1. RAHUL ARORA JR 3 , MEDICINE

2. WHAT IS EXTRAPYRMIDAL SYSTEM? DEFINITION ANATOMY FUNCTIONS APPROACH TO A CASE OF EXTRAPYRMIDAL DISORDER CLASSIFICATION OF EXTRAPYRMIDAL DISORDER DEFINATION ETIOLOGY PATHOPHYSIOLOGY DISTINGUISHING FEATURES BRIEF DISCUSSION ON PARKINSONISM HUNTINGTON DISEASE 3. The term extrapyramidal system, coined by British neurologist Kinnier Wilson, refers to the basal ganglia and an array of brain stem nuclei (red nucleus, reticular formation etc.) to which they are connected. Components of the extrapyramidal system include the red nuclei, vestibular nuclei, superior colliculus and reticular formation in the brain stem, all of which project via discrete pathways to influence spinal cord motor neurons. Cerebellar projections are also included since they influence not only these brainstem motor pathways, but also the motor cortex itself via the dentatothalamic projection. 4. Basal ganglia Subcortical nuclei Caudate, putamen & globus pallidus : corpus straitum Caudate & putamen : straitum Globus pallidus & putamen : lentiform nuclei Globus pallidus : pallidum 5. Perhaps the most important structures to retain an extrapyramidal definition are the basal ganglia, Sub cortical cell stations for the extra pyramidal motor pathway The neostriatum (caudate and putamen) receives widespread cortical afferents, including those from high order sensory association and motor areas, and projects mainly to the globus pallidus. The latter nucleus is the major outflow for the basal ganglia and, via the ventral anterior thalamus, exerts its major influence on premotor and hence the motor cortices. This pattern of connections suggests that the basal ganglia are involved in complex aspects of motor control, including motor planning and the initiation of movement. 6. pyramidal system extrapyramidal system function Skilful volitional movements Modulate volitional motor movements Finalizes an act Initiate an act connection Direct linkage to spinal cord Multi neuronal and multi synaptic via descending tracts Cortico bulbar and cortical spinal tract reticulo-spinal, rubro-spinal, olivo-spinal and vestibulo-spinal tract. Clinical features spasticity Rigidity( lead pipe/ cog wheel) Reflexes brisk normal Power diminished Usually not affected Planters extensor flexor Involuntary movements absent present 7. Phylogenetically, corpus striatum is primarily responsible for stereotyped motor activities to maintain tone, posture, locomotion and automatic associated movement. Regulation of voluntary motor activity Control of the muscle tone Maintenance of emotional and associative movements 8. It is now clear that in many extrapyramidal disorders there are specific changes in neurotransmitter profile rather than discrete anatomical lesions 1. Disturbance in the control of voluntary motor activity resulting in involuntary movements which may be of two main types: Rhythmic and regular as in parkinsonism Dysrhythmic and irregular as in chorea, athetosis and dystonia 2. Disturbance in the normal muscle tone resulting in hypertonia (rigidity) 3. Disturbance in the maintenance of emotional and associated movements resulting in bradykinesia (mask face, infrequent blinking and loss of swinging during walking) 9. Extrapyramidal disorders are classified broadly on clinical grounds into: 1. The akinetic-rigid syndromes in which poverty of movements predominates 2. The dyskinesisas in which there are a variety of excessive involuntary movements 10. Akinetic-rigid syndromes Idiopathic Parkinson's disease Drug-induced parkinsonism (e.g. phenothiazines) MPTP-induced parkinsonism [methylphenyltetrahydropyridine] Postencephalitic parkinsonism Parkinsonism-plus Childhood akinetic-rigid syndrome Dyskinesias Essential tremor Chorea Hemiballismus Myoclonus Tic or 'habit spasms' Torsion dystonias Paroxysmal dyskinesias 11. Rhythmical Tremor Irregular Slow or sustained (Athetosis / dystonia) Rapid Controllable (Tics) Uncontrollable Distal (Chorea) Proximal (Ballismus) Multifocal (Myoclonus) 12. Only Cogwheel rigidity or rest tremor (Parkinsonism) Cognitive, language, upper motor neuron or sensory sign (Degenerative disease with parkinsonism) 13. Age- age of disease onset is very important tourette syndrome, typically begins in the first decade, parkinsons disease usually occurs in late age Past history About infection (rheumatic fever), jaundice(wilsons disease) Medical history & Toxin exposure Drug history- of current, previous & recreational use should be taken details : parkinsonism & dystonia may be produced by dopamine receptor blocking agent Family history should be taken and make a pedigree chart if necessary (huntington disease) 14. Associated neuropsychiatric features Wilson disease, Huntington disease Autonomic symptoms- dizziness, bladder complaints, impotence etc may be prominent & early in MSA, neurodegenerative disease Alcohol responsiveness, essential tremor is characteristically response to alcohol 15. Specific distribution- Chorea/ athetosis - mainly in the distal groups Hemiballismus- mainly proximally Parkinsons disease- mainly unilateral & asymmetric Blepherospasm- affect both eye Specific action & relationship to voluntary movement- task specific tremor (intention tremor) during pick up a glass of water Task specific dystonia eg: Writers cramp, musician cramp 16. Speed of movement- Rhythm- Continuous tremor Intermittent astrexis Relationship to sleep- Palatal myoclonus, segmental myoclonus, fasciculation & myokymia, persist during sleep , Dystonia diminished on sleep Supresibility- tics may be voluntary suppressed Slow Intermediate Fast Parkinsonism Chorea Myoclonus Dystonia Tremor Tics Athetosis 17. Aggravating or precipitating factor- stress and anxiety worsen all movement disorder Myoclonus may be triggered by specific stimuli- sudden loud noise or touch Carbohydrate heavy meal, fatigue may precipitate paroxysmal dystonia Associated sensory symptom- RLS associated with pain or discomfort, tics may be associated with vague discomfort or abnormal sensation Ameliorating factor- alcohol dramatically improved essential tremor and myoclonic dystonia 18. 2nd commonest neurodegenerative disease of neurons in the nigrostrial dopamine system Clinical Features of Parkinson's Disease Cardinal Features Other Motor Features Nonmotor Features Bradykinesia Rest tremor Rigidity Gait disturbance/postural instability Micrographia Masked facies (hypomimia)equalize Reduced eye blink Soft voice (hypophonia) Dysphagia Freezing Anosmia Sensory disturbances (e.g., pain) Mood disorders (e.g., depression) Sleep disturbances Autonomic disturbances Orthostatic hypotension Gastrointestinal disturbances Genitourinal disturbances Sexual dysfunction Cognitive impairment/Dementia 19. 1- Static tremors Rhythmic occuring at a rate of 4-8 / second May start in one hand and spread to other parts of the body Characteristically pill-rolling movements between the thumb and the forefinger are seen Tremors increase with emotional, anxiety and fatigue and disappear during sleep and during active voluntary movements 20. 2- Rigidity of the muscles More proximal than distal Flexors are affected more than extensor On clinical examination the resistance may be continuous throughout the act to the same degree (lead pipe rigidity) or interrupted by the tremors (cog wheel rigidity) Stiffness of the limbs develops causing difficulty in starting movements and walking (slow, shuffling gait) 21. 3- Akinesia: Loss of emotional and associative movements resulting in: Immobile face with infrequent blinking (mask face) Monotonous speech Loss of swinging of the arms during walking 22. Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intracytoplasmic proteinaceous inclusions known as Lewy bodies. neuronal degeneration with inclusion body formation can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system. Indeed, there is evidence that pathology begins in the peripheral autonomic nervous system, olfactory system, and dorsal motor nucleus of the vagus nerve in the lower brainstem, and then spreads in a sequential manner to affect the upper brainstem and cerebral hemispheres. These studies suggest that dopamine neurons are affected in midstage disease. Several studies suggest that symptoms reflecting nondopaminergic degeneration such as constipation, anosmia, rapid eye movement (REM) behavior sleep disorder, and cardiac denervation precede the onset of the classic motor features of the illness. 23. Differential Diagnosis of Parkinsonism Parkinson's Disease Genetic Sporadic Dementia with Lewy bodies Atypical Parkinsonisms Multiple-system atrophy Cerebellar type (MSA-c) Parkinson type (MSA-p) Progressive supranuclear palsy Corticobasal ganglionic degeneration Frontotemporal dementia Secondary Parkinsonism Drug-induced Tumor Infection Vascular Normal-pressure hydrocephalus Trauma Liver failure Toxins (e.g., carbon monoxide, manganese, MPTP, cyanide, hexane, methanol, carbon disulfide) Other Neurodegenerative Disorders Wilson's disease Huntington's disease Neurodegeneration with brain iron accumulation SCA 3 (spinocerebellar ataxia) Fragile Xassociated ataxia-tremor- parkinsonism Prion disease Dystonia-parkinsonism (DYT3) Alzheimer's disease with parkinsonism 24. Modern immunocytochemical techniques and genetic findings suggest that Parkinson-plus syndromes can be broadly grouped into 2 types: synucleinopathies and tauopathies. Clinically, however, 5 separate Parkinson-plus syndromes have been identified, as follows: 1. Multiple system atrophy 2. Progressive supranuclear palsy 3. Parkinsonism-dementia-amyotrophic lateral sclerosis complex 4. Corticobasal ganglionic degeneration 5. Diffuse Lewy body disease Parkinson-plus syndromes respond poorly to the standard treatments for Parkinson disease (PD). 25. In addition to lack of response to levodopa/carbidopa (Sinemet) or dopamine agonists in the early stages of the disease, other clinical clues suggestive of Parkinson-plus syndromes include the following: History and Examination Features Suggesting Diagnoses Other Than Parkinson's Disease Symptoms/Signs Alternative Diagnosis to Consider History Falls as the first symptom PSP Exposure to neuroleptics Drug-induced parkinsonism Onset prior to age 40 If PD, think genetic causes Associated unexplained liver disease Wilson's disease Early hallucinations Lewy body dementia Sudden onset of parkinsonian symptoms Vascular parkinsonism Physical Exam Dementia as first symptom Dementia with Lewy bodies Prominent orthostasis MSA-p Early dysarthria MSA-c Lack of tremor Various Parkinson's-plus syndromes High frequency (810 Hz) symmetric tremor Essential tremor 26. Diagnosis of PD clinical examination No disease-specific biological marker available Positron Emission Tomography (PET) or Single-photon Emission Computed Tomography (SPECT) with dopaminergic radioligands Exclusion of several causes of secondary Parkinsonism 27. (A) Dopamine Carbidopa/l-dopa Dopamine agonists: Apomorphine(off phenomenon), s/c, i.v. Cabergoline Ropinirole, Pramipexole COMT inhibitors: Entacapone MAO Inhibitors: e.g. Selegiline (B-type) Inhibitors of dopamine re-uptake: Amantadine (2) Acetylcholine Anticholinergic Antihistaminics 28. Drugs commonly used in the treatment of Parkinson disease MEDICATION STARTING DOSE TARGET DOSE MAIN BENEFIT SIDE EFFECTS Carbidopa-L-dopa (Sinemet) 25/100 tid empty stomach Up to 50/250 q 3 h Reduction of tremor and bradykinesia; less effect on postural difficulties Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion, arrhythmia Controlled release carbidopa-L-dopa 25/100 tid Up to 50/200 q 4 h Dopamine agonists Ropinirole(D3) 0.125 mg tid 0.5 to 1.5 mg/day Moderate effects on all aspects; reduced motor fluctuations of L-dopa, neuroprotective, neurotrophic Orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations, impulse control disorders Pramipexole(D2) 0.25 mg tid 8 to 24 mg/day Glutamate agonist Amantadine (Symmetrel) 100 mg/day 100 mg bid-tidSmoothing of motor fluctuations Leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia Anticholinergics Benztropine (Cogentin) 0.5 mg per day Up to 4 mg per day Tremor reduction, less effect on other features, drug induced parkinsonism Atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosisTrihexyphenidyl (Artane) 0.5 mg bid Up to 2 mg tid MAO-B inhibitor selegiline, 5mg/day bd Neuroprotection, adjuntive therapy Insomnia Rasagiline 1mg/day COMT inhibitors Entacapone 200 mg with L-dopa Urine discoloration, diarrhea, increased dyskinesias 29. Stereotactic neurosurgery: pallidotomy, thalamotomy ,sub thalamotomy Indications 1.idiopathic parkinsons 2.levodopa unhelpful 3.intractable PD 4.drug dyskinesias Deep brain stimulation: dyskinesia Tissue transplantation: Experimental transplantation of fetal or autologous dopamine-containing adrenal medulla or stem cell research has produced no promising results in PD to date. Physiotherapy and physical aids Neuropsychiatric aspects: Cognitive impairment and depression are common as PD progresses. SSRIs are the drugs of choice for depression. 30. Sudden, brief, rapid, jerky, purposeless, non- repetitive, involuntary movement Most characteristically in distal parts of upper extremity but may also involved proximal part, lower extremity, trunk, face & tongue PATHOLOGY Damage to caudate nucleus 31. Disease characterized by chorea: Inherited disorder: Huntington disease, wilson disease, benign hereditry chorea, neuroacanthocytosis Infectious causes: Rheumatic chorea (sydenham chorea), HIV disease Structural lesion of the basal ganglia- infarct, neoplasm, trauma Chorea of systemic disease: SLE, thyrotoxicosis, polycythemia vera, hyperosmolar non-ketotic hyperglycemia Pregnancy (chorea gravidarum) Drugs: Neuroleptics, OCP, excessive dose of levodopa or dopamine agonist, phenytoin cocaine 32. Hypotonia Pronator sign Milkmaids grip Spooning sign Pendular knee jerk hung up reflex Lizard tongue Increased by excitement, diminished by sleep Sydenham chorea (Saint vitus dance) more common in female and childhood (5-15yrs), associated with prior exposer to group a streptococcal infection, late manifestation Huntington's disease progressive fatal autosomal dominant disorder characterized by motor, behavioral & cognitive dysfunction, in early stages chorea is focal or segmental but it progress over time to involve multiple body region 33. Etiology HD is caused by an increase in the number of polyglutamine (CAG) repeats (>40) in the coding sequence of the huntingtin gene located on the short arm of chromosome 4. The larger the number of repeats, the earlier the disease is manifest. Treatment multidisciplinary approach Dopamine-blocking agents may control the chorea. Tetrabenazine depression and anxiety can be greater problems, and patients should be treated with appropriate antidepressant and antianxiety drugs and monitored for mania and suicidal ideations. Psychosis can be treated with atypical neuroleptics such as clozapine, quetiapine, and risperidone There is no adequate treatment for the cognitive or motor decline 34. Slow, distal, purposeless, writhing involuntary movement They are more sustained and larger in amplitude than those in chorea The mainly involved the extremities (distal portion, fingers & hands) face, neck & trunk Movement are characterized by any combination flexion, extension, abduction, pronation, & supination often alternating and in varying degree Predominant pathologic changes are in the putamen 35. Causes: cerebral palsy, perinatal injury to basal ganglia, wilson disease Choreoathetosis: the movement live between chorea & athetosis in rate and rhythmicity eg: cerebral palsy ( Neonatal jaundice) Pseudoathetosis: (sensory athetosis) undulating & writhing movement of extremities due to loss of position sense as a result of parietal lobe lesion, tabes dorsalis, peripheral nerve disease 36. A wild, flinging, large amplitude movements on one side of the body Proximal upper limb muscles predominantly affected Ballastic movement of hemiballismus resemble that of chorea but are more pronounced, rapid & forceful Movement ceaseless during the walking state and disappear only with the deep sleep 37. Usually self limiting and tends to resolve spontaneously after weeks to months Due to infarction or hemorrhage in the regions of contralateral subthalamic nucleus, results in disinhibition of the motor thalamus and cortex resulting in contralateral hyperkinetic movement. Treatment: Dopa blocking agent Pallidotomy can be done. 38. Sustained or repetitive involuntary muscle contraction leading to twisting movements and abnormal posture Can involve individual muscle or multiple muscle groups. Often affect the extremities neck, trunk, eyelids, face & vocal cords Dystonic movements are patterned tending to recur in same location When duration is very brief less than one second- dystonic spasm, when for several seconds, dystonic movement & when prolonged minutes to hours- dystonic posture Pathophysiology of Dystonia not known. co-contracting synchronous bursts of agonist and antagonist muscle groups due to loss of inhibition at multiple levels of the nervous system as well as increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of at least some types of dystonia as there are alterations in blood flow and metabolism in basal ganglia structures. Further, ablation or stimulation of the globus pallidus can both induce and ameliorate dystonia. 39. Dystonia can be generalized or focal: primary or secondary Generalized dystonia is mainly primary dystonia involving larger portion of body often producing distorted posture of limbs & trunk (Torsion dystonia) Idiopathic torsion dystonia (dystonia musculorm deformance) is predominantly childhood onset form of dystonia with autosomal dominant pattern of inheritance May starts distally usually in the foot in the planter flexation & inversion & speed to opposite side, upper extremity trunk & face There is peculiar axial involvement of spine (twisting) 40. Dopa responsive dystonia ( Segawa variant) dominantly inherited form of dystonia in early childhood 1-12yrs typically present with foot dystonia resulting in gait disturbance and there is excellent response to small doses of levodopa. Diurnal variation, worsen with day progresses Focal dystonia is a most common, 4th to 6th decade and more common in female: Blephero spasm Oromandibular dystonia Spasmodic dysphonia Cervical dystonia Limb dystonia (writers cramp) 41. Secondary dystonia: Due to drugs: Neuroleptics, (Phenothiazine, Butyrophenone), chronic levodopa treatment in parkinsons disease Discrete lesion in the stratum, palladum, thalamus, cortex & brain stem Dystonia plus syndrome: May occur in the neurodegenerative condition (Huntington disease, Wilson disease, parkinson disease, corticobasal degeneration & progressive supranuclear palsy) 42. symptomatic Levodopa should be tried in all cases of childhood-onset dystonia to rule out DRD. High-dose anticholinergics (e.g., trihexyphenidyl 20120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of cognitive impairment with hallucinations. Oral baclofen (20120 mg), Tetrabenazine (the usual starting dose is 12.5 mg/d and the average treating dose is 2575 mg/d) may be helpful in some patients, but use may be limited by sedation and the development of parkinsonism. Botulinum toxin has become the preferred treatment for patients with focal dystonia, particularly where involvement is limited to small muscle groups such as in blepharospasm, torticollis, and spasmodic dysphonia. Surgical therapy is an alternative for patients with severe dystonia who are not responsive to other treatments. Peripheral procedures such as rhizotomy and myotomy were used in the past to treat cervical dystonia, but are now rarely employed. DBS of the pallidum can provide dramatic benefits for patients with primary DYT1 dystonia Supportive treatments such as physical therapy and education are important and should be a part of the treatment regimen. 43. Sudden, brief (