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Psychosis and Hallucinations in Frontotemporal Dementia with the C9ORF72 Mutation: A Detailed Clinical Cohort

Kertesz, Andrew MD*; Ang, Lee Cyn MD; Jesso, Sarah BA*; MacKinley, Julia BA*; Baker, Matt BA; Brown, Patricia BA; Shoesmith, Christen MD*; Rademakers, Rosa PhD; Finger, Elizabeth C. MD*

Cognitive And Behavioral Neurology: September 2013 - Volume 26 - Issue 3 - p 146–154
doi: 10.1097/WNN.0000000000000008
Original Studies
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Objective: To specify the presenting symptoms and clinical course of patients with frontotemporal dementia (FTD) and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion.

Background: The 2011 discovery of the C9ORF72 repeat expansion causing familial FTD and amyotrophic lateral sclerosis has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish carriers of the C9ORF72 mutation from other patients with FTD. Prior reports identified a subset of patients with FTD who had an unusually high prevalence of psychosis, although their specific symptoms had not yet been fully described.

Methods: From a cohort of 62 patients with FTD, we conducted a retrospective chart review of 7 patients who had C9ORF72 mutations on genetic testing, and 1 untested sibling of a C9ORF72 carrier.

Results: Detailed histories revealed a higher prevalence of psychosis, including visual and auditory hallucinations and delusions, in the 8 C9ORF72 carriers than in our patients with sporadic FTD.

Conclusions: This cohort confirms and adds clinical details to the reports of a high prevalence of psychotic phenomena in patients who have C9ORF72 mutations as well as FTD or amyotrophic lateral sclerosis.

Departments of *Clinical Neurological Sciences and

Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

Department of Neuroscience, Mayo Clinic, Jacksonville, FL

The authors declare no conflicts of interest.

Reprints: Elizabeth C. Finger, MD, Cognitive Neurology Clinic, Parkwood Hospital, 801 Commissioners Road East, ON, Canada N6C 5J1 (e-mail: elizabeth.finger@lhsc.on.ca).

Reader Benefit: Decades before they develop other symptoms of frontotemporal dementia, patients who have C9 mutations can present with a range of neuropsychiatric symptoms that may be diagnosed as primary psychiatric disorders.

ALS=amyotrophic lateral sclerosis; bvFTD=behavioral variant frontotemporal lobe dementia; C9ORF72 (gene)=chromosome 9 open reading frame 72; FTD=frontotemporal dementia; MRI=magnetic resonance imaging; TDP-43=transactive response DNA-binding protein 43 kDa (kiloDaltons).

In 2011, expanded GGGGCC hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9ORF72) gene were first reported in patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and combined ALS-FTD (DeJesus-Hernandez et al, 2011; Millecamps et al, 2012; Renton et al, 2011). According to Millecamps et al (2012), these expanded repeats are now known to be the most common genetic cause of both the familial and sporadic forms of ALS (Gijselinck et al, 2011; Mahoney et al, 2012; Majounie et al, 2012; Morris et al, 2012). The most common presenting syndromes in patients with the C9ORF72 mutation are behavioral variant FTD (bvFTD) and primary progressive aphasia with concomitant ALS (Majounie et al, 2012; Simon-Sanchez et al, 2012).

In a multicenter survey, Majounie et al (2012) found that 6% of Europeans with sporadic FTD (59 of 981) had the mutation, as did 25% of Europeans with familial FTD (99 of 400). Several comparisons of the presenting neuropsychiatric symptoms in patients with FTD showed a higher prevalence of delusions in C9ORF72 mutation carriers than in noncarriers (Sha et al, 2012; Snowden et al, 2012).

Neuroimaging shows predominant temporal atrophy in about half of all patients with FTD; C9ORF72 carriers with FTD also show significantly more thalamic and parietal atrophy than noncarriers (Sha et al, 2012). Pathologic examination of brain tissue from patients with the C9ORF72 mutation has nearly always revealed frontotemporal lobar degeneration-transactive response DNA-binding protein 43 kDa (FTLD-TDP-43) protein inclusions of variable type, size, and morphology (Hsiung et al, 2012; Simon-Sanchez et al, 2012; Snowden et al, 2012).

To help clarify the clinical phenotype of this important newly discovered mutation, we reviewed the cases of 7 patients with FTD, plus 1 patient’s sister, who had autopsy-proven FTD but never underwent genetic testing. We were struck by the high prevalence of psychosis in this cohort, beyond the otherwise severe behavioral manifestations of FTD.

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METHODS

Patients

From 2004 to 2012, our center diagnosed 350 patients with FTD. Before 2011, we based clinical diagnoses on the Neary criteria (Neary et al, 1998). For diagnoses made during 2011 and 2012, we used the newly available revised consensus criteria for bvFTD (Rascovsky et al, 2011).

Of the 350 patients with FTD, 62 consented to participate in research protocols that tested them for C9ORF72 expanded repeats. Of these 62 patients, 23 had been diagnosed with bvFTD, 18 had semantic dementia, 6 had progressive nonfluent aphasia, 7 had FTD and motor neuron disease, 5 had corticobasal syndrome, and 3 had progressive supranuclear palsy.

Informed consent was obtained from all patients and caregivers for genetic testing for mutations related to FTD. The study procedures were approved by the Human Subject Research Ethics Board at the University of Western Ontario.

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Genotyping

As described by Stewart et al (2012), we used a 2-step protocol to find C9ORF72 mutations. First, we PCR amplified the hexanucleotide repeat using 1 fluorescently labeled primer; then we analyzed fragment length on an automated Applied Biosystems Inc 3730 DNA Analyzer (Life Technologies, Grand Island, NY) (DeJesus-Hernandez et al, 2011). For all patients whose samples appeared homozygous in this 2-step assay, we analyzed further using the repeat primed PCR method. We considered “a characteristic stutter amplification pattern on the electropherogram… [to be] evidence of a pathogenic repeat expansion” (Stewart et al, 2012).

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Chart Review

Of the 62 people tested, 7 patients from 6 different families had expanded repeats in C9ORF72. We describe these 7 patients in detail below. We also describe an additional patient from 1 of the 6 families; this last patient did not undergo genetic testing, but we followed her at our center and believe it likely that she had expanded repeats in C9ORF72 because her brother had them and because she herself had autopsy-proven FTD. Table 1 summarizes key clinical and neuroanatomic findings for the 8 patients.

TABLE 1

TABLE 1

The 8 case histories are drawn from information that 2 neurologists (A.K. and E.C.F.) extracted and reviewed from the patients’ clinic charts on symptoms, family histories, neuropsychological testing, neuroimaging, and autopsy results. We also reviewed the charts that were available for 44 of the 55 tested patients who did not have C9ORF72 expanded repeats; in these charts we sought reports of hallucinations, delusions, and other psychotic symptoms.

We performed χ2 analyses on the frequency of psychotic symptoms in C9ORF72 carriers versus noncarriers. We set significance at P<0.05.

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CASE HISTORIES

Patient 1

Prediagnosis Behavior

Patient 1 was a retired minister and courier driver with 16 years of education who was living with his family. At age 24 he had had a psychotic breakdown, during which he reported that he “saw the devil” and he thought he was dying. In his thirties he had again been hospitalized because he thought he was possessed by the devil and believed that people were talking about him and were out to get him.

His FTD symptoms began at age 57, a year before he was evaluated at our center. He developed food “fads” and uncontrolled eating of sweets. He hoarded orange soda pop in his refrigerator and would eat a box of chocolates or a whole cake in 1 sitting. He started eating dinner before anyone else at the table, and he would eat off of others’ plates. He stored food in his mouth without swallowing it.

Because of his behavior, his employer demoted him from driving to working in a warehouse. Eventually, he was fired because he was found to be eating spoiled food that was left over from shipments and intended for the garbage.

He started giving money indiscriminately to charities and door-to-door solicitors. His family had to intervene to stop his overspending. His personal hygiene also suffered. He stopped bathing and brushing his teeth on his own, and he was very resistant to suggestions to do so. When his family challenged him, he would say that it was none of their business. He also became indifferent to family issues and events. He spoke less and stopped engaging in conversation. He started mumbling and lost his normal inflection and singing voice. He was arrested for assaulting his second wife. In the year before evaluation, he had 6 syncopal episodes.

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Diagnostic Evaluation

Patient 1 was referred to our clinic at age 58, initially for loss of initiative and changes in his voice and language. On examination, he was noted to lack spontaneous speech. When asked a question, he responded in clichés, with mumbling and stuttering. He made orofacial movements consistent with tardive dyskinesia caused by neuroleptic medications. His posture was slouched, he moved slowly, and he had a shuffling gait with decreased arm swing. He sometimes held his right hand in a curled position.

His family history was notable for dominantly inherited FTD/ALS. His brother, Patient 2 (described below), had bvFTD with ubiquitin-positive inclusions. His mother and a maternal uncle had early-onset dementia, probably FTD. A maternal aunt had ALS. The family had no other known history of psychiatric disease.

Neuropsychological testing showed word-finding and comprehension difficulties, semantic paraphasias, and circumlocutions. His Mini-Mental State Examination (Folstein et al, 1975) score was a normal 29/30. Raven’s Colored Progressive Matrices were also normal (Raven et al, 2003); he had problems drawing a clock to instruction, although he was able to copy a clock well. His Frontal Behavioral Inventory (Kertesz et al, 1997) score was 45, diagnostic of FTD; scores ≥27 are considered sensitive and specific for bvFTD.

Magnetic resonance imaging (MRI) showed considerable left parietal atrophy in addition to more diffuse frontal and temporal atrophy.

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Postdiagnosis Course

At follow-up 7 years after initial evaluation, the patient was living in a group home. He walked around the house inappropriately dressed, borrowed large amounts of money from short-term loan agencies at high interest rates, took food off the plates of strangers, drank large quantities of Coca-Cola®, and held his right arm rigid up in the air, suggesting corticobasal degeneration. He continued to have visual hallucinations, now of his deceased relatives.

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Patient 2

Prediagnosis Behavior

Patient 2, a telephone technician and the brother of Patient 1, was 52 years old when his wife died. After her death, he appeared somewhat detached, inattentive, and confused about what to do. He did not seem to be listening to what was being said to him. He also became careless with his money, giving it away to a church and other charitable organizations. After he ran red traffic lights and was in several car accidents, his driver’s license was withdrawn.

Later he developed disinhibition and bizarre behavior. From being a shy person, he turned rather bold. He joined a group of seniors who walked to and around a shopping mall. He became obsessed with getting to his walking group on time and became very upset if he could not go. However, after a while he stopped caring about walking with the group. Instead, he roamed incessantly around the mall. When the group was finished walking for the day, he often continued roaming on his own and then went home by taxi.

He also developed strange eating habits. He did not seem to know when to stop eating. He would finish a chocolate cake if it was left in front of him. When he ate at another person’s home or even at a restaurant, he always asked for seconds. Once at the mall he reached over a stranger’s shoulder to grab a handful of her popcorn.

He would pick up napkins from each vendor in the mall’s food court and take them home. He would sit down at another person’s table and take a section of the person’s newspaper without asking. On his walks, he collected soda pop cans, crushed them, and stuffed them into his pockets, ruining his jacket. Once he took a book from a store without paying for it.

He neglected his hygiene and had to be reminded to shower. He repeated questions, sounding like an echo. When his daughter asked him to pass the salt, he would repeat under his breath, “Pass the salt…pass the salt …pass the salt.” He also repeated phrases that he had heard on the radio.

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Diagnostic Evaluation

We evaluated Patient 2 at age 55. On examination he had a vacuous smile and echoed what was said to him, repeating instructions such as, “Hold your hands out.” He had a persistent glabellar tap reflex and “gegenhalten” (paratonia). On the Frontal Behavioral Inventory (Kertesz et al, 1997), his daughter confirmed many of his symptoms, such as impulsivity, restlessness, social inappropriateness, poor judgment, excessive jocularity, perseverations, obsessions, disorganization, personal neglect, concreteness, inflexibility, indifference, aspontaneity, and apathy.

The patient did not undergo neuroimaging studies.

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Postdiagnosis Course

The patient’s language became impoverished, he did not speak spontaneously as much as before, and he had difficulty finding words. His childish stubbornness and single-mindedness seemed like “tunnel vision.” He was put on trazodone, which modestly decreased his restlessness.

He entered a supervised day-care program and adapted quickly to the new routine. He particularly enjoyed dancing. At the day-care center he would take other people’s food from the refrigerator. Once he followed the custodian up onto the roof. He was impatient and impulsive. If he had to wait for something for as long as a few minutes, he would walk around rubbing his hands and clapping his thighs, and then he might wander off.

Over time, he developed severe apraxia and “parkinsonism” that was doubtfully responsive to levodopa. He became progressively more rigid and mute; his only sounds were echolalic whispers, songs, and lip synching to movies. He had marked axial neck and asymmetric limb rigidity and dystonic plantar responses. He had a strong grasp reflex in his right arm; he would grip his own left arm so hard that he bruised himself. He lost the ability to manipulate objects with his right hand, acting as if his right arm did not belong to him. He had fixed, dystonic facial expressions, grimacing, rhisus sardonicus, and frontalis hypertonicity. He also had a partial vertical gaze palsy and square wave horizontal saccades.

Seven years after his symptoms began, at age 59, he died in a nursing home.

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Neuropathology

Autopsy showed widespread cortical atrophy, most severe in the frontal lobes, with ubiquitin-positive, tau-negative inclusions and degeneration of the basal ganglia, thalamus, and substantia nigra. TDP-43 immunostaining revealed cytoplasmic expression of TDP-43 in the cortical neurons, dentate granular neurons, hippocampal pyramidal neurons, and spinal motor neurons. There was also some staining in the white matter tracts, compatible with type B of the Mackenzie classification for FTLD-TDP (Mackenzie et al, 2011).

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Patient 3

Prediagnosis Behavior

Patient 3 was a mechanic with 13 years of education. At age 43 he first noticed some word-finding difficulty, but did not think much of it. Later he seemed unable to understand what was being asked of him, and he repeated things over and over. He would even perseverate with single words. A friend who lived far away described the patient’s speech over the telephone as sounding as though he was drunk. When he could not follow a telephone conversation with his wife, he would hang up on her.

By age 44 the patient was speaking much less and his telephone conversations were limited to “yes” and “no” responses. He would begin to cry easily. He had no ambition to do anything and he quit his job. He did not like to go out to see people. When people came to visit, he would get up and leave the room so that he could be alone. He was stubborn and rigid in his thinking. His personal hygiene declined. He took only 1 shower in 3 weeks. His wife had to tell him to change his clothes. He refused to share money in childish ways.

He became gluttonous. He would eat 2 large plates of food at supper time. He grabbed at food and shoved it into his mouth with his hands. He also developed a sweet tooth and began to eat ice cream, which he had never liked before, by the bowl full. Social disinhibition was evidenced by his compulsion to tell everyone that he had to go to the bathroom. He was inattentive, easily distracted, and disorganized. He was unaware of any changes in his behavior and denied them when asked.

His family history included a maternal uncle who had received a clinical diagnosis of Pick disease.

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Diagnostic Evaluation

We evaluated Patient 3 at age 45. On examination he had dysarthric speech that was borderline fluent and perseverative, with some paraphasias, repetition, and word-finding difficulties. His Mini-Mental State Examination (Folstein et al, 1975) score was 23/30, but he remained well oriented to place. His drawings of a pentagon and a clock were spatially correct, but he could not set the clock hands correctly—apparently, a result of his language problem. He did poorly on a logical memory paragraph. On the Western Aphasia Battery (Kertesz, 1982), his overall Aphasia Quotient was 80.6, indicating mild anomic aphasia. He showed difficulties with reading, spelling, drawing, and praxis. His Dementia Rating Scale-2 (Jurica et al, 2001) score was 100/144, in the significantly impaired range. The Frontal Behavioral Inventory (Kertesz et al, 1997) revealed severe disinhibition behaviors, perseveration, apathy, indifference, aspontaneity, obsessions, irritability, and inappropriateness.

We gave the patient a clinical diagnosis of Pick disease, but because his dysarthria was atypical, we also considered motor neuron disease and brainstem vascular abnormalities.

Computed tomography, MRI, and single-photon emission computed tomography imaging showed left, predominantly perisylvian, frontotemporal atrophy.

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Postdiagnosis Course

The patient died at age 46, 3 years after his symptoms began. His family declined a request for an autopsy.

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Patient 4

Prediagnosis Behavior

Patient 4 was a man who worked part-time as a bus driver and part-time in a warehouse. At age 56, his personality changed. He became angry and repetitive in both his words and his actions. He had episodes of road rage, while at the same time acting apathetic and disinterested. He started to eat ice cream all the time. He developed rigid routines, eating ice cream and cereal at the same time from the same bowl. While eating, he rubbed his hands repetitively and he appeared restless. He also began having trouble finding words and his speech slurred. His arms became so weak that he could not lift them above his head.

At age 54, he started to choke on liquids.

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Diagnostic Evaluation

We evaluated Patient 4 at age 59. When asked, he acknowledged hearing voices. On examination he was restless and dysarthric, with severe verbal and orofacial apraxia. Significant weakness in his deltoids, biceps, hip flexors, and legs was associated with fasciculations, including in his tongue. He could not complete cognitive testing, but, in addition to his dysarthria, he was noted to have word-finding problems and difficulty comprehending complex sentences.

His family history was negative for similar illnesses.

Computed tomography and MRI showed bifrontal and left perisylvian atrophy.

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Postdiagnosis Course

We diagnosed the patient with FTD/ALS and referred him to the ALS unit. There electrodiagnostic studies confirmed motor neuron disease and he was admitted to palliative care. He died within a year of his diagnosis, at age 60. His family declined a request for an autopsy.

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Patient 5

Prediagnosis Behavior

Patient 5 was a housewife. When she was in her 40’s, people had commented on her echolalia. However, she had been well until age 53, when her husband died suddenly. Afterward, she was said to be depressed, increasingly bizarre, and delusional, coming to believe that she had inherited a home from another man whom she knew.

The patient’s daughter noticed a significant decline in her personal hygiene. Her baths were infrequent and brief, and she rarely changed her clothes. She followed her daughter everywhere and became very dependent on her. The patient ate quickly, shoveling food in; she even guzzled down hot coffee. She became apathetic, slept a lot, and took no interest in speaking with her children or grandchildren when they called or visited.

Over time, her withdrawal changed to a childlike excessive jocularity and impulsiveness. When the family took her to Wal-Mart, she approached babies. When she walked past a playground, she rode on the swings. She seemed to lose her manners, often burping in public. On one occasion, she emailed a picture of her daughter’s deceased baby to acquaintances. She became restless, fidgety, and made frequent humming noises.

Because of her decline in mental status, she was admitted to a nursing home. She seemed apathetic and uninterested in most things, but loved to participate in music. The staff became unable to manage her because she kept leaving the building, wandering off to look for the children whom she believed she had with the other man.

She was transferred to a psychiatric unit. There she was initially diagnosed with psychotic depression and treated with electroconvulsive therapy, olanzapine, and intramuscular risperidone. She developed parkinsonism, presumably from the psychotropic medications.

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Diagnostic Evaluation

Patient 5 was 56 years old when she was referred to our Cognitive Neurology Clinic for evaluation of dementia. We weaned her off her medications and her tremor improved.

Her family history suggested FTD and ALS in a dominantly inherited pattern. Of her 3 brothers and 3 sisters, 1 sister had been diagnosed with depression, and another had been diagnosed with ALS with probable cognitive changes in her 50s. The patient’s mother had been diagnosed with a dementia, thought to be Alzheimer disease, that had started in her 60s.

On neurologic examination the patient displayed a childlike affect. Her speech was sparse but she engaged in near-constant echolalia, mumbling, and small humming noises. She was able to follow verbal commands and imitate gestures. She could name 4 of the 6 pictured items on the NIH Stroke Scale (National Institutes of Health, National Institute of Neurological Disorders and Stroke), but could not give the meaning of more complicated words such as “mortgage” or “asparagus.” She displayed a mild action tremor in the left arm, bilateral grasp reflexes, and a positive snout reflex.

On neuropsychological testing, the patient scored only 14/30 on the Mini-Mental State Examination (Folstein et al, 1975), indicating dementia, but she was correctly oriented to the month, year, day, and city. She lost points for attention, concentration, repetition, following commands, writing, and copying the design. Her visuospatial skills, as assessed with clock drawing, were generally good; she misplaced the hands on the clock, but did better when copying. On the Trail Making Test Part A (Corrigan and Hinkeldey, 1987), she scored at the 10th percentile; she could not complete Part B.

Throughout the testing, she was notably laughing and quite childlike. Several times she said spontaneously, “I love country music.”

A computed tomogram showed medial frontal and bilateral anterior temporal lobe atrophy.

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Postdiagnosis Course

The patient suffered a progressive decline in her language and speech. She began to say “yup” or “okay” in a stereotypic way, even when it was an inappropriate response to the question. She developed mild dysphagia and became incontinent of urine. At the most recent follow-up, at age 59, she was living in a nursing home.

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Patient 6

Prediagnosis Behavior

Patient 6 was an accountant. At age 67, he began to forget the names of things. His wife noted that he would say “that thing there” instead of using specific nouns. When putting away the dishes, a familiar chore, he often asked, “Where does this go?” He did not ask what particular words meant, but once asked, “What’s this?” about the tire gauge that he typically carried with him when driving. On another occasion he confused strawberries with raspberries. When speaking, he stressed the wrong syllable. He once spent $500 on Reader’s Digest books, convinced that he would win a prize. On another occasion, he ordered many compact discs but never took them out of their plastic covers. He told other people so many details about his medical condition that they became embarrassed.

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Diagnostic Evaluation

We evaluated Patient 6 at age 68. Although he was very aware of a familial history of disease, he had no insight into the changes in himself. On examination he had mildly impaired semantic fluency and mildly to moderately impaired phenomic fluency. He made a few phonemic paraphasic errors, calling a kite a “pipe” or a “pike,” and calling a flag a “flang.”

His family history was significant for FTLD-TDP-43 type B in his sister.

MRI showed mild bilateral frontal, temporal, and parietal atrophy.

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Postdiagnosis Course

At the most recent follow-up, the patient was 71 years old and living at home with his wife and son. He had become very routine-bound and was easily upset by change. He was still described as being emotionally sensitive. Often unable to find an object, he would think that someone had “stolen it.” He accused his son of stealing food from the refrigerator. His hoarding tendencies had increased. He was reluctant to throw out old food that has passed its “sell by” date. He had developed obsessive behaviors, such as using a saline nasal spray so often that he ended up with nosebleeds.

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Patient 7

Prediagnosis Behavior

Patient 7 had been an accountant. At about age 42, he had started having visual hallucinations of people. He saw the people only at night when he was in a dark room. Their faces were not full or recognizable. He described them as funny and friendly, and he would at times laugh out loud when having a conversation with them, meaning that he probably had concurrent auditory hallucinations. One night his wife came downstairs and found him in the dark, telling the hallucinations to be quiet because otherwise his wife was going to wake up and come down and find them. He refused to see a doctor, because he did not want to be diagnosed with Pick disease, like his sister (she is Patient 8; see below). He continued having hallucinations for at least the next 20 years.

At age 52, the patient became argumentative, disinhibited, and socially inappropriate. He yelled at coworkers and brought noisy ornaments to the company Christmas party. Eventually, he lost his job. Later, his previously serious, aggressive personality became malleable, indifferent, and “happy-go-lucky.”

He developed incontinence, possibly related to his constantly drinking Diet Coke®. When his wife had surgery at Halloween, he went out trick or treating instead of staying home to take care of her. He obsessively collected fishing gear, phonograph records, and audiotapes. He did not change his clothes. Even though he was an accountant, he spent impulsively and lost interest in managing his finances.

At age 57, he developed a chronic cough, which progressed to dysarthria and dysphagia. Nine months before evaluation, his speech slurred and he began to drool. A few months before the evaluation, his legs became weak.

His family history showed an autosomal-dominant pattern of FTD. His sister (Patient 8, below) had been diagnosed with FTD. His mother had ALS; she was described as “very goofy,” although she had not been given a formal diagnosis of dementia. Two maternal uncles and 1 maternal cousin had ALS. Another maternal uncle was said to have dementia, a relative in Europe had “creeping paralysis,” and a maternal aunt in Europe was described as “crazy.”

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Diagnostic Evaluation

We evaluated Patient 7 when he was 62 years old. He had a jovial disposition but a spastic dysarthria and fasciculations in the tongue and arms. Reflexes were brisk in the left arm and both legs. He had a brisk jaw jerk and positive rooting reflex.

Neuropsychological testing showed a loss of executive functions, with generally preserved memory, language, and visuospatial performance.

MRI showed moderate bitemporal and inferior frontal atrophy.

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Postdiagnosis Course

At the most recent follow-up, at age 64, the patient remained jovial. His visual hallucinations had subsided. His bulbar symptoms continued to progress, consistent with ALS, but he remained active, without weakness in his limbs.

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Patient 8

Prediagnosis Behavior

Patient 8 was the sister of Patient 7. At age 47, she was fired from her job as a receptionist at Weight Watchers because of her change in behavior. She had started to eat too much, eg, finishing a whole bag of candies in 1 sitting. She became indifferent about her family. She began to shop excessively—buying thousands of dollars’ worth of clothes from catalogs at Christmas—and to hoard her clothes. She perseverated about irrelevant topics. She often appeared impatient, watching the clock and walking ahead of her companions. She told her doctor that he was “cute,” she hugged and kissed the neighbors’ teenage son, she danced inappropriately in public places, and she spoke to strangers and touched them as if they knew each other.

Starting around age 53, she also described visual hallucinations similar to those of her brother. At night in dark rooms, she saw visions of people and often had conversations with them. She would try to keep them quiet so they would not wake up her husband, who was sleeping next to her. Like her brother, she probably also had concurrent auditory hallucinations.

By age 55, she had become inattentive and her conversation was simple and childish. She often laughed without reason. She was apathetic and disorganized, had stopped cooking, and neglected her hygiene. She could no longer understand movies.

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Diagnostic Evaluation

We evaluated Patient 8 at age 55. On examination she appeared euphoric, hugging the examiner. At different times during the session, she interrupted her daughter, spoke tangentially, had echolalic speech, and for long periods did not talk at all. She was apraxic on alternating hand movements, and had low test scores for executive function.

Her family history was the same as that of Patient 7.

Computed tomography and MRI showed severe bifrontal atrophy as well as temporal atrophy that was worse on the right side than the left.

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Postdiagnosis Course

During the period after her evaluation, she felt compelled to touch everything around her, and she particularly liked to stroke velvet. She claimed to “hate food” but ate very well. She continued to report nightly visual hallucinations. She developed incontinence and signs of motor neuron disease, including drop foot. She died 9 years after evaluation, at age 64.

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Psychosis, Hallucinations, and Delusions in Patients with FTD but withoutC9ORF72Expanded Repeats

We reviewed the charts of 44 of our patients who did not have C9ORF72 expanded repeats. We found that 2 of these patients had visual hallucinations: 1 saw a dog on the ceiling; the other saw dead people as well as snakes, dogs, and bulls. None of the 44 patients had auditory hallucinations.

We found that 8 of the 44 patients had delusions. Five had paranoid delusions common to Alzheimer disease, of theft or spousal infidelity. Another patient wrongly believed—and told strangers—that her children had been killed in a car crash. The other 2 patients were sisters, both of whom were convinced that other people were being encouraged to be physically abusive toward them.

χ2 analysis demonstrated a significant association between C9ORF72 status and the presence of any psychotic symptom: χ2(1)=8.68, P<0.005.

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DISCUSSION

From our clinically diagnosed FTD population of 350 patients, we tested 62 for C9ORF72 repeat expansions and found 7 affected patients. We have described those 7 patients in detail, along with a patient’s untested but affected sister. Of these 8 patients, 3 had prominent psychiatric histories or presenting symptoms. Patient 1 had been treated for a psychotic breakdown at age 24, and Patient 4 acknowledged at age 59 that he had auditory hallucinations. Patient 5 was hospitalized because of paranoid delusions and psychotic depression at age 53. Patient 6 was mildly paranoid, without an actual psychiatric diagnosis—which is not uncommon in FTD or Alzheimer disease. Patients 7 and 8 both had prodromal visual hallucinations.

Most of the patients presented with bvFTD, with a pattern of disinhibition, compulsions, gluttony, indifference, and irritability not different from those seen in patients with other confirmed TDP-43 disorders or tauopathies. The exceptions were Patient 3, who was mildly aphasic at the onset, and Patient 1, who had psychosis 20 years before the onset of FTD. Patients 2 and 5 were echolalic but not obviously aphasic. Patients 5 and 6 had elements of semantic dementia.

Our 8 patients with C9ORF72 expanded repeats had a 50% prevalence of hallucinations, versus 5% for our 44 patients who did not carry the C9 mutation and whose charts we were able to review. We found delusions in 25% of the C9ORF72 mutation carriers, in contrast to 18% of the noncarriers.

The 11% prevalence of this newly discovered mutation in the tested members of our clinic population is commensurate with the combined experience of other centers. The reported prevalence of hexanucleotide C9ORF72 repeat expansions in European cohorts ranges from 25% to 28% in families with FTD, and from 2% to 6% in patients with sporadic FTD (Majounie et al, 2012; Simon-Sanchez et al, 2012). The mean age at onset in our cohort was 52.4 years (range, 43 to 58), compared to 56.9±8.3 years (range, 39 to 76) in the Simon-Sanchez et al (2012) study.

In our group of 8 patients, the initial diagnosis was bvFTD in 6 patients, aphasia in 1, and depression in 1. All of the patients eventually developed the typical pattern of marked behavioral disturbance, food obsessions and gluttony, loss of hygiene, indifference, inattention, irritability, and disinhibition. Two of the patients had elements of semantic dementia. Eventually, all but Patient 7 became aphasic.

Two of our 8 patients developed ALS: Patient 4, the typical spinal and bulbar type with rapid progression, and Patient 7 with only bulbar features as far as he was followed up. The other 4 families also had a history of ALS. Patients 2, 4, and 8 developed apraxia, and Patients 1 and 2 developed an extrapyramidal disorder resembling corticobasal syndrome after a typical course of bvFTD. Patient 5 developed parkinsonism, presumably after taking antipsychotic medication.

Lindquist et al (2012) reported corticobasal syndrome and parkinsonism with the C9ORF72 mutation. In our series, although only 2 of the 8 patients (Patients 4 and 7) met criteria for probable ALS and 1 (Patient 3) for possible ALS, this is still a higher prevalence than the ∼15% that we would expect in a general FTD clinic population (Lomen-Hoerth et al, 2002).

The most notable difference between our patients with C9ORF72 mutations and the general FTD population is the prevalence of psychosis with visual or auditory hallucinations or psychotic delusions in 4 patients and paranoid ideation in a fifth. Observations of psychiatric illness in the bvFTD literature have typically described the florid behavioral abnormality that is the essence of bvFTD. Psychosis in FTD or FTD/ALS has been considered rare, and in some reports has been listed as an exclusion criterion (Mendez et al, 2007).

In a previous paper, we reported the case of a woman with sporadic bvFTD with visual hallucinations and sexual delusions or erotomania (deClerambault syndrome) who had frontotemporal and parietal atrophy, and was shown on autopsy to have TDP-43 pathology (Tartaglia et al, 2008). In a small series, patients meeting criteria for both FTD and Lewy body dementia with hallucinations were also noted to have TDP-43 pathology (Claassen et al, 2008). Other reports described psychosis and parkinsonism in C9-linked families before the specific mutation was discovered (Pearson et al, 2010), as well as in patients with progranulin mutations (Gabryelewicz et al, 2010).

While psychosis is not considered a feature of ALS, Nitrini and Rosemberg (1998) described 3 patients who had FTD/ALS and psychosis with visual hallucinations. Lillo et al (2010) reported that delusions affect more patients with FTD/ALS than with FTD alone.

Arighi et al (2012) described psychiatric presentations in 3 patients with C9ORF72 mutations, but 2 of the patients had “psychiatric symptoms” compatible with bvFTD and 1 had “mystical delirium with auditory hallucinations” at age 44 and did not develop neurologic symptoms during 7 years of follow-up. In Snowden et al’s (2012) series of 32 patients with the C9ORF72 mutation, 38% presented with psychosis and another 28% were paranoid or delusional.

Snowden et al (2012) wrote, “Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.” Sha et al (2012) found delusions in 22% of patients with FTD or ALS and C9ORF72 mutations, as rated on the Neuropsychiatric Inventory (Cummings et al, 1994), but Sha did not find delusions in noncarriers. Our Patient 7 experienced visual hallucinations 20 years before being diagnosed with FTD; one could argue that he had an independent psychiatric illness. In the depressed Patient 5, the delusional content of her psychiatric illness had some possible basis in reality because the “other man” truly existed, even if he did not give her a house or children. In the other 2 patients (Patients 4 and 8) with paranoid ideation and auditory hallucinations, we elicited the symptoms on direct questioning and did not treat the hallucinations as a psychiatric illness.

In this case series of 8 patients with FTD and C9ORF72 mutations, we found a higher-than-expected prevalence of psychosis, hallucinations, and delusions. In several of the patients, the psychotic symptoms long predated other changes more typical of bvFTD, often resulting in initial misdiagnosis of a psychiatric disorder. The series is also notable for the frequent confluence of ALS and hallucinations.

Larger and more detailed studies will be needed to determine whether and how psychotic symptoms in patients with bvFTD who carry the C9ORF72 mutation differ from the symptoms in patients with primary psychiatric disorders.

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Keywords:

frontotemporal dementia; psychosis; C9ORF72 mutation; motor neuron disease

© 2013 by Lippincott Williams & Wilkins.