Two centuries of struggle to define “a tedious and most distressing malady”

It was in 1817 that James Parkinson first described the condition that carries his name, and we are still refining the diagnostic criteria. What did Parkinson himself say about the characteristics of the disease, and how has recent research modified our understanding?

In his celebrated early nineteenth century Essay, James Parkinson detailed what he took to be key features of the “shaking palsy”. Patients suffered from “involuntary tremulous motion” in parts of the body that were not in action, and the tremor was present even when the limbs were supported. Secondly, he noted, sufferers were likely to bend the trunk forward, and to be impelled to “pass from a walking to a running pace”. 

He also characterised the disease by what it was not: the senses and intellect were unimpaired. 

The condition was progressive, but the anatomical basis for it unproven (though Parkinson did have his own ideas, which are considered below). 

Fifty years later, the French neurologist Jean-Martin Charcot refined our understanding of typical Parkinson’s Disease (PD) as a condition of tremor at rest, rigidity, impassive facial expression, and unusual gait and posture.1 Charcot was the first to recognise the importance of Parkinson’s work and named the disease after him.

From early on, there has been an awareness that the neurological signs of PD are not entirely consistent. Interestingly, Parkinson himself did not include absence of facial expression and muscular rigidity in his account. Charcot emphasised bradykinesia, but noted that tremor was not always present in Parkinsonian patients.2

Recently, there has been increasing understanding that PD – especially in its early stages – is not just a movement disorder, and not just a disease of the brain. It is not even a disease defined entirely by dopamine. 

In the new diagnostic criteria, motor abnormalities remain core symptoms. But non-motor aspects of PD are also recognised as relevant, and perhaps even dominant in early stages

Interview LIC Final

Refining diagnostic criteria

Updated criteria for the diagnosis of PD -- developed by a twenty-strong Task Force of the Movement Disorder Society co-chaired by Daniela Berg and Ron Postuma -- were published in 2015.3,4  In a parallel publication, the Movement Disorder Society (MDS) has also produced the first ever research criteria for prodromal PD, including calculations showing the probability that an individual has the disorder.5 Prodromal PD will be considered in detail in another posting. 

The intent of the Task Force’s clinical criteria was to make the process of diagnosis more systematic, more reproducible across centres, and more applicable to clinicians less expert in the disease. The proposals were developed through brainstorming teleconferences and a face-to-face meeting, and then evaluated in patients by neurologists not involved in their development. The criteria now published are the result of this process. 

Motor abnormalities retain their central place. But non-motor aspects of the disease are also recognised as relevant, and perhaps even dominant -- particularly in the prodromal phase when early signs or symptoms of neurodegeneration are present but the classical signs are not. 

The MDS criteria, as with previous systems, involve two stages. The first defines Parkinsonism as bradykinesia in combination with either rest tremor or rigidity or both. The second stage aims to establish whether this Parkinsonism is due to PD rather than other conditions such as multiple system atrophy (MSA) or progressive supranuclear palsy (PSP). 

To facilitate this process, the guidelines describe three categories of factors. First are those which exclude PD. These include unequivocal cerebellar abnormalities, downward vertical supranuclear gaze palsy, Parkinsonian symptoms affecting only the lower limbs for more than three years, and normal functional imaging of the presynaptic dopaminergic system. 

Then come “red flag” features suggestive of alternative pathology. These must be counterbalanced by supportive criteria if PD is to be diagnosed. Red flags include impairment of gait requiring frequent wheelchair use within five years of onset, and the development of severe autonomic failure within the same period. 

Finally, there are positive features that increase confidence in the diagnosis of PD. One of these is a clear and dramatic response to dopaminergic therapy; another is evidence of olfactory loss or cardiac sympathetic denervation. 

Presentation

Two centuries of struggle to define “a tedious and most distressing malady”

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MDS clinical diagnostic criteria (2015) – clinically established Parkinson’s disease
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The Movement Disorder Society (MDS) clinical diagnostic criteria were created to standardise the diagnosis of PD, making it both accurate and reproducible.1 The MDS criteria provide expert guidance for clinicians, particularly those with less experience in the field of PD, by setting out clear and unambiguous clinical diagnostic criteria.1

The MDS method is similar to the UK Parkinson Society Brain Bank Clinical Criteria in that it first requires a diagnosis of parkinsonism, which can then be either supported or excluded by additional criteria.1 As with the UK Parkinson Society Brain Bank Clinical Criteria, there is a category of absolute exclusion criteria, such as an absence of a response to levodopa therapy, and sensory–cortical loss.1 There are also additional ‘red flag’ criteria which, if present, require counterbalancing by additional supportive evidence of PD.1

A diagnosis of clinically-established PD requires the absence of any absolute exclusion criteria, along with at least two supportive criteria, and no red flags.1

  1. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30 (12): 1591–1601. ​
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MDS clinical diagnostic criteria (2015)​ – clinically probable Parkinson’s disease​
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A diagnosis of ‘clinically-probable’ PD requires the absence of any absolute exclusion criteria along with sufficiently counter-balanced supportive criteria.1 Up to two ‘red flags’ are allowed, but should be offset by an equal number of supportive criteria.1

 

  1. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30 (12): 1591–1601. ​
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MDS research criteria for prodromal Parkinson’s disease (2015)​
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The Movement Disorder Society (MDS) research criteria for identification of prodromal PD were designed solely for research purposes since, for now at least, the lack of effective treatments that are able to halt the progression of prodromal PD makes their clinical use unwarranted.1 Ethical considerations may prevent the disclosure of a potentially distressing diagnosis in a non-clinical context, particularly if the research participant has not yet sought medical treatment for their symptoms, if present.1

When used correctly, the MDS criteria have at least 80% accuracy in diagnosing prodromal PD.1 A total score is calculated, which combines background risk, including environmental exposures and genetic traits, and the results of diagnostic markers, such as clinical symptoms (constipation, sleep disorder, impaired sense of smell, etc.) and biomarkers.1

 

  1. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord 2015; 30 (12): 1600–1611.​

Allowing for uncertainty

The new MDS system is also helpful in that it distinguishes between two levels of certainty in diagnosis: clinically established PD, and probable PD. This has the virtue of acknowledging  that, even in specialist centres, the initial diagnosis may need to be reconsidered on subsequent visits. For example, it is not uncommon for patients to be reclassified as having MSA. 

For a patient to have clinically established PD, there must be no absolute exclusion criteria, at least two supportive criteria, and no red flags. For clinically probable PD, the absence of absolute exclusion criteria is again mandatory; there must be no more than two red flags present – and, in the presence of one or two such features, each has to be counterbalanced by the presence of supportive criteria. 

Allowing for uncertainty recognises the significant implications for patients and carers of a definitive diagnosis of Parkinson’s Disease. And it may also aid research by allowing the search for causative factors -- including genetic variants – to be concentrated on people who clearly have the condition. 

An aspect of diagnosis that continues to prove challenging is the presence of dementia. The UK Parkinson’s Disease Society Brain Bank criteria of the late 1990s, which continue to be widely used, regarded dementia as an exclusion criterion -- despite the fact that the existence of PD dementia had moved into the clinical foreground. 

The new MDS criteria do not consider dementia as excluding PD, irrespective of the timing of its onset in relation to that of Parkinsonism. But the status of patients with a diagnosis of dementia with Lewy bodies (DLB) is likely to be a continuing source of controversy. 

Acknowledging diagnostic uncertainty helps both clinical practice and research

The MDS Task Force accepts that future developments may see the incorporation into their diagnostic guidelines of biomarkers in tissue, CSF and blood. And imaging techniques may also become sufficiently well validated to allow them a role in diagnosis. 

The Task Force was also concerned to make their criteria compatible with future developments in the expanding field of prodromal PD. 

Being confident in our ability to identify “pre-PD” would give us the chance to research novel, potentially disease-modifying treatments, offering the prospect of early intervention to slow or even prevent the development of classical PD. But that requires the development of genuinely neuroprotective agents. 

 

Disturbed sleep and constipation play a part

Both diagnostic and research criteria will need continuous updating as our understanding of PD and its antecedents evolves. Refinements in our diagnostic criteria offer the possibility of distinguishing between subtypes of the disease that would allow treatment to be tailored to the clinical circumstances of the individual patient.6, 7 

The patient is “irresistibly impelled to take much quicker and shorter steps, and thereby to adopt unwillingly a running pace”

Although commonly supposed to have been a physician, James Parkinson’s role in early nineteenth century London was that of surgeon apothecary. He was something like a general practitioner of today, but also compounded and sold drugs from the family shop. And of course he was an astute observer of all that attracted his clinical interest. 

Looking back to 1817, we see that Parkinson was perhaps prescient in several respects. First, he recognised that the chances of effectively relieving PD -- and perhaps even of cure -- depended on intervening “before the disease had been too long established”.

Secondly, he realised non-motor symptoms were involved. “Sleep,” he wrote, “Becomes much disturbed”. And the bowels, “which had been all along torpid, now, in most cases, demand stimulating medicines of very considerable power”. Although he could not explain how such a connection between brain and bowels might come about, Parkinson thought it possible that disorder of the gut could induce a “morbid action” and “derangement of structure” in the nervous system.8, 9  

Thirdly, he realised that achieving a cure would be more difficult than developing a way of slowing the advance of the disease. Parkinson foresaw that “some remedial process may ... be discovered by which at least the progress of the disease may be stopped”. 

As for when such a breakthrough might occur, he hoped that it would be “ere [before] long”. In fact, it would be almost 150 years before the introduction of dopamine replacement therapy, and that had of course to wait until we had solid post-mortem evidence for severe dopamine deficits in the substantia nigra.10

Parkinson had argued that anatomical examination was “the only sure foundation for pathological knowledge”. But, with little anatomical evidence, he was left largely with conjecture. 

He speculated that the “proximate cause of the disease is in the superior part of the medulla spinalis”. The great mobility of the cervical vertebrae might cause injury to the region, Parkinson hypothesised. This perhaps led to “slow inflammation”, which then spreads to the medulla oblongata as the disease progresses from one affecting only the arms to one involving functions such as speech and swallowing. 

But it was by application of reason – based on “the absence of any injury to the senses or intellect” -- that he concluded that “the morbid state does not extend to the encephalon”. With increased interest in the cognitive sequelae of PD, that is an idea we would now challenge. But we may judge James Parkinson to have done well with the clinical knowledge and conceptual framework then at his disposal.

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