Diagnosis of Coma and Stupor Flashcards
What is ‘lethargy’ defined as?
individual is sleepy but easily aroused with stimulation.
What is ‘hypersomnia’ defined as?
Hypersomnia describes someone who is excessively sleepy and requires vigorous stimulation but shows normal cognition once aroused.
What is ‘obtundation’ defined as?
Obtundation refers to an individual who in addition to severe lethargy shows cognitive dysfunction
What is ‘stupor’ defined as?
Stupor refers to severe obtundation and is distinguished from coma only because the eyes open briefly.
What is ‘coma’ defined as?
. In coma, the eyes fail to open to the most vigorous stimulation
Delirium usually refers to a disoriented, confused patient who fluctuates between lethargy and agitation. These terms are not always used in the same way by all physicians so it is essential that you describe a patient’s response to stimulation.
For example, “eyes again failed to open after nail-bed pinching but the upper limbs moved slightly for the first time” conveys much more useful and precise information than “remains comatose”
What is abulia?
Awake but apathetic, no spontaneity. With vigorous stimulation, cognitive function may be normal. (bilateral frontal lobe disease, lobotomized)
Term describing patients in the aftermath of coma
What is akinetic mutism?
Silent, alert-appearing immobility. No mental activity with vigorous stimulation (disease of frontal lobes and hypothalamus)
Term describing patients in the aftermath of coma
What is a minimally conscious state? vegatative state?
Minimally conscious state: fragments of awareness
Vegetative state: awake, no awareness or meaningful interaction with the environment
Terms describing patients in the aftermath of coma
Overlap & transitions exist between these conditions so you need to describe stimuli for arousal and the patient’s response
Patients in coma generally develop eye-opening and sleep-wake cycles after 2 to 4 weeks regardless of the cause of coma. A number of terms have been used to describe these patients.
A patient is abulic when he has his eyes open but demonstrates no spontaneous interaction with the environment. One sees this after severe bifrontal lobe damage (lobotomy at its worst), but with vigorous stimulation, these patients answer questions correctly.
If no evidence of mental activity can be elicited with vigorous stimulation, the patient may be said to show “akinetic mutism” or be in a “vegetative state.”
The term “vegetative” refers to the so-called “vegetative functions” of the brainstem that include maintaining sleep-wake cycles, respirations, heart rate, blood pressure and visceral autonomic regulation. A patient who appears vegetative but then shows fragments of awareness and meaningful interaction with the environment is said to be in “minimally conscious state” or MCS. Such patients may reach for objects, grunt or gesture in response to a command, visually fixate and track but are unable to do much more. It is important to realize that these conditions may not be static but can undergo transitions over time. That is typically the case when the news media reports on individuals awakening after many years spent in “coma.”
Now that we know the terms used to describe altered consciousness, let us look a little deeper into what constitutes normal consciousness. “How would you describe or define consciousness?”
The idea that the brain was responsible for an individual’s self-awareness, emotions and cognition is an ancient concept. Hippocrates wrote: “And men should know that from nothing else but the brain come joys, delights, laughter and jests, and sorrows, grief, despondency and lamentations. And by this, in an especial manner, we acquire wisdom and knowledge, and see and hear and know what are foul and what are fair, what sweet and what unsavory…”
In the 19th century consciousness was thought to reflect the sum total activity of the cerebral hemispheres and that consciousness disappeared only if both hemisphere were damaged. However, post-mortem exams of unconscious patients dying from Wernicke’s encephalopathy disclosed lesions in the peri-aqueductal grey matter and the caudal part of the third ventricle, while the cerebral hemispheres were left undamaged. This suggested that the anatomy of consciousness was more complicated.
One useful way to address what constitutes consciousness is to recognize that there are actually two components to consciousness. What are they?
One is arousal or wakefulness and the other is the content of consciousness.
Wakefulness is achieved by neural circuits that mediate sleep-wake cycles and involves a specific area of the upper brainstem commonly referred to as the:
“reticular activating system” but more accurately named the “ascending arousal system.”
Disruption of this system causes stupor and coma and is the primary focus of this presentation.
The second component of consciousness involves the content of consciousness. This refers to what?
the cerebral activity responsible for self-awareness, cognition and purposeful interactions with the environment. These behaviors are premeditated and not reflex in nature. The neural networks in the cortex drive this brain activity.
Disease affecting the content of consciousness causes dementia. It should be obvious that a person must be in an awake state in order to engage in any cognitive task.
While the role of the cortex in maintaining consciousness seems obvious, what do we know about the brain’s arousal systems?
In the last century, the anatomy of consciousness became better defined through the work of Baron Constantine von Economo. In 1916, von Economo noticed cases of a new and not previously described type of encephalitis that caused a “sleeping sickness” he termed encephalitis lethargica. This disease became a world-wide epidemic that did not subside until a decade later. This epidemic should not be confused with the huge influenza pandemic of 1918 that killed millions and whose recombinant progeny H1N1 has recently threatened the world.
The virus causing Von Economo’s encephalitis lethargica has never been identified. What did the sleeping sickness look like?
Individuals slept for 20 hours a day, awakening only to eat or go to the toilet. Some patients died, and von Economo’s post-mortem studies revealed lesions in the rostral periaqueductal grey matter and posterior 3rd ventricle.
Some patients with encephalitis would sleep at most only a few hours a day and had lesions in the rostral hypothalamus.
Among the survivors, there was a recovery phase several months after the acute encephalitis when some patients developed sleep attacks and cataplexy. These patients died later from other causes and were found to have lesions in the posterior lateral hypothalamus lying between a sleep promoting area in the rostral hypothalamus and a wakefulness promoting area in the upper midbrain.
What is cataplexy?
Cataplexy refers to the sudden involuntary loss of muscle tone during emotional excitement, such as intense laughter, causing the individual to fall down. These patients had what we now call “narcolepsy.”
Further research has identified the sleep promoting area as:
the ventrolateral preoptic nucleus, whose destruction causes profound insomnia.
What causes narcolepsy?
Narcolepsy is caused by a loss of neurons that can be histochemically stained with antibodies against the neuro-peptide neurotransmitter “orexin”.
The electroencephalogram or EEG was invented in 1929. An array of electrodes on the scalp surface could generate patterns of cortical electrical activity in which wakefulness was readily distinguished from sleep. Soon afterwards, animal studies determined where lesions placed in different parts of the brain disrupted consciousness.
Thus, a brainstem transection at the level of the cervical medulla caused quadriplegia and respiratory arrest requiring mechanical ventilation. While these motionless animals appeared unconscious, the EEG showed a “desynchronized” brain wave pattern characteristic for the awake state. Successive lesions marching upwards (rostrally) toward the midbrain produced the same effect until a cut was made where?
at the level of the posterior colliculi (quadrigeminal plate). At this level, the EEG became “synchronized” showing high voltage slow waves typical of the pattern seen in sleep and in some patients with coma. In other words, lesions of the brainstem did not affect wakefulness, as defined by the EEG pattern, until the lesion reached the upper pontine and midbrain level.
A number of neuropathological lesion have been associated with causing coma. Name them.
The first, represented by A, involves severe sudden bilateral hemispheric disease. It is unusual, however, to have such an extensive global insult without affecting the upper brainstem as well.
The other pictures, B through E, are notable for involving some region of the upper brainstem but always including “reticular grey formation” whether found in the thalamus, hypothalamus, mid-brain peri-aqueductal grey or upper third of the pons.
What is not shown is that often, the damage to these regions are often secondary to a herniation syndrome affecting one or both cerebral hemispheres. In any event, people noticed that the reticular grey formation was affected and that led to the concept of the “reticular activating system” as mediating arousal.
What is the “reticular grey formation”?
Among the cranial nerve nuclei and other clearly demarcated cell groups in the brainstem, anatomists had found diffuse aggregations of neurons of different types and sizes, separated by a wealth of fibers traveling in all directions. When stained to visualize the neuronal processes, a net-like or reticular pattern emerged as shown in this photomicrograph of a section stained to show fibers (myelin) and cell bodies.
The term “reticular formation” was born.
What does the reticular grey formation do?
It was known that sensory pathways on their way to the thalamus would often send a collateral axon to synapse in the reticular formation. It seemed reasonable that sudden major sensory changes might well benefit from a heightened alertness before the sensory information ever got processed by the parietal cortex. A startle response to a sudden noise behind you, or a movement in a nearby brush, or an unexpected nudge to your side, whatever, might mean the difference between life and death in evolutionary terms. It turns out, however, that the reticular formation does much more, and furthermore, it is not a diffuse, undifferentiated structure but quite the contrary.
Cytoarchitectonic differences exist between different areas of the reticular formation and the various cell groups have highly specific connections.
What is the minimal amount of reticular formation that can be damaged in the upper brainstem and still produce coma?
Working at the Mayo Clinic, Parvizi and Damasio performed a combined MRI neuropathological study of comatose individuals with brainstem injury in whom the diencephalon (that is the thalamus and hypothalamus) and most of the midbrain were spared. In other words they excluded patients with so-called “top of the basilar” stroke.
Among 9 patients, the most common lesion site is shown in red and orange. It is the paramedian tegmental area just ventral to the aqueduct of Sylvius from the midbrain to the rostral pons.This study suggests that lesions confined to the upper pons can cause coma in the absence of midbrain and thalamic injury. This explains why some patients with pontine hemorrhage are comatose.
T or F. Lesions below the rostral pons disrupt the corticospinal and corticobulbar tracts bilaterally to leave a patient quadriplegic with a paralyzed lower face, unable to speak, swallow or breathe on his own, yet the patient is conscious, aware, can see and hear, and usually retain some control over vertical eye movements and blinking through which he can communicate with the outside world.
T. Thus other patients with slightly more caudal pontine hemorrhage appear to be in coma but are actually awake and “locked-in”. From a humane aspect, it is essential to make a correct diagnosis and to treat locked-in patients at the bedside as fully conscious and mentally competent individuals.
Thus areas of the reticular formation that produce coma when damaged became known as the reticular activating system or RAS. The RAS extends where?
from the upper third of the pons through the midbrain tegmentum (tegmentum means floor), the floor of the third ventricle and into the thalami as demarcated by the asterisks. These are the areas that injury of any kind, traumatic, ischemic, inflammatory, metabolic, whatever, will suppress wakefulness and cause coma.
The concept of the reticular activating system or RAS underlying arousal is ingrained in medical jargon. Work by Cliff Saper and others, however, has shown that reticular nuclei are not the source of arousal. Damage to these areas destroys axons from specific nearby nuclei that pass through the RAS territory. The nuclei shown in red and yellow are the ones actually responsible for arousal and are more accurately identified as:
the ascending arousal system.
Describe the ascending arousal system
In yellow, two cholinergic nuclei project to the thalamic relay nuclei and inhibit their firing. This inhibition increases wakefulness and places the thalamus “in transmission” mode for filtering and relaying sensory information to the cortex. Without this inhibition, the thalamic relay neurons spontaneously continue their periodic electrical “bursting” and with their widespread connections to the cortex, these thalamic relay neurons synchronize cortical electrical activity and induce sleep.
The monoaminergic systems shown in red (part of the ascending arousal system) also have widespread connections to the cortex, both direct and indirect. What is their role?
Their role is to improve the signal to noise ratio for messages from the thalamus and thereby prevent any misperception of incoming sensory stimuli. When this system fails, sensory hallucinations and confusion result, causing delirium.
Note that different neurotransmitters are responsible for the normal maintenance of consciousness and perturbations in any of them can lead to delirium. Knowledge of these transmitters also offers potential therapeutic targets in the treatment of delirium.
What is the ‘sleep promoting center’?
The ventro-lateral preoptic nucleus or VLPO is the sleep promoting center that von Economo found causes insomnia when destroyed.
How does the VLPO work?
VLPO uses the inhibitory GABA and an inhibitory neuropeptide, galanin, to inhibit the many centers that promote wakefulness in the ascending arousal system.
Notice that one nucleus, the VLPO, singlehandedly counterbalances the influence of multiple arousal nuclei to promote sleep.
What drugs that have GABA-like properties in the brain induce sedation in part by promoting the inhibitory effects of the VLPO on the ascending arousal system?
Ethanol, benzodiazepines and other drugs
Finally, it should be noted that the Ascending Arousal System receives feedback from many sources including:
the thalamus, the limbic system, the frontal and association cortex.
These pathways mediate emotional memories and permit concentrated attention to one sensory modality when necessary. Loss of this feedback from brain injury causes apathy and indifference to sensory stimuli. When the damage is severe, abulia or akinetic mutism can result.
Plum and Posner divided coma into two broad categories, structural and metabolic, that required dramatically different kinds of intervention. How are structural causes handled?
Structural causes typically required neurosurgical intervention such as evacuating a cerebellar hemorrhage or placing a shunt for acute hydrocephalus.
Raised intracranial pressure was common and caused specific signs and symptoms. They included headache made worse with recumbency, nausea, vomiting, transient visual obscurations, papilledema, focal deficits on exam and an abnormal CT or MRI disclosing a mass lesion or other distortions of the brain.
Let’s start with a case. A 30 year old man is assaulted and struck on the right head with a bat. The resulting skull fracture lacerates the middle meningeal artery which produces an epidural hematoma as shown in the picture.
The mass effect pushes the right temporal lobe medially and down across the tentorium cerebelli. This is called transtentorial herniation of the medial temporal lobe or the uncus of the temporal lobe. Another term is uncal herniation. What is compressed first?
The oculomotor nerve lies between the herniating uncus and the midbrain and diencephalon. It is therefore compressed first, before pressure on the midbrain and diencephalon produce ischemia and cause increasing lethargy, stupor and coma. In fact the nerve fascicle mediating pupillary constriction lies superficially and may be the first part of the oculomotor nerve to be compressed. At the bedside, the right pupil becomes widened and slower to react to direct and indirect light compared to the left side. This pupillary abnormality may precede the ptosis and weakness of ocular movement caused by ocular motor nerve paresis. It often precedes the increased lethargy and the development of contralateral hemiparesis and a contralateral Babinski sign.
Here is another case of herniation. A large malignant tumor caused the medial temporal lobe to herniate around the tentorium and compress the brainstem. You can see the indentation of the tentorium into the temporal lobe as shown by the arrows. The compression of the brainstem often causes small hemorrhages called:
Duret’s hemorrhages as shown by the large arrow.
Here are two more examples of transtentorial herniation leaving a groove in the temporal lobe. What do you think gets caught between the herniating temporal lobe and the upper brainstem?
The oculomotor nerve. It is numbered 6 in the picture and note its proximity to the edge of the tentorium. You should be able to visualize how the temporal lobe traps and compress the oculomotor nerve during the herniation process when examining this picture.
The same point can be made here. Note the proximity of the oculomotor nerve to the tentorium.
Finally, you can see the oculomotor nerve resting on the uncus of the temporal lobe on the right side.
This slide shows an uncal herniation that is unilateral. It also shows that the herniation can involve both hemispheres. How?
The latter can occur when trauma produces bilateral subdural hematomas or the hemispheres are severely and irreversibly damaged by certain metabolic insults such as hypoxia or the cerebral edema that accompanies fulminant liver failure or hydrocephalus. Under such circumstances, there is diffuse and symmetric pressure on the brain both medial and downward to produce central herniation.
Some lesions cause both a transtentorial and central herniation syndrome. The contribution from the former can be monitored by the accompanying lateral signs and by neuro-imaging.
Structural lesions may also lie below the cerebellar tentorium in the posterior fossa. They can be intrinsic and directly damage the brainstem or extrinsic and indirectly damage the brainstem by compression.
Respiratory patterns in coma depend on site of the lesion.
The most important pattern here is the Cheyne-Stokes respirations since this can be an early warning sign of:
transtentorial or central herniation.
If you walk into the rooms and see one of the other patterns, “call a code”. These are essentially patterns that quickly terminate in respiratory arrest. You probably will not see these patterns unless you are the one who calls the code. Most patients will either die, or be placed on a respirator, and the patterns will be obscured by the ventilator.
The motor response is very important in the evaluation of the unconscious patient. When the patient fails to awaken to your voice or to shaking, you apply a noxious stimulus and observe the response. Pressure on the supraorbital nerve, nail bed pinch and sternal rub are relatively painful yet leave no marks. In contrast, nipple pinch or twisting, still used by some physicians, often leaves a bruise and is likely to appear sadistic to any family member who learns of this.
So what are the motor responses. There is a hierarchy of motor responses following brain injury.
For prognosis, the best response is following a complex motor command such as “show me two fingers with your right hand”. With slightly greater brain injury, the patient may follow only the simplest command such as moving a limb when asked to lift it. When there is no motor response to voice command, a painful stimulus is introduced and the highest level of response is localizing the pain and pushing away the offending hand. The next decrement in response involves purposeful withdrawal to pain. That is followed by semi-purposeful withdrawal from pain.
Then come the reflex, stereotypic responses to pain, a definite deterioration.
You first see flexion of the arms or so-called “decorticate posturing.” Prognosis is worse with extensor posturing, also called “decerebrate posturing.”
Shown is the Glasgow coma scale in which a patient receives a score for eye opening, motor response and verbal response
The highest score is 15, and patients with head trauma who have an initial score of 12 or better have an excellent prognosis. Scores of 8 or below usually means nursing home care and a score of 3 usually means death.
Lab tests that can be helpful are shown in this slide. Many of the routine metabolic panels actually provide a great deal of useful information that excludes causes of metabolic coma.
Blood testing, for example, can screen for hyperglycemia, hypoglycemia, acid-base and electrolyte abnormalities, uremia, liver failure, thyroid disease, Addison’s disease , sepsis and various kinds of poisoning. CSF studies are especially useful for diagnosing infectious and inflammatory causes of coma.
Where would you place the lesion?
This was a trick question. There is no organic lesion of the nervous system although there is a psychiatric problem. This is a case of psychogenic unresponsiveness. The clues are everywhere.
The vital signs are normal which would be highly unusual in a bona fide coma of such depth that pain produced no motor response. The neurological exam is negative. Note that the oculocephalic reflex tested by the Doll’s head maneuver shows no movement of the eyes. This happens with visual fixation. If Frenzel lenses had been placed on the patient to suppress visual fixation, then one would have seen movement of the eyes in the direction opposite to the head turn. Finally it doesn’t take a lot of ice water to be placed in the external auditory canal to induce nystagmus. In a deeply comatose patient with the brainstem structurally intact, 50 cc of ice water or more might be necessary to show some modest movement of the eyes.
What is the diagnosis? What ethical concerns might this case raise?
This is a classic case of “locked-in” syndrome. The problem here is that the patient is mentally intact and aware, yet cannot easily communicate with the outside. Typically these patients become terribly depressed and often express the wish “I want to die.” What would you do if your patient asked that he be given morphine and the ventilator be stopped?
In the past, most of these patients would expire in the ICU after a month or two. In the past decade, however, some of these patients have elected to continue life and deal with it as best as possible. One such patient has even written a book about his “locked-in” experience.
More often than not, there is no book contract and there an unfortunate outcome.
He had a left ptosis, enlarged left pupil unreactive to light, and left oculomotor nerve paresis. The remainder of the neuro-exam was negative.
The CT showed subarachnoid blood. There bright substance is blood and in mixing with CSF the blood has obscured the cortical sulci and the Sylvian fissure. What do think may have caused this?
Case 3: On the left side, you can see a posterior communicating artery aneurysm that is unruptured and on the right, you see a ruptured aneurysm with fresh clot on its dome.
Here is a typical circle of Willis. Note the proximity of the oculomotor nerve to the PCOM , the posterior communicating artery, and the relationship to the medial temporal lobe. The point to stress is that structural lesions causing coma such as the rupture of a PCOM aneurysm and transtentorial herniation from other causes often compress the oculomotor nerve, dilate the pupil and do so early in disease.
Here is a diagram of the posterior communicating artery and its relationship with the oculomotor nerve. Note the close approximation between the two so that the oculomotor nerve becomes entrapped and stretched by the physical expansion of the aneurysm. This is yet another instance in which the pupil is affected early by structural disease, here because any subarachnoid hemorrhage has occurred.
The vital signs are all “depressed” including temperature, respirations, heart rate and blood pressure. This was due to a phenobarbital overdose and with ICU supportive care, the patient made a full recovery.
