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Keywords:

  • Intractable;
  • Epilepsy;
  • Young children;
  • Mortality

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Purpose:  To determine the prevalence and identify predictors of medical intractability in children presenting with epilepsy before 36 months of age, and to assess the effect of medical intractability on long-term mortality and intellectual function.

Methods:  Children with newly diagnosed epilepsy before 36 months between 1980 and 2009 while resident in Olmsted County, MN, were identified. Medical records were reviewed to collect epilepsy-specific variables and long-term outcome data. Medically intractable epilepsy was defined as either (1) seizure frequency greater than every 6 months at final follow-up and failure of two or more antiepileptic drugs for lack of efficacy, or (2) having undergone epilepsy surgery after failure to respond to two or more antiepileptic drugs.

Key Findings:  One hundred twenty-seven children with new-onset epilepsy were identified and followed for a median of 78 months. Medically intractable seizures occurred in 35%, and significant predictors on multivariate analysis were age ≤12 months at diagnosis (odds ratio [OR] 6.76, 95% confidence interval [CI] 2.00, 22.84, p = 0.002), developmental delay at initial diagnosis of epilepsy (OR 20.03, 95% CI 3.49, 114.83, p = 0.0008), neuroimaging abnormality (OR 6.48, 95% CI 1.96, 21.40, p = 0.002), and focal slowing on initial EEG (OR 5.33, 95% CI 1.14, 24.88, p = 0.03). Medical intractability occurred early in the course in most children, being seen in 61% by 1 year, and 93% by 5 years after initial diagnosis. Mortality was higher (20% vs. 0%, p < 0.001) and intellectual outcome poorer (p < 0.001) if epilepsy was medically intractable.

Significance:  One third of children presenting with epilepsy before 36 months will be medically intractable, and significant predictors are identified. Medically intractable epilepsy is associated with increased mortality risk and significant intellectual disability.

Epilepsy is one of the most common neurologic disorders in children and has its highest incidence in the younger ages, with rates of 102.4 per 100,000 per year in the first year of life (Camfield et al., 1996; Wirrell et al., 2011).

Although population-based studies in children with epilepsy have shown a relatively favorable long-term outcome, with nearly two thirds achieving seizure freedom and nearly one half being able to discontinue antiepileptic drugs (Brorson & Wranne, 1987; Camfield & Camfield, 2003; Sillanpaa & Schmidt, 2006), no population-based study has specifically addressed outcomes in very young children. Epilepsy in early childhood may have a less favorable outcome for a number of reasons. Electroclinical syndrome remains one of the most robust predictors of outcome (Berg et al., 2001), and many severe epileptic encephalopathies, including West, Dravet, and Lennox-Gastaut syndromes, present early in life. Furthermore, specific etiologies including cortical dysplasias and other structural abnormalities (Semah et al., 1998), neurometabolic disorders, and perinatal brain injury are highly correlated with intractability and usually present in early childhood.

Early onset epilepsy is frequently associated with significant comorbidity. Intellectual disability frequently coexists with epilepsy in young children as a result of the underlying symptomatic cause of the seizures. However, there is also evidence that further decline in intellectual function may result from the sequelae of poorly controlled seizures in the developing brain (Berg et al., 2004b), emphasizing the importance of early recognition and effective therapy of intractable epilepsy in early childhood. Furthermore, the underlying structural and metabolic brain disturbances that lead to epilepsy, as well as ongoing uncontrolled seizures may result in greater morbidity and mortality due to profound neurodevelopmental delay. In a study that focused only on those with symptomatic generalized epilepsy, nearly one fourth had died, and most survivors had mental retardation and were highly dependent (Camfield & Camfield, 2007, 2008).

The goals of this study were to determine the prevalence and predictors of medical intractability in children with onset of epilepsy before 36 months of age, and to assess long-term mortality and intellectual function in those who met criteria for medical intractability.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

We performed a retrospective chart review of our 30-year, population-based cohort of all children who had new-onset epilepsy before 36 months of age.

Case identification

Cases were ascertained by screening of the complete diagnostic indexes of the Rochester Epidemiology Project. These indexes include inpatient diagnoses, as well as diagnoses at the time of outpatient and emergency room visits at all medical care facilities in Olmsted County, Minnesota (Melton, 1996). Charts were screened using a diagnostic rubric that included all seizure and convulsion diagnosis codes, and all identified charts were reviewed by a pediatric epileptologist. We identified children aged 1–36 months with new-onset epilepsy diagnosed while residing in Olmsted County, Minnesota, between 1980 and 2009. Date of epilepsy diagnosis was defined as the date the child was first given the diagnosis of epilepsy by a physician.

The Rochester Epidemiology project also records deaths of all patients while resident in Olmsted County. For those who died during the follow-up period, death certificates were reviewed to ascertain cause of death. For subjects who moved away and were no longer under follow-up, death records were not searched to determine deaths that occurred after their last follow-up. This study was approved by the Mayo Clinic Institutional Review Board.

Definitions

Epilepsy was defined as a predisposition to unprovoked seizures. Most subjects had two or more unprovoked seizures. However, patients with a single unprovoked seizure who were determined to be at higher risk of seizure recurrence and commenced on prophylactic antiepileptic drug treatment were also included. An abnormal neurodevelopmental examination, focal abnormality on brain imaging, initial presentation in status epilepticus, or specific electroencephalography (EEG) findings (epileptiform discharge, intermittent rhythmic focal delta activity) were considered indicative of a higher risk of recurrence. Patients who were treated after a single seizure, but who lacked any of the preceding features were excluded. We included children who had two afebrile seizures occurring within 24 h, as these children likely have epilepsy (Camfield & Camfield, 2000).

Children presenting with acute symptomatic seizures alone, defined as “seizures at the time of a systemic insult or in close temporal association with an acute neurological insult” were excluded (Beghi et al., 2010). Similarly, children who had only febrile seizures were excluded. Children with neonatal seizures were included only if their seizures recurred after 1 month of age.

For each patient, epilepsy was classified using the new International Leagues Against Epilepsy (ILAE) Commission on Classification and Terminology 2005–2009 Report (Berg et al., 2010). Factors considered in the classification included seizure type(s) based on descriptive semiologies from the medical record, EEG and neuroimaging findings, cognitive function, and for some specific syndromes, age at onset. For each case, epilepsy was classified based on mode of onset at presentation (generalized/bilateral cortical or subcortical, focal/networks limited to one hemisphere, unknown, or spasms), etiology (genetic, structural/metabolic or unknown), and electroclinical syndrome or constellation, if applicable.

Children were deemed to have developed medically intractable epilepsy if they met the following criteria: (1) failure of two or more antiepileptic drugs with seizure frequency of more than every 6 months in the year immediately before final follow-up, or (2) having undergone resective epilepsy surgery or callosotomy after failure of two or more antiepileptic agents.

Data obtained from chart abstraction

Data variables abstracted from the medical charts included demographic information (age at onset and follow-up, sex), history (perinatal complications, gestational age, postnatal brain injury, febrile seizures), epilepsy details (seizure type(s), frequency, history of status epilepticus), investigations (neuroimaging, EEG results, other metabolic or genetic studies), family history of epilepsy in first-degree relatives, and neurologic examination findings. Magnetic resonance imaging was not routinely used until 1984. The initial EEG reports were reviewed for the presence of background slowing (divided into generalized vs. focal) and presence and location of epileptiform discharge.

Epilepsy outcome at 1, 2, 3, 5, 10, 15, and 20 years after epilepsy onset, and at final follow-up regarding both seizure control (ongoing seizure frequency or seizure-free for the previous year or longer at each time point) and antiepileptic drug treatment (type and number of current medications and number of medications failed for lack of efficacy at each time point) was noted. Subjects followed for fewer than 20 years had data collected up until their last follow-up. In addition, epilepsy surgery procedures (resection, corpus callosotomy or vagal nerve stimulator placement) and use of a ketogenic diet were recorded. Development was assessed both at the time of seizure onset and last follow-up. Either formal neuropsychological testing (if available) or best clinical assessment by the reviewer (based on developmental milestones and academic achievement recorded in the patient history) were used to classify development as normal (estimated or measured developmental quotient of 80 or higher), mildly delayed (estimated or measured developmental quotient of 50–79), or severely delayed (estimated or measured developmental quotient of <50).

Data analysis

What proportion of children with epilepsy onset before 36 months was medically intractable?

The proportion of children with medically intractable epilepsy was described as a percentage. Details of these children including mode of onset, electroclinical syndrome, etiology, timing to diagnosis of medical intractability, and surgical interventions performed were reviewed.

What are the significant predictors of medical intractability in children with epilepsy onset before 36 months?

Children were divided into two groups, based on whether or not they had medically intractable epilepsy. Potential predictors of intractability were assessed by chi-square analysis for categorical variables, and t-test for continuous variables. Potential predictors assessed included gender, age at onset, developmental delay at diagnosis, abnormal neurologic examination, perinatal complications (need for hospitalization >1 week at birth, excluding for maternal reasons alone), prior febrile seizures, prior atypical febrile seizures, history of status epilepticus at diagnosis, mode of onset, etiology, number of seizures at initial diagnosis, first-degree family history of epilepsy, abnormal neuroimaging, presence and type of epileptiform discharge on initial EEG and focal or generalized background slowing on initial EEG. Variables that were significant on univariable logistic regression analysis were then considered as candidates for multivariable logistic regression model.

How does medical intractability affect mortality and cognitive outcome?

Mortality rates and intellectual outcome at final follow-up were compared using chi-square analysis for children with and without medically intractable epilepsy.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

One hundred twenty-seven children were identified over the 30-year study period with new-onset epilepsy before 36 months of age, while resident in Olmsted County, MN, accounting for 27.2% of all children aged 1 month through 17 years with new-onset epilepsy. The cohort consisted of 65 (51.2%) male patients and median follow-up was 78.1 months (interquartile range 42.2–172.7 months). Overall, 120 children (94.5%) were followed longer than 12 months, and 108 (85.0%) were followed longer than 24 months. The clinical details of our cohort are summarized in Table 1. Formal neuropsychological testing was available in only 38 subjects (29.9%) and comprised a range of evaluation tools including the Differential Abilities Scale, the Bayley Scales of Infant Development, and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI).

Table 1.   Clinical characteristics of cohort (N = 127)
VariableFrequency
  1. a 22, single focus; 5, two foci; 4, hemispheric; 36, multifocal; 9, generalized; 6, generalized plus focal; 5, hypsarrhythmia.

  2. b 4, focal slowing; 37, generalized slowing; 19, both focal and generalized slowing.

Male gender (%)65 (51)
Age at diagnosisMedian (quartiles) 1.1 years (0.4, 1.9)
Developmental delay at onset (%)63/122 (52)
Abnormal neurologic examination (%)58 (46)
Perinatal complications (%)38 (30)
Neonatal seizures (%)20 (16)
Prior febrile seizures (%)25 (20)
Prior status epilepticus (%)29 (23)
Mode of onset (%) 
 Generalized21 (17)
 Focal84 (66)
 Unknown 8 (6)
 Spasms14 (11)
Etiology (%) 
 Genetic23 (18)
 Structural/metabolic50 (39)
 Unknown54 (43)
MRI (%) 
 Not done25 (20)
 Done and normal51 (40)
 Mild, nonspecific abnormalities 9 (7)
 Significant abnormality42 (33)
Epileptiform discharge on first EEG (%)87 (69)a
Background slowing on first EEG (%)60 (47)b

What proportion of children with epilepsy onset before 36 months was medically intractable?

Forty-four children (35%) met criteria for medical intractability. In these children, mode of onset of seizures was focal in 33 (75.0%), generalized in 2 (4.5%), and spasms in 9 (20.5%). Of the 33 children with focal onset seizures, 27 had structural etiologies (12 remote brain injury, 11 malformations of cortical development [2 with dual pathology—cortical dysplasia and mesial temporal sclerosis in one and cortical dysplasia with congenital cytomegalovirus in another], 3 tuberous sclerosis, and one vascular malformation), 2 had genetic or presumed genetic causes (one 18p-, one with multiple congenital anomalies but normal chromosomes), and 4 were of unknown cause. Of the two with generalized-onset seizures, both had diffuse malformations of cortical development. Of the nine patients with spasms, seven had structural causes (four malformations of cortical development, two tuberous sclerosis, one remote brain injury), one had a genetic cause (Sotos syndrome), and one was of unknown cause. All children with unknown etiologies had undergone magnetic resonance imaging (MRI) with normal results. At the time of diagnosis, 12 of 44 had a clearly defined epilepsy syndrome including 10 with West syndrome (one of whom initially had unrecognized focal seizures but was not diagnosed with epilepsy until onset of spasms, one with Ohtahara syndrome, and one with continuous spike-wave in slow sleep.

Of these 44 children, 7 (16%) had undergone epilepsy surgery (2 extratemporal resection, 4 hemispherectomy, one callosotomy), and of these, four (57%) were seizure-free at last follow-up.

Medical intractability was most commonly seen early: 61% met criteria by the end of the first year, 86% by the end of the third year, and 93% by the end of the fifth year after initial diagnosis of epilepsy. Intractability after 1 year was similar in children with focal onset (21/33, 63.6%) and generalized seizures/spasms (8/11, 72.7%). Of those with focal seizures, 90.9% met criteria for intractability by the third year after diagnosis.

What are the significant predictors of medical intractability in children with epilepsy onset before 36 months?

Table 2 shows which factors were predictive of medical intractability in our cohort. The strongest predictors of intractability on univariate analysis included younger age at diagnosis of epilepsy, developmental delay at onset, abnormal neurologic examination, structural or metabolic etiology, abnormal neuroimaging, and both focal and generalized background slowing and epileptiform discharge on initial EEG (all p < 0.001). Among children with epileptiform discharges on EEG, those with multifocal discharges or hypsarrhythmia had higher rates of intractability than those with focal, hemispheric, or generalized epileptiform discharge alone (p < 0.001). Other significant predictors included neonatal seizures (p = 0.004), perinatal complications (p = 0.006), lack of both febrile seizures (p = 0.006) and complicated febrile seizures (p < 0.05), nongeneralized mode of onset (p = 0.011), and prior status epilepticus (p = 0.031).

Table 2.   Potential predictors of medical intractability
VariableOdds ratio (95% CI)p-Value
Female gender1.64 (0.78, 3.42)0.19
Age at onset0.31 (0.18, 0.53)<0.001
Developmental delay at diagnosis37.10 (8.38, 164.21)<0.001
Abnormal neurologic examination at diagnosis12.48 (5.03, 30.94)<0.001
Abnormal perinatal course3.01 (1.37, 6.63)0.006
Neonatal seizures4.49 (1.64, 12.33)0.004
Febrile seizure0.06 (0.01, 0.44)0.006
Atypical febrile seizure0.13 (0.02, 0.99)0.049
Prior status epilepticus2.55 (1.09, 5.95)0.031
Generalized mode of onset0.14 (0.03, 0.64)0.011
Structural/metabolic etiology22.18 (8.51, 57.78)<0.001
Number of seizures prior to diagnosis1.00 (0.99, 1.02)0.52
Background slowing on initial EEG  
 Generalized slowing6.56 (2.90, 14.82)<0.001
 Focal slowing8.08 (2.89, 22.61)<0.001
Epileptiform discharge on initial EEG  
 Any discharge5.69 (2.04, 15.90)<0.001
 Multifocal discharge or hypsarrhythmia8.32 (3.63, 19.05)<0.001
Abnormal neuroimaging26.63 (9.99, 70.97)<0.001
First degree family history of epilepsy0.48 (0.18, 1.29)0.14

Variables that were significantly associated with medical intractability on univariate analysis were then entered into a logistic regression model. The risk of medical intractability is higher for younger children. Based on clinical judgment, we stratified age into ≤12 months versus >12 months. Four variables were found to be predictive of intractability on multivariable logistic regression analysis including age ≤12 months at diagnosis (odds ratio [OR] 6.76, 95% confidence intervals [CI] 2.00, 22.84, p = 0.002), developmental delay at initial diagnosis of epilepsy (OR 20.03, 95% CI 3.49, 114.83, p = 0.0008), neuroimaging abnormality (OR 6.48, 95% CI 1.96, 21.40, p = 0.002), and focal slowing on initial EEG (OR 5.33, 95% CI 1.14, 24.88, p = 0.03). For this multivariable logistic regression model, the area under the curve is 0.93, which shows the model has outstanding discrimination for development of medically intractable epilepsy (Hosmer & Lemeshow, 2000).

Table 3 illustrates the proportion of children with the factors predictive of intractability on multivariable logistic regression, and the probability of intractability. For the five children for whom developmental history was not available at the time of diagnosis of epilepsy, development at initial diagnosis was estimated based on history in the first year of follow-up. Based on the number and specific combination of variables present, the probability of medical intractability could be estimated and ranged from 0.01 to 0.97.

Table 3.   Probabilities of medically intractable epilepsy based on the combinations of predictive variables
Age at diagnosis (≤1 year)Developmental delay at initial diagnosis of epilepsyNeuroimaging abnormalityFocal slowing on initial EEGNumber of risk factors presentp-Value
NoNoNoNo00.01
NoNoNoYes10.03
YesNoNoNo10.04
NoNoYesNo10.04
NoYesNoNo10.11
NoNoYesYes20.17
YesNoNoYes20.18
YesNoYesNo20.21
NoYesNoYes20.39
NoYesYesNo20.44
YesYesNoNo20.45
YesNoYesYes30.58
NoYesYesYes30.80
YesYesNoYes30.81
YesYesYesNo30.84
YesYesYesYes40.97

What is the long-term mortality and intellectual outcome in children with medically intractable epilepsy?

Mortality was significantly higher in children with medically intractable epilepsy than in the nonintractable group (9/44 [20%] vs. 0/83 [0%], p < 0.001). Causes of death for the intractable cohort included respiratory etiologies unrelated to seizures in eight of nine and aspiration due to a seizure in one of nine. Median age at death was 4.0 years (interquartile range 1.1, 7.4 years). No deaths occurred in the children who had previously undergone epilepsy surgery.

Intellectual outcome was also significantly worse in those with medically intractable epilepsy compared to the nonintractable group (p < 0.001), with 5% vs. 64% having normal development, 32% vs. 19% having mild delay, and 64% vs. 17% having severe delay. Within the medically intractable group, children who had previously undergone epilepsy surgery had a better intellectual outcome than the nonsurgical cohort, with 5/7 (71%) vs. 11/37 (30%) having either normal outcome or mild delay and 2/7 (29%) vs. 26/37 (70%) having severe delay (p = 0.048).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

In our population-based cohort, more than one third of children with onset of epilepsy in the first 3 years of life were medically intractable. This proportion is higher than in previously published population-based studies in new-onset childhood epilepsy, and is likely reflective of specific etiologies being more prevalent in very young children. In our cohort, we found structural causes to be extremely common, with malformations of cortical development and tuberous sclerosis accounting for nearly half, and other structural abnormalities (predominantly remote brain injury) accounting for one third of all medically intractable cases. Genetic syndromes accounted for only 7% of cases, and only 11% were of unknown etiology. Although all “unknown” etiology cases had undergone MRI, the majority presented with focal-onset seizures, and may have had less extensive forms of cortical dysplasia that are not well seen on MRI. Furthermore, the ability of MRI to detect cortical dysplasia can be limited in children between 6 and 24 months, due to evolution of myelination (Colombo et al., 2003). Specific epilepsy syndromes presenting early in life are known to be highly correlated with intractable epilepsy. In our cohort, a specific syndrome was identifiable at diagnosis in just over one fourth of medically intractable cases, with the majority being West syndrome. These syndromes are individually rare, and the number of affected patients is too low to reach statistical significance in most population-based studies.

Not all children with early onset epilepsy will do poorly, however. We found four significant predictors of medical intractability on multivariate analysis: age ≤12 months at diagnosis, developmental delay at initial diagnosis, abnormal neuroimaging, and focal slowing on initial EEG. These predictors, which are identifiable at the time of initial diagnosis, allowed more accurate prognostication of seizure outcome in our cohort presenting with epilepsy before 3 years of age. The association with medical intractability increased with the presence of each additional variable. In the absence of any variable, the probability of intractability was 0.01, whereas in the presence of all four variables, that probability rose to 0.97.

Our results are consistent with earlier work that has noted poorer outcomes in children with neuroimaging abnormalities, early onset seizures, and concomitant neurologic handicaps (Brorson & Wranne, 1987; Sillanpaa et al., 1995; Semah et al., 1998; Ko & Holmes, 1999; Camfield & Camfield, 2003). These findings support the concept that congenital or early acquired brain lesions frequently result in intractable epilepsy with significant impact on neurologic and cognitive function and suggest early surgical intervention should be considered for such cases.

Few studies have examined the predictive value of initial EEG on medical intractability in children. Similar to our results, Berg et al. (2001) found that focal slowing was predictive for intractability, however, in her study, interictal epileptiform discharges were not. Focal slowing may be seen postictally or represent an underlying cerebral dysfunction due to the epileptogenic lesion. Arts et al. (1999) reported that EEG abnormalities at intake were not significant, although such abnormalities at 6 months were predictive of poor outcome. In contrast, we found the presence of epileptiform discharges on initial EEG to be a significant risk factor for intractability. Furthermore, the type of epileptiform discharge was important—children with multifocal discharges or hypsarrhythmia were significantly more likely to develop intractable epilepsy than those with focal, hemispheric, or generalized discharge. Prior studies have noted that multifocal spikes are commonly seen in children with hypsarrhythmia on previous or follow-up EEG studies and that etiologies associated with multifocal spikes included the majority of diseases that afflict the brain early in life, often in a diffuse manner (Noriega-Sanchez & Markand, 1976; Blume, 1978; Kotagal, 1995).

Previous work has suggested that a substantial proportion of focal epilepsy may not become clearly intractable for many years after onset (Berg et al., 2003). Indeed, Berg et al. (2006) reported that 40% of children with focal epilepsy presented with delayed intractability (defined as >3 years after epilepsy onset). We found delayed intractability to be much less of a problem in this very young cohort. Medical intractability could be defined early in most children; 61% met criteria for intractability by 1 year and 86% by 3 years after initial diagnosis of epilepsy. In children with focal onset epilepsy, nearly two thirds were intractable by 1 year after onset, and nearly all (91%) met criteria by 3 years after onset.

Outcome in young children with medically intractable epilepsy was concerning. Twenty percent of our cohort had died after long-term follow-up, the majority due to conditions unrelated to their epilepsy, but as a result of their severe neurologic disability. Previous population-based or community-based cohort studies have shown mortality rates of 2.1–3.8% after long-term follow-up, and similar to our results, found that most deaths were unrelated to epilepsy (Camfield et al., 2002; Berg et al., 2004a). These studies have identified functional neurologic deficit, symptomatic etiology, and epileptic encephalopathy as predictors of higher mortality.

Because our study was retrospective, no consistent neuropsychological battery was regularly used, which limits a more detailed assessment of cognitive function. However, based on our best clinical assessment, we found intellectual disability to be prominent in our cohort of children with early onset medically intractable epilepsy, with only 5% having normal development, and nearly two thirds showing evidence of severe delay at final follow-up. Underlying structural abnormalities of the brain likely explain much of this disability. However, ongoing intractable seizures, very frequent epileptiform discharge and high doses of multiple medications contribute to epileptic encephalopathy and adversely affect development. Children who underwent epilepsy surgery showed lesser developmental disability after long-term follow-up, presumably due to greater likelihood of achieving seizure control, reduction of frequent epileptiform discharges on EEG, and reduced exposure to high-dose or multiple antiepileptic medications.

In summary, the results of our population-based, retrospective chart review show that just over one third of children with new-onset epilepsy before 36 months of age will develop medical intractability. Using the four main predictors of seizure outcome identified on multivariate analysis (age ≤12 months at onset, developmental delay at initial diagnosis, neuroimaging abnormalities, and focal slowing on initial EEG), outlined in Table 3, seizure outcome can be predicted with reasonable accuracy in the majority of young children with new-onset epilepsy before 36 months. Children with greater numbers of predictors should be monitored carefully, as intractability usually presents early in the course. Such children should be considered promptly for epilepsy surgery, if they are candidates, as medical intractability is associated with high mortality and significant intellectual disability.

Acknowledgment

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

This study was supported by a CR20 Research award from the Mayo Foundation, and made possible by the Rochester Epidemiology Project (Grant no. R01-AR030582 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases).

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

None of the authors has any conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References