Disorders of Motor Function PDF

Disorders of Motor Function SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Identi...

Disorders of Motor Function SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Identify the important signs and symptom of myasthenia gravis, Parkinson’s disease 2. Identify the most important neurotransmitters that are involved with myasthenia gravis and Parkinson disease and describe their normal activity/ role 3. Identify the key structures of the basal ganglia and their normal role 4. Describe the pathophysiologic processes for a myasthenia gravis and Parkinson’s disease 5. Define dopamine‘s role in the coordination of muscle movement and how that translates to signs and symptoms of Parkinson’s disease 6. Differentiate the effects of dopamine (or lack of dopamine) on the D1 and D2 dopamine pathways 7. Identify and describe the cardinal symptoms associated with Parkinson’s disease Topics Myasthenia Gravis Parkinson Disease  Normal NMJ Function ACh packaged in vescicles ACh released upon stimulation ACh binds to ACh receptors (post-synaptic) Sufficient binding stimulates muscle contraction via Na Channel depolarization Terminated by ACh- esterase Myasthenia Gravis Motor end plate dysfunction (Neuromuscular junction) ○ Autoimmune disorder Depletion of post-synaptic acetylcholine receptors ○ IgG antibodies mediated processes  Complement cascade activation ○ Destruction of post-membrane integrity  Antigenic Modulation ○ Accelerate AChR turnover & endocytosis ○ Decreased number of ACh receptors  Blockade of ACh receptors (minor etiology) Complement Cascade Activation Complement activation forms membrane attack complex (MAC) loss of synaptic folds and post-synaptic Na channels J Clin Invest 2024:134;e179742  Antigenic Modulation and Receptor Blockade Myasthenia Gravis ○ Initiation of IgG antibodies  75% of patients have abnormal thymus ○ Thymus express Ach receptors triggering autoimmune response  Antibodies to other receptors ○ Affects AChR clustering Muscle-specific kinase (MuSK) – 10% Lipoprotein receptor-related peptide 4 (LRP4) – 3% Myasthenia Gravis Sufficient stimulation (depolarization) of post- synaptic membrane required to trigger muscle contraction ○ MG could result in  Failure to trigger muscle contraction  Decreases amplitude of muscle cell action potential ○ Repetitive firing decreases amount of presynaptic Ach release resulting in progressive weakening of muscle activity (myasthenia fatigue) ○ Muscle activity returns once new Ach produced  Clinical Presentation Characteristic pattern of muscle fatigue Symptoms typically worsen throughout day, improve with rest ○ Cranial muscles  Extraocular muscles ○ Diplopia  Eyelids ○ Ptosis  Facial muscles ○ Snarl when attempting to smile ○ Weakness in chewing  Oropharynx ○ Difficulty swallowing (dysphagia) Regurgitation/aspiration of contents ○ Speech impairment ○ May progress to generalized MG to involve limbs  Unlikely to generalize if confined to ocular involvement at 3 years  Proximal > distal muscles are affected ○ Myasthenia crisis  Involvement of respiratory muscle resulting in respiratory compromise/collapse Treatment Treatment ○ Ach-esterase inhibitors  Pyrostigmine, pyridostigmine ○ Immune suppressants  Corticosteroids – decrease Ab response  Azathioprine ○ Complement blockade  Eculizumab  Ravulizumab  Zilucoplan ○ FcRn inhibition (IgG recyclingfacilitation IgG removal)  Efgartigimod  Rozanolixizumab ○ Thymus removal (AChR Ab+) Drugs of interest (at NMJ) ○ Block ACh release  Aminoglycoside antibiotics (gentamicin, tobramycin, amikacin)  Botulinum toxin (e.g Botox) ○ Block motor end place ACh receptors – neuromuscular blockers (e.g. rocuronium) ○ Block ACh-esterase – instecticides (organophosphates)  Parkinson Disease Basal Ganglia Overview Basal ganglia control learned/automatic movements ○ Start/stop/adjusting intensity Key structures ○ Cortex ○ Thalamus ○ Substantia nigra (SN) ○ Globus pallidus ○ Nigrastriatal pathway  SN ⬄ Striatum (putamen + Caudate) Parkinsonism ○ Repeated concussions/head trauma ○ Exposure to toxins (pesticides) ○ Genetic mutations  More commonly associated with early-onset ○ Dopamine blocking medications (reversible)  Antipsychotics (Haloperidol)  Metoclopramide  Idiopathic = Parkinson Disease  Parkinson ○ Risk > 60 years of age ○ Male > female Nigrostriatal degradation ○ Loss of parkin enzyme – decreases removal of defective protein aggregation (lewy bodies) neuronal cell death ○ Oxidative stress (free radicals) --- ↓activity __ ↑ activity __ Inhibitory pathway __ Stimulatory pathway Normal Normally thalamus under inhibitory control of globus pallidus internal (GPi) Direct pathway (D1–dopamine 1) ○ Inhibits GABA inhibition of thalamus Indirect pathway (D2–dopamine 2) ○ Glutamate stimulates thalamus PD Net result is ↑muscle activity PD: Lack of dopamine ○ D1 greater GABA inhibitory effect on thalamus ○ D2 less stimulation of GPi ○ Net result ↓muscle activity Pathophysiology Loss of dopaminergic neuronsdecreased dopamine availability Responsible for stimulating movement ○ Loss of dopamine, less initiative to move and slowness of movement ○ video  Movement-related Clinical Manifestations Highly learned/automatic movements affected Tremor ○ At rest; disappears with activity & sleep ○ Affects hands, feet, head, neck, face, lips, tongue ○ Unilateral initiallybilateral as disease progresses Rigidity ○ Ratchet-like;jerky movements ○ Unilateral initiallybilateral as disease progresses Bradykinesia*** (must have for PD diagnosis) ○ Slowness in initiating/executing movements ○ Affects unconscious voluntary movements  Walking – shuffle steps, lean forward (balance), difficulty changing stride, lack of arm swing  turning, freezing in place,  Executing in steps rather than continuous, coordinated movement Postural instability also common but late manifestation ○ Fall risk – especially backward Video Other Motor Clinical Manifestations Facial muscles ○ Movements limited/slow ○ Become expressionless; masklike Eyelid blinking slows/absent Tongue, palate, throat muscles slow ○ Difficulty swallowing, drooling, impaired speech ○ Speech tone is soft, monotonous, poorly articulated Micrographia Other Clinical Manifestations ANS ○ Excessive sweating and salivation ○ Orthostatic hypotension ○ Constipation Cognitive ○ Dementia/impaired memory (20%) ○ Unable to multitask Sleep disturbances Mood changes ○ Depression, anxiety, apathy Olfactory changes  Treatment Dopamine and dopamine agonists Anticholinergics