Dipeptidyl-peptidase-like protein 6 encephalitis treated with immunotherapy

Abstract

This case describes a middle-aged man with anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis who exhibited the triad of memory loss, diarrhea, and tremor. The progression of his disease resembled neurodegenerative disease, and his first presentation at our department was 2 years after the first onset of symptoms. Antibodies against DPPX were positive in both serum and cerebrospinal fluid. No related tumor was found. The patient was initially treated with corticosteroid therapy and plasmapheresis. Despite moderate response to this treatment, corticosteroids were ceased because of adverse effects such as Cushing syndrome, deep vein thrombosis, and osteoporosis. After five cycles of treatment with rituximab, the patient experienced no further progression of neurologic symptoms and no adverse effects. The case adds to the understanding of the diagnosis, treatment, and potential prognosis of anti-DPPX encephalitis.

DPPX (dipeptidyl-peptidase-like protein 6) antibody–associated encephalitis is a rare type of autoimmune encephalitis caused by cell surface autoantigens to DPPX proteins. DPPX proteins are largely expressed in neurons of the hippocampus, striatum, cerebellum, and myenteric plexus¹ and are components of native voltage-dependent K+ (Kv) channels.^2,3 Due to the rarity of anti-DPPX encephalitis, there is no consensus on a specific therapeutic strategy. Although most patients with anti-DPPX encephalitis have been reported to respond to immunotherapy,⁴ the long-term follow-up of patients with immunotherapy is seldom reported. In this report, we present a close long-term follow-up of a patient with typical symptoms of anti-DPPX encephalitis after first- and second-line immunotherapy.

CASE PRESENTATION

In 2017, a 53-year-old man presented with a progressive cognitive deficit for 2 years, which cost him his job. He also developed tremor of hands and legs, unstable gait, and hyperekplexia. He complained about an increased need for sleep, which could be up to 36 hours at a time. Meanwhile, the patient reported a 30-kg weight loss and severe diarrhea for the past 2 years. In a detailed neuropsychological examination, the patient was oriented, with unremarkable performance on reading, mental arithmetic, and language. However, there were marked deficits in saving and recalling from memory. In the Montreal Cognitive Assessment (MoCA), the patient scored 25 out of a possible 30 points. His attention span was mildly reduced and his reaction time was slightly slowed. In addition, he was mildly depressed, lacked motivation, and lost interest. There was no abnormal finding in brain magnetic resonance imaging (MRI) and an electroencephalogram. Cells, lactate, and proteins in cerebrospinal fluid (CSF) were normal. However, antibodies against DPPX were positive in both serum (1:1000 titer) and CSF (1:10 titer). We diagnosed the patient with DPPX antibody-associated encephalitis. Since anti-DPPX encephalitis was reported to be associated with tumors, especially B-cell lymphomas,^4–6 we performed comprehensive examinations including positron emission tomography–computed tomography, but failed to find neoplasms.

Immunotherapy was immediately started. A total of 1 g per day of methylprednisolone was intravenously administered over 5 days, which was followed by a slow tapering dose of prednisone over 1 year. The DPPX titer in the CSF was reduced to 1:1 directly after the intravenous methylprednisolone pulse therapy. As illustrated in Figure 1, better performance on the MoCA (27 points) was documented at 2-month follow-up, but the patient didn’t subjectively notice any improvement in memory, and a mild depression persisted. Due to the unsatisfactory response to corticosteroid therapy, additional plasmapheresis was performed. The 8-month corticosteroid therapy with an additional plasmapheresis resulted in a significant reduction of DPPX titer to 1:100 in the serum and led to amelioration of hyperekplexia, but the patient reported a progressive short-term memory loss, a lack of motivation, and an increasing gait unsteadiness. Moreover, Cushing syndrome, signs of osteoporosis, and thrombosis of the right femoral vein were observed. Therefore, we changed the therapy to rituximab (500 mg intravenous infusion every 6 months). Given the increased risk of reactivation of chronic viral infections from rituximab therapy, before treatment initiation the patient was checked for serostatus of JC virus und vaccinations such as hepatitis B and varicella-zoster virus. The DPPX titer rebounded to 1:1000 after discontinuation of corticosteroid treatment but decreased to 1:320 immediately after the first cycle of rituximab administration and reduced to 1:100 after five cycles of rituximab. The latest MoCA was 25 points, the same as his cognitive baseline in 2017. Currently the patient works in a sheltered workshop for 32.5 hours per week and receives a rituximab infusion every 6 months. To date, no side effects from rituximab have been observed.

Figure 1.

Overview of the change of DPPX titers and Montreal Cognitive Assessment (MoCA) score during treatment. The x axis demonstrates months of follow-up after the first presentation in August 2017. The left y axis shows the DPPX titer in serum, while the right y axis presents the MoCA points.

DISCUSSION

This report demonstrates the impact of both first-line and second-line immunotherapy on anti-DPPX encephalitis over a long period of time. The triad of prodromal weight loss or gastrointestinal symptoms, altered cognitive function, and CNS hyperexcitability in our patient has been reported to be typical of anti-DPPX encephalitis.⁴ The most frequent diagnostic criteria of encephalitis rely on rapid progression, neuroimaging findings suggesting inflammation, electroencephalogram alteration, and CSF pleocytosis.⁷ However, different from other autoimmune encephalitis, anti-DPPX encephalitis can follow a more chronic course, mimicking neurodegenerative diseases. Moreover, the absence of CSF pleocytosis as well as the lack of signal changes in brain MRI and electroencephalogram suggest that CNS inflammatory abnormalities are not essential for anti-DPPX encephalitis, and confirm the proposal that evidence of CNS inflammation should not be the criterion of autoimmune encephalitis.^7,8

The treatment strategy for autoimmune encephalitis is a stepwise escalation of immunotherapy. First-line therapy involves corticosteroids, intravenous immunoglobulins, and plasma exchange. Corticosteroids broadly inhibit the inflammatory process. A couple of patients were reported to nearly completely recover within months to years after corticosteroid therapy.^4,9 Rituximab is one of the most commonly used second-line agents in autoimmune encephalitis.¹⁰ It appears to be effective in multiple autoimmune encephalitis, including DPPX encephalitis.^11,12 However, in our case, responses to both corticosteroid therapy and rituximab were unsatisfactory. The relatively late treatment could be a reason. The patient came to us 2 years after symptoms began, but the average time to disease peak is reported to be 8 months after onset.⁴ Moreover, the patient was switched to rituximab rather late, after 8 months of corticosteroid treatment with one plasma exchange. Although rituximab can deplete B cells peripherally, which is a major contributor to autoimmune disease, it cannot permeate the blood-brain barrier.¹²