Episodes Of Muscle Weakness Research Articles

Efficacy and Safety of Dichlorphenamide for Primary Periodic Paralysis in Adolescents Compared With Adults

BackgroundPrimary periodic paralyses are rare, hereditary skeletal muscle diseases characterized by episodic muscle weakness. Dichlorphenamide was effective and well tolerated in two studies, including one with adolescents. This analysis describes effects of dichlorphenamide among adolescents and adults. MethodsPatients with primary periodic paralyses in a double-blind, controlled, crossover study were randomized to dichlorphenamide or placebo for nine weeks, with a nine-week or longer between-treatment washout period. Attack rate and severity-weighted attack rate during the final eight weeks of each treatment phase were calculated for adolescents and adults separately. ResultsSeven adolescents (10 to ≤17 years) and 66 adults were enrolled; five of seven adolescents were evaluable for efficacy and six for safety. Dichlorphenamide total daily dosing among adolescents was 50 mg (n = 1) or 100 mg (n = 5), and in adults was 105.7 mg (mean; n = 61). In adolescents, the median decrease from baseline in frequency of weekly attacks was greater with dichlorphenamide (−0.96) than with placebo (−0.57), similar to findings in adults (dichlorphenamide, −0.83; placebo, −0.24). Severity-weighted attack frequency was likewise reduced more with dichlorphenamide than with placebo in adolescents and adults. The most common adverse event with dichlorphenamide in adolescents was skin rash (two of six [33%]). In adults, numbness was the most common adverse event (26 of 54 [48%]); skin rash occurred less frequently (10 of 54 [19%]). ConclusionsDichlorphenamide was comparably effective and tolerated among a small number of adolescents as well as adults, although types of adverse events differed between groups.

Ailesel Hipokalemik Periyodik Paralizi: Olgu Sunumu

Hypokalemic periodic paralysis is a congenital disorder which is characterized by intermittent episodes of muscle weakness or paralysis. The attacks can occur everyday or once a year, may last for a few hours or for several days. Serum potassium level is low during the attack. But serum potassium levels are normal between two attacks. There is no potassium deficiency in the whole body. In this report, a 16 years old boy, whose grandfather, father and uncle had the same semptoms, and had his first attack of familial hypokalemic periodic paralysis following a grand exercise were presented according to the clinical and laboratory features.

Primary hyperaldosteronism presenting as hypokalaemic periodic paralysis

Hypokalaemic periodic paralysis is episodic painless muscle weakness associated with areflexia (1). Hypertension and hypokalaema are the classic presentation of primary hyperaldoteronism though some patients can be normokalaemic (2). Hypokalaemic paralysis is occasionaly seen in patients with hyperaldosteronism (1). This middle aged female presented with her 3rd episode of hypokalaemic periodic paralysis and later diagnosed to have primary hyperaldosteronism due to unilateral adrenal hyperplasia, cured after adrenalectomy.

Case Report: Recurrent hypokalemic periodic paralysis associated with distal renal tubular acidosis (type 1) and hypothyroidism secondary to Hashimoto's thyroiditis

Background: Hypokalemic periodic paralysis (HypoKPP) is characterized by transient episodes of flaccid muscle weakness. We describe the case of a teenaged boy with HypoKPP and hyperthyroidism due to Hashimoto's thyroiditis with initial manifestation of renal tubular acidosis. This combination is rare and little described previously in men. Case presentation: A 17-year-old boy was admitted after three days of muscular weakness and paresthesia in the lower limbs with an ascending evolution, leading to prostration. Decreased strength was found in the lower limbs without a defined sensory level, reduced patellar and ankle reflexes. Positive antithyroid antibodies were found. He received hydration treatment, IV potassium and levothyroxine, with which there was a clinical improvement. Other examinations led to the diagnosis of type 1 renal tubular acidosis. Conclusion: HypoKPP is a rare disorder characterized by acute episodes of muscle weakness. Type 1 renal tubular acidosis can occur as a consequence of thyroiditis, which is explained by the loss of potassium. This combination is unusually rare, and has not been described before in men. The etiopathogenesis of the disease as well as a dynamic explanation of what happened with the patient are discussed in this report.

Case Report: Recurrent hypokalemic periodic paralysis associated with distal renal tubular acidosis (type 1) and hypothyroidism secondary to Hashimoto´s thyroiditis

Background: Hypokalemic periodic paralysis (HypoKPP) is characterized by transient episodes of flaccid muscle weakness. We describe the case of a teenaged boy with HypoKPP and hyperthyroidism due to Hashimoto's thyroiditis with initial manifestation of renal tubular acidosis. This combination is rare and little described previously in men. Case presentation: A 17-year-old boy was admitted after three days of muscular weakness and paresthesia in the lower limbs with an ascending evolution, leading to prostration. Decreased strength was found in the lower limbs without a defined sensory level, reduced patellar and ankle reflexes. Positive antithyroid antibodies were found. He received hydration treatment, IV potassium and levothyroxine, with which there was a clinical improvement. Other examinations led to the diagnosis of type 1 renal tubular acidosis. Conclusion: HypoKPP is a rare disorder characterized by acute episodes of muscle weakness. Type 1 renal tubular acidosis can occur as a consequence of thyroiditis, which is explained by the loss of potassium. This combination is unusually rare, and has not been described before in men. The etiopathogenesis of the disease as well as a dynamic explanation of what happened with the patient are discussed in this report.

Bioinformatics characterisation of the (mutated) proteins related to Andersen-Tawil syndrome.

In the last two decades, a group of proteins whose mutations are associated with a disease manifested by episodes of muscle weakness (periodic paralysis), changes in heart rhythm (arrhythmia), and developmental abnormalities has been under constant study. This malady is known as Andersen-Tawil syndrome, with ~60% of cases of this syndrome being caused by 16 mutations in the KCNJ2 gene [UniProt ID: P63252-01-P63252-17]. In this work, we present a computational study designed to obtain a fingerprint of Andersen-Tawil mutated proteins and differentiate them from mutated proteins associated with Brugada syndrome and from functional groups of proteins belonging to APD3, UniProt, and CPPsite databases. We show here that Andersen-Tawil mutated proteins are characterized by specific features that can be used to differentiate, with a high level of certainty (90%), proteins carrying these mutations from similar functional groups, such as mutated proteins associated with Brugada syndrome, and from different functional protein and peptide groups, such as antimicrobial peptides, Cell-Penetrating Peptides, and intrinsically disorder proteins. Therefore, our main results allow us to conjecture that it is possible to identify the group of the Andersen-Tawil mutated proteins by their "PIM profile". Furthermore, when we applied this "fingerprint PIM profile" on the UniProt database, we observed that one protein found in humans [UniProt ID: Q9NZV8], and six of all "reviewed" proteins found in living organisms, possess a very similar PIM profile as the Andersen-Tawil mutated protein group. The bioinformatics "fingerprint" of the Andersen-Tawil mutated proteins was retrieved using the in-house bioinformatics system named Polarity Index Method® and supported-at residues level- by the algorithms for the prediction of intrinsic disorder predisposition, such as PONDR® FIT, PONDR® VLXT, PONDR® VSL2, PONDR® VL3, FoldIndex, IUPred, and TopIDP.

Secondary hypokalemic periodic paralysis: A study of a case series

Background: Periodic paralysis is a group of heterogeneous disorders of different etiologies, with episodic, short-lived, and hyporeflexic skeletal muscle weakness, with or without myotonia. There is neither sensory deficit nor loss of consciousness. They can be familial (primary) or acquired (secondary). Secondary periodic paralysis is due to demonstrably known causes. The interictal potassium level is abnormal in these cases. Hypokalemic paralysis is more common than hyperkalemic. Materials and Methods: This is a prospective observational study elucidating the clinical profile of the cases of secondary hypokalaemic periodic paralysis seen in our care over a period of 14 months. Results: In this study, we present nine patients with hypokalemic periodic paralysis, in which four were diagnosed with thyrotoxicosis and five with dengue. They were given potassium correction under judicious cardiac monitoring. Antithyroid drugs and beta-blockers were used in thyrotoxicosis. Dengue patient received adequate fluid and antipyretic cover. All the patients made complete recovery, without any neurological sequelae. Conclusion: Secondary hypokalemic periodic paralysis should always be kept in mind as a differential in the setting of acute, painless, flaccid motor paralysis, especially in young patients with no significant family history or risk factors for stroke or Guillain–Barre Syndrome. A clinician must be aware of causes of secondary periodic paralysis as recognition and diagnosis can completely prevent further attacks of periodic paralysis. Routine estimation of thyroid levels should be the initial line of investigation even if features of thyrotoxicosis are absent. In the presence of acute febrile illness, ordering serology for dengue, after ruling out thyrotoxicosis, is the preferred approach in India.

A204E mutation in Nav1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs

Periodic paralyses (PP) are characterized by episodic muscle weakness and are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Nav1.4 — the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4 or Cav1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysis who was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Nav1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4 activation was strengthened in low concentration of extracellular K+. Our data prove the existence of a phenotype combining signs of hyperPP and hypoPP due to dominant Nav1.4 mutations. The hyperPP component would result from gain-of-function effects on Nav1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non-negligible role of Nav1.4 loss-of-function in familial hypoPP.

Variable penetrance of Andersen-Tawil syndrome in a family with a rare missense KCNJ2 mutation

Andersen-Tawil syndrome is an autosomal dominant potassium channelopathy characterized by episodic flaccid muscle weakness (periodic paralysis), cardiac abnormalities (ventricular arrhythmias, prolonged QT interval, and prominent U waves), and characteristic skeletal features (low set ears, ocular hypertelorism, small mandible, fifth digit clinodactyly, syndactyly, short stature, scoliosis, and broad forehead).1 Mutations in the KCNJ2 gene on chromosome 17q23 are found in about 60% of the patients with Andersen-Tawil syndrome.2 In the absence of a genetic change in KCNJ2 , diagnosis of Andersen-Tawil syndrome is established by the presence of well-defined clinical findings. The distinctive clinical triad of Andersen-Tawil syndrome is present in 60%–80% of patients with KCNJ2 mutations.1,2 KCNJ2 encodes the pore-forming subunit of an inward-rectifying potassium channel protein, Kir2.1, helping in skeletal and cardiac muscle resting membrane potential stabilization. Mutations in this gene cause loss of function and dominant-negative suppression effects on the Kir2.1 protein, leading to disruption of the cardiac and skeletal muscle excitability.2,3 KCNJ2 mutations in Andersen-Tawil syndrome affect multiple tissues and results in a wide phenotypic variability causing diagnostic difficulties and delay.2 We describe the varied clinical characteristics of Andersen-Tawil syndrome in a Caucasian family (mother and her 2 daughters) with a rare missense mutation in KCNJ2 .

Familial Normokalemic Periodic Paralysis Associated With Mutation in the SCN4A p.M1592V

Periodic paralysis (PP) is an uncommon inherited disorder causing recurrent episodes of muscle weakness, with an incidence of 0.001%. Normokalemic periodic paralysis (NormoKPP) as the rarest subtype of PP contains both familial and sporadic. Familial NormoKPP caused by the p.M1592V mutation of the skeletal muscle sodium channel alpha subunit (SCN4A) gene is rarely reported. Only three pedigrees of NormoKPP related to mutations in the SCN4A p.M1592V have been previously reported. We herein presented a family case of NormoKPP associated with the SCN4A p.M1592V mutation, in which respiratory muscle paralysis occurred in the proband while not in his children. Moreover, we conducted a thorough literature review. To our knowledge, this is the first report of respiratory muscle paralysis as a symptom of NormoKPP associated with mutation in the SCN4A p.M1592V.

What the internist should know about hereditary muscle channelopathies

Objectives: Non-dystrophic myotonia, periodic paralysis and, to a certain extent, myotonic dystrophies are rare hereditary skeletal muscle channelopathies, charactarized by myotonia or episodic muscle weakness. This review highlights the diagnostic challenges and treatment options.Results: Some of these rare skeletal muscle disorders are associated with a broad range of systemic and nonspecific muscle symptoms. Consequently, patients are often referred to the internist before seeing a neurologist. This article provides clinical clues to better diagnose an tackle these unique disorders.Conclusion: A increased knowledge will reduce the diagnostic delay, improve monitoring and treatment, and might even prevent potentially life-threatening conditions as seen in DM.

The link between narcolepsy and autonomic cardiovascular dysfunction: a translational perspective

Narcolepsy is a rare disease that entails excessive daytime sleepiness, often associated with sudden episodes of muscle weakness known as cataplexy. Narcolepsy with cataplexy (NC) is due to the loss of hypothalamic neurons that release the neuropeptides orexin A and B. Orexin neuron projections prominently target brain structures involved in wake-sleep state switching and the central autonomic network. This review provides an updated summary of the links between NC and autonomic cardiovascular dysfunction from a translational perspective. The available evidence suggests that, compared with control subjects, the heart rate in patients and animal models with NC is variable during wakefulness and normal to high during sleep. Responses of the heart rate to internal stimuli (arousal from sleep, leg movements during sleep, defense response) are blunted. These alterations result from orexin deficiency and, at least during wakefulness before sleep, involve decreased parasympathetic modulation of the heart rate. On the other hand, NC in patients and animal models is associated with a blunted fall in arterial blood pressure from wakefulness to sleep, and particularly to the REM state, coupled to a variable decrease in arterial blood pressure during wakefulness. The former effect is caused, at least in part, by deranged control of the heart, whereas the latter may be due to decreased vasoconstrictor sympathetic activity. Systematic studies are warranted to help clarify whether and how the links between NC and autonomic dysfunction impact on the cardiovascular risk of patients with narcolepsy.

Thyrotoxic Periodic Paralysis in a 20-Year-Old Nigerian Male

Background: Thyrotoxic Periodic Paralysis (TPP) is a rare complication of hyperthyroidism characterised by hypokalaemia and recurrent episodes of muscle weakness. Increased awareness will promote early diagnosis and prompt treatment of the condition. Objective: To highlight an uncommon case of TPP in a Nigerian male with normokalaemia on presentation. Case: A 20-year-old male patient on treatment for hyperthyroidism (Grave’s disease) who was referred to the endocrine clinic on account of recurrent episodes of acute symmetrical painful lower limb muscle weakness. He had experienced a total of 5 episodes approximately 2-3 months apart with each attack lasting between 10-36 h there was a positive history of strenuous activities preceding each attack. Limb pain was relieved by analgesics and weakness resolved spontaneously without any specific medications after 2-3 days. Investigations revealed elevated T3 and T4 (212.3 ng/ml and 18.3 μg/ml respectively), reduced TSH (<0.1 mIU/ ml), low-normal serum potassium (3.6 mmol/L) on presentation and hypokalaemia (2.5 mmol/L) during an episode and hypocalcaemia (2.0 mmol/L). He was placed on 30 mg of carbimazole, propranolol 120 mg in divided doses and low dose oral potassium chloride. He showed remarkable response to treatment with reduction in the frequency of attacks and eventual resolution of symptoms.

Management of childhood Gitelman syndrome: a case study

Gitelman syndrome is a rare, autosomal recessive, renal tubular salt wasting disorder characterized by hypokalemia, and metabolic alkalosis in combination with significant hypomagnesemia and hypocalciuria.1,2 The prevalence is estimated to be 1 in 40,000 individuals. The condition affects both males and females of all ethnic backgrounds. The prevalence of heterozygotes is approximately 1% in Caucasian populations.2,3In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Symptoms, such as transient episodes of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever, are often seen in Gitelman syndrome patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance of chondrocalcinosis at adult age that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those Gitelman syndrome patients with severe hypokalemia and hypomagnesemia.2,4

Efficacy and safety of two administration modes of an intra‐detrusor injection of 750 units dysport® (abobotulinumtoxinA) in patients suffering from refractory neurogenic detrusor overactivity (NDO): A randomised placebo‐controlled phase IIa study

Assess the efficacy and safety of abobotulinumtoxinA (Dysport®) in adult patients with neurogenic detrusor overactivity (NDO). This Phase IIa, international, multicentre, double-blind, randomised, placebo controlled, pilot study enrolled 47 patients with NDO and urinary incontinence resulting from spinal cord injury (SCI) or multiple sclerosis (MS). Patients were treated with 15 intra-detrusor injections of Dysport 750 U or the equivalent placebo (n = 16 and 7) or 30 injections of Dysport 750 U or the equivalent placebo (n = 17 and 7). Primary endpoint was change from baseline in mean number of daily incontinence episode frequency (IEF) at day 84. Secondary endpoints included change from baseline in urodynamic parameters and quality of life (QOL). A safety assessment was also conducted. Adjusted mean changes from baseline in IEF were -3.2 (-76%) and -1.7 (-15%) for 15 injections Dysport and placebo groups, respectively, (P = 0.1103) and -3.2 (-88%) and -2.6 (-73%) for 30 injections Dysport and placebo groups, respectively, (P = 0.0686). Statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure and volume at first contraction were reported in the Dysport groups compared with placebo (P < 0.05). Improvements in QOL were reported. Three muscle weakness episodes were reported as serious adverse events in two tetraplegic and one paraplegic patient, all in the 15 injections Dysport group. Both 15 and 30 injections administration modes of Dysport decreased daily IEF and resulted in significant improvements in urodynamic parameters in NDO patients with MS or SCI. Reduction to 15 injection sites did not appear to be associated with any impact on efficacy. Neurourol. Urodynam. 36:457-462, 2017. © 2016 Wiley Periodicals, Inc.

Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis.

The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (HyperKPP) are not fully understood. Using a knock-in HyperKPP mouse model harboring the M1592V NaV1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin-sensitive Na(+) influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K(+)]e, myofiber-type composition, and myofiber damage. In situ EMG activity was greater in HyperKPP than wild-type gastrocnemius, whereas spontaneous muscle contractions were observed invitro. We suggest that both the greater EMG activity and spontaneous contractions are related to periods of hyperexcitability during which fibers generate action potentials by themselves in the absence of any stimulation and that these periods are the cause of the muscle stiffness reported by patients. HyperKPP muscles had a greater sensitivity to the K(+)-induced force depression than wild-type muscles. So, an increased interstitial K(+) concentration locally near subsets of myofibers as a result of the hyperexcitability likely produced partial loss of force rather than complete paralysis. NaV1.4 channel protein content reached adult level by 3weeks postnatal in both wild type and HyperKPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V HyperKPP muscles results from defective function of mutant NaV1.4 channels rather than other changes in protein expression after the first month and (ii) that the lag in onset during the first decade and the progression of human HyperKPP symptoms during adolescence are a function of NaV1.4 channel content.

P162 – 2473: Andersen-Tawil syndrome with myopathy: Case report

Introduction Andersen-Tawil syndrome (ATS) is a rare autosomal dominant potassium channelopathy characterized by periodic paralysis, ventricular arrhythmias, and dysmorphic features. We present a 14-year-old boy with characteristic features of ATS, and childhood onset myopathy. Case report Fourteen years old boy admitted to our clinic with progressive muscle weakness and also described periods of severe weakness attacks for the last two years. Birth and family history were normal except 37 weeks of prematurity. At the age of four he started to fall down while walking and he descibed tiredness. At the age of 6 cardiac arrhythmia was detected. Investigations for muscle weakness showed that serum creatine kinase level was 625 U/L. Electromyography showed myopathic changes. The muscle biopsy didn't demonstrate any specific finding. On his examination there was orbital hypertelorism, micrognathia, low set ears, clinodactyly, short stature, proximal muscle weakness of both upper and lower extremities. Deep tendon reflexes were hypoactive, Gowers sign was positive. On his electrocardiogram ventricular extrasystoles and U waves were seen. With the findings of severe worsening of limb weakness and dysmorphic features with cardiac arrhythmia ATS was suspected. Genetic testing confirmed a heterozygous mutation (R218W) in KCNJ2. After acetazolamide treatment attacks of severe muscle weakness and Gowers sign disappeared. Conclusion Although ATS is charactized with episodes of muscle weakness, fixed myophaty had been reported only in two patients previously. All these two patients and our patient had heterozygous mutation (R218W) in KCNJ2. Because of the life threatening cardiac arrhythmias ATS must also be kept in mind in patients with fixed myophaty.

Clinical and Electron Microscopic Findings in Two Patients with Mitochondrial Myopathy Associated with Episodic Hyper-creatine Kinase-emia

Mitochondrial myopathy with episodic hyper-creatine kinase (CK)-emia (MIMECK) is a new disease entity characterized by episodic or persistent muscle weakness and elevated CK levels. We herein report two cases of MIMECK with the findings of histopathological studies. Histopathological examinations revealed strongly succinate dehydrogenase-reactive vessels. Electron microscopy showed abnormal mitochondria in the vessels and proliferating and vacuolated mitochondria under the sarcolemma. Both patients exhibited recurrent severe myalgia, weakness and increased CK levels. L-arginine treatment significantly ameliorated their muscle symptoms. These findings indicate that mitochondrial angiopathy plays an important role in the pathophysiology of MIMECK. L-arginine may be a potential therapeutic agent for this disorder.

Hypokalemic periodic paralysis: an unusual presentation

Hypokalaemia Periodic paralysis is a heterogeneous group of muscle disorder with episodic, short-lived, and hypo-reflexic skeletal muscle weakness, without loss of consciousness and with or without myotonia but without sensory deficit. We report a rare autoimmune disorder in a 23year male patient who had presented with complaints of weakness of both lower limbs since 1 day which is of sudden onset. He was unable to move limbs or walk or climb up stairs. Based on symptoms and laboratory investigations he was diagnosed with Hypokalaemia Periodic Paralysis. Therapy was primarily started with potassium supplements.

Animal models of REM dysfunctions: what they tell us about the cause of narcolepsy and RBD?

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a subpopulation of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic premotor-neurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A direct or indirect pathway activated during positive emotion from the central amygdala to the SLD PS-on neurons would induce such activation. In normal conditions, the activation of SLD neurons would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus gating the activation of the PS-on SLD neurons.