International Journal of Neuroscience ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ines20 Pontine warning syndrome and restless legs syndrome secondary to paramedian pontine infarction: a case report Guo-Mei Shi , Xiao-Rong Wang , Wu Xu , Min-Wang Guo , Chun-Qin Ding & Ru-Juan Zhou To cite this article: Guo-Mei Shi , Xiao-Rong Wang , Wu Xu , Min-Wang Guo , Chun-Qin Ding & Ru-Juan Zhou (2020): Pontine warning syndrome and restless legs syndrome secondary to paramedian pontine infarction: a case report, International Journal of Neuroscience, DOI: 10.1080/00207454.2020.1849187 To link to this article: https://doi.org/10.1080/00207454.2020.1849187 Accepted author version posted online: 11 Nov 2020. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ines20 Running title: PWS and RLS secondary to pontine infarction Pontine warning syndrome and restless legs syndrome secondary to paramedian pontine infarction: a case report Guo-Mei Shi1, Xiao-Rong Wang1, Wu Xu1, Min-Wang Guo1, Chun-Qin Ding1, and Ru-Juan Zhou1,2,* 1 Department of Neurology, The Taixing People’s Hospital, Taixing, Jiangsu, 225400, China 2 cr ip t Department of Geriatrics Stroke Center, The Taixing People’s Hospital, Taixing, Jiangsu, 225400, China us *Corresponding author: Ru-Juan Zhou, Department of Neurology; Department of Geriatrics Stroke Center, The Taixing People’s Hospital. No. 1 Changzheng Road, Taixing 225400, Jiangsu, China. Tel: +86-523-88979607; Fax: +86-523-88979607; E-mail: zhourujuan123@163.com an Abstract M Pontine warning syndrome (PWS) occurs rarely and is characterized by recurrent, stereotyped episodes of motor or sensory dysfunction, dysarthria, or ophthalmoplegia leading to pontine infarction. Restless legs syndrome (RLS) is a distinct neurological sensorimotor disorder. Pontine infarction is a rare but possible cause of RLS. Here, we report the pt ed case of a 58-year-old woman who experienced unilateral RLS in concomitance with stereotyped episodes of left-sided weakness and dysarthria, and developed an acute paramedian pontine infarction eventually. To the best of our knowledge, no other cases of PWS coinciding with RLS in the progression of pontine infarction have been reported in the literature. Furthermore, we discussed the potential mechanisms of PWS and RLS secondary to pontine infarction, which may be ce helpful for managing such patients. Ac Keywords: Pontine warning syndrome; restless legs syndrome; ischemic stroke; pontine infarction Introduction Stroke warning syndrome is a rare clinical syndrome that is characterized by recurrent, stereotyped episodes of transient neurological symptoms and associated with a high risk of infarction in the corresponding anatomical site [1]. Pontine warning syndrome (PWS) is a subtype of this atypical presentation of stroke/transient ischemic attack and thought to be difficult to diagnosis in clinical practice. Restless legs syndrome (RLS) is a common disorder, featured with an irresistible urge to move the limbs, usually accompanied by unpleasant sensations in the legs. These symptoms are typically worsened at night and partially or totally relieved by movement [2]. More than 60% of RLS patients are primary idiopathic forms, secondary RLS is mainly associated with iron deficiency, uremia, pregnancy, Parkinson's disease, multiple sclerosis, and stroke [3]. RLS secondary to pontine infarction is extremely rare, although pontine infarction is a common type of stroke. We herein report the first case of a 58-year-old woman experiencing eight stereotyped episodes of left-sided hemiplegia and hemiplegia within 24 hours in concomitance with unilateral RLS leading to paramedian pontine infarction. Case report an us cr ip t A 58-year-old, right-handed woman with a past medical history of hypertension, experienced recurrent episodes of left-sided hemiplegia and dysarthria at 5:00 PM, June 11, 2019. The initial episode lasted for 10 minutes and disappeared spontaneously. At 6:10 PM, she developed severe left-sided hemiplegia and moderate dysarthria, which lasted for 2 hours without recovery. Then she entered our emergency department. Upon arrival at the emergency room, she got complete recovery that she could walk by herself and speak fluently. Her general examination revealed a blood pressure of 194/98 mmHg, and neurological examination did not reveal focal deficits. Initial computed tomography (CT) showed old lacunes in bilateral basal ganglia, but there were no new infarctions. She was treated with antiplatelets (aspirin 100 mg and clopidogrel 75 mg) and statin (atorvastatin 20 mg) immediately. Ac ce pt ed M During the first 24 hours of hospitalization, she experienced episodes of dysarthria and left hemiparesis lasting 10 to 30 minutes for 8 times. Later in the evening, during the repetitive episodes of neurologic deficit, she described an irresistible urge to move her left leg, accompanied by uncomfortable and unpleasant sensations. The symptoms occurred at rest, worsened in the evening and interfered with sleep disturbances, which fulfilled the criteria of the International study group for diagnosis of RLS [2]. She was evaluated as severe on the International RLS Study Group (IRLSSG) Rating Scale (26/40) [2]. Her neurologic status fluctuated between 3 and 11 on the National Institutes of Health Stroke Scale (NIHSS) and she could not relieve completely after the last episode with left mild hemiparesis and dysarthria (NIHSS 3). Family history of RLS was denied by this patient. Laboratory investigations, including hemoglobin, creatinine, ferritin and iron levels, were unremarkable. Brain magnetic resonance imaging (MRI) demonstrated a suspicious small focus of high diffusion-weighted image (DWI) signal in the right pontine 4 hours after the onset of the fixed hemiplegia (Fig. 1A). Magnetic resonance angiography (MRA) showed diffused mild atherosclerosis, and there was no significant stenosis or occlusion within major intracranial arteries (Fig. 1B). A transthoracic echocardiogram did not reveal cardiac source of embolism. Medical management then switched to a combination of aspirin (100 mg daily), statin (atorvastatin 20 mg daily), dopamine agonists (piribedil 25 mg nightly) and thrombin inhibitor (argatroban infused continuously at a dose of 60 mg/d for the first 2 days, followed by twice daily infusion, at a dose of 10 mg over 3 hours, for 5 days). There were no more episodes later, and the RLS also partially relieved. Repeated MRI showed an acute infarction on right paramedian pontine 7 days after the onset of the fixed hemiplegia (Fig. 1C). After 2 weeks of hospitalization, she was discharged with mild left hemiplegia (NIHSS 1) and mild RLS (IRLSSG Score 3). Piribedil was slowly tapered, and there was no relapse of RLS or PWS at 12 months of follow-up. Discussion an us cr ip t PWS is a distinct form of transient ischemic attack, clinically located at pontine that usually leads to early infarction. The mechanisms of PWS remain controversial, although many hypotheses have been put forward (e.g. branch atheromatous disease of the proximal portions of the penetrating artery, microembolism from artery to artery or from the heart, vasospasm, hemodynamic impairment, or peri infarct depolarizations) [1, 4, 5]. In this case, the infarction was restricted to paramedian branches of basilar artery. Hypertension is the only stroke risk factor, and the blood pressure was "high" when she arrived at the emergency room. Besides, she had no obvious occlusive or stenosis in the basilar artery, and we could not evaluate the paramedian branches of basilar artery by MRA. Her cardiac evaluation helped us rule out cardiac source of embolism. We presumed that there was severe atherosclerotic stenosis of the paramedian branches of basilar artery in the proximal position, which subsequently involved in the pathogenesis of her pontine infarction. Previous studies using high-resolution MRI suggested that atherosclerotic plaques were discovered at branching point of the penetrating arteries, which could partially explain the underlying pathophysiology of capsular warning syndrome [6, 7]. Along with the development of neuroimaging techniques such as high-resolution MRI, our understanding of the pathophysiological mechanisms of PWS may be extending and expanding. Ac ce pt ed M A recent study conducted in a Chinese population showed that 49 out of 376 (13.03%) stroke patients had RLS, including pontine infraction in eight [8]. After stepwise logistic regression, lesions located in pontine, body of caudate nucleus were significantly associated with post-stroke RLS [8], which may be of great value indicating a pontine lesion rather than other possible locations that could also associate with the occurrence of RLS. The potential pathophysiology of RLS secondary to pontine infarction remains poorly understood, with controversial data from the literature [9-11]. Lee et al investigated the lesion sites of stroke-related RLS, and found that all RLS secondary to pontine infarction had an ischemic lesion in the tegmentum where the reticular formation is located [9]. This finding demonstrated that disinhibition phenomena and reticulospinal excitatory responses might be involved in the development of RLS [9]. However, Ruppert and colleagues reported that the reticular formation located in the tegmentum was spared, lesioning was observed in the corticospinal tract, the pontine nuclei, and the pontocerebellar fibers by millimetric MRI sections, suggesting a specific pontocerebellar circuitry involved in the pathophysiology of RLS [10]. In addition, Guo et al pointed out that three supra-pontine structures with direct projections to the spinal cord, including the basal ganglia-cortico-spinal, cerebello-rubro-spinal, and hypothalamic A11 descending projections related to the development of RLS-like movements in animal models [11]. As pontine is a brainstem pattern generator, we speculated that pontine infarction might disrupt these circuit nodes, which may be implicated in RLS pathogenesis. In our case, the lesion located in paramedian pontine, which is the area that pyramidal tracts go through. Therefore, dysfunction in this area may cause abnormal sensorimotor functioning of the lower limbs. Moreover, we successfully treated RLS in our patient with dopamine agonists piribedil, also supporting that the dopaminergic pathway may play an integral role in the occurrence and development of stroke-related RLS. Besides, the occurrence of RLS secondary to stroke may also require predisposing genetic risk factors [12]. Furthermore, the structural and functional abnormalities in idiopathic RLS have been found by diffusion tensor imaging (DTI), voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies [13-15]. Unfortunately, thus far, there is no neuroimaging research aiming at RLS secondary to pontine infarction. Further studies using structural and functional MRI might be helpful to clarify the pathophysiological mechanisms of RLS related to pontine infarction. cr ip t Currently, there is no consensus on optimal treatment for PWS. General treatment includes hydration, antiplatelet agents, anticoagulation, intravenous thrombolysis as well as intracranial artery angioplasty [1, 5, 6]. We initially treated our patient with aspirin, clopidogrel and atorvastatin. However, these therapies were ineffective in the acute phase of PWS, and cerebral infarctions ultimately occurred. We used argatroban, which was effective and safe in stopping recurrent and fluctuating symptoms in patients with PWS. For RLS, dopamine agonists and calciumα2δ ligands are first-line therapy. In our case, piribedil was used early in the course of RLS onset and the effect was satisfactory. At the 12-month follow-up, there was no relapse of RLS or PWS. M Disclosure statement an us In conclusion, we provide the first case of a patient presented with recurrent PWS as well as acute-onset RLS that were manifestations of a paramedian pontine infraction. Further studies are encouraged to improve our understanding about the pathophysiology of RLS secondary to pontine infarction. Early recognition of the clinical presentations and the accompanying stroke mechanisms may guide the initial management and prognosis. pt ed No potential conflict of interest was reported by the authors. Compliance with ethical standards Ac Funding ce We have obtained the patient’s permission and informed consent for the publishing of her information and images. Not applicable. Acknowledgements Not applicable. References [1] Tassi R, Cerase A, Acampa M, et al. Stroke warning syndrome: 18 new cases. J Neurol Sci. 2013;331(1-2):168-171. [2] Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873. [3] Gonzalez-Latapi P, Malkani R. Update on Restless Legs Syndrome: from Mechanisms to t Treatment. Curr Neurol Neurosci Rep. 2019;19(8):54. ip [4] Donnan GA, O'Malley HM, Quang L, et al. The capsular warning syndrome: pathogenesis and cr clinical features. Neurology. 1993;43(5):957-962. us [5] Enriquez-Marulanda A, Amaya-Gonzalez P, Orozco JL. 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Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat. Sci Rep. 2017;7(1):9905. [12] Khan FH, Ahlberg CD, Chow CA, et al. Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome. J Neurol. 2017;264(8):1634-1641. [13] Belke M, Heverhagen JT, Keil B, et al. DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome. Brain Behav. 2015;5(9):e00327. [14] Xu Z, Han T, Li T, et al. Increased Gray Matter Density and Functional Connectivity of the Pons in Restless Legs Syndrome. Nat Sci Sleep. 2020;12:221-230. [15] Ruppert E, Bataillard M, Namer IJ, et al. Hyperdopaminergism in lenticulostriate stroke-related an us cr ip t restless legs syndrome: an imaging study. Sleep Med. 2017;30:136-138. Ac ce pt ed M Figure 1. DWI showed a suspicious small focus of hyper-signal intensity in the right pontine 4 hours after the onset of the fixed hemiplegia (A, arrow). MRA showed no significant stenosis or occlusion within major intracranial arteries (B). A repeat DWI showed an acute infarction on right paramedian pontine 7 days after the onset of the fixed hemiplegia (C, arrow).