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GAD antibodies associated neurological disorders: Incidence and phenotype distribution among neurological inflammatory diseases
Journal of Neuroimmunology 227 (2010) 175–177
Contents lists available at ScienceDirect
Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
GAD antibodies associated neurological disorders: Incidence and phenotype distribution among neurological inflammatory diseases Sabrina Matà a,⁎, Gian Carlo Muscas a, Massimo Cincotta b, Maria Letizia Bartolozzi c, Stefano Ambrosini a, Sandro Sorbi a a b c
Department of Neurological and Psychiatric Sciences, Azienda Ospedaliero-Universitaria di Careggi, Florence, Italy Neurology Unit, Piero Plagi Hospital, Florence, Italy Neurology Unit, San Giuseppe Hospital, Empoli, Italy
a r t i c l e
i n f o
Article history: Received 30 March 2010 Received in revised form 5 July 2010 Accepted 16 July 2010 Keywords: Stiff-person syndrome Limbic system Depression Immunology Diabetes mellitus
a b s t r a c t We investigated the prevalence and the clinical association of high titer of antibodies against glutamic acid decarboxylase (hGADAb) among unselected patients with inflammatory/autoimmune disorders of the nervous system. By indirect immunofluorescence examination of samples from 1435 patients, we identified 7 cases (0.48%) with hGADAb. Although stiff-person plus syndrome was the commonest clinical accompaniment, most of the patients presented with a combination of different symptoms, including psychiatric disturbances and intestinal motility disorders. Diagnosis delay and chronic evolution were common findings. In two cases persistently high values of hGADAb over the years were observed. The rarity and the phenotype heterogeneity of hGADAb clinical association should not discourage clinicians from antibody screening, at least in selected cases, as an early immunotherapy can change the otherwise chronic progression of this complex disorder spectrum. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Patients and methods
Glutamic acid decarboxylase (GAD) is an intracellular enzyme that catalyzes the decarboxylation of glutamate to GABA, the chief inhibitory neurotransmitter in the mammalian CNS. Antibodies against GAD (GADAb) have been firstly demonstrated in association with type 1 diabetes mellitus (T1DM), stiff-person syndrome (SPS) and epilepsy (Solimena et al., 1988). Since this description, the spectrum of neurological disorders associated with high titer of GADAb (hGADAb) has been broadened to include ataxia, limbic encephalopathy, and brainstem syndromes, with possible involvement of the extrapyramidal system, as well as the spinal cord (Honnorat et al., 1995; Matà et al., 2008; Meinck et al., 2001; Pittock et al., 2006). So far, most of the studies related to hGADAb have described single case report or cohorts of mainly selected patients. The aim of this study was to further characterize the clinical associations of hGADAb in an unselected patients population.
Between September 1, 2006, and December 31, 2009, we performed retrospective and prospective autoantibody screening on serum and, when available, cerebrospinal fluid (CSF) samples from 2500 patients with a suspected neurological autoimmune disease. All the patients were consecutively admitted to the inpatient and outpatient neurological units of the North-East Tuscany (Firenze, Prato and Empoli) from 1997 to 2009. The samples, collected for diagnostic purposes (oligoclonal band, cell count, albumin ratio, and autoantibody determination), were stored at −80°C at the Neuroimmunology Laboratory of Firenze. Paraneoplastic (including neuronal nuclear or cytoplasmic, and neuropil) IgGs, Neuromyelitis Optica (NMO)-IgGs and GAD IgGs were searched by indirect immunofluorescence (IIF) screening assay using paraformaldehyde perfused rat cerebellum, spinal cord, hippocampus and stomach sections at a serum dilution of 1:400 and CSF dilution of 1:5. The antibody levels were further analyzed by titration with consecutive twofold dilutions and eventual intermediate dilutions. Anti-GAD reactivity was confirmed by RIA using 125I-recombinant human GAD65. Neuronal antibodies were confirmed by immunoblot using recombinant antigens (Hu, Ri, CV2, Ma2, Amphiphysin, Yo), while other autoantibodies were searched (anti-thyroid, anti-nuclear, anti-transglutaminase, anti-muscle actetylcholine receptor) or confirmed (anti-gastric parietal cell) by the Careggi's Immunology Laboratory
⁎ Corresponding author. Department of Neurological and Psychiatric Sciences, Azienda Ospedaliero-Universitaria di Careggi, Viale Morgagni 85, Florence, Italy. Tel.: +39 055 7949788; fax: +39 055 4271380. E-mail address: masa@unifi.it (S. Matà). 0165-5728/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2010.07.011
176
S. Matà et al. / Journal of Neuroimmunology 227 (2010) 175–177
with standard procedures. The medical records of the hGADAb positive patients were reviewed, including the clinical status at last follow-up. The study was approved by the local Ethics Committee.
3. Results 3.1. Clinical and immunological data Of the 2500 neurological patients, 1435 were finally diagnosed with an autoimmune disease (multiple sclerosis, post-infectious demyelinating disorders, paraneoplastic and autoantibody-associated non paraneoplastic diseases, vasculitis, demyelinating acute and chronic neuropathies). We identified 7 patients whose serum IgG bound to CNS tissue with a pattern consistent with GAD specificity (titer, 1:400–1:51,200) (Table 1). The intrathecal synthesis index was N3 in all the patients whose CSF was tested. All samples were confirmed by RIA, with values (range, 74–160 UI/ml) significantly correlated with IIF titers (Spearman rank correlation test, p b 0.01). None of the 7 patients were seropositive for any other paraneoplastic or non paraneoplastic neuronal autoantibody tested; patients with hippocampal pathology and with temporal lobe epilepsy were both negative for P/Q-type voltage-gated calcium channel and for voltage-gated potassium channel antibodies (courtesy of Dr Angela Vincent). No malignancy was identified at disease onset and at follow-up (median follow-up duration: 24 months); one patient had a past history (N5 years) of breast cancer, without recurrence. Clinical, CSF study and brain MRI
findings are summarized on Table 1. The time from onset of symptoms to diagnosis ranged from 1 month to 6 years (median, 4 years). Four patients had motor symptoms (muscle rigidity and/or spasms) of the SPS spectrum; however, only one fulfilled SPS clinical criteria (Brown and Marsden, 1999), while the others were diagnosed with a stiffperson plus syndrome, either in the form of progressive encephalomyelitis with rigidity and myoclonus (PERM) (Pt no. 5), or with the limited variant of stiff-limb syndrome (Pts nos. 6 and 7). In 4 cases an association of symptoms of 2 or more CNS anatomo-functional areas, including brainstem and cerebellum, was observed.
3.2. Therapy and evolution Four patients received immunomodulatory treatments (Table 1). Only one patient (no. 3) experienced marked, although transitory, clinical improvement after corticosteroids. In most cases the neurological symptoms stabilized after 6–12 months from disease onset, but continued to slowly deteriorate over years. Nine serum samples from two patients were obtained during 6 and 5 years of follow-up, respectively. In one case (no. 1) GADAb titer mildly declined after corticosteroid and plasmapheretic treatment, but increased to a stable level during the follow-up (Fig. 1). In the other patient (no. 6) an increase of GADAb levels after 3 years of disease was associated with a worsening of her symptoms. GADAb titer continued to increase despite the association of low-dose azathioprine (1 mg/kg/day) to the previous IVIg treatment for a coincident dysimmune chronic neuropathy.
Table 1 Neurological syndromes associated with GAD Ab IF seropositivity. Case no./sex/age ADO (years) GAD Ab IF titer (serum/CSF) Neurological history autoimmunity
Associated conditions
Associated
1/F/52
20,000/200
TPO Ab ANA
Anxiety
2/F/67
3200/200
T1DM
Anxiety
3/F/32
51,200/np
4/F/61
400/np
5/M/56
800/10
6/F/19
25,600/640
7/F/42
12,800/32
Anterograde amnesia and temporal lobe epilepsy (limbic encephalitis); chronic evolution⁎; Brain MRI: increase of T2 signal (nonenhancing) over both hippocampal regions. CSF: mildly increased protein; increased IgG Link, multiple oligoclonal bands. Stabilization with CCs and PLEX. Progressive ataxia; right arm myoclonus; Brain MRI: normal. CSF: mildly increased protein, multiple oligoclonal bands; EMG: normal. No improvement with IVIg. Generalized rigidity and hyperlordosis (stiff-person syndrome); Brain MRI: normal. Temporal lobe epilepsy, resistant to multidrug Antiepileptic therapy; MRI: normal. Improvement with CCs. Vertigo, nausea, ophtalmoplegia (brainstem syndrome); rigidity and posture myoclonus in the legs, tremor, visual allucinations. CSF: multiple oligoclonal bands; brain MRI: multiple areas of white matter hyperintensity on T2 weighted images. EMG: unspecific changes. Improvement with clonazepam. Tongue deviation; progressive distal weakness and hypoestesia, and muscular atrophy. Hand spasms. EMG: signs of demyelinating polyradiculoneuropathy, with partial motor conduction blocks and signs of active denervation. Brain MRI: normal. CSF: normal (one isolated IgG band). EEG: normal. Temporary improvement with IVIg; stabilization with azathioprine. Episodes of eylid and perioral mycoclonus associated with left arm spasms. EMG: unspecific changes. EEG: normal. CSF: normal. Improvement with clonazepam.
GPC Ab, Pernicious anemia Pernicious anemia TPO Ab, Vitiligo
Depression, IMD
GPC Ab, ANA T1DM
Major depression; IMD (gut biopsy: degeneration of myenteric neurons) Pernicious anemia
ANA GM1 IgM Vitiligo CIDP
IMD
ANA T1DM
Major depression.
Ab = antibody; ADO = at disease onset; CCs = corticosteroids; CIDP = chronic inflammatory demyalinating polyneuropathy; CSF = cerebrospinal fluid; T1DM = type 1 diabetes mellitus; EEG: electroencephalogram; EMG = electromyography; GAD = glutamic acid decarboxylase; GPC = gastric parietal cell; IMD = intestinal motility disorder; IVIg = intravenous immunoglobulin; MRI = magnetic resonance imaging; PLEX = plasma exchange; TPO: thyroid peroxidase. ⁎ Patient 1 has already been reported on a previous paper [Matà et al., 2008].
S. Matà et al. / Journal of Neuroimmunology 227 (2010) 175–177
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disease course, generally because of difficult diagnosis, and almost never they are treated with long-term immunosuppression (Pittock et al., 2006). This is probably due to the diffuse skepticism regarding the meaning of hGADAb positivity in a so variable clinical panorama, and to the lack of definite evidences for GADAb pathogenetic role. However, it should be kept in mind that hGADAb associated syndromes may have a chronic evolution, with severe long-term neurological impairment if untreated, while a successful treatment may be obtained with early aggressive and sustained immunemodulatory therapy (Saidha et al., 2010). Although GADAb titers do not correlate with disease severity, the persistence of their production over years, as observed in our cases and recently demonstrated even in rituximab treated patients (Rizzi et al., 2010), could explain the tendency toward disease progression. Fig. 1. Glutamic acid decarboxylase (GAD) antibody (Ab) immunofluorescence (IF) serum titers from two patients followed-up for 6 and 5 years, respectively. The first patient (Pt no. 1), affected by limbic encephalitis, showed a mild decline of Ab levels after corticosteroid therapy (asterisk), that was associated with a stabilization of her clinical symptoms. GADAb titers increased gradually during the follow-up. The second patient (Pt no. 6), experienced a moderate worsening of her symptoms (hand spasms associated with peripheral symptoms due to chronic inflammatory demyelinating polineuropathy) associated with increase of Ab levels, that further increased after the introduction of azathioprine therapy (arrow).
4. Discussion The incidence of hGADAb among our neurological patients was 0.28% (95% CI, 0.073–0.48), which raised to 0.48% (95% CI, 0.12–0.83) considering only the cases with ascertained neurological autoimmune diseases. In this unselected patients population we observed a high variability of hGADAb associated neurological phenotype, being the SPS spectrum, especially the stiff-person plus syndrome, the commonest clinical manifestation. Of note, psychiatric and gastrointestinal disorders were frequent accompaniment of CNS dysfunctions in our patients cohort. Symptoms outside the strictly neurological point of view have been rarely considered in hGADAb positive patients. Phobic symptoms have been found in a high proportion of SPS patients (Henningsen and Meinck, 2003); however, they have been interpreted as a reaction to disability (Ameli et al., 2005). In our patients anxiety or major depression needing appropriate therapy had been diagnosed prior to the neurological symptoms onset in most of the cases, indicating that this is not just a secondary phenomenon. On the other hand, the presence of psychiatric symptoms, possibly related to an impairment of GABAergic transmission in the primary motor cortex (Koerner et al., 2004; Rossi et al., 2009), is consistent with the role of GABA within psychic functions (Goldman-Rakic, 1999). Similarly, the high prevalence of gastrointestinal motility disorders among hGADAb seropositive neurological patients could be attributed, besides the consequences of DM, to the effect of autoantibodies on GABA neurotransmission, whose role in the enteric nervous system has been well documented (Miki et al., 1983). Regarding the long-term evolution of hGADAb related disorders, it has been already emphasized that hGADAb positive neurological patients usually undergo immunomodulatory therapy late in the
Acknowledgment S.A. is supported by the Ente Cassa Di Risparmio di Firenze (grant no. 2009-0752). References Ameli, R., Snow, J., Rakocevic, G., Dalakas, M.C., 2005. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 64, 1961–1963. Brown, P., Marsden, C.D., 1999. The stiff man and stiff man plus syndromes. J. Neurol. 246, 648–652. Goldman-Rakic, P.S., 1999. The “psychic” neuron of the cerebral cortex. Ann. NY Acad. Sci. 868, 13–26. Henningsen, P., Meinck, H.M., 2003. Specific phobia is a frequent non-motor feature in stiff man syndrome. J. Neurol. Neurosurg. Psychiatry 74, 462–465. Honnorat, J., Trouillas, P., Thivolet, C., Aguera, M., Belin, M.F., 1995. Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch. Neurol. 52, 462–468. Koerner, C., Wieland, B., Richter, W., Meinck, H.M., 2004. Stiff-person syndromes: motor cortex hyperexcitability correlates with anti-GAD autoimmunity. Neurology 62, 1357–1362. Matà, S., Muscas, G.C., Naldi, I., Rosati, E., Paladini, S., Cruciatti, B., Bisulli, F., Paganini, M., Mazzi, G., Sorbi, S., Tinuper, P., 2008. Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J. Neuroimmunol. 199, 155–159. Meinck, H.M., Faber, L., Morgenthaler, N., Seissler, J., Maile, S., Butler, M., Solimena, M., DeCamilli, P., Scherbaum, W.A., 2001. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J. Neurol. Neurosurg. Psychiatry 71, 100–103. Miki, Y., Taniyama, K., Tanaka, C., Tobe, T., 1983. GABA, glutamic acid decarboxylase, and GABA transaminase levels in the myenteric plexus in the intestine of humans and other mammals. J. Neurochem. 40, 861–865. Pittock, S.J., Yoshikawa, H., Ahlskog, J.E., Tisch, S.H., Benarroch, E.E., Kryzer, T.J., Lennon, V.A., 2006. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin. Proc. 81, 1207–1214. Rizzi, M., Knoth, R., Hampe, C.S., Lorenz, P., Gougeon, M.L., Lemercier, B., Venhoff, N., Ferrera, F., Salzer, U., Thiesen, H.J., Peter, H.H., Walker, U.A., Eibel, H., 2010. Long-lived plasma cells and memory B cells produce pathogenic anti-GAD65 autoantibodies in Stiff person syndrome. PLoS ONE 5 (5) May 26. Rossi, S., De Capua, A., Tavanti, M., Calossi, S., Polizzotto, N.R., Mantovani, A., Falzarano, V., Bossini, L., Passero, S., Bartalini, S., Ulivelli, M., 2009. Dysfunctions of cortical excitability in drug-naïve posttraumatic stress disorder patients. Biol. Psychiatry 66, 54–61. Saidha, S., Murphy, S., Ronayne, A., McCarthy, P., Hennessy, M.J., Counihan, T., 2010. Treatment of anti-glutamic acid decarboxylase antibody-associated limbic encephalitis with mycophenolate mofetil. J. Neurol. 2010 (257), 1035–1038. Solimena, M., Folli, F., Denis-Donini, S., Comi, G.C., Pozza, G., De Camilli, P., Vicari, A.M., 1988. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J. Med. 318, 1012–1020.
Contents lists available at ScienceDirect
Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
GAD antibodies associated neurological disorders: Incidence and phenotype distribution among neurological inflammatory diseases Sabrina Matà a,⁎, Gian Carlo Muscas a, Massimo Cincotta b, Maria Letizia Bartolozzi c, Stefano Ambrosini a, Sandro Sorbi a a b c
Department of Neurological and Psychiatric Sciences, Azienda Ospedaliero-Universitaria di Careggi, Florence, Italy Neurology Unit, Piero Plagi Hospital, Florence, Italy Neurology Unit, San Giuseppe Hospital, Empoli, Italy
a r t i c l e
i n f o
Article history: Received 30 March 2010 Received in revised form 5 July 2010 Accepted 16 July 2010 Keywords: Stiff-person syndrome Limbic system Depression Immunology Diabetes mellitus
a b s t r a c t We investigated the prevalence and the clinical association of high titer of antibodies against glutamic acid decarboxylase (hGADAb) among unselected patients with inflammatory/autoimmune disorders of the nervous system. By indirect immunofluorescence examination of samples from 1435 patients, we identified 7 cases (0.48%) with hGADAb. Although stiff-person plus syndrome was the commonest clinical accompaniment, most of the patients presented with a combination of different symptoms, including psychiatric disturbances and intestinal motility disorders. Diagnosis delay and chronic evolution were common findings. In two cases persistently high values of hGADAb over the years were observed. The rarity and the phenotype heterogeneity of hGADAb clinical association should not discourage clinicians from antibody screening, at least in selected cases, as an early immunotherapy can change the otherwise chronic progression of this complex disorder spectrum. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Patients and methods
Glutamic acid decarboxylase (GAD) is an intracellular enzyme that catalyzes the decarboxylation of glutamate to GABA, the chief inhibitory neurotransmitter in the mammalian CNS. Antibodies against GAD (GADAb) have been firstly demonstrated in association with type 1 diabetes mellitus (T1DM), stiff-person syndrome (SPS) and epilepsy (Solimena et al., 1988). Since this description, the spectrum of neurological disorders associated with high titer of GADAb (hGADAb) has been broadened to include ataxia, limbic encephalopathy, and brainstem syndromes, with possible involvement of the extrapyramidal system, as well as the spinal cord (Honnorat et al., 1995; Matà et al., 2008; Meinck et al., 2001; Pittock et al., 2006). So far, most of the studies related to hGADAb have described single case report or cohorts of mainly selected patients. The aim of this study was to further characterize the clinical associations of hGADAb in an unselected patients population.
Between September 1, 2006, and December 31, 2009, we performed retrospective and prospective autoantibody screening on serum and, when available, cerebrospinal fluid (CSF) samples from 2500 patients with a suspected neurological autoimmune disease. All the patients were consecutively admitted to the inpatient and outpatient neurological units of the North-East Tuscany (Firenze, Prato and Empoli) from 1997 to 2009. The samples, collected for diagnostic purposes (oligoclonal band, cell count, albumin ratio, and autoantibody determination), were stored at −80°C at the Neuroimmunology Laboratory of Firenze. Paraneoplastic (including neuronal nuclear or cytoplasmic, and neuropil) IgGs, Neuromyelitis Optica (NMO)-IgGs and GAD IgGs were searched by indirect immunofluorescence (IIF) screening assay using paraformaldehyde perfused rat cerebellum, spinal cord, hippocampus and stomach sections at a serum dilution of 1:400 and CSF dilution of 1:5. The antibody levels were further analyzed by titration with consecutive twofold dilutions and eventual intermediate dilutions. Anti-GAD reactivity was confirmed by RIA using 125I-recombinant human GAD65. Neuronal antibodies were confirmed by immunoblot using recombinant antigens (Hu, Ri, CV2, Ma2, Amphiphysin, Yo), while other autoantibodies were searched (anti-thyroid, anti-nuclear, anti-transglutaminase, anti-muscle actetylcholine receptor) or confirmed (anti-gastric parietal cell) by the Careggi's Immunology Laboratory
⁎ Corresponding author. Department of Neurological and Psychiatric Sciences, Azienda Ospedaliero-Universitaria di Careggi, Viale Morgagni 85, Florence, Italy. Tel.: +39 055 7949788; fax: +39 055 4271380. E-mail address: masa@unifi.it (S. Matà). 0165-5728/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2010.07.011
176
S. Matà et al. / Journal of Neuroimmunology 227 (2010) 175–177
with standard procedures. The medical records of the hGADAb positive patients were reviewed, including the clinical status at last follow-up. The study was approved by the local Ethics Committee.
3. Results 3.1. Clinical and immunological data Of the 2500 neurological patients, 1435 were finally diagnosed with an autoimmune disease (multiple sclerosis, post-infectious demyelinating disorders, paraneoplastic and autoantibody-associated non paraneoplastic diseases, vasculitis, demyelinating acute and chronic neuropathies). We identified 7 patients whose serum IgG bound to CNS tissue with a pattern consistent with GAD specificity (titer, 1:400–1:51,200) (Table 1). The intrathecal synthesis index was N3 in all the patients whose CSF was tested. All samples were confirmed by RIA, with values (range, 74–160 UI/ml) significantly correlated with IIF titers (Spearman rank correlation test, p b 0.01). None of the 7 patients were seropositive for any other paraneoplastic or non paraneoplastic neuronal autoantibody tested; patients with hippocampal pathology and with temporal lobe epilepsy were both negative for P/Q-type voltage-gated calcium channel and for voltage-gated potassium channel antibodies (courtesy of Dr Angela Vincent). No malignancy was identified at disease onset and at follow-up (median follow-up duration: 24 months); one patient had a past history (N5 years) of breast cancer, without recurrence. Clinical, CSF study and brain MRI
findings are summarized on Table 1. The time from onset of symptoms to diagnosis ranged from 1 month to 6 years (median, 4 years). Four patients had motor symptoms (muscle rigidity and/or spasms) of the SPS spectrum; however, only one fulfilled SPS clinical criteria (Brown and Marsden, 1999), while the others were diagnosed with a stiffperson plus syndrome, either in the form of progressive encephalomyelitis with rigidity and myoclonus (PERM) (Pt no. 5), or with the limited variant of stiff-limb syndrome (Pts nos. 6 and 7). In 4 cases an association of symptoms of 2 or more CNS anatomo-functional areas, including brainstem and cerebellum, was observed.
3.2. Therapy and evolution Four patients received immunomodulatory treatments (Table 1). Only one patient (no. 3) experienced marked, although transitory, clinical improvement after corticosteroids. In most cases the neurological symptoms stabilized after 6–12 months from disease onset, but continued to slowly deteriorate over years. Nine serum samples from two patients were obtained during 6 and 5 years of follow-up, respectively. In one case (no. 1) GADAb titer mildly declined after corticosteroid and plasmapheretic treatment, but increased to a stable level during the follow-up (Fig. 1). In the other patient (no. 6) an increase of GADAb levels after 3 years of disease was associated with a worsening of her symptoms. GADAb titer continued to increase despite the association of low-dose azathioprine (1 mg/kg/day) to the previous IVIg treatment for a coincident dysimmune chronic neuropathy.
Table 1 Neurological syndromes associated with GAD Ab IF seropositivity. Case no./sex/age ADO (years) GAD Ab IF titer (serum/CSF) Neurological history autoimmunity
Associated conditions
Associated
1/F/52
20,000/200
TPO Ab ANA
Anxiety
2/F/67
3200/200
T1DM
Anxiety
3/F/32
51,200/np
4/F/61
400/np
5/M/56
800/10
6/F/19
25,600/640
7/F/42
12,800/32
Anterograde amnesia and temporal lobe epilepsy (limbic encephalitis); chronic evolution⁎; Brain MRI: increase of T2 signal (nonenhancing) over both hippocampal regions. CSF: mildly increased protein; increased IgG Link, multiple oligoclonal bands. Stabilization with CCs and PLEX. Progressive ataxia; right arm myoclonus; Brain MRI: normal. CSF: mildly increased protein, multiple oligoclonal bands; EMG: normal. No improvement with IVIg. Generalized rigidity and hyperlordosis (stiff-person syndrome); Brain MRI: normal. Temporal lobe epilepsy, resistant to multidrug Antiepileptic therapy; MRI: normal. Improvement with CCs. Vertigo, nausea, ophtalmoplegia (brainstem syndrome); rigidity and posture myoclonus in the legs, tremor, visual allucinations. CSF: multiple oligoclonal bands; brain MRI: multiple areas of white matter hyperintensity on T2 weighted images. EMG: unspecific changes. Improvement with clonazepam. Tongue deviation; progressive distal weakness and hypoestesia, and muscular atrophy. Hand spasms. EMG: signs of demyelinating polyradiculoneuropathy, with partial motor conduction blocks and signs of active denervation. Brain MRI: normal. CSF: normal (one isolated IgG band). EEG: normal. Temporary improvement with IVIg; stabilization with azathioprine. Episodes of eylid and perioral mycoclonus associated with left arm spasms. EMG: unspecific changes. EEG: normal. CSF: normal. Improvement with clonazepam.
GPC Ab, Pernicious anemia Pernicious anemia TPO Ab, Vitiligo
Depression, IMD
GPC Ab, ANA T1DM
Major depression; IMD (gut biopsy: degeneration of myenteric neurons) Pernicious anemia
ANA GM1 IgM Vitiligo CIDP
IMD
ANA T1DM
Major depression.
Ab = antibody; ADO = at disease onset; CCs = corticosteroids; CIDP = chronic inflammatory demyalinating polyneuropathy; CSF = cerebrospinal fluid; T1DM = type 1 diabetes mellitus; EEG: electroencephalogram; EMG = electromyography; GAD = glutamic acid decarboxylase; GPC = gastric parietal cell; IMD = intestinal motility disorder; IVIg = intravenous immunoglobulin; MRI = magnetic resonance imaging; PLEX = plasma exchange; TPO: thyroid peroxidase. ⁎ Patient 1 has already been reported on a previous paper [Matà et al., 2008].
S. Matà et al. / Journal of Neuroimmunology 227 (2010) 175–177
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disease course, generally because of difficult diagnosis, and almost never they are treated with long-term immunosuppression (Pittock et al., 2006). This is probably due to the diffuse skepticism regarding the meaning of hGADAb positivity in a so variable clinical panorama, and to the lack of definite evidences for GADAb pathogenetic role. However, it should be kept in mind that hGADAb associated syndromes may have a chronic evolution, with severe long-term neurological impairment if untreated, while a successful treatment may be obtained with early aggressive and sustained immunemodulatory therapy (Saidha et al., 2010). Although GADAb titers do not correlate with disease severity, the persistence of their production over years, as observed in our cases and recently demonstrated even in rituximab treated patients (Rizzi et al., 2010), could explain the tendency toward disease progression. Fig. 1. Glutamic acid decarboxylase (GAD) antibody (Ab) immunofluorescence (IF) serum titers from two patients followed-up for 6 and 5 years, respectively. The first patient (Pt no. 1), affected by limbic encephalitis, showed a mild decline of Ab levels after corticosteroid therapy (asterisk), that was associated with a stabilization of her clinical symptoms. GADAb titers increased gradually during the follow-up. The second patient (Pt no. 6), experienced a moderate worsening of her symptoms (hand spasms associated with peripheral symptoms due to chronic inflammatory demyelinating polineuropathy) associated with increase of Ab levels, that further increased after the introduction of azathioprine therapy (arrow).
4. Discussion The incidence of hGADAb among our neurological patients was 0.28% (95% CI, 0.073–0.48), which raised to 0.48% (95% CI, 0.12–0.83) considering only the cases with ascertained neurological autoimmune diseases. In this unselected patients population we observed a high variability of hGADAb associated neurological phenotype, being the SPS spectrum, especially the stiff-person plus syndrome, the commonest clinical manifestation. Of note, psychiatric and gastrointestinal disorders were frequent accompaniment of CNS dysfunctions in our patients cohort. Symptoms outside the strictly neurological point of view have been rarely considered in hGADAb positive patients. Phobic symptoms have been found in a high proportion of SPS patients (Henningsen and Meinck, 2003); however, they have been interpreted as a reaction to disability (Ameli et al., 2005). In our patients anxiety or major depression needing appropriate therapy had been diagnosed prior to the neurological symptoms onset in most of the cases, indicating that this is not just a secondary phenomenon. On the other hand, the presence of psychiatric symptoms, possibly related to an impairment of GABAergic transmission in the primary motor cortex (Koerner et al., 2004; Rossi et al., 2009), is consistent with the role of GABA within psychic functions (Goldman-Rakic, 1999). Similarly, the high prevalence of gastrointestinal motility disorders among hGADAb seropositive neurological patients could be attributed, besides the consequences of DM, to the effect of autoantibodies on GABA neurotransmission, whose role in the enteric nervous system has been well documented (Miki et al., 1983). Regarding the long-term evolution of hGADAb related disorders, it has been already emphasized that hGADAb positive neurological patients usually undergo immunomodulatory therapy late in the
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