Marika Vianello

Glutamic acid decarboxylase autoantibodies and neurological disorders

Abstract. 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.

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.

Increased spontaneous activity of a network of hippocampal neurons in culture caused by suppression of inhibitory potentials mediated by anti-gad antibodies

Introduction: Anti-glutamic acid decarboxylase autoantibodies (GAD-Ab) are commonly considered the marker of autoimmune diabetes; they were first described in patients affected by stiff-person syndrome and recently, in ataxic or epileptic patients. The pathogenetic role of GAD-Ab remains unclear but inhibition of GABA synthesis or interference with GABA exocytosis are hypothesized. The aim of the study was to assess whether GAD-Ab interfere with neuronal transmission. Patients and methods: Serum from a GAD-Ab positive epileptic patient (by IHC and RIA), serum from a GAD-positive (only by RIA) diabetic case, sera from two epileptic GAD-Ab negative patients and a normal control were selected. Post-synaptic inhibitory potentials (IPSPs) were registered on hippocampal neurons in culture before and after the application of diluted sera in a patch clamp study. Results: A significant increase in the frequency of IPSPs was observed after application of GAD-positive epileptic serum, while no effect was noted using sera from negative controls. Conclusion: The inhibition in neuronal transmission only after application of GAD-positive epileptic serum, suggests an interference with GABA function and consequently with neuronal inhibition supporting a pathogenetic role of GAD-Ab in the development of epilepsy.

X-linked adrenoleukodystrophy with olivopontocerebellar atrophy

X‐linked adrenoleukodystrophy (X‐ALD) is a rare neurological disorder characterized by adrenal, gonadal and nervous system dysfunction. Patients usually develop spinal cord degeneration with involvement of the cerebral white matter. While a spinocerebellar variant has been described, the selective involvement of cerebellar white matter is very rare. We report the case of a patient affected by X‐ALD whose clinical and magnetic resonance imaging (MRI) results resembled olivopontocerebellar atrophy. He was a 29‐year‐old mentally retarded man, who began to complain of slowly progressive gait ataxia after an 8‐year history of Addisons disease. Serial MRI revealed marked cerebellar atrophy involving the inferior cerebellar vermis and brainstem, but sparing the supratentorial white matter. The diagnosis of X‐ALD was confirmed by elevated levels of very long‐chain fatty acids in the serum. After 2 years follow‐up, the patient developed spastic paraparesis. The patient represents an unusual clinical presentation of X‐ALD, as further confirmed by the MRI results. Consequently, cerebellar symptoms should be considered as a clinical presentation of X‐ALD. Early recognition of this rare disorder would be useful for genetic counselling and therapy.

Peculiar labeling of cultured hippocampal neurons by different sera harboring anti-glutamic acid decarboxylase autoantibodies (GAD-Ab)

Immunological derangement is assumed to be present in a subgroup of patients affected by drug-resistant epilepsy with serum harboring anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). To further investigate the specific reactivity of GAD-Ab with target cells, we tested sera from drug-resistant epileptics harboring GAD-Ab on cultured fetal rat hippocampal neurons. As a control, we tested sera from GAD-Ab-negative epileptics and GAD-Ab-positive patients affected by Stiff Person Syndrome (SPS), ataxia or diabetes. A specific pattern of reactivity, varying according to disease, was detected on application of sera from GAD-Ab-positive patients with epilepsy, SPS and ataxia, but no specific labeling was found on application of sera from patients with GAD-Ab-negative epilepsy or from GAD-Ab-positive diabetic controls.

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.

Clinical, Immunological and Therapeutic Aspects of Autoimmune Encephalitis

Autoimmune encephalitis is a heterogeneous group of disorders probably resulting from a reaction of the immune system against antigens of the central nervous system. Historically, the autoimmune hypothesis was based on the neuropathological discovery of an immune cellular infiltrate in the brain parenchyma and around the cerebral blood vessels, resembling a form of viral encephalitis without any detectable viral antigens. These syndromes can be divided into forms with prevalent grey matter involvement, forms with prevalent white matter damage and forms in which the target of the immune process is the vessels. In this paper, we review recent knowledge about the syndromes belonging to the first group. This group encompasses syndromes in which there is neuronal loss and antibodies directed against antigens expressed in the neurons (anti-neuronal antibodies) are frequently detected in the sera or cerebrospinal fluid. These antibodies are not necessarily the cause of neurological impairment but are important markers for these syndromes. It is essential to acquire knowledge on these disorders since they are an important cause of rapidly progressive cognitive decline and behavioural problems which may remain underrecognized, but often improve with immunomodulatory therapies.

Multiple cranial nerve involvement in Bannwarth’s syndrome

Bannwarth’s syndrome is a tick-transmitted neurological disease caused by spirochetes of the Borrelia burgdorferi group. Neurological manifestations of the disease occur after skin erythema and include: neuritic pain, lymphocytic pleocytosis without headache and sometimes cranial neuritis. We present the case of a man who complained of a neurological syndrome without evidence of tick bite and concurrent manifestation of the infection, for whom serological analysis only revealed the infection after testing repetitive specimens. We discuss the need to start early therapy when clinical manifestations are suggestive of the disease in endemic areas.SommarioLa sindrome di Bannwarth è una malattia neurologica causata dalla trasmissione dell’infezione della spirocheta Borrelia Burgdoferi dopo puntura di zecca. Le manifestazioni neurologiche della malattia compaiono dopo l’eritema cronico migrante e comprendono dolore neuropatico, pleiocitosi linfocitaria senza cefalea e, qualche volta, l’interessamento dei nervi cranici. Presentiamo il caso di un uomo che ha manifestato i sintomi neurologici della malattia in assenza sia della conferma anamnestica di puntura di zecca che di concomitanti manifestazioni sistemiche dell’infezione. Indagini sierologiche, inizialmente negative, hanno confermato l’infezione solo dopo test ripetuti. Il caso presentato sottolinea la necessità di iniziare precocemente la terapia antibiotica quando le manifestazioni cliniche sono suggestive per la malattia nelle aree endemiche.

CHAPTER 68 – Paraneoplastic Neurologic Diseases: Autoimmune Responses to Tumor Antigens

Publisher Summary This chapter discusses paraneoplastic neurologic diseases (PND) that are a heterogeneous group of disorders associated with systemic malignancies but never related to invasion or compression of, or metastasis to, the nervous system. According to level of involvement of the nervous system and the presence of Ab, PND includes encephalomyelitis, limbic encephalitis, brain stem encephalitis, myelitis, and motor neuron syndrome. This chapter provides a classification of PND according to specific antibody detected, neurologic syndrome, and the most frequently associated tumor. Moreover, pathogenesis of PND is still not known, but an immune-mediated mechanism is hypothesized. This theory is supported by the detection of antineuronal Ab in PND patients CSF, which indicates intrathecal endogenous synthesis. Furthermore, the diagnosis of PND is difficult because not all patients with paraneoplastic disorders harbor antineuronal Ab and a neoplasm is not detected in all patients with antineuronal Ab. These criteria divide PND into “definite” and “possible” based upon clinical and immunologic data.