Parkinsons Disease update. Sindhu R Srivatsal MD MPH Virginia Mason Medical Center

Transcription

1 Parkinsons Disease update Sindhu R Srivatsal MD MPH Virginia Mason Medical Center

2 PARKINSONISM Vs PARKINSON S Parkinsonism Bradykinesia: slowness of movements (essential feature) PLUS one of Tremor: resting form (absent 30% of the time) Rigidity Postural instability

3 WHAT IS PARKINSON S DISEASE Spontaneous Parkinsonism without any other etiology (drug/ toxin) With no evidence of red flags Early gait impairment, dementia, autonomic issues With robust medication responsiveness

4 Contd.. Causes for parkinsonism Parkinson s disease (commonest) Parkinson plus (Multiple systems atrophy, dementia with lewy body, Progressive supranuclear palsy) Vascular parkinsonism Drug/ Toxin induced parkinsonism Alzheimer's with parkinsonian features

5 MOTOR FEATURES Bradykinesia Arm swing, dexterity, hypomimia, stooped posture Rigidity Pain, stiffness, shoulder ROMS Tremor Pill rolling rest tremor

6 PARKINSON COMPLEX- Tip of the iceberg anology

7 PREVALENCE: > 1 MILLION people currently diagnosed with PD in USA 1 in 100 Americans over the age of 60 ETIOLOGY: A combination of genetic susceptibility and exposure to environmental toxins and this may vary from person to person Monogenic forms: Autosomal dominant: SNCA, LRRK2 Autosomal recessive: PARKIN, PINK1, DJ-1, rarer < 10% of parkinsons is familial,

8 ENVIRONMENTAL FACTORS Risks: Rural residence X 1.56 Well water X 1.26 Living on a farm X 1.42 Pesticide (rotenone, paraquat) X 1.94 Protective: Smoking X 0.59 Coffee X 0.69

9 BRAAK HYPOTHESIS Doty, R. L. (2012) Olfactory dysfunction in Parkinson disease Nat. Rev. Neurol. doi: /nrneurol

10 DIAGNOSIS Essentially a clinical diagnosis, levodopa responsiveness used as a diagnostic tool. Imaging such as MRI BRAIN used to eliminate mimics DAT SPECT used at times to distinguish between essential tremor and Parkinson s/ parkinsonian syndromes

11 STAGES OF PARKINSON S

12 CHANGES IN DOPAMINE RESPONSE IN PARKINSON S

13 Rx Motor: Tremor Rigidity bradykinesia Dyskinesias Non Motor Mood disorders, cognitive dysfunction, Sleep disorders, GI issues, GU issues, Autonomic issues

14 MOTOR MAOB-Is Selegiline, rasagiline Safinamide Dopamine agonists Pramipexole, ropinirole, Rotigotine, Apomorphine E F F I C A C Y COMT inhibitors: Entacapone, tolcapone Anticholinergics:Trihexypheni dyl, Amantadine/ ER Carbidopa/levodopa ER/ IR Rytary

15 HOW DO MEDS WORK.. accessed sept 2014

16 CARBIDOPA/LEVODOPA Most Potent PD medication, often used for diagnostic and therapeutic trial Levodopa: 3,4-dihydroxy l-phenylalanine Levodopa- prodrug, converts to Dopamine in brain Carbidopa: blocks peripheral conversion

17 Formulations Sinemet IR (immediate release): 25/100, 25/250 Elimination half life 1.5 hrs Sinemet CR (controlled release): 25/100, 50/

18 RYTARY- Combined immediate and extended release levodopa Elimination half life 5 to 6 hrs, doses tid to qid Microbeads dissolve at different times Less dyskinesias and less wearing off

19 INTERACTIONS & SIDE EFFECTS Dietary protein intake Amino acid transporter competition Protein redistribution vs low protein Side effects: nausea, vomiting, Dizziness/ lightheadedness Drowsiness (peak dose) Rarely hallucinations/ confusion

20 DOPAMINE AGONISTS Less potent, less likely to cause motor fluctuations More even response, longer acting, once day possible Pramipexole: Mirapex 0.125/0.25/0.5 mg (max dose 4.5mg) Ropinirole: Requip 0.25/0.5/1mg (max dose mg) Rotigotine patch : Neupro 2-8 mg/24 hr

21 APOMORPHINE (dopamine agonist) Subcutaneous injectable form, for sudden and unpredictable off periods Can cause severe nausea, used with tigan Orthostatic hypotension is a serious side effect Very fast acting (10 min onset), but needs to be injected, Subcutaneous infusion being tested

22 SIDE EFFECTS Nausea, vomiting (worse with Apomorphine) Drowsiness and sleep attacks Impulse control problems: compulsive gambling, shopping (preferential Mesolimbic involvement) Confusion, hallucinations Ankle swelling

23 ANTICHOLINERGICS Trihexyphenidyl (Artane -1-2 mg bid/ tid) or Benztropine (Cogentin 1-2 mg bid/ tid) Can help tremor more than other symptoms Useful as additive therapy Fallen out of favor due to cognitive side effects. Other side effects include dry mouth/ eyes, urinary retention, may worsen gait

24 MAOB-I and COMT Reduce turnover of levodopa and dopamine

25 MAOB-I Monoamine Oxidase B inhibitor Selegiline (Deprenyl 5mg), Rasagiline (Azilect 1mg) Block Monoamine oxidase enzyme, reduces breakdown of dopamine and prolongs effect of levodopa Mild symptomatic effect, useful in reducing need for levodopa, dyskinesias and freezing of gait SE: similar to levodopa except selegiline breakdown produces amphetamine byproducts causing insomnia? Disease modifiers.

26 Unique mechanism MAO B inhibitor SAFINAMIDE new drug NMDA receptor antagonist Approved March 2017 as adjunct for on time without dyskinesia (Xadago)

27 Catechol-O-methyl transferase INHIBITORS Inhibit enzyme COMT enzyme Block peripheral and central (tolcapone) breakdown of levodopa,» Entacapone (comtan 200mg), and in combination with sinemet (Stalevo 50/75/100/125/150/200)» Tolcapone (Tasmar): rarely used due to liver toxicity» Opicapone approved in European union (2016), once a day dose

28 AMANTADINE Blocks NMDA receptor, effects are mild on parkinson symptoms» Reducing dyskinesias, can improve gait» Side effects: ankle swelling, hallucinations, confusion, livedo reticularis» TID dosing, comes as 100 mg dose» Extended release amantadine approved 2017» (Gocovri), once a day dose

29 Early to advanced parkinsons treatment spectrum

30 DEEP BRAIN STIMULATION FDA approved in 2002 Considered in the following situations: motor fluctuations not fully controlled on maximum medical therapy Disabling tremor not controlled by medications Rarely: intolerance of medications Data for early DBS before motor fluctuations is rising

31 BASAL GANGLIA STRUCTURE

32 DBS TARGET Subthalamic nucleus or Globus pallidus interna 94/brain%20implant.PNG

33 TARGETING Mapping, Micro electrode recording, Macro stimulation

34 OUTCOMES Deuschl 2006

35 RISKS AND BENEFITS BENEFITS: Increase on time and improve off state mobility, better than best medical therapy Reduce levodopa dose requirements and dyskinesias RISKS: Infection, bleeding Lead fracture

36 LEVODOPA INTESTINAL GEL Continuous levodopa infusion during waking hours with basal and bolus infusions Mimics natural dopamine release Circumvents gut absorption issues

37 SIDE EFFECTS/ ADVERSE EFFECTS Procedural issues Kinking of tube Invasive, needs G-J tube Abdominal pain and distension Generalized polyneuropathy Other side effects similar to levodopa

38 NON MOTOR SYMPTOMS IN PD

39 DEPRESSION Very common in PD, may precede onset Prevalence of Depression in PD: 20-40% Major depression: 5-10% Rx: Evidence for Amitriptilline (side effects limit use), SSRIs comparable, watch for seratonin syndrome Pramipexole can help sometimes

40 HALLUCINATIONS/ PSYCHOSIS Often a side effect of medications (Dopamine Agonists/ Amantadine > levodopa) Independent risk factor for Nursing home placement Cognitive impairment Visual hallucinations: a predictor for cortical Lewy bodies

41 Rx Consider discontinuing Dopamine Agonist (DA), amantadine Rule out infection Consider lowering total levodopa dose Discontinue other offending drugs including anticholinergics, opiates etc

42 PIMAVANSERIN (new drug) FDA approved specifically for treating pyschosis in PD and DLB (Nuplazid) MOA: Selective 5HT2A blocker, taken once a day Unlike antipsychotics doesn t make PD worse Dose 34 mg taken as two 17 mg tabs together Side effects: nausea, dizziness, constipation, confusion, prolongs QT

43 DEMENTIA Presents after years of PD, but can have Mild cognitive impairment early on Attentional and executive function problems Implicit and explicit memory problems Visuo-spatial dysfunction Fluency and confrontational naming issues Trails B: good paper and pencil test to estimate driving ability

44 PREVALENCE Average is 30-40%, Dementia at onset or within a year of parkinsons = DLB Percentage affected grows over time: 16-21% in 5 years 37% in 10 years 50-80% in 20 years

45 Rx Cholinesterase inhibitors mainstay Rivastigmine only FDA approved medication for treatment of dementia associated with PD. (1.5 to 6 mg bid) Donepezil (5-10 mg qday) and galantamine also used in clinical practice (off-label) Potential for worsening tremors Memantine as an adjunctive option (off-label)

46 SIALORRHEA- DROOLING Due to decreased automatic swallowing resulting in pooling of saliva Flexed posture of neck impairs swallow Rx: Sucking hard candy and chewing Atropine eye drops 1% 4 drops under the tongue every 4 hours (off-label) Ipratropium spray may bypass systemic effects (1-2 sprays up to 4 times a day) (off-label) Botulinum toxin injections to salivary glands (off-label)

47 CONSTIPATION Colon transit time is prolonged in PD Slowing occurs in 80% of PD patients Average CTT in PD is twice as long: 44 hours vs. 20 hours (Edwards et al.) Rx Increase fluid and fiber intake (20-35 grams of fiber/day), prunes Add stool softener, Consider lactulose/miralax, and enemas Lubiprostone effective in a small study (activates Chloride channel),

48 BLADDER ISSUES Urinary frequency, urgency and nocturia Anticholinergics: Oxybutynin ( can cross BBB and cause confusion) Tolterodine, solifenacin and darifenacin preferable Reduce caffeine/ bladder irritants (citrus agents, chocolate) Mirabegron (Myrbetriq) has effects on beta adrenergic system and hence no cognitive side effects Urinary Hesitancy: Less common, rule out other conditions e.g., prostate enlargement May need bethanechol

49 REM BEHAVIOR DISORDER May affect up to 50% of persons with PD, sign of synucleinopathy Talking and shouting while asleep, Intense, and sometimes violent, movements Involves "acting out" dreams, REM Atonia is lost May precede typical motor features of PD by decades

50 Rx Treat when it affects patient s/ partner s sleep, Eliminate potentially offending medications Antidepressants, Cholinesterase inhibitors, Beta blockers, Tramadol, Caffeine Melatonin, Well-tolerated and available OTC (3-9 mg) Clonazepam (0.25 mg) Favorable response in up to 90% of patients Others (e.g., gabapentin, clozapine)

51 VIT D in Parkinsons Disease Cross sectional studies: Vit D levels correlate with mood, UPDRS scores, HY stage, verbal fluency (causation vs reverse causation) Higher Vit D levels associated with milder PD (HY and UPDRS) I small randomized trial in PD patients showed Vit D 1200 units for 12 mo reduced progression of HY scale slightly

52 CAFFEINE IN PD Shown to reduce LID (levodopa induced dyskinesias Risk for PD less in men drinking coffee (2cups/dy), similar results in women not on HRT? can help motor symptoms

53 QUESTIONS? THANK YOU!!