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When you hear hoofbeats, think horses and zebras: The importance of a wide differential when it comes to frontotemporal lobar degeneration
Asian Journal of Psychiatry 47 (2020) 101875
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
When you hear hoofbeats, think horses and zebras: The importance of a wide differential when it comes to frontotemporal lobar degeneration
T
Milankumar Nathani, Vijaya Jaleel, Ana Turner, Caitlin Dirvonas, Uma Suryadevara*, Rajiv Tandon University of Florida, 10348 SW 27th Pl, 32608, Gainesville, United States
A R T I C LE I N FO
A B S T R A C T
Keyword: Frontotemporal lobar degeneration
Frontotemporal lobar degeneration (Frontotemporal dementia in DSM 4/FTD) is a progressive brain disease which frequently presents with neuropsychiatric symptoms. Prevalence of FTD is low, however the prognosis is poor. Early identification of FTD may improve quality of life, minimize behavioral disturbances and help with end of life planning. Diagnosis of FTD is often a diagnostic challenge as it has wide differentials. Authors discuss three clinical cases with their initial clinical presentation, diagnostic complexity and subsequent management.
1. Introduction Fronto-temporal lobar degeneration or dementia (FTD) is characterized by significant changes in social behavior, decrease in language proficiency, and impairment of executive functioning, accompanied by degeneration of the frontal and/or temporal lobes. There are multiple variants of the disease: behavioral variant FTD, and the language variants, which include the nonfluent and semantic variants of primary progressive aphasia. FTD is a common cause of dementia in patients aged < 65 years old but also is increasingly prevalent in patients > 65 years of age. The onset of disease is typically in the sixth decade but may have a wide range of onset. Behavioral variant FTD (bvFTD) is the most common subtype of FTD and accounts for more than 50 % of all diagnosed FTD (Olney et al., 2017). The hallmark of bvFTD is a progressive deterioration in personality and behavior as observed by a physician or caregiver (Weder et al., 2007). The diagnosis of bvFTD is primarily based on the clinical presentation and clinical assessment. Possible behavioral variant FTD requires three out of all the following clinical features: a) early behavioral disinhibition, loss of decorum, b) apathy, c) loss of sympathy/empathy, d) compulsive behaviors, e) hyperorality, f) dysexecutive neuropsychological profile (American Psychiatric Association, 2013). Probable FTD includes the criteria mentioned above but also has imaging suggestive of frontal and temporal atrophy. The imaging options may include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT) imaging. Definitive bvFTD is diagnosed when the above criteria for possible bvFTD is
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met along with histopathological evidence of FTD or another mutation. Below are three cases that are unique in their presentations and diagnostically challenging. These cases are to illustrate how the presentations can be very different. Consent has been obtained from all three patients and their families for publication purposes. 2. Case: 1 A 43-year-old homeless white male with no history of psychiatric illness was escorted by police to the emergency department for evaluation after reportedly making homicidal statements about "sniping people." The patient’s medical history was significant for fungal infection of both feet, traumatic brain injury (over occipital area), and seizures (diagnosed 15 years ago, most recent seizure having occurred 5 years earlier). The patient had reportedly attained a master’s level education in finance and was working most recently in construction. At the time of evaluation, he was unable to give a reliable history and per chart review had been noted to fabricate information in the past. He appeared disinhibited, impulsive and lacked ability to appreciate personal boundaries with staff. His speech was pressured and hyperverbal with circumstantial thought process. He displayed poor insight and judgment into his current state. He was cheerful in appearance with notable psychomotor activation. He voiced homicidal thoughts towards someone who had threatened him in the distant past. When asked further about details, he stated that he was joking. He denied any signs or symptoms of depression or anxiety. He denied any auditory or visual hallucinations and thoughts of suicide. Routine labs including complete blood count, metabolic panel, urinalysis, and
Corresponding author. E-mail address: suryadevara@ufl.edu (U. Suryadevara).
https://doi.org/10.1016/j.ajp.2019.101875 Received 4 September 2019; Received in revised form 4 November 2019; Accepted 5 November 2019 1876-2018/ Published by Elsevier B.V.
Asian Journal of Psychiatry 47 (2020) 101875
M. Nathani, et al.
FDG PET/CT images point to the hypo-metabolism of the corresponding regions of the brain. Pt also had a lumbar puncture and cerebrospinal fluid (CSF) analysis for Venereal Disease Research Laboratory (VDRL), protein, glucose and cell count, which were all unremarkable. The case was a diagnostic challenge given the presentation initially. But once diagnosed, patient’s mother was able to get the legal guardianship, patient’s symptoms improved slightly requiring frequent redirections in addition to psychotropic medications. Family requested to take patient with them to their home state and place the patient in a local hospital with inpatient psychiatric care. Based on family’s request treatment team arranged transportation to transfer the patient to a hospital facility near to his family in family’s home state.
thyroid stimulating hormone were within normal limits. Urine drug screen was negative and blood alcohol level was undetectable. Patient was not prescribed any medications prior to this admission, though did report approximately one year of treatment with phenytoin for seizure disorder. Patient had no known allergies. He had no family history of psychiatric illness except his father reportedly had opioid use disorder and died by heroin overdose. Patient was admitted to inpatient psychiatry with preliminary diagnosis of bipolar disorder and subsequently experienced an extended hospitalization mainly due to inability to care for self along with impulsive and disinhibited behaviors. Initial work up included head computed tomography (CT) which was unremarkable for any acute abnormalities. However, a focal low-attenuation lesion in the right occipito-parietal region was found which could have been related to encephalomalacic changes from previous head injury. Electroencephalogram was also unremarkable. Over the course of his hospitalization, multiple psychotropics were trialed including selective serotonin reuptake inhibitors, mood stabilizers/anticonvulsants and antipsychotics, all without significant improvement. Patient showed mild improvement in impulsive and disinhibited behaviors on carbamazepine with subsequent decompensation and progressive worsening after three-week trial off. Subsequently, carbamazepine was reinitiated and continued at 400 mg twice daily. Quetiapine was eventually added and titrated to 600 mg twice daily for additional mood stabilization and with option of a low dose as needed for agitation. He was hospitalized for almost ten months partially due to symptoms but also partially due to psychosocial barriers for placement. Throughout hospitalization, the patient continued to be intrusive with need for frequent redirection by nursing staff. He appeared to have lost any sense of prior social decorum, making untactful remarks along with inappropriate behavior. He frequently made sexual comments to staff, patients, and to his family during visits. His mother maintained these behaviors were relatively new, and were not present a year prior. He demonstrated emotional blunting and loss of empathy, especially while he was discussing emotionally sensitive issues in his life. He appeared self-oriented, without concern for family, friends, or others. Patient was placed in seclusion numerous times for the safety of himself and others due to inappropriate behavior and agitation refractory to attempts to redirect. He was intrusive, unable to follow the floor rules and policies, demonstrated repetitive and stereotyped behaviors. He was fixated on talking about certain varieties of foods and often looking for these types of food in garbage cans. During this hospitalization, the patient started biting objects such as paper and glass with his teeth. The Saint Louis University Mental Status exam (SLUMS), Montreal Cognitive Assessment (MoCA), Modified Mini-Mental State Examination (3MS) were administered to assess memory and cognition. Although tests scores were borderline normal limits, domains in which patient demonstrated deficiency in suggested mild impairment of delayed recall, executive function and abstraction. Frontotemporal dementia Rating Scale (FRS) was administered during his hospital stay and his score indicated severity category of “severe”. Repeat CT of the head was ordered after several months during the hospitalization which showed mild cortical atrophy of the frontal and anterior temporal lobes and focal low-attenuation lesion in the right occipito-parietal region was again noted. For further evaluation Magnetic resonance imaging (MRI) was done, which showed mild cortical atrophy of the frontal and anterior temporal lobes. After further discussion amongst the multidisciplinary treatment team, a positron emission tomography (PET) scan was ordered. The PET impression revealed decreased radiolabeled [18F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake and cortical atrophy of the frontal and anterior temporal lobes, and findings were suggestive of Fronto-Temporal Lobar Degeneration or Dementia (FTD). Prior CT and PET scan images comparison are shown in Fig. 1 below. The arrows on the CT images point to the temporal and frontal lobe atrophy. The arrows on the fused 18F-
3. Case: 2 Mr. X is a 64-year-old Caucasian Male who was admitted for necrotizing infection of his right hand. He had a history of nail biting that started roughly about 1 year ago. He described it in a matter-of-fact way as to how he would ‘slowly bite off the entire nail and he would swallow the nails as opposed to spitting them out’. The wife reported observing blood on multiple occasions around his mouth and on his hands from the nail biting. Eventually, the nails and the surrounding tissue got infected. Patient could not give any details related to this habit. He denied anxiety contributing to his nail biting or relief of negative symptoms. He denied any rituals or obsessive behaviors associated with this habit and the wife confirmed the same. Family noticed a 9-year history of gradual decline where patient became less involved in daily activities and stopped visiting family as much. Patient denied any appetite change or weight changes, spends most of his day sleeping. Per patient and family, there were no other symptoms of depression and mania and there were no symptoms of psychosis like hallucinations or delusions. He was admitted to the surgical floor for debridement of right-hand necrotizing infection and transmetacarpal amputation of the right hand. After the amputation, he was very nonchalant about the entire incident, denied being worried about daily function despite losing his dominant hand. Vitals signs were stable, and his mental status exam was notable for inappropriate affect while describing the situation. On multiple visits, patient was noted to exhibit a blunted and nonchalant affect. Language, and speech appeared appropriate. He scored 26/27 MoCA, and the executive clock drawing part of the MoCA was deferred secondary to dominant hand amputation. Routine labs were grossly within normal limits and included a complete blood count, comprehensive metabolic panel, urine drug screen, syphilis, folate and vitamin B12 levels, thyroid stimulating hormone, Clostridia difficile, Methicillin Resistant Staphylococcus Aureus (MRSA), lipid panel and urinalysis. After ruling out multiple etiologies, we considered various neurocognitive disorders. Delirium was ruled out as patient did not exhibit any fluctuation in symptoms or level of consciousness. The nail biting and the consumption of nails are suspected to be a manifestation of hyperorality. Patient's growing social withdrawal and lack of contact with his seven children and grandchildren are suspicious for apathy. Considering those concerns, we recommended brain MRI and neuropsychological testing to assess for neurocognitive disorder, particularly fronto-temporal lobar degeneration or dementia. Patient was seen by staff psychologist and completed portions of repeatable battery for the assessment of neuropsychological status (RBANS), portions of the Wechsler Adult Intelligence Scale-4th edition (WAIS-IV), portions of the Delis-Kaplan Executive Function System (D-KEFS). Patient was noted to demonstrate significant decrement in executive control, including flexibility of thought, abstract reasoning and inhibitory control, which suggests a neurocognitive disorder primarily affecting the frontal region. During the interview with the psychologist, patient twice stopped the task at hand and stated he must go to the bathroom but proceeded to urinate/defecate while in his seat. The neurocognitive tests 2
Asian Journal of Psychiatry 47 (2020) 101875
M. Nathani, et al.
Fig. 1. CT head and PET scan brain images.
As per his son, he became increasingly difficult to deal with, frequently making inappropriate comments in public and often displaying poor judgment. He spent a substantial amount of money purchasing objects including guns online. As a result, his son applied for durable power of attorney and became the proxy for patient’s finances and health care. Within a few days, he was psychiatrically hospitalized due to his impulsivity, agitation, and poor decision making. It was during these hospitalizations that Frontotemporal Dementia, behavioral variant was considered due to the history of a notable change in personality that could not be explained by any other medical or psychiatric condition. Despite treatment, the symptoms never resolved completely. Patient continued to make inappropriate comments and his comments varied from being plain rude to racist or sexually inappropriate. He never gained any insight into his behavior or illness despite multiple repeated psychiatric hospitalizations and attempts at psychoeducation. We obtained an MRI which showed generalized cerebral atrophy without focality and multiple areas of small vessel ischemic change in the subcortical deep white matter. His medical history was significant for osteoarthritis, hyperlipidemia, prostate cancer that was treated. There was no family history of mental illness or substance abuse. He denied using any illicit drugs. He had a significant history of alcohol use when he was in the marines, but he denied any alcohol use recently. Mini Mental State Exams (MMSEs) were performed several times during the hospitalization and scores ranged from 21 to 25/30. Completing the MMSE or MOCA was hard due to his impulsivity, intrusiveness and attitude towards the test. On physical examination there were no significant abnormalities.
confirmed our suspicion, and patient was diagnosed with fronto-temporal dementia. Patient refused the MRI and the wife did not want to proceed with it as we had the results of the neuropsychological evaluation. Patient and his wife were made aware of the natural course of dementia and the need to begin planning process, in particular, medical decision making and finances. 4. Case: 3 75-year-old male, who was recently diagnosed with Bipolar Disorder, was admitted to psychiatric inpatient unit for agitation. Three years prior, he was a high functioning insurance executive, living by himself and doing well. His son described him as a very successful, polite individual who was never rude and never harmed anyone. Around a year or so ago (prior to presentation), he had a change in his temperament, had become increasingly agitated, was psychiatrically hospitalized for the first time and given a diagnosis of adjustment disorder. After his discharge patient went on to spend hundreds of thousands of dollars in six months on cars, tractors, music equipment which was very atypical for him. He was also charged with domestic violence charges for being physically aggressive towards his son. He was then arrested for violating a domestic violence injunction by making verbal threats and harassing phone calls to his second wife and other family members. While in jail, patient was given a diagnosis of Bipolar Disorder and treated with Valproic Acid. Upon release from jail, he fought with his Primary Care Physician (PCP) and was discharged from the PCP clinic. 3
Asian Journal of Psychiatry 47 (2020) 101875
M. Nathani, et al.
He finally agreed to do a neuropsychological evaluation which revealed relative weakness on the measure of Attention and Working memory, falling within the low to average range (21 %). Patient’s impulsive and hurried response style competed with performance on attention and working memory demands. On an arithmetic mental computation task involving a basic multiplication problem, his impulsive approach resulted in error. Verbal conceptual reasoning was also noted to be impaired. During his most recent hospitalization, we also attempted to obtain a PET scan, but it was not authorized by his insurance. The patient continued to resist treatment due to lack of insight. We continued the Valproic acid and added Risperidone to help with the mood stabilization. The symptoms were not as intense as before admission and he was discharged to a locked assisted living care unit for further treatment. He was later seen in clinic after discharge from the unit. After a few months, his cognition got much worse and the symptoms of hyperorality, lack of empathy, social disinhibition, ritualistic behaviors got worse. Overall, it took nearly three years to diagnose this case as possible Frontotemporal Dementia, behavioral variant. The diagnosis helped the son obtain legal guardianship and assist him with decisions. This example serves to illustrate that there is still much progress that needs to be made in the early diagnosis and treatment of dementia, behavioral variant of frontotemporal dementia in particular.
Below is a table with the common psychiatric differential diagnosis and their presenting signs and symptoms. The similarities in symptoms highlight the challenges associated with diagnosing FTD.
Differential diagnosis for FTD- Psychiatric
Prominent Signs/Symptoms
Bipolar Disorder
Manic/Hypomanic episodes; earlier onset These episodes may alternate with severe episodes of depression May have delusions/ hallucinations during an acute manic or depressive episode History of multiple mood episodes Inter episodic complete or partial symptom remission Delusions that are culturally inappropriate or completely impossible Persistent or episodic hallucinations, predominantly auditory hallucinations Disorganized speech or behaviors Negative symptoms; earlier onset History of multiple depressive episodes Family history of mood disorders Inter episodic complete or partial symptom remission Cognitive impairment limited to the depressive episode Repetitive, compulsive behaviors. Pervasive pattern of preoccupation with orderliness, perfectionism.
Schizophrenia
Depressive Disorders
Obsessive Compulsive Disorder
5. Discussion FTD, a progressive brain disease characterized by atrophy of the frontal and anterior temporal regions of the brain, was first described in 1892 by Arnold Pick and hence also known as Pick’s disease (Weder et al., 2007). The core FTD spectrum disorders include behavioral variant (bvFTD) and language variants, the nonfluent variant primary progressive aphasia and semantic variant primary progressive aphasia (American Psychiatric Association, 2013). The behavioral variant is the more common form of FTDs and accounts for about 60 % of the FTD cases (Olney et al., 2017). The behavior variant is associated with frontal lobe involvement and the language variant is associated with temporal lobe involvement (American Psychiatric Association, 2013). The risk factors associated with FTD include head injury and family history of FTD (Olney et al., 2017); Deutsch et al., 2014; (Perry et al., 2012). Prevalence of FTD is low. The mean survival from diagnosis varies between three and ten years (Riedl et al., 2014; Warren et al., 2013). The mean age at presentation for by FTD is approximately 58 years, although cases presenting as early as the second decade and as late as the ninth decade have been reported (Pressman and Miller, 2014).There have been major advances in the field over the last few decades, but the diagnostic challenges continue to prevail especially with the behavioral variant FTD. Difficulty in diagnosing bvFTD mostly stem from lack of reliable biomarkers that are available in routine clinical practice. Conventional cognitive tests such as planning, set-shifting and problem solving are not sensitive to the early changes in this variant of FTD. The progression of the disease is variable and the slow progressors tend to have no abnormalities on the imaging studies including MRI, FDG-PET scans. Many of the initial symptoms of behavioral variant FTD patients can be mistaken for symptoms of psychiatric disorders making the diagnosis more complicated. In FTD, these symptoms correlate with atrophy in the frontal and temporal regions of cortex (Pressman and Miller, 2014). In our second case, patient exhibited indifference towards his diagnosis, complications and how this is impacting his family or other care providers. This indifference is called “frontal anosodiaphoria” (Mendez and Shapira, 2011). The apathy seen in that case could be easily misdiagnosed as depression. The ritualistic behaviors seen in our first case could come across as obsessive-compulsive behaviors. These behaviors can be due to loss of grey matter in bilateral globus pallidus, left putamen and lateral temporal pole (left middle and inferior temporal gyri) (Perry et al., 2012).
Progressive supranuclear palsy, frontotemporal dementia with motor neuron disease and corticobasal syndrome patients are also noted to have changes in cognition and behavior that overlap with bvFTD (Olney et al., 2017). FTD is also heritable via an autosomal dominant pattern, observed in the families of 10–25% of patients (Goldman et al., 2005). The three main genes identified are microtubule-associated protein tau (MAPT), progranulin (GRN), and C9OF72 (Olney et al., 2017). Neuroimaging can provide support and neuropsychological testing can be helpful in diagnostic and treatment formulations (Olney et al., 2017). Neuroimaging is not a definitive diagnostic criterion because the imaging often appears normal in early disease, and even in later stage imaging only demonstrate focal frontal or temporal atrophy in about half of the patients. However, brain MRI is still required to exclude structural pathology, such as infarction, tumors, abscess or trauma. Patients with early bvFTD typically score well on the executive function portion of the neuropsychological testing. This is because dorsolateral prefrontal cortex and frontal lobe are both involved in executive function. In early disease dorsolateral prefrontal cortex is often spared, so the impairment is often not noticeable until later stages. Below is a table with the common differential diagnosis and the presenting signs and symptoms.
Common Differential Diagnosis for FTD Frontotemporal Dementia
Presenting Signs/Symptoms
Prominent behavioral changes; profound apathy; prominent aphasia; cognitive changes are not always as prominent Alzheimer’s disease Decline in cognitive and executive functioning; onset is usually later Traumatic injury History of a head injury; mood lability along with cognitive changes at times Vascular Dementia Abrupt onset; stepwise decline; neurological focal deficits Prion Diseases Rapid decline; EEG changes at times; myoclonus Normal pressure hydroce- Ataxia; urinary incontinence; cognitive decline phalus Dementia with Lewy body Prominent fluctuations in cognitive abilities; clearly formed/vivid visual hallucinations; sleep disorders Progressive Supranuclear Behavioral disinhibition; personality changes; executive Palsy impairment; apathy; ocular changes
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Asian Journal of Psychiatry 47 (2020) 101875
M. Nathani, et al. Delirium
Acute onset; fluctuating cognition and consciousness; decreased ability to focus, sustain or shift attention; in general has underlying cause(s)
Acknowledgement The authors thank Ronald C. Walker, MD; Professor of Clinical Radiology & Radiological Sciences, Vanderbilt University Medical Center for providing his comments, suggestions and selection of brain images for this article.
Atrophy predominantly of the medial frontal, orbitofrontal, and anterior cingulate and insular cortex regions of the frontal lobes leads to progressive personality changes and behavioral disturbances (Riedl et al., 2014; Kipps et al., 2009). Atrophy in the medial prefrontal lobes and anterior cingulate correlate with apathy in these patients (Olney et al., 2017). Difficulty in reasoning, judgment, organization and planning is frequent, as is abstraction, mental flexibility, and reduction in spontaneous conversation (Kertesz et al., 2007; De Souza et al., 2014). Changes in eating pattern are very common; often with a craving for sweet food, a tendency to overeat and a restriction in food preferences (Kertesz et al., 2007; Ahmed et al., 2014). FTD patients may express social disinhibition, impulsivity, stereotype behaviors often ritualistic in presentation, making offensive remarks, lose the ability to empathize with others, being insensitive to others’ distress, or become distant and detached in their relationships (Riedl et al., 2014; Pressman and Miller, 2014; Kipps et al., 2009). Pharmacological and nonpharmacological treatments are well described in recent literature (Bott et al., 2014; Jicha, 2011; Kimura and Takamatsu, 2013; Tsai and Boxer, 2014). There is no cure or definitive treatment is available at this time for FTD, but early diagnosis may improve a patient’s overall quality of life. Some improvement in FTD behavior symptoms was reported by use of Selective Serotonin Reuptake Inhibitors (SSRIs) and stimulants (Young et al., 2018). There is some evidence that acetylcholinesterase inhibitors may make FTD symptoms worse (Kimura and Takamatsu, 2013). Although significant clinical advances have been made in recent years, the clinical diagnosis remains a challenge (Riedl et al., 2014; Bott et al., 2014). But once diagnosed early, symptoms may improve with caregiver education and environmental modifications to minimize unwanted behaviors (Rascovsky et al., 2011, 2007). Early diagnosis also helps with developing a good advanced care plan which would positively impact the quality of end of life care. This minimizes the uncertainty associated with the progression of the illness and change in symptoms.
References Olney, N.T., et al., 2017. Frontotemporal dementia. Neurol. Clin. 35 (2), 339–374. Weder, N.D., et al., 2007. Frontotemporal dementias: a review. Ann. Gen. Psychiatry 6, 15. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. . Deutsch, M.B., et al., 2014. Interactions between traumatic brain injury and frontotemporal degeneration. Dement. Geriatr. Cogn. Disord. 17 (39 (3-4)), 143–153. Perry, D.C., et al., 2012. Voxel-based morphometry in patients with obsessive-compulsive behaviors in behavioral variant frontotemporal dementia. Eur. J. Neurol. 19 (6), 911–917. Riedl, L., et al., 2014. Frontotemporal lobar degeneration: current perspectives. Neuropsychiatr. Dis. Treat. 10, 297–310. Warren, J.D., et al., 2013. Frontotemporal dementia. Br. Med. J. 347, f4827. Pressman, P.S., Miller, B.L., 2014. Diagnosis and management of behavioral variant frontotemporal dementia. Biol. Psychiatry 75 (7), 574–581. Goldman, J.S., et al., 2005. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65, 1817. Kipps, C.M., et al., 2009. Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing. Brain: a journal of neurology 132 (Pt 3), 592–603. Kertesz, A., et al., 2007. The diagnosis and course of frontotemporal dementia. Alzheimer Dis. Assoc. Disord. 21, 155. De Souza, L.C., et al., 2014. Frontal lobe neurology and the creative mind. Front. Psychol. 5, 761. Ahmed, R.M., et al., 2014. Quantifying the eating abnormalities in frontotemporal dementia. JAMA Neurol. 71 (12), 1540–1546. Mendez, M.F., Shapira, J.S., 2011. Loss of emotional insight in behavioral variant frontotemporal dementia or "frontal anosodiaphoria. Conscious. Cogn. 20 (December 4), 1690–1696. Bott, N.T., et al., 2014. Frontotemporal dementia: diagnosis, deficits and management. Neurodegener. Dis. Manag. 4 (6), 439–454. Jicha, G.A., 2011. Medical management of frontotemporal dementias: the importance of the caregiver in symptom assessment and guidance of treatment strategies. J. Mol. Neurosci. 45 (November 3), 713–723. Kimura, T., Takamatsu, J., 2013. Pilot study of pharmacological treatment for frontotemporal dementia: risk of donepezil treatment for behavioral and psychological symptoms. Geriatr. Gerontol. Int. 13 (April 2), 506–507. Tsai, R.M., Boxer, A.L., 2014. Treatment of frontotemporal dementia. Curr. Treat. Options Neurol. 16 (November 11), 319. Young, J.J., et al., 2018. Frontotemporal dementia: latest evidence and clinical implications. Ther. Adv. Psychopharmacol. 8 (1), 33–48. Rascovsky, K., et al., 2011. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain: a journal of neurology 134, 2456. Rascovsky, K., et al., 2007. Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis. Assoc. Disord. 21, S14.
Financial disclosure The authors have no financial disclosure for this article. Declaration of interest None
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Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
When you hear hoofbeats, think horses and zebras: The importance of a wide differential when it comes to frontotemporal lobar degeneration
T
Milankumar Nathani, Vijaya Jaleel, Ana Turner, Caitlin Dirvonas, Uma Suryadevara*, Rajiv Tandon University of Florida, 10348 SW 27th Pl, 32608, Gainesville, United States
A R T I C LE I N FO
A B S T R A C T
Keyword: Frontotemporal lobar degeneration
Frontotemporal lobar degeneration (Frontotemporal dementia in DSM 4/FTD) is a progressive brain disease which frequently presents with neuropsychiatric symptoms. Prevalence of FTD is low, however the prognosis is poor. Early identification of FTD may improve quality of life, minimize behavioral disturbances and help with end of life planning. Diagnosis of FTD is often a diagnostic challenge as it has wide differentials. Authors discuss three clinical cases with their initial clinical presentation, diagnostic complexity and subsequent management.
1. Introduction Fronto-temporal lobar degeneration or dementia (FTD) is characterized by significant changes in social behavior, decrease in language proficiency, and impairment of executive functioning, accompanied by degeneration of the frontal and/or temporal lobes. There are multiple variants of the disease: behavioral variant FTD, and the language variants, which include the nonfluent and semantic variants of primary progressive aphasia. FTD is a common cause of dementia in patients aged < 65 years old but also is increasingly prevalent in patients > 65 years of age. The onset of disease is typically in the sixth decade but may have a wide range of onset. Behavioral variant FTD (bvFTD) is the most common subtype of FTD and accounts for more than 50 % of all diagnosed FTD (Olney et al., 2017). The hallmark of bvFTD is a progressive deterioration in personality and behavior as observed by a physician or caregiver (Weder et al., 2007). The diagnosis of bvFTD is primarily based on the clinical presentation and clinical assessment. Possible behavioral variant FTD requires three out of all the following clinical features: a) early behavioral disinhibition, loss of decorum, b) apathy, c) loss of sympathy/empathy, d) compulsive behaviors, e) hyperorality, f) dysexecutive neuropsychological profile (American Psychiatric Association, 2013). Probable FTD includes the criteria mentioned above but also has imaging suggestive of frontal and temporal atrophy. The imaging options may include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT) imaging. Definitive bvFTD is diagnosed when the above criteria for possible bvFTD is
⁎
met along with histopathological evidence of FTD or another mutation. Below are three cases that are unique in their presentations and diagnostically challenging. These cases are to illustrate how the presentations can be very different. Consent has been obtained from all three patients and their families for publication purposes. 2. Case: 1 A 43-year-old homeless white male with no history of psychiatric illness was escorted by police to the emergency department for evaluation after reportedly making homicidal statements about "sniping people." The patient’s medical history was significant for fungal infection of both feet, traumatic brain injury (over occipital area), and seizures (diagnosed 15 years ago, most recent seizure having occurred 5 years earlier). The patient had reportedly attained a master’s level education in finance and was working most recently in construction. At the time of evaluation, he was unable to give a reliable history and per chart review had been noted to fabricate information in the past. He appeared disinhibited, impulsive and lacked ability to appreciate personal boundaries with staff. His speech was pressured and hyperverbal with circumstantial thought process. He displayed poor insight and judgment into his current state. He was cheerful in appearance with notable psychomotor activation. He voiced homicidal thoughts towards someone who had threatened him in the distant past. When asked further about details, he stated that he was joking. He denied any signs or symptoms of depression or anxiety. He denied any auditory or visual hallucinations and thoughts of suicide. Routine labs including complete blood count, metabolic panel, urinalysis, and
Corresponding author. E-mail address: suryadevara@ufl.edu (U. Suryadevara).
https://doi.org/10.1016/j.ajp.2019.101875 Received 4 September 2019; Received in revised form 4 November 2019; Accepted 5 November 2019 1876-2018/ Published by Elsevier B.V.
Asian Journal of Psychiatry 47 (2020) 101875
M. Nathani, et al.
FDG PET/CT images point to the hypo-metabolism of the corresponding regions of the brain. Pt also had a lumbar puncture and cerebrospinal fluid (CSF) analysis for Venereal Disease Research Laboratory (VDRL), protein, glucose and cell count, which were all unremarkable. The case was a diagnostic challenge given the presentation initially. But once diagnosed, patient’s mother was able to get the legal guardianship, patient’s symptoms improved slightly requiring frequent redirections in addition to psychotropic medications. Family requested to take patient with them to their home state and place the patient in a local hospital with inpatient psychiatric care. Based on family’s request treatment team arranged transportation to transfer the patient to a hospital facility near to his family in family’s home state.
thyroid stimulating hormone were within normal limits. Urine drug screen was negative and blood alcohol level was undetectable. Patient was not prescribed any medications prior to this admission, though did report approximately one year of treatment with phenytoin for seizure disorder. Patient had no known allergies. He had no family history of psychiatric illness except his father reportedly had opioid use disorder and died by heroin overdose. Patient was admitted to inpatient psychiatry with preliminary diagnosis of bipolar disorder and subsequently experienced an extended hospitalization mainly due to inability to care for self along with impulsive and disinhibited behaviors. Initial work up included head computed tomography (CT) which was unremarkable for any acute abnormalities. However, a focal low-attenuation lesion in the right occipito-parietal region was found which could have been related to encephalomalacic changes from previous head injury. Electroencephalogram was also unremarkable. Over the course of his hospitalization, multiple psychotropics were trialed including selective serotonin reuptake inhibitors, mood stabilizers/anticonvulsants and antipsychotics, all without significant improvement. Patient showed mild improvement in impulsive and disinhibited behaviors on carbamazepine with subsequent decompensation and progressive worsening after three-week trial off. Subsequently, carbamazepine was reinitiated and continued at 400 mg twice daily. Quetiapine was eventually added and titrated to 600 mg twice daily for additional mood stabilization and with option of a low dose as needed for agitation. He was hospitalized for almost ten months partially due to symptoms but also partially due to psychosocial barriers for placement. Throughout hospitalization, the patient continued to be intrusive with need for frequent redirection by nursing staff. He appeared to have lost any sense of prior social decorum, making untactful remarks along with inappropriate behavior. He frequently made sexual comments to staff, patients, and to his family during visits. His mother maintained these behaviors were relatively new, and were not present a year prior. He demonstrated emotional blunting and loss of empathy, especially while he was discussing emotionally sensitive issues in his life. He appeared self-oriented, without concern for family, friends, or others. Patient was placed in seclusion numerous times for the safety of himself and others due to inappropriate behavior and agitation refractory to attempts to redirect. He was intrusive, unable to follow the floor rules and policies, demonstrated repetitive and stereotyped behaviors. He was fixated on talking about certain varieties of foods and often looking for these types of food in garbage cans. During this hospitalization, the patient started biting objects such as paper and glass with his teeth. The Saint Louis University Mental Status exam (SLUMS), Montreal Cognitive Assessment (MoCA), Modified Mini-Mental State Examination (3MS) were administered to assess memory and cognition. Although tests scores were borderline normal limits, domains in which patient demonstrated deficiency in suggested mild impairment of delayed recall, executive function and abstraction. Frontotemporal dementia Rating Scale (FRS) was administered during his hospital stay and his score indicated severity category of “severe”. Repeat CT of the head was ordered after several months during the hospitalization which showed mild cortical atrophy of the frontal and anterior temporal lobes and focal low-attenuation lesion in the right occipito-parietal region was again noted. For further evaluation Magnetic resonance imaging (MRI) was done, which showed mild cortical atrophy of the frontal and anterior temporal lobes. After further discussion amongst the multidisciplinary treatment team, a positron emission tomography (PET) scan was ordered. The PET impression revealed decreased radiolabeled [18F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake and cortical atrophy of the frontal and anterior temporal lobes, and findings were suggestive of Fronto-Temporal Lobar Degeneration or Dementia (FTD). Prior CT and PET scan images comparison are shown in Fig. 1 below. The arrows on the CT images point to the temporal and frontal lobe atrophy. The arrows on the fused 18F-
3. Case: 2 Mr. X is a 64-year-old Caucasian Male who was admitted for necrotizing infection of his right hand. He had a history of nail biting that started roughly about 1 year ago. He described it in a matter-of-fact way as to how he would ‘slowly bite off the entire nail and he would swallow the nails as opposed to spitting them out’. The wife reported observing blood on multiple occasions around his mouth and on his hands from the nail biting. Eventually, the nails and the surrounding tissue got infected. Patient could not give any details related to this habit. He denied anxiety contributing to his nail biting or relief of negative symptoms. He denied any rituals or obsessive behaviors associated with this habit and the wife confirmed the same. Family noticed a 9-year history of gradual decline where patient became less involved in daily activities and stopped visiting family as much. Patient denied any appetite change or weight changes, spends most of his day sleeping. Per patient and family, there were no other symptoms of depression and mania and there were no symptoms of psychosis like hallucinations or delusions. He was admitted to the surgical floor for debridement of right-hand necrotizing infection and transmetacarpal amputation of the right hand. After the amputation, he was very nonchalant about the entire incident, denied being worried about daily function despite losing his dominant hand. Vitals signs were stable, and his mental status exam was notable for inappropriate affect while describing the situation. On multiple visits, patient was noted to exhibit a blunted and nonchalant affect. Language, and speech appeared appropriate. He scored 26/27 MoCA, and the executive clock drawing part of the MoCA was deferred secondary to dominant hand amputation. Routine labs were grossly within normal limits and included a complete blood count, comprehensive metabolic panel, urine drug screen, syphilis, folate and vitamin B12 levels, thyroid stimulating hormone, Clostridia difficile, Methicillin Resistant Staphylococcus Aureus (MRSA), lipid panel and urinalysis. After ruling out multiple etiologies, we considered various neurocognitive disorders. Delirium was ruled out as patient did not exhibit any fluctuation in symptoms or level of consciousness. The nail biting and the consumption of nails are suspected to be a manifestation of hyperorality. Patient's growing social withdrawal and lack of contact with his seven children and grandchildren are suspicious for apathy. Considering those concerns, we recommended brain MRI and neuropsychological testing to assess for neurocognitive disorder, particularly fronto-temporal lobar degeneration or dementia. Patient was seen by staff psychologist and completed portions of repeatable battery for the assessment of neuropsychological status (RBANS), portions of the Wechsler Adult Intelligence Scale-4th edition (WAIS-IV), portions of the Delis-Kaplan Executive Function System (D-KEFS). Patient was noted to demonstrate significant decrement in executive control, including flexibility of thought, abstract reasoning and inhibitory control, which suggests a neurocognitive disorder primarily affecting the frontal region. During the interview with the psychologist, patient twice stopped the task at hand and stated he must go to the bathroom but proceeded to urinate/defecate while in his seat. The neurocognitive tests 2
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Fig. 1. CT head and PET scan brain images.
As per his son, he became increasingly difficult to deal with, frequently making inappropriate comments in public and often displaying poor judgment. He spent a substantial amount of money purchasing objects including guns online. As a result, his son applied for durable power of attorney and became the proxy for patient’s finances and health care. Within a few days, he was psychiatrically hospitalized due to his impulsivity, agitation, and poor decision making. It was during these hospitalizations that Frontotemporal Dementia, behavioral variant was considered due to the history of a notable change in personality that could not be explained by any other medical or psychiatric condition. Despite treatment, the symptoms never resolved completely. Patient continued to make inappropriate comments and his comments varied from being plain rude to racist or sexually inappropriate. He never gained any insight into his behavior or illness despite multiple repeated psychiatric hospitalizations and attempts at psychoeducation. We obtained an MRI which showed generalized cerebral atrophy without focality and multiple areas of small vessel ischemic change in the subcortical deep white matter. His medical history was significant for osteoarthritis, hyperlipidemia, prostate cancer that was treated. There was no family history of mental illness or substance abuse. He denied using any illicit drugs. He had a significant history of alcohol use when he was in the marines, but he denied any alcohol use recently. Mini Mental State Exams (MMSEs) were performed several times during the hospitalization and scores ranged from 21 to 25/30. Completing the MMSE or MOCA was hard due to his impulsivity, intrusiveness and attitude towards the test. On physical examination there were no significant abnormalities.
confirmed our suspicion, and patient was diagnosed with fronto-temporal dementia. Patient refused the MRI and the wife did not want to proceed with it as we had the results of the neuropsychological evaluation. Patient and his wife were made aware of the natural course of dementia and the need to begin planning process, in particular, medical decision making and finances. 4. Case: 3 75-year-old male, who was recently diagnosed with Bipolar Disorder, was admitted to psychiatric inpatient unit for agitation. Three years prior, he was a high functioning insurance executive, living by himself and doing well. His son described him as a very successful, polite individual who was never rude and never harmed anyone. Around a year or so ago (prior to presentation), he had a change in his temperament, had become increasingly agitated, was psychiatrically hospitalized for the first time and given a diagnosis of adjustment disorder. After his discharge patient went on to spend hundreds of thousands of dollars in six months on cars, tractors, music equipment which was very atypical for him. He was also charged with domestic violence charges for being physically aggressive towards his son. He was then arrested for violating a domestic violence injunction by making verbal threats and harassing phone calls to his second wife and other family members. While in jail, patient was given a diagnosis of Bipolar Disorder and treated with Valproic Acid. Upon release from jail, he fought with his Primary Care Physician (PCP) and was discharged from the PCP clinic. 3
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He finally agreed to do a neuropsychological evaluation which revealed relative weakness on the measure of Attention and Working memory, falling within the low to average range (21 %). Patient’s impulsive and hurried response style competed with performance on attention and working memory demands. On an arithmetic mental computation task involving a basic multiplication problem, his impulsive approach resulted in error. Verbal conceptual reasoning was also noted to be impaired. During his most recent hospitalization, we also attempted to obtain a PET scan, but it was not authorized by his insurance. The patient continued to resist treatment due to lack of insight. We continued the Valproic acid and added Risperidone to help with the mood stabilization. The symptoms were not as intense as before admission and he was discharged to a locked assisted living care unit for further treatment. He was later seen in clinic after discharge from the unit. After a few months, his cognition got much worse and the symptoms of hyperorality, lack of empathy, social disinhibition, ritualistic behaviors got worse. Overall, it took nearly three years to diagnose this case as possible Frontotemporal Dementia, behavioral variant. The diagnosis helped the son obtain legal guardianship and assist him with decisions. This example serves to illustrate that there is still much progress that needs to be made in the early diagnosis and treatment of dementia, behavioral variant of frontotemporal dementia in particular.
Below is a table with the common psychiatric differential diagnosis and their presenting signs and symptoms. The similarities in symptoms highlight the challenges associated with diagnosing FTD.
Differential diagnosis for FTD- Psychiatric
Prominent Signs/Symptoms
Bipolar Disorder
Manic/Hypomanic episodes; earlier onset These episodes may alternate with severe episodes of depression May have delusions/ hallucinations during an acute manic or depressive episode History of multiple mood episodes Inter episodic complete or partial symptom remission Delusions that are culturally inappropriate or completely impossible Persistent or episodic hallucinations, predominantly auditory hallucinations Disorganized speech or behaviors Negative symptoms; earlier onset History of multiple depressive episodes Family history of mood disorders Inter episodic complete or partial symptom remission Cognitive impairment limited to the depressive episode Repetitive, compulsive behaviors. Pervasive pattern of preoccupation with orderliness, perfectionism.
Schizophrenia
Depressive Disorders
Obsessive Compulsive Disorder
5. Discussion FTD, a progressive brain disease characterized by atrophy of the frontal and anterior temporal regions of the brain, was first described in 1892 by Arnold Pick and hence also known as Pick’s disease (Weder et al., 2007). The core FTD spectrum disorders include behavioral variant (bvFTD) and language variants, the nonfluent variant primary progressive aphasia and semantic variant primary progressive aphasia (American Psychiatric Association, 2013). The behavioral variant is the more common form of FTDs and accounts for about 60 % of the FTD cases (Olney et al., 2017). The behavior variant is associated with frontal lobe involvement and the language variant is associated with temporal lobe involvement (American Psychiatric Association, 2013). The risk factors associated with FTD include head injury and family history of FTD (Olney et al., 2017); Deutsch et al., 2014; (Perry et al., 2012). Prevalence of FTD is low. The mean survival from diagnosis varies between three and ten years (Riedl et al., 2014; Warren et al., 2013). The mean age at presentation for by FTD is approximately 58 years, although cases presenting as early as the second decade and as late as the ninth decade have been reported (Pressman and Miller, 2014).There have been major advances in the field over the last few decades, but the diagnostic challenges continue to prevail especially with the behavioral variant FTD. Difficulty in diagnosing bvFTD mostly stem from lack of reliable biomarkers that are available in routine clinical practice. Conventional cognitive tests such as planning, set-shifting and problem solving are not sensitive to the early changes in this variant of FTD. The progression of the disease is variable and the slow progressors tend to have no abnormalities on the imaging studies including MRI, FDG-PET scans. Many of the initial symptoms of behavioral variant FTD patients can be mistaken for symptoms of psychiatric disorders making the diagnosis more complicated. In FTD, these symptoms correlate with atrophy in the frontal and temporal regions of cortex (Pressman and Miller, 2014). In our second case, patient exhibited indifference towards his diagnosis, complications and how this is impacting his family or other care providers. This indifference is called “frontal anosodiaphoria” (Mendez and Shapira, 2011). The apathy seen in that case could be easily misdiagnosed as depression. The ritualistic behaviors seen in our first case could come across as obsessive-compulsive behaviors. These behaviors can be due to loss of grey matter in bilateral globus pallidus, left putamen and lateral temporal pole (left middle and inferior temporal gyri) (Perry et al., 2012).
Progressive supranuclear palsy, frontotemporal dementia with motor neuron disease and corticobasal syndrome patients are also noted to have changes in cognition and behavior that overlap with bvFTD (Olney et al., 2017). FTD is also heritable via an autosomal dominant pattern, observed in the families of 10–25% of patients (Goldman et al., 2005). The three main genes identified are microtubule-associated protein tau (MAPT), progranulin (GRN), and C9OF72 (Olney et al., 2017). Neuroimaging can provide support and neuropsychological testing can be helpful in diagnostic and treatment formulations (Olney et al., 2017). Neuroimaging is not a definitive diagnostic criterion because the imaging often appears normal in early disease, and even in later stage imaging only demonstrate focal frontal or temporal atrophy in about half of the patients. However, brain MRI is still required to exclude structural pathology, such as infarction, tumors, abscess or trauma. Patients with early bvFTD typically score well on the executive function portion of the neuropsychological testing. This is because dorsolateral prefrontal cortex and frontal lobe are both involved in executive function. In early disease dorsolateral prefrontal cortex is often spared, so the impairment is often not noticeable until later stages. Below is a table with the common differential diagnosis and the presenting signs and symptoms.
Common Differential Diagnosis for FTD Frontotemporal Dementia
Presenting Signs/Symptoms
Prominent behavioral changes; profound apathy; prominent aphasia; cognitive changes are not always as prominent Alzheimer’s disease Decline in cognitive and executive functioning; onset is usually later Traumatic injury History of a head injury; mood lability along with cognitive changes at times Vascular Dementia Abrupt onset; stepwise decline; neurological focal deficits Prion Diseases Rapid decline; EEG changes at times; myoclonus Normal pressure hydroce- Ataxia; urinary incontinence; cognitive decline phalus Dementia with Lewy body Prominent fluctuations in cognitive abilities; clearly formed/vivid visual hallucinations; sleep disorders Progressive Supranuclear Behavioral disinhibition; personality changes; executive Palsy impairment; apathy; ocular changes
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Acute onset; fluctuating cognition and consciousness; decreased ability to focus, sustain or shift attention; in general has underlying cause(s)
Acknowledgement The authors thank Ronald C. Walker, MD; Professor of Clinical Radiology & Radiological Sciences, Vanderbilt University Medical Center for providing his comments, suggestions and selection of brain images for this article.
Atrophy predominantly of the medial frontal, orbitofrontal, and anterior cingulate and insular cortex regions of the frontal lobes leads to progressive personality changes and behavioral disturbances (Riedl et al., 2014; Kipps et al., 2009). Atrophy in the medial prefrontal lobes and anterior cingulate correlate with apathy in these patients (Olney et al., 2017). Difficulty in reasoning, judgment, organization and planning is frequent, as is abstraction, mental flexibility, and reduction in spontaneous conversation (Kertesz et al., 2007; De Souza et al., 2014). Changes in eating pattern are very common; often with a craving for sweet food, a tendency to overeat and a restriction in food preferences (Kertesz et al., 2007; Ahmed et al., 2014). FTD patients may express social disinhibition, impulsivity, stereotype behaviors often ritualistic in presentation, making offensive remarks, lose the ability to empathize with others, being insensitive to others’ distress, or become distant and detached in their relationships (Riedl et al., 2014; Pressman and Miller, 2014; Kipps et al., 2009). Pharmacological and nonpharmacological treatments are well described in recent literature (Bott et al., 2014; Jicha, 2011; Kimura and Takamatsu, 2013; Tsai and Boxer, 2014). There is no cure or definitive treatment is available at this time for FTD, but early diagnosis may improve a patient’s overall quality of life. Some improvement in FTD behavior symptoms was reported by use of Selective Serotonin Reuptake Inhibitors (SSRIs) and stimulants (Young et al., 2018). There is some evidence that acetylcholinesterase inhibitors may make FTD symptoms worse (Kimura and Takamatsu, 2013). Although significant clinical advances have been made in recent years, the clinical diagnosis remains a challenge (Riedl et al., 2014; Bott et al., 2014). But once diagnosed early, symptoms may improve with caregiver education and environmental modifications to minimize unwanted behaviors (Rascovsky et al., 2011, 2007). Early diagnosis also helps with developing a good advanced care plan which would positively impact the quality of end of life care. This minimizes the uncertainty associated with the progression of the illness and change in symptoms.
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Financial disclosure The authors have no financial disclosure for this article. Declaration of interest None
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