Cases that Test Your Skills
From active to apathetic
Once energetic and outgoing, Mr. A, age 66, is tired and withdrawn. His physical and social skills are rapidly deteriorating. Can you determine what is causing his sudden decline?
Presentation: Strange change
Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.
Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.
His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.
Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.
Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.
Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.
Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.
Frontotemporal dementia subtypes and their clinical features
Onset around age 60
Symptoms may be unilateral at first and progress slowly
Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
Eventual inability to walk
Frontotemporal dementia with motor neuron disease
Behavioral changes, emotional lability
Decreased spontaneous speech
Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17
Behavioral disturbance, cognitive impairment, parkinsonism
Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)
Trouble remembering words
Loss of semantic memory, although episodic memory is good
Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia
Behavioral changes rare
Global cognition declines over time
Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved
The authors’ observations
Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:
- decline in social interpersonal conduct
- emotional blunting
- loss of insight
The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.2
FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.
FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.
Behavioral changes associated with FTD include:
- Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.3
- Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
- Dietary changes—typically overeating (hyperorality) with a preference for sweets.4
Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.
Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.3
Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.3
Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD. 5 Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.
Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,6 patients with FTD exhibited:
- early loss of social awareness
- early loss of personal awareness
- progressive loss of speech
- stereotyped and perseverative behaviors
- and/or hyperorality.
Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.6
The authors’ observations
Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.
Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.
On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.
The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores. 4 Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.4
Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.7 Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.4
Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.
Treatment: Taking aim at apathy
Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.
Medications shown beneficial for treating FTD
Possible side effects
Cognition functions including memory
Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)
Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)
Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Behavioral disturbances, somnolence
Insomnia, increased irritability, poor appetite, weight loss
Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor
Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.
On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:
- marked delays in processing and acting on information
- diminished working memory
- trouble understanding spatial functions
- decreased speech
- moderate to severe executive function impairments
- severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
We also noticed several perseverative behaviors.
Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.
Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.
The authors’ observations
Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.
Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.5
In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.8
In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.9
Dopamine use in FTD can contribute to behavioral dysregulation. D2 blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D1 and D2 dopaminergic agonist, may improve select frontal features and perseveration in dementia.10
In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.11
Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.
Conclusion: The 15-month mark
We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.
We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.
Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.
The authors’ observations
Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.
No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.12
Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.