Neurology: A Clinician's Approach (Cambridge Medicine (Paperback)), 1st Ed.

4. Dementia

History

Dementia is the chronic and progressive (at least 6 months in duration) loss of memory and at least one other cognitive function (language, praxis, object knowledge, or executive function) that interferes with a person’s ability to perform the activities of daily living.1 Although the history is the most important means of establishing the diagnosis, most patients with dementia provide only a vague account of their cognitive deficits, often stating that nothing is wrong or focusing on a minor respiratory, gastrointestinal, or orthopedic complaint. The patient frequently lacks awareness of their deficits, and collateral history must be obtained from a family member or friend. Because this narrative history may also be vague and unhelpful, directed questioning about specific deficits is often the only effective strategy to establish the exact nature of the problem.

Memory

The first memory problem that families report is often that the patient repeats himself or asks the same question in the space of a few minutes. A demented patient misplaces their keys, eyeglasses, or wallet more frequently than would be expected of someone who was simply absentminded. Other memory problems include forgetting to purchase items from the grocery store, missing appointments, and getting lost. Memory problems may lead to difficulty with the finances, as the patient often forgets charges or receipts when balancing their checkbook or preparing their taxes. Although all dementias include at least a component of memory problems, these are particularly important in Alzheimer’s disease (AD).

Language

Word-finding difficulties are an early deficit in many dementias, especially AD and primary progressive aphasia (PPA). The patient seems to search for the proper word for an excessive amount of time or has a tendency to substitute less specific words such as “thing,” “that,” or “the place” for more precise ones. Intermittent episodes in which speech appears to be slurred or garbled are a feature of dementia with Lewy bodies (DLB).

Praxis

Praxis is the ability to perform skilled movements, and deficits in praxis (apraxia) are an important feature of many dementias, especially corticobasal ganglionic degeneration and AD. Early evidence of apraxia includes difficulty with operating computers, DVD players, and other relatively newer technologies. Other patients have problems with planning and preparing meals. As dementia progresses, simpler tasks such as brushing the hair or teeth or eating become difficult.

Visuospatial function

Visuospatial deficits include problems with getting lost, applying makeup, and driving or parking. These problems are especially common in patients with DLB, but may be features of any of the dementias. Patients with more advanced dementia may have difficulties dressing properly.

Behavioral abnormalities

Behavioral abnormalities occur as early symptoms in frontotemporal dementia (FTD). Socially inappropriate behaviors including lewd comments, aggression, and excessive risk-taking are features of FTD, as are abulia in which the patient seems unmotivated, spending most of their time in bed or watching television. Personal hygiene also suffers in many demented patients. Hallucinations, particularly visual ones, are a core feature of DLB. Be cautious when asking about hallucinations, as the patient may be hesitant to admit to things that might lead to psychiatric hospitalization. To ease into inquiries about hallucinations, ask first about vivid dreams and then about seeing unusual things, and, if the patient does not endorse either of these, ask them specifically about hallucinations. Finally, ask about features of rapid eye movement (REM) sleep behavioral disorder such as punching, kicking, or screaming out in the middle of sleep, which may predate other symptoms of DLB by many years.

Gait difficulties

Although gait difficulties are common and somewhat nonspecific in the elderly (Chapter 18), they may point to specific causes of dementia including normal pressure hydrocephalus (NPH), vascular dementia, and progressive supranuclear palsy.

Relevant medical history

Obtain a complete medical history in all patients who present with suspected dementia. A history of human immunodeficiency virus (HIV) infection, cardiac surgery, renal or hepatic failure, or hypothyroidism may point to explanations for cognitive decline other than one of the degenerative dementias. It is also helpful to screen briefly for sleep disorders, disabling pain, and depression. These medical problems often mimic dementia and, because they are reversible, it is important to identify and treat them as soon as possible. Medications, especially narcotics, benzodiazepines, and anticonvulsants, may also produce reversible cognitive dysfunction.

Age of onset, tempo, and fluctuations

Noting the age of onset is often helpful in generating a differential diagnosis for dementia: while most demented patients are older than 65, FTD and early-onset AD may begin in patients in their 40s or 50s. Deficits in most dementias are acquired in a gradual fashion, but some are characterized by a subacutely progressive onset over a few weeks to months (Creutzfeldt–Jakob disease or Hashimoto’s encephalopathy), or a sudden stepwise onset (vascular dementia). Fluctuation of deficits is a key feature of DLB. Examples of fluctuation include daytime drowsiness and lethargy, daytime naps lasting at least 2 hours, staring into space for long periods, and episodes of disorganized speech.2

Examination

Mental status examination

The mental status examination begins informally as the history is being obtained. Make note of any word-finding difficulties, repetition of details, or vague answers. Patients with moderate-to-severe dementia may not be able to provide any relevant history whatsoever. Observe for bizarre comments or general sluggishness as might be expected in FTD, or bradykinesia or bradyphrenia, which may reflect DLB.

Keep in mind that poor performance on components of the mental status examination may represent the patient’s cognitive baseline rather than an acquired cognitive problem. Before judging any deficiencies, inquire about the length of the patient’s formal education, occupation, and level of intellectual activity prior to the onset of cognitive decline.

Mental status testing is often time-consuming. In some cases, thorough cognitive assessment may require more detail than a single office visit allows, particularly in the early stages of dementia when the problems may be subtle or when the patient has a high premorbid level of function. The mini mental status examination is a good brief screening examination, but is generally not good at diagnosing or classifying dementia or milder deficits.3 The brief mental status examination summarized in Table 4.1 and described in detail in this chapter may be performed in 10 minutes and provides both a general picture of a patient’s cognitive abilities and details about problems in specific cognitive domains.

Attention

A variety of bedside tests is available to assess attention (Chapter 1). After establishing basic orientation to person, place, and time, ask the patient to recite the months of the year backwards to determine whether they are sufficiently attentive to complete the remainder of the mental status examination. Attention is relatively preserved until the advanced stages of AD, while it may be affected earlier in the course of FTD or DLB.

Language

Chapter 3 provides more detailed instructions for the assessment of language. Perhaps the most important components of language evaluation in a patient with suspected dementia are tests of semantic and phonemic fluency.

Semantic fluency

To test semantic fluency, ask the patient to name as many animals as they can in 1 minute. More specific normative values stratified by age and educational level are available, but a normal older person will be able to

Table 4.1 Summary of mental status examination

Table 4.1

name roughly 12 different animals in a minute.4 Early loss of semantic fluency compared with phonemic fluency suggests the possibility of AD or semantic dementia.5 These patients may be able to name only four or five animals in 1 minute, often repeating more familiar animals several times during the course of the test.

Phonemic fluency

To test phonemic fluency, ask the patient to generate a list of words, exclusive of proper nouns, beginning with the letter “S.” It may be helpful to perform this test several minutes after testing semantic fluency: many patients who perform the tests consecutively will restrict their responses to animals that begin with the letter “S.” Again, there are normative values stratified by age and educational level. A healthy older person should be able to name roughly ten “S” words in 1 minute.4 Although there is some variability in the literature, patients with DLB and FTD generally show loss of phonemic fluency that is greater than or at least equal to semantic fluency, which is distinct from patients with AD in whom phonemic fluency is relatively preserved compared with semantic fluency.5

Memory

Asking the patient to tell you about a few current events or sports stories is a good screening test for memory problems. If they cannot tell you anything spontaneously, try to trigger their memory by providing hints about an item in the news. If they still draw a blank, ask the patient to name the president, governor, or best player on the local baseball or football team. If they are not capable of doing even this last task, ask them if they know the date or season.

Verbal recall of a four-word list is a good test of episodic memory. Begin by telling the patient that you will ask them to recall four words in 5 minutes. When selecting target words, use both words that have physical manifestations such as “apple” and also conceptual ones to which visual tags cannot be so readily assigned, such as “wisdom.” Present the word list at least three times and instruct the patient to repeat it back to you after each presentation. A patient who cannot repeat the word list has attentional problems that will prevent accurate assessment of their recall abilities. Complete the remainder of the mental status examination, and ask the patient to recall the four words after 5 minutes have elapsed. Older patients are generally able to recall three or four of the words, and usually can select the fourth word from a multiple-choice list or recall it if you give them a hint about the category to which the item belongs. Patients with AD have problems not only with recalling the words but also with recognizing them from a list or guessing them from a category. In the very early stages of memory problems, a four-item list may not be sensitive enough to detect memory deficits, and a more detailed neuropsychological evaluation may be required.

Praxis

Apraxia is defined as the inability to perform a learned movement in response to the stimulus that normally produces it. In order for the label of apraxia to be appropriate, all elemental neurological functions such as strength, sensation, language, and attention must be preserved. Apraxia was originally described by Liepman, and his division of apraxia into ideomotor, ideational, and limb-kinetic forms largely persists to this day, despite substantial controversies. Interested readers are referred to Ochipa and Gonzalez Rothi’s review on the topic, as I will discuss only one type, ideomotor apraxia, in a limited format here.6

Ideomotor apraxia is characterized by errors in positioning, orientation, sequencing, and timing of limb movements. The manifestations and localizations of ideomotor apraxia may roughly be understood with a simplified connectionist model (Figure 4.1).6 Verbal, visual, or somatosensory inputs synapse with movement representations in the left inferior parietal lobule. These, in turn, activate motor programs in the supplementary motor area of the left frontal lobe. These

Figure 4.1

Figure 4.1 Axial section of the brain showing simplified schematic of ideomotor apraxia. Multimodal sensory information is processed by the left inferior lobule (IPL). This in turn activates motor programs in the left supplemental motor area (SMA), which projects to the left motor cortex and, via the corpus callosum (CC), to the right motor cortex.

motor programs activate movement of the right side of the body via synapses with the motor cortex of the left hemisphere. They also cross to the motor cortex of the right hemisphere via the corpus callosum, thereby activating movements of the left side of the body. Thus, lesions of the left inferior parietal lobule or supplementary motor area might be expected to produce ideomotor apraxia of both sides of the body while lesions of the corpus callosum might lead to apraxia of only the left side of the body.

A variety of tests is available to investigate for apraxia. Commonly used bedside tests include asking the patient to perform the following actions to command:

1. Wave goodbye.

2. Blow a kiss.

3. Pretend that they have a toothbrush in their hand and ask them to use it to brush their teeth.

4. Pretend that they have a hammer, and use it to put a nail into a board.

5. Pretend that they have a brush, and use it to brush their hair.

Look for errors in positioning, orientation, sequencing, and timing. If they cannot perform these actions to command, they should try to imitate them. It is also important to watch the patient use actual tools. For hospitalized patients, readily available tools include pencils, forks, remote controls, and flashlights.

Apraxia may be due to vascular, traumatic, neoplastic, or degenerative disorders involving the left frontal or parietal lobes. It is particularly common in patients with AD and corticobasal degeneration. The two most important applications of praxis testing are in patients with suspected corticobasal degeneration in whom apraxia is a prominent early finding and in patients with callosal lesions in whom isolated left limb apraxia reflects disconnection between the left supplementary motor cortex and the right motor cortex.

Construction

Common tests of construction include drawing a house and drawing a clock. When a patient draws a house, study its general outline as well as specific details such as doors, windows, and chimneys. Patients who can draw the overall outline of the house but miss the details are more likely to have right hemisphere lesions, while those who draw a poorly outlined house with preserved details are more likely to have left hemisphere lesions. When analyzing a clock drawing, look first for evidence of poor planning such as crowding all the numbers on the right hand side of the circle. Evidence for perseveration (a sign of frontal lobe dysfunction) includes repeating the same number several times or continuing to number the clock beyond “12.” Patients with visuospatial deficits may place the numbers outside the circle or draw the numbers in a spiral that closes in on itself. Visuospatial abilities and construction impairments tend to be more severe in patients with DLB than in those with other forms of dementia.

Mental flexibility

Mental flexibility, including the ability to switch quickly between different cognitive tasks, is governed largely by the frontal lobes. The Luria and Stroop tests are two useful bedside tests for patients with suspected frontal lobe disorders.

Luria test

The Luria test is a popular tool to evaluate metal flexibility. The patient is first asked to sequentially tap a table or other flat suface with the first, then with the palm, and then with the side of the hand. Instruct the patient to repeat this sequence several times in succession. Some patients with comprehension problems, apraxia, or severe frontal disorders have difficulty with even this first sequence. If the patient correctly learns and performs this sequence several times in succession, however, switch the sequence from fist–palm–side to fist–side–palm. Observe whether the patient is capable of switching to the second sequence, or whether they remain stuck in set and follow the original sequence.

Stroop test

This test exists in a variety of forms, one of which consists of a grid of 30–40 words written in different colors. The first several targets are color names written in the same color as the text. For example, the word “green” is written in the color green. After eight to ten such targets, the words are written in colors different from the text. For example, the word “green” is written in the color purple. To perform the Stroop test, first ask the patient to simply read the words. After they have read through the entire list, instruct them to read the list from start to finish again, this time saying not the written word, but rather its color. Patients with frontal dysfunction will remain stuck in set and continue to read the word rather than the color. Even after being corrected, they may continue to make the same kind of mistake.

Processing speed

Processing speed difficulties are signs of frontal lobe dysfunction and are often evident in the way the patient answers questions. A gestalt of processing speed may be estimated at the bedside by simple observation of the other parts of the mental status examination, particularly the “A” cancellation test described in Chapter 1 or by a Trails B-type test in which the patient is asked to “connect the dots” between alternating letters and numbers (Figure 4.2). A variety of formal tests performed during neuropsychological evaluation are superior at detecting and quantifying processing speed abnormalities.

Frontal release signs

The so-called frontal release signs or primitive reflexes are found in patients with moderate to severe dementia. The grasp sign is elicited by dragging a finger over the patient’s opened palm, and is positive when the patient clutches at the finger. The palmomental sign is observed when the chin puckers slightly upon gently stroking the palm. The snout or rooting reflex is present when stroking the cheek at the corner of the mouth results in a twitching of the mouth or lips.

Figure 4.2

Figure 4.2 Example of a Trails B-type test. Instruct the patient to begin at the number “1” and then to connect the dots between alternating letters and numbers. The correct sequence is, therefore, 1–A–2–B–3–C–4–D, etc. Observe the speed at which the patient performs the test and whether they can follow the instructions or instead connects the dots between consecutive numbers or letters. This test is sensitive to frontal lobe dysfunction.

The glabellar sign is the failure to suppress continued blinking when the forehead is quickly tapped with an index finger.

The general neurological examination

The remainder of the neurological examination should focus on finding deficits that help to establish the diagnosis of a specific dementia. As a general rule, patients with AD and FTD have otherwise normal neurological examinations. The following is a brief summary of some of the more common and important examination abnormalities in demented patients.

Cranial nerve examination

A patient with FTD has difficulty following visual field examination instructions. When told to fix their attention on the examiner’s nose, any stimulus such as wiggling fingers in the periphery will instantly draw their attention and prevent accurate visual field examination. Progressive supranuclear palsy leads to impaired downward saccade generation that corrects with oculocephalic maneuvers.

Motor examination

Parkinsonism is a core feature of DLB, but rigidity and bradykinesia may be minimal or absent at the time of initial presentation. Myoclonus, although classically associated with Creutzfeldt–Jakob disease, may be a feature of any advanced dementia. Paratonia is an increased involuntary resistance to passive movement that worsens despite instructions to relax, and is seen in frontal lobe disorders. Weakness, fasciculations, hyperreflexia, and other evidence of motor neuron disease are found in approximately 15% of patients with FTD.

Sensory examination

Because polyneuropathies are common in the elderly, any sensory abnormalities should be interpreted cautiously, as they are usually unrelated to the dementing process. Vitamin B12 deficiency may lead to impaired vibratory sensation and joint position in the lower extremities. Corticobasal ganglionic degeneration is accompanied by asymmetric loss of higher cortical sensory functions such as graphesthesia and stereognosis.

Gait

Normal pressure hydrocephalus results in a gait abnormality characterized by poor initiation and short, slow steps with the feet narrowly spaced. This pattern is also observed in some patients with vascular dementia. Elderly patients commonly have a multifactorial gait disorder that does not actually reflect any specific dementia and may confuse the diagnostic process.

Diagnostic testing

The diagnosis of dementia is made mostly from the history and mental status examination. Diagnostic testing is performed mainly to exclude reversible medical problems that masquerade as degenerative ones and, in some cases, to establish the diagnosis of a specific primary dementia.

Bloodwork

Every patient with dementia should undergo bloodwork including tests of thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin. While the yield of any of these studies is quite low, the associated abnormalities are all reversible causes of cognitive decline. Be cautious, however, when attributing cognitive dysfunction to any of these laboratory findings, as mild abnormalities are common and their presence does not necessarily exclude a degenerative dementia.

Structural neuroimaging

It is essential to perform a neuroimaging study in all patients with dementia to exclude structural lesions such as tumors, abscesses, subdural hematomas, and hydrocephalus. A noncontrast head CT is generally sufficient to demonstrate these problems. MRI, however, offers better neuroanatomic resolution and allows quantification of medial temporal lobe atrophy in AD (Figure 4.3) or frontal and anterior temporal lobe atrophy in FTD.7,8 Changes consistent with vascular dementia including leukoaraiosis (Figure 4.4), cortical infarcts, and lacunar infarcts are also easier to visualize using MRI.

Functional neuroimaging

Functional neuroimaging studies include positron emission tomography (PET), single photon emission computed tomography (SPECT), functional MRI (fMRI), and magnetic resonance spectroscopy (MRS). These studies will likely play a more prominent role in the differential diagnosis and prognostication of dementia as they are refined and tested in larger groups of patients. For now, they are used mostly on a research

Figure 4.4

Figure 4.4 Axial fluid attenuation inversion recovery (FLAIR) MRI of the brain showing periventricular white matter hyperintensities (arrows) in a patient with vascular dementia.

Figure 4.3

Figure 4.3 Coronal MRI of the brain demonstrating medial temporal lobe atrophy (arrow) in a patient with Alzheimer’s disease.

basis or to help distinguish among AD, DLB, and FTD in difficult cases.911

Lumbar puncture

Lumbar puncture plays a limited role in evaluating dementia. It is particularly useful, however, for patients with rapid progression, as it may disclose infectious, inflammatory, or neoplastic causes of cognitive decline. Lumbar puncture and timed gait analysis is the essential test to evaluate for NPH. Spinal fluid showing decreased amyloid β42 and increased CSF-tau may be helpful to make a diagnosis in unclear cases of AD, although these tests are usually not required.12

Genetic testing

Genetic testing is available for several different dementias but is rarely employed in patients without clear familial histories of early-onset dementia.

Causes of dementia

Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia. The typical patient with AD is 65 years or older and has a dementia characterized mainly by slowly progressive memory problems. Early-onset and rapidly progressive forms of AD, however, are uncommon but important variants. As the disorder progresses, memory deficits worsen, and essentially any cognitive domain may be affected. The diagnosis is established by history and mental status examination. Finding medial temporal atrophy on MRI may support the clinical diagnosis.7

The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine (Table 4.2) are modestly effective in improving cognitive deficits but do not alter disease progression. The most common adverse effects of these medications are nausea, vomiting, and diarrhea: patients who do not tolerate one agent may find more success with a different one. The N-methyl-D-aspartate (NMDA) receptor antagonist memantine may be effective for patients with moderately severe disease, especially when used in combination with an acetylcholinesterase inhibitor. Side effects of memantine including dizziness and confusion are uncommon. As AD progresses, medications are of limited value, and treatment focuses on assistance with activities of daily living including bathing and eating, and control of behavioral symptoms. Ultimately, AD progresses

Table 4.2 Medications used to treat Alzheimer’s disease

Table 4.2

and patients with advanced disease require nursing home placement.

Dementia with Lewy bodies

This is the second most common of the degenerative dementias and, like AD, tends to occur in older people. The three core clinical features of DLB are cognitive fluctuations (discussed above), visual hallucinations, and parkinsonism. Visual hallucinations are initially nonthreatening and may take the form of people, animals, or brightly colored objects. As the disease progresses, the hallucinations may become more threatening. Parkinsonism is often subtle or absent in the early stages of DLB: if it is present early in the course of the disease or is the main symptom, consider a form of parkinsonism other than DLB.13 Development of REM sleep behavioral disorder, in which a patient acts out their dreams, may precede the development of other DLB symptomatology, often by many years.

On mental status examination, episodic memory is relatively preserved in the early stages of the disease. Both semantic and phonemic fluency may be affected. Visuospatial impairments are more prominent than in patients with AD. Extrapyramidal findings tend to involve axial more than appendicular musculature, and tremor is usually absent. Laboratory and radiological testing is of limited utility: 18F-fluorodeoxyglucose PET scanning may demonstrate occipital lobe hypometabolism, but the diagnosis is still established by history and neurological examination.14

Treating DLB with acetylcholinesterase inhibitors may be effective. Levodopa is generally less useful for parkinsonism in DLB than it is in Parkinson’s disease. Levodopa and dopamine agonists should be used cautiously as they may worsen hallucinations and other behavioral problems. In the early stages, hallucinations are not typically disturbing to the patient, and therefore do not require treatment. For patients with bothersome hallucinations, low-dose quetiapine (25 mg prn) is preferred, as it usually does not worsen extrapyramidal symptoms. Clozapine may also be used to treat hallucinations, although any patient who takes this medication requires periodic complete blood counts to monitor for agranulocytosis.

Frontotemporal dementia

Frontotemporal dementia is often first evaluated by a psychiatrist rather than a neurologist, as behavioral changes rather than memory impairment are usually the earliest symptoms of the disorder. Patients with FTD tend to be younger than those with AD and DLB, often developing symptoms in their 40s or 50s rather than in their 60s or later. Abnormal behaviors in FTD may be broadly clustered into socially inappropriate and withdrawn behaviors:

• Examples of socially inappropriate behavior include a reduced sense of social decorum including rude or often lewd comments and uncharacteristic risk-taking behaviors such as excessive gambling or alcohol consumption. Other features of FTD include bizarre preferences for certain types of foods (especially sweets), hoarding behaviors, and an obsession with generating artwork. The inappropriate patient is often evaluated and treated for bipolar or psychotic disorders before coming to neurological attention.

• The patient with the withdrawn phenotype of FTD is apathetic, showing little interest in work, family, or hobbies. They spend most of their time in bed, watching television, or simply staring into space. Personal hygiene is compromised. They may be evaluated and treated for depression before coming to neurological attention.

Examination shows impaired mental flexibility, slowed processing speed, and early frontal release signs. Episodic memory is generally preserved in the initial stage of the disease. Although a general neurological examination is usually normal, approximately 15% of patients with FTD also have motor neuron disease (Chapter 10). MRI may disclose disproportionate frontal and anterior temporal atrophy, which helps to distinguish FTD from AD.8

Treatment of FTD is often disappointing: acetylcholinesterase inhibitors are usually not effective and may actually worsen behavior.15 Selective serotonin reuptake inhibitors may help to control some of the behavioral symptoms. Most patients with FTD, unfortunately, require close supervision and often need early nursing home placement.

Vascular dementia

The term “vascular dementia” encompasses three different disorders: multi-infarct dementia, subcortical white matter disease, and strategic-infarct dementia.

Multi-infarct dementia

Multi-infarct dementia is the condition that most neurologists would describe as vascular dementia. This form of dementia is characterized by the stepwise accumulation of neurological deficits from multiple, clinically apparent cerebral infarctions. While the strokes do not necessarily involve areas of the brain that are critical for memory, their cumulative effect is dementia. Although mental status testing in patients with multi-infarct dementia may resemble that of the other dementias (most commonly AD), abnormalities on the general neurological examination suggestive of prior infarctions such as hemiparesis and visual field cuts help to make the diagnosis. There is considerable overlap between multi-infarct dementia and AD, and distinguishing between the two on clinical or even radiological grounds is often difficult. From a treatment perspective, the distinction may not necessarily be crucial, as patients with multi-infarct dementia, like those with AD, benefit from acetylcholinesterase inhibitors.16 Obviously, it is important to look for and treat risk factors for vascular disease such as hypertension, diabetes, and hyperlipidemia. While correcting these risk factors does not necessarily improve cognitive symptoms, it is important from a general health perspective.

Subcortical white matter disease

Subcortical white matter disease is known by a variety of names including Binswanger’s disease, periventricular white matter disease, and leukoaraiosis. It is characterized by the progressive accumulation of multiple, often clinically silent infarctions in the subcortical white matter. Patients most commonly present with bradyphrenia, impaired executive function, memory loss, and frontal gait abnormalities. Patients tend to resemble those with the withdrawn/abulic form of FTD or NPH. Typical risk factors for vascular disease such as hypertension, hyperlipidemia, and diabetes are present. In rare young patients, subcortical white matter disease may be a consequence of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) secondary to a NOTCH3 gene mutation.17Unfortunately, subcortical white matter disease responds poorly to any treatments, and care is largely supportive.

Strategic infarct dementia

Strategic infarct dementia is produced by infarction of an area of the brain that is critical for memory. It is not strictly a dementia, as it is acute in onset and tends to be static rather than progressive. Nonetheless, the persistent memory deficits that occur as a consequence of strategic-infarct dementia force it to be considered here. Vascular territories associated with sudden-onset memory loss include the polar artery, paramedian thalamic artery, and the medial temporal branch of the posterior cerebral artery.18 Patients with strategic infarct dementia may improve over time, unlike those with other dementias. The mainstay of treatment is preventing stroke recurrence.

Normal pressure hydrocephalus

The well-known clinical triad of NPH is dementia, urinary incontinence, and gait impairment. This simple summary, however, is misleading, and because the triad is rather nonspecific, it leads to many unnecessary referrals for “NPH evaluations.” In brief, many demented patients will develop both urinary incontinence and gait impairment as their dementia progresses, and few of them will actually have NPH.

Although there is considerable heterogeneity in the clinical presentation of NPH, the features that are most consistent with the diagnosis are abulia (resembling FTD in some cases) and frontal gait abnormality. This frontal gait is characterized by slow initiation and shortened stride length to the point that the patient appears to be stuck to the floor by a magnetic force (Chapter 18). It is often incorrectly called ataxic or apraxic. This pattern is perhaps somewhat nonspecific, as it may also occur as a consequence of arthritic degeneration of the spine, hips, and knees, or parkinsonism. The urinary incontinence of NPH, while it tends to not be urge incontinence, has few features that distinguish it from incontinence of other causes.

Despite its relative rarity, consider NPH evaluation for patients with frontal dementia and frontal gait disorder, as the disorder may be treatable by CSF shunting. All patients with NPH should undergo a CT scan or MRI of the brain to document hydrocephalus (Figure 4.5) and to exclude ventricular system outflow obstruction. A modified version of the CSF tap test is the most common way to make the diagnosis:19

1. Admit the patient to the hospital.

2. Measure the amount of time and number of steps it takes to walk 60 feet. Repeat this walking test twice, encouraging the patient to do their best each time.

3. Remove 30–50 cc CSF by lumbar puncture.

4. Repeat the timed walking test immediately after and at 30-minute intervals up to 2 hours after lumbar puncture.

An improvement in the time and number of steps required to walk 60 feet predicts a positive response to CSF shunting. Although it is difficult to quantify what actually constitutes an improvement, a reduction in the time needed to cover 60 feet by 50% is strongly suggestive of the diagnosis. Monitoring mental status testing before and after lumbar puncture is less reliable than timed gait analysis.

Consider ventriculoperitoneal shunting in a patient with a disease duration of <2 years, a positive CSF tap test, and a low burden of both cortical atrophy and periventricular white matter disease. Prior to surgery, it is important to inform the patient and their family about possible complications from an indwelling shunt including meningitis, subdural hygroma or hematoma formation, and chronic headache.

Primary progressive aphasia

Aphasia is a feature of many dementias, including AD, FTD, and corticobasal degeneration. Primary progressive aphasia (PPA) is a progressive dementia characterized by language deficits that are out of proportion to other deficits, and dominate the first 2 years of disease.20 While our understanding of this disorder is still in its relative youth compared with other types of dementia, there are three generally recognized forms of PPA:21

• Nonfluent progressive aphasia, characterized by a lack of fluency, poor syntax, and comprehending difficulties with complex structures. Atrophy is

Figure 4.5

Figure 4.5 Axial fluid attenuation inversion recovery (FLAIR) MRI showing ventricular dilation in a patient with normal pressure hydrocephalus.



usually seen in the left inferior frontal and insular cortices.

• Semantic dementia, characterized by a fundamental loss of word meanings. Fluency is preserved and comprehension is poor. Atrophy tends to affect the left anterior temporal lobe.

• Logopenic progressive aphasia, characterized by decreased fluency with relatively good but simple syntax. Comprehension is good. Atrophy characteristically involves the left inferior parietal lobule and posterior temporal cortex.

Alcohol and dementia

Chronic alcohol abuse may result in rather nonspecific long-term cognitive changes. The classical alcohol-related dementia, however, is Korsakoff’s dementia, in which anterograde and retrograde amnesia are profound and out of proportion to other cognitive deficits. Korsakoff’s dementia often develops in a patient recovering from Wernicke’s encephalopathy. Because patients with Korsakoff’s dementia have severe memory deficits but preserved attention, they are prone to confabulation. They will fabricate explanations as to why they are in hospital, relationships to the examiner, and current events. They actively seek environmental clues that sustain the impression that their memory is preserved. Mammillary body atrophy visualized on MRI helps to establish the diagnosis of Korsakoff’s syndrome. Unfortunately, the memory deficits do not tend to improve, even with alcohol discontinuation and thiamine supplementation.

Human immunodeficiency virus dementia

Human immunodeficiency virus (HIV) patients develop dementia with an incidence of approximately 1% per year, a figure that is decreasing with more widespread use of highly active antiretroviral therapy (HAART).22 Presenting symptoms include psychomotor slowing and memory deficits, but as the disease progresses any cognitive domain may be affected. The diagnosis is confirmed radiologically by finding cortical and subcortical atrophy and confluent, subcortical white matter hyperintensities. Other sources of dementia specific to patients with AIDS, such as progressive multifocal leukoencephalopathy, toxoplasmosis, and CNS lymphoma, must be excluded. Treatment with HAART may improve cognitive symptoms or slow their progression.

Neurosyphilis

General paresis of the insane (GPI), a form of tertiary neurosyphilis, was a common cause of dementia in the preantibiotic era. It is now vanishingly rare, but should be considered as a possible source of dementia in patients with a history of syphilis (which usually precedes the dementia by 5–20 years) and in HIV-positive patients. Finding an abnormal CSF venereal disease research laboratory (VDRL) confirms the diagnosis. If the index of suspicion is high and the VDRL is negative, check the fluorescent treponemal antibody absorption (FTA-ABS) test.23 The standard treatment of GPI is penicillin (3–4 g IV q6h for 14 days). This treatment, however, may not result in a cognitive recovery.

Dementia and movement disorders

Dementia frequently accompanies movement disorders, especially corticobasal ganglionic degeneration, progressive supranuclear palsy, and Parkinson’s disease (Chapter 13). In general, these dementias are of the subcortical type, characterized by slow processing speed and difficulty with switching sets. Corticobasal ganglionic degeneration, however, may produce a dementia with prominent cortical features, especially asymmetric limb apraxia.

Mild cognitive impairment

Mild cognitive impairment (MCI) occupies the transitional state between normal cognitive function and overt dementia. In MCI, cognitive abnormalities are present but do not yet meaningfully impact on activities of daily living. Approximately 10% of patients with MCI will progress to AD (amnestic MCI) or to one of the other dementias (nonamnestic MCI) per year, far exceeding the 1% annual conversion rate of otherwise normal adults older than 65.24Acetylcholinesterase inhibitors do not clearly delay the progression of MCI to dementia, although they are commonly prescribed.25

Pseudodementia

Several conditions may lead to progressive cognitive deficits that may resemble dementia. When a patient presents with progressive cognitive decline, it is important to consider these mimics of dementia, as they generally respond better to treatment than do the degenerative processes discussed above.

Depression

Cognitive complaints, especially memory loss, are common in patients with depression. It is a classical teaching but not a universal truth that patients with depression are aware of their memory problems, unlike patients with dementia who lack awareness. Separating patients with dementia from those with depression by mental status examination is often challenging. Inquiring directly about depression may bring the problem to light in some cases. In others, a screening questionnaire such as the Beck Depression Inventory or similar tool may be helpful.26 Psychiatric consultation and antidepressants may improve symptoms of depression and the associated cognitive complaints.

Obstructive sleep apnea and other sleep disorders

Patients with obstructive sleep apnea (OSA) complain of difficulty concentrating during the daytime, an urge or need to take naps, snoring, and morning headaches. In some cases, memory difficulties or other cognitive complaints may be the chief complaint. Although cognition is often impaired in patients with OSA, it is not clear whether OSA is actually the cause of the problem.27 Physical examination findings suggestive of OSA include obesity, increased neck circumference, and a crowded oropharynx. Patients with unexplained cognitive complaints should undergo screening for OSA or other sleep disorders with a polysomnogram and formal sleep medicine consultation. Mask ventilation, if used properly, may reverse many of the cognitive complaints associated with OSA.

Pain

Patients may find it difficult to sleep or concentrate due to chronic, unresolved pain, or may have cognitive difficulties as a result of excessive pain medications. Because successful pain treatment or modification of existing pain treatment regimens may lead to an improvement in mental status, it is a good idea to review any ongoing pain symptoms and medications with all patients referred for cognitive complaints.

Adult attention deficit hyperactivity disorder

Although adult attention deficit hyperactivity disorder (ADHD) is a disorder that begins in childhood, it may go undiagnosed until adulthood, especially in people who grew up before the diagnosis was recognized with any frequency. Attention deficit hyperactivity disorder is perhaps the most common diagnosis in patients who are evaluated for cognitive dysfunction in their 20s and 30s. Patients with ADHD are impulsive, disorganized, and have difficulty concentrating. They may complain of memory problems, but their real problem is with sustaining attention. Stimulants including methylphenidate (started at 10 mg bid), dextroamphetamine (started at 5 mg bid), and atomoxetine (started at 40 mg qd) are the mainstays of pharmacological treatment for ADHD. Cognitive–behavioral therapy also plays an important role.

Conversion disorders and malingering

These two psychiatric disorders may mimic any neurological symptom and, unless you maintain a high degree of suspicion, they may be difficult to detect. In many cases, neuropsychological evaluation is necessary to tease apart these psychiatric disorders from organic dementia.

Postconcussion syndrome

Mild traumatic brain injury (TBI), defined as a head injury that produces a loss of consciousness of <30 minutes in duration or a Glasgow Coma Scale 13 (Chapter 21Table 21.4), is associated with a variety of neuropsychological complaints.28 Three months after TBI, approximately 60–80% of patients will complain of one or more neurological problems including headache, dizziness, memory loss, irritability, and inattention. The term postconcussion syndrome is often used to describe this cluster of complaints, although most patients lack one or more elements of the complete “syndrome.” Complaints lasting for more than a year are less frequent, occurring in perhaps 10% of patients. The mechanism of postconcussive symptoms is unclear, but axonal injury, secondary gain including unresolved legal disputes, and preexisting or superimposed psychiatric disorders such as anxiety and depression all contribute.28 Fortunately, many of the problems resolve spontaneously in a few weeks to months after TBI. Although cognitive rehabilitation may help, there is no single treatment for postconcussion syndrome, and the individual complaints must be isolated from each other and treated independently.

Subacute and rapidly progressive dementias

Although dementia is operationally defined as a disorder lasting for at least 6 months, a subpopulation of patients declines more rapidly over a period of weeks to just a few months. The diagnosis may ultimately prove to be one of the more common degenerative dementias such as AD or vascular dementia, but the following conditions must be considered first when evaluating a patient with rapidly progressive dementia:

Creutzfeldt–Jacob disease

The prion disease Creutzfeldt–Jacob disease (CJD) is the prototypical rapidly progressive dementia. In addition to producing any pattern of cognitive deficits, patients with CJD may have a variety of other signs and symptoms including seizures and abnormalities of the cerebellar, pyramidal, and extrapyramidal systems. Creutzfeldt–Jacob disease develops years to decades after exposure to infected brain tissue such as dural grafts, human pituitary hormones, or improperly sterilized neurosurgical equipment. In most patients, however, the source cannot be identified. Beyond the cognitive deficits, the best-known sign of CJD is myoclonus (see Chapter 14). If it is not visible at rest, myoclonus or an enhanced startle response may be elicited by suddenly clapping your hands or dropping your keys on the ground. Bear in mind, though, that myoclonus may be a feature of any dementia in its advanced stages and is not pathognomonic for CJD. The single best noninvasive diagnostic test for evaluating CJD is diffusion-weighted MRI of the brain that shows cortical and basal ganglionic hyperintensities (slowed diffusion).29 Other laboratory findings of CJD include EEG showing periodic sharp waves with a biphasic or triphasic morphology, elevated 14–3-3 protein in the CSF, and elevated neuron-specific enolase in the CSF. Brain biopsy showing spongiform changes and abnormal prion protein histochemistry make the diagnosis when noninvasive tests fail to do so. Unfortunately, there is no effective treatment for CJD, and patients have a uniformly fatal outcome, generally within several weeks to months of diagnosis.

Hashimoto’s encephalopathy

Hashimoto’s encephalopathy is a rapidly progressive, somewhat controversial dementia that clinically resembles CJD in many ways. Originally described in patients with hypothyroidism, the symptoms are not actually the result of thyroid hormone abnormalities, but are more likely secondary to an autoimmune process.30 Systemic symptoms suggestive of thyroid dysfunction are usually not present, and the degree of cognitive dysfunction is not correlated with serum thyroxine or thyrotropin levels. The diagnosis of Hashimoto’s encephalopathy is established by finding antithyroid peroxidase or antithyroglobulin antibodies. MRI may show nonspecific atrophy. CSF analysis characteristically shows elevated protein, with a small proportion of patients demonstrating a lymphocytic pleocytosis. Hashimoto’s encephalitis responds to treatment with corticosteroids, often dramatically.

Leptomeningeal metastasis and limbic encephalitis

Cancer may produce subacutely progressive cognitive dysfunction by direct infiltration of the nervous system or via a paraneoplastic mechanism, as discussed in Chapter 1.

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