Maja Tippmann-Peikert

REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century

Background: Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). Methods: We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome. Results: Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients. Conclusions: These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.

Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists

Pathologic gambling is an impulse control disorder previously reported to complicate dopamine agonist therapy in patients with Parkinson disease. It has not been described in association with dopamine agonist therapy of other conditions. We report three patients treated in our sleep disorders center who developed pathologic gambling while receiving treatment with dopamine agonists for restless legs syndrome.

Treatment outcomes in REM sleep behavior disorder

OBJECTIVE REM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam. METHODS We surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008-2010 to describe RBD-related injury frequency-severity as well as RBD visual analog scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency. RESULTS Forty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and two received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (p(m) = 0.0001, p(c) = 0.0005). Melatonin-treated patients reported significantly reduced injuries (p(m) = 0.001, p(c) = 0.06) and fewer adverse effects (p = 0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 ± 29.5 months, and for melatonin 27.4 ± 24 months, p = 0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam-treated patients discontinuing treatment (p = 0.43). CONCLUSIONS Melatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed.

REM sleep behavior disorder initiated by acute brainstem multiple sclerosis

REM sleep behavior disorder (RBD) is defined by loss of normal skeletal muscle atonia during REM sleep, resulting in excessive, often violent motor activity, frequently associated with dreaming.1 RBD is typically a chronic disorder occurring idiopathically or accompanying neurologic disease, particularly the neurodegenerative synucleinopathies of Parkinson disease, multiple-system atrophy, and dementia with Lewy bodies.2 Acute RBD may be associated with alcohol and psychoactive substance intoxication or withdrawal and structural brain lesions. The anatomic lesion site and time course of acute RBD are not well known. We report RBD arising following a severe attack of dorsal pontine demyelination from multiple sclerosis (MS). A 51-year-old woman with MS developed acute vertigo, ataxia, diplopia, dysarthria, and bifacial weakness. She had been in clinical remission for 24 years without immunomodulatory therapy. Following repeated courses of IV corticosteroids and therapeutic plasma exchange (TPE), her symptoms improved markedly, and subcutaneous interferon β-1a was initiated. One week later, the patient’s husband of 28 years described that she exhibited nightly sleep-related groaning, screaming, limb jerking, flailing, and violent thrashing, punching her husband’s jaw once. She did not recall these events or any associated dream content. There were no prior parasomnias or spousal reports of …

DPPX potassium channel antibody Frequency, clinical accompaniments, and outcomes in 20 patients

Objective: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. Methods: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. Results: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13–75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. Conclusions: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.

Idiopathic rapid-eye-movement sleep disorder: associations with antidepressants, psychiatric diagnoses, and other factors, in relation to age of onset.

BACKGROUND A retrospective, case-control chart review was performed to examine the relationship between the age of onset of idiopathic RBD and secondary associations. METHODS Forty-eight idiopathic RBD patients were divided into early-onset and late-onset groups, compared to each other, and to their respective non-RBD controls. RESULTS There were more females in the early-onset group as compared to their older counterparts (45% vs. 11%, p=0.007). Early-onset patients also had significantly more past and present psychiatric diagnoses [85% (both categories) vs. 46% and 36%, respectively, p<0.01 for both comparisons] and antidepressant use (80% vs. 46%, p=0.02) than the late-onset group. In comparison to non-RBD controls, early-onset patients again exhibited more psychiatric diagnoses (odds ratio=17.0 [3.5-83.4], equivalent for past and present diagnoses) and antidepressant use (odds ratio=12.0 [2.7-53.3]). Late-onset patients also had a higher frequency of past (odds ratio=7.2 [1.8-29.6]) and present (odds ratio=4.6 [1.1-19.3]) psychiatric diagnoses as compared to their non-RBD controls, but did not demonstrate a statistically significant difference in antidepressant use. There were otherwise no significant intergroup or intragroup differences with respect to the other assessed variables. CONCLUSIONS Although causality cannot be inferred, numerous implications can be entertained, particularly in the early-onset group, including direct or indirect correlations with medication use and/or psychopathology and the development of RBD. The relatively high number of females in the early-onset group suggests a unique clinical profile for a condition typically characterized as male-predominant.

Sleep manifestations of voltage-gated potassium channel complex autoimmunity.

OBJECTIVE To identify the spectrum of sleep disorders associated with autoantibodies reactive with voltage-gated potassium channel (VGKC) complexes. DESIGN Case series of all patients with neurologic disorders of VGKC autoimmunity evaluated in the Mayo Clinic Center for Sleep Medicine (Rochester, Minnesota) between January 1, 1994, and February 1, 2010. SETTING Academic referral center. PATIENTS Fifteen consecutive patients were identified with limbic encephalitis (n = 5), Morvan syndrome (n = 4), and overlapping features (n = 6). INTERVENTION Ten patients received immunotherapy (corticosteroids, cyclophosphamide, or mycophenolate mofetil). MAIN OUTCOME MEASURE Response to immunotherapy. RESULTS The median VGKC autoantibody value at presentation was 1.51 nmol/L (range, 0.09-4.86 nmol/L). Neoplasms were discovered in 5 patients (33%) (thymoma [n = 2], prostate adenocarcinoma, colon adenocarcinoma, and melanoma). In 14 patients (93%), serious sleep disturbances were identified (insomnia, dream enactment behavior, suspected nocturnal epilepsy, and hypersomnia). Severe insomnia occurred in 9 patients (60%), regardless of neurologic presentation. Polysomnography at presentation (7 patients) revealed a mean sleep efficiency of 19% (4 patients had complete absence of sleep). Dream enactment behavior occurred in 8 patients (53%), including 3 of 5 with limbic encephalitis and all 4 with Morvan syndrome. Two of 7 polysomnograms demonstrated loss of rapid eye movement sleep muscle atonia; absent or minimal rapid eye movement sleep precluded interpretation in 4 patients. Sleep disorders resolved completely or almost completely in 8 of 10 patients who received immunotherapy. CONCLUSIONS Sleep disorders are cardinal manifestations of VGKC complex autoimmunity in association with a spectrum of neurologic presentations. They may respond favorably to immunotherapy.

Factors associated with injury in REM sleep behavior disorder

OBJECTIVE As factors associated with injury in rapid eye movement (REM) sleep behavior disorder (RBD) remain largely unknown, we aimed to identify such factors. METHODS We surveyed consecutive idiopathic (iRBD) or symptomatic RBD patients seen between 2008 and 2010 regarding RBD-related injuries. Associations between injuries and clinical variables were determined with odds ratios (OR) and multiple logistic regression analyses. The primary outcome variables were injury and injury severity. RESULTS Fifty-three patients (40%) responded. Median age was 69 years, and 35 (73.5%) were men. Twenty-eight (55%) had iRBD. Twenty-nine (55%) reported injury, with 37.8% to self and 16.7% to the bed partner. 11.3% had marked injuries requiring medical intervention or hospitalization, including two (4%) subdural hematomas. iRBD diagnosis (OR = 6.8, p = 0.016) and dream recall (OR = 7.5, p = 0.03) were associated with injury; and iRBD diagnosis was independently associated with injury and injury severity adjusting for age, gender, DEB frequency, and duration. Falls (p = 0.03) were also associated with injury severity. DEB frequency was not associated with injury, injury severity, or falls. CONCLUSIONS Injuries appear to be a frequent complication of RBD, although the relatively low response rate in our survey could have biased results. iRBD patients are more likely to suffer injury--and more severe injuries--than symptomatic RBD patients. In addition, recall of dreams was also associated with injury, and dream enactment behavior (DEB)-related falls were associated with more severe injuries. One in nine patients suffered injury requiring medical intervention. The frequency of DEB did not predict RBD-related injuries, highlighting the importance of timely initiation of treatment for RBD in patients having even rare DEB episodes. Future prospective studies will be necessary to define predictors of injury in RBD.

Characteristics of REM sleep behavior disorder in childhood.

STUDY OBJECTIVE To describe our experience regarding the clinical and polysomnographic features of REM sleep behavior disorder (RBD) in childhood. METHODS This was a retrospective chart review of children and adolescents with RBD and REM sleep without atonia. Demographics, and clinical and polysomnographic information were tabulated. Our findings were compared with those in the existing literature. RESULTS The 15 subjects identified (13 RBD and 2 having REM sleep without atonia) had a mean age at diagnosis of 9.5 years (range 3-17 years); 11/15 (73%) were male. Nightmares were reported in 13/15 and excessive daytime sleepiness in 6/15. Two children had caused bodily harm to bedmate siblings. Comorbidities, which were multiple in some subjects, included anxiety (8/15), attention deficit disorder (10/15), nonspecific developmental delay (6/15), Smith-Magenis syndrome (1/15), pervasive developmental disorder (1/15), narcolepsy (1/15), idiopathic hypersomnia (1/15), and Moebius Syndrome (1/15). Abnormal MRI scans were seen in 5/8 evaluated subjects. Treatments consisted of clonazepam (10/15), melatonin (2/15), and discontinuation of a tricyclic agent (1/15), with a favorable response in 11 of 13. Two of 15 patients with REM sleep without atonia did not require pharmacotherapy. CONCLUSIONS RBD in children may be associated with neurodevelopmental disabilities, narcolepsy, or medication use. It seems to be modestly responsive to benzodiazepines or melatonin. The etiology is distinct from that of common childhood arousal parasomnias and RBD in adults; congenital and neurodevelopmental disorders, medication effect, and narcolepsy coexisted in some, but none had an extrapyramidal neurodegenerative disorder.

Lesional REM sleep behavior disorder localizes to the dorsomedial pons

REM sleep behavior disorder (RBD) is characterized by dream enactment behaviors (DEB) and REM sleep without atonia (RSWA). A key structure in REM sleep muscle tone regulation in the rodent model is the sublateral dorsal (SLD) tegmental nucleus in the dorsomedial pons.1 Lesions of an analogous structure, the subceruleus (SC) nucleus are thought to mediate RSWA in humans, enabling DEB.1,2 However, in vivo human studies of discrete dorsomedial pontine lesions causing RBD in isolation have been limited.2–4 We report such a case of lesional RBD due to vasculitis. The Mayo Clinic Institutional Review Board approved this study.