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Anti-glutamic acid decarboxylase anti-bodiesЧThe missing link between epilepsy and diabetes.

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problem in the general practice of neurology in which
most MS patients are first diagnosed, and often initially treated, because more and more neurologists rely
primarily on the interpretation of the MRI by radiologists who frequently have nothing more to go on than
the cryptic note “MS?”
A series of typical MRIs of DEM should be made an
integral part of MS diagnostic criteria, or, at a minimum, reference should be made to publications containing them.
Department of Neurology, Harvard Medical School,
Beth Israel Deaconess Medical Center, Boston, MA
References
1. Polman C, Reingold S, Edan G, et al. Diagnostic criteria for
multiple sclerosis: 2005 revisions to the 2001 McDonald criteria.
Ann Neurol 2005;58:840 – 846.
2. Kesselring J, Miller D, Robb S, et al. Acute disseminated encephalomyelitis. MRI findings and distinction from multiple sclerosis.
Brain 1990;113:291–302.
3. Poser C. The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994;36:S231–S243.
4. Brinar V. Non-MS recurrent demyelinating disease. Clin Neurol
Neurosurg 2004;106:197–210
5. Weinshenker B. Cited in: Sullivan M. Updated MS criteria rely
on two MRIs. Clin Neurol News 2005;1:3.
6. Poser C. Misdiagnosis of MS and beta-interferon. Lancet 1997;
349:1915.
DOI: 10.1002/ana.20826
An Association between Type 1 Diabetes and
Idiopathic Generalized Epilepsy
Serge Vulliemoz, MD, and Margitta Seeck, MD
We read with special interest the article by McCorry and
colleagues.1 These authors report an epidemiological study
comparing the prevalence of type 1 diabetes (T1D) in
150,000 subjects 15 to 30 years old and a cohort of 518
age-matched patients with idiopathic generalized epilepsy
(IGE). They found that T1D was significantly more prevalent in the IGE cohort with an odds ratio of 4.4. The authors report this as first evidence of an association between
T1D and IGE, suggesting that this association supports an
autoimmune hypothesis of IGE. In fact, we think that some
evidence already exists, as briefly pointed out below.
In 1990, Baekkeskov and colleagues2 first recognized glutamic acid decarboxylase antibodies (GAD-Abs) as an important marker in T1D. GAD-Abs are directed against secretory
vesicles in the pancreatic islet cells and play an important
pathogenic role in the development of T1D in children and
adults. They are the immune marker of highest diagnostic
sensitivity in T1D, and they identify latent autoimmune diabetes in adults, sometimes years before the clinical onset.3
Autoimmune processes and the search for pathogenic antibodies recently have received increased attention also in epilepsy. GAD-Abs are implicated in various neurological conditions, including stiff-person syndrome, cerebellar ataxia,
and epilepsy. That they interfere with ␥-aminobutyric acid
synthesis or action makes them a suitable candidate for low-
728
Annals of Neurology
Vol 59
No 4
April 2006
ering the seizure threshold and promoting epilepsy. Generalized and focal epilepsy syndromes with or without lesion are
described in association with GAD-Abs, including juvenile
myoclonic epilepsy (also associated with T1D1), temporal
lobe epilepsy with or without hippocampal sclerosis, and cortical dysplasia.4 Therefore, GAD-Abs deserve careful attention in the search for an association between T1D and IGE.
Interestingly, although GAD-Abs related to neurological
conditions appear to be different from those involved in
T1D,3 a patient with both T1D and focal cryptogenic epilepsy associated with GAD-Abs recently has been reported.5
Given that the authors now describe seven more patients
with diabetes and epilepsy, it would be interesting to know
whether GAD-Ab titers are implicated in their patients with
both T1D and IGE. We agree with the authors that such
associations are susceptible to being overlooked. Further research might support their hypothesis and help to better understand the full spectrum of idiopathic epilepsy syndromes.
Department of Neurology, University Hospital of Geneva,
Geneva, Switzerland
References
1. McCorry D, Nicolson A, Smith D, et al. An association between
type 1 diabetes and idiopathic generalized epilepsy. Ann Neurol
2006;59:204 –206.
2. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of
the 64K autoantigen in insulin-dependent diabetes as the GABAsynthesizing enzyme glutamic acid decarboxylase. Nature 1990;
347:151–156.
3. Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci 2002;
23:145–151.
4. Kwan P, Sills GJ, Kelly K, et al. Glutamic acid decarboxylase
autoantibodies in controlled and uncontrolled epilepsy: a pilot
study. Epilepsy Res 2000;42:191–195.
5. Yoshimoto T, Doi M, Fukai N, et al. Type 1 diabetes mellitus
and drug-resistant epilepsy: presence of high titer of antiglutamic acid decarboxylase autoantibodies in serum and cerebrospinal fluid. Intern Med 2005;44:1174 –1177.
10.1002/ana.20830
Anti-Glutamic Acid Decarboxylase Anti-bodies—
The Missing Link between Epilepsy and Diabetes
Stephan Rüegg MD
The highly interesting article of McCorry and colleagues1
identifies an association between type 1 diabetes (T1D) and
idiopathic generalized epilepsy (IGE). They found an approximately fourfold increase in T1D among their cohort of
IGE patients in an urban northern England population.
There was no obvious sign for a genetic association between
the two diseases and no family history for either of the diseases, except in one patient. In all six patients with IGE and
T1D, the latter disease became manifest years (range, 2–13)
before the onset of IGE.
T1D is considered to be a T-cell–mediated autoimmune
disorder, but also associated with autoantibodies (Abs), such
as anti-islet Abs or anti–glutamic acid decarboxylase antibodies (GAD-Abs). Pancreatic ␤ cells, the main target of the
autoimmune destructive process in T1D, express GAD-
converting glutamic acid into ␥-aminobutyric acid (GABA),
which is involved in the negative feedback control of insulin
secretion.2 Anti–GAD Abs reducing the GABA levels may
interrupt this control and contribute to T1D. GABA is the
main inhibitory transmitter of the central nervous system.
Anti–GAD Abs are involved in the pathogenesis of several
neurological disorders, such as stiff-person syndrome, Batten’s disease, and cerebellar degeneration.3 In one study,
anti–GAD Abs were present in 16% of patients (8/51) with
therapy-resistant partial epilepsy, but in none of a matched
population with IGE (0/49).4 In addition, none of the 124
patients with T1D in this study had epilepsy. Although this
dismissed an association of GAD, T1D, and IGE, alterations
of the GABA pathway or its receptor subunit composition
are linked to some forms of IGE.5 In addition, the sample
size of Peltola and colleagues’4 study might have been too
small or the anti–GAD Ab assay was too unspecific to be
detected. Twelve years ago, Kim and colleagues6 first described the important antigenic differences between the
epitopes recognized by anti–GAD Abs of diabetic patients
and those of patients with neurological disorders; this could
explain the heterogeneity of results among studies using different anti–GAD Abs. It has also been shown that anti–
GAD Abs titers are low in T1D patients, whereas they may
be 25- to 500-fold higher in patients with neurological disorders, such as cerebellar degeneration or stiff-person syndrome.7
Evaluating patients with T1D and IGE for the presence of
anti–GAD Abs by a highly specific assay may be important
to test the hypothesis that anti–GAD Abs may be the missing link between the increased frequency of IGE in T1D
patients. Confirmation of this hypothesis would expand the
spectrum of neurological diseases associated with anti–GAD
Abs, newly including IGE.
Division of Clinical Neurophysiology, Department of
Neurology, University Hospital Basel, Basel, Switzerland
References
1. McCorry D, Nicolson A, Smith D, et al. An association between
type 1 diabetes and idiopathic generalized epilepsy. Ann Neurol
2006;59:204 –206.
2. Shi Y, Kanaani J, Menard-Rose V, et al. Increased expression of
GAD65 and GABA in pancreatic ␤-cells impairs first-phase insulin secretion. Am J Physiol Endocrinol Metab 2000;279:
E684 –E694.
3. Pearce DA, Atkinson M, Tagle DA. Glutamic acid decarboxylase
autoimmunity in Batten disease and other disorders. Neurology
2004;63:2001–2005.
4. Peltola J, Kulmala P, Isojärvi J, et al. Autoantibodies to glutamic
acid decarboxylase in patients with therapy-resistant epilepsy.
Neurology 2000;55:46 –50.
5. Cosette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an
autosomal dominant form of juvenile myoclonic epilepsy. Nat
Genet 2002;31:184 –189.
6. Kim J, Namchuk M, Bugawan T, et al. Higher autoantibody
levels and recognition of a linear NH2-terminal epitope in the
autoantigen GAD65, distinguish stiff-man syndrome from
insulin-dependent diabetes mellitus. J Exp Med 1994;180:
595– 606.
7. Honorat J, Saiz A, Giometto B, et al. Cerebellar ataxia with antiglutamic acid decarboxylase antibodies. Arch Neurol 2002;58:
225–230.
10.1002/ana.20838
Annals of Neurology
Vol 59
No 4
April 2006
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