Parkinsonism, Parkinson’s Disease Mov10 Parkinsonism, Parkinson’s Disease



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Parkinsonism, Parkinson’s Disease

Last updated: April 4, 2016



Pathology 1

Macroscopy 1

Microscopy 1

Etiology 3

Pathophysiology 4

Parkinsonism 4



Epidemiology 5

Clinical Features 5

Motor Features 5

Non-Motor Features 6

Diagnosis 7

CSF 7


Imaging 7

Early diagnosis 7



Rating Scales 7

Unified Parkinson's Disease Rating Scale (UPDRS) 7

Movement Disorder Society a revision of UPDRS (MDS-UPDRS) 8

Hoehn & Yahr (H&Y) staging 8

“Step-second test” of gait 8

Classification, Differential Diagnosis 8

Treatment - Medical 8

Dopamine precursors 9

COMT inhibitors 10

Direct D receptor agonists 11

Dopamine release stimulators & re-uptake blockers & NMDA antagonists 12

MAO-B inhibitors 12

Antimuscarinics 12

Antihistamines with anticholinergic action 12

Other symptomatic treatment 12

Treatment - Surgery 12

Destructive Surgery 13

Constructive Surgery 13

Treatment – Lifestyle 13

Exercise 13



Treatment - Algorithm 13

Prognosis 14



Parkinson’s disease (PD) - idiopathic, slowly progressive, neurodegenerative disorder.

  • 4th most common neurodegenerative disease of elderly.

  • first reported by James Parkinson in 1817.

Pathology



In substantia nigra:

    1. Depigmentation & neuronal loss (→ gliosis)

      • occurs normally with aging, but is greatly accelerated in parkinsonism.

      • degenerating cells in SN normally synthesize dopamine.

      • 60-85% nigral neurons are lost prior to development of symptoms.




    1. Lewy bodies - pathologic hallmark of disease!!! - eosinophilic cytoplasmic inclusions in surviving neurons.

      • single or multiple, round to elongated; dense core surrounded by pale halo.

      • composed of neurofilament, tubulin, α-synuclein and ubiquitin.

      • also seen in Alzheimer's disease, Hallervorden-Spatz disease, ataxia-telangiectasia, rarely in patients without clinical neurological disease.




    1. Pale bodies - composed of neurofilament interspersed with vacuolar granules.

      • also present in basal ganglia, cortex, brain stem, spinal cord.

Degenerative process is highly localized at illness beginning - area first affected is pars compacta in ventrolateral SN.



Macroscopy

Left: pale substantia nigra in PD. Right: normally pigmented substantia nigra.

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinson gross.jpg

Source of picture: “WebPath - The Internet Pathology Laboratory for Medical Education” (by Edward C. Klatt, MD) >>


d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinson microscopy2.jpg
A. Normal substantia nigra.

B. Depigmented substantia nigra in PD.

C. Lewy bodies in substantia nigra neuron stain bright pink.

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinson morphology.jpg

Source of picture: Ramzi S. Cotran “Robbins Pathologic Basis of Disease”, 6th ed. (1999); W. B. Saunders Company; ISBN-13: 978-0721673356 >>


Microscopy

Left: normal number of normally pigmented neurons in substantia nigra.

Right: decreased neurons and pigment in PD.

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinson microscopy.jpg

Source of picture: “WebPath - The Internet Pathology Laboratory for Medical Education” (by Edward C. Klatt, MD) >>


Left: rounded pink cytoplasmic Lewy body (H & E stain).

Right: immunoperoxidase staining with antibody to ubiquitin (demonstrates Lewy bodies more readily).

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinson (lewy bodies).jpg

Source of picture: “WebPath - The Internet Pathology Laboratory for Medical Education” (by Edward C. Klatt, MD) >>


Surviving pigmented neuron in substantia nigra contains intracytoplasmic rounded eosinophilic inclusion (Lewy body, L):







In Parkinson's disease (PD), there is loss of pigmented neurons from the substantia nigra and remaining neurons may be very sparse (A). Lewy bodies can be observed in residual neurons (A, inset) and are highlighted, together with Lewy neuritis, using α-synuclein immunohistochemistry (B). Lewy bodies and Lewy neurites may be present in significant numbers in the neocortex (C, frontal cortex).

In multiple system atrophy (MSA), α-synuclein is primarily deposited in the form of glial cytoplasmic inclusions in oligodendrocytes (D, putamen) and may also form inclusions in neuronal cytoplasm and nuclei (arrow) (E, pontine nuclei). In progressive supranuclear palsy tau forms, aggregates in neurons and glia, giving rise to tufted astrocytes (F, caudate) and neurofibrillary tangles (G, pontine nuclei).

Characteristic feature of corticobasal degeneration (CBD) is the astrocytic plaque, formed from aggregated tau in the distal processes of astrocytes (H, parietal cortex). In CBD, tau also accumulates in neurons in the form of neurofibrillary tangles (H, inset a) and in oligodendrocytes as coiled bodies (H, inset b).

(A) Haematoxylin and eosin; (B–D) α-synuclein immunohistochemistry; (F–H) tau immunohistochemistry.

Source of picture: Dr Janice Holton, Queen Square Brain Bank for Neurological Disorders, London.



Etiology

Most actively studied hypothesis - selective oxidative stress.



  • source may be:

  1. exogenous toxin (e.g. such as MPTP, CO, manganese) – see p. Mov11 >>

Gianni Pezzoli, MD and Emanuele Cereda, MD, PhD “Exposure to pesticides or solvents and risk of Parkinson disease” - exposure to bug or weed killers and solvents increased risk of developing Parkinson's disease by 33-80%

  1. endogenous substance; e.g. metabolism of dopamine generates numerous toxic byproducts (incl. H2O2, superoxide anions, -OH radicals) → lipid peroxidation, membrane disruption.

      • dopamine auto-oxidation generates superoxide radicals; dopamine metabolized by monoamine oxidase generates H2O2.

      • superoxide dismutase catalyzes conversion of superoxide to H2O2, which is converted by glutathione peroxidase and catalase to water; however, H2O2 can also react with ferrous iron to form highly reactive -OH radicals.

  • supporting findings (in SN):

      1. markedly reduced glutathione peroxidase (normally is reduced with oxidative stress).

      2. increased elemental iron (facilitates formation of free radicals).

      3. decreased or normal concentration of ferritin (iron-chelating protein) – i.e. no compensatory increase to handle free iron.

      4. specific enzymatic activity defects in complex 1 of mitochondrial respiratory chain.

Actual precipitant (whether genetic, environmental, dietary, or multifactorial) remains to be determined.



No specific cause has been found!
Mutations in Parkin gene are associated with early-onset Parkinson's disease.

Pathophysiology

Norma see p. A103 >>

DA neurons inhibit and ACh neurons excite GABAergic output from striatum:
d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinsonism pathogenesis2.jpg


black arrowsexcitation;

speckled arrowsinhibition.
GPi = globus pallidus internal segment;

GPe = globus pallidus external segment;

STN = subthalamic nucleus;

SNr = pars reticularis of substantia nigra;

SNc = pars compacta of substantia nigra;

thal = thalamus.



d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\basal ganglia - connections.gif

  • striatum acts via 2 pathways:

direct pathway inhibits GPi / SNr;

indirect pathway stimulates GPi / SNr.

  • normally, dopaminergic input activates direct pathway neurons that express D1 receptors and inhibits indirect pathway neurons that express D2 receptorsnet effect is decreased stimulation of GPi / SNr.

Parkinsonism



dopaminergic underactivity (less than 20% of normal) at nigrostriatal projection* → relative muscarinic cholinergic overactivity (ACh > DA) in striatum → increased GABAergic output from striatum (to indirect pathway).

*fibers to putamen are most severely affected.



d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinsonism pathogenesis4.gif

SMA – supplementary motor area



d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinsonism pathogenesis3.gif





Due to nigrostriatal deficiency:

  • indirect D2–mediated pathway is activated → stimulation of GPi.

  • direct D1–mediated pathway is deactivated → loss of inhibition on GPi.

  • in addition, D2 receptors are compensatory increased (upregulated), whereas D1 receptors are reduced (downregulated).

  • net effect – hyperactivity of GPi → thalamic inhibition → less cortical activation → hypokinesia.

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\parkinsonism pathogenesis.jpg

PPN - pedunculopontine nuclei


Direct lesioning of subthalamic nucleus / GPi / thalamus can relieve hypokinesia


N.B. D2 receptors are more important in mediating parkinsonian symptoms!
In concert, there appears to be altered phasic responsiveness by GPi to proprioceptive stimuli - numbers of responding cells increase, and receptive field becomes less specific → loss of directional effects and responses from multiple joints (account for rigidity and for altered timing and coordination of volitional movements in hypokinesia).


  • other pigmented nuclei also degenerate:

locus ceruleus → norepinephrine↓

dorsal raphe → serotonin↓



Epidemiology

prevalence 107-187 per 100,000 population.

  • PD affects 1% of those ≥ 65 yr old.

  • at least 1/3 of elderly exhibit some parkinsonian evidence.

  • male : female ratio is 3 : 2.


Risk factors:

  1. family history of PD.

    • one autosomal dominant pedigree (in Italy) - gene locus in 4q21.23 (Ala53Thr substitution in α-synuclein gene).

    • one pedigree in Iowa – four copies (instead of normal two) of normal α-synuclein gene.

α-synuclein (synaptic protein of undetermined function) is component of Lewy bodies!

    • another autosomal recessive form (in Japan) - mutation of parkin (protein associated with ubiquitination) on chromosome 6.

Lewy bodies are rich in ubiquitin!

    • in general, familial cases are uncommon.

  1. insecticide / herbicide exposure, rural residency, well water exposure

  2. nut or seed eating 10 years prior to diagnosis.

  3. essential tremor (PD and ET coexist relatively frequently!)

Numerous controversial reports suggest that PD frequency is decreased with cigarette smoking.



Clinical Features

Mean age of clinical onset is 55 years, but range is very wide (20-80 years) and bell-shaped!

onset at < 20 years is juvenile parkinsonism (pathology different from PD)


  • onset is insidious.

  • young patients often present with tremor-predominant disease; elderly patients - with gait dysfunction and akinesia.

  • early in course, signs are usually asymmetrical (disease may be confined for one body side even for several years!) but eventually become bilateral and progressively worse.

vs. secondary parkinsonism or Parkinson-plus syndromes - almost always symmetric!

Motor Features

  • Parkinson's disease has both hypokinetic and hyperkinetic features (“paralysis agitans”, “shaking palsy”):




  1. Resting tremor - hyperkinetic feature see p. Mov1 >>

  • first symptom in 70% cases.

  • occurs in 80% patients with idiopathic PD.

  • rarely is seen in Parkinson-plus syndromes or secondary parkinsonism (except in drug-induced and MPTP-induced parkinsonism).

N.B. resting tremor helps distinguish idiopathic PD from other causes of parkinsonism!

  • most patients also have postural tremor (re-emergence of rest tremor or coexistent essential tremor).




  1. Rigidity - hyperkinetic feature see p. Mov3 >>

  • tendon reflexes are normal.




  1. Bradykinesia, akinesia see p. Mov1 >>

Term “hypokinetic syndrome” is synonymous with “parkinsonism”

N.B. hypokinesia is not caused by rigidity!



  1. slowing of activities of daily living.

  2. difficulty in turning in bed / rising from deep chair / getting out of automobiles.

  3. loss of gesturing, patient sits motionless.

  4. rapid alternating movements are performed slowly with decreasing amplitude (decrementing).

  5. masked facies (hypomimia) with rare blinking (staring expression).

d:\viktoro\neuroscience\mov. movement disorders, ataxias\00. pictures\types of face (bates-95) - parkinson disease.jpg

Source of picture: Barbara Bates “A Guide to Physical Examination”, 3rd ed. (1983); J.B. Lippincott Company; ISBN-13: 978-0397543991 >>




  1. speech abnormalities:

  • soft (hypophonia);

  • monotonous voice with lack of inflection (speech aprosody).

  • not clear enunciation (dysarthria), do not separate syllables clearly - running words together (tachyphemia).

  1. failure to swallow spontaneously → sialorrhea (drooling).

  • patients can swallow properly when asked to do so, but only constant reminders allow them to keep swallowing.

  • dysphagia in advanced disease → choking and aspiration.

  1. slow small handwriting (micrographia).

  2. freezings” (motor block) – sudden transient (maximum several seconds) inability to perform active movements.

  • most often affects legs when walking; see p. Mov7 >>

  • also can involve eyelid opening (apraxia of lid opening), speaking (palilalia), writing.




  • bradykinesia is commonly misinterpreted by patients as “weakness”.

  • fatigue is common complaint (related to bradykinesia or rigidity).

  • despite severe bradykinesia, patients may rise suddenly and move normally for short burst of motor activity (kinesia paradoxica).

  • patient eventually sits much of day and is inactive unless encouraged to exercise.



  1. Postural instability: pro-, latero-, retropulsion (tendency to fall when center of gravity is displaced) → festinating gait, fallings.

  • pathophysiology may be related to bradykinesia and not to unique postural response deficit.

  • specific parkinsonian gait with flexed posture see p. Mov7 >>

  • "pull test" - examiner stands behind patient and, with advance warning, tugs briskly on shoulders:

  • normal person can recover in one step.

  • patient takes several small steps backward (retropulsion), possibly falling into examiner's arms.

  • patient collapses into chair on attempting to sit down (sitting en bloc).



Tremor, rigidity, flexed posture are positive phenomena (s. release phenomena);

In general, positive phenomena are amenable to surgery!



Bradykinesia, loss of postural reflexes, freezing are negative phenomena.

In general, negative phenomena are more disabling!



Non-Motor Features

    1. Behavioral changes, depression (at least 1/3 patients; develops 2% per year) – due to degeneration of noradrenergic locus ceruleus.

  • patient slowly becomes more dependent, fearful, indecisive, passive.

  • most common delusion (in case of drug-induced psychosis in Parkinson's disease) is of spousal infidelity, problem that is often not shared with neurologist owing to embarrassment by both patient and spouse.




    1. Dementia (not as severe as in Alzheimer); due to degeneration of dopaminergic mesocortical & mesolimbic pathways.

  • frontal release signs are common, even early in disease! (e.g. sustained glabellar blink response - Myerson sign).

  • apathy; patient is slow in responding to questions (bradyphrenia) - correct answer can be obtained if patient is given enough time.

  • 75% of patients develop dementia after 8 years,3 possibly rising to 83% at 20 years

  • 15-20% patients develop profound dementia (concurrent Alzheimer disease or diffuse Lewy body disease*).

*it is not known whether spread of Lewy bodies into cortex is feature of Parkinson disease progression or distinct entity.

  • dementia limits tolerance of antiparkinsonian agents (because they increase confusion and produce psychosis; anti-dementia cholinergic treatment worsens parkinsonism!!!).




    1. Sleep disruption (fragmented sleep, frequent awakenings) - REM behavioral disorder.




    1. Akathisia, restless legs syndrome




    1. Sensory symptoms (≈ 50%) – pain (often misdiagnosed as arthritis / bursitis), burning, coldness, numbness, ↓sense of smell.




    1. Autonomic disturbances (due to dopamine depletion in hypothalamus) - seborrhea (particularly in face), constipation, neurogenic bladder (inadequate bladder emptying), erectile dysfunction, hypotension.




    1. 6-fold increased risk of skin melanoma.

Diagnosis



Parkinson’s disease = all four cardinal signs + brisk response to levodopa!!!

N.B. cases of presynaptic secondary parkinsonism (e.g. MPTP, postencephalitic) and many Parkinson-plus syndromes in early stages (e.g. multiple system atrophy) also respond to levodopa.


Diagnosis of definite parkinsonism - at least two of following features (with at least one being either tremor at rest or bradykinesia-hypokinesia):

      1. tremor at rest

      2. bradykinesia-hypokinesia

      3. rigidity

      4. flexed posture

      5. loss of postural reflexes

      6. freezing phenomenon.

There is no diagnostic test to confirm diagnosis!


CSF
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