Abstract
Behavioral syndromes are central to the clinical presentation of frontotemporal dementia. The authors review the behavioral changes seen in frontotemporal dementia and describe pharmacologic interventions for these behavioral syndromes.
Despite the fact that Pick’s disease was originally described in 1892,1 the diagnostic accuracy for this syndrome has remained so poor that more than 100 years later, in a 1993 report, 18 of 21 patients with Pick’s disease at autopsy were misdiagnosed as suffering from AD during life.2 Even today, the unwillingness of many dementia research centers to recognize frontotemporal dementia (FTD) as a distinctive disorder has greatly retarded the development of treatments for FTD. Unlike AD, in which there have been systematic attempts to ameliorate the cognitive and behavioral symptoms, to slow progression, and even to prevent disease onset, treatment approaches to FTD are still in their infancy. In addition, many of the therapies developed for AD may not work for FTD because the two disorders have different behavioral, cognitive, neurochemical, and molecular underpinnings. The recent discovery of mutations in the tau gene3 and the development of mouse models for FTD should eventually lead to more rational therapies. However, currently the treatment of FTD is directed toward the psychiatric alterations that characterize this disorder.
In this review we begin by describing the behavioral syndromes associated with FTD, with subsequent emphasis on the differences between patients with right-sided and left-sided disease. The denial of symptoms that characterize right-sided patients can lead to underestimation of the treatable component of these patients. Additionally, the neurochemical deficits that underlie these behaviors associated with FTD are described, and the known experience with treatment of these deficits is outlined. Finally, strategies that can be adopted by caregivers are suggested.
Behavioral symptomatology.
Frontotemporal dementia is the most common of the neurodegenerative syndromes produced by frontotemporal lobar degeneration.4 In contrast to AD, FTD is more characterized by the pattern of behavioral deficits than by neuropsychological impairment. Although the last decades of research in AD has led to the emergence of a distinct neuropsychological profile,5-7⇓⇓similar attempts to define the neuropsychological impairments of FTD have had far less success. Despite theories that FTD could be distinguished neuropsychologically from AD on the basis of a significant impairment on “frontal lobe” tests in the absence of severe amnesia, aphasia, or perceptuospatial disorder,4 analysis of the results of such comparative studies shows a less clear-cut difference. Indeed, attempts to differentiate FTD from AD on the basis of memory or attention and executive dysfunction have often met with contradictory results.8-11⇓⇓⇓
It has, therefore, become increasingly clear that FTD is primarily a neurobehavioral disorder rather than a neuropsychological one, and this is reflected in the core diagnostic features outlined in a recent consensus on clinical diagnostic criteria.4 These features include an insidious onset and gradual progression, early decline in social interpersonal conduct and regulation of personal conduct, early emotional blunting, and early loss of insight. Further features believed to be supportive of a diagnosis of FTD include decline in personal hygiene and grooming, mental rigidity and inflexibility, distractibility and impersistence, hyperorality and dietary changes, perseverative and stereotyped behavior, and utilization behavior.
Because of these early behavioral symptoms, patients with FTD may initially present to neurologists or psychiatrists, and this in itself may influence the differential diagnosis that is initially entertained. In a review of 12 cases of FTD, Gregory et al.12 found that seven patients had initially seen a psychiatrist and five a neurologist. One third of the patients received an initial psychiatric diagnosis, which included schizophreniform psychosis, depression, and psychogenic memory impairment, depression with obsessive–compulsive features, and alcohol dependency with hypomanic features. Patients with less overt behavioral features may present more readily to a neurologist, and AD is the most common differential diagnosis. Thus, although behavioral abnormalities are not confined to FTD and may also be present in AD, late-life depression (LLPD), and schizophrenia, each condition has its own pattern of behavioral symptoms that are related to the underlying neuroanatomical and neurochemical abnormalities.
Studies comparing FTD with AD or late-life depression have demonstrated marked qualitative as well as quantitative behavioral differences.12-15⇓⇓⇓ The depressive symptoms typical of AD are characterized by sadness, tears, anhedonia, decreased appetite with weight loss, insomnia, and guilt. FTD subjects tend to show an atypical mood disturbance with more marked irritability, increased appetite with weight gain, anhedonia, withdrawal, and alexithymia. Suicidal ideation and guilt, typical of the late-life depression group, is noticeably absent in the patients with FTD.
Despite similar proportions of AD and FTD patients having symptoms of depression, the relationship of depression to apathy in the two groups appears to differ. In AD and late-life depression apathy and depressive symptoms usually coexist.13 The same is not true of FTD, in which patients tested with the Neuropsychiatric Inventory combined high scores for apathy with low scores for depression,14 often with apathy and disinhibition occurring together. Thus a paradoxical and interesting combination of symptoms is seen in which patients with FTD exhibit a combination of passivity and psychomotor retardation together with intermittent outbursts of disinhibited restlessness, pacing, or socially inappropriate behavior.13 Apathy may also coexist with social and emotional withdrawal and a reduction in both amount and volume of speech output.
Psychosis has been recognized as a major behavioral symptom in FTD since Gustafson16 reported that six of 20 patients with FTD had psychotic episodes and three of the case histories described by Miller17 featured delusions. Delusions have also been reported as a common feature of AD—often misidentifications and a persecutory element in which patients perceive family members to be plotting against then and stealing their objects. Whereas delusions in AD are seen in the middle to late stages of the disease, and tend to be misidentifications or to have a persecutory element, they may be among the presenting symptoms in FTD. Delusions in FTD are rarely persecutory and can be jealous, somatic, or religious and often bizarre. Auditory hallucinations and delusions of reference, which are common in LLPD, are typically absent in FTD.13 In contrast, euphoria, which is rare in AD and absent in LLPD, was reported in one third of patients with FTD by both Gustafson16 and Levy.18 Euphoric symptoms may take the form of elevated mood, inappropriate jocularity, and exaggerated self-esteem and, when occurring with restlessness, may mimic hypomania.
A loss of empathy, although not often noted in early reports of FTD and not assessed by measures such as the Neuropsychiatric Inventory, has been increasingly reported as a symptom that dramatically affects the well-being of those caring for patients with FTD. When Gregory et al.12 assessed patients with FTD on an informant interview of neurobehavioral symptoms they found reduction of empathy in 12 of 15, with five of these patients describing an inability to feel or experience emotion in the usual way. Patients are described as flat, cold, distant, and uncaring about the emotional states of others around them. It is sometimes the case that these patients may have a preserved conceptual knowledge of the appropriate reaction in a given emotional situation but seem incapable of responding.
Dietary changes, especially carbohydrate craving, are seen in up to 80% of patients.13 These cravings for sweet foods, combined with a reduction in satiety, cause weight gain of often 15 to 40 pounds over a year. Later in the course of the disease, other features of the Klüver–Bucy syndrome may be observed, e.g., patients may eat bizarre combinations of food or put nonfood items in their mouths and chew them. Oral exploratory behavior and hypersexuality are less commonly reported,19 with a reduction in sexual drive common.15
Compulsions are a frequent symptom in FTD. In a clinicopathologic review of 46 patients with FTD, Ames et al.20 found that 78% had repetitive behaviors ranging from motor stereotypes to complex obsessive–compulsive disorder. Compulsions were a presenting feature in a third of patients sampled by Mendez21 and occurred in two thirds of patients in studies by Miller et al.15 and Swartz13 and 40% of those studied by Gregory.12 They usually consist of repetitive checking of locks, windows, etc.; repetitive hygiene rituals, such as repetitive urination or tooth brushing; counting or hoarding of items, especially food; drinking beverages in a specific order; or picking up coins. Behavior may become rigid as reported in the case of a patient who wanted to eat the same Chinese meal from the same restaurant every day at 4 pm.22 In a subtle twist of logic, this patient’s anxiety, which would increase through the afternoon until 4 pm, eventually became such that he turned all the clocks in the house forward to enable him to go to the restaurant earlier. Patients may start to immerse themselves in simple, tedious, and repetitive tasks for hours on end, and several have been noted to endlessly play ‘’search and circle” games. Although the compulsions of FTD appear to be like those of obsessive–compulsive disorder, the obsessions are usually lacking. It is possible that a lack of insight among these patients may prevent them from reporting obsessional experiences. Early loss of insight remains one of the core diagnostic features of FTD.4 This may range from a total denial of all symptoms to the more subtle loss of insight seen earlier in the disease, in which patients may recognize that their behavior has changed but appear to lack an emotional understanding of its consequences.
Neuroanatomical and neurochemical correlates of behavioral symptoms.
The frontotemporal lobar degenerations may affect both right and left frontal and temporal lobes to differing degrees. Although all “quadrants” are affected to some degree, even at presentation, many patients present with asymmetric atrophy. Those who present with predominantly right-sided atrophy exhibit more severe, and a wider range of, behavioral symptoms than those whose locus of pathology is predominantly left-sided.
Patients who present with predominantly left temporal lobe atrophy typically have features of a progressive language deficit of either a nonfluent or fluent type. Those with a progressive fluent aphasia have a profound and circumscribed deficit in semantic memory (our knowledge-based memory for words, objects, concepts, and their meaning),22 which has led the use of the term semantic dementia.23,24⇓ Although bilateral frontotemporal degeneration invariably results in disordered social conduct, in the early stages of left temporal disease patients often remain socially appropriate despite severe semantic deficits. Behavioral symptoms that may be more typical of left-sided disease include the use of “catch phrases” and a tendency toward depression and self-deprecation.
The recognition that patients with right-sided disease presented with more behavioral symptoms came from a detailed neurobehavioral study of five patients by Miller et al.25 All five of these patients with right-sided hypoperfusion exhibited behavioral symptoms at presentation that had dramatic effects on their ability to work and to maintain social relationships. Behavioral disinhibition and bizarre ideas are present in all such patients, as is a marked change in affect. Spouses often complain that they have “lost” their husbands or wives, who become “different people” or seem “alien.” The nuances of social interactions are lost with a lack of the usual facial expressions that we commonly use to communicate not only how we feel, but also to show our feelings to others. Because these patients no longer give us the reassuring facial signals that we have come to expect in social interaction, they can appear hostile and can induce unease in others. Reactions to spousal crises are usually inappropriate and appear cold-hearted, with no apparent regard for how others may be feeling. A “pet-like” passivity is seen, humor is lost, and features such as hypergraphia, hyperreligiosity, and interest in word games seem more typical of patients with right-sided degeneration.
Although pathologic studies have shown us the extent of disease in its end stages, more recent quantitative neuroimaging techniques suggest that the regions affected early in the disease are the anterior temporal poles and orbitomedial frontal lobes.26 The involvement of these particular areas is especially interesting given the mounting evidence for their link to behavioral symptoms of compulsions, disinhibition, and emotional processing. There is a growing consensus that abnormalities of the orbitofrontal cortex, cingulate gyrus, and basal ganglia are linked to compulsive behaviors in obsessive–compulsive disorder, with functional imaging studies showing increased orbitofrontal and caudate activity that improves after either pharmacologic or behavioral therapy.27-30⇓⇓⇓
The invariable damage to anterior temporal and orbitomedial frontal lobes may also explain the dramatic deficits in emotional responsiveness and social nuances seen in FTD. Lesions of the orbitomedial frontal lobes have been shown to cause impairments of social behavior, despite intact intellectual functions,31 and recent re-examination of the skull of the famous “crowbar case,” Phineas Gage, has suggested that damage to his orbitofrontal regions may explain the personality and emotional changes that mystified his doctors.32,33⇓ The amygdala, situated in the anterior temporal lobe and invariably damaged in FTD, is now widely recognized as a critical neural substrate in fear conditioning34,35⇓ and possibly in the processing of other emotions as well.36 The orbitomedial frontal lobe and its interconnections with the amygdala play an important part in how we use emotional cues in social contexts and support emotional learning by attaching emotional values to stimuli.37-40⇓⇓⇓
Bilateral amygdala damage predisposes to features of the Klüver–Bucy syndrome. Originally described in primates with bilateral temporal lobe lesions,41 this syndrome is characterized by symptoms that may include compulsive eating and hyperorality, hypersexuality, visual agnosia, and passivity.42 Although some of the features, noticeably hyperorality and passivity, are frequently present in FTD,19 it is difficult to explain why patients seem more likely to have reduced rather than increased sexual drive.15
There is currently a relative lack of data on the neurochemical deficits in FTD. Whereas AD has been associated with a deficit in cholinergic transmission,43,44⇓ comparative studies of FTD have failed to find a similar lack of acetylcholinesterase and choline acetyltransferase in the temporal, frontal, and parietal cortices of patients with FTD.45-47⇓⇓ Dopamine has also been reported to be unaffected, and reports of monoamine oxidase activity are inconclusive.48 Of more interest is the finding of decreased serotonin binding, both presynaptic and postsynaptic, in the frontal and temporal poles and hypothalamus of patients with FTD,49 which gives the possibility of pharmacologic intervention.
Pharmacologic treatment.
Although new acetylcholinesterase drug treatments for AD,50,51⇓ targeted to improve cholinergic transmission, have shown slight cognitive improvement in AD, the site of the beneficial action of these drugs is uncertain. Although a cortically mediated action would suggest that patients with FTD are unlikely to benefit,45-47⇓⇓ an improvement mediated via the nucleus basalis of Meynert (nbM), where cholinergic activity is decreased in both AD52 and FTD,49 would suggest that similar benefits might be expected in FTD. Currently, with the site of action of acetylcholinesterases not clearly defined, there is little theoretical support for administering such drugs until controlled trials show efficacy in FTD.
Despite the lack of cognitive therapies for FTD, the more debilitating behavioral symptoms are amenable to treatment. Several of the behavioral symptoms that occur in FTD are also seen in nondemented populations in which disinhibition, impulse control, and aggression toward others have been linked with a reduction in serotoninergic transmission.53,54⇓ Given that they respond to treatment that increases serotonin activity,55-57⇓⇓ and decreased serotonin binding in temporal and frontal cortices has been found in FTD, there are valid reasons for predicting a beneficial effect on these behaviors. Other symptoms commonly seen in FTD, such as compulsions and carbohydrate craving, may also have a basis in serotoninergic deficiency49 58⇓ and may benefit from selective serotonin reuptake inhibitors (SSRI). In a recent study by Swartz et al.,59 11 subjects with FTD were administered SSRI and evaluated for a change in behavioral symptoms 3 months later. After treatment, disinhibition improved in six of nine subjects, carbohydrate craving improved in five of nine, and compulsions in four of seven. Treatment with SSRI is well tolerated, and they are currently the drugs of choice for behavioral control in FTD.
Aggressive behavior can be problematic for families of patients with FTD, and pharmacologic intervention is often requested. Benzodiazepines and high doses of neuroleptics can be extremely counterproductive and harmful and should be avoided. If neuroleptics are to be used, small doses of risperidone or olanzapine may be more effective than traditional antipsychotics,60 although there is increasing support for using atypical antidepressants such as trazodone.61 Drugs typically used as anticonvulsants, such as sodium valproate and carbamazepine, have also been shown to be beneficial in modulating agitation and aggression in dementia,60 and carbamazepine has also been used effectively in the Klüver–Bucy syndrome.62 Other drugs that have been used for the symptoms of the Klüver–Bucy syndrome include propanolol for aggression and leuprolide, an LH/RH agonist, for treatment of sexually aggressive and inappropriate behaviors.63 SSRI have also been shown to work well,64 and because they are safe and well tolerated they are probably the drugs to try first.
Caregiver strategies.
Various strategies can be adopted by caregivers to prevent or to minimize the impact of behavioral symptoms in FTD, and although many rely on little more than common sense, if kept in mind they can be very effective. It is necessary to remember that FTD affects judgment, and caregivers should avoid allowing patients into situations in which judgment is important. In this disease, caregivers lose the intellectual and emotional support of an adult partner and have to assume the role of a parent. Patients with FTD should not be allowed to drive because of numerous reported incidents including hit and run accidents, running red lights, and even driving too slowly. If patients continue to work, they should be guided into roles that do not entail financial decision making because unethical accounting and poor financial management may occur. Other problems encountered in the work place include sexual impropriety and aggression toward others, often with the patient unaware that they have transgressed social boundaries. It is also unwise to leave patients with FTD in charge of others, especially children, because of the potential risks of abandonment or exploitation.
Although cognition is largely unresponsive to therapy, behavioral symptoms are treatable if approached with a realistic attitude to targeting specific symptoms and accepting small gains. Approaches to patients that other caregivers have shown to work include being direct, but without force, and remaining calm and unwavering. The behavioral symptoms that caregivers have to face day-in and day-out are exhausting, and accepting that the burden has to be shared can be hard for many. Having people to help for a few hours a day or arranging respite care for several days or weeks can improve a seemingly hopeless situation. If full-time care is considered, it is well to plan ahead and to confront decisions that may have to be made regarding subsequent treatment of infections or methods of feeding should patients become unable to swallow. With increasing sensitivity to the diagnosis of FTD and recognition of its behavioral symptoms, more support groups, specifically for caregivers of patients with FTD, are being formed. As with AD, they will hopefully become a source of information, support, and advice from those who understand the disease best, the families of those with FTD.
Conclusions.
Frontotemporal dementia is a progressive neurobehavioral syndrome characterized by early decline in social interpersonal conduct, early impairment in the regulation of personal conduct, early emotional blunting, and early loss of insight. Although both right and left frontal and temporal lobes are effected, the presentation may be markedly asymmetrical, with language deficits predominating in a left temporal presentation and a severe behavioral disorder being typical of right-sided disease. Symptoms associated with right-sided FTD include hyperorality, disinhibition, compulsions, delusions, and a profound deficit in empathy and emotional processing. Compulsions are likely to be related to disruption of orbitofrontal-striatal circuits as in obsessive–compulsive disorder, and the loss of empathy and emotional unreactivity may be caused by damage to the amygdala and its connections to the orbitomedial cortex. Information on neurochemical abnormalities in FTD is sparse, but decreased serotoninergic binding in frontal and temporal lobes and the hypothalamus may underlie carbohydrate craving, disinhibition, and aggression. Although treatment of cognitive symptoms is unrewarding, many behavioral symptoms are amenable to drug therapy. Treatment with selective SSRI is often effective in combating behavioral symptoms such as carbohydrate craving and disinhibition, whereas aggression and agitation, unresponsive to SSRI, may be treated with atypical neuroleptics such as olanzepine and risperidone and anticonvulsants such as carbamazepine and valproate.
References
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