Intrathecal baclofen use in children with spasticity – a physicians' survey

infrequent by 24%. Mechanical and infection events werereported in the following frequencies: rare 41.5%, infrequent41.5%, common or very common 17%. Baclofen withdrawalevents were rare in 65%, infrequent in 27%, and common in 8% ‘Intrathecal baclofen use in children with spasticity – a physi- of respondents’ experience. No difference in reported compli- cations was found on the basis of experience or activity (num- SIR–The use of intrathecal baclofen (ITB) during the past two ber of pumps inserted and managed per year). decades has resulted in major advances in the management of Those surveyed were asked about what rates they may antic- complex spasticity.1 There is increasing use of ITB in children ipate of life and non-life threatening complications in children for managing spasticity in a number of conditions, with evi- of GMFCS Levels III, IV, or V. Respondents indicated that they dence for effect across a range of functional domains.2 would tolerate the highest rate of both life and non-life threat- However, significant complications have been reported.3,4 ening events in the most severely impaired children (GMFCS These can be broadly divided into three groups: (1) mechani- Level V) compared with those less impaired (p<0.005). When cal; (2) central nervous system effects from dose excess or with- asked whether they believed that the overall safety of ITB had drawal; and (3) infections. In conducting a multicentre survey, been adequately established in terms of the current evidence, our primary aim was to describe the experience of individual almost equal numbers replied yes (43%) and no (44%) and a physicians with ITB management in children, specifically with small number (13%) did not know. An overwhelming majority regard to extent of use and complications noted.
(96%) of respondents indicated that an international database A survey was conducted of physicians working with chil- for ITB-related safety and complication issues would be essen- dren with physical disabilities. This was mailed to 165 physi- tial or useful. No difference was seen in terms of responses to cians randomly selected from the membership register of the section 4 between ITB users and non-users.
American Academy for Cerebral Palsy and Developmental To our knowledge, this is the first survey on the use of Medicine, and to an additional 35 physicians identified as intrathecal baclofen specifically in children. We deliberately ITB users on the basis of articles authored in the literature.
chose to explore the complications issue in this survey as there The questionnaire asked for single choice responses and is little known about this from a systematic perspective. Cur- requested information in four key areas: (1) demographics; rently there are no universally agreed guidelines on the opti- (2) patient selection factors; (3) frequency of actual compli- mal selection and management of children with ITB. The cations; and (4) beliefs about potential complications and responses on selection factors indicate that there is a large access to safety data. Those physicians not currently involved degree of variability in the decision-making process. One-third with ITB were asked only to fill out section (4).
of respondents indicated that ITB withdrawal events occur in Eighty-five physicians (43%) completed the survey; 69% of more than 5% of recipients. ITB withdrawal can be difficult to the overall sample was involved in the use of ITB. Of the ITB diagnose, may be life-threatening, and, importantly, is largely users, 40% had between 2 and 5 years’ experience and 44% had preventable.6 To our knowledge, there has been no reporting more than 5 years’ experience. Seventy-six per cent of respon- on ITB withdrawal in children other than by case report.7–9 dents were working in centers where up to 50 implanted We asked all respondents, regardless of their current use of pumps were managed in the previous year. In describing their ITB, what they believed to be acceptable cut-off rates for com- role in the phases of management, 91% responded that they plications in children of varying motor severity based on were involved in preoperative assessment of the child’s suit- GMFCS. Our hypothesis was that more physicians would con- ability for the device. Nineteen per cent were involved in the sider accepting higher complication rates in the more severely operative implantation and 73% in the ongoing care of recipi- impaired child, possibly as the need for benefit from ITB in a more motorically impaired child is greater than for a less When asked about a single minimum age criterion in iden- impaired child. The results indicate that most physicians tifying suitable candidates, 24% indicated that the child should would accept higher rates of both life and non-life-threatening be older than 5 years, 32% indicated older than 1 year, and complication in GMFCS Level V children compared with Level 39% believed that a minimum age was not relevant to the III or IV (p<0.005). This finding is challenging: are quality of selection process. With respect to the child’s weight, 37% life issues more important than safety issues to some physicians believed a minimum of 10kg was acceptable and 46% indicat- and families in deciding whether or not to choose ITB? ed a minimum weight of 20kg. Respondents were also asked While most physicians had access to information on com- to indicate what degree of motor impairment would describe plications in ITB, responses were split on whether respon- a suitability for ITB on the basis of the descriptions of gross dents believed that ITB is a safe procedure. Does this suggest motor ability from the Gross Motor Function Classification that broader concerns exist as to ITB as a procedure, or that System (GMFCS)5 for Levels III, IV, and V. Forty-two per cent of physicians need more information on which to make an respondents would consider a child who ambulated with informed judgment? Beyond data obtained from reports assistive mobility devices (Level III) for ITB. Sixty-seven per published in peer-reviewed journals, a single manufacturer cent would consider a child with very limited ambulatory of ITB pumps collects information from centres using ITB. In skills who relied more on power mobility (Level IV), and 91% the face of limited free availability through journals, the would consider a non-ambulatory child (Level V). question of whether a third party should collect and dissemi- In order to improve recall and facilitate analysis the frequen- nate safety-related information on ITB, in the form of an cy of events were grouped in the following manner: rare (<5% international registry, is an important issue. This would cre- of recipients); infrequent (5–15%); common (16–25%); very ate a more transparent reporting and access system for ITB common (>25%). Dose-related events in the postimplanta- safety information and could allow greater use of data in tion period were reported as rare by 75% of respondents and determining optimal and at-risk candidates. The need for Developmental Medicine & Child Neurology 2006, 48: 1006–1011 greater access to education and strategies on pump problem menarche since this is a very salient event, and can be recalled accurately many years later. Data were available for 38 womenwith an ASC, diagnosed by psychiatrists using International Classification of Diseases-10th revision3 criteria. Their meanage was 31 years 6 months (SD 9y 10mo; range 18y 11mo–57y 9mo). Specific diagnoses were available for 35 of the women.
Ten were diagnosed with autism, two with high functioning autism, and 23 with Asperger syndrome. Several also hadcomorbid diagnoses including severe learning disability,* aPaediatric Rehabilitation Service, The Royal Children’s Tourette syndrome, attention-deficit disorder, dyslexia, dys- praxia, epilepsy, depression, and anxiety. They were recruited bDivision of Developmental Paediatrics, University of British via the National Autistic Society (UK), specialist clinics, and adverts in relevant newsletters/web-pages. Data from an age-matched comparison group of 38 females without ASC were *Correspondence to: also collected (mean age 32y 2mo [SD 9y 1mo]; range 19y–36y5mo). This was not significantly different from the group withASC, t(74)=–0.10, p=0.92, d=0.07. All women were asked the References1. Penn RD, Kroin JS. (1984) Intrathecal baclofen alleviates spinal following question: ‘How old were you when you had your first cord spasticity. Lancet 1: 1078. (Letter) period?’. They were asked to indicate age in years and months.
2. Butler C, Campbell S. (2000) Evidence for the effects of They were also asked ‘What date was it (month/year)?’ If partic- intrathecal baclofen for spasticity and dystonic cerebral palsy. ipants answered both questions, recalled age was used in the Dev Med Child Neurol 42: 634–645.
subsequent analysis as this is remembered more accurately. In 3. Murphy NA, Nicole Irwin MC, Hoff C. (2002) Intrathecal baclofen therapy in children with cerebral palsy: efficacy and four women with classical autism the participant’s mother complications. Arch Phys Med Rehabil 83: 1721–1725.
responded; analyses were run with and without these cases.
4. Gooch JL, Oberg WA, Grams B, Ward LA, Walker ML. (2003) Participants were excluded if they reported having a hormonal Complications of intrathecal baclofen in children. Pediatr condition that could influence the variable being tested, such 5. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B.
as thyroid gland abnormalities, diabetes, and anorexia. Three (1997) Development and reliability of a system to classify gross women were removed from the ASC group for exclusionary motor function in children with cerebral palsy. Dev Med Child conditions. Because timing of menarche differs among ethnic groups,1 only participants with a Caucasian background were 6. Coffey RJ, Edgar TS, Francisco GE, Graziani V, Meythaler JM, included in this study. The reported study was approved by the Ridgely PM, Sadiq SA, Turner MS. (2002) Abrupt withdrawal fromintrathecal baclofen: recognition and management of a potentially Cambridge Psychology Ethics Comittee. Informed consent was life-threatening syndrome. Arch Phys Med Rehabil 83: 735–741.
7. Alden TD, Lytle RA, Park TS, Noetzel MJ, Ojemann JG. (2002) Three of the women in the ASC group had their first period Intrathecal baclofen withdrawal: a case report and review of the at a very late age (20y 3mo, 20y 1mo, and 20y). One woman in literature. Childs Nerv Syst 18: 522–525. 8. Samson-Fang L, Gooch J, Norlin C. (2000) Intrathecal baclofen the control group had a delayed age at menarche (17y 8mo).
withdrawal simulating neuroleptic malignant syndrome in a This represents a significant minority of the women with ASC.
child with cerebral palsy. Dev Med Child Neurol 42: 561–565.
Even excluding these women, a t-test showed that women 9. Dawes WJ, Drake JM, Fehlings D. (2003) Microfracture of a with ASC, on average, began their periods at a later age than baclofen pump catheter with intermittent under- and overdose.
the women in the control group (13y 4mo vs 12y 7mo respec- 10. Yeh RN, Nypaver MM, Deegan TJ, Ayyangar R. (2004) Baclofen tively), t(69)=1.95, p=0.055, d=0.45. Levene’s test4 indicated toxicity in an 8-year-old with an intrathecal baclofen pump. equal variance. The probability of a type I error was main- tained at 0.05. A significant difference was also found whenparticipants whose mother’s responded were excluded, (13y6mo vs 12y 7mo), t(67)=1.95, p=0.02, d=0.60. The cause ofthis delay remains open to investigation.
‘Age of menarche in females with autism spectrum conditions’ One possibility is the influence of prenatal androgen. It SIR–Studies in typical populations show that the timing of has recently been suggested that high testosterone may be a pubertal development has important behavioural and psy- risk factor for autism.5 Our results are compatible with this chosocial consequences.1 In children with autism spectrum theory in that female rhesus monkeys exposed to high levels conditions (ASC), puberty may produce changes in symptoms.
of androgens early in gestation experience delayed menar- Some studies report that between one-tenth and one-third of che.6 Females with ASC show other markers of high testos- children with ASC experience deterioration and aggravation of terone including a low 2nd to 4th digit ratio, potential symptoms soon after entering puberty; this may be particularly somatic hypermasculinization,5 and a more masculine pat- the case for females.2 Given the potential impact of the puber- tern of play (Knickmeyer et al. unpublished).
tal transition on symptom severity and the possibility that Another major candidate is body mass index (BMI).
females with ASC share some of the same vulnerabilities that Females who are obese tend to enter puberty at an earlier age arise from early or delayed maturation in the general popula- than their peers, while strict training in activities such as tion, a better understanding of puberty timing in these individ- sports or ballet dancing delays menarche.1 Children with autism often have dietary abnormalities which could affect In this letter, we report the results of a cross-sectional sur- vey of age at menarche in women with ASC. We focused on North American usage: mental retardation.
their BMI. Stress is also thought to affect menarche, but due to 6. Abbott DH, Dumesic DA, Eisner JR, Kemnitz JW, Goy R. (1997) the highly subjective nature of this phenomenon, it is difficult The prenatally androgenized female rhesus monkey as a model to study. Given that our study included no clinical controls, our for PCOS. In: Azziz R, Nestler JE, Dewailly D, editors. AndrogenExcess Disorders in Women. Philadelphia: Lippincott–Raven.
results could reflect stress associated with having a clinical con- dition. Females with cerebral palsy and females with severe 7. Evans AL, McKinlay IA. (1988) Sexual maturation in girls with cognitive impairment may also have delayed puberty.7,8 How- severe mental handicap. Child Care Health Dev 14: 59–69.
ever, females with Down syndrome experience menarche at an 8. Worley G, Houlihan CM, Herman-Giddens ME, O’Donnell ME, Conaway M, Stallings VA, Chumlea WC, Henderson RC, Fung EB, earlier age than the general population. Age of menarche Rosenbaum PL, et al. (2002) Secondary sexual characteristics in shows no deviation in fragile X syndrome.9 The factors produc- children with cerebral palsy and moderate to severe motor ing this variation across conditions merit further study, but may impairment: a cross-sectional survey. Pediatrics 110: 897–902.
include activity level (acting through BMI) as well as physiologi- 9. Burgess B, Partington M, Turner G, Robinson H. (1996) Normal cal factors specific to the conditions. Individuals with clinical age of menarche in fragile X syndrome. Am J Med Genet 64: 376.
conditions may have taken medications which alter their meta-bolic or endocrine status, thereby affecting timing of menarche.
In conclusion we found a significant minority of women ‘Ferritin as an indicator of suspected iron deficiency in chil- with autism have an extremely late onset of menarche. We have dren with autism spectrum disorder: prevalence of low serum since been contacted by another woman with autism who, at the age of 26, has never experienced menarche. Even exclud- SIR–Children with autism spectrum disorder (ASD) often have ing these extreme cases, menarche was delayed in women with limited iron intake1 as shown by Latif et al.2 who found children ASC compared with age-matched controls by 8 months. Whilst with ASD to have a high prevalence of low serum ferritin levels, intriguing, our findings are limited in that they included only a a widely-used screening test for depleted iron stores.2–4 The single ethnic group and relied on participants recalling their cut-off values used for low ferritin differ across centers (<6ug/L age at menarche and self-reporting exclusionary clinical condi- to <22ug/L25–8), limiting its accuracy for detecting the pres- tions; the study was also of a relatively small sample size. A com- ence of iron deficiency. The World Health Organization9 prehensive study of pubertal development, which takes reports a geometric mean of normal ferritin levels of 34ug/L account of nutritional status, medication, and other variables whilst Milman et al.7 reported a mean of 38.5ug/L. The relevant to pubertal development in women with ASC, is need- American Association for Clinical Chemistry uses a range of 6 to ed before any strong conclusions can be drawn. Our results 24ug/L (1–5y) and 10 to 55ug/L (6–9y).6 The National Health suggest that such a study would be worthwhile. and Nutrition Examination Survey (NHANES)5 chose the fer-ritin level cut-off that fell near the fifth centile for age.
In this retrospective chart review, all 96 children (78 males, 18 females) who had undergone an ASD diagnostic assessment at the tertiary level Child Development Centre (1998–2003), located in The Hospital For Sick Children, Toronto, Canada, were included, regardless of their nutri- tional history. In our center’s population of children withASD, although the ferritin level was initially measured only in aDepartment of Psychiatry, University of North Carolina- those whose nutritional history suggested risk for iron defi- Chapel Hill, Neurosciences Hospital, Chapel Hill, NC, USA. ciency, the frequent finding of low ferritin levels led to the bThe Autism Research Centre, Departments of Experimental clinical practice of routine measurement of serum ferritin Psychology and Psychiatry, University of Cambridge, concentration in 1998 during all diagnostic assessments of children with ASD in order to screen more formally for iron cDepartment of Biological Psychology, Vrije Universiteit, deficiency. In the current study, ferritin levels were recorded and mean corpuscular volume (MCV; <80fL10) and haemo-globin (Hb; <110g/L in 2–4-year-olds and <120g/L in 5–10-year- *Correspondence to: olds10) were used as measures of iron deficient erythropoei-sis because ferritin by itself does not indicate the severity of iron deficiency once iron stores are fully depleted.11 To com- 1. Weichold K, Silbereisen K, Schmitt-Rodermund E. (2003) Short- pare the prevalence of low ferritin in children with ASD to term and long-term consequences of early versus late physical that of iron deficiency in the general population, we used the maturation in adolescents. In: Hayward C, editor. Gender same cut-off values as those described in the Center for Differences at Puberty. Cambridge: Cambridge University Press. p 241–276.
Disease Control and Prevention (CDC) recommendations to 2. Gillberg C. (1984) Autistic children growing up: problems during prevent and control iron deficiency.3,12 Their data were drawn puberty and adolescence. Dev Med Child Neurol 26: 122–129.
from NHANES,5 using a cut-off of <10ug/L for preschool chil- 3. World Health Organization. (1994) International Classification dren (age 1–5y) and <12ug/L for school-aged children (6y and of Diseases, 10th edn. (ICD-10) Geneva, Switzerland: WorldHealth Organization.
older). A weakness of our design was the lack of multiple mark- 4. Levene H. (1960) Robust tests for equality of variances. In: Olkin I, ers available for iron deficiency; these could have been benefi- Ghurye S, Hoeffding W, Madow W, Mann H, editors. Contributions cial because ferritin lacks a uniform reference range in the to Probability and Statistics: Essays in Honor of Harold Hotelling. literature and ferritin can become falsely elevated by physiolog- Stanford, CA: Stanford University Press. p 278–292.
ical fluctuations.11,13 χ2 test or Fisher’s exact test were used to 5. Baron-Cohen S, Knickmeyer RC, Belmonte MK. (2005) Sex differences in the brain: implications for explaining autism.
test the difference between two proportions, two-indepen- dent sample t-tests or Mann–Whitney U tests were used to test Developmental Medicine & Child Neurology 2006, 48: 1006–1011 differences in means between two samples, and Pearson’s cor- 3. Centers for Disease Control and Prevention, US Department of Health and Human Services. (1998) Recommendations to prevent relation was used for patterns of association between continu- and control iron deficiency in the United States. MMWR The mean age of the 61 preschoolers (1–5y) and 35 school- 4. Borch-Iohnsen B. (1995) Determination of iron status: Brief review aged children (6–10y) was 5 years 5 months. Median ferritin of physiological effects on iron measures. Analyst 120: 891–893.
5. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. (1997) was 17.1ug/L (range 2.5ug/L–49.2ug/L). Two preschool chil- Prevalence of iron deficiency in the United States. JAMA dren had an outlying ferritin level (168.4ug/L and 175.5ug/L).
Ferritin did not appear to differ with age (preschool children 6. Soldin SJ, Brugnara C, Hicks JM. (1999) Pediatric Reference Ranges, [17.2ug/L], school-aged children [16.6ug/L]; p=0.61). 3rd edn. Washington, DC: American Association for Clinical Ferritin was low in 1/12 of 1–2-year-olds with ASD, similar to 7. Milman N, Backer V, Laursen EM, Graudal N, Ibsen KK, Jordal R.
the 7% prevalence of iron deficiency reported in the general (1994) Serum ferritin in children and adolescents. Results from population at that age;5,12 it was also low in 7/49 of 3–5-year- population surveys 1979 and 1986 comprising 1312 individuals.
olds, more than double the 5% typical prevalence,5,12 and in 7/35 of 6–10-year-olds, fivefold greater than the 4% typical 8. Murthy JN, Hicks JM, Soldin SJ. (1995) Evaluation of the technicon immuno I random access immunoassay analyzer and calculation of prevalence.5,12 MCV was low in 48% (44/91), associated with pediatric reference ranges for endocrine tests, T-uptake, and median ferritin 17.4ug/L; Hb was low in 19% (17/91). A ferritin ferritin. Clin Biochem 28: 181–185.
level above 12ug/L was present in 34/43 of those children with 9. DeMaeyer EM. (1989) Preventing and Controlling Iron Deficiency low MCV and in 16/17 of those with low Hb. Lower ferritin val- Anaemia through Primary Health Care – A Guide for Health ues were correlated with higher ADOS14 communication Administrators and Programme Managers. Geneva, Switzerland:World Health Organization. p 7–38.
scores (p=0.005), indicative of more severely impaired com- 10. Lewis SM, Dacie JV, Bain BJ, Bates I. (1991) Dacie and Lewis munication, which could reflect more restricted diets in Practical Haematology, 7th edn. Oxford: Churchill Livingstone. impaired children, or that behavioural difficulties are exacer- 11. Cook JD, Baynes RD, Skikne BS. (1992) Iron deficiency and the measurement of iron status. Nutr Res Rev 5: 189–202.
Assuming low ferritin indicates iron deficiency in this popu- 12. Centers for Disease Control and Prevention. (2002) US lation, this study confirmed a much higher prevalence of iron Department of Health and Human Services. Iron Deficiency- deficiency in children with ASD than in the general population.
United States, 1999–2000. MMWR 51: 897–899.
This may be associated with more severe ASD impairment. The 13. Madanat F, El-Khateeb M, Tarawaneh M, Hijazi S. (1984) Serum high rate of microcytosis supports the presence of iron defi- ferritin in evaluation of iron status in children. Acta Haematol71: 111–115.
ciency, but its associated high prevalence of ferritin above cut- 14. Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, off values suggests that ferritin measurements may miss some Pickles A, Rutter M. (2000) The autism diagnostic observation children with iron deficiency and supports the need for multi- schedule-generic: a standard measure of social and ple markers.13 In conclusion, children with ASD represent a communication deficits associated with the spectrum of autism. J Autism Dev Disord 30: 205–223.
high risk group for iron deficiency, and need close monitoring,even at school-age, in accordance with the CDC3 recommenda-tion to screen populations at risk for iron deficiency.
‘Interobserver reliability of visual interpretation of electro- encephalograms in children with newly diagnosed seizures’ SIR–Stroink and colleagues recently addressed the important question of interobserver reliability in electroencephalograms (EEGs) of children with newly diagnosed seizures and con- cluded that ‘the reliability of the visual interpretation of EEGs in children is almost perfect as regards the presence of epilepti- form abnormalities’.1 The methods of this study should make us skeptical of the generalizability of this conclusion.
First, their case mix differs from the typical clinical case mix.
The authors selected two groups of EEGs from their first aGlenrose Rehabilitation Hospital, University of Alberta, seizure/newly diagnosed epilepsy study. In the first group, 56 of 72 (78%) had been read by the first EEG reader as abnormal.
bDepartment of Psychology, York University; In the second, 37 of 39 were interpreted abnormal. In standard cChild Development Centre, The Hospital For Sick Children, clinical practice, EEGs are ordered in a much more diverse mix University of Toronto, Toronto, Ontario; of patients. Even in comparable first seizure or epilepsy dDepartment of Public Health Sciences, University of patients, the proportion of EEGs that will show abnormalities Alberta, Edmonton, Alberta, Canada. is far lower. So, conclusions drawn on the basis of this case mixmay not be generalizable to all situations where EEGs are per-formed in children.
*Correspondence to: Second, these authors are experienced clinical neurophysi- ologists who have been collaborating in epilepsy research for years. Thus, one would expect them to have worked to reduce 1. Cornish E. (1998) A balanced approach towards healthy eating in interobserver variation, and that over time a convergence in autism. J Hum Nutr Diet 11: 501–509.
2. Latif A, Heinz P, Cook R. (2002) Iron deficiency in autism and EEG interpretation would occur. This may partly explain the Asperger syndrome. Autism 6: 103–114.
high level of agreement. However, there is no reason to think that neurologists trained at a wide variety of institutions for the prognostic value of EEGs in studies of children with varying periods of time would currently achieve this high level epilepsy or a first seizure.2 Gilbert et al. concluded that a large variation exists in the conditions of children referred In fact, evidence from other large studies shows that inter- for EEG and a large interreader variation because of diverg- observer reliability is much lower than the authors report. If ing specificity and sensitivity of the EEG between studies. We the reliability of EEG reading is ‘almost perfect’ in children, one investigated the interrater reliability of the EEG in children would expect that the test characteristics of EEGs would be diagnosed with epilepsy by experienced paediatric neurolo- highly consistent across studies in children. However, our gists. We think that our results do not conflict but agree with meta-analysis of studies involving over 2000 children showed most of the findings of Gilbert et al.1,2 sensitivity ranged from 33 to 91% and specificity from 13 to A seizure and epilepsy need to be diagnosed on the basis 80%. Moreover, the readers’ interpretation threshold varied, of the history of the events and, if available, on (home) and this significantly influenced the predictive accuracy of EEG videos. EEG may support the diagnosis of epilepsy only if the for seizure recurrence.2 In the community setting, we found, in clinical suspicion of epileptic seizures is already high. The reviewing 2500 EEG interpretations by six experienced clinical interictal EEG should be used predominantly to classify neurophysiologists, that the probability that an EEG would be epilepsy syndromes and to help choose the right drug when interpreted as epileptiform varied significantly depending on treatment is indicated, and it may have prognostic value in the neurologist reader.3 Taken together, these results show that some specific circumstances.3 The diagnosis of epilepsy agreement in visual interpretation of EEGs across centers and based solely on EEG results without adequate knowledge of within a single community is not ‘almost perfect’.
the clinical signs of seizures, or rejection of this diagnosis For diagnostic purposes, it is worth noting that classification because of normal interictal EEG findings, are frequent mis- of epilepsy syndromes includes more specific interpretations takes, as shown in the literature.1–5 If paroxysmal events are of the type and location of epileptiform discharges than Stroink not straightforward epileptic seizures by history, one has to et al. required for their study. When neurologists’ readings on consider alternative diagnoses, wait until the events become more specific epileptic findings are compared, agreement is clearer in time, request a home video if possible, request a also lower. In a random sample of 255 neurologists asked to video-EEG, or refer the child to an experienced paediatric read 10-second samples of 12 EEGs, among the 100 who neurologist or epileptologist. Thus, an EEG should be agreed to participate there was wide variation in interpreta- obtained only if the clinical suspicion of epileptic seizures is high, as was the case in our study,8 and not when children pre- The authors have done a commendable job in showing us sent unclear events or non-epileptic complaints.1–5 that it is possible for visual EEG interpretations in selected situ- Two of the five clinical neurophysiologists in our study ations to have high agreement. However, there is more work to were co-authors of our paper. None of these five was a mem- be done before we can tell our patients and colleagues that ber of our study group DSEC. However, they are all full-time, neurologists interpret EEGs consistently.
board-certified clinical neurophysiologists with a great dealof experience. This has probably influenced our results, as has the selection of the children. Moreover, in daily practicethe quality of EEG reports and consequent diagnosis and classification of epilepsy in children depends on regular dis- Cincinnati Children’s Hospital Medical Center, USA. cussion between clinicians and clinical neurophysiologists.
This method of working may alone be an important factor in Correspondence to: improving the interrater reliability, as Gilbert remarks.
Another factor causing diverging EEG results, not mentioned by Gilbert, may be the interval between seizure and EEG.3,6 A 1. Stroink H, Schimsheimer RJ, de Weerd AW, Geerts AT, Arts WF, longer interval lowers the chance of epileptiform discharges.
Peeters EA, Brouwer OF, Boudewijn Peters A, van Donselaar CA.
(2006) Interobserver reliability of visual interpretation of We only performed an interrater study for EEG abnormalities electroencephalograms in children with newly diagnosed and did not study syndrome classification (we published such seizures. Dev Med Child Neurol 48: 374–377.
a study earlier7). Epilepsy classification depends on the results 2. Gilbert DL, Sethuraman G, Kotagal U, Buncher CR. (2003) Meta- of the EEG in combination with the clinical symptoms. For analysis of EEG test performance shows wide variation among example, if a clinician requests an EEG because of seizures studies. Neurology 60: 564–570.
3. Gilbert DL, Gartside P. (2002) Factors affecting the yield of with diminished consciousness, automatisms, and postictal pediatric EEGs in clinical practice. Clin Pediatr (Phila) 41: 25–32.
confusion and the EEG shows centrotemporal spikes with a 4. Williams GW, Luders HO, Brickner A, Goormastic M, Klass DW.
normal background pattern, the EEG findings do not match (1985) Interobserver variability in EEG interpretation. Neurology the clinical symptoms; they are probably coincidental and do Gilbert has previously shown that EEGs are regularly requested unjustifiably without a high suspicion of epilepticseizures and even for other reasons, and that prognostic value varies widely between studies. We showed that the interob- SIR–We thank Dr Gilbert for his valuable comments, however, server reliability of EEG descriptions can be high with the use we feel that the object of our study was somewhat different of criteria for EEG abnormalities, when EEGs are requested by from the studies of Gilbert et al.1,2 They investigated the experienced physicians for children with a high suspicion of value of electroencephalograms (EEGs) of children request- epilepsy and are seen and read by experienced, certified clini- ed during daily practice1 and performed a meta-analysis of Developmental Medicine & Child Neurology 2006, 48: 1006–1011 Much work needs to be done in teaching physicians and ‘Genetic testing for myotubular myopathy despite muscle clinical neurophysiologists treating children with paroxysmal biopsy without centrally located nuclei’ events on how to improve the quality of diagnosis and treat- SIR–I commend your journal and authors de Goede et al. on ment of these children. Preferably, only a few selected physi- the fascinating article ‘Muscle biopsy without centrally locat- cians in a general paediatric practice will see children with ed nuclei in a male child with mild X-linked myotubular possible epilepsy, to gather enough experience and training myopathy’.1 The authors described a male with a congenital within this field. EEGs should be read by experienced clinical myopathy, who lacked a more specific diagnosis despite neurophysiologists who discuss the results with the clini- various tests including repeat muscle biopsy (which did not cians. In case of doubt, the child should be referred to an show centrally located nuclei). Years later, the child’s mother experienced paediatric neurologist or epileptologist. learned that her cousin’s son had a clinically similar myopa-thy where muscle biopsy indeed did show centrally locatednuclei, prompting genetic testing which, in both children, was positive for the same MTM1 (myotubularin) mutation,thus making the diagnosis of X-linked myotubular myopathy This is a landmark article, clearly showing the growing importance of genetic testing for myotubular myopathy (MTM) and other forms of centronuclear myopathy (CNM).
Many other cases in practice and in the literature have shown that a conclusive diagnosis of XL-MTM cannot be made mere- ly based on centrally located nuclei on muscle biopsy, which looks similar in congenital myotonic dystrophy as well as among the various different forms of MTM/CNM. Meanwhile,family histories are limited by memory, undisclosed paterni- Departments of Paediatric Neurology at: ty, and lost contact with relatives. Further, the clinical presen- tations show substantial variability and overlap among these bMedical Centre Haaglanden, the Hague; myopathies. Thus, we have known for years that myopathy cDutch Epilepsy Clinics Foundation, Zwolle; patients with centrally located nuclei need genetic testing to more definitively diagnose the specific myopathy. However, eUniversity Medical Centre, Groningen; this article presents a novel revelation that MTM/CNM genet- fUniversity Medical Centre, Utrecht, the Netherlands. ic testing is indicated even in myopathy cases where the mus-cle biopsy does not show centrally located nuclei. *Correspondence to: The knowledge gained from this single article has the potential to shift substantially the diagnostic algorithm in congenital myopathies, leading to increased genetic testing 1. Gilbert DL, Gartside PS. (2002) Factors affecting the yield of and more accurate diagnoses. This, in turn, would allow for pediatric EEGs in clinical practice. Clin Pediatr 41: 25–32.
more accurate genetic counselling for affected families and 2. Gilbert DL, Sethuraman G, Kotagal U, Buncher CR. (2003) Meta- relatives, as well as an increased likelihood of appropriate analysis of EEG test performance shows wide variation among patient identification for research studies and eventual gene- studies. Neurology 60: 564–570.
3. Stroink H, Brouwer OF, Arts WF, Geerts AT, Peters AC, van specific treatments. I praise the authors and this journal, and Donselaar CA. (1998) The first unprovoked, untreated seizure in I hope that the medical and research community worldwide childhood: a hospital-based study of the accuracy of the will take note of this article’s importance and implications.
diagnosis, rate of recurrence, and long term outcome afterrecurrence. Dutch study of epilepsy in childhood. J Neurol Neurosurg Psychiatry 64: 595–600.
4. Stroink H, van Donselaar CA, Geerts AT, Peters AB, Brouwer OF, Arts WF. (2003) The accuracy of the diagnosis of paroxysmal events in children. Neurology 60: 979–983.
University of Medicine and Dentistry of New Jersey, New 5. Chadwick D, Smith D. (2002) The misdiagnosis of epilepsy. BMJ Jersey Medical School, Newark, New Jersey, USA. 6. King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell LA, Silvapulle MJ, Berkovic SF. (1998) Epileptology of the first-seizure Correspondence to: presentation: a clinical, electroencephalographic, and magneticresonance imaging study of 300 consecutive patients. Lancet352: 1007–1011.
7. Stroink H, van Donselaar CA, Geerts AT, Peters AC, Brouwer OF, 1. de Goede CG, Kelsey A, Kingston H, Tomlin PI, Hughes MI.
van Nieuwenhuizen O, de Coo RF, Geesink H, Arts WF. (2004) (2005) Muscle biopsy without centrally located nuclei in a male Interrater agreement of the diagnosis and classification of a first child with mild X-linked myotubular myopathy. Dev Med Child seizure in childhood. The Dutch study of epilepsy in childhood. J Neurol Neurosurg Psychiatry 75: 241–245.
8. Stroink H, Schimsheimer RJ, de Weerd AW, Geerts AT, Arts WF, Peeters EA, Brouwer OF, Boudewijn Peters Avan Donselaar CA.
(2006) Interobserver reliability of visual interpretation ofelectroencephalograms in children with newly diagnosedseizures. Dev Med Child Neurol 48: 374–377.


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