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Recent advances in the management of parkinson disease

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Recent advances in the management of parkinson disease

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Recent advances in the management of parkinson disease

  1. 1. By. Dr. Sumit Kamble Dept. of Neurology GMC, Kota
  2. 2. INTRODUCTION  Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population over 55 years of age.  Disease is characterized by the loss of ~50–70% of the dopaminergic neurons in the substantia nigra, a profound loss of dopamine (DA) in the striatum, and the presence of intracytoplasmic inclusions called Lewy bodies (LB). 2
  3. 3. PREVALENCE OF PARKINSONISM IN INDIA  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. 3
  4. 4. CLINICAL FEATURES  Four cardinal symptoms:  resting tremor  bradykinesia  muscle rigidity  postural insatability 4
  5. 5. UK PDS BRAIN BANK CRITERIA FOR THE DIAGNOSIS OF PARKINSON'S DISEASE  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. 5
  6. 6.  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 6
  7. 7.  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. 7
  8. 8. HOEHN AND YAHR STAGING  Stage I: Unilateral involvement only usually with minimal or no functional disability  Stage II:Bilateral or midline involvement without impairment of balance  Stage III: Bilateral disease; mild to moderate disability with impaired postural reflexes; physically independent  Stage IV: Severely disabling disease; still able to walk or stand unassisted  Stage V: Confinement to bed or wheelchair unless aided 8
  9. 9. 9 Section 1. Communication Section 2. Diagnosis and Progression Section 3. Treatment A. Pharmacological therapy for motor symptoms in early PD B. Pharmacological therapy for motor symptoms in later PD C. Surgery D. Other Treatment Options Section 4. Non-motor Features and Their Treatment A. Mental Health B. Sleep disorders C. Autonomic dysfunction Guidelines on Parkinson’s Disease – overview
  10. 10. 10 AAN - American Academy of Neurology NICE - National Institute for Health and Clinical Excellence EFNS - European Federation of Neurological Societies
  11. 11. SIMPLIFIED GRADING SCHEME FROM NICE, EFNS AND AAN GUIDELINES Recomme- ndation grade Evidence A • Established as effective, ineffective, or harmful for the given condition in the specified population B • Probably effective, ineffective, or harmful for the given condition in the specified population. C • Possibly effective, ineffective, or harmful for the given condition in the specified population D • Expert opinion, formal consensus U • Data inadequate or conflicting given current knowledge, treatment is unproven GPP • Good practice point. 11
  12. 12. COMMUNICATION  Because people with PD may develop impaired cognitive ability, a communication deficit and/or depression, they should be provided with: both oral and written communication throughout the course of the disease, which should be individually tailored and reinforced as necessary; and consistent communication from the professionals involved. NICE Level D (GPP) 12
  13. 13. DIAGNOSIS AND PROGRESSION  Parkinson’s disease should be suspected in people presenting with tremor, stiffness, slowness, balance problems and/or gait disorders. NICE Level D (GPP)  Determining the presence of the following clinical features in early stages of disease should be considered to distinguish PD from other parkinsonian syndromes:  1) falls at presentation and early in the disease course;  2) poor response to levodopa;  3) symmetry at onset; 13
  14. 14.  4) rapid progression (to Hoehn and Yahr stage 3 in three years);  5) lack of tremor; and  6) dysautonomia (urinary urgency/ incontinence and fecal incontinence, urinary retention requiring catheterization, persistent erectile failure or symptomatic orthostatic hypotension). AAN Level B D (GPP) 14
  15. 15.  In patients with newly diagnosed PD, older age at onset and rigidity/hypokinesia as an initial symptom should be used to predict more rapid rate of motor progression. AAN Level B  The presence of associated comorbidities (stroke, auditory deficits, and visual impairments), Postural Instability/Gait difficulty (PIGD), and male sex may be used to predict faster rate of motor progression. AAN Level C 15
  16. 16. 16
  17. 17. PHARMACOLOGICAL THERAPY FOR MOTOR SYMPTOMS IN EARLY PD  The decision about initiation of pharmacologic therapy in PD patients should be tailored to the individual with the goal of reducing motor symptoms, and improving quality of life without causing side effects.  Factors that influence this decision include: symptom severity, whether the symptoms affect the dominant hand, embarrassment, ability to continue working and/or participate in activities such as hobbies, cost, and patient preference.  If symptoms are very mild, the patient may choose not to begin therapy. 17
  18. 18. SITES OF ACTION OF ANTI-PD DRUGS 18
  19. 19. NEUROPROTECTIVE THERAPY  Vitamin E should not be used as a neuroprotective therapy for people with PD. NICE Level A  Co-enzyme Q10, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors should not be used as a neuroprotective therapy for people with PD, except in the context of clinical trials. NICE Level B 19
  20. 20. LEVODOPA  Levodopa remains the most effective medication for the treatment of motor symptoms. It is always given in combination with carbidopa to prevent decarboxylation in the periphery.  Levodopa used as a symptomatic treatment for people with early PD. NICE Level A  The dose of levodopa should be kept as low as possible to maintain good function in order to reduce the development of motor complications. NICE Level A  Modified-release levodopa preparations should not be used to delay the onset of motor complications in people with early PD. NICE Level A 20
  21. 21. DOPAMINE AGONISTS  Dopamine agonists stimulate dopamine receptors directly, and unlike levodopa, do not need to be converted in the brain to be active.  Dopamine agonists are the second most potent class of medication (after levodopa) for control of motor symptoms in PD with good evidence that they can be used in early PD with success.  Dopamine agonists have less likelihood of producing fluctuations in early disease, but are less effective, and are associated with a higher prevalence of side effects and they are also more expensive than levodopa. 21
  22. 22.  Dopamine agonists may be used as a symptomatic treatment for people with early PD. NICE Level A  A dopamine agonist should be titrated to a clinically efficacious dose. If side effects prevent this, another agonist or a drug from another class should be used in its place.NICE Level D (GPP) 22
  23. 23.  MAO-B inhibitors may be used as a symptomatic treatment for people with early PD. NICE Level A  Amantadine may be used as a treatment for people with early PD but should not be a drug of first choice. NICE Level D (GPP) 23
  24. 24.  Anticholinergics may be used as a symptomatic treatment typically in young people with early PD and severe tremor,but should not be drugs of first choice due to limited efficacy and the propensity to cause neuropsychiatric side effects. NICE Level B  Beta-adrenergic antagonists may be used in the symptomatic treatment of selected people with postural tremor in PD, but should not be drugs of first choice. NICE Level D (GPP) 24
  25. 25. PHARMACOLOGICAL THERAPY FOR MOTOR SYMPTOMS IN LATER PD  Up to 50% of patients on LD for 5 years’ experience motor fluctuations and dyskinesia.  These symptoms are, especially, common in patients with onset of PD before 50 years of age.  they are unique to LD, and are not produced by the other anti-Parkinson drugs.  Wearing off is the most common type of MF. It refers to the predictable return of parkinsonian symptoms in the hours before the next dose as the plasma level of the drug falls below the critical level. 25
  26. 26.  On/off is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of anti-parkinsonian drugs are expected to be within the target of therapeutic range.  Delayed on is delay in the onset of symptom relief after a dose.  Dose failure is a complete failure to develop a favorable response to an incremental dopaminergic dose.  Protein-related offs occur when the transport of LD across the intestinal wall is impeded by competition for facilitated transport by large amounts of neutral amino acids. 26
  27. 27.  Manipulation of the dose or frequency of levodopa can be a first strategy but eventually the emergence of dyskinesias will preclude this.  For patients with PD with motor fluctuations the available evidence suggests: Entacapone and rasagiline should be offered to reduce off time. AAN Level A  Selegiline is associated with 2.2 hrs reduction in total number of off hours compared to placebo ( waters et al 2004). 27
  28. 28.  Entacapone, a COMT inhibitor and rasagiline, a MAO-B inhibitor, have both been shown in clinical trials to reduce off time by approximately 1.5 waking hours per day  Pramipexole and ropinirole should be considered to reduce off time.AAN Level B  Dopamine agonists such as pramipexole, ropinirole and bromocriptine have been shown in clinical trials to reduce off time by approximately 15%. 28
  29. 29.  Modified-release levodopa preparations may be used to reduce motor fluctuations in people with later PD but should not be drugs of first choice. NICE Level B  Modified release levodopa remains most useful in addressing overnight wearing off.  Amantadine may be considered for patients with PD with motor fluctuations in reducing dyskinesias. AAN Level C 29
  30. 30. TREATMENT - SURGERY  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.  The most used current targets for PD are: the thalamus (Vim nucleus), the subthalamic nucleus (STN), and the globus pallidus internus (GPi). 30
  31. 31.  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. Patients need to be counselled regarding the risks and benefits of this procedure. AAN Level C  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. 31
  32. 32.  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. 32
  33. 33.  Preoperative response to levodopa should be considered as a factor predictive of outcome after DBS of the STN. AAN Level B  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. AAN Level C 33
  34. 34.  Bilateral GPi stimulation may be used in people with PD who: • have motor complications that are refractory to best medical treatment • are biologically fit with no clinically significant active comorbidity • are levodopa responsive • have no clinically significant active mental health problems, for example depression or dementia. NICE Level D 34
  35. 35.  GPi DBS may be perticularly useful for patients who may have troublesome dyskinesia as well as mild cognitive or behavioral impairment, whereas bilateral STN DBS may be a choice for patients who are cognitively intact but in whome reduction in levodopa dosage is primary goal. 35
  36. 36.  Thalamic DBS may be considered as an option in people with PD who predominantly have severe disabling tremor and where STN stimulation cannot be performed. NICE Level D  Eliminate contralateral rest tremors in 75% to 85% of patients , but there is less effect on rigidity and no effect on bradykinesia. 36
  37. 37. OTHER TREATMENT OPTIONS  Physical and exercise therapies should be available for people with PD. Particular consideration should be given to: • gait re-education, improvement of balance and flexibility • enhancement of aerobic capacity • improvement of movement initiation • improvement of functional independence, including mobility and activities of daily living • provision of advice regarding safety in the home environment. NICE Level B 37
  38. 38. PARKINSON’S MEDICINES IN THE PIPELINE  A gene therapy in development comprises an adeno-associated virus (AAV) vector that delivers the gene for aromatic L-amino acid decarboxylase (AADC) to cells in a part of the brain that controls movement.  An intraduodenal gel formation in development is a com-bination of levodopa and carbidopa, which helps prevent levodopa from being degraded before it reaches the brain. This mechanism of delivery helps prevent levodopa degradation and promotes faster absorp-tion, and maintenance of more constant levels of levodopa. 38
  39. 39.  deacetylase inhibitors -target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study is published (15 October 2014) month in Nature Communications.  Nicotine- Intake of nicotine has shown to slow the degeneration of neurons.Acts similar to levodopa.  Melatonin-Serotonin derivative that helps insomnia. Also shown to cause a reduction in production of neurodegenerative radicals 39
  40. 40.  Apomorphine (subcutaneous infusion or injections)-Apomorphine is the most potent dopamine receptor agonist and it can provide symptom relief similar to that of L-dopa. Apomorphine is rapidly absorbed, with onset of effect within 5-15 minutes of subcutaneous injection. 40
  41. 41. NON-MOTOR FEATURES OF PD - MENTAL HEALTH  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  Amitriptyline may be considered in the treatment of depression associated with PD. AAN Level C  6. ECT in severe refractory cases 41
  42. 42.  Psychotic Symptoms  1. 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  2. Atypical antipsychotics for problematic psychosis:  3. Cholinesterase inhibitors may have anti-psychotic effects in PD  4. ECT in severe refractory cases 42
  43. 43.  Dementia-  Discontinue potential aggravators; • Anticholinergics. EFNS Level B • Amantadine, tricyclic antidepressants, benzodiazepines, tolterodine and oxybutynin. EFNS Level C  Donepezil should be considered for the treatment of dementia in PD. AAN Level B  Rivastigmine should be considered for the treatment of dementia in PD or Dementia with Lewy Bodies. AAN Level B 43
  44. 44.  Sleep Disorders-  Good sleep hygiene should be advised in people with PD with any sleep disturbance and includes NICE Level D (GPP)  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. NICE Level D (GPP)  Modafinil may be considered for daytime hypersomnolence in people with PD. NICE Level D(GPP) 44
  45. 45.  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. EFNS (GPP)  Constipation  For gastrointestinal motility problems in PD: • apply general measures for treating constipation. These include diet, laxatives, etc • Reduce or discontinue drugs with anticholinergics activity. EFNS (GPP) • Add domperidone. EFNS Level B 45
  46. 46.  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 46
  47. 47. Management of Parkinson’s Disease  REM behaviour disorder -Family history  Anosmia -Gene carrier  Constipation Pre diagnostic -Abnormal imaging  Reduced cardiac features -(dopamine marker) R-R variability - ? Biomarker Classic Feature Increased liklhood of diagnosis  Bradykinesia if following are present :  Rest Tremors Diagnosis based on -Rest tremor  Rigidity U K Brain bank crieteria -Asymmetry  Gait disturbances and supported by -Good response to levodopa prediagnostic features -? Imaging of dopamine system Disease Modification - Seligiline ? ? Non pharmacological - Rasagiline? approach -Dopamine agonist??? -Exercise,education ,nutrition pramipexol,ropinirol -Social and mentle activity 47
  48. 48. Functional impairement No Yes monitoring Symptomatic therapy MAO-B inhibitors Levodopa preparations Dopamine agonist -Mild to moderate -Good efficacy -Moderate efficacy efficacy -Risk of motor -reduced risk of motor -Good safety profile complications complications -once a day dosing (less risk with -risk of somnolence -possibly disease modifying <400 mg/day) and impulse disorder (pathologic gambling) -complex tiration scedule 48
  49. 49. 49 Polypharmacy L-DOPA —Titrate in small increments ± COMT inhibitor; ± Dopamine Agonist; ± MAO-B inhibitor ? Others—eg, anticholinergics, amantidine Advancing Disease With advancing disease , increase Levodopa dose in small increments, and avoid using doses > 400 mg (if possible) by using polypharmacy Motor Complications Wearing Off o Manipulate levodopa dose ± COMT inhibitor ± Dopamine agonist ± MAO-B inhibitor o Apomorphine—as rescue agent Dyskinesia o Manipulate levodopa dose o Manipulate polypharmacy o Amantadine Non-motor, non-dopaminergic problems are now considered to be important components of PD disability and must be addressed Non-Dopamine/Non-Motor Problems -Freezing/Postural Instability/Falling -Dysphagia/Drooling -Autonomic Disturbances o Orthostatic hypotension o Gastrointestinal o Genitourinary o Sexual -Sleep Disturbances o Sleep fragmentationSurgery :Deep Brain Stimulation of GPi or STN -Neuropsychiatric Problems Depression/Anxiety/Apathy/Psychosis
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