Archives of Neurology

Kutt, Henn;Penry, J. Kiffin

doi: 10.1001/archneur.1974.00490410031001pmid: 4138035

Abstract Monitoring the blood levels of anti-epileptic drugs has increased the efficiency and safety of drug therapy in epilepsy. It facilitates individualization of dosage regimen, reveals irregular drug intake, and identifies the responsible agent In intoxicated patients on multiple drug therapy. Blood levels should not be adjusted arbitrarily, however, but used as information in formulating the clinical judgment for each patient. Effective and toxic blood level ranges, as well as the range of levels expected with a given dose (applicable to the majority of patients), are given for the major antiepileptic drugs. These include diphenylhydantoin, phenobarbital, primidone, ethosuximide, and carbamazepine. Indications for ordering blood level determinations are outlined. References 1. References 1-4, 10, 16, 28-30, 32, 33, 35, 36. 2. References 1-3, 16, 18, 28, 35, 37, 38. 3. References 1-5, 16, 26, 27, 35, 37, 38. 4. References 1-5, 16, 26, 27, 32, 35, 37, 38. 5. Buchthal F, Lennox-Buchthal MA: Diphenylhydantoin: Relation of anticonvulsant effect to concentration in serum , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 193-209. 6. Buchthal F, Lennox-Buchthal MA: Phenobarbital: Relation of serum concentration to control of seizures , in Woodbury DM: Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 335-343. 7. Kutt H: Diphenylhydantoin: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 211-218. 8. Sherwin AL, Robb JP: Ethosuximide: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 443-448. 9. Buchthal F, Svensmark O: Aspects of the pharmacology of phenytoin (Dilantin) and phenobarbital relevant to their dosage in the treatment of epilepsy . Epilepsia 1:373-384, 1960.Crossref 10. Penry JK, Porter RJ, Dreifuss FE: Ethosuximide: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 431-441. 11. Sherwin AL, Robb JP, Lechter M: Improved control of epilepsy by monitoring plasma ethosuximide . Arch Neurol 28:178-181, 1973.Crossref 12. Lascelles PT, Kocen RS, Reynolds EH: The distribution of plasma phenytoin levels in epileptic patients . J Neurol Neurosurg Psychiatry 33:501-505, 1970.Crossref 13. Gibberd FB, et al: Supervision of epileptic patients taking phenytoin . Br Med J 1:147-149, 1970.Crossref 14. Bochner F, et al: Effect of dosage increments on blood phenytoin concentrations . J Neurol Neurosurg Psychiatry 35:873-876, 1972.Crossref 15. Solow EB, Green JB: The simultaneous determination of multiple anticonvulsant drug levels by gas-liquid chromatography . Neurology 22:540-550, 1972.Crossref 16. Rose SW, Smith LD, Penry JK: Blood Level Determinations of Antiepileptic Drugs: Clinical Value and Methods . Bethesda, Md, National Institutes of Health, 1971. 17. Penry JK: Usefulness of serum antiepileptic drug levels in the treatment of epilepsy . Epilepsia , to be published. 18. Lund M, Jørgensen RS, Kühl V: Serum diphenylhydantoin (phenytoin) in ambulant patients with epilepsy . Epilepsia 5:51-58, 1964.Crossref 19. Serrano EE, et al: Plasma diphenylhydantoin values after oral and intramuscular administration of diphenylhydantoin . Neurology 23:312-317, 1973.Crossref 20. Borofsky LG, Louis S, Kutt H: Diphenylhydantoin in children: Pharmacology and efficacy . Neurology 23:967-972, 1973.Crossref 21. Dawson KP, Jamieson A: Value of blood phenytoin estimation in management of childhood epilepsy . Arch Dis Child 46:386-388, 1971.Crossref 22. Booker HE: Phenobarbital, mephobarbital and metharbital: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 329-334. 23. Sherwin AL: Does monitoring of antiepileptic drugs lead to improved seizure control? in Meijer JWA, et al (eds): Methods of Analysis of Antiepileptic Drugs . Amsterdam, Excerpta Medica Foundation, 1973, pp 1-5. 24. SvensmarkO, Kristensen P: Determination of diphenylhydantoin and phenobarbital in small amounts of serum . J Lab Clin Med 61:501-507, 1963. 25. Dill WA, et al: Studies on 5,5′-diphenylhydantoin (Dilantin) in animals and man . J Pharmacol Exp Ther 118:270-279, 1956. 26. Chang T, Glazko AJ: Quantitative assay of 5,5-diphenylhydantoin (Dilantin) and 5-(p-hydroxyphenyl)-5-phenylhydantoin by gas-liquid chromatography . J Lab Clin Med 75:145-155, 1970. 27. Glazko AJ, Dill WA: Ethosuximide: Chemistry and methods for determination , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 413-415. 28. MacGee J: Rapid determination of diphenylhydantoin in blood plasma by gas-liquid chromatography . Anal Chem 42:421-422, 1970.Crossref 29. Kupferberg HJ: Quantitative estimation of diphenylhydantoin, primidone and pheno-barbital in plasma by gas-liquid chromatography . Clin Chim Acta 29:283-288, 1970.Crossref 30. Kutt H, et al: Diphenylhydantoin metabolism, blood levels, and toxicity . Arch Neurol 11:642-648, 1964.Crossref 31. Gallagher BB, Baumel IP: Primidone: Biotransformation , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 361-366. 32. Meinardi H: Carbamazepine , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 487-496. 33. Cereghino JJ, et al: Preliminary observations of serum carbamazepine concentration in epileptic patients . Neurology 23:357-366, 1973.Crossref 34. Cereghino JJ, et al: Carbamazepine for epileptic patients: A controlled prospective evaluation . Neurology 24:401-410, 1974.Crossref 35. Booker H: Primidone: Toxicity , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 377-383. 36. Buchthal F, Svensmark O: Serum concentrations of diphenylhydantoin (phenytoin) and phenobarbital and their relation to therapeutic and toxic effects . Psychiatr Neurol Neurochir 74:117-136, 1971. 37. Remmer H, Hirschmann J, Greiner I: Die Bedeutung von Kumulation und Elimination für die Dosierung von Phenytoin (Diphenylhydantoin) . Dtsch Med Wochenschr 94:1265-1272, 1969.Crossref 38. Gordon N: Use of diphenylhydantoin in epilepsy treatment . Dev Med Child Neurol 11:111-112, 1969.Crossref 39. Haerer AP, Grace JB: Studies of anticonvulsant levels in epileptics . Acta Neurol Scand 45:18-31, 1969.Crossref 40. Kutt H: Biochemical and genetic factors regulating Dilantin metabolism in man . Ann NY Acad Sci 179:704-722, 1971.Crossref 41. Triedman HM, Fishman RA, Yahr MD: Determination of plasma and cerebrospinal fluid levels of Dilantin in the human . Trans Am Neurol Assoc 85:166-170, 1960. 42. Travers RD, Reynolds EH, Gallagher BB: Variation in response to anticonvulsants in a group of epileptic patients . Arch Neurol 27:29-33, 1972.Crossref 43. Fincham RW, Schottelius DD, Sahs AL: The influence of diphenylhydantoin on primidone metabolism . Arch Neurol 30:259-262, 1974.Crossref 44. Gallagher BB, et al: Primidone, diphenylhydantoin and phenobarbital: Aspects of acute and chronic toxicity . Neurology 23:145-149, 1973.Crossref 45. Cucinell SA, et al: Drug interactions in man: I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (Dicumarol) and diphenylhydantoin (Dilantin) . Clin Pharmacol Ther 6:420-429, 1965. 46. Kutt H, et al: The effect of phenobarbital on plasma diphenylhydantoin level and metabolism in man and in rat liver microsomes . Neurology 19:611-616, 1969.Crossref 47. Hansen JM, Siersbaek-Nielsen K, Skovsted L: Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man . Clin Pharmacol Ther 12:539-543, 1971. 48. Kutt H: Diphenylhydantoin: Interactions with other drugs in man , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 169-180. 49. Letteri JM, et al: Diphenylhydantoin metabolism in uremia . N Engl J Med 285:648-652, 1971.Crossref 50. Odar-Cederlöf I, Lunde P, Sjöqvist F: Abnormal pharmacokinetics of phenytoin in a patient with uraemia . Lancet 2:831-832, 1970.Crossref 51. Reindenberg MM, et al: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function . N Engl J Med 285:264-267, 1971.Crossref 52. Kiørboe E: Phenytoin intoxication during treatment with Antabuse (disulfiram) . Epilepsia 7:246-249, 1966.Crossref 53. Olesen OV: Disulfiram (Antabuse) as inhibitor of phenytoin metabolism . Acta Pharmacol Toxicol 24:317-322, 1966.Crossref 54. Hansen JM, et al: Sulthiame (Ospolot) as inhibitor of diphenylhydantoin metabolism . Epilepsia 9:17-22, 1968.Crossref 55. Olesen OV, Jensen ON: Drug-interaction between sulthiame (Ospolot) and phenytoin in the treatment of epilepsy . Dan Med Bull 16:154-158, 1969. 56. Kutt H, et al: Diphenylhydantoin intoxication: A complication of isoniazid therapy . Am Rev Respir Dis 101:377-384, 1970. 57. Hansen JM, et al: Dicoumarol-induced diphenylhydantoin intoxication . Lancet 2:265-266, 1966.Crossref 58. Solomon HM, Schrogie JJ: The effect of phenyramidol on the metabolism of diphenylhydantoin . Clin Pharmacol Ther 8:554-556, 1967. 59. Christensen LK, Skovsted L: Inhibition of drug metabolism by chloramphenicol . Lancet 2:1397-1399, 1969.Crossref 60. Garrettson LK, Perel JM, Dayton PG: Methylphenidate interaction with both anticonvulsant and ethyl biscoumacetate . JAMA 207:2053-2056, 1969.Crossref 61. Vajda FJE, Prineas RJ, Lovell RRH: Interaction between phenytoin and the benzodiazepines . Br Med J 1:346, 1971.Crossref 62. Siersbaek-Nielsen K, et al: Sulfamethizoleinduced inhibition of diphenylhydantoin and tolbutamide metabolism in man, abstracted . Clin Pharmacol Ther 14:148, 1973. 63. Frantzen E, et al: Phenytoin (Dilantin) intoxication . Acta Neurol Scand 43:440-446, 1967.Crossref 64. Kutt H, McDowell F: Management of epilepsy with diphenylhydantoin sodium . JAMA 203:969-972, 1968.Crossref 65. Kutt H, et al: Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity . Neurology 14:542-548, 1964.Crossref 66. Louis S, Kutt H, McDowell F: Intravenous diphenylhydantoin in experimental seizures: II. Effect on penicillin-induced seizures in the cat . Arch Neurol 18:472-477, 1968.Crossref 67. Louis S, Kutt H, McDowell F: Modification of experimental seizures and anticonvulsant efficacy by peripheral stimulation . Neurology 21:329-336, 1971.Crossref 68. Levy LL, Fenichel GM: Diphenylhydantoin activated seizures . Neurology 15:716-722, 1965.Crossref 69. Dam M, Olesen V: Intramuscular administration of phenytoin . Neurology 16:288-292, 1966.Crossref

Lund, Lars

doi: 10.1001/archneur.1974.00490410037002pmid: 4212949

Abstract In 32 ambulant epileptic patients, the plasma levels of diphenylhydantoin were measured gas chromatographically monthly to bimonthly for three years. The mean diphenylhydantoin plasma levels were increased from 6.1 ± 2.9μg/ml during the first year to 11.7 ± 3.3μg/ml during the second and 15.0 ± 2.5μg/ml during the third year. The annual mean number of grand mal seizures per patient decreased from 5.8 to 4.1 and 1.6, respectively. The optimal diphenylhydantoin plasma levels varied between patients and depended on the severity of the epilepsy. In some cases it was close to or above 20μg/ml. Acute cerebellar side effects were rare and reversible. The overall data strongly suggest that monitoring of the diphenylhydantoin plasma levels is a valuable aid in the management of patients with generalized epileptic seizures. References 1. Buchthal F, Svensmark O, Schiller PJ: Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin . Arch Neurol 2:624-630, 1960.Crossref 2. Kutt H, McDowell F: Management of epilepsy with diphenylhydantoin sodium . JAMA 203:969-972, 1968.Crossref 3. Lund L: Effects of phenytoin in patients with epilepsy in relation to its concentration in plasma , in Davies DS, Prichard BNS (eds): Biological Effects of Drugs in Relation to Their Plasma Concentrations . London, Macmillan Co, 1973, pp 227-238. 4. Triedman HM, Fishman RA, Yahr MD: Determination of plasma and cerebrospinal fluid levels of Dilantin in the human . Trans Am Soc Neurol 85:166-170, 1960. 5. Haerer AF, Grace JB: Studies of anticonvulsant levels in epileptics . Acta Neurol Scand 45:18-31, 1969.Crossref 6. Stensrud PA, Palmer H: Serum phenytoin determinations in epileptics . Epilepsia 5:364-370, 1964.Crossref 7. Travers RD, Reynolds EH, Gallagher BB: Variation in response to anticonvulsants in a group of epileptic patients . Arch Neurol 27:29-33, 1972.Crossref 8. Sjöqvist F, Bertilson L: Plasma concentration of drugs and pharmacological response in man , in Davies DS, Prichard BNS (eds): Biological Effects of Drugs in Relation to Their Plasma Concentrations . London, Macmillan Co, 1973, pp 26-40. 9. BorgåO, Lund L, Sjöqvist F: Bestämning av difenylhydantoin (DFH) i plasma hos patienter med epilepsi . Lakartidningen 66:89-98, 1969. 10. Berlin A, Agurell S, Borga O, et al: Micro-method for the determination of diphenylhydantoin in plasma and cerebrospinal fluid: A comparison between a gas chromatographic and a spectrophotometric method . Scand J Clin Lab Invest 29:281-287, 1972.Crossref 11. Gastaut H: Clinical and electroencephalographic classification of epileptic seizures . Epilepsia 11:102-113, 1970.Crossref 12. Merlis JK: Proposal for an international classification of the epilepsies . Epilepsia 11:114-119, 1970.Crossref 13. Dill WA, Kazenko A, Wolf LM, et al: Studies on 5,5-diphenylhydantoin (Dilantin) in animals and man . J Pharmacol Exp Ther 118:270-279, 1956. 14. Lund L: Clinical significance of generic inequivalence of three different pharmaceutical preparations of phenytoin . Eur J Clin Pharmacol 7:119-125, 1974.Crossref 15. Roseman E: Dilantin toxicity: A clinical and electroencephalographic study . Neurology 11:912-921, 1961.Crossref 16. Glaser GH: Diphenylhydantoin: Toxicity , in Woodbury DM, Penry J, Schmidt RR (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 219-235. 17. Lunde PKM, Rane A, Yaffe SJ, et al: Plasma protein binding of diphenylhydantoin in man . Clin Pharmacol Ther 11:846-855, 1970. 18. Lund L, Berlin A, Lunde PKM: Plasma protein binding of diphenylhydantoin in patients with epilepsy . Clin Pharmacol Ther 13:196-200, 1972. 19. Reidenberg MM, Odar-Cederlöf I, von Bahr C, et al: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function . N Engl J Med 285:264-267, 1971.Crossref 20. Diphenylhydantoin side effects and serum albumin levels. The Boston Collaborative Drug Surveillance Program . Clin Pharmacol Ther 14:529-533, 1973. 21. Vajda F, Williams FM, Breckenridge A: Brain, cerebrospinal fluid and plasma concentration of diphenylhydantoin and phenobarbital in man . Clin Pharmacol Ther , to be published. 22. Sherwin AL, Eisen AA, Sokolowski CD: Anticonvulsant drugs in human epileptogenic brain: Correlation of phenobarbital and diphenylhydantoin levels with plasma . Arch Neurol 29:73-77, 1973.Crossref

Landis, Dennis M. D.;Rosenberg, Roger N.;Landis, Story C.;Schut, Lawrence;Nyhan, William L.

doi: 10.1001/archneur.1974.00490410043003pmid: 4370236

Abstract Thirty-three persons in the Schut-Swier kindred at risk for autosomal dominant olivopontocerebellar degeneration have been examined and nine new cases identified. These affected individuals manifested severe cerebellar deficits; abnormalities of cortical, bulbar, and spinal motor neurons; and posterior column dysfunction. Cerebellar biopsy material from two patients revealed extensive progressing loss of Purkinje cells, degeneration of cortical afferents, and variable loss of granule cells. Vermiform tubules that resemble paramyxovirus nucleocapsids were found in association with crystalline inclusions in both biopsy specimens. References 1. Greenfield JG: The Spinocerebellar Degenerations . Springfield, Ill, Charles C Thomas Publisher, 1954. 2. Konigsmark G, Weiner L: The olivoponto-cerebellar atrophies: A review . Medicine 49:227-241, 1970.Crossref 3. Currier R, et al: Spinocerebellar ataxia: Study of a large kindred . Neurology 22:1040-1043, 1972.Crossref 4. Schut J: Hereditary ataxia: Clinical study through six generations . Arch Neurol Psychiatry 63:535-568, 1950.Crossref 5. Schut J, Haymaker W: Hereditary ataxia: A pathological study of five cases of common ancestry . J Neuropathol Clin Neurol 3:183-213, 1950. 6. Chan-Palay V, Palay S: Tendril and glomerular collaterals of climbing fibers in the glomeruli of the rat's cerebellar cortex . Z Anat Entwicklungsgesch 133:247-273, 1971.Crossref 7. Cammermeyer J: The importance of avoiding 'dark' neurons in experimental neuropathology . Acta Neuropathol 1:245-270, 1961.Crossref 8. Mugnaini E: "Dark cells" in electron micrographs from the central nervous system of vertebrates . J Ultrastruct Res 12:235-236, 1965. 9. Grant G, Westman J: The lateral cervical nucleus in the cat: IV. A light and electron microscopical study after midbrain lesions with demonstration of indirect Wallerian degeneration at the ultrastructural level . Exp Brain Res 7:51-67, 1969.Crossref 10. Herndon R: Lamellar bodies, an unusual arrangement of the granular endoplasmic reticulum . J Cell Biol 20:338-342, 1964.Crossref 11. Karlsson U, Schultz RL: Fixation of the central nervous system for electron microscopy by aldehyde perfusion: III. Structural changes after exsanguination and delayed perfusion . J Ultrastruct Res 14:47-63, 1966.Crossref 12. Van Nimwegen D, Sheldon H: Early postmortem changes in cerebellar neurons of the rat . J Ultrastruct Res 14:36-46, 1966.Crossref 13. Del Cerro MP, Snider RS: Studies on dilantin intoxication: I. Ultrastructural analogies with the lipidoses . Neurology 17:452-466, 1967.Crossref 14. Peat A, Field EJ: An unusual structure in kuru brain . Acta Neuropathol 15:288-292, 1970.Crossref 15. Toga M, Bernard-Badier M, Gambarelli-Dobos D: La dystrophie neuraxonale infantile ou maladie de Seiterlberger . Acta Neuropathol 15:327-350, 1970.Crossref 16. Howell J, Ishmael J: Changes in the central nervous system of lambs following the administration of sodium diethyldithiocarbamate . Acta Neuropathol , 1970, pp 197-207. 17. Mugnaini E: The histology and cytology of the cerebellar cortex , in Larsell O, Jansen J (eds): Comparative Anatomy and Histology of the Cerebellum . Minneapolis, University of Minnesota Press, 1972, vol 3, pp 201-264. 18. Raine CS, et al: Ultrastructural study of long-term measles infection in cultures of hamster dorsal root ganglion . J Virol 8:318-329, 1971. 19. Raine CS, et al: Subacute sclerosing panencephalitis virus in cultures of organized central nervous tissue . Lab Invest 28:627-640, 1973. 20. Baringer JR: Tubular aggregates in endoplasmic reticulum in Herpes-simplex encephalitis . N Engl J Med 285:943-945, 1971.Crossref 21. Hirano A, Dembitzer HM: Cerebellar alterations in the weaver mouse . J Cell Biol 56:478-486, 1973.Crossref 22. Rakic P, Sidman RL: Weaver mutant mouse cerebellum: Defective neuronal migration secondary to abnormality of Bergmann glia . Proc Nat Acad Sci 70:240-244, 1973.Crossref 23. Herndon HM: Thiophen induced granule cell necrosis in the rat cerebellum. An electron microscopic study . Exp Brain Res 6:49-68, 1968.Crossref 24. Baringer JR, Griffith JF: Experimental measles encephalitis . Lab Invest 23:335-346, 1970. 25. Cohen EG, Pappas GD: Dark profiles in apparently normal central nervous system . J Comp Neurol 136:375-396, 1969.Crossref

Ziegler, Dewey K.;Van Speybroech, Nancy W.;Seitz, Elson F.

doi: 10.1001/archneur.1974.00490410056004pmid: 4414767

Abstract Clinical features and pathologic findings of slowly progressive spinocerebellar disease were found in a woman with no family history of the disorder. There was a history of infrequent seizures until pregnancy when she developed a continuous myoclonus, intractable to medication and with features of rhythmicity and asymmetry, suggesting epilepsia partialis continua. The patient died after aspiration. Pathologic findings included atrophy of the dentate nucleus and superior cerebellar peduncle and loss of Purkinje cells. Possibly, the release (disinhibition) of epileptic phenomena was generated by massive damage to the cerebellum. References 1. Hodskins B, Yakovlev PI: Anatomico-clinical observations on myoclonus in epileptics and on related symptom complexes . Am J Psychiatry 9:827-848, 1930. 2. Bradshaw JPP: A study of myoclonus . Brain 77:138-157, 1954.Crossref 3. Skre H, Loken AC: Myoclonus epilepsy and subacute presenile dementia in heredo-ataxia . Acta Neurol Scand 46:18-42, 1970.Crossref 4. Cooper IS, Amin I, Gilman S: The effect of chronic cerebellar stimulation upon epilepsy in man . Trans Am Neurol Assoc 98:192-194, 1973. 5. Hunt JR: Dyssynergia cerebellaris myoclonica-primary atrophy of the dentate system: A contribution to the pathology and symptomatology of the cerebellum . Brain 44:490-538, 1921.Crossref 6. Adams RD, Sidman RL: The spinal cord , in Introduction to Neuropathology . New York, McGraw-Hill Book Co, 1968, chap 15. 7. McLeod JG: An electrophysiological and pathological study of peripheral nerves in Friedreich's ataxia . J Neurol Sci 12:333-349, 1971.Crossref 8. Brown JE: Diseases of the cerebellum , in Baker AB, Baker LH (eds): Clinical Neurology , New York, Harper & Row Publishers, 1973, vol 2, chap 29. 9. Wilson SAK: Spino-cerebellar types: Fried-reich's disease , in Bruce AN (ed): Neurology , ed 2. Baltimore, Williams & Wilkins Co, 1955, vol 2, chap 60. 10. Greenfield JG: System degenerations of the cerebellum, brain stem and spinal cord , in Blackwood W, McMenemey WH, Meyer A, et al (eds): Greenfield's Neuropathology . Baltimore, Williams & Wilkins Co, 1963, chap 10. 11. Christophe J, Gruner J: La dyssynergie cérébelleuse myoclonique de Ramsay Hunt . Rev Neurol 95:297-309, 1956. 12. Harriman DGF, Millar JHD: Progressive familial myoclonic epilepsy in three families: Its clinical features and pathological basis . Brain 78:325-349, 1955.Crossref 13. Gilbert GJ, McEntee WJ III, Glaser GH: Familial myoclonus and ataxia: Pathophysiologic implications . Neurology 13:365-372, 1963.Crossref 14. Carrea RME, Mettler FA: Physiologic consequences following extensive removal of the cerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate . J Comp Neurol 87:169-288, 1947.Crossref 15. Carpenter MB: Functional relationships between the red nucleus and the brachium conjunctivum . Neurology 7:427-437, 1957.Crossref 16. Carrea RME, Mettler FA: Functions of the primate brachium conjunctivum and related structures . J Comp Neurol 102:151-322, 1955.Crossref 17. Dow RS, Moruzzi G: The Physiology and Pathology of the Cerebellum . Minneapolis, The University of Minnesota Press, 1958. 18. Watson CW, Denny-Brown D: Studies of the mechanism of stimulus-sensitive myoclonus in man . Electroencephalogr Clin Neurophysiol 7:341-356, 1955.Crossref 19. Foley JM, Denny-Brown D: Subacute progressive encephalopathy with bulbar myoclonus . J Neuropathol Exp Neurol 16:133-136, 1957. 20. Nelson JR, Leffman H: The human diffusely projecting system: Evoked potentials and interactions . Arch Neurol 8:544-556, 1963.Crossref 21. Cooke CM, Snider RS: Some cerebellar influences on electrically-induced cerebral seizures . Epilepsia 4:19-28, 1955.Crossref 22. Dow RS, Fernandez-Guardiola A, Manni E: The influence of the cerebellum on experimental epilepsy . Electroencephalogr Clin Neurophysiol 14:383-398, 1962.Crossref 23. Dow RS: Extrinsic regulatory mechanisms of seizure activity . Epilepsia 6:122-140, 1965.Crossref 24. Hutton JT, Frost JD Jr, Foster J: The influence of the cerebellum in cat penicillin epilepsy . Epilepsia 13:401-408, 1972.Crossref

Carpenter, Stirling;Karpati, George;Andermann, Frederick;Gold, Reynold

doi: 10.1001/archneur.1974.00490410060005pmid: 4153361

Abstract A 3-year, 9-month-old boy had signs of mild gait impairment that started at age 2. He had strikingly curly, pale hair, unlike that of his parents. On chemical analysis his hair showed a decrease in disulfide bonds and an increase in thiol groups. Greatly enlarged axons packed with neurofilaments were found on biopsy in motor and sensory nerves. The diagnosis of giant axonal neuropathy may be suspected from the presence of signs of peripheral neuropathy in a patient with tightly curly, pale scalp hair, unlike that of his parents. The diagnosis can be proved by sural nerve biopsy. References 1. Karpati G, Carpenter S, Watters GV, et al: Infantile myotonic dystrophy: Histochemical and electron microscopic features in skeletal muscle . Neurology 23:1066-1077, 1972.Crossref 2. Leach SJ: The reaction of thiol disulphide groups with mercuric chloride and methylmercuric iodide (simple thiols and soluble proteins) . Aust J Chem 13:520-546, 1960.Crossref 3. Leach SJ: The reactions of thiol disulphide groups with mercuric chloride and methylmercuric iodide (fibrous keratins) . Aust J Chem 13:547-566, 1960.Crossref 4. Engel WK, Brooke MN: Muscle biopsy in ALS and other motor neuron diseases , in Norris FH, Kurland LT (eds): Motor Neuron Diseases: Research on Amyotrophic Lateral Sclerosis and Related Disorders . New York, Grune & Stratton, 1969, pp 154-155. 5. Gold RT, Scriver CR: Properties of hair keratin in an autosomal dominant form of ectodermal dysplasia . Am J Hum Genet 24:549-561, 1972. 6. Asbury AK, Gale MK, Cox SC, et al: Giant axonal neuropathy: A unique case with segmental neurofilamentous masses . Acta Neuropathol 20:237-247, 1972.Crossref 7. Berg BO, Rosenberg SH, Asbury AK: Giant axonal neuropathy . Pediatrics , 49:894-899, 1972. 8. Asbury AK, Arnason BG, Adams RD: The inflammatory lesion in idiopathic polyneuritis . Medicine 48:173-215, 1969.Crossref 9. Bérard-Badier M, Toga M, Gammbarelli E, et al: Infantile neuroaxonal dystrophy: II. Peripheral nerve involvement: Electron microscopic study in one case . Acta Neuropathol , (supplement 5) , 1971, pp 30-39. 10. Martin JJ, Martin L: Infantile neuroaxonal dystrophy: Ultrastructural study of the peripheral nerves and of the motor end plates . Eur Neurol 8:239-250, 1972.Crossref 11. Sengel A, Stoevner P: Intérêt de la biopsie neuro-musculaire dans le diagnostic de la dystrophie neuro-axonale infantile: Etude ultrastructurale de trois cas dont deux familiaux . Acta Neuropathol 21:109-116, 1972.Crossref 12. Ule G: Progressive neurogene Muskelatrophie bei neuroaxonler Dystrophie mit Rosenthalschen Fasern . Acta Neuropathol 21:332-339, 1972.Crossref 13. Suzuki K, David E, Kutschman B: Presenile dementia with "Lafora-like" intraneuronal inclusions . Arch Neurol 25:69-80, 1971.Crossref 14. Asbury AK, Nielsen SL, Telfer R: Glue sniffing neuropathy. Read before the 49th annual meeting of the American Association of Neuropathologists, Freeport, Grand Bahama, 1973. 15. Lampert PW, Schochet SS: Demyelination and remyelination in lead neuropathy: Electron microscopic study . J Neuropathol Exp Neurol 27:527-544, 1968. 16. Friede RL, Martinez AD: Analysis of the process of sheath expansion in swollen nerve fibers . Brain Res 19:165-182, 1970.Crossref 17. Morris JH, Hudson AR, Weddell G: A study of degeneration and regeneration in the divided rat sciatic nerve based on electron microscopy: III. Changes in the axons of the proximal stump . Z Zellforsch 124:131-164, 1972.Crossref 18. Horoupian BS, Wiśniewski H: Neurofilamentous hyperplasia in inferior olivary hypertrophy . J Neuropathol Exp Neurol 30:571-582, 1971.Crossref 19. Klatzo I, Wiśniewski H, Streicher E: Experimental production of neurofibrillary degeneration: I. Light microscopic observations . J Neuropathol Exp Neurol 24:187-199, 1965.Crossref 20. Terry RD, Pena C: Experimental production of neurofibrillary degeneration: II. Electron microscopy, phosphatase histochemistry and electron probe analysis . J Neuropathol Exp Neurol 24:200-210, 1965.Crossref 21. Shelanski ML, Wiśniewski H: Neurofibrillary degeneration: Induced by vincristine therapy . Arch Neurol 20:199-206, 1969.Crossref 22. Schochet SS Jr, Lampert PW, Earle KM: Neuronal changes induced by intrathecal vincristine sulphate . J Neuropathol Exp Neurol 27:645-658, 1968.Crossref 23. Schleppfer WW: Vincristine-induced axonal alterations in rat peripheral nerve . J Neuropathol Exp Neurol 30:488-505, 1971.Crossref 24. Bradley WG, Lassman LP, Pearce GW, et al: The neuromyopathy of vincristine in man: Clinical electrophysiological and pathological studies in man . J Neurol Sci 10:107-131, 1970.Crossref 25. Wiśniewski H, Terry RD: Experimental colchicine encephalopathy: I. Induction of neurofibrillary degeneration . Lab Invest 17:577-587, 1967. 26. Wiśniewski H, Shelanski ML, Terry RD: Effects of mitotic spindle inhibitors on neurotubules and neurofilaments in anterior horn cells . J Cell Biol 38:224-229, 1968.Crossref 27. Lampert P: A comparative electron microscopic study of reactive, degenerating, regenerating, and dystrophic axons . J Neuropathol Exp Neurol 26:345-368, 1967.Crossref 28. Janota I: Ultrastructural studies of an hereditary sensory neuropathy in mice (dystonia musculorum) . Brain 95:529-536, 1972.Crossref 29. Chou SM, Hartman HA: Axonal lesions and waltzing syndrome after IDPN administration in rats . Acta Neuropathol 3:428-450, 1964.Crossref 30. Schochet SS Jr, Hardman JM, Ladewig PP, et al: Intraneuronal conglomerates in sporadic motor neuron disease: A light and electron microscopic study . Arch Neurol 20:548-553, 1969.Crossref 31. Carpenter S: Proximal axonal enlargement in motor neuron disease . Neurology 18:841-851, 1968.Crossref 32. Cancilla PA, Barlow RM: Structural changes of the central nervous system in swayback (enzootic ataxia) of lambs: II. Electron microscopy of the lower motor neuron . Acta Neuropathol 6:251-259, 1966.Crossref 33. Prineas JB: The pathogenesis of dying-back polyneuropathies: II. An ultrastructural study of experimental acrylamide intoxication in the cat . J Neuropathol Exp Neurol 28:598-628, 1969.Crossref 34. Pannese E: Investigations on the ultrastructural changes of the spinal ganglion neurons in the course of axon regeneration and cell hypertrophy: II. Changes during cell hypertrophy and comparison between the ultrastructure of nerve cells of the same type under different functional conditions . Z Zellforsch 61:561-586, 1963.Crossref 35. Terry RD: Neuronal fibrous protein in human pathology . J Neuropathol Exp Neurol 30:8-19, 1971.Crossref 36. Menkes JH, Alter M, Steigleder GK, et al: A sex linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration . Paediatrics 29:764-779, 1962. 37. Ghatak NR, Hirano A, Peon TP, et al: Trichopoliodystrophy: II. Pathological changes in skeletal muscle and nervous system . Arch Neurol 26:60-72, 1972.Crossref 38. Danks DM, Campbell PE, Stevens BJ, et al: Menke's kinky hair syndrome: An inherited defect in copper absorption with widespread effects . Paediatrics 50:188-200, 1972.

Brody, Irwin A.

doi: 10.1001/archneur.1974.00490410065006pmid: 4369465

Abstract Denervation of the rat hind limb was found to increase the K+-independent p-nitrophenylphosphatase (basic pNPPase) activity of the isolated sarcolemma. There was no change in K+-stimulated p-NPPase and Na+, K+-stimulated adenosine triphosphatase. This increased enzyme activity might underlie the postspike increase in K+ conductance of denervated sarcolemma in view of the proposal that basic p-NPPase activity is related to the rate of passive flux of K+. References 1. Lüllmann H: Über die Ursache spontaner Fibrillationen denervierter Skeletmuskulatur . Klin Wochschr 38:1169-1171, 1960.Crossref 2. Thesleff S: Spontaneous electrical activity in denervated rat skeletal muscle , in Gutmann E, Hnik P (eds): The Effect of Use and Disuse on Neuromuscular Functions . Amsterdam, Elsevier Publishing Co, 1962, pp 41-51. 3. Lenman JAR: Effect of denervation on the resting membrane potential of healthy and dystrophic muscle . J Neurol Neurosurg Psychiatry 28:525-528, 1965.Crossref 4. Albuquerque EX, Thesleff S: Comparative study of membrane properties of innervated and chronically denervated fast and slow skeletal muscles of the rat . Acta Physiol Scand 73:471-480, 1968.Crossref 5. Klaus W, Lüllmann H, Muscholl E: Der Kalium-Flux des normalen und denervierten Rattenzwerchfells . Pfluegers Arch 271:761-775, 1960.Crossref 6. Hubbard SJ: The electrical constants and the component conductances of frog skeletal muscle after denervation . J Physiol 165:443-456, 1963. 7. Brody IA: Myotonia induced by monocarboxylic aromatic acids: A possible mechanism . Arch Neurol 28:243-246, 1973.Crossref 8. Sulakhe PV, Fedelesova M, McNamara DB,et al: Isolation of skeletal muscle membrane fragments containing active Na+-K+ stimulated ATPase: Comparison of normal and dystrophic muscle sarcolemma . Biochem Biophys Res Commun 42:793-800, 1971.Crossref 9. Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the folin phenol reagent . J Biol Chem 193:265-275, 1951. 10. Sulakhe PV, Drummond GI, Ng DC: Adenosine triphosphatase activities of muscle sarcolemma . J Biol Chem 248:4158-4162, 1973. 11. Severson DL, Drummond GI, Sulakhe PV: Adenylate cyclase in skeletal muscle: Kinetic properties and hormonal stimulation . J Biol Chem 247:2949-2958, 1972. 12. Garrahan PJ, Pouchan MI, Rega AF: Potassium activated phosphatase from human red blood cells: The mechanism of potassium activation . J Physiol 202:305-327, 1969. 13. Nagai K, Izumi F, Yoshida H: Studies on potassium dependent phosphatase: Its distribution and properties . J Biochem 59:295-303, 1966. 14. Bryant SH, Morales-Aguilera A: Chloride conductance in normal and myotonic muscle fibers and the action of monocarboxylic aromatic acids . J Physiol 219:367-383, 1971. 15. Woodin AM, Wieneke AA: Role of leucocidin and triphosphoinositide in the control of potassium permeability . Nature 220:283-286, 1968.Crossref 16. Woodin AM, Wieneke AA: The cation-sensitive phosphatases of the leucocyte cell membrane . Biochem Biophys Res Commun 33:558-562, 1968.Crossref 17. Greengard T, Straub RW: After-potentials in mammalian non-myelinated nerve fibers . J Physiol 144:442-462, 1958. 18. Johnson EM, Ueda T, Maeno H, et al: Adenosine 3', 5-monophosphate-dependent phosphorylation of a specific protein in synaptic membrane fractions from rat cerebrum . J Biol Chem 247:5650-5652, 1972. 19. DeLorenzo RJ, Walton KG, Curran PF, et al: Regulation of phosphorylation of a specific protein in toad-bladder membrane by antidiuretic hormone and cyclic AMP, and its possible relationship to membrane permeability changes . Proc Natl Acad Sci USA 70:880-884, 1973.Crossref 20. Appel SH, Locher C: Changes in synapse membrane protein phosphorylation following electroconvulsive shock . Neurology 23:410, 1973. 21. Andrew CG, Appel SH: Macromolecular characterization of muscle membranes: I. Proteins and sialic acid of normal and denervated muscle . J Biol Chem 248:5156-5163, 1973. 22. Dunham PB, Gunn RB: Adenosine triphosphatase and active cation transport in red blood cell membranes . Arch Intern Med 129:241-247, 1972.Crossref

Markesbery, William R.;McQuillen, Michael P.;Procopis, Peter G.;Harrison, Alvin R.;Engel, Andrew G.

doi: 10.1001/archneur.1974.00490410068007pmid: 4414743

Abstract A 61-year-old woman had proximal muscle weakness since 38 years of age. Eventually, her distal muscles became affected and she showed widespread muscle wasting, absent tendon reflexes, and electromyographic findings of a neuropathy. On biopsy, there was a lipid storage myopathy, lipid-containing vacuoles in leukocytes, and vacuoles in Schwann cells. The muscle carnitine level was abnormally low, but the serum carnitine level was normal. The findings are consistent with a generalized disorder of carnitine metabolism that may involve carnitine transport across cell membranes. References 1. Engel AG, Angelini C: Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: A new syndrome . Science 179:899-902, 1973.Crossref 2. Anderson DR: A method of preparing peripheral leukocytes for electron microscopy . J Ultrastruct Res 13:263-268, 1965.Crossref 3. DiMauro S, Scott C, Penn AS, et al: Serum carnitine: An index of muscle destruction in man . Arch Neurol 28:186-190, 1973.Crossref 4. Marquis NR, Fritz IB: Enzymological determination of free carnitine concentrations in rat tissues . J Lipid Res 5:184-187, 1964. 5. Fritz IB: Carnitine and its role in fatty acid metabolism , in Paoletti R, Kirtchevsky D (eds): Advances in Lipid Research . New York, Academic Press, 1963, vol 1, pp 285-334. 6. Lindstedt G: Hydroxylation of γ-butyrobetaine to carnitine in rat liver . Biochemistry 6:1271-1282, 1967.Crossref 7. Broquist HP, Tanphaichitr V: Site of carnitine (carn) biosynthesis in the rat . Fed Proc 32:884, 1973. 8. Cederblad G, Lindstedt S: A method for the determination of carnitine in the picomole range . Clin Chim Acta 37:235-243, 1972.Crossref 9. Engel AG, Angelini C, Nelson RA: Identification of carnitine deficiency as a cause of human lipid storage myopathy, in Milhorat AT (ed): Exploratory Concepts in Muscle: II. Control Mechanisms in Development and Function of Muscle and Their Relationship to Muscular Dystrophy. International Congress Series, Amsterdam, Excerpta Medica Foundation, to be published. 10. Jordans GHW: The familial occurrence of fat containing vacuoles in the leukocytes diagnosed in two brothers suffering from dystrophia musculorum progressiva (ERB) . Acta Med Scand 145:419-423, 1953.Crossref 11. King B, Emery AEH: Leucocyte fatty acid oxidation in hereditary neuromuscular disorders . J Neurol Sci 20:297-302, 1973.Crossref 12. Fessel WJ: Fat disorders and peripheral neuropathy . Brain 94:531-540, 1971.Crossref 13. Sandbank U, Bechar M, Bornstein B: Hyperlipemic polyneuropathy . Acta Neuropathol 19:290-300, 1971.Crossref 14. Sandbank U, Bubis JJ: Hyperlipaemic neuropathy . Brain 96:355-358, 1973.Crossref 15. Wittels B, Bressler R: Biochemical lesion of diphtheria toxin in the heart . J Clin Invest 43:630-637, 1964.Crossref 16. Fisher CM, Adams RD: Diphtheritic polyneuritis: A pathological study . J Neuropathol Exp Neurol 15:243-268, 1956.Crossref 17. Webster H deF, Spiro D, Waksman B, et al: Phase and electron microscopic studies of experimental demyelination . J Neuropathol Exp Neurol 20:5-34, 1961.Crossref 18. Price HM, Gordon BG, Munsat TL, et al: Myopathy with atypical mitochondria in type I skeletal muscle fibers . J Neuropathol Exp Neurol 26:475-497, 1967.Crossref 19. Bradley WG, Hudgson P, Gardner-Medwin D, et al: Myopathy associated with abnormal lipid metabolism in skeletal muscle . Lancet 1:495-498, 1969.Crossref 20. Engel WK, Vick NA, Glueck CJ: A skeletal-muscle disorder associated with intermittent symptoms and a possible defect of lipid metabolism . N Engl J Med 282:697-704, 1970.Crossref 21. Blass JP, Kark RAP, Engel WK: Clinical studies of a patient with pyruvate decarboxylase deficiency . Arch Neurol 25:449-460, 1971.Crossref 22. Bradley WG, Jenkison M, Park DC, et al: A myopathy associated with lipid storage . J Neurol Sci 16:137-154, 1972.Crossref 23. Engel AG, Siekert RG: Lipid storage myopathy responsive to prednisone . Arch Neurol 27:174-181, 1972.Crossref 24. Johnson MA, Fulthorpe JJ, Hudgson P: Lipid storage myopathy: A recognizable clinicopathologic entity? Acta Neuropathol 24:97-106, 1973.Crossref 25. VanDyke DH, Markesbery WR, DiMauro S, et al: Hereditary carnitine deficiency of muscle, abstracted . Neurology 24:531, 1974.Crossref

Allen, John P.;Kendall, John W.;McGilvra, Rebecca;Lamorena, Thelma L.;Castro, Albert

doi: 10.1001/archneur.1974.00490410073008pmid: 4369763

Abstract The effect of pneumoencephalography on plasma and cerebrospinal fluid (CSF) adrenocorticotrophic (ACTH) and growth hormone concentrations was studied in patients with and without hypothalamicpituitary disorders. In those without hypothalamic-pituitary disease, basal plasma and CSF ACTH levels were approximately equal, whereas plasma growth hormone levels were higher than CSF levels. Associated with the stress of the procedure, both ACTH and growth hormone concentrations increased in the plasma without a corresponding change in CSF levels of these two hormones. In two patients with suprasellar extension of either an ACTH or growth hormone secreting pituitary tumor, basal CSF ACTH or growth hormone levels were higher than in those without suprasellar extension. In contrast, those patients with nonendocrine active pituitary tumors that extended above the sella turcica did not have elevation of CSF ACTH or growth hormone levels. References 1. Linfoot JA, Garcia JF, Wei W, et al: Human growth hormone levels in cerebrospinal fluid . J Clin Endocrinol Metab 31:230-232, 1970.Crossref 2. Kleerekoper M, Donald RA, Posen S: Corticotropin in cerebrospinal fluid of patients with Nelson's syndrome . Lancet 1:74-76, 1972.Crossref 3. Nelson DH, Meakin JW, Dealy JB Jr, et al: ACTH-producing tumor of the pituitary gland . N Engl J Med 259:161-164, 1958.Crossref 4. Allen JP, Cook DM, Kendall JW, et al: Maternal-fetal ACTH relationship in man . J Clin Endocrinol Metab 37:230-234, 1973.Crossref 5. Rees LH, Cook DM, Kendall JW, et al: A radioimmunoassay for rat plasma ACTH . Endocrinology 89:254-261, 1971.Crossref 6. Glick SM, Roth J, Yalow R, et al: Immunoassay of human growth hormone in plasma . Nature 199:784-787, 1963.Crossref 7. Greenwood FC, Landon J, Stamp TCB: The plasma sugar free fatty acid, cortisol, and growth hormone response to insulin: I. In control subjects . J Clin Invest 45:429-436, 1966.Crossref 8. Brostoff J, James VHT, Landon J: Plasma corticosteroid and growth hormone response to lysine-vasopressin in man . J Clin Endocrinol Metab 28:511-518, 1968.Crossref 9. Lieberman AH, Leutscher JA Jr: Stimulation of adrenocortical secretion after air encephalography, abstracted . J Clin Invest 36:91, 1957. 10. Wise BL, Hilf L, Pileggi VJ: Effect of pneumoencephalography on fluid and electrolyte metabolism . Arch Surg 77:113-116, 1958.Crossref 11. Janches M, Caputto JD, Laszlo M, et al: Comments on the evaluation of plasma cortisol during pneumoencephalography . J Clin Endocrinol Metab 33:862-864, 1971.Crossref 12. McCann SM, Fruit A: Effect of synthetic vasopressin on release of adrenocorticotropin in rats with hypothalamic lesions . Proc Soc Exp Biol Med 96:566-567, 1957.Crossref 13. Gwinup G: Studies on the mechanism of vasopressin-induced steroid secretion in man . Metabolism 14:1282-1286, 1965.Crossref 14. Strott CA, Nakagawa K, Nankin H, et al: A phenylalanine-lysine-vasopressin test of ACTH release . J Clin Endocrinol Metab 27:448-451, 1967.Crossref 15. Makara GB, Stark E, Palkovits M: Afferent pathways of stressful stimuli: Corticotropin release after hypothalamic deafferentation . J Endocrinol 47:411-416, 1970.Crossref 16. Thomas FJ, Lloyd HM, Thomas MJ: Radioimmunoassay of human growth hormone: Technique and application to plasma, cerebrospinal fluid, and pituitary extracts . J Clin Pathol 25:774-782, 1972.Crossref

Moser, Hugo W.;O'Brien, John S.;Atkins, Leonard;Fuller, Thomas C.;Kliman, Allan;Janowska, Stasia;Russell, Paul S.;Bartsocas, Christos S.;Cosimi, Benedict;Dulaney, John T.

doi:

North, J. Brian;Jennett, Sheila

doi: 10.1001/archneur.1974.00490410086010pmid: 4411797

Abstract Breathing patterns were recorded by impedance pneumograph or pneumotachograph and capnograph in 227 patients in a neurosurgical unit; most had recent head injury, intracranial tumor, or ruptured aneurysms. The site of brain damage was determined from clinical investigation or autopsy, and the outcome three months later was classified. Abnormal patterns were recorded at some time in 60% of patients. Periodic breathing, irregular breathing, and tachypnea were equally common. All patients with a lesion in the medulla had abnormal patterns; medullary and pontine lesions were frequently associated with irregular breathing. Only gross irregularity of breathing was of localizing value in these acutely brain damaged patients, by contrast with previous reports of other associations in more chronic neurological disorders. Tachypnea (frequency >25/min) and hyperventilation (arterial carbon dioxide pressure <30 mm Hg) were associated with a poor prognosis when they were combined. References 1. Cheyne J: A case of apoplexy in which the fleshy part of the heart was converted into fat . Dublin Hosp Rep 2:216-223, 1818. 2. Biot MC: Contribution a l'etude du phenomene respiratoire de Cheyne-Stokes . Lyon Med 23:517-528, 561-567, 1876. 3. "Meningitic" breathing , editorial. JAMA 165:1568, 1957. 4. Plum F, Posner JB: Diagnosis of Stupor and Coma , ed 2. Philadelphia, FA Davis Co, 1972, pp 25-32. 5. Plum F: Examination of the unconscious patient . Br Med J 1:49, 1972.Crossref 6. Frowein RA: Zentrale atemstorungen bei schadel-hirn-Verletzungen und bei Hirntumoren . Berlin, Springer-Verlag, 1963. 7. Rout MW, Lane DJ, Wollner L: Prognosis in acute cerebrovascular accidents in relation to respiratory pattern and blood gas tensions . Br Med J 3:7-9, 1971.Crossref 8. Vapalahti M, Troupp H: Prognosis for patients with severe brain injuries . Br Med J 3:404-407, 1971.Crossref 9. North JB, Jennett S: Impedance pneumography for detection of abnormal breathing patterns associated with brain damage . Lancet 2:212-213, 1972.Crossref 10. Kelman GR, Nunn JF: Nomograms for correction of blood PO2, PCO, pH and base excess for time and temperature . J Appl Physiol 21:1484-1490, 1966. 11. Sambrook MA, Hutchinson EC, Aber GM: Metabolic studies in subarachnoid hemorrhage and strokes . Brain 96:171-190, 1973.Crossref 12. Plum F, Swanson AG: Abnormalities in central regulation of respiration in acute and convalescent poliomyelitis . Arch Neurol Psychiatry 80:267-285, 1958.Crossref 13. Plum F: Hyperpnea, hyperventilation and brain dysfunction . Ann Intern Med 76:328, 1972.Crossref 14. Plum F, Swanson AG: Central neurogenic hyperventilation in man . Arch Neurol Psychiatry 81:535-549, 1959.Crossref 15. Brown HW, Plum F: The neurologic basis of Cheyne-Stokes respiration . Am J Med 30:849-860, 1961.Crossref 16. Plum F, Brown HW: The effect on respiration of central nervous system diseases . Ann NY Acad Sci 109:915-931, 1963.Crossref