When Laughing Is No Joking Matter

Clinical Note

The most common side effects of cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) include cholinergic side effects of diarrhea, nausea, vomiting, and bradycardia (can be symptomatic with syncope) (Farlow et al, 2008; Gill et al, 2009). The tolerability of memantine does not differ from placebo, with potential side effects of constipation, dizziness, confusion, and headache (Farlow et al, 2008). The reversible ageusia and anosmia reported by Mr A are not reported side effects with these medications.

Based on the clinical history alone, which do you believe is most accurate?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

All attendees were in agreement that Mr A had a progressive neurodegenerative dementia as evident by the workup thus far. On the basis of the group responses, there remained uncertainty regarding the etiology of the dementia, and further workup would be required. Those who chose FTD argued that there were significant early behavioral changes and language disturbances that are symptoms more consistent with FTD. Those who chose Alzheimer’s disease stated that memory complaints, specifically in terms of names and places, were Mr A’s first presenting feature and more consistent with Alzheimer’s disease, especially coupled with the family history. Many conference attendees could not commit to either FTD or Alzheimer’s disease given the information obtained thus far.

A MMSE (Folstein et al, 1975) score generally correlates with disease severity. Scores ≤ 9 can indicate severe dementia, between 10-20 can indicate moderate dementia, and > 20 can indicate mild dementia (Mungas, 1991). MMSE scores vary by age and education. MMSE scores and age have an inverse relationship, with scores ranging from a median of 29 for people aged 18 to 24 years, to a median of 25 for individuals over the age of 80. MMSE scores and years of education have a direct relationship. Those with 0 to 4 years of education have a median MMSE score of 22, whereas those with at least 9 years of education have a median MMSE score of 29 (Crum et al, 1993).

Based on the clinical history alone, what would you expect his MMSE score to be?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Mr A scored 25 out of 30 points on the MMSE. He missed 1 point on orientation, 3 points on delayed recall, and 1 point on the written sentence. Given that Mr A was having difficulty recalling names of people and places that he was familiar with, coupled with the inability to handle cash, 82% of conference attendees expected a slightly lower score on this test. Mr A’s pentagon copy (Figure 1) and written sentence (Figure 2) from the MMSE are shown. The pentagon copy was correct, but Mr A missed a point for the sentence.

The MoCA (Nasreddine et al, 2005) is a 30-point test that assesses several cognitive domains. Because it is more challenging than the MMSE, it has greater sensitivity for mild cognitive impairment and early stages of dementia. With a cutoff score < 26, the sensitivity for detecting mild cognitive impairment (N = 94) was found to be 90% and the specificity 87%.

Based on the clinical history alone, what would you expect his MoCA score to be?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Mr A scored 14 out of 30 points on the MoCA, a lower score than was expected given the clinical history, and the majority of respondents had assumed he would score above 19 (Figure 3). This result illustrates the apparently greater sensitivity of the MoCA in early stages of dementia as compared to the MMSE.

In the Category Retrieval Test, the examiner asks the patient to name as many animals as possible in 1 minute. Performance on this measure is influenced by age; unimpaired people in their 60s should name about 18 animals, whereas people in their 80s should name about 15 (Mitrushina et al, 2005). There is no hard-and-fast cutoff for impairment. However, patients who name 4 or more animals less than expected raise concerns. Note that bilingual individuals are at a disadvantage on this test and in other measures of verbal fluency (Gollan et al, 2002).

Based on the clinical history alone, what would you expect his Category Retrieval Test score to be?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Mr A’s Category Retrieval Test score was 4, with 1 error. The results are included in Figure 4.

At this time, what tests, if any, would you like to order?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Although the majority of respondents chose both an FDG-PET scan and formal neuropsychological testing, the treating physician chose to order just the FDG-PET scan. The treating physician reasoned that if the FDG-PET scan resulted in an unequivocal diagnosis of either FTD or Alzheimer’s disease, then this would be sufficient to give a conclusive diagnosis. If the FDG-PET result was ambiguous, then neuropsychological testing would be ordered.

Given the issues with driving, what should be done at this time, if anything?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Of the conference attendees, 7% believed that driving must stop given the diagnosis of dementia and the family reporting that the patient was driving “aggressively.” Because there had been no accidents, citations, or reports of not following the “rules” of driving and no confusion in intersections, 93% believed that a formal on-road driving safety evaluation was indicated. The treating physician believed that driving should be stopped on the basis of the report from the family. Of note, the history regarding Mr A’s driving ability was taken from the family while the patient was not present, as they could not discuss this issue in front of him. Had Mr A known that the family reported aggressive driving to the doctor, he would have been livid and directed his anger toward the family. The treating physician told Mr A that, on the basis of the results of cognitive testing, there were concerns regarding driving ability and that a formal driving safety evaluation was required should he wish to continue to drive.

THE TREATING PHYSICIAN’ S IMPRESSION

Mr A, a 70-year-old man who presented for a cognitive evaluation, had a clinical history and cognitive findings consistent with dementia. Given the predominance of behavioral changes, the clinical history suggested FTD. Alzheimer’s disease was also a consideration. Further workup with an FDG-PET can help distinguish between these 2 types of dementia.

THE TREATING PHYSICIAN’ S PLAN

1. Order FDG-PET scan of the brain.
2. Increase galantamine to 8 mg/d (with extended-release formulation).
3. Continue citalopram 40 mg/d for now. The family reports no benefit with this medication. There will be a low threshold to change to a different medication.
4. The patient’s family has been referred to the caregiver class and the planning for the future class.
5. The patient’s family will be scheduled to meet with one of our nurse specialists to help understand the patient’s condition and formulate a nonpharmacologic treatment plan in reacting to his abnormal behaviors.
6. Although the patient may not have FTD, the FTD dementia support group may be beneficial for the patient’s family as he displays significant behavioral changes.
7. We discussed the issue of driving. At this time, I do not feel that the patient should be driving unless he passes a formal driving evaluation. I recommended that the patient have a formal on-road driving safety evaluation.
8. The patient will follow up with me after the FDG-PET scan has been completed.

FDG-PET Results

The results of Mr A’s FDG-PET scan are shown in Figure 5. FDG-PET scans measure cerebral metabolic rate of glucose metabolism. This computational image shows the outer and inner surfaces of the brain. Blue areas represent significant glucose hypometabolism. Red outlined regions represent areas expected to be affected in Alzheimer’s disease, including the parietotemporal region, posterior cingulate, and precuneus, and also a part of the frontal region expected to be affected in advanced Alzheimer’s disease. The results show significant hypometabolism in the bilateral frontal and temporal regions consistent with FTD. The FDG-PET results and diagnosis of FTD were given to the patient’s wife over the phone by the treating physician.

DISCUSSION

Frontotemporal dementia is a clinical syndrome of a group of neuropathologically heterogeneous disorders associated with degeneration of the frontal and temporal lobes. Frontotemporal dementia generally presents with progressive changes in personality and social behavior but also can include prominent disturbances in language and executive function. Some patients also develop motor-neuron disease (MND), a syndrome designated FTD-MND. In these cases, patients can have progressive muscular atrophy with fasciculations. Bulbar muscles can be affected (leading to dysarthria and dysphagia) as well as extremity muscles. The age at onset is generally younger than with Alzheimer’s disease, affecting people in their 50s and 60s. The median duration of FTD from onset to death is 6 to 8 years (range, 2-20 years) with equivalent survival across FTD subgroups (Hodges et al, 2003; Snowden et al, 1996). FTD-MND is associated with a median survival of only 3 years (Hodges et al, 2003; Neary et al, 1990).

There are 3 main categories of the clinical FTD syndrome: behavioral variant, nonfluent primary progressive aphasia, and semantic dementia. There is, however, considerable overlap between these categories, and it can be difficult to clearly classify a patient in a given category. The behavioral variant is the most common presentation of FTD. There are personality changes, lack of insight or social awareness, lack of empathy, and stereotyped behaviors. Cognitive testing may be relatively intact in the early stages of FTD. The progressive nonfluent aphasia variant manifests with impairment of expressive language and gradually worsening spontaneous speech in the context of generally preserved word comprehension. Ultimately, comprehension can be affected as well. The semantic variant manifests with impaired comprehension and semantic paraphasias with normal fluency.

Characteristics of FTD include a sex distribution of approximately 50:50 for men and women, respectively; an age of onset of 45 to 65 years (range, 21-85 years); a duration of illness of 6 to 8 years (3 years in FTD-MND); and a family history in 40% to 50% of patients (Neary et al, 2005). The presenting problem is typically behavioral change, and cognitive features include executive deficits and changes in speech and language. Neurologic signs are commonly absent in the early stage, parkinsonism is present in the late stages, and MND is present in a small proportion of patients. Abnormalities in frontotemporal lobes are present, especially on functional imaging (Neary et al, 2005).

Follow-Up

Mr A returned to the clinic 5 weeks later for follow-up. He continues to have socially inappropriate behaviors such as making funny faces to kids and walking up to people he does not know, as well as instances of flatulence and eructation in public with inappropriate laughter. He has outbursts of anger with minimal provocation. The increase in galantamine dose has had no obvious benefits. Since the last visit, Mr A’s primary care physician discontinued the citalopram and initiated paroxetine 20 mg without benefit. Mr A has not yet had a formal driving evaluation.

Should the cholinesterase inhibitor be adjusted?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Of the conference attendees, 80% believed that the galantamine should be increased, and 20% recommended discontinuation of galantamine. The treating physician chose to stop galantamine because cholinesterase inhibitors have not been shown in case reports to improve cognition in FTD and can sometimes worsen behaviors (Kertesz et al, 2008; Mendez et al, 2007; Moretti et al, 2004); however, no controlled trials have been conducted to guide practice. (Had Mr A been diagnosed with Alzheimer’s disease, the treating physician would have increased the galantamine despite lack of obvious benefit.)

There are currently no US Food and Drug-approved medications for treatment of FTD. Pharmacologic treatment of FTD is limited and targets the symptoms. Although selective serotonin reuptake inhibitors are often used to manage behavioral symptoms, their reported effectiveness is variable (Mendez, 2009). Other medications that can be used are atypical antipsychotics, antiepileptic drugs, and memantine.

Should the antidepressant be adjusted?

Your colleagues who attended the Banner Alzheimer’s Institute Case Conference answered as follows:

Of the conference attendees, 56% suggested switching paroxetine to another agent and 44% suggested increasing the dose. Given the anticholinergic properties and lack of reported efficacy in this patient, the treating physician discontinued the paroxetine and initiated divalproex sodium extended release 250 mg/d.

The patient returned 2 months later for follow-up. The family noted that Mr A was calmer since starting the divalproex sodium extended release, but he had gained 10 lb. Mr A continues to have gradual worsening language difficulties. The divalproex sodium extended release was increased to 500 mg/d in an attempt to gain further behavior benefit.

Mr A passed a formal on-road driving safety evaluation performed by a local company. The family continues to state that he is a driving hazard and is a danger due to impulsive decisions and aggressive behavior. Mr A was therefore instructed to stop driving. As expected, he resisted, but he eventually acquiesced and reluctantly agreed to discontinue driving.

Mr A returned 3 months later for follow-up. His language expression and comprehension have continued to worsen. He continues to be significantly disinhibited, and personal hygiene has declined. He continues to be compulsive with exercise. His family utilizes a GPS tracking device to monitor his whereabouts when mountain biking and jogging. He has not gotten lost. Although he was initially angry regarding driving cessation, Mr A seldom brings up the topic. The increase in divalproex sodium extended release had no further benefit, and the dose was reduced back to 250 mg/d. We can consider initiating an antitypical antipsychotic such as quetiapine if behavioral symptoms significantly worsen in the future.

Disclosure of off-label usage

The authors have determined that, to the best of their knowledge, citalopram, divalproex, donepezil, galantamine, memantine, paroxetine, quetiapine, rivastigmine, and simvastatin are not approved by the US Food and Drug Administration for the treatment of frontotemporal dementia.

FINANCIAL DISCLOSURE

Dr Yaari is a consultant for Amedisys Home Health. Dr Tariot is a consultant for Acadia, AC Immune, Allergan, Eisai, Epix, Forest, Genentech, MedAvante, Memory Pharmaceuticals, Myriad, Novartis, Sanofi-Aventis, Schering-Plough, and Worldwide Clinical Trials; has received consulting fees and grant/research support from Abbott, AstraZeneca, Avid, Baxter, Bristol-Myers Squibb, GlaxoSmithKline, Elan, Eli Lilly, Medivation, Merck, Pfizer, Toyama, and Wyeth; has received educational fees from Alzheimer’s Foundation of America; has received other research support only from Janssen and GE; has received other research support from National Institute on Aging, National Institute of Mental Health, Alzheimer’s Association, Arizona Department of Health Services, and Institute for Mental Health Research; is a stock shareholder in MedAvante and Adamas; and holds a patent for “Biomarkers of Alzheimer’s Disease.” Drs Seward, Burke, Fleisher and Mss Brand and Dougherty have no personal affiliations or financial relationships with any commercial interest to disclose relative to the activity.

Funding/Support

None reported.

DISCLAIMER

The opinions expressed are those of the authors, not of Banner Health or Physicians Postgraduate Press.