Week 2 Neuro Course Pack 2022 PDF

NEUROSCIENCES BLOCK Course Pack Week 2 31 January 2022 Learning Topics LT 01 Neurotransmission and Neurotransmitters of the Basal Ganglia LT 02 Parkinsonism and Idiopathic Parkinson's disease...

NEUROSCIENCES BLOCK Course Pack Week 2 31 January 2022 Learning Topics LT 01 Neurotransmission and Neurotransmitters of the Basal Ganglia LT 02 Parkinsonism and Idiopathic Parkinson's disease LT 03 Principles of Management of Idiopathic Parkinson's disease (IPD) LT 04 Iatrogenic Movement Disorders LT 01. Neurotransmission and Neurotransmitters of the Basal Ganglia Aim To study the mechanism of neurotransmission and the neurotransmitters of the basal ganglia. Delivery objectives 1. Describe the synthesis, storage and release of neurotransmitters. 2. Describe the two major kinds of neurotransmitter receptors. 3. Describe the mechanism underlying fast versus slow neurotransmission. 4. Describe the mechanism involved in neurotransmitter inactivation. 5. Discuss the neurotransmitters of the basal ganglia. Content Several sequential steps are essential for neurotransmission to occur across synapses: (i) Synthesis of the neurotransmitter (ii) Storage (iii) Release and diffusion across synapses (iv) Action on receptors and (v) Termination of action Numerous different neurotransmitters including small molecules, e.g. glutamate and dopamine, and larger neuropeptides can be released from nerve terminals to mediate neurotransmission across synapses. Drugs that specifically modify the actions of different neurotransmitters can do so by changing the availability of neurotransmitter within synapses, or by directly acting on neurotransmitter receptors. i. Synthesis of neurotransmitters Small molecule neurotransmitters are synthesised in nerve terminals by specialised enzymes and neuropeptides are cleaved from larger precursors produced by the normal protein synthetic machinery of the cell. For example, the sequence of synthesis of dopamine involves: 1. Uptake of tyrosine into nerve terminals, 2. Conversion to L-DOPA by tyrosine hydroxylase (rate limiting step), 3. Conversion to dopamine by DOPA decarboxylase. The latter two enzymes are found only in cells that synthesise catecholamines. 1 ii. Storage Neurotransmitters are stored in high concentrations in synaptic vesicles. Some drugs disrupt storage by Mimicking the storage process of the natural neurotransmitter e.g. guanethidine is stored and released from noradrenergic nerves but does not activate adrenoceptors. Blocking transport into storage vesicles e.g. tetrabenazine depletes catecholamines leading to release of “empty” vesicles. iii. Release Neurotransmitter is released and diffuses to the post–synaptic membrane primarily by calcium dependent exocytosis of vesicular stores. Calcium concentrations are elevated in terminals during depolarization produced by the action potential spreading down the cell membrane. The mechanisms underlying the release process is modulated by terminal receptors (or presynaptic autoreceptors). These receptors function as a negative feedback mechanism to inhibit exocytosis when synaptic transmitter concentrations are saturated. iv. Receptors There are two major kinds of neurotransmitter receptor; ligand gated ion channels and second messenger coupled receptors. Fast neurotransmission (milliseconds) mediates rapid transfer of excitatory and inhibitory information. Fast transmission occurs because the receptors for the neurotransmitter in the postsynaptic cell membrane are ligand gated ion channels which produce the functional response to binding of the neurotransmitter in less that one millisecond in most cases. Slow neurotransmission occurs over hundreds of milliseconds to many seconds Both small e.g. dopamine and glutamate, and large neuropeptides mediate slow neurotransmission. The transmission is slow because the receptors are generally G-Protein coupled. These mediate their response by producing metabolic changes within the cell membrane or cytoplasm via second messengers. Each neurotransmitter acts on a variety of specific receptors which are differentially expressed in different tissues and different locations in the synapse, e.g. there are five distinct genes encoding dopamine receptors. D1-like receptors (D1,D5) are coupled to generally excitatory second messengers and D2-like receptors (D2, D3, D4) are generally inhibitory. Drugs can act as agonists (mimic neurotransmitter) or antagonists (block) with distinct selectivities for receptor types. v. Inactivation The duration of neurotransmitter action within the synapse is ultimately limited by diffusion (over hundreds of milliseconds) but this is too slow for rapid information transfer in the nervous system. Small molecule neurotransmitters are therefore inactivated by enzymes (e.g. catechol-O-methyl transferase [COMT] and monoamine oxidase [MAO] inactivate dopamine), and /or “re-uptake” transporters which effectively pump the transmitter back into the terminal. Re-uptake is the principal mechanism for inactivation of the actions of dopamine in the synapse. Drugs that inhibit these enzymes (e.g. selegiline for MAOB) or that block re-uptake of the neurotransmitter (cocaine increase the concentration of neurotransmitters in the synapse. NEUROTRANSMITTERS IN THE BASAL GANGLIA 2 Y-Aminobutyric Acid (GABA) This neurotransmitter is generally inhibitory in the peripheral and central nervous systems (CNS).It is synthesised by striatal neurons. Glutamic acid dehydrogenase, in the terminals of GABAergic neurons in the CNS synthesises GABA from glutamate. GABA transaminase (GABA-T) is the principal degradatory enzyme. GABA binds to 3 subclasses of receptors GABA A, GABA B, GABA C. Glutamate This is the principal excitatory neurotransmitter in the brain. It is synthesised within neurons in the CNS and in glia. Glia contain glutamine synthetase which converts glutamate to glutamine. Glutamine is subsequently transferred to neurons where it is deaminated to glutamate by glutaminase. Release of endogenous stores of glutamate in pathological settings causes neuronal damage. This process is called excitotoxicity. Acetylcholine (ACh) This neurotransmitter is synthesised from choline and acetyl coenzyme A (CoA). This is catalysed by the enzyme choline acetyl transferase (CAT). The hydrolysis of ACh is via acetyl cholinesterase (AChE). ACh binds to specific receptors in the central and peripheral nervous system and the neuromuscular junction. Ach binds to 2 types of receptors: nicotinic and muscarinic. Dopamine This is a catecholamine that is synthesised from L-tyrosine. tyrosine hydroxylase catalyses the conversion of L-tyrosine to L-DOPA, and DOPA decarboxylase converts L-DOPA to dopamine. Dopamine is transported into storage vesicles for later release as a neurotransmitter. Optimising dopaminergic neurotransmission remains central to the treatment of Parkinson’s Disease. Coordination of cortical motor commands is achieved by motor loop pathways that pass information from the cortex through the basal ganglia and thalamic nuclei, then back to the cortex. These motor loops utilise the above neurotransmitters. Paper-based resources 1. References and Additional Reading: 1.1 Basic and Clinical Pharmacology, Bertram G. Katzung, Pgs 70 – 74 ; 301 - 304 1.2. Neurology in Clinical Practice. Volume 1 Chapter 50, 867 -890, Bradley, Darof et al. WHSL Homepage LT 02. Parkinsonism and Idiopathic Parkinson's Disease Aim To study the epidemiology, clinical features, differential diagnosis and underlying neurotransmitter deficit in idiopathic Parkinson's disease. Delivery objectives 1. Describe the neurotransmitter deficit in IPD. 2. Describe and define the clinical features of IPD. 3. Describe the pathology of IPD. 3  4. List the causes of Parkinsonism. 5. Distinguish between Parkinsonism with IPD. Content Complex circuitry in the basal ganglia allows the thalamus to mediate cortical function. In Parkinson’s disease, the major deficit lies in the substantia nigra: Lack of dopamine Relative excess of ACh Idiopathic Parkinson’s Disease (IPD) This disease occurs secondary to the degenerative decline in the number of dopaminergic cells in the substantia nigra. As the dopaminergic cells die, the nigrostriatal pathway degenerates. As a result, the corpus striatum is in a state of inadequate dopaminergic stimulation. Patients thus cannot activate motor plans for normal rapid movements. The loss of dopaminergic input to the basal ganglia loop decreases the output from the basal ganglia to the thalamus. There is increased inhibitory control of the thalamus, which leads to a loss of excitatory drive to the motor cortex. (See lecture on Basal Ganglia and Movement.) Epidemiology Parkinson’s disease occurs throughout the world, in all ethnic groups, and affects both sexes roughly equally or with a slight predominance among males. Age of onset: between 40–70 years with a peak at 60 years. Clinical Features The symptoms of IPD generally start insidiously and progress slowly but inexorably. The main initial symptoms are tremor and slowness, stiffness or clumsiness, usually of an arm; less common are hypophonia (soft voice), dysarthria, gait difficulty and depression. Symptoms tend to be unilateral or asymmetrical at the onset. The main signs are : Difficulty in initiating movement (akinesia) Slowness in the execution of movement (bradykinesia) Expressionless face (hypomimia) with a diminished blink rate A typical stooped, festinant, slow shuffling gait A rhythmic tremor at rest about 4Hz in frequency and described as ‘pill rolling' It usually affects the arms, but the legs or lower jaw may also be affected. Cogwheel rigidity They may develop a hypophonic, monotonous speech Their writing may become smaller (micrographia) and more untidy. Dementia occurs in up to 30% of patients Postural instability – often have disturbances of posture and equilibrium. These can occur at any stage, but loss of orthostatic stability (with falling) usually occurs in advanced stages of the disease. Other late features are freezing episodes, dysphagia and abnormalities of whole body movement, including difficulty arising from a chair or turning over in bed. 4 Pathology of IPD Degeneration of the substantia nigra o Loss of pigmented cells o Loss of neurons o Gliosis o Many of the remaining cells in the substantia nigra and other pigmented nuclei (e.g. locus ceruleus) contain eosinophilic cytoplasmic inclusions called LEWY BODIES. Diagnosis Conventional laboratory studies do not contribute to the diagnosis and management of IPD.CT scan or magnetic resonance imaging (MRI) of the brain is normal or shows only variable degrees of atrophy. Differential Diagnosis Parkinsonism is a clinical syndrome found in several different disease states. Idiopathic Parkinson’s disease is the most common cause of this syndrome. The remainder of the Parkinsonian syndromes are distinguished from IPD by their poor response to L-DOPA and the presence of additional clinical features such as: Prominent autonomic dysregulation (multiple system atrophy) Impaired vertical gaze (Progressive supranuclear palsy) Causes of Parkinsonism Pharmacologic o Drugs that interfere with dopamine synthesis, storage or release (especially antipsychotics & anti-emetics). o Drugs that block dopamine receptors. Toxins o Substantia Nigra ▪ MPTP (1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine) o Globus pallidus ▪ Carbon monoxide ▪ Carbon disulphide ▪ Cyanide ▪ Manganese Degenerative Diseases o Predominantly dopaminergic neurones ▪ IPD o Multisystem degenerations ▪ Progressive supranuclear palsy ▪ MSA (Multiple System Atrophy) ▪ Corticobasal ganglionic degeneration ▪ Diffuse Lewy body disease ▪ Alzheimer’s disease ▪ Pick’s disease o Hereditary ▪ Wilson’s disease ▪ Huntington’s disease ▪ DOPA responsive dystonia with Parkinsonism Metabolic 5  o Hypoparathyroidism o Chronic hepatocerebral degeneration o Calcification of the basal ganglia Infectious o Encephalitis ▪ Encephalitis lethargica ▪ AIDS Progressive Supranuclear Palsy (PSP) PSP is a progressive illness; onset is after age of 50.The initial symptoms are an unsteady gait with sudden falls, dysarthria, intellectual and psychiatric deficits. The main clinical signs are: a vertical supranuclear gaze palsy, pseudobulbar palsy, axial rigidity (i.e. more of the trunk than the limbs) and dementia. Impaired vertical gaze (progressive supranuclear palsy) There is no effective treatment for this illness, although there may be a mild, transitory response to levodopa. Multiple System Atrophy (MSA) Multiple system atrophy (MSA) is a unifying term that brings together a group of neurodegenerative syndromes —characterized by various degrees of autonomic dysfunction, cerebellar abnormalities, parkinsonism, and corticospinal degeneration The main clinical features of MSA are akinetic-rigid parkinsonism, autonomic failure including urogenital dysfunction, cerebellar ataxia, and pyramidal signs in varying combinations. The onset of disease is marked by the initial clinical manifestation of any of its characteristic motor or autonomic features. The motor presentations of MSA are classified into two separate but overlapping clinical subtypes :MSA with predominant parkinsonism (MSA-P) subtypeMSA with predominant cerebellar ataxia (MSA-C) subtype.Dysautonomia is a feature of both MSA –P and -C.All types of MSA have poor response to treatment with LDopa. Cortico-Basal Ganglionic Degeneration (CBGD) CBGD has features of dysfunction in both the cerebral cortex and basal ganglia. Onset is in the sixth decade of life or later. Typical basal ganglia manifestations are parkinsonism (rigidity, bradykinesia and disequilibrium) and limb dystonia. apraxia, cortical sensory loss and the alien limb phenomenon (inability to voluntarily control the actions of a limb) signal cerebral cortical involvement. This condition is relentlessly progressive, with death occurring about 5 years after its onset. Postencephalitic Parkinsonism Between 1916 and 1927, a worldwide epidemic of encephalitis lethargica (sleeping sickness) affected as many as 750 000 people. Approximately one third of them died acutely, one third recovered completely and the remainder was left with chronic neurological deficits. Most of these patients with chronic postencephalitic complications exhibited parkinsonism. No new epidemics have occurred, but it is believed that sporadic cases continue to occur. Other Parkinsonian Syndromes Vascular disease may account for cases of parkinsonism affecting the predominantly lower body, with severe gait disturbances and freezing. Parkinsonism is a rare complication of head trauma. Repetitive trauma, as seen in boxers, may result 6  in progressive parkinsonism as well as dementia (dementia pugalistica). Drug induced parkinsonism is discussed in learning topic 4. Acute poisoning with carbon monoxide or cyanide and chronic exposure to manganese can result in parkinsonism. Paper-based resources 1. References and Additional Reading: 1.1. Adams and Victors Principles of Neurology Chapter 39, Pg 1128 – 1137, Victor M, Rooper A. 1.2. Neurology in clinical Practice, Chapter 75 Pg 1889 – 1930, Bradley G,Daroff R WHSL Homepage LT 03. Principals of Management of Idiopathic Parkinson's Disease (IPD) Aim To study the pharmacological and non-pharmacological therapy of IPD. Delivery objectives 1. Discuss the mainstay of pharmacological therapy in IPD. 2. Discuss the mechanism of action of L-DOPA. 3. Discuss the major benefit of L-DOPA. 4. Discuss the main problems with L-DOPA. 5. Discuss other pharmacological therapies used in the treatment of IPD. 6. Describe the surgical options for the treatment of IPD. 7. Describe the place of non-pharmacological therapies in the management of IPD. Content Treatment of IPD remains purely symptomatic, and the decision to treat is based mainly on the patient’s degree of disability. Pharmacological Therapy LEVODOPA Mainstay of treatment is the oral administration of L-DOPA (L-dihydroxyphenylalanine), the metabolic precursor of dopamine. This increases dopamine synthesis in the surviving dopamine producing cells. The drug is absorbed from the gut, crosses the blood brain barrier (BBB) and is converted to dopamine in the brain by the enzyme DOPA decarboxylase. It is administered with a decarboxylase inhibitor which does not penetrate the BBB. It prevents decarboxylation in the peripheral tissues, thus preventing peripheral side effects such as hypotension and nausea. Major benefits o mainly improvement is in the bradykinesia and tremor. Problems 1. As the illness progresses and more dopaminergic neurons die, the response will be less complete – larger and more frequently administered doses required. 2. Elevation of dopamine levels in the corpus striatum results in involuntary choreo athetoid movements (dyskinesias). 7  The patients may then abruptly fluctuate from the immobility of the Parkinsonian state to a mobile dyskinetic state – “on-off’” phenomenon. DOPAMINE AGONISTS These agents directly stimulate post synaptic receptors.Associate with fewer dyskinesias than LDopa.Less potent than Ldopa in managing the main features of Parkinsondieases.They are often used in first line therapy especiialy inyounger patients and modulating effects of Ldpoa later. Examples include: Bromocriptine Ropinirole Pramipexole INHIBITORS OF DOPAMINE BREAKDOWN COMT INHIBITORS These agents inhibit the enzyme catechol-0-methyl transferase which is involved in the breakdown of extrasynaptic dopamine. They thus prolong the duration of and half life of levodopa by increasing its availability to the brain. MAO B INHIBITORS Monoamine oxidases are involved in the conversion of dopamine into inactive metabolites. MAO B is the predominant form of MAO in the brain. It is concentrated within and in the vicinity of dopaminergic nerves. Selegiline inhibits MAO B and improves therapeutic efficacy of L-DOPA. It has also been hypothesised that Selegiline may slow the progression of dopaminergic degeneration in Parkinson’s disease possibly due to inhibition of formation of toxic metabolites by MAO B. AMANTADINE It is believed that this antiviral drug may exert its therapeutic benefits through the inhibition of N- methyl-D-aspartate receptors (NMDA). It has limited beneficial effect on the akinesia, rigidity and tremor. It however is the only anti-Parkinsonian drug that can decrease the severity of the levodopa induced dyskinesias. Common side effects include leg oedema, livido reticularis and psychiatric disturbances. ANTICHOLINERGIC DRUGS These agents by blocking muscurinic receptors antagonise the transmission Ach by striatal interneurons. They are most effective in reducing the tremor, but have little beneficial effect on the bradykinesia. Their use is limited by their numerous adverse effects - dry mouth, blurred vision, urinary retention and confusion. Examples include: trihexphenidyl and benztropine. SURGICAL OPTIONS 8 Surgery is reserved for disabling and medically refractory problems. Deep brain stimulation has largely replaced ablative therapy.Deep brain stimulation of subthalmaus and globus pallidus interna in well selected patients with medically refractory parkinsons.. Non-Pharmacological Therapy This consists of a multi disciplinary approach that entails Psychosocial support Addressing issues that may impact on activities of daily living such as : o mobility o postural stability o working with small objects (buttons) A multidisciplinary team approach is essential and physiotherapists, occupational therapists and speech therapists are invaluable in the management of these patients. Paper-based resources 1. Adams & Victors Principles of Neurology, Chapter 39; 1128 -1137, Victor M, Ropper A. WHSL Homepage LT 04. Iatrogenic Movement Disorders Aim To study the drugs that induce movement disorders and to consider a few of these movement disorders. Delivery objectives 1. List the drugs causing drug induced movement disorders. 2. Describe the movement disorders causes by neuroleptic drugs. 3. Describe the clinical features of the neuroleptic malignant syndrome. Content 1) A number of drugs used in the treatment of neuropsychiatric disorders are known to produce movement disorders. In psychiatry, these drug-induced movement disorders (DIMD) are most commonly associated with antipsychotic drugs, but can also be caused by antidepressant drugs, alcohol and mood stabilizing drugs. In neurology, dopamine agonists and anticonvulsants are commonly implicated. Calcium channel antagonists and oral contraceptives are other drugs that may induce movement disorders. 2) The movement disorders caused by neuroleptic drugs can broadly be classified into acute effects and delayed-onset (or tardive) effects. The acute syndromes of particular note are dystonia, drug- induced parkinsonism (with rigidity, resting tremor, bradykinesia), akathisia (literally, an inability to sit) and the rare neuroleptic malignant syndrome (NMS - fever, muscle rigidity, altered sensorium and autonomic instability, associated with raised creatine kinase level and leucocytosis). NMS, if not detected early, may be fatal in some patients. The development of involuntary movements in some patients on chronic neuroleptic therapy has been a cause for much concern as these movements are potentially irreversible. Most often these movements are choreo-athetoid and the syndrome is called tardive dyskinesia (TD), but tardive dystonic, akathisic, myoclonic and tic-like movements have been described. The newer and atypical neuroleptics have a much lower propensity to produce movement disorders. These movement disorders have been reported with other dopamine antagonists used in medicine, e.g. metoclopramide. 9 3) Drugs reported to cause DIMD include : Tricyclic antidepressants – often a cause of hand tremor and myoclonic jerks. Selective serotonin reuptake inhibitors (SSRIs) – Parkinsonian symptoms, dystonia, dyskinesia and akathisia. Lithium is commonly associated with a mild action tremor, which becomes coarse when toxic levels are reached. It may also cause myoclonus. Stimulants (sympathinomemetic drugs, caffeine) may result in a tremor. Anticonvulsants (phenytoin,valproic acid) are associated with chorea, tremor, and in toxic doses result in nystagmus, ataxia and dysarthria. Dopamine agonists (levodopa, bromocriptine, pergolide) are commonly associated with chorea, dystonia and myoclonus, especially prominent in the late stages of Parkinson’s disease. Oral contraceptives have been associated with chorea. 4) DIMD are usually attributed to the actions of these drugs on dopamine and serotonin systems. As these movement disorders are often resistant to treatment, prevention is the best strategy, especially for disorders like TD. It is worthwhile also noting that many of these movement disorders were described in psychiatric patients long before the advent of specific pharmacological therapies and there may be intrinsic factors that predispose certain patients to DIMD. Paper-based resources Adams & Victors Principles of Neurology, Chapter 4; Pg 77-85, Victor M, Roppel A WHSL Homepage 10