410
The value of the EAE model for MS remains controversial.8 Our observation of a case of MS which developed under long-term sulfasalazine treatment offers no proof for the inefficacy of this drug but may contribute to more realistic expectations. Max Planck Society Clinical Research Unit for Multiple Sclerosis, and Department of Neuroradiology. University of Wurzburg, D-8700 Wurzburg, West Germany
1.
RALF GOLD LUDWIG KAPPOS THOMAS BECKER
Prosiegel M, Neu I, Mallinger J, et al. Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition. Acta
Neurol Scand 1989; 79: 223-26. Prosiegel M, Neu I, Ruhenstroth-Bauer G, et al. Suppression of experimental autoimmune encephalomyelitis by sulfasalazine. N Engl JMed 1989; 321: 545-16. 3. Heun R, Kappos L, Bittkau S, et al. Magnetic resonance imaging and early diagnosis of multiple sclerosis. Lancet 1988; ii: 1202-03. 4. Miller DH, Ormerod IEC, Rudge P, et al. The early risk of MS following isolated acute syndromes of the brainstem and spinal cord. Arm Neurol 1989; 26: 635-39. 5. Minuk GY, Lewkonia RM. Possible familial association of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1986; 314: 586. 6. Rang EH, Brooke BN, Hennon-Taylor J. Association of ulcerative colitis and multiple sclerosis. Lancet 1982; ii: 555. 7. Sadovnick AD, Paty DW, Yannakoulias G. Concurrence of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1989; 321: 762-63. 8. Amason BGW. Relevance of EAE to multiple sclerosis. Neurol Clin 1983; 1: 765-81.
2.
Copper-induced dystonia secondary to cholestatic liver disease StR,—The accumulation of copper in the liver has been demonstrated in several forms of cholestatic liver disease, and in some patients copper deposition in the cornea (Kayser-Fleischer rings) has been reported.1,2 However, neurological damage due to copper deposition has been described in only one patient.3 This young girl had cholestasis from birth, with unusually rapid progression of her liver disease resulting in severe hepatic copper retention and dystonic brain damage. Her parents refused penicillamine treatment and she died at 5 years. The basal ganglion contained 286 Jlgjg dry weight of copper. I describe here a second patient with cholestatic liver disease, massive accumulation of copper in the liver, and severe dystonia. Her neurological disability worsened when penicillamine was administered but she responded to ammonium tetrathiomolybdate and zinc sulphate. The patient was 19 when referred by a neurologist who wondered if her progressive muscle weakness and dystonia might be related to her history of prolonged cholestatic jaundice, for which I had treated her from age 19 months to 13 years. She had had pale stools, jaundice, and itching at the age of 11 months, and the itching and jaundice had persisted until puberty. Her liver was enlarged throughout childhood, but there was never significant splenomegaly. Liver biopsies revealed progressive portal fibrosis with some disruption of lobular pattern up to age 13. The facies was not typical of the Alagille syndrome. She never had xanthomas, but her serum cholesterol was very high (12-15 mmol/1). At age 9 years her liver contained 3500 ug copper/g dry weight and she was treated with penicillamine, hepatic copper being 2119 Jlgj g at 11 years and 2502 Jlgjg at 14 years. At 13 years, her care had been transferred to another hospital and her parents decided to stop penicillamine despite biopsy evidence of gross copper retention. She had difficulty in walking at age 161and muscle biopsy at 17 years revealed fibre damage. When she was seen at 19 years her leg movements were grossly dystonic with muscle spasms but no
involuntary writhing movements. She was dependent upon a wheelchair for mobility. There was no jaundice and no clinical indications of liver disease. Because it seemed likely that her neurological disease was caused by copper damage to the basal ganglia pencillamine was started at a dose of lg daily but over the next 3 days she deteriorated, with dystonia in her arms and worsening dystonia in her legs. Penicillamine was replaced by ammonium tetrathiomolybdate (25 mg thrice daily) and zinc sulphate (220 mg [50 mg zinc] thrice daily). Over the next 2 weeks she improved, and got steadily better over the next 18 months before a stationary phase was reached. She has returned to work as a typist and computer operator. Dystonia and abnormal posture in
her right leg with hyperextension of her knee and plantarflexion of right foot persist. Liver biopsy was deferred but even after 3 months of treatment the copper content was 4330 )ig/g. After 15 months, however, it had fallen to 176 )ig/g. The tetrathiomolybdate dose had been reduced to 25 mg twice daily after 6 months, then 25 mg daily. She is now on zinc sulphate only. The highest serum molybdenum level recorded was 3 Eunol/1 and copper levels and blood cell counts were always normal In both patients,3cholestatic disease had been present from an early age and accumulation of copper in the liver was recognised early in the disease. The age of onset and severity of cholestasis is incompatible with Wilson’s disease. In both patients, penicillamine seemed to be controlling the copper accumulation but the treatment was discontinued. I hope that this report will prompt others to look for copper accumulation in young patients with cholestatic liver disease. Acute worsening of neurological symptoms after start of penicillamine therapy, though uncommon, is well described,4 and mobilisation of copper from the liver may be the mechanism. In the above patient tetrathiomolybdate was probably responsible for most of the improvement in neurological function and reduction in liver copper. This is a very potent decoppering agent,5,6 and a valuable addition to the drugs available for Wilson’s disease with severe neurological symptoms. Prolonged use should be monitored very carefully because bone marrow toxicity has been described;7 indeed, we have chosen to continue the long-term treatment with zinc alone. The role of zinc in the recovery cannot be dismissed, and a synergistic action of the two agents is very possible. Zinc blocks copper absorption by inducing high levels of metallothionein in the intestinal mucosa.9 Tetrathiomolybdate complexes copper in the intestinal lumen, and in plasma and tissues also. Dr Arnold Smith assisted in the early management of the patient; Dr Les Sedal recognised the possible connection between the neurological and liver disease; Ms Hayley Vogel did the trace element assays; and Dr Jeff Gawthome provided the ammonium tetrathiomolybdate. Murdoch Institute. Royal Children’s Hospital, Melbourne, Victoria 3052, Australia
D. M. DANKS
Kaplinsky C, Sternlieb I, Javitt N, Rotem Y. Familial cholestatic cirrhosis associated with Kayser-Fleischer rings. Pediatrics 1980; 65: 782-88. 2. Fleming CR, Dickson ER, Wahner HW, Hollenhorst RW, McCall JT. Pigmented corneal rings in non-Wilsonian liver disease. Ann Intern Med 1977; 86: 285-288. 3. Smith AL, Danks DM. Secondary copper accumulation with neurological damage in children with chronic liver disease. Br Med J 1978; ii: 1400-01. 4. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol 1987; 1.
44: 490-93.
SR, Howell JMcC, Gawthorne JM. Intravenous administration of thiomolybdate for the prevention and treatment of chronic copper poisoning in sheep. Br J Nurr 1981; 46: 457-80. 6. Mason J, McQuaid A, Pheiffer H. Can Wilson’s disease patients be decoppered? Lancet 1989; i: 1455. 7. Harper PL, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate. Br J Haematol 1986; 64: 851-53. 8. Hoogenraad TU, Van den Hamer CJA, Van Hattum J. Effective treatment of Wilson’s disease with oral zinc sulphate: two case reports. Br Med J 1984; 289:
5. Gooneratne
273-76. 9. Brewer GJ, Yuzbasiyan-Gurkan V, Lee DY. Copper balance, regulation and molecular genetics of its impairment. In: Proceedings of second meeting of International Society for Trace Element Research in Humans. New York: Alan R Liss (in press).
Pathogenesis of acute Kawasaki disease SiR,—Dr Leung and colleagues (Dec 2, p 1298) postulate
a
sequence of
cytokine-induced endothelial cell activation followed by endothelial cell damage by circulating anti-endothelial cell antibodies in Kawasaki disease.
They speculate on the factors leading to excess cytokine production by blood mononuclear cells. We have previously documented the presence of anti-neutrophil cytoplasm autoantibodies (ANCA) in ten of eleven children with Kawasaki disease.1 ANCA are found in the sera of patients with systemic vasculitides such as Wegener’s granulomatosis and microscopic polyarteritis, and they bind to cytoplasmic targets in monocytes as well as
The value of the EAE model for MS remains controversial.8 Our observation of a case of MS which developed under long-term sulfasalazine treatment offers no proof for the inefficacy of this drug but may contribute to more realistic expectations. Max Planck Society Clinical Research Unit for Multiple Sclerosis, and Department of Neuroradiology. University of Wurzburg, D-8700 Wurzburg, West Germany
1.
RALF GOLD LUDWIG KAPPOS THOMAS BECKER
Prosiegel M, Neu I, Mallinger J, et al. Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition. Acta
Neurol Scand 1989; 79: 223-26. Prosiegel M, Neu I, Ruhenstroth-Bauer G, et al. Suppression of experimental autoimmune encephalomyelitis by sulfasalazine. N Engl JMed 1989; 321: 545-16. 3. Heun R, Kappos L, Bittkau S, et al. Magnetic resonance imaging and early diagnosis of multiple sclerosis. Lancet 1988; ii: 1202-03. 4. Miller DH, Ormerod IEC, Rudge P, et al. The early risk of MS following isolated acute syndromes of the brainstem and spinal cord. Arm Neurol 1989; 26: 635-39. 5. Minuk GY, Lewkonia RM. Possible familial association of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1986; 314: 586. 6. Rang EH, Brooke BN, Hennon-Taylor J. Association of ulcerative colitis and multiple sclerosis. Lancet 1982; ii: 555. 7. Sadovnick AD, Paty DW, Yannakoulias G. Concurrence of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1989; 321: 762-63. 8. Amason BGW. Relevance of EAE to multiple sclerosis. Neurol Clin 1983; 1: 765-81.
2.
Copper-induced dystonia secondary to cholestatic liver disease StR,—The accumulation of copper in the liver has been demonstrated in several forms of cholestatic liver disease, and in some patients copper deposition in the cornea (Kayser-Fleischer rings) has been reported.1,2 However, neurological damage due to copper deposition has been described in only one patient.3 This young girl had cholestasis from birth, with unusually rapid progression of her liver disease resulting in severe hepatic copper retention and dystonic brain damage. Her parents refused penicillamine treatment and she died at 5 years. The basal ganglion contained 286 Jlgjg dry weight of copper. I describe here a second patient with cholestatic liver disease, massive accumulation of copper in the liver, and severe dystonia. Her neurological disability worsened when penicillamine was administered but she responded to ammonium tetrathiomolybdate and zinc sulphate. The patient was 19 when referred by a neurologist who wondered if her progressive muscle weakness and dystonia might be related to her history of prolonged cholestatic jaundice, for which I had treated her from age 19 months to 13 years. She had had pale stools, jaundice, and itching at the age of 11 months, and the itching and jaundice had persisted until puberty. Her liver was enlarged throughout childhood, but there was never significant splenomegaly. Liver biopsies revealed progressive portal fibrosis with some disruption of lobular pattern up to age 13. The facies was not typical of the Alagille syndrome. She never had xanthomas, but her serum cholesterol was very high (12-15 mmol/1). At age 9 years her liver contained 3500 ug copper/g dry weight and she was treated with penicillamine, hepatic copper being 2119 Jlgj g at 11 years and 2502 Jlgjg at 14 years. At 13 years, her care had been transferred to another hospital and her parents decided to stop penicillamine despite biopsy evidence of gross copper retention. She had difficulty in walking at age 161and muscle biopsy at 17 years revealed fibre damage. When she was seen at 19 years her leg movements were grossly dystonic with muscle spasms but no
involuntary writhing movements. She was dependent upon a wheelchair for mobility. There was no jaundice and no clinical indications of liver disease. Because it seemed likely that her neurological disease was caused by copper damage to the basal ganglia pencillamine was started at a dose of lg daily but over the next 3 days she deteriorated, with dystonia in her arms and worsening dystonia in her legs. Penicillamine was replaced by ammonium tetrathiomolybdate (25 mg thrice daily) and zinc sulphate (220 mg [50 mg zinc] thrice daily). Over the next 2 weeks she improved, and got steadily better over the next 18 months before a stationary phase was reached. She has returned to work as a typist and computer operator. Dystonia and abnormal posture in
her right leg with hyperextension of her knee and plantarflexion of right foot persist. Liver biopsy was deferred but even after 3 months of treatment the copper content was 4330 )ig/g. After 15 months, however, it had fallen to 176 )ig/g. The tetrathiomolybdate dose had been reduced to 25 mg twice daily after 6 months, then 25 mg daily. She is now on zinc sulphate only. The highest serum molybdenum level recorded was 3 Eunol/1 and copper levels and blood cell counts were always normal In both patients,3cholestatic disease had been present from an early age and accumulation of copper in the liver was recognised early in the disease. The age of onset and severity of cholestasis is incompatible with Wilson’s disease. In both patients, penicillamine seemed to be controlling the copper accumulation but the treatment was discontinued. I hope that this report will prompt others to look for copper accumulation in young patients with cholestatic liver disease. Acute worsening of neurological symptoms after start of penicillamine therapy, though uncommon, is well described,4 and mobilisation of copper from the liver may be the mechanism. In the above patient tetrathiomolybdate was probably responsible for most of the improvement in neurological function and reduction in liver copper. This is a very potent decoppering agent,5,6 and a valuable addition to the drugs available for Wilson’s disease with severe neurological symptoms. Prolonged use should be monitored very carefully because bone marrow toxicity has been described;7 indeed, we have chosen to continue the long-term treatment with zinc alone. The role of zinc in the recovery cannot be dismissed, and a synergistic action of the two agents is very possible. Zinc blocks copper absorption by inducing high levels of metallothionein in the intestinal mucosa.9 Tetrathiomolybdate complexes copper in the intestinal lumen, and in plasma and tissues also. Dr Arnold Smith assisted in the early management of the patient; Dr Les Sedal recognised the possible connection between the neurological and liver disease; Ms Hayley Vogel did the trace element assays; and Dr Jeff Gawthome provided the ammonium tetrathiomolybdate. Murdoch Institute. Royal Children’s Hospital, Melbourne, Victoria 3052, Australia
D. M. DANKS
Kaplinsky C, Sternlieb I, Javitt N, Rotem Y. Familial cholestatic cirrhosis associated with Kayser-Fleischer rings. Pediatrics 1980; 65: 782-88. 2. Fleming CR, Dickson ER, Wahner HW, Hollenhorst RW, McCall JT. Pigmented corneal rings in non-Wilsonian liver disease. Ann Intern Med 1977; 86: 285-288. 3. Smith AL, Danks DM. Secondary copper accumulation with neurological damage in children with chronic liver disease. Br Med J 1978; ii: 1400-01. 4. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol 1987; 1.
44: 490-93.
SR, Howell JMcC, Gawthorne JM. Intravenous administration of thiomolybdate for the prevention and treatment of chronic copper poisoning in sheep. Br J Nurr 1981; 46: 457-80. 6. Mason J, McQuaid A, Pheiffer H. Can Wilson’s disease patients be decoppered? Lancet 1989; i: 1455. 7. Harper PL, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate. Br J Haematol 1986; 64: 851-53. 8. Hoogenraad TU, Van den Hamer CJA, Van Hattum J. Effective treatment of Wilson’s disease with oral zinc sulphate: two case reports. Br Med J 1984; 289:
5. Gooneratne
273-76. 9. Brewer GJ, Yuzbasiyan-Gurkan V, Lee DY. Copper balance, regulation and molecular genetics of its impairment. In: Proceedings of second meeting of International Society for Trace Element Research in Humans. New York: Alan R Liss (in press).
Pathogenesis of acute Kawasaki disease SiR,—Dr Leung and colleagues (Dec 2, p 1298) postulate
a
sequence of
cytokine-induced endothelial cell activation followed by endothelial cell damage by circulating anti-endothelial cell antibodies in Kawasaki disease.
They speculate on the factors leading to excess cytokine production by blood mononuclear cells. We have previously documented the presence of anti-neutrophil cytoplasm autoantibodies (ANCA) in ten of eleven children with Kawasaki disease.1 ANCA are found in the sera of patients with systemic vasculitides such as Wegener’s granulomatosis and microscopic polyarteritis, and they bind to cytoplasmic targets in monocytes as well as
