Parkinson's Disease

Diagnosis

Parkinson’s disease (PD) has an insidious onset and the earliest symptoms are often not identified by people with PD or their physicians. Individual physical findings are not specific to PD as there are many causes of Parkinsonism. The diagnosis of PD, therefore, is often reached by exclusion of other possible causes of presenting signs and symptoms, response to treatment and progression of the disorder.

In the very early symptomatic stages of PD, signs and symptoms are often quite subtle and asymmetry hardly apparent. At that stage, some other signs may be helpful in indicating possible PD. These include:

• digital impedance (ie a tendency for rapid alternating movements to block or to assume a tremor  rhythm)
• lack of arm swing when walking
• lack of the Babinski sign (ie extension of the great toe and abduction of the other toes instead of the normal flexion reflex to plantar stimulation).

As PD develops, it is clinically characterised by the insidious onset of unilateral symptoms slowly progressing over many years, with the eventual appearance of two or more of four cardinal signs of the disease:

• bradykinesia/akinesia
• 4–6Hz resting tremor
• rigidity
• postural instability (rare in early PD).

Clinical Criteria for Diagnosis
Several sets of clinical criteria have been proposed for the definition of PD, which often grade diagnostic confidence as ‘possible’, ‘probable’ or ‘definite’. Two of these criteria, the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria (UK PDSBB) (Litvan et al, 2003) and a set published by Gelb et al. and sponsored by the Advisory Council of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health (Gelb et al, 1999), are outlined in Table 1 and Table 2a, 2b and 2c. A third set of criteria that involve some specialised, technical assessments and that were developed specifically to bring greater consistency to patient selection in clinical trials (CAPIT/CAPSIT) are not presented here, but details can be found in Langston et al, 1992 and Defer et al, 1999.

Before death there is no PD-specific biological marker, with consequent misdiagnosis in many cases – particularly in early disease. Confirmation of PD is only possible at autopsy and false-positive and false-negative rates for the diagnosis of PD are often quite high, even among neurological specialists (Litvan et al, 1996; Rajput et al, 1991). Difficulties diagnosing PD arise partly from the variability and subtlety of symptoms in early disease; in particular the fact that the ‘cardinal symptoms’ may be absent and symptoms are shared with other movement disorders. An early study found that only 69–75% of people with autopsy-confirmed PD had at least two of the cardinal signs and 20–25% of people with two of these signs had a pathological diagnosis other than PD. Moreover, 13–19% of people who demonstrated all three of the cardinal features had a pathological diagnosis other than PD (Ward and Gibb, 1990).

Using the UK PDBB criteria, Hughes et al. reviewed 100 people with probable PD. Hughes and co-workers found that of the people who had symptoms consistent with PD, only 82% had a diagnosis of PD confirmed at autopsy. Upon further review, it was found that only 65% of patients with an autopsy had all three of the cardinal signs (Hughes et al, 1992).

However, in another review of the clinical and pathological features of 143 people with Parkinsonism, specialists achieved a positive predictive value of 98.6% for the clinical diagnosis of PD – demonstrating that diagnostic accuracy can be improved by stringent application of well-defined criteria (Hughes et al, 2002).

Litvan et al. used six raters to differentiate PD from Lewy body dementia and found the median sensitivity for the first visit diagnosis of PD (3 years after first symptoms) was 73.3%, rising to 80.0% at the last visit. Median specificity increased from 85.6% to 92.2% from the first to last visit. Among neurologists, the sensitivity for the diagnosis of PD at both visits was high (93.3%), but the specificity was lower. At both visits, false-negative diagnoses were uncommon. However, misdiagnoses by at least three of the six raters at the first visit were numerous (Litvan et al, 1998).

These investigators found that asymmetrical Parkinsonism (tremor or rigidity) and levodopa response (moderate to excellent response or levodopa-induced dyskinesias) were the most important discriminative features suggestive of PD. Other significant predictors were rest tremor and the absence of pyramidal or oculomotor signs.

Taken together, these findings illustrate the difficulty of differential diagnoses of Parkinsonism disorders using clinical criteria, whilst showing also that the precision of the clinical diagnosis can be improved to very respectable levels when rigorous criteria are carefully employed.

Clinical Investigations for Diagnosis
The high rate of misdiagnosis in PD reflects the fact that there is yet no reliable test for the disease. Various imaging techniques have been tried, including:

• MRI – magnetic resonance imaging
• PET – positron emission tomography
• SPECT – single photon emission computed tomography.

Both PET and SPECT are able to detect changes characteristic of PD even at the preclinical stage of the disease, but neither is yet sufficiently convenient or inexpensive to be used routinely. At present, PET and SPECT are most useful in clinical trials of new treatments. Neither PET nor SPECT can distinguish between causes of dopamine deficiency. Any lesion to the nigral system may cause reduced PET and SPECT signals and the tracer technique alone is insufficient for a diagnosis.

As a positive diagnosis will often prove impossible in the early stages of PD and other conditions that cause Parkinsonism, case reviews at regular intervals will be required. Over the longer term, a definite diagnosis should be possible in the majority of cases.

As an accurate diagnosis has fundamental implications for treatment selection, response, prognosis and quality of life, the effort, time and cost to establish a proper diagnosis are all warranted.

Parkinson's-Plus Disorder and the Differentiation of Parkinson's Disease from other Disorders

Differentiating PD from other disorders is problematical. This is mainly due to the difficulty in differentiating PD from other Parkinson’s-Plus disorders (PD-Plus) and from conditions that display specific features of PD.

The main PD-Plus disorders are listed in Table 3 and the most common of these, together with other conditions that complicate the diagnosis of PD, are discussed below.

Essential Tremor
The most common early sign of PD – in about three-quarters of cases – is a 4–6 Hz, unilateral resting tremor. However, the much more common essential tremor (incidence about 10 times that of PD) is often mistaken for the tremor of PD and may account for many mistaken diagnoses. The cardinal difference between essential tremor and the tremor of PD is that the former is associated with voluntary movements or postures and is absent at rest, whilst the tremor of PD is present at rest.
Other characteristics that may help to distinguish essential tremor from that of PD include:

• onset early in adult life when PD is rare
• bilateral onset
• head and voice tremor
• family history
• other features of PD are absent
• unresponsive to levodopa
• alcohol responsiveness
• beta-blocker or primidone/gabapentin responsive
• positional and kinetic tremor.

Binswanger's Disease
Binswanger's disease and other subcortical vascular diseases may lead to symptoms such as rigidity and slowness that resemble PD. However, these symptoms can be distinguished by corticospinal tract signs and features of a spastic bulbar palsy.

Normal-pressure Hydrocephalus
Normal-pressure hydrocephalus (NPH) may be associated with Parkinsonism, with gait and postural instability and with bradykinesia. NPH is clinical characterised by the triad of altered mentation, gait difficulties and sphincter disturbances, together with ventricular dilation and normal pressure of the cerebrospinal fluid at lumbar puncture.

Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a PD-Plus disorder with an incidence about 1/20th that of PD, which causes rigidity, a tendency to fall during early stages (in PD falls occur late), immobile features with a fixed gaze, and dystonic neck and shoulder positions. Some of these features are virtually indistinguishable from PD, hence its inclusion among the PD-Plus disorders. Exceptionally low blink rates have also been reported. Many cases of PSP can be distinguished from PD by the characteristic cardinal sign of early failure of the downward saccadic movement. PSP is correlated with tau pathology and the PSP disease process involves formation of plaques and neurofibrillary tangles .

Multiple System Atrophy
Multiple system atrophy (MSA) is another PD-Plus disorder and its incidence is similar to that of PSP. The pathology of MSA is characterised by oligodendroglial cytoplasmic inclusions and is similar to that of PD, with formation of alpha synuclein inclusion bodies in the central nervous system. However, unlike PD, no Lewy bodies are seen in the brains of people with MSA.

There are Two Variants of MSA:

• MSA-p (previously striato-nigral degeneration), which resembles PD but is later unresponsive to levodopa or dopamine agonists
• MSA-c (previously olivopontocerebellar atrophy), characterised by early and severe difficulty with balance.

As the majority of patients with MSA have some degree of autonomic dysfunction, the terms MSA-p (Parkinson) and MSA-c (Cerebellar) are currently used; historical terms are striato-nigral degeneration and olivopontocerebellar atrophy, respectively.

Parkinsonism, autonomic failure, cerebellar and pyramidal dysfunction in any combination characterise MSA. Clinical features that can help to differentiate MSA from PD include:

• presence of cerebellar, pyramidal or early dysautonomic signs
• symmetrical onset
• more rapid progression of disability
• lack of response to dopaminergic therapy (although 25% of people with MSA have excellent levodopa response for several years).

Dementia with Lewy Bodies
Whilst about 20–40% of people with PD develop a clinically significant dementia during the course of their disease, dementia with Lewy bodies (DLB) should not be apparent within the first year. For proper treatment and management, DLB must be ruled out before a diagnosis of PD is established. DLB is characterised by fluctuating cognitive functions, prominent visual hallucinations and Parkinsonism. DLB patients also exhibit increased sensitivity to neuroleptic treatment.

Drug-induced Parkinsonism
Many drugs can induce Parkinsonism that may be clinically indistinguishable from PD. Bradykinesia is usually the first, the most common and often the only symptom. Akinesia and rigidity can occur, as well as postural abnormalities and tremor – all of which may confound differentiation from PD.

Apart from a thorough clinical history and current therapy, some characteristics of drug-induced Parkinsonism may help in differentiating it from PD:

• onset is usually acute or subacute
• symptoms at onset are generally bilateral and symmetric
• anticholinergic effects may be prominent
• tremor, if present, is usually bilateral and symmetric, but can be asymmetrical and unilatera
• generally remits when the precipitating agent is withdrawn, but may be permanent in about 10% of people with drug-induced Parkinsonism.

Corticobasilar Ganglionic Degeneration
Corticobasilar ganglionic degeneration (CBD) is a rare PD-Plus disorder, accounting for less than 1% of Parkinsonism. Neuropathology and presentation of CBD resemble that of PSP, but in the early stages of CBD people tend to present with unilateral difficulties, whereas people with PSP present with bilateral difficulties. People with CBD experience prominent cortical sensory motor defects, sometimes manifested as an ‘alien limb’ phenomenon. Rigidity is often more problematic in CBD than in PSP and gaze may or may not be affected.

Secondary Parkinsonism

The diagnostic challenge of PD is far from trivial as some secondary Parkinsonism is clinically indistinguishable from PD. Some notable causes of secondary Parkinsonism are listed in Table 4.

A number of other degenerative disorders, shown in Table 5, may produce akinesia and/or rigidity during their natural course. Any details of these disorders lie outside the remit of this discussion.

Parkinson's Disease Rating Scale

The quantitative assessment of PD through imaging techniques remains outside routine clinical use and standardised qualitative assessments – rating scales – remain the optimum method for assessing and tracking the progress of people with PD.

The most widely used of these rating scales is the Unified Parkinson’s Disease Rating Scale (UPDRS) this consists of 42 items, each scored on a five-point scale (0–4). The scale allows relatively consistent assessment of a person’s mental status, activities of daily living, motor function and complications of therapy.

The UPDRS may be augmented, in particular with the ‘Second Step’ test to assess the level of disability. In addition, people with PD often suffer from comorbid disorders [Link to Comorbidity section of the Parkinson’s disease section] such as depression; the use of scales specific for these conditions will often be approproate during the management of PD.