Abstract
Rituximab and other B cell depleting agents are increasingly used for haematological, immunological and neurological diseases. In a small minority, immunosuppression leads to increased virulence of normally mild infections. Brainstem encephalitis has been described occurring after infection from enteroviruses, more commonly in the paediatric population, but also in immunosuppressed adults. In this paper, we describe an enteroviral brainstem encephalitis in a rituximab-immunosuppressed patient. The enterovirus identified was Coxsackie A16, which has never yet been reported to cause brainstem encephalitis in an adult.
Keywords: infection (neurology), brain stem/cerebellum, neuro Itu, haematology (incl blood transfusion)
Background
The Enterovirus genus, within the family Picornaviridae, comprises common endemic viruses such as Coxsackie viruses, echoviruses and other enteroviruses. While enteroviruses are common in the human population, they rarely result in serious infections. Most human infections are asymptomatic or lead to non-specific febrile illnesses with or without rash. Enteroviruses are the most common cause of viral meningitis, but encephalitis is rare. Brainstem encephalitis is a rare but often devastating complication of enterovirus infection. Enterovirus serotypes such as Coxsackievirus A9, A10 and B5; Echoviruses 4, 5, 9, 11, 19 and 30 and Enterovirus 71, 75, 76 and 89 have been reported in encephalitis cases around the world.1–5
Several previous outbreaks of Enterovirus 71 have resulted in a small proportion of children developing brainstem encephalitis as well as life-threatening non-cardiogenic pulmonary oedema. A prospective clinical trial in Sarawak identified several outbreaks of enterovirus 71, with 10%–30% of children developing central nervous system (CNS) complications, of which 58% were brainstem encephalitis.6 An outbreak of enterovirus 71 has also been documented in Sydney.7 In the absence of effective antiviral therapy, intravenous Ig for treatment of brainstem encephalitis has evolved although no randomised efficacy data are available.
Enterovirus rarely causes brainstem encephalitis in adults, presumably due to immunological maturation and acquired immunity due to prior enteroviral exposure. Humoral immunity is believed to be central to the control of enteroviral infection and replication. Several case reports of enteroviral brainstem encephalitis exist in adult patients with defects of humoral immunity, such as those treated with the anti-CD20 B cell-depleting agent rituximab. Here, we describe a case of rituximab-associated brainstem encephalitis. The enterovirus identified was Coxsackie A16 rather than the more common Enterovirus 71. Only two other cases of brainstem encephalitis associated with this serotype, both in children, have been reported in the literature.8
Case presentation
A 41-year-old male patient presented to our hospital complaining of 1 week of intermittent fever, headache, double vision and gait unsteadiness. Stage 4 follicular lymphoma had been diagnosed 4 years prior. He had initially received six cycles of R-CHOP chemotherapy (a regimen consisting of rituximab, cyclophosphamide, doxorubicin,vincristine and prednisolone) followed by 3-monthly maintenance rituximab. He was considered to be in remission. He had no CNS involvement by his lymphoma. He had developed mild vincristine-related peripheral neuropathy but had not suffered any other side effects.
Six weeks prior to presentation, the patient’s son had developed a febrile illness consistent with hand, foot and mouth disease but did not require hospitalisation. The patient himself was noted to have developed a rash in his mouth and hands when he was reviewed for his rituximab dose 4 weeks prior to presentation. Approximately 1 week later, his rash had settled but he began to develop fevers. Initially, these were managed with antipyretics but gradually worsened to the point of presentation. Fever was accompanied by chills and low back pain, and he was advised to take prednisolone 25 mg for 3 days by his haematologist.
On presentation, the patient was febrile at 39.0°C. The patient complained of intermittent slurred speech, gait unsteadiness and double vision, but no objective neurological signs other than mild ataxia were found. The patient was not meningitic. Blood tests demonstrated a mild neutrophilia, lymphopaenia and anaemia. Chest X-ray and CT of the brain were normal. A lumbar puncture showed an elevated cerebrospinal fluid (CSF) protein level (1.06 g/L) and CSF lymphocytosis (26 white cell count/mm3 89% mononuclear cells, 11% polymorphs), with CSF glucose 66 mg/dL (3.7 mmol/L). He was treated initially with empiric antibacterial therapy and acyclovir. No organisms were seen on Gram stain of the CSF, and no bacterial growth was obtained.
The following day the patient’s condition worsened with increasing drowsiness, dysarthria and ataxia. MRI of the brain performed on day 2 of admission was normal. Enterovirus PCR on his CSF returned as positive. This was subsequently identified by sequencing as Coxsackie A16 virus. By day 3 of admission, he required transfer to the intensive care unit due to drowsiness, confusion, hypertonia, hyper-reflexia and gaze-evoked nystagmus. A diagnosis of brainstem encephalitis was made.
Treatment, outcome and follow-up
Though he remained persistently obtunded, with hypertonia and hyper-reflexia, the patient remained haemodynamically stable and did not require endotracheal intubation. Based on previous experience in immunosuppressed children, and in the absence of targeted antiviral therapy, he was managed with high-dose intravenous immunoglobulin (Ig) at a dose of 2 g/kg per day for 3 days.
An electroencephalogram (EEG) performed on day 4 showed an absent alpha rhythm and persistent symmetrical slow wave activity. By day 5, he gradually began to become more alert. A progress MRI brain scan on day 8 was also normal. EEG performed on day 9 had improved, with more evident alpha rhythm. He was discharged to a rehabilitation facility on day 12. At follow-up after 1 month, he continued to have impairment of fine motor tasks, mild intention tremor as well as the inability to tandem gait. He ultimately made a complete recovery within 6 months.
Discussion
Rituximab is a chimeric monoclonal antibody which targets B cells which express CD20. The B cell suppression can last for months and induced hypogammaglobulinaemia can occur despite a limited effect on plasma B cells. Several cases of rituximab-related brainstem encephalitis have been reported in the literature (see table 1).9–19 Many of these cases were also undergoing concurrent immunosuppression with other chemotherapeutic agents or as part of a previous stem cell transplant. Nevertheless, the rituximab was often the most recent agent, as in our case.
Table 1.
Reference | Year | Country | Enterovirus identified (if reported) |
Age | Underlying disease | Time since rituximab | MRI change? | Symptoms/signs | Treatment | Outcome |
9 | 2003 | France | Echovirus 13 | 53 | Follicular lymphoma | 6 months | Myelitis | Fever, headache, paraesthesia, diplopia | Intravenous Ig pleconaril |
Recovered fully |
10 | 2006 | UK | 75 | DLBCL | 7 months | Nil | Confusion, fever, | Intravenous Ig | Died at 14 wks | |
11 | 2006 | USA | 46 | DLBCL | 1 month | 1st: nil 2nd: FLAIR hyperintensity in thalamus, basal ganglia |
Dysarthria, nystagmus | Intravenous Ig planned not given | Died of lymphoma | |
12 | 2008 | Japan | EV71, C4 | 37 | Nil | N/A | Pons, midbrain hyperintensity | Diplopia, dysarthria, ataxia, hyporeflexia | Methylprednisolone | Recovered fully |
13 | 2009 | UK | 53 | DLBCL | 1 week | Left temporal lobe enhancement | Fever, ataxia, dysarthria | Intravenous Ig | Died at 3 months (sepsis) | |
14 | 2009 | Belgium | 61 | DLBCL | 4 months | T2 hyperintensities?incidental | Confusion, ataxia, dysphasia | Intravenous Ig | Recovered fully | |
15 | 2010 | Holland | 64 | Marginal zone lymphoma | 1 month | Nil | Fever, nausea, fatigue | Intravenous Ig | Recovered fully | |
16 | 2011 | Australia | EV71 | 63 | NHL | 3 months | Thalamus, frontal hyperintensities | Fever, myoclonus, hemiparesis, aphasia | Intravenous Ig | Died 12 weeks |
17 | 2011 | Canada | Coxsackie A9 | 65 | Follicular | 5 months | Not reported | Fever, hepatitis, rash | Nil | Recovered fully |
18 | 2012 | France | 66 | Follicular | 2 months | Day 6: normal Day 13: myelitis |
Fever, asthenia, aphasia Facial paralysis, spasticity |
Intravenous Ig | Died day 32 | |
19 | 2015 | USA | Coxsackie B3 | 28 | Evan’s syndrome ITP |
13 years | White matter changes | Fever, cognitive decline | Intravenous Ig | Died at 3 months |
DLBCL, diffuse large B-cell lymphoma; EV71, Enterovirus 71; FLAIR, fluid-attenuated inversion recovery sequence; ITP, immune thrombocytopaenic purpura; N/A, not applicable; NHL, non-Hodgkin’s Lymphoma.
This case highlights the susceptibility of humorally immunosuppressed patients to endemic viral infections. Previous reports of rituximab-treated adults have described various enteroviruses causing brainstem encephalitis and outcomes are often fatal (see table 1). Although both Enterovirus 71 and Coxsackie A16 cause hand, foot and mouth disease, Enterovirus 71 is considered to have greater virulence in the CNS. We were surprised when the result returned as Coxsackie A16 virus since this enteroviral serotype has been less commonly associated with CNS complications.8
The extent of humoral suppression and low immunoglobulin levels are likely the best predictor of susceptibility to this type of infection and, conversely, antibody production (or exogenous administration) may assist recovery. Enterovirus encephalitis in children has been reported to improve after administration of high-dose intravenous immunoglobulin. Despite this, the disease carries a high mortality rate.
Clinicians are advised to consider this condition in patients manifesting a brainstem syndrome while being immunosuppressed after rituximab administration. Enterovirus PCR testing should be swiftly sought, since early use of intravenous immunoglobulin may be lifesaving.
Learning points.
In the immunosuppressed population, normally indolent viruses, such as Coxsackie can cause severe infections of the central nervous system.
Viral PCR testing should be swiftly sought if viral encephalitis is suspected.
Brainstem encephalitis may occur in the absence of MRI changes, particularly in the early stages.
Early use of intravenous Ig may be lifesaving.
The use of high-dose intravenous Ig has not been trialled in viral brainstem encephalitis, yet remains our most suitable treatment, based on past experience in the paediatric population.
Footnotes
Contributors: All three authors cared for the patient in hospital. The case report was conceptualised and designed by RCS and JHO’N. The draft manuscript and literature review was written by RCS. The manuscript was reviewed and revised by JHO’N and DA.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Obtained.
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