Delirium: Encephalopathy/Acute

confusion

Vikas Kumar, MD PhDSSM Neurosciences

Disclosures

• None

Encephalopathy Definition• Greek: Inside the head, suffering

• Brain disease, disorder or damage: temporary or permanent condition that affects brain structure and function

• Acute or subacute syndrome characterized by disturbance of consciousness, orientation, attention, cognitive function, sleep wakefulness cycle and fluctuation

• Global disturbance of cerebral function

• Hallmark of encephalopathy is altered mental state (AMS), delirium, confusional state

• Can progress to Coma

www.ninds.nih.gov/disorders/encephalopathy/encephalopathy.htm

Delirium or Acute encephalopathy

- Two different terms describing the same condition.- Delirium represents the mental manifestation while encephalopathy

identifies the underlying pathophysiologic process. - DSM-5 classifies acute toxic and metabolic encephalopathic states as

delirium and does not use encephalopathy in its definitions.- ICD-9 and ICD-10 use “encephalopathy” to classify what DSM-5 calls

delirium. Examples include:* Toxic encephalopathy due to phenytoin, causing delirium* Delirium due to metabolic encephalopathy

Incidence- Increases after the age of 65 years.

- People older than 75 years, who reside in nursing homes have a 60% chance of developing encephalopathy.

- Encephalopathy occurs in 10–40% of hospitalized patients older than 65 years.

- Encephalopathy has being registered in 12–16% of patients with thiamine deficiency, every year

- In patients with cirrhosis, the hepatic encephalopathy develops in 45–80% of cases, depending on the severity of liver damage

Causes of encephalopathy• Toxic Metabolic Encephalopathy (TME): Hepatic

(hyperammonemia), uremia, electrolyte imbalance, alcohol, organ failure, chemotherapy

• Drugs: Barbiturates, narcotics, TCAs, Anticholinergics, Phenothiazines, anticonvulsants (VPA, TPM, CBZ etc) corticosteroids, Cephalosporin (cefepime), etc

• Hypertension

• Epileptic

• Hypoxic ischemic

• B1 deficiency (Wernicke)

• Infection: HIV, UTI, pneumonia, lyme, sepsis, pancreatitis etc

• Infectious: Prion disease/CJD, Transmissible spongiform encephalopathy

• Thyroid: Hashimoto

• Glycine

• Paraneoplastic

• PRES

• Mitochondrial encephalomyopathy, MELAS

• NMDAR encephalitis

• Trauma: CTE

• Industrial and environmental toxins: organic solvents, heavy metals

Causes of encephalopathy

Encephalopathy Symptoms/Signs

• Altered mental state: Delirium

• Impairment of alertness, attention, concentration, memory.

• Feeling confused, lethargic, psychomotor hyperactivity, agitation, hallucination

• Physical symptoms: involuntary eye and muscle movements (Roving eye movements, asterixis, myoclonus), seizures

• Autonomic symptoms: insomnia, nausea, heart rhythm disorders

Diagnosis• Clinical history and neurological exam

• Laboratory tests: CBC, CMP, blood culture, ammonia, TSH, Toxicological screen, B12, B1, ESR, CRP, procalcitonin, lactic acid, ABG, U/A, Heavy metal screen, HIV, lactate, pyruvate, NMDAR Ab, paraneoplastic panel, lyme panel

• CSF exam: cell count, protein, glucose, culture, 14-3-3 protein,

• Neuroimaging

• EEG: generalized slowing or focal suppression, FIRDA, PLEDs, Triphasic waves

Pathophysiology- Inflammation —> endothelial activation in the brain —> malfunction of the blood–brain barrier. —> release of inflammatory mediators such as cytokines and chemokines —> damage to the cellular metabolism —> oxidative stress and mitochondrial dysfunction —> disruption of neurotransmission —> apoptosis.

- The cholinergic, GABA, beta-adrenergic, and serotonergic systems are altered and neurotransmission functioning is damaged, especially in the neocortex and hippocampus.

- Release of excitatory amino acids, hyperglycemia, neurotoxic pharmacological agents, hemodynamic changes, coagulopathy, and hypoxemia.

- Increase in the glutamine and glutamate complex peak in magnetic resonance (MR) spectroscopy illustrates the neuronal and astrocytic excitotoxic injury.

- The combined antiepileptic valproate and topiramate therapy causes reduction of topiramate metabolism through cytochromeP 450 pathway.

- Cephalosporins may also induce encephalopathy through GABA A receptor inhibition.

- Decrease in the central cholinergic activation and an increase in the proinflammatory cytokine concentrations (interleukin 8, TNF alpha, interleukin 10)

Pathophysiology

Treatment• Correct the cause

• ABCs

• Hashimoto’s/Thyroiditis: Steroid responsive encephalopathy

• Wernicke: High dose Thiamine IV

• Uremic encephalopathy: Dialysis

• Anticonvulsants

• Sympathomimetic drugs

Prion disease (CJD): Cortical signal abnormality

Day 1 Day 11 Day 18

- Rapidly progressive, invariably fatal neurodegenerative disorder - Caused by an abnormal isoform of a cellular glycoprotein

known as the prion protein. - Estimated annual incidence to be about one case per

million population.

Periodic discharges

Hepatic/Uremic encephalopathy

Type A, which is associated with acute liver failure. Type A are more likely to have edema in the brainType B, which is associated a portosystemic shunt (a shunt that bypasses the liver) with no existing liver disease presentType C, which is associated with scarring and poor function of the liver (cirrhosis)

Wernicke encephalopathy- Most important encephalopathy due to a single vitamin (B1

Thiamine) deficiency- Triad of ocular findings, cerebellar dysfunction and

confusion- Most often associated with chronic alcoholosim, poor

nutrition, malabsorption, increased metabolic requirements/systemic illness, renal dialysis hyperemesis of pregnancy, bariatric surgery etc

Autoimmune encephalitis

Autoimmune encephalitis

Figure 1 Flowchart of samples and results ADS = acquired demyelinating syndromes; GBS = Guillain-Barré syndrome; LEMS = Lambert-Eaton myasthenic syndrome; OMS = opsoclonus myoclonus syndrome; SC = Sydenham chorea; VGKC = voltage-gated potassium channel.

Yael Hacohen et al. Neurology 2015;85:967-975

© 2015 American Academy of Neurology

NMDA receptor encephalitis

• Paraneoplastic encephalitis

• Psychiatric features

• Involuntary movement

• Autonomic instability

• 80% of patients are female and around 50% have underlying tumor (ovarian teratoma, Lung cancer, thyroid tumor, breast, cancer, colon, neuroblastoma etc)

https://www.rarediseasereview.org/publications/2017/2/9/recent-updates-in-anti-nmda-receptor-encephalitis-research

Immunologic triggers in anti–NMDA receptor (NMDAR) encephalitis

Josep Dalmau Neurology 2016;87:2471-2482

© 2016 American Academy of Neurology

Brain reactivity of autoantibodies against neuronal cell surface or synaptic proteins

Josep Dalmau Neurology 2016;87:2471-2482

© 2016 American Academy of Neurology

Ongoing Clinical trials