A 31-year-old right-handed man was referred with possible behavioral variant frontotemporal dementia (bvFTD) due to a 4-year history of a frontal dementia syndrome and gastric upset. He was premorbidly jovial, equable, very independent, and self-sufficient. Although he had no known learning disability, he was historically a below-average student, earning Cs and Ds in high school. He married at age 22, worked in a welding shop while studying applied technology in college, but required some tutoring. His marriage was characterized by mismanaged finances by him and his wife and his wife's substance abuse. He divorced at age 27 and moved in with his parents due to financial hardship. His mother noted behavioral changes, including apathy and poor judgment, a decline in his personal hygiene, and his needing frequent reminders to bathe. He also became irritable and impulsive, displaying angry outbursts disproportionate to the offending trigger. At around the same time, he developed constipation requiring frequent laxative use. Several months later he developed episodes of vomiting and diarrhea with abdominal pain. The episodes occurred suddenly, dissipated gradually after 5-7 days, and would recur every 6-10 weeks. Anti-emetics provided only partial relief of vomiting. At age 28, he quit his third year of college due to financial hardship and difficulty with coursework. He retained his current job and began a second one. At age 29, he was fired from both jobs; he had difficulty comprehending directions from supervisors and forgot to complete tasks despite frequent reminders. He subsequently became a busboy. Four months later, he displayed violent irritability and impulsivity, and was fired after threatening to harm coworkers and "blow up" the workplace. At home, during these occasional outbursts, he would hit his parents and 12-year-old brother. At age 30, he displayed new behavioral changes, addressing a former co-worker by a racial slur and stating out loud private thoughts. His speech became "broken and choppy," he had long pauses during conversation, and his words were occasionally out of order. His speech was also more effortful with and occasional gibberish words ("just in the flak of the fug") and word substitutions ("skill" instead of "school"). At around age 31, the patient developed clumsiness and balance problems. It was subsequently noted that his nausea and vomiting responded best to topical promethazine. His agitation responded to lorazepam 1 mg orally as needed. Quetiapine worsened his agitation, whereas donepezil, memantine, risperidone, and dextroamphetamine/amphetamine had no effects.
His past medical history included depression, hypertension, morbid obesity, and erectile dysfunction. He lost more than 200 pounds, at least partially intentionally, during the previous 5 years owing to changes in diet and exercise. At age 19, he had a concussion with brief loss of consciousness (less than 5 min) following a motor vehicle accident. He smoked half to one pack per day for 8 years until quitting at age 27. He drank heavily in college, with unknown quantity/frequency consumption but with no alcohol dependence. He had a remote history of prescription narcotics and marijuana use during marriage, but frequency and duration of use were unknown. His history also included visual hallucinations, beginning at age 5-7, when he periodically saw a man (a stranger) walk through his house. This figure appeared repeatedly for 11-13 years. At age 18, his family moved to a new house, and he stopped seeing the man. Beginning around this time, he saw a woman (a stranger) walk through his house. This figure appeared 2-3 times over 9 years. He stopped reporting hallucinations by age 27.
His mother was still alive at 52 and maternal family history was non-contributory. His paternal family history, however, was significant for an autonomic and cognitive disorder with neuropathy and gastric upset (Fig. 1). His 56-year-old father (II-2) was asymptomatic. His paternal uncle (II-1), who died at age 52, developed a digestive disorder in his 40 s, characterized by frequent postprandial loose stools, followed by memory and behavioral changes. In his 40 s, he uncharacteristically changed his profession numerous times before stopping work altogether. He asked questions repeatedly, and eventually required help with activities of daily living. The paternal grandfather (I-1), who died at age 51, had neuropathy, dysautonomia, and gastric upset beginning at age 45. At onset, he was hospitalized for frequent syncope due to severe orthostatic hypotension, abdominal pain, and lower extremity paresthesias (from knees to feet). He had erectile dysfunction, an unusual sweat pattern (predominantly truncal, left greater than right, with minimal groin and axilla involvement), unexplained weight loss over an unknown period of time, renal calculi and plantar ulcers. At age 48, he developed diarrhea, urinary incontinence, and memory impairment, which progressed to "nocturnal confusion." He had behavioral changes, becoming agitated and paranoid. An infusion urogram showed bilateral calcifications within the collecting systems. A large flaccid bladder showed a markedly trabeculated contour consistent with chronic cystitis. A follow up study showed a left distal ureteric calculus with obstructive hydronephrosis. A computed tomography of the abdomen showed retroperitoneal lymphadenopathy. An exploratory abdominal laparotomy revealed adhesions and enlarged nodes. Excisional biopsies of omental, retroperitoneal, and gastro-celiac lymph nodes were consistent with chronic lymphadenitis with sinus histiocytosis. At age 50, his employer asked him to retire early because he was unable to perform his job duties. Two months later he was hospitalized for severe dysautonomia associated with hypotensive episodes leading to renal failure from recurrent hypoperfusion. He was noted to have poor lacrimation leading to exposure keratitis, bilateral Adie's pupil, presenile dementia, and plantar ulcers. His hypotension partially responded to fludrocortisone 0.2 mg per day and ergotamine 1 mg twice a day. Methylphenidate caused agitation and diarrhea. His cerebrospinal fluid (CSF) was remarkable only for elevated protein at 118 mg/dL. A computed tomography of the brain was noted to have "unexplained" atrophy. He died five months after this hospitalization and his dysautonomia was attributed to postinfluenzal autonomic neuropathy. No autopsy was performed. The grandfather's brother (I-3), who died at age 63, developed unspecified digestive and cognitive problems in his 40 s. The grandfather's brother has a son (II-4), age 50, with a similar condition. The grandfather's sister (I-2), who died at age 48, developed gastric upset at age 39. At age 42, she was hospitalized for recurring diarrhea without abdominal pain and unexplained weight loss over 3 years. At age 45, she had a second hospitalization for recurring nausea, vomiting, and diarrhea. At age 46, she was diagnosed with depression. At age 47, she developed orthostatic hypotension, which occasionally alternated with hypertension. At age 48, she had episodes of confusion diagnosed as a mild "organic brain syndrome," but seven months later was diagnosed with Shy-Drager syndrome. Her cognitive syndrome worsened, and at age 51, she was diagnosed with presenile dementia and Shy-Drager syndrome. Shortly thereafter she was hospitalized due to flank pain, exposure keratitis, and renal calculi requiring nephrostomy, and died during this hospitalization. Autopsy showed enlarged ventricles, neuritic plaques, and neurofibrillary tangles in her hippocampi and midbrain oculomotor nuclei, as well as plaques in the cerebellum, all attributed to AD. The paternal family was of Austrian, Scottish, and Irish descent.
On physical examination at his first UCSF visit, 4 years after onset, he was moderately hypertensive, alert, and socially appropriate. His Mini-Mental State Exam score was 3/30, earning points only for orientation, one component of the 3-step command, and following the written command (Table 1). He was alert and cooperative, but his comprehension fluctuated throughout the exam, and he had difficulty following simple instructions. Speech was halting, effortful, but not dysarthric. He made grammatical errors, used neologisms, and his speech output was frequently unintelligible. Additional cognitive testing showed severe impairment in working and visual memory, speech/language (apraxia with relatively spared semantics), and frontal-executive function. Calculation and visuospatial skills were impaired, though he had poor comprehension of test directions. Verbal memory, though moderately impaired, was a relative strength. His pupils were slightly midriatic and he had an irregular left pupil and with sluggish constriction. He had decreased sense of temperature and joint position, with intact touch and vibration in the distal lower extremities. Deep tendon reflexes were preserved and symmetric. He had mildly increased tone, a postural hand tremor, a wide-based gait, and mild retropulsion. Brain MRI at the first visit revealed severe white matter atrophy (likely contributing to) enlarged ventricles in the bilateral temporal horns (Fig. 2), widened Sylvian fissures, and severe atrophy of orbitofrontal cortex, left greater than right parietal lobes, bilateral angular gyri, and bilateral anterior cingulate. The occipital lobe and cerebellum had relatively intact volumes. T2 and FLAIR sequence showed no cortical or subcortical signal abnormalities, and DWI and ADC sequences showed no evidence of restricted diffusion (not shown).
By seven months later, at a second visit, his apathy had worsened: his activity was restricted to sitting around at his mother's workplace and watching TV at home. He was less irritable and impulsive. His physical aggression had stopped, but he still had occasional verbal outbursts, typically when he was asked to do tasks he did not want to do, for example, putting away laundry. He had reduced verbal output, and his verbal and reading comprehension were diminished. He enjoyed having the newspaper, but the extent to which he read it or understood content was unclear. He had new pain, numbness, and tingling in his hands and feet. His gait worsened mildly, and he required banister or wall support when descending stairs. He dressed, bathed, and ate independently, but needed assistance with toileting. He had bladder and bowel incontinence. Neurologic exam at the second visit showed no significant changes from the previous evaluation. He had no orthostatic hypotension. Sensory testing was invalid due to poor comprehension of interviewer commands. He was unable to follow instructions during many cognitive measures, but no significant changes were observed in testable domains. He continued to have severely impaired working memory, speech/language (speech apraxia with relatively spared semantics), and frontal-executive function (Table 1). Repeat brain MRI revealed no significant changes.
CSF collected at the second visit showed normal cell count, protein, glucose, and immunoglobulin G index, and no oligoclonal bands. Total tau (National Prion Disease Pathology Surveillance Center, NPDPSC) was normal at 183xpg/mL. CSF 14-3-3 (NPDPSC) was negative, and neuron-specific enolase (Mayo Laboratories, Rochester, MN) was normal at 9.8 ng/mL (reference <15 ng/mL). EEG revealed diffuse background slowing and attenuated cerebral activity, without epileptiform potentials or periodic discharges.
By six months later, at his third UCSF visit, he had developed new compulsive eating behaviors; he ate every food morsel he was served, regardless of the serving size and quantity of food he just previously consumed. He sought food in between meal times, and hoarded food in his room. He ate quickly and occasionally choked while eating solid foods. He drank liquids without choking. Despite these changes, his weight remained stable. He continued to have verbal outbursts, occurring a few times per week and usually during instances when his overeating was discouraged, but he responded to behavior redirection, and calmed down after a few minutes. He continued to accompany his mother to work, but now became upset if he could not follow her or not stand by her side around the office or at home. He developed insomnia, falling asleep nightly, but waking 4-6 hours later. Once awake, he compulsively turned on lights, opened cupboards looking for food, and released his pet dogs from their overnight kennel. He napped during the day, but had no excessive daytime somnolence. He compulsively chewed on pens, his fingernails, and nasal mucous. Verbal output declined further. He spoke in one- or two-word utterances only. Gabapentin 300 mg three times a day was attempted to treat neuropathic pain, but it was discontinued due to leg swelling. Nevertheless, he complained less frequently of pain, numbness, and tingling in his hands and feet. His gait remained unsteady with several near falls. He used no assistive device for ambulation. He needed more help with independent activities of daily living, including bathing and shaving. He was still able to comb his hair and make a cup of coffee. He no longer required assistance with toileting. Neurologic exam at the third visit showed no significant changes from the previous evaluation. Sensory testing was again invalid. He had no orthostatic hypotension. Cognitive testing revealed no significant changes in most domains, although language measures elicited some semantic loss (Table 1). Structural brain MRI and CSF showed no significant changes. Nerve conduction studies performed at the third visit provided evidence of a length-dependent primarily axonal sensorimotor polyneuropathy (Table 2).