Movement Disorders - PDF

Movement disorders By Dr Osama Elshafei Lecturer of neurology ILOs 1st part (Parkinson’s disease) Rapid introduction and review about the BG Identify the pathophysiology and presentation of PD...

Movement disorders By Dr Osama Elshafei Lecturer of neurology ILOs 1st part (Parkinson’s disease) Rapid introduction and review about the BG Identify the pathophysiology and presentation of PD How to diagnose PD? How to treat a patient with PD? 2nd part (Other movement disorders) Identify other types of movement disorders Identify the commonest causes for each type of them INTRODUCTION Basal ganglia are a collection of subcortical structures consisting of several connected nuclei located in the brain. -Basal ganglia are a part of the extrapyramidal system and they participate in the movement modulation -They include caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra 3 INTRODUCTION Input signals from the cortex are processed within the basal ganglia, which then create a focused output signal to the thalamus that ends up within the motor neurons of the frontal lobe and brainstem. 4 The afferent portion of the basal ganglia is the striatum (putamen and caudate nucleus) The efferent portion of the basal ganglia is the globus pallidus Globus (GPi & GPe) From the striatum, two main pathways arise  the direct and indirect pathway. The direct pathway is excitatory and is in charge for the initial part of the movements, while the indirect pathway is inhibitory, and it prevents the unnecessary movements. Nigrostriatal pathway This pathway projects from the SN pars compacta to the striatum It utilizes dopamine. This pathway has the modulatory effect on the BG: It excites the direct pathway It inhibits the indirect pathway (The different effect on the direct and indirect pathway is explained by the activation of the different dopamine receptors ) D1 receptors are found on the striatal neurons in the direct pathway. D2 receptors are found on the neurons in the indirect pathway. 6 INTRODUCTION Named after James Parkinson who published 'An Essay on the Shaking Palsy' in 1817, which established Parkinson’s as a recognised medical condition. It is a chronic progressive neurodegenerative disorder affecting movement and characterized by loss of dopaminergic neurons in the substantia nigra of the brain. 7 Pathophysiology PATHOPHYSIOLOGY Loss of dopaminergic neurons in Substantia Nigra pars compacta and Locus Coeruleus 9 PATHOPHYSIOLOGY For PD to occur, at least 75% of SN’s melanin containing nerve cells are lost PD is a multifactorial illness with genetic and environmental determinants. 10 PATHOPHYSIOLOGY Two common pathways Mitochondrial Impairment of dysfunction/ oxidative Ubiquitin Proteosomal stress system Due to: Due to: 1. Environmental toxins as MPTP, 1. Environmental toxins as MPTP, herbicides, pesticides herbicides, pesticides 2. Genetic factors (mutation of α - 2. Genetic factors (mutation of α - synuclein, parkin) synuclein, parkin) Oxidative stress and Aberrant protein mitochondrial injury accumulation Nigrostriatal degeneration 11 α – SYNUCLEIN IN LEWY BODIES α-synuclein monomers become oligomers (protofibrils), which coalesce into fibrils and then aggregate into Lewy body inclusions Dysfunction of Ubiquitin Proteasome System 12 PATHOPHYSIOLOGY Presence of Lewy Bodies (inclusion bodies with eosinophilic cytoplasm surrounded by halo) is a pathological hallmark in PD Lewy bodies stained strongly with antibodies of α – synuclein 13 NEURODEGENERATION SYMPTOMS Basal Ganglia Selection Theory: – Basal ganglia are involved in the selection of motor programs – Bradykinesia due to failure to select or engage appropriate motor programs – Dyskinesia due to failure of basal ganglia to suppress inappropriate motor programs 14 Epidemiology Incidence Increase dramatically with age Onset at 50-60 years old Overall incidence is 15-25/100.000 4-10% onset before 40 years old:  Young onset PD: before 40 years old  Juvenile onset PD: before 20 years old More common in males More common on exposure to pesticides and toxins, well water and family history 16 Clinical Picture Clinical Picture Typical PD – Insidious onset and progressive course – Starts unilateral then bilateral Bradykinesia Postural Parkinson’s instability disease Rigidity Resting Tremor 18 Clinical Picture 1) Bradykinesia – Difficulty in initiation and slowness of voluntary movements – Decreased facial expression ( mask face and infrequent blinking) 19  Clinical Picture 2) Tremors – Regular, rhythmic oscillatory involuntary movements – Resting tremors (distal > proximal) – Affects mainly ULs, neck, jaw and LLs – Increases by stress and emotions – Decrease by sleep and voluntary movement 20 Clinical Picture 3) Rigidity – Affects muscles of the limbs, neck and trunk – Proximal > distal – Flexed posture (Gorilla attitude) 21 Clinical Picture 4) Loss of postural reflexes – Retropulsion and propulsion 5) Loss of associative and emotional movements – As swinging of the arms during walking 22 Clinical Picture 6) Gait – Shuffling, short steppage and festinant (running to reach the center of gravity) 23 CLINICAL FEATURES 7) Non-Motor Impairments – Autonomic Dysfunction Orthostatic hypotension, sweating dysfunction, sphincter dysfunction and erectile dysfunction – Cognitive and Neurobehavioral Abnormalities Dementia, Depression, anxiety, hallucinations – Sleep Disorders REM Behavior Disorder – Sensory Abnormalities Olfactory dysfunction, Paresthesia, Akathisia 24 Diagnosis DIAGNOSTIC TESTING 1) Careful neurological examination 2) Blood tests: to exclude other causes of tremors. 3) MRI brain: to exclude secondary causes 4) PET and SPECT: can detect the dopamine level in the striatum and differentiate PD from other conditions 26 Differential Diagnosis 1) Parkinsonian tremors – Essential tremors Kinetic &/or postural Absent at rest and increase with movement – Psychogenic and other types of tremors 27 Differential Diagnosis 2) Secondary Parkinsonism a) Vascular parkinsonism Vascular risk factors Rigidity is predominant Pyramidal signs Mainly affects the LL Early cognitive impairment Poor response to L dopa 28 Differential Diagnosis 2) Secondary Parkinsonism b) Post-encephalitic parkinsonism Any age Pyramidal signs Mental changes Other neurological deficits 29 Differential Diagnosis 2) Secondary Parkinsonism c) Post-traumatic parkinsonism Repetitive head trauma 30 Differential Diagnosis 2) Secondary Parkinsonism C) Drug or toxin induced parkinsonism d) Wilson disease e) Hydrocephalic parkinsonism 31 Management TREATMENT STRATEGIES Drugs – L-Dopa and Dopamine Agonists – MAO Inhibitors and COMT Inhibitors Gene therapy Surgical Interventions – Stem cell therapy – Lesion surgeries and Deep Brain Stimulation Physiotherapy 33 GOALS OF MEDICAL TREATMENT No cure currently exists Treatment does not stop the progression of the disease Offers symptomatic relief Can temporarily restore function Can enhance Quality Of Life Each individual responds to drugs differently 34 GOALS OF MEDICAL TREATMENT Basic abnormality is: dopamine and acetylcholine in BG Medical treatment aims to: dopamine and acetylcholine 35 LEVODOPA Used since the 1960’s Remains the ‘gold standard’ of treatment L-dopa is a dopamine precursor that cross the BBB It is used with dopa decarboxylase inhibitor (either carbidopa or benserazide)to decrease the peripheral side effects and increase level of L- dopa available to the brain 36 LEVODOPA Abbreviations: COMT - Catechol- O-methyltransferase 3-OMD - 3-O-methyldopa AAAD - Aromatic amino acid decarboxylase MAO - Monoamine oxidase DOPAC - 3,4-dioxyphenylacetic acid HVA - Homovanillic acid 37 LEVODOPA Side effects -Nausea &Vomiting -Confusion -Visual hallucinations -Delusions Long Term effects: -Gradually ineffective after several years. -Episodes of immobility (freezing). -Levodopa-induced involuntary movements. 38 LEVODOPA SIDE EFFECTS Loss of Dopamine Substantial release of Regulation DA in pulsatile fashion Motor Fluctuations Dyskinesia - Long Duration - Peak Dose Dyskinesia Response and Short - Biphasic Dyskinesia Duration Response - On-Off Effect 39 DOPA AGONISTS Dopamine agonists act directly on the receptors in the brain to which dopamine binds. 40 DOPA AGONISTS Includes: 1. Ergot derivatives: As Bromocriptine and Pergolide Less potent Carry more side effects as retro-peritoneal and pulmonary fibrosis 2. Newer drugs: As Pramipexole and ropinirole More potent Less side effects 41 MAO INHIBITORS AND COMT INHIBITORS Selegiline and Rasagiline Neuroprotective nature MAO Inhibitors Entacapone and Tolcapone Used in conjunction with levodopa and an AAAD inhibitor COMT Inhibitors 42 ANTI-CHOLINERGIC DRUGS The least potent in treating PD, but effective in for tremors control As: Trihexyphenidyl and Benztropine Side Effects:  Blurring of vision  Retention of urine  Dry mouth and constipation  Tachycardia  Confusion and hallucinations 43 SURGICAL TREATMENT 1) Strereotactic ablative surgery a) Thalamotomy: to control contralateral tremors b) GPI pallidotomy: to improve dyskinesia, rigidity, bradykinesia and tremors c) Subthalamotomy: as pallidotomy 44 SURGICAL TREATMENT 2) DEEP BRAIN STIMULATION (DBS) 45 COMPLICATIONS ASSOCIATED WITH DBS Surgical Hemorrhage, ischemic lesions, seizures, infections,and misplaced leads Procedures Occurrence: ~ 5% DBS Electrode Failure, Lead breakage, cranial lead migration, Infection, Erosion, Malfunction Hardware Occurrence: ~ 20% Dystonic posturing, dysarthria, dyskinesia, Stimulation limb and facial muscle spasms, depression, mood changes, visual disturbances, and pain 46 GENE THERAPY Genes to produce TH delivered virally (HSV) into Dopamine striatum Synthesis Genetically delivered AAADC using an AAV Multiple genes – VMAT and TH Viral vectors have been used to deliver GDNF to the striatum and SNc Neurotrophins In vivo lentiviral delivery of a modified neurturin construct produced neuroprotection of rat nigrostriatal projections. Lentiviral delivery to increase expression of the normal Parkin gene in the substantia nigra of rats Parkin Gene AAV carrier to deliver Hsp-70 to the substantia nigra of MPTP-treated mice 47 STEM CELL THERAPY Hormonally induce stem cell differentiation into nigrostriatal dopaminergic neurons or their precursors and then to transplant them into patients’ SN 48 PHYSIOTHERAPY Supplementary Therapy Help with movement, posture and balance Relieve muscle and joint stiffness and discomfort Exercises to maintain or improve muscle strength 49 Now take a deep breath and refresh your memory Answer the following simple questions Q1 Which of the following is not characteristic to primary Parkinsonian disease a) Associated with postural instability b) Associated with +ve Babinski sign c) Associated with rigidity d) Associated with bradykinesia 51 Q2 Which of the following is not characteristic for Parkinsonian tremors a) Occurring at rest and sleep b) Occurring at rest and increase by emotional stress c) Occurring at rest, pill rolling d) Occurring at rest, distal 52 Q3 The definitive curative line of treatment for PD is: a) Dopaminergic drugs b) L-dopa c) Anti-cholinergic drugs d) Only symptomatic treatment available 53 ILOs 1st part (Parkinson’s disease) Rapid introduction and review about the BG Identify the pathophysiology and presentation of PD How to diagnose PD? How to treat a patient with PD? 2nd part (Other movement disorders) Identify other types of movement disorders Identify the commonest causes for each type of them  Classification of movement disorders 1. Akinetic-rigidity syndrome 2. Hyperkinetic-hypotonic syndrome Idiopathic Parkinson’s disease Tremor benign essential tremor Postencephalitic parkinsonism cerebellar tremor Drug-induced parkinsonism Chorea Huntington's disease Symptomatic parkinsonism rheumatic chorea multiinfarct dementia benign hereditary chorea Alzheimer's disease Myoclonusepileptic myoclonus head injury symptomatic myoclonus manganese intoxication post-anoxic anoxia cerebellar degeneration Multiple system atrophy essential myoclonus Shy-Drager syndrome Tics Gilles de la Tourette syndrom striatonigral degeneration Torsion dystonia olivopontocerebellar hereditary dystonia degeneration symptomatic dystonia Progressive supranuclear palsy paroxysmal dystonia Wilson's disease focal dystonias Hallervorden-Spatz disease spasmodic torticollis Pallido-pyramidal degenerations blepharospasm  Chorea Definition :- Irregular, Random Brief and Abrupt Distal Predominance Purposeless Facial grimacing and abnormal respiratory sounds Chorea Causes:- Medications (e.g., tardive dyskinesia) Haldol, other antipsychotics Huntington’s Disease Hemiballism (Stroke) Post-Infectious (Strep Infection) Pregnancy Other Disorders (metabolic,immunologic..) Sydenham’s Chorea Clinical presentation :- Occur in 5-10% of cases Mainly in girls of 5-15 yrs age May appear even 6-12 mos after the attack of rheumatic fever Clumsiness, deterioration of handwriting, emotional lability or grimacing of face Clinical signs: pronator sign, jack in the box sign , milking sign of hands  Athetosis slower and more sustained than choreiform movements affect primarily the distal portions of the extremities, more or less continuous slow, snakelike movements Lesion: outer segment of the putamen. Dystonia Involuntary, sustained muscular contractions or sustained postures. It can appear either in a familial, usually generalized form, or as a focal disorder, then either as an idiopathic phenomenon or as a consequence of focal brain damage. Focal Dystonia Blepharospasm Contraction of orbicularis oculi muscle. Oromandibular dystonia Involuntary movements of the tongue and mouth. Spasmodic (spastic) dysphonia Laryngeal muscles are involved. Writer’s cramp Discomfort in the hand. Abnormal posturing is typical.  Myoclonus Sudden, shock-like muscle contractions Focal, Multifocal, or Generalized May be regular and rythmic, but usually irregular and jerky Epileptic or Non-Epileptic Cortical (Epileptic) Brainstem or Spinal Segmental (Non-Epileptic) Tics and Tic Disorders Tics are intermittent, repeated, stereotyped movements or sounds that may occur in an infrequent or almost continuous manner. Tics may be "simple," such as a cough, grunt, facial twitch, or shoulder shrug, or "complex," such as a word, phrase, or a stereotyped sequence of movements. Although tics appear similar to normal movement, they are not voluntary.  Tics are very common in children. Tics are less common in girls. Most tics resolve spontaneously and do not require treatment, unless the symptoms interfere with school or social interactions. The cause of tics is unknown; however, several family members may be affected, suggesting a genetic component. The severity and nature of tics change throughout life.