Polyvinyl Chloride To the Editor.\p=m-\Therecent discovery of the association of polyvinyl chlo-
ride with primary hemangiosarcomas of the liver has received much publicity.1-3 The systematic detection program as outlined by Makk et al4 is certainly a step in the right direction in identifying the population at risk; however, as mentioned, there is as yet no specific chemical abnormality that could be used as an indicator in
screening tests. Carcinoembryonic antigen and \g=a\-fetoprotein determinations have been negative in all cases of hemangiosarcomas, as opposed to hepatocellular carcinomas where they have been quite useful.5 Recently, we performed an autopsy in a case of proved primary hemangiosarcoma of the liver. (The case
referred to the Center for DisControl.) We would like to report a finding that we think could perhaps be used in an early detection system. The production of sulfated acid mucopolysaccharides is characteristic of malignant vascular tumors of the skin. With the aid of special staining techniques, some pathologists use this feature as a diagnostic aid." In our case, we employed a stain for acid was
ease
mucopolysaccharides (Alcian blue; pH, 2.5), and it gave strongly positive
results in sections taken from liver. Although this is a rather crude tech¬ nique, it is consistent with an in¬ crease in the production of sulfated acid mucopolysaccharides (chondroitin sulfate A, B, C). Currently, we are attempting to analyze sections of fresh tissue, but these analyses are not easily performed in most clinical laboratories. We would like to suggest that those individuals involved with the present investigations make an attempt to qualitate and quantitate the produc¬ tion of acid mucopolysaccharides in the neoplasms, serum, and urine of those at risk. The mucopolysaccharide urine spot test is quite easily em¬ ployed as a gross screening test in the inherited mucopolysaccharidoses and could be used as an initial examina¬ tion.7 Possibly, such work has been Edited
by John D. Archer, MD,
Senior Editor.
done and proven ineffective; we, how¬ are not aware of it. If not, we feel such work should he attempted.
ever, K.
Ishak, MD, of the Armed Forces Institute of Pathol¬ diagnosis.
ogy, verified the
Ronald J. Barr, MD Michael Bonin, MD
University Hospital Diego, Calif
San
1. Creech JL Jr, Johnson MN: Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Occup Med 16:150-151, 1974. 2. Block JB: Angiosarcoma of the liver following vinyl chloride exposure. JAMA 229:53-54, 1974. 3. Falk H, Creech JL Jr, Heath CW Jr, et al: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63, 1974. 4. Makk L, Creech JL, Whelan JG Jr, et al: Liver damage and angiosarcoma in vinyl chloride workers: A sys-
tematic detection program. JAMA 230:64-68, 1974. 5. Kohn J, Weaver PC: Serum alpha fetoprotein in hepatocellular carcinoma. Lancet 2:334-336, 1974. 6. Girard C, Johnson WC, Graham JH: Cutaneous angiosarcoma. Cancer 25:868-883, 1970. 7. Stanbury JB (ed): The Metabolic Basis of Inherited Disease, ed 3. New York, McGraw-Hill Book Co, Inc, 1972.
Diagnosis Malignant
and Treatment of Carcinoid Syndrome
To the Editor.\p=m-\Thearticle, "Diagnosis and Treatment of Malignant Carcinoid Syndrome," by Dr. A. L. Ureles (229:1346, 1974) contains several serious errors. In this letter I shall concentrate on those that have substantial patient-care implications. Documentation of the statements I shall make may be found in a recent textbook chapter1 that will also provide access to the primary literature from which they are derived. I shall restrain myself from taking issue with the several incorrect statements that are likely to be more of interest to professional pedants than to practicing physicians who wish to understand how to safely and effectively diagnose and treat the carcinoid
syndrome.
The dose of epinephrine that Dr. Ureles designates for intravenous administration to perform the epinephrine provocative test is 5 mg. He concludes: "Reports of severe vascular collapse and paradoxical hypertension would suggest, however, that pressor amines should be avoided in the evaluation of this syndrome." A hypertensive response to this dose of ep¬ inephrine is not paradoxical. Most in¬ dividuals with or without carcinoid syndrome would manifest alarming cardiovascular responses to such a dose. I was pleased to see that some
Downloaded From: http://jama.jamanetwork.com/ by a UCSF LIBRARY User on 05/27/2015
anonymous benefactor has initiated negotiations to lower the recom¬ mended dose (230:551, 1974). He was successful to the extent of lowering it by one logarithmic order of magni¬ tude to 0.5 mg. The correct dose is more than two "logs" lower: the ini¬ tial dose is l|Ug (0.001 mg); subsequent doses—if, and only if, the lower dose yields no response—are 2¿ig, 5ftg, and lOjug. A positive response is usually seen at 5/xg or less. At lOjug, a nega¬ tive result is usually indicated by a
nonparadoxical increase in blood pressure
associated
with
facial
blanching.
The correct procedure for perform¬ and interpretation of the epi¬ nephrine provocative test is discussed in detail in the previously cited chap¬ ter1; it has also been described earlier in The Journal (186:905,1963). When done properly, this test is safe, highly specific, and yields rare false-nega¬ tive results—these being almost ex¬ clusively in patients who do not at any time in the course of their dis¬ eases exhibit spontaneous flushing. Dr. Ureles correctly notes that hypotensive episodes may be provoked by anesthesia in patients with carcinoid syndrome. However, his sugges¬ tion that these "probably can be off¬ set by serotonin antagonists" is dangerously misleading. Serotonin is not the mediator of hypotension asso¬ ciated with carcinoid flushes. In most cases, it appears that the mediator is bradykinin. In fact, serotonin is itself a vasoconstrictor. When hypotension that requires vasopressor administration develops in patients with carcinoid syndrome associated with flushing, the drugs of choice are direct-acting agonists of the adrenergic a-receptors (eg, ance
phenylephrine); any sympathomimetic agent that acts by norepinephrine re¬ lease (eg, metaraminol) or that other¬ wise has a stimulating effect on ^-re¬ ceptors is likely to produce a (truly) paradoxical hypotensive response, thus making matters worse. An al¬ ternative pressor agent that might be used without danger of paradoxical response is angiotensin, a peptide whose vasopressor effects are not me¬ diated by any adrenergic receptor. In his paragraph on pharmacologie treatment, Dr. Ureles lists in one sen¬ tence most of the drugs that have been tried and concludes: "In order to be effective, doses must be large and, unfortunately, are often accompanied by disturbing side effects." This is most unfair. He has taken no trouble
to describe which drugs are likely to be effective for which indications. If used thoughtfully, many of these agents may produce gratifying relief of otherwise disabling symptoms. Thus, for example, the serotonin an¬ tagonists—methysergide and cyproheptadine—may afford striking and prolonged relief of diarrhea; on the other hand, their administration in order to control flushing would be at least a waste of time. Methyldopa is effective only in those patients who have the rare variant tumors that lack the enzyme, aromatic L-amino acid decarboxylase; these are the tu¬ mors that secrete the serotonin pre¬ cursor 5-hydroxytryptophan. Use of
adrenergic a-receptor antagonists (eg, phenoxybenzamine) is recom¬ mended only for symptomatic treat¬ ment of flushing. I mean to state these only as examples; other state¬
ments on pharmacotherapy contained in Dr. Ureles's article must also be in¬ terpreted cautiously. Further, he ne¬ glects to mention some other agents of known value in the treatment of carcinoid syndrome, eg, niacin. The following statement is mis¬ leading in the context in which it is used: "The malignant carcinoid syn¬ drome is usually associated with 5-hydroxyindoleacetic acid [5-HIAA] uri¬ nary levels in excess of 25 mg/day." Some patients with functioning carci¬ noid tumors and severe flushing may have normal values (in most labora¬ tories, below 9 mg/day) for 5-HIAA excretion. In general, these patients tend not to have diarrhea. Most pa¬ tients with diarrhea due to carcinoid syndrome have urinary 5-HIAA ex¬ cretions far in excess of 25 mg/day. Thus, the problem in differential diagnosis based on urinary 5-HIAA values between malabsorption syn¬ drome and carcinoid syndrome is more theoretical than real. Carcinoid
syndrome can produce malabsorption syndrome, which is responsive to treatment with serotonin antagonists. These patients almost always have very high urinary levels of 5-HIAA. When malabsorption syndrome is as¬
sociated with 5-HIAA levels between 10 and 25 mg/day, it is almost never due to carcinoid syndrome. I promised at the outset not to cavil over issues that do not have major patient-care implications. Those who are interested are referred to the pre¬ viously cited textbook chapter.1 There
they may discover, among other things, that bradykinin is not a vasoactive amine; that the patient
with the
rare
5-hydroxytryptophan-
producing tumor will ordinarily have high levels of 5-HIAA in his urine;
and that the inhibitor of tryptophan is spelled p-chlorophenylalanine and that there are much better reasons for being unenthusiastic about its use than its rare procliv¬ ity to produce hypothermia (it also
hydroxylase
commonly produces psychosis eosinophilic syndromes). Finally, Dr. Ureles mentioned that
more
and
carcinoid tumors have been re¬ to produce insulin, adrenocorticotropic hormone, and melanocyte-stimulating hormone. In fact, carcinoid tumors—particularly those of foregut origin-have been reported to produce quite a variety of hor¬ mones.12 Similarly, the list of other tumors that might be expected on oc¬ casion to produce hormones generally thought to be characteristic of the carcinoid tumor has been expanded.12 some
ported
Robert J. Levine, MD Yale
University
School of Medicine New Haven, Conn 1. Levine RJ: Serotonin and the carcinoid syndrome: Histamine and mastocytosis, in Bondy PK, Rosenberg LE (eds): Duncan's Diseases of Metabolism, ed 7. Philadelphia, WB Saunders Co, 1974, chap 27.
2. Levine RJ, Metz SA: A classification of ectopic hortumors. Ann NY Acad Sci 230:533-546, 1974.
mone-producing
Acute
Carbamazepine Encephalopathy To the Editor.\p=m-\We are presenting a case of encephalopathy secondary to a
massive overdose of carbamazepine (Tegretol). The clinical picture is nonspecific and may be confused with the postictal state in those patients who have access to this anticonvulsant.
Report of a Case.\p=m-\A16-year-old boy was brought to the Neurological Institute after having failed to recover from a presumed psychomotor seizure. The patient had suffered three previous episodes in the preceding year and therapy had recently been started with carbamazepine, 200 mg twice daily. On admission, the patient was seen in profound stupor. He neither responded to speech nor made spontaneous vocalizations. Minimal painful stimuli would elicit semipurposeful movements of the extremities. Strength, tone, and deep tendon reflexes appeared to be unimpaired. Exami-
nation of the cranial nerves showed normal fundi, brisk corneal reflexes, and normal pupillary responses. Nevertheless, biplanar disconjugate gaze (skew deviation) and an absent response to the doll's head maneuver were also present. Similarly, ir¬ rigation of the external auditory canals also did not elicit vergence movements. The patient was sufficiently aroused by needle electrodes to prevent a successful
Downloaded From: http://jama.jamanetwork.com/ by a UCSF LIBRARY User on 05/27/2015
electroencephalographic recording to be made on the day of admission. Results of routine laboratory studies were unremark¬ able and the patient was assumed to be postictal. An electroencephalogram on the second hospital day showed bilateral slowing and was read as being consistent with the post¬ ictal state. During the same morning, he briefly awoke and strongly resisted any at¬
to engage him in conversation. For the duration of this acute confusional epi¬ sode, the visual axes became congruent and the patient spontaneously vocalized. Five minutes later, he lapsed back into the deep stupor in which he had been ad¬ mitted. At this point, a plasma carbamaze¬ pine level was obtained (10.1fig/ml), and the patient began to emerge from this stu¬ por on the second evening. By the fourth hospital day, he was fully alert and oriented; the plasma carbamazepine level had become unmeasurable. The patient re¬ vealed that 36 hours prior to our first blood sample, he had ingested twenty-nine 200mg capsules of carbamazepine.
tempts
Comment.—Carbamazepine is rap¬ idly absorbed from the gastrointesti¬ nal tract.1 Our patient weighed 50 kg (110 lb) and received a dose of 116 mg/kg (undivided), 36 hours prior to a
serum level of 10.1jug/ml. It is en¬ tirely possible that his peak drug level (by extrapolation) was above 30jug/
ml. Observations of the human re¬ sponse to such levels has not been
previously made, although serum car¬ bamazepine levels of 20jug/ml have been reported.2 The widely held belief that carbamazepine is an innocuous drug is clearly unwarranted. Its ef¬
fects on other systems have been dis¬ cussed elsewhere.1-2 Neither the clinical features nor the electroencephalographic findings in this case of acute encephalopa¬ thy due to carbamazepine overdosage serve to differentiate it from other acute intoxications or metabolic causes of stupor. Only a careful his¬ tory and a high index of suspicion will serve to alert the clinician to the pos¬ sibility of a carbamazepine overdosage. In our case, the diagnosis was delayed through consideration of a second possible neurologic process, the postictal state, capable of creat¬ ing this clinical picture in the major¬ ity of patients who have access to the
drug.
Michael
Salcman,
MD
Charles E. Pippenger, PhD
Columbia
University College of Physicians and Surgeons
New York
1. Meinardi H: Carbamazepine, in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs. New York, Raven Press, 1972, pp 487-496. 2. Cereghino JJ, Van Meter JC, Brock JT, et al: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 23:357-366, 1973.
ride with primary hemangiosarcomas of the liver has received much publicity.1-3 The systematic detection program as outlined by Makk et al4 is certainly a step in the right direction in identifying the population at risk; however, as mentioned, there is as yet no specific chemical abnormality that could be used as an indicator in
screening tests. Carcinoembryonic antigen and \g=a\-fetoprotein determinations have been negative in all cases of hemangiosarcomas, as opposed to hepatocellular carcinomas where they have been quite useful.5 Recently, we performed an autopsy in a case of proved primary hemangiosarcoma of the liver. (The case
referred to the Center for DisControl.) We would like to report a finding that we think could perhaps be used in an early detection system. The production of sulfated acid mucopolysaccharides is characteristic of malignant vascular tumors of the skin. With the aid of special staining techniques, some pathologists use this feature as a diagnostic aid." In our case, we employed a stain for acid was
ease
mucopolysaccharides (Alcian blue; pH, 2.5), and it gave strongly positive
results in sections taken from liver. Although this is a rather crude tech¬ nique, it is consistent with an in¬ crease in the production of sulfated acid mucopolysaccharides (chondroitin sulfate A, B, C). Currently, we are attempting to analyze sections of fresh tissue, but these analyses are not easily performed in most clinical laboratories. We would like to suggest that those individuals involved with the present investigations make an attempt to qualitate and quantitate the produc¬ tion of acid mucopolysaccharides in the neoplasms, serum, and urine of those at risk. The mucopolysaccharide urine spot test is quite easily em¬ ployed as a gross screening test in the inherited mucopolysaccharidoses and could be used as an initial examina¬ tion.7 Possibly, such work has been Edited
by John D. Archer, MD,
Senior Editor.
done and proven ineffective; we, how¬ are not aware of it. If not, we feel such work should he attempted.
ever, K.
Ishak, MD, of the Armed Forces Institute of Pathol¬ diagnosis.
ogy, verified the
Ronald J. Barr, MD Michael Bonin, MD
University Hospital Diego, Calif
San
1. Creech JL Jr, Johnson MN: Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Occup Med 16:150-151, 1974. 2. Block JB: Angiosarcoma of the liver following vinyl chloride exposure. JAMA 229:53-54, 1974. 3. Falk H, Creech JL Jr, Heath CW Jr, et al: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63, 1974. 4. Makk L, Creech JL, Whelan JG Jr, et al: Liver damage and angiosarcoma in vinyl chloride workers: A sys-
tematic detection program. JAMA 230:64-68, 1974. 5. Kohn J, Weaver PC: Serum alpha fetoprotein in hepatocellular carcinoma. Lancet 2:334-336, 1974. 6. Girard C, Johnson WC, Graham JH: Cutaneous angiosarcoma. Cancer 25:868-883, 1970. 7. Stanbury JB (ed): The Metabolic Basis of Inherited Disease, ed 3. New York, McGraw-Hill Book Co, Inc, 1972.
Diagnosis Malignant
and Treatment of Carcinoid Syndrome
To the Editor.\p=m-\Thearticle, "Diagnosis and Treatment of Malignant Carcinoid Syndrome," by Dr. A. L. Ureles (229:1346, 1974) contains several serious errors. In this letter I shall concentrate on those that have substantial patient-care implications. Documentation of the statements I shall make may be found in a recent textbook chapter1 that will also provide access to the primary literature from which they are derived. I shall restrain myself from taking issue with the several incorrect statements that are likely to be more of interest to professional pedants than to practicing physicians who wish to understand how to safely and effectively diagnose and treat the carcinoid
syndrome.
The dose of epinephrine that Dr. Ureles designates for intravenous administration to perform the epinephrine provocative test is 5 mg. He concludes: "Reports of severe vascular collapse and paradoxical hypertension would suggest, however, that pressor amines should be avoided in the evaluation of this syndrome." A hypertensive response to this dose of ep¬ inephrine is not paradoxical. Most in¬ dividuals with or without carcinoid syndrome would manifest alarming cardiovascular responses to such a dose. I was pleased to see that some
Downloaded From: http://jama.jamanetwork.com/ by a UCSF LIBRARY User on 05/27/2015
anonymous benefactor has initiated negotiations to lower the recom¬ mended dose (230:551, 1974). He was successful to the extent of lowering it by one logarithmic order of magni¬ tude to 0.5 mg. The correct dose is more than two "logs" lower: the ini¬ tial dose is l|Ug (0.001 mg); subsequent doses—if, and only if, the lower dose yields no response—are 2¿ig, 5ftg, and lOjug. A positive response is usually seen at 5/xg or less. At lOjug, a nega¬ tive result is usually indicated by a
nonparadoxical increase in blood pressure
associated
with
facial
blanching.
The correct procedure for perform¬ and interpretation of the epi¬ nephrine provocative test is discussed in detail in the previously cited chap¬ ter1; it has also been described earlier in The Journal (186:905,1963). When done properly, this test is safe, highly specific, and yields rare false-nega¬ tive results—these being almost ex¬ clusively in patients who do not at any time in the course of their dis¬ eases exhibit spontaneous flushing. Dr. Ureles correctly notes that hypotensive episodes may be provoked by anesthesia in patients with carcinoid syndrome. However, his sugges¬ tion that these "probably can be off¬ set by serotonin antagonists" is dangerously misleading. Serotonin is not the mediator of hypotension asso¬ ciated with carcinoid flushes. In most cases, it appears that the mediator is bradykinin. In fact, serotonin is itself a vasoconstrictor. When hypotension that requires vasopressor administration develops in patients with carcinoid syndrome associated with flushing, the drugs of choice are direct-acting agonists of the adrenergic a-receptors (eg, ance
phenylephrine); any sympathomimetic agent that acts by norepinephrine re¬ lease (eg, metaraminol) or that other¬ wise has a stimulating effect on ^-re¬ ceptors is likely to produce a (truly) paradoxical hypotensive response, thus making matters worse. An al¬ ternative pressor agent that might be used without danger of paradoxical response is angiotensin, a peptide whose vasopressor effects are not me¬ diated by any adrenergic receptor. In his paragraph on pharmacologie treatment, Dr. Ureles lists in one sen¬ tence most of the drugs that have been tried and concludes: "In order to be effective, doses must be large and, unfortunately, are often accompanied by disturbing side effects." This is most unfair. He has taken no trouble
to describe which drugs are likely to be effective for which indications. If used thoughtfully, many of these agents may produce gratifying relief of otherwise disabling symptoms. Thus, for example, the serotonin an¬ tagonists—methysergide and cyproheptadine—may afford striking and prolonged relief of diarrhea; on the other hand, their administration in order to control flushing would be at least a waste of time. Methyldopa is effective only in those patients who have the rare variant tumors that lack the enzyme, aromatic L-amino acid decarboxylase; these are the tu¬ mors that secrete the serotonin pre¬ cursor 5-hydroxytryptophan. Use of
adrenergic a-receptor antagonists (eg, phenoxybenzamine) is recom¬ mended only for symptomatic treat¬ ment of flushing. I mean to state these only as examples; other state¬
ments on pharmacotherapy contained in Dr. Ureles's article must also be in¬ terpreted cautiously. Further, he ne¬ glects to mention some other agents of known value in the treatment of carcinoid syndrome, eg, niacin. The following statement is mis¬ leading in the context in which it is used: "The malignant carcinoid syn¬ drome is usually associated with 5-hydroxyindoleacetic acid [5-HIAA] uri¬ nary levels in excess of 25 mg/day." Some patients with functioning carci¬ noid tumors and severe flushing may have normal values (in most labora¬ tories, below 9 mg/day) for 5-HIAA excretion. In general, these patients tend not to have diarrhea. Most pa¬ tients with diarrhea due to carcinoid syndrome have urinary 5-HIAA ex¬ cretions far in excess of 25 mg/day. Thus, the problem in differential diagnosis based on urinary 5-HIAA values between malabsorption syn¬ drome and carcinoid syndrome is more theoretical than real. Carcinoid
syndrome can produce malabsorption syndrome, which is responsive to treatment with serotonin antagonists. These patients almost always have very high urinary levels of 5-HIAA. When malabsorption syndrome is as¬
sociated with 5-HIAA levels between 10 and 25 mg/day, it is almost never due to carcinoid syndrome. I promised at the outset not to cavil over issues that do not have major patient-care implications. Those who are interested are referred to the pre¬ viously cited textbook chapter.1 There
they may discover, among other things, that bradykinin is not a vasoactive amine; that the patient
with the
rare
5-hydroxytryptophan-
producing tumor will ordinarily have high levels of 5-HIAA in his urine;
and that the inhibitor of tryptophan is spelled p-chlorophenylalanine and that there are much better reasons for being unenthusiastic about its use than its rare procliv¬ ity to produce hypothermia (it also
hydroxylase
commonly produces psychosis eosinophilic syndromes). Finally, Dr. Ureles mentioned that
more
and
carcinoid tumors have been re¬ to produce insulin, adrenocorticotropic hormone, and melanocyte-stimulating hormone. In fact, carcinoid tumors—particularly those of foregut origin-have been reported to produce quite a variety of hor¬ mones.12 Similarly, the list of other tumors that might be expected on oc¬ casion to produce hormones generally thought to be characteristic of the carcinoid tumor has been expanded.12 some
ported
Robert J. Levine, MD Yale
University
School of Medicine New Haven, Conn 1. Levine RJ: Serotonin and the carcinoid syndrome: Histamine and mastocytosis, in Bondy PK, Rosenberg LE (eds): Duncan's Diseases of Metabolism, ed 7. Philadelphia, WB Saunders Co, 1974, chap 27.
2. Levine RJ, Metz SA: A classification of ectopic hortumors. Ann NY Acad Sci 230:533-546, 1974.
mone-producing
Acute
Carbamazepine Encephalopathy To the Editor.\p=m-\We are presenting a case of encephalopathy secondary to a
massive overdose of carbamazepine (Tegretol). The clinical picture is nonspecific and may be confused with the postictal state in those patients who have access to this anticonvulsant.
Report of a Case.\p=m-\A16-year-old boy was brought to the Neurological Institute after having failed to recover from a presumed psychomotor seizure. The patient had suffered three previous episodes in the preceding year and therapy had recently been started with carbamazepine, 200 mg twice daily. On admission, the patient was seen in profound stupor. He neither responded to speech nor made spontaneous vocalizations. Minimal painful stimuli would elicit semipurposeful movements of the extremities. Strength, tone, and deep tendon reflexes appeared to be unimpaired. Exami-
nation of the cranial nerves showed normal fundi, brisk corneal reflexes, and normal pupillary responses. Nevertheless, biplanar disconjugate gaze (skew deviation) and an absent response to the doll's head maneuver were also present. Similarly, ir¬ rigation of the external auditory canals also did not elicit vergence movements. The patient was sufficiently aroused by needle electrodes to prevent a successful
Downloaded From: http://jama.jamanetwork.com/ by a UCSF LIBRARY User on 05/27/2015
electroencephalographic recording to be made on the day of admission. Results of routine laboratory studies were unremark¬ able and the patient was assumed to be postictal. An electroencephalogram on the second hospital day showed bilateral slowing and was read as being consistent with the post¬ ictal state. During the same morning, he briefly awoke and strongly resisted any at¬
to engage him in conversation. For the duration of this acute confusional epi¬ sode, the visual axes became congruent and the patient spontaneously vocalized. Five minutes later, he lapsed back into the deep stupor in which he had been ad¬ mitted. At this point, a plasma carbamaze¬ pine level was obtained (10.1fig/ml), and the patient began to emerge from this stu¬ por on the second evening. By the fourth hospital day, he was fully alert and oriented; the plasma carbamazepine level had become unmeasurable. The patient re¬ vealed that 36 hours prior to our first blood sample, he had ingested twenty-nine 200mg capsules of carbamazepine.
tempts
Comment.—Carbamazepine is rap¬ idly absorbed from the gastrointesti¬ nal tract.1 Our patient weighed 50 kg (110 lb) and received a dose of 116 mg/kg (undivided), 36 hours prior to a
serum level of 10.1jug/ml. It is en¬ tirely possible that his peak drug level (by extrapolation) was above 30jug/
ml. Observations of the human re¬ sponse to such levels has not been
previously made, although serum car¬ bamazepine levels of 20jug/ml have been reported.2 The widely held belief that carbamazepine is an innocuous drug is clearly unwarranted. Its ef¬
fects on other systems have been dis¬ cussed elsewhere.1-2 Neither the clinical features nor the electroencephalographic findings in this case of acute encephalopa¬ thy due to carbamazepine overdosage serve to differentiate it from other acute intoxications or metabolic causes of stupor. Only a careful his¬ tory and a high index of suspicion will serve to alert the clinician to the pos¬ sibility of a carbamazepine overdosage. In our case, the diagnosis was delayed through consideration of a second possible neurologic process, the postictal state, capable of creat¬ ing this clinical picture in the major¬ ity of patients who have access to the
drug.
Michael
Salcman,
MD
Charles E. Pippenger, PhD
Columbia
University College of Physicians and Surgeons
New York
1. Meinardi H: Carbamazepine, in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs. New York, Raven Press, 1972, pp 487-496. 2. Cereghino JJ, Van Meter JC, Brock JT, et al: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 23:357-366, 1973.
