CNS Spectr. 2008;13(3):202-208
Faculty Affiliations and Disclosures
Dr. Mendez is professor in the Departments of Neurology and Psychiatry & Biobehavioral Sciences at the David Geffen School of Medicine at the University of California–Los Angeles and director in the Neurobehavior Unit at the Veterans Affairs Greater Los Angeles Healthcare System. Dr. Shapira is clinician-researcher in the Department of Neurology at the David Geffen School of Medicine at the University of California–Los Angeles.
Faculty Disclosures: The authors do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.
Submitted for publication: August 8, 2007; Accepted for publication: January 31, 2008.
Please direct all correspondence to: Mario F. Mendez, MD, PhD, Neurobehavior Unit (116AF), Veterans Affairs Greater Los Angeles Healthcare, 11301 Wilshire Boulevard, Los Angeles, CA 90073; Tel: 310-478-3711 ext 42696, Fax: 310-268-4181; E-mail: mmendez@UCLA.edu; or Jill S. Shapira, RN, PhD; E-mail: firstname.lastname@example.org.
• Recurrent thoughts and behaviors with onset in middle or late life may be an early manifestation of frontotemporal dementia (FTD).
• FTD results in a wide spectrum or recurrent events, from obsessional thoughts to complex tics and perseveration.
• In FTD, recurrent thoughts and behavior are probably due to abnormal response inhibition from disturbances of an orbitofrontal-basal ganglia network.
This article describes the spectrum of recurrent thoughts and behaviors that can result from frontotemporal dementia (FTD) and its variants. Although repetitive behaviors can result from a range of brain disorders, FTD is the most common neurologic cause of new-onset recurrent thoughts and behaviors in middle or later life. Patients with FTD can manifest typical or bizarre compulsions, hoarding, verbal and motor stereotypies and complex tics, self-injurious acts, perseverations, and fixed, obsessional thoughts. The frequency and variability of these repetitive behaviors suggest a common disturbance of orbitofrontal-basal ganglia circuits involved in response inhibition. The amelioration of these recurrent events with the administration of serotonin selective reuptake inhibitors further suggests a serotonergic deficit.
Frontotemporal lobar degenerations are common causes of new-onset neuropsychiatric symptoms in middle or late life.1-4 These degenerative processes have circumscribed lobar atrophy of the frontal or adjacent anterior temporal regions with gliosis, microvacuoles, and frequent inclusion bodies.5-7 Previously termed “Pick’s disease” due to the presence of argentophilic, tau-positive intranuclear inclusions (Pick bodies),8,9 many patients have tau-negative, ubiquitin-positive inclusions.10,11 The most common clinical manifestation of these pathological changes is frontotemporal dementia (FTD), a clinical syndrome that typically presents in the 50s with behavioral symptoms.4,12-14
During the first few years after FTD onset, repetitive and other behavioral symptoms are more prominent and disruptive than memory or other cognitive deficits.2,4,15-20 For example, among 61 patients with frontotemporal lobar degeneration on pathology, 90% had presented with neuropsychiatric features, including abnormal recurrent behaviors.5 Clinicians frequently miss these behavioral symptoms early in the course of FTD.21-23 Recurrent thoughts and behaviors in FTD involve obsessions (intrusive thoughts that increase anxiety), compulsions (repetitive, ritualistic behaviors that decrease anxiety), hoarding, stereotypical movements (repetitive, coordinated movements that resemble purposeful acts), self-injurious behaviors, complex tics, and perseverations.
This review discusses recurrent thoughts and behaviors in FTD and exemplifies the spectrum of these disturbances with four illustrative case reports. Although these examples are, coincidentally, all women, FTD is actually slightly more common among men.4
A 69-year-old woman had a 2-year history of a progressive personality change with inattentiveness, disengagement from usual activities, socially inappropriate behavior, and a decline in personal grooming and hygiene. In addition, she developed a distressing tendency to compulsive counting. She kept counting her steps and the cracks on the floor. She began eating junk food all the time, became fixated on viewing and reviewing certain video tapes, and would repeatedly go the bathroom without needing to go. Her medical history was otherwise unremarkable, and her family history was positive for dementia in her grandparents in their 80s.
On examination, she had decreased spontaneous verbal output, a fixed grin with an occasional inappropriate laugh, and poor or limited insight into her condition. During the examination, she kept eating bags of junk food and, when the bags were discarded, would retrieve them and look for more to eat. She scored 29 out of 30 on the Mini-Mental State Examination (MMSE)24 missing the specific day only. Her digit span was six forward and two backward. Language was fluent with intact auditory comprehension and repetition. She generated a word list of one animal and 10 “F” words in 1 minute, and had difficulty on confrontational naming. Memory was one out of four verbal items at 15 minutes. Visuospatial constructions were intact for two-dimensional and three-dimensional drawings and a clock drawing.25 The patient was concrete on unfamiliar proverbs. She was able to complete the Luria alternating hand programs, but she totally failed the Go-No-Go test.25 The rest of the neurologic examination was normal, including the absence of frontal-release signs.
The patient met Consensus Criteria for FTD with prominent compulsive-like behavior.1 Neuroimaging confirmed the clinical diagnosis. Magnetic resonance imaging (MRI) showed focal atrophy in the anterior part of the frontal lobes bilaterally with compensatory enlargement of the frontal horns, and single photon admission tomography showed bilateral bifrontal hypoperfusion. Receiving sertraline 100 mg/day, resulted in a decrease of her compulsive-like behaviors.
A 71-year-old, right-handed woman presented with 2 years of an insidious and progressive change in behavior with prominent disinhibition and inappropriate behavior. Examples included spitting and cursing in public, making personal comments to or touching strangers, cutting in lines, putting her hands in food and going behind the counter at restaurants, and shouting at her daughter to help her cheat on the driver’s examination. She appeared unable to recognize some familiar people and lost the meaning of some words. In addition, she developed compulsive-like behaviors. She constantly repeated the same phrases, kicked leaves into the gutter, watched a certain game show, and uncharacteristically attended church daily. She looked at her watch every few minutes and would point to it stating the time. She ate nothing but clam chowder, a certain brand of potato chips, and chocolate and vanilla ice cream. Her medical history was otherwise unremarkable. However, the patient’s family history was positive for bipolar spectrum disorders in her mother and a sibling.
On examination, this was an older woman who was animated, talkative, and extremely disinhibited, sometimes breaking out in song. She did not display insight or concern for her behaviors. She could not inhibit touching hairy arms and eyebrows. At one point, she fondled a medical student’s earrings and made an obscene gesture to her husband. Her commentary included stereotypical repetitive phrases (eg, “I love you”), which were repeated almost every third sentence. On the MMSE, she scored 27 out of 30. She missed the three memory items only. Her digit span was seven forward and three backwards. She had a word list of seven animals in 1 minute and two “F” words in 1 minute. She had difficulty with one (house) out of 15 on the short version of the Boston Naming Test. She did not know the meaning of many of the words. The patient was able to remember three out of four verbal items at 15 minutes. She was able to do 2-D and 3-D drawings, a clock face, and the Rey-Osterrieth complex figure drawing.25 She was given a series of famous faces to look at and she could not recognize current faces, even the current president. Her proverb interpretation was concrete. She could not perform the Luria alternating programs or the Go-No-Go task. The rest of her neurologic examination, including cranial nerves, gait, motor, reflex, and sensory exams, was normal.
This patient met Consensus Criteria for FTD confirmed by neuroimaging.1 MRI scan showed anterior temporal atrophy, and positron emission tomography showed frontotemporal hypometabolism, worse in the anterior temporal region, especially on the left. She was treated with quetiapine 10 mg TID with behavioral improvement.
A 54-year-old right-handed woman had a 1–2-year history of personality changes marked by inappropriate statements to strangers. She made comments to young people about their sexual orientation, to overweight individuals about their diets, and to smokers about their smoking. She was also obsessed with imaginary personal relationships with select male movie actors. She would talk about this constantly, yet would readily endorse that it was in her “head.” Still, she could not stop herself from thinking about it. The patient had repetitive counting and would frequently interrupt her conversational discourse to go into a series of continuous counting. She developed stereotypical movements including a grinning or tensing of her mouth, picking at her fingers, and tapping her knees. Her medical history was positive for two possible prior generalized seizures. Her family history was negative for any dementing illnesses.
On examination, she locked her gaze on the examiner in an almost “visual grasp.” She endorsed an awareness of her behavior with strangers and that it was “wrong” but could not stop it. Her MMSE score was 30 out of 30. Digit span was six forward, three backward. Language was fluent with good repetition, confrontational naming, and auditory comprehension. The patient generated a word list of 10 animals in 1 minute and seven “F” words in 1 minute. She scored 15 out of 15 on the mini-Boston Naming Test.25
On an auditory-verbal learning test, she recalled four out of the 10 words at 15 minutes. On the recognition portion of the test, she got nine out of the 10 words correct and had no false positives. Constructions were normal, both at the 2-D and 3-D level, and she drew a clock within the proper time limit without difficulty. She was concrete on proverb interpretation and was unable to perform the Luria alternating hand programs or the Go-No-Go test. The rest of her neurologic examination showed her to have repetitive tensing of her mouth or a forced grimacing, picking and excoriation of her fingers, and repetitive tapping of her knees. There were no other neurologic findings.
The patient met Consensus Criteria for FTD with stereotypical movements of face and hands not related to medications or other known factors.1
Her MRI revealed frontally predominant atrophy, and her single photon admission tomography scan showed hypoperfusion predominant in the right frontal and right anterior temporal lobes, and to a lesser degree in the left frontotemporal region. She was started on quetiapine, but this was ineffectual, and she was eventually treated with sertraline 100 mg/day with some decrease in repetitive behaviors.
A 66-year-old woman had a history of behavioral changes that began with hoarding. She began piling up large amounts of unopened mail in the house and collected piles of clothes. In addition, she collected large quantities of magazines. The patient had gone on repeated buying sprees and bought >$1,000 of magazines from salesmen, including magazines that she had no use for. Over a 2-year period, she became disengaged, apathetic, inattentive, and disorganized with disinhibited behavior and a decline in social graces. The patient’s family further complained that she had become obsessed with the thought that her husband was inattentive to her and that he “minimized” her. Her family denied that she was truthfully correct, yet the patient talked about it almost constantly. In the past, the patient had been similarly obsessed with her urinary function and “frequency” despite negative urological evaluations. Her medical history or family history were otherwise unremarkable.
On examination, she was friendly and loquacious but without insight into her illness or behavior. At one moment, she reported being angry and upset over the discussion and a moment later she would be laughing or light-hearted. Her MMSE was 23. She missed five orientation and two memory items. Her digit span was six forward and four backward. Her language was fluent except for some word-finding hesitancy. The patient’s auditory comprehension and repetition were normal. She generated word lists of 13 animals in 1 minute and six “F” words in 1 minute. She scored 13 out of 15 on the mini-Boston Naming Test.25
On a verbal-learning task, she recalled zero out of 10 words at 15 minutes but recognized nine of them. Visuospatial constructions were normal at the 2-D and 3-D levels. Her clock drawing had incorrect placement of the hands, but correct placement of the numbers. She was concrete on proverbs, such as “Rome was not built in a day” or “don’t judge a book by its cover.” The patient was unable to perform the Luria alternating programs or the Go-No-Go test. The rest of her neurologic examination, including cranial nerves, gait, motor, reflex, and sensory testing, was normal.
This patient met Consensus Criteria for FTD with hoarding and obsessional thoughts.1
Her MRI showed mild global atrophy. Her positron emission tomography scan was consistent with decreased frontal metabolism and probably anterior temporal as well, right greater than left. Memantine 10 mg BID and escitalopram 10 mg/day were added to her regimen with improvement in her recurrent thoughts and behavior.
These patients illustrate the range of recurrent thoughts and behaviors among patients with FTD. They included fixed obsessions (intrusive, troubling, ego-dystonic); typical counting compulsions, less typical compulsions, such as fixation on certain foods and water-drinking or repeated trips to the bathroom, repetitive disinhibited behaviors, collecting and hoarding, verbal stereotypical phrases, and stories, and motor stereotypies. Other patients with FTD have had complex tics or simple stereotypies, such as clapping, humming, or lip-smacking, and compulsive-like behaviors, such as checking, cleaning, and wandering a fixed route.19,26-29 More complex rituals include compulsive hoarding, pathological gambling, and self-injurious behaviors, such as trichotillomania and picking and excoriating their fingers.23,30 Furthermore, these patients are prone to frontally mediated perseverations, or previously acquired motor responses that, although no longer appropriate, cannot be inhibited.
In the absence of drug or other specific causes, new-onset recurrent thoughts and behaviors after 50 years of age result from neurologic disease.31 New-onset repetitive behaviors can result from traumatic brain injury,33-35 strokes,34,36-39 Huntington’s disease,40,41 brain tumors,34,40-42 or infections of the central nervous system.34,43 The most common neurologic cause of new-onset repetitive behaviors after 50 years of age, however, is FTD.1,25,27,44-48 Approximately 80% of FTD patients eventually have repetitive behaviors,48 which is much more than in other dementias.13 These repetitive behaviors have special diagnostic importance because of the increasing numbers of patients with FTD with the peak of the baby-boomer generation, the absence of a clinical biomarker for this disorder, and the fact that instruments, such as the MMSE, are not useful in detecting FTD. Recurrent thoughts and behavior are among the most salient presenting symptom of FTD.21,46,49 Early clinical and clinicopathological studies19,44 have suggested that stereotypical and perseverative behavior were one of the best discriminants for FTD. Among 14 patients with Alzheimer’s disease and 14 with suspected FTD, investigators described compulsive-like behavior in 64% of the frontal dementia patients compared to only 14% of those with Alzheimer’s disease.47 Recurrent thoughts and behavior often occurred quite early and could be severely disabling. In a comparison of compulsive-like behaviors as presenting symptoms in 29 patients with FTD compared with 48 patients with Alzheimer’s disease,26 compulsive behaviors occurred in 11 (38%) of the FTD patients versus five (10%) of the Alzheimer’s disease patients (Table 1). There are no differences between sporadic or genetic causes of FTD in producing stereotypies and ritualistic behavior.50,51
There have been a few systematic studies of recurrent thoughts and behaviors in FTD. Using their Stereotypy Rating Inventory, Shigenobu and colleagues52 found much higher scores among 26 patients with a frontotemporal lobar degeneration compared to 46 Alzheimer’s disease patients, 26 vascular dementia patients, and 40 normal controls. Using a Stereotypic and Ritualistic Behavior subscale, Nyatsanza and colleagues53 found that 18 frontal-variant FTD and 13 semantic dementia patients had significantly higher scores than 28 Alzheimer’s disease patients. In this study, stereotypic behaviors were not correlated with either disease severity or the extent of cognitive impairment in the FTD group. Using a stereotypical movements scale, Mendez and colleagues54 evaluated 18 FTD and 18 Alzheimer’s disease patients and found more patients with stereotypical behaviors (eight; 44.4%) among the FTD patients, compared with one of the Alzheimer’s disease patients (5.6%) (Table 2). All the FTD patients with stereotypical movements had additional compulsive behaviors, suggesting a similar pathophysiologic cause.
The neuroanatomical regions implicated in repetitive behavior are the orbitofrontal cortex, the basal ganglia, and the pathways between them. The medial orbitofrontal cortex is involved in reward and incentive motivations as well as stimulus response learning, whereas the lateral orbitofrontal cortex is involved in response suppression and motor inhibition. Both orbitofrontal regions connect with the basal ganglia for the generation of a coherent stream of behavior. Among FTD patients, simple stereotypical behaviors correlate with right frontal or orbitofrontal hypoperfusion or hypometabolism.55-57 Complex, intentional, or time-consuming compulsions and rigidity correlate with temporal lobe involvement, but probably affect the closely adjacent orbitofrontal cortex as well.58-61
Data from obsessive-compulsive disorder (OCD), developmental rituals, and acquired repetitive behaviors from brain lesions support a relationship of recurrent thoughts and behaviors with orbitofrontal-basal ganglia dysfunction. First, OCD is often associated with impairments of executive control,62 particularly with a tendency to greater interference effect and problems with response inhibition.63,64 Clinical OCD is linked to hyperactivation of the lateral orbitofrontal cortex, adjacent anterior cingulate cortex, and the basal ganglia, particularly the caudate nuclei, possibly for effortful response inhibition for anxiety reduction. Second, normal rituals among 2-year-olds (or abnormal among autistic children) may be related to maturation of the lateral orbitofrontal cortex and excessive demand on its developing response inhibition system.65 Finally, repetitive behaviors can follow strokes and other brain lesions that involve the basal ganglia, including the caudate nuclei, putamen, substantia nigra, and globus pallidus.36,39,66 Involvement of basal ganglia suggests that the burden of behavioral control shifts from an automatic basal ganglia mechanism to an effortful orbitofrontal one. Patients with recurrent events from FTD may not be able to suppress responses to internal or physiologic urges or to salient external stimuli when they are environmental dependent.56,57,67
Recurrent thoughts and behaviors are a symptom of FTD, and FTD is a window to the nature of recurrent thoughts and behaviors. In the absence of approved medications for FTD, symptomatic treatments, such as serotonin selective reuptake inhibitors, can be helpful in ameliorating recurrent thoughts and behaviors. The literature suggests55-61
that, in these patients, repetitive events are related to orbitofrontal-basal ganglia dysfunction with inability to inhibit responses to internal or external stimuli. Further work and investigation will be required to establish this hypothesized mechanism for recurrent thoughts and behavior in FTD.
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