1554
Long follow-up of tuberous sclerosis treated with vigabatrin SIR,—Epilepsy in patients with tuberous sclerosis appears to therapy, but there are reports of good response to vigabatrin, especially for infantile spasms.2,3 We report a case with long follow-up. A 2 year-old girl was initially admitted to our paediatric unit at age 4 months with daily infantile spasms. Electroencephalogram (EEC) during wakefulness and sleep showed generalised bursts of sharp waves and/or atypical spikeand-wave complexes. Computed tomography (CT), demonstrated a hyperdense lesion in the left temporal region, whereas magnetic resonsance imaging (MRI) appeared normal. Neurodevelopmental resistant
status showed a clear retardation of motor patterns and poor interactive behaviour. The patient received valproate 150 mg per day, which was discontinued after 4 months because she did not
respond (seizure frequency unchanged). At the age of 8 months, a second EEG showed bursts of and asymmetric spike-and-wave complexes; CT demonstrated three lesions in the left hemisphere. Positron emission tomography (PET) with fluorodeoxyglucose showed hypometabolic areas in the frontomesial cortex with a left prevalence and in the left parieto-occipital region. The unsatisfactory response to sodium valproate and the results of these investigations suggested the use of vigabatrin at a standard daily dose of 375 mg, which was progressively increased to 500 mg up to a final dose of 800 mg. After 2 months of therapy, seizures reduced to a single daily episode. Physiotherapy was started at the same time. Psychomotor evaluation showed spasticity of the limbs and good head control. The patient was able to follow moving objects, smiled on social contacts, and formed syllabic sounds but not words. After 5 months of vigabatrin, EEG showed multifocal, independent epileptic abnormalities in the left frontal and parietooccipital regions. The localisation of the interictal epileptic foci was the same as in the hypometabolic areas, as previously described. Psychomotor evaluation showed that the patient was able to sit up without support, to crawl, and to express polysyllabic sounds. Infantile spasms had disappeared, while short-duration absence attacks occurred daily. After 9 months of vigabatrin, the seizure frequency decreased to two per week, always as absence attacks. Although the patient was still on vigabatrin at the age of 24 months, MRI revealed an increase in number of lesions to six (three on each hemisphere). At the last psychomotor examination, the child walked with one hand held, even though limb spasticity persisted; she was able to partly feed herself; and she had good interactive
asynchronous
capacity (laugh, smile, talk). Our report details
20-month
follow-up, including clinical, neuroradiological, neuropsychological, and neurophysiological evaluation, of the effect of vigabatrin on epileptic seizures in tuberous sclerosis. Although epileptic manifestations and the psychomotor development improved, neuroimaging (MRI and PET) showed progressive deterioration of the cerebral lesions. a
Neurological and Paediatric Clinics, Universitá degli Studi di Roma "Tor 00173 Rome, Italy
Vergata",
M. G. MARCIANI G. L. GIGLI L. ORLANDI
1. Yamamoto N, Yatanabe K, Negoro T, et al. Long-term prognosis of tuberous sclerosis with epilepsy in children. Brain Dev 1987; 9: 292-95. 2. Luna D, Dulac O, Pajot N, Beaumont D. Vigabatnn m the tresatment of childhood epilepsies: a single-blind placebo-controlled study. Epilepsia 1989; 30: 430-37. 3. Chiron C, Dulac OD, Luna L, et al. Vigabatrin in infantile spasms. Lancet 1990; 335: 363-64.
disturbances and cytokine concentrations: cytokines would induce the synthesis of NO in the vascular wall of the brain circulation, which would then diffuse into the brain parenchyma and affect neurological function. We present experimental data that do not support this view. On infection with Plasmodium berghei ANKA, mice of susceptible strains, such as CBA/Ca, develop a neurological syndrome, which includes coma and seizures, and show high concentrations of circulating TNF.1 Such a syndrome is lethal in all untreated cases, but heals without sequelae in those which are successfully treated.2 The crucial part played by TNF in the pathogenesis of the syndrome has been doclunented.1,3,4 We investigated a possible pathogenetic role of NO in the cerebral complications of P berghei ANKA infection, by testing the effect of inhibiting NO synthesis on development. For the 9 days after infection with P berghei ANKA, ten CBA/Ca mice were injected intraperitoneally twice daily with 0-2 ml of normal saline, ten with 2 mg N-monomethyl-L-arginine (L-NMMA), and ten with 2 mg N-monomethyl-D-arginine (D-NMMA) dissolved in 0-2 ml normal saline. L-NMMA and D-NMMA are arginine analogues; L-NMMA inhibits NO synthase, the enzyme that produces NO from L-arginine, which is at variance with D-NMMA, which is inactive and was used as control reagent.5 The frequency of neurological syndrome did not differ significantly in the three groups of mice (Fisher’s exact test): 9 mice treated with normal saline and all mice treated with L-NMMA or D-NMMA showed cerebral complications. We conclude that NO has no role in the development of the neurological syndrome that complicates P berghei ANKA infection. Since this syndrome shows the same features that Clark and colleagues find in cerebral malaria and related conditions and postulate to be suggestive of a physiopathological role for NO, we believe that our data contradict their hypothesis. Furthermore, since plasmodial growth,1 leucocyte adhesion to vascular endothelium,2 and platelet aggregation (G.E.G., unpublished), which are all inhibited by nitric oxide,6-8 contribute to the development of this syndrome we believe that it is more likely that NO might have a protective rather than a damaging role in this condition. L-NMMA and D-NMMA were provided by Prof S. Moncada and Dr F. Y. Liew (Wellcome Research Laboratories, Beckenham, Kent), who also advised on the therapeutic regimen. WHO
Immunology Research and Training Centre, Department of Pathology, University of Geneva,
1211 Geneva, Switzerland, and Landesinstitut fur Tropenmedizin,
Berlin, Germany
GIORGIO SENALDI PETER G. KREMSNER GEORGES E. GRAU
1. Grau
GE, Piguet P-F, Vassalli P, Lambert P-H. Tumour necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev 1989;
112: 49-70. 2. Grau GE, Pointaire P, Piguet P-F, et al. Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria EurJ Immunol 1991; 21: 2265-67. 3. Grau GE, Fajardo LF, Piguet P-F, Allet B, Lambert P-H. Tumour necrosis factor/cachectin as an essential mediator in murine cerebral malaria. Science 1987; 237: 1210-12. 4. Kremsner PG, Grundmann H, Neifer S, et al. Pentoxifylline prevents murine cerebral Dis 1991; 164: 605-08. malaria. Infect J 5. McKenna T. Prolonged exposure of rat aorta to low levels of endotoxin in vitro results in impaired contractility. Association with cytokine release. J Clin Invest 1990; 86: 160-68. 6. Green SJ, Mellouk S, Hoffman SL, Meltzer MS, Nacy CA. Cellular mechanisms of
nonspecific immunity to intracellular infection; cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes. Immunol Lett
Nitric oxide and cerebral malaria
1990; 25: 15-19.
SIR,-Dr Clark and colleagues (Oct 10, p 894) draw attention to features shared by cerebral malaria, heat stroke, postoperative transitory syndrome, and the neurological syndrome that may develop as a result of treatment with tumour necrosis factor (TNF) or interleukin-2 (IL-2). Some features (mental disturbances such as coma and seizures, and high concentrations of circulating proinflammatory cytokines such as TNF and IL-1) are reversible in non-fatal cases; but, cerebral malaria, for example, is invariably lethal if untreated. Clark and colleagues postulate that nitric oxide (NO) represents the physiopathological link between mental
Furlong B, Henderson AH, Lewis MJ, Smith JA. Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol 1987; 90: 687-92. 8. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leucocyte adhesion. Proc Natl Acad Sci USA 1991; 88: 4651-55. 7.
CORRECTION Protective efficacy ofserogroup B meningococcal vaccine in Sao Paulo, Brazil.-In this article by Dr Cassio de Moraes and colleagues (Oct 31, p 1074), the name of the seventh author should have been Ilka M. Landgraf.
Long follow-up of tuberous sclerosis treated with vigabatrin SIR,—Epilepsy in patients with tuberous sclerosis appears to therapy, but there are reports of good response to vigabatrin, especially for infantile spasms.2,3 We report a case with long follow-up. A 2 year-old girl was initially admitted to our paediatric unit at age 4 months with daily infantile spasms. Electroencephalogram (EEC) during wakefulness and sleep showed generalised bursts of sharp waves and/or atypical spikeand-wave complexes. Computed tomography (CT), demonstrated a hyperdense lesion in the left temporal region, whereas magnetic resonsance imaging (MRI) appeared normal. Neurodevelopmental resistant
status showed a clear retardation of motor patterns and poor interactive behaviour. The patient received valproate 150 mg per day, which was discontinued after 4 months because she did not
respond (seizure frequency unchanged). At the age of 8 months, a second EEG showed bursts of and asymmetric spike-and-wave complexes; CT demonstrated three lesions in the left hemisphere. Positron emission tomography (PET) with fluorodeoxyglucose showed hypometabolic areas in the frontomesial cortex with a left prevalence and in the left parieto-occipital region. The unsatisfactory response to sodium valproate and the results of these investigations suggested the use of vigabatrin at a standard daily dose of 375 mg, which was progressively increased to 500 mg up to a final dose of 800 mg. After 2 months of therapy, seizures reduced to a single daily episode. Physiotherapy was started at the same time. Psychomotor evaluation showed spasticity of the limbs and good head control. The patient was able to follow moving objects, smiled on social contacts, and formed syllabic sounds but not words. After 5 months of vigabatrin, EEG showed multifocal, independent epileptic abnormalities in the left frontal and parietooccipital regions. The localisation of the interictal epileptic foci was the same as in the hypometabolic areas, as previously described. Psychomotor evaluation showed that the patient was able to sit up without support, to crawl, and to express polysyllabic sounds. Infantile spasms had disappeared, while short-duration absence attacks occurred daily. After 9 months of vigabatrin, the seizure frequency decreased to two per week, always as absence attacks. Although the patient was still on vigabatrin at the age of 24 months, MRI revealed an increase in number of lesions to six (three on each hemisphere). At the last psychomotor examination, the child walked with one hand held, even though limb spasticity persisted; she was able to partly feed herself; and she had good interactive
asynchronous
capacity (laugh, smile, talk). Our report details
20-month
follow-up, including clinical, neuroradiological, neuropsychological, and neurophysiological evaluation, of the effect of vigabatrin on epileptic seizures in tuberous sclerosis. Although epileptic manifestations and the psychomotor development improved, neuroimaging (MRI and PET) showed progressive deterioration of the cerebral lesions. a
Neurological and Paediatric Clinics, Universitá degli Studi di Roma "Tor 00173 Rome, Italy
Vergata",
M. G. MARCIANI G. L. GIGLI L. ORLANDI
1. Yamamoto N, Yatanabe K, Negoro T, et al. Long-term prognosis of tuberous sclerosis with epilepsy in children. Brain Dev 1987; 9: 292-95. 2. Luna D, Dulac O, Pajot N, Beaumont D. Vigabatnn m the tresatment of childhood epilepsies: a single-blind placebo-controlled study. Epilepsia 1989; 30: 430-37. 3. Chiron C, Dulac OD, Luna L, et al. Vigabatrin in infantile spasms. Lancet 1990; 335: 363-64.
disturbances and cytokine concentrations: cytokines would induce the synthesis of NO in the vascular wall of the brain circulation, which would then diffuse into the brain parenchyma and affect neurological function. We present experimental data that do not support this view. On infection with Plasmodium berghei ANKA, mice of susceptible strains, such as CBA/Ca, develop a neurological syndrome, which includes coma and seizures, and show high concentrations of circulating TNF.1 Such a syndrome is lethal in all untreated cases, but heals without sequelae in those which are successfully treated.2 The crucial part played by TNF in the pathogenesis of the syndrome has been doclunented.1,3,4 We investigated a possible pathogenetic role of NO in the cerebral complications of P berghei ANKA infection, by testing the effect of inhibiting NO synthesis on development. For the 9 days after infection with P berghei ANKA, ten CBA/Ca mice were injected intraperitoneally twice daily with 0-2 ml of normal saline, ten with 2 mg N-monomethyl-L-arginine (L-NMMA), and ten with 2 mg N-monomethyl-D-arginine (D-NMMA) dissolved in 0-2 ml normal saline. L-NMMA and D-NMMA are arginine analogues; L-NMMA inhibits NO synthase, the enzyme that produces NO from L-arginine, which is at variance with D-NMMA, which is inactive and was used as control reagent.5 The frequency of neurological syndrome did not differ significantly in the three groups of mice (Fisher’s exact test): 9 mice treated with normal saline and all mice treated with L-NMMA or D-NMMA showed cerebral complications. We conclude that NO has no role in the development of the neurological syndrome that complicates P berghei ANKA infection. Since this syndrome shows the same features that Clark and colleagues find in cerebral malaria and related conditions and postulate to be suggestive of a physiopathological role for NO, we believe that our data contradict their hypothesis. Furthermore, since plasmodial growth,1 leucocyte adhesion to vascular endothelium,2 and platelet aggregation (G.E.G., unpublished), which are all inhibited by nitric oxide,6-8 contribute to the development of this syndrome we believe that it is more likely that NO might have a protective rather than a damaging role in this condition. L-NMMA and D-NMMA were provided by Prof S. Moncada and Dr F. Y. Liew (Wellcome Research Laboratories, Beckenham, Kent), who also advised on the therapeutic regimen. WHO
Immunology Research and Training Centre, Department of Pathology, University of Geneva,
1211 Geneva, Switzerland, and Landesinstitut fur Tropenmedizin,
Berlin, Germany
GIORGIO SENALDI PETER G. KREMSNER GEORGES E. GRAU
1. Grau
GE, Piguet P-F, Vassalli P, Lambert P-H. Tumour necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev 1989;
112: 49-70. 2. Grau GE, Pointaire P, Piguet P-F, et al. Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria EurJ Immunol 1991; 21: 2265-67. 3. Grau GE, Fajardo LF, Piguet P-F, Allet B, Lambert P-H. Tumour necrosis factor/cachectin as an essential mediator in murine cerebral malaria. Science 1987; 237: 1210-12. 4. Kremsner PG, Grundmann H, Neifer S, et al. Pentoxifylline prevents murine cerebral Dis 1991; 164: 605-08. malaria. Infect J 5. McKenna T. Prolonged exposure of rat aorta to low levels of endotoxin in vitro results in impaired contractility. Association with cytokine release. J Clin Invest 1990; 86: 160-68. 6. Green SJ, Mellouk S, Hoffman SL, Meltzer MS, Nacy CA. Cellular mechanisms of
nonspecific immunity to intracellular infection; cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes. Immunol Lett
Nitric oxide and cerebral malaria
1990; 25: 15-19.
SIR,-Dr Clark and colleagues (Oct 10, p 894) draw attention to features shared by cerebral malaria, heat stroke, postoperative transitory syndrome, and the neurological syndrome that may develop as a result of treatment with tumour necrosis factor (TNF) or interleukin-2 (IL-2). Some features (mental disturbances such as coma and seizures, and high concentrations of circulating proinflammatory cytokines such as TNF and IL-1) are reversible in non-fatal cases; but, cerebral malaria, for example, is invariably lethal if untreated. Clark and colleagues postulate that nitric oxide (NO) represents the physiopathological link between mental
Furlong B, Henderson AH, Lewis MJ, Smith JA. Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol 1987; 90: 687-92. 8. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leucocyte adhesion. Proc Natl Acad Sci USA 1991; 88: 4651-55. 7.
CORRECTION Protective efficacy ofserogroup B meningococcal vaccine in Sao Paulo, Brazil.-In this article by Dr Cassio de Moraes and colleagues (Oct 31, p 1074), the name of the seventh author should have been Ilka M. Landgraf.
