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Cholinesterase inhibitors (ChEIs) are effective in treating visual hallucinations (VH) in dementia with Lewy bodies (DLB). Nonetheless, approximately 35% of patients treated with rivastigmine showed no significant improvement according to the psychosis subscores of the Neuropsychiatry Inventory (NPI).1 We conducted an observational study in our memory clinic and we report the characteristics of patients who showed resistant hallucinations (RH) to ChEIs.
We carried out an observational study of outpatients with DLB with hallucinations treated with ChEIs over 4 years. Probable DLB was diagnosed according to the second consensus criteria, and the severity of dementia was assessed using the Mini‐Mental State Examination (MMSE) score. We excluded patients who required concomitant medications other than ChEIs that influence hallucinations or if they were treated with antipsychotics. Episodes of delirium were determined using clinical assessment (DSM‐IV), and a standard biological screening was performed when hallucinations appeared. Patients with concomitant cerebrovascular pathology were excluded.
The consultant initiated ChEIs in accordance with the criteria of the first double blind placebo controlled trial in DLB with rivastigmine.1 Rivastigmine was chosen preferentially, and donepezil or galantamine was proposed when rivastigmine was not tolerated or when a single daily dose was desirable. The dose of ChEIs was titrated monthly to the maximum tolerated dose. The minimal daily efficient dose of rivastigmine (6 mg), donepezil (5 mg) or galantamine (16 mg) was the threshold under which patients were excluded. Patients were followed for 6 months.
Different modalities of hallucinations were assessed at baseline and during the follow‐up period and were quantified using the global hallucinations subscore of the NPI (HS‐NPI) scored on 12 points. Efficacy of ChEIs was evaluated as the number of patients whose HS‐NPI score improved by at least 30% from baseline. Patients who fell below the threshold level of improvement were classified as RH patients.
Thirty‐six DLB patients (18 females/18 males) were included. Mean age was 65.9 (9.1) years. Mean MMSE score was 24.7 (4.2). Baseline severity of dementia was mild (MMSE 18) in 33 patients and moderate (10< MMSE <18) in three patients. Hallucinations appeared, on average, 2.2 (1.4) years after the onset of the disease. The mean HS‐NPI was 7.1 (3.1). Twenty‐two patients were treated with rivastigmine, nine with donepezil and five with galantamine; none had stopped ChEIs treatment. The mean decrease in HS‐NPI was 3.5, and was significant (7.2 (3.1) vs 3.7 (3.2); U=−4.9, p<0.0001). Nine patients (24%) had RH (22% with rivastigmine, 22% with donepezil and 40% with galantamine). The characteristics of the two groups are described in table 11.. We performed a logistic regression analysis to clarify which factors had independent prognostic value in RH. When we entered severity of dementia, HS‐NPI baseline score, type of hallucinations, delusion, depressive symptoms and type of ChEIs into the model, delusion (odd ratio 0.29, 95% CI 0.001 to 0.64) predicted resistance of ChEIs on VH. Non‐visual hallucinations and depressive symptoms were more frequent in patients with RH, but this was not significant.
The frequency of patients with RH was 24%, in agreement with the literature data. This observational study has proposed that delusions are associated with RH. Various biological abnormalities have been described between patients with hallucinations and those with delusions. This may explain the variable response to ChEIs. Muscarinic M1 receptors2 are only increased in patients with delusions whereas M4 receptors are only increased in patients with VH.3 Moreover, plaques and tangles staging are associated with VH and not with delusions.4
The data, although limited by the open label design of the study and the small number of patients, need to be confirmed in double blind studies using behavioural scales with subscores to assess each psychotic symptom. Hallucinations associated with delusions might require different treatment than isolated VH.
Funding: This work was supported by grant EA 2691.
Competing interests: None.