Joan Santamaria

Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study

BACKGROUND Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviours related to unpleasant dreams and loss of muscle atonia during REM sleep. RBD may be idiopathic or associated with neurological disease. Available data suggest that in some cases RBD might be the initial manifestation of a neurodegenerative disease. We sought to determine the frequency and nature of neurological disorders developing in patients diagnosed with idiopathic RBD at our sleep centre. METHODS We retrospectively assessed 44 consecutive patients (39 men and five women with a mean age of 74 years), with at least 2 years of clinical follow-up after a diagnosis of idiopathic RBD, through a detailed clinical history, complete neurological examination, rating scales of parkinsonism, and neuropsychological tests. FINDINGS 20 (45%) patients developed a neurological disorder after a mean of 11.5 years from the reported onset of RBD and a mean follow-up of 5.1 years from the diagnosis of idiopathic RBD at our sleep centre. Emerging disorders were Parkinsons disease in nine patients, dementia with Lewy bodies in six, multiple system atrophy with predominant cerebellar syndrome in one, and mild cognitive impairment in four in whom visuospatial dysfunction was prominent. Patients with longer clinical follow-up developed a neurological disease (OR 1.512, 95% CI 1.105-2.069; p=0.010). INTERPRETATION Our study indicates that in people presenting to sleep centres, RBD often antedates the development of a neurodegenerative disorder. Close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative disease. This finding may be of great interest when early effective treatment strategies and neuroprotective drugs become available.

Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study

BACKGROUND We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinsons disease (PD) or dementia with Lewy bodies (DLB). METHODS Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB. FINDINGS Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (-1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case. In these three patients, neuronal loss and Lewy pathology (α-synuclein-containing Lewy bodies and Lewy neurites) were found in the brainstem nuclei that regulate REM sleep atonia. INTERPRETATION Most IRBD individuals from our cohort developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD and DLB in IRBD, such as decreased striatal DAT binding. Our findings indicate that in most patients diagnosed with IRBD this parasomnia represents the prodromal phase of a Lewy body disorder. IRBD is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process. FUNDING None.

Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD

Objective: To compare the clinical and video-polysomnographic (VPSG) characteristics of idiopathic REM sleep behavior disorder (RBD) vs the RBD seen in multiple system atrophy (MSA) and Parkinson disease (PD). Methods: Clinical features and VPSG measures were evaluated in 110 consecutive nondemented subjects (26 MSA, 45 PD, and 39 idiopathic RBD) free of psychoactive medications referred for suspected RBD to our sleep unit over a 5-year period, with extended follow-up (mean 26.9 ± 21.3 months). Results: Across the three groups studied, logistic regression analysis demonstrated that there were no differences in the quality of RBD symptoms (e.g., nature of unpleasant dream recall or behaviors witnessed by bed partners), most PSG variables, abnormal behaviors captured by VPSG, and clinical response to clonazepam. When compared to subjects with PD, however, patients with MSA had a significantly shorter duration of disease, a higher REM sleep without atonia percentage, a greater periodic leg movement index, and less total sleep time. Subjects with idiopathic RBD, as compared to those with either MSA or PD, were more often male, had greater self-reported clinical RBD severity, and were more often aware of their abnormal sleep behaviors. Conclusions: REM sleep behavior disorder (RBD)-related symptoms and neurophysiologic features are qualitatively similar in RBD subjects with the idiopathic form, multiple system atrophy (MSA), and Parkinson disease (PD). Polysomnographic abnormalities associated with RBD in the setting of MSA are greater than in PD, suggesting a more severe dysfunction in the structures that modulate REM sleep.

The EEG of Drowsiness in Normal Adults

The EEG of Drowsiness in Normal Adults Joan Santamaria;Keith Chiappa; Journal of Clinical Neurophysiology

Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study

BACKGROUND Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinsons disease. In patients with Parkinsons disease, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT detects striatal dopamine dysfunction resulting from nigral pathology whereas transcranial sonography (TCS) shows increased substantia nigra echogenic size, even before parkinsonism is clinically evident. We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction. METHODS In our prospective study, we identified patients with IRBD from individuals referred to our sleep disorders centre in Barcelona, Spain. At baseline, we assessed dopamine transporter [corrected] uptake by use of ¹²³I-FP-CIT SPECT, and estimated echogenicity of the substantia nigra by use of TCS. After a follow-up of 2·5 years, participants were clinically assessed to establish whether they had developed neurodegenerative syndromes. Data were compared with those of matched healthy controls. FINDINGS 43 individuals with IRBD agreed to participate in the study. We found reduced ¹²³I-FP-CIT binding in the striatum (p=0·045) in 17 (40%) of 43 participants compared with 18 controls, and substantia nigra hyperechogenicity in 14 (36%) of 39 participants with IRBD, compared with 16 (11%) of 149 controls (p=0·0002). Tracer uptake reduction was more pronounced in the putamen than it was in the caudate nucleus. 27 (63%) participants had reduced ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. Eight (30%) of these participants developed a neurodegenerative disorder (five Parkinsons disease, two dementia with Lewy bodies, and one multiple system atrophy). Individuals with normal neuroimaging results remained disease-free. Sensitivity of combined ¹²³I-FP-CIT SPECT and TCS to predict conversion to synucleinopathy after 2·5 years was 100% and specificity was 55%. INTERPRETATION In patients with IRBD, ¹²³I-FP-CIT SPECT and TCS can detect subclinical changes much the same as those typically seen in patients with early Parkinsons disease. Decreased striatal ¹²³I-FP-CIT binding and substantia nigra hyperechogenicity might be useful markers to identify individuals at increased risk for development of synucleinopathies. FUNDING None.

Prevalence and clinical importance of sleep apnea in the first night after cerebral infarction

ObjectiveTo determine the prevalence of sleep apnea (SA) during the first night after hemispheric ischemic stroke and its influence on clinical presentation, course, and functional outcome at 6 months. MethodsThe first night after cerebral infarction onset, 50 patients underwent polysomnography (PSG) followed by oximetry during the next 24 hours. Neurologic severity and early worsening were assessed by the Scandinavian Stroke Scale and outcome by the Barthel Index. Patients were evaluated on admission, on the third day, at discharge, and at 1, 3, and 6 months. ResultsThere were 30 males and 20 females with a mean age of 66.8 ± 9.5 years. Latency between stroke onset and PSG was 11.6 ± 5.3 hours. Thirty-one (62%) subjects had SA (apnea–hypopnea index [AHI] ≥ 10). Of these, 23 (46%) had an AHI ≥20 and 21 (42%) an AHI ≥25. Sleep-related stroke onset occurred in 24 (48%) patients and was predicted only by an AHI ≥25 on logistic regression analysis. SA was related to early neurologic worsening and oxyhemoglobin desaturations but not to sleep history before stroke onset, infarct topography and size, neurologic severity, or functional outcome. Early neurologic worsening was found in 15 (30%) patients, and logistic regression analysis identified SA and serum glucose as its independent predictors. ConclusionsSA is frequent during the first night after cerebral infarction (62%) and is associated with early neurologic worsening but not with functional outcome at 6 months. Cerebral infarction onset during sleep is associated with the presence of moderate to severe SA (AHI ≥ 25).

The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases

REM sleep behavior disorder (RBD) is characterized by vigorous movements associated with unpleasant dreams and increased electromyographic activity during REM sleep. Polysomnography with audiovisual recording is needed to confirm the diagnosis of RBD and to exclude other sleep disorders that can mimic its symptoms including obstructive sleep apnea, nocturnal hallucinations and confusional awakenings. RBD may be idiopathic or related to neurodegenerative diseases, particularly multiple system atrophy, Parkinsons disease and dementia with Lewy bodies. RBD may be the first manifestation of these disorders, antedating the onset of parkinsonism, cerebellar syndrome, dysautonomia, and dementia by several years. RBD should thus be considered an integral part of the disease process. When effective, neuroprotective strategies should be considered in subjects with idiopathic RBD. Patients with other neurodegenerative diseases, though, such as spinocerebellar ataxias, may also present with RBD. When clinically required, clonazepam at bedtime is effective in decreasing the intensity of dream-enacting behaviors and unpleasant dreams in both the idiopathic and secondary forms. When part of a neurodegenerative disorder the development of RBD is thought to reflect the location and extent of the underlying lesions involving the REM sleep centers of the brain (e.g., locus subceruleus, amygdala, etc.), leading to a complex multiple neurotransmitter dysfunction that involves GABAergic, glutamatergic and monoaminergic systems. RBD is mediated neither by direct abnormal alpha-synuclein inclusions nor by striatonigral dopaminergic deficiency alone.

Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study

BACKGROUND Serial dopamine transporter (DAT) imaging in patients with Parkinsons disease (PD) and other synucleinopathies shows progressive nigrostriatal dopaminergic dysfunction. Because idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can precede the classic symptoms of PD and other synucleinopathies, we postulated that serial DAT imaging in patients with IRBD could be used to detect decline in striatal tracer uptake, indicating progressive nigrostriatal cell degeneration. METHODS In a prospective study, 20 patients with IRBD (mean age 70·55 years [SD 6·02]) underwent serial DAT imaging with (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT at baseline and again after 1·5 years and 3 years; 20 age-matched and sex-matched control participants (69·50 years [6·77]) underwent imaging at baseline and 3 years. The striatum to occipital cortex uptake ratios were calculated for the putamen and caudate nucleus in each hemisphere. In patients, the ratio was judged to be reduced when it was less than two SD of the mean ratio in controls at the same timepoint. Differences in (123)I-FP-CIT uptake between patients and controls in each striatal region and rates of decline were assessed by use of multivariate ANOVA (MANOVA). FINDINGS Compared with controls, patients had significantly reduced mean (123)I-FP-CIT binding in all four striatal regions at baseline and after 3 years. Striatal (123)I-FP-CIT uptake was reduced compared with that in controls in ten patients at baseline and in 13 patients after 3 years. In patients, the mean reduction in (123)I-FP-CIT uptake from baseline to 3 years was 19·36% (95% CI 15·14 to 23·59) in the left putamen, 15·57% (10·87 to 20·28) in the right putamen, 10·81% (6·49 to 15·18) in the left caudate nucleus, and 7·14% (2·74 to 11·56) in the right caudate nucleus. After adjustment for the baseline (123)I-FP-CIT uptake ratios, the decline in (123)I-FP-CIT binding at baseline to 3 years was significantly greater in patients than in controls in the left putamen (9·78% difference between groups, 95% CI 3·22 to 16·32), right putamen (5·43%, 1·99 to 12·86), and left caudate nucleus (8·07%, 1·44 to 14·70), but not in the right caudate nucleus (4·16%, -3·00 to 11·34). At the 3-year assessment, three patients were diagnosed with PD. These patients had the lowest (123)I-FP-CIT uptake at baseline and a mean reduction in (123)I-FP-CIT uptake at 3 years of 32·81% in the left putamen, 30·40% in the right putamen, 26·51% in the left caudate nucleus, and 23·75% in the right caudate nucleus. INTERPRETATION In patients with IRBD, serial (123)I-FP-CIT SPECT shows decline in striatal tracer uptake that reflects progressive nigrostriatal dopaminergic dysfunction. Serial (123)I-FP-CIT SPECT can be used to monitor the progression of nigrostriatal deficits in patients with IRBD, and could be useful in studies of potential disease-modifying compounds in these patients. FUNDING Fondo de Investigaciones Sanitarias of Spain.

Diagnosis and the premotor phase of Parkinson disease

Clinical, neuroimaging, and pathologic studies have provided data suggesting that a variety of nonmotor symptoms can precede the classic motor features of Parkinson disease (PD) by years and, perhaps, even decades. The period when these symptoms arise can be referred to as the “premotor phase” of the disease. Here, we review the evidence supporting the occurrence of olfactory dysfunction, dysautonomia, and mood and sleep disorders, in this premotor phase of PD. These symptoms are well known in established PD and when presenting early, in the premotor phase, should be potentially considered as an integral part of the disease process. Even though information on the premotor phase of PD is rapidly accumulating, the diagnosis of premotor PD remains elusive at this time. Should a safe and effective treatment with disease-modifying or neuroprotective potential in PD become available, identifying individuals in the premotor phase will become a serious priority.

Neurodegenerative Disorder Risk in Idiopathic REM Sleep Behavior Disorder: Study in 174 Patients

Objective To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Methods Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. Results The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. Conclusions In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.