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Rapidly Progressive Cognitive Decline Associated with Teprotumumab in Thyroid Eye Disease Thanh Duc Hoang ‍ ‍ ,1,2 Nguyen T Nguyen,1 Eva Chou,3 Mohamed KM Shakir1,2

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Rapidly Progressive Cognitive Decline Associated with Teprotumumab in Thyroid Eye Disease Thanh Duc Hoang ‍ ‍ ,1,2 Nguyen T Nguyen,1 Eva Chou,3 Mohamed KM Shakir1,2 Case report BMJ Case Rep: first published as 10.1136/bcr-2021-242153 on 10 May 2021. Downloaded from Rapidly progressive cognitive decline associated with teprotumumab in thyroid eye disease Thanh Duc Hoang ,1,2 Nguyen T Nguyen,1 Eva Chou,3 Mohamed KM Shakir1,2 1Endocrinology, Walter Reed SUMMARY he showed significant improvement of diplopia National Military Medical Teprotumumab (Tepezza), an insulin-lik e growth factor and proptosis after three infusions. Following the Center, Bethesda, Maryland, type 1 receptor antagonist, was approved for treatment fourth infusion, his daughter noted 6 weeks of USA of thyroid eye disease in 2020. Teprotumumab is rapidly progressive cognitive decline characterised 2Medicine, Uniformed Services administered intravenously every 3 weeks for a total by behavioural changes, confabulation, memory University of the Health Sciences deficit and delirium/delusions/mania. He became F Edward Hebert School of of eight doses. Common side effects include nausea, Medicine, Bethesda, Maryland, diarrhoea, muscle spasms, hearing impairment, unable to carry out tasks that he had performed his USA dysgeusia, headaches, dry skin, infusion reactions and entire life, especially tasks requiring motor plan- 3Ophthalmology, Walter Reed hyperglycaemia. We report here a 76- year- old man ning; he was unaware of these deficiencies. These National Military Medical with Graves- related thyroid eye disease who developed episodes initially presented as short, isolated inci- Center, Bethesda, Maryland, a rapidly progressive cognitive decline after receiving dents. However, over a 6- week period of time, USA four out of eight doses of teprotumumab (cumulative they become more persistent and protracted. He dose 4620 mg). He was admitted for workup and was admitted to the hospital for evaluation and Correspondence to teprotumumab infusions were discontinued. Intravenous teprotumumab treatment was discontinued. On Dr Thanh Duc Hoang; physical examination, vital signs were notable for tdhdthanh@ gmail. com glucocorticoids and immunoglobulin were given which showed no improvement in clinical symptoms. He a blood pressure of 143/74 mm Hg and heart rate of 95 beats/min. He was otherwise afebrile with Accepted 17 April 2021 subsequently underwent plasmapheresis with resolution of his symptoms, suggesting a teprotumumab-induced normal oxygen saturation. He was awake and alert encephalopathy. Further studies involving larger to person and place, but not to date, situation or populations and longer durations are needed. current president. He was agitated with a flat affect and monophonic, hypophonic speech. He was unable to perform serial sevens or accurately draw a clock. He was not able to provide an accurate BACKGROUND medical history. He had fluent spontaneous speech Teprotumumab (Tepezza), a fully human insulin- with intact reading, simple repetition, comprehen- like growth factor type 1 receptor (IGF- 1R)—inhib- http://casereports.bmj.com/ sion and naming without semantic or paraphasic itory monoclonal antibody (mAb), was approved errors; however, he had significant difficulty with for treatment of thyroid eye disease (TED) in 2020. complex comprehension and prolonged sentence The effect of blocking IGF- 1R activation and signal- repetition. Cranial nerves II–XII were grossly ling pathways of teprotumumab is the first treat- intact with normal deep tendon reflexes. Exam- ment shown to be beneficial in reducing proptosis ination of heart, lungs, abdomen and extremities and diplopia. Teprotumumab is administered intra- was otherwise unremarkable. A brain MRI and venously every 3 weeks for a total of eight doses magnetic resonance angiograph (MRA) (figure 1) (10 mg/kg initial dose followed by 20 mg/kg for the next seven doses). Common side effects include nausea, diarrhoea, muscle spasms, hearing impair- on September 24, 2021 by guest. Protected copyright. ment, dysgeusia, headaches, dry skin, infusion reactions, alopecia, paresthesia, weight loss and hyperglycaemia. Other reported serious effects may include optic neuropathy, Hashimoto’s encephalop- athy (HE), Escherichia infection, urinary retention and inflammatory bowel disease.1 CASE PRESENTATION © BMJ Publishing Group A- 76- year old man was diagnosed with Graves' Limited 2021. Re- use disease in 2018. He was euthyroid on methimazole permitted under CC BY- NC. No 2.5 mg every other day. His TED manifestations commercial re- use. See rights and permissions. Published included diplopia, proptosis and exposure kera- by BMJ. topathy. His medical history was significant for hypertension, hyperlipidaemia and benign pros- To cite: Hoang TD, tate hyperplasia. There was no family history of Nguyen NT, Chou E, et al. BMJ Case Rep neurodegenerative processes. Before initiation of 2021;14:e242153. treatment, he lived independently, walking several doi:10.1136/bcr-2021- miles a day and captaining his own fishing boat. Figure 1 MRI/magnetic resonance angiograph showing 242153 Teprotumumab therapy was initiated for TED and amyloid angiopathy. Hoang TD, et al. BMJ Case Rep 2021;14:e242153. doi:10.1136/bcr-2021-242153 1 Case report BMJ Case Rep: first published as 10.1136/bcr-2021-242153 on 10 May 2021. Downloaded from Table 1 Thyroid antibodies levels and thyroid function tests Box 1 Human leucocyte antigen (HLA) tests, performed Before After by LabCorp Burlington DNA, Burlington, North Carolina. teprotumumab teprotumumab After Tests therapy therapy plasmapheresis HLA haplotypes TSI (0.00–0.55 IU/L) 1.04 1.06 0.35 ► HLA- A*01:01:01G TgAb (0–0.9 IU/mL) <1.0 18.4 <1.0 ► HLA- A*68:03:01G TPO (0–34 IU/mL) <6 14 <9 ► HLA- B*08:01:01G TRAb (<1.0 U/L) 1.6 1.2 <1.10 ► HLA- B*40:02:01G TSH (0.27–4.2 µIU/mL) 0.311 1.64 1.01 ► HLA- C*07:01:01G FT4 (0.93–1.7 ng/dL) 1.52 1.61 1.41 ► HLA- C*- ► DRB1*03:01:01G Total T3 (80–200 ng/dL) 104.7 93.7 86.1 ► DRB1*11:01:01G FT4, free thyroxine; T3, triiodothyronine; TgAb, thyroglobulin antibody; TPO, ► DRB3*01:01:02G thyroperoxidase antibody; TRAb, thyrotropin receptor antibody; TSH, thyrotropin; TSI, thyroid stimulating immunoglobulin. ► DRB3*02:02:01G ► DQB1*02:01:01G ► DQB1*03:01:01G showed cerebral amyloid angiopathy without intracranial arte- rial stenosis or aneurysms, cortical atrophy or nonspecific T2 signal abnormality in the subcortical white matter. Intravenous underwent five sessions of plasmapheresis with complete resolu- glucocorticoids and immunoglobulin were given which showed tion of his symptoms. no improvement in clinical symptoms. The patient subsequently INVESTIGATIONS The patient underwent an extensive testing. His cerebrospinal fluid analysis was normal except for an elevated protein of 76 mg/ Table 2 Serum autoimmune encephalopathy panel (performed by dL (ref 15–45). An electroencephalogram showed no epilepti- Mayo Clinic Laboratories) form activity. A brain MRI/MRA showed cerebral amyloid angi- Result name Result Reference value opathy without stenosis or aneurysms in the intracranial arterial Glutamic acid decarboxylase 65 antibody 0.28 nmol/L ≤0.02 vasculature or subcortical lesions (figure 1). Acetylcholine receptor Ganglionic Neuronal Ab 0.00 nmol/L ≤0.02 Thyroid function tests were normal before, during and after discontinuation of teprotumumab. However, thyroid antibody AMPA- R Ab CBA Negative Negative levels noticeably changed during treatment (table 1). Amphiphysin Ab Negative <1:240 An evaluation for autoimmune encephalopathy (table 2) and AGNA-1 Negative <1:240 human leucocyte antigen (HLA) genetic testing (box 1) were also ANNA-1 Negative <1:240 http://casereports.bmj.com/ obtained. ANNA-2 Negative <1:240 Other labs, including interleukin-2, interleukin-6, erythrocyte ANNA-3 Negative <1:240 sedimentation rate, C reactive protein, heavy metals, immuno- CASPR2- IgG CBA Negative Negative globulin G (IgG), immunoglobulin M, SARS-CoV -2, vitamins B , CRMP-5- IgG Negative <1:240 1 B and B , were all within normal limits. DPPX Ab IFA Negative Negative 6 12 GABA- B- R Ab CBA Negative Negative DIFFERENTIAL DIAGNOSIS GFAP IFA Negative Negative The patient presented with rapid cognitive decline and enceph- IgLON5 IFA Negative Negative alopathic symptoms of unclear aetiology. Nevertheless, the LGI1- IgG CBA Negative Negative presence of high protein level in the cerebrospinal fluid, as well on September 24, 2021 by guest. Protected copyright. mGluR1 Ab IFA Negative Negative as rapid improvement of symptoms with plasmapheresis, indi- NIF IFA Negative Negative cated a possible immunologic cause supporting the diagnosis NMDA- R Ab CBA Negative Negative of autoimmune encephalitis syndrome.2 Although this disorder N- type calcium channel Ab 0.00 nmol/L ≤0.03 is more commonly associated with antibodies to neuronal cell P/Q- type calcium channel Ab 0.00 nmol/L ≤0.02 surfaces/synaptic proteins and paraneoplastic syndromes, it has Purkinje cell cytoplasmic Ab type 1 Negative <1:240 been reported to occur in the absence of cancer. Our patient Purkinje cell cytoplasmic Ab type 2 Negative <1:240 had no known underlying malignancy. Moreover, the increase Purkinje cell cytoplasmic Ab type Tr Negative <1:240 in the levels of thyroid antibodies after teprotumumab treat- GAD65 Ab is consistent with predisposition to thyrogastric disorders, including thyroiditis, ment suggested the possibility of autoimmune activation, raising pernicious anaemia and type 1 diabetes, but has low specificity for autoimmune the possibility of autoimmune encephalitis associated with encephalopathy. GAD65 antibody values less than 2.00 nM have a lower positive predictive
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