Volume 6 Number 3 pp. 297–304 297 RASSF1A Promoter Methylation Viera Kajabova*, Bozena Smolkova*, Levels Positively Correlate with Iveta Zmetakova*, Katarina Sebova*,Tomas Krivulcik*, Vladimir Bella†, Karol Kajo‡, Estrogen Receptor Expression Katarina Machalekova‡ and Ivana Fridrichova* in Breast Cancer Patients1,2 *Laboratory of Cancer Genetics, Cancer ResearchInstitute of Slovak Academy of Sciences, Bratislava,Slovakia; †Department of Senology, St Elizabeth CancerInstitute, Bratislava, Slovakia; ‡Department of Pathology,Slovak Medical University and St Elizabeth CancerInstitute, Bratislava, Slovakia
DIFFERENT TYPES OF DELIRIUM: WHAT ARE THE DIFFERENCES? OR HOW DO WE DIFFERENTIATE BETWEEN THEM AND ARE THERE DIFFERENCES IN OUTCOMES?Joint Annual Meeting of the Swiss Society of Cardiology (SSC) and the Swiss Society of Cardiac and Thoracic Vascular Surgery (SSCS) June 10-12, 2015, Kongresshaus Zurich Dr. Dimitrios Adamis DISCLOSURE STATEMENT Competing interests: none to declare WHY WE SUBTYPE DELIRIUM? Delirium is a common neuropsychiatric syndrome with considerable different aetiologies and
It is important to subtype delirium:
As this could produce homogenous clinical manifestations which possible represent different
aetiologies and possible different neuropathological mechanisms.
Different subtypes could have different treatment and outcomes.
However subtypes of delirium with unique and definitely characteristics are not widely accepted.
Here I will attempt to present the most common subtypes of delirium and I will focus on motor
(psychomotor) subtyping as this is the most often discussed and the most obvious in the clinical
SUBTYPING ACCORDING TO A CLEAR AETIOLOGY Alcohol or substances withdrawn delirium vs delirium due to a medical This distinction is widely accepted and it has been implemented in the classification systems. (ICD-10, DSM-IV, and DSM-5) Alcohol (and substance) withdrawal delirium, or delirium tremens, shares common symptoms with delirium But severe agitation, tremor and physical symptoms like tachycardia, tachypnoea, and hypertension are often present. In addition withdrawal seizures. This form of delirium occurs approximately three to five days after the cessation of ACCORDING TO ANATOMICAL BRAIN AREA 1. Cortical vs Subcortical 2. Anterior vs posterior cortical 3. Right vs left hemisphere All those subtypes arise mostly of studies with delirium after brain injury. However EEG data, Polysommography, Evoked potential, CT and MRI techniques showed no clear evidence that there is an anatomical distinction in delirium. Given that areas of the brain are interconnected an anatomical location of delirium is difficult (if not unlikely) to be determined. ACCORDING TO OUTCOME 1. Reversible or recovered delirium vs no reversible or persistent delirium An older definition was acute vs chronic delirium Closely related to the concept of ‘recovery' are issues of ‘response' (which typically relates to initial reduction in symptom load), ‘remission' (which typically refers to a sustained initial period without major symptoms) and ‘resolution' (which usually refers to complete symptom reduction) Adamis et al ACCORDING TO SEVERITY AND NUMBER OF • Sub-syndromal (SSD) vs full syndromal (FSD) • SSD delirium is described as evidence of delirium features without full diagnostic criteria for delirium diagnosis. Accurate definition remains uncertain as it is unclear about the number, type and severity of symptoms required to warrant a label of SSD.
• This leads to categories vs dimensions in the diagnostic philosophy ACCORDING TO TIME • Prodromal delirium -delirium- residual delirium This subtyping also interferes with the classification of subsyndromal vs full syndromal and the recovery process when we are not sure about the onset ACCORDING TO CO-MORBIDITY Delirium vs delirium superimposed in dementia Difficult to diagnose dementia in the course of delirium. IQCODE (information from relatives) ACCORDING TO PHENOMENOLOGY 1. Psychotic vs non-psychotic 2. Psychomotor/ motor subtypes PSYCHOMOTOR/MOTOR/VIGILANCE SUBTYPES OF Two subtypes recognised since Hippocrates Phrenitis (hyperactive) Lethargus (hypoactive) Hippocrates used the term phrenitis to describe an acute onset of behavioural problems, sleep disturbances and cognitive deficits which were usually associated with fever, while he used the term lethargus to describe inertia and dulling of the senses. He believed that lethargus can change to phrenitis and vice versa. (mixed subtype) Adamis et al 2007 This distinction remained until recently (Lipowski 1989), Camus et al 2000(factor analysis) Consciousness level was the predominant distinction.
Hypoactive, hyperactive and mixed Koponent et al 1989; Liptzin and Levkoff, 1992; Meagher et al 1989 A third "mixed" category was added in recognition that many patients experience elements of both within short time frames Hypoactive, Hyperactive, mixed and none O'Keefe and Lavan, 1999; de Rooij et al., 2006; Meagher, 2009 as well as with the assistance of electronic motion analysis (Godfrey et al., 2008; Van Uitert et al., 2011) Two studies use Latent Class Analysis (Yang et al., 2009; Meagher et al 2014) which confirm the four motor subtypes. The status of no subtype patients is also somewhat unclear, with studies suggesting that these patients have less severe, or even questionable delirium (Meagher et al., 2012). However the last two studies also emphasises that motor disturbances lack absolute specificity for delirium since they are relatively common in hospitalized patients without delirium and some delirious patients have only minimal motor disturbances.
STABILITY ACROSS THE TIME OF MOTOR SUBTYPES (LONGITUDINAL STUDIES) • Subtypes were stable within delirium episodes Meagher et al 2012 (palliative care); Albrecht et al 2015 (post-operative hip fracture patients); MAPLE study Amsterdam (post-operative hip fracture patients) Adamis et al 2015 (abstract).
Fann et al. (2005) Hypoactive subtype tended to persist through course of a • Subtypes variable? (Slor et al 2013) Few studies, but seems that motor subtypes are stable during delirium. PHENOMENOLOGY AND MOTOR SUBTYPES DO DIFFERENT MOTOR SUBTYPES HAVE DIFFERENT Ross et al (1991): hallucinations and delusions more often in hyperactive Meagher et al (2000): hyper more severe delirium and more often delusions, mood lability, sleep- awake disturbances and variability of symptoms Gupta et al. (2005): Hyperactive patients had greater sleep–wake cycle disturbance and mood lability. Hypoactive patients had greater language disturbance De Rooij et al. (2006): medical elderly (2 subtypes hypo vs no-hypoactive) Affective lability less prominent in hypoactive patients.
Leonard et al 2011(palliative care): mixed subtype more severe delirium, more often sleep-awake disturbances, hallucinations, delusions, languages abnormalities Meagher et al 2011 (palliative care, longitudinal): mixed type more severe delirium: subtypes different only in delusions and affective lability. Mixed subtype more often delusions. Boettger and Bereibart 2011(palliative care: two subtypes). Significant difference between hypo-hyper in delusions and hallucinations. High prevalence of delusions and hallucinations in hypoactive.
Boettger et al 2011: (2 subtypes) hyperactive more severe delirium (MDAS) more impaired cognition, thinking disorganisation, and perception. Grover et al (2014) liaison patients (4 subtypes) motor subtypes differ only in non- cognitive symptoms. Mushtaq et al 2015 (2 subtypes) hypoactive delirium more cognitive impairment compared to hyper. AETIOLOGY (RISK FACTORS) AND MOTOR SUBTYPES O'Keeffe and Lavan (1999) elderly medical: No difference in aetiological factors Morita et al (2001), palliative care: hyperactive symptoms associated with drug induced delirium, dehydratiation relate pathology with hypoactive Peterson et al (2006) ICU: Hypoactive is associated with older age Sagawa et al (2009) cancer patients: No relation between motor subtypes and causes of delirium Robinson et al (2011) post-operative ICU. Hypoactive older, more anaemic, often ulcers. Mixed type more behaviour Stransky et al (2011) post-cardiac operation ICU: Risk for hypoactive: hx of depression, transfusion, older age, use of Meagher et al (2012) palliative care: hyperactive: younger age, less exposure to corticoids more likely the cause of delirium to be a metabolic disorder.
Franco et al (2014). Disorientation in place and time and visual-construction disturbances predict hypoactive or mixed MOTOR SUBTYPES AND TREATMENT Platt et al. (1994) Response to antipsychotic treatment similar in hypo and hyperactive patients Olofsson et al (1996) cancer pt. retrospective (3 subtypes based in alertness) Hyperalert delirium less amount of haloperidol Meagher et al (1996): More frequent use of antipsychotics in hyperactive delirium Breitbarrt et al (2002) low response rates in patients with hypoactive delirium treated with olanzapine MOTOR SUBTYPES AND TREATMENT Lam et al. (2003) Medication use less in hypoactive subtype Liu et al (2004) no differences in response rates between motor subtypes and risperidone treatment Atalan et al (2013) In hyperactive delirium after cardiac surgery morphine is superior to haloperidol Boettger et al (2014). Response to antipsychotics is similar between hypo and hyper subtypes. Higher dose of antipsychotics needed to control symptoms in hyperactive delirium MOTOR SUBTYPES AND OUTCOMES hypoactive poor outcomes (mainly mortality and function)
Liptzin and Levkoff (1992), Olofsson et al (1996), O'Keeffe and Lavan (1999), Rabinowitz
(2002) Kiely et al (2007), Yang et al (2009), Meagher et al (2011) Robinson et al (2011).
Stransky et al (2011) hypoactive prolonged ICU staying, prolonged mechanical ventilation timeMohamed et al (2015) hypoactive more cognitive decline and higher mortality Kobayashi et al (1992), Liu et al (1997): mixed has the worst outcome
Marcantonio et al 2002: Hypoactive better outcomes
MOTOR SUBTYPES AND OUTCOMES No difference between outcomes and motor subtypes reported by:
Santana Santos et al 2005; Slor et al 2013; Boettger et al 2014 No conclusive results. It seems that hypoactivity is associated with a relatively poorer prognosis SCALES / INSTRUMENTS FOR MOTOR SUBTYPING Actiwatch, Actigraphs studies no conclusive results. Some no relation with subtypes, eg Eeles 2009 others partial (Godfrey et al 2009) and others identify four factors Honma et al (1998) • Visual analog scales (eg Ross et al. 1991) • Clinical eg Olofsson et al. (1996) SCALES / INSTRUMENTS FOR MOTOR SUBTYPING • DSI Liptzin and Levkoff, 1992 • DAS O'Keeffe & Lavan (1999) • MDAS eg Marcantonio et al. (2002) • DRS-R98 e.g. Gupta et al. (2005) De Rooij et al. (2006) • RASS eg Peterson et al. (2006) Robinson et al (2011) Hyperactivity Items
(1) Increased activity levels
(1) Decreased amount activity
(2) Increased speed of actions
(2) Decreased speed of actions
(3) Involuntary movements (3) Apathy / listlessness
(4) Loss of control of activity
(4) Decreased amount of speech
DMSS 30 ITEMS, 13 (5) Restlessness
(5) Decreased speed of speech
ITEMS AND 4 ITEMS (6) Wandering
(6) Decreased Volume of speech
(7) Increased speed of speech (7) Decreased alertness
(8) Increased amount of speech (8) Withdrawal/unawareness
(9) Hypersomnolence (10) Abnormal content of verbal output (11) Hyperalertness (12) Distractibility (14) Irritability (16) Uncooperativeness (17) Combativeness (19) Hallucinations (20) Persistent thoughts (21) Tangentially / irrelevant talk WHY DIFFERENT RESULTS? Different studied populations (ICU, elderly medical, post-operative, palliative care, Liaison referrals) possible biases: Liaison population s more often hyperactive cases, palliative care more often hypoactive, ICU more often mixed subtypes. Non subtype often reported in SSD (Leonard et al 2014).
Different categories of motor subtypes have been used e.g. Hypo vs hyper vs mixed Power of the study Hypo vs hyper vs mixed vs none WHY DIFFERENT RESULTS? Different definitions of motor subtypes Not purely motor, often psychomotor (behaviour), mixed with levels of consciousness, or alertness or other phenomenology (attention) e.g. abnormal hand movements (carfology, floccillations) or dysgraphia (pure motor phenomena) have been reported in hypo and hyper subtypes (Holt et al 2015) Different methods-instruments for motor subtyping E.g. clinical, visual analog scales, or items of different scales DSI, DRS, DRS-98R, MDAS, DMSS, DMSS-4. Low agreement between those methods 34% in palliative care (Meagher et WHY DIFFERENT RESULTS? 5. Use of the same scale to assess delirium, delirium severity and motor Eg mixed subtypes seems with more severe delirium IS WORTH TO CONTINUE RESEARCH IN MOTOR a) Everyday clinical practise shows that there are different motor subtypes in delirium. If motor scales cannot capture motor subtypes, improvement of the scales is necessary!!! b) However motor subtypes are not unique to delirium. Motor disturbance not always are due to delirium. E.g. depression, schizophrenia catatonia, manic states.
c) Motor subtyping help in better identification of delirium (hypoactive more often is missed) d) Perhaps different physiopathology reflected from the different subtypes (domaminergic system involve more with hyperactive, achetylcholinergic more with hypoactive. Pro inflammatory cytokines with sickness behaviour (hypoactivity) • Not universal agreement how to subtype delirium
• Motor subtyping more obvious
• 4 motor subtypes
• Motor subtypes fairly stable during delirium
• Possible different aetiological factors but not clear link
• Hypoactive perhaps worst prognosis, but often missed
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POSEIDO. 2013;1(3) 165 Post-‐extraction implant: immediate vs delayed restoration Research article Immediate versus delayed restorations for implants placed in fresh extraction sockets: a 1-year comparative cohort study Antonio Barone,1,2,* Valentina Borgia,2 Fortunato Alfonsi,2 Paolo Toti,1,2 and Ugo Covani.1,2 1 Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy