Restless legs syndrome from the spinal cord perspective: A flexor reflex circuitopathy? (2018)

In this issue of the Journal of Sleep Research, Dafkin, Green, Olivier, McKinon, & Kerr, 2018; investigate flexor withdrawal reflex and crossed extensor reflex responses in a small cohort of 12 patients with primary restless legs syndrome (RLS), measuring responses electromyographically and kinematically, and comparing them during the day and at night-time. A significant circadian variation for both reflexes, characterized by hyperexcitability in the evening, was seen in kinematic parameters in the ankle in RLS patients, which was not present in controls. The study of flexor reflex has been proposed as a tool for investigating RLS, as it closely resembles periodic limb movements of sleep (PLMs), usually associated with RLS (Bara-Jimenez, Aksu, Graham, Sato, & Hallett, 2000), although also occurring in several other conditions (Ferri, Koo, Picchietti, & Fulda, 2017). The findings of lower threshold and greater spatial spread of the flexor reflex in RLS patients suggest increased spinal cord excitability as a possible clue to RLS pathophysiology (Aksu & Bara-Jimenez, 2002; Bara-Jimenez et al., 2000). The flexor reflex circuit is a composite, multitasking structure encompassing a basic loop devoted to the withdrawal reflex in response to nociceptive stimuli, and a more complex overlapping network, fuelled by multisensory inputs, repurposed for incorporating flexor reflex patterns in locomotor activity (Sandrini et al., 2005). This organization recapitulates the motor aspects of RLS phenomenology, which includes the urge to move translating into withdrawal-like movements at rest, and relief of symptoms by walking. In addition, flexor reflex afferents can be implicated in the dysesthesic and painful symptoms of RLS. The activation level of the flexor reflex is finely modulated in a state-dependent (sleep/wake) and phase-dependent (rest/activity) manner (Sandrini et al., 2005); thus its dysregulation seems consistent with the RLS features of circadian variability and quiescegenic elicitation. RLS can be regarded as a network disorder, potentially involving several interacting neural structures (Trenkwalder & Paulus, 2010). In this context, the flexor reflex circuitry could play a pivotal role, as a generator of RLS sensorimotor manifestations, when abnormally modulated by other relays in the network. According to the dopamine hypothesis (Clemens, Rye, & Hochman, 2006; Ondo, He, Rajasekaran, & Le, 2000), a key structure in RLS pathophysiology is represented by the diencephalic A11 area, close to the suprachiasmatic nucleus controlling circadian rhythms. This area gives origin to the diencephalospinal pathway, identified as the primary source of dopaminergic projections to the spinal cord (Skagerberg, Bjorklund, Lindvall, & Schmidt, 1982). Although A11 damage has never been demonstrated, even by autoptic studies in RLS (Earley, Allen, Connor, Ferrucci, & Troncoso, 2009), the dopamine hypothesis is indirectly supported by the RLS response to dopaminergic treatment (Akpinar, 1982). Furthermore, RLS and/or PLMs can be associated with myelopathy (Hartmann, Pfister, & Pfadenhauer, 1999; Yokota, Hirose, Tanabe, & Tsukagoshi, 1991), and in particular PLMs may occur despite a complete lesion of the motor and sensory pathways at the level of the cervical spinal cord (Salminen et al., 2013), in line with the hypothesis that the expression of a spinal generator may be released by interrupting descending inhibitory spinal pathways. PLMs associated with spinal cord transection are strongly suppressed, like PLMs in RLS, by the dopamine-agonist pramipexole (Salminen et al., 2013), suggesting that the suppression of PLMs by dopamine-agonists is mediated by dopamine receptors located within the spinal cord (Formenti, Martina, Plebani, & Mancia, 1998; Taniguchi et al., 2011; Zhu, Clemens, Sawchuk, & Hochman, 2007), or even presynaptically in the peripheral afferents (Taniguchi et al., 2011). The dysfunction of the dopaminergic diencephalospinal pathway could cause an enhanced spinal excitability leading to RLS motor symptoms (Clemens et al., 2006), as well as central sensitization of the dorsal horns generating dysesthesias (Stiasny-Kolster, Pfau, Oertel, Treede, & Magerl, 2013). On the other hand, it is also conceivable that abnormal sensory inputs originating by peripheral neuropathy strongly influence spinal excitability, with emergence of RLS motor symptoms, along with sensitization of the dorsal horns (Gemignani, Vitetta, Brindani, Contini, & Negrotti, 2013). Indeed, it has been shown that peripheral painful inputs are also subjected to circadian variability with a night-time peak (Odrcich, Bailey, Cahill, & Gilron, 2006). The findings of Dafkin et al., 2018 integrate previous works on the flexor reflex in RLS (Aksu & Bara-Jimenez, 2002; Bara-Jimenez et al., 2000), demonstrating that hyperexcitability is restricted to the night-time, and involves also the crossed extensor reflex. This pilot study has some limitations, as acknowledged by the authors, and its results will have to be confirmed in larger series. It is noteworthy that the findings have been demonstrated with kinematic parameters, but not with electromyographic measures; thus, the reliability of this method deserves further assessment. It is yet to be defined if the abnormalities in the circadian rhythm of flexor reflex excitability are a general feature or are specific to definite RLS subtypes and/or phenotypes. Nonetheless, this study confirms the role of the flexor reflex as a useful tool for investigating the RLS mechanisms ‘from the spinal cord perspective’ (Clemens et al., 2006), with special regard to the aspects of circadian fluctuation.