Post-ganglionic autonomic neuropathy associated with anti-glutamic acid decarboxylase antibodies

Purpose

Antibodies to glutamic acid decarboxylase (GAD-Abs) have been associated with several conditions, rarely involving the autonomic nervous system. Here, we describe two patients complaining of autonomic symptoms in whom a post-ganglionic autonomic neuropathy has been demonstrated in association with significantly elevated serum and CSF GAD-Abs levels.

Methods

Patients underwent nerve conduction studies, sympathetic skin response testing, evaluation of autonomic control of the cardiovascular system and skin biopsy. Also, serum screening to exclude predisposing causes of peripheral neuropathy was performed. Anti-GAD65 antibodies were evaluated in serum and CSF.

Results

GAD-Abs titer was increased in both serum and CSF in both patients. Sympathetic skin response was absent and skin biopsy revealed a non-length-dependent small-fiber neuropathy with sympathetic cholinergic and adrenergic post-ganglionic damage in both patients. Nerve conduction studies and evaluation of autonomic control of the cardiovascular system were normal in both patients. Both patients were treated with steroids with good, but partial, (patient 2) recovery of the autonomic dysfunctions.

Conclusions

Although the pathophysiological mechanisms involved are not fully defined, GAD-abs positivity in serum and CSF should be searched in patients with autonomic neuropathy when no other acquired causes are evident. This positivity may help to clarify autoimmune etiology and, subsequently, to consider immunomodulatory treatment.

     

Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies

Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. Here we have characterized the clinical and laboratory features of two patients presenting with subacute onset, and chronic evolution, of anterograde amnesia and drug-resistant epilepsy associated with thyroid autoimmunity and in absence of tumoral pathology despite long follow-up. Antibodies against onconeural antigens, voltage gated potassium channel and glutamate receptors, which may accompany paraneoplastic as well as non-paraneoplastic LE, were negative. However, biochemical studies showed high titers, and sustained intrathecal synthesis, of antibodies directed against neuronal glutamic acid decarboxylase (GAD). In one patient, plasma exchange determined a dramatic improvement of the neurological deficits along with the decrease of autoantibodies.     

Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies

Anti-glutamic acid decarboxylase (GAD) antibodies are described in stiff-person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy. This paper reports the case of a patient who had chronic focal epilepsy, upbeat nystagmus and cerebellar ataxia, associated with a polyautoimmune response including anti-GAD antibodies. Both gait and nystagmus improved markedly after immunosuppressive treatment with corticosteroids and azathioprine. After the introduction of benzodiazepines, previously refractory seizures were completely controlled. Anti-GAD antibodies should be actively sought out in pharmacoresistant epilepsy, particularly if other neurological abnormalities are present. Combined treatment with immunosuppressants and gammahydroxybutyric acidergic agents may be highly effective.     

Antigenic differences between neurological and diabetic patients with anti-glutamic acid decarboxylase antibodies

Antibodies to glutamic acid decarboxylase (GADAb) are found in Stiff-Person syndrome, type 1 diabetes, cerebellar ataxia and other neurological disorders (such as epilepsy and myoclonus) involving the GABAergic ways. GADAb are usually detected by immunohistochemistry (IHC), radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). This study analysed the serum of 14 patients with neurological disorders who were positive by IHC for GADAb. The performance of a commercial RIA was compared with in-house immunoblotting and ELISA methods using recombinant GAD65 (rGAD65). RIA was positive in 14 of 14, immunoblotting was positive in seven of 14 and ELISA in 12 of 14. There was no correlation between the RIA result and the ELISA optical densities. Using a sodium thiocyanate chaotrope system with ELISA to determine antibody affinity, we found no significant correlation between antibody affinity and the RIA result. A consensus should be defined concerning which assay could be used as the gold standard for detecting GADAb. The most intriguing finding was that GAD antibodies from uncomplicated diabetics do not appear to recognize GAD in frozen sections from the rat cerebellum, whereas GAD antibodies from neurologically compromised diabetics do. A working proposal is therefore that type 1 diabetic patients with unusual neurological symptoms should be tested for GADAb both by RIA and IHC.     

Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies

Recent reports describe the detection of high titres of antibodies to glutamic acid decarboxylase (GAD-Ab) in the serum and cerebrospinal fluid (CSF) of patients with cerebellar ataxia. Most of these cases are females with Polyglandular Autoimmune Disorder who develop a chronic cerebellar syndrome. The CSF profile is in keeping with an autoimmune disorder and intrathecal GAD-Ab synthesis has been demonstrated. The ataxia could reverse after immunomodulatory treatments suggesting a possible pathogenetic role for GAD-Ab.     

GABA-A receptor impairment in cerebellar ataxia with anti-glutamic acid decarboxylase antibodies

Antibodies against glutamic acid decarboxylase (GAD-Abs) are associated with cerebellar ataxia, which is refractory to treatment with GABAergic drugs. To investigate the GABAergic neuronal system in vivo, we performed a combined positron emission tomography (PET) study with [¹¹C]-flumazenil and [¹⁸F]-fluorodeoxyglucose (FDG) in three patients with cerebellar ataxia with GAD-Abs. The GABA-A receptor function was investigated using flumazenil, which is a selective GABA-A receptor ligand, while FDG-PET using a three-dimensional stereotactic surface projection analysis was performed to estimate the metabolic rates of glucose (MRGlc) in the patients. GABAergic drugs showed no efficacy for the cerebellar ataxia in all three patients, and all three displayed a significant decrease in flumazenil binding in the cerebellum. No MRGlc decrease in the cerebellum was found in the two patients who presented with amelioration of cerebellar ataxia following intravenous immunoglobulin (IVIG) therapy, whereas a significant MRGlc decrease in the cerebellar hemisphere was observed in another patient who showed severe cerebellar atrophy on magnetic resonance images and no response to the IVIG therapy. The decreased flumazenil binding in the present patients indicated cerebellar GABA-A receptor impairment, which may be due to either neuronal cell loss, as demonstrated by the decreased MRGlc, or a dysfunction in GABAergic neuronal inhibition. Although GAD-Abs have been postulated to prevent the synthesis of GABA, resulting in decreased GABAergic transmission, the GABA-A receptor impairment may play another pathogenic role in cerebellar ataxia associated with GAD-Abs resulting in a condition refractory to GABAergic drug therapy.     

Cerebellar degeneration and polyglandular autoimmune syndrome with anti-glutamic acid decarboxylase antibodies

Journal of Neurology -     

Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients

BACKGROUND: Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man syndrome, and, recently, in a few patients with cerebellar ataxia. OBJECTIVES: To show a link between GAD-Ab and some patients with cerebellar ataxia and to clarify their clinical and immunologic profiles. METHODS: Serum samples were selected from 9000 samples of 4 laboratories. The selection criterion was an immunohistochemical pattern compatible with GAD-Ab that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man syndrome and 14 with cerebellar ataxia and GAD-Ab. RESULTS: Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women, and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients studied. The level of GAD-Ab of these patients was similar to those with stiff-man syndrome and significantly higher than those with IDDM or with polyendocrine autoimmunity (P<.001). However, the GAD-Ab levels of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those of patients with cerebellar ataxia. CONCLUSIONS: These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.     

抗谷氨酸脱羧酶65抗体脑炎临床特点分析

目的 探讨抗谷氨酸脱羧酶65(GAD65)抗体脑炎患者的临床特点。方法 回顾性总结分析2016年4月至2022年3月就诊于中南大学湘雅医院神经内科的9例抗GAD65抗体脑炎患者的临床资料。结果 9例患者发病年龄为14～76(31.2±20.5)岁;男女比例为4∶5。1例有前驱感染史。首发症状：癫痫发作3例、头痛2例、头晕1例、听力下降与幻嗅1例、不自主运动1例、面部感觉异常1例。临床表现：边缘性脑炎5例、单纯癫痫发作1例、边缘性脑炎伴小脑性共济失调1例、僵人综合征伴脑干脑炎1例、癫痫发作伴僵人综合征及小脑性共济失调1例。9例患者中,合并胰岛素依赖型糖尿病2例、合并甲状腺功能亢进1例、血抗甲状腺过氧化物酶抗体阳性4例。9例均进行了头部磁共振(MRI)检查,海马或颞叶异常信号3例、小脑萎缩1例。有7例患者在急性期进行了脑电图检查,4例合并癫痫样放电,均累及额颞区,其中有3例还累及双侧。9例患者均接受免疫治疗,单用一线治疗3例、一线联合二线治疗6例。6例接受了抗癫痫药治疗,其中4例需联合应用2种及2种以上的抗癫痫药。对9例患者进行了随访,失访1例;6例预后良好,其中2例症状完全缓解,4例部分...     

Tremor of the mouth floor and anti-glutamic acid decarboxylase autoantibodies

Involuntary movements of the mouth can present as palatal tremor, which is frequently associated with hypertrophy of the inferior olivary nucleus and can be accompanied by contraction of other muscles of the head. We report the case of a 39-year-old man with autoimmune thyroiditis and diabetes who complained of involuntary rhythmic tremor involving the muscles of the floor of the mouth, which interfered with breathing and swallowing. Cerebrospinal fluid (CSF) examination showed the presence of oligoclonal bands and screening for anti-neuronal antibodies revealed high titres of anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). Tremor responded to treatment with benzodiazepines. The correlation between the tremor and antibody positivity is unclear although an alteration of the gabaergic system mediated by the antibodies may be hypothesised on the basis of an inflammatory CSF profile.     

Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases

High prevalence of autoantibodies against glutamic acid decarboxylase (GAD-Ab) in stiff man syndrome (SMS) not only helps diagnosis, but also suggests immune mediated impairment of GABAergic functions. However, the presence of GAD-Ab has also been reported in other neurological syndromes. Therefore the prevalence of GAD-Ab was investigated in SMS, progressive encephalomyelitis with rigidity and myoclonus (PERM), and in other neurological diseases (OND).Serum antibodies against the GAD isoforms, GAD65 and GAD67, were investigated with radioimmunoassays in 13 patients with SMS, nine with PERM, 279 consecutive patients with OND, and in 100 normal controls. RESULTS: Prevalence of GAD65Ab was around 80% in patients with SMS/PERM compared with 5% in patients with OND and 1% in normal controls. Prevalence of GAD67Ab was 60% in SMS/PERM, 2% in patients with OND, and 1% in normal controls. Raised GAD-Ab clustered in an OND subgroup with sporadic progressive ataxia, but not in OND subgroups with recognised neuroimmunological diseases. In conclusion, increased GAD-Ab is neither a non-specific epiphenomenon of neuronal damage nor a common feature of recognised neuroimmunological disorders. In neurological diseases, GAD-Ab may be a pathogenetic agent or a marker for an ongoing autoimmune process, or both.     

Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia

Anti-glutamic acid decarboxylase antibody is associated with the development of progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus. Previously, the neurophysiological characteristics of IgG in the cerebrospinal fluid of a patient with anti-glutamic acid decarboxylase antibody-associated progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus were reported. Using a voltage-gated whole-cell recording technique, it was observed that the IgG in the cerebrospinal fluid of the patient selectively suppressed the inhibitory postsynaptic currents in the Purkinje cells. The patient died from aspiration pneumonia. Postmortem examination showed almost complete depletion of the Purkinje cells with Bergmann gliosis. Therefore, the main cause of cerebellar ataxia observed in this case may be attributed to the near-complete depletion of the Purkinje cells. In this paper, the pathomechanisms underlying Purkinje cell damage are discussed.     

Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies: a case series

Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients including stiff person syndrome, cerebellar ataxia, refractory epilepsy, limbic and extralimbic encephalitis. GAD antibodies-related limbic encephalitis cases are well described; reports of extralimbic involvement are limited. We describe four cases of GAD antibody-related autoimmune encephalitis. Three of them had extralimbic involvement and only one had limbic encephalitis.     

Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies

Anti-glutamic acid decarboxylase autoantibodies (GAD-Abs) are found in some patients with cerebellar ataxia. We reported previously that CSF IgGs depress cerebellar GABAergic synaptic transmissions by a presynaptic mechanism. Using whole-cell recordings from rat cerebellar slices, we found in the present study that CSF IgG-induced depressive effects were abolished by absorption of GAD-Abs using recombinant GAD. Furthermore, forskolin, an activator of cAMP, recovered the CSF IgG-induced reduction of GABA release. Our results provide evidence that GAD-Abs in the CSF elicited physiopathological effects on cerebellar GABA synapses in vitro and that such synaptic impairment was reversible.     

Stiff-person syndrome with anti-glutamic acid decarboxylase autoantibodies: Complete remission of symptoms after intrathecal baclofen administration

A female patient, aged 61 years, who developed a severe immobilizing stiff-person syndrome in conjunction with insulin-dependent diabetes mellitus, is described. In addition to the typical clinical symptoms, diagnosis was proven by the presence of autoantibodies against glutamic acid decarboxylase in serum and cerebrospinal fluid. Symptomatic treatment with continuous intrathecal application of baclofen administered by a subcutaneous pump resulted in rapid clinical improvement so that the patient became ambulatory. Intermittent withdrawal from intrathecal baclofen therapy led to complete remanifestation of stiff-person syndrome within 18 h; after re-introduction of intrathecal therapy stiffness disappeared completely within 48 h. The clinical course has been stable now for over 24 months and stiffness has completely disappeared. The effect of baclofen in this patient is discussed in the light of the suggested pathophysiological mechanisms in stiff-person syndromes.     

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood Part II. Glutamic acid decarboxylase activity in cerebrospinal fluid of children with neurological diseases

Glutamic acid decarboxylase (GAD) activity in cerebrospinal fluid (CSF) was determined in 53 patients with neurological diseases as follows: Epilepsy (n:17), febrile convulsions (n:3), meningoencephalitis (n:17), encephalopathies (n:10), CNS leukemia (n:3), congenital hydrocephalus (n:2) and pseudoileus neonatorum (n:1). Compared with the mean normal value (5.2 +/- 2.5 pmol CO2 formed/hr/ml) reported in Part I, a significant increase of GAD activity in CSF was demonstrated in patients with uncontrolled epileptic seizures (11.4 +/- 3.9 pmol CO2 formed/hr/ml), febrile convulsions (13.5 +/- 8.7), viral meningitis with or without encephalitis (20.3 +/- 13.6), encephalopathies (30.0 +/- 25.9), CNS leukemia (11.1 +/- 5.0), congenital hydrocephalus (20.5 +/- 7.3) and pseudoileus neonatorum (28.6). Markedly high GAD activity was found in patients with CNS leukemia several days after intrathecal injection of methotrexate (39.8 +/- 18.0). On the other hand, significantly low GAD activity was shown in patients with bacterial meningitis or brain abscess (1.3 +/- 1.2). This suggests that some bacterial factors may be inhibitory toward GAD activity in CSF. High GAD activity in CSF may be useful as an indicator of aseptic brain dysfunction, although it was not always correlated with the severity of symptoms.