Sabrina Matà

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.

Clinical presentation and outcome of Guillain-Barré and related syndromes in relation to anti-ganglioside antibodies

We correlated the clinical features of 78 patients with Guillain-Barré syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P<0.00001), the other clinical forms were not associated with a specific anti-ganglioside reactivity. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse disability at 6 month than other or no reactivity and, similarly to anti-GM2 antibodies, with a more frequent respiratory impairment. Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS and, in all but one patient, with a complete recovery; still they were found in only 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies, though always associated with ophthalmoplegia and ataxia in both MFS and GBS, were found in only 36 and 26%, respectively, of patients with these symptoms. Even if different anti-ganglioside antibodies tend to be associated with some clinical features possibly suggesting that they may influence the clinical presentation or outcome, with the exception of anti-GQ1b antibodies for ophthalmoplegia and ataxia, they do not permit to predict the clinical presentation or outcome in individual patients.

Temporal profile of anti-ganglioside antibodies and their relation to clinical parameters and treatment in Guillain–Barré syndrome

Elevated anti-ganglioside antibody levels mainly of anti-GM1 and anti-GD1a specificities have been reported in THE serum of patients with Guillain-Barré syndrome (GBS). The relevance of anti-ganglioside antibodies other than anti-GM1 and anti-GD1a IgG antibodies and the temporal profile of anti-ganglioside antibodies in GBS is less clear. We studied serum antibodies to GM1, GD1a, GD1b, GQ1b, sulfatide and cardiolipin of the IgM, IgG and IgA classes over the course of GBS in patients who were untreated or treated with high dose intravenous immunoglobulin (IvIg). Antibodies to GD1b, GQ1b, sulfatide and cardiolipin were not detected in the sera of the GBS patients examined in this study. Anti-GM1 IgG titers peaked around 40 days and anti-GD1a IgM around 90 days after GBS onset. Titers of anti-GM1 IgG antibodies decreased following IvIg treatment. Patients with antibody peaks, defined as fivefold or higher increase in antibody titer compared to the lowest antibody titer over the course of GBS, had higher disability scores during the first two weeks of GBS and a worse clinical outcome (anti-GM1 IgG and anti-GD1a IgM antibody peaks) and axonal damage (anti-GD1a IgM antibody peaks), compared to patients without peak antibody titers. Anti-GM1 IgG and anti-GD1a IgM antibodies are thus strongly associated with more severe- and predominantly axonal cases of GBS. The appearance of anti-GM1 IgG and anti-GD1a antibody peaks in the serum after the termination of the acute phase of GBS suggests that these antibodies are produced secondary to nerve damage in GBS. The data does not exclude the possibility that secondarily secreted anti-GM1 IgG and anti-GD1a IgM antibodies may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.

Cytokine pattern in the cerebrospinal fluid from patients with GBS and CIDP

Macrophage-colony stimulating factor (M-CSF) and, less frequently, IL-1 beta and IL-6 were detected in the cerebrospinal fluid (SF) from Guillain-Barré syndrome (GBS) patients. IL-1 alpha, IL-2, IL-10, TNF alpha, and IFN gamma were not found. Detectable cytokine levels were not observed in chronic inflammatory demyelinating polyneuropathy (CIDP) SF nor in any of the sera studied. These findings suggest a prominent intrathecal activation of cells of the monocyte/macrophage lineage (Mø) in GBS, and further support the hypothesis of a crucial role for Mø in GBS immunopathology.

Plasma exchange for anti GAD associated non paraneoplastic limbic encephalitis.

Limbic encephalitis (LE) is a neurological syndrome usually presenting in a paraneoplastic form. Recently many cases were reported with no concurring neoplasia, presenting with specific antibodies for voltage-gated potassium channel or for neuronal membrane antigens. Anti-glutamic acid decarboxylase (GAD) antibodies act against GABAergic receptors of the central nervous system. These antibodies were found in coeliac disease serum and in neurologic patients. We are reporting a case of a 21-year-old coeliac woman manifesting complex multiple-daily partial drug-resistant seizures for 7 years. The diagnosis was of a non paraneoplastic limbic encephalitis, unresponsive to high dose cortisone and IGIV infusion. The use of therapeutic plasma exchange (TPE) has resulted in an improvement in symptoms with quite a long disease-free period of time. When the frequency of the procedures was decreased, seizures appeared again and, after suspension of TPE, the clinical status worsened. The role of TPE in the treatment of LE still has to be defined.

A synthetic glycopeptide of human myelin oligodendrocyte glycoprotein to detect antibody responses in multiple sclerosis and other neurological diseases

Glycopeptides of hMOG(30-50) containing a glucosyl moiety on the side-chains of Asn, Ser or Hyp at position 31 were synthesised. Antibody titres to hMOG(30-50) and to its glucoderivatives were measured by ELISA in sera of patients affected by different neurological diseases. Anti-hMOG(30-50) antibodies were detected only using the glycopeptide [Asn31(N-Glc)]hMOG(30-50).

Cerebrospinal fluid anti-cardiolipin antibodies in neurological diseases

We studied, with sensitive ELISAs, the anti-cardiolipin antibodies of the G, A, and M classes in the cerebrospinal fluid (CSF) and serum of 179 neurological patients. The CSF and serum of 2 systemic lupus erythematosus (SLE) patients presented IgG anti-cardiolipin antibodies in corresponding levels. Anti-cardiolipin antibodies were produced within the central nervous system in neurosyphilis (A and M classes), in some patients affected by multiple sclerosis (G or M class), in two cases of Guillain-Barré syndrome (G and A classes), and in one AIDS patient (G class). The CSF anti-cardiolipin antibodies detected in our study suggest a local immune reaction against brain phospholipids in SLE and in human demyelinating disorders.

Anti-ganglioside antibodies and elevated CSF IgG levels in Guillain-Barré syndrome

Anti‐ganglioside antibody production and dysfunction of blood‐cerebrospinal fluid (CSF) barrier (BCB) are frequent findings in dysimmune neuropathy patients, whereas intrathecal synthesis of immunoglobulins is still a matter of debate. We examined the CSF, immunological and electrophysiological characteristics from a cohort of patients with Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), and from patients with other neurological diseases as control. Thirty‐eight percent of GBS patients and 28% of CIDP patients had detectable serum titers of anti‐ganglioside antibodies, which were associated with a high incidence of motor conduction block and increased F wave latencies. In GBS patients, but not in CIDP or control patients, there was an association between anti‐ganglioside antibodies and increased CSF immunoglobulin‐G (IgG) levels as determined by the IgG index. However, none of the GBS patients had CSF oligoclonal bands (OBs) or indications of intrathecal anti‐ganglioside antibody synthesis. The possibility of an abnormal CSF concentration of immunoglobulins from serum through dysfunctional BCB or damaged nerve roots, and the role of serum anti‐ganglioside reactivity in this process are discussed.

Motor nerve damage is associated with anti-ganglioside antibodies in diabetes.

Abstract  Few reports exist on the association between the humoral immune response to glycolipids and neuropathic findings in diabetes. To address this issue, we assayed serum anti‐GM1, GD1b, GD1a, and sulfatides IgG and IgM in a group of 85 non‐selected diabetic patients, and correlated these antibodies to clinical and electrophysiological findings. Diabetic patients had higher mean titers of anti‐GM1 (IgM), GD1b, GD1a, and sulfatide (IgG) antibodies when compared to healthy controls. Patients with a positive titer of anti‐ganglioside antibodies had significant alterations of motor conduction parameters. The statistical significance increased when considering those patients with both anti‐ganglioside reactivity and a high value for glycosylated hemoglobin. Production of antibodies to ganglioside may follow the exposure of hidden motor nerve epitopes in damaged motor nerves and contribute to the neuropathy.

Human herpesvirus 6-associated limbic encephalitis in adult recipients of unrelated umbilical cord blood transplantation.

Human herpesvirus 6-associated limbic encephalitis in adult recipients of unrelated umbilical cord blood transplantation