DIAGNOSIS

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DIAGNOSIS TREATMENT OF PARKINSONS DISEASE

• May 7, 2008
• Sadhana Prasad
• Symposium on Changes and Challenges in Geriatric
  Care

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Disclosures

• Work with various pharmaceutical companies
  intermittently
• Honorarium will be donated

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OBJECTIVES

• 1. Illustrate medications and conditions that may
  mimic PD
• 2. Describe the early symptoms of Parkinsons
  Disease (PD)
• 3. Discuss initiating and stopping medications

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Parkinsons Disease

• Characterized by (Slow,Stiff,Shaky)
• Bradykinesia
• Rigidity
• Rest tremor--3-6Hz pill-rolling (absent 1/3)
• Postural instability

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Parkinsons Disease (PD)

• First description 1817
• Parkinson, James An Essay on the Shaking
  Palsy, Sherwood, Neely, and Jones, London
• Progressive neurodegenerative disease
• Affects ages 40 onwards, mean age at diagnosis
  70.5
• Complex disorder with motor, non-motor,
  neuropsychiatric features

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Disease vs Syndrome

• Disease a morbid process having characteristic
  symptoms pathology, etiology, and prognosis may
  be known
• Syndrome a set of symptoms occurring together
  different etiologies but similar presentation

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Parkinsons Syndromes

• Metabolic causes--
• Hypothyroidism
• Hypoparathyroidism
• Alcohol withdrawl (pseudoparkinsonism)
• Chronic liver failure
• Wilsons disease

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P. Syndromes

• Medications/chemicals
• neuroleptics (typicals more than the atypicals),
• SSRI (selective serotonin reuptake inhibitors),
• metoclopromide/maxeran,
• Reserpine,
• MPTP,
• in Methcathinone (ephedrone) users high plasma
  Manganese levels (NEJM Mar 6, 2008)
• CO, cyanide, organic solvents, carbon disulfide

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P. Syndromes

• Structural Causes
• Strokes
• Tumors
• Chronic subdurals
• NPH (Normal Pressure Hydrocephalus)

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P.Syndromes

• Lewy Body spectrum of Diseases (DLBDementia with
  LB)---
• ---early onset visual (or other) hallucinations
• ---fluctuating cognitive abilities
• ---sleep disorders
• ---neuroleptic sensitivity, even to atypicals

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P. Syndromes

• PSP (progressive supranuclear palsy)or Steeles
  Richardson Olszewski Syndrome
• ---gaze abnormalities
• ---postural instability, early unexplained falls
• ---bulbar featuresdysphonia, dysarthria,
  dysphagia
• ---rapidly progressive---median 6 yrs.

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P. Syndromes

• CBD (cortico basal degeneration)---
• ---Asymmetric parkinsonism
• ---postural instability
• ---ideomotor apraxia
• ---aphasia
• ---alien limb phenomenon
• ---impaired cortical sensations

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P. Syndromes

• Multi System Atrophy-- (alpha-synuclein glial
  cytoplasmic inclusions, autonomic dysfunction,
  pyramidal signs)
• Shy Drager Syndrome,
• Olivopontocerebellar atrophy,
• Striatonigral degeneration

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P. Syndromes

• Other Neurodegenerative Disorders
• Alzheimers Disease, later stages
• Huntingtons Disease (rigid form)
• Frontotemporal Dementia with Parkinsonism,
  Chromosome-17 linked (FTDP-17)
• Spinocerebellar ataxias

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P. Syndromes

• Infections---
• encephalitis
• HIV/AIDS
• Neurosyphilis
• Toxoplasmosis
• CJD (Creuzfeld Jakob)--prion disease
• Progressive multifocal leukoencephalopathy

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P. Syndrome

• Essential Tremor---
• ---action tremor (not rest tremor)
• ---more rapid (greater than 3-6 Hz)
• ---usually hands, but can also affect legs,
  head/chin, voice, trunk
• ---can present with falls if legs and trunk
  involved

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P. Disease

• ??DIAGNOSIS??

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P. Dis -- Diagnosis

• A clinical diagnosis
• Cardinal features Bradykinesia, rigidity
• Trial of sinemet (Levodopa/carbidopa)
• Confirmatory test neuropathologic (autopsy)

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P. Disease-Diagnosis

• 1/3 will not respond to levodopa therapy
• 1/5 with P. Syndrome will respond to levodopa
• ---Follow- up with time needed to clarify
  diagnosis

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P. Disease---Diagnosis

• Minimum therapeutic dose
• ---300mg levodopa per day in divided doses
• ---can be lower in biologically old old
• ---vast majority will need 400-600mg levodopa
  daily to achieve significant benefit

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P. Disease- Diagnosis

• Consider alternative diagnosis if
• Early falls (postural instability)
• Poor response to levodopa
• Dysautonomia (urinary retention/atonic bladder,
  incontinence, orthostatic hypotension, impotence)
• No rest tremor (in 1/3)

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P. Disease-Diagnosis

• Alternative Diagnosis contd
• Cerebellar signs
• Positive Babinski
• Apraxia
• Gaze abnormailities
• Dementia concurrently with Parkinsonism
• Strokes

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P. Disease

• INVESTIGATIONS
• TSH
• Calcium, albumin
• CT head

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OBJECTIVES

• 1. Illustrate medications and conditions that may
  mimic PD
• 2. Describe the early symptoms of Parkinsons
  Disease (PD)
• 3. Discuss initiating and stopping medications

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PD- CASE

• Mr AB, married, active farmer, stressed
  care-giver
• Drove his wife to the clinic, wife to see me re
  agitated dementia
• One son also attended
• Mr AB stressed care-giver, on paxil (SSRI)

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PD- case

• Mr. AB--- stressed caregiver
• Slightly flexed posture
• Slightly bradykinetic
• Slightly diminished facial expression
• No difficulty turning, getting in/out of armless
  chair

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PD-case

• I dont have Parkinsons Disease!!

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PD- case

• Mr. AB---
• 1 month later, referred re ? PD??
• CT head, TSH, Ca normal
• Slowing down x 1 yr, hypophonia, denied trouble
  turning in bed but took 5 tries in clinic,
  trouble getting out of soft chair, stopped taking
  baths x 3 years, mild rest tremor R hand, trouble
  doing up buttons and laces

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IADLInstrumental Activities of Daily Living

• S shopping
• H housework
• A accounting
• F food preparation
• T transportation

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ADLActivities of Daily Living

• D dressing
• E eating
• A ambulation
• T toiletting
• H hygiene

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PD- case 1
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PD-case 1

• clock

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PD Case 1

• Diagnosis
• Parkinsons disease ---Hoehn Yahrs stage 2

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Hoehn and Yahr scale

• 1. Unilateral involvement only, usually with
  minimal or no functional disability
• 2. Bilateral or midline involvement without
  impairment of balance
• 3. Bilateral disease mild to moderate disability
  with impaired postural reflexes physically
  independent
• 4. Severely disabling disease still able to walk
  or stand unassisted
• 5. Confinement to bed or wheelchair unless aided
• Hoehn, MM, Yahr, MD. Parkinsonism onset,
  progression and mortality. Neurology 1967
  17427.

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PD- case 1

• MTO notified, not to cancel license
• Paxil
• Sinemet regular 100/25 mg ½ tid, increase by ½
  weekly till 1 tid
• Calcium and vitamin D3
• 2 months later, smiling, clock better, moving
  better, still flexed, no falls

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PD-case 1

• clock

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PDother issues

• Depression
• Dementia
• Driving
• Falls
• Neuropsychiatric features
• slowing down of thought processes (the clock in
  Mr AB)
• Constipation

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PD-Treatment

• ????

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OBJECTIVES

• 1. Illustrate medications and conditions that may
  mimic PD
• 2. Describe the early symptoms of Parkinsons
  Disease (PD)
• 3. Discuss initiating and stopping medications

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PD--Treatment

• Geared towards mobilitylevodopa, dopamine
  agonists, MAO B inhibitors
• Rest tremor, cosmeticanticholinergics (may
  worsen cognition)
• Postural imbalanceno pharmacological treatment
  exercise, gait aids, prevent fractures (Ca, Vit
  D3, /- bisphosphonates)
• Dyskinesias-- ?amantadine (no clear evidence)
  Almeida,QJ, Recent Patents on CNS Drug Discovery,
  20083, 5--54

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PD--Which pharmaceutical?

• In Elderly--
• Levodopa/ carbidopa (sinemet) regular vs CR
  (controlled release)
• or
• Levodopa/ benserazide (prolopa) regular vs HBS
• COMT- inhibitor entacapone (comtan)

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PD- medications

• Levodopa
• Well-established, for bradykinesia and rigidity
• SE nausea, orthostatic hypotension
• Combined with peripheral decarboxylase inhibitor
  (carbidopa, benserazide) to prevent conversion
  to dopamine in the periphery before it crosses
  blood brain barrier

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PD- medications

• Levodopa (l-dopa)
• -- l-dopa / carbidopa sinemet reg. or CR
• -- l-dopa / benserazide prolopa, medopar or
  medopar HBS
• Competes with amino acids from protein for GI
  absorption
• Regular-- before meals, quick in quick out, T1/2
  90 min
• CR--- With meals,Controlled Release, slow in slow
  out, need 30 more to achieve same effect as reg.
  dose, erratic absorption in elderly

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PD-medications

• L-dopa contd
• SE- Nausea (Rx Domperidone)
• -Hallucinations (Rx lower dose, atypical
  n neuroleptics)
• -somnolence, confusion, agitation
• -motor fluctuations- after sev yrs of Rx

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PD- medications

• L-dopa contd
• Motor fluctuations (in 50, after 5-10yrs)
• -wearing-off Rx COMT inhibitor, ?CR
• -dyskinesias (??Rx amantadine??)
• -dystonias
• -variety of complex fluctuations in motor
  function

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PD- medications

• L-dopa contd
• Discontinuation
• gradually over weeks,
• to prevent malignant neuroleptic like syndrome or
  akinetic crisis

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PD-medications

• L-dopa contd
• Dopaminergic dysregulation syndrome
  (DDS)tolerance to mood elevating effects
• Compulsive use of dopaminergic drugs
• Early onset males
• Cyclical mood disorder
• Impulse control disorder (hypersexuality,
  pathologic gambling)
• Giovannoni, G, Hedonistic homeostatic
  dysregulationJ. Neurol Neurosurg Psychiatry
  2000 68243

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PD- medications

• COMT inhibitor
• -Catechol-O-Methyl Transferase Inhibitor
• -((eg Tolcapone (Tasmar)---off market due to
  fulminant hepatitis causing 3 deaths))
• -eg Entacapone (Comtan)
• -for wearing-off at end-of-dose of L-dopa
• -dose 200mg-1600mg, divided, daily, with L-dopa
• -SE-diarrhea in 5, due to increased
  dopaminergic stimulation from L-dopa availability

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PD-medications

• Dopamine Agonists adjunct Rx to L-dopa.
• -Ergotaminesbromocriptine, ((pergolide)),
  ((cabergoline))
• SE-same as L-dopa, uncommon Raynauds,
  erythromelalgia, retroperitoneal/pulmonary
  fibrosis
• -Non-Ergotpramipexole, ropinirole, ((transdermal
  rotigotine))
• SEsame as L-dopa, Sudden somnolence caution
  with driving

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PD-medications

• MAO-B inhibitors--adjunct Rx to L-dopa
• -eg selegiline (eldepryl), rasagiline
• -somewhat helpful in young, early in disease
• -neuroprotective properties in animal models only
• Arch Neurology. 2002 591937

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PD-medications

• Anticholinergicsadjunct Rx to L-dopa, best
  avoided in elderly
• -acetylcholine (ACh) and dopamine in balance in
  basal ganglia
• -decrease Ach to balance decrease in L-dopa
• -eg trihexyphenidyl (artane), benztropine
  (cogentin), orphenadrine, procyclidine
  (kemadrin)
• -SE-confusion, hallucinations, dry mouth, blurred
  vision, constipation, nausea, u. retention,
  glaucoma

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PD-medications

• Amantadine-adjunct to L-dopa, best avoided in
  elderly
• -for dyskinesias
• -Antiviral agentmechanism unknown
• -NMDA-receptor antagonist properties-interferes
  with excessive glutamate
• -SE-livedo reticularis, ankle edema,
  hallucinations

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PD- Medications

• When do you stop the medications?
• --ALWAYS taper gradually over days to weeks to
  avoid NM-like syndrome
• --unable to take meds (dysphagia)
• --significant, intolerable SE impairing QOL
• --end-stage--- infection comes as a friend

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OBJECTIVES

• 1. Illustrate medications and conditions that may
  mimic PD
• 2. Describe the early symptoms of Parkinsons
  Disease (PD)
• 3. Discuss initiating and stopping medications