Abnormal consciousness is caused by pathologies that specifically alter the function of a neuronal network responsible for causing awareness and alertness. Understanding of the basic concepts of this arousal system and the pathophysiologic mechanisms underlying its alteration are imperative in the diagnosis, treatment, and long-term management of coma. This chapter will focus on the definition of consciousness, the physiology of arousal, the pathologies underlying coma, the neurologic examination of the comatose patient, management of coma, and assessment of prognosis. Each section is accompanied by a case to illustrate the different clinical scenarios in which coma can present.
CASE 36-1
A 57-year-old woman presented to the emergency department with acute loss of consciousness. She has no relevant past medical history. Her coworkers state she had complained of the worst headache in her life 2 weeks ago that has since resolved. On observation, the patient’s eyes are closed and her respiratory pattern appears irregular. Blood pressure at the bedside is 180/90 mmHg, and heart rate is 54 beats per minute. General examination reveals neck stiffness and bilateral retinal hemorrhages. On neurologic examination, pupillary and corneal responses are present. The patient exhibits no eye opening or motor response to noxious stimuli. Her FOUR score is 6. She is sent for emergent neuroimaging that reveals diffuse subarachnoid hemorrhage (SAH) and obstructive hydrocephalus.
Consciousness is a state of full awareness to both self and environment, and is divided into two major categories:1
Content
Defined as the cognitive and affective responses, which are mediated at a cortical level.
Includes language, right and left orientation, reading, writing, behavior, and recognition of faces and colors.
Linked closely with the arousal system to maintain the behavioral appearance of wakefulness.
Diffuse damage of cortical structures (ie, Alzheimer) can cause a reduced content consciousness.
Arousal
The ascending arousal system is a diffuse network of afferent mesopontine and diencephalic neurons.
Interneurons regulate the relationship between sleep/wake cycles and coordinate phase transition during sleep (ie, non-REM to REM).
Ascending neurons target cortical structures, integrating the behavioral and cognitive components of consciousness.
Focal or diffuse lesions of the arousal system (ie, infarction) can produce acute alterations in level of consciousness.
Delirium:
An acute medical condition defined by agitation, clouding of consciousness, and changes in attention that develop over a short period of time.
Obtundation:
A mild-to-moderate reduction in alertness, accompanied by a lesser interest in the environment, shown clinically by slower responses to stimulation and increased number of sleep hours.
Stupor:
A moderate-to-severe reduction in consciousness, with or without cognitive impairment, from which a subject can be aroused only with vigorous and continuous stimulation.
Coma:
A state of unresponsiveness in which the patient lies with eyes closed and cannot be aroused even with vigorous stimulation.
Etiologies of Coma
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Coma can be classified into five subgroups:
Supratentorial lesions
Infratentorial lesions
Diffuse brain dysfunction
Diffuse metabolic dysfunction
Psychogenic unresponsiveness
CASE 36-2
A 68-year-old man with a notable history of atrial fibrillation presents to the hospital for alteration in consciousness. The wife states she was unable to wake the patient from sleep. Vital signs are stable, and the neurologic examination reveals preserved brainstem reflexes with eye opening and motor localization to painful stimuli. CT scan of the brain is negative for acute pathology. MRI of the brain shows restricted diffusion in the bilateral paramedian nuclei of the thalamus. Conventional cerebral angiography confirms evidence of an artery of Percheron. The patient is diagnosed with bilateral thalamic infarction, the etiology of his stuporous state.
What are the anatomic structures involved in the ascending arousal system, and what is the physiology behind its activation (Illustration 36-1)?
Ascending arousal system:4
The ascending arousal system is a paramedian mesopontine structure composed of the dorsal pedunculopontine (PPT) and laterodorsal tegmental (LDT) relay nuclei (cholinergic), and ventral monoaminergic groups including the locus coeruleus (NE), the dorsal raphe nucleus (5HT), as well dopaminergic cells.
Cholinergic
Afferents from the PPT and LDT nuclei project via the paramedian reticular formation to thalamic relay nuclei to augment cortical activation.
Monoaminergic
Afferents project via the paramedian reticular formation to the hypothalamic cell groups that augment cortical activation.
Dopaminergic cell groups also project to thalamic relay nuclei.
Hypothalamus:
Receives input from the ventral monoaminergic ascending arousal system and projects afferent relay neurons to the basal forebrain and prefrontal cortex.
Several hypothalamic cell groups participate in cortical activation.
Histaminergic tuberomamillary nucleus
Orexins
Melanin-concentrating hormone
Also contains the ventrolateral preoptic nucleus (VLPO), which mediates activation of sleep/wake cycles.
Thalamus:
Receives input from the dorsal cholinergic ascending arousal system and projects afferent relay neurons through the paramedian and intralaminar nuclei to innervate the distal frontal cortex.
Cortex:
Cortical layers (I through VI) receive afferent input from both the VLPO in the hypothalamus and the reticular nucleus in the thalamus.
Cortical stimulation plays an important role in the switching between on and off states in arousal and sleep.
In normal functioning behavior, the human brain exists in one of three states:
Wakefulness
Non-REM (NREM) sleep
REM Sleep
Sleep is an intrinsically regulated inhibition of the arousal system resulting in lack of thalamo-cortical activation and thus a reduced level of consciousness.
Coma is a condition in which inhibition of the arousal system results from pathophysiologic dysfunction of the reticular formation or cortical activating systems.
The most important difference between coma and sleep is that comatose patients do not cycle between NREM and REM sleep.
Three distinctive lesions are known to cause stupor or coma (Figure 36-1):
Extensive bilateral cortical lesions
Bilateral diencephalic lesions
Mesopontine lesions
Bilateral cortical lesions:
Result in dysfunction of intraneural cortical afferents.
Occur most commonly in the context of hypoxic-ischemic injury, but also occur in the setting of diffuse brain trauma.
In the setting of hypoxia, cortical layers III and V and the CA1 region of the hippocampus are commonly affected.
Bilateral diencephalic lesions:
Result in dysfunction of thalamo-cortical afferents, the largest ascending component of the arousal system, or hypothalamic inputs to the basal forebrain and prefrontal cortex.
Occur in bilateral thalamic lesions and less commonly in hypothalamic lesions.
Thalamic lesions can occur with basilar thrombosis, cerebral venous sinus thrombosis, artery of Percheron infarction, and thalamic hemorrhage.
Hypothalamic lesions can occur in the setting of pituitary tumors, lymphoma, and sarcoid granulomas.
Mesopontine lesions:
Result in dysfunction of the paramedian cholinergic and monoamineregic tegmental nuclei and ascending reticular formation.
Occur in the setting of ischemic infarction, vasculitis, rhomboencephalitis, brainstem glioma, intraparenchymal hemorrhage, or trauma.
Lesions resulting in alteration of consciousness can be either localized and small, or diffuse and large.
The intracranial contents exist within a fixed structure built to hold a finite amount of anatomy. The volume of such structures is in constant equilibrium so as to maintain adequate cerebral function. The intracranial compartments are made up of brain tissue (87%), CSF (9%), blood vessels (4%), and the meninges, which form a negligible volume. If a lesion exists within the intracranial compartments, volume averaging occurs, thus distorting function and consciousness.
Impairment of consciousness may occur in several different ways:
Elevation of ICP
ICP elevation indirectly affects cerebral arterial blood supply, causing a decrease in cerebral perfusion pressure and a loss of intracranial compliance.
Direct distortion of the arousal system
Focal ischemia
Compressive cerebral edema
Herniation
Diffuse or toxic-metabolic coma results from impairment of the normal physiologic and biomechanical mechanisms needed to sustain adequate cerebral metabolism. Pathogenesis can occur in the cortical, diencephalic, or mesopontine structures responsible for arousal.
Acute brain dysfunction can occur due to:
Impaired oxygen or substrate delivery
Hypoxia, hypoglycemia, carbon monoxide poisoning
Impaired cellular metabolism
Nutritional deficiency, cyanide toxicity
Alterations in neuronal excitability
Electrolyte disorders, acid–base imbalance
Increased brain volume from edema
Ketoacidosis, fulminant hepatic failure
Evidence suggests that diffuse or toxic-metabolic coma alters the synthesis and function of neurotransmitters and their receptors
Excitatory neurotransmitters undergo accelerated metabolism
Inhibitory neurotransmitters undergo accelerated synthesis
CNS inflammation is another pathophysiologic form of injury resulting from various infectious and inflammatory processes that lead to increased permeability of the blood–brain barrier and penetration of neuromodulatory chemokines.
Penetration into the blood–brain barrier leads to localized immune-mediated responses that cause neuronal and glial cell dysfunction.
Autoimmunity can occur as a result and cause further dysfunction (ie, autoimmune paraneoplastic syndromes).
CASE 36-3
A 48-year-old man with a past medical history notable for hypertension presents to the emergency department as being found down at work. Examination reveals a comatose patient with preserved pupillary responses, ocular bobbing on primary gaze, absent horizontal oculocephalic reflexes, facial diplegia, and absent motor responses. Emergent CT scan reveals a large contiguous pontine hemorrhage. Coma secondary to infratentorial ICH is diagnosed, and the patient is transferred to the neurological ICU for further care.
Diagnostic Approach to the Comatose Patient
| History |
| Time of onset and time course |
| Patient age and demographics |
| Recent medical complaints |
| Medical history |
| Trauma history |
| Medication reconciliation |
| General Examination |
| Airway, breathing, circulation |
| Nuchal rigidity |
| Signs of trauma |
| Signs of systemic illness |
| Signs of drug abuse |
| Neurologic Examination |
| Verbal response |
| Eye opening, eye movements |
| Pupillary/Fundoscopic examination |
| Oculomotor examination |
| Corneal examination |
| Oculovestibular examination |
| Motor responses |
| Muscle stretchreflexes |
| Muscle tone |
The diagnostic approach to a comatose patient should be multifaceted to include a detailed history, a thorough general medical examination, and a comprehensive neurologic examination.
History should be obtained from all available family members, bystanders, and medical personnel. The two key historical factors leading to accurate etiologic diagnosis of coma are patient age and time of onset.
Sudden onset coma of the young and healthy can be due to drug poisoning, SAH, or head trauma.
Sudden onset coma of the elderly is more frequently due to intracerebral hemorrhage (ICH) or cerebral infarction.
Gradual-onset coma in all age ranges is most likely due to a metabolic disturbance.
The general medical examination is an important tool that can give important clues to the etiology of altered consciousness. Evaluation of the skin, the neck, the cardiovascular system, and respiratory patterns can provide valuable information in the assessment of central nervous system (CNS) dysfunction.
Skin:
Symmetric periorbital bruising or blood behind the tympanic membrane (Battle’s sign) can clue the examiner toward traumatic basilar skull fracture.
The presence of petechiae can be found with meningitis or disseminated intravascular coagulation (DIC).
Neck:
Resistance to neck flexion with preserved lateral rotation can be present with meningeal inflammation.
Circulation:
Acute hypotension is seen with compromise of the descending sympathetic pathways and is seen in spinal cord transection, diencephalic lesions, and hypothalamic lesions.
Acute hypertension is seen with compression of the basal cisterns (Cushing reflex) or hypothalamic dysfunction.
Respiratory patterns:
Cheyne–Stokes respirations are seen with damage to forebrain, the diencephalon, and in metabolic comatose states.
central neurogenic hyperventilation can be seen with metabolic encephalopathy.
Apneustic breathing can be seen with direct injury to the parabrachial pontine respiratory centers.
Ataxic breathing patterns are seen with damage to the ponto-medullary junction.
Central neurogenic apnea can be seen with damage to the ventrolateral medulla
Examination of the comatose patient should be performed in a logical and orderly manner to provide accurate assessment and localization. The examination should be performed in a stepwise fashion as follows:
Level of consciousness (coma scales)
Pupillary examination
Ocular motor examination
Corneal examination
Motor examination
Assessment of consciousness is performed using a set of comatose scales that test a patient’s response to both verbal and painful stimuli, respiratory patterns, and brainstem reflexes (Table 36-3).
The Glasgow Coma Scale (GCS) examines eye response, motor response, and verbal response in relation to various stimuli. The GCS has been repeatedly validated for its use in traumatic brain injury; however, it lacks the examination of brainstem reflexes and respiratory patterns necessary for localization with nontraumatic brain injury.
A second validated coma scale, the Full Outline of Unresponsiveness (FOUR score) coma scale, includes eye and motor responses as well as brainstem reflexes and respiratory patterns. Additionally, the verbal component of the GCS is not included, so patient scores are not skewed by intubation. This scale provides more in-depth detail to assist in localization and has been validated in both traumatic and nontraumatic coma.
Unlike the GCS, the FOUR score coma scale can identify locked-in syndrome and persistently vegetative states, and thus is more valuable in the neurological intensive care unit.
In comparison, every 1 point increase in the GCS or FOUR score coma scale relates to an in-hospital mortality reduction of 26% and 20%, respectively.
Pupillary examination:
The pupillary examination utilizes bright light stimulation to test both sympathetic (dilation) and parasympathetic (constriction) pathways.
The examination provides important localizing value and allows for differentiation between structural and metabolic causes of coma.
Structural:
Diencephalon—small, reactive
Pretectal—large, fixed, hippus
Midbrain—midposition, fixed
Cranial nerve III—unilateral dilation, fixed
Pons—pinpoint
Metabolic:
Small, reactive
If pupillary responses are preserved in the setting of other signs of midbrain dysfunction, then a metabolic cause of the coma is likely.
Ocular motor examination:12
The oculomotor examination relies on observation of the eyelids, ocular movements during primary gaze, corneal reflexes, motor function of cranial nerves (CN) III, IV, and VI, and vestibular sensory input.
The oculomotor system is composed of both peripheral and central components.
Peripheral
CN III, CN IV, and CN VI
Central
Frontal eye fields
Vertical and horizontal eye movements
Superior colliculus
Descending input
Paramedian pontine reticular formation (PPRF), medial longitudinal fasciculus (MLF), oculomotor nucleus, and abducens nucleus
Lateral saccades
Rostral interstitial MLF (riMLF), interstitial nucleus of Cajal
Vertical saccades
Vestibular system, vestibulocerebellum
Angular and linear deceleration
Accuracy of saccadic eye movements
Examination of eyelid tone is important to help distinguish between structural and metabolic coma. Resistance to eye opening is typically seen with metabolic encephalopathy.
Observation of spontaneous eye movements in primary gaze can provide specific localizing value:
Roving eye movements—metabolic encephalopathy
Conjugate lateral deviation—destruction of frontal eye fields
Conjugate vertical deviation—thalamic hemorrhage or oculogyric crisis
Dysconjugate deviation—CN palsy
Skew deviation—pontomedullary or vestibulocerebellum dysfunction
Ocular bobbing—pontine hemorrhage
Seesaw nystagmus—interstitial nucleus of Cajal dysfunction
CN VI palsy—increased intracranial pressure (ICP)
Examination of the corneal response is accomplished with a wisp of cotton or instillation of sterile saline onto the cornea. Stimulation of the corneal responses implies that the mesopontine structures including CN V and CN VII are intact.
Examination of motor and vestibular function is accomplished by testing vestibulo-ocular reflexes (doll’s eye maneuver). Both vertical and horizontal motion should be tested. With an intact vestibulo-ocular system, ipsilateral head movement should initiate contralateral eye movement with a slow return to midposition.
The absence of ocular motor function implies mesopontine damage.
Caloric vestibulo-ocular responses are used in certain instances, most notably brain death, and can assist in evidence of an intact brainstem. Instillation of cold water onto the tympanic membrane inhibits ipsilateral vestibular neurons, causing tonic ipsilateral deviation of the eyes.
The presence of nystagmus in a comatose patient implies psychogenic unresponsiveness.
Bilateral vestibular failure can occur with phenytoin and tricyclic antidepressant (TCA) toxicity.
Motor examination:
Examination of the motor system in coma includes motor tone at rest, motor responses to mechanical stimulation, and deep tendon reflexes.
Motor tone in the comatose patient can vary to include spastic rigidity, parkinsonian rigidity, and paratonic rigidity.
Motor responses are tested by mechanical stimulation to assess symmetry of movements and for postural responses in relation to the grading in comatose scales.
Decorticate posturing:
Flexion of the upper extremities and extension of the lower extremities
Produced by lesions involving the forebrain down to the rostral midbrain sparing the red nucleus
Decerebrate posturing:
Extensor posturing of the both the upper and the lower extremities
Produced by lesions between the superior and the inferior colliculus
Examination of the deep tendon reflexes can help distinguish between a unilateral or diffuse cerebral dysfunction.
Bilateral Babinski signs imply a likely diffuse cerebral disturbance.
Unilateral Babinksi sign likely implies a contralateral localizable lesion.
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