Overview of frontotemporal dementia
Frontotemporal lobar degeneration (FTLD) results in clinical syndromes, which include (1) behavioral variant frontotemporal dementia (bvFTD) with initial changes noted in personal conduct and/or interpersonal behavior, and (2) language variant frontotemporal dementia (lvFTD), where a language disorder emerges as the most salient impairment during initial stages of illness (Rabinovici and Miller, Reference Rabinovici and Miller2010). Both forms are progressive, eventually resulting in more generalized dementia. FTD is more commonly associated with an earlier onset of clinical illness compared with Alzheimer's dementia (McMurtray et al., Reference McMurtray, Clark, Christine and Mendez2006). Because of the predominant behavioral manifestations with bvFTD, it may be difficult to clinically differentiate it from primary psychiatric illness like schizophrenia (Vanderzeypen et al., Reference Vanderzeypen, Bier, Genevrois, Mendlewicz and Loststra2003).
A positive family history has been reported for about one third to one half of patients with FTD (Seelaar et al., Reference Seelaar, Rohrer, Pijenburg, Fox and van Swieten2011). More than 100 genetic mutations have been identified with familial FTD, most commonly involving the progranulin and microtubule-associated protein tau genes on chromosome 17. Familial FTD due to the C9ORF72 mutation is linked with psychiatric disturbance, with up to 50% of patients exhibiting delusions or hallucinations (Snowden et al., Reference Snowden2012; Takada and Sha, Reference Takada and Sha2012). In addition, suicide has been shown to be the first manifestation of this illness in some patients (Synofzik et al., Reference Synofzik2012). Brain immunohistochemistry of FTLD associated with the C9ORF72 mutation reveals intracytoplasmic staining for the TAR DNA-binding protein 43 (TDP-43) and ubiquitin, making C9ORF72 FTLD a subgroup of FTLD associated with TDP43 pathology (Hsiung et al., Reference Hsiung2012).
Case
This 67-year-old man presented with catatonic stupor. Cognitive impairment was first noted following a traumatic brain injury (TBI) after a motor vehicle accident at the age of 40 years, which left him with impairment in judgment and problem-solving that resulted in loss of employment. He remained cognitively stable and independent in self-cares and some home responsibilities until one year prior to presentation when he experienced the onset of gradually progressive cognitive and functional deterioration coincident with the death of a close friend. At the time, his symptoms were presumed to be related to an index case of depression. Six months prior to presentation, he attempted suicide by driving his car into a river and was treated with citalopram 30 mg/day. Three months prior to admission he demonstrated excessive and disorganized motor behavior and speech with periods of staring and decreased appropriate interaction with his family. Citalopram was reduced. He was subsequently admitted for agitated and violent behavior and treated with haloperidol. He was transferred for a medical evaluation after becoming mute and non-responsive. The patient was diagnosed with cognitive impairment by occupational therapy assessment (Allen Cognitive Level [ACL] 3.0), pneumonia, and dehydration (Holm et al., Reference Holm1999).
Pneumonia and dehydration were treated with no improvement of the psychiatric condition and he was transferred to our inpatient treatment program. The Bush–Francis Catatonia Rating Scale (BFCRS) score, a reliable and valid measure for catatonia, was 15 decreasing to 4 after 2 mg of intravenous lorazepam followed by a schedule of oral lorazepam (Bush et al., Reference Bush1996). The patient was then treated with a combination of oral lorazepam 0.5 mg four times daily and venlafaxine 225 mg/day. He also underwent six electroconvulsive therapy (ECT) treatments (total seizure time = 231 sec). Catatonia resolved (BFCRS = 0) and cognitive performance improved (ACL 4.2). The patient was discharged to home with a diagnosis of dementia secondary to TBI with depression complicated by catatonia.
Following his return to home, the patient continued to do well for two months, with improvements noted in cognition and behavior. Six months after his hospitalization, the patient became increasingly anxious and experienced insomnia with frequent restless movements and persistent verbalizations during sleep. Daytime speech was characterized by stereotypes and impulsivity. The patient was treated with a series of eight ECT treatments and ECT maintenance every three weeks. Elements of depression, including insomnia, isolation, and negativity, promptly resolved but verbigerative speech and occasional mannerisms persisted. Impairments in executive function and attention did not improve. Three months later, cognition and behavior again deteriorated. Inpatient treatment with ECT, venlafaxine, and lorazepam again seemed to resolve depression, but cognitive impairments as well as elements of catatonia persisted. Discontinuation of ECT with maintenance of medications alone resulted in rapid worsening of depression and catatonia (BFCRS = 18). ECT was resumed with improvement but not resolution of catatonia (BFCRS = 6).
During the patient's final hospitalization, he was visited by his older brother who was noted to have abnormal behavior suggestive of a frontal lobe disorder. The brother subsequently underwent magnetic resonance imaging (MRI) of the brain, with images showing an atrophy pattern consistent with bvFTD. Additional family history identified a history of progressive behavioral and neurological deterioration over 20 years in the patient's mother prior to her death in 1990. Maternal brain autopsy findings had revealed extreme atrophy in the frontal and temporal lobes, with severe symmetrical dilatation of the lateral ventricles, moderately severe atrophy of the amygdala, and severe atrophy of the hippocampi. The histologic diagnosis was dementia lacking distinctive histologic features (DLDH).
The patient was unable to tolerate MRI testing; however, non-contrast computed axial tomography of the brain revealed mild prefrontal and cerebellar atrophy. Genetic sequencing for the C9ORF72 repeat expansion mutation was positive by PCR assay. Subsequent analysis of the patient's mother's stored brain tissue yielded positive intracellular (without intranuclear) staining for ubiquitin and TDP-43. Based on the patient's symptoms, laboratory testing, and family history, he was diagnosed with familial FTD due to C9ORF72 mutation. His clinical condition has remained stable since discharge to a long-term care facility with a treatment regime, including venlafaxine, lorazepam, and maintenance ECT.
Discussion
The frequent occurrence of psychiatric disturbances in familial FTD due to C9ORF72 mutations makes the consideration of the interface between psychiatric illness and neurodegeneration germane. The circumstance of prolonged clinical illness as noted in this patient's mother coupled with possible incomplete and somewhat age-dependent penetrance of the C9ORF72 mutation and its proclivity for behavioral presentations, including psychoses, can make the differentiation of this form of familial FTD from psychiatric illness challenging. This case highlights that FTD associated with the C9ORF72 mutation can present with depression and suicidal tendencies complicated by catatonia. Catatonia can be attributed to frontal-subcortical dysfunction (Lauer et al., Reference Lauer2001), although differentiating catatonia caused by neurodegenerative versus psychiatric illness can be difficult. This diagnostic challenge was well described by Suzuki and colleagues (Reference Suzuki, Takano and Matsuoka2009), who reported a case of catatonia that clinically resembled bvFTD. In their report, symptomatic reduction after ECT was used to diagnose a psychiatric basis for the patient's behavioral problems. The current case highlights that FTD due to the C9ORF72 mutation can present with depression, suicidal tendencies, and catatonia, and that these problems can respond to standard psychiatric therapies, including ECT. This case complements an earlier report of a 72-year-old woman with suspected FTD, depression, and Cotard's syndrome whose behavioral symptoms and delusions were reduced when treated with ECT (Kobayashi et al., Reference Kobayashi, Inoue, Shioda and Kato2012). Therefore, initial responsiveness to psychiatric therapy, including ECT, may not be a reliable tool to rule out FTD.
Note that elements of the clinical presentation, including late-onset depression and the development of a rapid eye movement (REM) behavior disorder during treatment, suggested the possibility of a neurodegenerative etiology. This case highlights that some of the behavioral signs included in the recently revised criteria for bvFTD that could be attributable to catatonia should not imply immutability secondary to neurodegeneration (Rascovsky et al., Reference Rascovsky2011). In addition, this case demonstrates that the phenotypic evolution of bvFTD is accompanied by the evolution of behavioral manifestations of this illness and the responsiveness of these manifestations to standard therapies over time.
Conflict of interest
None.
