Parkinson's disease

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Parkinson's disease (PD) is a neurodegenerative disease. Described by James Parkinson in his essay on the shaking palsy in 1817. The disease was named after him by Jean-Martin Charcot, the French neurologist. It should be distinguished from Parkinsonism which can be caused by this as well as many other conditions that have a different prognosis and responses to treatment. The term Parkinson's Syndrome is used by some to cover conditions which do not clearly fit a diagnostic label by reason of features and which can be like PD a synucleinopathy.

Contents

Aetiology

An imbalance of neurotransmitter and neurone function associated with a loss of dopaminergic neurones in the substantia nigra and basal ganglia. Other types of neurons and wider parts of the nervous system are also affected. The underlying aetiology is unknown although the monogenetic forms are suggestive that several pathways contribute and in animal models the gut biome is permissive (in otherwords you do not get parkinsonism with a sterile gut in mice genetically predisposed to a synucleinopathy)[1]. Oxidative damage, viral infection, and environmental toxins have all been suggested. The negative association of parkinsonism with smoking [2] and positive one with pesticide exposure[3] which may be more important in late onset parkinsonism[4] are consistent with mitochondrial metabolism producing chronic neurotoxins but the likely large separation in time between initiating cause(s) and the complex polygenetics make this extremely difficult to unravel.[5] Indeed there are other associations such as the one with malignant melanoma that may well have a genetic basis but have distracted doctors into blaming therapy (levodopa).[6] The genetics are a factor in the age of onset, as has been confirmed with the mutations of the glucocerebrosidase encoding gene that increase the risk of the condition by over 5 times[7]. The well characterised monogenetic forms of familial Parkinsons's disease are extremely rare and usually present in patients aged in their early 30s or before.

Epidemiology

The world wide prevalence is increasing. The Netherlands, Italy and Israel may be bucking this trend recently but the burden represented by China has followed the usual industrialisation trajectory, countries such as Saudi Arabia and Iran have created exceptional trajectories and some claim a pandemic is in the making. [8] The condition was very rare (if not unknown as some might believe) before James Parkinson described it. The associations with certain environmental exposures are rather compelling given animal studies. H These include exposure to paraquat (only since the 1960s)[9] and the natural pesticide rotenone found in Yam bean, Pachyrhizus sp. (used for centuries to kill fish, only since 1848 more widely)[10]. Some of the protective factors such as smoking which are decreasing in most populations due to interventions actually increase the mortality and morbidity of Parkinson's disease in those that got the condition despite smoking.

Risk factors for Parkinsons Disease
Risk Factor Environmental Genetic[11]
Increased risk association Prior head injury
Pestcide exposure (Paraquat)
 Rural lifestyle or agricultural occupation (but see rotenone)
 Water supply from wells
β-blockers (in particular propanolol)
Rotenone from pulses
GBA
INPP5F
STK39
LRRK2 (found in 1% sporadic, also associated with autosomal dominant monogenetic parkinsonism)
SIPA1L2
BST1
RAB7L1/NUCKS1
VPS13C
DDRGK1
GPNMB
CCDC62
MIR4697
BCKDK/STX1B
Decreased risk association Smoking
Coffee
NSAIDs
Calcium channel blockers
Alcohol
Salbutamol
SNCA (codes for α-synuclein the protein in Lewy bodies, head injury risk factor is modulated by the size of the Rep1 repeat in the promotor region - also associated with autosomal dominant monogenetic parkinsonism)
MAPT
TMEM175/GAK/DGKQ
HLA/DQB1
MCCC1
ACMSD/TMEM163
GCH1
RIT2
FAM47E/SCARB2
FGF20
SREBF1/RAI1
CYP1A2 (modulates caffeine consumption risk)
GRIN2A (modulates caffeine consumption risk)
Type Environmental modulators Genetic[12]
Monogenetic autosomal dominant SNCA (missense mutations or dublication)
LRRK2 (found in 4% monogenetic parkinsons, missense mutations - usually Gly2019Ser)
VPS35 (encodes an endosome protein - missense mutation Asp620Asn)
EIF4G1 (missense mutations)
DNAJC13 (codes an endosome traffiking protein - missense mutation Asn855Ser)
CHCHD2 (missense mutations or splice-site alteration)
TMEM230 (encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking)[13]
Monogenetic autosomal recessive PARKIN (early onset monogenetic parkinsons - codes for mitochondrial protein involved in removing damaged mitochondria - exon rearrangements)
PINK1 (encodes for mitochondrial protein involved in removing damaged mitochondria -missense or nonsense mutations, sometimes exon deletion or dublication)
DJ-1 ( protein may protect mitochondria from oxidative stress - missense mutations, exon rearrangements or rarely splice-site alerations)
VPS13C causes an early onset parkinsonism dementia presentation[14]

Pathology

See Pathology of Parkinson's disease

Symptoms

  • Tremor
  • Difficulty with fine movements e.g. trouble doing buttons or deteriorating handwriting
  • Deteriorating mobility with or without shuffling gait
  • Muscle stiffness
  • Falls
  • Fatigue
  • Constipation
  • Lethargy
  • Aches
  • Reduced sense of smell or taste
  • Impotence
  • Depression - a major cause of morbidity in PD. Should be actively sought and treated
  • Dementia - typically late in disease. Early onset may suggest dementia with lewy bodies

Signs

Some use the acronym 'TRAP'

  • Tremor - pill rolling tremor, predominantly at rest 6-8Hz
    • Characteristically brought out by activity in the other limb and upper limb assymmetrical (in idiopathic parkinsons disease)
    • Does not involve the head
  • Rigidity - lead pipe or with tremor becomes cogwheel
  • Akinesia or bradykinesia
    • Must be present to make diagnosis according to Brain bank criteria. Further specialists look for fatigue in the bradykinesia as other conditions such as depression or cerebrovascular disease do not usually produce this
  • Postural Instability

These are the cardinal signs of parkinsonism with bradykinesia being the key sign and postural instability depreciated due to its presence in many other common conditions that never strictly manifest parkinsonism.

In the early stages of Parkinson's disease, the signs are typically asymmetrical and most commonly affect the upper body. Symmetrical and/or lower body Parkinsonism should raise the possibility of an alternate diagnosis.

Other signs

Diagnosis

Most specialists make the diagnosis by observation over time, which can be as short as a single consultation. Presently this luxury relative to other conditions exists as no licensed treatment is neuroprotective and there is no specific investigation for idiopathic parkinson's disease. This does not stop investigation, mainly to exclude other conditions.

Differential diagnosis

Investigations

These are done for the exclusion of the wide range of other conditions that can cause or mimic Parkinsonism. While certain types of PET and SPECT scans can give consistent information, they do not add to the clinical formulation in most patients, so are not usefully routinely. A DAT scan can be useful in certain tremor presentations, as the initial differential diagnosis of patients presenting with parkinsonian tremor alone can be narrowed earlier than would otherwise be the case.

A particular MRI imaging sequence is being currently studied as to technique and specificity and sensitivity that will allow use with standard moderate field clinical scanners[15]

Treatment

The Team

Patients widely perceive that a consistent and comprehensive approach appropriate to their current disease manifestations is most effective. In advanced disease they may be interacting routinely with several, or almost all of a general practitioner, district nurses, professional carers, Parkinson's disease nurse, speech therapist, physiotherapist, occupational therapist, geriatrician, pyschiatrist, neuropsychologist, neurologist and neurosurgeon. Increasingly in the UK such services are being networked with usually geriatricians and neurologists with a subspeciality interest providing best access to core support services like the Parkinson's disease nurse and dealing with the more complex patient.

The coordination of the team

This remains a challenge in a number of ways, including informatics, human relations and disruption due to resource allocation.

Education

This has been the subject of numerous studies. There is a wide range of educational material available and evidence for successful approaches, including support networks. Guidance on this range of material can be an important role for the clinical team, particularly as the available material or information previously known may not be relevant to the patient.

Diet

This is likely to have importance as for example the amino acid content will interact with drug absorption as will some dietary components[16]. Several dietary components could be factors in the aetiology of Parkinsons but for none is the evidence so strong as the protective effect of plant beverages that contain caffeine (ie tea and coffee) and in this case we know its not the caffeine component[17] that is beneficial[18]. There is increasing evidence that PD is associated with changed gut microbiome. As in other fields of medicine there is often preliminary evidence that a food supplement can improve outcomes, which when tested against diet intervention to achieve the same aim, rather than "usual" diet shows little or no effect of the food supplement. It is quite possible that increasing food intake ratios of known components in a health diet, such as mannitol[19] or curcumin[20] that work in animal models of the disease will influence favourably the course of the disease but this is not proven. Food supplements with preliminary evidence of effectiveness so intake should be maximised in a health diet include omega-3 fatty acids and vitamin E[21]

Drug therapy

LogoKeyPointsBox.png*Levodopa has been shown in comparative RCT to be drug of first choice for best outcome at 7 years (compared to dopamine agonists or MAOI type B inhibitors
  • Currently no licensed therapy has been proved to be neuroprotective
  • Up to 40 weeks after diagnosis of mild Parkinson's disease delay in starting levodopa therapy has no outcome implications at 80 weeks

Levodopa with a peripheral decarboxylase inhibitor is now the evidenced based first line therapy in all age groups who need treatment of motor symptoms and who do not have patient specific reasons for another drug class[22] Add-in therapy is a patient specific choice amongst COMT inhibitors, MAO B inhibitors and the non-ergoline dopamine antagonists.

  • L-Dopa The remarkable benefits of L-Dopa was accepted following a paper in the New England Journal of Medicine in 1967 although it had been convincingly demonstrated in 1961 by Birkmayer and Hornykiewicz (archive film exists). Significant benefits were seen on a group of patients with Parkinsonian features. With the addition of a peripheral decarboxylase inhibitor in the early 1970s the side effects and dose of drug could be increased and efficacy improved. The COMT inhibitors work by inhibiting catechol O-methyltransferase which increases levodopa availabilty by stopping its metabolism to 3 O-methyldopa.
    • Maximum benefit can take 2 to 20 weeks to develop and deterioration after withdrawal can take up to 10 days to start to manifest.
    • Its reported lack of benefit in say tremor has been biased by failure of objective observation over the 4 months it can take to work
    • Various modes of delivery are being explored to address the variable gastrointestinal absorption. Direct infusion into the duodenum works but is expensive in terms of health care resources.
  • Dopamine agonists These drugs have been introduced more recently. Since 2014 there has been a marked move amongst English specialists away from using this group of drugs either firstline for Parkinson's disease or as first line adjunctive therapy given alongside l-Dopa. Early use of these drugs alone in younger patients is associated with delay in the onset of motor complications, particularly dyskinesias and their advantages in ON times are mitigated by poorer long term tolerability. They provide less symptomatic relief than levodopa prepartions and tend to have poor clinical effectiveness or large incidence of adverse effects in conditions other than idiopathic Parkinson's disease. They include:
    • The Ergot alkaloids -whose use is increasingly being depreciated to third line with limits on total exposure due to risk of valvular heart disease. The long half life of carbergoline was a major advantage. Effectively they have no place in standard therapy now.
    • The non-ergoline dopamine antagonists- use as add-in therapy - these presently have an evidence base for use in early disease in young patients. In those over seventy this is not the case where use is best in later disease
    • Apomorphine - The last resort, and a very effective one in some it is too.
  • Anticholinergic agents The first effective drug treatment for Parkinson's disease. Rarely used nowadays especially in the elderly as they tend to cause profound confusion as the disease progresses and effectively dementia in long term use. May be more beneficial in tremor dominant disease.
  • COMT inhibitors
    • These tend to be the add on treatment of choice for motor fluctuations in the elderly due to their tolerability
    • Entacapone
    • Tolcapone - requires special monitoring for hepatotoxicity but more effective than entacapone
    • Opicapone - more effective than entacapone
  • MAO B inhibitors
    • These are tending to be the add on treatment of choice for motor fluctuations in younger patients. Used until recently first line in some health economies.
    • Selegiline
    • Rasagiline
    • Safinamide
  • Other
    • Amantadine This drug with a limited but distinct role has multiple neurotransmitter actions and with increasing knowledge of the properties of other neurotransmitter specific drugs yet to come on the market is perhaps best left unclassified. Used with tremor and dyskinesias
    • Sildenafil and similar drugs may be prescribed at NHS expense for men with Parkinson's disease. [23]

Non motor symptoms

  • Domperidone is often needed to treat nausea induced by dopamine agonist treatment. The population risk of QTc arrhythmias associated with this drug in Parkinson's disease patients has been studied and is a 22% non statistically significant relative risk increase mainly confined to those with cardiac disease with an absolute risk of 3.3 in every 1000 on the drug per annum[24].
  • Clonazepam is useful in REM sleep disorder
  • Botulinum toxin can be used to treat muscle spasm (more common in MSA ) and excess salivation. Use of anticholingerics in this latter indication is discouraged due to their side effects. Radiotherapy yo the salivary glands is another option.
  • Laxatives are often necessary with bulk forming stimulants being more useful
  • Hallucinosis and psychosis is a specialised area with most antipsychotics contraindicated and specific therapy expected to be available from 2017.

The future

The goal is to develop neuroprotective strategies or ways of regenerating or transplanting in neurons. A potential approach is to use drugs such as nilotinib or bosutinib at doses that allow neuronal recovery between doses but such therapy will be a trade off against the long term toxicity of the agent. The most likely important change in the near future is more effective therapies to treat neuropsychiatric symptoms without aggravating the Parkinsonism. To date transplantation strategies with say stem cells have modulated disease progression in some patients[25]. It is possible to induce astrocytes to transform into dopamine producing neurons using the transcription factors, NEUROD1, ASCL1 and LMX1A with modulation by microRNA but similar approaches would probably be needed with cholinergic interneurons for such techniques to address all functionality lost in Parkinsons disease[26].

Surgery

Has a place in selected patients. The proven techniques rely on neurostimulation and are:

Complex complications

There are many with some specific treatments including:

Tools exist for evaluating theses symptoms : see NMSQuest and NMSS

NICE Key Recommendations

In June 2006 NICE published guidelines for England and Wales. A revision is in consultation for 2017. This will recommend levodopa first line. The key recommendations which are edited for brevity were:

  • Referral to expert for accurate diagnosis
    • People with suspected PD should be referred quickly and untreated to a specialist with expertise in the differential diagnosis.
  • Diagnosis and expert review
    • The diagnosis of PD should be reviewed regularly and reconsidered if atypical features develop.
    • Acute challenge tests should not be used in the differential diagnosis of parkinsonian syndromes.
  • Regular access to specialist nursing care for:
    • Clinical monitoring and medication adjustment
    • A continuing point of contact for support, including home visits
    • Information about clinical and social matters of concern to patients and their carers,
  • Access to physiotherapy for:
    • Gait re-education, improvement of balance and flexibility
    • Enhancement of aerobic capacity
    • Improvement of movement initiation
    • Improvement of functional independence, including mobility and activities of daily living
    • Advice regarding safety in the home.
  • Access to occupational therapy for:
    • Maintenance of work and family roles, employment, home care and leisure activities
    • Improvement and maintenance of transfers and mobility
    • Improvement of personal self-care activities
    • Environmental issues to improve safety and motor function
    • Cognitive assessment and appropriate intervention.
  • Access to speech and language therapy for:
    • Improvement of vocal loudness and pitch range, including speech therapy programmes such as Lee Silverman Voice Treatment (LSVT)
    • Teaching strategies to optimise speech intelligibility
    • Ensuring effective means of communication throughout the course of the disease, including use of assistive technologies
    • Review and management to support the safety and efficiency of swallowing and to minimise the risk of aspiration.
  • Palliative care
    • Requirements for this should be considered throughout all phases of the disease.
    • Patients and their carers should be given the opportunity to discuss end-of-life issues with appropriate healthcare professionals.

Prognosis

Relatively good for a progressive neurodegenerative disease. It is interesting that during the first three years after diagnosis mortality appears to be less than that in the general population but by 20 years follow up matters are much more bleak. The death rate is 74% by then, three times that of the matched population, with only 4.5% of the original cohort escaping either death or dementia by then[27]. Prognosis is also highly dependent on age of presentation, which is suspected to reflect other pathologies that are commoner in old age. Aspiration pneumonia is the commonest cause of acute hospital admission and should be assumed to be the diagnosis for any pneumonia in a patient with Parkinson's disease. Apart from dementia very advanced Parkinson's disease is associated with:

See Also

Video http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/parkinsons2.html an excellent medium for demonstrating this condition. Birmingham University.

References

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