The central feature of DLB is a progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function, whereas core clinical components comprise fluctuating cognition, recurrent and persistent visual hallucinations, and extrapyramidal signs (EPS). Supportive features may increase diagnostic sensitivity, though exclusion criteria also need to be considered (Table 1). Depression and REM sleep behavior disorder (RBD) have been suggested as additions to the list of supportive features (4).
From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
Consensus Criteria for Clinical Diagnosis of Probable and Possible DLB
1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social and occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent.
2. Two of the following core features are essential for a diagnosis of probable DLB and one is essential for possible DLB:
a. fluctuation of cognition with pronounced variations in attention and alertness b. recurrent visual hallucinations that are typically well formed and detailed c. spontaneous motor features of parkinsonism
3. Features supportive of the diagnosis are:
a. repeated falls b. syncope c. transient loss of consciousness d. neuroleptic sensitivity e. systematized delusions f. hallucinations in other modalities g. REM sleep behavior disorder (4)
h. depression (4)
4. A diagnosis of DLB is less likely in the presence of:
a. stroke disease, evident as focal neurological signs or on brain imaging b. evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture
Adapted from ref. 3.
A meta-analysis of 21 controlled comparisons has shown a clear and profound pattern of visual-perceptual and attentional-executive impairments in DLB (5). In terms of group differences, patients with DLB always do worse than age-matched controls on neuropsychological tasks, with particularly poor performance on visual perceptual and learning tasks, visual semantic tasks, and praxis tasks. Simple global measures of performance (e.g., the Mini Mental State Examination [MMSE]) are usually equivalent to those of patients with AD of comparable severity, highlighting the insensitivity of these tests to executive dysfunction. There are trends for better performance in DLB than AD patients on verbal memory and orientation tasks, for example, logical memory from the Wechsler Memory Scale. Patients with DLB lack the poor retention over delay intervals and increased propensity to produce intrusion errors in the cued recall condition, typical of AD. Performance on visual tasks, particularly praxis tasks, for example, Block Design from the Wechsler Adult Intelligence Scale, is consistently more impaired in DLB than in AD. A DLB patient will perform more poorly on simple bedside constructional tasks, for example copying a clock face, than an AD patient of comparable MMSE (6).
The neuropsychological changes with progression of DLB are not well characterized, though the clinical impression is that differences with AD are particularly pronounced in the early stages and, as the disease evolves, these lessen. Rate of progression, as evidenced by change in mental test scores, is equivalent to that seen in AD and vascular dementia (7).
Variation in cognitive performance is commonly observed in all the major late-onset dementias. It is frustrating to carers and has a major impact upon the patient's ability to reliably perform everyday activities. Fluctuating cognition (FC) may present in several ways, previously described as
"sundowning" or "intermittent delirium," depending upon the severity and diurnal pattern. FC occurs in 80% or more of DLB patients. The profile of attentional impairment and fluctuating attention in DLB is indistinguishable from that recorded in PDD (8).
The severity of FC can be judged by experienced clinicians and is highly correlated with variability in performance on computer-based attentional tasks. The variation can be detected over very short periods of time (on a second-to-second basis), suggesting that FC derives from dysfunction of continuously active arousal systems (9). Questions posed to the carer such as "are there times when his or her thinking seems quite clear and then becomes muddled" may be useful probes for this symptom. Substantial variability in attentiveness may also be observed throughout the consultation, or between one appointment and the next. The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale are validated instruments to record FC, correlating with both neuropsychological and electrophysiological measures of fluctuation (10).
A majority of DLB patients (80%) experience neuropsychiatric symptoms, particularly hallucinations, delusions, apathy, anxiety, and depression, at some stage of their illness (11). These symptoms may be quantified using the Neuropsychiatric Inventory (NPI), a 12-item interview with the caregiver rating frequency, severity, and associated carer distress of delusions, hallucinations, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and appetite disturbances (12). The NPI-4, comprising delusions, hallucinations, depression, and apathy, may represent a sufficiently sensitive abbreviated form of the NPI for practical use in the busy clinic setting for patient assessment (13).
Visual hallucinations (VHs) are a core feature in the Consensus Criteria for the clinical diagnosis of DLB. They are present in 33% of patients at the time of presentation (range 11-64%) and occur at some point in the course of the illness in 46% (13-80%) (14).
VHs are the most common form of hallucination in DLB, although tactile, olfactory, and auditory hallucinations may also occur. The VHs are complex in type, often containing detailed scenes featuring mute people and animals (15). Affective responses to the hallucinations vary from indifference, to amusement, or fear and combativeness. VHs and delusions often coexist, common delusions being phantom border delusions (i.e., the belief that strangers live in the home), or paranoid delusions of persecution, theft, and spousal infidelity. Delusions and hallucinations often trigger other behavioral problems, such as aggression and agitation, leading to profound caregiver distress and precipitating early nursing home admission.
VHs in DLB correlate strongly with Lewy body density in parahippocampal and inferior temporal lobe cortices (16). See also Chapter 11.
The frequency of parkinsonian features at presentation in DLB ranges between 10% and 78%, with 40-100% of DLB cases displaying EPS at some stage of the illness (17-19), with differences likely to represent ascertainment bias, use of neuroleptic agents, and variable definition of clinical phenomenology.
The Phenomenology of the Extrapyramidal Syndrome in DLB
Louis and coworkers compared EPS in 31 DLB and 34 PD pathologically confirmed cases (17). Clinical information was obtained prospectively in some patients. DLB patients presenting with parkinsonism were, on average, 10 yr younger than the DLB patients presenting with neuropsychiatric features (60.0 vs 70.9 yr). Of the DLB patients, 92% had at least one sign of parkinsonism, with 92% having either rigidity or bradykinesia. A tremor of any type or a specific rest tremor was recorded in 76% and 55%, respectively, of the DLB patients. This compared with 88% and 85%, respectively, of the PD group. Myoclonus was documented in 18.5% of the DLB patients but none of the PD group.
A trial of levodopa was used in 42% of the DLB group, with a clinical response recorded in 7 of the 10 patients (70%). The dose of levodopa required and the precise nature of the response were not stated. In attempting to differentiate DLB from PD on the basis of the Parkinsonian syndrome, the authors concluded that patients with DLB were 10 times more likely to have one of four clinical features (myoclonus, absence of rest tremor, no perceived need to treat with levodopa, and no response to levodopa). The positive predictive value for having DLB, given any one of these features was 85.7% (sensitivity 66.7%, specificity 85.7%).
Gnanalingham and colleagues reported a comparison of clinical features, including EPS, in 16 DLB, 15 PD, and 25 AD patients, diagnosed according to published clinical criteria (20). Nine of 16 DLB patients (56%) presented with EPS and 15 (94%) qualified for a "second diagnosis" of PD. A greater rigidity score, assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), and lower scores on a finger-tapping test were more frequently noted in the DLB patients compared with the PD group, whereas resting tremor and left/right asymmetry were less common. Twelve of 16 (75%) DLB patients had received levodopa at some stage of their disease, and 10 were taking anti-parkinsonian drugs at the time of the study. All cases were noted to have treatment "responsiveness," although the degree of motor improvement and the doses required were not stated.
An international, multicenter study reported parkinsonism in 92.4% of 120 DLB patients (19). There was a small but statistically significant difference between male and female patients on a five-item UPDRS subscale (the UPDRS-5), with male DLB patients more severely affected. This modified subscale comprising rest tremor, action tremor, bradykinesia, facial expression, and rigidity, is independent of the severity of cognitive impairment (21). Older DLB patients tended to have higher UPDRS scores, but the difference was not statistically significant. Cases with severe cognitive impairment (MMSE < 18) had significantly more severe EPS than those with less cognitive decline using the full UPDRS part III, but when this relationship was reexamined using the UPDRS-5 there was no difference between the groups. Patients with more severe dementia may thus have difficulty understanding and executing some of the instructions. It is thus likely that severity of parkinsonism is independent of cognitive decline.
Aarsland and colleagues compared EPS in 98 DLB and 130 PD patients (18). The DLB group was older at time of assessment and had a shorter duration of disease compared with the PD patients. Sixty-seven of the DLB patients (68%) had EPS. More severe action tremor, rigidity, bradykinesia, difficulty arising from a chair, greater facial impassivity, and gait disturbance were described in the DLB group.
The Spectrum of Parkinsonism in PD With and Without Dementia and DLB
Does the parkinsonian syndrome associated with DLB differ fundamentally from that seen in PD? This seems highly improbable, and though clinical series may describe higher or lower frequencies of certain EPS in DLB compared with PD, there are no absolute discriminating features. The pattern of EPS in DLB does, however, seem to show an axial bias (e.g., greater postural instability and facial impassivity), with a tendency toward less tremor, consistent with greater "non-dopaminergic" motor involvement. According to the classification proposed by Jankovic based upon the UPDRS II and III (22), the postural instability-gait difficulty (PIGD) phenotype of parkinsonism is overrepresented in DLB, as indeed it may be in PDD (23). EPS in PD, PDD, and DLB may thus be a spectrum, with a shift toward greater non-dopaminergic motor system involvement through PD to DLB. This is consistent with previous studies reporting motor features mediated by non-dopaminergic pathways (speech, posture, and balance) correlating with incident dementia in PD (24).
DLB patients with established parkinsonism have an annual increase in severity, assessed using the UPDRS, of 9%, a figure comparable with PD (25). In contrast, and again in common with PD, progression is more rapid in DLB patients with early parkinsonism (49% increase in motor UPDRS score in 1 yr).
Falls, Syncope, Sleep Disorders, and Other Neurological Features
A retrospective clinical analysis of pathologically confirmed cases of PD and DLB revealed that falls occurred at some point in the disease duration in 91% of 11 and 79% of 14 cases, respectively (26). The mean latency to onset of recurrent falls was, however, much shorter in the DLB group at 48 months, compared with 118 mo in the PD group. In a prospective study, multiple falls (defined as more than five falls) occurred in 37% of 30 DLB patients and only 6% of 35 AD patients (27). The falls often resulted in injury. Other than having DLB, multiple falls were associated with parkin-sonism, previous falls, greater impairment of activities of daily living, and older age.
Several pathophysiological mechanisms could underlie the falls in DLB, including degeneration of brainstem nuclei, for example, the pedunculopontine nucleus, and impaired visuospatial processing. Orthostatic hypotension, vasovagal syncope, and carotid sinus hypersensitivity, collectively referred to as neurovascular instability, are common in patients with neurodegenerative dementia, and also contribute to falls. Cardioinhibitory carotid sinus hypersensitivity occurs in over 40% of DLB patients, compared with 28% AD cases and may reflect monoaminergic neuronal loss within cardioregulatory brainstem centers (28).
A supranuclear gaze paresis has been described in DLB (29-31). In combination with cognitive impairment and falls, this may cause diagnostic confusion with Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy [PSP]). Other neurological features rarely described in DLB include an alien limb (32), chorea and dystonia (33).
Sleep disturbance is more common in DLB than in AD, as are daytime drowsiness and confusion on waking (34). RBD is characteristic of synucleinopathic disorders and frequently commences before the onset of dementia in DLB, sometimes by up to 20 yr (35). Over 90% of patients with RBD and degenerative dementia meet criteria for possible or probable DLB (36).
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