Overview of frontotemporal dementia and the variety of its clinical presentations

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Chapter 3 Overview of frontotemporal dementia and the variety of its clinical presentations


Matthew Jones and David Neary




Introduction


Frontotemporal dementia (FTD) is the name given to a group of syndromes that are characterized by progressive atrophy of the frontal and temporal lobes of the brain. These neurodegenerative conditions are non-Alzheimer dementias and are linked by a range of pathologic processes collectively referred to as frontotemporal lobar degeneration (FTLD) spectrum pathology. The range of pathologic changes seen can broadly be split into three, according to the major protein seen deposited at post-mortem brain examination: tau, transactive response DNA-binding protein of 43 kDa (TDP-43), and the tumor-associated protein fused in sarcoma (FUS). Around a third of patients have a positive family history and the heterogeneity of these conditions is further underlined by the range of genetic mutations now found in association with them. The commonest mutations seen are in the genes encoding progranulin (GRN), microtubule-associated protein tau (MAPT), and chromosome 9 open reading frame 72 (C9orf72).


Whilst once considered a rare diagnosis that could not be made on clinical grounds in life, these syndromes are now recognized as being amongst the commoner forms of early-onset dementia. Three principle syndromic variants are described. The commonest is behavioral variant frontotemporal dementia (often abbreviated to simply FTD or bvFTD) and accounts for approximately half of the FTD spectrum cases seen. Then there are two presentations defined by disorders of language and/or conceptual function – semantic dementia (SD, also referred to as semantic variant primary progressive aphasia [PPA]) and progressive non-fluent aphasia (PNFA, also referred to as non-fluent variant primary progressive aphasia [nfvPPA]). Overlap with other neurodegenerative conditions is increasingly recognized; some patients with FTD may develop amyotrophic lateral sclerosis (ALS or motor neuron disease [MND]) or symptoms of a parkinsonian disorder. In particular there are close overlaps with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). In this chapter we aim to offer an introduction to the clinical features of this heterogeneous group of conditions.



Epidemiology


Estimations of how common FTD is have varied greatly between research groups. Part of this may reflect genuine geographic variations in prevalence, but some of the discrepancies are likely accounted for by differences in case ascertainment method and use of different diagnostic criteria.


In the Netherlands the overall prevalence was estimated at 1.1 per 100 000, although in the Zuid Holland region this rose to 2.7 per 100 000 [1]. In this study prevalence was calculated to be highest in the 60- to 69-year bracket at 9.4 per 100 000. In Northern Italy overall prevalence was found to be considerably higher at 17.6 per 100 000 [2]. In Southern Italy a door-to-door survey revealed a rate of FTD of 3.5% in all those over the age of 50 [3]. In Japan a number of outpatient clinic surveys have revealed rates of FTD to be between 6.8% and 12.7% amongst consecutive clinic patients with dementia [4]. In Cambridge (UK) the prevalence of FTD has been estimated at 15 per 100 000 in the 45- to 64-year-old age range [5]. A recent study from the USA calculated that the prevalence of FTD is 15–22 per 100 000 in 45- to 64-year-olds, which is broadly consistent with the Cambridge, UK estimation [6]. Based on those figures there are an estimated 20 000–300 000 people with FTD in the USA. Estimations on prevalence of FTD in developing countries are largely lacking [7].


FTD most commonly presents between the ages of 45 and 64, as indicated in the above studies. There is, however, a broad range of ages at which patients can present; experience from pathologic series in the UK indicates the age range for FTD presentation to be between 21 and 86 years [8, 9].



Classical features of frontotemporal dementia spectrum syndromes



Behavioral variant FTD (bvFTD)


Abnormalities in behavior are the hallmark of this disorder. It is the commonest of the FTD spectrum disorders and accounts for approximately half of all cases caused by FTLD pathology. Like all neurodegenerative conditions the symptoms start insidiously and gradually progress. Often initial behavioral symptoms are attributed to something else such as an affective disorder or stress. Changes in behavior may be subtle to begin with and a loss of interpersonal skills and altered conduct in social situations may be the first evidence of the condition clinically. The condition is associated with varying degrees of atrophy involving the frontal lobes, but anterior temporal atrophy is also often present.


Patients with bvFTD usually lack insight and thus do not seek medical attention for their symptoms. The next of kin or friends of the patient are usually responsible for bringing the situation to medical attention. Patients may lack social emotions such as sympathy and empathy. Patients lack the ability to infer the emotional feelings of others and may struggle to see other people’s perspective. These deficits in social cognition and specifically theory of mind and empathy have become recognized as important aspects of bvFTD [10, 11]. These symptoms readily lead to lapses in normal social behavior that initially could be viewed as embarrassing, but as they progress may become increasingly hard to manage. Patients with bvFTD struggle to express emotion and may appear blunted in affect.


Significant phenotypic variation occurs in the behaviors seen in patients with bvFTD. Some patients present with overactivity and disinhibition, whereas others predominantly suffer from apathy and lack of drive. Whether disinhibited or apathetic, patients with bvFTD suffer from a loss of interest in their usual activities. Patients with bvFTD may manifest repetitive motor acts or verbal utterances. These may be simple stereotypies or sometimes more complex repetitive activities and phrases. Case studies 1 and 2 highlight some of the features of and differences between the disinhibited and apathetic presentations of bvFTD.


A change in eating behavior and dietary preferences is often seen in bvFTD. Patients may exhibit a preference for sweet foods, have food fads, or display gluttony. A tendency to overeat and stuff food into the mouth can be seen. Patients may place inedible objects into their mouth.


Patients with bvFTD may have altered responses to sensory stimuli. This can manifest as a lack of normal response to pain or, conversely, as an overreaction to innocuous stimuli [12].


In addition to altered behavior, psychiatric symptoms may be present in a minority of bvFTD cases. Some patients manifest delusional beliefs or suffer from hallucinations. Such psychiatric features are reported to occur more commonly in patients carrying a C9orf72 hexanucleotide repeat expansion [13].


The behavioral features of bvFTD can be elicited by careful history taking from the patient, but often more critically, from a close relation of the patient. A structured approach to this is helpful so as not to overlook symptoms that patients and carers would otherwise fail to disclose spontaneously. A number of the behaviors described above can be embarrassing for carers to discuss and time spent with the informant away from the patient is usually necessary. Some of the described behaviors can be observed directly by the physician even in the relatively brief period of a standard outpatient consultation.


The cognitive features of bvFTD are usually those of a dysexecutive syndrome. These can be detected on neuropsychological testing. Patients may struggle with tasks requiring planning, problem-solving, mental flexibility, judgment, and attention. Other cognitive abilities such as language, visuospatial functioning, and memory, being more posterior cortical functions, are generally well preserved. However, patients with bvFTD may appear to score badly on a range of cognitive measures and here the qualitative nature of their performance is of vital importance. Test performance is often overall characterized by inattention, difficulty changing set, impulsivity, and problems with impulse inhibition. Any of these problems may lead a patient to fail a given task, although not necessarily due to a deficit in the domain ostensibly being tested. For instance, poor memory test scores may be due to poor attention or a lack of spontaneous generation of response. In addition to testing the standard range of neuropsychological domains it is becoming increasingly common for tests of social cognition to be incorporated into bvFTD assessments.


Physical signs on neurologic examination are often absent at the time of presentation. Patients may have primitive reflexes such as grasp or snout reflexes and these may become more apparent as the illness progresses. Some patients have evidence of extrapyramidal signs in the form of rigidity and bradykinesia. A proportion of patients with bvFTD develop, or present with, evidence of ALS. Additional details on bvFTD are reviewed in .



Semantic dementia (SD)


This disorder, also known as semantic variant PPA in the latest classification system [14], is often initially characterized by a loss of memory for words. The condition is strongly associated with asymmetric atrophy of the anterior and inferior temporal lobes, usually left more than right.


Patients speak fluently but are relatively anomic with empty speech. Grammar and phonology are intact. In addition to the output problem, comprehension for words is affected, particularly for lower frequency or less familiar words. The disorder affects all aspects of semantic knowledge and thus patients have difficulty recognizing objects visually and identifying sounds and smells (associative agnosia). None of these problems is due to an elementary perceptual deficit, but rather a breakdown in the semantic knowledge of what the object is.


Patients will often substitute more familiar, within category (coordinate), words for an item but progressively use more general terms or make superordinate category errors. This can be evident in spontaneous speech and is also detected on neuropsychological naming tests. When reading aloud patients may make regularization errors, pronouncing irregularly spelt words phonetically (pint said to sound like hint).


Failure to recognize objects can lead to misuse of household items or tools. Patients with SD may have significant difficulty in recognizing the faces (prosopagnosia) of those previously familiar to them. This particular feature has been linked to right-sided temporal atrophy [15]. Case studies 3 and 4 exemplify the features of patients with SD; Case 3 is typical of a patient with predominantly right temporal atrophy at presentation and Case 4 with predominantly left temporal atrophy.


Behavioral changes are common in SD [12], although patients tend to have a greater degree of insight than those with bvFTD. Some patients appear garrulous and can be hard to interrupt during spontaneous speech. Patients with SD may display an increased level of interest in a narrower range of activities. Many patients develop obsessions with word or number puzzles. Patients may clock watch and become obsessed with time and routine. Conversational themes become limited and repetitive. Similarly, food preference may become highly selective with dietary fads. Many of these behavioral changes can be conceptually linked to the loss of semantic knowledge; patients engage in an ever-narrowing range of behaviors and conversational topics, reflecting their loss of semantic meaning.


Physical examination is usually normal in SD. A small proportion of patients develop ALS. Further details on SD are reviewed in Chapter 5.



Progressive non-fluent aphasia (PNFA)


This syndrome, known as nfvPPA in the latest classification system [14], is a disorder of language production and comprehension. The syndrome has been associated with atrophy in the left perisylvian region. In contrast to SD, which is a tightly defined clinical entity, there is much heterogeneity in what can be considered PNFA. At least part of the reason for this is that “non-fluency” can be caused by a number of different language problems. Consensus criteria in 1998 highlighted the importance of agrammatism, phonemic paraphasias, and anomia [16]. The 2011 classification system requires the presence of one or both of agrammatism and apraxia of speech (AOS). AOS refers to a problem with the planning of oral movements necessary for speech and, when present, results in effortful sounding speech distortions [17]. Patients with PNFA have a relative preservation of word meaning but can struggle to interpret syntactically complex sentences.


Other cognitive domains often remain remarkably intact and patients may function relatively independently early in the course of their illness. As the condition progresses speech becomes increasingly difficult, resulting in eventual mutism. Even at the stage of severely limited speech many patients continue to be able to communicate in writing although this too usually becomes affected.


Initally neurologic examination may be normal but in time some patients develop parkinsonism and/or limb apraxia. Signs of ALS may be seen in a minority.


In the 2011 PPA classification system a third aphasia syndrome is described: logopenic variant PPA. In this disorder patients exhibit word retrieval problems and struggle to repeat sentences and phrases. The features of semantic variant and non-fluent variant PPA are otherwise absent. This syndrome has more often been associated with underlying Alzheimer’s pathology [18] but as it is the most recently described of the progressive aphasias more data are needed regarding the accuracy with which this syndrome can predict underlying pathology. At this stage it cannot be considered as part of the FTD spectrum of disorders. Further details on these forms of PPA are reviewed in Chapter 5.



Atypical presentations and the differential diagnosis of FTD


The diagnosis of FTD spectrum disorders rests upon a carefully taken history from the patient and caregiver and a full neurologic examination of the patient. Neuropsychological testing can be enormously helpful in delineating the cognitive basis for a clinical deficit and may also uncover unexpected deficiencies in other cognitive domains. Neuropsychology is especially helpful in the assessment of progressive aphasia syndromes. Structural and functional neuroimaging are important in helping to confirm the diagnosis as well as excluding other, non-neurodegenerative etiologies.



Differentiating FTD from Alzheimer’s disease


In patients with an insidious onset and gradual progression to their symptoms the principle differential diagnosis to be made is from other neurodegenerative conditions. The disease that most often enters this differential diagnosis is Alzheimer’s disease (AD). Whilst generally AD is a condition affecting older individuals there is considerable overlap in the range of ages of onset between AD and FTD, and AD has been found to be the commonest cause of early-onset dementia in a number of studies [19, 20]. AD is typically associated with deficits in episodic memory and a constellation of more posterior cortical deficits such as visuospatial and constructional difficulties, however, considerable heterogeneity in the clinical presentation of AD is recognized [21, 22]. In a recent study of the accuracy of the 2011 FTD diagnostic criteria, the majority of cases that met FTD criteria, yet had alternative pathologies at post-mortem, were due to AD [23]. In several of these cases typical AD deficits of memory and visuospatial impairments were present on neuropsychological testing yet the patients met FTD criteria because of the presence of behavioral change and executive problems. The study did also highlight cases where patients may present with a circumscribed frontal lobe syndrome and even have frontal atrophy on structural imaging, yet have AD pathology at post-mortem. Indeed it is recognized that early-onset AD due to mutations in the presenilin 1 gene (PSEN1) may present with a FTD-like syndrome [24].


Whilst AD is known to masquerade clinically with a frontal lobe presentation, it is also recognized that some patients presenting with more typical AD symptoms can have FTLD spectrum pathology. In particular, amnesia has been reported to occur prominently in some patients with FTLD pathology [23, 25].


The recognition that AD is not clinically uniform is crucially important in accurately diagnosing early-onset dementias. Not only can AD occasionally present with frontal lobe symptoms, but it can also cause focal cognitive presentations characterized almost solely by visuospatial problems, language disturbance, or apraxia. In the case of these latter two situations this heterogeneity in AD presentation can cause further confusion in the diagnosis of FTD spectrum disorders. Several studies have highlighted that patients presenting with SD or PNFA may have underlying AD pathology [21, 26] and the accurate pathologic diagnosis of progressive aphasia syndromes in life remains challenging. The most recent classification system for PPA has been assessed to determine whether the clinical classification criteria predict underlying pathology [27]. In this pathologically confirmed cohort study, patients meeting criteria for semantic variant PPA all had TPD-43 pathology. Seventy-five percent of patients meeting criteria for nfvPPA had FTLD spectrum pathologies (a mixture of tau-positive and TDP-43 types). Criteria for logopenic variant PPA were the least specific with patients exhibiting a broad range of pathologies, although AD was commonest. This would suggest that simply applying published criteria to patients with progressive language disorders might not be a sufficiently accurate way of predicting pathology. In a separate study of clinicopathologic correlation very high rates of diagnostic accuracy have been reported [28]. This study emphasized two overarching principles in achieving diagnostic success. First, patients with posterior cortical deficits and/or amnesia were likely to have AD and patients with anterior cortical symptoms of behavioral change were likely to have FTLD pathology. Second, patients in whom a striking specificity of neuropsychological deficit was observed (e.g., impaired semantics with preserved phonology and syntax) were more likely to have FTLD spectrum pathology. These studies serve to highlight that diagnostic criteria, whilst useful in standardizing research and clinical practice, are no substitute for the careful clinical assessment of experienced practitioners.


Because of these difficulties in symptom overlap between some cases of AD and FTD the differential diagnosis will always be challenging on clinical grounds alone in certain patients. Patterns of regional atrophy on structural imaging may also overlap, so more specific biomarker technology may be of assistance. The advent of amyloid positron emission tomography (PET) imaging and improvements in cerebrospinal fluid (CSF) biomarker analysis should help to make the ante-mortem distinction between AD and FTLD pathologies easier.



Differentiating FTD from other neurodegenerative conditions


Although AD is the neurodegenerative condition that most commonly mimics FTD spectrum disorders, there can be occasions where other diseases enter the differential diagnosis. One such example is dementia with Lewy bodies (DLB). Generally the presence of more posterior cortical deficits, fluctuations, parkinsonism, and hallucinations make this diagnosis straightforward. However, as previously discussed, parkinsonism may occur in a subset of patients with FTD and some patients also have delusions and hallucinations. Additionally, the tangential line of thought seen in DLB can appear similar to the unmonitored output of some patients with FTD. In a study of FTD diagnostic criteria accuracy some patients met FTD criteria yet had DLB or mixed DLB and AD pathology [29]. Previous reports have suggested that a subgroup of FTD patients may mimic DLB [30] and that small numbers of patients with clinical DLB have mutations in C9orf72 and could be atypical FTD cases [31].


Occasionally patients presenting with a disorder compatible with FTD or progressive aphasia may be ultimately found to have prion pathology [23, 27, 31, 32] but typically the rapid progression of dementia and development of other neurologic symptoms makes this diagnosis relatively easy.



Differentiation from cerebrovascular disease


Vascular dementia (VaD) is a common cause of cognitive impairment and diagnostic criteria emphasize the importance of deficits in multiple cognitive domains, abnormal findings on neurologic examination, and vascular findings on neuroimaging [33]. The presence of vascular risk factors is also important. The advent of readily available magnetic resonance imaging (MRI) has undoubtedly made the diagnosis easier. However, alterations in behavior are known to occur in VaD and may make differentiation from FTD difficult. Accordingly, some patients that meet diagnostic criteria for FTD may have vascular pathology at autopsy [23]. Specific behavioral features that have been found to help differentiate FTD from VaD include loss of basic emotions, food cramming, pacing a fixed routine, and the absence of insightfulness [34]. However, that is not to say that these features cannot be seen in VaD, albeit with less frequency. Other work has highlighted cognitive differences between the two syndromes with FTD patients performing better on digit span and constructional tasks [35].



Differentiation from psychiatric conditions


As can be seen from the description of some of the symptoms in FTD there is significant overlap between certain features of this neurodegenerative disease and some psychiatric conditions. The apathy of FTD can be mistaken for the low mood of depression. Similarly, the altered emotional reactivity seen in FTD can be confused with the symptoms of an affective disorder. Hallucinations and delusions are first-rank symptoms of schizophrenia and can also occur in some FTD patients. Patients with psychiatric disorders may score poorly on neuropsychological testing so the qualitative interpretation of how they perform is important.


Patients with FTD are much more likely than those with other neurodegenerative diseases to have received a prior diagnosis of a psychiatric disorder, most commonly depression or bipolar affective disorder, but also occasionally schizophrenia [36]. There are, however, important differences in behavior between patients with FTD and those with psychiatric conditions. In FTD it is unusual for patients to complain of subjective sadness, unlike in depression. Patients with FTD are unlikely to show remorse for their abnormal behavior whereas patients with mania generally do. FTD patients are less likely to have insight. In healthcare consultations the spontaneous behavior of FTD patients has been found to differ from that of patients with psychiatric conditions: Verbal or physical interruption of the consultation occurred more often in patients with SD and a lack of concern for the clinicians expectations was more common in FTD patients [37].


The nature of the clinical course of a behavioral syndrome can also help differentiate the neurodegenerative etiologies from the psychiatric. In general those patients with neurodegeneration will have a typical insidious onset and gradual but relentless progression. In addition, patients with neurodegenerative disease should have atrophy on brain imaging either at presentation or on follow-up. However, these general rules have been called into question by the identification of patients fulfilling diagnostic criteria for FTD at initial presentation but then either very slowly progressing or failing to progress at all [3840]. These patients are described as being different to progressive FTD patients by having little or no atrophy on MRI and performing better on neuropsychological tasks and measures of activities of daily living. There is a striking male predominance. The status of such patients remains unclear and they are sometimes referred to as FTD “phenocopies.” They may represent a group with no neurodegenerative disease at all and the possibility of the symptoms being due to an Apserger spectrum-type condition has been raised [38]. However, there are also reports of some such patients genuinely progressing, albeit very slowly, and showing evidence of FTLD pathology at autopsy [41]. Intriguingly there are now reports of some slowly progressive FTD patients being positive for the C9orf72 mutation [42], suggesting this may be a potential cause of the slowly progressive phenotype.


The association of psychotic symptoms with the C9orf72 mutation merits specific attention. In one study characterizing the clinical phenotype of C9orf72 mutation carriers, psychosis was present in 38% of individuals versus < 4% of non-mutation carriers [13]. These patients had all initially received a psychiatric diagnosis prior to referral to the neurology clinic. Many of the patients had florid, mono-delusional psychosis and bizarre irrational behavior. Case study 5 describes one such patient as an example. Other studies have also uncovered high rates of psychotic features in patients with C9orf72 mutations [43, 44]. Thus the presence of late-onset psychosis, particularly if characterized by florid mono-delusional beliefs and irrational behavior, should prompt consideration of neurologic referral.


Because of the obvious difficulties in diagnosing this spectrum of disorders we have developed a highly structured approach in our own clinic to maintain high rates of diagnostic accuracy. We use a semi-structured neurologic history tool to extract uniform clinical information and all patients have full neurologic examination. Where possible the neuropsychologist joins the neurologist for this process before taking the patient away for a standardized neuropsychological test battery. This also gives the neurologist time with the caregivers to further discuss behavioral aspects that many relatives prefer not to speak about in front of the patient. Following structural neuroimaging all cases are discussed in a multidisciplinary meeting to reach a consensus diagnosis. Once this process is complete the patient and caregivers are invited back to discuss the results in a separate appointment.



Clinical course


As a neurodegenerative disease, FTD inevitably results in progressively worse cognitive impairment with time. Although patients present initially with behavioral and cognitive symptoms, neurologic symptoms and signs become increasingly prevalent as the disease progresses. Disorders of gait and reduced mobility should be anticipated. Communication reduces with time in all forms of FTD, albeit for different underlying reasons. Many patients develop swallowing difficulties and become prone to choking. In some patients limb apraxia can become disabling. Patients with FTD may become incontinent of urine and feces and appear unconcerned by this.


Despite the fact that the condition progresses in general not all behavioral features worsen over time. For instance, patients in whom disinhibited behavior is prominent at presentation often become progressively more apathetic over time. The overeating that can characterize the dietary disturbance in many patients often evolves eventually into a gradual reduction of oral intake. Because of disease progression the majority of patients will eventually require some form of institutional care.


Because FTD is a heterogeneous condition the clinical course and prognosis varies greatly between patients. Survival has been assessed in a number of studies but comparison between studies is hindered by differing use of diagnostic criteria, the degree of autopsy verification of diagnosis, and inclusion of different clinical phenotypes.


In one large series of patients, survival rates in FTD were not seen to differ from those in AD. The mean duration of illness was 8.3 +/− 2.7 years [45]. Other studies have suggested that FTD progresses to death faster than AD [46]. In one study median survival of patients with FTD was 6 +/− 1.1 years for FTD alone and 3 +/− 0.4 years for FTD with MND. A subset of patients with tau pathology had a longer median survival time of 9 +/− 0.9 years [47]. However, in a pathologically proven cohort from the USA where MND cases were excluded, tau-positive cases had a poorer survival rate [48]. Overall median survival from symptom onset was 6.7 years. In Germany median survival from symptom onset in FTD spectrum disorders (excluding MND cases) was 11.8 years [49]. This study found longer survival in SD, shortest in bvFTD, and survival in PNFA to be intermediate between the two. The commonest cause of death was a respiratory disorder (27%, mostly pneumonia and choking on food) followed by a circulatory system disorder (19%), followed by cachexia (14%). The most consistent finding across studies is that unsurprisingly the presence of clinical MND shortens survival. Unresolved issues surrounding the status of slow-progressing or “phenocopy” FTD cases makes prediction of survival and overall prognosis very difficult at the time of diagnosis, unless neurologic signs of MND are present.



Managing FTD


The management of FTD poses a unique set of problems. The majority of patients diagnosed with this spectrum of dementias is of working age and may have dependents such as children still in full-time education. The early loss of insight and altered behavior of patients puts great strain on family and social relationships. Some patients are diagnosed with FTD only having already been diagnosed with and treated for a psychiatric condition. Compounding all of this is the fact that general awareness and understanding of FTD is low amongst primary care physicians and some mental health clinicians to whom the patient and family are likely to initially present. This means that by the time a patient and their family reach the point of diagnosis in a specialist dementia or neurology clinic they can already feel short-changed by the healthcare system they have been through to that point. Recognizing this is crucial and management of FTD is about trying to help the caregivers as well as the patients. In our clinic we use a separate appointment, after completion of the clinical and radiologic assessment, to break the news of the diagnosis. This usually involves explanation of the condition and its symptoms, addressing the issue of hereditability where appropriate, discussion of prognosis, and time spent with a specialist social worker to address practical and financial concerns.



Caregivers


FTD has a devastating effect not only on the patient but also on members of the family who typically become caregivers. Those looking after and living with patients with FTD are under a greater degree of burden than those caring for patients with other dementias such as AD [50, 51]. Rates of depression are higher in caregivers of FTD patients compared with those of AD patients [52]. The apathy, behavioral changes, and loss of insight of FTD patients has been found to particularly affect carers [53, 54]. Unsurprisingly the severity of a patient’s FTD symptoms was found to correlate positively with measures of caregiver burden and negatively with their mental health. Caregivers report valuing the support and information they receive from healthcare workers who are knowledgeable about the condition. Informing and educating caregivers about the nature of the patient’s disease and helping them to understand the symptoms is a critical step in managing the condition.


In our own clinic we have found the early involvement of a specialist social worker to be of value to carers. This helps to address some of the very real practical issues that inevitably occur. Families need advice on how to access the most appropriate community support and financial assistance or benefits where available. Time needs to be given for planning periods of respite care and eventually to planning the transition of the patient to institutional care. We find that providing written information on the patient’s condition to be valuable; caregivers can then share this information with other family members, friends, or their primary healthcare physicians. Support groups can offer another valuable source of help to caregivers, particularly if a disease-specific support group can be located.


Given the strong genetic influence in FTD a patient’s family may have worries and questions regarding hereditability of the disease. It is therefore crucial to have close links with an experienced clinical genetics department to help facilitate appropriate genetic counseling.



Patients


Currently there are no therapeutic interventions proven to alter the disease progression in any FTD spectrum disorder. Management therefore tends to revolve around attempting to control or deal with patients’ symptoms by environmental modification, pharmacologic treatments, and caregiver education.


There are currently no licensed medications even for symptomatic control in FTD. Despite this, rates of “off-label” medication use in FTD are reported to be high. One study in the USA found that use of Food and Drug Administration (FDA)-approved AD drugs was as common in FTD as in AD [55]. Over 40% of FTD patients had been prescribed a cholinesterase inhibitor, almost 30% memantine, and 43% an antidepressant.


A number of drugs have been subject to mostly small-scale studies in FTD. The rationale for trying most of these therapies has been the evidence that some brain neurotransmitter systems are altered in FTD. The data on the serotonergic system overall support serotonin deficiency in FTD [56]. Accordingly, a number of studies of antidepressants that boost serotonin levels have been undertaken; most are small, uncontrolled, and of short duration. A meta-analysis of the results indicated an improvement in scores on a neuropsychiatric outcome measure [56]. This accords with many physicians’ anecdotal experience that selective serotonin reuptake inhibitors (SSRIs) can be modestly beneficial in FTD. However, the first randomized, double-blinded, placebo-controlled study (using paroxetine) showed no beneficial effect and suggested a possible worsening of cognition in the study drug group [57]. One possible explanation comes from a post-mortem neurochemical study of FTD, AD, and control brains [58]. This work suggested that the changes seen in FTD brains could lead to an excess of extraneural serotonin (5-HT), so perhaps therapy with a 5-HT1A receptor antagonist would be more beneficial. Trazadone, a serotonergic agent with a different mechanism to SSRIs, demonstrated an improvement in behavior in a randomized, double-blinded, placebo-controlled study of FTD [59].


Although there is little evidence of cholinergic disturbance in FTD [56] cholinesterase inhibitors have been trialled as a treatment for FTD. Galantamine failed to show a beneficial effect in a group of patients with bvFTD and PPA [60].


There are no high-quality trials of antipsychotic drugs in FTD but they are sometimes prescribed on the basis of their known beneficial effects on symptoms such as agitiation, hallucination, and delusions in other conditions. Patients with FTD may have parkinsonism as part of their clinical syndrome and neuroimaging supports dysfunction of the dopaminergic system [61]. It is perhaps unsurprising therefore that, when used in FTD, dopamine-blocking antipsychotic drugs carry a high risk of extrapyramidal side effects [62].


Memantine, a recently approved drug for use in AD, has been subject to investigation in FTD. Initial open label studies suggested the drug to be well tolerated [63, 64] but a randomized, double-blinded, placebo-controlled study in 81 FTD patients showed no beneficial effect of the drug [65].


On the basis that oxytocin may improve performance on social cognition tasks in healthy adults [66] intranasal administration has been tested in patients with FTD, yielding positive short-term benefits in behavior, although further studies need to be carried out [67].


Few data exist on the best non-pharmacologic interventions for patients with FTD. Education of the caregivers is important to help them understand and manage the patient’s behavior day to day. At least in the early stages the involvement of speech and language specialists, occupational therapists, and neuro-rehabilitation has been recommended [68].

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Jul 12, 2018 | Posted by in NEUROLOGY | Comments Off on Overview of frontotemporal dementia and the variety of its clinical presentations

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