Neurobiology of DELIRIUM

1. Neurobiology of DELIRIUM Michael Hill MD Professor of Psychiatry UNC Chapel Hill November 2006

2. DELIRIUM • Definition - transient, usually reversible, dysfunction of global cerebral metabolism or physiology that has an acute or subacute onset manifested by a wide array of neuropsychiatric abnormalities, and often associated with life-threatening medical disorders • AKA acute organic brain syndrome, acute encephalopathy

3. Delirium (signs and sx) • Symptoms: Impairments of alertness (arousal) and attention are the core deficits. Symptoms will wax and wane as alertness and attention decreases and increases. Functions that depend on attention and alertness including orientation, perception, working memory and awareness will be impaired leading to a host of potential secondary sx such as psychosis, sleep-wake cycle disturbances, agitation, anxiety, and neurological abnormalities (dysgraphia, constructional apraxia, tremor, etc.) • Signs: EEG slowing, asterixis, sleep/wake cycle changes, S100B* elevations in CSF? *(S100B is a 21-kDa calcium-binding protein produced and released primarily by astrocytes in the CNS, where it exerts neurotropic and gliotropic actions. Several studies have investigated the potential role of S100B as a peripheral biochemical marker of neural injury.

4. DSM-IV DIAGNOSIS • Criteria A. Disturbance of consciousness with decreased attention/focus B. Change in cognition or development of perceptual disturbances C. Develops rapidly and fluctuates over time • Code as ‘Delirium due to...’ 1. General Medical Condition (specify) 2. Substance Intoxication/Withdrawal 3. Multiple Etiologies 4. NOS

5. Epidemiology of Delirium • Very Common - 10-15% med/surg inpatients (30%+ if elderly); 2/3 of patients admitted from NH have delirium • 30% of Adult Burn Patients • 80% of delirious patients have pre-existing dementia • Mortality rates for elderly hospitalized patients with delirium is as high as 65% in some studies • As many as two thirds of deliria go undetected • Annual costs exceed $8 billion • All sudden mental status changes in dementia patients should be considered a delirium until proven otherwise

6. Etiology of delirium • many potential causes • often multifactorial (only 56% have a single probable etiology) • infections, metabolic derangements, anoxia, drug intoxications, withdrawals, CNS disease, toxins, fevers, etc. • susceptibility increased by aging, brain injury (esp. dementia and CV disease), polypharmacy (esp. anticholinergic load), malnutrition and fever • suspect UTI, dehydration and/or pneumonia in dementia patients with delirium

7. Neurobiology of Delirium • Neurobiological substrates of alertness, attention, and memory are very complex and interrelated. Many anatomical pathways are involved as are many neurotransmitter systems. • Delirium may result from either a failure lower brain activating systems or a disconnection of the interrelated systems that support higher cognitive functioning. A final common pathway has been hard to specifically identify.

8. Consciousness ? • An emergent property of the brain that is dependent on a number of interrelated brain systems that support: • Alertness (arousal) Executive Function • Awareness Working memory • Attention Motivation • Sensation/perception

9. Young, G. B. et al. Arch Neurol 1999;56:153-157.

10. Arousal Systems • Essential for all other higher cognitive (cortical) functions • No activity equates with coma (or death) • Reduced (or ineffective) activity correlates with delirium • Neurobiological substrate is the Reticular Activating System (RAS) – • Diffuse brainstem projections (tegmentum) to the thalamus (‘gating’ function) • Thalmo-cortical projections maintain cortical arousal (i.e arousal leads to awareness) • Extrathalamic pathways (basal forebrain and hypothalamus) important as well

11. Other arousal systems • Basal Forebrain cholinergic projections • Cholinergic neurons from nucleus basalis project diffusely to cortex • These are generally excitatory and may produce the cortical EEG rhythms • Hypothalamic-cortical projections • Projections from posterolateral HT go directly to cortex • These neurons are gabaminergic and histaminic • Hepatic encephalopathy may affect this circuitry • Brainstem neuronal groups • Monoaminergic nucleii in pons and midbrain project diffusely to cortex (serotonin, norepinephrine, dopamine and acetylcholine) • Neuropeptidessuch as TRH, somatostatin, substance P, and neuropeptide Y have all been shown to have a role in cortical activation

12. Attention • This is a control process that enables a person to select from a number of alternative choices and perform some action • Being awake and alert are prerequisites • Concentration is the ability to focus attention despite distracting stimuli (neurologically this may occur at the thalamus by control of its gating properties). Concentration is an executive function. • Neurobiological substrates include the anterior cingulate, dorsolateral PFC, certain thalamic nuclei, midbrain tegmentum (i.e. RAS) and superior colliculus • Primary neurotransmitters are dopamine and NE

13. Awareness • Highest level of cognitive functioning • Perception refers to the ‘awareness’ of the significance of a sensation • Self-awareness is probably synonymous with consciousness • Full awareness requires all systems to be intact (including memory) thus subtle impairments in consciousness might be missed in the delirious patient (i.e a delirious patient might not be as aware as they might otherwise be)

14. Memory • Full awareness (consciousness) requires a functioning ‘working memory’. This is where information from explicit memory is held ‘in consciousness’ • Anterograde memory (i.e. learning) is dependent on hippocampal and limbic structures if it’s explicit. Implicit memory bypasses consciousness for the most part.

15. Executive Function • Frontal lobe functions that impact greatly on decision-making regarding information held in working memory (i.e. consciousness). • These functions include inhibitory control of impulses, novelty detection, sustained focus and attention, and prioritizing and organizing information • Since working memory is not sustainable in delirium, executive function will be impaired

16. Pathophysiology of delirium • Probably no specific final common pathway; delirium is likely the result of multiple neurotransmitter abnormalities resulting in reduced arousal (though in withdrawal deliria there may be hyperarousal with reduced awareness due to ineffective activation or over stimulation) • On a deeper level however, cerebral metabolic insufficiency due to impaired glucose metabolism may be a universal finding • The concept of cognitive reserve refers to the brain’s ability to resist this metabolic insufficiency • Interestingly, anticholinergic drugs have been shown to cause a dose-dependent decrease in glucose metabolism by radiographic studies

17. DELIRIUM - General Treatment • Treatment: • Must look for medical cause(s) and treat as the primary intervention • Secondary symptoms can be helped by drugs such as haloperidol or risperidone (unless the cause of the delirium is NMS) and by reorientation strategies • Avoid anticholinergic, antihistaminic, and sedating drugs

18. Specific Treatments • Anticholinesterases may be useful if cholinergic systems are impaired (which may be the case in most deliria) • Thiamine for W-K, benzodiazepines for etoh/sedative withdrawal delirium • Benzodiazepine antagonists have been useful in some cases of hepatic encephalopathy • What about stimulants?