Extrapyramidal disorders

1. EXTRAPYRAMIDAL DISORDERS RAHUL ARORA JR 3 , MEDICINE

2. OUTLINE 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. Definition 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. ANATOMY 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. Differences between pyramidal and extrapyramidal system 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. Functions of the extrapyramidal system 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. Disturbance of extrapyramidal functions 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. APPROACH TO EXTRAPYRAMIDAL DISORDER Extrapyramidal disorders are classified broadly on clinical grounds into: The akinetic -rigid syndromes in which poverty of movements predominates The dyskinesisas in which there are a variety of excessive involuntary movements

10. Movement disorders 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. HYPERKINETIC MOVEMENT Rhythmical Tremor Irregular Slow or sustained (Athetosis / dystonia) Rapid Controllable (Tics) Uncontrollable Distal (Chorea) Proximal (Ballismus) Multifocal (Myoclonus)

12. HYPOKINETIC MOVEMENT Only Cogwheel rigidity or rest tremor (Parkinsonism) Cognitive, language, upper motor neuron or sensory sign (Degenerative disease with parkinsonism)

13. HOW TO APPROACH 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. HOW TO ANALYZE 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. PARKINSON DISEASE 2 nd 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. CLINICAL PICTURE 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. CLINICAL PICTURE 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. CLINICAL PICTURE 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. Pathology and pathogenesis 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 X–associated ataxia-tremor-parkinsonism Prion disease Dystonia -parkinsonism (DYT3) Alzheimer's disease with parkinsonism Parkinsonism is a general term that is used to define a symptom complex manifest by bradykinesia with rigidity and/or tremor

24. PARKINSONISM PLUS SYNDROME 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: Multiple system atrophy Progressive supranuclear palsy Parkinsonism-dementia-amyotrophic lateral sclerosis complex Corticobasal ganglionic degeneration 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 (8–10 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. Strategy of Treatment (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-tid Smoothing 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 psychosis Trihexyphenidyl (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. OTHER LINES OF THERAPY 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. CHOREA 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. Cardinal features Hypotonia Pronator sign Milkmaid’s 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. ATHETOSIS 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. HEMIBALLISMUS 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: D opa blocking agent Pallidotomy can be done.

38. DYSTONIA S ustained or repetitive i nvoluntary 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, 4 th to 6 th decade and more common in female: Blephero spasm Oromandibular dystonia Spasmodic dysphonia Cervical dystonia Limb dystonia (writer’s 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. Treatment: Dystonia symptomatic Levodopa should be tried in all cases of childhood-onset dystonia to rule out DRD . High-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of cognitive impairment with hallucinations. Oral baclofen (20–120 mg), Tetrabenazine (the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 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. MYOCLONUS Sudden, brief (< 100ms) shock like, jerky involuntary movement consisting of single or repetitive muscle discharges Myoclonus is seen principally in the muscles of extremities and trunk but the involvement is often multifocal, diffuse or wide spread Can often spontaneously, association with voluntary movement (action myoclonus ) or in response to external stimulus (reflex or startle myoclonus ) Myoclonic jerks defer from tics in that they interfere with normal movement and not suppressible

44. Symptomatic causes of myoclonus : Metabolic endogenous- Hypoxia, uraemia , hepatic failure, hypoglycemia, hyponatraemia , non- ketotic hyperglycemia Degenerative : Alzheimer’s disease, Huntington disease, multisystem atrophy, corticobasal degeneration Infectious: Creutzfeldt – Jakob disease, EBV etc Autoimmune : Multiple sclerosis Neoplastic : Neuroblastoma , paraneoplastic disorders (ovarian, lung & breast) Frequently associated with epilepsy, electric shock, heat stroke Drugs : Amantadine , lithium , metoclopramide , levodopa & dopamine agonist, cocaine, strychnine

45. Opsoclonus - Myoclonus ( Kinsbourne syndrome)- Dancing eye & dancing feet Due to the post infectious encephalopathy or as a paraneoplastic syndrome due to neuroblastoma Palatal myoclonus - involuntary rhythmic movement of soft palate and pharynx the movements are generally not influenced by drugs or sleep palatal myoclonus occur with lesions involving the connections between the inferior olivary , dentate & red nuclei Astrexis : particularly in hepatic encephalopathy, negative myoclonus inability to sustained normal muscle tone presenting with slow & irregular flapping motion

46. DRUG INDUCED MOVEMENT DISORDERS (NEUROLEPTICS) Acute- Dystonia is most common acute drug reaction can develop within minutes of exposure typically generalized in children and focal in adults Treatment: parenteral administration of anticholinergics ( benztropine or diphenhydramine ) or benzodiazepines ( lorazepam or diazepam). Subacute - A kathisia is commonest reaction it consist of motor restlessness within in need to move and that to elevated by movement. Treatment: Removing the offending agent.If not possible, give benzodiazepines, anticholinergics , blockers, or dopamine agonists for symptomatic improvement.

47. Chronic - Tardive syndrome after months to years after initiation of treatment A typically comprises choreiform movement involving the mouth lip, tongue, and in severe cases trunk, limbs and respiratory muscles can be affected Is more common in elderly women & with underlying organic cerebral dysfunction ( Schrizophrenia ) Treatment stopping the offending agent. replacement with an atypical antipsychotic should be tried. Abrupt cessation of a neuroleptic should be avoided TD can persist after withdrawal of antipsychotics and can be difficult to treat. Benefits may be achieved with valproic acid, anticholinergics , or botulinum toxin injections. Refractory cases : tetrabenazine , baclofen (40–80 mg/d), clonazepam (1–8 mg/d), or valproic acid (750–3000 mg/d).

48. THANK YOU

49. TICS Brief, repeated, sterotyped muscle contraction that often suppressible Quick, irregular, seemingly purposeful act but relatively involuntary Patient have some degree of awareness of movement and in response to urge of some compelling inner forces Exaggerated by emotional strain and tension and stop during sleep May involved any portion of body

50. Eg: Repetitive blinking, facial contortions, shoulder shrugging, also involved vocal tract producing throat clearing Gilles de la Tourette Syndrome characterized by multiple motor tics and vocalizations Motor tics can be simple/ complex & vocal tics can be simple (grunting) or complex (echolalia) Tourette syndrome is a disease of early childhood in the first decade and mainly in Boys an associated with some regressive behaviour

51. 1- L-Dopa Contrary to dopamine, it can pass into the brain where it is decarboxylated into dopamine Levodopa is combined with a peripheral L-AA decarboxylase inhibitor e.g. carbidopa or benserazid to  delivery of l-dopa into the brain  peripheral adverse effects of dopamine  Carbidopa if peripheral adverse effects are prominent It has dramatic initial response, decreases with time ( wear off ) due to the progressive loss of neurons

52. L-Dopa: Action & Use Combined with carbidopa is the most potent oral therapy for Parkinson’s disease Symptoms of Parkinson’s disease but does not stop the progression (deterioration) of the disease i.e. Symptomatic treatment From the third year its efficacy declines

53. L-Dopa : Adverse effects Peripheral: GIT : Nausea & Vomiting CVS : Orthostatic hypotension, Dysrhythmias Blood dyscrasias & Positive reaction to Coombs test Mydriasis and Brownish discoloration of urine & saliva CNS Effects : Visual & Auditory hallucinations & vivid dreams Dyskinesias: opposite of Parkinsonian symptoms Mood changes, depression & Anxiety Long-term levodopa Complications: Wearing off (fluctuations), Dyskinesias

54. Dopamine Receptor Agonists Ergot alkaloid derivatives : Bromocriptine & Pergolide Non-ergot alkaloid derivatives : Pramipexole & Ropinirole

55. DA Receptor Agonists Have longer duration  less fluctuation Have less tendency to induce dyskinesia Ineffective in patients not responding to leveodopa Can be used in early cases to delay use of levodopa (in levodopa-naïve patients) & in advanced cases to augment levodopa and to decrease fluctuations to its response

56. DA Agonists: Ergot derivatives Pergolide is more potent than Bromocriptine Their side effects limit their use and slow rapid build up of doses (over 2-3 Months) Side effects include levodopa side effects in addition to spasmogenicity & fibrosis (of serous membranes)

57. DA Agonists: Non Ergot derivatives Pramipexole & Ropinirole Pramipexole : is cleared by renal excretion Ropinirole : is cleared by metabolism Side effects as levodopa with less dyskinesia and fluctuation and No spasmogenicity and fibrosis

58. Amantadine Antiviral (influenza) drug The mode of action is unknown # NMDA glutamate receptors (the primary action) # Muscarinic receptors Increases release of dopamine It has little effect on tremors & Tolerance develops rapidly

59. Anti-Muscarinic drugs: (Beztropine, Trihexyphenidyl, Biperiden) Augment the effect of dopamine Weak and play an adjuvant role They are the same in efficacy but with some inter-individual variation in response Side effects: Mood changes Xerostomia , blurred vision, constipation, urinary retention Hallucination, confusion C/I: in glaucoma, SPH, Pyloric stenosis

60. PARKINSONISM PLUS SYNDROME Parkinson-plus syndromes respond poorly to the standard treatments for Parkinson disease (PD). 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: Early onset of dementia Early onset of postural instability Early onset of hallucinations or psychosis with low doses of levodopa / carbidopa or dopamine agonists Ocular signs, such as impaired vertical gaze, blinking on saccade, square-wave jerks, nystagmus , blepharospasm , and apraxia of eyelid opening or closure Pyramidal tract signs not explained by previous stroke or spinal cord lesions Autonomic symptoms such as postural hypotension and incontinence early in the course of the disease Prominent motor apraxia Alien-limb phenomenon Marked symmetry of signs in early stages of the disease Truncal symptoms more prominent than appendicular symptoms Absence of structural etiology such as a normal-pressure hydrocephalus (NPH)

61. TREMOR Tremor is rhythmic, involuntary, purposeless oscillatory movement of body part due to intermittent muscle contraction Types: i. Rest ii. Postural iii. Intention Rest Tremor : is maximum at rest & becomes less prominent with activity eg: parkinson disease, Postural Tremor : is maximum while limb posture is actively maintained against gravity (arm outstretched) eg: Essential tremor, enhanced physiologic tremor, Intention Tremor : Most prominent during voluntary movement toward a target eg: cerebellar disease

62. Etiology: Parkinsonism Essential tremor Physiologic tremor Alcohol Anxiety Thyrotoxicosis Cerebellar disease Wilson disease Red nuclear tremor Drugs ( -2agonist, sympathomimetics, methylxanthine, amphetamine, anticonvulsant, Poison (Mercury, MPTP)

63. Essential tremor : Most common involuntary movement disorder High frequency, coarse mainly distal upper extremity & later become bilateral symmetrical Maximum when trying to maintain a posture Autosomal dominant pattern of inheritance Characteristically improve with alcohol & -blocker Parkinsonism is a slow (4-6 Hz) coarse, rest tremor typically appears unilaterally, pill rolling tremor

64. Physiologic Tremor : In normal individual 8-12Hz, mainly young adults Cerebellar tremor : intention tremor, coarse & irregular Thyrotoxic tremor : fine & rapid but may be complicated by choreiform involuntary movement Red nuclear tremor : the severe, large amplitude, slow 2-5 Hz, involve both proximal & distal muscle present at rest but made worse with action

65. FASICULATION Fine rapid, flickering or vermicular twitching movements due to contraction of a bundle or fasciculus of muscle fibers Fasciculations are much more gross than fibrillation and can be seen through intact skin and this continue during sleep Exaggerated by fatigue, cold, cholinergic drugs, caffine Characteristic feature of motor neuron disease, anterior horns cell disease

66. MYOKYMIA Involuntary, spontaneous, localized, transient or persistent quivering movement that affect a few muscle bundles with in a single muscle Coarse, slower, worm like, usually more prolonged and involved in wide local area than fasciculation Not affected by motion or position and persist during sleep Most commonly present in orbicularis oculi Generalized myokymia (Isaac’s syndrome) generalized muscle stiffness and persistent contraction due to underlying continuous muscle fiber activity

67. MYORHYTHMIA Slow 2-3Hz rhythmic alternating movement resemble tremor Wide spread involvement, may involved multiple body parts Absent during sleep May be intermittent or continuous, synchronous or asynchronous Eg: CNS whipple’ disease