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Certain clinical features may indicate bvFTD, and off-label treatments may provide benefits.
HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.
Clinical Features and Diagnosis
The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.
A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.
“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.
Pathology
Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with
Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.
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.
—Adriene Marshall
Suggested Reading
Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.
Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.
Certain clinical features may indicate bvFTD, and off-label treatments may provide benefits.
Certain clinical features may indicate bvFTD, and off-label treatments may provide benefits.
HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.
Clinical Features and Diagnosis
The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.
A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.
“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.
Pathology
Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with
Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.
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.
—Adriene Marshall
Suggested Reading
Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.
Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.
HILTON HEAD, SC—Behavioral variant frontotemporal dementia (bvFTD), a clinically and pathologically heterogenous condition, can be difficult to distinguish from other forms of dementia or frontotemporal disease. “Although clinical symptoms vary based on which part of the brain is affected, there is a significant amount of overlap, with different pathologies causing the same type of syndrome,” said Richard Ryan Darby, MD, Assistant Professor of Neurology at Vanderbilt University Medical School in Nashville. “In a large proportion of patients, behavioral changes can lead to criminal behavior.” Future research examining brain lesion networks may shed light on this condition, said Dr. Darby at the 41st Annual Contemporary Clinical Neurology Symposium.
Clinical Features and Diagnosis
The incidence of bvFTD is equal to that of Alzheimer’s disease. However, patients with bvFTD tend to be younger: between the ages of 45 and 65. “Social and behavioral features predominate,” said Dr. Darby. “If a patient in this age range with no previous psychiatric history presents to you with a new psychiatric diagnosis such as schizophrenia or bipolar disease, this should raise your suspicion of bvFTD.” These psychiatric problems often cause considerable disruptions in patients’ lives. They often have problems at work and lose their source of income. “Patients often have no insight about their symptoms,” said Dr. Darby.
A differential diagnosis of bvFTD is possible in patients with three or more of the following six clinical features: socially inappropriate behavior (eg, eating from the trash or walking around naked at inappropriate times); lack of empathy; apathy; stereotyped or repetitive behavior (eg, saying things repeatedly, pacing); hyperorality (eg, eating uncontrollably, particularly sweet foods); and executive dysfunction, especially when memory is preserved.
“When you talk to caregivers, they often say, ‘This is not the person I married,’ or, ‘This is not my father. He seems like a different person,’” said Dr. Darby. An MRI or a PET scan showing changes in the frontotemporal lobes is a firm basis for a diagnosis of bvFTD, said Dr. Darby. Genetic testing for autosomal dominant mutation or pathology or an autopsy provides a definite diagnosis.
Pathology
Between 40% and 50% of patients with bvFTD have tau pathology, said Dr. Darby. This pathology includes the classic Pick body form of tau, tufted astrocytes (which are associated with clinical symptoms of progressive supranuclear palsy), and astrocytic plaques (which are associated with symptoms of corticobasal degeneration). Similarly, between 40% and 50% of patients with bvFTD have a TAR DNA-binding protein 43 (TDP-43) pathology. TDP-43 Type A pathology is associated with perirolandic seizures, Type B is associated with
Mutations in C9orf72 occur in 13% to 50% of patients with bvFTD who have genetic mutations. ALS and parkinsonism are common clinical presentations in patients with this genetic mutation. MAPT and GRN mutations are present in 5% to 20% of cases, and each can present clinically as parkinsonism.
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.
—Adriene Marshall
Suggested Reading
Darby RR, Horn A, Cushman F, Fox MD. Lesion network localization of criminal behavior. Proc Natl Acad Sci U S A. 2018;115(3):601-606.
Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017;140(12):3329-3345.