Dementia, bizarre creatures, and a white knight to the rescue

In the hospital, medical and neurologic workups rule out organic causes for her symptoms and signs. MRI is consistent with imaging from 6 months earlier. Focal neurologic signs are absent. Blood work is within normal limits, failing to reveal any pathology that would suggest a cause for her symptoms and signs, such as syphilis, vitamin deficiency, and Lyme disease.

Ms. L’s symptoms were consistent with consensus guideline criteria for a clinical diagnosis of DLB (Table 1).^11-18

She is started on low-dose quetiapine, which she tolerates poorly with worsening confusion, rigidity, tremor, and gait instability. Because other agents failed, Ms. L’s providers and family decide on a trial of clozapine.

Within 24 hours after the first dose of clozapine, 25 mg, sleep improves, the tactile component of hallucinations diminish, and she begins to spend increasing periods of time “observing the creatures” rather than fighting with them.

Over the next few days, Ms. L’s attitude towards the creatures changes. Now, as she sits observing them intently, the hallucinations evolve: rather than tormenting her and causing distress, the plant-creatures burst apart and a miniature knight on horseback charges out. The rest of the creatures then gather into a rank and file and the knight leads them to the nearest exit.

Clozapine is titrated to 50 mg/d, which she tolerates well without exacerbation of cognitive symptoms or movement disorder. The only notable adverse effect at the time of her discharge is sialorrhea.

The authors’ observations

Ideally, in psychosis, antipsychotics eliminate positive symptoms such as hallucinations and delusions. In DLB, the aim is to alleviate the agitation and suffering brought on by the psychotic symptoms without exacerbating other motor and cognitive symptoms. The hallucinations are obstinate, and it is a well-known quality of this disorder that patients are exceptionally susceptible to a range of antipsychotic side effects including cognitive impairment, fatigue, neuroleptic malignant syndrome, and parkinsonism.¹⁹

Treatment in DLB requires trial and error, and medications with fewer associated risks should be administered first. Patients with DLB treated with neuroleptics have an increased risk of death compared with those who are not treated.¹⁹ Moreover, prescribing information for clozapine includes a black-box warning that the drug:

• is not approved for dementia-related psychosis and
• is associated with an increased risk of death in elderly patients with these conditions, similar to what is seen with other neuroleptics.²⁰

Despite these well-known concerns, it remains difficult for clinicians not to try to treat the distress caused by these symptoms.

We chose clozapine for Ms. L because:

• other neuroleptics failed
• acetylcholinesterase inhibitors did not alleviate Ms. L’s psychosis and associated behavioral disturbance
• there is substantial evidence that the drug can be effective in Parkinson’s disease with psychosis.

There is controversy regarding use of clozapine in DLB. In one case series, clozapine trigger extreme neuroleptic reactions in some patients, similar to what occurs with other second-generation antipsychotics.²¹ Another case series provides examples of the drug’s efficacy in treating hallucinations and delusions with minimal adverse effects.²²

It is important to emphasize that Ms. L’s hallucinations did not go away; rather, they changed to a more benign presentation that she could manage and, occasionally, found pleasant. Ultimately, her agitation—the primary target of treatment—improved markedly with the arrival of the knight in shining armor.

Treatment recommendations

If neuropsychiatric symptoms in DLB are the primary concern of the patient and family, we recommend the following:

• Begin treatment with a cholinesterase inhibitor. The best evidence exists for rivastigmine and donepezil. These drugs have a low risk of side effects, which are primarily gastrointestinal effects with some reports of worsening extrapyramidal symptoms.^23-25
• If the patient obtains minimal benefit or develops a significant adverse effect from cholinesterase inhibitors, consider memantine. Its efficacy is under examination and results are mixed; it can be used in combination with cholinesterase inhibitors.^26-28
• If psychotic symptoms are upsetting and refractory to other therapies, consider antipsychotics. Avoid first-generation antipsychotics. The American Psychiatric Association recommends aripiprazole or quetiapine initially, although there is little evidence comparing neuroleptics in DLB.²⁹ Because of its risks, reserve clozapine for refractory cases. An exception might be made for patients sensitive to extrapyramidal effects, in whom clozapine could be considered earlier.

There are no formal neuroleptic dosing guidelines beyond a general urging towards minimalism. Mosimann and McKeith³⁰ recommend clozapine, 12.5 mg/d; olanzapine, 2.5 mg/d; risperidone, 0.25 mg/d; or quetiapine, 12.5 mg/d. Such dosages might be effective while producing only minimal side effects.^9,31