Dementia with Lewy Bodies
INTRODUCTION

This text has been compiled with the help of Dr. Graham Lennox

Dementia with Lewy bodies is a preferred term which describes several common disorders causing dementia. In many hospitals this is the second commonest cause of dementia after Alzheimer's disease. The name for the disease comes from the presence of abnormal lumps which develop inside nerve cells called Lewy bodies. Following increasing pathological recognition, core clinical diagnostic features have been identified to allow diagnosis in life.

These diseases have been given a variety of names by different workers.

  • Diffuse Lewy body Disease
  • Cortical Lewy body Disease
  • Lewy Body Dementia
  • Senile Dementia Of Lewy Type
  • Lewy Body Variant of Alzheimer's Disease

The main features of these conditions are
  • development of dementia with features overlapping with those of Alzheimer's disease
  • development of features of Parkinson's disease
  • fluctuation in severity of condition on a day-to-day basis
  • Early development of hallucinations


PATHOLOGICAL FEATURES

Several key areas of the brain undergo degeneration in this form of disease

  • There is degeneration of an area in the brain stem called the substantia nigra as would be seen in Parkinson's disease. Normally the substantia nigra is populated by nerve cells which contain a dark-brown pigment called neuromelanin.. The cells of the substantia nigra are responsible for making the neurotransmitter dopamine. In both Parkinson's disease and Lewy body dementia these cells die and so the substantia nigra appears abnormally pale in comparison to normal. Remaining nerve cells contain abnormal structures called Lewy bodies. which are a pathological hallmark of the disease process.
  • Degeneration of the cortical areas of the brain with many or all of the features seen in Alzheimer's disease
  • Degeneration of the cortical areas of the brain with formation of abnormal structures inside nerve cells called cortical Lewy bodies which can be detected by immunochemical staining for the protein ubiquitin.
The protein alpha synuclein is a major component of Lewy bodies.




When the brain from a patient with Lewy body dementia is examined at autopsy loss of nerve cells is seen from the midbrain region where the substantia nigra is located. Shrinkage of the brain is particularly seen in the temporal lobe, parietal lobe and the cingulate gyrus.


PATHOLOGICAL FEATURES ASSOCIATED WITH DLB
  • Essential for diagnosis of DLB
    • Lewy bodies
  • Associated but not essential
    • Lewy-related neurites
    • Plaques (all morphological types)
    • Neurofibrillary tangles
    • Regional neuronal loss - especially brain stem (substantia nigra and locus coeruleus) and nucleus basalis of Meynert
    • Microvacuolation (spongiform change) and synapse loss
    • Neurochemical abnormalities and neurotransmitter deficits

A recently published paper on pathological features of DLB is available. This is taken from a Symposium on Non-Alzheimer Dementias published in the Journal Brain Pathology, April 1998.

Dementia with Lewy Bodies. A Distinct Non-Alzheimer Dementia Syndrome?

Paul G. Ince1, 2, Elaine K. Perry1, Chris. M. Morris1

MRC Neurochemical Pathology Unit1, University of Newcastle upon Tyne, and Department of Neuropathology2, Newcastle General Hospital, Newcastle upon Tyne

This paper is published with the permission of the authors and the Editor of Brain Pathology and is Copyright to Brain Pathology 1998. It must not be reproduced or copied without the permission of the Editor of Brain Pathology.


CLINICAL FEATURES AND DIAGNOSIS OF DLB

The core feature of DLB is a progressive dementia.

  • Clinically, this condition can present as a dementia which is often initialy diagnosed as either Alzheimer's disease or vascular dementia.
  • Alternatively, many patients start with classical Parkinson's disease and later go on to develop dementia.
  • Only a minority of patients present with the simultaneous onset of both dementia and parkinsonism
A combination of key clinical features has allowed workers in many centres to diagnose this condition and distinguish it from other causes of dementia.

  • Most patients initially complain of impaired recent memory.

  • In other patients the main problem is behavioural disturbance with preserved memory.
  • Speech block, problems with word-finding, visuospatial difficulties (such as problems in following an unfamiliar route) may happen early in the disease.

  • Features, such as inattention, mental inflexibility, indecisiveness and lack of judgement, together with loss of insight, may also develop in the early stages of the disease and are useful in suggesting the possibility of a non-Alzheimer form of dementia.

  • An important feature which helps to distinguish DLB from Alzheimer's disease is the presence of striking fluctuations in cognitive performance during the early stages of the disease. By way of example, one day a patient may be able to hold a sustained conversation, the next they may be drowsy, inattentive and almost mute. Some patients have periods of frank stupor, which often causes clinicians to search (in vain) for an intercurrent diseases such as infection or stroke. The basis of these fluctuations is not clear.

  • Another very characteristic clinical feature is the presence of visual hallucinations. The hallucinations are typically complex and detailed. For example, patients may see images of people or animals that they recognise. Some patients see coloured patterns or shapes. Interestingly, the hallucinations are not always distressing to patients and many learn to distinguish between real and unreal images: some people actually come to enjoy them. In many patients visual hallucinations are accompanied by delusions which tend to have a persecutory theme.

  • A third characteristic clinical feature is the presence of clinical features of parkinson's disease. These develop spontaneously in most patients who have initially presented with dementia, and may be relatively mild. The typical features are
    • a flexed posture
    • a shuffling gait
    • reduced armswing
    • a tendency to falls.
    • a paucity of spontaneous movement
    • Tremor is the least common parkinsonian feature in patients who have presented with dementia.

  • Myoclonus, is common. It is usually mild, spontaneous and multifocal. Some patients have very prominent myoclonus early in disease, and this can raise concerns about the possibility of Creutzfeldt-Jakob disease (CJD).

  • Patients with DLB are often abnormally sensitive to neuroleptic therapy, developing parkinsonism even if they have not shown such signs before drug administration. The associated parkinsonism is often prolonged, profound and may even be fatal.

  • In almost all patients disease is relentless and progressive: the dementia becomes global and severe. Eventually patients become profoundly demented and immobile, and usually succumb to pneumonia or intercurrent illness after an average of 7 years from the onset of symptoms.

  • A small proportion of patients have a rapidly progressive illness, becoming profoundly demented within months and again raising diagnostic concerns regarding CJD.

  • A minority of patients start their disease with typical levodopa responsive Parkinson's disease and later go on to develop dementia.
    • This sequence of events is commoner in older patients and accounts for 30% of patients overall.
    • Typically cognitive decline starts with depression or mild forgetfulness.
    • Many patients then go on to develop visual hallucinations or delusions which appear to be related to their anti-parkinsonian therapy.
    • These problems often resolve once anticholinergic drugs or dopamine agonists are withdrawn, only to recur months or years later as the dementing process becomes more severe.
    • Depression can complicates clinical assessment and may make the cognitive impairment seem more severe than it really is.


CLINICAL DIAGNOSTIC CRITERIA

Clinical diagnostic criteria have recently been assembled at a recent Consortium meeting to produce a new set of criteria (McKeith et al, 1996).

  1. The central requirement 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 frontal-sub-cortical skills and visuospatial ability may be especially prominent.

  2. Two of the following are required for a probable, and one for a possible diagnosis of dementia with Lewy bodies:
    • Fluctuating cognition with pronounced variations in attention and alertness
    • Recurrent visual hallucinations which are typically well-formed and detailed
    • Spontaneous motor features of parkinsonism

  3. Features supportive of the diagnosis are:
    • Repeated falls
    • Syncope or transient loss of consciousness
    • Neuroleptic sensitivity
    • Systematised delusions
    • Hallucinations in other modalities

  4. A diagnosis of dementia with Lewy bodies is less likely in the presence of:
    • Stroke disease, evident as focal neurological signs or on brain imaging
    • Evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture


CLINICAL INVESTIGATIONS

There are no specific diagnostic tests for DLB.

  • Detailed psychometry may help confirm the clinical impression of the pattern of dementia
  • Routine blood tests are normal.
  • Structural brain imaging with CT or MRI may show generalised cerebral atrophy, sometimes with a discernible frontal predominance
  • Electroencephalography typically reveals generalised slowing of background activity; occasional patients with rapidly progressive dementia will show periodic complexes reminiscent of CJD.
  • Brain biopsy is not routinely justified in suspected cases of DLB.


DIAGNOSTIC PROBLEMS

In most patients the main diagnostic issue is to distinguish DLB from the commoner Alzheimer's disease (AD).

  • The presence of fluctuations, hallucinations and spontaneous parkinsonism all have value in suggesting a diagnosis of DLB
  • To a lesser extent, frequent falls and severe neuroleptic-induced parkinsonism also point to DLB rather than AD.
  • All of the above features can sometimes happen in patients with AD occurring either alone or in combination with brainstem Lewy body Parkinson's disease.

A more common diagnostic error is to attribute the clinical features of DLB to cerebral vascular disease such as multi-infarct dementia or Binswanger's disease.

  • CT or MR imaging frequently reveal mild and essentially incidental vascular disease which can lure the clinical towards a diagnosis of multi-infarct dementia.
  • CT or MR imaging often show diffuse subcortical white matter changes in degenerative diseases such as DLB, and these can be so striking as to lead to a radiological diagnosis of Binswanger's disease.


MANAGEMENT AND THERAPY

There is no specific therapy that can stop the process of neurodegeneration in this form of dementia.

Therapy is limited to managing neuropsychiatric disturbances and the associated movement diosorders.

DLB causes several clinical problems with management. There are conflicting requirements in trying to treat the neuropsychiatric disturbance as well as the parkinsonism such that treatments for hallucinations, delusions and behavioural disturbance tend to make the movement disorder worse and vice versa.

Small scale studies suggest that the newer atypical neuroleptics such as clozapine and olanzapine may be able to treat psychotic symptoms without precipitating excessive parkinsonism.

These drugs may even be successful in treating hallucinations and delusions in patients with Parkinson's disease who are starting to dement. This would be a great advantage, because the traditional management involves the withdrawal of anti-parkinsonian medication, a process which often leaves the patient lucid but immobile. It is still reasonable to try to simplify anti-parkinsonian medication as a first step, particularly withdrawing drugs of lower potency (and particular tendency to cause confusion) such as anticholinergics and selegeline; where possible dopamine agonists should also be withdrawn, leaving most patients on levodopa alone.

Some studies in this area of therapy advise caution.

Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. (Lancet Vol 351 4 April 1998 pages 1032-33) Authors: Clive Ballard, Janet Grace, Clive Holmes.

The research letter to the Lancet is from the Newcastle group.

McKeith and colleagues originally reported that about half of all patients with Dementia with Lewy bodies (DLB) exposed to neuroleptic drugs experienced a severe adverse drug reaction which included deterioration in cognitive function, parkinsonism, drowsiness and some features of so-called neuroleptic malignant syndrome. Such patients has a three fold increase in mortality compared to those not exposed to such drugs (McKeith et al BMJ 1992; 305: 673-678). This may also occur in association with atypical neuroleptic drugs (McKeith et al Lancet 1995; 346: 699)

In the study that they now report in the Lancet the group have looked at the incidence if neuroleptic sensitivity in a group of 80 patients, 40 with pathologically confirmed Alzheimer's disease and 40 with pathologically confirmed DLB.

  • 53% of DLB patients were given neuroleptics

  • 38% of AD patients were given neuroleptics

  • 29% of DLB patients had a definite severe sensitivity reaction to neuroleptics. No severe reactions were seen in the AD group.

  • 10% of the DLB patients had a mild sensitivity reaction to neuroleptics. Mild sensitivity reactions were seen in 47% of the AD group.

  • Severe sensitivity reactions were seen in DLB patients despte low doses and the use of newer neuroleptics (47% of the neuroleptics used were newer, atypical compounds).

  • All severe reactions happend within 2 weeks of neuroleptic administration or a dose change and were associated with a reduction in survival.

The authors make the following two recommendations:

  • Before use of neuroleptic agents in patients with dementia other pharmacological and psychological therapies should be explored first.

  • If it is felt that there is no option but to use neuroleptic therapy in patients with DLB this should be done in the context of a hospital setting under close monitoring, either in the first week of therapy or after a dose change.

The pharmaceutical industry is starting to recognise that the cognitive impairment of DLB may, because of its neurochemical differences, be more amenable to drug therapy than Alzheimer's disease.Initial anecdotal experience with cholinergic therpy in DLB has shown some promise.


THE CAUSE OF DLB

The cause of this form of neurodegenerative disease is uncertain. There are overlaps between Alzheimer's disease and Parkinson's disease. Genetic studies are making some progress in revelaing a matrix of different genes which may contribute to development of DLB. This appears to be complex but may explain firstly the relationship of DLB to the other primary Lewy body disorders including Parkinson's disease and secondly the association with Alzheimer's disease. It remains to be seen whether genetic testing will be sufficiently simple to help in clinical diagnosis.