Auditory and visual hallucinations after influenza vaccine: a case report

Introduction

Vaccination against influenza was found in geriatric patients to correlate with a reduced risk of death, hospitalization and costs on health system [Nichol et al. 1994]; vaccination against influenza is indeed recognised by the World Health Organization as an efficacious strategy to prevent the health-threatening effects of influenza viruses [World Health Organization, 2012]. As with all drugs, the vaccine against influenza is associated with some adverse drug reactions (ADRs) [Vaxigrip, 2015]; while some neurological and psychiatric ADRs have been reported no evidence of visual and auditory hallucination exists. A case of extended hallucinations is now reported.

Case

The patient is an 82-year-old woman affected by vascular parkinsonism and cerebral vasculopathy diagnosed in 2014, and then treated daily with 12.5 mg carbidopa, 50 mg levodopa, 200 mg entacapone, 250 mg ticlopidine and 20 mg atorvastatin. On November 2015, she received the anti-influenza vaccine [0.5 ml containing 45 µg hemagglutinin (HA), with 15 µg HA of each of the following three virus strains: A/California/7/2009 (H1N1), A/South Australia/55/2014 (H3N2), and B/Phuket/3073/2013]. At 3 days after vaccination, episodes of visual and auditory hallucinations increased in timespan and severity (2–3 h; she had visions of conversing unreal persons in her home).

The patient was administered haloperidol (1 mg/day) to control hallucinations, and the resolution was achieved in 48 h. The patient did not take herbs or other products, thus excluding concomitant factors possibly contributing to the hallucinations. In the absence of clinical conditions that could justify these hallucinatory experiences, they were identified as ADRs to the vaccine. The relationship between events and vaccine were defined as probable according to the Naranjo algorithm [Naranjo et al. 1981].

Discussion

This is the first case describing visual and auditory hallucinations after influenza vaccine in the absence of other concurring events. Hallucinations after vaccination were indeed reported, but they occurred in the presence of tramadol in a condition in which the culprit was the analgesic, whose concentration was increased by the vaccine due to a pharmacokinetic interaction [Pellegrino et al. 2013, 2015]. How hallucinations have occurred after vaccination in the absence of other predisposing events cannot be established with certainty. Vaccine-induced dysregulation in cytokine levels leading to changes in specific brain activities is a likely possibility. Interleukin (IL)-6 promotes the dopaminergic activity in the hippocampus, the area involved in hallucinations, and a stimulated dopaminergic transmission was associated with hallucinatory experiences [Amad et al. 2014]. Increases of serum and plasma IL-6 and tumour necrosis factor (TNF)-α levels were observed in schizophrenia, narcolepsy and Alzheimer’s disease, characterised by hallucinations [Chen et al. 2013; Kronfol and Remick, 2000]; furthermore a decrease in the levels of IL-2, TNF-α, interferon(IFN)-γ, IL-6 and its receptors has been suggested to contribute to the efficacy of neuroleptic agents, such as haloperidol, in these disease conditions [Kronfol and Remick, 2000; Schleuning et al. 1989; Handley et al. 2016]. Vaccination can increase IL-6 and TNF-α levels [van der Beek et al. 2002; Tsay et al. 2005] and IL-6 levels are positively correlated with age [Kim et al. 2012; Howell et al. 2016]; increasing cytokine levels induced by the vaccine may have thus contributed to the onset of hallucinations in our patient, likely via the same pathways identified for the neuropsychiatric disorders described above.

We cannot exclude that vascular parkinsonism or levodopa, administered to the patient, played a role in the ADR, however their role as primary cause of hallucinations is unlikely because: (1) vascular parkinsonism is seldom associated with hallucinations [Glass et al. 2012], (2) the patient had been treated with levodopa in a chronic way before vaccination, without any hallucinations having occurred. The insurgence of hallucinatory episodes 3 days after vaccine administration, is a timing consistent with the time needed by the vaccine to increase IL-6 and TNF-α levels [van der Beek et al. 2002; Hacker et al. 1998] and its increased levels in elderly. Nevertheless, since the association with hallucinations is known for levodopa, this drug could have acted as an important and critical secondary cause of the ADR.

The impact that neuropsychiatric ADRs, such as hallucinations, have on the quality of life of patients and their caregivers is severe. A recent study showed that even nonserious ADRs, such as the one we observed, impact seriously on the patients’ life, in terms of a negative impact on the disease or inducing changes in treatment until therapy discontinuation [Pozzi et al. 2013].

Conclusion

We report occurrence of reversible auditory and visual hallucinations in a geriatric patient after influenza vaccine administration. Based on a single case we cannot make causal inferences. An immune-mediated mechanism is possible but also other mechanisms are possible. Further studies and observations are needed to find out whether geriatric patients with neuropsychiatric disorders are more susceptible to such adverse effects than healthy geriatric subjects.

This would allow appropriate management of these reactions without limiting the access of geriatric patients to vaccination, which has to be encouraged.