An Iranian family with congenital myasthenic syndrome caused by a novel acetylcholine receptor mutation (CHRNE K171X) P Soltanzadeh, J S Müller, A Ghorbani, A Abicht, H Lochmüller and A Soltanzadeh J. Neurol. Neurosurg. Psychiatry doi:10.1136/jnnp.2004.059436 Updated information and services can be found at: References This article cites 5 articles, 3 of which can be accessed free a
UntitledDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY Survival of individuals with cerebral palsy receiving continuousintrathecal baclofen treatment: a matched-cohort study LINDA E KRACH1 | ROBERT L KRIEL2 | STEVEN M DAY3 | DAVID J STRAUSS3 1 Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN, USA. 2 Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA. 3 Life Expectancy Project, San Francisco, CA, USA.
Correspondence to Dr Linda E Krach at the Department of Physical Medicine and Rehabilitation, University of Minnesota, MMC 297, 420 Delaware Street SE,Minneapolis, MN 55455, USA. E-mail: firstname.lastname@example.org AIM To determine whether intrathecal baclofen (ITB) changes mortality risk in Accepted for publication 17th June 2009.
METHOD Records were reviewed for all persons with CP who were managed withITB for hypertonicity at a specialty hospital in Minnesota between May 1993 and August 2007. A comparison cohort was randomly selected from clients of the CDER Client Development Evaluation Report California Department of Developmental Services who were initially evaluated between 1987 and 1990 and were matched to those with ITB for age, sex, Gross Motor Function Classification System (GMFCS) level, presence or absence of epilepsy, and feeding-tube use. Survival probabilities were estimated using the Kaplan–Meier method, and differences were tested via log-rank.
Provision of data from the California Depart- RESULTS Three hundred and fifty-nine persons with CP (202 males, 157 females) ments of Developmental Services and Health receiving ITB for hypertonicity (mean age 12y 8mo, SD 7y 9mo, range 3y 1mo to Services is gratefully acknowledged. We are 39y 9mo) were matched to 349 persons without ITB pumps (195 males, 154 grateful to Elissa Downs for assistance with females; mean age 12y 7mo, SD 8y 4mo, range 2y 7mo to 40y). The proportion extraction of information from Gillette medical of patients at different GMFCS levels in the ITB and in the non-ITB cohorts, respectively, was as follows: level II 3% and 3%, level III 16% and 16%, level IV38% and 37%, and level V 43% and 44%. Survival at 8 years of follow-up was92% (SD 1.9%) in the ITB cohort and 82% (SD 2.4%) in the non-ITB cohort(p<0.001). After adjustment to account for recent trends in improved survival inCP, 8-year survival in the non-ITB cohort was 88%, which was not significantlydifferent from the ITB cohort (p=0.073).
INTERPRETATION ITB therapy does not increase mortality in individuals with CPand may suggest an increase in life expectancy.
Cerebral palsy (CP) is the most common congenital cause used to treat hypertonicity associated with CP.2–4 In addi- of disability in children, affecting approximately 2 to 3 per tion to the long-term reduction of hypertonicity, authors 1000 live births.1 Spasticity is reported in approximately have reported improvement in comfort, positioning, ease 70% of those with CP and is thought to interfere with of care provision, and motor function in select groups of function and comfort. Baclofen is a derivative of gamma- individuals, and a reduction in the anticipated need for aminobutyric acid that is used to treat spasticity. The effec- orthopedic surgery.2,5,6 Progression of hip dislocation may tiveness of oral baclofen is limited by its sedating side be reduced with ITB, although the effect of ITB on the effects, so the drug is often administered intrathecally by progression of scoliosis is controversial.7–10 continuous infusion to deliver it to the site of action, the ITB therapy involves the surgical implantation of a pro- spinal cord. Intrathecal baclofen (ITB), which was grammable pump with a reservoir for the continuous deliv- approved by the US Food and Drug Administration in ery of baclofen to the intrathecal space. As such, it is 1996 for use in individuals with CP, is effective in the associated with risks related to surgery, hardware, and the reduction of spasticity as well as dystonia and is frequently drug itself: for example, the presence of a foreign body ª The Authors Journal compilation ª Mac Keith Press 2009 results in a risk of infection, hardware can malfunction, Developmental Services (DDS) who used the services at acute withdrawal of ITB can result in a potentially life- least once between January 1987 and December 1990.
threatening syndrome, and significant overdose of ITB can This period was selected to ensure that the control cohort was not receiving ITB therapy (as it was before the ITB is most frequently used in individuals with severe approval of ITB for use in CP) and to allow sufficient fol- motor impairment who are at the greatest risk of reduced low-up time to estimate survival to approximately 8 years.
life expectancy compared with their typically developing Services provided by the DDS include medical treatment, peers. Numerous studies have identified factors associated occupational or physical therapy, case management, and with mortality and survival of persons with CP. Mortality social services. Individuals receiving services from the rates are higher, and survival probabilities lower, for those DDS are evaluated approximately once a year with a struc- with more severe CP, severity being measured by simple tured interview known as the Client Development Evalua- functional variables including gross and fine motor skills tion Report (CDER);19 this instrument contains over 200 (ambulation, rolling, or crawling) and feeding ability.12–16 psychological, medical, functional, behavioral, and cogni- Comparisons of survival rates in persons with CP in the tive items, and the reliability of the functional items has USA, the UK, and Australia that have accounted for been assessed and judged to be satisfactory.20 these basic functional variables reveal remarkably similar From the medical records of the Minnesota ITB and results.17 Epilepsy and degree of mental retardation* can California non-ITB cohorts, we extracted information on further adversely affect survival.16,18 The purpose of the each person’s age, sex, presence or absence of epilepsy, use present study was to determine whether ongoing man- of feeding tubes, presence of spasticity or dystonia, and agement of hypertonia with ITB is associated with an functional status. In the Minnesota ITB cohort, functional increase in the long-term risk of mortality in persons status was determined by one of the authors (LEK), who determined the Gross Motor Function Classification Sys-tem (GMFCS)21 level at the time-point closest to the date of pump implantation when the patient had sufficient After University of Minnesota Institutional Review information recorded in the medical chart. In the Califor- Board approval, medical records were reviewed and nia non-ITB cohort, functional status was measured using abstracted for a consecutive series of persons followed the CDER and converted to a GMFCS level using the at Gillette Children’s Specialty Healthcare in St Paul, CDER variables of rolling and sitting, crawling and stand- MN, USA, who were receiving ITB for management of increased muscle tone due to static encephalopathy, and Each person in the Minnesota ITB cohort was placed who had their pumps placed between May 1993 and into one of 240 bins according to the following criteria August 2007. Those with acquired brain injury, neuro- measured at time of pump placement: age (in 5-year degenerative disorders, or spinal-cord injury were groupings: 2y 6mo to <7y 6mo, 7y 6mo to <12y 6mo, 12y excluded, as was one person who was 57 years old at 6mo to <17y 6mo, 17y 6mo to <22y 6mo, and 22y 6mo to the time of pump placement and thus more than 2SD <27y 6mo, with a final group of 27y 6mo to <40y), sex, above the average age and more than 17 years older presence or absence of epilepsy, feeding-tube use, and than the next oldest person. The overall size of the cohort was determined by the number of individuals Persons from the California non-ITB cohort were also who were receiving ITB management at the hospital on placed into one of the 240 bins described above, with the a regular basis, excluding those who had their implant criteria measured at the earliest DDS evaluation between surgery at the hospital but planned all pump manage- 1987 and 1990, so that the numbers in each bin were simi- ment at a location closer to their homes. The hospital lar to those for the Minnesota ITB cohort. In a few cases, serves a wide geographic area, including the US states insufficient numbers were available in the California non- of Minnesota, North Dakota, South Dakota, Iowa, and ITB cohort, so the final number is 10 fewer than in the Minnesota ITB cohort. A complete description of the A control cohort with CP but not receiving ITB treat- selection of the California non-ITB cohort and matching ment and excluding those with brain damage of postnatal origin, such as traumatic brain injury or near drowning, In the Minnesota ITB cohort, most individuals were degenerative disorders, or genetic anomalies, was randomly followed periodically. If they were not receiving their selected from clients of the California Department of routine pump care at Gillette, a simple survey inquiringabout the status of the individuals and their ITB pump was sent to the last known address after institutional Developmental Medicine & Child Neurology 2009 Congenital anomalies (e.g.,congenital heart defect, braindefect) (n=315)Chromosomal anomalies random selectionsare made tomatch individualsin the Minnesota DevelopmentEvaluation Reportof: 5 Gross Motor Figure 1: Selection of the California cohort of persons with cerebral palsy (CP) without intrathecal baclofen (ITB) pumps.
review board approval for that contact. If letters to patients or their families were returned without a for- Survival probabilities were estimated for each cohort using warding address, the last known pump-managing pro- the Kaplan–Meier method, and differences were tested by vider was contacted for information. If contact could the log-rank test.23 Time zero was the date of implantation not be established, the Minnesota Death Certificate of the ITB pump for the Minnesota cohort or earliest DDS Index (http://people.mnhs.org/dci/search.cfm) and North evaluation between 1987 and 1990 for the California non- Dakota Department of Public Health Public Death ITB cohort. Those in the ITB cohort who were continuing (https://secure.apps.state.nd.us/doh/certificates/ follow-up at Gillette were censored on 31 December 2007.
Persons in the Minnesota ITB cohort without recent fol- whether a date of death could be found for those indi- low-up who did not respond to the mailed survey were cen- viduals. For the California non-ITB cohort, we obtained sored at 1.5 months after last contact. Of the 359 persons mortality information from electronic files from the in the Minnesota ITB cohort, 12 (3%) were lost to follow- California Department of Health Services.22 up and were therefore censored 1.5 months after their last Survival with Intrathecal Baclofen in CP Linda E Krach et al.
contact. For those in the California non-ITB cohort, the Table I: Demographics of persons with cerebral palsy with (Minne- corresponding rule was to censor 6 months after last DDS sota) and without (California) intrathecal baclofen (ITB) pumps evaluation or on 31 December 1995, whichever was earlier.
This rule applied to approximately 15% of the entire California non-ITB cohort (and to a similar proportion ofthe final random sample).
To estimate how much of the difference in survival probabilities may have been due to overall improvement in survival from the earlier period of the California non-ITB cohort follow-up to the later period of the Minnesota ITB cohort follow-up, an adjustment was made based on a decline in mortality rate of 3.4% per year reported by Strauss et al.15 for children with severe CP (roughly equivalent to GMFCS levels IV and V) and children and Statistical analyses were carried out using SAS ⁄ STAT version 6.12 (SAS Institute, Cary, NC, USA), with S-PLUS version 4.0 (Insightful Corp. ⁄ Tibco Spotfire, Palo After exclusions, 359 participants with ITB pumps from Gillette (Minnesota) were identified (202 males, 157 females; mean age 12y 8mo, SD 7y 9mo, range 3y 1mo to 39y 9mo). The number in the comparison cohort from California without ITB pumps matching these was 349 (195 males, 154 females; mean age 12y 7mo, SD 8y 4mo, range 2y 7mo to 40y). The distribution of participants byGMFCS level, gastrostomy versus oral feeding, presence aYear pump placed in the Minnesota ITB cohort. GMFCS, Gross or absence of epilepsy, and age is shown in Table I.
Motor Function Classification System.
The mean follow-up was 6 years 2 months (SD 3y) in the Minnesota ITB cohort and 6 years 2 months (SD 2y 6mo) in the California non-ITB cohort. During follow-upthere were 21 deaths in the Minnesota ITB cohort and 50 deaths in the California non-ITB cohort. Survival at8 years after time zero was 92% (SD 1.9%) in the Minne- sota ITB cohort and 82% (SD 2.4%) in the California non-ITB cohort (Fig. 2). These were statistically signifi- cantly different (p<0.001). However, the cohorts were not matched for calendar year; with an approximate adjustmentto account for recent trends in improved survival in CP as reported by Strauss et al.,15 the 8-year survival in the Cali- Years since pump implantation (MN) or age at matching (CA) fornia non-ITB cohort increases to 88% (Fig. 3). Assumingthe adjustment to be exact and using adjusted observed andexpected numbers of deaths in the California non-ITB Figure 2: Survival of persons with cerebral palsy with (Minnesota, cohort in calculating the log-rank statistic, the difference MN) and without (California, CA) intrathecal baclofen pumps.
in survival curves was no longer significant (p=0.073).
DISCUSSIONITB pumps are usually implanted in persons with CP who further adversely affect survival. We are reassured that our are most at risk for premature death, so we were concerned study has shown that survival is comparable to, or some- that the risks known to be associated with ITB might what better than, a matched cohort without pumps. The Developmental Medicine & Child Neurology 2009 levels or were older and not fed via gastrostomy, the adjust-ment (from Figs 2 and 3) may overestimate the improve- ment in survival in the California non-ITB cohort. In anyevent, it is unclear how much of the improved survival over recent years might be attributable to improvements andinnovations in medical care and treatment, which may California with secular adjustment (lower curve, dashed) Another limitation relates to the assignment of GMFCS level, and thus the matching of the cohorts by level ofmotor function. Assignment of GMFCS levels was meth- odologically different for the two cohorts, and conversion Years since pump implantation (MN) or age matching (CA) of motor function information on the California CDER toGMFCS level has not been validated. Assuming that the Figure 3: Survival of persons with cerebral palsy with (Minnesota, matching of GMFCS levels is appropriate, there is a fur- MN) and without (California, CA) intrathecal baclofen pumps, with ther limitation relative to the survival analyses, as, within a secular adjustment. CI, confidence interval.
given level of GMFCS, differences in level of gross motorfunction may still exist and can affect survival.
Finally, the analyses were retrospective and involved survival in California has been shown to agree closely with cohorts followed by different professionals at different that in the UK and Australia (matched for important func- locations, and with different frequencies of follow-up. For tional variables).17 The only outcome addressed in our persons who were lost to follow-up, data were censored study is survival; other benefits of ITB therapy have been 1.5 months after last contact in the Minnesota ITB cohort previously reported and include tone reduction, comfort, and 6 months after last DDS evaluation in the California ease of care, and decrease in number of anticipated ortho- non-ITB cohort. These censoring rules were used (rather than censoring exactly at time after the last visit or evalua- The most obvious limitation of the present study was tion), as visits typically occurred every 3 to 6 months in that the cohorts were not prospectively randomly assigned.
Gillette (Minnesota), and annually in California. However, However, blinding of observation would not be relevant variations in the censoring rule, including censoring at with the outcome measure of survival, and implementation time of last contact, had only a marginal impact on the of a randomly assigned study would be impossible in cur- actual estimates of survival. For example, censoring exactly rent practice. In addition to the lack of random assignment at the time of last contact changed the estimated 8-year to treatment groups that could have lead to selection bias, probability of survival from 92.0% to 91.9% for the Min- our comparison was further compromised by the fact that nesota ITB cohort and from 82.0% to 81.8% for the the cohorts were not contemporaneous, and secular trend adjustments can only be approximate. The adjustment Notwithstanding the stated limitations, clinicians can made to account for the decline in mortality rates from find some reassurance in the finding that survival in per- 1988 to 2000 was based on results for children aged up to sons with CP who have severe motor impairment appears 15 years with the most severe impairments due to CP and not to be adversely affected, and could possibly be for children and adults who were fed by gastrostomy improved, with ITB therapy. It will be challenging to tube.15 As approximately 36% of the California non-ITB design and implement a study to address this question cohort in the present study were functioning at higher 3. Albright AL, Gilmartin R, Swift D, Krach 1. Matthews DJ, Wilson P. Cerebral palsy. In: Molnar GE, Alexander MA, editors. Pediat- term intrathecal baclofen therapy for severe 5. Gerszten PC, Albright AL, Johnstone GF.
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