Parkinsonism is a major feature of several dementing diseases whose features are characteristic of Parkinson’s disease. This movement disorder is characterised by rigidity and bradykinesia, with rest tremors and gait instability also sometimes being realised. Dementia with Lewy bodies is commonly referred to as a ‘parkinson-plus’ syndrome, which are neurodegenerative disorders characterised by parkinsonism and at least one other nonparkinsonian neurological manifestation; these can be ‘frontal-subcortical’ cognitive deficits such as mental slowness, inertia and lack of initiative, forgetfulness, decreased executive functions, visuospatial deficits or mood disturbances. Other ‘parkinson-plus’ syndromes include progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy and amyotrophic lateral sclerosis/ parkinsonism-dementia complex of Guam.
Dementia with Lewy bodies is by far the most common of these, as it is now the preferred term for a variety of clinical diagnoses, including diffuse Lewy body disease, dementia associated with cortical Lewy bodies, the Lewy body variant of Alzheimer’s disease, senile dementia of Lewy body type and Lewy body dementia.
Dementia with Lewy bodies describes a parkinsonian dementia with a widespread distribution of Lewy bodies – eosinophillic cytoplasmic inclusions (refer to section 1.5.3). In addition to the parkinsonian movement disturbance, typical features are visuospatial and executive function cognitive impairments that fluctuate over time (lasting minutes and hours, rather than days), and neuropsychiatric symptoms such as fixed delusional visual hallucinations. The order of emergence of these cognitive disturbances and parkinsonism are variable, though they usually appear within a year of one another. Dementia with Lewy bodies parkinsonism includes rigidity, bradykinesia and disturbances of posture and equilibrium, with the absence of resting tremor being typical. The cognitive fluctuations seen in dementia with Lewy bodies are most commonly realised in marked variations in attention, as well as periods of confusion, inattention or decreased responsiveness.
The neuropsychiatric manifestations of dementia with Lewy bodies are among the most fascinating aspects of the disease, and are extremely helpful in conveying clues for its correct diagnosis. The majority of dementia with Lewy bodies patients experience psychiatric disturbances involving visual hallucinations, which are most commonly fully formed and animate, and often involve deceased relatives, complete strangers or animals.
Depression, apathy, anxiety, insomnia, paranoia and paramnestic phenomena (dreams confused with reality) also frequently occur in dementia with Lewy bodies, which often prove very difficult to manage owing to the characteristic pharmalogical sensitivities exhibited by dementia with Lewy bodies patients. Furthermore, a number of other features, which are variable in occurrence, have also been associated with Dementia with Lewy bodies. These include orthostatic hypotension (low blood pressure when standing), unexplained falls or syncopy (unconsciousness through a fall in blood pressure) and Rapid Eye Movement Sleep Behaviour Disorder (REMSBD) – a disorder characterised by vocalisation and gesticulations with patients acting out their dreams while asleep.
Dementia with Lewy bodies is third most common cause of dementia after Alzheimer’s disease and vascular dementia, accounting for about fourteen to twenty percent of patients (McKeith et al. (1999)). Two thirds of dementia with Lewy bodies patients are male (Barber et al. (2001), Klatka et al. (1996)), though it is unclear whether this is due to increased male susceptibility to the disease or reduced male survival. Classical epidemiological studies to ascertain age and sex variation and potential risk factors for dementia with Lewy bodies have yet to be reported.
Dementia with Lewy bodies may realise Lewy bodies that are widely distributed – they can occur in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, nucleus basalis, cholinergic neurons in the basal ganglia, hypothalamus, cerebellar cortex, spinal cord intermediolateral cell column, and autonomic ganglia including submucosal ganglia of lower esophagus. Dependent upon the distribution of the Lewy bodies, dementia with Lewy bodies can be categorised into three types – Type A (involving the brainstem and cortex), Type B (limbic or transitional predominant), or Type C (brainstem predominant). The severity of cognitive impairment in dementia with Lewy bodies has been shown to correlate with Lewy body densities in the frontal and temporal neocortex, as well as Lewy neuritis in the hippocampus (Haroutunian et al. (2000), Mattila et al. (2000)). Furthermore, visual hallucinations seem to correlate with the presence of Lewy bodies in the parahippocampal and inferior temporal cortices (Harding et al. (2002)). The hippocampus also shows significant atrophy and pathology in dementia with Lewy bodies, involving spongiform (sponge-like) and vacuolar changes (Harvey et al. (1999)). Moreover, magnetic resonance imaging (MRI) discloses whole brain atrophy with disproportionate atrophy of the temporal lobes (located on the side of the cerebrum), although not to the extent seen in Alzheimer’s disease (McKeith et
al. (1999), Barber et al. (2001)). In addition to the characteristic Lewy bodies, the majority of
dementia with Lewy bodies patients exhibit senile plaques and neurofibrillary tangles – both characteristic features of Alzheimer’s disease pathology (Londos et al. (2002), McKeith et al. (1998)). Dementia with Lewy bodies brains have also been shown to have decreased concentrations of various neurotransmitters in the putamen and neocortex, including dopamine, serotonin and norepinephrine.
The treatment of dementia with Lewy bodies presents the clinician with several challenges; as although the pathological features have become increasingly well described, there is still controversy in the interpretation of the histological features, i.e. do they indicate a variety of Alzheimer’s disease, a variety of Parkinson’s disease, a separate distinct entity, a coexistence between the two, or indeed a spectrum disorder? A recent proposal for the reclassification of neurodegenerative disorders into synucleinopathies (or tauopathies) may help clarify its nosological (medical classification) status.
Though this nosological uncertainty must be borne in mid when discussing dementia with Lewy bodies, the treatment of established dementia with Lewy bodies will now be briefly discussed. One main approach in the current treatment of dementia with Lewy bodies, similar to that of Alzheimer’s disease, is the use of cholinesterase inhibitors (AChEIs) to counter the severe cholineacetyltransferase deficiency, which is more profound than that seen in Alzheimer’s disease. Second generation AChEIs are beginning to be used, and in one randomised trial of 120 patients, significant differences in neuropsychiatric symptoms were found in favour of the treated group over the placebo at 20 weeks. Many similar studies show a comparable benefit of treatment (Byrne et al. (2005)). Other putative therapeutic agents aimed at enhancing cholinergic function in dementia with Lewy bodies are muscarinic agonists and nicotinic agonists.
Although dopamine levels are reduced in post-mortem studies in dementia with Lewy bodies, and CSF homovanillic acid levels are reduced in autopsy-confirmed cases, there has been little systematic enquiry into the effects of L-dopa therapy in dementia with Lewy bodies. Early studies however, found little or no L-dopa response in those that were treated, plus acute confusional states (delirium) and other adverse effects which are associated with L- dopa therapy, may all account towards the lack of enthusiasm to use these drugs in dementia with Lewy bodies therapy (Byrne et al. (2005)).
Psychiatric symptoms, especially visual hallucinations, are common and troublesome in dementia with Lewy bodies, which are caused by increased sensitivity to neuroleptics. Although neuroleptic sensitivity is not an inevitable consequence of neuroleptic medication in dementia with Lewy bodies, it is certainly common and commonly severe (Byrne et al. (2005)). Treatment of psychotic symptoms in dementia with Lewy bodies include the use of
GABAergic agents such as chlormethiazole, which reduce or even obviate visual hallucinations, help in associated sleep disorders and also has neuroprotective effects. (GABA has been suggested as an important transmitter in delirium, and also has an important function in motor control). (Byrne et al. (2005)).