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Vigabatrin and behaviour disturbance
970
genital lesions
were in remission and the other lesions did not progress further. Sera collected since 1987 were repeatedly negative by enzyme immunoassay and western blot. A sample taken in 1989 was negative for p24 antigen. DNA from peripheral blood mononuclear cells was tested for specific HIV sequences by polymerase chain reaction (PCR), and this too excluded HIV infection in December, 1989, and February, 1990.6 months ago the interferon was stopped and no relapses have been observed. The patient’s immune status remains normal (T4/T8 ratio 2 to 1; T4 cells 498/µ1). We are aware of several additional reports of KS in HIVseronegative homosexual men.2-s Patients described were homosexual or bisexual with epidemic KS and a more benign form of disease limited to the skin and with a good prognosis. Our patient had visceral involvement but regression of cutaneous lesions was obtained with interferon. Evidence on the aetiology of
KS suggests a multifactorial cause, perhaps mainly involving one or infectious agents, probably sexually transmitted.6 We suggest that epidemic KS in HIV-uninfected patients has a more benign course (probably related to a norma. T4 cell number) and a better response to interferon.
more
We have previously recorded severe exacerbation of epilepsy with abrupt vigabatrin withdrawal,1,2 but are not aware of any report of psychosis following withdrawal. Exacerbation of seizures did not seem to be the mechanism involved. In our studies of vigabatrin1-4 drowsiness was the commonest behavioural side-effect. However, in view of the useful antiepileptic effect of the drug, we were surprised by the frequency of reversible depression. 8 of 33 patients had variable degrees of mood disturbance, in 3 of whom the drug had to be stopped. Most patients, however, had no change of mood or an improved mood associated with better seizure control. We believe the adverse effect on mood is a direct action of the drug since this effect is consistent with those of y-aminobutyric acid administration in healthy volunteers.5 The disagreement between our experience and that of Sander and Hart may be explained in part by differences in the study populations (including our exclusion of patients with a history of major psychiatric disorder), and by the higher doses of vigabatrin used at Chalfont-none of our patients received more than 3 g daily. Department of Neurology, Maudsley Hospital, London SE5 8AZ, UK
Department of Dermatology, Hospital Sant Pau, 08025 Barcelona, Spain, Infectious Diseases Unit, Hospital de Badalona "Germans Trias I Pujol", and Retrovirus Laboratory, National Institutes of Health, Bethesda, Maryland, USA
M. P. GARCÍA MURET V. SORIANO R. M. PUJOL I. HEWLETT B. CLOTET J. M. DE MORAGAS
1. Garcia Muret
MP, Pujol RM, Puig L, Moreno A, de Moragas JM. Disseminated Kaposi’s sarcoma not associated with HIV infection in a bisexual man. J Am Acad Dermatol (in press). 2. Afrasiabi R, Mitsuyasu RT, Nishanian P, et al. Characterization of a distinct subgroup of high-risk persons with Kaposi’s sarcoma and good prognosis who present with normal T4 cell number and T4.T8 ratio and negative HTLV-III/LAV serologic test results. Am J Med 1986; 81: 969-73 3. Marquart KH, Oehlschlaegel G, Engst R. Disseminated Kaposi’s sarcoma that is not associated with acquired immunodeficiency syndrome in a bisexual man. Arch Pathol Lab Med 1986; 110: 346-47. 4. Archer CB, Spittle MF, Smith NP. Kaposi’s sarcoma in a homosexual-10 years on Clin Exp Dermatol 1989; 14: 233-36. 5. Lowdell CP, Glasser MG. Long term survival of male homosexual patients with Kaposi’s sarcoma. J R Soc Med 1989; 82: 226-27. 6. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28.
Vigabatrin and behaviour disturbance SIR,-Dr Sander and Dr Hart (Jan 6, p 57) report 7 epileptic patients with psychotic reactions in 145 treated with vigabatrin and suggest that "forced normalisation" rather than a direct effect of the
drug may be the mechanism involved. Like Dr Dam (March 10, p 605) and Dr Betts and Dr Thomas (March 10, p 605) our experience has been rather different. In 60 patients treated with vigabatrin in the past three years, we have seen only 1 with psychosis-a 25-year-old man in whom the drug was inadvertently abruptly withdrawn. He had had intractable complex partial seizures (CPS) and occasional tonic clonic seizures since age 16. Predisposing factors were forceps delivery at birth and two febrile convulsions in infancy. He had a low average intelligence quotient, but his computed tomographic brain scan was normal. Electroencephalography (EEG) showed epileptiform discharges in the left temporal region. He had no past or family history of psychiatric disorder. Vigabatrin 3 g daily was added to his treatment (phenytoin 525 mg daily and sodium valproate 2-5 g daily, both with optimum blood levels). Seizure frequency and severity improved modestly such that he had one CPS about every ten days. After eight months on vigabatrin he discontinued this treatment when his supply ran out but remained on his standard medication. Two days later he had a single brief CPS and the following day he became acutely psychotic, presenting with agitation, persistent delusional beliefs, and visual hallucinations. The next day EEG did not show any epileptiform activity and he was restarted on vigabatrin together with chlorpromazine. Five days later his mental state had returned to
normal.
H. A. RING E. H. REYNOLDS
Reynolds EH, Ring H, Heller A A controlled trial of gamma-vinyl-GABA (vigabatrin) in drug resistant epilepsy Br J Clin Pract 1988, 42 (suppl 61). 33. 2. Ring HA, Heller AJ, Farr IN, Reynolds EH. Vigabatrin rational treatment for chronic epilepsy J Neurol Neurosurg Psychiatry (in press). 3. Birbeck KA, Ossetin J, Ring HA, et al. Vigabatnn and mood (18th Epilepsy International Congress, New Delhi, October, 1989). 4. Reynolds EH. Vigabatrin: rational treatment for chronic epilepsy Br Med J 1990; 300: 1.
277-78
5. Numberger JI, Berrettini WH, Simmons-Alling S, et al. Intravenous GABA administration is anxiogenic in man Psychiat Res 1986; 19: 113-17.
Agranulocytosis and thrombocytopenia, Blackfan-Diamond anaemia, and oral chelation SIR,-Hoffbrand et all reported on a 28-year-old woman with Blackfan-Diamond anaemia who had significant agranulocytosis and thrombocytopenia while receiving the oral chelator Ll. They state that "immune disturbances, including thrombocytopenia and neutropenia, have been described in the Blackfan-Diamond syndrome"1 and that "Blackfan-Diamond anaemia is a condition in which neutropenia is well recognised".’ / I would like to set the record straight on cytopenia in Blackfan-Diamond anaemia, which is a presumably inherited form of pure red cell aplasia. A review of 400 published cases shows that total white cell counts of less than 3000/ul were reported in only 5% of cases. Clinically significant agranulocytosis was not reported.
Thrombocytopenia (below 150 000/u.I) was reported only transiently in 25%, again without clinical significance. There is no evidence that the transient leucopenia or thrombocytopenia in Blackfan-Diamond anaemia is on an "immune basis". The sudden acute depression of these blood counts is also not a feature of Blackfan-Diamond anaemia. The abrupt drop in cell counts in a patient on Ll should not be simply ascribed to a bone-marrow failure syndrome. Since decreased counts were noted in animals given Ll,3A and there is no proof that additional cytopenias regularly occur in BlackfanDiamond anaemia, the possibility of Ll causing occasional marrow suppression cannot be excluded. The use of new oral iron chelators such as L1 in patients requires thorough animal toxicity studies and great caution. Division of Hematology, Mt Sinai School of Medicine, New York, NY 10029, USA
B. P. ALTER
1 Hoffbrand
AV, Bartlett AN, Veys PA, O’Connor NTJ, Kontoghiorghes GJ Agranulocytosis and thrombocytopema in patient with Blackfan-Dia nond anaemia during oral chelator trial. Lancet 1989; ii: 457. 2. Kontoghiorghes GJ, Hoffbrand AV. Clinical trials with oral iron chelator L1. Lancet 1989, ii: 1516-17 3. Porter JB, Hoyes KP, Abeysinghe R, Huehns ER, Hider RC Animal toxicology of iron chelator L1. Lancet 1989, ii: 156-57. 4. Kontoghiorghes GJ, Nasseri-Sina P, Goddard JG, Barr JM, Nortey P, Sheppard LN. Safety of oral iron chelator L1. Lancet 1989; ii: 457-58
genital lesions
were in remission and the other lesions did not progress further. Sera collected since 1987 were repeatedly negative by enzyme immunoassay and western blot. A sample taken in 1989 was negative for p24 antigen. DNA from peripheral blood mononuclear cells was tested for specific HIV sequences by polymerase chain reaction (PCR), and this too excluded HIV infection in December, 1989, and February, 1990.6 months ago the interferon was stopped and no relapses have been observed. The patient’s immune status remains normal (T4/T8 ratio 2 to 1; T4 cells 498/µ1). We are aware of several additional reports of KS in HIVseronegative homosexual men.2-s Patients described were homosexual or bisexual with epidemic KS and a more benign form of disease limited to the skin and with a good prognosis. Our patient had visceral involvement but regression of cutaneous lesions was obtained with interferon. Evidence on the aetiology of
KS suggests a multifactorial cause, perhaps mainly involving one or infectious agents, probably sexually transmitted.6 We suggest that epidemic KS in HIV-uninfected patients has a more benign course (probably related to a norma. T4 cell number) and a better response to interferon.
more
We have previously recorded severe exacerbation of epilepsy with abrupt vigabatrin withdrawal,1,2 but are not aware of any report of psychosis following withdrawal. Exacerbation of seizures did not seem to be the mechanism involved. In our studies of vigabatrin1-4 drowsiness was the commonest behavioural side-effect. However, in view of the useful antiepileptic effect of the drug, we were surprised by the frequency of reversible depression. 8 of 33 patients had variable degrees of mood disturbance, in 3 of whom the drug had to be stopped. Most patients, however, had no change of mood or an improved mood associated with better seizure control. We believe the adverse effect on mood is a direct action of the drug since this effect is consistent with those of y-aminobutyric acid administration in healthy volunteers.5 The disagreement between our experience and that of Sander and Hart may be explained in part by differences in the study populations (including our exclusion of patients with a history of major psychiatric disorder), and by the higher doses of vigabatrin used at Chalfont-none of our patients received more than 3 g daily. Department of Neurology, Maudsley Hospital, London SE5 8AZ, UK
Department of Dermatology, Hospital Sant Pau, 08025 Barcelona, Spain, Infectious Diseases Unit, Hospital de Badalona "Germans Trias I Pujol", and Retrovirus Laboratory, National Institutes of Health, Bethesda, Maryland, USA
M. P. GARCÍA MURET V. SORIANO R. M. PUJOL I. HEWLETT B. CLOTET J. M. DE MORAGAS
1. Garcia Muret
MP, Pujol RM, Puig L, Moreno A, de Moragas JM. Disseminated Kaposi’s sarcoma not associated with HIV infection in a bisexual man. J Am Acad Dermatol (in press). 2. Afrasiabi R, Mitsuyasu RT, Nishanian P, et al. Characterization of a distinct subgroup of high-risk persons with Kaposi’s sarcoma and good prognosis who present with normal T4 cell number and T4.T8 ratio and negative HTLV-III/LAV serologic test results. Am J Med 1986; 81: 969-73 3. Marquart KH, Oehlschlaegel G, Engst R. Disseminated Kaposi’s sarcoma that is not associated with acquired immunodeficiency syndrome in a bisexual man. Arch Pathol Lab Med 1986; 110: 346-47. 4. Archer CB, Spittle MF, Smith NP. Kaposi’s sarcoma in a homosexual-10 years on Clin Exp Dermatol 1989; 14: 233-36. 5. Lowdell CP, Glasser MG. Long term survival of male homosexual patients with Kaposi’s sarcoma. J R Soc Med 1989; 82: 226-27. 6. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28.
Vigabatrin and behaviour disturbance SIR,-Dr Sander and Dr Hart (Jan 6, p 57) report 7 epileptic patients with psychotic reactions in 145 treated with vigabatrin and suggest that "forced normalisation" rather than a direct effect of the
drug may be the mechanism involved. Like Dr Dam (March 10, p 605) and Dr Betts and Dr Thomas (March 10, p 605) our experience has been rather different. In 60 patients treated with vigabatrin in the past three years, we have seen only 1 with psychosis-a 25-year-old man in whom the drug was inadvertently abruptly withdrawn. He had had intractable complex partial seizures (CPS) and occasional tonic clonic seizures since age 16. Predisposing factors were forceps delivery at birth and two febrile convulsions in infancy. He had a low average intelligence quotient, but his computed tomographic brain scan was normal. Electroencephalography (EEG) showed epileptiform discharges in the left temporal region. He had no past or family history of psychiatric disorder. Vigabatrin 3 g daily was added to his treatment (phenytoin 525 mg daily and sodium valproate 2-5 g daily, both with optimum blood levels). Seizure frequency and severity improved modestly such that he had one CPS about every ten days. After eight months on vigabatrin he discontinued this treatment when his supply ran out but remained on his standard medication. Two days later he had a single brief CPS and the following day he became acutely psychotic, presenting with agitation, persistent delusional beliefs, and visual hallucinations. The next day EEG did not show any epileptiform activity and he was restarted on vigabatrin together with chlorpromazine. Five days later his mental state had returned to
normal.
H. A. RING E. H. REYNOLDS
Reynolds EH, Ring H, Heller A A controlled trial of gamma-vinyl-GABA (vigabatrin) in drug resistant epilepsy Br J Clin Pract 1988, 42 (suppl 61). 33. 2. Ring HA, Heller AJ, Farr IN, Reynolds EH. Vigabatrin rational treatment for chronic epilepsy J Neurol Neurosurg Psychiatry (in press). 3. Birbeck KA, Ossetin J, Ring HA, et al. Vigabatnn and mood (18th Epilepsy International Congress, New Delhi, October, 1989). 4. Reynolds EH. Vigabatrin: rational treatment for chronic epilepsy Br Med J 1990; 300: 1.
277-78
5. Numberger JI, Berrettini WH, Simmons-Alling S, et al. Intravenous GABA administration is anxiogenic in man Psychiat Res 1986; 19: 113-17.
Agranulocytosis and thrombocytopenia, Blackfan-Diamond anaemia, and oral chelation SIR,-Hoffbrand et all reported on a 28-year-old woman with Blackfan-Diamond anaemia who had significant agranulocytosis and thrombocytopenia while receiving the oral chelator Ll. They state that "immune disturbances, including thrombocytopenia and neutropenia, have been described in the Blackfan-Diamond syndrome"1 and that "Blackfan-Diamond anaemia is a condition in which neutropenia is well recognised".’ / I would like to set the record straight on cytopenia in Blackfan-Diamond anaemia, which is a presumably inherited form of pure red cell aplasia. A review of 400 published cases shows that total white cell counts of less than 3000/ul were reported in only 5% of cases. Clinically significant agranulocytosis was not reported.
Thrombocytopenia (below 150 000/u.I) was reported only transiently in 25%, again without clinical significance. There is no evidence that the transient leucopenia or thrombocytopenia in Blackfan-Diamond anaemia is on an "immune basis". The sudden acute depression of these blood counts is also not a feature of Blackfan-Diamond anaemia. The abrupt drop in cell counts in a patient on Ll should not be simply ascribed to a bone-marrow failure syndrome. Since decreased counts were noted in animals given Ll,3A and there is no proof that additional cytopenias regularly occur in BlackfanDiamond anaemia, the possibility of Ll causing occasional marrow suppression cannot be excluded. The use of new oral iron chelators such as L1 in patients requires thorough animal toxicity studies and great caution. Division of Hematology, Mt Sinai School of Medicine, New York, NY 10029, USA
B. P. ALTER
1 Hoffbrand
AV, Bartlett AN, Veys PA, O’Connor NTJ, Kontoghiorghes GJ Agranulocytosis and thrombocytopema in patient with Blackfan-Dia nond anaemia during oral chelator trial. Lancet 1989; ii: 457. 2. Kontoghiorghes GJ, Hoffbrand AV. Clinical trials with oral iron chelator L1. Lancet 1989, ii: 1516-17 3. Porter JB, Hoyes KP, Abeysinghe R, Huehns ER, Hider RC Animal toxicology of iron chelator L1. Lancet 1989, ii: 156-57. 4. Kontoghiorghes GJ, Nasseri-Sina P, Goddard JG, Barr JM, Nortey P, Sheppard LN. Safety of oral iron chelator L1. Lancet 1989; ii: 457-58