Textbook of Psychiatry/Dementia, Delirium, and Psychiatric Symptoms Secondary to General Medical Conditions

In this chapter, we consider three related types of medical psychiatric disorders, usually accompanied by behavioral abnormalities: dementia, delirium, and neurobehavioral disorders due to general medical conditions. The common factor in these admittedly diverse conditions is a pathological alteration of brain structure and/or function, leading to abnormalities in cognition, affect, perception, or behavior. In the older U.S. literature, the term "organic brain syndrome" was often used to distinguish these conditions from so-called functional psychiatric disorders, such as schizophrenia or major depression. Indeed, the "organic" designation is retained in the ICD-10 classification (ICD-10, 1993). In our view, however, the terms "organic" and "functional" suggest a false dichotomy. As we have learned more about the pathophysiology of common psychiatric disorders, such as schizophrenia or depression, the conceptual demarcation between these conditions and those discussed in the present chapter has become less distinct. For example, decreased metabolic function in frontal brain regions may be observed in both dementia and major depression, though the course and prognosis of these conditions differ markedly. Similarly, abnormalities in the cholinergic system may be present in both Alzheimer’s Disease and schizophrenia (Raedler et al. 2007), notwithstanding the many differences between these disorders. Advanced neuroimaging techniques, genetic studies, as well as abnormal neurobiologic function in several animal models suggest receptor and circuit disturbances, even in the absence of traditional neurological abnormalities such as stroke or tumor. For all these reasons, we generally avoid the term "organic" in this chapter, but do use it when a particular study, author, or context justifies it.

The term "cognitive disorder" is often used to encompass delirium, dementia, and related conditions. This term appropriately emphasizes that a disturbance in memory, language, or attention is usually a cardinal feature of these disorders. However, the term "cognitive disorder" is far from ideal, since other aspects of consciousness, mood, and behavior may be strikingly abnormal in delirium, dementia, and related conditions. For example, the patient with frontal lobe dementia may show marked behavioral disinhibition, while the patient with Parkinson’s Disease and dementia may show signs of major depression. The disorders discussed in this chapter are seen in many health-care environments, and are by no means confined to psychiatric settings. For example, between 11-16% of inpatients on general medical units may experience delirium at some time during their admission (Levkoff et al. 1991). In skilled nursing facilities, at least 14 % of residents may suffer from some form of dementia (Sabbagh et al. 2003), with some studies finding that more than 50% of nursing home beds are occupied by patients with Alzheimer’s Disease (Sadock & Sadock, 2007, p. 329). And while there are no reliable prevalence statistics for psychiatric symptoms due to general medical conditions (GMCs), these disorders appear to be common in emergency department (ED) settings, where they often go undiagnosed. Indeed, in one study (Tintinalli et al. 1994) the chart was documented "medically clear" in 80% of ED patients in whom medical disease should have been identified. Finally, a word about diagnostic systems: in most respects, there are more similarities than differences between the DSM-IV and ICD-10 classifications of the disorders discussed in this chapter; indeed, our discussion emphasizes common features rather than the specific criteria set forth in these two systems. However, when significant differences are clinically relevant, we will note them.

Phenomenology (Characteristic Features of the Dementias)
Dementia may be broadly defined as a progressive, acquired impairment of cognitive function sufficient to cause functional decline, and occurring in a relatively normal ("clear") level of consciousness; i.e., in the absence of delirium (Sadock & Sadock, 2007; Apostolova & Cummings, 2008). We shall see, however, that there are some notable exceptions to this generalization, and that it is often more useful to define specific types of dementia. Global impairment of the intellect is a cardinal feature of dementia. More specifically, most dementia syndromes demonstrating the following neurobehavioral deficits:
 * Memory impairment (either impaired ability to learn new information, or to recall previous information), usually evident for at least 6 months
 * Deterioration in judgment, planning, and organizing (e.g., impaired shopping, cooking, handling money)
 * Absence of "clouding of consciousness" for a period long enough to demonstrate decline in memory
 * Decline in emotional control or motivation; or a change in social behavior (e.g., emotional lability, irritability, apathy, loss of social graces). DSM-IV specifically emphasizes a significant impairment in social and/or occupational functioning, as a result of the aforementioned deficits
 * DSM-IV emphasizes one or more of the following: aphasia (language disturbance), apraxia (impaired ability to carry out motor activity despite intact motor function), agnosia (failure to recognize objects despite normal sensory function); and disturbance in executive functioning (planning, organizing, sequencing, abstracting). In partial contrast, ICD-10 regards these as essentially supportive findings for diagnosis of dementia.

The epidemiology, clinical features, and pathogenesis of dementia vary considerably, depending on the subtype; for example, dementia of the Alzheimer type (DAT), Vascular Dementia, Lewy Body Dementia, etc. Nevertheless, it is common to encounter elderly patients in the clinical or nursing home setting who carry only the syndromic diagnosis of "dementia" (Jacobson et al. 2007). It is worth noting that not all definitions of dementia require memory impairment as a diagnostic criterion; indeed, some patients with frontotemporal dementia (FTD) may be severely affected with behavioral disturbances before memory impairment is prominent (Jacobson et al. 2007). Dementia must be distinguished from so-called mild cognitive impairment (MCI), which appears to represent an intermediate stage between normal aging and dementia (Apostolova & Cummings, 2008). Unlike those with dementia, MCI patients do not show significant impairment in activities of daily living.

Epidemiology of the Dementias
Dementia of some type may afflict as many as 28 million individuals world-wide, with direct costs for care estimated at 156 billion U.S. dollars (Wimo et al. 2006). Of the total number of demented individuals worldwide, the largest proportion (5.2 million, or 18.5%) lives in China (Wimo et al. 2006). If one groups all dementias together, the estimated prevalence is about 5% in the general population older than age 65, and 30% in those older than age 85 (Sadock and Sadock, 2007 p. 329). Findings on racial variations in dementia are somewhat equivocal, but most studies have reported higher frequencies of dementia among nonwhite persons (Husaini et al. 2003). Disproportionately high rates of dementia among African-Americans may be due, in part, to a higher prevalence of both hypertension and stroke among elderly African-Americans. Women generally have higher rates of dementia than men, largely because women live longer (Husaini et al. 2003). However, vascular dementia appears to be more common in men. Dementia of the Alzheimer’s Type (DAT, "Alzheimer’s Disease") is by far the most common type of dementia, making up roughly 35%-60% of cases worldwide (Mendez & Cummings, 2003; Sadock and Sadock, 2007, p. 329). The wide range of these figures is due in part to some controversy over the classification of Lewy Body Dementia (LBD); i.e., if LBD is considered a variant form of DAT (Sadock and Sadock, 2007, p. 329), the prevalence figure for DAT tends toward the higher end of the range. Many geriatric psychiatrists consider LBD to be the second most prevalent dementia subtype ("tied" with mixed vascular dementia/DAT), with a prevalence of about 15%. About 10% of dementias are said to be represent pure vascular dementia, while another 5% represent fronto-temporal dementia (Mendez and Cummings, 2003; Jacobson et al. 2007). Some data suggest that the DAT/vascular dementia ratio is comparatively higher in South America and lower in Asia (Lopes & Bottino, 2002), though the reasons for these trends are not clear. Miscellaneous causes of dementia—including cases due to Huntington’s Disease, Creutzfeld-Jakob Disease, Parkinson’s, HIV infection, and other conditions—probably constitute fewer than 5% of the total. That said, there is a paucity of autopsy-based studies of dementia prevalence, which would presumably be more accurate than those based on clinical diagnosis alone. In one of the few such studies (Fu et al. 2004), 202 demented patients underwent brain-only autopsies, and the following types of dementia were found: 129 (63.8%) cases showed changes of severe Alzheimer disease; 21 (10.4%) showed combined neuropathologic abnormalities (Alzheimer disease plus another type of lesion, such as significant ischemic infarcts or diffuse Lewy body disease), 12 (5.9%) cases of relatively pure ischemic vascular dementia, 13 (6.4%) cases of diffuse Lewy body disease, and 8 (4.0%) cases of frontotemporal dementia. The remaining 19 (9.4%) patients showed various neuropathologic diagnoses, including normal pressure hydrocephalus and progressive supranuclear palsy. Notably, the authors concluded that, had these diagnoses been known ante mortem, the clinical care of the patients might well have been different (Fu et al. 2004).

Clinical Features of Dementia Subtypes
Cortical vs. subcortical distinction

The older literature on dementia often describes two broad subtypes that encompass many of the more pathologically-specific types of dementia. Though the distinction between so-called cortical and subcortical dementias is controversial, it remains a useful conceptual tool in preparation for understanding more specific forms of dementia (Turner et al. 2002). Although there is no specific neuropsychological pattern in subcortical dementia, this group of disorders is generally characterized by cognitive slowness, concomitant motor abnormalities, and a relatively low frequency of aphasias and apraxias, compared with Alzheimer-type dementia (Turner et al. 2002). The principal differences between cortical and subcortical dementias are summarized in Table 1. It is important to note that some conditions—such as multiple small strokes and certain toxic-metabolic disorders—produce symptoms of both cortical and subcortical dysfunction (Cummings, 1985). Furthermore, the cortical/subcortical distinction has become less useful as our understanding of specific dementia syndromes has increased (Turner et al. 2002). Indeed, Lerner and Riley (2008) have pointed out that the dementias of Huntington’s and Parkinson’s Disease—two putative "subcortical" dementias—are as different from each other as they are from Alzheimer’s Disease, the classic "cortical" dementia. Furthermore, these authors note that "…the pathological basis for dementia in (Parkinson’s Disease) is now known to lie in the cerebral cortex…effectively rendering its designation as a "subcortical" dementia untenable." (p. 908). In short—though useful as a rough, first-pass approximation—the designations "cortical" and "subcortical" are likely to be modified with more specific pathoanatomical and descriptive assessments.

Table 1: Putative Differences in Cortical vs. Subcortical Dementias

Cummings, 1985; Turner et al. 2002; Sadock & Sadock, 2007; Apostolova & Cummings, 2008.


 * Dementia of the Alzheimer Type (DAT)

Case vignette: Mrs. A, a 91-year-old widowed Caucasian woman in good general health, was seen by her family physician for complaints of "forgetting things a lot lately." Mrs. A’s daughter, who often helped her mother with household chores, had noticed a change in her mother’s thinking and behavior over the past two years. "Mom used to be sharp as a tack and never forgot a thing," she reported. "Nowadays, she has trouble remembering even simple things, like turning off the stove, or in what room she keeps all her bills and papers. The other day, I found that she had left the bath running for over an hour, and it flooded the whole upstairs. Sometimes, Mom confuses me with her sister, who died over twenty years ago. When I try to explain who I am, Mom sometimes gets kind of irritable with me, and says I’m trying to confuse her." There was no history suggestive of stroke, sudden change in mental status, or loss of gross motor or sensory function. On mental status exam, the patient was pleasant, socially appropriate, and in no acute distress. She was oriented to the year, but not to month, day, or date. She recalled only one word item after three minutes. She could not remember the name of the two most recent U.S. Presidents, but was able to speak knowledgeably about the Presidents during the U.S. Great Depression (1929-1941). When asked to name three objects on the physician’s desk (stapler, paper clip, and calendar), she named them as "stapler, paper grip, and day book." A provisional diagnosis of "dementia, probably of the Alzheimer’s type" was made by the physician. AS the vignette suggests, DAT (Alzheimer’s Disease) is characterized most saliently by a gradual onset and progression of cognitive decline. Frank signs and symptoms of DAT often follow a prodromal stage of mild memory impairment that does not markedly interfere with activities of daily living. With disease progression, the patient shows more global cognitive decline, with disturbance in language, visuospatial skills, executive functioning, and social interaction. Typical of progressive DAT is a transcortical sensory aphasia, in which the patient shows fluent word output and preserved ability to repeat spoken language, but impaired speech comprehension (Apostolova & Cummings, 2008). With further progression of DAT, the patient shows impaired judgment and reduced ability to carry out activities of daily living. Disturbances in sleep-wake cycle or appetite often ensue. Although depression is often considered a hallmark of subcortical dementias, it is actually a common feature in DAT. However, only about half of patients with depression/dysphoria in DAT meet full criteria for major depression (Apostolova & Cummings, 2008). Irritability, agitation (including pacing, "fidgeting" or verbal outbursts) and psychotic features (such as visual hallucinations and delusions of having been robbed) are also common in DAT, and impose great emotional burdens on the patient’s family and caregivers. Patients with early-onset DAT (see under Pathogenesis) may show atypical features, such as prominent aphasia, myoclonic jerks, emotional lability, or obsessive-compulsive symptoms (Apostolova & Cummings, 2008). Vascular dementia (VaD) is considered the third leading cause of dementia in the elderly, after DAT and Dementia with Lewy Bodies (Apostolova & Cummings, 2008). However, some experts regard VaD as a heterogeneous syndrome, rather than a distinct disorder, in which the underlying cause is some type of cerebrovascular disease and the end result is dementia (Wright, 2007). Several subtypes of VaD are recognized. Multi-infarct dementia (MID)—the older term for VaD—involves multiple, relatively large infarctions, usually due to recurrent cerebral emboli originating from the heart, thromboembolic events, or atherosclerotic plaques. Single, strategically-placed infarct; lacunar state; and Binswanger’s Disease (subcortical arteriosclerotic encephalopathy (SAE) due to arteriosclerotic narrowing of deep penetrating white matter arterioles) are also considered VaD subtypes (see below). In partial contrast to DAT, vascular dementia often shows a subcortical pattern, with prominent psychomotor slowing, executive dysfunction, and mood changes. Speech difficulties (dysarthria) are common. Compared with DAT, memory deficits in VaD are more often related to retrieval than to initial encoding of memories; for example, the patient with VaD may be unable spontaneously to "retrieve" the name of a recently specified object (such as "chair"), but can do so if provided a clue ("It rhymes with hair"). In contrast to the course of DAT, VaD of the multi infarct variety may have a "stuttering" course, with a stepwise progression of cognitive deterioration, often accompanied by lateralizing neurological deficits (Sadock & Sadock, 2007). SAE often has an insidious course that may be temporally difficult to distinguish from DAT. The neurological findings of multi-infarct dementia may include focal findings such as weakness, spasticity, rigidity, and extensor plantar reflex (positive Babinski sign). Compared with DAT, VaD has a higher incidence and greater severity of new-onset depression, especially in older individuals; this is sometimes referred to as "vascular depression." Psychosis is also relatively common in VaD. Barely recognized only 20 years ago, Dementia with Lewy Bodies (DLB) is now believed to be the second most prevalent dementia of old age, accounting for some 15-20% of cases (McKeith et al. 1996). Compared with DAT, memory impairment in DLB is less pronounced, but cognitive fluctuations are severe. Variability in the patient’s attention, alertness, and level of consciousness may reach the proportions of frank delirium (see below, Delirium). Recurrent visual hallucinations are also one of the hallmarks of DLB. DLB shares features with the dementia of Parkinson’s Disease (PD), and diagnosis is conventionally determined by the temporal pattern of motor symptoms: if these precede cognitive decline by more than 12 months, PD is diagnosed, whereas motor symptoms occurring within a year of cognitive decline would be diagnosed as DLB (Apostolova & Cummings, 2008). Bradykinesia, rigidity, resting tremor, and gait disturbance are commonly seen in DLB, but cases of DLB without extrapyramidal symptoms are reported. Other clues to the presence of DLB include a history of falls or syncopal episodes; REM (rapid eye movement) sleep behavior disorder (such as violent behaviors during REM sleep); and extreme sensitivity to neuroleptics and atypical antipsychotics (Apostolova & Cummings, 2008; Jacobson et al. 2007—see under Treatment).
 * Vascular Dementias
 * Lewy Body Dementia
 * Fronto-temporal dementia

Fronto-temporal dementia (FTD) is actually a group of three related disorders, involving focal atrophy of the frontal and/or temporal lobes, accompanied by characteristic neurobehavioral impairments (Apostolova & Cummings, 2008). So-called Frontal Variant FTD is also known as Pick’s Disease and makes up the majority of FTD cases. (Primary Progressive Aphasia and Semantic Dementia are less common FTD variants, and will not be discussed here). Patients with Frontal Variant FTD typically do not complain of cognitive problems to the same extent as patients with DAT; rather, they show insidious but profound alterations in personality, social skills, and impulse control. However, neuropsychological testing does reveal deficits in verbal fluency, abstract thinking and planning, and verbal memory, often with sparing of visual memory. Compared to DAT patients, those with FTD usually have more mood disturbance, behavioral disinhibition, and abnormal motor behavior. Curiously, nearly half of all FTD patients—two years after diagnosis--will show one or more stereotyped or obsessive-compulsive behaviors. These may include hand clapping, hoarding, and repetitive or ritualistic behaviors (Mendez & Perryman, 2002; Apostolova & Cummings, 2008). Twenty per cent of FTD patients may develop a form of Kluver-Bucy Syndrome (hyperorality, hypersexuality, and abnormal exploratory behavior) two years after diagnosis (Mendez & Perryman, 2002). Case vignette: Mr. J. was a 57-year-old married white male, with a two-year history of marked "change in personality", according to his wife. "It’s like night and day," she told the neurologist, "compared to the way Fred used to be. He was the kindest, gentlest man I ever knew. Now, it’s like Jekyll and Hyde—I’m afraid to look at him cross-eyed, for fear he will scream at me, or worse." Mr. J. had always been a very empathic individual, but now seemed unconcerned with the wishes or needs of others. His hygiene and personal grooming had deteriorated over the past year, and he had begun to engage in bizarre rituals every morning; for example, counting to 100 before getting out of bed, then eating exactly six large muffins, without saying a word to his wife. Most of the time, Mr. J. seemed "flat" and apathetic; however, when his wife questioned any of his actions, he would shout at her or throw some object across the room. A neurological evaluation found evidence of significant frontal lobe dysfunction and positive "grasp reflex", but was otherwise within normal limits.
 * Miscellaneous Dementia Syndromes

In addition to the aforementioned types of dementia, about 5% of patients will have dementia due to miscellaneous causes, including Huntington’s Disease, Creutzfeld-Jakob Disease, Parkinson’s Disease, HIV infection, and other conditions. Huntington’s Disease (HD)—an autosomal dominantly-transmitted, progressive disorder—has its peak onset in the fourth and fifth decade, though a smaller peak occurs in the 20s. The classic presentation for HD is a combination of chorea and dementia, in the setting of a positive family history; however, the earliest presentation may be with affective or psychotic symptons (Lerner & Riley, 2008). A "tendency toward suicide" in HD was recognized by Huntington himself, and suicidal ideation may be the presenting problem. Creutzfeld-Jakob Disease (CJD) is caused by an abnormal protein called a prion, and typically presents as a rapidly-progressive dementia, accompanied by ataxia and multi-focal myoclonic jerks. A third of patients with CJD show a prodrome of fatigue, headache, insomnia, malaise, or depression (Apostolova & Cummings, 2008). Dementia due to Parkinson’s Disease (PD) occurs in roughly 30% of patients with PD, with a larger percentage afflicted as age increases (Lerner & Riley, 2008). However, cognitive symptoms can occur at any stage of PD, and are often characterized by slowed mentation (bradyphrenia), impaired visuo-spatial skills (such as facial recognition and operating objects in space) and executive dysfunction. Affective disturbance—especially depression—is very common in PD, and may be present in over 60% of cases. Anxiety is also commonly seen in PD, although less frequently than depression (Lerner & Riley, 2008). Psychosis is also encountered in PD, usually related to dopaminergic effects of anti-Parkinsonian medication (Lerner & Riley, 2008). Cognitive deficits associated with HIV infection are considered part of a continuum, known as HIV-1-associated cognitive-motor complex (HCMC). Frank HIV dementia is the most serious form of HCMC, and occurs in roughly 30% of HIV-infected individuals (Fernandez & Tan, 2008). The early clinical picture in HCMC is usually characterized by subcortical features (see Table 1), including reduced information processing speed; motor slowing or dyscoordination; and depressed mood. However, as the illness progresses, more classically "cortical" features may develop, including aphasia, agnosia, apraxia, and frontal lobe symptoms (Fernandez & Tan, 2008). Behavioral disinhibition, mania, and psychotic features are often found in the later stages of HIV-associated dementia. Assessment and Diagnostic Testing

In addition to obvious abnormalities in the mental status exam, the patient with dementia may show a variety of deficits on more sophisticated screening instruments and neuropsychological assessments, and on neuroimaging studies. Considering the diverse subtypes of dementias, it is difficult to generalize about findings on mental status exam. Furthermore, the clinician must proceed with the caveat that a patient cannot be diagnosed with dementia, in the presence of active delirium (see Delirium, section). Nonetheless, if we "average out" the differences between cortical and subcortical dementia presentations, the following mental status exam could be considered typical of the patient with moderately severe dementia: The patient appears alert, but apathetic and somewhat agitated, and is seen to be twisting her fingers through her hair. Her speech is fluent and well-articulated, but she uses many long, meaningless phrases (such as, "The thing of it is, you see, I need the thing to be, you know, whatever."). She is oriented to year, but not the month or day. She recalls only 1 of three named items, after a three minute interval of distraction. She cannot remember the names of the college from which she graduated, and gave an incorrect response when asked, "Who is the current president of the U.S.?" When shown a picture of a cup, she calls it a "vase", and identifies the examiner’s stethoscope as a "hearing aid." She is able to subtract 10 from 100 correctly, but cannot do serial 10’s accurately ("90, 85, 75, 65, 50, 40…"). She produces a poorly-constructed drawing when asked to copy a cube, and her drawing of a clock reading "ten past two" was incorrect (with the big hand placed at the "10" position). When asked to interpret the proverb, "The early bird catches the worm," her response is very concrete ("The bird that gets up early will catch the worm."). When asked if she has any particular fears lately, she replies, "I don’t know what the neighbors think of me, but I know they steal from my bedroom" (Spitzer et al. 1994). The most widely-used screening instrument for dementia is the Mini-Mental State Exam (MMSE) developed by Folstein ( Folstein et al. 1975), an 11-item test that evaluates orientation, registration, attention and calculation, recall, and language. The maximum score on the MMSE is 30 and—depending on age and education--a score of 28 or higher is usually considered "normal." A "low normal" score (24 or higher) appears to predict development of dementia after three years (Braekhus et al. 1995). The MMSE does not specifically examine executive cognitive function. An expanded version of the MMSE (the 3MS) does include some executive function items, and may be more sensitive, specific and predictive of functional outcome than the MMSE (Grace et al. 1995). Neither the MMSE nor the 3MS is ideally suited to detecting features of "milder" or subcortical dementia, or detecting impairments in social or operational functioning. For HIV-related dementia, the HIV dementia scale or the Mental Alternation Test may be better alternatives (van Harten et al. 2004; Billick et al. 2001). More complete neuropsychological assessment of dementia usually includes use of the Wechsler Adult Intelligence Scale-III (WAIS-III), the Wechsler Memory Scale (WMS), the Rey Complex Figure, and Trail Making Test (Howieson & Lezak, 2008), among others. These ancillary tests may be helpful in pinpointing specific functional impairments and their neuroanatomical correlates.
 * Prototypical mental status findings in dementia
 * Screening instruments and neuropsychological assessments
 * Neuroimaging studies

Neither the ICD-10 nor the DSM-IV criteria for dementia require any corroborative evidence obtained from neuroimaging studies. Nevertheless, neuroimaging techniques such as magnetic resonance imaging (MRI) or positron emission tomography (PET) may be helpful in clarifying diagnosis and ruling out other types of brain disease, such as normal pressure hydrocephalus. Indeed, the American Academy of Neurology recommends a non-contrast structural image (CT or MRI) in the initial evaluation of cognitive impairment (Apostolova & Cummings, 2008). With DAT, global cerebral atrophy, especially in mesial temporal and parietal regions, is the usual finding on CT or MRI. On PET or SPECT (single-photon emission computed tomography), DAT patients usually show bilateral hypometabolism in mesial temporal and parietal regions. Recently, a novel radio-labeled PET imaging agent, 18F-AV-45, has been developed, and may eventually provide a practical approach for routine brain imaging for Alzheimer's Disease (Alzheimer’s Association, 2008). In dementia with Lewy Bodies (DLB), bilateral parietal and occipital hypoperfusion is seen. The latter helps distinguish DLB from DAT, and may explain the high prevalence of visual hallucinations in DLB. Structural imaging (CT, MRI) is not helpful in diagnosing DLB (Lerner & Riley, p. 919). In frontotemporal dementia (FTD), the expected hypometabolism is seen in frontotemporal regions, using PET scanning (Apostolova & Cummings, 2008). Structural imaging (such as MRI) shows distinct profiles for the three main subtypes of FTD, though some degree of frontal and/or temporal lobe involvement is seen in all three subtypes. In vascular dementia, both CT and especially MRI can be useful in defining cortical and white matter abnormalities. In multi-infract or lacunar states, evidence of prior infarct can be seen. In SAE, periventricular white matter abnormalities can frequently be seen, although limited periventricular abnormalities just anterior or proximal to the lateral ventricle can also be seen in normal aging. Periventricular abnormalities of greater size or distance from the ventricles, or extending into the centrum semiovale, are more likely to represent evidence of clinically significant disease. Given the uncertainties of early dementia diagnosis, there has been great interest in a "blood test" or other valid biomarker for DAT, the most common type of dementia. Recently, for example, researchers in Germany found differences in levels of CD-69, a protein involved in white blood cell growth and production, in normal subjects versus those with DAT or Parkinson's-related dementia (Alzheimer’s Association, 2008). Irish researchers have focused on the enzyme beta-secretase (BACE1) activity in the brain. (BACE1 is one of two enzymes involved in the pathological processing of amyloid precursor protein (APP)—see below, under Pathogenesis). High levels of BACE1 in the spinal fluid appear to be correlated with development of DAT. At present, these remain promising, but only investigational, techniques (Alzheimer’s Association, 2008).
 * Investigational Biomarkers

Pathogenesis of Dementias

 * Biogenetic determinants and pathophysiology

Dementia of the Alzheimer Type From the biogenetic standpoint, Alzheimer’s Disease (DAT) appears to be of two main types: late-onset (sporadic) and early-onset. When DAT begins after age 65 (late onset), its mode of inheritance appears to involve a constellation of genes, probably influenced by epigenetic factors (i.e., influences that do not change DNA sequence) such as diet and exercise. However, increasing age is the most important risk factor, with rates of DAT rising to 40% in those 85 years or older. Increasing age acts synergistically with the apolipoprotein E (APOE) gene polymorphism on chromosome 19. The APOE gene takes three major forms (alleles), termed ApoE2, ApoE3, and ApoE4. APOE4 (E4) greatly increases the likelihood of late-onset DAT; i.e., individuals with two E4 genes develop DAT eight times more frequently than do those with no E4 gene. (Sadock and Sadock, 2007 p. 330; Apostolova & Cummings, 2008). It appears that E4 promotes aggregation of amyloid ? (A?), which leads to a variety of pathological changes in brain tissue (see below). In early-onset DAT, instead of—or possibly in addition to—APOE4, three autosomal dominant mutations appear to be important: the APP gene mutation on chromosome 21; the presenilin-1-gene mutation on chromosome 14; and the presenilin-2 gene mutation on chromosome 1. As noted above, early-onset DAT may be associated with atypical features, as well as shorter survival time (Apostolova & Cummings, 2008). The classic pathological findings in DAT is the presence of senile plaques, neurofibrillary tangles, neuronal and synaptic loss, and granulovascular degeneration of neurons (Sadock & Sadock, 2007, p. 330). The pathophysiology of DAT is integrally related to the over-production or accumulation of amyloid ? (A?). The "amyloid cascade hypothesis" of DAT posits that abnormal enzymatic processing of beta-amyloid precursor protein (?APP) leads to overproduction of neurotoxic A? peptides. These abnormal peptides polymerize (form chains) and "clump together", forming several types of destructive, extracellular inclusion bodies called plaques. The first plaques appear in temporal-occipital association regions in patients with DAT. In addition, DAT may involve abnormal phosphorylation of a structural protein called tau, which is involved in microtubulular transport—the intracellular "highway system" that transports vital constituents within neurons (Apostolova & Cummings, 2008). In DAT, hyper-phosphorylated tau forms distructive intracellular inclusions called neurofibrillary tangles (NFTs). Together, these plaques and tangles "choke off" normal neuronal function and neurotransmitter production in DAT, particularly affecting the production of acetylcholine (ACh) and norepinephrine. Degeneration of cholinergic neurons is present in the nucleus basalis of Meynert in persons with DAT, and low brain levels of ACh and choline acetyltransferase are also found. Cholinergic deficits provide the rationale for use of cholinesterase inhibitors in the treatment of DAT (see below, Treatment). In addition, overactivation of NMDA receptors by the excitatory neurotransmitter, glutamate, is believed to play a role in DAT, and is the basis for one pharmacological treatment (see below re: memantine). Recently, it was discovered that elevated serum levels of amyloid ? are associated with reduced cognitive function even in healthy older adults, similar to patterns observed in early DAT (Gunstad et al. 2008). Vascular Dementia VaD is caused by cumulative ischemic or hemorrhagic brain damage, usually secondary to cerebrovascular and cardiovascular pathology, and is often seen in association with hypertension, diabetes and hyperlipidemia (Apostolova & Cummings, 2008). There are somewhat conflicting data regarding the contribution of the ApoE gene to the pathogenesis of VaD, but any such contribution appears smaller than that in DAT (Higuchi et al. 1996). Multi-infarct dementia (MID)—the older term for VaD—usually involves infarcts in the territory of the middle cerebral artery and surrounding ("watershed") regions. The middle cerebral artery is the largest cerebral artery and is the vessel most commonly affected by cerebrovascular accident. It supplies most of the outer convex brain surface, nearly all the basal ganglia, and the posterior and anterior internal capsules (Slater, 2008). In VaD, infarcts are also seen in the basal ganglia and periventricular white matter. Subacute Arteriosclerotic Encephalopathy (SAE) and Lacunar state both involve the small vessels of the brain. SAE is caused by thickening and narrowing (arteriosclerosis) of arteries that feed subcortical areas of the brain. SAE produces widespread, microscopic areas of damage to the deep layers of white matter. (NINDS, 2008). Lacunar state (lacunar disease) is due to occlusion of small, penetrating cerebral arteries, leading to extremely small but deep infarctions (lacunes). Sometimes, these lacunes are so small as to produce no obvious deficits, or only pure motor or sensory deficits (Robinson & Starkstein, p. 707). Lacunar state is often associated with hypertension and/or diabetes. The cavitary lesions (lacunae) characteristic of this condition are often found in the internal capsule, deep grey matter nuclei, and white matter. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare, hereditary type of VaD that affects small blood vessels in the brain. An abnormality in the muscle cells surrounding these blood vessels gradually destroys the blood vessel cells. This may lead to migraines, emotional disturbance, stroke-like episodes, dementia, and other impairments (CADASIL Foundation, 2008). CADASIL involves mutations of the Notch 3 gene on chromosome 19 (Joutel et al. 1996). There are also a growing number of genetically uncharacterized but familial small vessel diseases (Low et al. 2007). Dementia with Lewy Bodies (DLB) DLB does exist in genetic forms, including some autosomal dominant forms (Lerner & Riley, p. 919). There is significant pathophysiological overlap between DLB and Parkinson’s Disease (PD), on the one hand; and DLB and SDAT, on the other. Thus, alpha-synuclein is a protein that appears to modulate synaptic transmission, and constitutes the major component of Lewy bodies. These structures are the pathological hallmark of both PD and DLB, whether of a sporadic or familial origin (Lerner & Riley, p. 914). There is considerable overlap between DLB and DAT. For example, neuritic plaques and neurofibrillary tangles are seen in autopsy studies of both DAT and DLB, though fewer neurofibrillary tangles are found in DLB (Samuel et al. 1997). Moreover, amyloid ? (A?) pathology—one of the hallmarks of DAT—is often seen in DLB. Indeed, there is an interesting synergy between pathophysiological elements of DLB and DAT. For example, alpha- synuclein is a potent inducer of tau fibrillization, while A? has been shown to promote Lewy body pathology in animal models (Giasson et al. 2003; Masliah et al. 2001). Fronto-temporal dementia There appears to be a strong genetic loading in FTD. About 40% of FTD patients have a family history of a similar disorder in close relatives, and in the vast majority of cases, there is an autosomal dominant inheritance pattern. Autosomal dominant mutations in the tau gene on chromosome 17 have been discovered in FTD, and—like DAT-- FTD is generally considered a "tauopathy." However, "tau-negative" forms of FTD have been described, including one form that often presents with concomitant amyotrophic lateral sclerosis (ALS) (Apostolova & Cummings, 2008; Lantos & Cairns, 2001). Pick’s Disease (frontal variant FTD) produces striking frontal, temporal, or combined (fronto-temporal) atrophy. Microscopically, the hallmark are spherical, tau-based inclusion bodies, termed Pick’s bodies, which may be seen in neurons and glial cells. Neuronal loss and swelling are also commonly seen in Pick’s Disease. In tau-negative forms of FTD, neuronal loss, gliosis, and microvacuolation are the sole microscopic findings.


 * Ethno-cultural and racial factors in dementia

Ethnic, cultural, and racial factors play a role in the assessment of dementia and, to some extent, on its course and outcome. For example, most diagnostic tests for dementia are based on cognitive assessments not yet validated for various ethnic groups. Moreover, emigration of some ethnic groups may affect dementia prevalence, as demonstrated by higher rates of dementia among Japanese-Americans than among Japanese cohorts in Japan (Iliffe & Manthorpe, 2004). Ethnic and cultural factors may also affect caregiver attitudes and behavior. For example, Latina dementia caregivers may delay institutionalization significantly longer than female Caucasian caregivers, perhaps reflecting more tolerant Latino cultural attitudes toward caregiving (Mausbach et al. 2004). Similarly, Shaw et al. (1997) found lower rates of depressive symptoms in Chinese, as compared with American, caregivers of demented patients, possibly reflecting greater acceptance of traditional family roles among the Chinese subjects. Finally, ethnicity and race may play a role even in the symptomatic expression of dementia, with different ethnic and racial groups showing varying rates of aggressive behaviors, wandering, and hallucinations (Sink et al. 2004).

Pharmacotherapy
By far the most experience with pharmacotherapy has been in patients with DAT, and our discussion necessarily focuses on this condition. The mainstay of drug therapy in dementia is a group of agents called cholinesterase inhibitors (CIs), including donepezil, galantamine, and rivastigmine. (Another CI, tacrine, is rarely used nowadays in most industrialized countries, owing to its hepatotoxic effects). Comprehensive discussion of these agents may be found in Jacobson et al. 2007. All CIs act to inhibit the enzyme acetylcholinesterase, which metabolizes the neurotransmitter, acetylcholine. Rivastigmine also inhibits butyrylcholinesterase, and galantamine is an allosteric modifier of the nicotinic acetylcholine receptor. There is no convincing, randomized, controlled evidence showing any one of these drugs as markedly superior to the others. Indeed, the efficacy of this group of agents appears to be modest-to-moderate, with most studies of DAT finding that the CIs mainly slow the rate of cognitive decline and/or delay nursing home placement. One meta-analysis of 13 randomized, double blind, placebo controlled trials demonstrated that 6-12 months of treatment with donepezil, galantamine or rivastigmine in mild, moderate or severe DAT produced about a 3 point drop in scores on the 70-point ADAS-Cog Scale. Benefits were also seen on measures of activities of daily living and behavior. But as the authors note, "none of these treatment effects (is) large." (Birks, 2006). The other drug used in most countries for DAT is memantine, which blocks the action of glutamate at the NMDA receptor, under conditions of excessive glutamate activity (Jacobson et al. 2007). This is thought to slow neurodegeneration in DAT, and there is evidence of memantine’s benefits in moderate-to-severe DAT. In some instances, memantine may be combined with one of the CIs, but long-term data on outcome are few. Although atypical antipsychotics are often used—and sometimes, overused—in patients with DAT, they are not without risk in dementia-prone populations, particularly when vascular risk factors are present. In the U.S., the Food & Drug Administration (FDA) issued, in June 2008, an advisory to physicians, stating the following (FDA, Alert, 6/16/08):
 * Elderly patients with dementia-related psychosis treated with conventional or atypical antipsychotic drugs are at an increased risk of death.
 * Antipsychotic drugs are not approved for the treatment of dementia-related psychosis. Furthermore, there is no approved drug for the treatment of dementia-related psychosis.  Healthcare professionals should consider other management options.
 * Physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss this risk of increased mortality with their patients, patients’ families, and caregivers.

Notwithstanding these serious concerns, some patients with DAT and psychotic features and/or severe behavioral disturbance (e.g., extreme agitation or aggressive violence) may require and benefit from low doses of atypical antipsychotics; e.g., risperidone 0.5 mg/day or olanzapine 5 mg/day (Alexopoulos et al. 2004). However, attempts at behavioral modification (see below) and alternative therapies (such as the SSRI citalopram) should be considered (Pollock et al. 2007). As a recent review by Ellison (2008) put it: “…several of the atypical antipsychotics remain reasonable choices when used in patients whose vascular risk factors do not outweigh their behavioral treatment needs. The atypical antipsychotics have not been proved to control agitation over an extended period of time and should be used at the lowest effective doses and for the shortest interval necessary, with sufficient psychoeducation and disclosure of risks to caregivers and relatives.” Treatment of vascular dementia (VaD) should first focus on mitigation of known risk factors, such as hypertension, diabetes, atrial fibrillation, and hyperlipidemia. Studies regarding use of CIs for vascular dementia are plagued by methodological problems, such as inclusion of those whose dementia probably involves some DAT-type pathology and cholinergic system dysfunction; nonetheless, there is modest and growing evidence that the CIs may be helpful in subgroups of patients with VaD. Similarly, Dementia with Lewy Bodies (DLB) also involves reduction of brain acetylcholine—perhaps surpassing those seen in DAT--and the CIs may sometimes be useful in DLB (Jacobson et al. 2007). Patients with DLB are exquisitely sensitive to the extrapyramidal side effects of antipsychotics, and both typical and atypical agents (with the possible exception of clozapine) are generally to be avoided in DLB patients.

Psychosocial and behavioral interventions
Whenever possible, the clinician should initiate non-pharmacological interventions when managing behavioral disturbances in patients with dementia. Such behavioral approaches are aimed at ameliorating physical, environmental and psychosocial stressors that may lead to agitation, pacing, aggression, and related behavioral disturbances (Salzman et al. 2008). For example, dysfunctional verbal and physical behaviors—such as repetitive shouting, pacing, punching, etc.—may reflect unrecognized pain, loneliness, depression, boredom, or other social stressors. A variety of behavioral interventions may be helpful in this context; e.g., structured socialization, "pet therapy," viewing family videotapes, and training programs for family caregivers. It is also important to review the patient’s medical status and medications, since adverse drug effects or interactions may sometimes contribute to confusion and agitation (Jacobson et al. 2007; Salzman et al. 2008). There are relatively few well-controlled studies of non-pharmacological interventions in dementia; nevertheless, a number of promising investigational approaches are under investigation, including aroma therapy and music therapy (Raglio et al. 2008).

Special Populations

There are several subgroups of demented patients who merit special attention and interventions. Patients with HIV-related dementia in the late stages, for example, may exhibit behavioral disinhibition, mania, and psychotic features, such as delusions and hallucinations. Primary treatment of HIV/AIDs is aimed at suppression of viral load by means of anti-retroviral therapies. Some evidence suggests that the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine (also known as AZT) may attenuate the symptoms of HIV-related dementia and neurological impairment in some patients; however, zidovudine and related agents may themselves provoke neuropsychiatric complications, such as depersonalization, mania, and delirium (Fernandez & Tan, 2008). Cognitive functioning in HIV dementia patients may be improved by methylphenidate; psychotic symptoms may respond to atypical antipsychotics, such as risperidone or olanzapine. Depression in HIV/AIDS is not uncommon, but may stem from a complex mix of direct effects of HIV on the CNS, and psychosocial factors. Antidepressants such as citalopram and escitalopram may be useful, but this patient population is particularly susceptible to drug-related side effects and interactions. Thus, any pharmacotherapy aimed at neuropsychiatric symptoms must be very carefully monitored in this population (Fernandez & Tan, 2008). As noted above, Dementia with Lewy Bodies (DLB) poses particular management problems. Psychotic symptoms, including visual hallucinations, are a central feature of DLB, and the sensitivity of these patients to antipsychotics makes treatment especially challenging. Cholinesterase inhibitors, such as rivastigmine, may ameliorate some neuropsychiatric symptoms in DLB patients, including hallucinations, paranoid delusions, apathy, aggression, and agitation (Simard & van Reekum, 2004; Apostolova & Cummings, 2008). If an antipsychotic must be used in DLB with psychosis, classic neuroleptics should be avoided; initiating treatment with very low doses of quetiapine or clozapine is sometimes warranted (Jacobson et al. 2007). Depression as a feature of dementia represents a diagnostic and treatment challenge. As noted earlier, depression is commonly seen in patients with Parkinson’s Disease, Huntington’s Disease, DAT, and LBD, as well as in those with a history of stroke or other form of VaD. Depression may represent a prodrome to dementia or a feature of established dementia. The recently described amyloid-associated depression may represent such a prodome in DAT (Qiu et al. 2008). Vascular depression (Sneed et al. 2008; Alexopolous, 2006) may present as new-onset of depressive illness in those affected by diffuse or focal vascular lesions, and is increasingly recognized in older individuals. Conversely, the "dementia of depression" (formerly called depressive pseudodementia) is a reversible cognitive impairment directly related to the patient’s mood disorder. Features such as excessive guilt, low self-esteem, self-loathing, or persistent suicidal ideation, as well as delayed responses to cognitive questions, are useful "red flags" for the presence of depression in dementia. The Cornell Scale for Depression in Dementia may be helpful in detecting this problem. Depressed patients with dementia often respond to lower doses of antidepressants (such as citalopram or sertraline) than do non-demented depressed patients (Jacobson et al. 2007). Delirium is a common complication of both HIV-related dementia and DLB, and is discussed in the section on Delirium. Co-morbid dementia and delirium is also discussed in the section on Delirium. Case Vignette: Mr. J. was a 78-year-old nursing home patient with dementia of the Alzheimer type (DAT). The staff were concerned and distressed by Mr. J’s frequent "moaning" or "yelling," particularly in the evening, and believed these behaviors were adversely affecting the other residents of the home. Mr. J. was prescribed risperidone 1.0 mg at h.s. His yelling diminished after only two days of treatment. However, he developed significant orthostatic hypotension and akathisia, and continued to "moan" nearly every night. A comprehensive medical evaluation revealed that Mr. J. suffered from severe osteoarthritis, which was worsened with attempts by the "night shift" nurses to reposition Mr. J. in his bed. A combination of acetaminophen and local heat application led to considerable relief and marked reduction in Mr. J’s verbal outbursts. Risperidone was reduced to 0.25 mg at h.s., with significant improvement in Mr. J’s akathisia and hypotension.

Phenomenology (Characteristic Features of Delirium)
Delirium may be defined as an acute or subacute disturbance in cerebral functioning leading to impairment in one’s level of consciousness, orientation, memory, and attention, usually characterized by "waxing and waning" over hours or days. Common accompaniments of delirium include altered sleep-wake pattern; labile mood; speech disturbance; restlessness or agitation; perceptual abnormalities; and sometimes, psychotic features. Older terms for delirium include "acute organic brain syndrome," "cerebral insufficiency," and "acute confusional state." Not uncommonly, delirium may be superimposed on dementia, a condition sometimes termed "beclouded dementia" (Sadock & Sadock, 2007).

Epidemiology
Delirium is a very common problem, particularly in emergency, medical-surgical, inpatient, and geriatric settings, such as nursing homes (Levkoff et al. 1991). Substance-abuse and oncology treatment centers also have high rates of delirium (Tasman et al. 1998). Among medical inpatients, the prevalence of delirium ranges from 11-16%, while among elderly patients admitted for acute hospital care, the prevalence ranges from 24-65%. Among elderly patients over age 65, hospitalized for a general medical condition, 10-15% will develop delirium while in the hospital. In general delirium tends to be more common among the very young and the very old, but can affect anyone at any age. Delirium is associated with longer hospital length of stay and mortality in medical surgical inpatients. Subtypes of Delirium and Classification Delirium is sometimes characterized according to the predominant disturbance in motor behavior; i.e., as excited ("hyperactive"), lethargic ("hypoactive") or mixed delirium (Trzepacz & Meagher, 2008). Some evidence indicates that these motor subtypes have implications for etiology, pathophysiology, presence of non-motor symptoms, and prognosis. Thus, some evidence suggests that patients with hyperactive delirium may have a better prognosis and a lower mortality rate. Hypoactive delirium may be more likely to go undetected, as one might expect from the lack of obvious agitation. However, the definition of these subtypes varies considerably among clinicians and researchers, and their reliability has been questioned. Another way of considering delirium is expressed by the terms "excitatory" and "inhibitory" syndromes, which we will discuss under Pathogenesis (Ferner, 2003). Delirium with psychotic features—including delusional misidentification and hallucinations—may be particularly distressing to the patient, even after resolution of the delirium (Trzepacz & Meagher, 2008). There are several ways delirium may be classified. In the ICD-10 (1993), the main categories are: In contrast, the DSM-IV categorizes delirium according to four very broad etiologies: delirium due to general medical condition; substance intoxication delirium; substance withdrawal delirium; and delirium due to multiple etiologies. The number of general medical conditions (GMCs) causing delirium is legion. Some common GMCs include fluid and electrolyte abnormalities, hypoglycemia, infection or sepsis, head trauma, hepatic encephalopathy, viral encephalitis, renal failure, COPD and brain tumor or hemorrhage. A plethora of both prescribed and over-the-counter medications can provoke delirium, including analgesics, antibiotics, cardiac medications, anticholinergic agents, psychotropic agents, and a variety of botanicals, such as jimsonweed. (Sadock & Sadock, 2007)
 * Delirium, Not Induced By Alcohol And Other Psychoactive Substances
 * Delirium, Not Superimposed On Dementia,
 * Delirium, Superimposed On Dementia
 * Other Delirium

Case vignette: An 84 year-old woman with a history of mild congestive heart failure, osteoarthritis, and moderate cognitive impairment thought possibly due to very early DAT appeared confused, disoriented, and hallucinating. She complained of seeing "green faces" and was initially diagnosed as "psychotic." Physical exam and routine laboratory measures were within normal limits. Her regular medication included digoxin 0.25 mg/day (digoxin level = 0.6 ng/ml; therap=0.5-2.0). Owing to her arthritic pain, she recently had been started on ibuprofen 400 mg tid. A repeat digoxin level shortly after admission showed the level to be 1.2 ng/ml (WNL). An EEG showed slowing of alpha rhythm (7-8 Hz, normal=8-12). The increase in digoxin levels was attributed to the effect of the NSAID, ibuprofen (Goldfrank, 2002). Though the absolute level of digoxin was still within the normal range, its doubling within a short period of time evidently set off the patient’s confusion. Abnormal color perception—particularly in the green or yellow end of the spectrum (xanthopsia)—is a classic sign of digoxin toxicity (Piltz et al. 1993).

Assessment and Diagnostic Testing
Delirium remains a clinical diagnosis, with a careful history, physical exam, mental status exam, and review of medication and laboratory findings as the most useful diagnostic "instruments" (Sadock & Sadock, 2007). Typically, the onset of delirium is acute (over a period of hours, days, or in some cases weeks) and there is a marked change from the patient’s "baseline" cognitive state. A recent change in medication; recent substance abuse/discontinuation; or some recent medical or neurological event (fall, infection, stroke, etc.) may provide the critical historical clues. The classic findings on mental status include a fluctuating level of consciousness (e.g., the patient "nods off" or drifts in and out of awareness); inability to pay attention to the examiner; disorientation to date and place (though intact orientation does not rule out delirium); impaired recent memory (e.g., inability to recall 3 of 3 items after 5 minutes); and associated features, such as disorganized thought processes (tangentiality, loose associations), perceptual abnormalities (auditory, and particularly, prominent visual or tactile, hallucinations); and psychomotor abnormalities (agitation, slowing). Affect may be quite labile, and delusions may also be present. When delirium is superimposed upon dementia, it appears that delirium phenomenology generally overshadows that of the dementia. Thus, delirium tends to present similarly regardless of whether it is accompanied by dementia. The clinical maxim should be, "altered mental status reflects delirium until proven otherwise," in order to prevent misattribution of delirium to the more chronic brain syndrome of dementia (Trzepacz & Meagher, 2008, p. 451). History from family members or caregivers may provide critical information suggesting a more acute change in functioning. Physical examination may be difficult in an agitated, delirious patient, but every effort must be made to rule out head trauma, acute neurological events, and severe autonomic dysfunction (such as marked hypotension). Pulse, blood pressure, temperature, respirations should all be checked. An examination of the head and neck—including papillary function and extraocular movements—should be carried out. A basic assessment of heart, lungs, and neurological function should be obtained. Specific physical findings may provide a clue as to the etiology of the delirium. For example, a patient with papilledema and hypertension may be experiencing hypertensive encephalopathy; nuchal rigidity may point to meningitis or subarachnoid hemorrhage (Sadock & Sadock, 2007). One helpful clue may be pupillary findings: in cases of anticholinergic toxicity, pupils may be dilated but sluggish; in cases of "hyper-adrenergic" delirium (e.g., in sedative withdrawal, amphetamine/cocaine intoxication, or hyperthyroid storm), pupils may be dilated by briskly reactive (Ferner, 2003). Adjunctive screening instruments for detecting delirium include the CAM (Confusion Assessment Method); the CTD (Cognitive Test for Delirium); and the DRS-R98 (Delirium Rating Scale, Revised 98). The CAM is probably the most widely used delirium screening test in general hospital settings, and is based on DSM-III criteria (Trzepacz & Meagher, 2008). Recently, Fanjiang & Folstein (2001) developed a simple screening scale for use by medical students, called the Three Item Delirium Scale. This requires the presence of altered consciousness plus either cognitive impairment or hallucinations; preliminary data suggest good sensitivity and specificity for delirium (Trzepacz & Meagher, 2008). Laboratory measures and ancillary testing: There is no pathognomonic "test" for the diagnosis of delirium. However, it is important to obtain routine laboratory studies on all delirious patients, including—most urgently--complete blood count, electrolytes (including calcium, magnesium, and phosphate), renal and hepatic functions (including ammonia), serum glucose and erythrocyte sedimentation rate. Thyroid functions should also be checked. A blood and/or urine screen for drugs of abuse is helpful, and serologic tests for syphilis (such as VDRL) and HIV infection may also be indicated. An electrocardiogram (EKG) and chest radiograph are usually appropriate, in order to rule out cardiac arrhythmia, silent ischemia, or occult pneumonia among other causes. A bedside test for oxygenation is also useful. An electroencephalogram (EEG) is often advised as a standard study in the work up of delirium (Sadock & Sadock, 2007), since the EEG often reveals either generalized slowing or focal areas of hyperactivity. (Serial EEGs may also be helpful in following the "progress" of treatment, in that one may see restoration of normal (8-12 Hz) alpha rhythm as the delirium resolves). Depending upon history and specific medical presentations, ancillary tests, such as lumbar puncture, blood cultures, B12 level, and structural brain imaging (CT, MRI) may be clearly indicated. It is important to note that correction of underlying metabolic, electrolyte, or other abnormalities does not necessarily lead to immediate resolution of the delirium; typically, there is a "lag" between such corrections and the patient’s level of consciousness. This is particularly true in those circumstances where CNS drug levels (e.g., lithium) may normalize more slowly than blood levels; or when correction of blood abnormalities (such as high glucose or sodium) needs to occur slowly, in order to prevent CNS complications. One should treat the patient, not the "lab slip!"

Pathogenesis of Delirium
Even though delirium may arise from a multitude of underlying causes, several unifying hypotheses have been advanced to explain the general mechanisms of most delirious states (Ferner, 2003). One such hypothesis emphasizes the balance between excitatory and inhibitory neurotransmission in the brain, and derives a broad separation of brain syndromes on this basis. For example, excitatory delirium syndromes may involve excessive augmentation of excitatory neurotransmitters, such as glutamate, dopamine and norepinephrine (serotonin may also be considered excitatory to some degree). Antagonism of certain cholinergic receptors, on this view, also constitutes an "excitatory" effect. Thus, delirium syndromes as diverse as amphetamine toxicity and poisoning with the anticholinergic agent benztropine would be predicted to have similar excitatory effects, including agitation, tachycardia, hypertension and fever. (Anticholinergic syndromes may present with the classic and memorable findings of "hot as a hare, mad as a hatter, red as a beet, dry as a bone;" i.e., fever, agitated confusion or psychosis; red skin; and dry mouth). Inhibitory delirium syndromes, in Ferner’s view (Ferner, 2003), involve agents that augment the inhibitory neurotransmitter, GABA, or act as agonists at the mu opioid receptor. Thus, in large quantities, GABA agonists such as benzodiazepines (and to some degree, ethanol) or opioids such as morphine may cause delirious states characterized by drowsiness, ataxia, respiratory suppression, and slurred speech. Pathological alterations in GABA activity--perhaps amplified by an endogenous toxin that binds to benzodiazepine receptors--have also been implicated in hepatic encephalopathy (Rummans et al. 1995). In some cases of inhibitory syndromes, "paradoxical" agitation may result from disinhibition of higher brain centers that normally suppress aggression or agitation (Ferner, 2003). Another unifying hypothesis focuses specifically on low cholinergic and high dopaminergic transmission in delirium (Trzepacz & Meagher, 2008), as well as derangements in non-dominant, posterior parietal and prefrontal cortices. Other brain regions, including the brain stem, basal ganglia and thalamus, are likely to be involved. Importantly for the cholinergic hypothesis, a variety of disease states causing delirium are associated with cholinergic deficiency; e.g., thiamine deficiency, hypoxia, and hypoglycemia all reduce acetylcholine by affecting the oxidative metabolism of glucose and production of acetyl coenzyme-A (Trzepacz & Meagher, 2008). The pathogenesis of delirium must also consider predisposing medical risk factors, though, as Trzepacz and Meagher note, these must not be confused with causes of delirium. Predisposing factors include but are by no means limited to: genetic risk factors (such as APOE4 genotype); old age; pre-existing cognitive impairment; use of multiple medications (especially anticholinergic agents and opioids); pre-existing cerebrovascular accident/stroke; and vitamin (especially thiamine) deficiency (Trzepacz & Meagher, 2008). To some degree, psychological factors, as well as quality of hospital care, may also influence certain aspects of delirium. As Mohta et al. (2003) have pointed out, the experience of being in the intensive care or trauma unit may activate various psychological defense mechanisms, such as denial, regression, anger, anxiety and depression. Delirium itself may, in some cases, represent a regressive defense, though such psychodynamic hypotheses must never vitiate the clinician’s search for specific physiological precipitants. The likelihood of delirium may also be influenced by the kind of care the patient receives. For example, Inouye and coworkers (1999) evaluated 852 hospitalized older patients who were nonrandomly assigned to usual care or management with a multi-pronged intervention designed to minimize risk factors for delirium. These protocols included repeated reorientation of the patient; provision of cognitively stimulating activities; a nonpharmacologic sleep protocol; early mobilization activities and range of motion exercises; timely removal of catheters and physical restraints; use of eyeglasses and hearing aids; and early correction of dehydration. These interventions significantly reduced the incidence of delirium (15.0% in the usual care group versus 9.9% in the intervention group).

Treatment and Management of Delirium
The primary treatment of delirium entails diagnosing and correcting the underlying cause of the brain dysfunction. Thus, if an electrolyte disturbance appears to be the causal factor, one corrects it; if an infection seems to be "driving" the delirium, one treats it with appropriate anti-microbials (which may also provoke confusional states). If the patient’s delirium appears due to a newly-prescribed medication, that agent is held or discontinued immediately, if clinically safe and feasible. (If one must avoid a superimposed withdrawal syndrome, the offending agent is tapered off and discontinued as rapidly as possible). There are some "cause-specific" agents that treat a few narrowly-defined types of delirium. For example, in cases of known or suspected anticholinergic-induced delirium, the cholinesterase inhibitor, physostigmine, is indicated (and in the U.S., has FDA-approved labeling for this use). However, physostigmine is not without its own side effects, such as bradycardia. In cases of known or suspected alcohol withdrawal-related delirium (delirium tremens, "DTs"), a benzodiazepine is the treatment of choice. For benzodiazepine-induced delirium, limited data suggest that the benzodiazepine antagonist, flumazenil, may be useful (Olshaker & Flanigan, 2003). In many cases of delirium, a specific cause is not identified, or multiple causes are suspected. If, after a thorough medical evaluation, no specific etiology is found, one is left to "manage" the neurobehavioral complications of delirium as effectively and safely as possible—and without making matters worse. Unfortunately, many psychotropic agents used to manage the behavioral complications of delirium (such as agitation or disinhibted behavior) may themselves cause confusion or exacerbation of the delirium. Thus, treatment should be as conservative as possible, avoiding high doses, or agents whose mechanisms of action overlap with those of drugs implicated in causing the delirium. For example, the hallucinogen, phencyclidine ("PCP", "Angel Dust") has complex effects on acetylcholine (Helman & Habal, 2006) that may be exacerbated if one treats PCP-induced psychosis with a highly anticholinergic phenothiazine. For management of neurobehavioral complications of delirium (marked agitation, aggression, tearing out IV lines, etc.), the agents of choice remain the higher-potency neuroleptics, particularly haloperidol (5-40 mg/day, in divided doses) (Inouye, 2006a). Although larger doses have been used intravenously, particularly in ICU or SICU settings, these agents have risk of producing torsades des pointe arrythmias, which have been associated with lethal ventricular arrythmias, particularly in patients with hypovolemia, hypomagnesemia or other electrolyte abnormalities. (Hassaballa & Balk, 2003). There is, however, increasing interest in use of newer "atypical" antipsychotics in this setting, and some limited data suggest they may be safe and effective (Han & Kim, 2004). Although benzodiazepines, such as lorazepam, are often administered to delirious patients, this group of agents carries significant risks in this population; e.g., paradoxical "disinhibition," worsening, or prolongation of the patient’s confusion (Inouye, 2006 a,b). With the exception of delirium tremens, there are few instances of delirium in which benzodiazpines would be indicated. There is also considerable interest in—but only preliminary evidence for—the use of cholinesterase inhibitors such as donepezil (see above, re: DAT) in delirium. Preliminary evidence has been mixed, and clinical observation suggests that any beneficial effects on confusion and memory impairment are modest and slowly-achieved (Jacobson et al. 2007). One recent controlled study (Liptzin et al. 2005) was "…unable to demonstrate a benefit for donepezil in preventing or treating delirium in a relatively young and cognitively-intact group of elderly patients undergoing elective orthopedic surgery." Non-pharmacologic approaches to the delirious patient are an important part of good care, and include provision of "orienting cues," such as clocks and calendars; continuity of nursing care; placement of familiar objects (such as a family picture) near the patient; and therapeutic use of friends and family to create a familiar and calming environment (Rummans et al. 1995). Finally, primary prevention of delirium involves a comprehensive strategy, including: 1) recognizing and mitigating known risk factors such as dehydration, sleep deprivation, hearing impairment, etc. (Inouye et al. 1999); 2) proactive geriatric consultation, prior to planned surgery; and 3) education of staff charged with the care of high-risk patients (Trzepacz & Meagher, 2008).

Psychiatric Symptoms Secondary to General Medical Conditions
There is a complex and multidimensional relationship between psychiatric and medical illnesses. Psychiatric illness can be exacerbated by the presence of co-morbid medical illness and its management can be made more complex by pharmacologic or other management needs of medical illness. Psychiatric illness can present in general medical settings with medical symptoms secondary to psychiatric illness. Finally psychiatric disorders can be directly caused by the presence of known or occult medical/neurological illness. In this section, we will focus on this last category. In the DSM-IV, this heterogeneous group of diagnoses comprises six main categories: psychotic disorders, mood disorders, anxiety disorders, catatonic disorders, personality alterations, and amnestic disorders. In the ICD-10, the term "organic" is applied to the first five categories; e.g., organic hallucinosis and organic delusional disorder; organic mood [affective] disorder; organic anxiety disorder; organic catatonic disorder; and organic personality disorder. We have already alluded to what we view as philosophical problems with the term "organic". For this reason, we will use the neutral designation, psychiatric symptoms secondary to general medical conditions (Psy-GMCs) as a "bridging" term to encompass both the DSM and ICD categories.

Prevalence in selected settings
The community prevalence of psychiatric symptoms secondary to general medical conditions (Psy-GMCs) is not well-established, nor is it straightforward to determine. Data from a consultation-liaison service, however, provide some sense of how common Psy-GMCs may be in certain high-risk medical settings. For example, Rundell and Wise (1989) reviewed 755 cases seen by the psychiatric C-L service in a general hospital. Fully 38% of depressed patients had some underlying medical or neurological disorder as the likely cause of their depression. The most frequent diagnoses were cerebrovascular accident; Parkinson’s Disease; lupus cerebritis, HIV infection, hypothyroidism, and multiple sclerosis. With respect to manic syndromes on this C-L service, the findings were even more striking: 87% of manic patients had a diagnosis of "organic mood disorder." The most commonly-implicated causes of this "secondary mania" were corticosteroids, human immunodeficiency virus (HIV) infection, and temporolimbic epilepsy. Psychiatric clinic populations may also show a high prevalence of GMCs associated with psychiatric symptoms. Thus, Koranyi (1979) found that in a psychiatric clinic population, 18% had psychiatric symptoms that could be attributed solely to an underlying—and undetected—medical problem. On the other hand, in routine, non- general hospital, psychiatric inpatient settings, some types of Psy-GMCs may be quite rare. For example, Lo et al. (2007) found that the prevalence of "organic delusional disorder" according to DSM-III-R criteria was only 0.4% of total inpatient psychiatric admissions.

General features and phenomenology of Psy-GMCs
There are no pathognomonic signs that reliably distinguish psychiatric disturbances due to general medical  ("organic") conditions (Psy-GMCs) from those due to primary psychiatric disorders. For example, with respect to manifestations of the depression itself, there are no singular objective features that would unequivocally distinguish, say, depression due to folic acid deficiency from depression seen in a typical major depressive episode. However, careful attention to (1) the onset, history, and course of the present illness; (2) the patient’s age, prior medical and psychiatric illnesses, and family history; as well as (3) accompanying physical and laboratory findings, may all be of help. For example, depressive, manic, anxious, or psychotic symptoms that appear to "track with" (correspond closely in time and intensity) the course of an underlying medical disorder may prove to be secondary to that disorder (see Case Vignette). Similarly, the onset of psychiatric symptoms following the introduction, discontinuation, or change in dosage of a particular drug should always raise the prospect of a "secondary" psychiatric syndrome. The mental status exam may provide clues as to the "secondary" nature of the psychiatric disturbance; e.g., unusual cognitive deficits (such as severe memory impairment) in a patient presenting with anxiety (Goldman, 1992). Abnormal findings on physical examination (such as hypo- or hyperactive reflexes, signs of vitamin deficiency, etc.) and laboratory testing (such as anemia, decreased thyroid function, etc.) may also be helpful in discerning an underlying GMC. On the other hand, correction of an underlying physical abnormality or drug toxicity does not always translate into an immediate remission of secondary psychiatric symptoms; often, there is a "lag" between correction of the underlying medical or drug-related problem and return to euthymia or baseline mental state. Indeed, as Colon and Popkin observe, sometimes—despite correction of the underlying medical problem—the secondary psychiatric symptoms may develop "a life of their own" and persist for long periods (Colon & Popkin, 2006). Furthermore, as O’Brien et al. (2006) note, "In some cases (e.g., adrenal insufficiency), appropriate and continued treatment of the underlying condition results in resolution of the psychiatric symptoms. In others (e.g., SLE), treatment of the underlying condition may alleviate but may also exacerbate psychiatric symptoms." Advanced age, or older age of onset of psychiatric illness is sometimes a clue to an underlying GMC, though by no means an infallible one. Since the elderly (as well as the very young) are at greater risk for medical illnesses generally, the sudden appearance of apparent psychiatric symptoms in someone over the age of 55 ought to trigger a search for underlying medical factors (though one could say the same for a younger patient with a similarly abrupt onset of psychiatric illness). One’s level of suspicion is generally highest in an older patient whose family history is "negative" for psychiatric disorders, and whose symptoms appear temporally linked to a GMC or drug-related event. In this regard, Lo et al. (2007) reported that compared to patients with (functional) Delusional Disorder, those with "Organic Delusional Disorder" usually had an older age of onset, and less frequently had a relevant family psychiatric history. Similarly, patients diagnosed with "organic mood disorder" were more likely to have a negative family history of depression, compared to medically-ill patients with a diagnosis of major depression (Yates et al. 1991). The patients with organic mood disorder were also less likely than their counterparts to have recovered fully after four years, despite similar treatment as those with major depression. As noted above, patients with older age at onset of affective illness, and without family history of depression, are more likely to have evidence of vascular CNS abnormalities on MRI than those with earlier onset illness. With respect to temporal patterns, an important caveat is in order here: as Colon and Popkin (1996) judiciously observe: "Many clinicians are inclined to rely heavily on a temporal relation to establish an organic etiological relation. Although temporal relation is an instructive parameter, it may be misleading and subject to errors of recall. It is also apparent that psychiatric symptoms may antedate the clinical recognition of the physical illness—that is, anxiety and depression may be the first presenting features of a medical illness." (p. 413) Sometimes, the "phenomenology" of the syndrome may provide a clue as to its etiology, though this is far from universally the case. For example, when psychotic symptoms develop in the context of a GMC, they tend to present in a characteristic pattern. Thus, many secondary psychotic syndromes are characterized by paranoid delusions, persecutory thoughts, and ideas of reference. Delusions tend to be concrete and changeable, in contrast to the often elaborate, bizarre, and relatively stable delusions seen in, say, schizophrenia or mania. Lishman characterizes "organic delusions" as often persecutory in content, but typically "…poorly elaborated, vague, transient, and inconsistent…" (Lishman, 1998, p. 11). So, for example, the elderly patient in a nursing home who develops an "organic psychosis" may say, on Monday, "The nurses are trying to poison me." On Tuesday, the same patient may have no particular fears regarding the nurses, but may complain, "My roommate is stealing my jewelry." However, in organic delusional syndromes without clouding of consciousness, Lishman notes that "…the delusions may be more coherently organized, with a picture more closely resembling schizophrenia." With respect to GMCs associated with anxiety, Colon and Popkin (1996) note that, "…there are few current data to indicate whether panic emerging in the medical patient differs from that seen in the primary psychiatric setting. In addition, no data are available about factors such as course and onset in the medical setting." One exception is the finding by Starkman et al. (1985) showing that in patients (N=17) with pheochromocytoma—a GMC long-associated with anxiety-- none described the severe apprehension or fear characteristic of panic attacks, and none described agoraphobia. Depression in the medical setting is comprehensively reviewed by Rouchell et al. (1996). Again, there are no pathognomonic signs that clearly point to "secondary" or "organic depressive symptoms." In addition, the standard diagnostic criteria for major depression in DSM-IV have not been normed for individuals with co-morbid medical illness. However, Goldman (1992) offers the following clues suggesting an underlying medical cause: an atypical clinical picture; resistance to standard treatments; unexplained personality changes; and subtle cognitive findings on mental status exam. The course of Psy-GMCs depends to a large degree on the nature of the underlying medical condition and how responsive it is to primary treatment. The course is also influenced by the extent and success of symptomatic psychiatric treatment. For example, when there is a progressive or intermittently active degenerative CNS process at work, such as multiple sclerosis, course and outcome are likely to be less favorable. On the other hand, psychiatric symptoms due to acute anticholinergic toxicity may be resolved within a matter of hours, if diagnosis and treatment proceed expeditiously.

Psychotic Disorder Due to GMC

Psychotic symptoms may result from a multitude of medical and neurological disorders, as well as from numerous drug-related side effects. Some of the more common organic etiologies are shown in Table 2.

Table 2: Medical Conditions Often Associated with Psychosis

Condensed and modified from Soreff & McNeil, 1987 In the DSM-IV, Psychotic Disorder Due to GMC is sub-typed based on the predominant symptom; i.e., "with delusions" or "with hallucinations." Of course, the two often occur together. The DSM-IV also specifies that the symptoms must not occur exclusively while the patient is delirious, or be better explained by another mental disorder. Although a plethora of medical and neurological conditions may produce psychotic symptoms, particular attention should be focused on disorders affecting the occipital and temporal regions. For example, cerebral tumors in these regions may produce hallucinations in various modalities, as well as delusions (Sadock & Sadock, 2007). The differential diagnosis of "psychosis" is therefore extremely important. In one study (Malmud, 1967) 6 of 11 patients with temporal lobe tumors initially presented with a diagnosis of schizophrenia, though other studies of patients with temporal lobe tumors have shown much lower rates of psychotic symptoms. Complex partial seizures originating in the temporal or frontal regions may also produce psychotic-like symptoms, as well as olfactory or gustatory hallucinations. Case vignette: Ms. A, a 38-year-old white female with long history of vague medical problems, was brought to emergency room by her family because she had boarded up all the windows at her house and refused to come outside. The patient claimed her neighbors were "spying" on her and "want to do me in." She was fully oriented, and both recent and remote memory intact. There was no fluctuation in her level of consciousness. The patient denied any unusual perceptual changes, auditory, visual, or tactile hallucinations. Physical examination was essentially normal. However, laboratory studies revealed normocytic anemia, leukopenia, and red cell casts in urine. Subsequent testing for antinuclear antibody (ANA) was strongly positive; a provisional diagnosis of systemic lupus erythematosus (SLE) with cerebral involvement ("lupus cerebritis") was made. Mood disorder due to general medical condition

The DSM-IV recognizes four main subtypes of mood disorder due to a GMC: with depressive features; with major-depressive like episode; with manic features; and with mixed features. The ICD-10 uses a slightly different scheme, differentiating organic manic disorder; organic bipolar disorder; organic depressive disorder; and organic mixed affective disorder. As with the psychoses due to GMCs, secondary mood disorders may stem from a multitude of underlying medical and neurological conditions. In consultation-liason settings, as noted earlier, the most frequent underlying GMCs were cerebrovascular accident (including stroke); Parkinson’s Disease; lupus cerebritis, HIV infection, hypothyroidism, and multiple sclerosis (Rundell & Wise, 1989). Post-stroke depression merits special attention, in that as many as 50% of all post-stroke patients experience depressive illness. A similar percentage applies to patients with pancreatic cancer, and to about 40% of patients with Parkinson’s Disease (Sadock & Sadock, 2007). However, the diagnosis of depression in the medical setting is complicated by the substantial overlap between somatic symptoms related to the underlying GMC, and neurovegetative symptoms of depression (for review, see Harnett, 2001). For example, some data (Musselman et al. 1998) indicate that major depression is seen in approximately 15-20% of patients with coronary (ischemic) heart disease (IHD). However, depression may sometimes be over-diagnosed in this population if "lethargy" or "apathy" secondary to congestive heart failure is inappropriately counted as signifying major depression. There may also be over-diagnosis of depression in IHD patients who have become "demoralized"—but not clinically depressed—about their medical setbacks (Harnett, 2001). Indeed, the pathophysiological relationship between underlying medical illness and mood disorder is quite complex. For example, it is not always clear to what degree a depressed medical patient may be "reacting psychologically" to the incapacity stemming from a GMC; or experiencing subtle but direct biochemical and immunological effects on the brain, stemming from the GMC (Harnett & Pies, in press). One illustration of this is in the area of IHD. Depression-related immune dysfunction may worsen IHD via inflammatory cytokines (e.g., interleukin-6, tumor necrosis factor alpha). But IHD-related immune abnormalities may also contribute to depression (Kop et al. 2005). Moreover, social isolation, psychosocial stress, and low levels of perceived support are related to both depression and IHD, and could mediate bidirectional effects on these conditions (Barth et al. 2004; Lett et al. 2004). However depression is a well-established risk factor for increased mortality in post-myocardial infarction patients. In short, there are very complex relationships between underlying medical illness and the appearance of depressive symptoms. This is also true, to some degree, with medication-related mood alterations. Establishing a causal connection between ingestion of a particular drug and the development of clinical depression is far from straightforward, notwithstanding epidemiological evidence linking some drugs with depression (Rogers and Pies, 2008). Although often mentioned as causes of drug-induced depression, beta blockers and calcium channel blockers are only weakly-linked with this side effect. In contrast, some medications—such as alpha-interferon and isotretinoin—do appear strongly, if not causally, linked with new- onset depression (Bonaccorso et al. 2002; Wysowski et al. 2001)

Case vignette: Mr. A., a 65-year-old married male without prior psychiatric history presented with a one month history of "feeling really down." He also related that, for the past three weeks or so, he had experienced vague gastrointestinal distress; decreased appetite; and a 15-lb weight loss. One month earlier, a close friend had died after a long illness, and Mr. A. attributed his sadness to this recent loss. Mental status exam was notable for a pale, cachectic individual whose affect appeared somewhat blunted, with occasional tearfulness. Cognitive examination was essentially within normal limits. Physical examination revealed an enlarged, non-tender gallbladder, and slight jaundice. Urinary amylase levels were elevated. A CT scan of the abdomen revealed cancer of the head of the pancreas with obstruction of the gallbladder.

Anxiety disorder due to general medical condition

The DSM-IV defines three main subtypes of anxiety disorder due to GMC: with generalized anxiety, with panic attacks, and with obsessive-compulsive symptoms. Although the overall prevalence of anxiety due to GMCs is not known, there is substantial evidence that medically-ill individuals have higher rates of anxiety than does the general public (Sadock & Sadock, 2007). For example, one study of patients with Parkinson’s disease found that 38% of patients received a current DSM-III-R anxiety disorder diagnosis, including panic disorder, generalized anxiety disorder, and social phobia (Stein et al. 1990). Importantly, severity of anxiety was not correlated with severity of parkinsonian symptoms, cumulative duration of L-dopa exposure, or current dose of L-dopa. Similarly, among diabetic patients, the lifetime prevalence rates for phobic disorders and generalized anxiety disorders were 26.5% and 41%, respectively (Lustman et al. 1986).

As with other categories of secondary psychiatric symptoms, anxiety due to GMCs may stem from many underlying causes, as shown in Table 3. Endocrinopathies—notably, hyperthyroidism, hypo- and hyperparathyroidism, and pheochromocytoma—are commonly associated with anxiety (as well as with depression). Cardiac arrythmias may be both the cause, and the result, of anxiety, sometimes leading to a "vicious cycle." For example, an individual with underlying heart disease who develops a "run" of supraventricular tachycardia may become very anxious upon experiencing the sensation of "palpitations", and thereby exacerbate or prolong the tachycardia. Although mitral valve prolapse is mentioned in older textbooks as a cause of anxiety (especially panic attacks), the evidence for this link is actually tenuous. One recent review (Filho et al. 2008) concluded that, "the more elaborate the study methodology, the lower the chance to observe a significant relationship between these (two) conditions."

A number of degenerative brain diseases may be associated with marked anxiety, including Alzheimer’s Disease (DAT), Wilson’s Disease, and Huntington’s Disease. The frequency of anxiety in patients with DAT averages 48%, versus about 6% in elderly patients without DAT (Mega et al. 1996; Apostolova & Cummings, 2008).

The list of medications causing anxiety is very extensive, and includes bronchodilators, thyroid preparations, theophylline, psychostimulants (such as methylphenidate), antipsychotics, and antidepressants. A variety of over-the-counter remedies, such as antihistamines and herbal preparations, may also trigger or exacerbate anxiety. Recently, anxiety, tachycardia, and even seizures have been linked with various "energy drinks" containing high concentrations of caffeine (Clauson et al. 2008).

Table 3: Medical causes of Anxiety

Modified and condensed from Colon & Popkin, 1996; and Soreff & McNeil, 1987

Case vignette: A 67 year-old. bedridden female was brought to the emergency room by her son. The patient had been experiencing severe anxiety for the past two hours. She was alert and oriented, but appeared extremely anxious and tremulous. Her breathing was rapid and patient complained of palpitations and lightheadedness. She had learned the day before that she was facing eviction from her apartment. The provisional diagnosis was "Panic attack with hyperventilation, precipitated by threat of eviction." Physical exam was notable for a pulse of 120; diaphoresis; and localized wheezes upon auscultation of the chest. A chest radiograph was within normal limits. However, a perfusion scintiscan of the lung revealed acute pulmonary embolus, and the patient was immediately hospitalized.

Personality change due to general medical condition

DSM-IV recognizes five main subtypes of personality change due to general medical condition (PC-GMC); i.e., labile, disinhibited, aggressive, apathetic, and paranoid. However, "other" "combined" and "unspecified" subtypes allow for the almost infinite variations and combinations of personality alterations that may be observed clinically. The older term "organic personality syndrome" also subsumes these categories. A variety of medical and neurological conditions may lead to alterations in the individual’s usual personality, temperament, or life-long character traits. According to Reid (1989), the most common causes of PC-GMC ("organic personality syndrome") are head trauma, cerebrovascular accident, and space-occupying intracranial lesions. Other common causes include temporal lobe epilepsy, multiple sclerosis, chronic intoxications, endocrine disorders, and CNS infections such as neurosyphilis. It is useful to focus on personality alterations due to lesions or dysfunction in frontal-subcortical circuits and within the temporal lobes. Tekin & Cummings (2002) have identified five parallel frontal-subcortical circuits that link specific areas of the frontal cortex to the striatum, basal ganglia and thalamus. Lesions originating in the orbitofrontal region lead to personality changes characterized by disinhibition; e.g., the patient begins to use profanity or exhibit sexually provocative behaviors. Lesions originating in the anterior cingulate portion of the frontal cortex produce an apathetic picture; e.g., a once outgoing and vociferous individual becomes withdrawn, indifferent, and uninterested in his usual activities. Lesions or abnormal electrical activity in the temporal lobes also produce alterations in personality. For example, in temporal lobe epilepsy, the most common psychiatric abnormality is personality change (Chuang, 2006). Hyperreligiosity, hypergraphia, and hyposexuality are reportedly more common in patients with temporal lobe epilepsy than with other forms of epilepsy (Chuang, 2006), though not all neurologists accept this view. Tumors within or impinging upon the temporal lobes may also produce alterations in personality, including irritability, hypochondriasis, or an accentuation of neurotic traits. Some of these alterations may actually reflect temporal lobe epilepsy secondary to the tumor (Lishman, 1998). Case vignette: A 63 year-old banker was fired for inappropriate sexual advances toward employee. He was subsequently picked up by the police for urinating in parking lot of exclusive restaurant and shouting obscenities. His wife described him as "just not himself over the past couple of months—it’s like he has no self-control and no conscience." Neurological exam in the psychiatrist’s office was essentially within normal limits, with no "focal" findings, except for abnormal grasp reflex (a tongue depressor repeatedly placed in the patient’s hand led to his repeatedly grasping it). Magnetic resonance imagery (MRI) showed a large meningioma of the orbitofrontal cortex.

Catatonic Disorder Due to General Medical Condition

"Catatonia" is probably best conceptualized as a syndrome with markedly diverse etiologies. Fink and Taylor (2006) have proposed three catatonia subtypes (nonmalignant, delirious, and malignant) and four specifiers (secondary to: mood disorders, general medical conditions or toxic states, neurological disorders, or psychotic disorders). When no identifiable medical or neurological cause is present, about 40% of cases prove secondary to mood disorders, whereas only about 10% are associated with schizophrenia (Sadock & Sadock, 2007). Catatonic disorder due to GMC is not a well-studied phenomenon, and its prevalence has not been clearly established. Features include immobility, psychomotor agitation, mutism, negativism, grimacing, peculiar motor behaviors (such as assuming and maintaining unusual postures, sometimes characterized by "waxy flexibility"), echolalia, and echopraxia. Medical and neurological causes of catatonia include drug toxicity, including neuroleptic malignant syndrome (NMS), CNS neoplasms, encephalitis, head trauma, lesions of the fronto-subcortical circuit, and contralateral parietal lobe lesions (Ovsiew, 2008). When catatonia is accompanied by fever and autonomic instability, it may represent malignant catatonia, a potentially lethal form of catatonia which needs emergent treatment with electroconvulsive therapy (ECT) (Fink & Taylor, 2006).

Case vignette: A 53-year old male presented to a psychiatrist with a provisional diagnosis of "late onset schizophrenia." The man had in fact been functioning quite well until about a year ago, when he developed insidious signs of forgetfulness, apathy, and abulia (loss of spontaneity and effort). Recently, he had also developed leg weakness and "fainting spells." However, his presentation to the psychiatrist was one of mutism and marked decrease in voluntary movements of any kind; indeed, the psychiatrist described the patient as "grossly catatonic." Given the atypical age of onset for schizophrenia, and history of leg weakness, an MRI was ordered. It revealed "ventriculomegaly; hydrocephalus secondary to subthalamic mesencephalic tumor involving the third and the lateral ventricles." Surgical placement of a ventriculoperitoneal shunt led to resolution of the catatonia over a period of several days (Neuman et al. 1996).

Amnestic Disorder due to GMC

Amnestic disorders entail impairment in the ability to learn new information, or to recall previously learned information. Amnesia is most commonly found in patients with a history of alcohol abuse or head injury, in which bilateral damage to mid-temporal lobe structures (such as the hippocampus, mamillary bodies or amygdala) has occurred. In the DSM-IV, the two primary categories are amnestic disorder due to GMC, and substance-induced persisting amnestic disorder. Numerous GMCs may produce amnestic disorder, including thiamine deficiency, hypoglycemia, carbon monoxide poisoning, hypoxia, and herpes simplex encephalitis, all of which tend to produce bilateral hippocampal damage (Sadock & Sadock, 2007). Korsakoff’s Syndrome (KS) is characterized by marked amnestic symptoms in the presence of generally preserved cognitive function in other spheres. Essentially, KS is the chronic amnestic phase of Wernicke-Korsakoff Syndrome. Though the predominant defect in KS is usually anterograde amnesia—i.e., impaired ability to retain new memories--there is often a retrograde amnestic component as well. Usually, there is relative sparing of remote memory. Lishman (1998) has noted that the line between Korsakoff’s Syndrome and so-called alcoholic dementia is not always sharp, and there are most likely gradations or intermediate states between these two conditions. KS–though conventionally attributed to thiamine deficiency—is closely associated with alcohol abuse and dependence. Indeed, Lishman (1998) goes so far as to opine that, "…the rarity of a fully fledged Korsakoff syndrome as a residue of thiamine deficiency in non-alcoholics raises the possibility that a direct neurotoxic action of alcohol may play some part in the evolution of the condition (p. 582)."

Medical and Laboratory Evaluation for Psy-GMC
Given the prevalence of undetected medical illness in psychiatric populations, it is incumbent upon the physician to treat all putative "psychiatric" symptoms with a certain degree of skepticism. As noted earlier in this chapter, one’s degree of suspicion is raised when the patient presents with a recent change in mental status, particularly when this occurs in temporal proximity to a known medical illness or drug-related event. Atypical presentations; late-life onset; and illness that fail to respond to standard therapies should all raise ones suspicion of a medical cause. The basic "work up" of suspected psychiatric symptoms due to GMC is outlined in Table 4.

Table 4: Physical Evaluation, Laboratory and Other Investigations for Psy-GMC

Treatment of Psy-GMCs
Treatment of individual Psy-GMCs is beyond the scope of this chapter, since it necessarily focuses on primary treatment of the numerous underlying medical conditions. Symptomatic treatment with psychotropic agents may be conservative for Psy-GMCs, and depends on whether the predominant disturbance is in the realm of mood, reality testing (psychosis), anxiety, personality, etc. Though psychotropics aimed at a particular GMC-related symptom may sometimes be useful—e.g., antipsychotics for "organic" psychosis, or antidepressants for depression due to a GMC—most psychotropics run the risk of further clouding the patient’s mental state, or introducing side effects and drug-drug interactions. Nevertheless, there is a role for judicious use of psychotropics in certain instances; e.g., antidepressants in post-stroke depression, or depression related to Parkinson’s disease. Acknowledgment: The authors wish to express their appreciation to Mantosh Dewan MD, Chairman, Dept. of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, for his strong support and encouragement of this project.