3.4. Co-prescribed drugs
Antipsychotics use was reported in half of the cases (n=61, 49.6%). First-generation antipsychotics were used in most cases (n=58, 95.1%), the most frequently reported being haloperidol (n=30), chlorpromazine (n=16), thioridazine (n=4) and fluphenazine (n=4). Four patients used second-generation antipsychotics (olanzapine n=3 and quetiapine n=1).
Other reported psychotropic and non-psychotropic treatments are detailed in Table 1. The most frequently reported were antidepressants (n=14), anticonvulsants (n=10) and benzodiazepines (n=8).
3.5. Associated medical conditions
Fever and/or infection was reported in nearly half of the patients (n=59, 48%). Information on the presence of fever was absent in 9 patients with infection. The most frequent infection was pneumonia (n=12) [25, 29, 34, 40-45]. Probable or definite neuroleptic malignant syndrome was observed in 6 patients [22, 28, 35, 36, 46, 47], and heat stroke in one patient [23]. The other medical conditions (anorexia, surgery, dehydration, chronic kidney disease, alcohol use, etc.) are described in Table 1.
3.6. Type of neurological sequelae
Cerebellar sequelae were reported in most cases (n=97, 78.9%) and were the only neurological syndrome in 58 cases (60.4% of those with cerebellar symptoms). The other frequently reported neurological sequelae were cognitive deficits/dementia (n=17, 13.8%), choreoathetosis (n=12, 9.8%), parkinsonism (n=11, 8.9%), dyskinesia (n=9, 7.3%) and peripheral neuropathy (n=7, 5.7%). Other rare sequelae are described in Table 1.
3.7. Characteristics associated with occurrence of cerebellar sequelae
Multivariate analyses were performed in the sample of cases without missing data on the variables of interest (n=109, 88.6%). Two characteristics were independently associated with the occurrence of cerebellar sequelae (Table 2): plasma lithium level ≥ 2.5 mEq/l (moderate/severe toxicity) and (ii) presence of fever and/or infection. An association was found at trend level between age and type of sequelae, the proportion of patients aged 50 years and over being higher in the group with cerebellar sequelae. No association was found between type of sequelae and gender or antipsychotic use.
To further explore whether the impact of fever on the occurrence of cerebellar sequelae was modified by lithium plasma level, the interaction term “fever*lithium level” was entered in the multivariate model. As this interaction was significant (Wald test Chi2=6.31, p=0.01), we performed analyses stratified by maximum lithium plasma levels. This showed that the association between fever and/or infection and cerebellar sequelae was strong (OR=13.9, 95%CI 3.21-60.05) in cases with no/ mild lithium toxicity, while it was not significant in those with moderate/severe lithium toxicity (OR=0.92; 95%CI 0.12-7.10).
Sensitivity analyses using the variable “strictly defined fever” (i.e. cases with reported information on this symptom) showed comparable associations between fever and cerebellar sequelae: 40 (47.1%) patients with cerebellar sequelae had a history of fever vs. 4 (16.7%) of patients with other sequelae (OR=5.65, 95%CI 1.65-19.37, p=0.006).