Differential diagnosis

As mentioned above, diagnosis of dementia in patients with PD can be difficult because of several confounders, notably the presence of severe motor and speech impairment as well as co-morbid conditions such as depression, systemic disorders, and adverse drug events. The onset, the course, and the pattern of neuropsychological and behavioural symptoms and the presence or absence of systemic and laboratory findings are important factors in deciding whether the patient is suffering from dementia associated with PD or from conditions which can mimic dementia. Once these are excluded and a dementia syndrome is diagnosed, other disorders with combined motor and mental dysfunction should be excluded before diagnosing PD-D. As for PD-D, a Task Force of the MDS developed diagnostic criteria for mild cognitive impairment of PD (PD-MCI) [40]. These criteria are structured similarly to those for PD-D; applying both sets of criteria together would help to differentiate PD patients with cognitive impairment but no dementia from those with dementia. This may be particularly useful for research purposes as well as for treatment decisions.

The main prerequisite for the diagnosis of PD-D is that dementia develops in the background of established PD. Yet, this may not always be easy to ascertain, especially in those patients who develop dementia relatively soon after developing motor symptoms or when this temporal relationship cannot be determined. In such patients, other disorders that present with parkinsonism and dementia should be considered in the differential diagnosis, including other neurodegenerative diseases and symptomatic forms. Applying the Queen Square (UK) Brain Bank diagnostic criteria for PD as well as the diagnostic criteria for PD-D would easily exclude an alternative diagnosis in the majority of patients. There remains, however, a group of patients in whom a careful differential diagnosis becomes necessary. Other disorders which present with a combination of parkinsonism and cognitive dysfunction are listed in Table 20.6 and are briefly summarized below.

Table 20.4 Clinical features of dementia associated with Parkinson's disease (PD-D)

I. Core features

1. Diagnosis of PD according to Queen Square Brain Bank criteria

2. A dementia syndrome with insidious onset and slow progression, developing within the context of established PD and diagnosed by history, clinical, and mental examination, defined as:

• Impairment in more than one cognitive domain

• Representing a decline from pre-morbid level

• Deficits severe enough to impair daily life (social, occupational, or personal care), independent of the impairment ascribable to motor or autonomic symptoms

II. Associated clinical features

1. Cognitive features:

• Attention: impaired. Impairment in spontaneous and focused attention, poor performance in attentional tasks; performance may fluctuate during the day and from day to day

• Executive functions: impaired. Impairment in tasks requiring initiation, planning, concept formation, rule-finding, set-shifting or set maintenance; impaired mental speed (bradyphrenia)

• Visuospatial functions: impaired. Impairment in tasks requiring visual-spatial orientation, perception, or construction

• Memory: impaired. Impairment in free recall of recent events or in tasks requiring learning new material, memory usually improves with cueing, recognition is usually better than free recall

• Language: core functions largely preserved. Word-finding difficulties and impaired comprehension of complex sentences may be present

2. Behavioural features:

• Apathy: decreased spontaneity; loss of motivation, interest, and effortful behaviour

• Changes in personality and mood including depressive features and anxiety

• Hallucinations: mostly visual, usually complex, formed visions of people, animals or objects

• Delusions: usually paranoid, such as infidelity, or phantom boarder (unwelcome guests living in the home) delusions

• excessive daytime sleepiness

III. Features which do not exclude PD-D, but make the diagnosis uncertain

• Coexistence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of dementia, e.g. the presence of relevant vascular disease in imaging

• Time interval between the development of motor and cognitive symptoms not known

IV. Features suggesting other conditions or diseases as the cause of mental impairment, which, when present, make it impossible to reliably diagnose PD-D

• Cognitive and behavioural symptoms appearing solely in the context of other conditions such as: (1) acute confusion due to (a) systemic diseases or abnormalities or (b) drug intoxication; or (2) major depression according to DSM-Iv

• Features compatible with 'probable vascular dementia' criteria according to NINDS-AIREN (dementia in the context of cerebrovascular disease as indicated by focal signs in neurological examination such as hemiparesis, sensory deficits, and evidence of relevant cerebrovascular disease by brain imaging and a relationship between the two as indicated by the presence of one or more of the following: onset of dementia within 3 months after a recognized stroke, abrupt deterioration in cognitive functions, and fluctuating, stepwise progression of cognitive deficits)

Emre M, Aarsland D, Brown R, et al, Mov Disord, Clinical diagnostic criteria for dementia associated with Parkinson's disease, 22, 1689-1707 ©2007

Table 20.5 Diagnostic criteria for probable and possible PD-D

Probable PD-D

A. Core features: both must be present

B. Associated clinical features:

• Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains (impaired attention which may fluctuate, impaired executive functions, impairment in visuospatial functions, and impaired free recall memory which usually improves with cueing)

• The presence of at least one behavioural symptom (apathy, depressed or anxious mood, hallucinations, delusions, excessive daytime sleepiness) supports the diagnosis of 'probable' PD-D; however, lack of behavioural symptoms does not exclude the diagnosis

C. None of the group III features [Table 20.4] present

D. None of the group IV features [Table 20.4] present

Possible PD-D

A. Core features: both must be present

B. Associated clinical features:

• Atypical profile of cognitive impairment in one or more domains, such as prominent or receptive-type (fluent) aphasia, or pure storage-failure type amnesia (memory does not improve with cueing or in recognition tasks) with preserved attention

• Behavioural symptoms may or may not be present


C. One or more of the group III features present

D. None of the group IV features present

Emre M, Aarsland D, Brown R, et al, Mov Disord, Clinical diagnostic criteria for dementia associated with Parkinson's disease, 22, 1689-1707 ©2007

Table 20.6 Disorders which may present with parkinsonism and dementia

Degenerative disorders:

• Dementia with Lewy bodies

• Progressive supranuclear palsy

• Corticobasal ganglionic degeneration

• Frontotemporal dementia-parkinsonism complex

• (Multiple system atrophy)

Symptomatic forms:

• Cerebrovascular disease (subcortical vascular encephalopathy, lacunar state)

• Normal-pressure hydrocephalus

• Drug intoxications such as with neuroleptics, anticonvulsants

The main degenerative disorder which overlaps with PD-D is dementia with Lewy bodies (DLB). The clinical and pathological features of DLB and PD-D grossly overlap; clinically it is the time course of the symptoms and presenting features that differentiate these two disorders. The clinical and pathological overlap between these two conditions led to the suggestion that they represent two clinical entities on the spectrum of Lewy body-related dementias, with different temporal and spatial sequences of events [41, 42]. The original Consortium Criteria for DLB stipulated that mental dysfunction should precede motor symptoms by at least 1 year or that they should occur within 1 year of each other [43]. There is, however, no clinical or pathological basis to suggest a fixed time interval between the development of motor versus mental symptoms in differentiating PD-D from DLB. In fact, it is often difficult to determine retrospectively when cognitive or behavioural changes emerged in relation to motor symptoms. These aspects were acknowledged in the subsequent revision of the DLB criteria, and accordingly it was proposed that the ‘1-year rule’ between the onset of dementia and parkinsonism should be maintained in research studies in which distinction is made between DLB and PD-D [44]. In practice, however, it is suggested that a diagnosis of PD-D should be entertained when dementia develops following the diagnosis of idiopathic PD, whereas a diagnosis of DLB is warranted when the symptoms of dementia precede or coincide with the development of motor symptoms. The diagnostic difficulty mostly arises when the temporal relationship between the occurrence of motor versus mental dysfunction is unknown or uncertain. In cases where this temporal relationship cannot be determined, it may be easier to use a more generic term such as ‘Lewy body disease’.

Other degenerative disorders that can present with a combination of parkinsonism and mental dysfunction include progressive supranuclear palsy, corticobasal ganglionic degeneration, frontotemporal dementia-parkinsonism complex, and occasional cases of multiple system atrophy. Symptomatic forms of dementia associated with extrapyramidal features include cerebrovascular disease (in particular subcortical vascular encephalopathy and lacunar state), normal-pressure hydrocephalus, and drug intoxications, such as with neuroleptics or anticonvulsants, for example valproate.

A detailed history, including a review of current treatment, deliberate questioning for features known to be associated with PD-D, and use of appropriate neuropsychological tests, are the essential tools in differential diagnosis. Laboratory investigations and neuroimaging may reveal the presence of alternative aetiologies or may help to exclude them. The pattern of atrophy or the presence of vascular pathology in structural imaging, and the selective distribution of hypome- tabolism in functional imaging, may be helpful. FP-CIT SPECT may help to differentiate patients with PD-D from AD patients with extrapyramidal symptoms. Auxiliary investigations may be particularly helpful in the differential diagnosis of atypical or complex cases.

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