Sleep Medicine 16 (2015) 1502–1510 Contents lists available at ScienceDirect Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p Original Article Neuroimaging-evident lesional pathology associated with REM sleep behavior disorder Stuart J. McCarter a,b,c, Maja Tippmann-Peikert a,b,c, David J. Sandness a,b,c, Eoin P. Flanagan c, Kejal Kantarci d, Bradley F. Boeve a,b,c, Michael H. Silber a,b,c, Erik K. St. Louis a,b,c,*,1 a Mayo Center for Sleep Medicine, Mayo Clinic and Foundation, Rochester, MN, USA b Department of Medicine, Mayo Clinic and Foundation, Rochester, MN, USA c Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA d Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA A R T I C L E I N F O Article history: Received 17 April 2015 Received in revised form 3 July 2015 Accepted 31 July 2015 Available online 14 September 2015 Keywords: REM sleep behavior disorder Parasomnia Brain lesion Neuroimaging Outcome A B S T R A C T Background/Rationale: Rapid eye movement (REM) sleep behavior disorder (RBD) is a potentially injurious parasomnia characterized by dream enactment behavior and polysomnographic REM sleep without atonia (RSWA). Recently, RBD not only has been shown to be strongly associated with synucleinopathy neurodegeneration but has also been rarely reported to be associated with structural lesions involving the brainstem or limbic system. The aim of this study was to describe the clinical, neuroimaging, and outcome characteristics in a case series of patients with lesional RBD. Methods: This is a retrospective case series from a tertiary care referral center. Results: A total of 10 patients with lesional RBD were identified. Seven (70%) were men, with an average age of sleep symptom onset of 53.7 ± 17.0 years. Structural pathology evident on neuroimaging included four extraaxial (three meningiomas and one basilar fusiform aneurysm with brainstem compression) and six intraaxial (encephalomalacia, multiple sclerosis, vasculitis, autoimmune limbic encephalitis, and leukodystrophy) lesions. No patient developed parkinsonian features or cognitive impairment suggestive of synucleinopathy over an average of 45.4 ± 35.2 months of follow-up. Conclusions: RBD is rarely associated with non-synuclein structural lesions affecting the pons, medulla, or limbic system. The spectrum of lesional RBD comprises tumors, aneurysms, leukodystrophy, and autoimmune/inflammatory/demyelinating brain lesions. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is a complex and potentially injurious parasomnia involving dream enactment behavior (DEB) that often mirrors terrifying dream content of being attacked or chased, associated with REM sleep without atonia (RSWA) [1–3]. While RBD is a frequent initial sign of synucleinopathy neurodegeneration, several reported RBD cases have been linked to lesional pathology, most commonly disrupting the dorsal pontine tegmentum or limbic system [4–21]. A recent case series of 119 patients with acute cerebral infarcts found that six of 27 patients with brainstem infarcts had RBD (22%) and that only brainstem lesions were independently associated with RBD development [22]. While mechanisms governing control of REM muscle * Corresponding author. Departments of Medicine and Neurology, Mayo Center for Sleep Medicine, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA. Tel.: +1 507 266 7456; fax: +1 507 266 7772. E-mail address: stlouis.erik@mayo.edu (E.K. St. Louis). 1 Principal Investigator. http://dx.doi.org/10.1016/j.sleep.2015.07.018 1389-9457/© 2015 Elsevier B.V. All rights reserved. atonia remain incompletely understood, evidence from studies in the cat, rat, and mouse suggests that glutamatergic neurons in the dorsal pontine sublateral dorsal nucleus (SLD), also known as subcoeruleus, are key in the generation of REM sleep atonia. SLD glutamatergic neurons project to the trigeminal nucleus, ventromedial medulla, and spinal cord, synapsing on GABAA, GABAB, and glycinergic neurons in the medullary gigantocellularis nucleus and spinal inhibitory interneurons, resulting in hyperpolarization of trigeminal and spinal cord motoneurons and normal REM sleep atonia [23–25]. The most common structures exhibiting neuropathology or neurodegeneration in RBD patients comprise the SLD, gigantocellular reticular nucleus, dorsal raphe nucleus, and pedunculopontine nucleus [26]. Lesions of the ventromedial medulla, hypothalamus, substantia nigra, and limbic system have also been reported to accompany RBD symptoms [27]. In animals, the size and location of the lesion influence whether DEB involves only simple limb twitches or more complex attack behaviors [28]. Table 1 shows several case reports of RBD associated with brainstem and limbic system lesions that exist in the literature. However, to our knowledge, there has been no previous systematic case series describing common clinical and neuroimaging features of patients with lesional S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 2. Methods A diagnosis and text-based search yielded 10 patients having an RBD diagnosis with structural lesional pathology on magnetic resonance imaging (MRI). These 10 patients accounted for 0.67% of RBD cases seen at our center. Three cases were previously reported (Patient #1 [19], Patient #6 [18], and Patient #7 [7]). A chart review was performed to confirm (1) RBD, (2) presence of a neuroimaging lesion in a location known to be associated with RBD, and (3) extraction of relevant clinical and demographic data. Video polysomnographic (PSG) analysis was performed on eight (80%) patients to confirm the presence of RSWA. Since there are no consensus diagnostic criteria for lesional RBD, the suggested criteria of Iranzo and Aparicio was used, including (1) RBD onset temporally associated with a brain lesion; (2) RBD onset coincident with the onset of other symptoms potentially caused by the lesion; (3) lesion location in a brainstem or limbic system area known to regulate REM sleep; (4) lesion disappearance associated with remission or improvement of RBD symptoms; and (5) RBD not better explained by another disorder, such as synucleinopathy, medication use, or withdrawal [27]. This study was approved by the Mayo Clinic Institutional Review Board. 3. Results Dx = diagnosis, RBD = REM sleep behavior disorder; MS = multiple sclerosis; VGKC = voltage-gated potassium channel. Compta et al. [5] Iranzo et al. [10] RBD not improved with IVIG and methylprednisolone Remission of RBD with immunosuppression RBD + narcolepsy RBD 69/M 65/M Anti–Ma2-associated encephalitis VGKC Autoantibodies Zambelis et al. [21] Jianhua et al. [30] Iranzo and Aparicio [27] Provini et al. [15] Tribl et al. [31] RBD RBD RBD RBD + status dissociatus RBD Neurinoma B cell lymphoma Cavernous hemangioma Post cavernoma resection Wilson’s disease Left cerebellopontine angle Pontomesencephalic junction at upper/mid pons level Left medulla Pontomesencephalic tegmentum Pontine and mesencephalic tegmentum and mesencephalic tectum Bilateral amygdala and dorsolateral midbrain Bilateral mesial temporal lobes 59/M 30/M 81/M 28/M 22/M Mathis et al. [29] Plazzi and Montagna [14] Continued RBD symptoms Symptoms resolved with adrenocorticotropic hormone treatment Remission of RBD with tumor resection Chemotherapy improved RBD RBD decreased, but persisted with clonazepam RBD improved with 2 mg of clonazepam No treatment Inflammatory/MS Inflammatory/MS Dorsomedial pontine tegmentum Pons 30/M 25/F Reynolds and Roy [16] Kimura et al. [11] Xi and Luning [20] Peter et al. [13] Limousin et al. [12] 90% decrease in RBD and cataplexy symptoms with fluoxetine RBD under control with 0.25 mg of clonazepam RBD in remission with 0.25 mg of clonazepam Not reported RBD and sleepwalking improved with 9 mg of melatonin RBD + cataplexy RBD RBD RBD Overlap parasomnia disorder RBD + narcolepsy RBD Ischemic infarct Ischemic infarct Ischemic infarct Ischemic infarcts Inflammatory/unknown etiology Rostral medial pons, left of midline Left upper pons Right paramedian pons Bilateral cerebellar and pontine white matter lesions Right pontine tegmentum and right dorsal medulla 67/M 75/F 68/M 79/M 40/F Authors Sleep Diagnosis Lesion Type/Neuro Diagnosis Lesion Location Outcome RBD. We report 10 cases of RBD associated with structural pathology evident on neuroimaging studies. Age/Sex Table 1 Previously reported cases of RBD associated with MRI lesions in the literature. 1503 Table 2 and Figs 1–7 show individual patient demographic data and symptoms on presentation, radiographic features, and treatment outcomes. Seven patients (70%) were men, with an average age at RBD onset of 53.7 ± 17.0 years. Four (40%) patients were taking antidepressant medications. Of the nine patients with an average follow-up of 45.4 ± 35.2 months (one patient was lost to followup), no patient developed parkinsonian features or cognitive impairment suggestive of synucleinopathy. In all patients, except Patient #2, DEB or sleep symptoms began within 1–2 months of neurologic symptom onset, surgical procedure, or identification on MRI imaging. Patient #2 had a longer history of symptoms, probably due to the slowly progressive mass effect associated with an underlying meningioma (Fig. 1). Patient #10 (Fig. 7) presented with seizures, cognitive dysfunction, and DEB consistent with autoimmune limbic encephalitis, which proved to be associated with elevated antibody titers against voltage-gated potassium channels (VGKC), and initial left caudate enhancement as well as later evolution of typical mesiotemporal pathology. The DEB improved with corticosteroids and immunosuppression. The remaining patients had lesions involving brainstem structures known to be associated with REM sleep muscle control, with four (40%) patients having discrete lesions within or neighboring the dorsal pontine tegmentum. Two (20%) patients had complete remission of DEB following surgical resection or radiographic remission of the lesion (Table 2, Figs 1–2). In Patient #8 (Fig. 5), RBD symptoms began following neurosurgical resection of an underlying epidermoid cyst, suggesting that pontine damage resulting from the procedure likely caused RBD. 4. Discussion To our knowledge, this is one of the largest case series fulfilling the Iranzo/Aparicio criteria of lesional RBD associated with a range of structural pathology evident on neuroimaging, providing further supportive evidence that the pons and medulla, especially the dorsal pontine tegmentum and rostral ventromedial medulla, are responsible for the generation and maintenance of REM sleep muscle atonia [18,23,24,26,32,33], and that more rostral 1504 Table 2 Clinical, demographic, imaging, and outcome data. ID/Age/ Sex Neuro Signs and Symptoms Neuro Diagnosis DEB Onset in Relation to Neuro Symptoms DEB Onset in Relation to Imaging DEB Content Dream Recall MRI Findings Neuro Treatment RBD Treatment Outcome Follow-up 1/51/F Vertigo, diplopia, gait ataxia, horizontal gaze restriction Multiple sclerosis 1–2 months after 2 months after imaging Punching, screaming None Demyelinating right dorsal pontine lesion [19] Rebif Clonazepam 0.125 mg 116 months, no RBD 2/68/M Headaches, left facial paralysis, loss of pin and temperature sensation in V1,V2,V3 (Fig. 1) Cognitive difficulty (28/38 on Short Test of Mental Status), shuffling gait, action tremor, personality change (Fig. 2) Meningioma Unclear 3–4 months before imaging Punched wife, fell out of bed Fighting and being chased Left cerebellopontine angle meningioma with mass effect and upon the brainstem and compression of pons None Melatonin 9 mg RBD remission 45 months after onset w/radiographic remission of lesion “Near complete control of RBD symptoms” Meningioma Simultaneous onset 1–2 years before imaging Yelling, punching and kicking, punched wife Chased or attacked by livestock Surgical resection None RBD remission with decreased mass effect on pons and midbrain 21 months, no RBD 4/61/F Headaches, imbalance (Fig. 3) Meningioma Simultaneous with increased headaches 20 years after initial imaging Screaming, thrashing, kicking Being attacked or fighting intruders None None (Asymptomatic aneurysm noted on MRI) (Fig. 4) Fusiform basilar aneurysm No neuro symptoms Simultaneous onset with imaging Punches, fallen out of bed, riding bicycle Playing football, shooting a bow and arrow Clonazepam 0.75 mg + melatonin 9 mg Pramipexole 0.5 mg Fluctuating control of RBD symptoms 5/74/M 88 months, difficult-tocontrol RBD symptoms 43 months, no mention of RBD symptoms 6/47/M Dysarthria, dysphagia, right facial weakness, with right III and IV and bilateral VI, VII, X, and XII cranial neuropathies Difficulty walking, leg weakness, and bowel and bladder incontinence Central and peripheral nervous system vasculitis 3 weeks after neuro symptoms 3 weeks after imaging Pounding, punching, fall out of bed Being attacked by fire ants, falling through ice Right petroclival meningioma with moderate-marked distortion and displacement of the pons and midbrain to the left Right cerebellopontine meningioma indenting right pontomedullary junction Fusiform aneurysm of proximal and mid aspect of basilar artery with involvement of left intradural vertebral artery producing significant mass effect upon ventral and left aspect of the pons T2 hyperintensity in right pontomedullary junction extending inferiorly to level of medulla [18] Autosomaldominant, adult-onset leukodystrophy due to lamin B1 gene duplication Simultaneous with neuro symptoms 2 years before imaging Scream, flail arms, kick legs, fell out of bed Being attacked 3/62/M 8/48/M Gait ataxia, imbalance, cranial nerve VIII palsy (Fig. 5) Posterior fossa epidermoid cyst 1 month after surgical resection of epidermoid cyst simultaneous with neuro symptoms 3 years before imaging Punching, kicking, moaning None 9/10/F Headaches (Fig. 6) Unclear Unclear Kicking None 10/53/M Seizures and memory decline (Fig. 7) Benign nonenhancing focal lesion of undetermined etiology Voltage-gated potassium channel autoantibodies (associated with prostate adenocarcinoma) Simultaneous with neuro symptoms 1 month before imaging Talking, jerking, grabbing None Still sleep talks, but no thrashing of arms or legs CellCept, Prednisone, Cytoxan Melatonin 6 mg + buspirone 20 mg Significant decrease in RBD symptoms 32 months, DEB once per month Bilateral T2-signal hyperintensities in the anterior medulla, middle cerebellar peduncles, dorsal pontine tegmentum, midbrain, and subcortical white matter [7] Fluid collection in operative site with flattening of left cerebellar peduncle with subtle brainstem T2 hyperintensity with FLAIR signal change neighboring 4th ventricle Right nonenhancing dorsal pontine tegmental lesion with subtle mass effect None Melatonin 3 mg Significant decrease in RBD symptoms 18 months, DEB less than once per week None Melatonin 3 mg No follow-up No followup None Melatonin 3 mg No follow-up 17 months, no DEB FLAIR hyperintensity in left caudate, hippocampus, and parahippocampal gyrus IV methylprednisolone, CellCept None Improvement in neurologic symptoms, no mention of sleep disturbances 48 months, no mention of RBD symptoms Age = age at RBD symptom onset; Dx = diagnosis; Sx = symptoms; RBD = REM sleep behavior disorder; RSWA = REM sleep without atonia; DEB = dream enactment behavior; V1 = ophthalmic nerve, V2 = maxillary nerve; V3 = mandibular nerve, Rx = Treatment; mg = milligrams. S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 7/61/M None 38 months, RBD well controlled S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 Fig. 1. A 68-year-old man with a left cerebellopontine angle meningioma compressing the pons and medulla, associated with headaches, left facial paresis, and left facial hypesthesia, accompanied by vivid dream enactment behaviors of punching, kicking, and falling out of bed, which remitted following meningioma resection and melatonin treatment (Patient #2 in Table 2). 1505 structures in mesiotemporal limbic and also extralimbic neocortical pathology may also rarely facilitate DEB and (most likely indirectly) provoke dysregulation of REM sleep muscle tone. Two of the cases were cerebellopontine angle meningiomas similar to previous reports of RBD associated with a left cerebellopontine angle neurinoma [21]. Two additional novel structural pathologies not previously described were reported in association with RBD, a patient with a right petroclival meningioma and another with a basilar fusiform aneurysm, both resulting in pontine compression. Similar to a previous report [10], we also identified one patient with VGKC autoimmunity associated with an occult malignancy with improvement of DEB and neurologic symptoms following immunosuppression. We also report a patient who developed RBD postoperatively following removal of an epidermoid cyst, similar to a previous report of brainstem damage related to a surgical procedure inducing RBD [15]. Patient #4 (Fig. 3) did not undergo surgical resection of her right cerebellopontine angle meningioma and continued to have verydifficult-to-control RBD symptoms despite polytherapy with clonazepam and melatonin. However, Patient #2 (Fig. 1) and another previously reported patient having a left cerebellopontine angle mass had excellent response to pharmacologic therapy with 9 mg of melatonin and 1 mg of clonazepam, respectively [21]. Several of the brainstem and cortical lesions reported in our series were not bilateral, suggesting that a unilateral lesion may be sufficient to cause RSWA and RBD symptoms, similar to a previous lesional study showing that unilateral ventral mesopontine junction lesions were sufficient to cause RSWA in cats [28,34]. Given the diversity of different causative pathologies seen in this study and other prior reported cases, location of the lesion and not the underlying disease Fig. 2. A 62-year-old man with a right petroclival meningioma compressing the pons and medulla, associated with cognitive impairment and dream enactment behaviors of yelling, kicking, and punching his wife, all of which ceased following surgical resection of the meningioma (Patient #3 in Table 2). 1506 S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 Fig. 3. A 61-year-old woman with a right cerebellopontine angle meningioma compressing the pontomedullary junction, associated with headaches, imbalance, and dream enactment behaviors characterized by screaming, thrashing, and kicking movements, which remained refractory to polytherapy with clonazepam and melatonin (Patient #4 in Table 2). process (ie, inflammatory, infarct, tumor, surgery, etc.) appears to be the principle factor related to the development of RBD [7,11–14,16, 18,19,21,29]. However, Patient #1 (Fig. 1) had complete remission of RBD symptoms with radiographic remission of the lesion, whereas the patient with a vasculitic lesion in the same location (Patient #6 [18]) had continued RBD symptoms despite radiographic remission, indicating mechanistic difference between disease processes resulting in transient versus permanent damage. Furthermore, dream enactment and dream recall were similar in this series in comparison to that seen in patients with neurodegeneration-associated RBD (i.e., idiopathic RBD, Parkinson’s disease [PD]–RBD, multiple system atrophy [MSA]–RBD, dementia with Lewy bodies {DLB}–RBD) again S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 1507 Fig. 4. A 74-year-old man with a large fusiform basilar artery aneurysm, associated with dream enactment behaviors of bicycling movements and falling from bed. Treatment with pramipexole improved the frequency and severity of behaviors, which were reduced to sleep talking only (Patient #5 in Table 2). suggesting that location of damage was the predominant determination of RBD symptoms [35]. Most of the patients reported in this series had focal neurological deficits apart from RBD which warranted an MRI. However, given the expense of MRI, and the rarity of RBD cases associated with lesions evident on imaging (0.67% of RBD cases seen at our center) in typical RBD patients lacking focal neurological deficits, routine MRI is generally unnecessary. There are several limitations to this retrospective, single-center study. PSG was not performed on two patients; however, each gave an explicit DEB history, with complete remission of DEB following meningioma resection in one patient (Patient #3). Severe obstructive sleep apnea (OSA) has been reported to mimic symptoms of RBD [36], although Patient #5 (Fig. 4), who did not undergo PSG, had no symptoms or risk factors for OSA. Finally, four patients were taking antidepressant medications, associated with RBD and RSWA [1,2,37,38]. However, two patients (#4 and #8; Figs 3 and 5) were taking selective serotonin reuptake inhibitor (SSRI) medication at stable doses years before DEB onset (which was coincidental with the discovery of meningioma in Patient #4 (Fig. 3) and after surgical resection of epidermoid cyst in Patient #8; Fig. 5), Patient #5 (Fig. 4) had DEB before the initiation of SSRI therapy, and Patient #6 [18] had persistent DEB despite the cessation of SSRI therapy, indicating that the brain lesion was more likely to be responsible for RBD symptoms than the antidepressant medication. Some of the patients in this study could also have had an alternative underlying neurodegenerative process such as a synucleinopathy that remained covertly present as the primary cause of their RBD. However, several factors mitigate against this possibility: (1) DEB onset with close temporal proximity to other neurological symptoms and visible neuroimaging pathology; (2) a relatively long duration of follow-up in most patients, without any emerging evidence for characteristic overt motor, cognitive, or autonomic neurodegenerative symptoms; and (3) remission of RBD in several cases following lesion resolution or immunosuppressive therapy, suggesting that these patients had lesional RBD. Longitudinal follow-up and eventual autopsy will be necessary to confidently exclude underlying neurodegeneration. 5. Conclusions Our series supports predominant pontine localization governing REM sleep muscle atonia. In patients with abrupt onset of focal 1508 S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 Fig. 5. A 48-year-old male with history of a posterior fossa epidermoid cyst presented with gait ataxia, imbalance, cranial nerve VIII palsy, and a history of punching, kicking, and moaning in his sleep 1 month following the removal of the cyst. MRI revealed a fluid collection in the operative site compressing the left pons and medulla (Patient #8 in Table 2). neurological symptoms and associated DEB, a brainstem lesion or limbic encephalitis must be considered, as treatment of the underlying condition, such as resection of a tumor, or immunotherapy to decrease inflammation, may improve or resolve DEB and potentially prevent other neurological complications associated with a structural brain lesion. Patients who suffer brainstem injury through infarct or inflammatory processes should also be queried about possible DEB and followed carefully for possible development of RBD so that timely therapy may be initiated to prevent injury. Finally, patients presenting with RBD along with focal neurologic deficits are also recommended to undergo MRI; however, in RBD patients with a normal neurologic exam, MRI is generally not warranted. Fig. 6. A 10-year-old girl with an ill-defined ovoid hyperintense FLAIR lesion in the right dorsal pontine tegmentum, associated with headaches and dream enactment behaviors, characterized by kicking and arm movements during polysomnography with REM sleep without atonia (Patient #9 in Table 2). Conflicts of interest No off-label medication use. This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant Number 1 UL1 RR024150-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. SJ McCarter, DJ Sandness, M Tippmann-Peikert, and MH Silber report no disclosures. EK St. Louis reports that he received research support from the Mayo Clinic Center for Translational Science Activities (CTSA), supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through Grant Number 1 UL1 RR024150-01. K Kantarci serves on the data safety monitoring board for Pfizer Inc. and Jannsen Alzheimer’s Immunothrapy, Takeda Global Research & Development Center, Inc.; she is funded by the NIH [R01AG040042 (PI), P50 AG44170/Project 2 (PI) and R01 AG11378 (Co-I). BF Boeve has served as an investigator for a clinical trial sponsored by GE Healthcare. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009). He serves on the scientific advisory board of the Tau Consortium. He receives research support from the NIH (U01 AG045390, U54 NS092089, P50 AG016574, UO1 AG006786, RO1 AG015866, RO1 AG032306, RO1 AG041797) and the Mangurian Foundation. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/ j.sleep.2015.07.018. EP Flanagan has nothing to disclose. S.J. McCarter et al./Sleep Medicine 16 (2015) 1502–1510 1509 Fig. 7. A 53-year-old man with history of prostate carcinoma presented with seizures, mental status changes, and dream enactment behaviors evolving within 1 month of his other neurological symptoms. Sequential brain MRI initially demonstrated abnormal FLAIR signal hyperintensity in the left caudate, with later development of abnormal FLAIR signal in the hippocampus, and parahippocampal gyrus (Patient #10 in Table 2). Acknowledgments References This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant Number 1 UL1 RR024150-01. 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