ospital and Department of Neurology, Vanderbilt
Clinical experience seems to indicate two separate types of entry to coma. ome patients follow a pathway characterized by confusion, hallucinations’ mumbling delirium, myoclonic jerks, and seizures. The author has called this sequence of high road to coma and hypothesized that its basic underlying pathophysiology involves increased neuronal ther patients develop somnolence, lethargy, obtundation, and unresponsiveness without seizures or muscle twitches. This low road to coma involves either anatomical compression of the midbrain reticular formation or a metabolic or toxic disorder characterized by membrane stabilization and decreased neuronal excitability.
ou take the high road and I’ll take the low road, and I’ll be in tland afore ye”’ she sang in a low voice. lazily on the placid highland lake as the w boat bob of the ballad sifted through my thoughts. Visions of my patients intruded into my vacation reverie. The song blended with my memories and the confusing jumble of comatose people in my practice seemed to separate into two types. uddenly it all jelled and I said aloud: “‘I have just had a medical hypothesis!” The bonnie wee lass in the boat with me groaned and a pained look came over her face, for she was my wife and she had heard my hypotheses before. “In general”’ I began, “one can see two types of entry to coma. The more common path, which I call a low road, begins with mild confusion and sleepiness, proceeding to lethargy, obtundation, and then coma. The high road starts with a hyperexcitable person, perhaps somewhat confused, who can’t seem to sit down. As he becomes more ill he may suffer hallucinations. In the latter stages, the patient lies in bed mumbling undecipherable gibberish, usually has twitching movements of fingers, toes, hands, and feet, (socalled myoclonic jerks) and may suffer major motor tonicclonic seizures. A diagram may help explain this two road “. I quickly drew Figure 1 and handed it to my wife. what”’ said the wee bonnie lass as she stuffed the nto the tackle box, “every nurses’ aid on a neurology ws this.” ‘s that ripple over there my dear?” I pointed, deflect her steely eyes. “This differentiation of toxic brain syndromes can be of diagnostic value. In the first place I am aware of no anatomical lesion, that is no disease which directly destroys neural tissue like a stroke or tumor or hemorrhage, which produce the full high road o if one is faced with a delirious and syndrome. hallucinatory patient with myoclonic jerks one should look for metabolic derangements. Cerebral angiography and other evaluations of anatomic pathology should be secondary. On the other hand many patients slipping into coma along the low road have an expanding mass lesion pressing upon the midbrain reticular formation. In Plum
osner’s (1972) large series of comatose patients, those individuals with well defined anatomic lesions causing coma always had involvement of this region.” “That really is something”’ she replied. I beamed until I realized she was referring to the ripple in the lake rather than my observations. In mid-sentence she sensed my disappointment. ‘“That must be the famous . . . oh, of course, I’ve been listening. ou’ve said the low road is a lumplike problem and the high road a metabolic derangement. I think it’s coming toward us.” o, dear, the low road to coma is frequently caused by an anatomical lesi but it is also frequently a metabolic or toxic problem. articularly common is an overdose of sedative drugs such as barbiturates. In fact most drugs known to be membrane stabilizing agents produce low entry while the withdrawal of these agents after their chronic use produces the high road syndrome. The most common cause of acute delirium, sometimes following seizures, in my practice. , . ” uick, hand me the camera,” she interjected. . . is alcohol withdrawal delirium tremens. It’s nice of you to take a photo of me to commemorate the creation of this important idea. hy are you pointing the camera at that moss covered tree trunk jutting out of the water?” “ ‘t get this thing focused!” “ u are right as usual, my dear. The focus of my hypothesis is the biochemical or neurochemical mechanism underlying these two types of mental changes. Uttal (1975) dedicated his recent textbook on cellular neurophysiology to attempts to relate changes in neuronal firing rates to mental changes but he could suggest precious few correlations. If one compares the types of metabolic derangements associated with delirium and seizures, what I have called, the high road to coma, with those associated with lethargy and obtundation, one sees in general a correlation with agents which tend to increase or decrease neuronal firing rates or membrane stability. Let me jot this comparison down in table form. “Look out, it’s going to strike the boat!” The green log rose from the water and smashed down beside our small 82
RESTLESSNESS
The high road
HALLUCINATIONS
NORMAL BEHAVIOU
MWWBLING
DELIRIUM
1 URES
COMA
BRAIN
DEATH
I: Comparison of two entry modes to coma. High Road
Low Road Anatomical correlation:
Unclear, perhaps limbic system.
idbrain reticular formation.
Neurophysiological correlation:
Depression of neuronal firing rates
Neurochemical correlation:
Membrane stabilization.
Examples:
Barbiturate overdose.
Increase in neuronal excitability. mbrane destabilization (or sometimes Ethanol withdrawal after chronic use.
Enlarging posterior fossa or diencephalic mass.
enicillin toxicity. Hypocalcemia.
Hypercalcemia.
yperthyroidism with thyroid storm.
Hypothyroidism with myxedema.
Scopolamine overdose.
Progressive hypoxialischemia
craft. Spray drenched us but I managed to protect the table. ““A few points should be made about the table,” I said,, it at arm’s length. he boat rocked from side to side. choppy than I would have imagined a Scottish ost neurochemical discussion today centers on the role of neurotransmitter substances which act at synapses. recursors of serotonin produce drowsiness but nothing like the full low syndrome. The only synaptic agent on the list is scopolamine. In overdose it produces delirium with subsequent amnesia but without seizures. The delirium is rapidly reversed by the cholinergic agent physostigmine.” We’s coming back!” she shouted and I stuffed the table into the tackle box. “‘It seems therefore that cholinergic systems are involved
in the acute brain syndrome I have called the high road. ut . . . ” the log fell against the boat again, throwing us into the air, “the major neurochemical hypothesis is that membrane stabilizing agents produce the low road syndrome while, excitatory drugs which increase neuronal firing rates produce in overdosage the high road entry to fell into the water. “‘The antibiotic coma.” Splash. le,” I continued upon surfacing, “is penicillin, for ex injected into the cerebral cortex of experimental animals in order to produce epileptic lesions. any human cases of delirium, myoclonic jerks, and seizures have followed the intravenous overuse of penicillin.” Wet a hold on this oar,” my wife suggested. “You are wondering about the usefulness of this 83
istration funds. The major budgetary item was for the diving bell which recovered the tackle box, thereby incidentally proving that Loch Ness is not bottomless.
hypothesis, I imagine. The basic idea of two entry modes to the state of coma is a model upon which one can hang the facts, but too many exceptions exist to make it a really testable hypothesis. The neurochemical corollary, however, suggests different reactions in experimental animals as well as in patients following membrane depressants and excitants, as summarized in the table. Oh my gosh, where is the table?” hut up and keep kicking.”
1. Plum F: Posner JB.
ENCES
Diagnosis of Stupor and Coma. FA Davis &
Co., Phdadelphia, 1966,2nd ed. 1972.
2. Uttal WR.
Cellular Neurophvsiologv
and Integration.
Erlbaum Associates, Hillsdale, NJ, 1975.
This research has been supported by Veterans
84
Lawrence
Clinical experience seems to indicate two separate types of entry to coma. ome patients follow a pathway characterized by confusion, hallucinations’ mumbling delirium, myoclonic jerks, and seizures. The author has called this sequence of high road to coma and hypothesized that its basic underlying pathophysiology involves increased neuronal ther patients develop somnolence, lethargy, obtundation, and unresponsiveness without seizures or muscle twitches. This low road to coma involves either anatomical compression of the midbrain reticular formation or a metabolic or toxic disorder characterized by membrane stabilization and decreased neuronal excitability.
ou take the high road and I’ll take the low road, and I’ll be in tland afore ye”’ she sang in a low voice. lazily on the placid highland lake as the w boat bob of the ballad sifted through my thoughts. Visions of my patients intruded into my vacation reverie. The song blended with my memories and the confusing jumble of comatose people in my practice seemed to separate into two types. uddenly it all jelled and I said aloud: “‘I have just had a medical hypothesis!” The bonnie wee lass in the boat with me groaned and a pained look came over her face, for she was my wife and she had heard my hypotheses before. “In general”’ I began, “one can see two types of entry to coma. The more common path, which I call a low road, begins with mild confusion and sleepiness, proceeding to lethargy, obtundation, and then coma. The high road starts with a hyperexcitable person, perhaps somewhat confused, who can’t seem to sit down. As he becomes more ill he may suffer hallucinations. In the latter stages, the patient lies in bed mumbling undecipherable gibberish, usually has twitching movements of fingers, toes, hands, and feet, (socalled myoclonic jerks) and may suffer major motor tonicclonic seizures. A diagram may help explain this two road “. I quickly drew Figure 1 and handed it to my wife. what”’ said the wee bonnie lass as she stuffed the nto the tackle box, “every nurses’ aid on a neurology ws this.” ‘s that ripple over there my dear?” I pointed, deflect her steely eyes. “This differentiation of toxic brain syndromes can be of diagnostic value. In the first place I am aware of no anatomical lesion, that is no disease which directly destroys neural tissue like a stroke or tumor or hemorrhage, which produce the full high road o if one is faced with a delirious and syndrome. hallucinatory patient with myoclonic jerks one should look for metabolic derangements. Cerebral angiography and other evaluations of anatomic pathology should be secondary. On the other hand many patients slipping into coma along the low road have an expanding mass lesion pressing upon the midbrain reticular formation. In Plum
osner’s (1972) large series of comatose patients, those individuals with well defined anatomic lesions causing coma always had involvement of this region.” “That really is something”’ she replied. I beamed until I realized she was referring to the ripple in the lake rather than my observations. In mid-sentence she sensed my disappointment. ‘“That must be the famous . . . oh, of course, I’ve been listening. ou’ve said the low road is a lumplike problem and the high road a metabolic derangement. I think it’s coming toward us.” o, dear, the low road to coma is frequently caused by an anatomical lesi but it is also frequently a metabolic or toxic problem. articularly common is an overdose of sedative drugs such as barbiturates. In fact most drugs known to be membrane stabilizing agents produce low entry while the withdrawal of these agents after their chronic use produces the high road syndrome. The most common cause of acute delirium, sometimes following seizures, in my practice. , . ” uick, hand me the camera,” she interjected. . . is alcohol withdrawal delirium tremens. It’s nice of you to take a photo of me to commemorate the creation of this important idea. hy are you pointing the camera at that moss covered tree trunk jutting out of the water?” “ ‘t get this thing focused!” “ u are right as usual, my dear. The focus of my hypothesis is the biochemical or neurochemical mechanism underlying these two types of mental changes. Uttal (1975) dedicated his recent textbook on cellular neurophysiology to attempts to relate changes in neuronal firing rates to mental changes but he could suggest precious few correlations. If one compares the types of metabolic derangements associated with delirium and seizures, what I have called, the high road to coma, with those associated with lethargy and obtundation, one sees in general a correlation with agents which tend to increase or decrease neuronal firing rates or membrane stability. Let me jot this comparison down in table form. “Look out, it’s going to strike the boat!” The green log rose from the water and smashed down beside our small 82
RESTLESSNESS
The high road
HALLUCINATIONS
NORMAL BEHAVIOU
MWWBLING
DELIRIUM
1 URES
COMA
BRAIN
DEATH
I: Comparison of two entry modes to coma. High Road
Low Road Anatomical correlation:
Unclear, perhaps limbic system.
idbrain reticular formation.
Neurophysiological correlation:
Depression of neuronal firing rates
Neurochemical correlation:
Membrane stabilization.
Examples:
Barbiturate overdose.
Increase in neuronal excitability. mbrane destabilization (or sometimes Ethanol withdrawal after chronic use.
Enlarging posterior fossa or diencephalic mass.
enicillin toxicity. Hypocalcemia.
Hypercalcemia.
yperthyroidism with thyroid storm.
Hypothyroidism with myxedema.
Scopolamine overdose.
Progressive hypoxialischemia
craft. Spray drenched us but I managed to protect the table. ““A few points should be made about the table,” I said,, it at arm’s length. he boat rocked from side to side. choppy than I would have imagined a Scottish ost neurochemical discussion today centers on the role of neurotransmitter substances which act at synapses. recursors of serotonin produce drowsiness but nothing like the full low syndrome. The only synaptic agent on the list is scopolamine. In overdose it produces delirium with subsequent amnesia but without seizures. The delirium is rapidly reversed by the cholinergic agent physostigmine.” We’s coming back!” she shouted and I stuffed the table into the tackle box. “‘It seems therefore that cholinergic systems are involved
in the acute brain syndrome I have called the high road. ut . . . ” the log fell against the boat again, throwing us into the air, “the major neurochemical hypothesis is that membrane stabilizing agents produce the low road syndrome while, excitatory drugs which increase neuronal firing rates produce in overdosage the high road entry to fell into the water. “‘The antibiotic coma.” Splash. le,” I continued upon surfacing, “is penicillin, for ex injected into the cerebral cortex of experimental animals in order to produce epileptic lesions. any human cases of delirium, myoclonic jerks, and seizures have followed the intravenous overuse of penicillin.” Wet a hold on this oar,” my wife suggested. “You are wondering about the usefulness of this 83
istration funds. The major budgetary item was for the diving bell which recovered the tackle box, thereby incidentally proving that Loch Ness is not bottomless.
hypothesis, I imagine. The basic idea of two entry modes to the state of coma is a model upon which one can hang the facts, but too many exceptions exist to make it a really testable hypothesis. The neurochemical corollary, however, suggests different reactions in experimental animals as well as in patients following membrane depressants and excitants, as summarized in the table. Oh my gosh, where is the table?” hut up and keep kicking.”
1. Plum F: Posner JB.
ENCES
Diagnosis of Stupor and Coma. FA Davis &
Co., Phdadelphia, 1966,2nd ed. 1972.
2. Uttal WR.
Cellular Neurophvsiologv
and Integration.
Erlbaum Associates, Hillsdale, NJ, 1975.
This research has been supported by Veterans
84
Lawrence
