Parkinson’s disease

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  • MPTP. Minute doses of a pyridine compound, methylphen- yltetrahydropyridine (MPTP), a byproduct of illicit stimulant drug production, cause severe parkinsonism.
  • Genetic factors.
  • Mutations in the parkin gene on chromosome 6 have been found in families with autosomal recessive cases of PD and some young apparently sporadic cases.
  • Parkin mutations probably account for most PD cases with onset below the age of 40.

 

  • Pathology
    • In idiopathic PD, the pars compacta of the substantia nigra undergoes progressive neuronal degeneration
    • eosinophilic inclusion bodies (Lewy bodies) develop.
    • These contain protein filaments of ubiquitin and a synuclein.
    • There is loss of dopamine (and melanin) in the striatum.
  • Symptoms and signs
    • The combination of tremor, rigidity and akinesia develops slowly, over months or several years, together with changes in posture.
    • Common initial symptoms are tremor and slowness.
    • Limbs and joints feel stiff; they ache.
    • Fine movements become difficult.
    • Slowness causes difficulty rising from a chair or getting into or out of bed. Writing becomes small (micrographia) and spidery, tending to tail off. impassive face.
    • Idiopathic PD is almost always initially more prominent on one side.
  • Tremor
    • The characteristic 4–7 Hz pill-rolling tremor at rest (movements between thumb and forefinger) typically decreases with action.
  • Rigidity
    • Stiffness develops throughout movements and is equal in opposing muscle groups, in contrast to the selective increase in limb tone found in spasticity.
    • This lead pipe-like increase in tone (plastic rigidity) is usually more marked on one side and present in the neck and axial muscles.
    • Plastic rigidity is more easily felt when a joint is moved slowly and gently; tone increases when the opposite arm moves actively.
    • When stiffness occurs with tremor, smooth lead pipe rigidity is broken up into a jerky resistance to passive movement – cogwheeling (cogging).
  • Akinesia
    • Poverty/slowing of movement (bradykinesia) is an additional handicap, distinct from rigidity.
    • There is difficulty initiating movement.
    • Rapid fine finger movements, such as piano- playing, become indistinct, slow and tremulous.
    • Facial immobility gives a mask-like semblance of depression.
    • Frequency of spontaneous blinking diminishes, producing a serpentine stare.
  • Postural and gait changes
    • Stooping is characteristic.
    • Gait becomes hurrying (festinant) and shuffling with poor arm swinging. The posture is some- times called simian to describe the ape-like forward flexion, immobility and lack of animation.
    • Balance deteriorates, but despite this the gait retains a narrow base.
    • Falls, toppling like a falling tree, are common in later stages.
  • Speech
    • Pronunciation is initially a monotone and progresses to tremulous slurring dysarthria, the result of akinesia, tremor and rigidity.
    • Eventually, speech may be lost (anarthria).
  • Cognitive changes
    • Cognitive decline may occur early in the condition and is rarely absent in advanced disease.
    • Depression is common.
  • Gastrointestinal and other symptoms
    • These include constipation, sometimes an early symptom, heartburn, dribbling, dysphagia and weight loss.
  • Urinary difficulties are common, especially in men.
    • Skin is greasy and sweating excessive.
  • Natural history and other features
    • PD worsens over the years
    • Remissions are unknown except for rare, remarkable short-lived periods of release.
    • These can occur at times of emotion, fear or excitement, when the sufferer is released for seconds or minutes and able to move quickly.
    • While bradykinesia and tremor worsen, power remains normal until immobility makes its assessment difficult.
    • Patients often complain bitterly of limb and joint discomfort.
    • There is no sensory loss.
    • The reflexes are brisk; their asymmetry follows the increase in tone.
    • The plantar responses remain flexor.
    • Usually the course is over 10–15 years, with death resulting from bronchopneumonia with immobility and cognitive impairment.
  • Diagnosis
    • Other diffuse and multifocal brain diseases can cause features of parkinsonism, i.e. slowing, rigidity and tremor seen in idiopathic PD. Examples are Alzheimer’s disease, multi-infarct dementia, sequelae of repeated head injury , and late effects of severe hypoxia or CO poisoning.
    • Slowing also occurs in hypothyroidism, and in depression.
  • Treatment
    • While drugs alter little, if at all, the natural history of PD,
    • levodopa and/or dopaminergic agonists produce striking initial improvement.
    • antimuscarinics, e.g. trihexyphenidyl (benzhexol) remain of some value in severe tremor.
    • Levodopa
      • Levodopa is combined with an aromatic amino acid decarboxylase inhibitor – benserazide or carbidopa
      • The decarboxylase inhibitor reduces peripheral side-effects, principally nausea, of levodopa and its metabolites.
      • Levodopa treatment is commenced and gradually increased.
    • Unwanted effects of levodopa therapy
      • Nausea and vomiting are the most common immediate symptoms of excess levodopa.
      • Confusion, formed visual pseudo-hallucinations and chorea also occur. There are difficult issues with long-term therapy (e.g. levodopa-induced involuntary movements).
      • After several years levodopa gradually becomes ineffective, even with increasing doses. As treatment continues, episodes of immobility develop (freezing). Falls are common.
      • Fluctuation in response to levodopa also emerges, its effect turning on and off, to cause freezing alternating with dopa-induced dyskinesias, chorea and dys- tonic movements.
      • Levodopa’s duration of action shrinks, with dyskinesias becoming prominent several hours after a dose (end-of-dose dyskinesia).
      • The patient begins to suffer from a chronic levodopa-induced movement disorder.
      • Levodopa does not alter the natural progression of PD.
    • Approaches to treatment of these complications include:
      • Shortening the interval between levodopa doses and increasing each dose.
      • Monoamine oxidase B inhibitors inhibit catabolism of dopamine in the brain. They are used to smooth out the end-of-dose fluctuations with levodopa.
      • Dopaminergic agonists are added, or replace levodopa.
      •  Catechol-O-methyl transferase (COMT) inhibitors (entacapone and tolcapone) prevent the peripheral breakdown of levodopa, allowing lower doses to be used.
      •  Apomorphine by subcutaneous pump.
      • Dopamine receptor agonists
      • Bromocriptine, pergolide, cabergoline (all ergot derivatives), pramipexole, ropinirole and rotigotine are oral, directly acting dopamine receptor agonists, acting principally on D1 and D2 receptors, and also on receptors D3–5.
      • Of these, ropinirole is the usual drug of choice, as an alternative or an addition to levodopa therapy.
      • The ergot derivatives are associated with pulmonary, retroperitoneal and pericardial fibrotic reactions and are little used.
      • Dopamine receptor agonists are in general less effective than levodopa in treating symptoms, but cause fewer late unwanted dyskinesias.
      • What is the drug of choice
        • The trend is towards the use of receptor agonists as primary treatment (before levodopa) in cases below 65, and levodopa initially for older cases.
        • Apomorphine, a potent D1 and D2 agonist, given by sub- cutaneous metered infusion, is one method of attempting to smooth out fluctuations in response to levodopa.
        • Vomiting is common.
        • Haemolytic anaemia is an unusual side-effect.
        • Antioxidant compounds such as vitamins C and E as possi- ble neuroprotective agents are sometimes suggested; their role is uncertain and evidence of benefit is poor.
        • Amantadine, originally marketed as an antiviral drug, occasionally has a modest effect in PD.
        • Rasagiline and rivastigmine may help cognitive changes and possibly the movement disorder.
        • Stereotactic neurosurgery
          • Stereotactic lesions, usually unilateral in the ventrolateral nucleus of the thalamus or in the globus pallidus (pallidotomy), were used widely before levodopa.
          • Surgery still provides effective, if temporary improvement in tremor and dyskinesia with minor relief of bradykinesia.
          • Thalamic stimulation is used increasingly, sometimes with dramatic improvement.
        • Neuropsychiatric aspects
          • Cognitive impairment and depression are common as PD progresses. SSRIs are the drugs of choice for depression.
          • Tricyclic antidepressants (e.g. amitriptyline) have extrapyra- midal side-effects.
          • Type A MAO inhibitors (e.g. phenelzine) are contraindicated with levodopa.
          • All antiparkinsonian drugs can provoke visual hallucinations, especially at night, and exacerbate cognitive impairment.
        • Parkinsonism-plus
          • This term describes disorders in which there is parkinsonism with additional features and specific pathology.
          • Progressive supranuclear palsy (Steele–Richardson–Olzewski syndrome) is the commonest.
                • It consists of parkinsonism, axial rigidity, falls, dementia and inability to move the eyes vertically or laterally.
          • multiple system atrophies (MSA), such as olivo-ponto-cerebellar degeneration
            • Pathologically MSA shows a-synuclein positive glial cytoplasmic inclusions
          •  striatonigral degeneration and primary autonomic failure (Shy– Drager syndrome).
        • Drug-induced parkinsonism
          • Phenothiazines and butyrophenones (also reserpine and methyldopa, once used to treat hypertension) induce parkinsonism, usually with little tremor.
          • Tricyclic antidepressants also cause some slowing.

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