SPECTRUM OF PARKINSON'S DISEASE, PARKINSON'S DEMENTIA, AND LEWY BODY DEMENTIA

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DEMENTIA

SPECTRUM OF PARKINSON’S DISEASE, PARKINSON’S DEMENTIA, AND LEWY BODY DEMENTIA Ian G. McKeith, MD, FRCPsych, and David Burn, MD, FRCP

Dementia occurs more commonly in Parkinson’s disease (PD) than in the agematched general population; estimates of prevalence are between 20% and 45%, depending on the precise definition of dementia that is adopted. Overall the risk of dementia in PD is almost twice that of elderly controls without dementia. PD is often associated with other neuropsychiatic features including hallucinations and delusions.2It has been suggested that two fundamentally distinct dementia syndromes (subcortical and cortical) can be distinguished, and a variety of underlying pathologic processes and neurochemical deficits have been implicated to explain these. More recently, a primary dementia syndrome has been described that shares several pathologic and clinical characteristicswith PD. Dementia with Lewy bodiesSo(DLB) accounts for 15% to 20% of all autopsy-confirmed dementias in old age, making it second only to Alzheimer’s disease (AD) in prevalence. The relationships between DLB and dementia in PD have not yet been fully resolved, but may usefully be considered in terms of neuropathologicsubstrate,clinical features, and response to treatment. NEUROPATHOLOGY Lewy Bodies and Parkinson’s Disease

Lewy bodies (LB) are spherical, intracytoplasmic, eosinophilic, neuronal inclusions that have a dense hyaline core and a halo of radiating filamentscomprised From the Department of Old Age Psychiatry, Institute for the Health of the Elderly, Wolfson Research Centre (IGM); and the Department of Neurology, Regional Neuroscience Centre (DB), Newcastle General Hospital, Newcastle upon Tyne, United Kingdom NEUROLOGIC CLINICS VOLUME 18 * NUMBER 4 * NOVEMBER 2000

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of abnormally truncated and phosphorylated, intermediate neurofilament proteins, which also contain ubiquitin, a-synuclein, and associated enzymes. While working in Alzheimer's laboratory in Munich between 1910 and 1912, the German neuropathologist Friedreich Lewy first described these bodies in the brain stem nuclei of PD patients.I7Neuropathologically, PD is defined by the presence of LB and nerve cell loss in the substantia nigra (SN),particularly the ventrolateral tier. In most cases, LB also are found in the dorsal motor nucleus of the vagus (DMNV), the nucleus basalis of Meynert (nbM), the locus coeruleus (LC), the raphe nuclei, the midbrain Edinger-Westphal nucleus, the olfactory bulb, and some autonomic ganglia, and to a lesser extent in the cerebral cortex. Besides the SN, cell loss is also seen in the DMNV, nbM, and LC. The loss of nigrostriatal dopaminergic projection neurones is largely responsible for the extrapyramidal movement disorder and also may be responsible for subtle cognitivechanges.One such cognitive change is impaired simultaneous task performances, which occurs through deafferentation of complex frontocaudatefeedback loops that interconnectthe striatum and the frontal Moreover, dementia in PD has been associated with neuronal loss in the medial SN. Neurones from this part of the nigra project mainly to the caudate nucleus. The clinical correlates of other pathologic lesions in PD remain largely unresolved; vegetative function, cognitive dysfunction, and depression are commonly cited as consequences of impaired cholinergic, noradrenergic, and serotonergic neurotransmission. Cholinergic depletion in nbM is much higher (>70%) in patients with PD and dementia than in PD patients without dementia who may show neuronal loss ranging from only slightly higher than aged controls to as much as 60% depletion. It is possible that degeneration of the ascending cholinergic system may precede the onset of mental changes. There may be a critical threshold of 65% to 80% neuronal loss within nbM with equivalent cortical cholinergic denervation before dementia becomes apparent in PD.31

Lewy Bodies and Dementia

Although Woodardfflcites HasslerZ5as being the first to mention cortical LB in association with dementia, the first case reports specifically describing such patients did not appear until 1961 when Okazaki and colleaguesa published two such cases, both elderly men who presented with cognitive decline and subsequently developed severe dementia. Over the next 20 years a few similar cases were but the acknowledgment of LB disease as a frequent cause of dementia came only in the late 1980s after improvements in pathologic staining methods. Cortical LB lack the characteristiccore and halo appearance of their brain stem counterparts, making them difficult to identify with traditional hematoxylin and eosin stains. The development of antiubiquitin immunostains, which directly attach to the ubiquitinated fraction of LB, made the visualization of cortical lesions far easier.38A meticulous search can usually find a few cortical LB in most PD cases, even those without dementia, so it appears that the precise distribution and density of cortical LB are critical in determining effects on clinical symptoms, rather than their presence per se. The DLB syndrome certainly can occur in the presence of limbic and paralimbic, but not neocortical, LB.= Whether additional neocortical involvement further modifies the clinical presentation has not yet been Consistent correlationsbetween severity of neuropsychiatric symptoms , ~ ~ , ~ 5 with and LB load have not emerged from clinicopathologics t u d i e ~ , 2 ~consistent the suggestion that LB are end-stage markers of a disease process that is taking place at a more fundamental

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Evidence for this theory has emerged from the use of antibodies for a-synuclein that prove even more sensitive and specific than ubiquitin for labeling purified LB,35,78and additionally reveal an extensive pattern of neuritic degeneration that had not previously been suspected. Lewy neurites (LN) are composed of abnormal filaments similar to those in LB; they are found in the CA2/3 region of the hippocampus in DLB and in patients with PD and dementia but generally not in PD patients without dementia.15The finding of mutations in the a-synuclein gene on chromosome 4 in a small number of autosomal dominant PD pedigrees and the localization of a-synuclein immunostaining at the core of LB and in LN suggest that this synaptic protein plays a key role in the pathogenesis of LB disorders.

Other Cortical Pathologies

Patients with PD and dementia and those with DLB frequently have extraneuronal PA4 amyloid deposits in the form of diffuse and neuritic senile plaques that are similar to those found in AD.23,30 Neurofibrillary tangles (NFT) also are found in excess of age-matched normal individuals in transentorhinalcortex. High NFT densities, sufficient to meet neuropathologic diagnostic criteria for AD, are seen in only a minority (10% to 20%)of patients with PD and dementia or DLB cases and are not significantly correlated with severity of cognitive impairment. LB counts in the midfrontal cortex are negatively correlated with mini mental state examination (MMSE) score." LB- and Alzheimer-type lesions may contributesynergistically to cerebral dysfunction in many cases, but severe cognitive failure can occur in DLB in the absence of any Alzheimer-type pathology.34Possession of an apolipoprotein ~4allele on chromosome 19 is known to be a risk factor for bringing forward the onset of sporadic AD, and it may similarly be a risk factor for developing dementia in PD5 and for DLB.60

Extracerebral Pathology

In addition to subcortical and cortical pathologies, ID ' and DLB patients also show a variable degree of LB in the autonomic nervous system. The presence of LB in the autonomic nervous system is associated with cardiovascular abnormalities on formal assessment, and these abnormalities lead to postural hypotension and syncope in some patients.37LB and LN were present in the cardiac plexi of seven of seven patients with PD, in sympathetic but not parasympatheticganglia, and were associated with significant orthostatic hypotensi~n.~~

Summary

The majority of cases with LB disease are found at autopsy to have involvement at multiple sites; Alzheimer-type pathology and additional minor vascular changes also are common, particularly in older subjects with dementia. Autopsy cases represent end-stage disease, and it is unclear how the distribution of pathologies seen then reflects the evolution of disease through earlier stages. A simple conceptual approach is to construct a spectrum of LB-related disorders as follows:

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Parkinson’s disease, an extrapyramidalmovement disorder associated with focal degeneration of subcortical neurones, particularly in SN. Parkinson’s disease with dementia, which progresses from motor PD as a result of limbic LB involvement, additional Alzheimer-type pathology, or both. Dementia with Lewy bodies, a dementing disorder with prominent neuropsychiatric features, associated with degeneration of cortical neurones, particularly in frontal, anterior cingulate, insular, and temporal regions. Primary autonomic failure with syncope and orthostatic hypotension, associated with degeneration of sympathetic neurones in spinal cord.

A significant number of cases will fall between these categories and indeed may move from one to another over time. CLINICAL FEATURES Dementia in Parkinson’s Disease The precise diagnosis of a dementia syndrome in PD is problematic, particularly in the early stages. Minor performance deficits in set-shifting, retrieval of learned material, and reduced verbal fluency are very frequent and usually do not warrant a diagnosis of dementia, because although demonstrable on neuropsychologic testing, they fail to impact substantiallyon the person’s day-to-day functioning. Furthermore, in newly diagnosed, untreated patients with PD, there is evidence of a dissociation between cognitive deficits and motor disability. These phenomena are probably a consequence of diminished ascending cholinergicand dopaminergic projections to neocortical regions. The term subcortical cognitive dementia is helpful in clinical practice to describe bradyphrenia (mental slowing), memory dysfunction, dilapidation of complex mental functions, and mood and personality changes.I4Cognitive screening tools that have been developed for the detection of AD and predominantly examine for impairment in orientation, impairment in new learning, dysphasia, and dyspraxia are poorly sensitive to these subtle subcortical deficits. These signs can be usefully demonstrated in up to two thirds of PD clinic attenders by an appropriate battery incorporating timed tests of frontal and executive function, such as verbal fluency for letters and categories or Trail making (A & B), and set-shifting tasks such as the Stroop test. Significant disorientation, impairment in new learning, dysphasia, and dyspraxia that develop in the course of PD are indicative of more generalized cortical LB disease or other degenerative pathology, most commonly of the Alzheimer’s type. Risk factors for developing dementia in PD include later age of onset, current age, severity of motor impairment, prior history of depression, and poor response to levodopa.+ILevodopa-induced confusion and poor performance on verbal fluency may best be characterized as early manifestations of dementia in patients with PD rather than as risk factors per se2; when they occur, they should alert the clinician to be particularly vigilant in observing for further cognitive decline. Other NeuropsychiatricFeatures in Parkinson’s Disease Neuropsychiatric symptoms other than cognitive impairment are common in PD, particularly depression, hallucinations, delusions, anxiety, and apathy* *Aarsland D, Cummings JL, Larsen JP: Neuropsychiatric differences between Parkinson’s disease with dementia and Alzheimer’s disease. Manuscript in preparation.

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(Fig. 1). Depression appears equally common in the presence or absence of dementia and may represent a psychological reaction to disability or result from degeneration of monoaminergic neurones, particularly dopaminergic projections to mesolimbic structures and the orbitofrontal The frequency of depression in PD is approximately 46%, higher than in other chronic diseases, and is unrelated to the severity of motor disability, suggesting a predominantly endogenous etiology. Psychotic symptoms are by contrast strongly associated with cognitive impai1ment.~,6~ Other clinical correlates of psychosis in PD are old age, advanced PD, a history of depression, and coexistent sleep disorder including altered dream phenomena and sleep fragmentati~n.~~ Visual hallucinations and illusions of people or animals are the most common feature. Although a prevalence of 25% is generally quoted, up to 44% of PD clinic attenders may admit to visual hallucinations if directly asked.21Hallucinations in other modalities (auditory, tactile, kinesthetic) can occur but are uncommon. The affective response to hallucinations varies from indifference, pleasure, or fear. As cognitive impairment increases and insight is lost, delusional interpretations of the patient’s experiences are more likely to occur and lead to increasingly severe behavioral disturbances.

Cognitive Dysfunction in Dementia with Lewy Bodies

Symptoms of prominent or persistent memory impairment are not always present early in the course of DLB but are likely to develop in most patients as the disease progresses. They have a predominantly subcortical type retrieval deficit similar to that seen in PD, in contrast to AD where the major deficit lies in memory acquisition and consolidation. For example, at the time of first presentation with symptoms of dementia, only 30% of 21 autopsy-confirmed DLB patients scored 0/5 on a test of short-term recall, compared with 93% of AD cases

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Figure 1. Neuropsychiatricinventory (NPI) scores in Parkinson’s disease leftsolidbar(n = 42), dementia with Lewy bodies open bar (n = 60), and Alzheimer’s disease right solid bar (n = 42).

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(p = 0.001).55Only 3% of the AD patients scored 3 or more points on this test whereas 33% of DLB patients did so (p = 0.0013). Patients with DLB without Alzheimer-type pathology in particular lack the very poor retention over delay intervals and increased propensity to produce intrusion errors in the cued recall condition, which is typical of AD patients.74This relative sparing of memory function in DLB compared with AD may be understood in terms of not only the reduced burden of pathology in the hippocampus and related structures (entorhinal cortex and parahippocampal gyrus) that are thought to underlie memory storage (consolidation),but also the proposed neuromodulatory effects of the septa1 dopaminergic deficit on cholinergic neurotransmission in the archicortex. Disproportionate visuospatial impairment and visuoconstructional dysfunction, as evidenced by tests such as block design, clock drawing, or figure copying,8O may be useful indicators of diagnosis and disease progression in DLB. Even when only mildly globally impaired, 80% of DLB patients perform at floor levels on the Wechseter Intelligence Scale for Children-revised(W1SC-R)block design test74and are more severely impaired than AD patients on the copy condition of the clock drawing test, producing errors related to the spatial layout of the clock.I8 Nigro-striatal-frontal degeneration is thought to be a major determinant of executive dysfunction in PD patients who demonstrate a decreased ability to form concepts, difficulty both in maintaining and changing sets, and deficitsin planning and execution. Commonly used clinical tests of executive function include the Wisconsin Card Sorting tests, the Trail Making test, and the Stroop test; to a lesser extent, the verbal fluency test investigates the ability to maintain a mental set and generate a search strategy. One would predict that DLB patients, with their combination of cortical and nigro-striatal pathology, should be substantiallyimpaired on such tests of executive function, but they have not yet been extensively studied.59 DLB patients are significantly more impaired than AD patients on various tests of attentional function including digit span= and computer-based measures of simple and choice reaction time and digit Variability in attentional performance within a 90 sec period of repeated administration of a choice reaction test is significantly greater in DLB than in AD, the coefficient of variance being correlated with ratings of cognitive fluctuation derived from psychiatric assessm e n t ~ Comparisons .~~ with patients with PD and dementia and those without dementia have not yet been reported. Fluctuation in cognitive performance is present in 58% of DLB cases at the time of presentation (range 8% to 85%)and is observed at some point during the course of the illness in 75% (45%to 90%).&It is an important diagnostic feature in the differential diagnosis from other forms of dementia, particularly AD. Some patients identify the variable cognitive state themselves, but generally the most productive approach is to interview a reliable informant. Questions such as "are there episodes when his or her thinking seems quite clear and then becomes muddled?'' may be useful probes7 Substantial changes in mental state and behavior may be seen within the duration of a single interview or between consecutive examinations. Fluctuation includes, and indeed may be based on, pronounced variations in attention and alertness. Excessive daytime drowsiness with transient confusion on waking commonly occurs. These episodes may last from a few seconds to several hours and often lead to diagnosis of a transient ischemic attack, with obvious implications for misdiagnosis of dementia It has been suggested that REM sleep behavior disorder (RBD) in which vivid dreaming occurs in the absence of muscle atonia is characteristic of DLB, representing yet another facet of dyscontrol of attention and consciousness."

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Other Neuropsychiatric Features in Dementia with Lewy Bodies

Neuropsychiatric features other than fluctuating cognitive impairment are common in DLB, and patients are therefore more likely to be seen in psychiatric, rather than movement disorder, clinics. The qualitative experience of psychotic symptoms and mood disorders is similar to that reported in PD. Visual hallucinations are present in 33% of DLB cases at the time of presentation (range 11%to 64%) and occur at some point during the course of the illness in 46% (13%to SO%).&Well-formed, detailed, and animate figures are experienced, provoking varying emotional responses from fear to amusement or indifference, usually with some insight into the unreality of the episode once it is over. It is the persistence of visual hallucinations in DLB58that helps to distinguish this disorder from the episodic perceptual disturbances that occur transiently in dementias of other etiologies or during a delirium provoked by an external cause. Delusions are common in DLB, found in 56% of patients at the time of presentation and in 65% at some point during the illness.",55 Delusions are usually based on recollections of hallucinations and perceptual disturbances and consequently often have a fixed, complex, and bizarre content that contrasts with the mundane and often poorly formed persecutory ideas encountered in AD patients that are based on forgetfulness and confabulation. Auditory hallucinations occur in 19%of patients (range 13%to 30%)at presentation and 19%(range 13%to 45%) at any point in the illness. Together with olfactory and tactile hallucinations, these may be important features in some DLB cases and can lead to initial diagnoses of late-onset psychosis and temporal lobe epilepsy.55 Depressive symptoms are reported in 33% to 50%of DLB cases, a rate higher than in AD and similar to PD. Depression was diagnosed at presentation in 38% of DLB cases compared with 16%of AD patients, and was the primary reason for referral in five of the eight DLB patients in whom it was present.55Depression was reported in 14 of 28 (50%)DLB patients, 8 of 58 (14%)AD patients, and 15 of 26 (58%)PD cases with autopsy diagnosis.33

Other Clinical Features of Dementia with Lewy Bodies

The proportion of DLB cases demonstrating parkinsonian signs, either at presentation or at some stage during the illness, is unknown. It is likely, however, that earlier series tended to under-report the frequency of extrapyramidalfeatures. Estimates of parkinsonian features at presentation range between 10%and 78%.& In a series of 31 pathologically confirmed cases of DLB, 24% of cases had extrapyramidal features at presentation.a Parkinsonism occurs at some point during the course of the illness in 77% (50%to 100%)of DLB patients. There have been no prospective, pathologically confirmed series to investigate whether the extrapyramidal profile of signs found in DLB differs from that found in PD. Rigidity and bradykinesia are found in DLB with approximately the same frequency as in PD. Hypophonic speech, masked facies, stooped posture, and festinant gait are commonly found in DLB patients. The occurrence of any one of four clinical features (myoclonus,absence of rest tremor, no response to levodopa, or no perceived need to treat with levodopa) was ten times more likely to occur in DLB than PD in one series.4OThe same authors, however, also reported a high rate of levodopa responsiveness in an earlier cohort of patients:' emphasizing the need for a randomized placebo-controlled trial of antiparkinsonian treatment in DLB.

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The relatively high frequency of early postural instability in DLB patients in comparison with PD is likely to reflect more extensive brain stem involvement, including the pedunculopontine nucleus, and may serve as a discriminator between the extrapyramidal presentations of DLB and PD. Syncopal attacks with complete loss of consciousness and muscle tone may represent the extension of LB-associated pathology to involve the brain stem and autonomicnervous system. The associated phenomenon of transient episodes of unresponsiveness without loss of muscle tone may represent one extreme of fluctuating attention and cognition. Episodes of this type were recorded in 15%of DLB cases at presentation and in 46%during the whole course of i l l n e ~ s . ~ , ~ ~ DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF DLB AND DEMENTIA IN PARKINSON’S DISEASE

Several sets of clinical diagnostic criteria and symptom checklists for DLB were proposed in the early 1990s, but these have now been superseded by International Consensus criteria.50In addition to the characteristic profile of cogrutive and attentional deficits, three core diagnostic features are described: fluctuating confusion, persistent visual hallucinations, and spontaneous parkinsonism, two of which are needed for a diagnosis of probable DLB and one for a diagnosis of possible DLB (Table 1). These criteria were designed to discriminate DLB from other dementia subtypes, and seven studies have now reported on either their sensitivity(proportion

Table 1. CONSENSUS CRITERIA FOR THE CLINICAL DIAGNOSISOF PROBABLE AND POSSIBLE DEMENTIA WITH LEWY BODIES 1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social or 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 frontalsubcortical skills and visuospatial ability may be especially prominent. 2. Two of the following core features are essential for a diagnosis of probable DLB, one is essential for possible DLB. (a) Fluctuating 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

(Depression and REM sleep behavior disorder have been suggested as additional supportive features).54

4. A diagnosis of DLB is less likely in the presence of (a) Stroke disease, evident as focal neurologic 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 From McKeith IG, Ballard CG, Perry RH, et a1 Prospective validation of consensus criteria for the diagnosis of dementia with L e y bodies. Neurology (in press); with permission.

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of cases positively identified) or specificity (proportion of negative cases correctly identified) against neuropathologic diagnosis* (Table 2). The majority find the criteria for probable DLB to have a diagnostic specificity >0.8, a figure comparable with the best clinical criteria for AD and PD. Reported sensitivity rates for probable DLB are, however, much more variable and generally lower. The Second International Workshop on DLB recommended that the Consensus criteria should continue to be used in their current format, but that improvements in the way they are applied are needed to ensure their wider applicability and to facilitate better clinical case identification." Reliable identification of fluctuating confusion, one of the key diagnostic features, appears to be the major source of diagnostic difficulty. Two studies prospectively applying diagnostic criteria suggested that sensitivities of 0.58 and 0.83 could be a ~ h i e v e d ,but ~ , ~the ~ third study reported a sensitivity of only 0.22.27This study included nine DLB autopsy cases, at least five of whom were clinically identifiable as having LB disease when preexisting diagnoses of PD were allowed, increasing the sensitivity to 0.55. This finding illustrates one of the main limitations of the DLB criteria, which is that they do not adequately address the distinction between patients presenting with neuropsychiatric features (who do meet DLB criteria) and those who develop fluctuating confusion and hallucinations in the context of a preexisting clinical diagnosis of PD. The Consensus recommendation was that the term "PD with dementia" be used to describe patients who have had "motor only" symptoms for at least 12 months before the onset of fluctuating cognition and hallucinations. This period was recognized as purely arbitrary and the extent to which the emergence of such symptoms in a PD patient reflects cortical LB pathology remains to be determined.50Early onset of hallucinations and absence of balance disorder at onset, occurring in patients clinically diagnosed as having PD, have both been reported as predictive of DLB at In making the differential diagnosis between PD and DLB, it is important to pay attention to the presence of symptoms and also to their chronology to secure an early and correct diagnosis. In summary, the current criteria for probable DLB can be applied with high specificity,53and can therefore be used in their current form for recruiting patients for research studies and clinical trials. Core diagnostic features are found at presentation or early in the course of illness in the majority of cases." When a diagnosis is made based on the criteria it is likely to be correct, with a positive predictive value in excess of 90%. The criteria are less useful for screening for cases in the clinic; the less stringent "possible DLB category may have a role here, but physicians must be aware that diagnostic specificityfalls dramatically. Further work still is needed to examine the role of ancillary investigations. There is very limited information about the role of specific markers in the diagnosis of DLB. Detailed psychometric testing and expert neurologic examination are likely to be informative and should be carried out whenever DLB is suspected. Prominent atrophy of the medial temporal lobes on CT or MR images is indicative of AD rather than DLB.l0Medial temporal lobe atrophy was present in 9 of 11 AD cases and absent in 6 of 9 of DLB cases,6*all with autopsy confirmation. Two of the DLB cases with severe medial temporal lobe atrophy had concurrent mild Alzheimer-type pathology (Braak stage IV) in the temporal lobes. Periventricular lesions and white matter hyperintensities were additionally present in DLB cases, occipital white matter hyperintensities being associated with an absence of visual hallucinations and delusions.I1

*References27,39,42,48,57,58, 64.

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DLB,AD

AD,VaD,DLB

AD,DLB

19

9

6

50

40

102

18

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Papka et a1 199W McShane et a1 199857 Mega et a1 199658

0.57 0.83

CBD, PSP, PD, DLB, MSA

AD, VaD, DLB

1.00

0.89

/

0.91

0.87

0.90

1.00

Neuropathologic Assessment

Additional Comments

Prospective stanConsensus DLB Mixed pathologies dardized assessmore difficult to ment, but diagnodiagnose ses made after death Retrospective Consensus criteria Poor inter-rater checklist using reliability for case records fluctuation Retrospective, case Not specified Poor inter-rater summaries reliability for fluctuation Prospective Consensus criteria Mixed DLB/VaD cases most difficult to diagnose Retrospective, case Consensus criteria / records Prospective Neocortical Lewy / bodies Retrospective, case 1 or more cortical Poor inter-rater records Lewy body reliability for fluctuation

Clinical Assessment

Data from McKeith IG, OBrien JT, Ballard C Diagnosing dementia with Lewy bodies. Lancet 3541227-1228,1999

29

14

0.65

105

AD, DLD,AD + DLB

Litvan et a1 199839

23

0.22

56

AD,VaD,DLB

Sensitivity Specificity

Luis et a1 1999"

2

Sample Mix

80

Number of Clinical DLB Cases

Holmes et a1 199927

Study

Number of Cases

Table 2. STUDIES EXAMINING THE SENSITIVITY AND SPECIFICITY OF CLINICAL CONSENSUS CRITERIA FOR DLB

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Functional brain imaging using either photon emission tomograph (PET) 18fluoro (lSF)deoxyglucose or single photon emissions computerized tomography (SPECT) 99-technetium hexamethyl propyleneamine oxine (99mTcm-HMPAO) has demonstrated minor group differencesbetween DLB and AD patients, but to date these techniques are of limited value in routine differential diagnosis. More extensive metabolic reductions in cerebral and cerebellar cortices have been reported compared with AD using IsFDG PET6 and predominantly unilateral perfusion deficits, with earlier involvement of frontal and occipital lobes using wmT~-HMPAO SPECT.” 1Z31-FP-CIT is a fluoroalkyl analog of cocaine that binds to the presynaptic dopamine transporter system, mapping the presynaptic dopaminergic terminals of the nigro-striatal pathway in vivo. The method was developed to assist the early diagnosis of PD and discriminate it from benign age-associated tremor. Preliminary data suggest that 231-FP-CITSPECT may be useful in separating DLB from AD, the latter disorder generally showing minimal nigro-striatal degeneration, particularly in the early stages.s1The electroencephalogram is diffusely abnormal in most, if not all, DLB patients. Early slowing of dominant rhythms is associated with focal delta transients in the temporal lobes in 50% of cases.I3Early reports of a frontally dominant burst pattern at the time of mild to moderate dementia diagnosis have not been replicated. No specific genetic markers for DLB have been identified, and genetic testing cannot presently be recommended as part of the routine diagnostic process. Because DLB patients have an elevated apolipoprotein ~4allele frequency similar to that reported for AD,60a positive ~4test does not provide additional information in the differential diagnosis of AD and DLB.5ZPD patients without dementia do not appear to have an increased ~4frequency. CLINICAL MANAGEMENT

DLB and PD dementia patients pose substantial challenges in clinical management. The natural history, briefly summarized, is that cognitive test scores decline in DLB by a mean of 10% per annum? similar to rates of decline in AD; Extrapyramital features (EPF) worsen at 10% per annum, similar to PD8;and neuropsychiatric features, particularly psychosis, persist in DLB from the earliest stages, unlike AD in which they are generally absent at presentation but increase with severity of cognitive impairment. The clinician is faced, therefore, with at least two shifting baselines and a limited range of pharmacologic interventions, all of which have the potential to improve one symptom domain at the expense of exacerbating another. Motor Features

A detailed account of the management of motor symptoms in PD is outside of the scope of this article. A limited levodopa response has been reported in DLB, with only 40% to 50% of patients improving signifi~antly.~~ This may in part reflect failure to treat, or to underdose, because of concerns about exacerbatingpsychosis. A randomized placebo-controlled trial of antiparkinsonian treatment in DLB is urgently needed. Neuropsychiatric Features

Managing psychosis is one of the most difficult challenges in the care of patients with I’D and DLB. It is a major source of distress to patients, exacerbates

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care burden, and is a major determinant of earlier transfer to institutionalcare and predicts an increased mortality. Anti-parkinsonian medications usually are held responsible for hallucinations and confusion in PD, but probably only act as exacerbating agents in patients already predisposed to these problems. Factors associated with the development of visual hallucinosis are later age of onset of PD, total duration of illness, and the presence of cognitive impairment. Patients with hallucinations and those without hallucinations are distinguished neither by severity of motor disability nor by dosage of anti-parkinsonian medication. The emergence of psychotic symptoms is not related to the dose, duration, or number of dopaminergic agents? and hallucinations do not relate to plasma levels of levodopa or sudden changes in plasma 1e~els.I~ Thus, dopaminergic agents may act as precipitants in PD patients with a high risk for psychosis, but do not cause psychosis per se.

Management of Psychosis

The first step in the management of psychosis and cognitive impairment is to determine their exact nature by interview with the patients and their caregivers and to record symptom severity using standard scales. Patients and caregivers should be asked which of these symptoms are sufficiently distressing or disabling to warrant treatment.24The first pharmacologic treatment strategy is generally to reduce antiparkinsonian medications (Fig. 2) but the dosage reduction is often limited by worsening of extrapyramidalmotor symptoms. A cautious trial of neuroleptic agents, which are the mainstay of antipsychotic treatment in other patient groups, may then be justified. Severe neuroleptic sensitivity reactions can precipitate irreversible parkinsonism, further impair consciousness level, and induce autonomic disturbances reminiscent of neuroleptic malignant syndrome in DLB. They occur in 40% to 50% of neuroleptic-treated patients and are associated with a 2- to 3-fold increased m0rtality.45,~ Close monitoring during dose titration is therefore a wise precaution in a patient previously diagnosed with DLB. Regular assessment of motor, cognitive, and neuropsychiatric state by experienced personnel will detect the earliest signs of neuroleptic sensitivity reactions, which should in turn prompt drug w i t h d r a ~ a lAcute . ~ ~ D, receptor blockade is thought to mediate these effects,”71 and despite some promising initial reports, atypical and novel antipsychoticagents such as ri~peridone~~ and olanzapineS2 seem to be about as likely to cause adverse reactions as older drugs. Sedation, increased confusion, and worsening of parkinsonism are the most common side effects. Clozapine, an atypical antipsychotic agent with low D, receptor occupancy and thought to act via 5 hydroxytryptomine (5HT,) and D3receptors, is emerging as a potentially useful antipsychotic agent in PD. Weekly monitoring of white cell counts for the first 6 mo of treatment is necessary with this drug to detect agranulocytosis, which occurs in 0.6% to 1.2% of patients. In a randomized, doubleblind study of 60 patients with PD and psychosis, clozapine treatment in a mean dose of approximately 25 mg daily (range 6.25 to 50 mg) was associated with a fall in Brief Psychiatric Rating Scale score of 9.3 + / - 0.3 points for those on active drug compared with 2.6 + / - 0.2 points for those on placebo (p < 0.001). Seven patients treated with clozapine had an improvement of at least 3 points on a Clinical Global Impression Scale compared with only one on placebo (p < 0.01). These improvements are greater than those reported in most trials of antipsychotic drugs in schizophrenia. Clozapine treatment improved tremor and had no dele-

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terious effects on the severity of parkinsonism.n Open-label data suggest that similar benefits may be obtained with o1anzapine.m Non-Neuroleptic Management Strategies

Ondansetron,a 5HT3 antagonist, has been suggested to be useful in managing psychosis in PD by reducing serotonergic inhibition of cholinergic activity.= Its high cost and, as yet, limited evidence of efficacy are likely to severely limit its use in routine practice. PD and DLB patients with prominent nocturnal hallucinations and behavioral disturbance may be experiencing REM sleep behavior disorder and respond to a small dose of clonazepam taken at bedtime. Recently, interest has turned to the potential use of cholinesterase inhibitors in DLB and PD. Clouding of consciousness, confusion, and visual hallucinations are recognized effects of anticholinergic drug toxicity, and the summative effects of subcortical and cortical cholinergic dysfunction probably play a major role in the spontaneous generation of similar fluctuating symptoms in both syndromes. Activity of the cholinergic enzyme choline acetyltransferase [ChAt] is lower in DLB than in AD, particularly in the temporal and parietal cortexffiand these reductions are ~ o r r e l a t e dboth ~ ~ , ~with severity of cognitive impairment and the presence of hallucinations. An early study using tacrine in severely impaired PD patients with dementia and psychosis found large improvementsin hallucinations and h4MSE scores in addition to very significant motor improvements.28Similar case reports in DLB have suggested that somnolence, hallucinations, and delirium improve substantially with cholinesterase inhibitor~.3~,~6 Eleven DLB patients, mean age 78.5 years, treated with rivastigmine in an open-label study over 12 weeks had reductions in delusions (73%),apathy (61%),agitation (52%),and hallucinations (31%).Six of the patients (55%)experienced very significant clinical improvement that had not previously been achieved with other treatments including low-dose neur~leptics.~~ Medication was well tolerated. A double-blind placebo-controlled study of rivastigmine has broadly confirmed these findings, also demonstrating significant improvements in cognition, particularly in attention.* SUMMARY

Parkinson’s disease has long been associated with LB pathology, but the recognition of dementia and other neuropsychiatric features as common, core manifestations of LB disease has occurred only relatively recently. Improved neuropathologic detection using antiubiquitin immunocytochemistrywas the initial key to revealing how common LB disease is. The neurobiologic basis of symptom formation in these disorders is likely to be revealed by correlative studies that quantdy a-synuclein pathology, for example, in the form of Lewy neurites, rather than by using simple counts of LB density or distribution. Why in old age LB disease preferentially affects paralimbic and neocortical structures leading to a dementing illness, whereas in middle life it is more typically ‘McKeith IG, Spans PF, Del-Ser T, et a1 Efficacy of rivastigmine in dementia with Lewy bodies: Results of a randomised placebo-controlledinternational study. Submitted for publication.

I

Repeat measures in all three domains to monitor for benefiaal or adverse responses

anticholinergics L-deprenyl amantadine direct dopamine agonists COMT inhibitors levodopa

Gradually reduce, and if possible stop, antiparkinsonian medications in the following order

features as part of the disease, to patient and caraver. Determine how they respond to symptoms and identify opportunities for non-pharmacologic interventions.

IExplain the occurrence of hallucinations. delusions and other neuropsychiatric . _

Establish the severity of cognitive impairment. neuropsychiatric features and motor parkinsonism by interview with patient and caregiver. Determinethe extent to which these impair quality of life and require active treatment Record pretreatment scores for each using appropriate rating scales.

RESPONSE

MONITOR

REDUCE ANTIPARKINSONIANS

EDUCATION

BASELINE ASSESSMENT

STOP IF NEUROLEPTlC SENSlTlVlTY 1s SUSPECTED

Figure 2. Management of neuropsychiatric features in Parkinson’s disease and dementia with Lewy bodies.

-

Other psychotropic medications may offer short term benefits e.g., chlormethiazole for night sedation. Benzcdiazepinesincrease amnesia, somnolence and postural instability although clonazepam may help REM sleep behaviordisorder. SSRls may improve mood disorders ALTERNATIVE and behavioral disturbances.The best (most effective and safest) approach to treatment MEDICATIONS of psychosiswill probably be cholinesterase inhibition but this cannot be widely advocated until double-blind RCT data are available.

Neurolepticsshould be discontinued If parkinsonism appears for the first time in a DLB patient, and the dose substantiallyreduced or stopped in any patientwhose preexisting parkinsonismworsens. Severe neuroleptic sensitivity reactionsshould be treated as a medical emergency similar to neuroleptic malignant syndrome.

If psychoticsymptoms persist despite withdrawal of antiparkinsonians to a point where further motor impairment becomes unacceptable, a cautious trial of an antipsychotic may be justified as long as the patient and caregiver understand the potential risks of severe adverse side effects. Since most neurolepticsensitivity reactions occur during the NEURoLEPTIC first two weeks of treatment, it may be wise to admit patientsinto the hospitalduring initiationTRlAL -VERY of neuroleptic therapy. New atypical antipsychotics with low 02 and M i receptor occupancy LOW DOSE AND should produce least side effects - none have yet been demonstrated to be safer in SLOW TITRATION practice. Since side effects are dose related, treatment should start with the lowest possible dose e.g., risperidone 0.25 mg daily. Approximately 50% of patients are expected to tolerate medication.

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associated with subcortical pathology and extrapyramidal motor symptoms, is unresolved. The etiology of these disorders remains unknown. Future clinical developments include a need to refine clinical diagnostic criteria for DLB and in particular to standardize methods of assessing fluctuations in cognition. Diary keeping and cognitive test-retest variation are likely to be the most productive measures. Clinical trials are urgently needed to establish optimal protocols for management of both movement disorder and psychiatric features. Although early results from cholinesteraseinhibitors are encouraging, they clearly do not work in all cases and additional strategies need to be found. Further research, basic and clinical, will be greatly facilitated by closer collaboration between specialists in neurology, geriatric psychiatry, and elderly medicine. Without this collaboration we shall remain like the six blind men and the elephant, and fail to appreciate the true breadth of the spectrum of LB disorders.

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Address reprint requests to Ian G. McKeith, MD, FRCPsych Department of Old Age Psychiatry Wolfson Research Centre Newcastle General Hospital Westgate Road Newcastle upon Tyne United Kingdom NE4 6BE e-mail: [email protected]