The Prognosis of Glutamic Acid Decarboxylase Antibodies in Women With Hyperglycemia in Pregnancy.

CONTEXT: We recently reported that the presence of glutamic acid decarboxylase antibodies (GADA) was not associated with large-for-gestational-age infants in women with hyperglycemia in pregnancy (HIP). OBJECTIVE: We explored the association between the presence of GADA and other HIP-related adverse pregnancy outcomes. METHODS: This observational prospective study, conducted at a university hospital in a suburb of Paris, France, included 1182 consecutive women with HIP measured for GADA at HIP care initiation between 2012 and 2017. Post hoc analyses for outcomes included gestational weight gain, insulin therapy, cesarean delivery, hypertensive disorders, small-for-gestational-age infant, prematurity, and neonatal hypoglycemia. RESULTS: Of the 1182 women studied, 87 (7.4%) had positive (≥ 1 IU/mL) GADA. Although socioeconomic, clinical, and biological characteristics were similar across women in the positive and negative GADA groups, higher fasting plasma glucose values during early HIP screening were observed in the former (5.5 ± 1.5 vs 5.2 ± 0.7 mmol/L respectively, P < .001). At HIP care initiation, fructosamine levels were higher in women with positive GADA (208 ± 23 vs 200 ± 18 µmol/L; P < .05). In the homeostatic model assessment, insulin resistance (HOMA-IR) and beta secretion (HOMA-B) rates were similar in both groups. Gestational weight gain and the rates of all adverse outcomes were similar in both groups except for cesarean delivery (18.4 and 27.3% for positive and negative GADA, respectively; adjusted odds ratio 0.49 [95% CI, 0.26-0.92], P = .026). CONCLUSION: Universal measurement of GADA in women with HIP highlighted that 7.4% had positive GADA. No association was observed between GADA and HIP-related adverse pregnancy outcomes, except a lower risk of cesarean delivery.

Latent Autoimmune Diabetes in an Adult Male Presenting With Diabetic Ketoacidosis (DKA).

Latent autoimmune diabetes in adults (LADA) is a common but not well-studied entity and its features overlap between type 1 and type 2 diabetes mellitus (T1D, T2D). Although autoimmunity is a well-known factor associated with this diabetes subtype, environmental factors including excessive weight, physical inactivity, and smoking may also be associated with it. It is commonly misdiagnosed as T2D and generally treated by oral anti-diabetes medications that cause a delay in commencing insulin therapy. There are few cases mentioned in the literature of LADA presenting first time as diabetic ketoacidosis (DKA). Here, we report a case of latent autoimmune diabetes in an adult male who presented with DKA.

Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex.

Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether 'limbic encephalitis with GAD antibodies' is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern. We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration. In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis; three cases developed hippocampal sclerosis within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure-free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8+ cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early/active cases (but not in late/inactive stages) revealed 'T cell immunity' and 'Regulation of immune processes' as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation. Surgically treated patients with GAD-TLE go through an early active inflammatory, 'encephalitic' stage (≤6 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. 'Limbic encephalitis' with GAD antibodies should be subsumed under GAD-TLE. The early tissue damage explains why immunotherapy does not usually lead to freedom from seizures.

Super refractory status epilepticus secondary to anti-GAD antibody encephalitis successfully treated with aggressive immunotherapy.

Antibodies against glutamic acid decarboxylase are reported in association with a number of neurological conditions including limbic encephalitis. We report a case of anti-GAD-antibody associated encephalitis presenting with super-refractory status epilepticus. We describe the clinical course, management, and the outcome. In addition, we review the presentation and outcomes of reported cases of anti-GAD encephalitis. Similar to the reported cases of anti-GAD encephalitis, our case was refractory to treatment with conventional antiseizure medication. Treatment with intravenous immune globulin (IVIG), high dose corticosteroids, and plasmapheresis had partial response, but escalation of treatment to the use of tocilizumab was associated with significant clinical improvement.

Progressive Encephalomyelitis With Rigidity and Myoclonus With Thymoma: A Case Report and Literature Review.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is part of the variant type of the Stiff Person Syndrome (SPS) and is a rare neurological disease. We report here a patient with PERM who had thymoma and was positive for anti-glutamic acid decarboxylase (anti-GAD) antibodies. Her symptoms improved after treatment with hormones and gamma globulin. We also summarized the literature review of patients with PERM accompanied by tumors reported.

Autoimmune musicogenic epilepsy associated with anti-glutamic acid decarboxylase antibodies and Stiff-person syndrome.

Epilepsy should be suspected in patients with Stiff-person syndrome and new onset paroxysmal episodes. Musicogenic epilepsy may be a manifestation of anti-GAD-Ab spectrum, supporting an autoimmune workup in these patients. Appropriate treatment is not well established, and immunotherapy should be considered in patients with only partial response to antiepileptic drugs.

Clinical spectrum of glutamic acid decarboxylase antibodies in a Taiwanese population.

BACKGROUND AND PURPOSE: High levels of autoantibodies against glutamic acid decarboxylase (GAD-abs) are associated with stiff-person syndrome (SPS). However, the full clinical spectrum associated with GAD-abs in Asians is unclear. The clinical and immunological features of patients positive for GAD-abs were reviewed in a large Taiwanese series. METHODS: Retrospective case series and immunological investigations were conducted between July 2007 and July 2017 at a tertiary referral centre in Taiwan. Amongst 361 patients with GAD-ab reactivity, 185 with detailed clinical records were included. RESULTS: Twenty-seven patients (14.59%), with a mean age at assessment of 54.8 ± 13.9 years, presented with neurological symptoms. The major neurological presentations (mean GAD-ab concentrations) were SPS (n = 9, 33.3%; 135.45 ± 27.84 U/ml), cerebellar ataxia (n = 3, 11.1%; 95.61 ± 49.63 U/ml), encephalopathy (n = 2, 7.4%; 51.8 ± 49.64 U/ml) and epilepsy (n = 1, 3.7%; 83.3 U/ml). Notably, eight patients fulfilling the clinical diagnosis of multiple system atrophy had relatively lower GAD-ab concentrations (2.57 ± 0.82 U/ml), which has not been reported previously. There was no correlation between disease severity and GAD-ab concentration. Patients presenting with comorbid endocrinopathies (n = 15, 55.5%) had higher GAD-ab concentrations than those without endocrinopathies (n = 12, 44.4%; 104.45 ± 22.51 U/ml vs. 34.08 ± 21.83 U/ml, P = 0.04). Of 158 patients (85.4%) without a neurological presentation, 133 had type 1 diabetes mellitus and 20 had diabetes of other aetiologies (type 2 or gestational diabetes mellitus, or diabetes secondary to pancreatitis); the remaining four patients had pure thyroid disorders. CONCLUSIONS: A clinical and immunological evaluation of East Asian patients positive for GAD-abs is presented and a different clinical spectrum of anti-GAD syndrome is identified compared to Caucasians.

Stiff-Person Syndrome: A Case Report and Review of the Literature.

AIM: To report a case of sudden onset vertical diplopia, blurred vision, and muscle spasms. METHODS: This is a case report of a 57-year-old female who presented to the accident and emergency department with a one day history of vertical diplopia and a two week history of lower limb spasticity secondary to muscle spasms. RESULTS: The patient had no significant medical or ocular history. Orthoptic investigation initially revealed a left inferior rectus (IR) underaction. Possible diagnoses at this point were thought to be isolated IR weakness, myasthenia gravis or skew deviation. An urgent MRI scan was arranged and blood tests were taken. MRI showed no abnormalities. Blood tests were normal, however, the acetylcholine receptor antibody serum test (ACH-R) was 0.43 nmol/L, which is at the high end of normal. At the follow-up visit, the IR weakness had deteriorated and the patient had also developed gaze-evoked nystagmus. An appointment with the neurologist and neuro-ophthalmologist was expedited. When the patient returned, she reported that her neurologist had diagnosed her with stiff-person syndrome (SPS). The patient had also developed a laterally alternating skew deviation and reported that she had undergone a course of intravenous immunoglobulin (IVIG). The patient was prescribed diazepam and gabapentin. Due to the lack of recovery, persistent diplopia and oscillopsia, monthly IVIG have been prescribed. CONCLUSION: There is currently a paucity of literature relating to ophthalmic problems with SPS and how they are best treated. Previous reports have established that there is a link with myasthenia gravis, with many patients going on to develop myasthenia. Treatment of SPS is lacking large evidence-based studies. However, treatment with muscle relaxants and anticonvulsants has provided a good outcome for some. Further research is required to develop an evidence-based approach to treating the ophthalmological problems patients with SPS experience. This case report highlights the importance and value of orthoptists in investigating and monitoring patients with stiff-person syndrome.

Glutamate-Related Antibodies and Peripheral Insulin-Like Growth Factor in Bipolar Disorder and Lithium Prophylaxis.

AIMS: The aim of this study was to evaluate serum levels of the antineuronal antibodies anti-N-methyl-D-aspartate receptor (NMDAR) and anti-glutamic acid decarboxylase (GAD), and insulin-like growth factor 1 (IGF-1), in patients with bipolar disorder (BD), during manic and depressive episodes and in remission compared to euthymic patients receiving long-term lithium therapy. METHODS: Serum levels of anti-NMDAR and anti-GAD 450/620 antibodies, as well as IGF-1, were measured using the ELISA method in 19 manic and 17 depressed patients both in an acute episode and in remission after the episode. All of the subjects were under pharmacological treatment. The control group included 18 euthymic BD patients receiving lithium for 9-44 years (mean 22 ± 11) in whom a single measurement was performed. RESULTS: Serum levels of anti-NMDAR antibodies were higher in acute manic episodes than in lithium-treated patients. Serum levels of anti-GAD 450/620 antibodies were higher in acute manic and depressive episodes compared to remission after the respective episode. Their values in both acute manic and depressive episodes were higher than those in lithium-treated patients. Serum levels of IGF-1 were higher in acute manic episodes and in remission after mania than in lithium-treated patients. CONCLUSION: Higher levels of anti-NMDAR and anti-GAD antibodies during episodes may point to an abnormality in the glutamatergic system in BD. Increased levels of IGF-1 during an acute manic episode and in remission after mania may constitute a compensatory mechanism against excitotoxicity. Lower levels of anti-NMDAR, anti-GAD antibodies, and IGF-1 during long-term lithium treatment may reflect normalization of this processes, contributing to mood stabilization.

A Survival Case of Super-refractory Status Epilepticus due to Glutamic Acid Decarboxylase Antibodies-associated Limbic Encephalitis.

Limbic encephalitis (LE) is a neurological syndrome that mainly affects mesial temporal lobes. It may present in association with cancer or infection. Limbic encephalitis associated with glutamic acid decarboxylase antibodies (anti-GAD) is rare. Here, we report a case of anti-GAD limbic encephalitis to heighten the awareness of this rare cause of autoimmune encephalitis. Anti-GAD-associated epilepsy is often poorly responsive to seizure medications. Treatment is challenging. Early initiation of immunotherapy is important.

Severe dysautonomia as a main feature of anti-GAD encephalitis: Report of a paediatric case and literature review.

INTRODUCTION: Anti-glutamic acid decarboxylase (anti-GAD65) antibodies are a rare cause of autoimmune encephalitis. This entity is mainly recognized in adults and very few cases were reported in children. We report on a paediatric case of anti-GAD encephalitis with severe presentation and uncontrollable dysautonomia. CASE STUDY: A 9-year-old girl was referred to our department for refractory seizures and behavioral disturbances. Brain magnetic resonance imaging (MRI) was normal. Repeat screening for antineuronal antibodies showed negative results for anti-NMDA receptor antibodies but positive results for anti-GAD65 with a low positivity of anti-Ma2 antibodies. Although a transient improvement was noticed after immunomodulatory treatment, the patient developed severe intractable autonomic imbalance including dysrythmia, alternating bradycardia/tachycardia, hypotension/hypertension, hypothermia/hyperthermia and hyperhidrosis. She deceased six months after onset. CONCLUSION: Our report intends to raise awareness of autoimmune encephalitis with anti-GAD65 antibodies which may involve extralimbic brain regions and manifest with fatal dysautonomia. We highlight the need for prompt diagnosis and aggressive management for this underdiagnosed entity in children.

Anti-GAD Antibody-associated Syndrome Presenting with Limb Myoclonus.

Background: The clinical spectrum of anti-glutamic acid decarboxylase (GAD) antibody-associated neurologic syndromes is expanding, with focal, generalized, and atypical forms. Case Report: We describe a 59-year-old female showing continuous right lower limb myoclonus and mild encephalopathy. These symptoms started 2 weeks prior to evaluation. The patient had great improvement with intravenous steroids. An autoantibody panel was positive for anti-GAD. Discussion: Various clinical manifestations, including myoclonus, may relate to anti-GAD antibodies. The treatment options available include symptomatic drugs, intravenous immunoglobulin, steroids, and other immunosuppressant agents.

Hippocampus and Insula Are Targets in Epileptic Patients With Glutamic Acid Decarboxylase Antibodies.

Background: Antibodies to glutamic acid decarboxylase (GAD ab) have been found in patients with limbic encephalitis (LE) and chronic pharmacoresistant focal epilepsy (FE). The objectives of the study were to: (1) analyze the clinical and neuroimaging course of patients with FE+GAD ab, (2) compare these characteristics with a control group, and (3) describe the most affected cerebral areas with structural and functional imaging. Methods: Patients with FE + high titers of GAD ab and a follow-up of at least 5 years were selected. Titers of serum GAD ab exceeding 2,000 UI/ml were considered high. Evolutive clinical and radiological characteristics were studied in comparison to two different control groups: patients with bilateral or with unilateral mesial temporal sclerosis (BMTS or UMTS) of a non-autoimmune origin. Results: A group of 13 patients and 17 controls were included (8 BMTS, 9 UMTS). The most frequent focal aware seizures (FAS) reported by patients were psychic (5/13: 33%). Somatosensorial, motor, and visual FAS (4/13:32%) (p: 0.045), musicogenic reflex seizures (MRS), and a previous history of cardiac syncope were reported only patients (2/13:16% each) (p: NS). Comparing EEG characteristics between patients and controls, a more widespread distribution of interictal epileptiform discharges (IED) was observed in FE+ GAD ab patients than in controls (p:0.01). Rhythmic delta activity was observed in all controls in anterior temporal lobes while in patients this was less frequent (p: 0.001). No IED, even in 24 h cVEEG, was seen in 6 patients (46%).First MRI was normal in 4/5 (75%) patients. During the follow-up mesial temporal lobe (MTsL) sclerosis was observed in 5/8 (62%) of patients. All patients had abnormal FDG-PET study. MTL hypometabolism was observed in 10/11 (91%) patients, being bilateral in 7/11 (63%). In controls, this was observed in 16/17 (94%), and it was bilateral in 8/17 (47%) (p: NS). Insular hypometabolism was observed in 5/11 (45%) patients (P:0.002). Conclusions: Clinical, EEG, and FDG-PET findings in FE+GAD ab suggest a widespread disease not restricted to the temporal lobe. Progressive MTL sclerosis may be observed during follow-up. In comparison to what is found in patients with non-autoimmune MTL epilepsy, insular hypometabolism is observed only in patients with GAD ab, so it may be an important diagnostic clue.

Lesson of the month 2: Autoimmune sequelae of anti-GAD antibodies - thinking outside the box.

A 52 year-old female with no significant medical problems presented with left-sided weakness, unsteady gait and speech disturbance. It was thought that she had neuro-inflammation and she remained clinically stable. Several years later, she was diagnosed with latent autoimmune diabetes of adulthood. Her neurological symptoms deteriorated and she was admitted into hospital. The cerebrospinal fluid was normal, as were an array of blood tests. Imaging tests, including magnetic resonance imaging, computerised tomography and positron emission tomography scans were normal. However, her anti-glutamic acid decarboxylase antibody serum level, which had been taken in the diabetes outpatient clinic, returned at 2,000,000 IU/mL (normal range 0-10). This led to the diagnosis of glutamic acid decarboxylase (GAD) positive cerebellar ataxia. She was treated with plasma exchange and intravenous immunoglobulins and over next 12 weeks her symptoms improved. Our case highlights the need for appropriate treatment of patients with GAD positive cerebellar ataxia to achieve good outcomes.

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.

Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports.

BACKGROUND: "Classic" stiff person syndrome (SPS) features stiffness, anti-glutamic acid decarboxylase (anti-GAD) antibodies, and other findings. Anti-GAD antibodies are also detected in some neurological syndromes (such as ataxia) in which stiffness is inconsistently present. Patients with otherwise "classic" SPS may either lack anti-GAD antibodies or be seropositive for others. Hence, SPS cases appear to fall within a clinical spectrum that includes conditions such as progressive encephalomyelitis with rigidity and myoclonus (PERM), which exhibits brainstem and autonomic features. We have compiled herein SPS-spectrum cases reported since 2010, and have segregated them on the basis of likely disease mechanism (autoimmune, paraneoplastic, or cryptogenic) for analysis. METHODS: The phrases "stiff person syndrome", "PERM", "anti-GAD antibody syndrome", and "glycine receptor antibody neurological disorders" were searched for in PubMed in January 2015. The results were narrowed to 72 citations after excluding non-English and duplicate reports. Clinical descriptions, laboratory data, management, and outcomes were categorized, tabulated, and analyzed. RESULTS: Sixty-nine autoimmune, 19 paraneoplastic, and 13 cryptogenic SPS-spectrum cases were identified. SPS was the predominant diagnosis among the groups. Roughly two-thirds of autoimmune and paraneoplastic cases were female. Anti-GAD antibodies were most frequently identified, followed by anti-amphiphysin among paraneoplastic cases and by anti-glycine receptor antibodies among autoimmune cases. Benzodiazepines were the most commonly used medications. Prognosis seemed best for cryptogenic cases; malignancy worsened that of paraneoplastic cases. DISCUSSION: Grouping SPS-spectrum cases by pathophysiology provided insights into work-up, treatment, and prognosis. Ample phenotypic and serologic variations are present within the categories. Ruling out malignancy and autoimmunity is appropriate for suspected SPS-spectrum cases.

A case report of patient with cerebellar variant of stiff person syndrome.

Stiff person syndrome (SPS) is a rare autoimmune neurological disorder with antibodies against antigens involved in neurotransmission of gamma-aminobutyric acid (GABA). About 10% of patients with SPS may develop ataxia. This cerebellar variant is a distinct subset of SPS with more severe and complex clinical phenotype. We report the clinical, neuropsychological and neuroradiological findings in a 39-year-old female with cerebellar variant of SPS.

CTLA-4+49 A/G polymorphism and antiglutamic acid decarboxylase antibody-associated encephalopathy in Taiwanese children.

BACKGROUND: Anti-glutamic acid decarboxylase antibodies are associated with encephalopathy, an autoimmune central nervous system inflammatory disease. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)+49 A/G polymorphism has been shown to confer genetic susceptibility to positive anti-glutamic acid decarboxylase antibodies in patients with type 1 diabetes mellitus in Japan. We aimed to investigate the association of the CTLA-4+49 A/G (rs231775) polymorphism in Taiwanese children with anti-glutamic acid decarboxylase antibody-associated encephalopathy. METHODS: This was a case-control study from July 2011 to June 2012 performed at Chang Gung Children's Hospital in Taiwan. Genotyping of the CTLA-4+49 A/G polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Seventeen patients with anti-glutamic acid decarboxylase antibody-associated encephalopathy and 97 controls were enrolled. The genotype, allele and carrier frequencies of the CTLA-4+49 A/G polymorphism were equally distributed in the patients and controls, with no significant differences between the two groups. In addition, we found a positive trend between the level of anti-glutamic acid decarboxylase antibodies and the G allele of the CTLA-4+49 A/G polymorphism, although this trend was not statistically significant. CONCLUSIONS: Our results suggest that the CTLA-4+49 A/G (rs231775) polymorphism does not confer an increased susceptibility to anti-glutamic acid decarboxylase antibody-associated encephalopathy in Taiwanese children.