Case series: Immune checkpoint inhibitor-induced transverse myelitis.

Introduction: Increasing implementation of the highly efficacious immune checkpoint inhibitors (ICIs) has raised awareness of their various complications in the form of immune-related adverse events (irAEs). Transverse myelitis following ICIs is thought to be a rare but serious neurologic irAE and knowledge is limited about this distinct clinical entity. Cases: We describe four patients across three tertiary centers in Australia with ICI-induced transverse myelitis. Three patients had a diagnosis of stage III-IV melanoma treated with nivolumab and one patient had stage IV non-small cell lung cancer treated with pembrolizumab. All patients had longitudinally extensive transverse myelitis on magnetic resonance imaging (MRI) spine and clinical presentation was accompanied by inflammatory cerebrospinal fluid (CSF) findings. Half of our cohort had received spinal radiotherapy, with the areas of transverse myelitis extending beyond the level of previous radiation field. Inflammatory changes on neuroimaging did not extend to the brain parenchyma or caudal nerve roots, except for one case involving the conus medullaris. All patients received high dose glucocorticoids as first-line therapy, however the majority relapsed or had a refractory state (3/4) despite this, requiring escalation of their immunomodulation, with either induction intravenous immunoglobulin (IVIg) or plasmapheresis. Patients in our cohort who relapsed had a poorer outcome with more severe disability and reduced functional independence following resolution of their myelitis. Two patients had no progression of their malignancy and two patients had malignancy progression. Of the three patients who survived, two had resolution of their neurological symptoms and one remained symptomatic. Conclusion: We propose that prompt intensive immunomodulation is favored for patients with ICI-transverse myelitis in an attempt to reduce associated significant morbidity and mortality. Furthermore, there is a significant risk of relapse following cessation of immunomodulatory therapy. We suggest one treatment approach of IVMP and induction IVIg for all patients presenting with ICI-induced transverse myelitis based on such findings. With the increasing use of ICIs across oncology, further studies are required to explore this neurological phenomenon in greater detail to help establish management consensus guidelines.

Gamma-aminobutyric acid-B limbic encephalitis and asystolic cardiac arrest: a case report.

BACKGROUND: Gamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavioral disturbance, and may coexist with other autoantibodies. Many are paraneoplastic, most commonly associated with small cell lung cancer. Until now there have been no reports of cardiac dysrhythmias in these patients. CASE PRESENTATION: A 65-year-old Caucasian man presented with multiple seizures, dysarthria and behavioral disturbance of unclear etiology, with associated asystolic cardiac arrest. Antibody testing showed anti-Gamma-aminobutyric acid-B receptor and anti-Hu antibodies in serum and Gamma-aminobutyric acid-B receptor autoantibodies in cerebrospinal fluid. The diagnosis of small cell lung cancer was subsequently made after lung biopsy, and the patient showed improvement with chemotherapy and intravenous immunoglobulin. CONCLUSIONS: We present the case of a patient with Gamma-aminobutyric acid-B receptor limbic encephalitis associated with asystolic cardiac arrest, an association not previously described. This case illustrates how difficult it is to make the diagnosis on clinical grounds alone. We therefore propose more routine antibody testing in patients with similar symptomatology who remain undifferentiated after initial workup. We also recommend that in the acute setting, patients with Gamma-aminobutyric acid-B receptor encephalitis should receive cardiac monitoring, as further research is required to clarify its possible link with cardiac dysrhythmias.

A novel cause of chronic viral meningoencephalitis: Cache Valley virus.

OBJECTIVE: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients. METHODS: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen. RESULTS: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue. INTERPRETATION: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105-114.

The distinctive movement disorder of ovarian teratoma-associated encephalitis.

The movement disorder observed in four cases of ovarian teratoma associated encephalitis is described. The illness began with neuropsychiatric symptoms and was followed by prolonged unresponsiveness, respiratory failure, and autonomic instability. The movement disorder consisted of semirhythmic repetitive bulbar and limb movements and persisted during prolonged periods of unresponsiveness, diminishing as awareness returned. The characteristics of the movement disorder differed from recognized dyskinesias. It is suggested that interruption of forebrain corticostriatal inputs by anti-N-methyl-D-aspartate (NMDA) receptor antibodies removes tonic inhibition of brainstem pattern generators releasing primitive patterns of bulbar and limb movement. Recognition of the distinctive movements should prompt a search for an ovarian teratoma since the condition is responsive to tumor resection and immunomodulation.