Delirium is a cognitive disorder characterized by acute onset, fluctuating course, altered level of consciousness, inattention, disorganized thinking, disorientation, memory impairment, and perceptual and motor disturbances (American Psychiatric Association, 2000; World Health Organization, 2010). It occurs in hyperactive, hypoactive, or mixed forms in up to 42% of older hospital inpatients (Siddiqi et al., Reference Siddiqi, House and Holmes2006) and 70% of older long-term care residents (McCusker et al., Reference McCusker2011). In both settings, delirium is independently associated with poor outcomes (Siddiqi et al., Reference Siddiqi, House and Holmes2006; McCusker et al., Reference McCusker2010; Witlox et al., Reference Witlox2010).
Both DSM-IV-TR and ICD-10 diagnostic criteria for delirium require the coexistence of symptoms from multiple domains (American Psychiatric Association, 2000; World Health Organization, 2010). It is common, however, for older people to display one or more symptoms of delirium without having the full syndrome (Rockwood, Reference Rockwood1993; Kiely et al., Reference Kiely2003). The occurrence of such symptoms has been labeled as subsyndromal delirium (SSD) (Levkoff et al., Reference Levkoff1996).
The existence of SSD is controversial. Some investigators claim that SSD may be a clinically important condition that falls on a continuum between no symptoms and full delirium, perhaps a marker for underlying medical conditions (e.g. infection, drug toxicity) not severe enough to cause full delirium (Levkoff et al., Reference Levkoff1996; Cole et al., Reference Cole, McCusker, Dendukuri and Han2003). Others argue that distinguishing subsyndromal presentations from full delirium is not “clinically practical given the fluctuating course of delirium, as clinical manifestations may range from normality through subsyndromal to full syndromal delirium in a matter of hours” (Blazer and van Nieuwenhuizen, Reference Blazer and van Nieuwenhuizen2012).
To date, evidence for the existence of SSD is inconclusive. On the one hand, two studies of the course of SSD have reported that episodes of SSD appear to occur independently of full delirium, last for 1–133 days, and often end in recovery but often recur (Tan et al., Reference Tan2008; Cole et al., Reference Cole2012a). On the other hand, a systematic review of the studies of SSD has reported significant unexplained heterogeneity in the results of studies of prevalence, incidence, and some risk factors that may undermine the credibility of the findings of these studies (Cole et al., Reference Cole, Ciampi, Belzile and Dubuc-Sarrasin2012b).
Only further research will advance knowledge and determine whether or not SSD is a clinically important condition. To advance knowledge, such research must wrestle with six conceptual and methodological issues and try to avoid teleological reasoning and research design. These issues include the following: the types of symptoms of delirium required for the diagnosis of SSD, the number of symptoms required for diagnosis, the relationship of the symptoms present to full delirium, the measurement of the symptoms of delirium, prevalent versus incident SSD, and the selection of patient populations. Each of these issues is outlined below.
Types of symptoms of delirium
To date, three studies (Levkoff et al., Reference Levkoff1996; Cole et al., Reference Cole, McCusker, Dendukuri and Han2003; Liptzin et al., Reference Liptzin, Laki, Garb, Fingeroth and Krushell2005) have defined SSD as the presence of one or more symptoms of delirium; the symptoms were inattention, altered level of consciousness, disorientation, and perceptual disturbances. Five studies (Marcantonio et al., Reference Marcantonio, Ta, Duthie and Resnick2002; Bourdel-Marchasson et al., Reference Bourdel-Marchasson2004; Tan et al., Reference Tan2008; Leonard et al., Reference Leonard2009; Cole et al., Reference Cole2011) have defined SSD as the presence of one or more Confusion Assessment Method (CAM) core symptoms of delirium; the CAM core symptoms were acute onset and fluctuation, inattention, disorganized thinking, and altered level of consciousness. Three studies (Ouimet et al., Reference Ouimet2007; Ceriana et al., Reference Ceriana, Fanfulla, Mazzacane, Santoro and Nava2010; Skrobik et al., Reference Skrobik2010) have defined SSD as the presence of one to three symptoms of delirium on the Intensive Care Delirium Screening Checklist; the symptoms included altered level of consciousness, inattention, disorientation, hallucinations or delusions, agitation or retardation, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation. One study (Meagher et al., Reference Meagher, Adamis, Trzepacz and Leonard2012) has defined SSD as a severity score of 8–15 on the 13-item severity scale of the Delirium Rating Scale-98 (DRS-98); the severity scale includes disturbances in sleep–wake cycle, perception, thought form and content, affect, language, motor activity, orientation, attention, short- and long-term memory, and visuospatial ability. Finally, one study (Trzepacz et al., Reference Trzepacz2012) has defined SSD using a type of cluster analysis of the 13 severity items and two diagnostic items of the DRS-98. SSD was intermediate in severity between no symptoms and full delirium, but its phenotype was more like delirium; proposed criteria for SSD include acute change from baseline, thought disorder, disorientation to time and place and mild disturbances in sleep–wake cycle, inattention, and navigating in one's surroundings.
Of note, differences in the prevalence and incidence of SSD cannot be attributed to the diagnostic criteria used (Cole et al., Reference Cole, Ciampi, Belzile and Dubuc-Sarrasin2012b). Only one study has compared prevalence rates of SSD using two different sets of diagnostic criteria and reported little difference in the rates (Voyer et al., Reference Voyer, Richard, Doucet and Carmichael2009). The reason for the above findings may be that, despite differences in diagnostic criteria between studies, the symptoms that most frequently identify SSD are the same in all studies: to wit, two studies report that SSD was identified most often by the symptom of inattention (Cole et al., Reference Cole, McCusker, Dendukuri and Han2003, Reference Cole2011) and this symptom is common to all sets of diagnostic criteria.
Number of symptoms of delirium
Most studies of SSD have defined SSD by the presence of one or more symptoms of delirium, or two or more symptoms; consequently, it is difficult to evaluate the frequency or significance of the presence of one versus two versus three symptoms. That being said, three studies have compared the frequency of SSD defined by the presence of one versus two to three Confusion Assessment Method (CAM) core symptoms of delirium (Kiely et al., Reference Kiely2003; Dosa et al., Reference Dosa, Intrator, McNicoll, Cang and Teno2007; von Gunten and Mosimann, Reference von Gunten and Mosimann2010); and one study has compared the frequency and outcomes of SSD defined as the presence of one or more versus two or more CAM core symptoms (Cole et al., Reference Cole2011). Although the evidence is limited, it appears that the more the symptoms required for SSD diagnosis, the lower the prevalence and incidence rates and the poorer the outcomes.
Relationship of symptoms present to delirium
When SSD was described by Guainerio in 1517 (Diethelm, Reference Diethelm1971), “. . . he emphasized that a predelirious period . . . can be recognized which . . . may not lead to full delirium.” Similarly, Lipowski (Reference Lipowski and Lipowski1990) described a “prodromal phase . . . in which patients had one or more symptoms of delirium (decreased concentration and ability to think, restlessness, anxiety, irritability, drowsiness, hypersensitivity to stimuli, nightmares) that never progressed to full DSM-defined delirium.”
Many authors, however, have not distinguished between symptoms that do or do not progress to delirium (Kiely et al., Reference Kiely2003; Marcantonio et al., Reference Marcantonio2005; Dosa et al., Reference Dosa, Intrator, McNicoll, Cang and Teno2007; Voyer et al., Reference Voyer, Richard, Doucet and Carmichael2009; von Gunten and Mosimann, Reference von Gunten and Mosimann2010). DSM-IV-TR recognizes “subsyndromal presentations . . . with some but not all of the symptoms of delirium” and recommends that such presentations be coded as Cognitive Disorder Not Otherwise Specified (American Psychiatric Association, 2000). More recently, the DSM-V Neurocognitive Disorders Workgroup has discussed whether to add SSD as a subcategory of delirium in parallel with a new category, mild neurocognitive disorder (Jeste, Reference Jeste2010). Notably, neither DSM-IV-TR nor the DSM-V Workgroup distinguishes between subsyndromal presentations that do or do not progress to delirium.
Whether or not SSD occurs independently of delirium is a critical issue for research. Many symptoms of delirium appear to occur before and after episodes of delirium, at least in some populations (Cole et al., Reference Cole2012c). If the definition of SSD does not exclude symptoms that occur immediately before or after episodes of delirium, it may not be possible to distinguish the risk factors, course, and outcomes of SSD from those of delirium. If the definition of SSD excludes symptoms that occur immediately before or after episodes of delirium, it may be possible to distinguish the risk factors, course, and outcomes of SSD from those of delirium and investigate the possibility of a continuum of acute neurocognitive disorder in older people.
Of note, in 12 studies that excluded SSD progressing to delirium, the combined prevalence of SSD was 23% (95% CI = 9%–42%); the combined incidence was 13% (95% CI = 6%–23%); risk factors were older age, dementia, more cognitive and BADL impairment, admitted from an institution, increasing severity of medical illness, vision impairment, and more co-morbidity; outcomes (i.e. cognitive and functional decline, increased length of hospital stay and increased rates of admission to long-term care institutions, and death) were poor (Cole et al., Reference Cole, Ciampi, Belzile and Dubuc-Sarrasin2012b). In five studies that did not exclude SSD progressing to delirium, the reported prevalence of SSD ranged from 11.9% to 51%; the median rate was 39.5%. Two of these five studies reported risk factors similar to SSD not progressing to delirium and one reported outcomes similar to SSD not progressing to delirium. Notably, none of the five studies reported the proportions of subjects with SSD that did or did not progress to full delirium. Although the evidence is limited, it appears that the inclusion of subjects with SSD that may progress to delirium increases prevalence substantially but may not change risk factors or outcomes.
Measurement of symptoms of delirium
To date, the following four different instruments have been used to identify SSD: the Delirium Symptom Interview (Albert et al., Reference Albert1992), the Confusion Assessment Method (Inouye et al., Reference Inouye1990), the Intensive Care Delirium Screening Checklist (Bergeron et al., Reference Bergeron, Dubois, Dumont, Dial and Skrobik2001), and the Delirium Rating Scale-98 (Trzepacz et al., Reference Trzepacz2001). There do not appear to be consistent differences in the frequencies, risk factors, or outcomes of SSD when these different instruments are used (Cole et al., Reference Cole, Ciampi, Belzile and Dubuc-Sarrasin2012b), perhaps because a relatively small set of symptoms (e.g. inattention, disorganized thinking) identify most cases of SSD and are common to most of the instruments. Although the evidence is limited, the instrument(s) that best measure the small set of symptoms relevant to the detection of SSD are likely to be the most useful.
As yet, there is little consensus on the duration or frequency of measurement required to detect SSD. In published studies, the period of observation ranges from 5–180 days, median 7–8 days; when the period of observation has involved more than one assessment, the frequency of assessments has ranged from thrice per day to weekly, median daily (Cole et al., Reference Cole, Ciampi, Belzile and Dubuc-Sarrasin2012b).
Prevalent versus incident SSD
Prevalent SSD can be defined as a diagnosis of SSD at the time of first assessment. Incident SSD can be defined as a diagnosis of SSD following one or more assessments with no symptoms of delirium. Because prevalent SSD may represent the end of a resolving episode of delirium or even persistent symptoms of delirium (Cole, Reference Cole2010), inclusion of prevalent cases in studies of SSD may preclude the study of SSD, independent of delirium.
Selection of patient populations
The prevalence and incidence of delirium can vary enormously by type of population selected (e.g. community, emergency room, medical inpatients, surgical inpatients, nursing home residents) and the frequency of dementia in the population selected (McCusker et al., Reference McCusker2011). Risk factors for delirium tend to be similar among medical and surgical populations but may be different among nursing home populations (McCusker et al., Reference McCusker2011). Outcomes seem to be uniformly poor across all populations studied, perhaps worse among those with dementia (McCusker et al., Reference McCusker, Cole, Dendukuri, Belzile and Primeau2001). Because findings will probably be similar for SSD, it may be important to consider the populations selected to study SSD.
Conclusion
What is SSD? What is the clinical significance of SSD? Does SSD occur independently of delirium? Is SSD a marker for underlying medical conditions not severe enough to cause delirium? Is SSD a clinically important condition requiring medical attention? Or does SSD reflect only the fluctuating nature of delirium and the fact that infrequent assessments of symptoms of delirium miss the diagnosis of full delirium? To answer these questions, further research must grapple with six conceptual and methodological issues and try to avoid teleological reasoning and research design. The issues include the following: the types and number of symptoms of delirium required for the diagnosis of SSD, the relationship of the symptoms present to full delirium, the measurement of the symptoms of delirium, enrolment of prevalent versus incident SSD, and the selection of patient populations. Research that satisfactorily addresses these issues may advance knowledge of SSD.
Conflict of interest
None.
