RELATIONSHIP BETWEEN CHOLINESTERASE INHIBITORS AND PISA SYNDROME IN A COHORT OF FIVE FRENCH PATIENTS WITH ALZHEIMER'S DISEASE

To the Editor: The Pisa syndrome (or pleurothotonus) is an acquired, persistent truncal dystonia that appears to be reversible and is characterized by an involuntary side flexion (on either side) of the body and head and is associated with a backward axial rotation, so that the person seems to be leaning like the leaning tower of Pisa. Ekbom et al.1 have attributed the syndrome to a rare side effect of long-term classic neuroleptic medication, but it has also been reported with other drugs (antiemetics,2 valproic acid,3 and atypical antipsychotics4). Lately, it has been claimed that cholinesterase inhibitors alone can induce this syndrome.5, 6 In this letter, we report on the development of Pisa syndrome in five older French patients with probable Alzheimer's disease (AD) who were taking cholinesterase inhibitors. A 78-year-old woman was being treated with galantamine. After 11 months, she started leaning backward and to the right. Symptoms disappeared spontaneously after 10 days. Dystonia flared up a year later but resolved fully after a few days. Four months later, it reappeared. The patient was diagnosed with Pisa syndrome. The cholinesterase inhibitor was then stopped, and all signs of dystonia resolved fully within 15 days. A 75-year-old woman was being treated with rivastigmine in 2001. In 2002, rivastigmine was stopped and replaced by donepezil. In May 2006, she started leaning to the right side when she was seated. Dystonia resolved within 15 days after cholinesterase inhibitor discontinuation. A 72-year-old woman was first given donepezil daily and then galantamine in 2002. In 2003 and 2004, she developed two phases of dystonia. The symptom disappeared without treatment. In December 2004, she was seen leaning backward and to the left. After withdrawal of galantamine and initiation of rivastigmine, dystonia of the trunk disappeared. A 76-year-old woman was given donepezil. In 2003, a first phase of dystonia was observed. In August 2003, axial deviation was seen again, which disappeared spontaneously. In January 2005, she started leaning again to the right. Pisa syndrome was suspected, and donepezil was discontinued with partial resolution of signs of dystonia. In 2001, rivastigmine was initiated in a 79-year-old man. Dystonia was noted seven times in 2003 and 2004. Each time, the resident presented marked deviation to the right side that worsened while walking. Each time this symptom disappeared spontaneously. Dystonia was noted again three times in 2005. In the literature, we have found approximately nine cases of Pisa syndrome with cholinesterase inhibitors (Table 1). Those reports suggest the link between cholinesterase inhibitors and this characteristic dystonia.5-9 In our cases, the only three cholinesterase inhibitors available in France are implicated. The frequency of Pisa syndrome is not known because of the small number of cases reported. Some authors estimate the incidence at two per 10,000 patients per year with cholinesterase inhibitors, which is fewer than with antipsychotics.6 In a Canadian study, a prevalence of 8.3% has been reported, whereas a German study found a prevalence rate of 0.037%.2, 8 The underlying pathophysiology of drug-induced Pisa syndrome is not well known. A dopaminergic–cholinergic imbalance is thought to be the main factor (induced by cholinesterase inhibitors and whose resulting dystonia is resolved with cholinesterase inhibitor withdrawal).2, 5, 7, 8 There is no definite lateralization in the direction of the dystonic posturing. In our five cases, the trunk tilted to the right for four patients and to the left for one. The side of the axial deviation is always the same for the same patient even if the dystonia appears several weeks or years later. We believe that the widespread use of cholinesterase inhibitors may cause an increasing number of Pisa syndrome cases and therefore clinicians should be aware of this side effect. Several points remain to be examined or emphasized. The precise physiopathology of Pisa syndrome seems well-worth studying. There are few data on the prevalence and incidence of Pisa syndrome induced by cholinesterase inhibitors, because randomized trials do not study the long-term adverse reactions of drugs. The duration of cholinesterase inhibitor use before the onset of dystonia is variable (1 month–4 years). Is there any point in changing cholinesterase inhibitor type? In most of the cases reported, dystonia reappeared when the patient was given a different cholinesterase inhibitor. We do not know whether cholinesterase inhibitor–induced dystonia increases the risk of falling or whether patients with Pisa syndrome lean and do not fall, just like the tower of Pisa does…. The authors thank Evelyne Guillautou and Sylvie Demarle for their assistance. Financial Disclosure: No financial support. There are no financial conflicts of interest for any author. Author Contributions: All authors contributed to study concept, data analysis, interpretation of data, and manuscript preparation. Sponsor's Role: No sponsor.

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