Differential Diagnosis in Neurology

1.5. Hypoxic-Ischemic Encephalopathy

General Characteristics

• Decreased brain perfusion, oxygenation or both
• Decreased perfusion
  • Cardiac arrhythmia or arrest
  • Pump failure

The brain is differentially susceptible to hypoxia, hypoglycemia and hypoperfusion. In general, areas most susceptible to hypoxia have the greatest required metabolic rate for glucose utilization and ATP requirement. In the case of cardiac arrest, pump failure, ventilatory failure they suffer first and most severely.

In general, respiratory arrest without circulatory compromise carries a better prognosis. Complete circulatory arrest induces rheological changes that include endothelial cell swelling and viscosity changes that preclude reperfusion of cortical, basal ganglia and thalamic capillary networks. This constitutes the no-reflow phenomena. Hyperglycemia and acidosis at the time of arrest increase neuronal death. Pre arrest vascular compromise leads to distal field ischemia and stroke primarily in the anterior circulation in those under 40 and in the vertebral basilar system in elderly patients. Prolonged hypoperfusion and anoxia lead to border zone infarction (posterior zone between MCA/PCA) territory > anterior zone (MCA/ACA territory). Specific toxins or circumstance involve specific brain areas. Carbon monoxide preferentially affects the medial globus pallidus, cortex and cerebellum. Isolation of speech areas, from perisylvian involvement has also been described. Strangulation or hanging preferentially involves the medial globus pallidus as reversible decerebration. A single hypoxic event may cause a delayed but progressive leukoencephalopathy that begins 4–10 days following the insult. Cognitive dysfunction, irritability and apathy are prominent as is rigidity of the limbs and ataxia of gait. Some patients with delayed hypoxic leukoencephalopathy have reduced aryl sulfatase A activity.

Consciousness

The integrity of the reticular activating system (RAS) is requisite for consciousness. The lateral medullary reticular formation, the dorsal pontine tegmentum, periaqueductal grey of the midbrain, intra laminar thalamic nuclei are the most important nuclear areas that maintain consciousness. Both cerebral hemispheres must be involved to lose consciousness.

Bilateral vertebral disease or basilar artery infarction compromise the lateral medullary reticular formation and dorsal pontine tegmentum. Top of the basilar artery embolic stroke or thrombosis affects the midbrain periaqueductal grey or intra laminar thalamic nuclei. Hypoxic insults and prolonged hypoperfusion affect the cerebral hemispheres. Increased intracranial pressure (usually from edema) decreases cerebral perfusion at all levels and is a frequent concomitant of cardiac arrest.

Differential Susceptibility of Neurons to Hypoxia

• Hippocampus
  • Sumner's section V, amygdaloid complex
  • Pyramidal neurons
  • CA I zone
• Medial laminae of the cerebral cortex
  • III–V
  • Thalamic projecting neurons to the cortex
• Globus pallidus/caudate/putamen
  • Internal segment GPi
• Thalamus
  • Anteroventral nuclei
  • Dorsomedial nuclei
  • Pulvinar
• Cerebellum
  • Purkinje cells
• Brainstem tegmental nuclei
  • V, IX, X
  • Inferior caliculus
  • Superior alive
  • Vestibular nuclei
• Spinal cord
  • Renshaw cells
  • Anterior 2/3 of the cord
  • Distribution of the artery of Adamkiewicz

Border Zone Infarction

• Anterior; ACA/MCA
• Posterior; MCA/PCA
• Vascular stripe (between descending pial blood vessels and ascending lenticula striate arteries)
• Border zone of the cerebellum (level of the dentate)
• Subinsular cortical areas
• Cerebellar artery border zones
  • SCA/PICA
  • SCA/AICA

Clinical Patterns of Circulatory Arrest

Brain-Stem Coma

• Prolonged hypoperfusion-anoxia
  • Dilated pupils
  • Absent corneal reflexes
  • No doll's eye response (absent vestibular ocular response)
  • No response to ice-water caloric (absent VOR)
  • Frequent loss of spontaneous respiration
  • No spontaneous movement
    • decorticate or decerebrate posture may be seen
• Selective necrosis of brainstem nuclei
  • Affects children and infants most frequently; (Vth nerve involvement) occasionally seen in adults
  • No oculocephalic eye movements (VOR)
  • Loss of branchial muscle functioning including the gag reflex
  • Stiff extremities; no spontaneous movement
  • Automatic movements with stimuli
  • Autonomic disinhibition
    • Fluctuating blood pressure and cardiac rate
  • Loss of spontaneous respiration
• Brainstem coma secondary to bi-hemispheral coma
  • Patients regain brainstem reflexes
  • Spontaneous respiration occurs

Coma due to Bilateral Hemispheric Dysfunction

• Unresponsive to noise, bright light or voice
• Respond to painful stimuli
• Spontaneous movements of the extremities
• Pupils are normal or small; react to light
• Eye movements:
  • Roving from side to side
  • Midline
  • Deviated upward
  • Hyperactive doll's eyes
    • Loss of ocular fixation reflexes that inhibit the vestibular ocular reflex
  • Vertical eye movements present to VOR maneuvers:
    • May be difficult to deviate downward if patient has fixed upward deviation
• Gag reflex intact
• Branchial innervated movements are intact
  • Spontaneous blink and swallow reflexes

Corticospinal Tract Dysfunction

• Patients may have preserved:
  • Adduction/flexion of the shoulder, arms and wrists
• Noxious stimulation of extensor or flexor upper extremity surface:
  • Elicits flexion/adduction of the arms and shoulder
• Noxious stimulation of lower extremities
  • Extension/adduction of the lower limbs
• External rotation of the foot; cortical thumb

Intact Corticospinal Tract Signs

• Noxious stimuli elicits movements away from afferent input
• Movement of individual fingers
• Spontaneous or reactive extension of the upper extremity
• Abducting movements of the arm or forearm
• Lower limb noxious stimuli elicits
  • Flexion/adduction
• Supination of the arm at rest and normal position of the foot (extension)
• Thumb abducted

Progression from Bi-Hemispheral Coma

Specific features of selective vulnerability to the anoxic-ischemic episode may become prominent. Many patients demonstrate agitation, restlessness, confusion and delirium as they regain consciousness. If the insult has been primarily hypotensive with less generalized anoxia, border zone infarction may be prominent.

Posterior Border Zone Infarction

• Bilateral infarction of the MCA/PCA overlap territory
  • Parieto-occipital junction
• Complete or partial Balint's Syndrome
  • Simultagnosia
    • Inability to see all objects in the visual field
    • Inability to see all components of one object
    • Inability to maintain components of an object into a whole
    • Optic ataxia:
      • Damage to parietal area 5 and 7. Patients under reach for objects. They have poor eye/hand coordination
    • Apraxia of gaze
      • Poor initial scanning of a visual field
      • Inability to look at a specific object on command
      • Inability to break a fixed gaze

Anterior Border Zone Infarction

• Bilateral infarction of the anterior and middle cerebral artery border zone territories
• "Man in the Barrel" Syndrome
  • Shoulder and arm are primarily affected; hand stronger than shoulder; legs spared
  • Frontal eye fields involved (BA 8, BA 10)
    • Roving cortical eye movements (disinhibited from gaze centers)
    • Too easily obtained doll's eye maneuvers (uninhibited VOR)
• Asymmetries have been described:
  • Unilateral arm paralysis
  • Head and eye deviation to the more affected side
• Stupor from extensive bilateral lesions

Memory Loss

• Severe damage to the pyramidal cells of the hippocampus
  • CA I; Sumner's section V
  • Amygdaloid complex
  • Medial temporal lobes
• Clinical sequelae
  • Severe short term memory loss. Poor encoding of new memories over 3 minutes. Registration is intact (object recall ≤ 15 seconds). Long term memory and retrieval relatively spared

Laminar Necrosis

• Layers III–V of the cortex are damaged throughout. Speech, motor, and visual areas affected clinically more prominently than the parietal lobe.
• Isolation of the speech areas
  • Combination of laminar necrosis and anterior and poster border zone infarction
  • Transcortical motor and sensory aphasia
  • Complete perisylvian involvement
    • Patient can only repeat; cannot initiate or perceive speech
  • Severe dysarthria
    • Damage to corticobulbar fibers for speech emanating from the frontal operculum
• Clumsiness and dysarthria
• Ideomotor, limb kinetic, ideational apraxias
  • Laminar necrosis of area 6, 8 (ideomotor; callosal apraxia); posterior parietal areas (ideational apraxia)
• Cortical blindness
  • Laminal necrosis of the occipital cortex
  • Anton's Syndrome
• Seizures
  • Most often generalized
  • Difficult to treat
• Myoclonus
  • Multifocal
  • Generalized
  • Exaggerated by stimuli or movement
  • Repetitive and generalized > 30 minutes a bad prognostic sign following cardiac arrest
• Persistent Vegetative State
  • Severe laminar necrosis
    • Appear awake and have brain stem function
    • No response to stimuli
      • Eyes may track a moving object
    • Retain sleep-wake cycle
    • Eyes are open
• Cerebellar dysfunction
  • Metronomic eye movements; eyes rhythmically oscillate side to side
  • generalized ataxia
  • Lance Adams Syndrome
    • Spontaneous, arrhythmic fine and course movements
    • Exaggerated by voluntary movement
    • Action myoclonus
    • Associated with gait ataxia
    • Damage to dorsal raphe serotonergic neurons in addition to Purkinje cells and cerebellar pathways
    • Probable associated border zone cerebellar infarcts of the PICA/SCA and AICA
    • May progress after the initial insult

Basal Ganglia and Thalamus

• Prolonged partial ischemia:
  • Hypoxia precedes circulatory insult
  • Damage most severe in globus pallidus interna, caudate, putamen AV, DM and pulvinar nuclei of the thalamus
  • Hanging, strangulation, carbon monoxide produce a similar dissociation between blood flow and oxygenation
  • Clinical sequelae
    • Eyes open and fixate
    • Abnormal twitches and movements
    • Rigidity of extensor and flexor muscles
    • Decorticate posturing
    • Mute and unresponsive

Delayed Leukoencephalopathy

• Generally young patients who have suffered strangulation, drowning, inhalation of noxious gases or carbon monoxide poisoning
• Pathology:
  • Diffuse demyelination to hemorrhagic white matter necrosis
  • Basal ganglia involvement (GP)
  • Possible relationship to decreased Arylsulfatase A in some patients
• Clinical features:
  • Initial coma associated with:
    • Quadriparesis
    • Atonia
    • Involuntary limb movements
  • Progression to:
    • Dystonic rigid state
      • Relative preservation of the cortex
      • Severe damage to basal ganglia
      • Generalized demyelination
  • Delayed deterioration started between 4–10 days in some patients

Hypoxic-Ischemic Spinal Cord Damage

• Selective vulnerability of the spinal cord
  • Upper and lower thoracic cord most often involved
  • Territory of the great radicular artery of Adamkiewicz
    • Origin T10–T12 to L-2; supplies lumbar cord and the conus medullaris
  • Upper and lower thoracic regions border zones of anterior feeding vessels (those that comprise the unpaired anterior spinal artery) ASA
  • Sulcal arteries from the ASA supply the ventral horns; circumferential arteries from the posterior paired spinal arteries and the circumferential branches of the ASA supply the lateral components of the cord. The internal spinal cord watershed is the corticospinal tracts, the border zone between the sulcal and circumferential arteries. Paired dorsal spinal arteries supply the posterior columns
  • Clinical Sequelae:
    • Spinal cord hypotensive damage is unusual as the cord is perfused at a much lower pressure than the cerebral circulation (approximately 60 mg Hg)
    • Ischemic injury involves the anterior 2/3 of the cord
    • Flaccid paralysis of the lower extremities is noted early; spasticity supervene:
      • Loss of bowel and bladder continence
      • Sensory level to temperature and pin prick at lower thoracic levels
      • Atrophy and fasciculation of the legs/supervenes
    • Rare acute rigidity:
      • Renshaw cell involvement
      • Loss of glycine spinal cord inhibition

Prognostic Indicators in Patients that Have Suffered Ischemic-Hypoxic Injury

Early Vital Signs (minutes to 6 hours)

• Blood pressure
  • Severe hypertension
    • Increased ICP
    • Normal cardiac function
  • Profound hypotension
    • Severe cardiac damage
    • Vasomotor center damage (brainstem)
  • Fluctuating blood pressure
    • Vasomotor center or connections are damaged (dorsolateral medulla)
    • Autonomic disruption (posterior hypothalamus afferents to inter mediolateral column of the spinal cord)
  • Herniation
    • Hypertension to sudden hypotension
      • Disruption of the vasomotor center and its connections in the dorsolateral medulla
• Pulse
  • Regular full slow pulse (50–60/min)
    • Kocher–Cushing reflux of ICP
  • Thready rapid pulse (120 minute)
    • Cerebral herniation
    • Cardiac failure
    • Disruption of vasomotor center and its connections at a brainstem level
• Respiratory pattern by CNS Level
  • Cheyne's–Stoke-basal ganglia/thalamic
  • Periodic breathing-BG/thalamic
  • Central neurogenic-hyperventilation-midbrain
    • Acidosis
    • Low pO₂
    • Uninhibited Kölliker–Fuchs nucleus
      • Pneumotaxic center
    • Apneic-pons (grave sign)
    • Cluster-medullary
    • Ataxic-medullary
    • Biot's – medullary (couplet breathing)
• Temperature
  • General rule is that temperatures above 105 degree F° are central rather than from sepsis

Hyperthermia

• Anterior hypothalamic damage
• Drugs: D₂ (dopamine receptor D₂ agonists or their sudden withdrawal) agonists, INH cocaine, amphetamine, phenothiazine (rare)
• Blood in the 3rd ventricle

Hypothermia

• 92–93 degree F° (posterior hypothalamic damage)
  • Hypothyroidism; pan hypopituitarism
  • Drugs (phenothiazine based)
• 97–98 degrees
  • Endocrine failure
  • Hypoglycemia
  • Liver and renal failure
  • Phenobarbital

Level of Consciousness

Profound coma implies damage to the lateral medullary reticular formation, the dorsal pontine tegmentorum periaquaductal grey of the midbrain, intralaminar nuclei of the thalamus or bilateral cerebral cortex. The brainstem is much less vulnerable to hypoperfusion and anoxia than the cortex and therefore severe brainstem dysfunction implies hemispheric damage with a poor prognosis for a good functional recovery. A patient who is fully alert and awake 6 hours after a cardiac arrest or hypoxic-ischemic event improves rapidly over twelve hours and has a good prognosis. Twenty four hours to alertness may be a very important prognostic assessment time.

Levels to be assessed are:

• Fully alert
• Lethargic
• Obtunded
• Stuporous
• Comatose

Brainstem Reflex Assessment at 6 hours

• Gag reflex – IX, X (medulla)
• Corneal – V – pons
• Vestibuli ocular reflexes (VOR)
  • VIII nerve
  • Medial longitudinal fasciculus
  • VI and III nerve
• Pupils
  • Dilate to 4–5 mm after 3–4 minutes of cardio-pulmonary arrest
    • Rule out atropine or sympathomimetics during resuscitation
  • Cortical or pretectal level
    • Non-reactive to light
  • 3 mm and non-reactive to light or noxious stimuli
    • Midbrain
    • cadaveric
  • 2–3 mm
    • Reactive to light
    • Thalamic basal ganglia level
  • 0.5 mm
    • Pontine level
    • Reactive to light
  • 1 mm
    • Medullary level
    • Sympathetically denervated
    • R/O narcotics
      • Demerol may not affect pupils. 1/3 of the time it does.
    • R/O drugs with parasympathomimetic action
• Persistent pupillary dilatation poor prognostic indicator. Return of brainstem reflexes early is a good prognostic sign.

Evoked and Spontaneous Limb Movements

• Spontaneous limb movement – good prognostic sign
• Evoked decerebration and decortication – poor prognostic indicator
• Myoclonus:
  • Persistent and stimulus sensitive – poor prognostic sign
    • Loss of cortical inhibition
    • Damage to the nucleus gigantiocellularis of the brainstem
• Seizure
  • First 24 hours not prognostic
  • Status epilepticus – poor prognostic sign at anytime after an ictus

Late Prognostic Signs (more than 24 hours)

Good

• Awake and alert
• Return of brainstem reflexes
• Eye opening with ocular fixation reflexes
• noxious stimuli evoke withdrawal reflexes

Bad

• Persistent depressed level of consciousness
• Absent brainstem reflexes
• Noxious stimulation evoke decortication or decerebration
• Eyes open with:
  • Roving eye movements
  • Uninhibited doll's eye maneuver
  • Persistent vertical ocular deviation
• Spontaneous and evoked myoclonus
• Status epilepticus
• Persistently dilated pupils

Laboratory Evaluation

• MRI:
  • Watershed infarcts of cortical and deep territories
  • Cortical infarcts
  • Blurring of the grey white junction
  • Obliteration of the perimesencephalic cisterns with midbrain compression
  • T₂ weighted signal abnormalities of laminar necrosis
• EEG
  • Diffuse slowing in the delta and theta range
    • All survivors at some point
  • Periodic lateralizing epileptiform discharge
    • Isolated areas of cortex
  • Epileptiform activity
  • Alpha coma (bad prognostic sign)
    • 9–12 cycles/second
    • Transitory
    • Frontal central parietal rather than occipital distribution
    • Does not vary with external stimuli
• Brain Death
  • Absence of intracranial circulation by angiography, Doppler or SPECT