FEAT DAILY NEWSLETTER
Sacramento, California http://www.feat.org
February 14, 2002
News Morgue Search www.feat.org/search/news.asp
·
Autism Tragedies, Autism Inquest
·
Methodological Issues In Designing A Multisite Trial Of
Risperidone in children and adolescents with autism.
·
Vitamin B6 as Add-On Treatment In Chronic Schizophrenic
And Schizoaffective Patients: A Double-Blind, Placebo-Controlled Study.
·
Risperidone Treatment In Children And Adolescents With
Autism:
Short- And Long-Term Safety And Effectiveness.
[This special report is from Jane Pickett of the Autism
Tissue Program Research Park Princeton, NJ.]
Dennis Debbaudt summed up the sad news this week about
the little boy
of five who was missing and then found drowned in Pompano,
Florida, ‘Body of
missing autistic boy found in Pompano canal’
http://www.sun-sentinel.com/news/local/broward/sfl-0210missingboy.story?coll
=sfla%2Dnews%2Dbroward
“This all too common story illustrates yet another reason to
get ourselves and others educated about the risks associated with kids who have
autism”. Dennis is the author of “Avoiding
Unfortunate Situations”, the parent of a young adult son with autism, and a
25-year veteran of law enforcement in the private sector who has developed
police training materials and has presented this information to over 1,000 law
enforcement professionals.
He is absolutely correct about the need to assess risk in
the autism population. A publication
last month by Sherrard, Tonge and Ozanne-Smith Injury Risk in young people with
intellectual disability”, Journal of Intellectual Disability Research 46:6-16),
reported on risk assessment in young people with ID (Intellectual Disability)
in Australia.
Their abstract states:
Australia study demonstrates a largely unrecognized public
health problem of a high unintentional injury risk for young people with ID,
and identifies substantial and important risk factors. Injury prevention programmes with a
particular focus on this with highly disturbed behaviors or epilepsy, are
warranted in this population. Disruptive, self-absorbed, have communication
disturbance, are anxious, have problems relating socially or have ADHD symptoms
are at increased risk for injury. Age
sex and IQ not sign risk factors – a result in sharp contrast with the general
pop where injury incidence varies with age and males have approx double the
injury risk of females (Gallagher 1984).
I have received many questions about the recent
publication, ‘Causes of Death In Autism’, written with colleagues Drs. Robert
Shavelle and David Strauss. We report a
higher mortality rate among those with autism.
What follows is the rationale for the study was done and its
conclusions.
There were several reasons that prompted this study. One was a question from Dr. Bernie Rimland,
who asked if the Autism Tissue Program had autism mortality information, citing
a reference for a two-year-old study by Strauss and Shavelle reporting data
from the extensive California developmental disabilities registry, with 11,347
autistic individuals, that clearly showed that persons with autism are subject
to increased mortality risk, with an overall mortality ratio of 213% (mortality
ratio, MR, is observed deaths compared to expected deaths converted to a
percentage). The MR for females, 490%,
was notably higher than that for males, 167%.
The life expectancy of a 5-year-old in that cohort of was reduced by 6.1
years for boys and 12.3 years for girls.
About the same time, in the summer of 2000, the Autism
Tissue Program was contacted for the brain donation for a nine-year-old boy,
who died suddenly and unexpectedly.
Earlier that year, a girl, 7, and a boy, 8, died in other states. In September, another boy, 8, died at home
in Minnesota. All had a seizure
disorder; however, the disorder was not considered life-threatening, and, the
very first donor to the Autism Tissue Program was a child of 14, with no known
seizure disorder, died suddenly and unexpectedly of hyperthermia. These deaths raised questions about mortality. Also, in the summer of 2000, I met with
local autism advocacy leaders at the M.I.N.D. Institute to discuss mutual brain
research goals with the Autism Tissue Program.
In support of this collaborative relationship between NAAR, the ASA
Foundation and the M.I.N.D. Institute, the East Bay chapter of ASA gave the
Autism Tissue Program a donation of $10,000.
These funds were spent to further analyze California mortality data. The conclusions of the study follow
(references and/or reprints supplied on request – email atp@brainbank.org):
‘The aim of this study was to expand upon the initial
report of excess mortality in the California autism population (Strauss &
Shavelle, 1998) by exploring the cause of the death. We excluded the non-ambulatory, a group known to have a very high
mortality rate; even so, subjects had higher mortality than expected in the
general population, after adjustment for age and sex.
As medical records on cause of death were not
generally available, we
worked with computer codes and death certificates. It should
be noted that
the cause?specific SMRs reported here are conservative, as
in 16% of the
cases we were unable to determine the cause. Although these
sources are
frequently used in large epidemiologic studies, their
limitations are well
known (Lilienfeld & Lilienfeld, 1980). Resulting bias
may have been reduced,
however, because the same source (California mortality
computer tapes) was
used for the causes of death of both the subjects with
autism and the
reference California population.
In the no or mild mental retardation group, deaths by
seizures, nervous system dysfunction, drowning, and suffocation were all more
than three times higher than would be expected in the general population. For
the more severely retarded subjects, all categories of cause of death except cancer
and “all other causes >800” were more than three times higher. External causes of death excluding drowning
and suffocation, which were analyzed separately, were actually lower than
expected. This is largely because the general population death rate from
injuries climbs rapidly in the teen years, whereas many autistic teenagers may
lack the same opportunities for risky behavior.
Overall, children between the ages of 5 and 10 had the
highest SMRs, especially girls with an SMR of 16.8. Further research is needed on why some causes are elevated, and
on the male/female/age differences. Future studies might also examine medical
records and death certificates. The present
study reflects a fifteen-year period ending in 1997. Given the large increase in autism intakes into the California
system from the first to the second half of the last decade (148%, unpublished
data), a follow-up through 2000 should provide further information on the
younger age groups.
State databases and individual records are extremely
important in obtaining the numbers necessary to examine cause of death, or
other characteristics of interest in autism.
For instance, the prevalence of epilepsy for all ages in this study was
4.2 %. This figure is at the lower end
of the range of seizure frequency (4-60%) reported in various studies. The CDER contains fields for 8 seizure
types, frequencies for each, condition impact and whether the person takes
anticonvulsant medication. Further data
mining could assess age, level of cognitive function and type and degree of
language dysfunction pertinent to epilepsy (Tuchman, 2000). The potential of these data sources is
immense and work should continue to improve the accuracy and consistency of the
autism data in all states.
The prerequisite for accuracy of data is equally true for
mortality reporting. In the present
study, a review of ICD-9 codes for the 202 deaths showed many instances of
ill-defined causes of death. For
example, 3 were coded 299 (infantile autism); 13 coded 318 or 319 (moderate
mental retardation or mental retardation not otherwise specified); and 16 were coded
799 (unspecified causes). It is
estimated that sudden unexplained deaths (SUD) claims over 4000 persons between
the ages of 1 and 22 each year in the U.S. (Ackerman et.al., 2001). Ackerman and colleagues (1999, 2001) used
post-mortem ‘molecular’ tissue autopsies to link a KVLQT1 gene defect with
fatal cardiac arrhythmias associated with one form of inherited long QT syndrome
(LQTS) and swimming-triggered cardiac events.
Another autosomal-dominant LQT gene, HERG, is located on chromosome
7q35-36 (Wang et. al., 1998).
Deaths due to drowning and epilepsy are common in the
California autism population and deserve further forensic study as does the
possibility of ‘acquired’ LQTS from various medications. Ponti et. al (2001) have called for a
consensus to organize information on QT prolongation and occurrence of Torsades de Pointes, polymorphic ventricular
tachycardia thought to be initiated by early after-depolarizations in the
cardiac Purkinje system (Chiang & Roden, 2000), with non-antiarrhythmic
drugs.
Looking strictly at patient populations with epilepsy, the
rate of sudden, unexpected and unexplained death in epilepsy (SUDEP) exceeds
the expected rate of sudden death in the general population by nearly 24 times (Ficker,
et. al. 1998; Annegers & Coan, 1999).
The incidence and risk of SUD and SUDEP will only be fully ascertained
with careful postmortem examination and complete death narratives.
The information from this study is relevant to the Autism
Tissue Program (ATP), that recruits brain donors for biomedical research, as it
reveals age-trends in the number and causes of death. Without this data, one would
not know if a given group of brain tissue cases was representative of deaths in
the autism population, or simply an unusual sample. For example, the
twenty-three donations through June 2001, 43% of which were under the age of
15, may now be viewed as fairly typical.
The causes of death were: seizures (6, 2 of these in the SUDEP
category), drowning (5), external injury such as auto trauma (4), congestive
heart failure (2), hyperthermia (1), infection (1), GI bleeding and seizure
disorder (1), anoxia (1), sepsis from infected bowel (1), cardiac arrest, SUD
(1). Nevertheless, each donor represents
one or more potential subsets of autism characteristics or co-morbidity that
must be taken into account in brain tissue research. Hyperthermia was associated with at least three deaths and, in
two of these, neuroleptic malignant syndrome (Andreassen & Pedersen, 2000;
Kahn & Farver, 2000) was thought to contribute to the cause of death.
While the annual monetary cost of autism in the US is
estimated at roughly $26 billion (Maltby, 2000), the impact of higher mortality
is an incalculable emotional cost to families. There should be a concerted
effort to address autism aging, morbidity and mortality. We hope that this
initial study on causes of death in autism will lead to improvements in
prevention, care, and planning for this population.’ (end of conclusions to report)
Like many studies, more questions have been generated than
were answered. It should; however, help promote an inquest into autism injury risk
and deaths in California, the US and even other countries. It is important to
define the magnitude of the problem and identify the associated causes and risk
factors that contribute to mortality.
There is an excellent lecture on the subject of risk assessment on the
web (http://www.pitt.edu/~epi2670/)
by University of Pittsburgh Epidemiology Professor, Thomas J. Songer,
Ph.D. This discussion of monitoring and
risk assessment comes from that site. Death and injury monitoring, or surveillance,
is very important as a means to formulate reasonable injury and death
PREVENTION initiatives. Other injury
control measures such as airbags, helmets, seatbelts were implemented only
after it became apparent that injuries were occurring in relatively high
numbers. Effective injury control is based upon an understanding of injury
rates; i.e. how many injuries occur within a given population. The primary means to identify injuries is to
establish a surveillance system that is generally defined as the systematic
assessment of disease or injuries with a common method. Monitoring occurs over time and thus allows
researchers to evaluate changes. Death
certificates, medical records, surveys of medical facilities, coroner and
police reports all contain different and potentially useful information.
The first data source often examined in injury research is
death certificates. In the United States, the National Center for Health Statistics
(NCHS) maintains information on deaths and death certificates. The NCHS gathers this information from the
individual states. Each state, in turn, has a law that requires for death
certificates to be completed for all deaths. A standard death certificate form
is collected across the states. Thus,
the death certificate data compiled by the NCHS represents one of the few
sources that allow for comparisons across geographic regions and standard
demographic factors. Unfortunately, it is difficult to obtain adequate cause of
injury or death information. Moreover,
according to Dr. Songer, existing data
systems are often difficult to integrate together. Crime-based systems do not always assess injuries and emergency
medical transport systems do not always match up with emergency department or hospital
admission records.
Active studies employ regular outreach and monitoring of
surveillance sites. And what are these surveillance sites? They are most often state and federal
governmental surveys. One in particular that could provide information is the
CDC Behavioral Risk Factor Surveillance System that keeps statistics on asthma,
diabetes, alcohol consumption, etc., but not autism. Autism can be monitored if it becomes a ‘reportable’ condition -
the CDC reporting system is vast and might already have the capacity to monitor
autism injury and deaths.
The NCHS is also responsible for the government-based
health and health care surveys in the United States. Two important surveys for
injuries are the NHIS (National Health Interview Survey) and the NHAMCS
(National Hospital Ambulatory Medical Care Survey). The NHIS is used primarily to monitor the health of the
population. It includes several questions on physician diagnosed illnesses and
disability. It is based upon a sample of the population and represents a
cross-sectional survey. It is conducted annually. Injury-specific items are included in the NHIS. Two questions identify
injury and poisoning events. Both address events which occurred in the previous
3 months and which required medical attention. The recent redesign of the
survey has added further information on injuries. Data are now collected on external causes of injuries (E-codes),
and the circumstances that surround the injury (type, activity, place of occurrence).
A question is how useful is this data in 2002? The data in the NHIS apparently represent
only self-reported injuries. National
Health Interview Survey on Disability (NHIS-D) was last updated on
9/16/98. The NHAMCS is a survey from
the NCHS. It assesses the characteristics of ambulatory care use in hospital
settings. This included emergency department activities. Thus, it is of
interest to injury researchers. The NHAMCS is not an annual survey, though, and
the latest data available are for the years 1995-96.
Somehow, we need to begin the process of standardizing the
information that is collected on injuries and deaths in children with autism ad
related disorders. In this way, it will
be possible to have some comparisons between data systems and develop
responsible prevention programs.
Regarding brain tisue donation; no, it is not
counter-productive to the Autism Tissue Program to encourage prevention. It is estimated that around 4-5000 persons
with autism die annually (6300 Americans die each day, 2.3 mill each year
US). If even 1% of the families chose
to donate brain tissue after their loved one died, there would be almost more
cases in a year than exist now. Every
unexpected death of a child will prompt
an investigations and autopsy; the brain and other organs will be removed and examined. If not donated, the brain is returned to the
body cavity and funeral arrangements take place (viewing is possible). Also, being an organ donor does not mean
that brain tissue is automatically donated.
It is necessary to call 1-877-333-0999 for brain donation.
Everyone I work with at the Autism Tissue Program values
quality of life, protection of children and adults when needed, and research to
understand brain function and autism.
Jane Pickett, Ph.D. Director, Autism Tissue Program 99
Wall Street, Research Park Princeton, NJ 08540 1-877-333-0999 (24-hour) Fax: (609)
430-9163 Email: atp@brainbank.org Web: www.brainbank.org
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* * *
Methodological Issues In Designing A Multisite Trial Of
Risperidone in children and adolescents with autism.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ui
ds=11838820&dopt=Abstract <- - address ends here. Scahill L, McCracken J, McDougle CJ, Aman M,
Arnold LE, Tierney E, Cronin P, Davies M, Ghuman J, Gonzalez N, Koenig K,
Lindsay R, Martin A, McGough J, Posey DJ, Swiezy N, Volkmar F, Ritz L, Vitiello
B.
Research Unit on Pediatric Psychopharmacology Yale
University, New Haven,
Connecticut 06520, USA. lawrence.scahill@yale.edu
OBJECTIVE: To describe the methodological challenges and
decisions made in developing a multisite, controlled study of risperidone in
children and adolescents with autism.
METHODS: Review the design considerations for clinical
trials in children with autistic disorder accompanied by severe tantrums,
aggressive and/or self-injurious behaviors. These design considerations include
the definition of inclusion criteria that are relevant to clinical practice and
matching study design to the goal of evaluating short- and long-term effects.
Additional ethical and scientific issues concern the length of trial and sample
size.
RESULTS: We undertook a short-term, placebo-controlled
study to evaluate the efficacy and safety of risperidone in children and
adolescents with autistic disorder. This trial design was followed by an
extended open-label maintenance on risperidone to confirm durability of
treatment effects and to monitor safety. Finally, a placebo-controlled
discontinuation study tested the need for continuous treatment.
CONCLUSIONS: In the absence of standard pharmacological
treatment for children with autistic disorder, a placebo-controlled study
remains the most appropriate method of testing efficacy and safety. The
clinical relevance of this study is enhanced by the addition of an extended
maintenance phase followed by a placebo discontinuation.
PMID: 11838820 [PubMed - in process]
* * *
Vitamin B6 as Add-On Treatment In Chronic Schizophrenic
And Schizoaffective Patients: A Double-Blind, Placebo-Controlled Study.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ui
ds=11838627&dopt=Abstract <- - address ends here. Vitamin B6 as add-on treatment in chronic
schizophrenic and schizoaffective patients: a double-blind, placebo-controlled
study. Lerner V, Miodownik C, Kaptsan
A, Cohen H, Loewenthal U, Kotler M.
Ministry of Health Mental Health Center, Faculty of Health
Sciences,
Ben-Gurion University of the Negev, Be’er-Sheva, Israel. lernervld@yahoo.com
BACKGROUND: Vitamin B6, or pyridoxine, plays an intrinsic
role in the synthesis of certain neurotransmitters that take part in
development of psychotic states. Several reports indicate that vitamin B6 may
be a factor in a number of psychiatric disorders and related conditions, such
as autism, Alzheimer’s disease, hyperactivity, learning disability, anxiety
disorder, and depression. Moreover, there are anecdotal reports of a reduction
in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment
of patients suffering from schizophrenia or organic mental disorder. The aim of
this study was to examine whether vitamin B6 therapy influences psychotic
symptoms in patients suffering from schizophrenia and schizoaffective disorder.
METHOD: The effects of the supplementation of vitamin B6
to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic
and schizoaffective patients (DSM-IV criteria) were examined in a double-blind,
placebo-controlled, crossover study spanning 9 weeks. All patients had stable
psychopathology for at least 1 month before entry into the study and were
maintained on treatment with their prestudy psychoactive and antiparkinsonian
medications throughout the study. All patients were assessed using the Positive
and Negative Syndrome Scale (PANSS) for schizophrenia on a weekly basis.
Patients randomly received placebo or vitamin B6, starting at 100 mg/day in the
first week and increasing to 400 mg/day in the fourth week by 100-mg increments
each week.
RESULTS: PANSS scores revealed no differences between
vitamin B6- and placebo-treated patients in amelioration of their mental state.
CONCLUSION: Further studies with larger populations and
shorter duration of illness are needed to clarify the question of the possible efficacy
of vitamin B6 in treatment of psychotic symptoms in schizophrenia.
PMID: 11838627 [PubMed - in process]
* * *
Risperidone Treatment In Children And Adolescents With
Autism: Short- And Long-Term Safety And Effectiveness.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ui
ds=11837403&dopt=Abstract <- - address ends here. Malone RP, Maislin G, Choudhury MS, Gifford
C, Delaney MA.
MCP Hahnemann University, Philadelphia, PA, USA. richard.malone@drexel.edu
OBJECTIVE: Atypical neuroleptics, including risperidone,
are used to treat children with autism, despite limited efficacy and safety
data. Many clinicians believe that risperidone will not induce dyskinesias in
children. The authors investigated open
risperidone treatment in children with autism and included findings on
dyskinesias.
METHOD: The sample included 22 outpatients (mean age = 7.1
years) diagnosed with autism (DSM-IV). Treatment consisted of a 1-month short-term
phase followed by a 6-month long-term phase. At the end of the long-term phase,
drug was discontinued, and the need for further drug treatment and the
occurrence of withdrawal dyskinesias were assessed. Measures included the
Clinical Global Impressions (CGI), Children’s Psychiatric Rating Scale (CPRS),
and the Abnormal Involuntary Movement Scale.
RESULTS: The mean risperidone dosage was 1.2 mg/day.
Overall, the children had significant clinical improvement as assessed by the
CPRS and CGI. Untoward effects included sedation, increased appetite, and
weight gain. Two of 13 (15.4%) children treated long-term developed mild, reversible
withdrawal dyskinesias when risperidone was discontinued. No child developed
dyskinesias on risperidone.
CONCLUSIONS: Risperidone shows promise as a treatment in
autism. However, withdrawal dyskinesias
were noted. Further assessment of the risk of risperidone-related dyskinesias
is indicated.
PMID: 11837403 [PubMed - in process]
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