Management of parkinsons disease

MANAGEMENT OF PARKINSONS DISEASE

1. Presented by-Dr Sadaf Siddiqui Moderator- Prof.S.A.Azmi M anagement of Parkinson's disease

2. Introduction Parkinson's disease (PD) is the second commonest neurodegenerative disease, exceeded only by Alzheimer's disease (AD). It is estimated that approximately 1 million persons in the United States and 5 million persons in the world suffer from this disorder. The mean age of onset is about 60 years, but cases can be seen in patients in their 20s, and even younger.

3. Very few studies are available on the prevalence of PD in India. Different studies have shown that the crude prevalence rate (CPR) of PD is 14 per 100,000 in the north India, 27 per 100,000 in south India and 16 per 100,000 in east India. However, in one study of Parsis in Mumbai revealed a CPR of 328 per 100,000. The frequency of PD increases with aging, and based on projected population demographics, it is estimated that the prevalence will dramatically increase in future decades.

4. Clinically, PD is characterized by rest tremor, rigidity, bradykinesia , and gait impairment, known as the " cardinal features " of the disease.

5. Other motor features Micrographia Masked facies ( hypomimia )equalize Reduced eye blink Soft voice ( hypophonia ) Dysphagia Freezing

6. Nonmotor features 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

7. UK PARKINSON’S DISEASE SOCIETY BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA Step 1. Diagnosis of a parkinsonian syndrome Bradykinesia and at least one of the following: • muscular rigidity • rest tremor (4–6 Hz) • postural instability unrelated to primary visual, cerebellar , vestibular or proprioceptive dysfunction.

8. Step 2. Exclusion criteria for Parkinson's disease (PD) History of : • repeated strokes with stepwise progression • repeated head injury • antipsychotic or dopamine-depleting drugs • definite encephalitis and/or oculogyric crises on no drug treatment • more than one affected relative • sustained remission

9. Step 3. Supportive criteria for PD Three or more required for diagnosis of definite PD : unilateral onset excellent response to levodopa rest tremor present severe levodopa -induced chorea progressive disorder levodopa response for over 5 years persistent asymmetry affecting the side of onset most clinical course of over 10 years.

10. Idiopathic Genetic (<50 y/o) Exposure to unrecognized neurotoxins Oxidation reaction with generation of free radicals Reduced level of dopamine in the basal ganglia PATHOGENESIS:

11. 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.

12. This " nondopaminergic " pathology is likely responsible for the nondopaminergic clinical features 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.

13. WHAT CAN BE DONE TO HELP PARKINSON’S SUFFERERS?

14. Objectives To Understand the Goals in Management of Parkinson’s Disease. The Pharmacological Intervention in Parkinson’s Disease. The Non-Pharmacological Intervention in Parkinson’s Disease. The Surgical Treatments in Parkinson’s Disease.

15. Goals of Management Maintain the function Avoid drug-induced complications Bradykinesia Tremor Rigidity Abnormal posture Respond early in the illness

16. But… Cognitive symptoms Hypophonia Autonomic dysfunction Balance difficulties Respond poorly

17. Pharmacological Management of Parkinson’s Disease. Drugs used in PD Levodopa and Carbidopa Dopamine agonist Catechol-O- methyltransferase inhibitors (COMT inhibitors Monoamine oxidase type B (MAO-B)

18. 1-Levadopa Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared. No current medical or surgical treatment provides antiparkinsonian benefits superior to what can be achieved with levodopa . It benefits the classic motor features of PD, prolongs independence and employability, improves quality of life, and increases life span.

19. Dose- 200–1000 mg/d,2–4 times/d It is routinely administered in combination with the decarboxylase inhibitor carbidopa ( Sinemet ),with benserazide ( Madopar ). Carbidopa 25 mg daily,70-100 mg/day but not to exceed 200 mg/day.

20.  LCD-100/10mg LCD (125)-100/25mg  LCD(250mg)-200/50mg LCD (275)-250/25mg

21. Syndopa (110mg)-100/10mg Syndopa (275mg) 250/25mg  Syndopa CR200/50mg  Tidomet –CR-200/50mg  Tidomet Forte- 250/25mg  Tidomet LS-100/10mg  Tidomet PlusTorrent-100/10mg

22. Side effects Acute dopaminergic side effects include nausea, vomiting, and orthostatic hypotension. These are usually transient and can generally be avoided by gradual titration If they persist, they can be treated with additional doses of a peripheral decarboxylase inhibitor (e.g., carbidopa ) or a peripheral dopamine-blocking agent such as domperidone .

23. Levodopa -induced motor complications consist of fluctuations in motor response and involuntary movements known as dyskinesias . In more advanced states, patients may cycle between "on" periods complicated by disabling dyskinesias and "off" periods in which they suffer severe parkinsonism

24. On/off" Effect Occurs usually after 2 or more years on L Dopa Related with continous destruction of dopaminergic neurons. "On/off" Effect May Be Due to Composite of Amino Acids that use same Dopamine Transportor , causing extremely low levels of L Dopa in CNS thereby causing symptoms of Parkinsonism to reappear.

25. Treatment Adding a dopamine agonist, catechol -  O  - methyltransferase (COMT) inhibitor, or monoamine oxidase (MAO)-B inhibitor Dosing levodopa more frequently Increasing the levodopa dose Switching from immediate-release (IR) to sustained-release ( CR) levodopa / carbidopa or levodopa / carbidopa / entacapone

26. Behavioral alterations can be encountered in levodopa -treated patients. A dopamine dysregulation syndrome has been described where patients have a craving for levodopa and take frequent and unnecessary doses of the drug in an addictive manner. PD patients taking high doses of levodopa can also have purposeless, stereotyped behaviors such as the meaningless assembly and disassembly or collection and sorting of objects. This is known as punding .

27. 2-Dopamine Agonists ergot derivative Bromocriptine-D2 agonists 1.25 mg PO q12hr May increase dose by 2.5 mg/day q2-4Weeks not to exceed 100 mg/day. Pergolides -Stimulates both D1 and D2 More effective than bromocriptine 3 mg daily.

28. non-ergot dopamine agonists a- Pramipexole D2 receptor agonist strong affinity for D2 and D3 receptors 0.125 mg PO q8hr initially,increase at weekly intervals to target range of 1.5-4.5 mg/day PO divided q8hr.

29. b- Ropinirole Potent nonergoline dopamine agonist specific for D2 and D3 subtypes. 0.25 mg PO q8hr for 1 week initially, then increased weekly by 0.75 mg,if necessary after week 4, may be increased weekly by 1.5 mg/day up to 9 mg/day, then increased weekly by 3 mg/day up to 24 mg/day.

30. C- Apomorphine - It is generally administered SC as a rescue agent for the treatment of severe "off" episodes. It can also be administered by continuous infusion and has been demonstrated to reduce both "off" time and dyskinesia in advanced patients. 2 mg (0.2 mL ) SC,If no response, titrate every few days by 1-mg doses up to 6 mg SC q8hr; 3-5 times a day.

31. d- Rotigotine Non- ergolinic D3/D2/D1 dopamine agonist. Apply 2 mg/24 hr transdermal patch qDay for early-stage disease or 4 mg/24 hr for advanced-stage disease. May be increased as needed but Not to exceed 6 mg/24 hr.

32. Side effects Have more adverse effects than levodopa , including sleepiness, hallucinations, edema, and impulse control disorders. However, these adverse effects resolve upon lowering the dose or discontinuing the medication.

33. 3-MAO-B inhibitor used for early symptomatic treatment of Parkinson disease. These medications provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients.

34. Selegiline indicated as adjunctive therapy 5 mg every morning,maximum , 10 mg/day Rasagiline indicated as initial monotherapy-1 mg/day as adjunctive therapy 0.5-1.0 mg/day to levodopa . Potential side effects include nausea, headaches, and dizzines .

35. COMT Inhibitors Inhibitors of COMT increase the elimination half-life of levodopa and enhance its brain availability. Combining levodopa with a COMT inhibitor reduces "off" time and prolongs "on" time in fluctuating patients while enhancing motor scores.

36. Tolcapone central & peripheral metabolism. Hepatotoxic : less preferred. DOSE : 100 mg TDS

37. May increase dose to 200 mg. Failure to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), tolcapone should be discontinued. ENTACAPONE 200 mg Not to exceed 1600 mg/day

38. Side effects Postural hypotension Fatigue Somnolence Peripheral edema Nausea Constipation Dyskinesias Confusion Orange discoloration of urine.

39. Amantadine Antiviral agent that has antiparkinsonian activity. It appears to potentiate CNS dopaminergic responses,release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine . dose of 100 mg per day and slowly increased to an initial maintenance dose of 100 mg 2 or 3 times daily.

40. side effects confusion and hallucinations. Other Common side effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include anxiety and irritability, ataxia, livedo reticularis , peripheral edema, and orthostatic hypotension.

41. ACETYLCHOLINE BLOCKING AGENTS Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia Doc for drug induced parkinsonism One of the most commonly used anticholinergic is trihexyphenidyl . Dose-1 mg,Dosage can be titrated by 1 mg each week or so, until a total of 4-6 mg a day.

42. Pharmacological Therapy in early PD ‘Early disease’ refers to PD in people who have developed functional disability and require symptomatic therapy . There is no single drug of choice in the initial pharmacotherapy of early PD.

43. Options for initial pharmacotherapy in early PD

44. The dose of levodopa should be kept as low as possible to maintain good function in order to reduce the development of motor complications. Beta blockers used in the symptomatic treatment of selected people with postural tremor in PD. Anticholinergics may be used as a symptomatic treatment typically in young people with early PD and severe tremor

45. Pharmacological therapy in later PD ‘Later disease’ refers to PD in people on levodopa who have developed motor complications . There is no single drug of choice in the pharmacotherapy of later PD . So, Adjuvant drugs are taken alongside with Levodopa for it. Ex: COMT inhibitors, MAO-B inhibitors, Dopamine agonist, Amantadine… etc.

46. Options for adjuvant pharmacotherapy in later PD

47. Modified-release levodopa preparations may be used to reduce motor complications in people with later PD, but should not be drugs of first choice. MAO-B & COMT inhibitors may be used to reduce motor fluctuations and Amantadine may be used to reduce dyskinesia in people with later PD .

48. Neuroprotection Despite the many therapeutic agents available for the treatment of PD, patients can still experience intolerable disability due to disease progression and the emergence of features such as falling and dementia that are not controlled with dopaminergic therapies. Trials of several promising agents such as rasagiline , selegiline , coenzyme Q10, pramipexole , and ropinirole have had positive results in clinical trials consistent with disease-modifying effects.

49. However, it is not possible to determine if the positive results are due to neuroprotection with slowed disease progression or confounding symptomatic or pharmacologic effects that mask ongoing progression. If it could be determined that a drug slowed disease progression, this would be a major advance in the treatment of PD.

50. Surgical Treatment The surgical treatment for PD is currently considered in advanced patients when the optimized medical treatment has failed in treating motor symptoms (such as motor fluctuations and/or dyskinesia ). Although pallidotomy and thalamotomy might still be performed in selected patients, deep brain stimulation (DBS) is currently the surgical treatment of choice in advanced PD patients.

51. The most used current targets for PD are: the thalamus (Vim nucleus), the subthalamic nucleus (STN), and the globus pallidus internus ( GPi ). DBS of the STN may be considered as a treatment option in PD patients to improve motor function and to reduce motor fluctuations, dyskinesia , and medication usage.

52. The overall improvement of ADLs and motor UPDRS scores in the off medication/on stimulation condition has been reported to be on average 50% when compared to the off medications condition before surgery. Levodopa -induced dyskinesia has also been reduced by 69% on average after surgery

53. Adverse events (AEs) due to the surgical procedure include: Infections (6.1%), migration or misplacement of the leads (5.1%), lead fractures (5%), intracranial hemorrhage (3%), and skin erosion (1.3%) The most reported complications possibly related to the stimulation (especially STN DBS) and persistent in the long-term follow-up include: eyelid opening apraxia (1.8-30%), dysarthria / hypophonia (4-17%), gait disturbances (14%), postural instability (12.5%) weight gain (8.4%) and verbal fluency decline.

54. Age and duration of PD may be considered as factors predictive of outcome after DBS of the STN. Younger patients with shorter disease durations may possibly have improvement greater than that of older patients with longer disease durations.

55. Management of the Nonmotor and Nondopaminergic Features of PD Depression - 1. Consider emotional fluctuations associated with “OFF” periods → Reduce “OFF” time 2. Involvement of geriatric or neuro -psychiatrist; 3. SSRIs 5. Pramipexole may have antidepressant effects over and above its antiparkinsonian effects. Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised , double-blind, placebo-controlled trial.  Lancet Neurol . 2010 Jun. 9(6):573-80

56. Amitriptyline may be considered in the treatment of depression associated with PD. 6. ECT in severe refractory cases

57. Psychotic Symptoms R/o secondary (e.g., metabolic) causes. PD medications should be eliminated in the following order: anticholinergics → amantadine → DAs → MAO-B inhibitors. L-dopa has the greatest motor effect with the least mental SEs; the lowest dose that satisfactorily controls PD symptoms should be used.

58. Psychosis in PD often responds to low doses of atypical neuroleptics . Quetiapine is the atypical neuroleptic agent most commonly used.  It is usually introduced at a dose of 25 mg at bedtime and can be increased to 50 mg or more at bedtime as necessary.

59. Clozapine is the most effective Dose is 12.5–50 mg/d It can be associated with agranulocytosis , and regular monitoring is required. ECT in severe refractory cases.

60. Dementia Dementia in PD (PDD) is common, affecting as many as 80% of patients These patients are particularly prone to have hallucinations and diurnal fluctuations. Levodopa and other dopaminergic drugs can aggravate cognitive function in demented patients and should be stopped or reduced to try and provide a compromise between antiparkinsonian benefit and preserved cognitive function.

61. Drugs are usually discontinued in the following sequence: anticholinergics , amantadine , dopamine agonists, COMT inhibitors, and MAO-B inhibitors. Eventually, patients with cognitive impairment should be managed with the lowest dose of standard levodopa that provides meaningful antiparkinsonian effects and does not aggravate mental functions.

62. Anticholinesterase agents such as rivastigmine and donepezil reduce the rate of deterioration of measures of cognitive function in controlled studies and can improve attention. Memantine , an antiglutamatergic agent, may also provide benefit for some PDD patient.

63. Sleep Disorders- Good sleep hygiene should be advised in people with PD with any sleep disturbance. Care should be taken to identify and manage restless legs syndrome (RLS) and rapid eye movement (REM) sleep behaviour disorder in people with PD and sleep disturbance. Low doses of clonazepam are usually effective in controlling this problem Modafinil may be considered for daytime hypersomnolence in people with PD.

64. Autonomic dysfunction General measures for treating urinary urgency and incontinence include avoiding coffee before bedtime, limit water ingestion before bedtime, etc Add peripherally acting anticholinergic drugs

65. Constipation Apply general measures for treating constipation. These include diet, laxatives, etc Reduce or discontinue drugs with anticholinergics activity. Add domperidone .

66. Orthostatic hypotension (OH ) 1. Non-pharmacological: ↑ fluid intake, ↑ dietary salt, avoid alcohol / large meals (frequent small meals instead) / excessive warmth, elevate head of bed. Patients should be advised to rise slowly, especially in morning or after sitting/lying for a period of time 2.Discontinue unnecessary medications, e.g., antihypertensives 3. Fludrocortisone 4. Domperidone 5. Midodrin 6. Consider pyridostigmine

67. Non-Pharmacological Management of Parkinson’s Disease. It includes, Rehabilitation. Diet. Physiotherapy Speech & Language therapy Occupational therapy

68. Rehabilitation Physiotherapy It helps to improve the, Mobility. Flexibility. Strength. G ait speed. A erobic capacity. Quality of life.

69. Speech and language therapy Particular consideration should be given to : improvement of vocal loudness and pitch range. Ensuring an effective means of communication is maintained throughout the course of the disease. review and management to support safety and efficiency of swallowing and to minimise the risk of aspiration.

70. Occupational therapy Particular consideration should be given to : maintenance of work and family roles, home care and leisure activities. improvement and maintenance of transfers and mobility. improvement of personal self-care activities, such as eating , drinking, washing and dressing.

71. Diet Diet should include high fibre foods and plenty of water. W hen levodopa is introduced excessive proteins are discouraged due to competition between them to cross the BBB and intestine. So, To minimize interaction with proteins, levodopa is recommended to be taken 30 minutes before meals.

72. Future Treatments for Parkinson's Disease A2a antagonists new class of nondopaminergic medications Thought to provide antiparkinsonian benefit by reducing the overactivity of the striatopallidalpathway . levodopa formulations Levodopa / carbidopa intestinal gel (LCIG; Duodopa ) is an aqueous gel that contains 20 mg/ml levodopa and 5 mg/ml carbidopa effective to reduce motor fluctuations and dyskinesia in advanced

73. Antidyskinesia medications AFQ056 is a selective antagonist of the metabotropic glutamate receptor 5 (mGluR5). A robust antidyskinetic medication would be very helpful for the management of advanced PD, both to reduce the unwanted effects of dyskinesia and to allow more liberal use of dopaminergic medications.

74. Gene therapy Glutamic Acid Decarboxylase (GAD) Gene Transfer-GAD gene transfer in the STN modifies the phenotype of STN neurons from predominantly excitatory to predominantly inhibitory, thereby reversing excessive drive onGPi and SNr , and returning their output to a more normal state. Hauser RA. Future treatments for Parkinson's disease: surfing the PD pipeline.  Int J Neurosci . 2011

75. CASE VIGNETTE A tremor and stiffness develop in the left leg of a 49-year-old woman with a past history of anxiety and panic attacks; the diagnosis is PD. She has no history of neuroleptic use, toxin exposure, or other secondary causes of parkinsonism. She is treated with carbidopa / levodopa , entacapone , and clonazepam , and she does well for several years. Five years after the onset of PD, a death in the family triggers depression. Her motor symptoms worsen during this period, and a dopamine agonist ( ropinirole ) and selegiline are added.

76. Over the next year, her personality changes and she becomes increasingly irritable and begins to exhibit strange behaviors; she becomes delusional, falsely accusing her husband of infidelity. She becomes sexually promiscuous and begins to spend money frivolously. She separates from her husband. She is seen by a psychiatrist and is briefly hospitalized. She receives paroxetine , clonazepam , lithium, and risperidone in addition to her usual PD medications. Her tremors and stiffness worsen. The treating physician increases the ropinirole dosage from 6 mg to 12 mg daily, and eventually the risperidone is stopped.

77. The patient is referred for a second neurological opinion; the diagnosis is psychosis and impulse control disorders, which are a consequence of the dopaminergic therapies used to treat the PD. Entacapone and selegiline are discontinued; ropinirole is gradually tapered and discontinued. The patient is treated with carbidopa / levodopa 25 mg/100 mg before meals and at bedtime, which controls the motor symptoms. Quetiapine 25 mg at bedtime is added, and she continues on clonazepam 0.5 mg 3 times daily. Over the ensuing 9 months, the hallucinations and delusions stop and problems with impulse control are diminished

78. References Kaplan and sadock's comprehensive textbook of psychiatry 9th edition Harrisons principles of internal medicine P D samanta j, hauser ra . duodenal levodopa infusion for the treatment of parkinson’s disease. expert opin pharmacother . 2007;8:657–864. Hauser ra . future treatments for parkinson's disease: surfing the pd pipeline.  int j neurosci . 2011