IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease

A 49-year-old man developed cold intolerance as an isolated symptom 2 years prior to presentation. At age 48, he developed jerks in the trunk and lower limbs during the day and tapping movements in the arms during sleep. After 6 months, sleep disturbance worsened with talking and gesticulations, culminating in sleeping 1-3 hours per night with associated daytime somnolence. He developed mild slurred speech, hypersalivation, and dysphagia. He reported poor memory but was able to continue driving and working. He had been diagnosed with obstructive sleep apnea 4 years prior. On examination, the patient was alert with mildly impaired cognition (Addenbrooke Cognitive Examination-III 87/100). Vertical and horizontal saccades were hypometric but of normal velocity. At rest, he had subtle, continuous, low-amplitude regular contractions of the mentalis, tongue, and frontalis. Rhythmic palatal movements at a frequency of; 1 Hz were also present (video). Intermittent, isolated, truncal flexion movements at the hip occurring every 2-4 seconds were observed with the patient lying, sitting, or standing. Brain MRI was normal. 18-FDG PET scan showed striatal and brainstem hypermetabolism (figure). CSF and serum antineuronal antibodies (anti-GAD, Ma1/Ma2, CRMP-5, amphiphysin, Yo, PCA2, Hu, Ri) and surface neuronal antibodies (NMDA, CASPR2, LGI-1, GABAB, AMPA1, AMPA2) were negative. IgLON5 antibodies were positive with titers 1: 3,200 in serum and 1: 100 in CSF. CSF oligoclonal bands and 14-3-3 protein and PCR for Tropheryma whippelii and syphilis were negative. Familial fatal insomnia and Huntington disease were ruled out by genetic analysis. HLA-DRB1* 10: 01 and HLA-DQB1*05: 01 were positive. A polysomnographic study revealed an apnea/hypopnea index of 2.8, 33% sleep efficiency, and a total of 30 minutes REM sleep. Stereotactic brain biopsy was arranged because of the initial suspicion of CNS Whipple disease, before the IgLON5 Ab result was available. The frontal cortex showed mild thickening of the meninges with scattered histiocytes, CD3+ T lymphocytes around blood vessels, increased CD68+ and CD163+ microglia in cortical layer 1, and mild gliosis and focal edema in layer 1, which was more marked in deeper layers (figure). The cerebellar biopsy also showed patchy edema and gliosis as well as patchy loss of Purkinje cells. Immunostaining for tau, a-synuclein, ss-amyloid, phosphorylated-TDP43, and P62 were all negative. There were no microorganisms seen and PCR for T whippelii was negative. Treatment was initiated with plasma exchange, IV immunoglobulin, and rituximab.