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Frontotemporal dementia: Treatment

Frontotemporal dementia: Treatment
Author:
Suzee E Lee, MD
Section Editor:
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Dec 2022. | This topic last updated: May 04, 2022.

INTRODUCTION — Frontotemporal dementia (FTD) is a neuropathologically and clinically heterogeneous disorder characterized by focal degeneration of the frontal and/or temporal lobes [1]. Age of onset is typically in the late 50s or early 60s. The primary initial clinical manifestations include changes in personality and social behavior or language, progressing over time to a more global dementia affecting other cognitive domains. A subset of patients may also exhibit symptoms of extrapyramidal or motor neuron involvement during the disease course.

There are no current US Food and Drug Administration (FDA)-approved disease-modifying treatments for FTD. Since the underlying pathology of FTD usually consists of tau or TAR DNA binding protein (TDP-43) aggregates, treatments geared toward beta-amyloid reduction that appear promising in Alzheimer disease (AD) are not expected to be effective for FTD.

Symptomatic relief can be provided by a variety of agents. However, these medications are not FDA approved for FTD and have limited evidence of efficacy. These medications should be considered in conjunction with nonpharmacologic interventions, such as thoughtful evaluation of the patient's living environment.

This topic discusses treatment issues specific to patients with FTD. Epidemiology, pathology, clinical features, and diagnosis of FTD, and the management of other forms of dementia, are discussed separately. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis" and "Frontotemporal dementia: Clinical features and diagnosis" and "Treatment of Alzheimer disease" and "Treatment of vascular cognitive impairment and dementia" and "Prognosis and treatment of dementia with Lewy bodies" and "Management of neuropsychiatric symptoms of dementia" and "Management of the patient with dementia".)

NONPHARMACOLOGIC INTERVENTIONS — In addition to managing behavior, nonpharmacologic interventions focus on health maintenance and safety. Nonpharmacologic treatment requires a strong partnership with the patient's caregivers.

Safety and driving — Because of prominent behavioral changes and impulsivity, safety becomes a concern early on in FTD. Patients often need protection from serious consequences of impaired judgment; supervision of financial decision-making, early retirement, and driving safety should be assessed and discussed in initial office visits [2-4]. A practice parameter published by the American Academy of Neurology provides guidelines regarding driving safety and discontinuation of driving [5] (see "Approach to the evaluation of older drivers", section on 'Cognitive function'). Physical supervision may be required if patients demonstrate behavior that is dangerous to themselves or others. These issues are discussed in detail separately. (See "Management of the patient with dementia".)

Exercise and mobility — Regular cardiovascular exercise should be encouraged for both general health and also the enhancement of cognition in patients with dementia. Exercise programs have demonstrated benefits in both mood and cognition in patients with dementia, and their importance should not be underestimated. (See "Management of the patient with dementia", section on 'Exercise programs'.)

Mobility becomes a problem in patients with FTD later in the disease course, particularly for those with prominent parkinsonism or amyotrophic lateral sclerosis (ALS). Physical therapy can help with balance and help maintain physical activity [6]. Physical aids such as a raised toilet seat, commodes, and removal of unsecured rugs can help reduce the potential for injuries in the home [7].

Speech therapy — Speech therapy and the use of communication aids may provide benefit early on in patients with semantic variant or nonfluent variant primary progressive aphasia [6]. Later in the course of the illness, evaluation of swallowing is critical to prevent aspiration.

Behavioral modification — Nonpharmacologic behavioral modification techniques can be a useful adjunct in the management of the problematic behaviors in FTD. A behavioral monitoring log may help identify triggers that can be avoided or otherwise managed [7]. Distraction, redirection, and offering of simple choices can be effective alternatives to medications for disinhibition, compulsive habits or rituals, agitation, and anxiety, but require caregiver education and support [8]. A structured environment that avoids overstimulation can provide stability and predictability for the patient. Providing environmental cues for behaviors that should be encouraged (eg, laying out clothing, tools for self-care) and removing environmental cues for behaviors that should be discouraged (eg, car keys) can also be useful in some patients.

Caregiver stress is a significant problem in FTD. Respite care and support groups are available in most areas, often through the local agency on aging [4]. (See "Management of neuropsychiatric symptoms of dementia", section on 'Support for caregivers'.)

PHARMACOLOGIC TREATMENT — Pharmacologic treatment in FTD is symptomatic and aimed at alleviating neurobehavioral symptoms. Despite the fact that medications are commonly used for behavior symptoms, there is limited evidence regarding the efficacy of pharmacologic treatments in FTD [9].

Neurotransmitter systems — A neurochemical basis for FTD remains to be fully elucidated. Nonetheless, studies have indicated problems in certain neurotransmitter systems:

Abnormalities in serotonin activity have been demonstrated in autopsy, neuroimaging, and cerebrospinal fluid studies in patients with FTD [10,11]. In addition, serotonergic dysfunction has been linked to many of the behavioral problems that are common in FTD. However, these associations have been made, for the most part, in patients without rather than those with FTD [2,12-15].

Dopaminergic function can also be altered in patients with FTD, usually in proportion to the severity of extrapyramidal motor symptoms [16,17]. One study found that increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission were specifically associated with agitated and aggressive behavior, respectively [18].

The cholinergic system appears to be relatively preserved in FTD, in contrast to Alzheimer disease (AD) [10,11,14].

Cognitive dysfunction — No medications have been demonstrated to improve or stabilize cognitive deficits in patients with FTD.

The available data do not support the use of cholinesterase inhibitors in FTD. The primary exception is when there is uncertainty about whether the patient has FTD or AD. In such cases, a therapeutic trial of a cholinesterase inhibitor is reasonable, given data supporting modest symptomatic benefits in patients with AD. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Indications'.)

One placebo-controlled eight-week trial of galantamine in patients with FTD suggested a trend toward benefit in the subgroup of patients with primary progressive aphasia, but not in patients with behavioral variant FTD (bvFTD) [19]. An open-label study of rivastigmine found a benefit of treatment on measures of executive function but not global cognition as measured by the Mini-Mental State Examination [20]. Finally, an open-label study of donepezil found no benefit of treatment on cognitive measure; some patients developed worsened behaviors [21]. More recent studies have replicated these findings and have also found that discontinuation of donepezil sometimes resulted in improved behavior symptoms [22,23].

Behavioral changes

Considerations prior to treatment — Behavioral symptoms can be variable and include socially inappropriate behavior, apathy and inertia, agitation, and compulsions that manifest as hoarding or abnormal eating behaviors. These are described in detail separately. (See "Frontotemporal dementia: Clinical features and diagnosis", section on 'Behavioral variant FTD'.)

Behavioral symptoms arise early in bvFTD and may also be problematic in the other subtypes of FTD (semantic and nonfluent primary progressive aphasia). These symptoms contribute substantively to the care burden of patients with FTD and can be challenging to treat [24].

When neurobehavioral problems appear or worsen, clinicians should consider the possibility of delirium, pain, or discomfort as a cause for patients' symptoms before initiating treatment. (See "Diagnosis of delirium and confusional states" and "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

Patients with FTD are susceptible to adverse effects of medications (such as anxiolytics and antipsychotics) used to treat behavioral symptoms [25]. These adverse effects may include paradoxical behavioral reactions, extrapyramidal side effects, confusion, and sedation. These adverse effects are described in more detail separately (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects"). To mitigate these effects, we start with the lowest available dose, titrate the dose upward slowly, and frequently monitor for side effects. In our clinic, we use serotonergic medications as first-line treatments for behavioral symptoms.

Because the side effects of various medications may exacerbate behavioral symptoms, slow movement and reaction times, and contribute to confusion, the role of each medication should be continuously reevaluated; medications of unclear benefit should be tapered cautiously.

Serotonergic medications — A treatment trial of a serotonin reuptake inhibitor (eg, citalopram 10 to 20 mg once daily) or trazodone 25 mg once daily is suggested as initial pharmacotherapy for patients with troubling behavioral symptoms of FTD. Doses can be gradually titrated according to symptomatic improvement or may be limited by side effects, but are generally kept low. The evidence supporting the use of serotonergic medications is stronger than for other classes of medications. However, this evidence comes mostly from uncontrolled observations rather than from controlled clinical trials. In our clinic, we typically allow several weeks after a slow titration to evaluate whether the selective serotonin reuptake inhibitor (SSRI) is providing a benefit before trying a different medication in this class.

SSRIs (eg, sertraline, paroxetine, fluvoxamine) have been reported to decrease disinhibition, anxiety, impulsivity, repetitive behaviors, and eating disorders in case reports and small observational studies of patients with FTD [12,24,26-31]. Individual patients with sexual disinhibition have been treated with SSRIs with success [26,32]. In a case series of four patients, pathologic stealing behavior was not attenuated with SSRI therapy [33].

An unblinded, randomized trial of 16 patients compared the SSRI paroxetine (up to 20 mg per day) and piracetam (up to 1200 mg per day). At 14 months, treatment with paroxetine was associated with significant improvement in behavioral symptoms and decreased caregiver stress compared with piracetam-treated patients [27]. By contrast, another double-blinded, randomized crossover trial in 10 patients found that six weeks of paroxetine, rapidly escalated to a dose of 40 mg per day, was not associated with improvements in behavioral or executive function outcomes [34]. An open-label trial of citalopram in 15 patients with bvFTD showed improvement of behavioral symptoms over a six-week period [35].

Low doses of trazodone, an atypical serotonergic antidepressant agent, have been reported to be effective in treating agitation and aggression in patients with FTD in observational studies [10]. A double-blinded, randomized crossover trial of trazodone in 26 patients with FTD found a significant reduction in neuropsychiatric symptoms with trazodone as compared with placebo [36]. Benefits of treatment were most notable for irritability, agitation, depressive symptoms, and eating disorders.

Alternative medications

Antipsychotic medications — Atypical antipsychotic medications (eg, olanzapine, quetiapine, aripiprazole) can help with agitation and other neurobehavioral symptoms in FTD [24,26,37,38]. However, because of adverse effects and increased risk of mortality, antipsychotic medications should be considered a last resort only after trying behavioral modifications and SSRIs. In the United States there is a US Food and Drug Administration (FDA) black box warning for use of all antipsychotics in dementia, due to increased risk of cerebrovascular events and mortality [39]. If multiple trials of SSRIs do not help behavioral symptoms, low-dose quetiapine (eg, 12.5 mg starting dose) may be added and titrated slowly as needed, with careful monitoring for side effects. (See "Management of neuropsychiatric symptoms of dementia", section on 'Antipsychotic drugs'.)

In one case series, 17 patients with FTD were treated with olanzapine 2.5 to 10 mg per day and followed for 24 months [37]. Treatment was associated with a decrease in delusions and other neurobehavioral symptoms as well as reduced caregiver stress. Somnolence was observed in almost a third, but could be managed by dose reductions.

Patients with FTD are particularly vulnerable to the extrapyramidal side effects of antipsychotics. These medications should be used with great caution. Depot preparations, typical antipsychotic agents, and risperidone should be avoided [25,40,41]. Quetiapine has moderate D2 receptor antagonism relative to other antipsychotic medications and may cause fewer extrapyramidal side effects [42].

Patients and family members should be informed that use of antipsychotic medications has been associated with increased mortality in older adult patients with dementia. (See "Management of neuropsychiatric symptoms of dementia", section on 'Mortality risk' and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

Stimulants — The clinical evidence supporting the benefit of stimulants is very limited in patients with FTD, and we generally discourage their use. These medications can precipitate delirium in some patients.

The rationale for use of stimulants such as methylphenidate is that they may ameliorate dopaminergic deficits present in FTD and thus affect behavioral changes, in particular apathy. Methylphenidate increases synaptic levels of dopamine and norepinephrine.

A case report [43] and a small case series [44] reported behavioral improvements in apathy and disinhibition with methylphenidate and dextroamphetamine, respectively. A double-blind placebo-controlled crossover study using a single 40 mg dose of methylphenidate in eight FTD patients revealed that treatment was associated with diminished risk-taking behavior as assessed by the Cambridge Gambling Task [45].

Other agents

Memantine is not recommended for use in patients with FTD. Although initial small, open-label studies suggested that memantine improved behavioral symptoms in patients with FTD [24,46-50], two randomized double-blind trials failed to confirm these findings [51,52]. In one trial that included 49 patients with bvFTD randomized to receive either memantine or placebo for one year, there were no differences in clinical endpoints between the two groups [51]. A larger randomized trial also showed no change in neuropsychiatric measures or clinical status, and in fact, patients treated with memantine showed more frequent cognitive adverse events than those taking placebo [52].

Antiseizure medications (eg, carbamazepine, valproate, lamotrigine) have been used to manage neurobehavioral symptoms in other neurodegenerative dementias, but without convincing evidence of efficacy (see "Management of neuropsychiatric symptoms of dementia", section on 'Drugs with uncertain benefit'). One case report documented that topiramate was associated with improvement with alcohol use disorder but not other compulsive behaviors [53]. Other reports have noted that valproate therapy has been associated with reduced agitation and self-neglect [26,54].

There is sparse evidence for the use of monoamine oxidase (MAO) inhibitors in FTD. Selegiline improved behavior and attention in three patients with FTD [55]. In another report, six FTD patients taking moclobemide demonstrated improvements in depression, aggressivity, speech, and stereotyped behavior [56].

In one patient with inappropriate sexual behavior, conjugated estrogen (eg, Premarin) 0.625 mg per day appeared to be helpful [26].

Benzodiazepines are generally not recommended in FTD because they have negative effects on cognition and can precipitate paradoxical agitation.

Parkinsonism — Patients with FTD who have parkinsonism typically do not respond to dopaminergic medications such as levodopa or amantadine, although some patients have transient motor improvements on these medications [26]. Psychosis and vivid dreaming can be limiting side effects. Patients may receive a treatment trial of levodopa-carbidopa, although response to this medication is often minimal or transient [57,58]. A trial of dopamine agonists can also be considered in those who do not respond to levodopa-carbidopa, although the response can be poor. (See "Initial pharmacologic treatment of Parkinson disease".)

FUTURE APPROACHES — Disease-modifying approaches to the treatment of FTD and related disorders are underway. These experimental drugs include anti-tau antibodies, microtubule stabilizers, drugs to inhibit tau aggregation and acetylation, and drugs targeted toward disease-causing genetic mutations for FTD [59].

PROGNOSIS — FTD has a younger age of onset and appears to progress more rapidly than Alzheimer disease (AD) [60-62]. Survival from symptom onset is approximately 8 to 10 years and is often shorter in patients with the behavioral variant of FTD (bvFTD) than those with primary progressive aphasia [63-69]. Patients with bvFTD with motor neuron disease have the shortest disease duration of approximately two years [60,64].

PALLIATIVE CARE — In the terminal stages of dementia, patients and their caregivers are faced with a range of physical and psychosocial needs, and effective palliative care can improve patients' symptoms, lessen caregiver burden, and help ensure that treatment decisions are well informed and weighed in the context of patient and family goals and needs. Aspects of palliative care that are specific to patients with advanced dementia are discussed separately. (See "Care of patients with advanced dementia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

SUMMARY AND RECOMMENDATIONS

Treatment goals and other considerations – There are currently no effective disease-modifying treatments for frontotemporal dementia (FTD). Both pharmacologic and nonpharmacologic interventions are aimed at ameliorating symptoms, particularly the behavioral symptoms of FTD.

Patients with FTD are susceptible to adverse effects of medications including paradoxical behavioral reactions, extrapyramidal side effects, confusion, and sedation. Starting with the lowest available dose of medication, slow upward dose titration, and frequent monitoring for side effects are recommended. Medications should be regularly reevaluated. (See 'Considerations prior to treatment' above.)

Nonpharmacologic interventions – These are an important facet of the management of patients with FTD and can include an exercise program; modification of the home environment; increased supervision; physical, occupational, and speech therapy; behavioral modification techniques; and caregiver support and respite. (See 'Nonpharmacologic interventions' above.)

Limited role for cholinesterase inhibitors – Cholinesterase inhibitors do not have convincing evidence of benefit in patients with FTD and do not have a role in symptomatic management, unless there is diagnostic uncertainty, and a diagnosis of Alzheimer disease (AD) seems equally as likely as FTD. (See 'Cognitive dysfunction' above and "Cholinesterase inhibitors in the treatment of dementia".)

Neurobehavioral problems – When neurobehavioral problems appear or worsen, clinicians should consider the possibility of delirium, pain, or discomfort as a cause for these symptoms before initiating pharmacologic treatment. (See 'Considerations prior to treatment' above.)

For patients with troubling neurobehavioral symptoms of FTD despite nonpharmacologic interventions, we suggest a treatment trial of a serotonin reuptake inhibitor (eg, citalopram 10 to 20 mg once daily) or trazodone 25 mg once daily (Grade 2C). (See 'Serotonergic medications' above.)

Other treatment options include atypical antipsychotic agents to be used as a last resort. Patients with FTD need to be carefully monitored for extrapyramidal side effects, for which they are particularly vulnerable. If needed, we use a low dose of quetiapine (eg, 12.5 to 25 mg), which has fewer reported extrapyramidal side effects relative to other antipsychotic medications. The US Food and Drug Administration (FDA) has issued a black box warning for all antipsychotics in dementia due to increased risk of adverse events and mortality, and families should be warned about these risks with use of these medications in this setting. (See 'Antipsychotic medications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bruce L Miller, MD, who contributed to an earlier version of this topic review.

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