Several studies have reported common presentations accompanying immunoglobulin G (IgG)
antibodies targeting the neuronal cell adhesion protein IgLON5.
1
–
3
Complex sleep and movement disorders, gait imbalance, and bulbar symptoms are prominent
features. Here, we report an unusual manifestation of subacute onset encephalitis
with spontaneous recovery accompanying IgLON5 autoimmunity.
Case description
A 73-year-old man with a remote renal oncocytoma history, and 2 years of difficulty
with sleep initiation and maintenance, had 3 weeks of progressive gait imbalance,
constipation, worsened insomnia, and confusion, followed by 5 days of headache, subjective
chills, and fever. Initial testing revealed an elevated CSF protein level alone (103
mg/dL). Over 2 days, the patient continued to deteriorate, eventually requiring intubation
for airway protection. On transfer to Mayo Clinic, empiric antimicrobials, antiepileptics,
and dexamethasone initiated at the outside hospital were not continued. Repeat CSF
studies demonstrated an elevated protein level (194 mg/dL) and 50 nucleated white
blood cells/μL (normal ≤ 5/μL; monocyte predominant). Brain MRI revealed subtle T2
hyperintensities in the hypothalamus (figure, A and B). His neurologic status improved
briskly over days with supportive care alone. He was discharged to an acute rehabilitation
unit within 1 week and returned home thereafter. His serum and CSF from that hospitalization
both harbored IgLON5-IgG antibodies, detected by tissue-based indirect immunofluorescence
assay and confirmed by IgLON5-transfected cell-based assay.
3
Figure
Serial brain MRI of the patient with encephalitis and spontaneous recovery accompanying
IgLON5 autoimmunity
(A and B) Initial evaluation at Mayo Clinic during the subacute illness. (A) Coronal
T2/FLAIR image demonstrating hyperintensities in the hypothalamus (arrows). (B) Coronal
diffusion inversion recovery sequence demonstrating hyperintensities in the hypothalamus
(arrows). No diffusion restriction or abnormal enhancement was identified (not shown).
(C) Six-month follow-up evaluation at Mayo Clinic; coronal T2/FLAIR image demonstrating
residual hyperintensities in the hypothalamus (arrows).
At 6-month follow-up, the patient reported mild residual symptoms (fatigue and insomnia
without excessive daytime sleepiness, gait imbalance, and memory and word-finding
difficulties). He also described occasional dysphagia, hoarseness, sialorrhea, and
emotional lability, which were absent before his hospitalization. Urinary retention
present during his hospitalization had resolved within weeks of onset. There were
no reports of complex sleep behaviors or sleep breathing difficulties. His neurologic
examiation was normal. Repeat brain MRI showed residual T2 hyperintensities in the
hypothalamus (figure, C). His symptoms remained stable at 1 year. Polysomnography,
neuropsychological assessment, video swallow study, whole-body fludeoxyglucose–PET
(assessing for occult malignancy), and repeat brain MRI were recommended but declined
by the patient.
Discussion
Neurological dysfunction punctuated by an episode of subacute encephalitis, followed
by spontaneous recovery, is unusual for IgLON5 autoimmunity, which typically (but
not always) has an insidious onset and course without signs of CNS inflammation.
1
IgLON5 autoimmunity is known to be characterized by prominent disorders of sleep (parasomnias
and sleep-disordered breathing), movement (chorea, ataxia, myoclonus, dystonia, and
parkinsonism), brainstem dysfunction (gait instability, dysphagia, dysarthria, and
oculomotor abnormalities), neuropsychiatric abnormalities, and dysautonomia.
1,2,4
Other recent reports have described milder or more limited phenotypes, including isolated
dysphagia
5
and less pronounced sleep disorders.
3
Although our patient had prominent encephalitis from which he recovered, he also had
some subtle symptoms before and after the time frame of his subacute illness, supportive
of the commonly described features of IgLON5 autoimmunity. In particular, he endorsed
mild sleep, gait, bulbar/pseudobulbar, and cognitive complaints months after his encephalitic
illness, although these did not manifest as abnormalities on neurologic examination
and did not progress over 1 year of follow-up.
This patient had generic clues supportive of autoimmune encephalitis, including subacute
onset of neuropsychiatric, gastrointestinal, and urinary symptoms, CSF pleocytosis,
and subtle hypothalamic MRI abnormalities. Of note, the initial MRI findings of T2
hyperintensities in the hypothalamus in part paralleled previously reported autopsy
findings of 3-repeat and 4-repeat hyperphosphorylated tau preferentially deposited
in the hypothalamus, hippocampi, and brainstem tegmentum.
6
Based on the radiologic findings in our patient, we speculate that tau deposition
may be an end product of regional inflammation in IgLON5 autoimmunity.
Limitations of this report include the short duration of clinical follow-up and the
patient's preference not to pursue ancillary testing, including polysomnography, further
neuroimaging, and human leukocyte antigen typing, which may have elucidated additional
features. Although the lack of formal sleep evaluation is a limitation, the mild,
nonspecific features and lack of relentless progression make it unlikely that the
patient's chronic insomnia was the herald symptom of IgLON5 autoimmunity. In addition,
viral encephalitis cannot be ruled out as a cause of encephalitis, although multiple
negative PCR test results and clinical deterioration on antiviral therapy argue against
this.
We considered other reasons for encountering IgLON5 antibody in this patient. Incidental
paraneoplastic antibody testing occasionally can be ascribed to the presence or history
of cancer in patients without neurologic symptoms. However, IgLON5 antibody does not
have known paraneoplastic significance. The argument that the IgLON5 antibody is a
nonspecific “epiphenomenon” is weakened by the rarity of the finding (30 cases in
20 years in our laboratory), the consistent and unique neuropathology, and the fact
that occasional patients meaningfully improve with immunotherapy.
3,6,7
This report, among others, argues for a broadened perspective on the phenotypic scope
of IgLON5 autoimmunity, particularly early in the disease course where limited or
unusual presentations may occur.