Transcript s Disease
Integration Lecture Neurology Week 4 Unit Week 8 What we have learned… Recall: Embryology of the Nervous System 1. 2. 3. 4. 5. 6. 7. Neural plate Neural tube Flexures (eg: cephalic) Forebrain, midbrain, hindbrain vesicles Forebrain “outgrowths” laterally into hemispheres C-shaped cortex Folding (gyri & sulci) Dorsal Induction (Neural Tube Defects) Ventral Induction Cell Migration Dr. Heather MacLean Disorders of Neural Tube Formation Spina Bifida +/- Chiari Malformation Anencephaly Spina Bifida Disorders of Cell Migration Lissencephaly Heterotopic Gray Matter The Motor System Puzzle Finally Has All its Pieces!… Piecing Together Motor system puzzle Cerebellar clinical Ipsilateral ataxia hypotonia Upper Motor Neurons Cerebellar circuits (direct : Corticospinal and indirect: reticulo-, rubro- , tecto- , vestibulo-) UMN clinical syndrome Spastic paresis (pattern) Hypereflexia, Babinski Basal ganglia LMN clinical syndrome Lower Motor Neurons Basal Ganglia Clinical 1. Hypokinetic: parkinsonian 2. Hyperkinetic: chorea, tic, dystonia, etc Brainstem motor nuclei Spinal Anterior Horn cells Atrophy, hypotonic paresis Hyporeflexia, fasciculations Mostly similar to LMN NMJ , muscle Important specific features e.g: no fasciculations MG:Fatigue, oculo-bulbar Muscular Dystrophy: patterns Overview of the motor system Direct Path Indirect Path Cerebellar Circuit BG Circuit Upper and Lower Motor neurons UMN Syndrome vs. LMN Syndrome UMN Syndome weakness muscle bulk fasciculations muscle tone stretch reflexes clonus plantar reflex yes normal none LMN Syndrome yes wasting Increased/ spasticity yes decreased hyperactive hypoactive present upgoing (Babinski) absent downgoing Spasticity One part of the Upper Motor Neuron Syndrome Velocity dependant increase to passive stretch (tone) of muscle Often clasp knife phenomenom Often unidirectional, ie extensors OR flexors Associated with increased stretch reflexes, muscle spasms, increased cutaneous reflexes Can you pick out the UMN and the LMN disorders ? ALS Parkinson’s not directly an UMN disorder ! Ant spinal infarct MCA stroke Spinal muscular atrophy Occipital stroke Diabetic Sensorimotor polyneurop. Epidural hematoma We learned to localize basal ganglia Caudate Putamen G. Pallidus (Thalamus) Parkinson’s Disease : TRAP + … Tremor Rigidity Akinesia / bradyk Post. Instab. Depression Psychiatric Dysautonomia Cognitive / dementia Sleep Disorders Rigidity An “extra-pyramidal” sign Increased tone to passive movement that is NOT velocity-dependent All directions of movement Often association with tremor Lead-pipe Hence a cogwheeling component to the rigidity And often associated with bradykinesia and postural instability We “marveled” at the complex circuitry: BG modulate motor system Cortical Dopamine + Striato Thalamo Pallido Substantia Nigra comp We met the key neurotransmitter relevant to Parkinson’s Disease: Dopamine LDopa Dopamine Nigro-striatal pathway Both inhibitory and excitatory (it depends … net effect is a boost for movement !) Complicated loops: serial inhibitions … net output from basal ganglia is inhibition of thalamus ! Sinemet Boosting Dopamine stimulation A pharmacologist’s dream ! Ldopa-Cdopa Carbi Dopa – doesn’t enter CNS Dopamine L Dopa periphery Blood brain barrier CNS Decarboxylase L Dopa Picked up by SN neurons Dopamine Destroyed by COMT Dopamine receptors on striatal neurons Destroyed by MAO Dopamine agonists: Pramipexole, ropirinole COMT inhibitor entacapone MAO inhibitor rasagiline Other Neurotransmitters of Basal Ganglia • Lots of NT’s in the BG circuits • (Glutamate, serotonin, GABA, Substance p, somatostatin, enkephalin, cholecystokinin) • Dopamine vs acetylcholine balance is critical DOP ACH Role of Anti-Cholinergic Medications to amplify Dopamine activity Short term memory test What designer Medication would help a patient with Parkinson’s 1. 2. 3. 4. COMT enzyme enhancer Medication Blocking passage of LDopa across Blood Brain Barrier Medication Blocking Dopa Decarboxylase inside Substantia Nigra Neurons Medication stimulating striatal neuron dopamine receptors Clinical case # 1 You are asked to see a 22 year old man who has a 2 year history of rigidity and tremor of the upper limbs, as well as balance problems. He has become slow getting dressed, eating and walking. He and his girlfriend have done some research on Emedicine and they are now convinced this must be Parkinson’s disease. There is no family history of tremor or any extrapyramidal disease. For the past 2 years, he has been followed by a psychiatrist for anxiety and depression. O/E • Masked facies, sitting immobile in chair during history • Asymmetric leadpipe rigidity in arms and legs (L>R) • Tremor of outstretched hands, rapid and of wide amplitude, disappearing when the hands are resting on his lap or when he walks • Normal muscle power, reflexes, sensation Clinical case #1 questions 1. Do you agree there are features of a Parkinsonian syndrome ? Yes: Rigidity, akinesia, tremor 2. Is the tremor typical of Parkinson’s Disease ? No: resting is most typical, though some PD patients also get a postural tremor 3. Parkinson’s Disease is most unlikely because … • Age (22 years) • Asymmetric presentation (left sided rigidity) • Lack of family history of Parkinson’s 4. “Seeing a psychiatrist for the past 2 years” – What should we be asking about immediately ? Medications that could cause a parkinsonian syndrome e.g. dopamine antagonists, “neuroleptics” More info … You find out that he has a sister with unexplained liver failure ! This leads you to look more carefully at his eyes and you see Brown rim in periphery of cornea this A proud day in your medical Recessive Disorder of Copper metabolism career: you diagnose … Autosomal • Young onset extrapyramidal disorder (parkinsonian, flapping tremor) often with psychologic disorders Wilson’s Disease • Liver disease • Kayser-Fleicher rings (copper deposition, cornea) • Treatable ! • reducing copper intake (zinc) • chelation (to wash out copper load) • liver transplantation Parkinsonism = Hypokinetic disorder with features of TRAP Parkinson’s Disease Outside Parkinson’s Disease, what can cause a parkinsonian syndrome ? • Medications (dopamine antagonists) • • • • Progressive Supranuclear palsy Wilson’s disease Other degenerative diseases: “Multi-system atrophy”, advanced Alzheimer’s Rare: toxic, vascular, etc Can you match the descriptions ? Brief sudden jerk of the legs when falling asleep Painful twisting of the head towards the left shoulder, occurring several times a minute; not suppressible 1. Cerebellar ataxia 2. Dystonia 3. Myoclonus 4. Tic (Tourette’s) Rapid movements of the arms and fingers, constantly changing, as well as dancing gait pattern 5. Tardive dyskinesia Grimacing movements of the face and tongue in an elderly woman with history of bad depression 7. Essential tremor 6. Chorea 8. Unit III – anxiety disorder Mao ??? ALS Lou Gehrig’s David Niven S Hawking? Sue Rodriguez Remember the SLM ? ALS • Sporadic (90%) • Asymmetric progressive • Combined UMN –LMN • Survival 2-3 yr average SMA • • • • Genetic Symmetric Pure LMN Survival variable 1. Infantile – 1yr 2. Juvenile 3. Adult Can you figure out the relevant pathology ? SMA ALS Hand intrinsic muscle Diaphragm :recent denervation Normal Condition Neither: Huntington’s ! NMJ – Can you rapidly localize 1. Ca++ Channels 2.Na+ Channels 3.Acetyl Cholinesterase Voltage-gated Ca Channels: triggers release of vesicles Na channels linked to Ach receptors: depolarize muscle endplate Acetyl Cholinesterase In the folds of synaptic cleft Myasthenia Gravis • Fatiguable weakness • Extraocular, facial, pharyngeal and proximal muscles, also diaphragm • Temporary improvement with acetylcholinesterase inhibitor meds • Definitive treatment - steroids, immunosuppressants - limited role for thymectomy - all cases of thymoma - some others: recent onset, young, generalized / disabling Can you recognize these muscle diseases ? Inflammatory myopathy: Polymyositis, Dermatomyositis Proximal progressive painless weakness, high CK Duchenne Muscular Dystrophy Childhood onset, X-linked (boys), progressive Loss of motor milestones, calf hypertrophy Myotonic Dystrophy Most common adult onset, AD Facial, ptosis and Distal limb m Percussion myotonia, systemic disease: Cataracts, cognitive, digestive, cardiac conduction ! Clinical case challenge 60 year old man presents with frequent tripping due to progressive right foot drop. Gradual onset over the past month. He does have a history of low back pain and “sciatica” Frequent tingling paresthesia over top of right foot. O/E (positive findings) Normal muscle tone, mild atrophy right pretibial muscles Marked weakness of Right ankle DF, inversion, hip abductors. Slight relative pain perception over dorsum of right foot Normal/symmetrical knee and ankle reflexes, downgoing plantar responses Questions 1. Why are you certain this is not a Left mesial frontal lesion LMN picture overall: atrophy, tone, no reflexes or Babinski sign 2. Why are you certain this is not muscle disease Asymmetric/ distal, presence of sensory symptoms & signs 3. What is your favored PNS localization Right L5 radiculopathy 4. What is your most important diagnostic next step Imaging (MRI or CT) Spinal roots, numbering 8 Cervical roots (7 cervical vertebra) 12 Thoracic roots 5 Lumbar roots 5 Sacral 1 Coccygeal Common radiculopathies: C5 C6 C7 C8 L4 L5 S1 Cervical spine straightforward anatomy C5 root leaves horizontally between C4-5, gets compressed by C4-5 disk Note: numbering changes at T1 because there Are only 7 cervical vertebra but 8 cervical roots ! Lumbar spine Cauda equina (down-slopping roots) L5 root leaves under pedicle of L5 (between L5-S1) Most often compressed by lateral disk at L4-5 With Degenerative Disc Disease, usually disc “A-B” Affects nerve root “B”, no matter if it is cervical or lumbosacral with the exception of C7/T1 which compresses C8