Abstract
Dementia is a syndrome characterized by memory impairment and decline in other higher cortical functions. Its prevalence doubles every 5 years after age 60 years, increasing from 1% to 25% among those aged 85 years or older [1]. The clinical presentation of dementia almost always includes the presence of behavioural disturbances, such as psychosis (delusions and hallucinations), mood changes (depression, anxiety, euphoria and lability), personality changes (apathy, disinhibition, irritability and aggression), abnormal motor behaviour (pacing, wandering and falling), neurovegatitive changes (sleep, sexual and appetite) and agitation [2]. These behavioural problems are associated with greater personal distress, carer burden and economic costs.
In 1991, in the United Kingdom the total estimated cost of caring for patients with alzheimer's disease (AD), the most frequent cause of dementia in Western societies, was close to 18 billion Australian dollars [3]. This cost does not include the unpaid work of community carers or their substantial emotional and psychological burden. Carers are at increased risk of physical and mental health morbidity, which further augments health cost [4]. The level of carer burden and ill health often leads to the placement of patients with dementia into residential care facilities [4]. However, even in residential care settings, the behavioural symptoms of dementia are associated with staff burden, increased workloads and acute inpatient hospitalization – this all contributes to increase the financial burden on scarce health resources. Interventions that succeed in controlling the cognitive and behavioural symptoms of patients with dementia should have an enormous individual and social impact.
Two cholinesterase inhibitors have been recently listed on the pharmaceutical benefit scheme (PBS) in Australia as an authority item for mild to moderate AD. Approval for extended use is dependent on demonstrating an improvement in cognition. The PBS guidelines for extended use of a cholinesterase inhibitor state: Continuing treatment, following initial therapy, of mild to moderately severe AD in patients with demonstrated improvement in cognitive function as measured by an increase of at least 2 points from baseline on the minimental state examination (MMSE), or a decrease of at least 4 points from baseline on the AD assessment scale, cognitive subscale (ADAS-Cog) for patients with a MMSE baseline score of at least 25 points [5–7]. The present report describes the case of an elderly man with mild dementia and marked behavioural disturbance whose symptoms improved markedly with the introduction of a cholinesterase inhibitor.
Clinical features
A 90-year-old retired doctor who was living in an aged care hostel presented with a three-month history of disorientation, confusion and visual hallucinations at the time of referral to our community psychogeriatric service. The patient had no significant pre-existing health problems and he was on no medication. The referral was initiated because the staff at the hostel felt that they could no longer deal with or contain the patient's behavioural disturbance: prolonged periods of agitation, hyperarousal, irritability and combativeness lasting from three to 36 hours. During these episodes the patient was disoriented in place and time, and was unable to identify familiar staff members. He complained that strangers or animals had entered his room and had been seen speaking angrily, as though conversing with unseen intruders. Between episodes, the patient was described as lucid, polite, friendly and virtually independent in self-care, requiring only some minimal prompting. The staff also noted increasing memory difficulties over the previous nine months.
On review, the patient was calm and unaroused. He described vivid visual hallucinations, which caused him to become distressed and develop secondary persecutory delusions. There were no signs of mood disturbance. He acknowledged the presence of memory difficulties and his MMSE score was 24/30 [5]. Specifically there were difficulties in visuo-spatial/construction ability (as shown by the two intersecting pentagons and clock drawing), recall and new learning (list of words), and verbal fluency (animals category and words starting with the letters FAS). Physical examination revealed stooped posture, shuffling gait, positive glabella tap and bilateral palmomental reflexes, mild resting tremor in the left hand, mild cogwheel rigidity in both upper limbs, micrographia and dysphonic speech. There were no focal neurological or cerebellar signs.
A provisional diagnosis of dementia with lewy bodies (DLB) was made, as there was clinical evidence of decline in cognitive functioning, visual hallucinations, fluctuation of symptoms and parkinsonism, which are the core features of the consensus guidelines for the clinical and pathological diagnosis of DLB [8]. A computed tomography (CT) scan performed at this stage revealed a moderate degree of cortical atrophy, but no obvious signs of subcortical changes or focal lesions. Blood tests were all within the normal limits (FBC, TFT, LFT, calcium, B12, folate, syphilis serology, BSL, electrolytes, urea and creatinine).
Olanzapine (2.5 mg nocte) was then introduced with the aim of controlling psychotic symptoms, but had to be ceased due to marked deterioration in the patient's mental state (increased confusion, disorientation, irritability, and hallucinations). In addition, the patient developed repeated falls, increased muscle tone and tremor. Attempts to manage psychomotor agitation with benzodiazepines (oxazepam 7.5 mg and 15 mg) produced a paradoxical response with increased insomnia and agitation.
The patient was then transferred to a nursing home facility as a result of our inability to control his disruptive behaviour. On periodic review, it was clear that the subject's symptoms had not improved but, due to increased staff contact, he was more easily contained.
Six months after these events, the nursing home staff reported that they were no longer able to manage the patient, as his behaviour became increasingly more disruptive. At this stage his MMSE was 23/30 with little change compared to the initial assessment. We introduced donepezil 5 mg mane for three weeks increasing to 10 mg mane thereafter. Within a few weeks of its initiation the episodic agitation and psychotic symptoms ceased altogether and the patient regained much of his premorbid interests, motivation and sense of humour. His memory, attention, concentration and comprehension were also improved and he began reading again, which he had not done for 12 months. His mobility increased and he was able to write letters again but hypertonia and cogwheeling were still detectable in both upper limbs. The improvement has been sustained for six months after the introduction of donepezil. At the time of writing, the patient's MMSE was 27/30, with deficits in B.S. COULSON, S.G. FENNER, O.P. ALMEIDA 261 visuo-spatial abilities and recall. The patient and the nursing home staff reported that there were no behavioural disturbances.
Discussion
Dementia with lewy bodies is thought to account for 15–25% of all dementia cases [9]. Behavioural symptoms are usually universal in all forms of dementia and, in Australia, antipsychotic agents are the mainstay of treatment. It is well documented that antipsychotic medication can lead to marked sensitivity reactions among patients with DLB, including delirium, severe parkinsonism, states resembling neuroleptic malignant syndrome, and even sudden death [10]. In AD the use of typical and atypical antipsychotics are not without risk and may be only modestly effective in treating behavioural symptoms compared to placebo [11]. Olanzapine, an atypical antipsychotic, decreases behavioural symptoms in patients with AD when used in small doses (up to 5 mg) but, so far, available information is limited to 6 weeks of follow-up. Hence, the long-term consequences of this type of treatment (such as tardive dyskinesia) have not been properly addressed [12]. Of note, olanzapine does not have PBS listing for the treatment of psychotic symptoms in dementia.
Recent reports indicate that donepezil has psychotropic effects and can treat behavioural symptoms in both AD and DLB with minimal side-effects [13–15]. A recent review article by Daly et al. concluded that there is now considerable evidence that cholinesterase inhibitors do have a role in the symptomatic treatment of behavioural disturbance in AD, DLB, and possibly other related dementias with cholinergic deficits [16]. Rivastigmine, another cholinesterase inhibitor, was also shown to have good efficacy and side-effect profile for the treatment of patients with DLB [17]. This randomized, double-blind, placebo-controlled clinical trial showed that the MMSE scores of 41/92 DLB subjects who received rivastigmine increased 1.5 points (compared with placebo of a decline of 0.1 points) and that behavioural symptoms such as apathy, anxiety, delusions and hallucinations were markedly improved. In clinical practice, many of these patients would not have been eligible to continue treatment with a cholinesterase inhibitor according to Australian PBS guideline [7]. The trial also showed that psychotic and behavioural symptoms often re-emerge with the discontinuation of treatment [17].
The above case illustrates the exacerbation of extrapyramidal signs and behavioural symptoms that may occur when antipsychotic agents are used in the treatment of patients with DLB. It also shows a close temporal association between abrupt and sustained behavioural symptom reduction with the introduction of donepezil – this enabled us to avoid an acute hospital admission. It is unclear, at this point in time, whether the early introduction of donepezil would have averted the need to move the patient from the hostel to a nursing home with higher level of care – this would have considerably reduced the overall cost associated with his management.
The current Australian PBS guidelines for the prescription of cholinesterase inhibitors explicitly state that the use of these agents should be limited to patients with AD. The debate between the relationship of AD and DLB is ongoing and by no means settled, by using ICD-10 diagnostic criteria adults with DLB can be classified as AD [18]. However, the Australian PBS guidelines do not make any reference to the treatment of behavioural problems, which may have important ethical implications to practicing clinicians: What should we do if the cognitive performance of patients does not improve the required 2 points on the MMSE but the behavioural disturbances are effectively treated? Are we really decreasing the personal, social and financial costs associated with dementia care by limiting the use of antidementia drugs to the treatment of the cognitive aspects of the illness? The outcome of the case that we report here suggests that current PBS guidelines for the use of cholinesterase inhibitors may not always be appropriate. This is clearly an area that requires further discussion, research and review.
Footnotes
Acknowledgements
We wish to thank Nicola Lautenschlager for her advice and criticism of this report.