OFF 2 Oral L-dopa 4 6 hours L-dopa is absorbed in duodenum Absorption affected by poor gastric motility/ constipation and diet / protein load Unpredictable bioavailability makes it very difficult to hit narrow therapeutic window in advanced PD (for ON without dyskinesia) Direct delivery of L-dopa to duodenum via infusion pump potentially very useful strategy to manage motor fluctuations. But very cumbersome / expensive (20K/year) Does not affect disease progression Dopamine agonists • Bypass degenerating nigrostriatal neurons • Directly activate dopamine receptors. • No need for enzymatic conversion. • More stable and longer-acting. Dopamine agonists Different forumlations: • Pergolide (ergot), Cabergoline (ergot), • Ergot dopamine agonists no longer used due to cardiac/pulmonary fibrosis. • Pramipexole, Ropinirole (non-ergot) • Rotigotine (patch) • Apomorphine (subcutaneous infusion) All reduce frequency of motor complications Cons- Dopamine dysregulation syndrome Apomorphine s/c infusion Dopamine agonist: Given by subcutaneous (s/c) infusion Pros: Very effective Instant effect. Reduces dyskinesia by allowing continuous dopaminergic stimulation (pulsatile dopaminergic stimulation thought to prime basal ganglia for motor complications) Cons: Only for the right patients Skin nodules Non drug therapies Deep brain stimulation in PD Not clear how it works (but it does!) Probably high freq stimulation causing ‘jamming’(inhibition of neurons by depolarising block) Also disrupts abnormally synchronous basal ganglia rhythms Favoured target subthalamic nucleus (STN) for PD Also pallidum (for dystonia) and thalamus (for tremor) Disease will still progress and no effect on non-motor - dementia, - dysautonomia, - postural instability….. - Future – neurorestorative (stem cells) - Neuroprotective (growth factors) MRI focussed ultrasound therapy Disorders of movement Hyperkinetic movements Hyperkinesis Jerky movements Hemiballismus Tics Chorea Myoclonus Non-jerky movements Dystonia Tremor Hypokinetic movements Hypokinesis Parkinsonian conditions Disturbance of co-ordinationAtaxia Disturbance of planning Apraxia Learning outcomes  To describe the clinical features and pathophysiology of PD  The role of Dopamine as a treatment for Parkinson’s disease and the side effects of DA agonists.  To outline alternative treatment options to optimise control of Parkinson’s disease.  To describe other diseases related to basal ganglia dysfunction (Chorea, Tourette’s syndrome). The End