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
- Senile Dementia Of Lewy Type
- Lewy Body Variant of
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
development of hallucinations
Several key areas of the brain undergo degeneration in this form of disease
The protein alpha synuclein
is a major component of Lewy bodies.
- 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.
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
PATHOLOGICAL FEATURES ASSOCIATED WITH DLB
- Essential for diagnosis of DLB
- 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
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
FEATURES AND DIAGNOSIS OF DLB
The core feature of DLB is a progressive dementia.
A combination of key clinical features has allowed workers in many centres
to diagnose this condition and distinguish it from other causes of
- 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
- Most patients initially complain of impaired recent memory.
- In other patients the main problem is behavioural disturbance with preserved
- 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
- 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
- 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).
- 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.
- 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
- Spontaneous motor features of parkinsonism
- Features supportive of the diagnosis are:
- Repeated falls
- Syncope or transient loss of consciousness
- Neuroleptic sensitivity
- Systematised delusions
- Hallucinations in other modalities
- A diagnosis of dementia with Lewy bodies is less likely in the
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
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.
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
- 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
- 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.
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.
The authors make the following two recommendations:
- 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 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.
- 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
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.