Mental Status Testing

Mini-Mental State Examination (MMSE) (Fig. 7-1)

Physicians so regularly administer the MMSE that it has risen to the level of the standard screening test. Its results are reproducible and correlate with histologic changes in Alzheimer disease. In addition to detecting cognitive impairment, the MMSE has predictive value. For example, among well-educated individuals with borderline scores, as many as 10–25% may develop dementia in the next 2 years. The MMSE can also cast doubt on a diagnosis of Alzheimer disease as the cause of dementia under certain circumstances: (1) If scores on successive tests remain stable for 2 years, the diagnosis should be reconsidered because Alzheimer disease almost always causes a progressive decline. (2) If scores decline precipitously, illnesses that cause a rapidly progressive dementia become more likely diagnoses (see later).

FIGURE 7-1 Mini-Mental State Examination (MMSE). Points are assigned for correct answers. Scores of 20 points or less indicate dementia, delirium, schizophrenia, or affective disorders – alone or in combination. However, such low scores are not found in normal elderly people or in those with neuroses or personality disorders. MMSE scores fall in proportion to dementia-induced impairments in daily living as well as cognitive decline. For example, scores of 20 correlate with inability to keep appointments or use a telephone. Scores of 15 correlate with inability to dress or groom.

(Adapted from Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state:” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. © 1975, 1998 MiniMental LLC.)

Critics attack the MMSE. It is “too easy.” It permits mild cognitive impairment (MCI) and even early dementia to escape detection. Age, education, and language skills influence the score. The MMSE may also fail to test adequately for executive function and thereby miss cases of frontotemporal dementia. Also, because the MMSE depends so heavily on language function, it may be inadequate in measuring conditions, such as MS and toluene abuse, where the subcortical white matter receives the brunt of the damage.

Alzheimer Disease Assessment Scale (ADAS)

The ADAS consists of cognitive and noncognitive sections. Its cognitive section (ADAS-Cog) (Fig. 7-2) includes not only standard tests of language, comprehension, memory, and orientation, but also tests of visuospatial ability, such as drawing geometric figures, and physical tasks that reflect ideational praxis, such as folding a paper into an envelope. Patients obtain scores of 0–70 points in proportion to worsening performance.

FIGURE 7-2 The cognitive section of the Alzheimer Disease Assessment Scale (ADAS-Cog), the standard test for assessing pharmacologic intervention, has been designed to measure many important aspects of cognitive function that are apt to deteriorate in Alzheimer disease. The noncognitive section measures mood, attention, delusions, and motor activity, such as pacing and tremors. As dementia begins or worsens, patients’ responses change from no impairment (where the patient receives 0 points) to severe cognitive impairment (5 points). In other words, as dementia worsens, patients accumulate points. Total ADAS-Cog scores for patients with mild to moderate Alzheimer disease range from 15 to 25 and, as cognitive function declines, scores increase by 6–12 points yearly.

(From Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364. Reprinted with permission from the American Journal of Psychiatry, Copyright 1984. American Psychiatric Association.)

Compared to the MMSE, the ADAS-Cog is more sensitive, reliable, and less influenced by educational level and language skills. However, it is more complex and subjective. Test-givers, who need not be physicians, must undergo special training. The testing usually requires 45–60 minutes. Alzheimer disease researchers, especially those involved in pharmaceutical trials, routinely use the ADAS-Cog to monitor the course of Alzheimer disease and measure the effect of medication.

Montreal Cognitive Assessment (MoCA) (Fig. 7-3)

The MoCA, which has greater sensitivity than the MMSE, readily detects mild impairment. It is useful when a patient’s only symptom is memory impairment or physicians suspect cognitive impairment in individuals who score 25 points or better on the MMSE. Neurologists also administer the MoCA to patients with any neurodegenerative illness – a category that includes Alzheimer, Parkinson, and dementia with Lewy bodies diseases, and frontotemporal dementia. In Parkinson disease, the MoCA compared to the MMSE is more sensitive in detecting early cognitive impairment (see Chapter 18).

FIGURE 7-3 The Montreal Cognitive Assessment (MoCA). This assessment includes eight cognitive domains. As with the MMSE, the total score reaches 30 and values lower than 26 indicate cognitive impairment. However, some authors found that a cut-off of 23 gave a sensitivity and specificity of at least 95%.

(Copyright Z. Nasreddine MD. Reproduced with permission. The test and instruction may be accessed at www.mocast.org.)

Laboratory Evaluation in Dementia

Depending on the clinical evaluation, neurologists generally request a series of laboratory tests (Box 7-3). Although testing is expensive (see Appendix 2), it may allow a firm diagnosis or even detect a potentially correctable cause of dementia. In addition, certain tests may reveal the illness before individuals manifest cognitive impairment, i.e., in their preclinical or presymptomatic state. Neurologists modify the testing protocol if dementia has developed in an adolescent (see Box 7-2) or has progressed rapidly.

Because CT can detect most structural abnormalities associated with dementia, it is a sufficient screening test. However, MRI is superior because it is better able to diagnose multiple infarctions, white-matter diseases, and small lesions.

The EEG is not indicated for routine evaluation of dementia because the common dementia-producing illnesses cause only slowing or minor, nonspecific abnormalities. Moreover, those EEG abnormalities are often indistinguishable from normal age-related changes. On the other hand, an EEG may help if patients have shown certain unusual clinical features, such as seizures, myoclonus, rapidly progressive dementia, or stupor. In these cases, an EEG may show indications of Creutzfeldt–Jakob disease, subacute sclerosing panencephalitis (SSPE), or delirium (see later). An EEG can also contribute to a diagnosis of depression-induced cognitive impairment where it will be normal or show only mildly slowed background activity.

Likewise, a lumbar puncture (LP) is not a routine test, but possibly helpful in certain circumstances. For example, neurologists perform the LP to test the cerebrospinal fluid (CSF) when patients with dementia have indications of infectious illnesses, such as neurosyphilis, SSPE, or Creutzfeldt–Jakob disease. They also perform it to measure the pressure and withdraw CSF in cases of suspected NPH.

Physicians should reserve certain other tests for particular indications. For instance, if adolescents or young adults develop dementia, an evaluation might include serum ceruloplasmin determination and slit-lamp examination for Wilson disease; urine toxicology screens for drug abuse; and, depending on the circumstances, urine analysis for metachromatic granules and arylsulfatase-A activity for metachromatic leukodystrophy (see Chapter 5). Likewise, physicians should judiciously request serologic tests for autoimmune or inflammatory disease, serum Lyme disease titer determinations, and other tests for systemic illnesses.

Preclinical Alzheimer Disease

Neurologists no longer require any cognitive deficit, much less a disabling one, for a diagnosis of Alzheimer disease. They refer to asymptomatic individuals who have certain laboratory evidence as being in the preclinical or presymptomatic stage of the disease. Two recently introduced tests for biomarkers allow for the diagnosis of Alzheimer disease in its asymptomatic as well as its overt state. One test, amyloid imaging, uses Pittsburgh Compound B as a ligand that binds to amyloid in positron emission tomography (PET). It identifies, localizes, and quantifies an individual’s cerebral amyloid burden. Accumulation of amyloid in the cortex, especially in the frontal and parietal lobes, excluding the sensorimotor strip, serves as a marker for Alzheimer disease. The other test consists of CSF analysis for concentrations of amyloid and tau protein. The combination of low amyloid and elevated tau protein CSF concentrations serves as another marker for Alzheimer disease.

Mild Cognitive Impairment

Neurologists consider that MCI consists of impairment predominantly in either memory (amnestic) or nonmemory (nonamnestic) functions, such as executive ability or language function. Unlike individuals with dementia, those with MCI continue to work, socialize, maintain their hobbies, and function independently. Physicians assessing the situation might compare patients’ cognitive functions to those of their peers.

Representing a precursor to Alzheimer disease in many individuals, those with MCI progress to dementia at a rate of 10% yearly, but their unaffected peers progress at a rate of only 1–2% yearly. Risk factors for MCI progressing to dementia include the severity of cognitive impairment (particularly memory impairment) at the time of diagnosis and the standard risk factors for Alzheimer disease (see later). Cholinesterase inhibitors do not slow the deterioration of MCI to dementia.

Although the major implication of a diagnosis of MCI is that many cases progress to dementia, the cognitive impairment reverts to normal in as many as 30%. Researchers attribute this group’s improvement to treatment of psychiatric illnesses or toxic-metabolic disturbances.

Dementia

Alzheimer disease eventually produces dementia, but at different rates and in uneven trajectories for different patients. Cognitive reserve potentially explains some of the differences. In this explanation, education, occupation, and leisure-time activities insulate the brain. Well-educated individuals, for example, continue to maintain an intellectual perspective and employ alternate psychologic strategies that allow them to cope with decline in certain domains.

In the dementia stage, patients may remain superficially conversant, sociable, able to perform routine tasks, and physically intact. Nevertheless, the spouse or caregiver will report that they suffer from incapacitating memory impairment and inability to cope with new situations. Patients’ language impairment typically includes a decrease in spontaneous verbal output, an inability to find words (anomia), use of incorrect words (paraphasic errors), and a tendency to circumvent forgotten words – elements of aphasia (see Chapter 8).

Several other symptoms stem from deterioration in visuospatial abilities. This impairment explains why patients lose their way in familiar surroundings. It also explains constructional apraxia, the inability either to translate an idea into use of a physical object or to integrate visual and motor functions.

Physical Signs

Patients with Alzheimer disease characteristically have no physical impairment, except for one small but intriguing finding – anosmia (see Chapter 4). Even before the onset of dementia, Alzheimer disease patients require high concentrations of a volatile substance to detect and identify it. Neurologists also find anosmia in patients with Parkinson disease and dementia with Lewy bodies disease, but not in those with VCI or depression. Patients with TBI with or without dementia also have anosmia because they have had shearing of the olfactory nerve fibers at the cribriform plate (see Chapter 22).

Until Alzheimer disease advances to unequivocal dementia, patients usually remain ambulatory and able to feed themselves. The common sight of an Alzheimer disease patient walking steadily but aimlessly through a neighborhood characterizes the disparity between intellectual and motor deficits. When patients reach advanced stages of the illness, physicians can elicit frontal release signs (Fig. 7-4), increased jaw jerk reflex (see Fig. 4-13), and Babinski signs. Unlike patients with VCI, those with Alzheimer disease do not have lateralized signs. They eventually become mute, fail to respond to verbal requests, remain confined to bed, and assume a decorticate (fetal) posture. They frequently slip into a persistent vegetative state (see Chapter 11).

FIGURE 7-4 The snout and grasp reflexes – frontal lobe release reflexes – are frequently present in individuals with severe dementia. A, Physicians elicit the snout reflex by tapping the patient’s upper lip with a finger or a percussion hammer. This reflex causes the patient’s lips to purse and lower facial muscles to pout. B, Physicians elicit the grasp reflex by stroking the patient’s palm crosswise or the fingers lengthwise. The reflex causes the patient to grasp the physicians’ fingers and fail to release despite requests.

Laboratory Tests

When neurologists suspect Alzheimer disease, they order routine tests primarily to exclude other causes. The first EEG change is usually slowing of background activity; however, this change is not universal and overlaps the expected age-related slowing. In advanced disease, the EEG usually shows disorganized and slow background activity, which is diagnostically helpful but still nonspecific.

CT shows cerebral atrophy and a widened third ventricle, which is also suggestive but nonspecific. MRI shows sequential, progressive atrophy: first the hippocampus, then the temporal and parietal lobes, and eventually the frontal lobes. As with CT, MRI shows widening of the third ventricle as well as the atrophy. Although CT and MRI are both useful and one at least is necessary, neither can firmly diagnose Alzheimer disease because its most consistently visible abnormalities – cerebral atrophy, hippocampal atrophy, and an enlarged third ventricle – are also present in people with normal age-related changes and numerous illnesses, including trisomy 21, alcoholic dementia, HIV-associated dementia, and some varieties of schizophrenia.

In about one-half of Alzheimer patients, PET for glucose metabolism shows areas of decreased metabolism in the bilateral parietal and temporal association cortex (see Fig. 20-29). These hypometabolic areas are vague at first, but as the disease progresses, hypometabolism spreads to the frontal lobe cortex and becomes more distinct. PET remains unsuitable for routine testing, mostly because of its low sensitivity and specificity, as well as its cost. The changes are more specific and more cost-effective for frontotemporal dementia (see later). PET for amyloid accumulation is useful in the diagnosis of the preclinical stage of Alzheimer disease, but it is probably unnecessary in the symptomatic stage. Similarly, CSF analysis for depressed concentrations of amyloid and elevated concentrations of tau protein may be helpful in the preclinical stage, but superfluous in the symptomatic stage. Neurologists have not yet defined the role of PET and advanced CSF analysis in MCI.

Neurologists almost never request cerebral cortex biopsies for diagnostic purposes – mostly because routine evaluation is approximately 90% specific and sensitive.* In addition, histologic findings of Alzheimer disease differ mostly quantitatively, rather than qualitatively, from age-related changes. As a last resort, cerebral cortex biopsies can help establish a diagnosis of herpes simplex encephalitis, familial Alzheimer disease, and Creutzfeldt–Jakob disease or its variant.

Pathology

Compared to age-matched controls, brains of Alzheimer disease patients are even more atrophic. The cerebral atrophy in Alzheimer disease, although generalized, primarily affects the cortical association areas, such as the parietal–temporal junction, and the limbic system. It particularly strikes the hippocampus and prominently involves the locus ceruleus and olfactory nerve. The atrophy spares the cerebral regions governing motor, sensory, and visual functions, thus explaining the absence of paresis, sensory loss, and blindness in Alzheimer disease.

Cerebral atrophy naturally leads to compensatory dilation of the lateral and third ventricles. Of these, the temporal horns of the lateral ventricles expand the most. Nevertheless, in Alzheimer disease and most other illnesses that cause dementia, the anterior horns of the lateral ventricles maintain their concave (bowed inward) shape because of the indentation on their lateral border by the head of the preserved caudate nucleus (see Figs 20-2 and 20-18). The exception is Huntington disease, where atrophy of the head of the caudate nucleus permits the ventricle to expand laterally and assume a convex (bowed outward) shape (see Fig. 20-5).

On a histologic level, “plaques and tangles” remain the most conspicuous feature of Alzheimer disease. Although also present in normal aging and several other illnesses, in Alzheimer disease the plaques and tangles are more plentiful. Moreover, they do not distribute themselves randomly, but congregate, like the atrophy, in the cortex association areas, limbic system, and hippocampus.

The plaques, technically neuritic plaques, which are a form of senile plaques, consist of an amyloid core surrounded by abnormal axons and dendrites (neurites) that looks like a burned-out campfire. Up to 50% of the amyloid core contains an insoluble, 42-amino-acid peptide, amyloid beta-peptide (Aβ) (see later). Accumulation of Aβ is necessary, but alone is insufficient for the development of Alzheimer disease.

The tangles, neurofibrillary tangles, are also necessary but insufficient. They follow a somewhat different geographic distribution than plaques. They cluster within hippocampus neurons. The tangles appear as paired, periodic helical filaments within neurons and disrupt the normal cytoskeletal architecture. They consist mostly of hyperphosphorylated forms of tau protein, which is a microtubule binding protein that undergoes conformational changes. In other words, an abnormal intraneuronal protein – tau – aggregates in Alzheimer disease and contributes to the death of critical neurons. Although the concentration of plaques correlates with dementia, the correlation between neurofibrillary tangles and dementia is stronger. On the other hand, neurofibrillary tangles occur in other conditions, including progressive supranuclear palsy (PSP), frontotemporal dementia, and TBI.

Another histologic feature of Alzheimer disease is the loss of neurons in the frontal and temporal lobes. Neuron loss in the nucleus basalis of Meynert (also known as the substantia innominata), which is a group of large neurons located near the septal region beneath the globus pallidus (see Fig. 21-4), constitutes the most distinctive change. Their loss depletes cerebral acetylcholine (ACh: see later). Of all these histologic features, loss of neuron synapses correlates most closely with dementia.

Histologic examination of the majority of Alzheimer disease brains also reveals coexistent vascular disease. The reverse is also true: The brains of many VCI patients also show the histologic signs of Alzheimer disease. In other words, many cases of dementia have combinations of both pathologies.

Amyloid Deposits

Returning to the formation of Aβ, enzymes encoded on chromosome 21 cleave amyloid precursor protein (APP) to precipitate Aβ in the plaques (Fig. 7-5). Aβ differs from amyloid deposited in viscera as part of various systemic illnesses, such as multiple myeloma and amyloidosis. In Alzheimer disease, Aβ accumulates early and permanently in the cerebral cortex and vital subcortical regions.

FIGURE 7-5 The amyloid precursor protein (APP) consists of 770 amino acids. Three secretase enzymes (α-, β-, and γ-) cleave it into polypeptide fragments. In one pathway, α-secretase cleaves APP to form the polypeptide αAPP. Then γ-secretase cleaves αAPP into soluble, nontoxic polypeptides. In the other pathway, β-secretase cleaves APP into a different polypeptide, βAPP. Then γ-secretase cleaves βAPP to form the insoluble, toxic, 42-amino-acid polypeptide, Aβ.

Several lines of evidence have given rise to the amyloid cascade hypothesis or simply the amyloid hypothesis as the critical mechanism in Alzheimer disease. This hypothesis proposes that the enzymatic degradation of APP results in accumulation of Aβ, which causes inflammatory and oxidative cerebral damage. Evidence for this theory includes several powerful observations:

• All known genetic mutations associated with Alzheimer disease increase Aβ production (chromosomes 1, 14, 21) or Aβ aggregation (chromosome 19).

• The most powerful established genetic risk factor, which involves apolipoprotein-E (Apo-E), promotes Aβ deposition.

• Aβ is toxic in vitro probably because it binds to cerebral ACh receptors and poisons cerebral mitochondria.

• Accumulation of Aβ is a requirement for the development of Alzheimer disease.

• At least in some nonhuman studies, antibodies to Aβ reduce clinical and pathologic aspects of Alzheimer disease.

Biochemical Abnormalities

Under normal circumstances, neurons in the basal nucleus of Meynert synthesize ACh. Using the enzyme choline acetyltransferase (ChAT), these neurons convert acetylcoenzyme-A (acetyl-CoA) and choline to ACh:

Normally, neurons emanating from the basal nucleus of Meynert project upward to almost the entire cerebral cortex and the limbic system to provide cholinergic (i.e., ACh) innervation. A loss of neurons in the basal nucleus of Meynert characterizes Alzheimer disease. It leads to a marked reduction in ChAT activity, then cerebral cortex ACh concentrations, and finally cerebral cholinergic activity. As with the distribution of the macroscopic and microscopic changes in Alzheimer disease, ACh activity is particularly reduced in the cortical association areas and limbic system.

Alzheimer disease is also associated with reduced concentrations of other established or putative neurotransmitters: somatostatin, substance P, norepinephrine, vasopressin, and several other polypeptides. However, compared to the ACh loss, their concentrations are not decreased profoundly or consistently, and do not correlate with dementia.

The cholinergic hypothesis, drawn from these biochemical observations, postulates that reduced cholinergic activity causes the dementia of Alzheimer disease. In addition to the histologic and biochemical data, supporting evidence includes the finding that, even in normal individuals, blocking cerebral ACh receptors causes profound memory impairments. For example, an injection of scopolamine, which has central anticholinergic activity, induces a several-minute episode of Alzheimer-like cognitive impairment that can be reversed with physostigmine (Fig. 7-6). The cholinergic hypothesis led to the introduction of donepezil (Aricept) and other cholinesterase inhibitors in an attempt at preserving ACh activity by inactivating its metabolic enzyme, cholinesterase (see Fig. 7-6 and later).

FIGURE 7-6 Top, The enzyme choline acetyltransferase (ChAT) catalyzes the reaction of choline and acetyl-coenzyme A (ACoA) to form acetylcholine (ACh) in neurons of the central (CNS), peripheral (PNS), and autonomic nervous system. When released from its presynaptic neurons, ACh interacts with postsynaptic ACh receptors. Middle, However, various substances block ACh from interacting with its receptors. For example, scopolamine, which readily crosses the blood–brain barrier, blocks ACh–receptor interaction in the CNS. Likewise, atropine blocks ACh receptors, but predominantly those in the autonomic nervous system. (Unless its concentration is great, atropine does not cross the blood–brain barrier.) Bottom, Cholinesterase metabolizes ACh. Thus, enzyme degradation rather than reuptake terminates ACh activity. (In contrast, reuptake terminates most dopamine and serotonin activity.) Anticholinesterases or cholinesterase inhibitors block cholinesterase and preserve ACh concentrations. The most widely known application of this strategy is using donepezil (Aricept) and other cholinesterase inhibitors to preserve ACh activity in Alzheimer disease. Similarly, physostigmine, a powerful anticholinesterase medicine that can cross the blood–brain barrier, purportedly briefly corrects ACh deficits in tardive dyskinesia as well as Alzheimer disease (see Chapter 18). Physostigmine might also counteract excessive anticholinergic activity in tricyclic antidepressant overdose or reverse the effects of scopolamine or atropine. Using cholinesterase inhibitors is also applicable to PNS disorders. For example, edrophonium (Tensilon) and pyridostigmine (Mestinon) are anticholinesterases that restore neuromuscular junction ACh activity in myasthenia gravis (see Fig. 6-2). In the opposite situation, insecticides contain powerful anticholinesterases that create excessive ACh activity at neuromuscular junctions, which paralyzes insects by overstimulating muscle contractions.

Although the ChAT deficiency in Alzheimer disease is striking, it is not unique. Pronounced, widespread ChAT deficiencies are also present in the cortex of brains in trisomy 21, Parkinson disease, and DLB, but not in those of Huntington disease.

Risk Factors and Genetic Causes

Researchers have established several risk factors for Alzheimer disease. Living longer than 65 years is the most statistically powerful risk factor for Alzheimer disease because, beginning at that age, its incidence doubles every 5 years. Thus, the prevalence rises from 10% among individuals aged 65 years to almost 40% among individuals over 85 years.

Family history of Alzheimer disease is another well-established risk factor. Although most cases of Alzheimer disease occur sporadically, the disease develops in about 20% of patients’ offspring and 10% of second-degree relatives, but in only 5% of age-matched controls. Other risk factors include trisomy 21, several genetic mutations, and possessing Apo-E 3/4 or 4/4 allele pairs (see later). Studies have found other potential risk factors, but with influences that remain weak, inconsistent, or as yet unproven, such as myocardial infarction, elevated homocysteine levels, TBI, hypertension, hyperthyroidism, and exposure to aluminum.

Certain allele combinations of the gene coding for Apo-E, a cholesterol-carrying serum protein, confer substantial risk. Synthesized in the liver and brain, serum Apo-E binds to Aβ. Neuritic plaques accumulate the mixture. Chromosome 19 encodes the gene for Apo-E in three alleles: Apo-E2, Apo-E3, and Apo-E4. Everyone inherits one of three alleles (E2, E3, E4) from each parent, giving each person an allele pair (E2–E2, E2–E3, E2–E4, E3–E4, etc.). Approximately 10–20% of the population inherits E3–E4 or E4–E4, which are the pairs most closely associated with Alzheimer disease.

Having two E4 alleles (being homozygous for E4) – and, to a lesser degree, having one E4 allele (being heterozygous for E4) – significantly increases the risk of developing Alzheimer disease. Of individuals carrying no E4 alleles, only about 20% develop Alzheimer disease; of those carrying one E4 allele, 50% develop the disease; and of those carrying two E4 alleles, 90% develop it. Overall, more than 50% of Alzheimer disease patients carry one E4 allele. Not only does the E4 allele put the individual at risk for developing the disease, it also hastens the appearance of the symptoms. For example, compared to individuals carrying no E4 alleles, those carrying one E4 allele show Alzheimer disease symptoms 5–10 years earlier, and those with two E4 alleles show the symptoms 10–20 years earlier.

On the other hand, having one or even two E4 alleles is neither necessary nor sufficient for developing Alzheimer disease. The association is close, but not enough to be causal. Because E4 alleles remain a powerful risk factor and not a cause, neurologists refer to the Apo gene as a “susceptibility” gene. Physicians and some individuals might imagine that determining the Apo status would help diagnostically or prognostically, but the general neurologic consensus is that determining the Apo alleles provides little reliable or useful information, especially even compared to the clinical evaluation and other testing. Neurologists generally do not order Apo testing. However, patients learning that they carry Apo-E4 alleles show no significant short-term psychological risks.

Inheriting an Apo-E4 allele also serves as a marker for rapid progression from MCI to dementia in HIV disease and following severe TBI. However, the allele probably has little or no influence on the development of cognitive impairment in MS or Parkinson disease.

In contrast to these risk factors for Alzheimer disease, several factors in addition to cognitive reserve offer a decreased incidence or postponed onset of symptoms. Studies have shown that certain leisure activities – playing board games, reading, playing musical instruments, and ballroom dancing – provide some protection against dementia. Regular strenuous exercise, another nonpharmacologic intervention, also seems to provide some protection. Control of hypertension, lipidemia and cholesterol levels, and diabetes reduces the incidence of dementia, but probably because they reduce stroke-related cognitive impairment. Some studies have shown that certain genes may confer longevity and relative freedom from Alzheimer disease.

Treatment of Dementia

Physicians from time immemorial have attempted to enhance memory and other cognitive function in normal and overachieving as well as impaired individuals. They typically have prescribed medicines that neurologists call nootropics (Greek, nous, intellect; tropos, to turn). Aside from stimulants improving attentiveness and thus academic performance, purported nootropics have produced at most only modest improvements for limited periods.

In light of the plausibility of the cholinergic hypothesis and the finding that postsynaptic cholinergic receptors remain relatively intact, several widely prescribed nootropics aim at restoring ACh activity in Alzheimer disease patients. In attempting to replicate the strategy of administering a dopamine precursor, levodopa (L-dopa), to Parkinson disease patients, Alzheimer disease researchers administered ACh precursors, such as choline and lecithin (phosphatidyl choline), to drive the synthesis of ACh. Similarly, to reach the same end, they administered ACh agonists, such as arecoline, oxotremorine, acetyl-L-carnitine, and bethanechol. Whether given by intraventricular or traditional routes, none of these strategies produced a consistent, significant benefit.

A complementary strategy, similar to maintaining ACh neuromuscular junction activity in myasthenia (see Chapter 6), attempts to preserve or increase cerebral ACh concentration by reducing ACh metabolism by cholinesterases. In Alzheimer disease treatment, several commercially available cholinesterase inhibitors that penetrate the blood–brain barrier – donepezil, rivastigmine, and galantamine – produce modest, temporary (approximately 9–12-month) improvement in cognitive tests, “global evaluations,” and measurements of quality of life. They may either reduce certain troublesome symptoms, such as depression, psychosis, and anxiety, or make them amenable to psychotropics. The cholinesterase inhibitor, donepezil, reduces the risk of progression of dementia for as long as 1 year; however, by 36 months it has little or no effect. Cholinesterase inhibitors may also slow the progression of dementia in Parkinson disease and DLB, which are also characterized by an ACh deficit (see later), but not in the other neurodegenerative illnesses, MCI, pure VCI, TBI, or delirium.

Whatever their indication, cholinesterase inhibitors increase cholinergic (parasympathetic) activity – occasionally to the point of toxicity. Even routine doses increase intestinal activity and trigger unpleasant abdominal cramps. Patients have accidentally poisoned themselves by taking too many cholinesterase inhibitor pills or applying the medicated patches without removing expired ones. The overdoses superimposed delirium on dementia and caused all the physical manifestations of a choline crisis: nausea and vomiting; excessive salvation and sweating; bradycardia, hypotension, and lightheadedness. In extreme cases, overdose has led to respiratory depression, collapse, and convulsions.

Seeking a different approach, some therapeutic trials attempted to replenish other deficient presynaptic neurotransmitters, such as somatostatin and vasopressin. Despite their promise, these attempts were unsuccessful.

Another theory postulated that cholesterol-lowering medicines, commonly known as statins, would leach cholesterol from plaques and reduce the amyloid burden. Rigorous analysis showed that statin treatment failed to protect against, reverse, or even slow the progression of Alzheimer disease. On the other hand, statins reduce the risk of stroke and VCI, and thus may slow the progression of cognitive impairment.

Researchers initially expected that estrogen replacement therapy (ERT), which suppresses menopausal symptoms, would also reduce the risk or delay the onset of Alzheimer disease. However, women taking ERT still developed the disease at the same rate and followed the same or a more accelerated course.

Although reduced cerebral blood flow is a result, not a cause, of Alzheimer disease, researchers attempted to improve blood flow with cyclandelate (Cyclospasmol), a vasodilator. Studies found that the minimal improvement that followed this treatment was attributable to its antidepressant properties.

In an attempt to protect neurons, researchers administered an N-methyl-D-aspartate (NMDA) receptor antagonist, memantine (Namenda), with the expectation that it would block toxic glutamine excitatory neurotransmission. When given with donepezil or used alone, memantine produces modest improvement in memory and learning for several months in patients with moderate to severe Alzheimer disease. It also transiently suppresses agitation or aggression.

A completely different approach consisted of immunizations against amyloid. The expectation was that antibodies would attack and destroy amyloid plaques. Researchers first administered an antiamyloid vaccine to mice with an inherited Alzheimer-like illness and then to patients with Alzheimer disease and presymptomatic individuals destined to develop the disease because they were carrying mutations that doomed them to the illness. Although the vaccination program was successful in the mice, human volunteers derived no benefit or suffered inflammatory encephalitis. Looking toward a different method of reducing the amyloid burden, researchers attempted to interrupt the synthesis of Aβ by administering inhibitors of β–secretase or γ–secretase (see Fig. 7-5). However, a large clinical trial of a γ–secretase inhibitor exacerbated rather than helped the problem.

Studies have shown no benefit from a host of foodstuffs, additives, and complementary therapies, including tocopherol (vitamin E) and other antioxidants, gingko biloba, piracetam, acetyl-L-carnitine, folic acid, omega-3 fatty acid, and medium-chain triglycerides.

Trisomy 21

Almost all individuals with trisomy 21, if they live to 50 years, develop an Alzheimer-like dementia superimposed on their Intellectual Developmental Disorder. All their ancillary tests – CT, MRI, PET, and amyloid-binding studies – show Alzheimer-like changes. At autopsy, their brains show Alzheimer-like changes.

Even women who give birth to a child with trisomy 21 have a fivefold increase in Alzheimer disease. The striking relationship between trisomy 21 and Alzheimer disease led early on to the conclusion that having the extra chromosome 21 led to Alzheimer disease – not that the chromosome itself was abnormal.

Dementia with Lewy Bodies

DLB, previously called Lewy body disease or diffuse Lewy body disease, accounts for approximately 15% of cases of dementia. The preliminary DSM-5 includes it within Neurocognitive Disorder due to Lewy Body Disease.

Neurologists named DLB for its histologic signature: cortical spherical intracytoplasmic inclusions, Lewy bodies, composed of a circular, eosinophilic dense proteinaceous core surrounded by loose fibrils. The core contains mostly aggregates of α-synuclein – a 140-amino-acid protein encoded on chromosome 4 – and a less specific substance, ubiquitin. The concentration of the Lewy bodies correlates with the severity of dementia. (Lewy bodies are widely known as a marker for Parkinson disease, where they populate the basal ganglia rather than the cerebral cortex [see Chapter 18].)

Although tau accumulates in neurons in Alzheimer disease and α-synuclein accumulates in neurons in DLB, the two illnesses share several features. Both illnesses arise in older individuals and cause dementia. Also in both diseases, the brain concentration of ChAT and ACh is diminished and its deficit correlates with the degree of cognitive impairment; however, the loss of ChAT is greater in DLB than in Alzheimer disease. In DLB, as in Alzheimer disease, cholinesterase inhibitors stabilize cognitive function, although only for several months.

As if it were a hybrid, DLB also shares many features with Parkinson disease. The histology of both, of course, features Lewy bodies. Also, parkinsonism – a masked face, bradykinesia, rigidity, and gait impairment – although little or no tremor, characterizes DLB. However, in contrast to Parkinson disease, where cognitive impairment usually does not arise until 5 years into the illness, cognitive impairment, if not dementia, is characteristically present at the onset of DLB. In addition, PET shows widespread, profound cholinesterase deficiency in patients with DLB and Parkinson disease with dementia.

Visual hallucinations also plague DLB patients, but they occur at the onset as well as later in the course of their illness and correlate with Lewy bodies in the temporal lobes. In DLB, visions of people and animals and other hallucinations often appear so detailed and vivid that they provoke fear and precipitate confusion. As a classic symptom of DLB, an “impostor” replaces a close friend or relative (Capgras syndrome).

Another common symptom, which ultimately occurs in about 50% of DLB patients and often complicates Parkinson disease patients, is REM sleep behavior disorder (see Chapter 17). Normal individuals during REM sleep are rendered quadriparetic except for respiratory and ocular movement. In contrast, individuals with REM sleep behavior disorder, whether from DLB, Parkinson disease, or no apparent reason, resist the usual REM-induced paralysis and act as though they are participating in their dreams. For example, they make running, punching, and similar movements while dreaming. Long-acting benzodiazepines, such as clonazepam, suppress the REM sleep behavior disturbance in DLB disease as well as in its other causes.

DLB also characteristically causes sudden, unexpected changes in cognition, attentiveness, and alertness. These fluctuations in mental status may mimic episodes of delirium.

Physicians should be aware of several pitfalls in treating DLB patients. Although the illness’ extrapyramidal signs suggest Parkinson disease, L-dopa and similar Parkinson disease medicines provide little or no benefit in correcting these motor disturbances and, at the same time, often exacerbate the visual hallucinations. Another potential iatrogenic problem is that visual hallucinations might prompt a physician to administer dopamine-blocking antipsychotic agents; however, because DLB patients have a hypersensitivity, even small amounts of antipsychotic agents cause akinesia, board-like rigidity, and other exaggerated extrapyramidal signs.

Overall, DLB’s noncognitive aspects are so pronounced and distinctive that they define it. Neurologists usually diagnose DLB on the basis of three core features and two suggestive features:

Injuries

The frontal lobes contain the main centers for personality, emotions, and executive decisions. They also integrate various conventional cognitive functions, consider potential solutions, weigh probable outcomes, and initiate a response. Equally importantly, the frontal lobes also inhibit instinctive behaviors. Thus, individuals with frontal lobe damage from physical injury or disease characteristically display uninhibited physical, emotional, and behavioral disturbances.

Neuropsychologists and behavioral neurologists tend to describe at least three syndromes of frontal lobe dysfunction: dorsolateral, orbitofrontal, and mediofrontal. However, practicing neurologists rarely see these syndromes as discrete or readily diagnosable. After their examination, they rely on the MRI to confirm the presence and show location of frontal lobe damage.

Neurologists find several general manifestations of frontal lobe damage that vary and occur in different combinations. Patients are characteristically apathetic and indifferent to their surroundings, ongoing events, and underlying illness. They also have comparable cognitive slowness. Their impairments prevent them from making transitions, changing sets, and adopting alternate strategies. Patients also have slowed thinking (bradyphrenia), lack of emotions, and a paucity of speech that can range from reticence to silence (abulia). In addition, if an illness or injury damages their dominant frontal lobe’s language center, patients will have impaired verbal output and other signs of aphasia (see Chapter 8).

Their movements tend to be slow (bradykinetic), repetitive (perseverative), reduced, or absent (akinetic). Walking becomes awkward and uncertain (apraxic). Absence of voluntary movement can accompany an absence of speaking and expression (akinetic mutism). Viscous thinking and bradykinesia combine to cause psychomotor retardation.

Their impaired inhibitory systems allow flighty ideas, inappropriate comments, and unrestrained expression of sexual urges. In extreme cases, impaired inhibition causes bladder or bowel incontinence. Because patients cannot suppress a natural tendency to attend to new stimuli, they are easily distracted from their tasks. They may be so incapable of disregarding new stimuli that neurologists described them as “stimulus-bound.” For example, people entering a room, a soft noise, or an unrelated idea easily pulls their attention from an assigned task. Also, patients who have lost inhibition characteristically display a superficial, odd jocularity with uncontrollable, facetious laughter (witzelsucht).

Despite all its attendant neuropsychologic abnormalities, frontal lobe damage does not necessarily cause dementia. Patients with limited frontal lobe damage tend to retain memory, simple calculation ability, and visuospatial perception because these cognitive domains are either based largely in the parietal and temporal lobes or distributed throughout the cerebral cortex. Indeed, patients’ IQ tests or their MMSE often yield normal results. The Frontal Assessment Battery (see Dubois in References) and the MoCA, both bedside tests, are more reliable than the MMSE in detecting frontal lobe damage.

Slowly growing, especially nondominant frontal lesions may reach an enormous size before producing any signs of frontal lobe injury. At the onset, only subtle physical signs accompany these neuropsychologic abnormalities, but sooner or later, expanding frontal lobe lesions may cause pseudobulbar palsy, nonfluent aphasia, and frontal release reflexes (see later). Also, because of the olfactory nerves’ location on the undersurface of the frontal lobes, patients with frontal lobe injuries often have anosmia.

Commonly cited causes of bilateral frontal lobe damage include TBI, glioblastoma multiforme, metastatic tumors, metachromatic leukodystrophy, MS, ruptured anterior cerebral artery aneurysm, and infarction of both anterior cerebral arteries. In the abandoned frontal lobotomy, which physicians had introduced to control psychotic thought and behavior long before the first-generation antipsychotic agents, neurosurgeons injected sclerosing agents into the frontal lobe or severed its underlying large white-matter tracts (see Fig. 20-23). Patients who underwent the procedure showed less agitation, but usually at the expense of developing apathy, restricted spontaneous verbal output, indifference to social conventions, and impaired abstract reasoning.

In contrast to bilateral frontal lobe injury producing neuropsychologic impairments, modern-day surgical removal of the anterior, nondominant frontal lobe causes little, if any, impairment. For example, neurosurgeons routinely remove this “silent area” of the brain in cases of tumor, arteriovenous malformation, or seizure focus refractory to antiepileptic drugs (AEDs) (see Chapter 10).

Frontotemporal Dementia

Frontotemporal dementia, one of the frontotemporal lobar degenerations, consists of an insidious onset of dementia completely overshadowed by personality and behavioral disturbances. Occurring twice as frequently in men as in women, this illness has an average age of onset of 53 years and follows a fatal course lasting less than 4 years. Its preliminary DSM-5 equivalent is Frontotemporal Neurocognitive Disorder.

Major varieties of frontotemporal dementia include ones characterized by behavioral disturbances, nonfluent aphasia (see Chapter 8), and motor neuron signs (see Chapter 5). The behavioral variant, which is most important, reflects degeneration primarily of the frontal rather than the temporal lobes. As with other disorders resulting from frontal lobe degeneration, patients with the behavioral variant show a broad decline in affect and behavior. In fact, physicians may reasonably initially misdiagnose frontotemporal dementia as major depression, bipolar disorder, obsessive-compulsive disorder, or other psychiatric illnesses. Neurologic criteria for a “possible” diagnosis specifically require that patients show three of six disturbances:

A “probable” diagnosis requires only the addition of functional disability and compatible imaging studies (see later). A “definite” diagnosis requires histologic confirmation.

Notably, these criteria do not require the presence of dementia. From a practical viewpoint, patients have memory problems, but overall their cognitive impairments are neither specific nor pronounced. Routine cognitive assessment testing does not readily separate Alzheimer disease from frontotemporal dementia. However, astute clinicians will not confuse these two illnesses (Table 7-2).

TABLE 7-2 Features Distinguishing Alzheimer Disease and Frontotemporal Dementia

CT, computed tomography; MRI, magnetic resonance imaging.

Despite their impairments, patients with frontotemporal dementia characteristically retain their visuospatial ability – a function governed largely by the parietal lobes. For example, patients can copy a picture but cannot draw one from memory, i.e., they do not show constructional apraxia. Also, they do not lose their sense of direction, even in new surroundings.

Neuropathologists named DLB for its microscopic appearance, but they named frontotemporal dementia for its gross appearance: the frontal and anterior temporal lobes are atrophic, but the parietal and occipital lobes are preserved. Plaques and tangles are uncommon and ACh concentrations are normal – in marked contrast to Alzheimer disease.

Neuropathologists designate a minority of cases that have neurons containing argentophilic (silver-staining) inclusions (Pick bodies) as Pick disease. In other words, they consider Pick disease a histologic variant of frontotemporal dementia rather than a distinct illness. Most important, neuropathologists attribute frontotemporal dementia to an abnormality in tau metabolism. Thus, some neuropathologists, coining new terms, group Alzheimer disease, frontotemporal dementia, and perhaps PSP (see later) into tauopathies, and DLB and Parkinson disease into synucleinopathies.

Frontotemporal dementia may account for only 5–10% of all cases of dementia, but, with a mean age of onset of 53 years, it accounts for about 50% of individuals younger than 60 years. Many of them – 40% – have a family history of the same disease and they mostly follow an autosomal dominant pattern. Frontotemporal dementia is linked with a mutant gene on chromosome 17, which codes for tau.

PET often shows readily identifiable hypometabolism in frontal lobes but relatively normal metabolism in parietal and occipital lobes. Probably because ACh levels are normal, cholinesterase inhibitors provide no benefit for either its cognitive or behavioral impairments.

Progressive Supranuclear Palsy

Just as DLB represents a hybrid of Alzheimer and Parkinson diseases, PSP represents a hybrid of a dementia-producing illness and distinctive conjugate eye movement disorder (see Chapter 12). Preliminary DSM-5 nomenclature would include PSP as a Neurocognitive Disorder due to Another Medical Condition.

PSP patients, who show a slight male predominance, typically begin showing signs of their illness between 60 and 70 years. They inexorably (progressively) deteriorate over approximately 7 years. Like frontotemporal dementia patients, PSP patients generally show apathy, aberrant behavior, disinhibition, executive disability, reduced verbal output, and pseudobulbar palsy. Both groups of patients also share cognitive decline to the point of dementia.

PSP patients present with parkinsonism, except that they rarely have a tremor. They have predominantly axial rigidity that forces their head, neck, and entire spine to remain overly upright and unnaturally straight (Fig. 7-7). Their posture contrasts with the typical Parkinson disease patients’ flexed head and neck and kyphosis of the spine (see Fig. 18-9, A). In addition, their postural instability occurs at the onset of PSP and accounts for their falling, which is sometimes incapacitating or even fatal.

FIGURE 7-7 Axial rigidity and bradykinesia force progressive supranuclear palsy patients to hold themselves straight and walk slowly. They resemble Parkinson disease patients, but their erect posture differs from the flexed posture of Parkinson disease (see Fig. 18-9A).

Its pathognomonic feature, which may not appear until 3 years after the onset of parkinsonism, consists of patients’ losing their ability to look voluntarily in vertical directions and then laterally. After being unable to look upward or downward, they eventually lose lateral eye movement, and then their eyes stay fixed in a straight-ahead position. To circumvent the lack of supranuclear (cortical) input, neurologists can recruit the labyrinthine system and brainstem systems: They typically rock the patients’ head and neck up and down to elicit “doll’s eye” or oculocephalic vertical reflex movements. In PSP, this maneuver forces the eyes to move appropriately (Fig. 7-8). The limited voluntary vertical eye movement, but with the ability of the examiner to overcome it, constitutes the best clinical diagnostic test for PSP and separates it from other dementia-producing illnesses.

FIGURE 7-8 Left, Progressive supranuclear palsy patients typically have a scowl because of pseudobulbar-like continuous contractions of their facial muscles. Middle, This patient, who has characteristically lost his ability to look first in vertical then lateral directions, cannot comply with the examiner’s request to look downward. Right, However, when the examiner rocks the patient’s head back and forth (performs an oculocephalic maneuver), his eyes dip well below the meridian.

In PSP, the frontal cortex, basal ganglia, and upper brainstem undergo degeneration. PET also shows predominant frontal lobe hypometabolism, but not as distinctively as in frontotemporal dementia. In contrast to Alzheimer disease, where amyloid plaques accumulate, tau-containing neurofibrillary tangles accumulate in PSP. In other differences from Alzheimer disease patients, PSP patients do not carry particular Apo-E alleles and, despite an Alzheimer-like ACh deficit, they do not respond to medications that preserve ACh activity. As in DLB, levodopa replacement does not significantly correct the parkinsonism.

Vascular Cognitive Impairment

Also known among neurologists as “multi-infarct dementia” or “vascular dementia,” and psychiatrists as Vascular Neurocognitive Disorders according to the preliminary version of DSM-5, VCI is essentially the dementia that results from cerebral infarctions (strokes) or any other cerebral vascular disease (see Chapter 11). The disorder has consistent neuropsychologic characteristics. However, unlike Alzheimer disease, it rarely causes an isolated amnesia. In addition to having cognitive impairment, VCI patients may have aphasia, dyscalculia, anosognosia, or other neuropsychologic disorder depending on the location of underlying strokes. VCI’s primary distinction is that the underlying strokes also cause abnormal physical findings, such as hemiparesis, hemianopsia, dysarthria, ataxia, and pseudobulbar palsy. Gait impairment so regularly occurs that it places most cases of VCI into the category of subcortical dementia. In VCI – unlike in Alzheimer disease, DLB, and frontotemporal dementia – physical signs overshadow cognitive impairments. Finally, unlike those other dementia-producing illnesses, VCI typically follows a step-wise deterioration that presumably reflects a progressive accumulation of strokes.

Imaging studies usually confirm a clinical diagnosis of VCI. CT shows evidence of strokes if they are large enough. MRI, the more valuable test, shows periventricular white-matter changes, lacunes (0.5–1.5 cm. scars; see later), and large strokes. Although rarely necessary, PET shows multiple, almost random hypometabolic regions.

Strokes may lead to VCI by simply obliterating at least 50 grams of brain tissue, regardless of the extent or location of the destruction. Alternatively, small strokes may lead to VCI by striking strategic regions of the brain, particularly the limbic system. Another common mechanism consists of hypertension-induced multiple lacunes, predominantly in the subcortical white matter. These insults produce the histologic condition état lacunaire or Binswanger disease.

In a surprise finding, histologic studies in VCI have shown that the majority of patients with VCI have Alzheimer disease pathology. These studies indicate that most patients who seem to have VCI actually have a mixture of Alzheimer disease and VCI.

Among risk factors for VCI, pre-existing cognitive impairment – especially from Alzheimer disease – exerts the greatest influence. Risk factors for stroke are naturally risk factors for VCI (see Chapter 11). Even vascular disease in other organs, such as coronary artery disease, increases the risk for VCI. However, despite its importance in other circumstances, Apo-E4 is not a risk factor for VCI.

Cholinesterase inhibitors, according to some reports, retard the progression of VCI. However, their benefit might be attributable to their effect on the portion of the dementia that represents comorbid Alzheimer disease. Another therapeutic strategy is to assess and possibly treat VCI patients for depression, which is frequently comorbid.

Wernicke–Korsakoff Syndrome

Neurologists gather alcoholism-induced amnesia and other cognitive impairment accompanied by signs of central nervous system (CNS) and peripheral nervous system damage into the Wernicke–Korsakoff syndrome. This disorder should fall into the preliminary DSM-5 category of Substance-Induced Neurocognitive Disorder.

The cognitive impairment develops in proportion to the lifetime consumption of alcohol. It occurs in about 50% of all chronic alcoholics and characteristically begins with a global confusional state. However, alcoholism does not equally impair all cognitive domains. It mostly impairs short-term memory, abstract reasoning, and visual and psychomotor dexterity. In contrast, it impairs long-term memory and language function so little that, without formal testing, alcoholics sometimes appear to have normal intellect.

Wernicke–Korsakoff syndrome includes retrograde amnesia, but its hallmark is anterograde amnesia. By itself, amnesia – like aphasia and the frontal lobe syndrome – does not constitute dementia. If the amnesia worsens, however, it interferes with various memory-based cognitive functions, especially learning, and eventually evolves into an Alzheimer-like dementia. Contrary to classic descriptions, confabulation is usually absent or inconspicuous.

In its acute stages, Wernicke–Korsakoff syndrome includes combinations of ataxia and ocular motility abnormalities, including conjugate gaze paresis, abducens nerve paresis, and nystagmus. However, only a minority of patients display all these abnormalities. With alcoholism, with or without Wernicke–Korsakoff syndrome, patients develop a peripheral neuropathy and cerebellar atrophy. Because the cerebellar atrophy particularly affects the vermis (see Chapter 2), alcoholism leads to an ataxic gait (see Fig. 2-13).

CT and MRI may be normal or show cerebral and cerebellar atrophy. In acute Wernicke–Korsakoff syndrome, distinctive and potentially fatal petechial hemorrhages develop in the mamillary bodies and periaqueductal gray matter (see Fig. 18-2). The damage to these structures, which are elements of the limbic system (see Fig. 16-5), explains the amnesia. Also, because the periaqueductal gray matter is immediately adjacent to the nuclei of third and sixth cranial nerves and the medial longitudinal fasciculus, damage to this region explains the ocular motility abnormalities (see Chapters 4 and 12).

Wernicke–Korsakoff syndrome does not develop only in alcoholics. Similar clinical and pathologic changes have also occurred in nonalcoholic individuals who have undergone starvation, dialysis, chemotherapy, or gastric or bariatric surgery. On rare occasions, anorexia nervosa, prolonged vomiting, and self-induced fasting have also led to Wernicke–Korsakoff syndrome.

These observations and others have indicated that Wernicke–Korsakoff syndrome is not solely the result of alcohol toxicity. In fact, it probably results primarily from a nutritional deficiency of thiamine (vitamin B₁), an essential coenzyme in carbohydrate metabolism. Thiamine administration preventing or even partially reversing Wernicke–Korsakoff syndrome confirms this probability. Most neurologists immediately inject thiamine in equivocal as well as clear-cut cases. Although thiamine treatment may reverse acute Wernicke–Korsakoff syndrome, only 25% of patients recover from chronic alcohol-induced dementia.

Medication-Induced Dementia

Medication-induced cognitive impairment remains one of the few commonly occurring, correctable causes of dementia or delirium. Neurologists themselves prescribe many medicines – opioids, AEDs, antiparkinson agents, steroids, and psychotropics – that routinely produce cognitive impairment and other neuropsychologic side effects. Even medicated eye drops may seep into the systemic circulation and cause symptoms. Also, seemingly innocuous over-the-counter medicines, such as St. John’s wort, may themselves produce a side effect or cause an adverse medication interaction.

Normal-Pressure Hydrocephalus

NPH is a quintessential correctable cause of dementia. Most cases of NPH are idiopathic, but meningitis or subarachnoid hemorrhage often precedes it. In those cases, inflammatory material or blood probably clogs the arachnoid villi overlying the brain and impairs reabsorption of CSF. As CSF production continues despite inadequate reabsorption, excessive CSF accumulates in the ventricles and expands them to the point of producing hydrocephalus (Fig. 7-9).

FIGURE 7-9 A and B, Ventricular expansion, as in normal-pressure hydrocephalus, results in compression of brain parenchyma and stretching of the corticospinal and other tracts of the internal capsule (see Fig. 18-1). Gait impairment (apraxia) and urinary incontinence are prominent normal-pressure hydrocephalus symptoms because the ventricular expansion stretches and most disrupts the tracts that supply the legs and the voluntary muscles of the bladder. C, Also, internal pressure on the frontal lobes leads to cognitive impairment and psychomotor retardation.

NPH is essentially a syndrome of three elements: dementia, urinary incontinence, and gait apraxia. The dementia conforms to the subcortical classification because it entails slowing of thought and gait, but spares language skills. Although the dementia may bring the patient to a psychiatrist’s attention, gait apraxia is generally the initial, most consistent, and most prominent feature of NPH (Fig. 7-10). It is also the first to improve with treatment (see later). Urinary incontinence consists of urgency and frequency that progress to incontinence, and it also improves with treatment. The physical features of NPH easily separate it from Alzheimer disease and other dementia-producing illnesses.

FIGURE 7-10 Gait apraxia, the hallmark of normal-pressure hydrocephalus, appears in several aspects of gait testing. Patients with gait apraxia fail to alternate their leg movements and do not shift their weight to their forward foot. They tend to pick up the same leg twice and attempt to elevate their weight-bearing foot. When their weight remains on the foot that they attempt to raise, that foot has a tremor and appears to be stuck or “magnetized” to the floor. Gait apraxia is particularly evident when patients have a magnetic gait when they start a turn and then require multiple steps to complete 180°. Despite being unable to walk, they can typically step over a stick because their stepping reflex is relatively preserved.

In NPH, CT and MRI show ventricular dilation, particularly of the temporal horns (see Figs 20-7 and 20-19), and sometimes signs of CSF reabsorption across ventricular surfaces. They show minimal or no cerebral atrophy. Nevertheless, diagnosing NPH exclusively by CT and MRI is unreliable because the findings are nonspecific, particularly because they resemble cerebral atrophy with resultant hydrocephalus (hydrocephalus ex vacuo, see Fig. 20-3). The CSF pressure and its protein and glucose concentrations are normal.

One worthwhile test is simply to withdraw large volumes (30–60 mL) of CSF by LP or to perform a series of three LPs. Following the removal of large volumes of CSF, which presumably reduces hydrocephalus, improvement in the patient’s gait – not necessarily the dementia – indicates NPH and predicts a benefit from permanent CSF drainage. A negative test, however, does not preclude the diagnosis.

NPH can be relieved by a neurosurgeon inserting a shunt into a lateral ventricle to drain CSF into the chest or abdominal cavity. However, a clinically beneficial response occurs inconsistently and neurosurgical complications, which can be devastating, occur in up to 30% of cases.

Neurosyphilis

Caused by persistent Treponema pallidum infection, neurosyphilis had been largely of historic interest until the start of the acquired immunodeficiency syndrome (AIDS) epidemic. Not only do most cases of syphilis now occur in HIV-infected patients, syphilis infections follow an unusually aggressive course in them because they lack the immunologic capacity to fight it.

Neurologists may care for patients with acute syphilitic meningitis, which causes the usual symptoms and signs of meningitis, such as headache, fever, and nuchal rigidity. Alternatively, they might care for patients with meningovascular syphilis, which causes stroke-like insults to the spinal cord or brain.

Both neurologists and psychiatrists encounter patients with syphilis if the infection has spread to the substance of the CNS. Neuropathologists call an infection of either brain or spinal cord tissue “parenchymatous syphilis,” an infection of the brain “general paresis,” and the spinal cord “tabes dorsalis” (see Chapter 2).

General paresis, the brain infection, initially causes the insidious onset of nonspecific cognitive impairments and personality changes. If the infection remains untreated, patients develop dementia, hallucinations, and disordered thinking. However, delusions of grandeur, despite their notoriety, rarely arise. The cognitive impairments are often accompanied by any of a wide variety of physical abnormalities, including dysarthria, tremors, Argyll Robertson pupils (see Chapter 12), or loss of hearing or vision.

Imaging studies do not help because they reveal only nonspecific cerebral atrophy, although perhaps mostly of the frontal lobe. The screening test for syphilis is the rapid plasma reagin (RPR) serologic test; however, it is neither sufficiently sensitive nor specific for neurosyphilis. Only about 85% of neurosyphilis patients have a positive result. False-negative results, which are common, stem from naturally occurring resolution of serologic abnormalities; prior, sometimes inadequate, treatment; or HIV-induced immunologic impairment. False-positive results, also common, are usually attributable to old age, addiction, the antiphospholipid syndrome, and other autoimmune diseases (the “four As”) – all “biologic false-positives.”

The treponemal serologic tests, the fluorescent treponemal antibody absorption (FTA-ABS) and the treponemal microhemagglutination assay (MHA-TP), are more sensitive and more specific than the RPR. They yield positive results in more than 95% of neurosyphilis cases. Moreover, while other spirochete infections may produce false-positive FTA-ABS and MHA-TP test results, misleading results are otherwise exceedingly rare in syphilis. When evaluating a patient for neurosyphilis in whom the RPR test is negative, neurologists order an FTA-ABS or MHA-TP test.

Neurologists have patients undergo a LP for CSF testing if they have clinical presentation consistent with neurosyphilis and either a positive treponemal test or HIV infection. The Venereal Disease Research Laboratory (VDRL) test is the best for CSF testing. In about 60% of neurosyphilis cases, the CSF contains an elevated protein concentration (45–100 mg/dl) and a lymphocytic pleocytosis (5–200 cells/ml). A positive CSF VDRL result provides a generally accepted confirmation of neurosyphilis. On the other hand, in as many as 40% of cases, the CSF VDRL result is false-negative. Physicians can nevertheless diagnosies neurosyphilis and institute treatment relying on the clinical presentation and other aspects of the CSF profile.

Subacute Sclerosing Panencephalitis

SSPE is a rare, predominantly childhood-onset neurologic illness that probably results from a latent or mutant measles (rubeola) virus infection of neurons. Alternatively, the body’s aberrant response to this infection causes the illness. About 85% of patients develop SSPE at a mean of 12 years, but 15% develop it as adults. In most children and adolescents, routine measles precedes SSPE by about 6 years. Less than 10% of them had received a measles vaccination in childhood. In adults, measles precedes SSPE by about 20 years.

Symptoms and signs gradually arise. Early manifestations include nonspecific poor school work, behavioral disturbances, restlessness, and personality changes. Over weeks, cognition deteriorates into dementia and a weakness in one limb evolves into complete bodily paralysis. Patients may have partial or generalized seizures, but the hallmark of SSPE is myoclonus (see Chapter 18).

After lingering in a state of akinetic mutism, most patients succumb in 1–2 years and 95% within 5 years. Although antiviral treatment may slow or arrest its course, survivors usually remain in a vegetative state.

Clinicians can confirm a diagnosis of SSPE by finding an elevated CSF measles antibody titer. An EEG is also diagnostically helpful: It shows periodic sharp-wave complexes or a burst suppression pattern (see Fig. 10-6). (The EEG patterns in Creutzfeldt–Jakob disease and SSPE are similar, but their demography, clinical picture, and histology are entirely different.) Histologic examinations in SSPE reveal intranuclear eosinophilic inclusions (Cowdry bodies). By way of contrast, Lewy bodies are intracytoplasmic eosinophilic inclusions.

Creutzfeldt–Jakob and Related Diseases

Creutzfeldt–Jakob disease causes a similar triad of dementia, myoclonus, and periodic EEG patterns. Compared to Alzheimer disease, Creutzfeldt–Jakob disease appears at a younger age (50–64 years) and causes death more rapidly (in about 6 months). The preliminary DSM-5 includes Creutzfeldt–Jakob disease as Neurocognitive Disorder due to Prion Disease (see below).

Although the dementia of Creutzfeldt–Jakob disease lacks specific qualities, myoclonus almost always accompanies it at some time during the course of the illness. In addition, patients frequently have pyramidal, extrapyramidal, or cerebellar signs. Special laboratory tests and cerebral histology can confirm a clinical diagnosis.

While researchers cannot transmit Alzheimer disease, DLB, or VCI from patients to animals, they can transmit Creutzfeldt–Jakob disease to primates by inoculating their brains with brain tissue from Creutzfeldt–Jakob patients. Transmitting the illness to laboratory animals demonstrates that the illness is infectious and that interspecies transmission can occur. Although most cases have been sporadic, accidents involving corneal transplantation, intracerebral EEG electrodes, and neurosurgery specimens have transmitted the disease between humans, i.e., intraspecies transmission. For example, in a well-known tragedy, growth hormone extracted from human cadaver pituitary glands once transmitted the illness to a group of children undergoing treatment for pituitary insufficiency. Although researchers have deciphered the pathophysiology, neurologists cannot offer effective treatment.

Individuals with this disorder on a familial basis (Gerstmann–Straüssler–Scheinker [GSS]) disease, who comprise about 15% of the total, follow an autosomal dominant pattern and have an earlier age of onset. GSS patients presumably have a genetic susceptibility due to a mutation on the PrP gene (see later) situated on chromosome 20.

Variant Creutzfeldt–Jakob Disease

An alarm arose in the 1990s when many British citizens succumbed to the human counterpart of BSE, variant Creutzfeldt–Jakob disease (vCJD). Their illness probably represented an interspecies transfer of a prion illness. Victims, who were usually young adults (mean age 27 years), developed psychiatric disturbances, then painful paresthesias, and lastly neurologic dysfunction. The symptoms that appeared for the first 4 months consisted of dysphoria, withdrawal, and anxiety. Then more substantial disturbances – memory impairment, inattention, aggression, and disordered thinking – replaced them. Dementia, accompanied in many cases by myoclonus and decorticate posture, eventually supervened. Victims died after an approximately 14-month course.

Physicians should note two aspects of vCJD. It was one of the causes of dementia in adolescents and young adults (see Box 7-2). Its initial symptoms were largely psychiatric and unaccompanied by objective physical neurologic correlates.

About 200 individuals – almost all of them British citizens, visitors, or individuals who ate meat exported from Britain – died. A widespread slaughter of infected and potentially infected cattle ended the epidemics of both BSE and vCJD.

The EEG in vCJD shows nonspecific slowing rather than the characteristic periodic pattern of Creutzfeldt–Jakob disease. As in Creutzfeldt–Jakob disease, the MRI has characteristic abnormalities. Pharyngeal tonsil biopsy tissue in vCJD cases contains evidence of prion infection. Genetic testing found at least one gene that was a risk factor for vCJD.

Several conditions mimic Creutzfeldt–Jakob disease and vCJD. Lithium or bismuth intoxication or thyroid (Hashimoto) encephalopathy may produce myoclonus with dementia; however, these conditions usually cause more of a delirium than dementia, and all are readily diagnosable with specific blood tests. Paraneoplastic syndromes might also produce wasting, myoclonus, ataxia, and dementia (see Chapter 19).

Lyme Disease

Acute Lyme disease (neuroborreliosis), which involves the nervous system in less than 15% of cases, may cause facial palsy (cranial neuritis), headache, peripheral neuropathy or radiculopathy, lymphocytic meningitis, or encephalitis. With an acute CNS infection, patients may be delirious, but their serum and CSF tests are usually positive. The typical CSF profile consists of lymphocytic pleocytosis, elevated protein concentration, reduced glucose concentration, and Lyme antibodies.

A standard 2–4-week course of antibiotics cures almost every patient with an acute CNS infection. However, despite thorough treatment and resolution of CSF and serologic abnormalities, approximately 15% of patients, whom physicians label as having “chronic Lyme disease,” remain with numerous and variable symptoms, particularly muscle and joint pain, sleep disturbances, fatigue, inattention, memory impairment, and depressed mood. Patients, much more often than physicians, attribute their symptoms to persistent infection.

Studies have shown that many patients with chronic Lyme disease do not have a persistently positive serum Lyme titer. Even if their titer were persistently positive, the persistence would be analogous to lifelong abnormal serologies after successful syphilis treatment. Moreover, when Lyme tests are positive, the titers do not correlate with memory impairments. Confusing matters somewhat, because the infectious agent, Borrelia burgdorferi, is a spirochete as in syphilis, serum FTA-ABS and VDRL tests may turn positive in Lyme disease. Chronic Lyme disease patients often report that continual, multiple antibiotic or other nontraditional treatments keep their symptoms at bay, but large-scale studies do not support such claims. Nevertheless, the source of chronic Lyme symptoms remains enigmatic. Some symptoms fall into the realm of depression or chronic fatigue syndrome (see Chapter 6).

Human Immunodeficiency Virus-Associated Dementia

After a long evolution, current terminology among neurologists recognizes HIV-associated dementia (HAD) and its less severe and less extensive form, HIV-associated neurocognitive disorder (HAND). These terms would translate in preliminary DSM-5 to Neurocognitive Disorder due to HIV Infection. Medical advances have reduced the prevalence of HAD to 2% among HIV patients; however, HAND has a prevalence of 50%.

HIV primarily infects macrophages and microglia rather than neurons. The infection involves the subcortical as well as cortical structures. The duration of HIV infection and the deterioration of uncomplicated HIV infection to AIDS correlate most closely with the onset of HAD. Other risk factors for HAD are the nadir CD₄ count, advanced age, Apo-E4 alleles, anemia, low platelet count, substance abuse, TBI, and coinfection with hepatitis C, and depression.

In untreated patients, low CD₄ counts (usually below 200 cells/mm³) and high plasma viral loads also correlate with the onset of HAD. However, in HIV patients receiving antiretroviral medications, HAD may complicate their illness without the usual markers of susceptibility. In other words, occasionally HIV patients develop HAD despite relatively high CD₄ counts and low plasma and CSF viral loads. As a practical matter, if an HIV patient receiving antiretroviral therapy (ART) shows signs of HAD or HAND, physicians should check for the patient’s compliance with the medication regimen and be sure that all components of the regimen cross the blood–brain barrier.

Characteristics

Neurologists, like psychiatrists, initially diagnose delirium when patients have depressed or otherwise altered levels of consciousness, disorientation, and inattention – usually in the context of a medical illness or intoxication. Patients are typically amnestic and beset by perceptual disorders. They usually have autonomic system hyperactivity. However, some patients exhibit a hyperactive and hypervigilant state with fixed, undivided attention. Depending on the underlying illness, seizures may complicate the condition.

Symptoms arise over several hours to several days and then fluctuate hourly to daily. They usually resolve with successful treatment of the underlying medical problem. However, improvement occasionally lags (Fig. 7-11).

FIGURE 7-11 A distressing clinical situation occurs when patients deteriorate – become confused, lethargic, and agitated – after apparent correction of certain metabolic abnormalities. A, In cases of uremia or hyperglycemia, the brain and serum contain an approximately equal concentration of solute (dots). B, Overly vigorous dialysis or insulin administration clears solute more rapidly from the serum than the brain, leaving solute concentration in the brain much greater than in the serum. The concentration gradient causes free water to move into the brain, which produces cerebral edema.

When delirium and dementia coexist compared to when delirium occurs alone, the cognitive impairments are essentially inextricable. The MMSE is not a good test for delirium. Delirium in children and adolescents typically causes sleep disturbances and disorientation. In the majority of them, delirium also causes inattention, short-term amnesia, and agitation.

Some signs allow a bedside diagnosis of a specific underlying illness. For example, patients with Wernicke–Korsakoff syndrome typically have oculomotor palsies, nystagmus, ataxia, and polyneuropathy. Those with hepatic or uremic encephalopathy have asterixis (Fig. 7-12). Those with uremia, penicillin intoxication, meperidine (Demerol) treatment, and several other metabolic encephalopathies have myoclonus. Narcotic or barbiturate intoxication causes constricted pupils, but amphetamine, atropine, or sympathomimetic drug intoxication causes dilated pupils.

FIGURE 7-12 Neurologists elicit asterixis by having patients extend their arms and hands, as though they were stopping traffic. Their hands intermittently quickly fall forward and slowly return, as though waving goodbye.

EEG typically shows background slowing and disorganization (see Chapter 10); however, numerous conditions cause the same alterations. Some EEG findings suggest a specific etiology. For example, triphasic waves often indicate hepatic or uremic encephalopathy (see Fig. 10-5). Neurologists often attribute the EEG changes, as well as the patient’s depressed level of consciousness, to dysfunction of the reticular activating system. CT and MRI are usually normal, but they frequently show cerebral atrophy because of age-related atrophy or comorbid dementia-producing illness. Neurologists routinely order a CT or MRI to exclude a structural lesion as either a cause or complication of delirium. For example, they might order a CT to exclude an acute subdural hematoma in an alcoholic patient.

Most patients recover from delirium if the underlying illness responds to treatment. However, sometimes, as in anoxic encephalopathy, patients are left with permanent cognitive impairment. In the special case of central pontine myelinolysis, which some neurologists call the osmotic demyelination syndrome, physicians correct hyponatremia too rapidly – according to the dominant theory. Vulnerable patients, such as alcoholics with malnutrition, liver transplant recipients, and pregnant women with hyperemesis, lose myelin in their pons and are often left with permanent nystagmus, quadriparesis, and ataxia.

Risk Factors

Dementia represents the most powerful and most common risk factor for delirium. It may also explain why patients’ confusion sometimes persists – perhaps indefinitely – after medical treatment has corrected the underlying disorder. In actuality, delirium in a patient with dementia often precedes accelerated cognitive decline or imminent death.

In general, brain damage from any cause, including congenital injuries (cerebral palsy) and TBI, as well as Alzheimer disease, is a risk factor for delirium. An immature as well as a damaged brain leaves young children especially susceptible.

Hearing and visual impairments are also risk factors. Not only do these sensory deprivations frequently coexist with dementia in the elderly, they intensify the symptoms. As survivors of torture attest, sensory deprivation even in healthy young adults may cause disturbances akin to delirium.

Causes

Innumerable disorders, alone or in combination, may cause delirium; however, only a few account for the majority of cases in acute care hospitals and nursing homes (Box 7-4). Medicines are a frequently occurring, inapparent cause of delirium. Medicines administered in a standard, small dose, but given to a previously unexposed patient may have this unintended effect. Medicine-related problems also include the build-up of toxic concentrations because of inadequate hepatic metabolism or renal clearance, drug–drug interactions, or absorption of ocular or topical medicines. Ironically, medicines for psychiatric and neurologic disorders – anticholinergics, AEDs, antiparkinson agents, opioids, and serotonin agents – readily cross the blood–brain barrier and produce a delirium. In a surprising and paradoxical example, intramuscular injections of olanzapine administered for schizophrenia may produce confusion, agitation, anxiety, sedation, and more severely depressed levels of consciousness rather than calming the patient. Researchers have labeled this reaction the post-injection delirium/sedation syndrome and attribute it to the medicine seeping into the vasculature.

Another consideration is medicine withdrawal. Unlike the depressed sensorium typically associated with delirium, withdrawal from benzodiazepines, opioids, or nicotine may cause agitated delirium. In addition, withdrawal from alcohol, barbiturates, and benzodiazepines – but not nicotine – routinely causes seizures.

General Treatments

Even before arriving at an exact diagnosis or instituting specific treatment, physicians must ascertain that the patient has adequate cerebral oxygen, blood glucose, fluid and electrolytes, nutrition, and other necessities. Physicians must control pain with narcotics if indicated, but otherwise reduce or eliminate psychoactive drugs. Other preliminary measures consist of providing orientation clues, such as illumination, clocks, and calendars.

Antipsychotics can reduce dangerous and exhausting activity, hallucinations, and disordered thinking. Physicians should hesitate before prescribing antipsychotics or benzodiazepines to avoid respiratory depression. Sometimes physicians can calm a dangerously disruptive patient by restoring a missing substance or providing a reasonable facsimile, such as methadone, a nicotine patch, or even, in emergency, an alcoholic beverage.

Hepatic Encephalopathy

A particularly interesting and frequently occurring variety of delirium is hepatic encephalopathy. With hepatic insufficiency, mental function and consciousness steadily decline. Mild confusion with either lethargy or, less frequently, agitation may precede coma and overtly abnormal liver function tests. In classic cases, the neurologic examination demonstrates asterixis and the EEG shows triphasic waves.

Neurologists traditionally attribute hepatic encephalopathy to an elevated serum concentration of ammonia (NH₃). This mechanism occurs in the common scenario of gastrointestinal bleeding or high-protein meals precipitating hepatic encephalopathy in patients with cirrhosis. In these situations cirrhosis-induced portal hypertension shunts NH₃ released from protein in blood or food directly into the systemic circulation. Because NH₃ is a small and nonionic (uncharged) molecule, it readily penetrates the blood–brain barrier. As a treatment of hepatic encephalopathy, physicians often attempt to convert ammonia (NH₃) to ammonium (NH₄⁺), which is ionic and unable to penetrate the blood–brain barrier.

An alternative explanation for hepatic encephalopathy is that production of false neurotransmitters binds to benzodiazepine-gamma-aminobutyric acid (GABA) receptors and increases GABA activity. Thus, giving flumazenil, a benzodiazepine antagonist that interferes with benzodiazepine-GABA receptors and carries some risk of precipitating seizures, temporarily reduces hepatic encephalopathy symptoms.