Agrypnia Excitata and Supranuclear Vertical Gaze Palsy Linked to Anti‐Ma Encephalitis

Paraneoplastic neurological syndromes result from cancer's immune impact on the nervous system.1 Anti-Ma-associated encephalitis causes diencephalic, brainstem, and limbic symptoms such as memory loss, narcolepsy and rapid eye movement (REM) behavior disorder (RBD), eye movement abnormalities, and parkinsonism.2 It can precede cancer diagnosis, often linked to testicular tumors.3 Agrypnia excitata (AE) is a unique electroclinical syndrome that can disrupt sleep structure with changes in physiological cyclic organization, autonomic overactivity, and oneiric stupor episodes.4 We report on a patient with anti-Ma encephalitis who exhibits a diencephalic syndrome and AE, not previously reported to our knowledge. We present the case of a 53-year-old man who sought medical attention because of sudden onset hypersomnia, sleep talk, brief involuntary movements during sleep, and cataplexy. He had a history of obstructive sleep apnea (OSA) and a periodic limb movement disorder. At that moment, the neurological examination was normal. Neurophysiological assessment showed REM sleep without atonia, and a mean sleep latency of 1 minute during the multiple sleep latency test, with sleep onset REM periods observed in 3 of 4 naps. Cerebrospinal fluid (CSF) hypocretin-1 levels were 12, 42 pg/mL (normal >110 pg/mL), supporting the diagnosis of narcolepsy type 1 (NT1), notwithstanding, HLA DQB1*06:02 was negative. Treatment with modafinil and venlafaxine provided subtle improvement. Cataplexy affected primarily the face and triggered by emotional stress, emerged 1 year after the initial symptoms. Three months later, the cataplexy worsened, affecting the neck, limbs, and leading to frequent falls, so sodium oxybate was added without improvement. The initial brain magnetic resonance imaging (MRI) was unremarkable. Neuronal antibodies were assessed in the initial CSF and blood samples, and the results came back negative. Additionally, the serum/CSF immunoglobulin G (IgG) index was 0.53. Over time, 3 years later, the patient's symptoms worsened, including hypersomnia, abnormal sleep behavior, brief jerks during wakefulness, memory difficulties, unsteady gait with frequent falls, visual hallucinations, and daily complex behaviors. Even for his wife, distinguishing between sleep and wakefulness while he was sitting or lying down was challenging. Neurological examination revealed inattention, disorientation, bilateral vertical supranuclear gaze palsy (Video 1), loss of postural stability, and bradykinesia. Executive impairment and anosognosia were observed in the cognitive assessment. A new video-polysomnography (v-PSG) with auto continuous positive airway pressure (CPAP) revealed a disorganized sleep structure lacking physiological cyclic organization (Fig. 1), absence of slow-wave sleep, autonomic overstimulation as evidenced by the increase in heart rate, and episodes of oneiric stupor consistent with AE, with a total sleep time of 2 hours of 9 of the v-PSG (Video 1). The patient displayed intense dream enactment with blurred sleep–wake differentiation, and intermittent motor hyperactivity was evident in the electromyogram tone throughout the v-PSG. The behavior during the REM phase mimicked that of a dream, but the patient was unable to distinguish whether he was awake or asleep (Video 1). The ongoing presence of severe OSA was linked to excessive motor activity leading to improper mask placement, resulting in the ineffectiveness of CPAP therapy. Additionally, significant leaks were observed during the v-PSG. A new brain MRI revealed hyperintensities in the central area of the pons, suggestive of an inflammatory process. CSF analysis revealed 7 cells/uL, protein 49.9 mg/dL, and glucose 73 mg/dL, and CSF proteinogram showed an increase of α, β, γ globulins, τ, and intrathecal IgG synthesis. Anti-Ma antibodies were detected in both CSF and serum, confirmed with a cell-based assay, no other antibodies such as anti-leucine-rich-glioma-inactivated 1 (anti-LGI1), anti-contactin-associated protein-like 2 (anti-CASPR2), anti-N-methyl-d-aspartate (anti-NMDA), or anti-IgLON family member 5 (anti-IgLON5) were detected. Brain 18F-fluro-deoxyglucose positron emission tomography (18F-FDG-PET) showed hypometabolism areas in the dorsolateral and ventromedial frontal cortex, bitemporal with left-side predominance, and caudate nuclei with hypermetabolism in the bilateral motor cortex. In addition, the search for an underlying cancer was negative, with a whole-body 18F-FDG-PET and testicular ultrasound both normal. The patient was treated with high-dose pulse intravenous steroids and immunoglobulins (IVIG), but experienced only subtle improvement. Three months later received a second IVIG course without improvement; therefore, treatment with cyclophosphamide was suggested. A follow-up brain MRI and body 18F-FDG-PET 6 months later did not show changes, and v-PSG did not report any improvement (Table 1). Currently, a whole-body FDG-PET scan and a testicular ultrasound are scheduled every 6 months given the high cancer risk associated with anti-Ma encephalitis. We report a case of anti-Ma encephalitis, which started as an atypical NT1 with RBD that was later associated with supranuclear vertical gaze palsy and AE. This progression from a NT1 with a negative HLA DQB1*06:02 into an anti-Ma encephalitis over 3 years has not been documented formerly. Previous studies have established AE as a primary characteristic associated with anti-LGI1 encephalitis.4 Furthermore, it has been hypothesized that episodes of status dissociatus may be related to anti-NMDA encephalitis.5 Classical status dissociatus, named AE, is characterized by profound insomnia, oneiric stupor (involving hallucinations and enacted dreams with movements that mimic daily life activities), dysautonomia (fever, excessive sweating, rapid heart rate, fast breathing, and high blood pressure), and motor restlessness.6, 7 It occurs as a result of thalamolimbic GABAergic dysfunction, which releases hypothalamus and brainstem from corticolimbic control.5 Dalmau et al,2 described that patients with paraneoplastic syndromes with anti-Ma antibodies exhibited memory deficit in up to 63% of cases, vertical supranuclear gaze palsy in up to 34%, hypersomnia in up to 32%, diplopia and dysarthria up to 26%, unsteady gait or ataxia up to 18%, parkinsonism up to 11%, and low hypocretin levels in CSF with narcolepsy in 11% cases.2 RBD has been described in several cases, but the association with narcolepsy is more clearly established, up to 36%.8 Testicular tumors are commonly associated with anti-Ma2 encephalitis in young men, other neoplasms such as lung, pleural, and gastrointestinal tumors have also been reported. In some cases, no underlying cancer is found. Nevertheless, these antibodies are regarded as high-risk, and it is advisable to maintain close monitoring and follow-up9. Treatment with immunotherapy has shown slight clinical improvement in previous cases of anti-Ma2 encephalitis, similar to our patient's response.3 Currently, sleep–wake disorders are increasingly gaining recognition in the context of autoimmune neurological conditions associated with LGI1, CASPR2, and IgLON5 antibodies, which can lead to the presentation of AE.7 Notably, these disorders can precede the neurological manifestations, which offer a window for earlier recognition and treatment.10 In conclusion, this case underscores the significance of thoroughly investigating autoimmune origins when presented with patients exhibiting sleep disorders, emphasizing the critical role of sleep disturbances characterization. Within the realm of clinical practice, autoimmune disorders are emerging as increasingly prevalent contributors to rare electroclinical conditions such as AE. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. C.E.V: 1A, 1B, 1C, 3A. J.G.P.L: 3B. A.P.A: 3B. A.H.M: 1C, 3B. M.C.I: 3B. J.A: 3B. I.A.O: 1A, 1B, 1C, 3A, 3B. E.U: 1A, 1B, 1C, 3A, 3B. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent was taken from the patient. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: IAO have received speaking honoraria from Boston Scientific and Medtronic, along with travel and congress meeting support from Bial. CEV has received congress meeting support form Esteve and UCB. JA has received speaking honoraria and travel fee from Advanced Accelerator Application-Novartis, General Electric Healthcare, Life Molecular Imaging, Lilly and Siemens. There are no additional disclosures to report.