Ofatumumab and enteroviral encephalitis: a severe infectious complication as a class effect with anti-CD20 therapies

Abstract

Background:

Enteroviral encephalitis is a rare but potentially devastating infectious complication described under the anti-CD20 therapies rituximab and ocrelizumab.

Case:

A 37-year-old woman with multiple sclerosis (MS) on treatment with ofatumumab developed fever, confusion, seizures, and decreased level of consciousness. Magnetic resonance imaging (MRI) revealed bilateral, non-enhancing thalamic T2 hyperintensities, and cerebrospinal fluid showed pleocytosis with positive polymerase chain reaction (PCR) for enterovirus. The patient was treated with intravenous immunoglobulin and supportive care, and then pocapavir was given for ongoing neurologic deficits. She recovered over 6 weeks but continued to demonstrate neuropsychiatric symptoms.

Conclusion:

Enteroviral encephalitis is associated with anti-CD20 therapies for MS as a class effect including ofatumumab.

Case description

A 37-year-old woman presented with a 24-hour history of fever, confusion, and new-onset seizures and was intubated due to decreased level of consciousness (Figure 1). She had been diagnosed with relapsing-remitting multiple sclerosis (MS) 12 years earlier and was on treatment with ofatumumab, an anti-CD20 therapy. She had minimal disability at her neurology visit 1 month prior with an Expanded Disability Status Scale (EDSS) score of 1.5. Previous therapies had included dimethyl fumarate and ocrelizumab, with a transition from ocrelizumab to ofatumumab 18 months before. She had been noted to have three to four upper respiratory viral infections annually, without hospitalization, on ofatumumab, although her serum immunoglobulin G (IgG), leukocyte, neutrophil, and lymphocyte counts had always been within normal limits. She was born in Canada and had no recent travel history.

Figure 1.

The timeline of the case presented including key findings and decisions during the patient’s admission with enteroviral encephalitis.

Magnetic resonance imaging (MRI) revealed new bilateral, thalamic T2 hyperintensities which were non-enhancing (Figure 2). Cerebrospinal fluid (CSF) studies demonstrated mixed pleocytosis (200/µL, normal <5/µL; 39% neutrophils, 35% lymphocytes), elevated protein of 0.93 g/L (normal = 0.15–0.45 g/L), and glucose of 3.3 mmol/L (serum glucose = 5.1 mmol/L). She was started on ampicillin, ceftriaxone, vancomycin, and acyclovir. Serologic testing for HIV, syphilis, toxoplasmosis, Eastern Equine Encephalitis, West Nile Virus (WNV), Powassan virus, Rickettsia, Borrelia burgdorferi, California serogroup, and autoimmune encephalitis panel was all negative. CSF testing including bacterial, mycobacterial, and fungal cultures; TB polymerase chain reaction (PCR); Powassan PCR; California serogroup; cryptococcal antigen; viral PCR (cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella zoster virus (VZV)); John Cunningham virus (JC virus); and WNV immunoglobulin M (IgM) were negative, except for CSF enteroviral RNA which was detected. She had not had any symptoms of hand, foot, and mouth disease, and the respiratory panel including enteroviral PCR was negative. Acyclovir and antibiotics were discontinued after 3 and 8 days, respectively.

Figure 2.

The patient’s axial FLAIR images at the level of the thalamus before and after presentation with symptoms of encephalitis. (a) Routine multiple sclerosis monitoring scan 2 months before presentation. (b) After presentation with fever, confusion, decreased level of consciousness and seizures, bilateral T2 hyperintense lesions are seen in the thalami, which did not enhance with gadolinium. (c) Repeat imaging 5 months after presentation reveals resolution of thalamic hyperintensities.

The IgG level was unremarkable at 6.85 g/L (normal = 6.35–17.41 g/L), and IgM was mildly reduced at 0.28 g/L (normal = 0.35–2.81 g/L) at the time of admission; CD-19 cells were 0. Serum neurofilament light chain (sNfL) level was elevated at 37.20 pg/mL (normal = <1.88 pg/mL). Her level of consciousness improved, and she was extubated 1 week later but demonstrated expressive aphasia and neuropsychiatric changes, particularly disinhibition and severe anxiety.

Repeat imaging 11 days after admission showed near-resolution of the thalamic hyperintensities. However, given ongoing fevers, neurologic status, and immunosuppressed status, she was treated with intravenous immunoglobulin 1 g/kg/day for 2 days on admission days 18 and 19. We applied for off-label use of pocapavir but did not administer it initially as she began to improve neurologically. MRI brain on admission day 32 showed recurrent bithalamic diffusion-restricting signal abnormalities, and she had ongoing confusion and headaches; thus, pocapavir was initiated with 1600 mg po daily for 14 days. The patient’s speech gradually improved, and she was discharged to rehabilitation with EDSS 6.0. She had several re-admissions in the following months for behavioral and functional decompensation. Repeat CSF studies at 6 weeks and 5 months showed no pleocytosis and were negative for enteroviral PCR as well as other infectious work-up and autoimmune encephalitis antibody panel. At the last follow-up at 8 months, she demonstrated short-term memory impairment, anxiety, and shuffling gait with an EDSS of 4.5. Disease-modifying therapy was resumed with cladribine.

Discussion

Enteroviral meningoencephalitis has been reported in patients treated with rituximab and ocrelizumab,^{1 –5} two other anti-CD20 therapies used in MS, but to our knowledge never with ofatumumab. This case suggests that increased risk of enteroviral encephalitis may be a class effect related to anti-CD20 therapy, and it is important for clinicians to be aware of this rare but serious event regardless of the specific anti-CD20 agent. The clinical, imaging, and laboratory features observed in our case are similar to other reported cases on anti-CD20 therapy including the profound effects on level of consciousness and behavior, bilateral thalamic T2 hyperintensities, and CSF profile. Most but not all previous cases have been associated with low IgG levels.^{1 –3,5} While our patient had normal IgG levels, her IgM was reduced, as has been noted in another MS case. ³

Some authors have suggested that there may be a lower risk of severe infectious complications associated with the anti-CD20 therapy ofatumumab compared to ocrelizumab. ⁶ More rapid repletion of B-cells after discontinuation is a potential advantage of ofatumumab relative to ocrelizumab, with a median of 40 weeks for return of B-cells to normal levels on ofatumumab versus 72 weeks on ocrelizumab. ⁶ There was relative preservation of IgG levels in the ASCLEPIOS clinical trials and extension studies, with 98% demonstrating IgG levels above the lower limit of normal at 6 years. ⁷ Real-world data concerning infection risk with ofatumumab remain limited, although clinical trial extension data suggest that the risk of serious infection on ofatumumab is low (<2 per 100 patient-years) and stays stable over time. ⁷

Chronic cases of enteroviral infection have been noted on rituximab with positive CSF enteroviral PCR tests recurring months after the initial infection.^8,9 Our patient had a severe initial clinical presentation requiring intubation and a high sNfL level, suggesting extensive neuronal damage. She had a negative enteroviral PCR on subsequent CSF tests which may be attributable to more rapid B-cell repletion on ofatumumab compared to ocrelizumab or rituximab; however, she did experience residual neuropsychiatric deficits.

The mainstay of treatment for enteroviral meningoencephalitis remains supportive care. Case reports have described the use of immunoglobulin replacement in individuals on B-cell-depleting therapies which seems to be helpful.^1,4,5 Pocapavir is an antiviral capsid inhibitor which was studied in adults receiving monovalent oral poliovirus vaccine, and pocapavir compared to placebo accelerated viral clearance (10 vs. 13 days; p = 0.0019). ¹⁰ Pocapavir has been used off label to treat severe enteroviral infection in some neonates and immunocompromised individuals. ⁹ Potential side effects include headache, gastrointestinal (GI) symptoms, and transaminitis. While our patient had been extubated and shown some degree of improvement, we opted to use pocapavir after obtaining emergency compassionate access because of the significance of her remaining cognitive and psychiatric symptoms.

Conclusion

Anti-CD20 therapies have become widely used for the treatment of MS even in milder disease. Neurologists should be aware of severe cases of enteroviral encephalitis associated with anti-CD20 therapies including ofatumumab, ocrelizumab, and rituximab, as a class effect.