Michelle-Lee Jones Neurology PGY-3 July 15th, 2009

Coma & Brain Death - Outline COMA: –Definition –Pathophysiology –Aetiologies –Exam & relevant investigations –Differential diagnosis & related conditions –Prognostication BRAIN DEATH: –Definition –Determination, including the role of confirmatory testing –Ongoing controversies

COMA Definition: –Greek in origin – “deep sleep or trance” –It refers to an unconscious state characterised by a lack of both arousal and responsiveness

COMA Related disorders of consciousness: –Stupor (Latin “ to be stunned”): aroused by and responsive to only the most vigorous stimuli –Minimally conscious state: Markedly impaired consciousness with evidence of self or environmental awareness (intermittent rudimentary vocal or motor responses)

COMA Related disorders of consciousness: –Vegetative state: No awareness of self or environment, but basic cycling of arousal states & periodic eye-opening are present –Persistent vegetative state: Vegetative state persisting for at least 30 days

COMA Pathophysiology: –The ascending reticular activating system (ARAS) controls one’s level of arousal or alertness –The ARAS is comprised of the rostral brainstem tegmentum (cholinergic peribrachial nuclei*), the diencephalon and associated cortical projections –* pedunculopontine tegmental nucleus & lateral dorsal tegemental nucleus

COMA Pathophysiology: –The peribrachial nuclei project via 2 major pathways – dorsal & ventral pathways –Dorsal: glutaminergic projections from thalamic nuclei to various cortical areas –Ventral: histaminergic projections from the posterior hypothalamus (hypocretin, orexin also) & cholinergic projections from the basal forebrain to many cortical areas (McGill connection  Herbert Jasper 1961 & Barbara Jones 2000)

COMA Pathophysiology: –Sleep centre: Preoptic area of hypothalamus (GABAergic) –Notably, the ARAS pathways exhibit redundancy that may facilitate recovery of the arousal system (within 2-3 weeks if lesions are more rostral)

COMA PERIBRACHIAL NUCLEI (

COMA Dorsal & Ventral ARAS pathways (Jones, B.E. 2000)

COMA CAVEAT: Damage to the ARAS and associated structures or both hemispheres is usually necessary to cause a comatose state. Occasionally, left hemispheric dysfunction can per se lead to coma...

COMA Aetiologies –Structural lesions: Destructive & compressive Ischemic stroke, haemorrhage, tumours & inflammation/infection Long list including SDH, EDH, SAH, cerebral contusion, pontine hemorrhage, cerebellar hemorrhage/infarction, brain abscess, vasculitis, venous sinus thrombosis, etc.

COMA Aetiologies –Herniation Syndromes: Munro-Kellie doctrine to consider Lateral displacement of the diencephalon (e.g. basal ganglia bleed) – monitor via displacement of the calcified pineal gland; need 9 to 13 mm shift to produce coma; related to initial impairment of consciousness

COMA Aetiologies –Herniation Syndromes: Falcine herniation – –expanding mass causes the cingulate gurus & pericallosal/callosomarginal arteries to be compressed & displaced under the falx –Medial wall of hemisphere - infarction & edema –Diencephalic distortion via downward herniation or midline shift

COMA Aetiologies –Herniation Syndromes: Uncal hernation – –expanding mass causes medial and downward herniation of the medial temporal lobe into the tentorial notch –ipsilateral fixed & dilated pupil –ocular dysmotility –contralateral (uncus presses on nearby cerebral peduncle) or ipsilateral hemiparesis (Kernohan’s sign) –PCA infarction

COMA Aetiologies –Herniation Syndromes: Central transtentorial herniation - –expanding mass causes downward herniation of the diencephalon and pressure on the midbrain –Ischemia & infarction as feeder vessels are stretched and compressed –Diabetes insipidus with pituitary stalk avulsion

COMA Aetiologies –Herniation Syndromes: Tonsillar herniation - –Cerebellar tonsils forced down through foramen magnum e.g. SAH –Medullary compression  apnea & compensatory HTN Rostrocaudal deteriortion – downward displacement of pons/midbrain; Duret h. Upward brainstem herniation Posterior fossa lesion expands upward, compresses dorsal midbrain

COMA Herniation Syndromes net/Figures/88/5.26.jpg

COMA Aetiologies –Metabolic disturbances/toxins Hypoglycemia, hyperglycemic hyperosmolar state, diabetic ketoacidosis Hyper/hyponatremia, hyper/hypocalemia, hypo/hypermagnesemia, hyper/hypothroidism Uremic or hepatic encephalopathy Drugs such as alcohol, sympathomimetics, opioids, antidepressants, salicylates, etc. Hypothermia, porphyria, mitochondrial disorders –Ischemia/Hypoxia, inflammation, infections, seizures

COMA Physical Examination & Investigations –General inspection: Racoon eyes, Battle sign, hemotympanum, CSF rhinorrhea or otorrhea  basal skull fracture –Elevated BP: hypertensive encephalopathy (>250/150), intracerebral or subarachnoid hemorrhage; acute ischemic infarct –Respiratory status: Cheyne-Stokes, apneustic breathing, atactic respiration etc. –Hypothermia: ethanol or sedative drug intoxication, myxedema, Wernicke encephalopathy, hepatic encephalopathy hypoglycemia Coma with hyperthermia is seen in heat stroke, status epilepticus, malignant hyperthermia related to inhalational anesthetics,

COMA Physical Examination & Investigations –Hyperthermia: status epilepticus, malignant hyperthermia, anticholinergic drug intoxication, hypothalamic lesions, pontine hemorrhage, heat stroke –Meningeal irritation signs for meningitis or subarachnoid hemorrhage –Fundoscopic exam: papilledema, retinal hemorrhages (chronic or acute HTN); subhyaloid (superficial retinal) hemorrhages for subarachnoid hemorrhage

COMA Physical Examination & Investigations Pupil size, location & reactivity Likely site of pathology > 7 mm, non-reactive3 rd nerve compression; anticholinergic intox. Slightly smaller, reactiveEarly thalamic compression Fixed midsized pupils ≈ 5 mmMidbrain injury Pinpoint, minimally reactiveOpioid overdose; pontine injury, organophosphates, neurosyphilis

COMA Physical Examination & Investigations –Oculocephalic & oculovestibular reflexes: If the brainstem is intact, a comatose patient will demonstrate full conjugate horizontal eye movements during the oculocephalic testing and tonic conjugate movement of both eyes to the side of the ice-water irrigation during caloric testing. Absent oculovestibular responses in a comatose patient  pontine injury, sedative drug intoxication (can also see downward deviation of one or both eyes)

COMA Physical Examination & Investigations

COMA Physical Examination & Investigations –Metabolic, infectious, vasculitic, stroke W/U –CT, MRI, EEG (mild slowing to burst suppression – mortality rate for the latter?) –One study found that 8% of patients comatose secondary to brain injury are in NCSE – role for continuous EEG monitoring in the ICU?

COMA Differential Diagnosis – the pseudocomas: –Locked-in syndrome –Akinetic mutism –Catatonia –Psychogenic unresponsiveness (which tests can help us differentiate it from a true coma) –Minimally conscious –Vegetative states

COMA - Prognostication: AAN guidelines for coma post CPR

COMA - Prognostication Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright © The McGraw-Hill Companies. All rights reserved. Clinical Neurology > Chapter 10. Coma > Etiology > Diffuse Encephalopathies > Global Cerebral Ischemia > Prognostic Signs in Coma from Global Cerebral Ischemia. Comparison of the Findings in Two Studies (Clinical Neurology, Aminoff) Probability of Recovering Independent Function (%) Time Since onset of Coma (Days) Sign0137 Data from Levy et al 2 No verbal response13856 No eye opening11640 Unreactive pupils0000 No spontaneous eye movements 6520 No caloric responses5660 Extensor posturing18000 Flexor posturing14300 Absent motor responses4300 Data from Edgren et al 3 No eye opening to pain31800 Unreactive pupils17700

BRAIN DEATH Definition: –The irreversible loss of brain function, inclusive of the brainstem Determination: –Triad to remember: COMA, ABSENCE OF BRAINSTEM REFLEXES (pupil, corneal, VOR, pharyngeal & laryngeal) & APNEA –Exclusion of confounding clinical conditions (see table)

BRAIN DEATH Morenski et. al, 2003

BRAIN DEATH Determination continued:

BRAIN DEATH Spontaneous and reflex movements that may be seen in brain death:

BRAIN DEATH Ancillary tests: –Transcranial doppler US –Conventional angiography –EEG –Technetium-99m brain scan –SSEPs: N20-P22 absence bilaterally with median nerve stimulation

Morenski et. al, 2003

A few good references AAN Determining Brain Death in Adults Current guidelines Prediction of Outcome in Comatose Survivors after Cardiopulmonary Resuscitation Current guidelines July 2006 Plum and Posner's Diagnosis of Stupor and Coma, 4 th edition ( ☆☆☆☆☆ ) – great book!