MichelleLee Jones Neurology PGY3 July 15 th 2009

Michelle-Lee Jones Neurology PGY-3 July 15 th, 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 (Mc. Gill 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 (http: //www. nature. com/nature/journal/v 437/n 7063/images/nature 04284 f 2. 2. jpg)

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

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 http: //www. lfhk. cuni. cz/patfyz/I ntranet/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 • 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-reactive 3 rd nerve compression; anticholinergic intox. Slightly smaller, reactive Early thalamic compression Fixed midsized pupils ≈ 5 mm Midbrain injury Pinpoint, minimally reactive Opioid 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 Probability of Recovering Independent Function (%) Time Since onset of Coma (Days) Sign 0 1 3 7 Data from Levy et al 2 No verbal response 13 8 5 6 No eye opening 11 6 4 0 Unreactive pupils 0 0 No spontaneous eye movements 6 5 2 0 No caloric responses 5 6 6 0 Extensor posturing 18 0 0 0 Flexor posturing 14 3 0 0 Absent motor responses 4 3 0 0 Data from Edgren et al 3 No eye opening to pain 31 8 0 0 Unreactive pupils 17 7 0 0 Prognostic Signs in Coma from Global Cerebral Ischemia. Comparison of the Findings in Two Studies (Clinical Neurology, Aminoff)

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-99 m brain scan – SSEPs: N 20 -P 22 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!