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Neuroscientist OnlineFirst, published on December 5, 2007 as doi:10.1177/1073858407309995

PROGRESS IN CLINICAL NEUROSCIENCE

Unawareness of Illness in Neuropsychiatric Disorders: Phenomenological Certainty versus Etiopathogenic Vagueness MARIA D. ORFEI, ROBERT G. ROBINSON, PIETRO BRIA, CARLO CALTAGIRONE, and GIANFRANCO SPALLETTA

Awareness of illness is a form of self-knowledge concerning information about the pathological state, its functional consequence, and the way it affects the patient and his interaction with the environment. Unawareness of illness has raised much interest for its consequences on compliance with treatment, prognosis, and the patient’s quality of life. This review highlights the great complexity of this phenomenon both at phenomenological and etiopathogenic levels in stroke, traumatic brain injury, psychosis, dementias, and mood disorders. In particular, the clinical expression is characterized by failure to acknowledge being ill, misattribution of symptoms, and noncompliance with treatment. Unawareness of illness may also be linked with characteristics that are peculiar to each individual disturbance, such as symptom duration and cognitive impairment. Despite a long-lasting interest in the clinical characteristics of unawareness, only recently has the focus of research investigated pathogenic mechanisms, with sometimes controversial results. The vast majority of studies have pointed out a remarkable involvement of the right hemisphere. Specifically, functional and structural changes of the dorso-lateral prefrontal cortex and some other frontal areas have often been found to be associated with awareness deficit, as well as parieto-temporal areas and the thalamus, although to a lesser extent. These data indicate the present difficulty of localizing a specific cerebral area involved in unawareness and suggest the existence of possible brain circuits responsible for awareness. In conclusion, phenomenological manifestations of poor awareness are well outlined in their complexity, whereas neuroanatomic and neuropsychological findings are still too vague and sparse and need further, greater efforts to be clarified. NEUROSCIENTIST XX(X): xx–xx, XXXX. DOI: 10.1177/1073858407309995 KEY WORDS

Unawareness, Insight, Neuropsychiatry, Dementia, Psychosis, Mood disorders

Self-awareness can be defined as the ability to attend, encode, and retrieve information concerning the self (Leathem and others 1998). Johnson and colleagues (2002, p 1808) describe it as “a collection of schemata regarding one’s abilities, traits and attitudes that guide our behaviours, choices and social interactions.” The prefrontal cortex, the hippocampus, the entorhinal cortex, the medial and inferior gyri of the temporal lobe, the insula, the parietal cortex, and the anterior cingulate cortex are thought to be involved in self-awareness functions (Johnson and others 2002; Ochsner and others 2005). During the past decades, deficits of self-awareness were given growing attention because of their relevance in various medical conditions such as stroke, traumatic brain injury (TBI), dementias, schizophrenia, and mood From the IRCCS Santa Lucia Foundation, Rome, Italy (MDO, CC, GS); the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City (RGR); the Institute of Psychiatry, Catholic University of the Sacred Heart, Rome, Italy (PB); and the Department of Neuroscience, University of Rome “Tor Vergata,” Rome, Italy (CC, GS). Address correspondence to: Gianfranco Spalletta, MD, IRCCS Santa Lucia Foundation, Laboratory of Clinical and Behavioural Neurology, Via Ardeatina 306, 00179, Rome, Italy (e-mail: [email protected]).

Volume XX, Number X, XXXX Copyright © 2007 Sage Publications ISSN 1073-8584

disorders. Unawareness of illness consists of the inability to recognize being ill and to assign a correct meaning to deficits, symptoms, and their functional implications. These aspects do not constitute a unitary, coherent dimension but are best conceived as resulting from the interaction of several different neuropsychosocial determinants such as the patient’s attitudes, beliefs, coping skills, and cultural social context (Halligan 2006). Another debated issue is the conceptual and operational distinction between defensive (that is, psychological) and nondefensive (that is, neurobiological) forms of unawareness (Kortte and others 2003; Mateer and Sira 2006). The awareness disorders are an intriguing challenge for clinicians, not only for their theoretical implications but also because they can significantly affect the prognostic course. In fact, unawareness of illness is frequently associated with poor recovery and suboptimal benefit from rehabilitation (Cairns and others 2005; David and others 1995; Flashman and McAllister 2002; Prigatano and others 2005; Sherer, Bergloff, Boake, and others 1998). Thus, shedding light on faulty awareness can enhance our knowledge of consciousness phenomena and make therapeutic strategies more efficient (Fleming and Ownsworth 2006; Mateer and Sira 2006).

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Copyright 2007 by SAGE Publications.

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In this article, we will review an extensive literature to illustrate the main features of unawareness of illness in different neuropsychiatric disorders, focusing on behavioral manifestations, neurological correlates, and assessment procedures. We will highlight significant data and issues still to be explored and point out similarities and differences throughout various disorders in an attempt to delineate a synthetic and comprehensive view of unawareness phenomena.

relabel certain mental events as pathological, 2) the recognition of being affected by a mental disorder, and 3) the admission of the necessity of treatment and the consequent compliance with it. Finally, some authors underline the distinction between explicit and implicit manifestations of awareness because, for instance, some patients verbally deny their awareness of deficits although they behave like they are aware of them (Jehkonen and others 2006; Ownsworth and others 2006; see Table 1).

Method For our purposes, the database was selected using PubMed Services using the research words “awareness,” “insight,” “anosognosia,” “brain injury,” “dementia,” “mood disorder,” and “psychosis.” The articles highlighted in our searches are in English and French and span the period from January 1990 to July 2007. Papers reporting relevant clinical conceptualizations of anosognosia and insight, proposing significant pathogenic models centered on neurological and neuropsychological data, or reporting clinical trial studies were selected. Using the research word “anosognosia,” 197 articles were selected. Combinations such as “insight and dementia” highlighted 528 papers, “insight and mood disorders” 295 papers, “insight and psychosis” 266 papers, and “awareness and brain injury” 310 papers. We also considered the references reported in the different papers we collected. Historically remarkable or conceptually related articles were included as well. All articles cited in this manuscript were judged by MDO and GS to be relevant and to meet the scientific and conceptual criteria listed. Awareness of Illness, Insight, and Anosognosia The first clinical descriptions of poor awareness of illness can be traced back to 19th-century reports depicting the “belle indifference” in hysteria (Donohue and Harrington 2001; Gould and others 1986; Rice and Greenfield 1969) and to the “einsichtslos” described in psychosis by von Krafft-Ebing in 1878—that is, the patient’s inability to recognize his or her delirious condition. During the same period, Anton (1899) and Pick (1898) described some patients who could not recognize their hemiparesis, visual loss, or aphasia. Babinski (1914) termed anosognosia specifically as the lack of awareness of a sensorimotor deficit, and nowadays, anosognosia is defined as the condition of a patient affected by a brain dysfunction who does not recognize the presence or adequately appreciate the severity of deficits in sensory, perceptual, motor, affective, or cognitive functioning evident to clinicians and caregivers (Antoine and others 2004; Jehkonen and others 2006; Orfei and others 2007; Prigatano and others 2005; Starkstein and others 2006). On the other hand, the term “insight” is commonly used to indicate awareness of illness in psychosis and schizophrenia. Jaspers (1963) distinguishes “awareness of illness,” that is, the feeling of being ill and changed, from “insight,” which also implies the evaluation of the nature and severity of illness (Baier and others 1998; McEvoy and others 1989). The exhaustive definition of insight given by David (1990) implies the presence of 1) the ability to 2

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Unawareness of Illness in Neuropsychiatric Conditions Whereas most studies have focused on anosognosia following TBI or stroke (Orfei and others 2007), other investigations have focused on neuropsychiatric disorders. In schizophrenia, for example, impaired insight is commonly regarded as part and parcel of detachment from reality, and in dementia of Alzheimer type (AD) and fronto-temporal dementia (FTD), as a component of the global cognitive decline (Baier and others 1998; Beck and others 2004; Marková and Berrios 1992a, 1992b). However, these assertions are merely deductive and leave unresolved the underlying etiopathogenesis of impaired insight. Conversely, several recent studies have investigated neuroanatomical and neuropsychological correlates of poor insight in specific disorders. Stroke Anosognosia after right-hemisphere stroke is rather frequent. For instance, hemiplegic patients with anosognosia deny their deficit and assert that they are moving their handicapped limb. Similarly, subjects with bilateral cortical blindness or hemianopia claim that their vision is unaltered (Anton’s syndrome). Some aphasics do not seem to realize their erroneous speech production (Lebrun 1987). Anosognosics may partially acknowledge their functional difficulties but usually ascribe them to other causes (i.e., arthritis, tiredness, darkness in the room, etc.); others tend to overestimate their abilities and course of recovery and usually show neither a depressive mood nor catastrophic reactions (see Table 2). One of the best studied forms of impaired awareness in stroke patients is anosognosia for hemiplegia, the prevalence rate of which ranges from 8% to 73% (Orfei and others 2007). This variability probably results from heterogeneity in diagnostic criteria and assessment procedures. Recovery from anosognosia is more probable in the acute phase, usually within the first three months, than in the chronic phase (Cutting 1978; Jehkonen and others 2000; Marcel and others 2004). However, one-third of hemiplegic stroke patients still show anosognosia during the chronic phase of the illness (Pia and others 2004). The pathogenesis of anosognosia for motor impairment is still a matter of debate. The most recent pathogenic hypotheses (Orfei and others 2007) focus on the impairment of the cerebral system, which compares motor plans with sensory feedback (feed-forward hypothesis: Frith and others 2000; Heilman 1991; Heilman and others 1998; Marcel and others 2004; Vallar and others 2003). On the Unawareness in Neuropsychiatric Disorders

Table 1.

Conceptualizations and Definitions of Awareness of Illness

Authors

Insight Jaspers 1963 Greenfeld and others 1989 David 1990 Amador and others 1993 Fleming and others 1996 Marková and Berrios 1995, 2001 Beck and others 2004

Anosognosia Heilman and others 1998; Prigatano 2005 Antoine and others 2004

Definitions

The feeling of being ill and changed plus the ability to evaluate the nature and the severity of illness The acknowledgment of 1) pathological processes and unusual experiences, 2) need of a treatment, 3) possibility of relapse, 4) pressure by psychosocial stressors The presence of 1) the ability to relabel certain mental events as pathological, 2) the recognition of being affected by a mental disorder, and 3) the admission of the necessity of treatment and the consequent compliance with it The presence of 1) awareness of symptoms and 2) explanations about the causes of pathology (attribution) Three-level model of self-awareness: 1) awareness of the injury-related deficits, 2) awareness of the functional implications of deficits for everyday activities, 3) ability to set realistic goals and predict one’s future state accurately Form of self-knowledge concerning the illness or impairment, including not only information about the pathological state but also the way it affects the patient himself and his interaction with the environment; it is a construct, resulting from the patient’s and the clinician’s perspectives and from the interactive process between them Conceptualization of 1) intellectual insight (i.e., the patient repeats what he or she was told, not necessarily reflecting a real belief) versus emotional insight (i.e., sufficient self-awareness to modify his or her dysfunctional belief system) and 2) cognitive insight (i.e., the ability to self-reflect, acknowledge the possibility of being mistaken, be open to feedback, and refrain from overconfidence) Clinical phenomenon in which a brain-dysfunctional patient is not aware of impaired neurological or neuropsychological function that is obvious to the clinician and other reasonably attentive individuals; the lack of awareness appears specific to individual deficits and cannot be accounted for by hyperarousal or widespread cognitive impairment The impaired ability to recognize the presence or appreciate the severity of deficits in sensory, perceptual, motor, affective, or cognitive functioning

other hand, clinical-pathological studies have reported a high prevalence of anosognosia in right-hemisphere injuries (Friedlander 1964; Geschwind 1965; Ramachandran 1996; Turnbull and others 2005) and a significant involvement of prefrontal and parieto-temporal cortical areas (Berti and others 2005; Pia and others 2004; Starkstein and others 1992). Also, the thalamus and insula were frequently reported to be involved in anosognosia following stroke (Karnath and others 2005; Karussis and others 2000; Maeshima and others 1997; Pia and others 2004; see Table 3). Anosognosia for hemiplegia often co-occurs with unilateral spatial neglect, almost exclusively in patients with right-hemisphere damage (Bisiach and others 1986; Buxbaum and others 2004; Caltagirone and others 1977; Rode and others 1992; Spalletta and others 2007). This cooccurrence could simply result from the accidental involvement of neighboring cerebral areas. Indeed, Berti and colleagues (2005) found that unawareness of motor deficit

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and unawareness of personal space are double-dissociated and may be the result of lesions of different components of a common fronto-parietal network. A number of questionnaires were developed to diagnose anosognosia for sensorimotor deficits in stroke. The best known tools are the following: 1. Bisiach’s scale (Bisiach and others 1986), which differentiates four levels of severity of anosognosia for motor, sensitive, and visual defects; it has satisfactory sensitivity, but its semistructured form leaves some uncertainties about its administration; 2. Structural Awareness Interview (Marcel and others 2004), which is very detailed but easy to administer; 3. Anosognosia Questionnaire (Starkstein and others 1992), a four-point scale similar to Bisiach’s questionnaire; 4. Anosognosia for Hemiplegia Questionnaire (Feinberg and others 2000), which confronts the patient with the deficit through an alternation of questions and clinical trials.

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Table 2.

Behavioral Manifestations of Anosognosia in Stroke and Traumatic Brain Injury (TBI)

Authors

Disorder

Behavioral Manifestations

Bisiach and others 1986

Stroke

Marcel and others 2004

Stroke

Vuilleumier 2004

Stroke

Karnath and others 2005

Stroke

Turnbull and others 2005

Stroke

Jehkonen and others 2006

Stroke

Prigatano and Klonoff 1998

TBI

Critical underestimation to explicit, intractable denial of phenomena such as cortical blindness, cortical deafness, hemiplegia, word deafness, dyslexia, or dysphasia Denial of being paralyzed and that there is something wrong; partial admission of some weakness, but it is ascribed to a benign cause (e.g., sprained ankle or arthritis); continued attempts at activities involving the plegic limb although acknowledging the paralysis in conversation simultaneously; denial of hemiplegia but simultaneous will to stay in hospital Inability to notice and acknowledge the existence of the deficit, often despite blatant evidence of the handicap Conviction that the handicapped limb functions normally; patients asked to move the plegic/paretic limb may do nothing or may move the limb on the opposite side and declare that the plegic limb moved appropriately In its extreme form, the disorder presents as a manifest denial of paralysis, despite clear evidence of the contrary; in milder forms, the patient may become aware of the hemiparesis but deny that it causes any functional disability; false beliefs persist, resulting in strange argumentations or perceptual experiences Patients who, at a verbal level, admit they have hemiplegia may nonetheless attempt to walk; others may show abnormal attitudes toward their illness (lack of concern, hatred, bodily delusions) Lack of information about oneself, cognitive perplexity when given feedback regarding behavioral or functional limitations, and cautious willingness or indifference when asked to work with this new information

In summary, anosognosia in stroke has been most studied with regard to hemiplegia, possibly for its salience, frequency, and the relative ease of detecting it. In addition, despite the many pathogenic hypotheses suggested, much still has to be done to point out the underlying causal mechanisms of anosognosia in stroke. Neuroimaging studies appear to be the preferential way to provide fruitful contributions to this field. On the other hand, unawareness of aphasia or blindness has received less attention, possibly for the lower rate of incidence and for implicit difficulties in its assessment. Traumatic Brain Injury Anosognosia in TBI shares some phenomenological features with anosognosia in stroke, such as detrimental effects on compliance with rehabilitation, functional outcome, and quality of life (Evans and others 2005; Fischer and others 2004; Fleming and others 1998; Sherer, Bergloff, Levin, and others 1998); overestimations of one’s abilities; verbal denial or underestimations of deficits; unrealistic goals and expectations of recovery; and progressive recovery within the first months, except in some severe chronic forms (Bach and David 2006; Borgaro and others 2004; Mathias and Coats 1999; Prigatano 2005). However, some important differences must be highlighted. The clinical picture in TBI is often more complex than in stroke. In fact, moderate to 4

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severe TBI is frequently accompanied by loss of consciousness and bilateral and asymmetrical lesions throughout the brain (Prigatano and others 1990), and therefore, with fewer definite borders. TBI patients can show a wide range of impairments such as motor, cognitive, affective, and behavioral deficits. In particular, social behavior can be altered (Bach and David 2006; Borgaro and others 2004; Mathias and Coats 1999; Prigatano 2005). Most authors agree on asserting that unawareness in TBI concerns primarily cognitive, behavioral, and psychosocial deficits rather than physical impairments (Fischer and others 2004; Gasquoine 1992; Hart and others 2004; Pagulayan and others 2007; Prigatano and others 1990), which conversely are denied more frequently by stroke patients (Gauggel and others 2000). So, TBI patients often lack awareness of cognitive deficits, are not able to monitor their own behavior, and have poor awareness of their impaired interpersonal skills and the effect of these on others (Bogod and others 2003). Although a number of plausible neuropsychological models have been proposed to give account of anosognosia for hemiplegia, bases of anosognosia in TBI are still very vague. Crosson and colleagues (1989) illustrated a three-level hierarchical model of awareness. At the bottom, there is intellectual awareness—that is, the ability to recognize having a deficit; subsequently, there is emergent awareness—that is, awareness of disability as it is manifesting at the moment; Unawareness in Neuropsychiatric Disorders

Table 3.

Neuroanatomical and Neuropsychological Correlates of Anosognosia in Stroke

Authors

Sample

Awareness Assessment

Neuroimaging Technique

Bisiach and others 1986

97 right-stroke patients

Bisiach’s scale

CT

Starkstein and others 1992 Maeshima and others 1997

80 patients with acute stroke 50 patients with acute stroke 60 patients with stroke

Anosognosia questionnaire

CT

Semistructured interview

CT

Discrepancy score between patient’s and clinician’s evaluations on the Functional Independence Measure Various measurements

CT

Hartman-Maeir and others 2003

Pia and others 52 stroke 2004 studies (meta-analysis)

Autoptic examination, CT, MRI

Berti and others 2005

30 patients with stroke (with vs. without neglect)

Bisiach’s scale

MRI

Karnath and others 2005

27 patients with acute stroke 272 patients with acute stroke

Bisiach’s scale

MRI and CT


CT

Appelros and others 2007

Neuropsychological Assessment

Starkstein and others 1992

80 patients with acute stroke


Marcel and others 2004

64 patients with stroke

Awareness interview

Spalletta and others 2007

50 patients with right stroke

Bisiach’s scale

MMSE, recognition of facial emotion, receptive aprosody Verbal Fluency test, Digit Span, Category Identification Task, MMSE Modified version of the Mental Deterioration Battery

Neuroanatomical Correlates

Infero-parietal cortical regions, thalamus, lenticular nucleus Superior temporal and inferior parietal cortex, basal ganglia, thalamus Thalamus, putamen, anterior limb of the internal capsule Frontal and temporal cortical areas, capsular-putaminal involvement

Prevalence of fronto-parietal combination of lesions, frequent involvement of basal ganglia or insula Dorsal premotor cortex (BA 6), somatosensory and primary motor areas, BA 46, inferior parietal lobule, insula, BA 3, 4, and 44 Right posterior insula Fronto-parietal and parietal cortical areas, cerebellum Neuropsychological Correlates

Low scores on MMSE, recognition of facial emotions task and of emotionally intoned speech Low scores on the MMSE

Low score on the phonological verbal fluency task

Note: CT = computed tomography; MMSE = Mini Mental State Examination; BA = Broadmann areas; MRI = magnetic resonance imaging.


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and at the top, there is anticipatory awareness—that is, the ability to anticipate a deficit before it occurs and to set up compensatory strategies. Anosognosia would derive from the enablement of one of these levels. This model provides fruitful guidelines for rehabilitation but fails to explain actual causes of anosognosia (Bach and David 2006). Schacter (1990) illustrates two types of theoretical accounts for unawareness of illness. The former postulates damage to or disconnection of a system or process that generates awareness across multiple domains. Differently, the latter implies difficulties in gaining access to particular kinds of domainspecific information that are associated with aware expressions of knowledge in individual domains. However, these accounts are theoretical, and experimental evidence is required. Analogously, there is a striking paucity of neuroanatomical studies (see Table 4). Ranseen and colleagues (1990) found a higher underestimation of disabilities in right-hemisphere TBI patients, whereas Prigatano and colleagues (1990) did not note any significant difference in terms of location or laterality of lesions between unaware and aware TBI patients. More recently, Sherer and colleagues (2005) found that only the number of brain lesions was predictive of degree of impaired awareness in TBI, whereas neither greater volume of right-hemisphere lesions nor greater volume of frontal lesions was associated with anosognosia. On the contrary, Murrey and colleagues (2005) found significant differences in reporting and perceiving deficits between frontal TBI patients and nonfrontal subjects. These variable findings may result from methodological inconsistencies such as different subject-inclusion criteria and different time intervals from injury until scans were obtained. However, these few studies only provide suggestive cues; no information is given about specific brain areas involved, nor is an articulated hypothesis suggested. The attempts to develop assessment tools for anosognosia in TBI are definitely more satisfactory. Most of these measures require an evaluation on a wide range of abilities—that is, in motor, cognitive, affective, and social domains. Among the best known, we call to mind the following: 1. Patient Competency Rating Scale (Prigatano and others 1986), the questions of which are addressed both to the patient and to the caregiver. The scale assesses a wide range of functional abilities, interpersonal skills, and emotional status. Its items are easy to understand, but the reliance on the caregiver could lead to false conclusions; 2. Clinician's Rating Scale for Evaluating Impaired SelfAwareness and Denial of Disability After Brain Injury (Prigatano and Klonoff 1998), which focuses on anosognosia for cognitive impairment and consists of two subscales, one to assess the presence or absence and severity of anosognosia and one to assess the presence or absence and severity of denial. It evaluates the patient’s attitudes and behaviors, characterizing anosognosia or denial, respectively. This double questionnaire is a bit complex to administer but has the advantage of discriminating anosognosia based on brain pathology from psychological denial; 6

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3. Self Awareness of Deficits Interview (Fleming and others 1996), which considers three major areas of awareness of illness following brain injury, allowing a greater breadth of evaluation of the patient; 4. Awareness Questionnaire (Sherer, Bergloff, Boake, and others 1998), which asks the patient, the caregiver, and the clinician to evaluate a possible change in emotional, physical, and cognitive domains after brain injury.

In summary, anosognosia in TBI has been widely investigated in a descriptive view, and the assessment procedures also appear numerous and comprehensive. However, knowledge about etiopathogenesis is still unsatisfactory, possibly because of the high complexity of the disorder. Dementias Another field in which lack of awareness has been investigated is dementias. For instance, altered insight is a core diagnostic feature of FTD, which is present in the early phase (Grossman 2002; Neary and others 1998; O’Keeffe and others 2007) and particularly in the frontal variant of the disease (Neary and others 1998; Perry and Hodges 2000). Indeed, FTD patients show extensive loss of self-awareness associated with prominent social and dysexecutive impairments and fail to acknowledge any of their own behavioral changes (Eslinger and others 2005). Mendez and Shapira (2005) reported an association between deficits of insight in FTD and righthemisphere hypoperfusion or hypometabolism, especially in the frontal lobe. The authors also noted that poor insight was characterized by lack of concern—that is, anosodiaphoria—rather than a denial of the dysfunctional behaviors. Schroeter and colleagues (2006) conducted a meta-analysis of nine neuroimaging studies investigating altered cerebral areas in FTD. Interestingly, they found alterations in Broadmann areas 9 and 32, in the anterior medial frontal cortex, medial thalamus, and right anterior insula. Differently, AD patients demonstrate more selfawareness of their deficits, at least at the onset of the disease (Rankin and others 2005); therefore, patients who can still realize their initial cognitive failures may become depressed. As the disease progresses, unawareness of illness becomes evident in AD, and when dementia becomes moderate to severe, awareness definitely decreases. The underestimation of impairments leads AD patients not to develop behavioral compensatory strategies, increases the risk of dangerous behaviors, and makes caregivers’ burdens even greater (Kashiwa and others 2005; Starkstein and others 2007). Some authors suggest that AD patients show poor insight for affective and cognitive deficits, whereas awareness of psychiatric and behavioral problems is better preserved (KotlerCope and Camp 1995; see Table 5). Some studies have highlighted positive correlations between unawareness of illness in AD and some demographic and clinical variables such as age, age at onset, duration of illness (Kashiwa and others 2005), severe mood and/or behavioral changes (Starkstein and others Unawareness in Neuropsychiatric Disorders

Table 4.

Neuroanatomical and Neuropsychological Correlates of Anosognosia in Traumatic Brain Injury (TBI) Awareness Assessment


Authors

Sample

Ranseen and others 1990

13 patients with PCRS left hemisphere injured, 8 patients with right hemisphere injured, 11 bilaterally injured patients 64 TBI patients PCRS

CT

More severe unawareness in the right-injured group

CT or MRI

Sherer and others 2005

91 TBI patients

Awareness Questionnaire

CT

Murrey and others 2005

43 TBI patients with documented frontal lobe damage, 69 TBI patients without any finding of frontal lobe damage 20 patients with TBI and 20 controls

MPAI

Specified as neuroimaging studies

No differences for laterality nor for number of frontal lesions; higher unawareness related to greater number of lesions Association between the number of cerebral lesions and the degree of impaired awareness Highest unawareness in the frontal-damaged patients

PCRS

fMRI

Neural functioning in right anterior superior frontal gyrus is related to the level of self-awareness


Neuropsychological Correlates

Go-no-go task, Stroop Test, spatial working memory task (Self-Ordered Pointing Test), WAIS WAIS III, MMSE, Corsi Block Test, TAVEC, verbal memory task, visual memory task, WCST, Rey-Osterrieth Complex Figure, verbal fluency task, Boston Naming Test

Low IQ, deficit in all measures of executive functions

Prigatano and others 1990

Schmitz and others 2006

Bogod and others 2003

40 patients with TBI

DEX self-other questionnaire, SADI

Noé and others 2005

62 patients (41 subjects with TBI)

PCRS


Memory and executive function deficits

Note: PCRS = Patient Competency Rating Scale; CT = computed tomography; fMRI = functional magnetic resonance imaging; MPAI = Mayo-Portland Adaptability Inventory; DEX = Dysexecutive Questionnaire; SADI = Self-Awareness of Deficits Interview; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; MMSE = Mini Mental State Examination; TAVEC = Complutense Verbal Learning Test; IQ = intelligence quotient; WCST = Wisconsin Card Sorting Test; WAIS III = Wechsler Adult Intelligence Scale—III ed.


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Table 5.

Behavioral Manifestations of Deficits of Awareness in Dementias

Authors


Reed and others 1993 Gil and others 2001 Markovà and others 2004 Kashiwa and others 2005 Rankin and others 2005

Lack of awareness of behavioral disturbances, disinhibition, cognitive deficits Misattribution of amnestic failure Underestimation of limitations in activities of daily living, tendency to think to be able to continue to live without compensatory strategies Lack of verbal and behavioral admission to be ill

Starkstein and others 2006 Starkstein and others 2007

Inaccurate assessment of current personality, unawareness of personality change, descriptions of the self as before the disease onset Lack of awareness of deficits on instrumental or basic activities of daily living, behavioral changes, and mood problems Dangerous behaviors

2006), premorbid personality and illness-coping strategies (Gainotti 1975; Ownsworth and others 2006; Trouillet and others 2003), educational level, and professional status before the illness (Spitznagel and Tremont 2005). Another line of research focuses on the associations between anosognosia in AD and neuropsychological dimensions (see Table 6). For instance, Starkstein and colleagues (2006) examined a large sample of AD patients with variable severities of dementia and found a significant positive correlation between anosognosia and deficits in verbal memory and verbal comprehension. The correlation between unawareness of illness and cognitive deficits, however, although statistically significant, was not homogeneous in the sample. Thus, the authors argued that cognitive deficits alone cannot be considered sufficient to cause anosognosia in AD, and a specific cognitive profile underlying anosognosia in AD could not be found. Many authors stressed a high association between anosognosia and frontal function performances—in particular, those highlighted by the Wisconsin Card Sorting Test (Gil and others 2001; Michon and others 1994). However, it is not always easy to distinguish the relative contribution of selective frontal impairment compared with global cognitive deterioration to anosognosia. Recently, Kashiwa and colleagues (2005) found that part III of the Stroop Test was highly predictive of anosognosia in a sample of 84 probable AD patients, thus hypothesizing that unawareness of illness may be related to a disturbance of response inhibition— that is, to a specific impairment of orbito-frontal function. This hypothesis is consistent with the correlation found in other studies between severity of anosognosia and behavioral disinhibition, so that anosognosia in AD could be considered as a symptom of a wider emotional and/or behavioral disinhibition disorder (Starkstein and others 2006). The most recent data supporting a parieto-temporal dysfunction in anosognosia in AD have been reported by Starkstein and colleagues (2006), who found a correlation between poor awareness of illness and deficits on tasks of verbal memory, verbal comprehension, semantic verbal fluency, and visual memory (Salmon and others 2006).

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The findings obtained by neuroimaging techniques confirm a complex picture and support, at least partially, previous neuropsychological data. For instance, Reed and colleagues (1993) used single photon emission computed tomography (SPECT) measures of regional cerebral blood flow and found that anosognosia in a sample of AD patients was associated with diminished right dorso-lateral frontal lobe perfusion. Antoine and colleagues (2004) also found that unawareness in AD was associated with hypoperfusion of the right dorso-lateral frontal lobe. Derousné and colleagues (1999), using SPECT, found that among 88 probable AD patients, the discrepancy between caregivers’ and patients’ evaluations on the Cognitive Difficulties Scale (McNair and Kahn 1983) was significantly higher in patients with right frontal and fronto-temporal hypoperfusion compared to patients with other areas of hypoperfusion. Harwood and colleagues (2005) examined the relationship between poor awareness for cognitive and behavioral deficits and cortical hypometabolism with 18F fluorodeoxyglucose and positron emission tomography (FDG-PET) in 41 patients with AD. They found that poor insight was related to decreased brain glucose metabolism in the right lateral frontal cortex, namely Broadmann areas 6, 45, 8, and 9. Vogel and colleagues (2005) selected a sample of 36 AD, 30 mild cognitive impairment (MCI), and 33 control subjects and tried to correlate the discrepancy score of a memory ability awareness questionnaire (Michon and others 1994) with SPECT measures. They found that right inferior frontal gyrus hypoperfusion correlated significantly with anosognosia for amnestic deficits. Salmon and colleagues (2005), in a review study, hypothesized that anosognosia in AD is determined by defective metabolism in the superior frontal sulcus and temporo-parietal junction, subserving self-referential processes and perspective taking, respectively. One year later, the same authors (Salmon and others 2006) published a study partially supporting these hypotheses. It included a sample of 209 AD patients and examined their self-evaluation of awareness regarding 13 cognitive domains including memory, attention, temporal and spatial orientation, verbal fluency, and abstract thinking.

Unawareness in Neuropsychiatric Disorders

Table 6.

Neuroanatomic and Neuropsychological Correlates of Insight in Dementias

Authors

Sample

Reed and others 1993

20 patients with AD


24 AD patients (12 with anosognosia and 12 without anosognosia) 40 patients with AD Subsample of 78 patients with AD

Awareness Assessment



Four-point SPECT semistructured memory insight interview Article not SPECT available

Diminished relative perfusion in right dorso-lateral frontal lobe

SPECT

Decreased right temporooccipital perfusion Right hemisphere and frontal perfusion deficits

Marshall and others 2004

41 patients with AD

Clinical Insight Rating Scale Comparison of ratings from patients and caregivers on the Cognitive Difficulties Scale Clinical interview

Vogel and others 2005

SPECT

Harwood and others 2005

30 patients with Memory AD, 25 Questionnaire patients with (Michon and amnestic MCI others 1994), Anosognosia Rating Scale (Reed and others 1993) 41 patients with Neurobehavioral AD Rating Scale

Salmon and others 2006

209 patients with AD

Ott and others 1996 Derousné and others 1999

Mendez and Shapira 2005

Ruby and others 2007

SPECT

Necropsy data

PET

PET 13-item structured questionnaire completed by the patient and his caregiver 29 early FTD Items drawn from PET or SPECT patients Consortium to Establish a Registry in AD (Welsh and others 1994) 16 frontal-variant Patient-relative PET FTD discrepancy score on a personality assessment questionnaire and on a behavior prediction questionnaire

Diminished blood flow in the right frontal inferior and superior dorsal areas

Greater senile plaque density in the right prosubiculum of the hippocampus Right inferior frontal gyrus hypoperfusion

Glucose dysmetabolism in the right lateral frontal cortex (BA 6, 45, 8, 9) Decreased metabolism in the orbital prefrontal cortex and in medial temporal structures Right frontal hypometabolism or hypoperfusion

Anosognosia for social disability was associated with hypometabolism in the left temporal pole

(continued) Volume XX, Number X, XXXX

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Table 6.

(continued) Awareness Assessment


Authors

Sample

Reed and others 1993

57 patients with Four-point MMSE, CVLT, AD semistructured Boston Naming memory insight Test, Block interview Design from WAIS, Controlled Oral Word Association Test 24 patients with Discrepancy MMSE, WCST, AD score on a Verbal Fluency self-rating scale Test, Luria’s of memory graphic series, completed by Wechsler the patient and Memory Scale his caregiver 84 patients with Discrepancy MMSE, Digit Span, AD score between Word Fluency patient’s and Test, Trail caregiver’s Making Test, evaluation on a Stroop Test, structured Raven’s Colored questionnaire Progressive Matrices Test 36 patients with Memory MMSE, Danish AD, 30 Questionnaire, Adult Reading patients with Anosognosia Test, Boston amnestic MCI Rating Scale Naming Test, Trail Making Test, Stroop Test, WCST, Design Fluency, Verbal Fluency 209 patients 13-item MMSE, CVLT, with AD structured Rey’s figure questionnaire (delayed recall), completed by Forward Digit the patient and Span, Mental the caregiver Control subtest from WAIS, semantic verbal fluency, phonological verbal fluency 173 patients Anosognosia MMSE, Boston with AD Questionnaire Naming Test, for Dementia Controlled Oral Word Association Test, Buschke Selective Reminding Test, Digit Span, Block Design, Token Test

Michon and others 1994

Kashiwa and others 2005

Vogel and others 2005

Salmon and others 2006


Neuropsychological Correlates of Deficits of Awareness

More false positive recognition in the total correct long-delay recognition subtest of the CVLT

Frontal dysfunction as measured by a frontal score (sum of scores on verbal fluency task, Luria’s graphic series, frontal behavior tasks, WCST) Global cognitive impairment as assessed by the MMSE and frontal dysfunction as assessed by part III of the Stroop Test (response inhibition) Global cognitive impairment as assessed by the MMSE

Impairment in episodic memory as assessed by the CVLT and semantic and phonological verbal fluency

Global cognitive impairment, as assessed by the MMSE, and impairment in Buschke Selective Reminding Test (anterograde verbal memory) and Token Test (verbal comprehension)

Note: AD = Alzheimer’s disease; MCI = mild cognitive impairment; FTD = fronto-temporal dementia; SPECT = singlephoton emission computed tomography; PET = positron emission tomography; MMSE = Mini Mental State Examination; WCST = Wisconsin Card Sorting Test; WAIS = Wechsler Adult Intelligence Scale; BA = Broadmann areas; CVLT = California Verbal Learning Test. 10

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Lack of awareness was correlated with decreased metabolism in the right parahippocampal area and orbitofrontal cortex, and to a lesser degree, in the left superior frontal sulcus, right middle insula, and right middle temporal gyrus. These areas would be responsible for recollection of autobiographic information and for processing of semantic judgments and evaluation of conceptual information. The role of the hippocampus was pointed out by Marshall and colleagues (2004) in a retrospective study correlating neuropathological factors and awareness of illness in AD patients. The main result was that in unaware subjects, senile plaque density was significantly higher in the prosubiculum of the hippocampus, a region with numerous reciprocal projections with medial temporal and prefrontal areas. Recently, several questionnaires have been developed to assess loss of insight in dementia. In general, they focus mainly on awareness of amnestic failures and on executive and behavioral impairment. The most used are the following: 1. Memory Insight Scale (Markovà and others 2004), the questions of which are addressed both to the patient and the caregiver. It is detailed and reliable and investigates patients’ general functioning, memory, language function, and cognitive-executive function; 2. Clinical Insight Rating Scale (Ott and others 1996) and the Guidelines for the Rating of Awareness Deficits (Verhey and others 1993), which both allow one to draw a general picture of the level of awareness in dementia, investigating the main components of insight. Despite this, the scoring does not appear to discriminate among groups, and the unstructured form can give rise to uncertainties about the questionnaires’ administration; 3. Anosognosia Questionniare for Dementia (AQ-D) (Migliorelli and others 1995), which investigates two areas, that is intellectual functions and behaviour. It requires a comparison with caregivers' answers. It is detailed and easy to understand, with instances of daily activities.

The multidimensional and multilevel nature of unawareness during the progress of dementia has compelled some investigators to adapt some measures originally developed to assess awareness in other disorders to the assessment of insight in dementias. For instance, Bach and David (2006) modified some items of the Patient Competency Rating Scale (Prigatano and others 1986), focusing particularly on mental ability, whereas some authors used the Interpersonal Adjectives Scale (IAS: Wiggins 1995), based on the personality theory named the “circumplex model.” Although fascinating and informative, this scale is a bit complex to handle. However, these tools can be useful, particularly in FTD and in the later stages of AD. In summary, anosognosia in dementias has been widely studied, given its prominence and frequency. The phenomenology of unawareness in AD and FTD appears definite; in fact, quite satisfying descriptions of its outset, behavioral manifestations, and course are provided.


Moreover, differences between AD and FTD are well ascertained, and the detection of anosognosia in dementias appears rather easy, thanks also to a number of reliable measures. Despite this, the neuroanatomical bases of impaired awareness in AD, although widely investigated, are not yet clearly outlined. In particular, the involvement of frontal, parieto-temporal cerebral areas and the hippocampus has been reported in most of the studies, but the specific functional role of these areas in awareness processes has not been identified. However, the assumption of a neurobiological basis, although not definitely solved, may explain why authors frequently refer to awareness of illness in dementia as anosognosia (Antoine and others 2004; Dalla Barba and others 1995; Kashiwa and others 2005; Starkstein and others 1995), clearly evoking an analogy between unawareness in AD and stroke or TBI. Psychosis and Schizophrenia Since Kraepelin’s descriptions (Kraepelin 1919), lack of insight represents a relevant issue in psychosis and schizophrenia, both from a diagnostic and a descriptive point of view, because of its prognostic and therapeutic consequences. Modern approaches focus on a multidimensional construct of insight and therefore include a number of attributes. As a consequence, lack of full agreement on the definition of insight, the presence of different instruments, and sometimes arbitrary categorizations (Baier and others 1998) frequently undermine researchers’ efforts. However, generally speaking, patients affected by schizophrenia with good insight recognize that they are suffering from a mental illness, that some of their experiences are pathological, and that they need treatment. Some patients accept the logical assertion that they are suffering from a mental disorder and also that their unusual experiences are symptomatic, although they are not usually convinced of this. Beck and colleagues (2004) refer to this phenomenon as a split between intellectual insight and emotional insight, respectively. Patients with schizophrenia and low insight seem impermeable to corrective feedback, as they are not able to distance themselves from their distortions—that is, they lack the ability of self-reflection (see Table 7). Poor awareness of illness is often linked to poor adherence to the treatment, to severity of the illness, and to frequency of relapses (David and others 1995). In particular, the relationship between insight and perceived quality of life was investigated in psychotic subjects (Hasson-Ohayon and others 2006). Patients with higher levels of insight showed less emotional well-being, less satisfaction, and a lower professional status. In particular, it emerged that social stigma can lead to a decrease of personal motivation and a feeling of hopelessness in patients aware of their mental illness (Lysaker and others 2007; Rüsch and Corrigan 2002). However, patients who showed a higher insight for the necessity of a treatment reported a higher level of emotional wellness. In fact, relatively good insight can enhance the feeling of being able to manage the situation and can therefore encourage compliance with therapy. These results underlie a bidirectional relationship between

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Table 7.

Behavioral Manifestations of Poor Insight in Psychosis and Schizophrenia

Authors


McEvoy and others 1989

Lack of admission of the pathological meaning of unusual experiences and of distortion in superior cognitive processes; lack of perception of need for a treatment Lack of verbal admission to be affected by a mental illness or of need for a treatment; inability to relabel psychotic experiences as abnormal; lack of compliance with the treatment No verbal admission either about the illness in general or of the specific symptoms; misattribution of illness and unusual experiences; lack of acknowledgments of the benefits of the treatment; lack of acknowledgment of social impact of illness and of medical course Unawareness of the source of the symptoms or faulty attribution; lack of perception of need for treatment Lack of feeling ill; faulty perception of the severity of the illness; lack of acknowledgment of possibility of relapse Inability to distance oneself from distortions of experiences; impermeability to corrective feedback; overconfidence in conclusions and judgment

David 1990 Amador and others 1993 Birchwood and others 1994 Cuesta and Peralta 1994 Beck and others 2004; Warman and others 2007

different components of insight and quality of life, which can affect each other, with variable and even contrasting outcomes. Moreover, younger, middle-aged, and older outpatients with schizophrenia seem to show similar features (Pedrelli and others 2004). Notably, poor insight for negative symptoms seems more correlated with cognitive deficits, whereas the unawareness of positive symptoms seems to be caused by defensive mechanisms (Rüsch and Corrigan 2002). Moreover, Rossell and colleagues (2003) found that positive symptoms are highly correlated with low insight in schizophrenia. In particular, Warman (Warman and others 2007; Warman and Martin 2006), on the base of Beck’s model of cognitive insight (Beck and others 2004), noted that delusion proneness is related to high certainty in one’s beliefs and judgment. However, this should not necessarily impair the openness to external corrective feedback and the willingness to admit fallibility. Many questionnaires were developed to assess insight in psychosis, such as the following: 1. Insight and Treatment Attitude Questionnaire (ITAQ, McEvoy and others 1981), which is particularly suitable for hospitalized patients and focuses mainly on the present and future attitude to the treatment as a measure of compliance; 2. Scale to Assess Unawareness of Mental Disorder (SUMD, Amador and others 1993), designed to evaluate present and past awareness of mental illness and quite discriminative for various components and levels of insight; 3. Insight Scale (IS, Marková and Berrios 1992a; Marková and others 2003), which also investigates the influence of the awareness disorder on the interaction with environment; yet, the scale may be biased by the dichotomous scoring, in some cases less reliable than a Likert scale;

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4. Beck Cognitive Insight Scale (BCIS, Beck and others 2004), a self-report instrument with items inquiring about the patient’s objectivity, reflectiveness, openness to feedback, and decisionmaking processes. It aims to evaluate the relationship between the patient’s ability to reflect on himself or herself and to accept external feedback (self-reflectiveness) and how much he or she is convinced of faulty opinions (self-certainty). The higher the latter, the lower the insight function. This scale as a whole has shown good psychometric properties and generalizability to a wide range of psychotic patients (Pedrelli and others 2004); 5. Birchwood’s Insight Scale (Birchwood and others 1994), which is easy for the patient to understand and for the clinician to handle. Because of its brevity, it may appear limited in some cases, however, and the three-tiered scoring (agree, disagree, unsure) can fail to distinguish severity adequately (Sturman and Sproule 2003).

From an etiopathogenic point of view, the various models of lack of insight in psychosis can be summed up as follows (Cooke and others 2005): 1) clinical: the lack of awareness is a constitutive symptom of psychosis caused by the pathological process itself, but experimental data give little support to it, mainly because of its intrinsic unsatisfying ability to generate testable hypotheses; or 2) psychological: the lack of insight reflects a psychological defense mechanism (denial) to cope with a stressful event (the illness itself). Because this explanation focuses mainly on self-deception and psychological strategies to cope with the illness, it has rarely been verified. Subotnik and colleagues (2005), however, examined 52 recent-onset schizophrenic patients using measures of psychological defensiveness drawn from the Minnesota Multiphasic Personality Inventory (MMPI),


namely the L, K, and R scales. A defensive attitude was more evident in acute patients than in those in remission phase, and it affected more unawareness of medical effects and unawareness of mental disorder as measured by the SUMD. Another interesting pathogenic approach is 3) neuropsychological: in this model, poor insight can be traced back to neurological dysfunctions or brain abnormalities (see Table 8). Recent studies (Subotnik and others 2005) found that cognitive variables are the best predictors of unawareness of mental disorder. In particular, deficits of focused and sustained attention and target discrimination may inhibit a patient’s ability to recognize that he or she suffers from a mental disorder. This was true mainly in patients in the remission stage of the illness. The relationship between psychotic patients’ difficulty in error detection, perseveration, amnestic deficits, and their general cognitive deterioration and low intelligence quotient (IQ) has often been reported in literature. Aleman and colleagues (2006) conducted a meta-analysis on 35 studies in which various measures for insight assessment were administered and five cognitive domains were explored, namely global cognition, IQ, memory, frontal executive functions, and Wisconsin Card Sorting Test (WCST) abilities. The authors observed a small but significant positive relationship between insight and general cognitive functioning, although the correlation between insight and WCST scores was more significant than that between insight and IQ. This was true in patients with psychotic disorders in general but not in schizophrenic subjects only. On the contrary, in patients with schizophrenia, a significant peculiar association between insight and memory functions was found. The weak, although statistically significant, correlation between insight and IQ would support the hypothesis that a minimum IQ is required to formulate self-reflection judgments and to evaluate ambiguous and abnormal experiences (e.g., hallucinations). Cuesta and colleagues (2006) disagreed with these results. They conducted a longitudinal study on a sample of 75 patients after remission of an acute episode of schizophrenia, affective disorders with psychotic symptoms, or schizoaffective disorder. Patients were given a battery of three insight measures and a neuropsychological battery to test immediate and delayed verbal memory, verbal fluency, attention, and executive functions. The authors found that insight and neuropsychological performance were not significantly associated. Thus, they argued that loss of insight is a primary and semi-independent manifestation of psychosis and that it is a multidetermined symptom, affected by both neurological alterations and sociocultural factors. Therefore, it cannot be reduced to a single association with a specific neuropsychological impairment. To clarify this topic, Shad and colleagues (Shad, Tamminga, and others 2006) reviewed 34 studies, of which 21 reported a significant relationship between deficits in at least one dimension of insight and a cognitive measure of frontal function. In particular, when WCST was used, a high frequency of positive associations with


insight was observed. Likewise, when multidimensional insight questionnaires are administered, such as SUMD, ITAQ, or Schedule for Assessment of Insight (SAI-E), the same association with WCST is found. These two data could partially explain discrepancies among studies. In fact, insight may not be related to a global cognitive deficit but rather to specific cognitive dysfunctions such as frontal deterioration as measured by the WCST. Moreover, the more comprehensive the questionnaire, the more apparent it is that multidimensionality of insight is related to frontal lobe performances. In addition, different target populations may show different insight constellations (Aleman and others 2006), so that the more heterogeneous the sample, the more blurred the results. Likewise, the timing of the assessment is important. For example, time from onset of illness as well as testing during acute or remission phases can affect findings. Thus, the use of antipsychotics and the chronicity of illness can disguise the data. In addition to these three models, a fourth mechanism for insight has to be mentioned: that is 4) neuroanatomic (see Table 8). In fact, one of the most frequent descriptions in schizophrenia is the correlation between poor insight and structural changes of right cerebral frontal regions. For instance, Shad and colleagues (2004) studied first-episode antipsychotic-naïve patients and found that a significant volume reduction of right but not left dorsolateral prefrontal cortex (DLPFC) was associated with loss of insight. This correlation was independent of global cognitive functioning and negative or positive symptoms. The authors argued that insight deficits may be traced back to an abnormal maturation of prefrontal brain systems rather than to progressive brain deficits. In addition, they found that deficits in frontal cortical areas were associated with deficits in executive functions—that is, selfmonitoring and conceptual organization, which could be critical for awareness of illness. Thus, the authors hypothesized that insight deficits are related to impairments in executive functioning and working memory, which in turn are mediated by the prefrontal cortex. Two years later, the same authors (Shad, Muddasani, and others 2006) studied a sample of 14 first-episode antipsychotic-naïve schizophrenic patients at their first hospitalization. Although no correlations between awareness and age, gender, IQ, and handedness emerged, awareness of symptoms was again significantly related to a reduction of right DLPFC volume, and attribution of symptoms was related to an increase of right medial orbito-frontal cortex (OFC) volume. Thus, these two different dimensions of insight in first-episode drug-naïve schizophrenic patients seem to be associated with distinct neuroanatomical regions. In particular, DLPFC may be related to self-monitoring, and therefore, its structural alteration would result in an unawareness of symptoms, whereas a structural alteration of OFC would result in a misattribution of symptoms. Flashman and colleagues (2001) tried to correlate distinct dimensions of awareness with alterations of volume in cerebral regions. They found that smaller volumes of bilateral middle frontal gyrus, right gyrus rectus, and left

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Table 8.

Neuroanatomic and Neuropsychological Correlates of Insight in Psychosis Awareness Assessment

Authors

Sample

Flashman and others 2001

15 patients SUMD (12 schizophrenic, 3 schizoaffective)

Shad and others 2004

35 first-episode Insight item anti–psychoticfrom HDRS naïve patients (30 schizophrenic, 5 schizoaffective) Shad, 14 first-episode SUMD Muddasani, anti–psychoticand others naïve patients 2006 (schizophrenic and schizoaffective)



MRI

Volume reduction of bilateral middle frontal gyrus, right gyrus rectus, left anterior cingulated gyrus; misattribution of symptoms was associated with reduced superior frontal gyrus volumes Volume reduction of right DLPFC

MRI (only DLPFC)

MRI (only DLPFC and OFC)

Volume reduction of right DLPFC; misattribution of symptoms was associated with increased volume in right medial OFC


Shad and 35 first-episode Insight item others 2004 anti–psychoticfrom HDRS naïve patients (30 schizophrenic, 5 schizoaffective)

WCST, CVLT, Benton Judgment of Line Orientation Test, Quick IQ Test Subotnik and 52 psychotic SUMD CPT (visual others 2005 outpatients vigilance task (42 schizophrenic, and sustained 10 schizoaffective) attention under immediate memory load conditions task) Aleman and 35 studies Insight item MMSE, WAIS, others 2006 concerning from PANSS NART, Trail (metapsychotic or PSE, Making analysis) disorders SAI-E, SUMD, Test, WCST, ITAQ measures of attention, visual and verbal memory, and verbal fluency Shad, 34 studies SUMD, SAI-E, WCST, Trail Tamminga, concerning ITAQ, insight Making Test, and others patients with item from Verbal Fluency 2006 (metaschizophrenia PANSS, PSE, Test, Controlled analysis) HDRS, and Oral Word others Association Test, Stroop Test, WAIS, and others

Neuropsychological Correlates

High number of perseverative errors on the WCST

Deficits of focused attention, sustained attention, and target discrimination

Poor global cognitive functioning, WCST performance, and memory performance (only in schizophrenics)

Deficits in frontal functions (poor performances on WCST)

Note: SUMD = Scale to Assess Unawareness of Mental Disorders; HDRS = Hamilton Depression Rating Scale; PANSS = Positive and Negative Syndrome Scale; PSE = Present State Examination; SAI-E = Schedule for Assessment of Insight—expanded version; ITAQ = Insight and Treatment Attitude Questionnaire; WAIS = Wechsler Adult Intelligence Scale; MMSE = Mini Mental State Examination; NART = National Adult Reading Test; WCST = Wisconsin Card Sorting Test; MRI = Magnetic Resonance Imaging; CVLT = California Visual Learning Test; CPT = Continuous Performance Task; DLPFC = dorso-lateral prefrontal cortex; OFC = orbitofrontal cortex. 14

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anterior cingulate gyrus were correlated with greater unawareness of illness and that smaller volumes of superior frontal gyrus were associated with greater misattribution of symptoms. Thus, the authors deduced that because the DLPFC and the cingulated gyrus are both crucial components of the working memory circuitry, poor insight in schizophrenia might be seen as a deficit in comparing past and current experiences, and consequently, in interpreting symptoms. The minor discrepancies between the cited studies may be caused in part by various methodological factors. In fact, the characteristics of the samples vary from study to study. For instance, Shad and colleagues (Shad, Muddasani, and others 2006; Shad and others 2004) examined patients who were in their first psychotic episode and had not yet received any antipsychotic medication, whereas Flashman and colleagues (2001) studied patients who had received antipsychotic drugs for an average of seven years from the first hospitalization. In addition, different insight assessment tools were used, ranging from single categorical items to more comprehensive questionnaires such as SUMD or ITAQ. In summary, the initial studies about insight in psychosis were focused mainly on the conceptual definition, the behavioral or cognitive description, and assessment procedures of the phenomenon. Only in recent years, the focus shifted to the pathogenic mechanisms leading to poor insight in psychosis and schizophrenia. Whereas neuroimaging studies point out the role of prefrontal areas, neuropsychological studies have reported correlations not only between insight and frontal functions but also temporal functions, in particular, with amnestic tasks. It is evident that pathogenic information is still preliminary, and much has still to be clarified. In fact, as some authors (Baier and others 1998; Cuesta and others 2006) underlined, at the present there is a lack of reliability in empirical research in this field because of small sample sizes, inappropriate parametric statistical methods, and the failure to correct significance levels for multiple statistical comparisons. Mood Disorders Like schizophrenia, bipolar disorder appears to be a condition in which poor insight is a prominent characteristic and has shown a predictive value for medication adherence (Ghaemi and others 1996; Yen, Chen, Ko, and others 2005). Despite this, few studies have examined this issue, mainly focusing on the relationship between specific clinical features and poor insight. Peralta and Cuesta (1998) studied a sample of patients with manic or depressive episodes and noted that 1) manic patients had more severe insight impairment than depressed ones, 2) psychotic depressives had poorer insight than nonpsychotic ones, and 3) manic patients had poorer awareness irrespective of the type of psychotic symptoms. Also, Ghaemi and Rosenquist (2004) found a strict relationship between poor insight and mania and suggested lack of insight as a diagnostic criterion for the latter, consistent with findings of a fair number of analogous studies (Amador and others 1994; Dell’Osso and others


2000; Michalakeas and others 1994). In particular, Burdick and colleagues (2005) found a significant relationship between manic patients’ tendency to underestimate their own cognitive difficulties and mania symptom severity. In addition, Ghaemi and Rosenquist (2004) argued that insight in mania is not a traitlike condition, as it tends to be in schizophrenia, but is state-dependent because it tended to improve with resolution of the acute manic episode. Sturman and Sproule (2003) found differences in insight between the diagnostic groups only in the acute phase of the illness. A recent two-year prospective study (Yen and others 2007) reported changes in insight levels depending on different clinical courses. Thus, insight worsened during manic episodes, returning to a baseline insight level after remission in patients with a single manic episode but not in those with repeated episodes. On the contrary, in bipolar patients with single or repeated depressive episodes, insight level was steady across different illness stages. This would indicate a greater impairment and a higher statedependence in insight in manic individuals and a worse insight level in more serious manic patients. In a study conducted on a sample of bipolar patients in remission, Yen and colleagues (2004) found that being male, having a shorter duration of illness, and showing psychotic symptoms predicted poor awareness of illness. In particular, the authors found that bipolar patients whose illness lasted for a longer period showed better insight. Thus, they hypothesized that the longer the duration of illness, the greater the opportunity to acquire knowledge and learn to be aware of differences between illness and normal life. Moreover, they might be able to benefit from individual or group psychotherapy interventions to improve insight. The assessment procedures for insight in mood disorders are few. Sturman and Sproule (2003) proposed a revision of the Birchwood Scale for psychosis, resulting in the development of the Mood Disorders Insight Scale (MDIS). It is a short self-report instrument based on a broad definition of insight, integrating suggestions by David (1990) and Amador and colleagues (1994) about the awareness of symptoms, the attribution of symptoms to the illness, and compliance with the therapy. Although brief, it was used in some studies, showing satisfactory reliability. For instance, Yen, Chen, Lee, and colleagues (2005) used the MDIS to study insight in depressed patients and found that 1) younger and more severely ill subjects had a greater insight into their illness, 2) a major depressive disorder and a higher education were associated with an intact insight concerning the attribution of symptoms, and 3) subjects with a major depressive disorder were more likely to be aware of the need for treatment when compared to patients with other types of depressive disorders. Finally, the Hamilton Depression Rating Scale (Hamilton 1960) includes an item evaluating insight of depressive mood, rated on a 0–2 scale. Yet, it refers to the illness as a whole, not distinguishing the various components of awareness of the mood disorder. In conclusion, awareness of illness in mood disorders was underestimated for a long time, so at the present, our knowledge is limited to some clinical associations, whereas the pathogenesis remains obscure. Moreover, the few

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assessment measures used in this field are mainly adapted versions of other questionnaires or single items of scales measuring severity of depression symptoms, which risk being too generic and not sufficiently discriminative among different components of insight. Summary and Conclusions The purpose of this review was to examine unawareness of illness in neuropsychiatric disturbances in which it is frequently encountered, that is, stroke, TBI, psychosis and schizophrenia, dementias, and mood disorders. The evaluation of available data for each area and of analogies and differences throughout these medical conditions led us to draw some conclusions. A large number of studies focus on phenomenological manifestations of unawareness of illness and point out the high complexity of the phenomenon. This is evident within each medical domain and can be caused mainly by the multidimensional nature of the phenomenon itself and partially by different conceptualizations and theoretic approaches. On the other hand, unawareness of illness, regardless of the specific neuropsychiatric condition, may offer similar behavioral patterns (Lele and Joglekar 1998), that is, 1) disavowal of the symptoms, whatever form they show (delusions, hemiplegia, amnestic failures, etc.); 2) causal misattribution, when the symptom is admitted; 3) disavowal of the presence of a pathological process; 4) poor compliance with the rehabilitative or therapeutic course; 5) positive correlation between awareness of illness and depressive mood, on one hand, and between unawareness of illness and lack of concern, on the other hand; 6) modality-specificity, that is, the patient can be unaware of his symptoms but aware of other areas of his life; 7) graded phenomenology, that is, the patient can show various levels of severity of unawareness; and 8) association with poor prognosis (Cairns and others 2005; Jehkonen and others 2006; Rüsch and Corrigan 2002). Although these last observations suggest that unawareness of illness could be considered as a single deficit affecting different neuropsychiatric disorders, a more careful examination of the present state of knowledge prevents us from jumping to this conclusion. Supporting unawareness complexity, Markovà and Berrios (1992b, 2006) stressed that “awareness” is always “awareness of something”; indeed, it is defined by the object to which it refers. Thus, although at first glance, the manifestations of unawareness of illness in different disorders are quite similar, when carefully assessed, they cannot be grouped in a single clinical category but should be traced back strictly to the specific impaired domain (sensorimotor, cognitive, affective) and to the individual disorders. For instance, whereas anosognosia in stroke and TBI usually recovers within a few days to three months from the cerebral accident, either spontaneously or faster after rehabilitation treatment, in schizophrenia, unawareness is chronic if not treated adequately, and in dementia, it is even irreversible. The multifaceted nature of unawareness phenomena is also mirrored by the heterogeneity of diagnostic tools, which differ in discriminative power, psychometric properties, and target. For instance, different questionnaires may 16

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investigate different dimensions of insight. Scoring modalities such as dichotomous or Likert scales can vary from one tool to another, and again, some measures are self-rated, whereas others compare patients’ and caregivers’ scores. In the specific case of mood disorders, unfortunately, few measures of insight have been developed, so that more accurate assessment procedures are required. Despite a growing interest about phenomenology of unawareness disorders, which has permitted a clarification of its clinical aspects, etiopathogenic mechanisms are still underexamined and controversial. The analysis of this issue in our review has stimulated some observations. First, a moderate number of neuroanatomical and neuropsychological data have been collected in stroke and dementias, whereas in psychosis and schizophrenia, the interest for the neural substrate of poor insight is rather recent, as the initial focus was mainly on psychological and motivational aspects. Furthermore, in TBI and mood disorders, there is a striking void in this matter. Therefore, a greater effort in neuroanatomical and neuropsychological studies about lack of awareness is required. Second, analogously to what has been observed in the phenomenology, some findings seem to be more frequent within each disorder and shared by all the disorders examined. The vast majority of studies have pointed out a remarkable involvement of the right hemisphere. Specifically, frontal cortical areas, and in particular, dorsolateral portions, have often been found associated with awareness deficit, as well as parieto-temporal areas, although to a lesser extent. Also, neuropsychological studies have reported a frequent association between poor awareness and frontal and temporal functional deficits throughout various disorders. Again, these preliminary data would tempt us to conceive unawareness as a single clinical deficit. Yet, just as for phenomenology, within-disorder and between-disorder consistencies at the present do not suffice to speak of a single shared etiopathogenesis of awareness deficit. In fact, these common etiopathogenic features are accompanied by a number of heterogeneous findings within each disorder as well as between various disorders. This variability can be accounted for by methodological factors. Possibly, the use of different neuroimaging techniques to investigate mechanisms of insight, such as MRI, PET, and SPECT, contribute to heterogeneity of pathogenesis results also within the same medical domain. Also, factors such as selection bias, time elapsed from brain injury, acute or chronic phase in schizophrenia, pharmacological treatment, and severity of dementia may vary considerably from study to study. However, the high heterogeneity of neuropsychiatric disorders per se may account for the variability in results. In fact, each disorder cannot be considered as a monolithic entity but shows a partial internal etiopathogenic variability. For instance, under the label “stroke,” partially different conditions are grouped, characterized by different characteristics, not to mention the wider etiopathogenic gap that may separate various disorders from one another. So how can the coexistence of similar and different elements be explained? Self-awareness is a superior psychological function, the complexity of which cannot be accounted for by a single cerebral area. Rather, more Unawareness in Neuropsychiatric Disorders

plausibly, it is the product of a large and complex neural network (Appelros and others 2007; Orfei and others 2007). Thus, the cortical areas frequently associated with poor awareness in all these disorders, possibly prefrontal and parieto-temporal regions, in association with some subcortical areas such as the thalamus, could be the core of common awareness circuits, whereas different etiopathogenic factors could impair other components of these circuits, giving place to the heterogeneity observed in phenomenological and neuroanatomical data. The same logic could be suggested for within-disorder unawareness variability. In summary, neuroanatomical and neuropsychological consistencies throughout various medical conditions, although stimulating, still appear vague and merely suggestive of possible shared mechanisms. So, despite complex and multidimensional descriptions of the phenomenon of insight, a prevalent etiopathogenic vagueness still blurs our knowledge of unawareness of illness. Finally, we must consider that lack of insight is a multifaceted concept that also reflects a highly complex interaction of a number of factors, especially in psychosis and mood disorders. Ghaemi and colleagues (1996) support the view that poor insight in psychosis and in bipolar disorder, unlike anosognosia, would not be related only to a neural substrate, but rather, it would reflect the influence of psychological and social factors such as education, intelligence, and social learning. If so, the definition of anosognosia, centered on a verifiable cerebral damage, would not be exhaustive for all the forms of poor awareness. Unawareness of illness is a stimulating challenge for clinicians, not only for its theoretical implications but also for its diagnostic, rehabilitative, therapeutic, and prognostic implications. The understanding of awareness phenomena can also shed light on self-awareness and self-consciousness and on the correlation between them and other higher cerebral functions such as cognition and emotion. In light of the results of our review, we claim that future research will have to be focused on neuroanatomical and neuropsychological bases of unawareness of illness to clarify brain regions and cognitive mechanisms involved in this phenomenon. It is our opinion that a more exhaustive knowledge of etiopathogenesis of anosognosia and lack of insight is fundamental to enrich our knowledge of superior and complex psychological functions but also to develop accurate and efficient rehabilitative modalities. References Aleman A, Agrawal N, Morgan KD, David A. 2006. Insight in psychosis and neuropsychological function: meta-analysis. Br J Psychiatry 189:204-12. Amador X, Flaum M, Andreasen N, Strauss D, Yale S, Clark S, and others. 1994. Awareness of illness in schizophrenia and schizoaffective and mood disorders. Arch Gen Psychiatry 51:826-36. Amador X, Strauss D, Yale S, Flaum M, Endicott J, Gorman J. 1993. Assessment of insight in psychosis. Am J Psychiatry 150:873-9. Antoine C, Antoine P, Guermonprez P, Frigard B. 2004. Awareness of deficits and anosognosia in Alzheimer’s disease. Encephale 30:570-7. Anton G. 1899. Uber die Selbstwahrnehmung der herderkrankungen des gehirns durch den kranken bei Rindbenbindheit und Rindentaubheit. Archiv fur Psychiatrie 32:86-127. Appelros P, Karlsson G, Hennerdal S. 2007. Anosognosia versus unilateral neglect. Coexistence and their relations to age, stroke severity, lesion site and cognition. Eur J Neurol 14:54-9.


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