Un’anteprima dal Corso sui Disordini del Movimento
Proponiamo qui l’abstract dell’intervento della prof.ssa Angela Vincent, che sarà tenuto al “Corso avanzato di diagnosi e terapia dei disordini del movimento in età pediatrica” in programma a Milano dal 22 al 24 novembre 2018. Come di consueto è possibile iscriversi al Corso sul sito della FM, dove sono pubblicati tutti i dettagli sull’evento.
Al centro della relazione della Vincent, professore emerito di Neuroimmunologia dell’Università di Oxford, sarà il tema : Autoimmunità e disturbi del movimento.
Movement disorders are not uncommon in neuroinflammatory disorders and may be post-infectious, as in PANS, Tourette’s and Sydenham’s chorea. This talk will concentrate on the more recently described syndromes associated with movement disorders and specific neuronal antibodies. In the 1990s, we identified antibodies that immunoprecipitated the shaker type voltage-gated potassium channels (VGKC Kv1s. Subsequently, it was demonstrated that the antibodies were not directed to the VGKC Kv1 subunits themselves, but to other protein components of a VGKC-complex that exists in the brain. The two principal proteins help localise (CASPR2) and modify (LGI1) VGKC function. Patients with CASPR2 antibodies often have Morvan’s syndrome with insomnia, autonomic dysfunction as well as peripheral nerve hyperexcitability with muscle fasciculations and cramps. There is no distinct movement disorder associated with CASPR2 antibodies and they are rare in children but maternal antibodies to CASPR2 have been implicated in neurodevelopmental disorders (Coutinho et al Acta Neuropath 2017).
Patients with LGI1 antibodies usually have a limbic encephalitis often preceded by faciobrachial dystonic seizures; these are recently described brief dystonic movements of one arm and unilateral face, lasting seconds and very frequent (up to 200 per day). Although dystonic, with basal ganglia involvement demonstrated by PET in some cases, these events are thought to be an epilepsy rather than a movement disorder. These events and LGI1 antibodies are, so far, very infrequent in children.
The most common autoimmune form of encephalitis in children with movement disorders is associated with NMDA receptor antibodies. These are found mainly in younger patients, often women and small children, who develop a severe encephalopathy. The antibodies cause down-regulation of the NMDARs in excitatory synapses and also on inhibitory neurons. In some cases the disease follows a herpes simplex viral encephalitis, implying that NMDAR can be secondary to the virus-induced brain inflammation. The movement disorders are very varied and do not fit closely into a well-defined pattern but include choreoathetosis, dystonias and stereotypies (Varley et al. JNNP 2018).
High levels of antibodies to glutamic acid decarboxylase (GAD) are found in stiff person syndrome which is very rare in children. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is more severe and glycine receptor antibodies have been identified in some cases. Sensitivity to noise, touch or other stimuli causes spasms and rigidity which can be life-threatening. In children, glycine receptor antibodies can be associated with PERM or stiff person syndrome and sometimes epileptic encephalopathies.
Other less common antibodies in children are to the dopamine D2 receptor. Importantly, each of the antibodies bind to extracellular epitopes on the target proteins and there is growing evidence for their pathogenicity. The conditions, although rare, can now be diagnosed regularly by serum or CSF antibody tests and the patients treated with immunotherapies which lead to substantial improvement.
Singer HS. Autoantibody-Associated Movement Disorders in Children: Proven and Proposed. Semin Pediatr Neurol. 2017 Aug;24(3):168-179.
Varley JA et al. Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neurol Neurosurg Psychiatry. 2018 Epub ahead of print.
Coutinho E et al. Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero. Acta Neuropathol. 2017;134:567-583