Cognitive Impairment

David B. Arciniegas

Thomas W. McAllister

Daniel I. Kaufer

I. Background

A. Definitions

Arousal—refers to a state of wakefulness that underlies the capacity to respond appropriately to environmental stimuli. Arousal is a continuum of function, with coma at the severely deficient end of that continuum and hyperarousal (as manifested in some delirious, manic, psychotic, or anxious individuals) at the other end of that continuum.
Speed of processing—refers to the rate at which an individual is able to process and respond to a stimulus. Information processing speed is most often described clinically in terms of reaction time or response latency (latency between stimulus presentation and a behavioral response).
Attention—refers to the capacity to detect, select, and focus on a stimulus (external or internal). Several component processes of attention include: (a) Multimodal filtering of sensory and cognitive information to select a stimulus for processing (sensory gating and selective attention, respectively); (b) maintaining focus on a stimulus over time (sustained attention); and (c) simultaneously attending to two or more stimuli (divided attention).
Memory—refers to the ability to learn, store, and retrieve information. There are several different but overlapping types and ways of categorizing memory based on the type of information learned (e.g., spatial vs. verbal) and the temporal interval between learning and retrieving (immediate vs. short term vs. long term). Working memory describes the process of keeping information in mind or “on-line” for short-term use in processing additional information, and overlaps both conceptually and nosologically with registration and also immediate memory.
Declarative memory (also known as explicit memory) refers to the ability to learn and store (or encode) and to retrieve factual information. Declarative memory is generally divided into two subcategories: Semantic memory, or memory for general knowledge (“who, what, where”), and episodic memory, or memory for personal experiences that are tied to particular times and places. Declarative memory also encompasses spatial memory, the learning, storage, and retrieval of visual-spatial information, and verbal memory, the learning, storage, and retrieval of verbally encoded information. Procedural memory (also known as implicit memory) denotes the ability to learn, store, and retrieve how to do things; conceptually and clinically, procedural memory overlaps considerably with praxis (defined in the subsequent text). Short-term memory refers to the ability to retain information for a period of several minutes to a few days, and long-term memory refers to retention of information over a period of days of longer.
Language refers to the communication of thought using symbolic (verbal or written) means. Language is generally divided into four domains: (a) Fluency, the ability to produce syntactically normal phrase lengths of six or more words without undue word-finding pauses; (b) repetition, the ability to reproduce phrases without error; (c) comprehension, the ability to recognize written or spoken symbols across multiple sensory domains and to attach linguistic meaning to them; and (d) naming, the ability to identify actions and objects across multiple sensory domains accurately. Language is distinct from speech, the motor capacity for producing verbal output (impairment of which is described as dysarthria), and from voice, the laryngeal function required for phonation (impairment of which is described as dysphonia).
Prosody refers to the affective import and kinesics (gestural elements) of language. Prosodic modulation permits communication of the emotion associated with spoken (or written or signed) language. Changes in prosody also permit emphasis on particular words in a sentence so as to change the meaning of that sentence.
Recognition—refers to the ability to integrate sensory information at a cortical level regarding objects, people, sounds, shapes, or smells (cortically based perception) and to attach meaning to those percepts (association).
Praxis—refers to the ability to execute skilled purposeful movements on demand given normal comprehension of the request and the elementary motor abilities to execute it. Praxis is most often classified into three types: Limb-kinetic, ideomotor, and ideational. Limb-kinetic praxis describes the ability to make finely graded, precise, individual finger movements on demand. Ideomotor praxis refers to the ability to perform a single previously learned skilled movement on demand. Ideational praxis refers to the ability to carry out a specific sequence of tasks on demand.
Visuospatial function—refers to the ability to assess spatial relationships between objects in the environment and also between the environment and oneself. This function is also involved in spatial attention, working memory, and short-term memory.
Executive function—refers to a variety of cognitive processes that contribute to selection, planning, and execution of adaptive behavior. These include: Volition (conceptualize what one wants), planning (outline and sequence a set of behaviors to achieve a desired end), purposive action (initiation and maintenance of behaviors that increase the likelihood of a desired end), and monitoring (assess progress of previously decided sequence of behavior in the furtherance of the goal). Mental flexibility” (integrate feedback and consider alternative actions), insight (the ability to realistically appraise one’s capacities and deficits, and to recognize and accurately attribute aberrant behaviors to illness), and judgment (the capacity to assess current situation, potential future action options, assign outcome probabilities to those options and pursue the one that best fits the short- and long-term goals) are other examples of executive cognitive functions.

II. Neuroanatomy and neurochemistry of cognition

A. Arousal

Arousal is the most fundamental cognitive function, and is supported by a set of selective distributed reticulothalamic, thalamocortical, and reticulocortical networks.
The reticulothalamic portion of the arousal system consists of cholinergic projections arising from the pendunculopontine and laterodorsal tegmental nuclei. These projections terminate in the body of the thalamus as well as the reticular nucleus of the thalamus, the balance of activity between which appears to modulate the degree of thalamic activity.
Thalamocortical projections, which are predominantly glutamatergic, also contribute to arousal by activating cortex and preparing it for information processing.
Cortical readiness to engage in information processing is modulated by the reticulocortical portion of the arousal system. This portion of the arousal system consists of dopaminergic projections arising from the ventral tegmental area of the midbrain, noradrenergic projections arising from the locus ceruleus, serotonergic projections arising from the median and dorsal raphe nuclei, and cholinergic projections arising from the medial septal nucleus and vertical limb of the diagonal band of Broca (to medial temporal structures) and also from the nucleus basalis of Meynert (to neocortical, and especially frontal, parietal, and lateral temporal areas). The balance between and reciprocal influences of the reticulothalamic and reticulocortical systems on the diencephalic and cortical targets to which they project influence level of arousal.
Injury to or dysfunction of any of these elements of the arousal system may impair this most basic cognitive function.

B. Attention and processing speed

Attentional processes are mediated by several large-scale, selective distributed neural networks. These networks include those involved in arousal described in the preceding text. Additionally, primary and secondary sensory cortices, heteromodal parietal cortical areas, medial temporal (i.e., hippocampal and entorhinal) areas, the striatum and pallidum, several prefrontal (i.e., cingulate, inferolateral, and dorsolateral) cortices, and the axonal connections between them are components of these distributed attentional networks.
Electrophysiologic and functional neuroimaging studies suggest that the neurobiological bases of sensory gating, selective attention, and sustained attention differ from one another. Sensory gating appears most strongly related to the function of a cholinergically dependent hippocampal inhibitory circuit, and is a prerequisite for the development of selective attention within sensory cortical-hippocampal-thalamo-frontal networks. Sustained attention is most strongly related to the function of inferolateral frontal-subcortical and dorsolateral prefrontal-subcortical circuits.
The function of attentional networks is dependent on a complex set of interactions between the major neurotransmitter systems, including those regulating the availability and function of cortical dopamine, norepinephrine, serotonin, acetylcholine, glutamate, and γ-aminobutyric acid (GABA).
Acute or chronic structural and neurochemical dysfunction within the several networks serving attention contribute to impairments in this cognitive domain. Impairments in attention may also contribute to problems with the speed of information processing.

C. Declarative memory

Declarative memory is a hippocampally dependent process.
Highly processed multimodal sensory information is transmitted from the inferior parietal (heteromodal) association cortices to the entorhinal-hippocampal complex. When that information produces a sufficiently robust signal in the hippocampus (a process that is, at least in part, predicated on assignment of motivational, emotional, or other “survival-related” significance by amygdala–hippocampal interactions), the process of long-term potentiation (LTP) is initiated and that information is encoded for later recall.
Output from the hippocampus travels to several target sites. Most hippocampal output travels through the fornix to the mamillary bodies and anterior thalamus; this pathway is generally regarded as that through which the hippocampus participates most strongly in the process of declarative memory. A smaller portion of hippocampal efferents in the fornix split off anterior to the anterior commissure as the precommissural
fornix, from where they continue to their targets in the septal and preoptic areas, orbital cortex, and anterior cingulate cortex. Although these areas may also be important to the development of declarative memory, their function appears to be more closely tied to homeostatic processes mediated by the limbic system.
After information is communicated through the hippocampal-forniceal-mamillo-thalamic pathway, it is further distributed to frontal areas involved in the process of memory development (consolidation). The time required for consolidation is variable, ranging from only a few minutes to many months.
Following consolidation of memories, retrieving declarative information requires prefrontal structures to activate the selective distributed networks where that information was originally encoded.
By virtue of the distributed nature of the networks involved in encoding of declarative information, declarative memory is highly associative: Memories may be retrieved by reactivation of nearly any part of the network involved in the original encoding of that information or by activation of other networks whose constituent elements are shared by the network involved in the original encoding of that information.
Although the neurochemistry of declarative memory is complex, glutamate and acetylcholine appear to be particularly important. The action of glutamate at N-methyl-D-aspartate (NMDA) receptors is involved in the process of LTP. Acetylcholine appears to facilitate this process, possibly through its establishment of pre- and postsynaptic excitatory potentials in the neurons involved in the process of LTP.
Acute or chronic structural and neurochemical dysfunction within the several networks serving declarative memory may contribute to impairments in this cognitive domain.

D. Procedural memory

Procedural memory is predicated on the development and fine-tuning of the sensorimotor-frontal-subcortical-cerebellar networks that are required for learning and efficiently retrieving complex sensorimotor routines.
Procedural memory is not hippocampally dependent and its function and dysfunction are dissociable from declarative memory.
Procedural memory is not associative, but is instead dedicated: It is inflexibly limited to the context (i.e., the specific sensorimotor processes) in which it is acquired.
Normal performance in this domain is dependent on many of the same neurotransmitters required by the frontal-subcortical circuits involved in retrieval of declarative information.
Acute or chronic structural and neurochemical dysfunction within the several networks serving procedural memory may contribute to impairments in this cognitive domain.

E. Language

Language refers to the symbolic means of representing and communicating thought, and is in most cases a function of the dominant cerebral hemisphere.
Fluency is predicated on a network of frontal structures, including dorsolateral prefrontal motor association, and anterior insular cortices, white matter, and subcortical structures through which these areas are connected, and the frontal opercular (Broca) area. Output from this network of structures requires intact connections between primary motor cortex and the parts of the body used to communicate verbally or by writing. Communication impairments related to disturbances in elementary motor function are generally distinguishable from true language disturbances (aphasias).
Comprehension is predicated on a network of temporoparietal structures, including at least the superior temporal language association cortex (Wernicke area), inferior parietal heteromodal association cortex, and the white matter structures connecting them. Comprehension depends on the integrity of peripheral sensory structures, their connections to primary sensory cortices, and the connection of these areas to sensory association systems. Communication disturbances due to impairments in peripheral sensory organs, primary sensory cortices, and also the connections between them, are distinguishable from aphasias.
The neural networks serving fluency and comprehension are distinct and dissociable, resulting in the distinct patterns of language impairments referable to dysfunction in each of these networks.
Repetition is served by a distinct network composed of Wernicke area, a phonologic output area at the anterior border of Wernicke area, Broca area, and the arcuate fasciculus that connects the posterior and anterior language areas. Disruption in any of these areas results in impairment of repetition.
Naming is subserved by widely distributed neural networks that overlap substantially with those upon which fluency, comprehension, and repetition are predicated. Consequently, impairment of naming (anomia) usually accompanies impairments in these other areas of language.
The neurochemistry of language impairment, and other neurologic conditions.
Acute or chronic structural and neurochemical dysfunction within the several networks serving language may contribute to impairments in this cognitive domain.

F. Prosody

Prosody demonstrates a pattern of nondominant hemispheric specialization. The nondominant hemisphere structures and networks serving prosody are simplistically understood as roughly homologous with those in the dominant hemisphere serving the syntactic and semantic aspects of language.
Impaired function of the nondominant frontal structures involved in prosody may produce disturbances in the affective and kinesic aspects of language production, resulting in flat or monotonous expression that fails to communicate effectively its emotional relevance and nuance.
Impaired function of the nondominant temporoparietal structures involved in prosody results in disturbances in the appreciation of the affective and kinesic aspects of the communications of others.
At present, little is known about the neurochemistry of prosody.

G. Praxis

Praxis displays a pattern of dominant hemisphere specialization.
The dominant hemisphere neural networks subserving praxis are anatomically colocated, and may overlap, with those serving language. Consequently, the apraxias tend to be associated with the aphasias, and particularly the nonfluent aphasias.
The neurochemistry of praxis is not well established, but striatal dopaminergic function appears to play an important role in this cognitive function.
Acute or chronic structural and neurochemical dysfunction within the several networks serving praxis may contribute to impairments in this cognitive domain.

H. Visuospatial function

Visuospatial function displays a pattern of nondominant hemisphere specialization.
The nondominant hemisphere networks subserving visuospatial function (including spatial attention, spatial working memory, and spatial orientation) includes elements of the reticular system, thalamus, superior colliculus, striatum, posterior parietal cortex, frontal eye fields, and parietal cortex.
Most of the major neurotransmitter systems (i.e., glutamate, GABA, acetylcholine, and dopamine, among others) are involved in visuospatial function. Cortical noradrenergic projections, which have a right-hemisphere predilection, and cortical dopaminergic pathways, which are frontally predominant, may be particularly important for spatial attention.
Acute or chronic structural and neurochemical dysfunction within the several networks serving visuospatial function may contribute to impairments in this cognitive domain.

I. Executive function

Executive function is mediated primarily by the dorsolateral prefrontal-subcortical circuit, which integrates the processing, interaction, and output of other cognitive processes (i.e., language, memory) carried out elsewhere in the brain.
Although the role of the dorsolateral prefrontal-subcortical circuit is essential for executive function, there is evidence suggesting that the anterior cingulate and also the lateral orbitofrontal-subcortical circuits participate in the development of executive function as well.
The function of these circuits is dependent on a host of neurotransmitters including glutamate (serving as the primary excitatory neurotransmitter), acetylcholine, dopamine, norepinephrine, serotonin (serving various modulatory functions), and GABA (serving as the primary inhibitory neurotransmitter), among others.
Executive dysfunction may arise as a direct effect of injury to any element (cortical, subcortical, or axonal) of this circuit, the neurochemical systems that modulate function within this circuit, and/or the connections between the “basic” cognitive processing networks and this circuit.

III. Classification of cognitive impairment

The Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM-IV) (1) describes several disorders where cognitive impairment is the defining feature. These include delirium, the dementias, amnestic disorders, developmental disorders, and cognitive disorder not otherwise specified (NOS).
Delirium (see Chapter 2) is characterized by an alteration in attention, perceptual disturbances (i.e., hallucinations), and consciousness (altered and/or fluctuating). Other terms often used to describe delirium include acute confusional state and encephalopathy.
Amnestic disorders are characterized by deficits in memory in the absence of, or out of proportion to, deficits in other cognitive domains. The DSM-based classification system specifies three general categories of amnestic disorders: Amnestic disorder due to a general medical condition, substance-induced persisting amnestic disorder, and amnestic disorder NOS (i.e., amnesia due to any other cause). To meet criteria for an amnestic disorder, the memory impairment must represent a decline from a previous level of ability and be sufficiently severe to impair functioning in one or more important domains of activity (i.e., social, occupational, etc.). The DSM-based diagnosis of an amnestic disorder also requires that the impairment is not better accounted for by delirium, dementia, substance use or withdrawal, or another psychiatric disorder.
In the DSM-based classification system, dementia (see Chapter 4) is characterized by prominent impairments of memory and at least one other cognitive domain (e.g., attention, language, praxis, recognition, and/or “complex cognition” [executive function]). Additionally, the cognitive impairments must impair social, occupational, or other important daily functions. Although there is an explicit relationship between cognitive impairment and functional disability in this definition of dementia, recent evidence suggests that cognitive impairments contribute to, but do not entirely account for, functional
disability; other neuropsychiatric impairments (e.g., emotion, behavior, and/or elementary sensorimotor impairments) are likely contributors to functional disturbances as well. Dementias may be reversible (e.g., dementia due to hypothyroidism, and nutritional deficiencies), static (e.g., dementia due to TBI), or progressive (e.g., Alzheimer dementia).
The diagnosis of cognitive disorder NOS is used when the patient presents with functionally significant cognitive impairments that do not meet criteria for any of the other cognitive disorders listed in the DSM. For example, this diagnosis might be applied to a patient with isolated impairments of language (aphasia), praxis (apraxia), recognition (agnosia), visuospatial function, or executive function, particularly when such impairments occur in the absence of memory impairment (absent which they fail to meet DSM criteria for dementia). Although the DSM-IV-TR mentions “mild neurocognitive disorder” and “postconcussional disorder” as examples of cognitive disorder NOS, the criteria provided for these diagnoses are for research purposes only and should not be used in clinical practice.
Although not included presently in the DSM-based classification of disorders, mild cognitive impairment (MCI) is an emerging term that has been applied as a descriptor for impairment in any of the major domains of cognition (e.g., “mild memory loss,” or “mild problems with attention”). More recently, MCI has been used to describe a syndrome characterized by complaints of memory difficulty and (1) minimal or no functional impairment of usual activities of daily living, (2) normal general cognitive function, (3) abnormal memory test performance relative to age norms and the individual’s baseline memory function, and (4) does not meet criteria for clinical diagnosis of dementia.
Cognitive impairment may be a feature of other conditions where non-cognitive symptoms are the defining feature of the illness. For example, individuals with depression have measurable decrements in attention and memory, and individuals with schizophrenia frequently demonstrate impairments in visual and auditory information processing, sustained attention, working memory, verbal episodic memory, and executive function.

IV. Treatment of cognitive impairment

A. General issues

1. Epidemiology

Cognitive complaints are common among individuals with neurologic and neuropsychiatric disorders (e.g., TBI, stroke, Parkinson disease, multiple sclerosis, or HIV/AIDS, etc.). In some cases, for example, the dementias, cognitive impairment, and associated impairments in day-to-day function are the defining features of the clinical presentation and are therefore present among all individuals with such conditions. In other settings, for example, TBI, HIV/AIDS, and multiple sclerosis, cognitive impairments are a common but not
invariant element of a multidimensional set of neuropsychiatric problems. Across all of these conditions, the frequency and severity of cognitive complaints or impairments varies with a host of premorbid (e.g., age, or education), condition-specific (e.g., degenerative, traumatic, or demyelinating), and associated psychiatric, medical, and psychosocial factors. Despite the influence of these factors on clinical presentation, however, two points are clear: (1) Cognitive complaints and deficits can be the presenting symptom in all of these disorders, and (2) cognitive complaints and deficits are an important source of distress and disability in all of these disorders.

2. Prognosis

Treatment of cognitive deficits. The second includes individuals with delirium or dementing disorders that are reversible with appropriate treatment (e.g., dementia due to depression, endocrine or nutritional disorders, and/or infectious encephalopathies). The third consists of individuals with static brain insults that affect cognitive function (e.g., individuals with TBI, focal vascular events, radio- or chemotherapy-induced brain injury, neurodevelopmental disorders, etc.).
The prognosis and goals of treatment vary considerably with the cause and severity of such impairments. From a therapeutic standpoint, treatment for cognitive deficits may fall into the category of disease altering (correction of the underlying disorder), or symptomatic (treatment of the cognitive deficits that are causing excess disability).
There are at present no disease-altering treatments for individuals with progressive neurodegenerative disorders. Accordingly, the long-term prognosis for cognitive function in these populations is universally poor. Appropriate goals of treatment are to augment current cognitive functions to the greatest extent possible, to delay progression of symptoms when possible, and to improve quality of life despite persistence and/or progression of symptoms.
Among individuals with delirium or “reversible” dementia syndromes, the prognosis is generally favorable provided proper diagnosis is made and appropriate treatment provided. With prompt and effective treatment of the underlying medical/neurologic condition, the goal of treatment is to effect a “cure” of cognitive impairments resulting from that condition.
Among individuals with static neurologic disorders affecting cognitive function (e.g., TBI, stroke, or hypoxic-ischemic brain injury), the prognosis for recovery of cognitive function typically varies as a function of the nature, severity, and chronicity (i.e., time since onset) of the disorder. Facilitating
cognitive recovery to the greatest extent possible and improving quality of life despite persistent disability are appropriate treatment goals.

3. General management principles

a. Diagnosis

History—The diagnosis of cognitive impairment in neuropsychiatric disorders should follow a logical process. It is important to ask about the following areas:
- Complaints or deficits—Determine first whether the problem is subjective (cognitive complaints), objective (cognitive impairment), or both. This requires a careful history regarding premorbid factors (and especially the highest level of cognitive function obtained before symptom onset), the types of cognitive impairments experienced, their severity, and their functional consequences. Collateral history from reliable informants (e.g., observers, data describing prior function, etc.) is essential.
- Time course—Carefully outline the time course of the problem. Did the problem develop acutely or insidiously? Has the decline shown a continuous or interrupted trajectory? Answers to these questions help inform whether one is dealing with a static or progressive problem, and may yield important clues regarding the etiology of the problem.
- Relationship to other neurologic symptoms and events—Clarify whether the cognitive problems are an isolated symptom/syndrome, manifestations of an identifiable neurologic disorder, or associated features of a primary psychiatric disorder (e.g., depression, or anxiety). Identifying and interpreting cognitive complaints with respect to each of these possibilities is essential for developing a refined differential diagnosis for the patient’s clinical presentation and formulating appropriate treatment goals.
- Profile of symptoms and signs—Define the spectrum of symptoms and signs that are the target behaviors. Clarify whether the problems fall primarily within the domain of attention, memory, language, praxis, recognition, visuospatial function, executive function, or some combination of these. This assessment sheds light on the likely underlying etiology and will also help inform initial treatment. This process requires a careful history, “bedside” cognitive testing, and often additional assessments (see subsequent text).
Diagnostic assessment—Diagnostic assessments generally fall into two broad categories. The first involves characterizing the profile of cognitive complaints and capacities, and the second involves identifying the cause of these problems.
- Profile of cognitive deficits—Initial office or “bedside” assessment of cognition is the first step in characterizing whether one is dealing with cognitive complaints, cognitive deficits, or both. There are a variety of bedside assessments of cognition, the most commonly used of which include the Mini-Mental State Examination (MMSE), the Clock Drawing Test (including the CLOX), the EXIT25 (a measure of executive function), and the Frontal Assessment Battery (FAB). Each of these and similar measures have their individual strengths and weaknesses.
  
  Normative databases describing age- and education-adjusted performance expectations are available for many of these measures. Given the strong influence of age and education on performance on such measures, comparison of an individual patient’s score on these measures is strongly recommended over use of “cutoff” scores. Because the latter does not account for the influence of such variables on cognitive performance, some individuals with “normal” cognitive function will be misclassified as impaired, and vice versa, when cutoff scores are used.
  
  When screening assessments fail to identify impairments in the cognitive domains suggested by patient complaints or history, referral for formal cognitive assessments (neuropsychological testing) and performance of additional diagnostic testing (see subsequent text) is recommended. Formal neuropsychological testing should include indicators of psychiatric/psychological processes known to adversely affect performance on cognitive assessment measures, particularly anxiety, and depression.
- Physical examination—A general medical and neuropsychiatric examination is required on all patients.
- Additional diagnostic assessments—The selection of additional diagnostic assessments varies with the clinical context. Serum laboratory assessments for common reversible causes of cognitive impairment (i.e., vitamin B₁₂ and thyroid stimulating hormone) is recommended; when justified
  by the clinical history, other serum (e.g., HIV, rapid plasma reagin [RPR], antinuclear antibodies [ANA], liver function tests, electrolytes, and complete blood count, etc.) and urine (e.g., urinalysis, and urine toxicology) assessments may be appropriate. When epilepsy or delirium is suspected, electroencephalography (EEG) may inform the diagnostic assessment. Structural brain imaging is strongly recommended in the evaluation of all patients with cognitive impairment, and particularly among those in whom the clinical examination suggests existence of structural brain disease.

b. General treatment considerations

Development of a therapeutic alliance and promotion of treatment adherence—Many individuals with cognitive impairments may have limited awareness of the nature, severity, or functional consequences of their deficits. This can make developing a therapeutic alliance challenging. Patient “resistance” may reflect psychological denial (not wanting to be labeled as “brain damaged” or “demented”), a deficit in self-monitoring and awareness of illness (anosognosia), or both. Nonetheless, establishing such an alliance with these patients and, when relevant, their caregivers is essential for developing a realistic and effective treatment plan.
Treat comorbid conditions—A variety of conditions can produce or exacerbate cognitive impairments; among the most common are depression, anxiety, substance use disorders, sleep disorders, and physical discomfort or pain. Side effects from medications used to treat many medical, neurologic, and psychiatric conditions are also common causes of cognitive impairment. A thorough assessment of these issues is imperative before prescribing medications or nonpharmacologic treatments specifically for cognition. Optimizing treatment of comorbid conditions and reducing or eliminating medications with potentially adverse effects on cognition are important steps before treating cognition specifically.
Cognitive remediation or rehabilitation—Nonpharmacologic interventions may be effective for the treatment of cognitive impairments, particularly among individuals with static brain disorders (e.g., TBI, stroke, hypoxic-ischemic brain injury, and possibly schizo-phrenia). Such interventions for domain-specific cognitive impairments are described in the following sections of this chapter. Successful cognitive remediation or rehabilitation interventions generally include a
mix of stimulus modalities, complexity, and response demands, and active involvement of the therapist in terms of performance monitoring, feedback, and skills/strategy training. These interventions are “successful” to the extent that they generalize beyond the context of treatment—in other words, these interventions should be designed in such a way that they improve not only performance on the office-based tasks (e.g., attention training on a computerized test) involved but are applicable to everyday function (e.g., attentional processing in real-world settings).
Environmental strategies and approaches—Several strategies can be effective in minimizing the functional consequences of cognitive impairments.
- Time for performance—One of the core deficits associated with many neurologic disorders is reduced speed of information processing. “Absolute” function or task-accuracy may be reasonably normal if the patient is afforded sufficient time to perform. Simple interventions such as waiting longer for verbal responses (i.e., teaching others not to respond or perform immediately for the individual) and allowing longer intervals to accomplish tasks, whether in the context of activities of daily living, educational endeavors, or in vocational settings, may permit the individuals to maximize their “real-world” functional performance.
- Cognitive prosthetics—Encouraging the use of memory notebooks, timers with alarms and messages, tasks lists, and provision by others of verbal or nonverbal cues may permit the individuals to compensate for cognitive deficits and maximize their functional independence. The use of cognitive prosthetics may reduce affective responses (i.e., anxiety, anger/agitation) that may otherwise result from real or perceived cognitive failures.
- Technology—Assistive technologiesmay permit compensation for more severe cognitive impairments, and particularly language impairments. Consultation with speech and occupational therapists experienced in the selection and use of such technologies is recommended.
- Environmental accommodation—Stimulating environments may tax the ability of individuals to select and sustain attention appropriately, to process information at the speed demanded by the environment, and to develop flexible and adaptive responses to environmental demands. As suggested in the preceding text, overtaxing environments may produce cognitive failures and
  precipitate otherwise avoidable and unwanted affective and behavioral responses. Identifying environmental antecedents to cognitive failures and the affective–behavioral problems they produce may facilitate improvements in functional cognition, reduce disability, and alleviate patient and caregiver distress.
- Tailor demands to peak capacity—Individuals with cognitive impairment and neurologic disorders often struggle with physical and cognitive fatigue. Performance of tasks otherwise within the functional abilities of such individuals may decline significantly as they fatigue. It is helpful to outline daily events and challenges and schedule them to coincide with periods when the individual is well rested and refreshed.
Pharmacotherapy—Pharmacologic interventions for cognitive impairments are most usefully regarded as adjuncts to nonpharmacologic therapies. The individual response to treatment is highly variable, both with respect to specific agents and also doses. Although a “start-low, go-slow” approach is prudent when prescribing neuroactive agents to individuals with neurologic disorders, standard doses of such agents are often required. Because there are no U.S. Food and Drug Administration (FDA)-approved medications for the treatment of these cognitive impairments described in this chapter, individual treatment remains a matter of clinical judgment and empiric trial.
Integrate treatment from multiple clinicians—Patients with cognitive impairments receive treatment from multiple clinicians. Communication between clinicians is needed to ensure that treatments offered are not working at cross-purposes.
Document treatment effects—Serial assessment of cognition, whether by bedside or formal neuropsychological assessments, allows accurate recording of the degree of response (or lack thereof) to a given intervention, whether nonpharmacologic or pharmacologic, and avoids repeat administration of previously unsuccessful treatments.

V. Disorders of Arousal

A. Clinical background

1. Occurrence and prevalence

Disturbances of arousal may fall on the continuum from states of hyperarousal, as seen among individuals with mania, anxiety disorders, and some forms of delirium, to hypoarousal of varying degrees of severity. The former are considered elsewhere in this volume. Here
we consider impairments of arousal including coma, vegetative states (VS), including persistent vegetative states (PVS), and the minimally conscious state (MCS). TBI, hypoxic-ischemic brain injury, cerebrovascular events (especially subarachnoid hemorrhage), metabolic disturbances due to conditions such as hyper- or hypoglycemia, hepatic or renal failure, endocrine disorders (e.g., severe hypothyroidism), medication intoxications (both accidental and intentional), cerebral neoplasms, and congenital/developmental disorders are among the most common causes of impaired arousal. The frequency of coma and other states of impaired arousal (consciousness) varies with the type and severity of the underlying conditions.

2. Phenomenology

Coma represents a complete failure of the arousal system: Patients in coma appear unconscious, demonstrate no spontaneous eye opening, and are unable to be awakened by application of vigorous sensory stimulation. Patients in coma do not demonstrate evidence of sleep–wake cycles.
VS describes a condition in which “core” consciousness (simple arousal) is relatively preserved but “higher” consciousness (i.e., self- and environmental awareness) is completely absent. However, patients in VS may retain capacity for spontaneous or stimulus-induced arousal, and may demonstrate sleep–wake cycles. When such impairment lasts for more than a few weeks, the term PVS is used to describe the condition.
MCS is characterized by inconsistent but clearly discernable behavioral evidence of consciousness such as following simple commands, gestural or verbal yes/no responses (regardless of accuracy), intelligible verbalization, and purposeful behavior. The latter include movements or affective behaviors that occur in response to an understandable environmental stimulus and are not better attributable to reflexive behavior.

3. Course and prognosis

The course and prognosis impaired arousal varies with the type and severity of underlying illness as well as the depth and duration of the state of impaired arousal.

Emergence from coma within the first day after onset is generally associated with a more favorable prognosis. Conversely, persistence of impaired consciousness beyond the first 24 hours after onset, and certainly beyond the first week thereafter, is usually associated with a poor prognosis for recovery.
The transition from coma to VS is marked by fading of decerebrate reactions (when present initially), development of sleep–wake cycles, and the emergence of spontaneous or stimulus-induced arousal.
Patients with coma or PVS may progress to MCS; for some of these patients, MCS is a transient state during the process
of continued recovery, although for others MCS may become a permanent condition. The distinction between MCS and higher states of consciousness is somewhat arbitrary, but the development of functional interactive communication, functional use of at least two different objects (suggesting a capacity for object discrimination), or both is generally regarded as evidence supporting emergence from MCS. In a minority of individuals with severe congenital cerebral disorders, MCS may be a permanent outcome. MCS may also be a late feature of neurodegenerative disorders.

B. Neuropathogenesis

Coma and other states of impaired arousal reflect impairment of the brainstem, diencephalic, and cortical structural and neurochemical networks serving this basic domain of cognition. Impairment of the deeper (i.e., reticular, reticulothalamic, reticulocortical) elements of these systems is generally associated with more severe impairments of arousal such as coma and VS/PVS. Disruption of the thalamocortical elements of these networks is more often associated with VS/PVS and MCS.

C. Diagnosis

Although impaired arousal is usually evident on basic clinical examinations, the distinction between coma, VS/PVS, and MCS is challenging. Giacino et al.¹ recommend the following steps be taken to establish an accurate diagnosis:

Provide adequate stimulation to ensure that arousal is maximized.
Reduce factors that may impair arousal (e.g., sedating medications, or seizures, etc.).
Avoid verbal or other stimuli that provoke reflexive responses.
Design command-follow trials that are within the patient’s motor abilities.
Assess a broad range of behavioral responses using a broad range of eliciting stimuli.
Conduct examinations in an environment free of potentially distracting stimuli.
Perform serial reassessments using systematic observations and reliable measurement strategies to confirm findings from initial assessments.
Observe interactions between the patient and others; this may be useful for the purpose of data collection and for the development of assessment procedures tailored to the condition and capabilities of the patient.

Structural neuroimaging of individuals with impaired arousal using computed tomography and/or magnetic resonance imaging (MRI) Laboratory assessment
for metabolic, endocrine, toxic, and other medical conditions is also essential.

D. Treatment

1. Optimize the physical health

In light of the many and varied causes of states of impaired arousal, identification and treatment of the underlying cause is the first and most important intervention. Use of supportive measures and prevention of medical complications is essential.

2. Optimize the patient’s environment

Manage the patient’s environment to provide cues that may facilitate adaptive engagement while minimizing the potential for overstimulation and attendant behavioral disturbances. For example, it may be useful to structure the environment such that sleep–wake and feeding cues are provided in a manner that may entrain circadian rhythms. Avoiding unnecessary procedures and minimizing pain may also be useful. Although such interventions are intuitively appealing, the evidence supporting their effectiveness is lacking.

3. Nonpharmacologic interventions

The term “coma stimulation” refers to structured sensory stimulation in the service of promoting recovery of sensory awareness, and hence recovery from coma. Although three randomized controlled trials of such programs suggest a possible benefit of coma stimulation, a recent review of these and other studies concluded that the data is insufficient to definitively support or refute the effectiveness of such programs.⁴ However, the safety of this treatment is not a subject of controversy. Because it is unlikely to cause harm, we recommend use of a time-limited trial of coma stimulation in the treatment of individuals in coma, VS, PVS, and MCS.

4. Pharmacotherapy

There are no FDA-approved treatments for coma, VS, PVS, or MCS. The neurochemical bases of arousal predict that augmentation of cerebral catecholaminergic, glutamatergic, and/or cholinergic function might improve impaired arousal. The clinical literature most strongly supports the use of agents that directly or indirectly augment catecholaminergic function for this purpose. We recommend amantadine as a first-line agent for coma, VS, PVS, and MCS, based on its safety and demonstrated efficacy in two randomized, double-blind, placebo-controlled studies.⁵^,⁶

Amantadine is generally started at a dose of 50 mg twice daily, and is usually increased every week by 100 mg/day for either symptomatic improvement is achieved or medication intolerance develops. Amantadine 100 mg twice daily is often sufficient to improve these symptoms without undue side effects. The maximum dosage of amantadine should not exceed 400 mg daily. Common side effects include headache, nausea, diarrhea, constipation, anorexia, dizziness, lightheadedness, and orthostatic hypotension. Anxiety, irritability, depression, and hallucinations may also develop during treatment with this agent, but are relatively uncommon. At higher doses, psychosis and confusion may occur. Abrupt withdrawal of this agent
has been associated (rarely) with neuroleptic malignant syndrome. Additionally, coadministration of triamterene/hydrochlorothiazide may decrease renal excretion of amantadine, resulting in medication intolerance at doses that would ordinarily be regarded as within the usual therapeutic range. Amantadine also potentiates the effects of agents with anticholinergic properties. Adverse reactions to amantadine appear to occur more often in elderly patients than in younger patients. Amantadine may lower seizure threshold, and clinicians are advised to be vigilant for the development or worsening of seizures when using this agent.

References

1. Giacino JT, Ashwal S, Childs N et al. The minimally conscious state: Definition and diagnostic criteria. Neurology. 2002;58(3):349–353.

2. Brenner RP. The interpretation of EEG in stupor and coma. Neurologist. 2005;11(5):271–284.

3. Carter BG, Butt W. Are somatosensory evoked potentials the best predictor of outcome after severe brain injury? A systematic review. Intensive Care Med. 2005;31(6):765–775.

4. Lombardi F, Taricco M, De Tanti A et al. Sensory stimulation for brain injured individuals in coma or vegetative state. Cochrane Database Syst Rev. 2002;(2)CD001427.

5. Meythaler JM, Brunner RC, Johnson A et al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: A pilot double-blind randomized trial. J Head Trauma Rehabil. 2002;17(4):300–313.

6. Whyte J, Katz D, Long D et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study. Arch Phys Med Rehabil. 2005;86(3):453–462.

VI. Impairments of Attention and Processing Speed

A. Clinical background

1. Occurrence and prevalence

Impairments of attention and processing speed are common cognitive manifestations of many neurologic and neuropsychiatric conditions. However, firm estimates of the prevalence of such impairments both within and across these disorders is lacking. Impairment of attention is the cardinal feature of attention deficit hyperactive disorder (ADHD) and also delirium. The Centers for Disease Control and Prevention (http://www.cdc.gov/ncbddd/adhd/) estimate that, 4.4 million youth, ages 4 to 17, were diagnosed with ADHD during 2003.

2. Phenomenology

Attention is best understood as a category of cognitive function with several components; selective, sustained, and divided attention are the domains where clinical impairments are most often identified. Impairments of selective attention (including sensory gating) manifest as difficulties directing robust attention to even a single environmental or cognitive target. By contrast, impairments of sustained attention (concentration)
manifest as difficulty with continued attention to a target after its selection (distractibility). Impaired speed of processing generally manifests as delayed response or reaction times to stimuli or tasks, delayed completion times, and a general “slowing” of cognitive processing. The boundaries of these processes overlap with many other aspects of cognition, including arousal, perception, recognition, memory, and executive function. Accordingly, attention disturbances may exacerbate impairments in these other domains of cognition.

3. Course and prognosis

Impairments of attention and processing speed may be transient and reversible manifestations of some neurologic conditions (e.g., TBI, medication, other intoxication or withdrawal states, etc.), static problems in other conditions (e.g., ADHD), or progressive impairments in others (e.g., multiple sclerosis, neurodegenerative dementias such as diffuse Lewy body disease, Parkinson disease, etc.). Accordingly, the course and prognosis of such impairments vary with the underlying condition on which they are predicated.

B. Neuropathogenesis

Because attention is predicated on several large-scale selective distributed neural networks, dysfunction of the cortical, subcortical, brainstem, or axonal elements of these networks may produce impairments in attention. Electrophysiologic and functional neuroimaging studies suggest that the neurobiologic bases of sensory gating, selective attention, and sustained attention differ from one another.¹ Sensory gating appears most strongly related to the function of a cholinergically dependent hippocampal inhibitory circuit, and is a prerequisite for the development of selective attention within sensory cortical-hippocampal-thalamo-frontal networks. Sustained attention is most strongly related to the function of inferolateral frontal-subcortical and dorsolateral prefrontal-subcortical circuits. The function of these circuits is dependent on a complex set of interactions between the major neurotransmitter systems, including those regulating the availability and function of cortical dopamine, norepinephrine, serotonin, acetylcholine, glutamate, and GABA. Although the neuropathologic bases of impaired processing speed overlap substantially with those producing attention impairments, reduced speed of processing is most commonly attributed to disturbances in structure or function of the cerebral white matter.

C. Diagnosis

Identification of impaired attention and/or processing speed involves clinical interview of the patient and/or other reliable informants and also objective testing. In the DSM-based classification system, a diagnosis of ADHD requires not only subjective report of attention problems but also evidence of functional disturbances resulting from such problems in at least two important domains of daily activity (e.g., school, work, or interpersonal relationships, etc.). Most commonly used bedside measures of cognition are inadequate for the assessment of impairments in attention and processing speed. The use of continuous performance tasks such as the Paced Auditory Serial Addition Test, or other quantitative measures of accuracy and
reaction time, are recommended for the diagnosis and monitoring of impairments in attention and processing speed.

D. Treatment

1. Optimize the physical health

As with the treatment of any cognitive impairment, maximizing treatment of underlying neurologic, psychiatric, medical, or substance conditions is a prerequisite to the prescription of treatments (nonpharmacologic and somatic) for impairments in attention and processing speed.

2. Optimize the patient’s environment and lifestyle

It is important to address environmental factors that exacerbate or maintain problems with attention and processing speed. For example, identifying and minimizing potential sources of overstimulation and distraction may permit patients with such problems to make the most effective use of their innate attention abilities. Providing adequate time for completion of required tasks may allow an individual to perform more accurately and effectively on such tasks. Encouraging adequate rest and recovery after periods of intense or sustained mental effort may permit patients to maximize their functional abilities.

3. Nonpharmacologic interventions

The use of attention training exercises is a common component of cognitive rehabilitation programs, although the data regarding these interventions suggests that they are more effective during the late (rather than the acute) period after injury or stroke.²^,³ Although other reviews of attention training are less favorable,⁴^,⁵ our experience suggests that these interventions may be useful in highly-motivated patients with relatively mild impairments, particularly when tailored to generalize from the office to real-world contexts, and when conducted by a therapist with experience in their selection and administration. Pairing attention retraining with pharmacotherapy may maximize the benefit afforded by both interventions.⁶ We recommend this type of combined treatment of attention and processing speed impairments.

Although there are reports describing possible benefits of biofeedback (or “neurofeedback”) on attention and speed of processing, the cost–benefit ratio of such treatments precludes recommending their use presently.

4. Pharmacotherapy

There are several FDA-approved treatments for attentional impairments among individuals with ADHD⁷^,⁸; however, there are no FDA-approved treatments for impaired attention due to other neuropsychiatric or neurologic conditions. The neurochemistry of attention predicts that augmentation of cerebral catecholaminergic and cholinergic function may be useful targets for the treatment of attention and speed of processing impairments. Consistent with that hypothesis, several small-scale, randomized, double blind, placebo-controlled studies of methylphenidate⁹ and donepezil¹⁰ suggest that these agents are effective and safe for the treatment of impaired attention following TBI. A single-site, open-label study suggests that donepezil
may be similarly effective for the treatment of impaired attention due to multiple sclerosis.¹¹ There remains insufficient evidence on which to predicate the use of these agents for impairment attention in other conditions, but they are often used for this purpose nonetheless.

In clinical practice, we generally begin pharmacotherapy of attention and processing speed impairments with methylphenidate. Treatment with methylphenidate generally begins with doses of 5 mg twice daily and is gradually increased in increments of 5 mg twice daily until either beneficial effect or medication intolerance is achieved. Most studies suggest that optimal doses of methylphe-nidate are in the range of 20 to 40 mg twice daily (i.e., 0.15–0.3 mg/ kg/twice daily). This medication generally takes effect quickly (within 0.5 to 1 hour following administration), although this effect may wane after only a few hours. Therefore, the first issue in the administration of this agent is determining optimal dose and dosing frequency. Individuals requiring relatively high and frequent doses of methylphenidate may benefit from use of longer-acting preparations of this medication.

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