Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases

OBJECTIVE: Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate. METHODS: Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats. RESULTS: Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients. INTERPRETATION: These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.     

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.     

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.     

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.     

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

Journal of Neurology -     

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.     

The spectrum of antineuronal autoantibodies in a series of neurological patients

The aim of the present study is to identify the range of neurological disorders expressing antineuronal antibodies, evaluate the number of different patterns of reactivity that can be detected, and analyse the contribution of these studies to the identification of subgroups of patients.

The records of 882 patients were reviewed and their sera and cerebrospinal fluids tested for antineuronal antibodies. Patients were initially divided into four groups according to suspected clinical diagnosis. Autoantibodies were detected by immunohistochemistry, Western blot of gradient-separated neuronal and recombinant proteins and by RIA.

Cerebellar degeneration and sensory neuropathies were the most common neurological disorders in which paraneoplastic-related anti-neuronal antibodies were detected. However, in addition to PCA1/anti-Yo and ANNA1/anti-Hu antibodies, we found other reactivities in six patients with cerebellar degeneration: anti-GAD in three females and atypical in the other cases. The widest range of different anti-neuronal antibodies was detected in patients with peripheral sensory neuropathy. Few patients with Stiff-Person syndrome, temporal lobe epilepsy and myoclonus harboured anti-GAD antibodies. Atypical antibodies were detected in single cases with motor neuron disorder and multiple system atrophy. No anti-neuronal antibodies were detected in patients with neurological complications of connective tissue disorders other than Sjögren's syndrome, or in neurological diseases other than motor neuron disease and multiple system atrophy.

Our study shows that the spectrum of neurological disorders in which anti-neuronal antibodies can be detected is wider than previously thought. In addition, we found patterns of neuronal staining and Western blot reactivity that differed from those so far reported. This may permit identification of subgroups of patients in whom strategies directed at removing and/or suppressing antibody production could be of some benefit.     

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 autoantibodies and neurological disorders

Glutamic acid decarboxylase (GAD) is the enzyme that catalyses the production of GABA, a major neurotransmitter of the central nervous system. Antibodies to GAD (GAD-Ab) were first recognised in a patient affected by stiff-person syndrome; subsequently they were reported in a large number of cases with type 1 diabetes. Recently GADAb have been described in a number of patients affected by chronic cerebellar ataxia, drug-resistant epilepsy and myoclonus. These cases usually harbour other autoantibodies or are affected by organ-specific autoimmune diseases. The role of GAD-Ab is still unclear; the lack of experimental models makes it difficult to investigate their potential pathogenetic role. However two mechanisms have been suggested: the reduction by GAD-Ab of GABA synthesis in nerve terminals or the interference with exocytosis of GABA. Received: 16 May 2002 / Accepted in revised form: 10 July 2002 Correspondence to B. Giometto     

Paraneoplastic neurological syndromes in patients with carcinoid

Background: Paraneoplastic neurological syndromes (PNS) are mainly associated with small‐cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin‐related myopathy. We report four patients with a PNS associated with carcinoid. Patients and results: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti‐Hu, one anti‐Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated. Conclusion: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody‐associated PNS.     

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.     

Effects of antineuronal antibodies from patients with paraneoplastic neurological syndrome on primary-cultured neurons

Some patients with paraneoplastic neurological syndrome (PNS) produce autoantibodies against tumor and neuronal tissues of symptom-relevant areas. These characteristic antibodies are detected at early stages of the neurological disorder and are reliable markers for the diagnosis of PNS and underlying cancers. These antibodies are thought to be related directly to neuronal damage. However, the passive transfer of antibodies to rodents has been succeeded only in those in which the target antigens were expressed on the cell surface, like Lambert-Eaton myasthenic syndrome. The serum IgGs from patients with PNS and anti-Yo or anti-Hu antibody were not shown to induce the disease by passive transfer or active immunization with these antigen proteins to date. Instead, cytotoxic T lymphocytes (CTLs) against these antigen peptides-presenting targets could be induced in the peripheral blood of PNS patients. However, there is no direct proof of CTLs killing neurons. In this study, we examined the effects of the anti-Yo or anti-Hu antibody on mouse-brain-derived neurons in a primary culture system and found that these antibodies did not kill neurons, but induced the expression of cell adhesion molecules and accelerated neuronal differentiation. These effects of serum IgG fractions containing the anti-Yo or the anti-Hu antibody on the cultured neurons were the same, suggesting that their effects were not through the binding of the antibody to specific antigens, but to some other factors contained in IgG fractions.     

Recent advances and perspectives of postoperative neurological disorders in the elderly surgical patients

Postoperative neurological disorders, including postoperative delirium (POD), postoperative cognitive dysfunction (POCD), postoperative covert ischemic stroke, and hemorrhagic stroke, are challenging clinical problems in the emerging aged surgical population. These disorders can deteriorate functional outcomes and long‐term quality of life after surgery, resulting in a substantial social and financial burden to the family and society. Understanding predisposing and precipitating factors may promote individualized preventive treatment for each disorder, as several risk factors are modifiable. Besides prevention, timely identification and treatment of etiologies and symptoms can contribute to better recovery from postoperative neurological disorders and lower risk of long‐term cognitive impairment, disability, and even death. Herein, we summarize the diagnosis, risk factors, prevention, and treatment of these postoperative complications, with emphasis on recent advances and perspectives.     

SOX1 antibodies in sera from patients with paraneoplastic neurological syndromes

Objectives – SOX1 antibodies have been described in patients with Lambert–Eaton myasthenic syndrome (LEMS) in association with voltage‐gated calcium channel antibodies as serological markers of small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody‐positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical–immunological profile and associated tumours of patients with coexisting SOX1 antibodies. Methods– We retrospectively analysed sera from 55 patients with different PNS positive for well‐characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot. Results– Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non‐SCLC). One patient showed SOX1‐specific intrathecal antibody synthesis. Conclusions– We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well‐characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1‐specific anti‐glial antibodies.     

缺血性脑卒中患者血清SIRT1水平与早期神经功能恶化的相关性研究

目的 探讨缺血性脑卒中患者血清沉默信息调节因子1(Silent information regulator 1,SIRT1)水平与早期神经功能恶化(Early neurological deterioration,END)的相关性。方法 选取2020年1月-2021年6月于本院就诊的缺血性脑卒中患者136例,根据患者入院72 h内是否出现END,将其分为合并END组(41例)和非END组(95例),检测并比较2组血清SIRT1水平,采用Logistic回归法分析END发生的影响因素,采用受试者工作特征曲线(Receiver operating characteristic curve,ROC)分析SIRT1诊断END发生的临床价值。结果 2组患者年龄、糖尿病占比、冠心病占比、基线美国国立卫生院卒中量表(National institute of health stroke scale,NIHSS)评分比较差异显著(P<0.05); 与非END组比较,合并END组患者血清SIRT1水平较低,超敏C反应蛋白(High sensitivity C-reactive protein,hs-CRP)水平较高(P<0.05); 糖尿病史、年龄、hs-CRP水平及SIRT1水平是缺血性脑卒中患者发生END的独立危险因素(P<0.05); SIRT1预测缺血性脑卒中患者发生END的曲线下面积为0.753[95%CI=0.559～0.903,P<0.05],诊断特异度为81.49%,敏感度为89.15%。结论 SIRT1在缺血性脑卒中早期神经功能恶化患者血清中呈低表达,且其表达水平与缺血性脑卒中患者发生END有关。     

Correlations between obstetric complications and neurological soft signs in Tunisian patients with schizophrenia

The objective of this study was to examine the correlations between a history of obstetric complications (OC) and neurological soft signs (NSS) in Tunisian patients with schizophrenia. Forty‐six patients were assessed using the Krebs et al. NSS scale. History of OC was obtained from the patients' mothers using the McNeil–Sjöström scale. Although there was no significant difference in NSS between patients with and without OC, there were negative correlations between OC total score and motor coordination and integration sub‐scores. These negative correlations suggest that OC could enhance the effects of genetic risk factors for schizophrenia.     

Outcome and neurological sequelae of patients after tetanus

From 1969-1985, 106 people contracted tetanus in Finland. The outcome of the disease was good in 78 cases (returned to work), poor in 27 (12 died, 5 institutionalized and 10 retired) and unknown in 1. Poor outcome was the result of a disease requiring respirator treatment. Other clinical factors significantly correlated with poor outcome were blood pressure lability, hyperglycemia, hyperthermia, tachycardia and anticoagulation therapy. Forty people who were representative of the whole series with regard to sex, age and severity of disease attended a follow-up study on average 7 years and 4 months later. Forty age- and sex-matched controls had the same examinations, and compared with them, the 40 patients still had significantly more muscle fatigue and cramps, nervousness, decreased mental capacity and difficulties in balance, speech and memory. They also had more clinical findings, such as peripheral paresis, muscular atrophy, decreased or absent tendon reflexes and decreased mental capacity than the controls.