Clinical Neurology and Neurosurgery 121 (2014) 46–50
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Antithyroid antibodies as a potential marker of autoimmune-mediated late onset temporal lobe epilepsy Júlia Miró a,b,∗ , Rosa Fortuny c , Montserrat Juncadella a,b,c , Maria Aiguabella a , ˜ a,d , Mila Santurino a , Mercè Falip a,b Misericòrida Veciana a , Sara Castaner a
Epilepsy Unit, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain Cognition and Brain Plasticity Group [Bellvitge Biomedical Research Institute] IDIBELL, Barcelona, Spain c Neuropsychology Unit, Neurology Service, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain d IDI, Magnetic Resonance Unit, Institut Diagnostic per la Imatge, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain b
a r t i c l e
i n f o
Article history: Received 13 May 2013 Received in revised form 23 January 2014 Accepted 15 March 2014 Available online 25 March 2014 Keywords: Autoimmune disease Antithyroid antibodies Corticotherapy Epilepsy Immunological profile
a b s t r a c t In one third of patients with epilepsy starting in adulthood the aetiology remains undetermined. Some patients with late onset temporal lobe epilepsy (TLE) together with memory decline have elevated antithyroid antibodies. Purpose: To compare the prevalence of antithyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with known and unknown TLE aetiology (N = 42). Moreover, the sera of these patients was also assayed for antinuclear antibodies (ANA), anticardiolipin antibodies (ACL), anti glutamic acid decarboxylase antibodies (GAD) and antiglidadin antibodies. Results: Positive aTR-ab in the sera of patients with unknown aetiology was 11/23 (47.8%) vs. 1/19 (4.3%) in the group with known aetiology (p = 0.005). In 9/11 (81%) a pre-existing autoimmune disease was confirmed. Nine (81%) were women and five (45%) had memory impairment. There were 5/11 (45%) pharmacoresistant patients, and corticosteroid treatment was initiated in 3/5 with cognitive and seizure improvement. The results of other immunological tests were only remarkable for antiGAD antibodies with 3/11 (27%) positive patients, but this subgroup does not have any significant clinical differential feature. Conclusions: Late-onset TLE with positive aTR-ab tends to be middle-aged women with nonpharmacoresistant cryptogenic epilepsy plus cognitive decline and other associated autoimmune diseases. It could be advisable to test aTR-ab in TLE patients with an unknown aetiology, in order to improve diagnosis and resulting treatment. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Epilepsy starting in adulthood is frequently caused by cerebrovascular disease, head trauma, degenerative disorders or central nervous system (CNS) tumours. However, in one third of cases the aetiology remains undetermined. In recent years, an autoimmune origin has been suggested in patients with epilepsy but unknown aetiology and no other organ involvement. This group includes the primary autoimmune epilepsies: Rasmussen encephalitis [1], adult
∗ Corresponding author at: Hospital Universitari de Bellvitge, C/Feixa Llarga sn, Hospitalet de Llobregat 08907, Spain. Tel.: +34 932607711; fax: +34 932607882. E-mail addresses: [email protected], [email protected] (J. Miró). http://dx.doi.org/10.1016/j.clineuro.2014.03.017 0303-8467/© 2014 Elsevier B.V. All rights reserved.
patients with epilepsia partialis continua, and non-paraneoplastic and paraneoplastic limbic encephalitis (LE). Moreover, specific antibodies have been related to focal epilepsy: antibodies to voltage-gated potassium channel complex [2] and anti-glutamic acid decarboxilase antibodies (GAD-ab) [2–4]. In addition, recent findings suggest that autoimmune LE is not an infrequent event and may be a possible aetiology of temporal lobe epilepsy with adult onset hippocampal sclerosis [5]. On the other hand, positive antithyroid antibodies are frequently observed in adult populations (0.5–6% for overt and 4 to 10–15% for subclinical thyroid failure), increasing with age but without clinical significance in most cases [6]. Our purpose was to compare the prevalence of anthyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with an undetermined aetiology to that in patients with known
J. Miró et al. / Clinical Neurology and Neurosurgery 121 (2014) 46–50
aetiology. Moreover, we described the clinical profile of those patients with positive aTR-ab and searched for other autoantibodies expressed together with the antithyroid antibodies.
2. Methods 2.1. Patients The study comprises 42 consecutive patients with epilepsy onset above the age of 30 years with clinical, MRI and EEG features of mesial temporal lobe epilepsy (TLE), whether associated or not with hippocampal sclerosis (HS), attended in the epilepsy outpatient unit of our centre. Patients were prospectively recruited between January 2010 and September 2011. Forty-two healthy individuals matched for age and gender were also included in the study. Because the age at epilepsy onset in patients with epilepsy associated with HS and febrile seizures has a trimodal distribution [7], being adulthood onset (age over 30 years) the least common, a cut-off age of 30 years was established in order to expand the spectrum of other potential precipitating injuries. Patients without an established diagnosis of TLE on clinical or EEG findings were excluded. No other lesion apart from HS was accepted in the MRI studies, so no patients with dual pathology were included. All patients had a minimum period of 2 years’ follow-up from the time of diagnosis of epilepsy, with a median follow-up of 3 years (range: 2–4 years). All patients immunologic profile serum samples (and CSF samples in four of the aTR-ab+ patients), were tested in the time of TLE of unknown aetiology diagnosis was made in the hospital’s outpatient clinics (from 3 to 20 years since the epilepsy onset). The study was approved by the Ethical Committee of Bellvitge University Hospital. Patients were divided in two different groups. Known aetiology: nineteen patients with a confirmed risk factor or initial precipitating injury: 9 patients had viral encephalitis or meningitis, 5 had a personal history of complicated febrile seizures, and 5 had severe head trauma. Unknown aetiology: twenty-three patients (23/42, 55%) without initial precipitating injury and no family history of epilepsy.
3. Material MR imaging was performed in all patients with a 1.5-T unit (Philips Medical Systems, Best, The Netherlands) in the three orthogonal planes, including at least T1, T2 and FLAIR weighted images. A standard video-EEG was performed in all patients (64 channel digital Deltamed equipment); surface electrodes were located using the 10/20 International System. All patients underwent the following immunological tests: antinuclear antibodies (ANA), IgM and IgG anti-cardiolipin (ACL), Antigliadin antibodies (Antigliadin Ab), GAD-ab, antithyroglobulin (antiTG) (normal values 12) Aura Complex partial seizure (automotor) Pharmacoresistance Corticotherapy
9/11 (81%) 5/11 (45%) 4/11 (36%) 2/11 (18%) 5/11 (45%) 5/11 (45%) 5/11 (45%) 7/11 (63%) 5/11 (45%) 3/11 (27%)
6/12 (50%) 0/12 (0%) 1/12 (8%) 3/12 (25%) 1/12 (8%) 3/12 (25%) 7/12 (58%) 8/12 (67%) 10/12 (83%) 0/12 (0%)
0.19 0.01 0.15 1.00 0.69 0.40 0.68 1.00 0.08
Basic immuno. profilec
Serum (N) CSF(N)d
Serum (N)
Antithyroid Antibodies ANA ACL Antigliadin Ab GAD Ab
11/11 4/11 0/11 1/11 3/11 1/4d
0/12 0/12 0/12 0/12 1/12
Specific immuno. profilec
Serum (N) CSF(N)d
Serum (N)
Abnormal CSF cell-count, biochemistry Positive OCB Onconeuronal Ab NSA GABAb R
0/4d 0/4d 0/10 0/4d 0/10 0/4d 0/10 0/4d
0/12
aTR-ab+: positive antithyroid antibodies, aTR-ab−: negative antithyroid antibodies HS: hippocampal sclerosis. ANA: antinuclear antibodies, ACL: anticardiolipin antibodies, GAD Ab: antidecarboxylase of glutamic acid antibodies. OCB: oligoclonal bands, NSA: antibodies against neuronal surface antigens, GABAb R: antibodies against GABAb Receptor. a Other concomitant autoimmune diseases (polyglandular autoimmune disease, systemic lupus erythematous, Graves Basedow and rheumatoid arthritis). b Memory loss greater than might be expected due to their epilepsy alone, with evident memory impairment in both memories: verbal and visual even in right or left TLE. The Beck Depression Inventory was pathologic in the same patients. c All patients immunologic profile serum samples (and CSF samples in four of the aTR-ab+ patients), were tested from 3 to 20 years since the epilepsy onset. d CSF antiGAD and specific immunologic profile results.
with azathioprine has been started in order to withdraw corticosteroids. No impairment has been observed up to date (Fig. 2). The same patient presented initial general memory function within or below the normal range (10th percentile) with evidence of significant decline when compared to the predicted premorbid level of intellectual functioning. Impairments were particularly evident in visual memory tests (both immediate and delayed memory). After 3 months under corticosteroid treatment, she had improvement in all cognitive fields of from 1 to 4 points on the standard score, even in visual memory percentiles, despite her right HS. Three months later, improvement persisted even though corticotherapy dosage had been halved.
5. Discussion In our study we observed that up to 47.5% of the patients with a TLE of unknown aetiology had elevated antithyroid antibodies compared with just 4.3% of patients with known aetiology, or 7.1% of healthy controls. It is well established that, in general, immune functions deteriorate with advancing age, and the prevalence of autoantibodies increases progressively with age [6]. Furthermore, prevalence of anti-thyroid antibodies, has been described to be even higher in middle-aged healthy women (up to 26%) [11,12]. On the other hand, some studies conducted in centenarians have found that those with low comorbidity or little disability have fewer
Fig. 1. Pharmacoresistant patients with TLE and positive antithyroid antibodies. Neuropsychological findings: improvement in all cognitive fields in neuropsychological tests at 3 and 6 months following the start of corticotherapy with 1 mg/kg/day and 0.5 mg/kg/day respectively, compared to pretreatment state (basal). IverbalM: immediate verbal memory, DverbalM: delayed verbal memory, IvisualM: immediate visual memory, DvisualM: delayed visual memory, IfaceM: immediate face memory, DfaceM: delayed face memory, VerbalL: verbal learning.
J. Miró et al. / Clinical Neurology and Neurosurgery 121 (2014) 46–50
49
Fig. 2. Pharmacoresistant patient with TLE and positive antithyroid antibodies. Antithyroid antibodies and seizures (cps: complex partial seizures) decreased under oral corticoid treatment (mgr: milligrams), and increased in corticoid treatment reduction.
organ-specific autoantibodies, suggesting that this autoimmune phenomena in the elderly may be an expression of age-associated disease rather than being related to the ageing process per se [13,14]. We identified a clinical phenotype for this subgroup of epileptic patients: a middle-aged woman with non-pharmacoresistant epilepsy, together with cognitive decline and other associated autoimmune diseases or other organ specific autoantibodies (the most frequent antiGAD antibodies), that may be useful in clinical practice, as previously reported by McKnight [2]. Even though most of the clinical features are not statistically significant, probably due to small sample size, there is a strong trend towards this clinical phenotype. The subgroup of patients with positive antithyroid and antiGAD antibodies does not have any significant clinical differential feature. Antithyroid antibodies are not routinely measured in TLE patients with an undetermined aetiology, as it was reported in only one other case series [15]. We consider that TLE patients with positive antithyroid antibodies may be diagnosed with a progressive or subacute steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), also known as ‘Hashimoto’s encephalopathy’ (HE) [16–18]. HE is a rare autoimmune disorder independent of thyroid status and typically responsive to steroid treatment. Since Brain et al., 1966 [19], described a patient with HE, more than 100 patients have been reported [20]. To date, several other antibodies have been identified in several studies in patients previously diagnosed with HE: antibodies to voltage-gated potassium channel complex, antiGAD antibodies [2,21], and antibodies against glutamate receptor (GluR) epsilon2 [22]. These findings and the lack of epilepsy incidence in Hashimoto thyroiditis suggest that antithyroid antibodies may not play any aetio-pathogenic role. The finding of patients with other associated autoantibodies would lend support to this assumption. Although there is no evidence that antithyroid antibodies play a specific role in the pathogenesis of TLE, the corticosteroid treatment response suggests that such antibodies possibly represent a sensitive marker for another underlying autoimmune process involving hippocampal structures. In conclusion, it is important to determine antithyroid antibodies in TLE patients with unknown aetiology, and it would be advisable to start with corticosteroid treatment in pharmacoresistant cases. However, larger scale studies are required to accurately determine the clinical role of antithyroid antibodies in TL epilepsy. Financial disclosure Study funding: supported in part by a grant from the Spanish National Institute of Health (PI10/00738).
Conflicts of interest None of the authors has any conflict of interest to declare.
Acknowledgement I would like to thank Dr. J. Bruna for his constructive suggestions and comments.
References [1] Bien CG, Granate T, Antozzi C, Cross JH, Dulac O, Kurthen M, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis. A European consensus. Brain 2005;128:454–71. [2] McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, et al. Serum antibodies in epilepsy and seizure-related disorders. Neurology 2005;65:1730–6. [3] Saiz A, Blanco Y, Sabater L, Gonzalez F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies. Diagnostic clues for association. Brain 2008;131:253–63. [4] Peltola J, Julmala P, Isojärvi J, Saiz A, Latvala K, Palmio J, et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 2000;55:46–50. [5] Bien CG, Urbach H, Schramm J, Soeder BM, Becker AJ, Voltz R, et al. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 2007;69:1236–44. [6] Tomer Y, Shoenfeld Y. Ageing and autoantibodies. Autoimmunity 1988;1:141–9. [7] Janszky J, Janszky I, Ebner A. Age at onset in mesial temporal lobe epilepsy with a history of febrile seizures. Neurology 2004;63:1296–8. [8] Saiz A, Arpa J, Sagasta A, Casamitjana R, Zarranz JJ, Tolosa E, et al. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, lateonset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 1997;49:1026–30. [9] Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, et al. Treatment responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 2005;128:1764–77. [10] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):069–77. [11] Massoudi MS, Meilahn EN, Orchard TJ, Foley Jr TP, Kuller LH, Costantino JP, et al. Prevalence of thyroid antibodies among healthy middle-aged women. Findings from the tyroid study in healthy women. Ann Epidemiol 1995;5(3):229–33. [12] Prentice LM, Phillips DI, Sarsero D, Beever K, McLachlan SM, Smith BR. Geographical distribution of subclinical autoimmune thyroid disease in Britain: a study using highly sensitive direct assays for autoantibodies to thyroglobulina and thyroid peroxidise. Acta Endocrinol (Copenh) 1990;123(5):493–8. [13] Andersen-Ranberg K, Hoier-Madsen M, Wiik A, Jeune B, Hegedüs L. High prevalance of autoantibodies among Danish centenarians. Clin Exp Immunol 2004;138:158–63. [14] Pinchera A, Mariotti S, Barbesion G, Bechi R, Sansoni P, Fagiolo U, et al. Thyroid autoimmunity and ageing. Horm Res 1995;43(1–3):6–8. [15] Leyhe T, Morawetz C, Zank M, Buchkremer G, Eschweiler G. Epilepsy in an elderly patient caused by Hashimoto’s encephalopathy. Epileptic Disord 2007;9(3):337–40. [16] Castillo P, Woodruff B, Caselli R, Vernino S, Lucchinetti C, Swanson J, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 2006;63(2):197–202.
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[17] Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high antithyroid antibody titers—report of 5 cases. Neurology 1991;41:228–33. [18] Doherty CP. Possibly, probably definitely, Hashimoto encephalopathy. J Neurol Sci 2005;228(1):1–2. [19] Brain L, Jellink EH, Ball K. Hashimoto’s disease and encephalopathy. Lancet 1966;2:512–4. [20] Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth. Arch Neurol 2003;60:164–71.
[21] Tan KM, Lennon A, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70: 1883–90. [22] Shindo A, Ii Y, Sasaki R, Takahasahi Y, Yoneda M, Kuzuhara S. Non-herpetic acute limbic encephalitis-like manifestation in a case of Hashimoto’s encephalopathy with positive autoantibodies against ionotropic glutamate receptor epsilon2. Rinsho Shinkeigaku 2007;47:629–34.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Antithyroid antibodies as a potential marker of autoimmune-mediated late onset temporal lobe epilepsy Júlia Miró a,b,∗ , Rosa Fortuny c , Montserrat Juncadella a,b,c , Maria Aiguabella a , ˜ a,d , Mila Santurino a , Mercè Falip a,b Misericòrida Veciana a , Sara Castaner a
Epilepsy Unit, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain Cognition and Brain Plasticity Group [Bellvitge Biomedical Research Institute] IDIBELL, Barcelona, Spain c Neuropsychology Unit, Neurology Service, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain d IDI, Magnetic Resonance Unit, Institut Diagnostic per la Imatge, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain b
a r t i c l e
i n f o
Article history: Received 13 May 2013 Received in revised form 23 January 2014 Accepted 15 March 2014 Available online 25 March 2014 Keywords: Autoimmune disease Antithyroid antibodies Corticotherapy Epilepsy Immunological profile
a b s t r a c t In one third of patients with epilepsy starting in adulthood the aetiology remains undetermined. Some patients with late onset temporal lobe epilepsy (TLE) together with memory decline have elevated antithyroid antibodies. Purpose: To compare the prevalence of antithyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with known and unknown TLE aetiology (N = 42). Moreover, the sera of these patients was also assayed for antinuclear antibodies (ANA), anticardiolipin antibodies (ACL), anti glutamic acid decarboxylase antibodies (GAD) and antiglidadin antibodies. Results: Positive aTR-ab in the sera of patients with unknown aetiology was 11/23 (47.8%) vs. 1/19 (4.3%) in the group with known aetiology (p = 0.005). In 9/11 (81%) a pre-existing autoimmune disease was confirmed. Nine (81%) were women and five (45%) had memory impairment. There were 5/11 (45%) pharmacoresistant patients, and corticosteroid treatment was initiated in 3/5 with cognitive and seizure improvement. The results of other immunological tests were only remarkable for antiGAD antibodies with 3/11 (27%) positive patients, but this subgroup does not have any significant clinical differential feature. Conclusions: Late-onset TLE with positive aTR-ab tends to be middle-aged women with nonpharmacoresistant cryptogenic epilepsy plus cognitive decline and other associated autoimmune diseases. It could be advisable to test aTR-ab in TLE patients with an unknown aetiology, in order to improve diagnosis and resulting treatment. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Epilepsy starting in adulthood is frequently caused by cerebrovascular disease, head trauma, degenerative disorders or central nervous system (CNS) tumours. However, in one third of cases the aetiology remains undetermined. In recent years, an autoimmune origin has been suggested in patients with epilepsy but unknown aetiology and no other organ involvement. This group includes the primary autoimmune epilepsies: Rasmussen encephalitis [1], adult
∗ Corresponding author at: Hospital Universitari de Bellvitge, C/Feixa Llarga sn, Hospitalet de Llobregat 08907, Spain. Tel.: +34 932607711; fax: +34 932607882. E-mail addresses: [email protected], [email protected] (J. Miró). http://dx.doi.org/10.1016/j.clineuro.2014.03.017 0303-8467/© 2014 Elsevier B.V. All rights reserved.
patients with epilepsia partialis continua, and non-paraneoplastic and paraneoplastic limbic encephalitis (LE). Moreover, specific antibodies have been related to focal epilepsy: antibodies to voltage-gated potassium channel complex [2] and anti-glutamic acid decarboxilase antibodies (GAD-ab) [2–4]. In addition, recent findings suggest that autoimmune LE is not an infrequent event and may be a possible aetiology of temporal lobe epilepsy with adult onset hippocampal sclerosis [5]. On the other hand, positive antithyroid antibodies are frequently observed in adult populations (0.5–6% for overt and 4 to 10–15% for subclinical thyroid failure), increasing with age but without clinical significance in most cases [6]. Our purpose was to compare the prevalence of anthyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with an undetermined aetiology to that in patients with known
J. Miró et al. / Clinical Neurology and Neurosurgery 121 (2014) 46–50
aetiology. Moreover, we described the clinical profile of those patients with positive aTR-ab and searched for other autoantibodies expressed together with the antithyroid antibodies.
2. Methods 2.1. Patients The study comprises 42 consecutive patients with epilepsy onset above the age of 30 years with clinical, MRI and EEG features of mesial temporal lobe epilepsy (TLE), whether associated or not with hippocampal sclerosis (HS), attended in the epilepsy outpatient unit of our centre. Patients were prospectively recruited between January 2010 and September 2011. Forty-two healthy individuals matched for age and gender were also included in the study. Because the age at epilepsy onset in patients with epilepsy associated with HS and febrile seizures has a trimodal distribution [7], being adulthood onset (age over 30 years) the least common, a cut-off age of 30 years was established in order to expand the spectrum of other potential precipitating injuries. Patients without an established diagnosis of TLE on clinical or EEG findings were excluded. No other lesion apart from HS was accepted in the MRI studies, so no patients with dual pathology were included. All patients had a minimum period of 2 years’ follow-up from the time of diagnosis of epilepsy, with a median follow-up of 3 years (range: 2–4 years). All patients immunologic profile serum samples (and CSF samples in four of the aTR-ab+ patients), were tested in the time of TLE of unknown aetiology diagnosis was made in the hospital’s outpatient clinics (from 3 to 20 years since the epilepsy onset). The study was approved by the Ethical Committee of Bellvitge University Hospital. Patients were divided in two different groups. Known aetiology: nineteen patients with a confirmed risk factor or initial precipitating injury: 9 patients had viral encephalitis or meningitis, 5 had a personal history of complicated febrile seizures, and 5 had severe head trauma. Unknown aetiology: twenty-three patients (23/42, 55%) without initial precipitating injury and no family history of epilepsy.
3. Material MR imaging was performed in all patients with a 1.5-T unit (Philips Medical Systems, Best, The Netherlands) in the three orthogonal planes, including at least T1, T2 and FLAIR weighted images. A standard video-EEG was performed in all patients (64 channel digital Deltamed equipment); surface electrodes were located using the 10/20 International System. All patients underwent the following immunological tests: antinuclear antibodies (ANA), IgM and IgG anti-cardiolipin (ACL), Antigliadin antibodies (Antigliadin Ab), GAD-ab, antithyroglobulin (antiTG) (normal values 12) Aura Complex partial seizure (automotor) Pharmacoresistance Corticotherapy
9/11 (81%) 5/11 (45%) 4/11 (36%) 2/11 (18%) 5/11 (45%) 5/11 (45%) 5/11 (45%) 7/11 (63%) 5/11 (45%) 3/11 (27%)
6/12 (50%) 0/12 (0%) 1/12 (8%) 3/12 (25%) 1/12 (8%) 3/12 (25%) 7/12 (58%) 8/12 (67%) 10/12 (83%) 0/12 (0%)
0.19 0.01 0.15 1.00 0.69 0.40 0.68 1.00 0.08
Basic immuno. profilec
Serum (N) CSF(N)d
Serum (N)
Antithyroid Antibodies ANA ACL Antigliadin Ab GAD Ab
11/11 4/11 0/11 1/11 3/11 1/4d
0/12 0/12 0/12 0/12 1/12
Specific immuno. profilec
Serum (N) CSF(N)d
Serum (N)
Abnormal CSF cell-count, biochemistry Positive OCB Onconeuronal Ab NSA GABAb R
0/4d 0/4d 0/10 0/4d 0/10 0/4d 0/10 0/4d
0/12
aTR-ab+: positive antithyroid antibodies, aTR-ab−: negative antithyroid antibodies HS: hippocampal sclerosis. ANA: antinuclear antibodies, ACL: anticardiolipin antibodies, GAD Ab: antidecarboxylase of glutamic acid antibodies. OCB: oligoclonal bands, NSA: antibodies against neuronal surface antigens, GABAb R: antibodies against GABAb Receptor. a Other concomitant autoimmune diseases (polyglandular autoimmune disease, systemic lupus erythematous, Graves Basedow and rheumatoid arthritis). b Memory loss greater than might be expected due to their epilepsy alone, with evident memory impairment in both memories: verbal and visual even in right or left TLE. The Beck Depression Inventory was pathologic in the same patients. c All patients immunologic profile serum samples (and CSF samples in four of the aTR-ab+ patients), were tested from 3 to 20 years since the epilepsy onset. d CSF antiGAD and specific immunologic profile results.
with azathioprine has been started in order to withdraw corticosteroids. No impairment has been observed up to date (Fig. 2). The same patient presented initial general memory function within or below the normal range (10th percentile) with evidence of significant decline when compared to the predicted premorbid level of intellectual functioning. Impairments were particularly evident in visual memory tests (both immediate and delayed memory). After 3 months under corticosteroid treatment, she had improvement in all cognitive fields of from 1 to 4 points on the standard score, even in visual memory percentiles, despite her right HS. Three months later, improvement persisted even though corticotherapy dosage had been halved.
5. Discussion In our study we observed that up to 47.5% of the patients with a TLE of unknown aetiology had elevated antithyroid antibodies compared with just 4.3% of patients with known aetiology, or 7.1% of healthy controls. It is well established that, in general, immune functions deteriorate with advancing age, and the prevalence of autoantibodies increases progressively with age [6]. Furthermore, prevalence of anti-thyroid antibodies, has been described to be even higher in middle-aged healthy women (up to 26%) [11,12]. On the other hand, some studies conducted in centenarians have found that those with low comorbidity or little disability have fewer
Fig. 1. Pharmacoresistant patients with TLE and positive antithyroid antibodies. Neuropsychological findings: improvement in all cognitive fields in neuropsychological tests at 3 and 6 months following the start of corticotherapy with 1 mg/kg/day and 0.5 mg/kg/day respectively, compared to pretreatment state (basal). IverbalM: immediate verbal memory, DverbalM: delayed verbal memory, IvisualM: immediate visual memory, DvisualM: delayed visual memory, IfaceM: immediate face memory, DfaceM: delayed face memory, VerbalL: verbal learning.
J. Miró et al. / Clinical Neurology and Neurosurgery 121 (2014) 46–50
49
Fig. 2. Pharmacoresistant patient with TLE and positive antithyroid antibodies. Antithyroid antibodies and seizures (cps: complex partial seizures) decreased under oral corticoid treatment (mgr: milligrams), and increased in corticoid treatment reduction.
organ-specific autoantibodies, suggesting that this autoimmune phenomena in the elderly may be an expression of age-associated disease rather than being related to the ageing process per se [13,14]. We identified a clinical phenotype for this subgroup of epileptic patients: a middle-aged woman with non-pharmacoresistant epilepsy, together with cognitive decline and other associated autoimmune diseases or other organ specific autoantibodies (the most frequent antiGAD antibodies), that may be useful in clinical practice, as previously reported by McKnight [2]. Even though most of the clinical features are not statistically significant, probably due to small sample size, there is a strong trend towards this clinical phenotype. The subgroup of patients with positive antithyroid and antiGAD antibodies does not have any significant clinical differential feature. Antithyroid antibodies are not routinely measured in TLE patients with an undetermined aetiology, as it was reported in only one other case series [15]. We consider that TLE patients with positive antithyroid antibodies may be diagnosed with a progressive or subacute steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), also known as ‘Hashimoto’s encephalopathy’ (HE) [16–18]. HE is a rare autoimmune disorder independent of thyroid status and typically responsive to steroid treatment. Since Brain et al., 1966 [19], described a patient with HE, more than 100 patients have been reported [20]. To date, several other antibodies have been identified in several studies in patients previously diagnosed with HE: antibodies to voltage-gated potassium channel complex, antiGAD antibodies [2,21], and antibodies against glutamate receptor (GluR) epsilon2 [22]. These findings and the lack of epilepsy incidence in Hashimoto thyroiditis suggest that antithyroid antibodies may not play any aetio-pathogenic role. The finding of patients with other associated autoantibodies would lend support to this assumption. Although there is no evidence that antithyroid antibodies play a specific role in the pathogenesis of TLE, the corticosteroid treatment response suggests that such antibodies possibly represent a sensitive marker for another underlying autoimmune process involving hippocampal structures. In conclusion, it is important to determine antithyroid antibodies in TLE patients with unknown aetiology, and it would be advisable to start with corticosteroid treatment in pharmacoresistant cases. However, larger scale studies are required to accurately determine the clinical role of antithyroid antibodies in TL epilepsy. Financial disclosure Study funding: supported in part by a grant from the Spanish National Institute of Health (PI10/00738).
Conflicts of interest None of the authors has any conflict of interest to declare.
Acknowledgement I would like to thank Dr. J. Bruna for his constructive suggestions and comments.
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