Introduction

 Parkinson’s disease (PD), also known as primary or idiopathic parkinsonism, is a neurodegenerative condition of unknown aetiology. It is the chief cause of parkinsonism, a clinical syndrome characterised by extrapyramidal symptoms such as a resting tremor, muscular rigidity and bradykinesia. Parkinsonism is primarily a motor disorder; however non-motor symptoms, such as dementia and depression, can also feature.

 

Epidemiology

PD is diagnosed in 11-19 patients per 100,000 every year in Europe (1). It is estimated that 1-2% of people over the age of 65 years suffer from the condition (2). The causes of PD remain unknown; however it is associated with older age and non-smokers (3).  PD is rare in adults under the age of 50. It is more common in white Caucasians than Africans and Asians.  Genetic mutations are reported to be responsible for about 10% of PD (4).

Famous people with Parkinsonism

American boxer Mohammad Ali and back to the future star Michael J Fox are both diagnosed with PD (Ad

Pathophysiology

 Parkinsonian syndromes result from the depletion of the neurotransmitter dopamine in certain brain areas including the basal ganglia. The basal ganglia are a group of subcortical grey matter aggregates that have an important role in facilitating movements and posture. In PD, degeneration of dopaminergic neurons in the nigrostriatal pathways of the basal ganglia leads to dopamine depletion and a chemical imbalance with the neurotransmitter acetylcholine leading to the development of the motor signs and symptoms. Abnormal intracellular inclusions called Lewy-bodies may also accumulate in neurons. It is believed that these bodies are responsible for the development of dementia during the course of the disease. 

Histological appearance of the substantia nigra in parkinsonism (left) and an unaffected individual

Aetiology

 Primary parkinsonism

  • Idiopathic (90%)
  • Familial (10%)

 

Secondary parkinsonism

  • Drug-induced (E.g. dopamine antagonists such as metoclopramide, neuroleptics)
  • Intoxication (MPTP, carbon monoxide, lithium)
  • Vascular
  • Traumatic
  • Infections (CJD, subacute sclerosing panencephalitis)
  • Post-infectious (Encephalitis lethargica)
  • Neoplastic and paraneoplastic syndromes
  • Normal pressure hydrocephalus
  • Metabolic (Hypoxia, Wilson's disease)
  • Psychogenic

 

'Parkinson's plus' disorders

  • Multiple system atrophy
  • Progressive supranuclear palsy

 

Clinical presentation

Parkinsonian (extrapyramidal) signs and symptoms can be remembered using the mnemonic TRAP, where patients are trapped in their poorly mobile body. Symptoms typically start unilaterally before involving the contralateral part.

 

Tremor

  • A unilateral resting tremor (3-5Hz oscillation frequency) is the most common initial presentation of PD and may be seen in the hands or feet. In the hands it has a characteristic 'pill-rolling appearance'. In later stages of the disease it often becomes bilateral, though may remain amsymmetrical.

 

Rigidity

  • Rigidity describes the increased muscle tone (hypertonia) causing stiffness of limbs, neck and trunk. Rigidity can take 2 forms in PD;

 

  1. Lead-pipe rigidity describes the continuous increased muscle resistance felt on passive movements of joints
  2. Cogwheel rigidity describes the ratchet-like fluctuation of muscle resistance felt on passive movements of joints

 

  • Rigidity is different to spasticity, which is clasp-knife like hypertonia of muscles seen in upper motor neuron lesions. The clasp-knife phenomenon describes the rapid drop in resistance of a joint to passive movement after an initially high resistance (as if opening a clasp-knife) and is characteristic of pyramidal, not extrapyramidal deficit.
  • Rigidity of laryngeal muscles is thought to be responsible for the reduced volume of speech in patients with PD (hypophonia)

         

        Akinesia and bradykinesia

        • Akinesia describes the difficulty in the initiation of movement in PD, where patients show considerable delay when starting to walk or talk
        • Bradykinesia describe the reduced range and speed of movements. It is responsible for the following features;

         

        1. Reduced facial expressions (hypomimia) producing the classical masked faces
        2. Drooling, which occurs due to bradykinesia and rigidity affecting throat muscles rather than hypersalivation
        3. Problems in speech articulation (hypokinetic dysarthria)
        4. Small and spidery handwriting (micrographia)
        5. Gait disturbance including more frequent, shorter and shuffling steps (festinating gait), reduced arm swing, and slow-turning

                 

                Postural instability

                • Patients with PD often develop a flexed (stooped) posture
                • Falls are common

                 

                Typical signs of parkinsonism

                (adopted from http://www.healthybike.com/wp-content/uploads/2011/05/parkinsons.jpg)

                Diagnosis

                The diagnosis of PD is difficult due to the numerous causes of parkinsonism. It is diagnosed clinically as there is no biomarker or clinical test available to confirm the diagnosis.  NICE recommends using the diagnostic criteria developed by the UK Parkinson’s Disease Society Brain Bank Criteria (See Steps below). No imaging technology can give a definitive diagnosis, however NICE recommend the use of magnetic resonance imaging (MRI) for investigating the cause of parkinsonism, and single photon emission computed tomography (SPECT) to distinguish essential from parkinsonian tremor. A definite diagnosis of PD can only be made after brain autopsy.

                 

                STEP 1: Diagnosis of Parkinsonism

                Bradykinesia and at least one of the following:

                • Muscular rigidity

                • 4–6 Hz resting tremor

                • Postural instability not caused by primary visual, vestibular, cerebellar or Proprioceptive dysfunction

                 

                STEP 2: Features tending to exclude Parkinson’s disease as the cause of Parkinsonism

                • History of repeated strokes with stepwise progression of parkinsonian features

                • History of repeated head injury

                • History of definite encephalitis

                • Neuroleptic treatment at onset of symptoms

                • >1 affected relatives

                • Sustained remission

                • Strictly unilateral features after 3 years

                • Supranuclear gaze palsy

                • Cerebellar signs

                • Early severe autonomic involvement

                • Early severe dementia with disturbances of memory, language and praxis

                • Babinski's sign

                • Presence of a cerebral tumor or communicating hydrocephalus on CT scan

                • Negative response to large doses of levodopa (if malabsorption excluded)

                • MPTP exposure

                 

                STEP 3: Features that support a diagnosis of Parkinson’s disease (three or more required for diagnosis of definite Parkinson’s disease)

                • Unilateral onset

                • Tremor at rest present

                • Progressive disorder

                • Persistent asymmetry affecting the side of onset most

                • Excellent (70–100%) response to levodopa

                • Severe levodopa-induced chorea

                • Levodopa response for ≥5 years

                • Clinical course of ≥10 years 

                (Adapted from http://www.brainexplorer.org/tables/Table%201.pdf)

                 

                Differential diagnosis

                • Essential tremor 

                Classically, essential tremor is a postural tremor (in contrast with the resting tremor of parkinsonism). It often improves on alcohol consumption and responds well to the β-blocker propanolol. However occasionally it is difficult to differentiate from a parkinsonian tremor,  which is when SPECT scan can be helpful.

                 

                • Drug-induced parkinsonism

                A complete drug history should always be obtained from patients, asking specifically about antipsychotics and metoclopramide. The parkinsonian symptoms induced by medications are more symmetrical than those of primary parkinsonism.

                 

                • Wilson’s disease

                  Wilson's disease should be especially considered in young patients, and investigated by examining for kayser-fleischer rings, checking ceruloplasmin levels, and performing a liver biopsy.

                   

                  • Multiple-system atrophy (MSA) 

                  Characterized by cerebellar disturbance, preservation of cognitive function, poor response to L-dopa, and severe autonomic disturbance such as postural hypotension, urinary and rectal incontinence and impotence (5).

                   

                  • Progressive supranuclear palsy (PSP)

                  Earlier onset of falls, symmetrical bradykinesia, failure of downward saccadic vision, severe dysarthria, severe swallowing difficulties, and lack of response to L-dopa are features that favor the diagnosis of PSP rather than PD (6).

                   

                  • Lewy-body dementia

                  Lewy-body dementia is characterized by fluctuating cognitive function, visual hallucinations, parkinsonism, and severe sensitivity to antipsychotic medications

                   

                  Treatment

                  PHARMACOLOGICAL INTERVENTION

                  No cure is currently available for PD. Pharmacological therapy improves symptoms by correcting the neurochemical imbalance in the basal ganglia. Several therapy strategies are available; the choice of drugs should be based on the patient’s condition and preferences.

                   

                  First Line treatment for motor symptoms

                  • Levodopa (L-dopa)

                  L-dopa is a precursor of dopamine. It is a  commonly used drug in both early and late PD to replenish dopamine levels in the basal ganglia. Short term side effects of L-dopa include GI upset (treated with domperidone), agitation, insomnia, impulsive behavior, and poor BP control. L-dopa is commonly combined with carbidopa (Sinemet) or benserazide (Madopar, Prolopa). These are drugs that inhibit L-dopa conversion to dopamine outside the central nervous system by the enzyme dopa-decarboxylase, reducing peripheral side effects.

                  Long term pharmacological therapy with L-dopa is limited in several ways. Firstly, with time, symptoms become less responsive to the medications. Secondly, high concentrations of dopamine can lead to abnormal involuntary movements (dyskinesias) such as chorea and tics. Due to a narrowing of the therapeutic index with time, fluctuations in dopamine concentration produce ‘on-off’ phenomena, where high dopamine levels lead to dyskinesia (on), while low dopamine levels lead to bradykinesia and rigidity (off). This is also known as motor fluctuation. It is common practice to avoid early initiation of L-dopa therapy in order to delay the onset of these common complications.

                  • Dopamine agonists

                  Synthetic dopamine agonists such as ropinirole, pramiprexole, pergolide, and bromocriptine can be used instead of or alongside L-dopa to manage motor symptoms of PD. However, adverse effects including nausea, vomiting, dizziness, postural hypotension, insomnia, prepulmonary fibrosis (especially with pergolide), hallucinations and delusions may limit the use of these drugs. Apomorphine is a subcutaneously administered dopamine agonist that is used to manage motor fluctuations in late PD.

                  • Monoamine oxidase type B (MAO-B) inhibitors

                  Rasagiline and selegiline are examples of MAO-B inhibitors, a group of medications that inhibit the breakdown of dopamine, hence increasing its concentration. Their use has been validated for early PD.

                  • Catechol-O-methyl transferase (COMT) inhibitors

                  Drugs such as entacapone and tolcapone inhibit the metabolism of L-dopa. They are used in late PD to manage motor fluctuations by reducing L-dopa concentration variations. Combination preparations of L-dopa, carbidopa, and entacapone (Stalevo) are available.

                   

                  Other Medications

                  • Amantadine

                  Amantidine use in PD is a result of an accidental discovery, and is a weak dopamine antagonist. However, insufficient evidence is available regarding its efficacy and safety, therefore it is only used as second line for motor symptoms in early PD.

                  • Anticholinergics

                  Drugs such as trihexyphenidyl and benztropine restore neurochemical balance by antagonizing ACh. As with amantidine, anticholinergics are only recommended as second line therapy for motor symptoms. Their use is further limited by their side effects.  These include dry eyes, dry mouth, drowsiness, clumsiness, and psychiatric disturbance such as hallucinations, delusions, and confusion.

                  • Antidepressants

                  Depression is common in PD, and doctors should have a lower threshold for diagnosis mood disorders.

                  • Antipsychotics

                  Typical antipsychotics are contraindicated in PD as they worsen motor symptoms, however clozapine has been approved for use in PD. Agranulocytosis is a serious adverse effect of this drug, and so regular blood count monitoring is essential.

                   

                  SURGICAL INTERVENTION

                  Deep brain stimulation of the subthalamic nucleus or globus pallidus interna is used in patients with severe disease refractory to pharmacological therapy.

                  Pharmacology

                  (Adopted from http://epda.eu.com/medinfo/images/Levodopa.gif)

                  Deep brain stimulation

                  (Adopted from http://medical-trip.com/images-medical/dbs-web.gif)

                  References

                  (1) Von Campenhausen S, Bornschein B, Wick R, Botzel K, Sampaio C, Poewe W, Oertel W, Siebert U, Berger K, Dodel R. Prevalence and incidence of Parkinson's disease in Europe. Eur Neuropsychopharmacol. 2005;15(4):473–490.

                  (2) Fahn S. Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 2003;991:1–14

                  (3) Hernan MA, Zhang SM, Rueda-deCastro AM, Colditz GA, Speizer FE, Ascherio A. Cigarette smoking and the incidence of Parkinson’s disease in two prospective studies. Ann Neurol 2001; 50: 780–86.

                  (4) De Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006; 5: 525–35.

                  (5) Rehman HU. Multiple system atrophy. Postgrad Med J 2001;77:379-382

                  (6) Rehman HU. Progressive supranuclear palsy. Postgrad Med 2000;76:333–6.

                   

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