Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia—Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.

     

Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies

Journal of Neurology - To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). We retrospectively analyzed the clinical...     

Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto’s encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.     

Encéphalites auto-immunes à anticorps antirécepteurs-NMDA, une cause fréquente d’encéphalite en réanimation

Paraneoplastic autoimmune encephalitis results in rapidly evolving symptoms encompassing behavior changes, mood disorders, seizures, memory deficits, and possible decline of consciousness associated to an inflammation of the cerebrospinal fluid (CSF) and abnormalities on cerebral imaging. Among these encephalitis, the recently described anti-NMDA-receptor encephalitis seems more common. According to an epidemiological prospective study, this encephalitis represents up to 4% of all causes of encephalitis; the 5th cause of encephalitis after Herpes simplex virus, Varicelle zona virus (VZV), Mycobacterium tuberculosis infections, and acute demyelinating encephalomyelitis (ADEM), and thus the second cause of autoimmune encephalitis after ADEM. Anti-NMDA-receptor encephalitis predominantly affects young people, especially women. The clinical presentation is characteristic and includes rapidly evolving behavioral changes, prominent psychiatric symptoms with delusion and psychosis, seizures, abnormal movements, autonomic instability, and central hypoventilation. Admission to the intensive care unit is common for hypoventilation or decreased consciousness. Presentation is associated with the presence of an ovarian teratoma in two-third of the cases. Diagnosis is assessed based on the identification of specific antibodies against NMDA-receptor in the CSF, as well as indirect data obtained using electroencephalography and cerebral imaging. Treatment relies on immunotherapy, corticosteroids associated to intravenous immunoglobulins or plasma exchange, and resection of the germinal tumor. If diagnosed and treated early, anti-NMDA-receptor encephalitis has a mortality rate of 4% and a favorable outcome in about two-third of the patients.     

Brain immunohistopathological study in a patient with anti‐NMDAR encephalitis

Background and purpose: Anti‐N‐methyl‐d ‐asparate (NMDA) receptor encephalitis is thought to be antibody‐mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti‐NMDA receptor encephalitis. Methods: An immunohistochemical study was performed using CD3, CD68, CD20, CD138 and CD1a antibodies. Results: Prominent B‐cell cuffing was present around brain vessels accompanied by some plasma cells, while macrophages and T cells were scattered throughout the brain parenchyma. Conclusion: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells.     

Blood–brain interfaces and cerebral drug bioavailability

The low cerebral bioavailability of various drugs is a limiting factor in the treatment of neurological diseases. The restricted penetration of active compounds into the brain is the result of the same mechanisms that are central to the maintenance of brain extracellular fluid homeostasis, in particular from the strict control imposed on exchanges across the blood–brain interfaces. Direct drug entry into the brain parenchyma occurs across the cerebral microvessel endothelium that forms the blood–brain barrier. In addition, local drug concentration measurements and cerebral imaging have clearly shown that the choroid plexuses – the main site of the blood–cerebrospinal fluid (CSF) barrier – together with the CSF circulatory system also play a significant role in setting the cerebral bioavailability of drugs and contrast agents. The entry of water-soluble therapeutic compounds into the brain is impeded by the presence of tight junctions that seal the cerebral endothelium and the choroidal epithelium. The cerebral penetration of many of the more lipid-soluble molecules is also restricted by various classes of efflux transporters that are differently distributed among both blood–brain interfaces, and comprise either multidrug resistance proteins of the ATP-binding cassette superfamily or transporters belonging to several solute carrier families. Expression of these transporters is regulated in various pathophysiological situations, such as epilepsy and inflammation, with pharmacological consequences that have yet to be clearly elucidated. As for brain tumour treatments, their efficacy may be affected not only by the intrinsic resistance of tumour cells, but also by endothelial efflux transporters which exert an even greater impact than the integrity of the endothelial tight junctions. Relevant to paediatric neurological treatments, both blood–brain interfaces are known to develop a tight phenotype very early on in postnatal development, but the developmental profile of efflux transporters still needs to be assessed in greater detail. Finally, the exact role of the ependyma and pia-glia limitans in controlling drug exchanges between brain parenchyma and CSF deserves further attention to allow more precise predictions of cerebral drug disposition and therapeutic efficacy.     

Collapsin response‐mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition

The collapsin response‐mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down‐regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth‐promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule‐associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non‐phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non‐phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase‐3β (GSK‐3β), which can phosphorylate the wildtype protein but not the non‐phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin‐binding property of CRMP5. Therefore, CRMP5‐induced growth inhibition is dependent on T516 phosphorylation through the GSK‐3β pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth.