case report

Human Herpesvirus-7 Encephalitis Following Treatment with Obinutuzumab-CHOP in a Patient with Non-Hodgkin Follicular Lymphoma: A Case Report

Christina Apostolopoulou1, Periklis G. Foukas2, Matilda Papathanasiou3, Chryssa Arvaniti4, Georgios Velonakis3, Constantinos C. Loucari1, Niki Nana4, Konstantinos Gkontopoulos1, Anthi Bouchla1, Thomas Thomopoulos1, Efstathios Boviatsis5, Anastasia Antoniadou6, George Tsivgoulis4, Ioannis G. Panayiotides2, Vasiliki Pappa1, Sotirios G. Papageorgiou1*

1 Second Department of Internal Medicine and Research Unit, Hematology Unit, National and Kapodistrian University of Athens, "Attikon" University General Hospital, Athens, Greece

2 Second Department of Pathology, National and Kapodistrian University of Athens, "Attikon" University General Hospital, Athens, Greece

3 Second Radiology Department, National and Kapodistrian University of Athens, "Attikon" University General Hospital, Athens, Greece

4 Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece

5 Second Department of Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University, Athens Medical School, Athens, Greece

6 Fourth Department of Internal Medicine, University General Hospital "ATTIKO," National and Kapodistrian University of Athens, Medical School, Athens, Greece

*Correspondence author: Sotirios G. Papageorgiou , Consultant Hematologist, Second Department of Internal Medicine and Research Unit , Hematology Unit , National and Kapodistrian University of Athens, "Attikon" University General Hospital, 1 Rimini St., Haidari , 12462 Athens, Greece

Received Date: 15 September 2022

Accepted Date: 19 September 2022

Published Date: 21 September 2022

Citation : Apostolopoulou C, Foukas PG, Papathanasiou M, Arvaniti C, Velonakis G, et al. (2022) Human Herpesvirus-7 Encephalitis Following Treatment with Obinutuzumab-CHOP in a Patient with Non-Hodgkin Follicular Lymphoma: A Case Report. Ann Case Report 7: 953. DOI: https://doi.org/10.29011/2574-7754.100953

Abstract

Human herpesvirus-7 (HHV-7) is a lymphotropic virus that belongs to the Betaherpesviridae subfamily. Along with febrile disease and cutaneous manifestations, it can also cause neurological complications, including encephalitis, mostly in immunocompromised patients. The anti-CD20 monoclonal antibody, Obinutuzumab is increasingly used, in combination with chemotherapy, for the treatment of patients with chronic lymphocytic leukemia and follicular lymphoma (FL). We report a case of HHV-7 encephalitis in a young female patient with FL after receiving Obinutuzumab-based immunochemotherapy. Although it is quite rare in the clinical practice, physicians should be aware of the possibility of HHV-7 encephalitis in those who have received anti-CD20 monoclonal antibodies and develop signs of neurological deterioration.

Keywords: Anti-CD20 monoclonal antibody; Encephalitis; Follicular lymphoma; Immunochemotherapy; Human herpesvirus-7; HHV-7; Obinotuzumab

Introduction

Human herpesvirus-7 (HHV-7) is a lymphotropic virus that belongs along with HHV-6 and Cytomegalovirus (CMV) to the Betaherpesviridae subfamily [1,2]. Primary infection, in the majority of people, occurs in childhood, causing febrile disease with usually cutaneous manifestations (exanthem subitum) and is followed by a lifelong latent state [1,3,4]. Neurological complications of HHV-7 infection, including encephalitis, might occur, mainly in children as a primary infection or in immunocompromised hosts after reactivation [1-3,5,6]. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody, which induces direct cell death and has better antibody-dependent cellular cytotoxicity than rituximab. Obinutuzumab has been approved, in combination with chemotherapy, for the treatment of patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). However, the use of anti-CD20 monoclonal antibodies is accompanied by severe hypogammaglobulinemia and the development of opportunistic infections.

Despite several cases of roseolavirus-associated encephalitis occurring after combined immunochemotherapy (ICM), our patient with FL is, to the best of our knowledge, the first reported case who developed HHV-7 encephalitis after receiving obinutuzumab-based treatment.

Case Report

A 37-year-old woman was diagnosed in October 2018 with Follicular Lymphoma (FL) grade 1-2, Ann Arbor clinical stage IIIA and Follicular Lymphoma International Prognostic Index (FLIPI) score 3. After initial “watch and wait” strategy, the patient presented clinical and radiological progression and was treated with ICM with Obinutuzumab-CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Methylprednisolone) in September 2020.

Immediately after the 4th cycle of ICM, the patient reported transient episodes of horizontal diplopia although ophthalmologic examination was normal. After the 5th cycle of ICM and the reappearance of the symptoms she underwent magnetic resonance imaging (MRI) of the brain which revealed periventricular white matter increased signal on T2 weighted images in the frontal lobes bilaterally, with involvement of the genu of corpus callosum, interior right capsule, cerebral right peduncle, midbrain, cerebellar peduncles and the medulla oblongata (Figure 1A-C). Neurological examination and the electroencephalography (EEG) were unremarkable.

Laboratory workup was within normal range (except for mild anemia, Hb 10.6 mg/dl), as were thiamine levels, thereby excluding Wernicke encephalopathy. We performed cerebrospinal fluid (CSF) analysis (Table 1) which revealed only a slightly elevated total protein, with negative polymerase chain reaction (PCR) based tests (film array panel as performed in our institution including Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, CMV, Enterovirus, Herpes simplex virus 1 and 2, HHV6, Varicella zoster virus, Cryptococcus neoformans/gatti). CSF culture did not show any growth of bacteria, mycobacteria, or fungi and a cytological examination did not show any malignant cells. Moreover, there was a negative PCR test for JC virus. At that point, CSF was not tested for HHV-7. A serological test for human immunodeficiency virus (HIV) was negative. Similarly, serological tests for autoantibodies including rheumatoid factor and antinuclear antibodies, were all negative, as was myasthenia antibodies testing (anti–acetylcholine receptor- AChR, Muscle specific tyrosine kinase- MuSK, anti-titin). Repetitive nerve stimulation testing was negative for neurological function disorder.

In less than 2 weeks, the patient deteriorated regarding cognitive, visual and memory function, also showing transient amnesia and instability. The laboratory work-up revealed mild hyponatremia (127 mEq/L, normal range: 236-146 mmol/L) and on physical examination the patient had bradycardia. Following hospital admission, she presented an episode of aphasia followed by mild hyperthermia. The patient was treated with dexamethasone (24 g/day), ceftriaxone (2 g/day, 7 days), acyclovir (1,500 mg/day), amphotericin-B (350mg/day), vancomycin (2 g/day) and ampicillin (12 g/day) as a probable CNS infection.

A new MRI was performed which revealed extensive leukoencephalopathy sparing the subcortical U fibers, involving the cerebral white matter frontally, now extending into the temporal lobes, including the anterior commissure and extending into the body and splenium of corpus callosum which appeared enlarged, the corticospinal tracts including internal capsule, cerebral peduncles, midbrain, superior cerebellar peduncles, left middle cerebellar peduncle and left side of the medulla. There was moderate diffusion restriction in the corpus callosum (Figure 1D). No hemorrhage or contrast enhancement were seen. The differential diagnosis included toxic leukoencephalopathy, possible relapse of lymphoma and were not typical of PML. A second spinal tap was performed and the CSF analysis (Table 1) revealed pleocytosis with predominance of lymphocytes (94%), high protein levels, normal glucose, and normal LDH. CSF culture, cytological and PCR based tests including JC virus were all-negative, except for the HHV-7 DNA test which came out positive. Antibiotic treatment was stopped and the antiviral treatment was changed to foscarnet 3g three times per day (60 mg/kg every 8h) for 21 days with gradual tapering of dexamethasone.

New MRI and Magnetic Resonance Spectroscopy (MRS) were performed 15 days after the previous MRI. Conventional sequences revealed lesions expansion (Figure 1E-F) mainly in the external capsule bilaterally, subcortical white matter, cingulate, medial bilateral thalami, midbrain, pons, vermis and right cerebellar hemisphere. New finding was the appearance of contrast enhancement with areas of linear and nodular appearance (Figure 1G-H). MRS showed increased Choline (Cho) / Creatine (Cr) and Choline / N-Acetylaspartic acid (NAA) ratios, which were calculated 2.40 and 2.54 respectively (Figure 1I). However, these abnormalities were attributed to the low concentrations of Cr and NAA, given the constant concentrations of Cho and the reduction of Cr and NAA compared with the normal appearing brain parenchyma. There were no significant differences of relative cerebral blood volume and relative cerebral blood flow in MR perfusion. Imaging findings were suggestive of an inflammatory process, including a high possibility of immune reconstitution inflammatory syndrome (IRIS) associated with PML or another inflammatory process. Based on imaging findings, lymphoma relapse was considered less likely, however it could not be excluded. Due to the uncertainty of the diagnosis and the need to definitely exclude disease relapse in the CNS, the patient underwent a stereotactic brain biopsy. Microscopically, brain tissue showed a mainly perivascular lymphocytic inflammatory infiltrate, composed of CD3+ T cells and CD68+ histiocytes, whereas PAX5+CD20- B cells were very rare (Figure 2). These findings were considered compatible with the diagnosis of encephalitis. Repeated CSF tests confirmed the positive HHV-7 DNA result. Unfortunately, our laboratory could not perform a quantitative analysis of the HHV-7 DNA in the CSF neither HHV-7 serology, and a PCR test performed in a blood sample was negative for HHV-7 DNA. The patient showed total remission of symptoms and follow-up brain MRI after 3 weeks and after 3 months showed significant improvement of the lesions of the leukoencephalopathy (Figure 1J-K). CSF tests for HHV-7 DNA continued to produce positive results throughout the follow-up period. Neurological examination after 9 months of follow-up did not reveal any residual disability or signs of neurologic disorder.

CSF analysis

(Normal values)

Day -32

Day -20

Day 0

Day 6

Day 22

Color

Clear

Clear

Clear

Clear

Clear

Leukocyte count

(0-5/mm3)

0

2

30

0

5

Total Protein

(15-45 mg/dL)

57.3

61

77

41

38.2

Albumin

(mg/dL)

42

47.5

48

22

21.9

Glucose

(45-80 mg/dL)

52

54

77

78

63

LDH

(U/L)

15

24

17

16

12

Gram stain

(Negative)

Negative

Negative

Negative

NA

NA

Culture

(Sterile)

Sterile

Sterile

Sterile

NA

NA

Film array

+JC Virus

Negative

Negative

Negative

Negative

NA

West Nile

NA

NA

Negative

NA

NA

HHV-7

NA

NA

Positive

Positive

Positive

 

Table 1: CSF analysis of patient. Therapy was initiated on the day of the diagnosis (Day 0) (CSF: cerebrospinal fluid, NA: not applicable)

 

Figure 1: Serial MRI of HSV-7 encephalitis following Obinutuzumab-CHOP treatment.

Axial (A) and sagittal (B) FLAIR images demonstrate increased signal intensity in the frontal white matter bilaterally, corpus callosum (arrows A, B) anterior longitudinal ligament, midbrain (thick arrow B) and medulla oblongata. Axial T1 image (C) reveals hyperintensities in the basal ganglia (arrow C). Mild restriction is noticed on diffusion weighted imaging (DWI), mainly in the corpus callosum (arrow D). Lesions expansion is noticed 15 days later on axial FLAIR images (E, F) in the frontal subcortical white matter (arrow E), basal ganglia and midbrain (arrow F). Axial T1 images post contrast administration (G, H) reveal nodular (thin arrows G, H) and linear (thick arrow G) enhancement. Increased ratios of Choline (Cho) on MR spectroscopy (I) were attributed to the reduced concentrations of Creatine (Cr) and N-Acetylaspartic acid (NAA) compared with normal parenchyma. Follow up axial (J) and sagittal (K) FLAIR images demonstrate resolution of the abnormal signal.