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Abstract

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

Dyskinetic cerebral palsy (CP) is a movement disorder that is difficult to treat and which causes major disability. We report on two female patients (aged 5y and 8y) who experienced severe perinatal asphyxia and developed dyskinetic CP, clinically characterized by choreoathetosis. Neuropsychological testing of these children showed a low average developmental quotient and no attentional deficit. Monotherapy with levetiracetam was initiated to improve balance control and fine motor skills. Treatment was evaluated by use of video and the Visual Analog Scale. In both children an impressive improvement of balance control and fine motor skills was observed. No side effect occurred. Furthermore, both patients showed more interest and pleasure during activities according to their parents. In a recent multidisciplinary evaluation of the initiated therapy, the parents, the therapist, and the rehabilitation doctor all confirmed that the effect initially observed was still present at 14 and 26 months later. To our knowledge, this report on two patients with dyskinetic CP is the first suggesting that levetiracetam may offer an alternative to the standard therapy of involuntary, uncontrolled movements in this group of patients.

Cerebral palsy (CP) is a non-progressive disorder of posture or movement caused by a lesion of the developing brain. The Surveillance of Cerebral Palsy in Europe (SCPE) has classified CP into three main groups (spastic, dyskinetic, and ataxic), which are based on clear neurological signs indicating pathology in the cerebral motor systems. Dyskinetic CP presents involuntary, uncontrolled, recurring, and, occasionally, stereotyped movements. SCPE uses dystonic and choreoathetotic subtypes for subgrouping dsykinetic CP.1 The pathophysiology of dyskinesia in CP is not fully elucidated, but existing evidence suggests that disorders of the basal ganglia play a role in this entity.

The symptomatic treatment of this movement disorder is still very difficult. In a retrospective survey of 22 children with extrapyramidal CP, only a minority showed a functional improvement using trihexyphenidyl, which is a centrally active muscarinic antagonist.2

Several anticonvulsants seem to be efficacious for the treatment of (paroxysmal) involuntary movement disorders. On the basis of a recent report about levetiracetam efficacy in the treatment of movement disorders, we started levetiracetam in two patients with dyskinetic CP unresponsive to conventional drugs mostly used in such cases.3

To our knowledge, this report on two patients with dyskinetic CP, is the first suggesting that levetiracetam may offer an alternative to standard therapy of involuntary, uncontrolled movements in this group of patients.

Method

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

Informed consent of the parents was obtained for both patients. Levetiracetam was only started when the other available drugs usually prescribed failed. Baclofen (GABA-agonist) and artane (Muscarine-antagonist) were tried but did not show the desired effect. The initial dose of levetiracetam was 2.5mg/kg/day. The dosage was titrated over weeks to months, based on response as well as tolerability.

Cognitive functioning of both children was assessed using standardized instruments which could be used in children with serious disabilities, as formal testing with, for instance, the Wechsler Intelligence Scale for Children-III is not possible because of motor disabilities.4 We used the Peabody Picture Vocabulary Test – Third Edition (PPVT-III-NL)5 to describe receptive vocabulary, which is a commonly used screening test for verbal ability and a subtest from a standardized Dutch nonverbal intelligence test (Snijders-Oomen Nonverbal Intelligence Test)6 for which no motor response is necessary. Using the Child Behavior Checklist (CBCL), which is a by-proxy instrument of general behavioural functioning, especially the existence of attentional problems, was assessed.7

The patients were re-evaluated on a regular basis by an occupational therapist, using video. The parents regularly used the Visual Analog Scale (VAS), an ordinal scale that ranges from 0 to 10, to score improvements on goals defined before levetiracetam treatment was started. The VAS is known as a valid and reliable measure for rating pain intensity in adults and children of more than 6 years of age, and has recently been found useful for evaluating therapy in children with CP.8,9 When clinicians are raters, the VAS validly identifies the minimal clinically important difference on the Pediatric Evaluation of Disability Inventory.10

Based on these two parameters, combined with regular visits to our outpatient department (LS and JSHV), a decision was made with the parents either to continue the drug or taper it off.

Case 1

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

A 5-year-old female experienced severe perinatal asphyxia (umbilical artery pH 6.8). Pregnancy had been complicated by pre-eclampsia. Neurological examination was compatible with Sarnat II encephalopathy. During the first hours of life the infant experienced severe neonatal seizures, for which she was treated with midazolam. Electroencephalogram showed a burst suppression image with severe epileptic activity. Magnetic resonance imaging (MRI) showed abnormal signal intensity within the basal ganglia and thalami. Furthermore, focal signal abnormalities in the posterior limb of the internal capsules were observed.

From the beginning, she showed developmental delay and hypotonia. As time went by she developed a severe movement disorder characterized by involuntary, uncontrolled, and occasional stereotyped movements, which can be classified as dyskinetic CP. Psychological examination showed that her vocabulary quotient on the PPVT-III-NL was low average (quotient score 82). Matrix reasoning was in accordance with this level of verbal abilities (standard-score 85). Her behaviour, reported by the parents using the CBCL, did not reveal significant attentional problems.

At the age of 5 years she was presented to the outpatient clinic for further treatment. The following goals were formulated: to improve sitting independently (balance control) and to improve grasping for and pointing towards objects (fine motor skills). Monotherapy with levetiracetam was initiated, reaching a final dose of 5mg/kg/day. Raising this dose was suggested, but parents were satisfied as all the treatment goals were achieved.

Evaluation of therapy and obtainment of VAS scores were carried out on a regular basis. After 3 months the child’s parents rated her balance control limitations as 0 (before treatment: 8.2) and her limitations concerning grasping and fine motor skills as 3 (before treatment: 8.2). The patient is, for the first time in her life, able to drink independently from a cup with two handles. She is also now able to bring a fork to her mouth after being handed the fork and she needs less assistance when colouring. The patient shows more initiative, and pleasure shown during activities has increased according to her parents. At 6, 9, and 14 months VAS scores showed the same improvements.

Comparing videos before levetiracetam treatment and 3 months after initiating medication, fewer fidgety movements of the trunk, less overextension of arms and hands during actions, and less (dystonic) co-movements of arms and mouth were seen. To our surprise, she also showed marked improvement of speech and was now easier to understand. This was confirmed by a speech therapist. No side effect was noted.

In a recent multidisciplinary evaluation of the initiated therapy, the parents, the therapist, and the rehabilitation doctor all confirmed that the effect initially observed was still present 14 months later.

Case 2

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

An 8-year-old female was born by means of Ventouse delivery after normal pregnancy. She was suffering from severe peripartal asphyxia (pH 7.12) and had to be resuscitated.

From the beginning she showed developmental delay, axial hypotonia, constant abnormal tongue protrusion, and abnormal spontaneous motor activity. At the age of 7 years she was re-evaluated. Neurological examination showed a cooperative child with good social contact, but with a severe dyskinetic movement disorder, which, for example, made reaching for objects impossible. Furthermore, an MRI was performed and showed abnormal signal intensity within the lateral thalami and in the dorsal putamen on both sides.

Psychological examination showed that her vocabulary quotient on the PPVT-III-NL was in the low average range (quotient score 80). Her matrix reasoning was also low average (standard-score 78). CBCL behaviour report by the parents and teachers did not reveal significant attentional problems.

Therapy with levetiracetam was initiated to improve trunk balance and fine motor skills. The start dose was 2.5mg/kg/day and was titrated to a final dose of 10mg/kg/day. No side effect was noted.

Evaluation of therapy and obtainment of VAS scores were carried out on a regular basis. After 6 months, parents rated her balance control limitations as 5 (before treatment: 7) and her fine motor skills limitations as 6 (before treatment: 10). Again, the patient showed more interest in, and pleasure during, activities according to her parents.

Comparing videos before medication and 3 months after initiating medication one could see that she was now able to independently cut pieces of paper whereas before much assistance was needed. Both the number of uncontrolled movements and their ranges of motion decreased.

The child is now capable of holding a pencil with just three fingers and staying between the lines while previously she used her whole hand just to draw several uncontrolled crude lines. While working on her computer she used to be able to click on a 5cm square, but this has now decreased to a 2cm square.

In a recent multidisciplinary evaluation of the initiated levetiracetam therapy, the parents, the therapist, and the rehabilitation doctor all confirmed that the effect initially observed was still present 26 months later.

Discussion

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References

The main difficulties for patients with choreoathetoid CP relate to their involuntary movements, which can be very powerful and extremely difficult to interrupt, making purposeful movement impossible.11 In patients with Huntington disease, it was found that chorea, when moderate to severe, can cause major disability and have a significant negative impact on daily life.12 In Parkinson patients, it was found that dyskinesias are associated with a reduction of Quality of Life and with an increase in total health-related-costs.13 In children with choreoathetoid encephalopathy after cardiac surgery, it was found that restrictions in the range of activities in which children participated (e.g. hobbies, clubs, sports) and difficulties in peer and sibling relationships led to poor total adaptive competence.14

So one may conclude that choreoathetosis is a very disabling disorder. Various drugs have been tried but with no great success. We did not try the recommended presynaptic and postsynaptic dopamine antagonist because of lack of experience. Furthermore, tetrabenazine is not available for the treatment of children in the Netherlands.

To our knowledge, this is the first description of two patients with a non-progressive, non-paroxysmal, dyskinetic movement disorder who have been treated with levetiracetam to diminish choreoathetosis.

Evaluation of levetiracetam treatment was conducted both objectively (by video) and subjectively (by VAS).

After 6 months both video and VAS showed that (limitations by) choreoathetosis had decreased while no side effect had occurred. It is very unlikely that these positive effects are due to maturation or to training given the course over time. Reasons for not increasing the dose of medication any further were that parents felt that all the goals were accomplished and that adverse affects, such as somnolence, obtundation, and Parkinsonism, of which they were informed beforehand, should be avoided.15,16

Based on the results achieved with these two patients we may conclude that levetiracetam may be used as an alternative to treat unmanageable choreoathetosis of a non-progressive kind (e.g. in children with dyskinetic CP). This is important because choreoathetosis appears to be a very severe and disabling condition which is difficult to treat. This could partly be due to the differences in pathophysiology between the two aspects of the condition, i.e. athetosis can be treated by increasing dopaminergic activity in the basal ganglia, while chorea can be treated by decreasing dopaminergic activity.2

These findings and our results suggest that levetiracetam might reduce choreoathetosis by means of another pathway. So far, the synaptic vesicle protein SV2A has been identified as the binding site for levetiracetam, but the molecular action of SV2A is still unknown.17

Further and larger studies are needed to confirm the positive effects of levetiracetam on choreoathetosis in patients with a non-progressive, non-paroxysmal, dyskinetic movement disorder.

References

  1. Top of page
  2. Abstract
  3. Method
  4. Case 1
  5. Case 2
  6. Discussion
  7. References
  • 1
    Surveillance of Cerebral Palsy in Europe (SCPE). Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol 2000; 42: 81624.
  • 2
    Hoon AH Jr, Freese PO, Reinhardt EM, et al. Age-dependent effects of trihexyphenidyl in extrapyramidal cerebral palsy. Pediatr Neurol 2001; 25: 5558.
  • 3
    D’Amelio M, Callari G, Gammino M, et al. Levetiracetam in the treatment of vascular chorea: a case report. Eur J Clin Pharmacol 2005; 60: 83536.
  • 4
    Wechsler D. Wechsler Intelligence Scale for Children – Third Edition (WISC-III-NL). Dutch version by W Kort, M Schittekatte, P Dekker, et al. Amsterdam: Harcourt Test Publishers, 2005.
  • 5
    Dunn LM, Dunn LM. Peabody Picture Vocabulary Test Third Edition (PPVT-III-NL). Dutch version by L Schlichting. Amsterdam: Harcourt Test Publishers, 2004.
  • 6
    Tellegen PJ, Winkel M, Wijnberg-Williams B, Laros JA. Snijders-Oomen Nonverbal Intelligence Test. SON-R 2,5-7. Manual and Research Report. Lisse: Swets Test Publishers, 1998.
  • 7
    Achenbach TM, Edelbrock C. Manual for the Child Behavior Checklist and revised Child behavior profile. Dutch version by FC Verhulst, JM Koot & J van der Ende. Rotterdam: University Hospital, Department of Child and Adolescent Psychiatry, 1996.
  • 8
    Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the psychometric properties, interpretability and feasibility of self-report pain-intensity measures for use in clinical trials in children and adolescents. Pain 2006; 125: 14357.
  • 9
    Vles GF, De Louw AJ, Speth LA, et al. Visual Analogue Scale to score the effects of botulinum toxin-A treatment in children with cerebral palsy in daily clinical practice. Eur J Ped Neurol 2008; 12: 23138.
  • 10
    Iyer LV, Haley SM, Watkins MP, Dumas HM. Establishing minimal clinically important differences for scores on the pediatric evaluation of disability inventory for inpatient rehabilitation. Phys Ther 2003; 83: 88898.
  • 11
    Aicardi J, Bax M. Cerebral palsy. In: AicardiJ. Diseases of the nervous system in childhood. 2nd edn. London: Mac Keith Press, 1998: 21039.
  • 12
    Caine ED, Shoulson I. Psychiatric syndromes in Huntington’s disease. Am J Psych 1983; 140: 72833.
  • 13
    Péchevis M, Clarke CE, Vieregge P, et al., on behalf of the Trial Study Group. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol 2005; 12: 95663.
  • 14
    Du Plessis AJ, Bellinger DC, Gauvreau K, et al. Neurologic outcome of choreoathetoid encephalopathy after cardiac surgery. Pediatr Neurol 2002; 27: 917.
  • 15
    Zesiewicz TA, Sullivan KL, Hauser RA, Sanchez-Ramos J. Open-label pilot study of Levetiracetam (Keppra) for the treatment of chorea in Huntington’s disease. Mov Disord 2006; 21: 19982001.
  • 16
    Zesiewicz TA, Sullivan KL, Maldonado JL, Tatum WO, Hauser RA. Open-label pilot study of Levetiracetam (Keppra) for the treatment of Levodopa-induced dysinesias in Parkinson’s disease. Mov Disord 2005; 20: 120509.
  • 17
    Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004; 101: 986166.