Parkinsonism is a disorder that can be characterised when a patient presents with the cardinal sign of bradykinesia and at least one of the following three other cardinal signs. 

According to the UK PDS Brain Bank, criteria for the diagnosis of Parkinson’s disease (PD) are: 

• Rest tremor
• Rigidity (cogwheel and/or leadpipe) 
• Postural disturbances.¹

Parkinsonism is a chronic, progressive disorder that affects a significant proportion of the population in various combinations of symptoms. 

It has been approximated that one in every 200 people have Parkinsonism provided they are more than 65 years² with its prevalence increasing as age increases. 

Parkinsonism-plus syndromes

The most well documented of these syndromes is PD which is generally used to define Parkinsonism that is idiopathic. 

However, there are a number of other disorders, the “atypical Parkinsonian disorders” or the so-called “Parkinsonism-plus” syndromes that have a worse prognosis when contrasted to the standard of comparison, PD.

A common indicator to alert the clinician to the diagnosis of a Parkinsonism-plus syndrome is if the patient presents with Parkinsonism characteristics but no resting tremor.³ However, up to 30% of patients with PD can present without tremor⁴ and thus tremor is not conclusive to Parkinsonism-plus syndromes. 

Along with the cardinal signs of Parkinsonism these syndromes also possess other signs of neurological dysfunction, primarily autonomic, cerebellar, oculomotor or cortical dysfunction. 

The Parkinson’s Disease Foundation claims that up to 15% of patients attending movement disorder clinics may have Parkinsonism-plus syndromes.⁵ 

However, this figure has been shown to vary with ethnicity as a south London movement disorder clinic’s study has shown that the percentage of atypical Parkinsonism in the black African and African/Caribbean population was 22% and in the south Asian population it was 20% when compared to 7% reported in the white population.⁶

Initially it is very difficult to distinguish between idiopathic and Parkinsonism-plus syndromes but there are a few indicators:

• Obvious akinesia and rigidity at onset in the absence of tremor⁷
• Rapid progression of Parkinsonian symptoms⁷ 
• Evidence of neurological signs suggestive of disease outside the basal ganglia⁷
• Normal or mild-to-moderate hyposmia in Parkinsonism patients while moderate-to-severe hyposmia or anosmia in PD patients.⁸

However, in many clinical cases the first indicator that reveals the possible presence of a Parkinsonism-plus syndrome is a poor response to levodopa administration. 

These cases are subsequently investigated further and most reveal a degeneration of striatal and pallidal neurons as well as nigral neurons which causes the Parkinsonism signs.⁷

Levodopa response

Owing to the fact that the neurons in the striatum are no longer responsive to dopaminergic output from the nigral system, dopaminergic therapy fails.⁷ As a result these patients have a much worse prognosis compared to idiopathic Parkinsonism due to dopaminergic therapy being the most beneficial treatment available to Parkinsonism patients. 

It has been estimated that around 5% of brainstem Lewy body Parkinsonian cases which have been confirmed with post-mortem examinations show no levodopa response during life and 20% have only a poor response.⁹

Therefore, since a poor therapeutic benefit from levodopa can also be seen in idiopathic Parkinsonism, a poor response to levodopa is not a definitive diagnostic tool for atypical Parkinsonism.

The body part most affected by Parkinsonism is also a crucial factor in determining the impact of levodopa treatment. 

Appendicular symptoms like micrographia and hand movement fluency respond better to treatment compared to axial symptoms such as dysphagia, dysarthria, postural instabilities and gait disorders.⁸ Therefore, patients exhibiting only appendicular symptoms have a better prognostic outcome.

It has been documented that the older the age at onset of symptoms the worse the prognosis for that patient.⁸

It has been identified that there is an increased rate of progression of the disease, there is more rigidity, bradykinesia and axial impairment along with an increased risk of comorbidities such as stroke and visual deficits¹⁰ with an older age of onset. 

For younger patients, diagnosed at less than 40 years, they show a delay in cognitive decline in comparison to older patients.⁸

Generally patients presenting with tremor at onset develop dementia less often and at a later stage compared to patients at onset presenting with rigidity/bradykinesia only. 

For patients presenting with tremor, their course of disease progression will follow a more benign route with a longer therapeutic benefit from levodopa therapy.⁸

A useful test for the clinician to carry out is the postural instability-gait difficulty (PIGD) score. A high PIGD score shows strong evidence for a more rapid progression of disability in Parkinsonism.¹¹

Therefore, the higher the score achieved the worse the prognosis for the patient involved. 

There can be surprisingly substantial exacerbations of Parkinsonism symptoms due to contraction of everyday intercurrent illnesses such as the common cold and flu. 

It is now recognised that these episodes of decline have a much longer period of duration compared to the acute intercurrent illness.⁷

Common poor prognostic syndromes: MSA, PSP and CBD

The main Parkinsonism-plus syndromes that present in the clinic are multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). 

Multiple system atrophy

MSA is noteworthy for the deterioration in prognosis for the patient compared to PD. 

When diagnosed with this syndrome the patient can expect to experience early autonomic dysfunction within two to five years, wheelchair dependence (3.5-5 years), be bedbound (five to eight years) and death (six to 10 years) after onset of symptoms.¹²

There is no effective modifying or neuroprotective treatment with a poor/unsustained response to levodopa treatment for MSA,¹² with reports that some patients can get worse when treated with levodopa.⁷

Common secondary conditions can arise which are detrimental to the quality of life of the patient such as depression and sleeping disorders. 

There is a worse prognosis for those with an older age at onset and an earlier development of autonomic dysfunction than is normally seen. 

Problems with urodynamics (urinary urgency, frequency, retention and impotence) are noticed in all patients at some point in disease progression.⁸

Also, orthostatic hypotension is a common and disabling constituent of the disease often occurring early in disease progression,⁹ leading to faints/falls and an increased risk of severe injury from trauma.  

In addition, being female and a short period of time to the first clinical milestone of disability such as frequent falls, cognitive impairment, severe dysphagia, severe speech problems, being wheelchair-bound and the need for a urinary catheter are also risk factors for shorter survival.¹²

Sudden death is not out of the ordinary as the central regulation of cardiorespiratory function is progressively lost.⁷

Progressive supranuclear palsy

PSP is a degenerative condition that impacts on vision and movement¹³ which usually has a symmetrical onset.¹⁴  It is the most common degenerative form of the Parkinsonism-plus syndromes with a prevalence reported of 6.4/100,000 in the UK.¹⁵

With this disorder there is a slowing of the vertical saccades of the eyes with a limitation of the saccadic range closely following. Also, a limitation of the lateral gaze develops although this is not as pronounced as the vertical gaze impairments.¹⁵

Instability of fixation of the eyes¹⁴ makes it extremely difficult to focus on objects. 

These features present as a supranuclear gaze palsy which consequently leads to postural instability and falls. 

There are particular obstacles to daily living associated with PSP such as walking over uneven ground or steps or curbs without falling. This becomes extremely difficult due to the impairment of the down-gaze of the eyes.⁷

Falls are also common due to the motor recklessness associated with PSP such as swift pivot turns carried out by patients which commonly result in falling over backwards¹⁵ and thus the possibility of banging the head on the ground. Problems with eating are also frequent as the patient cannot look down at the food on their plate.⁷

The average age of onset for PSP is 62 years¹⁵ which is slightly higher than for PD which is 60 years, but there is a much worse prognosis for PSP patients. 

From the onset there is usually a quite rapid disease progression which is relentless in its course of action. The quality of life for PSP patients is significantly reduced as the majority become dependent on care from others within three to four years.¹⁵

For the bulk of patients, the treatments available for Parkinsonism symptoms are not effective¹⁵ and therefore their symptoms get worse and worse as it is impossible to control them. Furthermore, patients can struggle to recognise sources of possible danger due to a deficiency in orienting responses. This presents as the inability to turn the head or body towards the source of attention⁷ which could possibly be a source of potential danger. There is also the added element of frontal lobe dysfunction involved¹⁵ with cognitive impairment (50% of cases)¹⁴ and personality changes common. 

The median survival of 8.0 years is significantly lower for PSP¹⁶ when compared to PD, which has a median survival of 10.3 years reported in one study.¹⁷

Corticobasal degeneration

CBD is another neurodegenerative condition that presents with Parkinsonism features but is a poor prognostic indication when compared to PD. 

Studies show that CBD typically presents in the sixth to eighth decades of life with a mean onset age of 61-63 years.¹⁸

Reports suggest that CBD often presents at first as a cognitive or behavioural disturbance¹⁸ with motor features presenting later in the disease course. 

Motor symptom progression usually conforms in apraxia and rigidity beginning in one limb which then spreads to the other ipsilateral limb and then on to the contralateral limbs, with this occurring over a few years’ duration.⁷  

There is a poor prognosis associated with CBD due to the presence of signs and symptoms of frontal and parietal cortical dysfunction as well as the usual basal ganglia signs of Parkinsonism such as rigidity, bradykinesia⁷ and also an atypical tremor that is often increased by active or passive movement of the affected limb.

Additionally it is common for oculomotor dysfunction to be involved, with supranuclear gaze disturbances most prevalent. 

Behavioural changes are often seen with compulsive behaviour, agitation, irritability and social withdrawal to the forefront with the development of secondary conditions like depression also a regular feature.¹⁸

Over 90% of CBD patients experience speech deficits¹⁸ with communication problems often contributing to some of the behavioural changes observed. 

Although uncommon, “alien hand syndrome” can develop and can be a problematic element for the patient as they have no control over their limb movements and often the limb can interfere with the movements of the opposite hand⁹ and/or can end up in an unusual position which can be uncomfortable for the patient. 

As with MSA and PSP there is no beneficial treatment that is either neuroprotective or provides substantial symptomatic relief.¹⁸ The course of the disease is unrelenting and results in the patient being akinetic and anarthric within five to eight years.⁷

CBD is not the usual cause of death but, due to complications from immobility and dysphagia, which are CBD features, the patient usually dies from conditions like pneumonia and sepsis.¹⁸ In a study the median survival time was found to be 7.9 years,¹⁹ which is significantly lower than for PD.

Other poor prognostic conditions

Other conditions that carry poor prognostics are dementia with Lewy bodies and frontotemporal dementia with Parkinsonism. 

Dementia with Lewy bodies consists of the typical Parkinsonism signs and symptoms but also early-onset dementia with possible hallucinations, delusions and psychosis without dopaminergic therapy.¹⁴ There is also only a partial response to levodopa with wide fluctuations in cognitive status associated with the condition.¹⁴

In frontotemporal dementia with Parkinsonism, the Parkinsonism signs are only present in 40% of cases but there are extreme behavioural changes along with personality and social conduct transformations resulting in increased problems for the patient, their families and their carers.

Summary

Overall there are a wide variety of poor prognostic indicators for Parkinsonism with the most significant of these being an older age at onset, a lack of tremor at onset, a poor response to levodopa, early falls and early autonomic dysfunction.

When any of the last four signs are present the physician should consider the possibility of a Parkinsonism-plus syndrome, with MSA, PSP and CBD being the most common of these conditions. 

These are associated with substantial comorbidities, a reduced quality of life and a significant reduction in survival time when compared to idiopathic Parkinsonism. 

Moreover since these plus syndromes do not gain the benefits of dopaminergic treatment that is so effective in the vast majority of PD cases there are increased symptoms, signs and suffering for the patient.  

References

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