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An association between type 1 diabetes and idiopathic generalized epilepsy.

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An Association between
Type 1 Diabetes and
Idiopathic Generalized
Epilepsy
Dougall McCorry, MRCP,1 A. Nicolson, MD,1
D. Smith, MD,1 A. Marson, MD,1
Richard G. Feltbower, BSc, MSc,2 and
D. W. Chadwick, MD1
Objective: Idiopathic generalized epilepsies (IGEs) account for approximately 30% of all patients with epilepsy. Both the IGEs and type 1 diabetes mellitus (T1D)
represent serious worldwide problems, because of related
medical and social management costs. Clinical experience
suggested the two conditions were seen in individuals
more frequently than might be expected by chance. Methods: We compared the population prevalence of T1D in
15- to 30-year-olds to a cohort of 518 15- to 30-year-olds
with IGE. Results: We found a highly significant excess of
T1D in our IGE cohort, with an odds ratio of 4.4 (95%
confidence interval, 2.1–9.2). Interpretation: Our results
suggest that the prevalence of T1D is increased by a factor of four in young adults with IGE. To our knowledge,
this is the first published association between the two
conditions and expands the diseases known to be associated with T1D.
Ann Neurol 2006;59:204 –206
The idiopathic generalized epilepsies (IGEs) account
for approximately one third of all patients with epilepsy. They are characterized by generalized spike and
wave abnormalities on an electroencephalogram (EEG).
The main IGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, tonic-clonic seizures on
wakening and juvenile myoclonic epilepsy (JME). They
have no apparent cause other than a genetic predisposition. Both the IGEs and type 1 diabetes mellitus
(T1D) represent serious worldwide problems, because
of related medical and social management costs.
During D.W.C.’s 30 years of clinical practice, he
From the 1Department of Neurosciences, Walton Centre for Neurology and Neurosurgery, Fazakerly, Liverpool; and 2Paediatric Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom.
Received May 19, 2005, and in revised form Sep 19. Accepted for
publication Sep 24, 2005.
Published online Dec 27, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20727
Address correspondence to Dr McCorry, Department of Neurosciences, Walton Centre for Neurology and Neurosurgery, Lower
lane, Fazakerly, Liverpool, L9 7LJ Email: d.j.mccorry@liv.ac.uk
204
formed an impression that patients with IGE had coexisting T1D more frequently than might be expected
by chance alone. We asked colleagues in both fields
and conducted a PubMed search but could find no
published evidence of a previously recognized association. We considered the discovery of an association
could generate hypothesis for the cause of the IGEs.
During a project with a primary aim of investigating
the management and prognosis of the IGEs,1,2 we explored whether there could be an increased prevalence
of T1D in a young adult cohort with IGE.
Subjects and Methods
Between May 2001 and June 2002, a large cohort of patients
with IGE was gathered from the Partners in Epilepsy Database at the Mersey Regional Epilepsy Clinic. Data from patients attending these clinics have been computerized since
1989, with demographic data as well as diagnostic and treatment details. Adults with clinical and EEG evidence of idiopathic generalized epilepsy were identified, and a syndromic
diagnosis, based on the International League Against Epilepsy guidelines,3 was made for each patient. Data were recorded from the medical notes as outlined previously1,2 and
included whether a diagnosis of insulin-dependent diabetes
had been made previously. T1D was defined as requiring
insulin within 12 months of first presentation to a physician;
hospital records where the diagnosis was made were examined for confirmation. The population study of T1D prevalence was derived from the metropolitan city of Leeds in the
north of England, 70 miles east of Merseyside, whose population is comparable in respect to size, socioeconomic status, and the proportion of ethnic minorities4; the population
consisted of 150,000 15- to 30-year-olds. The primary aim
of this study was to determine the prevalence of diabetes in
the 0- to 30-year-olds; the prevalence of epilepsy or its syndromes was not determined within the Leeds population.
Methodology of its design has been published previously.5
Both studies where completed in 2002. We calculated the
number of occurrences of T1D in the IGE cohort and compared this with the number of individuals with T1D in the
population study by calculating the odds ratio (OR) and
95% confidence interval (CI).
Results
We identified a cohort of 518 patients aged 15 to 30
years with idiopathic generalized epilepsy. This cohort
contained seven cases of T1D. Details of the patients
diagnosed with T1D are shown in the Table. The
Leeds population survey of 150,000 15- to 30-yearolds showed 465 cases in the 15 to 30 age group. The
population survey would predict 1.6 cases of T1D in
our IGE cohort, whereas we detected 7 with an associated OR of 4.4 (95% CI, 2.1–9.2). Age of onset (see
Table), where available, demonstrates T1D preceded
the onset of IGE in each of the six cases (range, 2–13
years). One patient had a first-degree relative with
T1D and epilepsy (JME). None of the other cases with
IGE and T1D had a family history of either condition.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table. Demonstrating Characteristics of the IGE Patients with T1D
Patient
No.
Epilepsy Diagnosis
1
2
3
4
5
6
7
IGE-GTCS
JME
JME
JME
IGE-GTCS
IGE-GTCS
IGE-GTCS
only
only
only
only
Age Onset
DM (yr)
Age of Onset
EP (yr)
Family History of
Epilepsy in Firstdegree Relative
Family History of
T1D in Firstdegree Relative
⬍16
18
13
3
7
7
1.4
⬍16
22
15
16
14
15
8
No
No
Yes
No
No
No
No
No
No
Yes
No
No
No
No
IGE ⫽ idiopathic generalized epilepsy; T1D ⫽ type 1 diabetes mellitus; DM ⫽ diabetes mellitus; EP ⫽ epilepsy; EEG ⫽ electroencephalogram; GTCS ⫽ generalized tonic-clonic seizure; JME ⫽ juvenile myoclonic epilepsy.
Discussion
Our results suggest that the risk of T1D is increased
fourfold in young adults with IGE compared with the
background population, although we estimate the true
population risk to lie somewhere between 2 and 9. The
findings should, however, be interpreted with caution
for several reasons. First, confounding factors such as
social class were not measured, although there are no
known environmental factors associated with the development of the IGEs. However, this is unlikely to explain the entire excess of T1D in our IGE population.
Second, the IGE cohort was derived from referrals to
an epilepsy regional center. The prevalence of T1D in
our IGE cohort could be overestimated if patients with
diabetes and epilepsy are more likely to be referred
than patients with epilepsy alone. If patients with both
conditions are harder to diagnose or treat, then they
may be more likely to be seen in a specialist center.
Alternatively, the strength of the association could be
underestimated if patients with diabetes and epilepsy
were less likely to be seen at a specialist epilepsy center.
Seizures, presumed symptomatic to hypoglycemia, typically affect 10 to 15% of patients with T1D per year.6
This may lead to diagnostic difficulty in recognizing
the tendency for spontaneous (nonhypoglycemic induced) seizures. Epilepsy therefore may be underrecognized in the T1D population. Diabetics with epilepsy
may be more likely to be treated by a physician who
specializes in diabetes rather than referred for specialist
epilepsy care. We consider the strength of the association more likely to be an underestimate of the true
situation.
This is the first published evidence to our knowledge
to suggest there is an association between IGE and
T1D. It is of interest that Eeg-Olofsson7,8 previously
demonstrated an increased prevalence of paroxysmal
epileptiform activity in 11% of children with T1D
compared with 2.7% of normal controls. He further
noted that marked generalized paroxysmal slow-wave
abnormalities were confined to children with a history
of recurrent hypoglycemic seizures. He subsequently
hypothesized on the existence of “diabetic encephalopathy,”8 suggesting there is an individual sensitivity, presumably genetic in origin, to react to hypoglycemia
with seizures. Antiepileptic drug therapy to raise the
convulsive threshold in those diabetic children with recurrent seizures was recommended.
IGE has an increased prevalence in the T1D population than the general population if our observations
are correct. It is possible that a proportion of T1D who
react to hypoglycemia with seizures have subclinical
IGE (seizures exclusively precipitated by hypoglycemia)
or unrecognized IGE (precipitated and occasional
spontaneous seizures). Current epilepsy diagnostic criteria3 applied to T1D individuals with recurrent seizures might show a significantly higher prevalence of
IGE: this question deserves further study.
All seven of our patients had generalized spike and
wave abnormalities on their EEG specific to the IGE
syndromes. Absence epilepsy accounts for approximately 30% of our IGE cohort, yet none of those with
T1D suffered from this syndrome. This could be accounted for by chance or, alternatively, T1D may not
be associated with all the subdivisions of the IGEs.
The age of onset of T1D preceded IGE in six of
seven patients; this may reflect differing age of onsets
of the two conditions or could imply T1D causes IGE.
The characteristics of a larger cohort with both conditions is required before conclusions can be drawn.
This is the first published evidence to our knowledge
of an association between T1D and the IGEs. If confirmed, this would expand the known disorders associated with T1D. Interestingly other conditions associated with T1D all have an autoimmune hypothesis
involved in their pathogenesis. In these conditions, the
discovery of the association has been an important step
in developing the hypothesis of autoimmunity.
Further studies are required to independently replicate our findings. These should involve a larger number of patients across multiple centers. Ongoing work
is examining proband and sibling risk of autoimmune
disease in patients with IGE.
McCorry et al: Type 1 Diabetes and IGE
205
References
1. Nicolson A, Appleton RE, Chadwick DW, Smith DF. The relationship between treatment with valproate, lamotrigine, and
topiramate and the prognosis of the idiopathic generalised epilepsies. J Neurol Neurosurg Psychiat 2004;75:75–79.
2. Nicolson, A, Chadwick DW, Smith DF. A comparison of adult
onset and “classical” idiopathic generalised epilepsy. J Neurol
Neurosurg Psychiat 2004;75:72–74.
3. Commission on Classification and Terminology of the International
League Against Epilepsy. Proposal for the revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389 –399.
4. Feltblower RG, McKinney PA, Campbell FM, et al. Type 2 and
other forms of diabetes in 0-30 year olds: a hospital based study
in Leeds, UK. Arch Dis Child 2003;88:676 – 679.
5. National Office of Statistics. Census 2001. [CD supplement to
the National report for England and Wales and Key Statistics for
local authorities in England and Wales] ONS, 2003.
6. Jones TW, Davis EA. Hypoglycemia in children with type 1
diabetes: current issues and controversies. Pediatr Diabetes 2003;
4:143–150.
7. Eeg-Olofsson O, Petersen I. Childhood diabetic neuropathy. A
clinical and neurophysiological study. Acta Paediatr Scand 1969;
55:163–176.
8. Eeg-Olofsson, O. Hypoglycemia and neurological disturbances
in children with diabetes mellitus. Acta Paediatr Scand Suppl
1977;270:91–96.
Suppression of Mitoxantrone
Cardiotoxicity in Multiple
Sclerosis Patients by
Dexrazoxane
Evanthia Bernitsas, MD,1 Wei Wei, PhD,2
and Daniel D. Mikol, MD, PhD1
Objective: To explore the potential of dexrazoxane to
suppress subclinical cardiotoxicity in MS patients receiving mitoxantrone. Methods: An open-label study was performed to evaluate possible subclinical cardiotoxicity in
multiple sclerosis patients treated quarterly with mitoxantrone (48mg/m2 cumulative), with and without concomitant dexrazoxane, using blinded serial radionucleide
ventriculography. Results: No patient experienced symptoms of heart failure. Patients receiving dexrazoxane,
which is cardioprotective for anthracyclines, exhibited a
significantly lesser decline in left ventricular ejection
fraction (mean change, ⴚ3.80% vs ⴚ8.55%, p < 0.001).
Interpretation: These results support a cardioprotective
effect of dexrazoxane in mitoxantrone treated multiple
sclerosis patients.
Ann Neurol 2006;59:206 –209
Dose-dependent cardiomyopathies can result from anthracyclines and structurally related anthracenediones
such as mitoxantrone (MX), although cardiotoxic risk
is greater for anthracyclines.1 For doxorubicin, the
risk of congestive heart failure (CHF) is 3% at a
threshold of 400mg/m2, 7% at 550mg/m2, and 18%
at 700mg/m2.2 In view of an approximate potency
ratio of 1 to 5,3 700mg/m2 of doxorubicin corresponds to approximately140mg/m2 of MX (the recommended limit in MS); oncological studies suggest that
the risk of CHF at this threshold is approximately
2.6%.4
Subclinical decline in cardiac function likely occurs
more frequently than CHF.1,5 Of 1,378 MS patients
receiving a mean of 60.5mg/m2 MX, two cases of CHF
were seen, but of the 779 patients who underwent serial measurements, 17 (2.18%) had an asymptomatic
From the Departments of 1Neurology and 2Biostatistics, University
of Michigan, Ann Arbor, MI.
Received Jun 18, 2005, and in revised form Sep 22. Accepted for
publication Oct 15, 2005.
Published online Dec 27, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20747
Address correspondence to Dr Mikol, University of Michigan, Multiple Sclerosis Center, 1500 E. Medical Center Drive, Ann Arbor,
MI 48109-0322. E-mail: dmiko@umich.edu
206
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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