The main finding in this study is that OS is found in a wide array of disorders commonly related to frontal lobe dysfunction with seven of the eight focal lesion patients showing right frontal lobe damage. In addition, VBM showed that the neurodegenerative cases with OS had greater grey matter loss in the dorsolateral frontal lobes, compared to neurodegenerative patients without Othello's.
Previous smaller studies have linked OS to right hemisphere events such as strokes.(9
) In addition OS has been associated with right frontal lobe hypometabolism on single photon emission computer tomography in one study,(9
) and has also occurred after right orbitofrontal resection for a meningioma.(10
) Our study also found an association between the development of OS and frontal lobe, in particular right frontal lobe, dysfunction. Specifically frontal lobe lesions were a common theme in our lesion associated cases, and were independently identified in the neurodegenerative patients on VBM. One hypothesis linking right frontal lesions to delusions suggests that the loss of frontal lobe function impairs the ability to monitor interactions with oneself and with others leading to false beliefs that persist despite being incorrect. Impairments in monitoring reality, memory and familiarity due to a damaged right hemisphere may lead to the unopposed left hemisphere categorizing without emotional familiarity resulting in false explanations.(25
) There were also other reports that implicated the right hemisphere and/or right frontal lobe dysfunction to be associated with delusions in general. For example, in 1984, Levine and Grek described nine patients with right sided strokes who developed frequent delusions. These patients had strokes with underlying generalized atrophy.(26
) Using functional imaging, Staff et al. also demonstrated right frontal lobe hypoperfusion in Alzheimer's patients with delusions compared to Alzheimer's patients without delsusions.(27
Although there is strong evidence that links OS and delusions in general, to the right frontal lobe, delusional jealousy has also been associated with lesions in other regions of the brain. Indeed, in our study one patient developed OS after a left frontal stroke. Similarly, Silva and Leong describe delusional jealousy in a patient after left frontal stroke.(13
) A case of OS has also been attributed to a right-sided thalamic infarct, although this patient had 3 prior right hemispheric infarcts leaving him with a left hemiparesis.(14
Another important finding in this paper is the fact that six PD subjects without dementia developed OS after starting or increasing the dose of dopamine agonist. In support of the dopamine agonist as the cause of their delusional jealousy, the delusions stopped or significantly improved, when the medication was discontinued or the dose was decreased. OS has been described in a handful of cases after other dopamine therapy. Cannas et al. describe six young male PD patients without dementia who developed OS from dopamine therapy.(28
) Two of these patients were on pramipexole, while the others were on pergolide, ropinirole, levodopa and amantadine, levodopa and pergolide respectively.
All patients had a reduction or disappearance of jealousy after decreasing medication doses and adding an antipsychotic. Amantadine has previously been reported as a cause of OS.(4
) Dopamine appears to play an important role in producing OS. Interestingly, in our study, patients on pramipexole, adderall (a racemic mixture of amphetamine and dextroamphetamine), or methamphetamine also developed OS. All of these drugs affect dopamine. Methamphetamine is an analog of amphetamine which enters nerve terminals through the dopamine reuptake transporter system and changes the pH of the terminal to release dopamine from its vesicles causing dopamine to enter the synapse.(29
) Pramipexole is a dopamine agonist acting preferentially at the D3 receptor which is located in the frontal cortex, midbrain and limbic cortex.(30
) In our series, and the previously reported cases, three agonists (pramipexole, ropinirole, and pergolide account for the vast majority of OS with dopamine therapy in PD. Interestingly, all three have disproportionate affinity for the D3 receptor with pramipexole not surprisingly, having the highest affinity(32
) and hence accounting for the most cases in our series. Using PET imaging in primates, Black et al. demonstrated that pramipexole produced decreased cerebral blood flow in the bilateral orbitofrontal cortex, with greater decreases observed in the right hemisphere.(35
) A subject in our cohort developed OS after increasing the dose of valproic acid which resolved after decreasing the dose. Valproic acid has been shown to increase dopamine release in rat medial prefrontal cortex.(36
It should be noted that many individuals who take dopamine therapy with similar conditions never develop delusions and dopamine therapy has been linked to other delusions as well.
Antipsychotics were used with varying success to treat delusions in the neurodegenerative subgroups. These medications were unsuccessful in improving delusions in the vascular dementia or the lesion groups. The success of treatment was not dose dependent. Therefore, if someone does not respond to antipsychotic treatment, raising the dose and risking more side-effects is not recommended.
Our large number of patients allowed us to investigate clinical and demographic features of patients with OS. We found that 61.9% of the OS patients were male suggesting a slight male predominance associated with the syndrome. Unfortunately, the existing demographic data for OS is sparse. One previous report also found that OS occurs more frequently in males,(37
) although another study found that women outnumbered men two to one in a group of psychiatric patients with delusional jealousy.(38
We also found that OS occurred most commonly in patients with a neurological disorder (69.5%) and that the patients with neurological and psychiatric disorders were significantly older than those in the medication group. Although this latter finding could be due to a bias, since patients that are younger may be more likely to abuse drugs, the data suggests that OS is not an age dependent phenomenon. We also found that neurodegenerative disorders accounted for the majority of those with a neurological diagnosis (76.7%), in which DLBD was the most frequent. The DLBD group also had the highest frequency of hallucinations. It is perhaps not surprising then that we found visual hallucinations to be more commonly associated with OS in the context of a neurological disorder. In fact, the frequency of hallucinations in the LBD group was 76% which is significantly higher than the typically reported 40%.(15
) Perhaps, the higher than anticipated number of DLBD subjects with OS and hallucinations is related to the fact that four patients in our study had hallucinations specific to spousal infidelity. This association has been reported elsewhere. Sibisi reports that two LBD patients admitted to a psychiatric ward had hallucinations of sexual infidelity of the spouse resulting in delusional jealousy.(5
This study has a few limitations that show be mentioned. Firstly, premorbid personality may play a role in disease manifestation and the patients' families were not routinely asked about the patient's premorbid personality. Secondly, patients with sexual disorders such as impotence may be more likely to develop jealousy. Screening for these sexual disorders was not performed. Finally, neuropsychological data was not routinely performed in our patients.