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Adrenocorticotropic hormone and vigabatrin treatment of children with infantile spasms underlying cerebral palsy
ELSEVIER
Brain & Development
Q
1996; 18: 450-452
Communication
Adrenocorticotropic hormone and vigabatrin treatment of children with infantile spasms underlying cerebral palsy Dimitrios I. Zafeiriou
*, Eleutherios
E. Kontopoulos,
Ioannis G. Tsikoulas
1stPediatric Clinic, Aristotle Uniuersity of Thessaloniki, Egnatia Str. 106, 54622 Thessaloniki. Greece Received
11 February
1996; accepted 31 May 1996
Nine infants with an underlying static encephalopathy (confirmed as cerebral palsy in a later follow-up examination) and newly diagnosed infantile spasms were entered in an open study with adrenocorticotropic hormone (ACTH) and vigabatrin as the initial therapy regimen. The ACTH was discontinued after 4-6 weeks and the infants were maintained on vigabatrin alone. Following an initial response with complete suppression of spasms in all patients, a long term response maintained for a mean of 19.2 months was confirmed in all but one child. Tolerability appeared excellent with 7 of 9 patients reporting no side effects; vigabatrin related hypotonia presented in all patients and turned out to be a ‘positive’ side-effect on the abnormally increased muscle tone of these infants. Given the very poor prognosis of infantile spasms especially in such conditions as cerebral palsy, the combination of ACTH and vigabatrin appears to be an interesting therapy advance with very few side effects. Keywords:
Vigabatrin;
Adrenocorticotropic
hormone:
Infantile spasm: West syndrome;
Static encephalopathy;
Cerebral palsy
1. INTRODUCTION
2. PATIENTS
Infantile spasms usually start during the first year of life and constitute one of the most difficult types of epilepsy to treat [l]. They carry a very poor prognosis for both epilepsy and mental development, especially in those infants underlying a static encephalopathy, such as cerebral palsy [ 11. Adrenocorticotropic hormone (ACTH) is currently the most widely used form of therapy, but side effects are common, efficacy is often transient, and there is controversy about the long term benefits of steroids and their ability to prevent severe psychomotor impairment [ 1,2]. Results with ACTH are variable and other anticonvulsants such as benzodiazepines or sodium valproate are even less effective with severe side effects, too [l]. The efficacy of vigabatrin has been established in children with severe refractory epilepsy (as add-on therapy) [ 1,3,4]. There are few reports suggesting that vigabatrin is very reliable in the management of infantile spasms as monotherapy [5-91. Even in these studies, patients with an underlying static encephalopathy constituted the majority of the non-responders. We started using vigabatrin with ACTH as a first chaise therapy in nine infants with infantile spasms underlying cerebral palsy.
Nine infants with a static encephalopathy (confirmed as cerebral palsy at a later follow-up) and newly diagnosed infantile spasms were entered in an open study with ACTH (standard dose: 4 IU/kg/day; mean daily dose: 24.8 IU) and vigabatrin (dose range: 80-120 mg/kg/day; mean dose: 105.6 mg/kg/ day) as the initial therapy regimen. All patients were high-risk infants with the diagnosis of a severe central coordination disturbance who have developed infantile spasms during the first year of life, associated with hypsarrhythmia on EEG and developmental retardation. The treatment schedule began for the first 2 weeks with the above stated combination and if seizures had ceased and the EEG showed no paroxysms, ACTH treatment was tapered off over a 4-week period, and vigabatrin was further maintained. An assessment using the Griffiths Mental Development Scale was conducted prior to the onset of infantile spasms as well as at the end of the follow-up period. Comparison of the developmental quotients (DQ) as well as of the various subscales scores of the Griffiths test, were carried out using the r-test.
* Corresponding
author.
Tel./fax:
[email protected] 0387-7604/96/$15.00 Copyright PZZ SO387-7604(96)00045-9
(30) (31) 241845; e-mail:
AND METHODS
3. RESULTS The clinical data as well as the etiology and MRI findings (performed prior to the initiation of therapy) of the nine patients can be seen in Tables 1 and 2, respectively.
0 1996 Elsevier Science B.V. All rights reserved
D.I. Zafeiriou et al. /Brain
451
& Development 1996; 18: 450-452
Table 1 Clinical data of the nine patients Patient number
1
2
3
4
5
6
I
8
9
Sex Age of manifestation (months) (range: 2.5-7; mean: 4.6) Frequency of IS (days) (range: 3-7; mean: 4.8) Neurological examination
f 5.5
f 4.5
m 7
m 3
m 2.5
f 4.5
m 5
f 5
f 4
5
4
6
5
4
7
3
4
5
spastic diplegia
Duration of follow-up (months) (range: 17.5-23: mean: 19.2) Seizure relapse
17
spastic tetraplegia 20
spastic diplegia 19
spastic diplegia 21
spastic tetraplegia 18
spastic diplegia 19
spastic diplegia 18.5
spastic tetraplegia 17.5
spastic diplegia 23
_
_
relapse
_
_
Abbreviation:
_
_
IS, infantile spasms.
Following an initial response with complete suppression of spasms in all patients already from the first week of treatment (suggesting an ‘all-or-nothing’ phenomenon), a long term response maintained for a mean of 19.2 months was confirmed in all but one child, which relapsed after 9 months, presenting with two secondary generalised tonic-clonic seizures triggered by a febrile infection of the gastrointestinal tract. The above child is still free of seizures 10 months after relapse. Tolerability appeared excellent with seven of nine patients reporting no side-effects. Somnolence in one patient, Cushing syndrome in two, infection in one, arterial hypertension in two and excitation in one patient were the commonest problems at the beginning of the study (mostly attributed to ACTH) and were usually transient, disappearing in the ACTH tappering period. All nine patients showed a reduction in their initial increased muscle tone, a well known vigabatrin side-effect. Comparison of the developmental quotients as well as of the various subscales of the Griffiths test, showed no statistical differences before and after treatment, although a mild improvement, especially in locomotor and eye-hand coordination and performance scales was noted (scores before-after treatment: total DQ: 64.2-65.4; locomotor scale: 32.7-37.6; personal-social: 83.2-84.6; hearing and speech: 87.3-86.2; eye-hand coordination 65.3-67.2; performance: 66.3-68.0).
tion of vigabatrin with low-dose ACTH appears to be an interesting therapy advance with few side effects, especially in children with underlying static encephalopathy who seem to form the majority of the non-responders in previously published studies dealing with vigabatrin monotherapy in infantile spasms [6,8,9]. The above combination had no influence on the mean DQ of these patients, thus preventing further psychomotor retardation, which is of great importance for these already retarded patients. Furthermore, hypotonia, a well established side-effect of vigabatrin [1,3-lo], could balance the generalised hypertonia presenting in this special category of patients, thus having a therapeutic effect also in this direction (improvement in the locomotor scale score of the Griffiths test, although not statistically significant). The latter could be an argument for the use of vigabatrin alone or in combination in the treatment of infantile spasms underlying cerebral palsy; the above theory requires of course further justification. A controlled prospective trial versus vigabatrin alone is needed to establish the efficacy of this regimen, although because of the marked heterogeneity of the West syndrome regarding etiology and the small number of patients presenting in a single centre, controlled trials for individual etiologies are extremely difficult and of uncertain clinical importance [9].
REFERENCES 4. DISCUSSION Given the very poor prognosis of infantile spasms especially in such conditions such as severe cerebral palsy [ 1], the combina-
1. Aicardi J. Infantile spasms and related syndromes. In: Epilepsy in children. 2nd ed. New York: Raven Press. 1994: 18-43. 2. Riikonen R, Donner M. ACTH therapy in infantile spasms: side effects. Arch Dis Child 1980; 55: 664-72.
Table 2 Etiology and MRI findings of the nine patients Patient number
MRI findings
Etiology neonatal asphyxia-preterm term asphyxia neonatal asphyxia-preterm term asphyxia term asphyxia term asphyxia neonatal asphyxia-preterm prenatal malformation term asphyxia
Abbreviations:
MRI, magnetic
resonance
imaging;
delivery delivery
delivery-IVH
PVL, periventricular
Grade III
leukomalacia;
PVL cortical atrophy PVL periventricular and cortical atrophy periventricular and cortical atrophy cortical atrophy hydrocephalus Dandy-Walker cortical atrophy IVH, intraventricular
hemorrhage.
452
D.I. Zafeiriou et al. /Brain
& Deuelopment 1996; 18: 450-452
3. Dulac 0, Chiron C, Luna D. Vigabatrin in childhood epilepsy. Child Neurol 1991; 6 (Suppl): 2S30-2S37. 4. Gram L, Sabers A, Dulac 0. Treatment of childhood epilepsies with y-vinyl-GABA (Vigabatrin). 5. Chiron C, Dulac 0, Luna D, Palacios L. Vigabatrin in infantile spasms. Lancet 1990; 10:363-4. 6. Chiron C, Dulac 0, Beaumont D, Palacios L, Pajot N, Mumford 3. Vigabatrin in infantile spasms. J. Child Neural 1991; 6 (Suppl. 2): S52-S59.
7. Appleton RE, Montiel-Viesca F. Vigabatrin in infantile spasms. Why add-on? Luncet 1993; 341:962 (Letter). 8. Vles BIS, Van den Heyden AMHG, Ghils A, Troost J. Vigabatrin in the treatment of infantile spasms. Neuropediatrics 1993: 24: 230-l. 9. Appleton RE. A simple. effective and well-tolerated treatment for West syndrome. Deu Med Child Neurol 1995; 37: 185-7. 10. Grant SM, Heel RC. Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41: 889-926.
Brain & Development
Q
1996; 18: 450-452
Communication
Adrenocorticotropic hormone and vigabatrin treatment of children with infantile spasms underlying cerebral palsy Dimitrios I. Zafeiriou
*, Eleutherios
E. Kontopoulos,
Ioannis G. Tsikoulas
1stPediatric Clinic, Aristotle Uniuersity of Thessaloniki, Egnatia Str. 106, 54622 Thessaloniki. Greece Received
11 February
1996; accepted 31 May 1996
Nine infants with an underlying static encephalopathy (confirmed as cerebral palsy in a later follow-up examination) and newly diagnosed infantile spasms were entered in an open study with adrenocorticotropic hormone (ACTH) and vigabatrin as the initial therapy regimen. The ACTH was discontinued after 4-6 weeks and the infants were maintained on vigabatrin alone. Following an initial response with complete suppression of spasms in all patients, a long term response maintained for a mean of 19.2 months was confirmed in all but one child. Tolerability appeared excellent with 7 of 9 patients reporting no side effects; vigabatrin related hypotonia presented in all patients and turned out to be a ‘positive’ side-effect on the abnormally increased muscle tone of these infants. Given the very poor prognosis of infantile spasms especially in such conditions as cerebral palsy, the combination of ACTH and vigabatrin appears to be an interesting therapy advance with very few side effects. Keywords:
Vigabatrin;
Adrenocorticotropic
hormone:
Infantile spasm: West syndrome;
Static encephalopathy;
Cerebral palsy
1. INTRODUCTION
2. PATIENTS
Infantile spasms usually start during the first year of life and constitute one of the most difficult types of epilepsy to treat [l]. They carry a very poor prognosis for both epilepsy and mental development, especially in those infants underlying a static encephalopathy, such as cerebral palsy [ 11. Adrenocorticotropic hormone (ACTH) is currently the most widely used form of therapy, but side effects are common, efficacy is often transient, and there is controversy about the long term benefits of steroids and their ability to prevent severe psychomotor impairment [ 1,2]. Results with ACTH are variable and other anticonvulsants such as benzodiazepines or sodium valproate are even less effective with severe side effects, too [l]. The efficacy of vigabatrin has been established in children with severe refractory epilepsy (as add-on therapy) [ 1,3,4]. There are few reports suggesting that vigabatrin is very reliable in the management of infantile spasms as monotherapy [5-91. Even in these studies, patients with an underlying static encephalopathy constituted the majority of the non-responders. We started using vigabatrin with ACTH as a first chaise therapy in nine infants with infantile spasms underlying cerebral palsy.
Nine infants with a static encephalopathy (confirmed as cerebral palsy at a later follow-up) and newly diagnosed infantile spasms were entered in an open study with ACTH (standard dose: 4 IU/kg/day; mean daily dose: 24.8 IU) and vigabatrin (dose range: 80-120 mg/kg/day; mean dose: 105.6 mg/kg/ day) as the initial therapy regimen. All patients were high-risk infants with the diagnosis of a severe central coordination disturbance who have developed infantile spasms during the first year of life, associated with hypsarrhythmia on EEG and developmental retardation. The treatment schedule began for the first 2 weeks with the above stated combination and if seizures had ceased and the EEG showed no paroxysms, ACTH treatment was tapered off over a 4-week period, and vigabatrin was further maintained. An assessment using the Griffiths Mental Development Scale was conducted prior to the onset of infantile spasms as well as at the end of the follow-up period. Comparison of the developmental quotients (DQ) as well as of the various subscales scores of the Griffiths test, were carried out using the r-test.
* Corresponding
author.
Tel./fax:
[email protected] 0387-7604/96/$15.00 Copyright PZZ SO387-7604(96)00045-9
(30) (31) 241845; e-mail:
AND METHODS
3. RESULTS The clinical data as well as the etiology and MRI findings (performed prior to the initiation of therapy) of the nine patients can be seen in Tables 1 and 2, respectively.
0 1996 Elsevier Science B.V. All rights reserved
D.I. Zafeiriou et al. /Brain
451
& Development 1996; 18: 450-452
Table 1 Clinical data of the nine patients Patient number
1
2
3
4
5
6
I
8
9
Sex Age of manifestation (months) (range: 2.5-7; mean: 4.6) Frequency of IS (days) (range: 3-7; mean: 4.8) Neurological examination
f 5.5
f 4.5
m 7
m 3
m 2.5
f 4.5
m 5
f 5
f 4
5
4
6
5
4
7
3
4
5
spastic diplegia
Duration of follow-up (months) (range: 17.5-23: mean: 19.2) Seizure relapse
17
spastic tetraplegia 20
spastic diplegia 19
spastic diplegia 21
spastic tetraplegia 18
spastic diplegia 19
spastic diplegia 18.5
spastic tetraplegia 17.5
spastic diplegia 23
_
_
relapse
_
_
Abbreviation:
_
_
IS, infantile spasms.
Following an initial response with complete suppression of spasms in all patients already from the first week of treatment (suggesting an ‘all-or-nothing’ phenomenon), a long term response maintained for a mean of 19.2 months was confirmed in all but one child, which relapsed after 9 months, presenting with two secondary generalised tonic-clonic seizures triggered by a febrile infection of the gastrointestinal tract. The above child is still free of seizures 10 months after relapse. Tolerability appeared excellent with seven of nine patients reporting no side-effects. Somnolence in one patient, Cushing syndrome in two, infection in one, arterial hypertension in two and excitation in one patient were the commonest problems at the beginning of the study (mostly attributed to ACTH) and were usually transient, disappearing in the ACTH tappering period. All nine patients showed a reduction in their initial increased muscle tone, a well known vigabatrin side-effect. Comparison of the developmental quotients as well as of the various subscales of the Griffiths test, showed no statistical differences before and after treatment, although a mild improvement, especially in locomotor and eye-hand coordination and performance scales was noted (scores before-after treatment: total DQ: 64.2-65.4; locomotor scale: 32.7-37.6; personal-social: 83.2-84.6; hearing and speech: 87.3-86.2; eye-hand coordination 65.3-67.2; performance: 66.3-68.0).
tion of vigabatrin with low-dose ACTH appears to be an interesting therapy advance with few side effects, especially in children with underlying static encephalopathy who seem to form the majority of the non-responders in previously published studies dealing with vigabatrin monotherapy in infantile spasms [6,8,9]. The above combination had no influence on the mean DQ of these patients, thus preventing further psychomotor retardation, which is of great importance for these already retarded patients. Furthermore, hypotonia, a well established side-effect of vigabatrin [1,3-lo], could balance the generalised hypertonia presenting in this special category of patients, thus having a therapeutic effect also in this direction (improvement in the locomotor scale score of the Griffiths test, although not statistically significant). The latter could be an argument for the use of vigabatrin alone or in combination in the treatment of infantile spasms underlying cerebral palsy; the above theory requires of course further justification. A controlled prospective trial versus vigabatrin alone is needed to establish the efficacy of this regimen, although because of the marked heterogeneity of the West syndrome regarding etiology and the small number of patients presenting in a single centre, controlled trials for individual etiologies are extremely difficult and of uncertain clinical importance [9].
REFERENCES 4. DISCUSSION Given the very poor prognosis of infantile spasms especially in such conditions such as severe cerebral palsy [ 1], the combina-
1. Aicardi J. Infantile spasms and related syndromes. In: Epilepsy in children. 2nd ed. New York: Raven Press. 1994: 18-43. 2. Riikonen R, Donner M. ACTH therapy in infantile spasms: side effects. Arch Dis Child 1980; 55: 664-72.
Table 2 Etiology and MRI findings of the nine patients Patient number
MRI findings
Etiology neonatal asphyxia-preterm term asphyxia neonatal asphyxia-preterm term asphyxia term asphyxia term asphyxia neonatal asphyxia-preterm prenatal malformation term asphyxia
Abbreviations:
MRI, magnetic
resonance
imaging;
delivery delivery
delivery-IVH
PVL, periventricular
Grade III
leukomalacia;
PVL cortical atrophy PVL periventricular and cortical atrophy periventricular and cortical atrophy cortical atrophy hydrocephalus Dandy-Walker cortical atrophy IVH, intraventricular
hemorrhage.
452
D.I. Zafeiriou et al. /Brain
& Deuelopment 1996; 18: 450-452
3. Dulac 0, Chiron C, Luna D. Vigabatrin in childhood epilepsy. Child Neurol 1991; 6 (Suppl): 2S30-2S37. 4. Gram L, Sabers A, Dulac 0. Treatment of childhood epilepsies with y-vinyl-GABA (Vigabatrin). 5. Chiron C, Dulac 0, Luna D, Palacios L. Vigabatrin in infantile spasms. Lancet 1990; 10:363-4. 6. Chiron C, Dulac 0, Beaumont D, Palacios L, Pajot N, Mumford 3. Vigabatrin in infantile spasms. J. Child Neural 1991; 6 (Suppl. 2): S52-S59.
7. Appleton RE, Montiel-Viesca F. Vigabatrin in infantile spasms. Why add-on? Luncet 1993; 341:962 (Letter). 8. Vles BIS, Van den Heyden AMHG, Ghils A, Troost J. Vigabatrin in the treatment of infantile spasms. Neuropediatrics 1993: 24: 230-l. 9. Appleton RE. A simple. effective and well-tolerated treatment for West syndrome. Deu Med Child Neurol 1995; 37: 185-7. 10. Grant SM, Heel RC. Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41: 889-926.