From the Department of Neurology, University of Oklahoma Health Sciences
`Center, Oklahoma City.
`Received October 8, 1999. Accepted in final form December 10, 1999.
`Address correspondence and reprint requests to Dr. Neil R. Holland, 711
`S.L. Young Boulevard, Suite 215, Oklahoma City, OK 73104-5021; e-mail:
`neil-holland@ouhsc.edu
`
`Copyright © 2000 by the American Academy of Neurology
`
`References
`1. Fiske DN, McCoy HE, Kitchens CS. Zinc-induced sideroblastic anemia.
`Report of a case, review of the literature and description of the hemato-
`logic syndrome. Am J Hematol 1994;46:147–150.
`2. Schiffer RB. Zinc and multiple sclerosis. Neurology 1994;44:1987–1988.
`3. Stein EC, Schiffer RB, Hall WJ, Young N. Multiple sclerosis and the
`workplace: report of an industry-based cluster. Neurology 1987;37:1672–
`1677.
`4. Hader WJ, Irvine DG, Schiefer HB. A cluster-focus of multiple sclerosis
`at Henribourg, Saskatchewan. Can J Neurol Sci 1990;17:391–394.
`5. Irvine DG, Schiefer HB, Hader WJ. Geotoxicology of multiple sclerosis:
`the Henribourg, Saskatchewan, cluster focus. I. The water. Sci Total
`Environ 1989;84:45–59.
`6. Irvine DG, Schiefer HB, Hader WJ. Geotoxicology of multiple sclerosis:
`the Henribourg, Saskatchewan, cluster focus. II. The soil. Sci Total En-
`viron 1988;77:175–188.
`
`␥-Hydroxybutyric acid for alcohol-sensitive
`myoclonus with dystonia
`A. Priori, MD, PhD; L. Bertolasi, MD; A. Pesenti, MD;
`A. Cappellari, MD; and S. Barbieri, MD, PhD
`
`Alcohol-sensitive myoclonus can be associated with dystonic
`spasms.1 Conventional treatments and anticonvulsants occasionally
`produce some benefit, but not comparable with the improvement
`induced by alcohol.1 We report a patient with alcohol-sensitive myoc-
`lonus and dystonia who had a consistent and substantial benefit
`from oral ␥-hydroxybutyric acid (GHB). Oral GHB is a drug that is
`effective both in the treatment of alcohol withdrawal2,3 and in main-
`taining abstinence from alcohol.4
`Case report. A 37-year-old man was evaluated for severe dis-
`abling myoclonic jerks of the upper limbs, axial muscles, neck and
`cranial muscles, which were associated with dystonic spasms
`of the upper limbs and of the neck muscles. According to the
`Chadwick–Marsden Evaluation Scale for myoclonus,5,6 the pa-
`tient’s score was 26 points. The hyperkinesias were not stimulus
`sensitive. They worsened under emotional stress and during the
`day, but the patient could control involuntary movements almost
`completely for a few hours after consumption of more than one
`liter of beer. The patient’s clinical picture has been stable for the
`last 20 years. In the past, the patient was treated with the follow-
`ing drugs with little or no benefit: sulpiride, thioridazine, alprazo-
`lam, diazepam, clonidine, valproate, and clonazepam. Flunitrazepam
`and trihexyphenidyl produced some benefit, but the patient had two
`episodes of atrial fibrillation, which contraindicated anticholinergics,
`and flunitrazepam induced unacceptable sedation at the effective
`dose. The patient had had his symptoms since childhood. His parents
`reported that he had a difficult and prolonged delivery and had a
`“paretic upper limb” during childhood. Family history revealed that
`two aunts had been affected by “tics.”
`The patient’s neurologic examination did not show any abnor-
`malities besides the involuntary movements. There were no cogni-
`tive or major psychiatric disturbances. Results of blood tests were
`normal (including screening for Wilson’s disease and acanthocyte
`count). EEG, somatosensory evoked potentials, brainstem audi-
`tory evoked responses, and motor potentials evoked by transcra-
`nial magnetic brain stimulation were normal. Electromyography
`showed bursts with a duration of 80 to 300 msec in the affected
`muscles. CT and MRI of the brain were normal.
`The patient was treated with a progressively increasing dose of
`GHB (Alcover, Laboratorio Farmaceutico CT, Sanremo, Italy),
`starting from 1.575 g/day divided into four doses. At the dose of
`6.125 g/day, the patient had a consistent and substantial reduc-
`tion of involuntary movements (Chadwick–Marsden Scale score,
`8), which he referred to as comparable with the effect produced by
`alcohol but with no side effects. The patient reported a subjective
`average improvement of approximately 80%. Within 1 hour after
`each dose the involuntary movements disappeared almost com-
`pletely. Execution of daily activities, social relationships, sexual
`
`1706 NEUROLOGY 54 April (2 of 2) 2000
`
`Figure. (A) The patient’s signature before ␥-hydroxybutyric
`acid (GHB) treatment was unreadable. (B) The patient’s
`signature (only the first name for privacy) during GHB
`treatment is clearly readable.
`
`activity, and mood also improved. Writing was almost impossible
`before GHB treatment, but the patient was able to write quite
`clearly afterward (figure). After 4 months the therapeutic benefit
`is unchanged and there are no side effects.
`Discussion. Our patient had severe, disabling alcohol-sensitive
`myoclonus with dystonia, which responded very poorly to previous
`conventional treatments. Both conditions, however, were relieved
`markedly by GHB at a dose of 6.125 g/day. GHB is a drug that
`was introduced approximately 40 years ago, and in recent years
`has become widely used in the treatment of alcohol withdrawal
`and in maintaining abstinence from alcohol.2-4 Some of its actions
`probably involve changes at the level of dopaminergic pathways in
`the basal ganglia and, more importantly, are mediated by specific
`receptors in the brain.7 Although the drug is not devoid of side
`effects, and there are possible risks of overdose and abuse,3 GHB
`is safe and well tolerated when used properly for prolonged peri-
`ods. The efficacy of GHB in the management of alcohol depen-
`dence is probably due to the close similarity of the actions exerted
`by alcohol and GHB in the CNS.3 The neurochemical abnormali-
`ties of myoclonus associated with torsion dystonia are unclear, but
`the experience of our patient suggests that the GHB receptor
`might be involved specifically. In our patient, drugs acting on the
`GABAergic pathway produced a much smaller benefit.
`GHB should be tried in cases of severe myoclonus with dysto-
`nia, especially when the disorder is reported to be alcohol sensi-
`tive. This study prompts the assessment of this drug in other
`nonepileptic myoclonic and dystonic syndromes.
`Key words: Myoclonus—Dystonia—Alcohol-sensitive—Gamma-
`hydroxybutyric acid—Movement disorders.
`
`From the Istituto di Clinica Neurologica (Drs. Priori, Pesenti, Cappellari,
`and Barbieri), Universita` di Milano, IRCCS Ospedale Maggiore, Milan; the
`IRCCS Centro San Giovanni di Dio-Fatebenefratelli (Dr. Priori), Brescia;
`and the Clinica Neurologica (Dr. Bertolasi), Universita` di Verona, Poli-
`clinico Borgo Roma, Verona, Italy.
`Received November 17, 1999. Accepted in final form December 10, 1999.
`Address correspondence and reprint requests to Dr. Alberto Priori, Istituto di
`Clinica Neurologica, Universita` di Milano, IRCCS Ospedale Maggiore, Padigli-
`one Ponti, Via F. Sforza 35, Milan 20122, Italy; e-mail: alberto.priori@unimi.it
`
`Copyright © 2000 by the American Academy of Neurology
`
`References
`1. Quinn NP. Essential myoclonus and myoclonic dystonia. Mov Disord
`1996;11:119–124.
`2. Gallimberti L, Gentile N, Cibin M, et al. Gamma-hydroxybutyric acid for
`the treatment of alcohol withdrawal syndrome. Lancet 1989;2:787–789.
`3. Poldrugo F, Addolorato G. The role of ␥-hydroxybutyric acid in the treat-
`ment of alcoholism: from animal to clinical studies. Alcohol Alcohol 1999;
`34:15–24.
`4. Addolorato G, Cibin M, Caprista E, et al. Maintaining abstinence from
`alcohol with ␥-hydroxybutyric acid. Lancet 1998;351:38.
`5. Chadwick D, Hallett M, Harris R, et al. Clinical, biochemical and physi-
`ological factors distinguishing myoclonus responsive to 5-hydroxytryp-
`tophan, tryptophan with a monoamine oxydase inhibitor and clonaz-
`epam. Brain 1977;100:455–487.
`6. Marsden CD, Schachter M. Assessment of extrapyramidal disorders.
`Br J Clin Pharmacol 1981;11:129–151.
`7. Tunnicliff G. Sites of action of gamma-hydroxybutyrate (GHB)—a neuro-
`active drug with abuse potential. J Toxicol Clin Toxicol 1997;35:581–590.
`
`AMN1027
`IPR of Patent No. 8,772,306
`
`
`Center, Oklahoma City.
`Received October 8, 1999. Accepted in final form December 10, 1999.
`Address correspondence and reprint requests to Dr. Neil R. Holland, 711
`S.L. Young Boulevard, Suite 215, Oklahoma City, OK 73104-5021; e-mail:
`neil-holland@ouhsc.edu
`
`Copyright © 2000 by the American Academy of Neurology
`
`References
`1. Fiske DN, McCoy HE, Kitchens CS. Zinc-induced sideroblastic anemia.
`Report of a case, review of the literature and description of the hemato-
`logic syndrome. Am J Hematol 1994;46:147–150.
`2. Schiffer RB. Zinc and multiple sclerosis. Neurology 1994;44:1987–1988.
`3. Stein EC, Schiffer RB, Hall WJ, Young N. Multiple sclerosis and the
`workplace: report of an industry-based cluster. Neurology 1987;37:1672–
`1677.
`4. Hader WJ, Irvine DG, Schiefer HB. A cluster-focus of multiple sclerosis
`at Henribourg, Saskatchewan. Can J Neurol Sci 1990;17:391–394.
`5. Irvine DG, Schiefer HB, Hader WJ. Geotoxicology of multiple sclerosis:
`the Henribourg, Saskatchewan, cluster focus. I. The water. Sci Total
`Environ 1989;84:45–59.
`6. Irvine DG, Schiefer HB, Hader WJ. Geotoxicology of multiple sclerosis:
`the Henribourg, Saskatchewan, cluster focus. II. The soil. Sci Total En-
`viron 1988;77:175–188.
`
`␥-Hydroxybutyric acid for alcohol-sensitive
`myoclonus with dystonia
`A. Priori, MD, PhD; L. Bertolasi, MD; A. Pesenti, MD;
`A. Cappellari, MD; and S. Barbieri, MD, PhD
`
`Alcohol-sensitive myoclonus can be associated with dystonic
`spasms.1 Conventional treatments and anticonvulsants occasionally
`produce some benefit, but not comparable with the improvement
`induced by alcohol.1 We report a patient with alcohol-sensitive myoc-
`lonus and dystonia who had a consistent and substantial benefit
`from oral ␥-hydroxybutyric acid (GHB). Oral GHB is a drug that is
`effective both in the treatment of alcohol withdrawal2,3 and in main-
`taining abstinence from alcohol.4
`Case report. A 37-year-old man was evaluated for severe dis-
`abling myoclonic jerks of the upper limbs, axial muscles, neck and
`cranial muscles, which were associated with dystonic spasms
`of the upper limbs and of the neck muscles. According to the
`Chadwick–Marsden Evaluation Scale for myoclonus,5,6 the pa-
`tient’s score was 26 points. The hyperkinesias were not stimulus
`sensitive. They worsened under emotional stress and during the
`day, but the patient could control involuntary movements almost
`completely for a few hours after consumption of more than one
`liter of beer. The patient’s clinical picture has been stable for the
`last 20 years. In the past, the patient was treated with the follow-
`ing drugs with little or no benefit: sulpiride, thioridazine, alprazo-
`lam, diazepam, clonidine, valproate, and clonazepam. Flunitrazepam
`and trihexyphenidyl produced some benefit, but the patient had two
`episodes of atrial fibrillation, which contraindicated anticholinergics,
`and flunitrazepam induced unacceptable sedation at the effective
`dose. The patient had had his symptoms since childhood. His parents
`reported that he had a difficult and prolonged delivery and had a
`“paretic upper limb” during childhood. Family history revealed that
`two aunts had been affected by “tics.”
`The patient’s neurologic examination did not show any abnor-
`malities besides the involuntary movements. There were no cogni-
`tive or major psychiatric disturbances. Results of blood tests were
`normal (including screening for Wilson’s disease and acanthocyte
`count). EEG, somatosensory evoked potentials, brainstem audi-
`tory evoked responses, and motor potentials evoked by transcra-
`nial magnetic brain stimulation were normal. Electromyography
`showed bursts with a duration of 80 to 300 msec in the affected
`muscles. CT and MRI of the brain were normal.
`The patient was treated with a progressively increasing dose of
`GHB (Alcover, Laboratorio Farmaceutico CT, Sanremo, Italy),
`starting from 1.575 g/day divided into four doses. At the dose of
`6.125 g/day, the patient had a consistent and substantial reduc-
`tion of involuntary movements (Chadwick–Marsden Scale score,
`8), which he referred to as comparable with the effect produced by
`alcohol but with no side effects. The patient reported a subjective
`average improvement of approximately 80%. Within 1 hour after
`each dose the involuntary movements disappeared almost com-
`pletely. Execution of daily activities, social relationships, sexual
`
`1706 NEUROLOGY 54 April (2 of 2) 2000
`
`Figure. (A) The patient’s signature before ␥-hydroxybutyric
`acid (GHB) treatment was unreadable. (B) The patient’s
`signature (only the first name for privacy) during GHB
`treatment is clearly readable.
`
`activity, and mood also improved. Writing was almost impossible
`before GHB treatment, but the patient was able to write quite
`clearly afterward (figure). After 4 months the therapeutic benefit
`is unchanged and there are no side effects.
`Discussion. Our patient had severe, disabling alcohol-sensitive
`myoclonus with dystonia, which responded very poorly to previous
`conventional treatments. Both conditions, however, were relieved
`markedly by GHB at a dose of 6.125 g/day. GHB is a drug that
`was introduced approximately 40 years ago, and in recent years
`has become widely used in the treatment of alcohol withdrawal
`and in maintaining abstinence from alcohol.2-4 Some of its actions
`probably involve changes at the level of dopaminergic pathways in
`the basal ganglia and, more importantly, are mediated by specific
`receptors in the brain.7 Although the drug is not devoid of side
`effects, and there are possible risks of overdose and abuse,3 GHB
`is safe and well tolerated when used properly for prolonged peri-
`ods. The efficacy of GHB in the management of alcohol depen-
`dence is probably due to the close similarity of the actions exerted
`by alcohol and GHB in the CNS.3 The neurochemical abnormali-
`ties of myoclonus associated with torsion dystonia are unclear, but
`the experience of our patient suggests that the GHB receptor
`might be involved specifically. In our patient, drugs acting on the
`GABAergic pathway produced a much smaller benefit.
`GHB should be tried in cases of severe myoclonus with dysto-
`nia, especially when the disorder is reported to be alcohol sensi-
`tive. This study prompts the assessment of this drug in other
`nonepileptic myoclonic and dystonic syndromes.
`Key words: Myoclonus—Dystonia—Alcohol-sensitive—Gamma-
`hydroxybutyric acid—Movement disorders.
`
`From the Istituto di Clinica Neurologica (Drs. Priori, Pesenti, Cappellari,
`and Barbieri), Universita` di Milano, IRCCS Ospedale Maggiore, Milan; the
`IRCCS Centro San Giovanni di Dio-Fatebenefratelli (Dr. Priori), Brescia;
`and the Clinica Neurologica (Dr. Bertolasi), Universita` di Verona, Poli-
`clinico Borgo Roma, Verona, Italy.
`Received November 17, 1999. Accepted in final form December 10, 1999.
`Address correspondence and reprint requests to Dr. Alberto Priori, Istituto di
`Clinica Neurologica, Universita` di Milano, IRCCS Ospedale Maggiore, Padigli-
`one Ponti, Via F. Sforza 35, Milan 20122, Italy; e-mail: alberto.priori@unimi.it
`
`Copyright © 2000 by the American Academy of Neurology
`
`References
`1. Quinn NP. Essential myoclonus and myoclonic dystonia. Mov Disord
`1996;11:119–124.
`2. Gallimberti L, Gentile N, Cibin M, et al. Gamma-hydroxybutyric acid for
`the treatment of alcohol withdrawal syndrome. Lancet 1989;2:787–789.
`3. Poldrugo F, Addolorato G. The role of ␥-hydroxybutyric acid in the treat-
`ment of alcoholism: from animal to clinical studies. Alcohol Alcohol 1999;
`34:15–24.
`4. Addolorato G, Cibin M, Caprista E, et al. Maintaining abstinence from
`alcohol with ␥-hydroxybutyric acid. Lancet 1998;351:38.
`5. Chadwick D, Hallett M, Harris R, et al. Clinical, biochemical and physi-
`ological factors distinguishing myoclonus responsive to 5-hydroxytryp-
`tophan, tryptophan with a monoamine oxydase inhibitor and clonaz-
`epam. Brain 1977;100:455–487.
`6. Marsden CD, Schachter M. Assessment of extrapyramidal disorders.
`Br J Clin Pharmacol 1981;11:129–151.
`7. Tunnicliff G. Sites of action of gamma-hydroxybutyrate (GHB)—a neuro-
`active drug with abuse potential. J Toxicol Clin Toxicol 1997;35:581–590.
`
`AMN1027
`IPR of Patent No. 8,772,306
`
`
`
`γ
`-Hydroxybutyric acid for alcohol-sensitive myoclonus with dystonia
`A. Priori, L. Bertolasi, A. Pesenti, et al.
`Neurology
`2000;54;1706
`DOI 10.1212/WNL.54.8.1706
`
`This information is current as of April 25, 2000
`
`Updated Information &
`Services
`
`including high resolution figures, can be found at:
`http://www.neurology.org/content/54/8/1706.full.html
`
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`Neurology
`® is the official journal of the American Academy of Neurology. Published continuously since
`1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878.
`Online ISSN: 1526-632X.
`
`AMN1027
`IPR of Patent No. 8,772,306
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