Novel treatment of recurrent orbital venolymphatic malformation with sirolimus and rivaroxaban.

Orbital venolymphatic malformations are rare vascular malformations that typically appear early in life and harbor acute and chronic threats to vision. Historically, there are four categories of management: observation, medication, sclerotherapy, and surgery. Currently, there is neither a gold standard for treatment nor randomized control trials comparing treatments.The authors present a 20-year-old male who presented with spontaneous hemorrhage of an orbital venolymphatic malformation occurring with increased frequency and involving more of the posterior orbit. Surgery and sclerotherapy were not feasible options due to the extensive intraorbital and intracranial involvement of the venolymphatic malformation. Systemic steroids treated symptoms but was not curative. To this end, a combination of sirolimus, an mTOR inhibitor, and rivaroxaban, a factor Xa inhibitor, were used to reduce the size of the lesion and minimize the risk of thromboembolic events. This treatment has successfully kept the patient's symptoms in remission for greater than 2 years.

Rapidly Progressive Cognitive Decline and Varicella Zoster Blisters Associated With Teprotumumab in 2 Patients With Graves’ Orbitopathy

Introduction: Teprotumumab, an IGF-1R antagonist, was approved for treatment of Graves’ orbitopathy (GO) in 2020. Common side effects include nausea, diarrhea, muscle spasms, hearing impairment, dysgeusia, headache, dry skin, infusion reactions, and hyperglycemia. We report here 2 cases of unexpected adverse effects. Patient #1 is a 76-year-old man with Graves’ disease diagnosed in 2018, treated with methimazole 2.5mg every other day. His GO manifestations included diplopia, proptosis, and exposure keratopathy. Past history was significant for hypertension, hyperlipidemia, and prostate hyperplasia. He lived independently and walked several miles daily. Teprotumumab was initiated. Between the 4th and 5th doses, his family noted 6-weeks of rapidly progressive cognitive decline characterized by behavioral changes, confabulation, memory deficit, delirium/delusions/mania. He was admitted to neurology service and subsequent doses held. Lumbar puncture was unremarkable. TFT was normal before, during and after stopping teprotumumab. Thyroid antibodies were notable for elevated TSI but normal thyrotropin receptor Ab and TPO/TgAb. Other labs: IL2, IL6, ESR, CRP, heavy metals, IgG, IgM, SARS-CoV-2 IgM/IgGs, vitamins B1, B6, and B12 were all normal. His most recent repeat TPO Ab was 14 IU/mL (increased from <6), TgAb 18.4 IU/mL (increased from <1.0). EEG showed no epileptiform activity. Head MRI/MRA showed cerebral amyloid angiopathy without stenosis or aneurysms in the intracranial arterial vasculature. Symptoms progressed with IV glucocorticoids and IV Ig therapy. He subsequently underwent plasmapheresis with resolution of symptoms. Patient #2 is a 48-year-old man with Graves’ disease and GO diagnosed in 2018, initially treated with methimazole and subsequently underwent total thyroidectomy in 2019. Patient is euthyroid on levothyroxine. Ophthalmic signs and symptoms included significant proptosis and retrobulbar pain. He was started on teprotumumab infusions. After his 4th dose, he noted painful vesicles in a dermatomal distribution on his right posterior thigh. Direct fluorescent antibody stain was positive for varicella zoster, and rashes resolved with valacyclovir therapy. Discussion: Paraneoplastic/autoimmune encephalitis syndromes can be associated with antibodies to neuronal cell surfaces/synaptic proteins and may occur in the presence or absence of cancer. The incidence of varicella-zoster virus infection is associated with the immune status of the patient, disease-related immunocompromised, or iatrogenic immunosuppression, with age being the major risk factor for 90% of adult cases. This could be incidental, or related to other disorders, or perhaps teprotumumab may have activated auto-immunity. The exact mechanisms for rapidly progressive cognitive decline and shingles remains unclear.

Rapidly progressive cognitive decline associated with teprotumumab in thyroid eye disease.

Teprotumumab (Tepezza), an insulin-like growth factor type 1 receptor antagonist, was approved for treatment of thyroid eye disease in 2020. Teprotumumab is administered intravenously every 3 weeks for a total of eight doses. Common side effects include nausea, diarrhoea, muscle spasms, hearing impairment, dysgeusia, headaches, dry skin, infusion reactions and hyperglycaemia. We report here a 76-year-old man with Graves-related thyroid eye disease who developed a rapidly progressive cognitive decline after receiving four out of eight doses of teprotumumab (cumulative dose 4620 mg). He was admitted for workup and teprotumumab infusions were discontinued. Intravenous glucocorticoids and immunoglobulin were given which showed no improvement in clinical symptoms. He subsequently underwent plasmapheresis with resolution of his symptoms, suggesting a teprotumumab-induced encephalopathy. Further studies involving larger populations and longer durations are needed.