Parkinson’s disease

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slides created from standard latest edition neurology textbooks such as adam and victor and Brain's diseases of nervous system

slides created from standard latest edition neurology textbooks such as adam and victor and Brain's diseases of nervous system

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  • How PD medications work
    There are a number of medications available to help treat Parkinson’s disease. You’ll find your doctor may use several different medications to treat your symptoms. He or she will usually start with one, then add or change others as your symptoms change.
    The reason we can use these different medications together is because they each have different strategies for managing the decline of dopamine in the brain.
    Today, we’ll talk about 4 basic categories and how they work in the brain. What you are looking at is 2 neurons, or dopamine-producing cells in the brain, and the “D’s” represent dopamine.
    The types of medications we’ll talk about today are levodopa, COMT inhibitors, dopamine agonists, and MAO-B inhibitors.

Transcript

  • 1. Parkinson’s Disease PRESENTER: DR.C.RAMANAN, 2ND YEAR PG, GENERAL MEDICINE, RMMCH. MODERATOR: PROF. DR.M.SENTHILVELAN M.D;
  • 2. History  In Western medical literature it was described by the physician Galen as "shaking palsy" in 175 AD.  In 1817 a detailed medical essay was published on the subject by London doctor James Parkinson.  Jean-Martin Charcot was the first to truly recognise the importance of Dr.Parkinson's work and renamed the disease which was formerly named paralysis agitans (shaking palsy) after him. 2
  • 3. Famous personalities 3
  • 4. 4
  • 5. Natural history  Begins between 40 and 70 years of age.  Peak age of onset at sixth decade.  Infrequent before 30 years of age.  More common in men.  Trauma, emotional upset, overwork, exposure to cold, rigid personality etc. are suggested to be the predisposing factors to the disease but none have evidence.  Disease observed in all countries and all races. 5
  • 6. Parkinsonism and Parkinson’s disease (idiopathic).  Parkinsonism is a clinical syndrome characterised primarily by bradykinesia, with associated increased tone (rigidity), tremor and loss of postural reflexes. There are many causes but the most common is Parkinson’s disease (PD).  When parkinsonism features are present in a person without any established etiology it is called Parkinson’s disease. 6
  • 7. ETIOLOGY 7
  • 8. Genetics  Genetic abnormalities resulting in protein misfolding and accumulation and mitochondrial dysfunction ,are found to be responsible for causing PD.  Protein accumulation can be due to increased formation or impaired clearance.  Mutation in the Park1 gene encoding the protein alpha- synuclein, a main component of lewy body, on the chromosome 4q are seen in early onset (mean age 46 years) Parkinson’s disease. 8
  • 9. Genetics  Mutations in parkin (a ubiquitin ligase that attaches ubiquitin to misfolded proteins to promote their transport to the proteasome for degradation) and UCH-L1 (which cleaves ubiquitin from misfolded proteins to permit their entry into the proteasome) are causative in other cases of familial PD.  Mitochondrial dysfunction has also been implicated in familial PD. Genes involved (parkin, PINK1, and DJ1).  Having first degree relative with PD confers a 2-3 times increased risk of developing Parkinson’s disease. 9
  • 10. 10
  • 11. What is Parkinson’s Disease?  Defined as “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forward, and to pass from a walking to running pace : the senses and the intellects being uninjured” 11
  • 12. Clinically  The presence of two out of the three cardinal features of bradykinesia, rigidity and tremor; postural instability tends to occur later.  A good clinical response to levodopa; and  No ‘atypical’ features suggestive of another parkinsonian syndrome. 12
  • 13. Pathologically  There is extensive loss of pigmented dopaminergic substantia nigra neurones and the presence of lewy bodies. 13
  • 14. Anatomy 14
  • 15. CONNECTIONS OF BASAL GANGLIA MOTOR CORTICAL AREAS MOTOR NEURONES GP e SUB THALAMIC NUCLEUS GP i P U T A M E N SUBSTANTIA NIGRA THALAMUS EXITATORY INHIBITORY DIRECT PATHWAY INDIRECT PATHWAY Facilitates movements Inhibits movements D2 D1 15
  • 16. BASAL GANGLIA IN PARKINSON’S MOTOR CORTICAL AREAS MOTOR NEURONES GP e SUB THALAMIC NUCLEUS GP i P U T A M E N SUBSTANTIA NIGRA THALAMUS EXITATORY INHIBITORY DIRECT PATHWAY INDIRECT PATHWAY D1 D2 16
  • 17. CARDINAL FEATURES T E T R A D RIGIDITY LEAD PIPE -TRUNK &LOWER LIMB TRUNK -STOOPED AND FLEXED COG WHEEL –UPPER LIMB GAIT/POSTURAL REFLEXES DISTURBED DIFFICULTY IN MAINTAINING BALANCE SLOW TO START WALKING SHORTENED STRIDE RAPID SMALL STEPS (TENDENCY TO RUN) REDUCED ARM SWING DIFFICULTY IN STOPPING SUDDENLY IMPAIRED BALANCE ON TURNING HYPOKINESIA & BRADYKINESIA SLOWNESS IN INITIATING AND REPEATING VOLUNTARY MOVEMENTS DESPITE NORMAL STRENGTH TREMORS RESTING – 4 TO 6 Hz ↓ WITH MOVEMENT AND ATTENTION FINGERS (COMMON) POSTURAL -8 TO 10 Hz PERSIST ON MOVEMENT 17
  • 18. TREMORS  Often Involves the hand.  Pill-rolling tremors (four per second) involving thumb and fingers are characteristic.  Typically present when the hand is at rest ( hence the term RESTING TREMOR).  Voluntary movements dampens the tremors momentarily.  Complete relaxation ( sleeping) greatly reduces or abolishes the tremor .  Also known as alternating tremors due to alternating burst of activity in agonist and antagonist muscles in EMG. 18
  • 19. Second common type is  A fine, seven to eight per second tremors of the outstretched hands and fingers.  Persists throughout voluntary movements.  Not evident in resting position.  More easily suppressed by relaxation.  Lacks the alternating burst of action potential unlike resting tremors and resembles essential tremors.  Parkinson’s disease patients may have either type of tremor or both. 19
  • 20. RIGIDITY  Muscles are continuously or intermittently firm and tense.  Present when patient is in awakened state, even when appearing quiet and relaxed.  Unlike spasticity it lacks the initial “free interval” on passive flexion thus having the quality of bending a lead pipe.  Limb does not resume its original position as happens in spasticity. 20
  • 21.  Rigidity involves both flexor and extensor muscles but predominant in flexors.  Small muscles of face, tongue, larynx are also affected.  Cogwheel phenomenon: Rigidity with superimposed tremor. Passive flexion of hypertonic muscles causes rhythmically interrupted ratchet like resistance.  Once rigidity develops it is constantly present.  Initially unilateral later becomes bilateral.  Tendon reflexes are not enhanced.  Babinski is negative. 21
  • 22. HYPOKINESIA AND BRADYKINESIA Hypokinesia is defined as “Disinclination on the part of the patient to use an affected part and to engage it freely in all the natural actions of the body”.  The frequent automatic habitual movements are absent or reduced.  Blinking is infrequent & Face lacks expressive mobility.  Reduced arm swing while walking.  On looking to one side eyes moves but not the head.  There is a lack of the small “movements of cooperation” (as in arising from the chair without first adjusting the feet).  Handwriting becomes small (MICROGRAPHIA) 22
  • 23. Micrographia Normal After developing Parkinson’s disease 23
  • 24. Hypomimia Infrequency of blinking ,5-10 per min Soft voice and rapid monotonous speech Face lacks expressive mobility (masked facies or hypomimia) Drooling of saliva 24
  • 25.  Bradykinesia refers to reduced velocity of the movement, or the time from onset to completion of movement is slower than normal.  Reaction time ( time interval between the command and the first contraction of the muscle) is also increased.  Saliva is not swallowed as quickly as it is produced.  Inability to carry out quick (ballistic) movements.  Inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign). 25
  • 26. PARKINSONIAN GAIT  Involuntary flexion of the trunk limbs and the neck.  Hesitation in starting to walk.  Steps are short and the feet barely clears the ground as patient shuffles along.  Once walking started patient takes increasingly short and rapid steps as though trying to catch up to his centre of gravity (Festination).  Freezing briefly when encountering doorways or other obstacles. 26
  • 27.  Diminished or reduced arm swing.  Turning en bloc.  Inability to make appropriate postural adjustments to tilting and falling.  Anticipatory and compensatory righting reflexes are impaired. 27
  • 28. ADDITIONAL FEATURES PAIN:  Initially the only complaints may be of aching of the back, neck, shoulders, or hips and of vague weakness. DYSTONIA:  Persistent extension or clawing of the toes, jaw clenching, and other fragments of dystonia, often painful, may be present but are not usually early findings. (These are particularly resistant to treatment.) 28
  • 29. BEHAVIORAL CHANGES:  Depression, anxiety, dementia, hallucinations.  Impaired memory is usually not a major feature of PD.  Dementia correlates with increase in number of lewy bodies. AUTONOMIC DYSFUNCTION:  Hypotension (levodopa, dopa agonists)  Constipation (anticholinergics)  Bladder dysfunction.  Sleep disturbances.  Sexual dysfunction.  Hyperhidrosis.  Seborrhea.  Leg edema. 29
  • 30. Modified Hoehn And Yahr Staging  Stage 0 – No signs of disease.  Stage 1 – Unilateral disease.  Stage 1.5 – Unilateral plus axial involvement.  Stage 2 – Bilateral disease, without impairment of balance.  Stage 2.5 – Mild bilateral disease with recovery on pull test.  Stage 3 – Mild to moderate bilateral disease; some postural instability; physically independent.  Stage 4 – Severe disability; still able to walk or stand unassisted.  Stage 5 – Wheelchair bound or bedridden unless aided. 30
  • 31. UK Parkinson's disease society brain bank clinical diagnostic criteria 31
  • 32. Investigations  Only useful for research purpose.  Diagnosis is only based on clinical features.  Imaging can be useful in difficult cases or research studies.  Genetic testing may be useful in identifying at-risk individuals in research setting. 32
  • 33. TREATMENT Pharmacotherapy Surgery Physiotherapy 33
  • 34. Pharmacotherapy • Anticholinergics • Trihexyphenidyl, benztropine • MAOIs • Selegiline, rasagiline • Amantadine • Dopamine agonists • Pramipexole, ropinirole • Carbidopa/levodopa • COMT inhibitors • Entacapone, tolcapone 34
  • 35. Dopamine Synthesis 35
  • 36. Pharmacologic basis of treatment 36
  • 37. Mode of action 37
  • 38. How PD medications work MAO-B inhibitors preserve existing dopamine COMT inhibitors preserve levodopa Levodopa replaces dopamine Dopamine agonists mimic dopamine Dopamine-producing neuron 38
  • 39. Levodopa+Carbidopa:  The most effective symptomatic treatment for PD and the gold standard against other drugs.  Combination reduces oral doses and reduce Acute dopaminergic side effects like nausea, vomiting, and orthostatic hypotension.  Combinations of carbidopa-levodopa are available in a l:10 or 1:4 ratio and the benserizide-levodopa combination in a 1:4 ratio.  The initial dose of levodopa-carbidopa is typically one-half to one of a 25/100-mg tablet given two or three times daily and increased slowly until optimum improvement is achieved. 39
  • 40.  Dietry protein interferes with absorption of levodopa.  Taking medications 1 hour before food or 2 hours after food can lead to more predictable and effective absorption and improved stability.  Controlled release levodopa reduces the number of doses but associated with slow onset of action particularly in morning. Addition of conventional dose at this time can provide a initial ‘kick in’.  Mild off periods respond well to small supplemental doses in fast acting form like dispersible tablets which acts rapidly but short acting. 40
  • 41. Side effects of levodopa  Anorexia, nausea, and vomiting-stimulation of ctz.  Tachycardia, ventricular extra systoles and Hypotension.  Psychotic patients-exacerbation of symptoms.  Vitamin B6 [pyridoxine] increases peripheral degradation of levodopa 41
  • 42. Motor complications of levodopa: These are limitation of the long-term use of levodopa therapy "wearing off" phenomenon:  Each dose of levodopa effectively improves mobility for a period of time, perhaps 1-2 hours, but rigidity and akinesia return rapidly at the end of the dosing interval.  They occur at later stage of the disease.  Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias. 42
  • 43. On-Off phenomenon:  In more advanced states, patients may cycle between "on" periods complicated by disabling dyskinesias and "off" periods in which they suffer severe parkinsonism.  This may occur in a matter of minutes or from one hour to the next. Peak-dose dyskinesia :  Many patients develop dyskinesias at the time of maximal clinical benefit and peak plasma concentration.  They are usually choreiform in nature but can manifest as dystonia, myoclonus, or other movement disorders. Diphasic dyskinesias:  Occur as the levodopa dose begins to take effect and again as it wears off. 43
  • 44. Changes in motor response associated with chronic levodopa treatment 44
  • 45. 45
  • 46. COMT-inhibitors:  Reduces "off" time and prolongs "on" time and more beneficial in patients treated with levodopa+carbidopa combination having motor fluctuations.  Tolcapone and entacapone are approved drugs.  Side effects are dopaminergic(nausea ,vomiting ,increased dyskinesias).  Diarrhoea = tolcapone > entacapone.  Fulminant Hepatic necrosis reported with tolcapone so LFT monitoring is important.  It is not reported with entacapone.  Discolouration of urine is reported. 46
  • 47. MAO-B inhibitors:  Block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter.  Reduce "off" time when used as an adjunct to levodopa in patients with motor fluctuations.  Well tolerated and reduces the required dose of levodopa.  Early reports of possible neuroprotective effects of selegiline have not been supported by long-term studies.  Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia. But not rasageline.  High dose of these drugs can cause hypertensive crisis known as cheese reaction 47
  • 48. Amantadine:  Originally introduced as an antiviral agent.  It is the only anti parkinsonian drug that improves levodopa induced dyskinesia.  According to recent studies it acts by inhibiting NMDA receptors, increases presynaptic dopamine reuptake and release.  less efficacious than levodopa.  Has little effect on tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia.  Adverse effects are livido reticularis, ankle edema, urinary dysfunction, glaucoma, and particularly cognitive impairment. 48
  • 49. Dopamine agonists:  Longer duration of action than levodopa thereby causing lesser risk of developing dyskinesias.  Ergot derivatives are not used now due major cardiac side effects.  In early PD it delays the need to start levodopa therapy.  In late PD it helps to reduce the dose of levodopa.  Apomorphine is available only as I.V preparation.  Rotigotine is available as transdermal patches. 49
  • 50.  Adverse effects like hypersexuality and pathological gambling also seen.  Younger patients less than 60 yrs who are at more risk of developing dyskinesia are more likely to tolerate agonists.  Agonist monotherapy is associated with fewer motor complications.  Agonist monotherapy is unlikely to be adequate for more than 5 years.  Aim of agonist monotherapy is to delay the levodopa therapy and not to avoid it altogether. 50
  • 51. Anticholinergics:  Used in early stages when symptoms are not troublesome.  Useful against tremors but not against other symptoms of PD.  Side effects are dry mouth, blurring of vision, glaucoma, hallucinations and prostatic obstruction.  Use is limited in elderly due to the side effects. 51
  • 52. 52
  • 53. Surgery  Steriotactic lesions placed in motor cortex improved tremors but produced motor deficits.  lesions placed into the VIM nucleus of the thalamus reduced contralateral tremor without inducing hemiparesis.but not improved other symptoms.  Lesions placed in the GPi improved rigidity and bradykinesia as well as tremor.  Pallidotomy was also associated with marked improvement in contralateral dyskinesia.  These procedures were not optimal for patients withbilateral disease. 53
  • 54. Deep brain stimulation  An electrode is placed into the target area and connected to a stimulator.  DBS simulates the effects of a lesion without necessitating a brain lesion.  It does not require making a lesion in the brain and is thus suitable for performing bilateral procedures with relative safety.  DBS for PD primarily targets the STN or the GPi. It provides dramatic results, particularly with respect to "off" time and dyskinesias. 54
  • 55. Management of non-motor Symptoms  Depression- SSRI’s. Antidepressants should not be withheld, particularly for patients with major depression.  Anxiety-Short acting benzodiazepines.  Psychosis-low dose neuroleptics: Clozapine is most effective (A.E: Agranulocytosis). Quetiapine is also used.  Dementia-Levodopa and other dopaminergic drugs can aggravate cognitive function in demented patients and should be stopped or reduced.  Anticholinesterase agents such as rivastigmine and donepezil reduce the rate of deterioration. Memantine, an antiglutamatergic agent, may also provide benefit for some PDD patients. 55
  • 56.  Orthostatic hypotension- Adding salt to the diet and elevating the head of the bed. Low doses of fludrocortisol (Florinef) or midodrine control most cases.  Sexual dysfunction can be helped with sildenafil or tadalafil.  Urinary problems- cholinergics are helpful.  Constipation- Laxatives  Sleep disturbances- low dose clonazepam. 56
  • 57. Other aspects of management  Physiotherapy , Occupational therapy, Speech therapy are helpful in advanced cases with disability.  Intensive social support in the community is necessary.  Residential care may be the only option in some cases. 57
  • 58. Recent advances in treatment  Levodopa-carbidopa Gel [duodopa]: continuously deliverd through duodenostomy or jejunostomy tube into intestine. More invasive. Constant levels are maintained.  Dopamine agonists: PARDOPRUNOX, has progressed to Phase III trial. APLINDORE, is being studied in a Phase II trial. LISURIDE, which is in the form of a skin patch and is already marketed in Europe, has progressed to a Phase II trial. 58
  • 59.  MAO-B inhibitors: NEBICAPONE, has shown promising results in preliminary trials. SAFINAMIDE, is being studied in a Phase III trial.  Non dopaminergic agents: Adenosine A2A antagonist: ISTRADEFYLLINE, was taken to Phase III trials, but it failed to prove effective. FIPAMEZOLE (JP-1730), SCH-420814, BIIA-014 and Lu AA4707 — are in earlier phases of development. 59
  • 60.  FP0011, a compound that reduces central glutamate levels, is now being studied in a Phase II trial.  A metabotropic glutamate (mGlu5) receptor antagonist has completed a Phase I trial.  Cell-based therapies (such as transplantation of fetal nigral dopamine cells or dopamine neurons derived from stem cells), gene therapies, and trophic factors are under experimentation. 60
  • 61. Parkinsonism plus syndromes 61
  • 62. Multiple System Atrophy [MSA]  Characterised by parkinsonism, autonomic failure and cerebellar symptoms, with either parkinsonism (MSA-P) or cerebellar features (MSA-C) predominating.  Early falls, postural instability and lack of response to LD are clues for diagnosis.  The pathological hallmark is α-synuclein containing glial cytoplasmic inclusions found in the basal ganglia, cerebellum and motor cortex.  Management is symptomatic and the prognosis is less good than for PD, with mean survival from symptom onset of fewer than 10 years, and early disability.  Cognition is preserved. 62
  • 63. Progressive supranuclear palsy (PSP)  Presents with symmetrical parkinsonism, cognitive impairment, early falls and bulbar symptoms.  The characteristic eye movement disorder, with slowed vertical saccades leading to impairment of up and down gaze, may take years to emerge.  Pathology: Abnormal accumulation of tau (τ) proteins and degeneration of the substantia nigra, subthalamic nucleus and mid-brain.  There is no treatment, and the parkinsonism usually does not respond to LD. 63
  • 64. Corticobasal ganglionic degeneration  less common than MSA or PSP.  Clinical manifestations are variable, including parkinsonism, dystonia, myoclonus and ‘alien limb’ phenomenon, whereby a limb (usually upper) moves about or interferes with the other limb without apparent conscious control.  Cortical symptoms, especially apraxia, are common and may be the only features in some cases, including dementia.  CBD is a tauopathy with widespread deposition throughout the brain, and has similar survival rates to MSA and PSP. 64
  • 65. SYMPTOMS/SIGNS ALTERNATIVE DIAGNOSIS TO CONSIDER Falls as first symptom PSP Exposure to neuroleptics Drug-induced parkinsonism Onset prior to age 40 If PD think of genetic cause Associated unexplained liver disease Wilson’s disease Early Hallucinations Lewy body dementia Sudden onset of parkinsonian symptoms Vascular parkinsonism Demetia as 1st symptom Lewy body dementia Prominent orthostasis MSA-p Early dysarthria MSA-c Lack of tremors Various parkisonian plus syndromes High frequency (8-10 Hz) Symmetric tremors Essential tremor 65
  • 66. QUICK REVISION  Parkinsonism caused by disturbance in substantia nigra.  Tremor is typically at rest with frequency 4-8 Hz.  Normal deep Tendon reflexes.  Plantar – flexor (Negative Babinski).  Festinating gait.  Small handwriting.  Normal intelligence.  Emotional instability.  Masked expressionless face.  Slurred indistinct speech. 66
  • 67. THANK YOU