Endovascular clot retrieval for acute ischaemic posterior circulation stroke in children: a new effective therapy?

rotransmitters have been implicated in CTDs, but dopamine seems to play a particularly prominent role in the pathophysiology and treatment of CTDs. The investigation of how dopaminergic disturbances relate to tic severity is thus of great interest. Addabbo et al. address the link between the (detectable) expression of serum dopamine-D2-receptor autoantibodies and tic-severity fluctuations in children with CTDs, using a well-validated cell-based assay. Consistent with previous studies on CTDs and, for example, acute-onset psychosis, the authors show that, in their patient cohort, periods of symptom exacerbation, like periods of post-exacerbation (approximately 2 months after), were both selectively associated with increases in the expression of D2 autoantibodies for 8% of the patients (11/137 and 9/112 of the patients with data respectively). Given that the authors controlled for possible confounds and that medication usage, like other clinical and demographical features, did not differ between patients who had and who had no detectable variations in the expression of D2 autoantibodies over time, the reported results might conceivably suggest that, in some patients with CTDs, D2 autoantibodies can exacerbate symptoms. Consistent with such causal hypothesis, D2-reactive autoantibodies may cause hyperdopaminergia (Table 2 in Pollak et al.); thus, an overactivation of the direct compared to the indirect pathway of the motor cortico-basal gangliathalamo-cortical loop, which may promote the expression of tics. Like several other autoantibodies, D2 autoantibodies can cause hypofunction of the receptors they bind to, namely by promoting their internalization. Neuronal D2 receptors are inhibitory and split into two isoforms: D2S and D2L. In the striatum, D2S is mostly expressed presynaptically (in dopaminergic terminals), while D2L is mostly expressed postsynaptically (in medium spiny neurons and, e.g., cholinergic interneurons). Given that D2S has the highest affinity to dopamine, even if D2 autoantibodies target both isoforms similarly, the internalization of presynaptic D2 receptors may thus promote striatal hyperdopaminergia to a greater extent than the internalization of postsynaptic D2 receptors mimics hypodopaminergia. Consistent with this, low-dose D2 antagonists (e.g., amisulpride) seem to ameliorate the negative symptoms of schizophrenia by increasing extracellular dopamine levels, precisely, via presynaptic-receptor hypofunction. In contrast, low-dose D2 agonists seem to worsen Parkinson disease symptoms and to ameliorate tics by decreasing extracellular dopamine levels via presynaptic-receptor hyperfunction. The exact mechanistic effects of autoantibodies, however, are still poorly understood. Autoantibodies might also, for example, act as agonists or cause neuronal death via neuroinflammatory responses. Hypothetically, selective agonism to D2 receptors in dopaminergic neurons and selective death of dopaminergic neurons could both reduce excessive activation of the direct versus indirect motor pathway in CTDs. The existence of neurobiological mechanisms that can support such ‘compensatory’ effects, however, seems unlikely, especially because autoantibodies’ agonism to D2 receptors is likely to precede the abovementioned receptor internalization, which can go unnoticed unless using cell-based assays. Still, autoantibody-driven or subsequent hyperdopaminergia-driven internalization of D2L receptors cannot be disregarded. While changes in D2-autoantibodies expression may be purely epiphenomenal, extant evidence seems consistent with a role of D2 autoantibodies in the pathophysiology of CTDs. It will be extremely interesting to test whether that is truly the case and whether D1 autoantibodies are also similarly implicated, even if through different mechanisms.