Parkinson's Disease

Diseases, , ,

Synonyms:

Paralysis agitans:

Clinical features:

  • Triad of:
    • Bradykinesia
    • Rigidity.
    • Tremor: this is not essential for the diagnosis
  • Important characteristics: asymmetry, upper body is affected first, fluctuation in severity, postural instability later on
  • BP & postural BP: to exclude Shy-Dragger syndrome
  • Other clinical points:
    • Re-emergent tremor: on testing for postural tremour, initially there is no tremour then after a latency the tremour re-emerges.
    • +/-levodopa challenge
    • +/-negative CT or MRI imaging
  • Parkinson’s disease dementia:
    • Dementia that develops at least 2 years after the diagnosis of Parkinson’s disease

Pathology:

Gross:

  • Pallor of the substantia nigra & locus ceruleus

Microscopically:

  • In substatian nigra; decreased density of pigmented neurons, pigment laden macrophages, free pigment (pigment incontinence), astrocytic gliosis.
  • Lewy body formation= spherical eosinophilic intraneuronal cytoplasmic inclusions. Cortical Lewy bodies lack a halo. Lewy bodies in substatia nigra, locus ceruleus, nucleus basalis of Meynert, dorsal vagal nucleus, hypothalamus, olfactory bulb, Edinger-Westphal nucleus, raphe nuclei, intermediolateral column of the spinal cord, autonomic ganglia (sympathetic= paravertebral and celiac ganglia, parasympathetic= submandibular ganglion). Also in cortex (temporal, insular, cingulate gyrus). Pale bodies are also found in the substantia nigra. Extracellular Lewy neuritis= nerve fibres with eosinophilic material, occur.
  • Immunohistochemistry: Lewy bodies and extracellular Lewy neurites are alpha synuclein positive and also ubiquitin positive
  • Silver stain: also detects alpha synuclein.
  • Epicardial space nerve fibres: Tyrosine hydroxylase staining is decreased (cardiac denervation, sympathetic)

Braak Staging:

  • Stage 1:
    • Dorsal IX/X motor nucleus,
  • Stage 2:
    • Caudal raphe nuclei (nucleus raphes magnus, obscurus, pallidus),
    • Reticular formation (Gigantocellular reticular nucleus)
    • Coeruleus-subcerulus complex
  • Stage 3:
    • Midbrain lesions: pars compacta of substatia nigra
  • Stage 4:
    • Prosencephalic lesions.
    • Cortical involvement is confined to the temporal mesocortex (transentorhinal region) and allocortex (CA2-plexus). The neocortex is unaffected
  • Stage 5:
    • High order sensory association areas of the neocortex and prefrontal neocortex
  • Stage 6:
    • First order sensory association areas of the neocortex and premotor areas,
    • Occasionally mild changes in primary sensory areas and the primary motor field

Genetic forms:

Autosomal dominant:

  • Alpha-Synuclein= protein, SNCA gene chr. 4q21
  • Protein= Dardarin= Leucine-rich repeat kinase 2, LRRK2 gene chr. 12q12

Autosomal recessive:

  • PRKN gene a.k.a. PARK2 gene 6q25.2-q27, Parkin= protein: Autosomal recessive juvenile parkinsonism.
  • PTEN-induced putative kinase-1= PINK1 gene chr. 1p36
  • DJ1 gene chr. 1p36, protein= DJ1
  • PARK7 gene
  • ATP 13A2

Findings on Investigations:

Cardiac denervation by:

  • Cardiac SPECT 123I –labeled MIBG, reduced uptake
  • PET scan

Trancranial ultrasound:

  • Hyperechogenicity: substantia nigra & median raphe

PET:

  • Cardiac denervation
  • 18F-dopa PET: Images dopa decarboxylase activity at dopamine terminals (dopamine turnover)
  • Reduced uptake in putamen,
  • Initially increased & then decreased uptake in globus pallidus

DAT PET: images presynaptic dopamine transporters,

  • Reduced uptake in putamen
  • 11C-DTBZ PET: images vesicle monoamine transporter density in dopamine terminals,

SPECT:

  • DAT SPECT (123I-FP-CIT SPECT) “DaTscan”:
    • Images presynaptic dopamine transporters
    • Helps differentiate between PD (abnormal, reduced in putamen) and essential tremor (normal)

MRI:

  • Normal
  • Hippocampal & temporal atrophy in Parkinson’s with dementia
  • DWI MRI & ADC: normal, normal putamen, normal middle cerebellar peduncle.

MRI volumetry:

  • Reduced putamen volume

Autonomic function testing:

  • Tilt table testing, if orthostatic hypotension is present:
  • Upright tilt: BP declines progressively (not suddenly) until syncope occurs. No acute bradycardia
  • Valsalva maneuver, if orthostatic hypotension is present:
  • Beat-to-Beat BP responses: during straining after the nadir (lowest BP point) there is absence of normal BP increase. Also after straining (Valsalva) there is absence of normal BP overshoot.

Monitor & Scales:

Unified Parkinson’s Disease Rating Scale UPDRS:

Grading:

  • 0 best score
  • 199 worst score
  • Motor section: 40 is severe disability

UPDRS, Motor Section:

  • Speech
  • Facial expression
  • Tremour:
    • Tremour at rest:
      • Head, right & left upper extremities, right & left lower extremities
  • Action or postural tremour:
    • Right & left upper extremities
  • Rigidity:
    • Neck, upper extremities, lower extremities
  • Bradykinesia:
    • Finger taps
    • Hand movements
    • Rapid alternating movements (wrist)
    • Leg agility (heel tap/stomp)
    • Arising from chair
  • Posture
  • Gait
  • Postural stability
  • Mentation, Behaviour, and Mood Section:
    • Intellectual impairment
    • Thought disorder
    • Depression
    • Motivation/initiative

Activities of daily living ADL:

  • Speech
  • Salivation
  • Swallowing
  • Handwriting
  • Cutting food/Handing utensils
  • Dressing
  • Hygiene
  • Turning in bed/Adjusting bed clothes
  • Falling unrelated to freezing
  • Freezing when walking
  • Walking

Hoehen & Yahr staging:

  • Five stages
  • 0: Asymptomatic.
  • 1: Unilateral involvement only.
  • 2: Bilateral involvement without impairment of balance.
  • 3: Mile to moderate involvement; some postural instability but physically independent; needs assistance to recover from pull test.
  • 4: Severe disability; still able to walk or stand unassisted.
  • 5: Wheelchair bound or bedridden unless aided.

Schwab & England Activities of Daily Living scale (100-0 %) and others.

Treatment options:

Please see our disclaimer section. This as with all treatment sections are provided for education.
Treatment is tailored to the disease stage and current symptoms. Consider whether treatment is indicated at this point in time.
General measures:

  • Physical therapy:
    • Conventional musculoskeletal therapy.
  • Speech therapy & Aids for daily living
  • Avoid high protein diet in patients with ‘off’ periods, as it may decrease levodopa absorption
  • Drugs to avoid & other options:
  • Avoid metoclopramide. Instead, use cyclizine or diphenidol or domperidone.

Tremor, consider:

  • Antimuscarinics, start with small doses, try other antimuscarinics if the 1st one fails:
  • Trihexyphenidyl (benzhexol) P.O. Benzatropine (benztropine) p.o Procyclidine P.O. Orphenadrine P.O.
  • Amantadine P.O. BID also for hypokinesia
  • Dopamine therapy

Bradykinesia, consider:

  • MAO-B inhibitor
  • Amantadine P.O.
  • Dopamine therapy

Dopamine therapy, General points:

  • No long term difference between dopamine agonist & levodopa. [PDRG-UK, Sydney multicenter study]
  • Initial therapy with ropinirole causes less dyskinesias than levodopa in the first 5 years.
  • Initial therapy with pramipexole causes less dyskinesias than levodopa.
  • Levodopa gives better UPDRS scores than pramipexole.
  • Levodopa decreases fatigue in nondepressed patients but fatigue still remains. [ELLDOPA]

Dopamine agonist:

  • Nonergot: Pramipexole, Ropinirole
  • Ergot:  Cabergoline, bromocriptine. Pergolide has been withdrawn due to valvular heart disease
  • Rotigotine transdermal patch. Reduces off time & decreases dyskinesia. For early or advanced disease [PREFER study]
  • Levodopa +carbidopa:
    • Sinemet CR ® or Sinemet ®. The dose of levodopa needs to be increased when switching from CR to sinemet.
    • Usual levodopa maintenance dose is 200-600 per day. Keep carbidopa dose <150 mg/day
    • Consider adding a COMT inhibitor: Entacapone is better than Tolcapone due to side effects
  • Apomorphine pump:
    • Use domperidone P.O. 3 days before and during treatment to prevent vomiting

For levodopa induced dyskinesia LID:

  • Depends on type of dyskinesia:
    • Dystonia, try the drugs below
    • Chorea, reduce dose of levodopa & add dopamine agonists
    • Amantadine P.O.
    • Trihexyphenidyl P.O.
    • Baclofen P.O.
    • Clonazpam P.O.
  • MAO-B inhibitors Consider as add on, also a reasonable first choice for mild symptoms:
    • Selegiline P.O.
    • or rasagiline P.O.
    • Other Drugs: Zonisamide P.O.

Consider Deep brain stimulation DBS:

  • Thalamus ventralis intermedius VIM for tremor & dyskinesia
  • Globus pallidus for tremor, rigidity, and bradykinesia.
  • Subthalamic nucleus STN for tremor, rigidity, and bradykinesia:
  • High frequency stimulation >100Hz for tremor, rigidity, and bradykinesia & to reduce dyskinesia. [prospective]
  • Low frequency 60 Hz/high voltage for gait disturbance.
  • Contraindicated in dementia & atypical Parkinsonism

Consider surgery:

  • Subthalamotomy for tremor or bradykinesia
  • Thalamotomy for tremor
  • Pallidotomy for hypokinesia
  • Globus pallidus internal segment Gpi, contralateral benefits
  • Contraindicated in dementia & diffuse vascular disease

Parkinson dementia:

  • General measures of dementia
  • Rivastigmine

Related articles:

References:

  • Emre, M., et al., Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med, 2004. 351(24): p. 2509-18.
  • Wakabayashi, K., [Parkinson’s disease: the distribution of Lewy bodies in the peripheral autonomic nervous system]. No To Shinkei, 1989. 41(10): p. 965-71.
  • Sandmann-Keil, D., et al., Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in Parkinson’s disease are detectable by an advanced silver-staining technique. Acta Neuropathol, 1999. 98(5): p. 461-4.
  • Hely, M.A., et al., Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord, 2005. 20(2): p. 190-9.
  • Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. Jama, 2000. 284(15): p. 1931-8.
  • Schifitto, G., et al., Fatigue in levodopa-naive subjects with Parkinson disease. Neurology, 2008. 71(7): p. 481-5.
  • Rascol, O., et al., A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med, 2000. 342(20): p. 1484-91.
  • LeWitt, P.A., K.E. Lyons, and R. Pahwa, Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology, 2007. 68(16): p. 1262-7.
  • Watts, R.L., et al., Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology, 2007. 68(4): p. 272-6.
  • Weaver, F.M., et al., Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama, 2009. 301(1): p. 63-73.
  • Krack, P., et al., Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med, 2003. 349(20): p. 1925-34.
  • Katzenschlager, R., et al., Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology, 2008. 71(7): p. 474-80.
  • den, H.J.W. and J. Bethlem, The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry, 1960. 23: p. 283-90.
  • Uchihara, T., et al., Silver stainings distinguish Lewy bodies and glial cytoplasmic inclusions: comparison between Gallyas-Braak and Campbell-Switzer methods. Acta Neuropathol, 2005. 110(3): p. 255-60