RBD has been associated with several etiologies, including medications, autoimmune/limbic encephalitis, narcolepsy, structural lesions in the brainstem, and neurodegenerative disease [1
]. The few cases which have been studied with magnetic resonance imaging (MRI) have shown lesions in the dorsal pons [10
], yet the specific neuronal networks involved in human RBD pathogenesis have not been identified with certainty. Although ubiquitin and α-synuclein immunocytochemistry were not used in the case reported by Uchiyama et al. [4
], and the consensus criteria for the clinical and pathologic diagnoses of dementia with Lewy bodies (DLB) and LBD had not yet been published, the distribution of LBs suggests that their case would now be classified as brainstem-predominant LBD [6
]. Due to the severe neuronal loss and gliosis in the SN and LC in their case, the authors postulated that degeneration of brainstem monoaminergic neurons explained RBD [4
]. Additional cases of idiopathic RBD with neuropathologic examination are needed to confirm or refute this hypothesis.
Our patient had classic clinical and PSG features of RBD. Although he was not evaluated by a neurologist at any time after the diagnosis of RBD was made, he was seen by numerous physicians over his last year of life, and no neurologic symptoms or signs were apparent. Hence, our case is best characterized clinically as “idiopathic RBD.”
Histopathologic analysis in our case showed LBs and LNs, yet no significant neuronal loss or gliosis in the SN, LC, and RN. LBs, LNs, and degenerative changes were also present in the GCRF. Since symptomatology in LBD reflects neuronal loss more so than the presence of LBs and LNs [12
], the findings in this case argue against RBD reflecting degeneration in the SN, LC, and RN.
Although our patient did not have his tissue processed in a manner so that detailed neuronal quantification could be carried out, the fact that no significant degeneration was evident in the SN and LC calls into question the role of these nuclei in RBD, at least in our case. The pedunculopontine nucleus (PPN) and laterodorsal tegmental nucleus (LDTN) could be involved, but the minimal degenerative changes in the rostral pons in our case, and the increased cholinergic mesopontine neurons in the case reported by Schenck et al. [13
], argue against marked degeneration of the PPN and LDTN being central to RBD. But what other nuclei could be involved? To date, no detailed neuronal counts have been carried out on the GCRF – the most caudal nucleus that exerts inhibitory influences on the alpha-motor neurons in the spinal cord. LBs, LNs, and neuronal loss were present in the GCRF in our case, but the large size and poorly defined borders of the GCRF makes quantification of neuronal loss challenging. Studies in the cat implicate the ventral part of the oral pontine reticular nucleus (vRPO) being critical to REM sleep [14
]; this nucleus has not been studied in detail in humans. Very recently, lesions to the sublaterodorsal (SLD) nucleus (analogous to the subcoeruleus/peri-coeruleus region in cats) were found to cause disinhibition of spinal motoneurons, resulting in increased EMG tone during REM sleep [15
]. The SLD or homologous nucleus has not been examined rigorously in humans, but certainly this nucleus warrants further study. Clearly, further work in brainstem neuron quantification is necessary in RBD patients, yet one hindrance in deciphering RBD pathogenesis in patients with parkinsonism and/or dementia is that multiple neuronal systems degenerate, making it difficult to know which systems are truly central to the disorder. Analyses in patients with idiopathic RBD may be most enlightening, as the degenerative changes may be more mild and selective, and thus more revealing.