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Abstract
We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define “definite”, “probable” and “possible” diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A “definite” diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a “probable” diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A “possible” diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1591-8) contains supplementary material, which is available to authorized users.
Highlights
An intriguing progressive neurological disorder at the crossroads of autoimmunity and neurodegeneration was recently described in eight patients affected by a previously unknown disorder characterized by non-REM sleep (NREM) parasomnias, sleep apnea, and stridor [16]
Post-mortem findings in two patients suggested a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem without evidence of inflammation [16]
The initiation and re-entering of sleep after awakening were characterized by undifferentiated non-rapid eye movement (NREM) sleep with frequent vocalizations, stereotyped movements, and finalistic behaviors
Summary
An intriguing progressive neurological disorder at the crossroads of autoimmunity and neurodegeneration was recently described in eight patients affected by a previously unknown disorder characterized by non-REM sleep (NREM) parasomnias, sleep apnea, and stridor [16]. All patients had serum and CSF antibodies, mainly of the IgG4 subclass, against IgLON5, a neuronal cell-adhesion molecule with unknown function. All patients had the same HLA-DRB1*1001 and HLA-DQB1*0501 haplotype, which is very rare in the normal population [16]. These findings suggested an autoimmune disease, the symptoms did not respond to immunotherapy. Post-mortem findings in two patients suggested a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem without evidence of inflammation [16]. Eight additional cases have been identified (four of them reported) based on the combined recognition of the characteristic sleep disorder, presence of IgLON5 autoantibodies and, when available, demonstration of the same haplotypes described above [2, 7, 14, 17]
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