147 NeuroRehabilitation 38 (2016) 147–154 DOI:10.3233/NRE-161304 IOS Press Functional cerebral space theory: Towards an integration of theory and mechanisms of left hemineglect, anosognosia, and anosodiaphoria Andrew J. Smith, Ransom W. Campbell, Patti Kelly Harrison and David W. Harrison∗ Behavioral Neuroscience Laboratory, Department of Psychology, Virginia Polytechnic Institute, Blacksburg, VA, USA Abstract. BACKGROUND: The current case study presents a 43 year old African American woman admitted to a Tertiary Care Rehabilitation unit at a major medical center for concerns over left-sided anesthesia and weakness. Head scans indicate a right middle cerebral arterial distribution infarct altering blood flow in temporal, parietal, and occipital regions in the right cerebral hemisphere. OBJECTIVE: Physician and therapist reports (i.e., speech and occupational therapists) referred the patient for a neuropsychological evaluation for concerns over the patient’s capacity to recognize the severity of her deficits and self-care, with potential rule-outs indicated by the extant literature on right CVA for anosognosia, anosodiaphoria, and left hemibody/hemispace neglect. METHODS: The current case integrates interdisciplinary physician notation, magnetic resonance imaging and magnetic resonance angiogram, observations and reports from speech and occupational therapy, and neuropsychological assessment via standardized tests and neurobehavioral syndrome analysis. RESULTS: Evidence was found for co-occurring syndromes of moderate anosognosia, anosodiaphoria, and left hemibody/hemispatial neglect derived from shared functional cerebral space with overlapping temporal, parietal, and occipital damage. CONCLUSIONS: Clinical implications are discussed, including recommendations for therapy approaches based on functional cerebral space theory that may indicate the use of known techniques (e.g., for left hemibody neglect) that may also have therapeutic implications for treating other, more mercurial co-occurring syndromes of anosognosia and anosodiaphoria. Keywords: Left hemineglect, anosognosia, anosodiaphoria, middle cerebral artery, insight, cerebrovascular accident, stroke, neglect, neglect disorders, emotion, cerebral hemisphere 1. Introduction ∗ Address for correspondence: David W. Harrison, Director, Behavioral Neuroscience Laboratory, Department of Psychology, Williams Hall, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061-0436, USA. Tel.: +1 540 231 4422; E-mail: dwh@vt.edu. Originating with Babinski’s (1914) initial descriptions of a patient with left hemiplegia following cerebrovascular lesions to the right cerebral hemisphere, anosognosia is categorized as one of several syndromes belonging to the family of agnosias (a general lack of knowledge or failure of recognition) 1053-8135/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved 148 A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria known as the asomatagnosias (the loss of knowledge of a person’s sense of bodily condition) and is described as a lack of awareness of deficit, denial of illness or a failure to recognize and assign implication to personal deficits or afflictions (Bauer, 2012; Kolb & Whishaw, 2008; Orfei, Robinson, Bria, Caltagirone, & Spalletta, 2008; see also Harrison, 2015). Modern clinical definitions describe the phenomenon as a failure to maintain awareness of neuropsychological dysfunction resulting from impairment or disruption of cortical networks necessary for the operation of a particular function (Prigatano, 2010). Although often accompanied by a nearly delusional denial of deficit (Sandifer, 1946) and the corresponding presence of somatoparaphrenia (denial of ownership or ascribing ownership, of a body part, to another; see Critchley, 1957; Cutting, 1978; Gerstmann, 1942; Karnath & Baier, 2010), anosognosia may manifest in isolation as simply the patient’s apparent lack of awareness of deficit. This failure to recognize functional disabilities is often accompanied by minimal or absent emotional reaction by the patient with respect to the functional loss or acquired disability. Babinski (1914) describes this anosodiaphoria in his initial report as a lack of concern for the acquired deficits (Adair & Barrett, 2012; Critchley, 1957; Cutting, 1978; Heilman & Harciarek, 2010; McGlynn & Schacter 1989; see Harrison, 2015). Anosodiaphoria (the emotional disorder) is functionally and manifestly distinct from anosognosia (the recognition of the disabilities) with evidence suggesting that anosodiaphoria may persist beyond the resolution of the anosognosia (Bisiach et al., 1986; Critchley, 1957; Heilman & Harciarek, 2010; see Harrison, 2015). In the practical sense, patients with anosodiaphoria may be able to acknowledge the disorder in speech (e.g. “I can’t use my left arm.”) via the linguistic and logical analyzers of the intact left cerebral hemisphere. In the rehabilitation setting, this basic aspect of awareness of deficits might be addressed in therapies as an initial compensatory technique, through the provision of rationale and active verbal rehearsal focused on prompting the patient to verbally recognize deficits. However, this logical linguistic analysis may fall well short of the safety requirements for the patient to be capable of caring for him- or herself, as the emotional disorder persists as a function of the damage to the nonlinguistic emotional analyzers of the injured right cerebral hemisphere. Although the patient may acknowledge the disorder verbally, the patient remains a safety risk for initiating routine behaviors (e.g., driving, cooking and, for some, even heavy or inherently dangerous equipment operations) without caution. In this clinical example, language is just that: an isolated functional domain that is potentially devoid of the deeper emotional conveyance or “gist” for the content, which is more attributable to the damaged right cerebral regions (see Harrison, 2015), wherein patients may express no cause for concern or inhibition of activities that he or she was involved in prior to, for example, a cerebrovascular accident (CVA). The manifest similarities between anosognosia and unilateral left hemineglect may also present difficulties for the clinician in distinguishing whether or not the patient is unaware of a left side hemiparesis or hemianesthesia, or whether the patient is presenting with a neglect of the left side of the body. The argument has been made for double dissociation as patients presenting with hemispatial neglect may, despite being inattentive to the contralesional side of space, be aware of the basic functional impairments (e.g. hemiparesis or hemianesthesia of a limb; Bisiach et al., 1986). Conversely, the patient with anosognosia following right CVA, but presenting without a neglect syndrome, can be capable of attending to the contralesional side of space, while also failing to recognize their corresponding deficits (Bisiach et al., 1986). Thus, from this accounting anosognosia and unilateral spatial neglect may be distinguished based upon the behavior of the patient and functional presentation of the specific syndrome (Berti et al., 2005; Bisiach et al., 1986; Marcel, Tegner, & Nimmo-Smith, 2004). Alternatively, the allocation of these right sided brain regions may function for multiple concurrent tasking demands (see Functional Cerebral Space Theory; Kinsbourne & Hicks, 1978; Harrison, 2015). In this proposal, the parietal and temporal regions often are found to process the attentional and/or sensory components of left hemispace, with their dysfunction/deactivation underlying an attentional or sensory left hemineglect syndrome. However, these same brain regions are most intimate to discussions of arousal components underlying emotion and with particular relevance for negative emotional states (Heilman, Schwartz, & Watson, 1978). The evidence on negative emotional states extends in a multidimensional fashion to findings on the autonomic nervous system with these right cerebral systems contributing in a differential fashion to sympathetic tone (see Harrison, 2015, pp. 441-454). Now extending the discussion to the constructs of anosognosia, anosodiaphoria, and unilateral neglect, A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria damage to these systems may indeed result in component loss of left hemispace and the negative emotional analysis of one’s condition (akin to anosodiaphoria) with a failure to implement caution or to attribute negative emotional bias to one’s state of affairs (akin to anosognosia). If the proposed theoretical integration were to be found to have merit, then evidence based interventions for neglect disorder, itself, might convey import to the treatment of anosodiaphoria. Also, the location of the deficient neural systems would provide alternatives for remediation through the homologous and presumably intact systems in the other brain. This would be evident in the initial recovery of anosognosia prior to anosodiaphoria, through the implementation of logical verbal analysis and learning to verbally express one’s deficits, based on therapist’s rationale. 149 Understanding differences and similarities between anosognosia, anosodiaphoria, and unilateral neglect is not merely a problem for intellectuals over which to split hairs. Understanding patient insight to deficits (anosognosia), concern for deficits (anosodiaphoria), and the failure to attend to the left half of experience (unilateral neglect associated with right cerebral lesion) carries important implications across a number of domains, including public health policy, health care costs, provision of efficacious patient care/treatments, and decision making regarding patient capacity for self-care upon discharge from medical settings. In the current report, we present the case of a female patient at evaluation, following acute right CVA in the middle cerebral artery territories. The patient presents with left upper limb hemiplegia and Fig. 1. MRI depicting right middle cerebral artery distribution parietotemporal cerebrovascular accident in this patient with left hemineglect, anosognosia, and anosodiaphoria. 150 A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria Fig. 2. MRA images from coronal section (left) and horizontal section (right) depicting arterial distribution in this patient with left hemineglect, anosognosia, and anosodiaphoria. hemianesthesia, left hemispatial neglect, and an anosognosic/anosodiaphoric state of awareness. The patient is an active participant in a multidisciplinary team approach to her rehabilitation for her brain disorders, with each discipline working collaborating in her care. The current case takes an interdisciplinary approach to assessment and rehabilitation through a review of the medical history and physician notes; neuroradiological findings via magnetic resonance imaging (MRI; see Fig. 1) and magnetic resonance angiography (MRA; see Fig. 2); the behavioral observations and evaluations of her therapists from speech and occupational therapy disciplines; and the integrated neuropsychological evaluation combining the standardized test battery assessment with the neurobehavioral status examination and syndrome analysisbytheclinicalneuropsychologist.Altogether, the current case highlights the importance of patient assessment and patient care through interdisciplinary collaboration. 1.2. Patient information and history The patient is an actively employed 43 year old, right-handed, African-American female who initially presents to the medical center by a friend with complaints of acute onset left sided weakness. Following emergent care, she is seen for neuropsychological evaluation and multidisciplinary team treatment in the rehabilitation unit of a major medical center. Imaging with head scans conducted and interpreted upon admission reveal a large middle cerebral artery (MCA) distribution infarct within the right tempo- ral lobe which extends into parietal and occipital regions (see Fig. 1). The MRA of the head more specifically shows irregularity in the initial M1 segment along with diminished right middle cerebral arterial branches extending into the insular region. The patient has a prior history of a small infarct about 4 years prior to this admission with an area of encephalomalacia evident within the distribution of her acute CVA. Her medical history is remarkable for hypertension, hyperlipidemia, hypokalemia, and tobacco use (1.5 packs per day). 1.2.1. Review of physician notes documented upon admission Initial reports from her attending physician provide the first observations of difficulty with neglect in the left hemispace and the potential for the presence of diminished insight (anosognosia) and/or concern (anosodiaphoria) to her deficits. Medical notation indicates that “the patient was in no distress.” Physicians noted that she “intends more to the right hemispace and demonstrates a right gaze bias that she is able to overcome voluntarily when prompted.” Physician notation also documented left hemifacial weakness, increased tone at her left shoulder with decreased tone at her left elbow, decreased strength in her left upper extremity, and decreased sensation in her left lower extremity. Further, as of her second day of admission, notations indicate that she is “feeling better” and requesting to be discharged so that she could return home. Follow-up notes from the attending physician evaluation conducted 4 days post-admission show that A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria the patient is describing returned sensation in the left hemibody. The physician notation continues to highlight the patient’s preference for using her right hemibody for functional actions and that she continues to maintain a right gaze preference, albeit that her gaze is able to cross midline, thus marking a second time that the physician suggests that when prompted, the patient is able to attend to the left hemispace. Further, notation 4 days post-admission continues to describe the patient’s left lower extremity weakness, left hemi-anesthesia, and left hemifacial weakness. 1.2.2. Neuropsychological evaluation Several facets of the patient’s history and presentation led to evaluation for anosognosia, anosodiaphoria, and left hemi-neglect. In addition to physician note review, the extant literature on the location of the infarct in the distribution of the right MCA and extending into the temporal, parietal and occipital regions was suggestive for anosognosia as a right brain disorder (see Harrison, 2015, pp. 215-262). This was clinically indicated as a standard rule-out in any neuropsychological assessment involving damage to these regions. Additionally, her relative lack of concern over her deficits, as suggested in physician notes, suggested the possible presence of anosodiaphoria. Further, physician suggestions of right hemibody use preference, right gaze bias, left hemifacial weakness, and left hemibody weakness and anesthesia all suggested the potential presence of unilateral left hemispatial neglect. Further evidence is provided subsequent to consultation by the neuropsychologist among the multidisciplinary team of therapists. The speech and occupational therapists generated a list of ‘insight into deficits’ related comments by the patient. Therapist reports indicate that the patient does not have an appreciation for the severity of her left sided deficits; that the patient states that she is ready to leave the hospital and to return to active employment immediately; that she does not appreciate “any good reasons” as to why she should not drive; and that she planned to return to domestic duties (i.e., cooking) upon discharge from the medical center. These comments by the patient were of concern for the staff, leading to specific referral to the neuropsychologist. The evaluation of insight to deficits and the ability to appreciate her capacity for maintaining safety, self-care, and independent living shed light on seemingly impulsive behaviors in the hospital (e.g., attempting to get up and out of her wheelchair without assistance). 151 1.2.3. Standardized assessment Standardized testing for neuropsychological and mood-related difficulties was conducted using the Mini-Mental Status Exam, 2nd edition (MMSE-2; Folstein, Folstein, & McHugh, 1975); the Geriatric Depression Scale (GDS; Yesavage et al., 1983) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, Tierney, Mohr, & Chase, 1998). The patient performed in the impaired range on the MMSE-2 (22/30), demonstrating particular difficulties with recall memory, construction, and attention (evidence through difficulty with mental calculation on the ‘Serial 7s’ subtest). Administration of the GDS indicated no presence of depression symptoms, corroborating physician reports regarding the patient being in ‘no acute distress.’ The RBANS, which tests neuropsychological functioning across a number of circuits (immediate and delayed memory, visuospatial/constructional, language, attention, and an aggregated total score) indicated overall neuropsychological functioning in an impaired range (Total Score = 58, 3rd percentile, impaired range compared to same aged/educated peers, 95% CI [51–65]). She demonstrated relative strengths in language and logical linguistic speech (Language = 103, 58th percentile, average range compared to same aged/educated peers, 95% CI [89–117]). Conversely, and in accordance with her right MCA infarct extending from temporal through parietal and into occipital regions, the visuospatial/constructional index was severely impaired (visuospatial/ constructional = 62, 1st percentile, impaired range compared to same aged/educated peers, 95% CI [49–75]), with evidence for a 90 degree figure rotation during the Figure Copy subtest. She also demonstrated impaired attention (64, 1st percentile, impaired range, 95% CI [52–76]), immediate memory (49, <0.1st percentile, impaired range, 95% CI [39–59]), and delayed memory functioning (56,.2nd percentile, impaired range, 95% CI [44–68]). 1.2.4. Neurobehavioral syndrome analysis The neuropsychological evaluation provided evidence of mixed left hemineglect syndrome. Sensory examination yielded visual extinction at the left upper and lower visual quadrants, as well as left hemi-anesthesia with omission errors upon tactile confrontation with light brushing stimuli at the left hemibody. Motor examination demonstrated left upper extremity plegia and left lower extremity 152 A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria paresis, right frontal eye field dysfunction/left gaze impersistence, motor impersistence (to ‘eyes closed’ command), left side drooling, and left lingual paresis/spasticity. Speech examination showed left side lingual paresis. Dysarthria was present as a function of the left-sided tongue paresis. Further, the patient’s vocal prosody was blunted with a receptive aprosodia. Observations were also remarkable for frequent and recurrent involuntary spasm at the left nasolabial fold (mouth) and muscular spasm at the left eye. Notably, throughout testing, she demonstrated significant integrity for positive affect and social engagement using linguistic and languagebased analyzers. In order to provide a test of insight into neglectrelated deficits (i.e., anosognosia for problems in the left hemi-space), a multiple reporter strategy was employed using the Catherine Bergogo Scale (CBS; see Azouvi, Olivier, De Montety, Samuel, LouisDreyfus, & Tesio, 2003; Azouvi et al., 1996). The CBS is composed of 10-items referenced to a 4 point rating scale (0–3). The ‘behavioral assessment’ portion of the CBS is first completed by an independent assessor with a focus on rating observations of the extent to which the patient neglects left-hemi-body objects, both in problematic neglect behaviors for intra-individual space (e.g., neglect of hygiene at the left-hemibody) and neglect for objects located in extra-personal space (e.g., neglect of food on the left side of one’s plate) on a 0–3 scale (0 = no neglect; 1 = mild neglect; 2 = moderate neglect; 3 = severe neglect). Example questions include “Forgets to clean the left side of his/her mouth after eating” and “Has difficulty paying attention to noise or people addressing him/her from the left.” An example of the rating criteria is as follows: “a score of 2 (moderate neglect) was given if the patient showed clear and consistent left-sided omissions or collisions; and a score of 3 (severe neglect) was given if the patient was totally unable to explore the left hemispace” (Azouvi et al., 2003, pp. 52). In the current study, the CBS was completed independently the by primary speech pathology and occupational therapists involved in direct care for the patient. The patient’s occupational therapist completed the CBS, rating the patient’s left hemineglect behaviors at a 15 out of 30. The speech therapist’s rating totaled 18 out of 30. Patient-reported left hemineglect difficulties were then assessed through a parallel version of the CBS. During this ‘self-report’ portion of the CBS, the patient was asked to rate her perceived difficulty with attending to the left side of the world (0 = no difficulty to 4 = severe difficulty). The patient endorsed items and ratings that aggregated into a total score of 9 out of 30. In order to calculate ‘anosognosia as a function of left hemineglect insight’ behavioral assessment by the speech and occupational therapist was compared to the patient’s report on the same neglect behaviors as rated through a parallel form of the CBS, specifically by calculating the differences between the patient report and the behavioral observations from therapists. The patient demonstrated a clinically significant level of anosognosia for left-sided neglect/deficits in comparison to the speech therapist’s behavioral rating (18 – 9 = 9), the occupational therapist’s rating (15–9 = 6), as well as when taking the average of speech and occupational therapist ratings compared to the patient’ scores (16.5 – 9 = 7.5). The difference between the patient’s account of her deficits versus therapist’s ratings of the patient’s leftsided neglect related deficits (average = 7.5) indicates moderate anosognosia as a function of behavioral neglect severity (normalized range for moderate anosognosia as a function of behavioral neglect severity = 7.38 ± 7.04 [mean ± standard deviation]; see Azouvi et al., 2003). 2. Discussion Primary findings from this evaluation support diagnoses of anosognosia, anosodiaphoria, and left unilateral neglect. The findings of our interdisciplinary evaluation and the clinical diagnoses are commensurate with the extant literature on the effect that MCA CVAs may have as the result of altered right temporal, parietal, and occipital functions (contralaterally controlling the left hemibody and attention to the left hemispace; see Harrison, 2015). Regarding the neglect syndrome, the neuropsychological evaluation provided a significant diagnosis for mixed left hemibody neglect via demonstration of: (a) visual extinction in the left upper and lower quadrants when presented with concurrent or stereoscopic visual stimuli in bilateral hemispace; (b) left gaze impersistence, (c) preference for use of the right hemibody, (d) left-sided drooling, and; (e) left facial spasticity and paresis. Further, as per double-dissociation techniques, the neuropsychological evaluation demonstrated (a) relatively intact lingual analyzers and language systems (RBANS language score = 58th percentile) as part of the preserved left cerebral hemisphere, alongside left hemiparesis A.J. Smith et al. / Left hemineglect, anosognosia, and anosodiaphoria (likely related to old encephalomalacia in the right frontal lobe based on a CVA experienced 4 years prior), juxtaposed to (b) constructional apraxia (RBANS visuospatial functioning score = 1st percentile). Notably, the patient demonstrated ability to cross the midline into the left hemispace despite her right hemibody and rightward gaze preferences, suggesting that she is capable of attending to the left hemispace when prompted, a finding that has implications for therapy using prompts to attend to left hemispace and hemibody. With regard to anosognosia, the patient demonstrates the capability to verbalize her left hemibody difficulties when prompted (as per her score of 9 out of 30 on the patient-reported CBS for insight into left hemineglect), albeit that her capacity to recognize the severity of left hemibody problems is moderately impaired, as suggested by her ‘anosognosia as a function of left hemibody neglect’ score, calculated based on the difference between patient report and parallel behavioral ratings by the speech and occupational therapists. These findings corroborate concerns conveyed by the therapists that the client reports her intentions to return to pre-CVA activities (work, driving, and domestic duties) immediately, and suggest that she experiences moderate anosognosia, with initial therapies indicated for verbalizing and attending to left hemibody deficits and left hemispace. With regard to anosodiaphoria, we based our diagnosis on interdisciplinary observations, patient presentation, and administration of the GDS. Based on interdisciplinary physician report, therapist concerns (extrapolated from patient presentation), and the neuropsychological evaluation (including administration of the GDS assessing for depressed mood), the patient displays a lack of concern and distress over her deficits. She frequently requests to be discharged, although she shows no particular distress when this request is not granted. She shows no signs of depression or sadness related to her loss of function over the left hemibody. Notably, her old right encephalomalacia (due to a CVA 4 years prior to the current right MCA CVA), which is likely responsible for her prosodic deficits in speech production, may have implications for how others responds to the patient; she may in fact be experiencing some emotional lability with regard to her left hemibody deficits, but her blunted vocal prosody does not convey this. It could be that observations fail to detect lack of concern due to sparse affective prosody in her voice, suggesting that our interpretation of her apparent lack of distress over her deficits should be considered with this caution in mind. 153 Examining Kinsbourne’s functional cerebral space theory (Kinsbourne, 1980; Kinsbourne & Hicks, 1978) as an alternate explanation for the often comorbid nature of anosognosia and unilateral neglect, patients with space occupying lesions of areas traditionally believed to subserve functions of deficit awareness may also have corresponding deficits in attentional modulation due to the overlap of this function in shared cortical tissue. Thus the right parieto-temporal regions responsible for attention and sensation to left hemispace, may have overlap in the, still unidentified, systems underlying human self-awareness, particularly of their disabilities or dysfunction. Because of this, even a very localized and precise lesion in these areas may result in both a lack of awareness of left hemispace (anosognosia) and a failure to attend to left hemispace (hemispatial neglect). The same theoretical underpinnings could explain the anosognosia and anosodiaphoria interplay whereby patients seemingly become aware of deficits but do not seem to express an emotional reaction to these deficits, being described as unconcerned or even apathetic. This theoretical perspective remains to be explored in depth, but may pave the way for explaining the often difficult nature of clinically distinguishing and thereby dissociating among these various syndromes. The utility of appreciating the multi-functional role of any brain region is the implied effect of therapy for one disorder with overlay that positively translates to the other. This approach is inherently transdiagnostic in nature. Rehabilitative procedures have been put forth using various methods for unilateral neglect syndromes and extrapolating from this perspective therapies for neglect disorder may be equally effective as therapies for anosognosia and anosodiaphoria. Substantially more success has been made in the treatment of neglect disorders, with only minimal clinical impact observed on interventions for anosodiaphoria. For example, ambient sensory or light therapy at the left eye-cup has been used to alter left-hemi-spatial neglect. However, no comparable approach has been ventured for anosodiaphoria. The rehabilitative treatment of patients with anosognosia has been well documented and guidelines even exist to detail the procedures for the clinician faced with the treatment of anosognosia resulting from different neurological insult (Prigatano & Morrone-Strupinsky, 2010). 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