Prognostic Counseling for Patients With Idiopathic/Isolated Rapid Eye Movement Sleep Behavior Disorder: Should We Tell Them What's Coming? No

A recent episode from real‐world neurology: A 66‐year‐old male patient presented to our movement disorders clinic with hypokinetic‐rigid symptoms. The diagnostic workup confirmed the initial hypothesis of Parkinson's disease (PD). Furthermore, rapid eye movement (REM) sleep behavior disorder (RBD) was identified on video‐supported polysomnography. When diagnostic findings were discussed, his wife commented on the presence of RBD: “Oh, that…, but he's been doing that in his sleep for over 20 years! I always thought it was because of his difficult childhood!” When introduced to the concept that RBD is part of the synucleinopathy syndrome complex and may appear prodromal to motor manifestation of PD, the couple grew quite agitated and reproached themselves for neglecting to seek earlier medical counseling in the assumption that an early medical intervention at the stage of isolated RBD could have prevented the manifestation of PD. The attending neurologist had a hard time explaining that nothing was lost, there had been no negligence on their part, and that there was and currently is no preventive treatment available.

This episode illustrates the dilemma of physicians confronted with patients showing idiopathic/isolated RBD (iRBD): Phenoconversion may take quite a long time. During this period of life, a person is usually still in the midst of his or her professional life, is busy with family, career, and social life. An unconditional “yes” to full disclosure of a potentially developing debilitating and uncurable disease forging its way through the brain without any available disease‐modifying treatment to prevent, or at least delay its progression, may cause serious emotional or psychological distress.

However, patients have the right to be adequately informed about their diagnosis and advised on therapy and prognostic aspects according to evidence‐based medicine. To actively withhold information disrespects patients’ autonomy and violates the ethical codes of our profession. The scientific evidence underlining the association of iRBD with an alpha‐synucleinopathy, such as PD, Lewy body dementia, or MSA, is compelling and cannot be ignored. Over 20 years ago, the first study was published showing the conversion of iRBD into PD.1 Approximately 14 years after the onset of RBD, 81% of patients originally diagnosed with idiopathic RBD had developed parkinsonism and/or dementia.2 Other study groups confirmed these findings of RBD preceding a synuclein‐mediated neurodegenerative disease by more than a decade, with a neurological disease‐free survival rate from the time of iRBD diagnosis of 65.2% at 5 years and 7.5% at 14 years.3, 4, 5 Therefore, RBD is now recommended as a biomarker in clinical cohorts investigating prodromal PD.6 By now, this information is accessible to the general public and research, for example, an Internet search will reveal the association of iRBD to neurodegenerative disease very quickly. So we should meet patients’ need for trustworthy, up‐to‐date information. The question is whether unconditional disclosure of an impending neurodegenerative disease for all iRBD subjects at the time of polysomnographic confirmation of the diagnosis is truly appropriate.

The current lack of disease‐modifying treatments, as well as the potentially long gap between the first manifestation of the sleep disorder and phenoconversion to overt parkinsonism and/or dementia, has to be considered. A latency period from iRBD onset by the patient's history to clinically manifest PD of up to half a century has been described,7 and long‐term follow‐up data of patients remaining with iRBD have been published.8 Depending on age, comorbidities, and life expectancy, an individual diagnosed with iRBD may never during his or her lifetime experience clinically relevant manifestation of parkinsonism and/or dementia. Furthermore, it is still unclear whether or not prognostic data derived from iRBD cohorts presenting to specialized sleep centers because of violent dream enactment may be generalized to those in whom RBD or isolated REM sleep without atonia (RSWA) is an incidental finding during the diagnostic workup for other sleep disorders.8, 9, 10, 11

Of note, these long‐standing iRBD patients showed some prodromal PD markers such as anosmia, constipation, anxiety,9 mild parkinsonian motor signs, and reduced striatal uptake in dopamine transporter imaging.8 Interestingly, patients identified with isolated RSWA—which is discussed as a prodromal stage to full‐blown RBD—also showed at least one neurodegenerative biomarker.11 The significance of single prodromal biomarkers for a synucleinopathy should therefore be placed in the context of individual conversion risk profiles, taking into account that there might yet be unknown exacerbating factors for conversion of iRBD to clinical PD, MSA, or dementia with Lewy bodies (DLB), as well as potentially protective factors. Furthermore, autopsy studies have revealed Lewy bodies in 8% to 17% of neurologically normal people aged >60 years.12, 13 Thus, even the neuropathological hallmark of PD, MSA, and DLB may be incidental and not fully consistent with the clinical picture of neurodegenerative disease during a subject's lifetime. Therefore, the question “Should we tell them what's coming?” should be rephrased as “Should we tell them what might be coming?”.

More recently, a seminal study assessed the neurodegenerative disease risk and predictors of neurodegeneration in the largest worldwide multicenter cohort of iRBD subjects compiled so far.14 Prospective follow‐up data from 24 centers of the International RBD Study Group were collected, and data from 1,280 subjects with polysomnographically proven iRBD were included. Subjects underwent sleep, autonomic, cognitive, motor, and sensory testing at baseline and were then followed prospectively for the development of parkinsonism and/or dementia with an average follow‐up of 4.6 (range, 1–19) years. The annual conversion rate of iRBD to clinically manifest neurodegenerative disease was determined to be 6.3%. A total of 73.5% of iRBD subjects had converted after 12 years. Abnormal quantitative motor testing and standardized motor examination, impairment of smell, mild cognitive impairment, erectile dysfunction, motor symptoms, abnormal dopamine transporter imaging, color vision abnormalities, constipation, loss of atonia in REM, and age were identified with significant hazard ratios. The International Parkinson and Movement Disorder Society (MDS) prodromal criteria,15 which represent a combination of several variables, predicted phenoconversion with the highest hazard ratio of 5.37. Based on these clinical tests, of which the majority can be performed within the office, it seems possible to estimate an individual risk profile for phenoconversion, thus enabling the attending physician to be more specific in his or her counseling. Stratification of iRBD patients according to their personal conversion risk could then determine the information given ranging from classification as a stand‐alone condition without any further current implications other than keeping the patient and his or her bed partner safe at night up to imminent clinical manifestation of parkinsonism and/or dementia in those fulfilling MDS prodromal criteria.15 This approach would also facilitate identification of iRBD patients for disease‐modifying trials, should they become available, restricting patient selection to those who are considered likely to convert in the near future.

Last, but not least, we need to find out what patients expect. To the best of my knowledge, there are currently no structured, scientifically evaluated data available on the attitude of iRBD afflicted subjects toward disclosure of potential conversion to manifest neurodegenerative disease. Informal questioning among those attendees of my outpatient clinic who reported RBD prodromal to PD, whether they would have wanted to know about their risk for PD at the stage of stand‐alone iRBD, revealed a majority regarding earlier information as a considerable emotional burden attributed to the lack of specific preventive treatments. Of course, this impression cannot be generalized. A comparative study in two independent, racially and culturally different PD populations and caregivers from Asia and America showed distinctly different attitudes toward the possibilities of genetic testing in PD.16 The American cohort saw more potential medical benefit and more potential compromise for health and life insurance issues than the Asian cohort. Of note, these findings relate to patients with clinically manifest PD in various stages of the disease. However, they suggest that cultural background, knowledge, access to medical care and information, religious beliefs, and ethno‐social preconceptions of the disease may influence the degree of disclosure that iRBD patients around the world will be able to accept and integrate into their daily lives. Implications for health and life insurance, pension plans, and legal issues may also differ from country to country. The structured assessment of attitudes toward disclosure of a possibly impending neurodegenerative disease among attendees of sleep clinics would assist the development of counseling guidelines.

In conclusion, I propose a stratified approach: (1) Patients with an incidental finding of RBD should be reevaluated after treatment of their primary sleep condition before iBRD diagnosis is established. Disclosure of an upcoming neurodegenerative disease is not recommended at this stage. (2) iRBD patients are informed that the condition may eventually evolve into a neurodegenerative disease. Assessment of MDS research criteria for prodromal PD15 by a movement disorder specialist and a program of follow‐up visits are offered. (3) Disclosure of impending neurodegenerative disease is adapted to the estimated individual conversion risk. This approach offers the possibility for patient referral to disease‐modifying clinical trials at a premotor stage of PD.

Disclosures

Ethical Compliance Statement

The author confirms that the approval of an institutional review board was not required for this work. The author has read the Journal's position on issues involved in ethical publication and affirms that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The author reports no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months

During the past 12 months, Friederike Sixel‐Döring has received honoraria for lectures and consultancy from UCB and STADA Pharm. She has served on an advisory board for STADA Pharm.