The frontal/subcortical dementias - Frontotemporal Deme...

The frontal/subcortical dementias

Although the most common cause of dementia is Alzheimer's disease, many other common dementing illnesses in the elderly affect the frontal cortex and associated subcortical structures and present with very different symptoms. In general, these illnesses are not detected with typical bedside screening or with conventional dementia assessment tools, such as the Mini Mental State Exam. These illnesses are associated with prominent and disturbing behavioral changes, as well as difficulties with “higher-order” cognitive functions,such as planning and judgment. Common causes of frontal/subcortical dementia include vascular dementia, frontotemporal dementia, alcoholic dementia, dementia due to AIDS, and a number of movement disorders. Familiarity with this clinical picture is essential for recognition, diagnosis, and management of these illnesses, and for working with families and caregivers.

Key words: dementia • frontal lobe • basal ganglia • vascular dementia • frontotemporal dementia • alcoholic dementia

Drugs discussed: antiandrogenics • anticonvulsants • antidepressants • atypical neuroleptics • benzodiazepines • beta blockers • cholinesterase inhibitors


Over the past few decades, physicians have become much more cognizant of dementia in general and of Alzheimer's disease (AD) in particular. Although the majority of demented individuals have AD, there is a large group of dementing illnesses that present quite differently, with perhaps even more devastating effects on intellectual function and personality. These are the frontal/subcortical dementias—illnesses that affect the prefrontal cortex and connected subcortical structures.

The qualitative differences between AD, which initially affects parietal and temporal cortex, and frontal/subcortical dementias have been appreciated for almost a century.1,2 Compared with AD patients, those with frontal/subcortical dementias lack typical posterior cortical deficits (eg, aphasia, apraxia, agnosia), but show prominent executive deficits and personality changes as described in this article.2 These differences are summarized in table 1.

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Table 1. Comparison of Alzheimer's disease and the frontal/subcortical dementias

Alzheimer's disease
- Affects mainly parietal and temporal cortex
- Recent memory severely affected
- Aphasia, apraxia, agnosia common
- Various behavioral problems common
- MMSE accurately reflects severity

Frontal/subcortical dementia
- Affects prefrontal cortex, white matter, basal ganglia, thalamus
- Recent memory often normal or only mildly impaired
- Executive dysfunction common
- Loss of drive, disinhibition common
- MMSE useless, often near-normal

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MMSE = Mini Mental State Exam.
SourceCreated for Geriatrics by JTStewart, MD.
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The frontal/subcortical system is a distributed system consisting of connected cortical and subcortical structures, as shown in figure 1;1,3 all frontal/subcortical dementias affect either frontal (specifically, prefrontal cortical) or subcortical structures or both. Therefore, these same signs and symptoms will be seen in illnesses affecting the frontal cortex, the subcortical white matter (most of which subserves prefrontal cortexin humans), the striatum, the globus pallidus, or the thalamus.

The differential diagnosis of frontal/subcortical dementia is broad, and is listed in part in Table 2. As can be seen, many of these illnesses are common in clinical practice. All affect prefrontal cortex, white matter, the basal ganglia, and/or the thalamus. It should be noted that nearly all dementias (including AD) ultimately progress to involve these structures; thus, frontal/subcortical signs and symptoms will be seen late in the course of most dementias.4Also, while not strictly classified as dementia, most head injuries involve frontal cortex and/or subcortical structures, and these signs and symptoms will frequently be seen in head-injury patients.5

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Table 2. Common causes of frontal/subcortical dementia

- Vascular dementia

- Frontotemporal dementia and Pick's disease

- Alcoholic dementia

- Parkinson's disease (late in the course of the illness)

- Progressive supranuclear palsy

- Huntington's disease

- Wilson's disease

- AIDS dementia complex

- Neurosyphilis

- Lyme disease

- Multiple sclerosis

- Normal pressure hydrocephalus

- Anoxic encephalopathy

- Carbon monoxide poisoning

- Tumors

- Most head injuries

- Any advanced dementia

Source: Created for Geriatrics by JT
Stewart, MD.
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CLINICAL PRESENTATION

Frontal/subcortical dementias present significantly differently from AD. Specifically, aphasia (language disturbance), apraxia (inability to use objects) and agnosia (failure of visual recognition) are generally absent in these patients.1,2 More remarkably,recent memory may be only mildly impaired or even completely normal, often making it difficult for the family or physician to appreciate that the behavioral changes are indeed related to a dementia. Cognitive problems are generally within the “executive” realm and involve difficult and sometimes subtle concepts, such as the inability to anticipate the consequences of decisions or the inability to modify behavior in response to new or unexpected situations (loss of “behavioral plasticity”). Often, behavioral changes (usually loss of drive or disinhibition) are the most prominent feature, leading to incorrect attribution to a functional psychiatric illness.

As can be seen in figure 1, the frontal/subcortical system is actually composed of a number of distinct subsystems, three of which are involved in cognition and behavior (most illnesses involve more than one of these systems):1,3
> > The dorsolateral prefrontal system (originating in the convexity of the prefrontal cortexand coursing through the associated subcortical structures),
>> The anterior cingulate system (originating in the medial frontal cortex overlying the corpus callosum), and
>> The orbitofrontal system (originating in the basilar frontal cortex overlying the orbits).

DAMAGE TO THE DORSOLATERAL PREFRONTAL SYSTEM results in the most prominent cognitive changes.3 These changes include loss of the ability to set goals and formulate strategies, perseveration or impersistence, and general loss of “behavioral plasticity,”ie, the ability to modify behavior depending on the situation at hand and to solve problems never before encountered. Behavior may become simple and stereotyped, and the patient will have difficulties with tasks that require complex decision-making, such as planning a trip or managing a budget. Financial difficulties seem common in these patients, and they often fall prey to con artists and unscrupulous salespeople. Later, behavior becomes even less goal-oriented and more automatic; “utilization behavior” (automatically picking up or using objects, moving furniture, rummaging through drawers, etc., without any reason)6and other purposeless behaviors ensue.

DAMAGE TO THE ANTERIOR CINGULATE SYSTEM results in abulia, a loss of drive and initiative.3 Previously active and energetic patients may give up their usual activities and hobbies, and personal hygiene may suffer. Ultimately,theymay spend the entire day watching television or lying in bed and may become quite resistant to any suggested activity; resistiveness to personal care may eventually become problematic. The anterior cingulate syndrome is frequently mistaken for depression; however, these patients are not dysphoric and do not have the appetite disturbance and pessimism typical of depression.8 They are generally content doing nothing, in contrast to depressed patients who don't enjoy doing anything. These patients also often suffer from urge incontinence, as the paracentral lobule (which mediates urinary continence) is adjacent to the anterior cingulate gyrus.

DAMAGE TO THE ORBITO FRONTALSYSTEM generally results in the most disturbing behavioral changes. These patients are disinhibited, typically losing their manners and becoming crude and tactless.3 Flirtatiousness and undue familiarity with strangers is common, as is general impulsivity. As the syndrome progresses, more problematic behaviors ensue; petty crimes, such as shoplifting may occur, and the patient may become combative with trivial annoyances. Sexual disinhibition is an uncommon problem in dementia, butwhen it does occur, it is invariably related to damage to this system.8 These patients are often misdiagnosed as having a functional psychiatric illness (often mania or a personality disorder); a longitudinal history will clarify the diagnosis.


DETECTION

Detection of a frontal/subcortical dementia can be challenging, as the typical symptoms seen in AD (forgetfulness, aphasia, getting lost, etc.) are often absent.1,2 Detection is most reliably based on the history. Significantly, the Folstein Mini Mental State Exam (MMSE) is completely insensitive to frontal/subcortical dementia.9 Many patients with impairment necessitating nursing home placement will have a near-perfect MMSE score.

There are, however, a number of bedside tests for frontal/subcortical dementia. Perhaps the most straightforward is the contrasting-programs test.10In this test, the examiner will randomly hold up either one or two fingers; the patient is instructed to do the opposite, ie, to hold up two fingers when the examiner holds up one or vice-versa. Ten trials is customary; the patient with significant frontal/subcortical impairment will have trouble resisting the inclination to mimic the examiner and will hold up the same number of fingers. Another convenient bedside test is Luria's recursive figures.10 In this test, the patient is asked to copy one or more patterns that consist of alternating symbols; as can be seen in Figure 2, patients with frontal/subcortical impairment tend to perseverate, ie, to repeat one of the symbols over and over. There are also several standard assessments that can be done at bedside, including the Frontal Assessment Battery (FAB)11and the Executive Interview (EXIT).12 Finally, neuropsychological testing can be useful in detecting and quantifying frontal/subcortical impairments.

One important point, however, is that the tests described above, and even neuropsychological testing, only reliably detect dorsolateral prefrontal system impairments.3 Patients with mostly anterior cingulate or orbitofrontal system impairment may do well on these tasks, and the only sign will be the characteristic history.


DIFFERENTIAL DIAGNOSIS

The most common causes of frontal/ subcortical dementia are listed in table 2.

>> Vascular dementia accounts for approximately 20% of all dementias,and is the most common cause of frontal/subcortical dementia; most patients suffer from either large-vessel disease (multi-infarct dementia) or small-vessel disease (lacunar state or Binswanger's disease), or a combination of both.13 The cornerstone of managing these patients is control of vascular risk factors, including hypertension, hyperlipidemia, diabetes and smoking; control of hypertension is most clearly associated with reduction of risk.13,14 There is at least one prospective study demonstrating the utility of aspirin (325 mg/d) in slowing progression;15other trials are underway. Finally, there is some evidence that donepezil, and possibly other cholinesterase inhibitors, may have some modest beneficial effect in vascular dementia.16

>> Frontotemporal dementia is a histologically heterogeneous degenerative dementia that leads to focal atrophy of the frontal cortexand often the anterior temporal cortex. The focal nature of the atrophy on neuroimaging studies is often striking (figure 3). While previously believed to be rare, current opinion is that frontotemporal dementia may be as much as 25% as common as Alzheimer's disease.17 These patients are often younger than AD patients and have no specific risk factors (frontotemporal dementia is usually non-familial); some patients present with progressive aphasia.17 Histologically,about 25% of these patients have Pick bodies and balloon cells, and are properly considered to have Pick's disease.17 The diagnosis of frontotemporal dementia is usually suspected in a patient with frontal/subcortical dementia but no vascular risk factors or alcohol history; it is confirmed radiographically. There is no known treatment.

>> Alcoholic dementia is a chronic, arrestable but irreversible form of Wernicke-Korsakoff syndrome.18 Importantly, other treatable pathology (subdural hematoma, hepatic encephalopathy, etc.) must be ruled out in any alcoholic patient. Alcoholic dementia probably does not respond to thiamine, although progression will be arrested with abstinence.

>> AIDS dementia complex is related to direct retroviral infection of the brain; opportunistic infections must be ruled out. Its progression can be slowed or even reversed with antiretroviral treatment.19



TREATMENT

As in AD, treatment of the frontal/subcortical dementias is mostly nonpharmacologic in nature and involves caregiver support and education, as well as behavioral interventions.8

PATIENTS WITH DAMAGE TO THE DORSOLATERAL PREFRONTAL SYSTEM generally require amore or less “prosthetic environment,” due to their poor judgment and adaptability. These patients are often victimized financially; guardianship or other steps may be necessary. They often display poor safety awareness. Since memory and other “basic” cognitive functions are intact, caregivers may need to be convinced that the patient suffers from a dementia at all. In more severely impaired patients with utilization and other purposeless behaviors, a tolerant attitude and the provision of purposeful activities (for example, allowing the patient to help fold laundry) may be helpful.

PATIENTS WITH DAMAGE TO THE ANTERIOR CINGULATE SYSTEM are generally abulic, and caregivers must be educated about the neurologic, and non-depressive, nature of these changes. Once depression has been ruled out, typical management involves the limitation of goals and expectations, stressing the patient's contentment and quality of life. Some abulic patients become resistiveto personal care; the best strategies are to limit care to the minimum necessary, to take a slow, gentle approach, and to tell the patient that, “as soon as we're done with this, I'll leave you alone.”8 In patients with more severe resistiveness, premedication with a short-acting benzodiazepine (such as lorazepam [Ativan]) prior to care may be useful.8 There havebeen a fewcase reports of successful treatment of abulia with dopamine agonists, although the only controlled study to date failed to show any efficacy.20

PATIENTS WITH DAMAGE TO THE ORBITOFRONTAL SYSTEM typically have the most problematic behaviors. The highest priority is to teach caregivers about the neurologic nature of the disinhibition, as the behavior will often be perceived as volitional or “bad.” The importance of a tolerant environment cannot be overemphasized; it is essential to remove the patients from situations in which their behavior will not be tolerated (at formal social gatherings, for example, or in stores if the patient has been shoplifting).8

Disinhibited aggression related to trivial frustrations can be problematic in these patients; avoidance of situations likely to lead to aggression is paramount, but pharmacologic management will often be necessary.Typical options include low doses of atypical neuroleptics (risperidone [Risperdal], olanzapine [Zyprexa], quetiapine [Seroquel], ziprasidone [Geodon]), or anticonvulsants (valproic acid [Depakote], carbamazepine [Tegretol]).8 This type of aggression may also respond well to propranolol.8,21

Sexual disinhibition may also be seen in these patients. Again, a tolerant environment and redirection are the cornerstone of management; restrictive garments may also be helpful for some patients. Failing these options, pharmacologic treatment may be initiated to decrease the patient's sexually motivated behavior. Options include SSRI antidepressants such as paroxetine [Paxil], or antiandrogenic treatments, including leuprolide [Eligard] or medroxyprogesterone acetate [Provera].8 Medroxyprogesterone acetate is most commonly used; typical dosage is between 75 mg and 300 mg per week, given intramuscularly; adverse effects include loss of glycemic control and increased risk of deep venous thrombosis.


CONCLUSION

Frontal/subcortical dementias are common in clinical practice and can be extremely perplexing and frustrating for families and caregivers. With some basic understanding, the physician will be able to provide vital caregiver education and leadership in managing these patients.


REFERENCES

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Dr. Stewartis professor of psychiatry, University of South Florida College of Medicine, and chief, Geropsychiatry Section, BayPines VA Medical Center, Bay Pines, Fla.
Disclosure:The author reports no relevant disclosures to the topics discussed.

Stewart JT. The frontal/subcortical dementias. Common dementing illnesses associated with prominent and disturbing behavioral changes. Geriatrics 2006; 61(Aug):23-27.