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��ࡱ�>��	������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	���nbjbj����	4�����_f{�������ff������������8��T�A8�L(t���y���7�7�7�7�7�7�7$#:��<V�7��yy���7������7a$a$a$�������7a$��7a$a$��0|�1�����7�57������"�1�780A8"1�+=s#�+=$�1�1+=��2���a$������7�7a$���A8������������������������������������������������������������������������+=���������f �:	Case report: disturbed sleep in a patient with moyamoya disease.

Arina Bingeliene*, MD (1, 2), Colin M Shapiro, MD, PhD, FRCP(C) (1, 2), Dr. Sharon A Chung (3), PhD, Dr. Paul A. Hwang (4).

1 Department of Psychiatry, Faculty of Medicine, University of Toronto; Neuropsychiatry Program, Toronto Western Hospital, University Health Network

2 Sleep Research Laboratory, Toronto Western Hospital 

3 Sleep Research Unit, Department of Psychiatry, University Health Network

4 Department of Medicine, Institute of Medical Science, University of Toronto

*Corresponding Author:
Dr. Arina Bingeliene
Toronto Western Hospital
399 Bathurst Street, 7-Main, Rm. 422
Toronto, Ontario
M5T2S8
416-603-5273 (phone)
416-603-6919 (fax)
Arina.Bingeliene@uhn.ca

Abstract.

Background: Moyamoya disease is a chronic, progressive occlusion of the circle of Willis arteries that leads to the development of characteristic collateral vessels. The incidence of moyamoya disease is highest in Japan, with 0.35 cases per 100,000 people. At this time, moyamoya disease is believed to be hereditary and the pathogenesis is unknown.

Case report: This case report describes an 11-year-old Asian girl diagnosed with idiopathic moyamoya disease. The patient has a history of severe migraines and sleep disturbances and experienced a stroke-like event with balance, coordination, sensory and motor function impairment. She was subsequently treated with three revascularisation surgeries. Prior to her presentation, the patient experienced severe migraines attacks 4-5 times per week, with migraines representing a primary concern since the age of 5. She experienced difficulties falling asleep and maintaining sleep and developed mood-related problems. A full montage electroencephalogram (EEG) showed abnormal background activity and revealed epileptiform changes. Following treatment of her sleep disturbance with Tryptophan, her migraines improved and functional abilities were also enhanced. Her improvement in sleep function was quantified via repeated polysomnographic studies and actigraphy monitoring between 1/2012 and 2/2014. Along with the details of this case, this article provides a review of the literature related to this condition. 

Conclusion: This case report demonstrates that investigation of sleep-related concerns is able to provide a window into neurologic abnormalities, allowing for enhanced detection of these issues and improved therapeutic outcomes. A review of the literature indicates that little information is available related to the pathogenesis of moyamoya disease and that the presentation of sleep disturbances has not been widely reported. We believe this case report will help to improve understanding of the disease and its presentation.

Keywords: Moyamoya disease and sleep disturbances, puff of smoke, cerebral blood vessel occlusion. 

Background: 

Moyamoya disease is a rare, progressive cerebrovascular disorder of unknown pathogenesis that is characterized by blocked arteries in an area of the basal ganglia. The name �moyamoya� translates to �puff of smoke� in Japanese and describes the appearance of the tangle of collateral vessels formed to compensate for the blockage. The disease is characterized by constrictions primarily in the internal carotid artery, which often extend to the middle and anterior cerebral arteries (1). When the internal carotid artery becomes completely blocked, the fine collateral circulation that it supplies is obliterated. Patients are then dependent on collateral circulation from the posterior of the Circle of Willis, i.e. from the basilar artery.

Incidence, prevalence and genetics: Moyamoya disease was first described in Japan in the 1960s and has since been observed in individuals in the United States of America, Europe, Australia and Africa. Though prevalence rates vary, one study completed by Roy Sucholeiki et al. (1) indicated that in California and Washington the disease occurs in 0.086 cases per 100,000. The incidence of Moyamoya is highest in Japan, with 0.35 cases per 100,000 people�a rate roughly ten times higher than that found in western countries (2). 
Although it occurs primarily in Asians, moyamoya disease has also been observed (with varying degrees of severity) in Caucasians and in patients of African and Hispanic descent (1)The female-to-male ratio is 1.8:1 (3) and the age at diagnosis ranges from 6 months to 67 years, with the highest peak in the first decade and smaller peaks in the third and fourth decades of life (4). The disease is believed to be hereditary, with a family history of the condition reported in 10% of patients (4). Moreover, in 2006, Mineharu et al. (5) suggested that familial Moyamoya disease is autosomal dominant with incomplete penetrance that depends on age and genomic imprinting factors. Genetically susceptible loci have been found on 3p, 6p, 17q and band 8q23, with a specific gene locus, q25.3, on chromosome 17 (6).  

Clinical presentation: In children, the first symptom of moyamoya disease is often stroke, or recurrent transient ischemic attacks (TIA, commonly referred to as �mini-strokes�). These events are frequently accompanied by muscular weakness or paralysis affecting one side of the body, or seizures. Adults more often experience a hemorrhagic stroke due to recurring blood clots in the affected brain vessels. The symptom prevalence is: stroke (43%); transient ischemic attack (43%); seizures (6%); headaches (6%); choreiform movements (4%); intraventricular or intracerebral bleeding (3%) (7).
The symptoms and clinical course of the disease vary widely, with presentations ranging from asymptomatic manifestations to occasional transient events to the sudden development of severe neurologic deficits. Children in particular may experience hemiparesis, monoparesis, sensory impairment, involuntary movements, headaches, dizziness or seizures. Mental retardation or persistent neurologic deficits may also be present.
Although moyamoya disease has been observed in previously healthy individuals independent from other comorbid conditions, it is also often reported in connection with a number of other disease states. These include: endocrinologic (hyperthyreosis); infections (Leptospirosis, Tuberculosis); hematologic conditions (aplastic anemia, Fanconi anemia, sickle cell anemia, Systemic Lupus Erythematosus); congenital syndromes (Apert syndrome, Down syndrome, Marfan syndrome, Tuberous sclerosis, Turner syndrome, von Recklinghausen disease, Hirschsprung�s disease); vascular diseases (atherosclerotic disease, coarctation of the aorta and fibromuscular dysplasia, cranial trauma, radiation injury, parasellar tumors, hypertension). These associated conditions may not be causative, but they do warrant consideration due to their potential impact on treatment. 


Neuropsychological impairments: Due to frequent involvement of frontotemporal areas, neuropsychological impairments are often suspected in connection with moyamoya disease. A study conducted by Hsu et al. in 2012 (8) investigated the pattern of neuropsychological function in 13 children diagnosed with moyamoya disease. The results showed single-domain cognitive impairment in approximately 15% of patients and multiple-domain cognitive impairments in 23% of patients. The pattern of cognitive dysfunction observed was congruent with patterns often associated with lesions in frontotemporal areas. 
In 2011, a comprehensive preoperative neurocognitive assessment of 30 moymoya disease and moyamoya syndrome patients (mean age 10 years 10 months) was conducted (9). The study demonstrated that disease bilaterality was the main factor associated with cognitive deficits in these patients, suggesting that detrimental diffuse and prolonged ischaemic-hypoxic mechanisms play a significant role in determining cognitive outcomes. In terms of addressing neuropsychological effects of the disease, neurosurgery has been found to increase cognitive abilities (or prevent further decline) and to decrease stroke occurrence (10, 11). In one study conducted by Lee and colleagues (11), the preoperative and postoperative neurocognitive function of 65 patients with moyamoya disease was assessed using the Korean version of the Wechsler Intelligence Scale for Children-Revised (KEDI-WISC-R) and the Bender Gestalt Test (BGT). The results showed significant improvement in performance IQ and BGT scores postoperatively.
Further, researchers found that cerebral blood flow and cerebrovascular reserve measurement techniques including non-invasive tools like arterial spin labeling, brain magnetic resonance imaging and the CO2 challenge test can be used to increase the accuracy of revascularization surgery decisions in children with moyamoya and improve outcomes (11). This may be particularly pertinent given the finding by Weinberg and colleagues that moyamoya disease affects the cognition and daily function of pediatric patients to a greater extent than adult patients (12). Thus, early detection and intervention is recommended in order to support cognitive outcomes in pediatric populations.

Moyamoya and sleep disturbance: Sleep disturbances associated with moyamoya disease have not been extensively summarized, with only two known examples found in the literature. In one article published by Kurokawa et al. in 1985 (13), researchers reported clinical features of 29 children diagnosed with moyamoya disease. In 5 (17%) of those patients assessed, sleep-wake transition was found to be a precipitating factor for ischemic attack. 
A second study, published in 1979 by Kodama et al. (14), involved the analysis of the electroencephalogram (EEG) reports of 25 patients with moyamoya disease under the age of 13 years. In 17 of those assessed, posterior slow wave activity characterized by high-amplitude monorhythmic waves were observed. This activity was markedly decreased during sleep. Sleep spindle depression was found in 21 cases, corresponding with the side suggested by neurological symptoms. However, the degree of sleep spindle depression was not specified.  
Published more than three decades ago, these two reports represent the only literature available in relation to sleep disturbance in moyamoya disease. While this relationship is not well understood, it is clear that sleep-related conditions have the ability to significantly influence or exacerbate the symptoms of moyamoya disease. Sleep apnea and sleep-disordered breathing are known to be risk factors for ischemic stroke and have significant implications for the short- and long-term clinical outcomes in patients who have experienced ischemic events (15). Similarly, sleep deprivation is an established precipitant of epileptic seizures and may impact significantly on symptomatology (16). Finally, cognitive function in children has been showed to be impaired following only a single night of restricted sleep (17), suggesting that the neuropsychological impairments that often accompany moyamoya disease may be worsened by disrupted sleep. In this way, treatment of underlying sleep conditions may have vast implications for disease prognosis.

Prognosis: The natural history of moyamoya disease is not well known, though long-term outcomes for those who receive treatment appear to be good. Symptoms may improve almost immediately following surgical interventions such as indirect encephaloduroarteriosynangiosis, encephalomyosynangiosis, and multiple burr holes surgeries; however, it may take 6�12 months before new vessels develop and are able to provide sufficient blood supply to affected areas. In contrast, bypass surgery on the direct superficial temporal artery to middle cerebral artery will increase blood supply immediately. Following pial synangiosis, the majority of pediatric patients with�moyamoya�syndrome cease experiencing strokes and TIAs, and they appear to experience an excellent long-term prognosis (18).
Mortality resulting from moyamoya disease is usually the consequence of intracranial hemorrhage due to stoke. The outcome of the disease depends on the severity and nature of the hemorrhage, while the prognosis depends on recurrent attacks. Mortality rates postoperatively (19) are approximately 10% in adults and 4.3% in children. About 50-60% of affected individuals experience a gradual deterioration of cognitive function, presumably from recurrent strokes. Patients with moyamoya disease who present for treatment while symptoms are evolving have a better prognosis than do those who present with static symptoms (which may be indicative of a completed stroke). Once major stroke or bleeding takes place, the patient may be left with permanent loss of function, even with treatment. Thus, it is very important that patients receive prompt intervention.

Case presentation: 

Patient: D.M., born in 2002, is an 11-year-old female who presently lives in Waterloo with her parents, sister and dog. She has her own bedroom and the home environment was described as quiet. She is in the sixth grade. She has a number of environmental allergies. 
D.M.�s medical history is remarkable for moyamoya disease. She was born in China and immigrated to Canada when she was 18-months-old where she lives with her adoptive parents and adopted sister. She was diagnosed with moyamoya disease when she was 6-years-old.
She has received three revascularization surgeries. These interventions took place over a period of two years between 2008 and 2010. She also had ventriculoperitoneal shunt inserted. Her last surgery took place in November of 2010 following an ischemic stroke-like event. 
	Clinical presentation and sleep history: D.M. was initially referred to the Youthdale Child and Adolescent Sleep Centre in December of 2011 when she was 9-years-old. Listed reasons for referral included snoring, nocturnal enuresis, nightmares/night terrors, restless legs/periodic limb movements, difficulty with awakening in the morning, daytime tiredness, fatigue and irritability. D.M.�s reported sleep and wake times were fairly consistent on both weekdays and weekends. Her family history of sleep disorders was unknown as a result of her adoption. D.M.�s parents reported that she experienced difficulty falling asleep, snored frequently and had �heavy� or loud breathing. She would awaken unrefreshed and with headaches, and her teachers commented that they found her sleepy during the day. D.M. fidgeted, had concentration and attention issues, had difficulty organizing and completing tasks and activities and was easily distractible. 
On presentation, D.M. was a 9-year old girl in the 25th percentile of her height and weight category. She was soft-spoken but cooperative during the interview. No abnormalities were noted in terms of thought form, thought content, cognition, judgment, perception or insight. Her oropharynx was examined; she did have enlarged tonsils on the order of grade 3+ in size.
During the interview, she reported being �tired� during the day and that she would sometimes fall asleep during class. She snored, but no apneas had been witnessed. She did not report awakening with a choking or gasping sensation. She reported that her legs would become �sore�, but this issue has decreased in frequency since receiving surgery for her moyamoya disease which is suggestive of muscle spasticity due to stroke rather than possible periodic leg movements in sleep (PLMS) disorder. In the past, she would wake up screaming as a result of nightmares, but this issue abated following completion of her surgical treatment. There is no history of sleepwalking, night terrors or narcolepsy. 

Neuroimaging Investigations:

Brain Computer Tomography (CT): In 2010, (D. M. 8-years-old) hypodense ischemic change in the right caudate head was observed.

Magnetic Resonance Imaging of the brain with and without contrast (magnetic resonance angiography): On June 20, 2011 (D.M. 9-years-old), MRI revealed normal gray-white matter differentiation with no areas of restricted diffusion to suggest acute ischemia. Multifocal cystic encephalomalacic changes within the caudate nucleus on the right side were found, and were observed to be stable. Via magnetic resonance angiography, a single left vertebral artery was observed. A hypoplastic basilar artery with evidence of a persistent trigeminal artery on the right side of the lateral type was also found. There was non-visualization of the right posterior cerebral artery with multiple hypertrophic collaterals branches surrounding the right posterior cerebral artery (PCA) origin. A flow in the distal right PCA was observed. There was tortuosity of the intracranial segments of the internal carotid artery bilaterally. There was also severe narrowing with occlusion of the supraclinoid right ICA, with multiple hypertrophic lenticulostriate vessels. Flow within the right pial-synangiosis was found. There was also decreased flow in the anterior cerebral artery and the middle cerebral artery branches on the right side, likely retrograde filling. 
	On October 16, 2012, MRI of the brain with and without angiography was repeated (D.M. 10-years-old). Progression of vascular disease on the right and increased paucity of the basal collaterals was observed since prior assessment.
	
Postsurgical cerebral angiogram: On May 22, 2013 (D.M. 11-years-old), the right external carotid artery demonstrated a normal appearance, with superficial temporal and occipital synangiosis. The synangioses was found to feed the right cerebral hemisphere predominately.

Neurophysiology Investigations:

Polysomnography (PSG): On January 13, 2012, D.M. (10-years-old) underwent polysomnographic assessment. She experienced difficulties initiating and maintaining sleep. No evidence of significant sleep-disordered breathing or periodic limb movement disorder was observed. PSG detected features of a non-rapid eye movement (NREM) arousal parasomnia as well as a REM behavioral disorder. 

Electroencephalography: EEG assessment was completed at the time of PSG (January 13, 2012). It was found to be moderately abnormal. A disturbance in the organization of sleep stages was observed. In addition, there was an interhemispheric asymmetry with attenuation of cortical rhythms over the left hemisphere, predominantly involving the temporal region. Only one isolated sharp wave was recorded from the left infero-medial temporal structures, with the zygomatic recording proving to be insufficient for the diagnosis of complex partial seizures of temporal lobe origin. Conversely, the interhemispheric asymmetry observed suggests that the left hemisphere was relatively ischemic compared to the right hemisphere, despite recurrent cerebral perfusion with revascularization. Follow-up study after appropriate treatment was recommended, as clinically indicated. 

Actigraphy: Actigraphic assessment (20) was begun on June 7, 2012 and continued for 28 days to rule out a circadian rhythm disorder, given that D.M.�s parents had previously reported irregular sleep patterns. The study showed that, on the majority of nights assessed, D.M. experienced shortened sleep onset and that over the duration of the study she slept at approximately the same time period each night. Her sleep was mostly uninterrupted, with a few instances of increased activity for several minutes at a time, likely not due to awakening. On six of the days recorded, the patient napped for 30 minutes to an hour at varying times in the afternoon. 

Treatment:

Intervention: D.M. is currently being treated with Tryptophan tablets at a dose of 3750 mg each night, aspirin at 40 mg per day (for stroke prevention) and Montelukast (for reactive airways disease). 

Polysomnographic follow-up: On January 24, 2014 (D.M. 11-years-old), follow-up PSG assessment after the treatment with Tryptophan showed normal sleep onset latency (13 minutes) and decreased sleep efficiency after sleep onset (77%). D.M. experienced increased intermittent wakefulness, with one prolonged episode of wakefulness during the second part of the night. The arousal index was normal at a rate of 7 per hour. There were PSG features suggestive of a NREM arousal parasomnia. A normal amount of slow wave sleep was observed. 

Clinical assessment: The patient currently reports that her sleep has improved, both in terms of its duration and depth. The rate with which she experienced migraines has reduced from from 4 or 5 times a month to only once a month since she was first treated at the sleep clinic. Her father confirms that there has been a clear improvement in the state of her health.

Discussion: 

Moyamoya disease is a chronic and progressive obstruction of cerebral blood vessels. As a result of imaging assessment techniques and surgical intervention, it has recently become possible to extend the lifespan of patients living with the condition and to improve quality of life. This case report provides valuable evidence for the way in which a minor therapeutic intervention such as the use of Tryptophan to enhance sleep quality can significantly improve daytime performance, decrease migraine frequency and intensity and benefit the management of mood-related problems. Subjective reports on the part of the patient and her parents indicated improvements to the patient�s sleep pattern. This improvement was also objectively confirmed via PSG studies repeated at a two-year interval, which demonstrated a significant reduction in sleep onset latency and an increased amount of deep sleep. 
Addressing sleep-related problems can similarly improve the management of neurologic disorder symptoms (i.e. migraines) and behavioral problems. Poor sleep quality and sleep deprivation can also significantly decrease seizure threshold (16). The EEG assessment performed as part of this case report revealed abnormal background activity with one epileptiform spike and wave complex. The full montage EEG was analyzed as a part of the primary PSG assessment and was not created for epileptiform activity diagnosis. Further, specific functional assessments including hyperventilation and photic stimulation tests were also not conducted. Regardless, even a single epileptiform EEG element may suggest that this patient was predisposed to the manifestation of clinical seizures. By improving her sleep with Tryptophan, we were able to raise her seizure threshold and may have helped to play a preventive role in terms of seizure disorder development. 

Conflict of Interest:

Dr. Paul A. Hwang disclosures: Medical Advisor of UCB Pharma, ESAI, GSK and Sunovion. PI for EpLink � Ontario Brain Institute (OBI) and coordinator of EEG Platform for OBI.
Other Authors declare no conflict of interest. 


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 HYPERLINK "http://www.actigraphy.respironics.com" www.actigraphy.respironics.com










Running title: Case report: disturbed sleep in a patient with moyamoya disease.

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