Sleep Disorders In Parkinson's Disease Research Articles

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

Management of Psychiatric Disorders in Patients with Parkinson's Diseases.

Parkinson’s disease (PD) is a heterogeneous progressive neurodegenerative disorder, with a triad of motor symptoms with akinesia/bradykinesia, resting tremor (4–6 Hz), and rigidity. It is the second most common neurodegenerative disease after Alzheimer’s disease. The overall management of PD depends on the status of symptoms, functioning of the patients, impairment, disability, and its impact on quality of life. Depression, anxiety disorders, apathy, anhedonia, psychosis, cognitive impairments, dementia, and impulse control disorders (ICDs) are the common psychiatric symptoms/disorders comorbid with PD. Depression remains the most common psychiatric disorder reported to be comorbid with PD. Several pharmacological and nonpharmacological management strategies are used for the treatment of comorbid psychiatric disorders in PD. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are used to treat depression in patients with PD. The best evidence of efficacy in PD psychosis is for clozapine and pimavanserin. The treatment for cognitive impairments in PD remains poorly researched. Rivastigmine is the only approved treatment for PD as per the Food and Drug Administration. Pramipexole, a dopamine agonist (DA), is reported to cause improvement in the symptoms of decreased willingness in apathy. The treatment approaches for different sleep disorders in PD are different. Identifying the cause, reviewing the patient’s ongoing medications, and evaluating the impact of comorbid medical conditions and sleep hygiene are common to all conditions related to sleep disorders. The first approach for treating ICD symptoms is the reduction or discontinuation of DAs. The psychiatric symptoms in patients with PD are highly prevalent, and their management should be included in the basic treatment algorithm for PD. This paper summarizes common psychiatric symptoms/disorders in PD and their management approaches.

Zonisamide for the Efficacy of Sleep Abnormality in Parkinson's Disease (ZEAL Study): A Protocol for Randomized Controlled Trials

Background: Sleep disorders are one of the most frequent non-motor symptoms of Parkinson's disease (PD), and the efficacy of dopaminergic agents remains controversial. Clinical randomized control trials for the treatment of sleep disorders in PD are limited. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) improved motor symptoms and wearing-off in patients with PD. Patients with PD were reported to have dream-enacting behavior that was resolved after treatment with zonisamide. This study aimed to verify the safety and efficacy of zonisamide for sleep disorders and rapid eye movement (REM) sleep behavioral disorders using a mobile two-channel electroencephalography (EEG)/electrooculography (EOG) recording system.Methods and Analysis: The present study is a randomized placebo-controlled trial to determine the efficacy of zonisamide for sleep disorders in patients with PD. This study was designed to be single-blind, but the subject allocation is randomized by an independent allocation manager via computer-generated block randomization. The subjects in the treatment group took zonisamide (25 mg per day) before bedtime for 28 days. The sleep index is analyzed using a portable EEG/EOG recording system collected on two consecutive nights within 7 days prior to the intervention and reobtained on one night within 2 days after the 28-day administration of zonisamide. The amount of change in sleep efficiency before and after the 28-day administration will be compared between the zonisamide treatment group and placebo group concerning the primary endpoint. As for the secondary endpoint, the change in the ratio of other sleep parameters, including REM sleep without atonia, or sleep architecture will be evaluated.Ethics and Dissemination: The protocol was approved by the Nara Medical University Certified Review Board (CRB5200002). The trial was notified and registered with the Japan Registry of Clinical Trials (jRCTs051200160). Written informed consent will be obtained from every participant using informed consent approved by the CRB. The results of this trial will be disseminated through peer-reviewed scientific journals.

Pharmacological and Non-pharmacological Treatments of Sleep Disorders in Parkinson's Disease.

Sleep disorders are one of the most common non-motor symptoms in Parkinson's disease (PD). It can cause a notable decrease in quality of life and functioning in PD patients, as well as place a huge burden on both patients and caregivers. The most cited sleep disorders in PD included insomnia, restless legs syndrome (RLS), rapid eye movement (REM), sleep behavior disorders (RBD), excessive daytime sleepiness (EDS) and sleep disordered breathing (SDB), which can appear alone or several at the same time. In this review, we listed the recommended pharmacological treatments for common sleep disorders in PD, and discussed the recommended dosages, benefits and side effects of relative drugs. We also discussed non-pharmacological treatments to improve sleep quality, including sleep hygiene education, exercise, deep brain stimulation, cognitive behavior therapy and complementary therapies. We tried to find proper interventions for different types of sleep disorders in PD, while minimizing relative side effects.

Sleep Disorders in Parkinson Disease.

Sleep disorders in Parkinson disease have attracted the attention of clinicians and researchers for decades. Recently, major advances in their clinical characterization, polysomnographic description, pathophysiologic understanding, and treatment took place. Parkinson disease encompasses the whole spectrum of sleep medicine: every category of sleep disorder can be observed in these patients. Video polysomnography frequently is indicated, sometimes followed by multiple sleep latency/maintenance of wakefulness tests. Additional studies may include actigraphy, cardiorespiratory polygraphy, and dim light melatonin assessment. Treatment needs to be specific to the underlying sleep disorder and can include medications and nondrug treatments, for example, behavioral therapy and light therapy.

Sleep fragmentation as an important clinical characteristic of sleep disorders in Parkinson's disease: a preliminary study.

Background:Sleep disorders are one of the earliest non-motor symptoms of Parkinson's disease (PD). Sleep disorders could, therefore, have value for recognition and diagnosis in PD. However, no unified classification and diagnostic criteria exist to evaluate sleep disorders by polysomnography (PSG). Utilizing PSG to monitor sleep processes of patients with PD and analyze sleep disorder characteristics and their relationship with demographic parameters could aid in bridging this gap. This preliminary study aimed to evaluate the clinical characteristic of sleep disorders in PD using PSG.Methods:PSG was used to evaluate sleep disorders in 27 patients with PD and 20 healthy volunteers between August 2015 and July 2018 in Fujian Medical University Union Hospital. Total sleep time (TST), sleep efficiency (SE), total wake time, and other parameters were compared between the two groups. Finally, the correlation between sleep disorders and age, disease duration, Unified Parkinson's Disease Rating Scale-III scores, Hoehn-Yahr stage, and levodopa dose were analyzed. The main statistical methods included Chi-square test, two independent samples t test, Fisher exact test, and Pearson correlation.Results:Sleep fragmentation in the PD group was significantly increased (74.1%) while difficulty falling asleep and early awakening were not, as compared to healthy controls. No significant differences were found in time in bed, sleep latency (SL), non-rapid eye movement (NREM) stage 1 (N1), N1%, N2, N2%, N3%, and NREM% between PD and control groups; but TST (327.96 ± 105.26 min vs. 414.67 ± 78.31 min, P = 0.003), SE (63.26% ± 14.83% vs. 76.8% ± 11.57%, P = 0.001), R N3 (20.00 [39.00] min vs. 61.50 [48.87] min, P = 0.001), NREM (262.59 ± 91.20 min vs. 337.17 ± 63.47 min, P = 0.003), rapid-eye-movement (REM) (32.50 [33.00] min vs. 85.25 [32.12] min, P < 0.001), REM% (9.56 ± 6.01 vs. 15.50 ± 4.81, P = 0.001), REM sleep latency (157.89 ± 99.04 min vs. 103.47 ± 71.70 min, P = 0.034) were significantly reduced in PD group.Conclusion:This preliminary study supported that sleep fragmentation was an important clinical characteristic of sleep disorders in PD. Whether sleep fragmentation is a potential quantifiable marker in PD needs to be further investigated in the future study.

Disturbances of Sleep and Alertness in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Sleep dysfunction is one of the most common non-motor manifestations of PD that has gained significant interest over the past two decades due to its impact on the daily lives of PD patients, poorly understood mechanisms, and limited treatment options. In this review, we discuss the most common sleep disorders in PD and present recent investigations that have broadened our understanding of the epidemiology, clinical manifestations, diagnosis, and treatment of disturbed sleep and alertness in PD. The etiology of impaired sleep-wake cycles in PD is multifactorial. Sleep dysfunction in PD encompasses insomnia, REM sleep behavior disorder, sleep-disordered breathing, restless legs syndrome, and circadian dysregulation. Despite the high prevalence of sleep dysfunction in PD, evidence supporting the efficacy of treatment strategies is limited. We are at the opportune time to advance our understanding of sleep dysfunction in PD, which will hopefully lead to mechanisms-driven interventions for better sleep and allow us to approach sleep as a modifiable therapeutic target for other non-motor and motor manifestations in PD.

The effect of light exposure on insomnia and nocturnal movement in Parkinson's disease: an open label, retrospective, longitudinal study

Insomnia, hypersomnia and REM Sleep Behavior Disorder (RSBD) during sleep are major problems for patients suffering from Parkinson's disease (PD) but they are also used to predict its onset. While these secondary symptoms detract from the quality of life in PD patients, few treatment options are available due to limited efficacy or risk of complicating the treatment regimen. Light therapy (LT) has been suggested as a strategy for sleep disorders but it has only been implemented recently for use in PD. An open label, retrospective study was undertaken where PD patients had been undergoing LT, using polychromatic light, for four months to 15 years prior. It was found that 1 h exposure to light, just prior to retiring, significantly improved insomnia and reduced RSBD in as little as one month after commencing LT. In addition, the improvement was maintained as long as LT was continued over a four to six year period. The efficacy of LT in alleviating these sleep related conditions was not compromised by time since diagnosis or age of the patient. These results intimate the value of long term application of non-invasive techniques such as LT for treating sleep disorders in PD and justify further controlled trials on the long term efficacy of LT.

The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non-motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice.

Treatment of Sleep Dysfunction in Parkinson's Disease.

Impaired sleep and alertness affect the majority of Parkinson's disease (PD) patients, negatively impacting safety and quality of life. The etiology of impaired sleep-wake cycle in PD is multifactorial and encompasses medication side effects, nocturnal PD motor symptoms, and presence of co-existent sleep and neuropsychiatric disorders. The primary neurodegenerative process of PD involves brain regions that regulate the sleep-wake cycle, such as brainstem and hypothalamic nuclei. Sleep disorders in PD include insomnia, REM sleep behavior disorder (RBD), sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian disruption. Despite its high prevalence in the PD population, there is a paucity of clinical studies that have investigated treatment of sleep dysfunction associated with PD. Therefore, we aim to review available evidence and outline treatment strategies for improvement of disorders of sleep and wakefulness in PD patients. Evidence supporting the efficacy of pharmacological and non-pharmacological treatment strategies in PD is limited. There is thus a great need but also opportunity for development of well-designed clinical trials for impaired sleep and alertness in PD. Providing education about sleep hygiene and strategies for its implementation represents the initial step in management. Prompt diagnosis and treatment of co-existent primary sleep and psychiatric disorders are critical, as this may significantly improve sleep and alertness. While the optimal treatment for insomnia in PD has not been established, available strategies include cognitive-behavioral therapy, medications with soporific properties, and light therapy. Safety measures, clonazepam, and melatonin are the mainstay of treatment for RBD. Continuous positive airway pressure is an effective treatment for SDB in PD. The treatment algorithm for RLS associated with PD mirrors that used for idiopathic RLS. Circadian disruption has emerged as an important etiology of impaired sleep-wake cycles in PD, and circadian-based interventions hold promise for novel treatment approaches.

The Treatment of Sleep Disorders in Parkinson’s Disease: From Research to Clinical Practice

Sleep disorders (SDs) are one of the most frequent non-motor symptoms of Parkinson’s disease (PD), usually increasing in frequency over the course of the disease and disability progression. SDs include nocturnal and diurnal manifestations such as insomnia, REM sleep behavior disorder, and excessive daytime sleepiness. The causes of SDs in PD are numerous, including the neurodegeneration process itself, which can disrupt the networks regulating the sleep–wake cycle and deplete a large number of cerebral amines possibly playing a role in the initiation and maintenance of sleep. Despite the significant prevalence of SDs in PD patients, few clinical trials on SDs treatment have been conducted. Our aim is to critically review the principal therapeutic options for the most common SDs in PD. The appropriate diagnosis and treatment of SDs in PD can lead to the consolidation of nocturnal sleep, the enhancement of daytime alertness, and the amelioration of the quality of life of the patients.

Sleep Dysfunction in Parkinson's Disease.

The spectrum of sleep problems in Parkinson's disease (PD) is broad. These symptoms are recognized as being clinically relevant by the PD patients and may seriously affect their quality of life. Some studies reveal the occurrence of sleep disorders in more than half of the PD patients. The etiology is multifactorial and it mainly involves the degeneration of the sleep-regulating structures. Sleep disorders in PD can be classified into: disturbances of sleep and disturbances of wakefulness. Generic and specific scales were designed to help the screening and evaluation of sleep dysfunction. Further assessment can be done using sleep recording techniques, like actigraphy or polysomnography. All types of sleep disturbances may be encountered in PD: insomnia, excessive daytime sleepiness, rapid eye movement sleep behavior disorders, and restless legs syndrome. This chapter will focus on reviewing the main characteristics, pathophysiology, assessment, and management of the most frequent sleep disturbances encountered in PD.

New Pharmacological Approaches to Treating Non-Motor Symptoms of Parkinson's Disease.

Non-motor symptoms in patients with Parkinson's Disease (PD) are better predictors of quality of life changes, caregiver burden, and mortality than motor symptoms. Levodopa has limited, and sometimes detrimental, effects on these symptoms. In this review we discuss recent evidence on pharmacological treatments for non-motor symptoms. Breakthroughs have been made in the treatment of psychosis and sleep dysfunction. Pimavanserin has become the first FDA approved drug for PD psychosis. There is also new research supporting cholinesterase inhibitors for sleep disorders in PD. Other studies, including several novel treatments, have shown mixed results for apathy, depression, and fatigue. Further research is needed to develop treatments for non-motor symptoms in PD. Preclinical and postmortem studies indicate that non-motor symptoms in PD may arise from pathology in non-dopamine systems. Although sometimes used off-label, therapies that target such systems have been under-utilized in treating non-motor symptoms and warrant further clinical investigation.

Parkinson's Disease Sleep Scale 2: application in an Italian population.

Sleep disturbances and nocturnal disabilities are common in Parkinson's Disease (PD). The PD sleep scale, second version (PDSS-2), has been proposed as a helpful tool for measuring sleep disorders in PD. We aimed to validate the Italian version of the PDSS-2. One hundred and twenty-three consecutive PD outpatients (76 males) were evaluated by means of PDSS-2, Epworth Sleepiness Scale, Hamilton Depression Rating Scale, Parkinson's Disease Quality of Life Questionnaire (self-administered scales), Unified Parkinson's Disease Rating (motor section) and Hoehn and Yahr Scales, and Mini Mental State Examination. PDSS-2 internal consistency was satisfactory (Cronbach's α: 0.77) with significant item to total score correlation and high intra-class correlation coefficient for test-retest reliability (0.943). Total PDSS-2 score was correlated with the scores on all other clinical scales. The factor analysis identified five factors, related to five areas of nocturnal disturbances, similarly as the original PDSS-2. The five factors mainly reflected: (1) nocturnal movement-related problems, (2) quality of sleep, (3) dreaming distress, (4) fragmentation of sleep and (5) insomnia symptoms. The PDSS-2 scale has confirmed its usefulness in evaluating sleep problems in Italian PD patients.

Sleep disorders in Parkinson's disease

Abstract The clinical presentation of Parkinson's Disease (PD) encompasses a wide spectrum of non-motor symptoms, among which sleep disruption is one of the most common and occurs in virtually all patients with PD. Sleep disorders are complex including insomnia, restless legs syndrome, periodic limb movements of sleep, rapid eye movement sleep behavior disorder (RBD), sleep fragmentation and excessive daytime sleepiness. Sleep disturbances are independent and important determinant of poor quality of life, influence daily living and can be an important factor contributing to earlier institutionalization. Sleep disorders (RBD) are markers of prodromal PD, additionally they may influence the process of neurodegeneration. Sleep problems frequently remain undeclared by patients and under-recognized by healthcare professionals, leaving many patients without adequate treatment. In this work we review the current knowledge on sleep disorders in PD with the emphasis on therapeutic options including pharmacological and surgical procedures.

Rating scales and questionnaires for assessment of sleep disorders in Parkinson's disease: what they inform about?

Sleep disorders are very prevalent in Parkinson's disease (PD) and include a diversity of disturbances. Rating scales and questionnaires are widely used to assess the presence and severity of the sleep disorders. The objective is to review rating scales and questionnaires used for assessment of sleep disorders in PD. To this purpose, a description and update of the sleep scales reviewed by the ad hoc Movement Disorder Society task force (MDS-TF) and other sleep disorder assessments was performed. Two specific (Parkinson's Disease Sleep Scale and Scales for Outcomes in PD Sleep) and two generic scales (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale) were "Recommended" by the MDS-TF as they were used in PD patients, by researchers others than their developers and properly validated. Two other generic scales (Inappropriate Sleep Composite Score and Stanford Sleepiness Scale), "Suggested" due to incomplete validation, are also reviewed. Other instruments included in this review are three comprehensive PD-specific instruments for assessing multiple domains in addition to sleep problems (e.g., Non-Motor Symptoms Questionnaire, Non-Motor Symptoms Scale, MDS-UPDRS), and three generic instruments focused on particular disturbances (e.g., International Restless Legs Syndrome Study Group Rating Scale, REM behavioral disorders questionnaires), although these latter lack formal validation in PD populations. The "Recommended" instruments cover satisfactorily the needs for screening and evaluation of the nocturnal sleep disorders and daytime sleepiness in PD patients. It would be convenient to validate or complete the validation in PD populations of those instruments that cannot be recommended due to the lack of information on their clinimetric attributes.

Sleep disorders in Parkinson disease

The Journal of the Ceylon College of Physicians (JCCP) is a peer-reviewed, open access journal published bi-annually by the Ceylon College of Physicians (CCP) in the last week of June and December.The objective of the Journal is to promote good clinical practice and influence policy making across the medical world through publication of original research and peer reviewed articles on current issues and to foster responsible and balanced debate on issues that affect medicine and health care in Sri Lanka. Contributions to the JCCP reflect its national and multidisciplinary readership and include current thinking across a range of medical specialties.

Sleep disorders in Parkinson's disease.

Sleep disorders in patients with Parkinson's disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD.

Parasomnias in Parkinson's disease

Sleep disorders, as one of the most common non-motor manifestations of Parkinson's disease (PD), have caused serious impact on the quality of life in PD patients. Parasomnias as an important part of sleep disorders associated with PD, have become hot topics in recent years. Parasomnias include rapid eye movement sleep behavior disorder (RBD), sleep-related movement disorders and wakefulness disturbance, while wakefulness disturbance consists of excessive daytime sleepiness (EDS) and sleep attacks. Some of these disorders, including RBD and EDS may occur before the motor symptoms of PD and become potential early markers of the disease. Sleep-related movement disorders include restless legs syndrome (RLS) and periodic limb movement (PLM). In addition, a part of them such as EDS is related to pharmacologic treatment. So get a better knowledge of sleep disorders in PD, will not only help to improve the quality of life in PD through timely intervention, but make it possible to identify people at risk in developing PD and carry out neuroprotective therapy as early as possible.

Recognition and diagnosis of sleep disorders in Parkinson’s disease

Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson’s disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a ‘differential diagnostic’ order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly.