Diagnosis, Pathology, and Treatment of bvFTD Pose Challenges

Treatment

SSRIs, antipsychotics, anticonvulsants, and stimulants have been used to treat apathy, disinhibition, compulsive behaviors, agitation, and inappropriate behavior in patients with bvFTD. “There are no FDA-approved treatments for bvFTD, and the evidence for [these agents] has been mostly reported in case studies and small clinical trials,” said Dr. Darby. Among the SSRIs, paroxetine improved repetitive behavior in open-label trials, but not in a randomized controlled trial. Sertraline and citalopram have been studied in open-label trials, and trazodone was examined in a randomized controlled crossover trial involving 26 patients.

The FDA issued a black box warning against the use of atypical antipsychotics in patients with dementia because they entail a risk of cardiac- and infection-related mortality. “For patients with bvFTD tau pathology in particular, there is a risk of extrapyramidal adverse effects,” said Dr. Darby. A series of case reports of risperidone and aripiprazole provided evidence of symptom improvement, as did an open label study of olanzapine. Quetiapine improved agitation in a case series but failed to show benefit in a double-blind crossover trial of eight patients with FTD.

Case series have shown evidence that antiepileptic drugs (eg, valproic acid, topiramate, and carbamazepine) have a stabilizing effect. “Stimulants are tried in some patients, but should be used with caution,” said Dr. Darby.

Criminality

Between 37% and 57% of patients with bvFTD engage in criminal behavior. “Approximately 10% to 15% of the time, a patient’s getting in trouble with the law is the reason for the initial presentation,” said Dr. Darby. The types of crimes described in case reports include pedophilia, public masturbation, hit and run, traffic violations, and theft.

“Murder and violent crimes occur but are rare. Crimes committed by patients with bvFTD are usually reactive,” said Dr. Darby. “When asked, they can tell you whether a specific act is right or wrong; however, they don’t show remorse for criminal behavior.” It is not clear whether executive dysfunction and the inability to reason, social perception and the inability to empathize, or differences in moral decision making are the reasons for changes in patients’ behavior, he said.

“One idea is that a network of brain regions, not just one part of the brain, is responsible for formulating the complex concept of morality.” In 2017, Dr. Darby and colleagues systematically mapped brain lesions with a documented temporal association with criminal behavior in 17 patients who were identified through a literature search. Criminal behavior included white collar crimes, and 12 of 17 patients had committed violent crimes. Fifteen cases had no history of criminal behavior before the lesion, and the behavior resolved following treatment of the lesion in two cases.

No single brain region had been damaged in all cases. Because lesion-induced symptoms can arise from sites connected to the lesion location, the investigators identified these sites in the cases. The network of these sites included regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Darby and colleagues replicated these results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was plausible, but not definite.

Prior research suggests that the areas associated with criminal behavior in patients with brain lesions closely resemble the areas typically affected in patients with bvFTD. Prospective studies are needed to further elucidate these results, Dr. Darby concluded.