Primary Epstein-Barr virus infection in immunocompetent patients with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome as neurological manifestations

Abstract

Neurological manifestations of a primary Epstein-Barr virus (EBV) infection are rare. We describe a case with acute transverse myelitis and another case with a combination of polyradiculitis and anterior horn syndrome as manifestations of a primary EBV infection.

The first case is a 50-year-old immunocompetent male diagnosed with acute transverse myelitis, 2 weeks after he was clinically diagnosed with infectious mononucleosis. The second case is an 18-year-old immunocompetent male diagnosed with a combination of polyradiculitis and anterior horn syndrome while he had infectious mononucleosis. The first patient was treated with methylprednisolone. After 1 year, he was able to stop performing clean intermittent self-catheterisation. The second patient completely recovered within 6 weeks without treatment.

Primary EBV infection should be considered in immunocompetent patients presenting with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome. Antiviral treatment and steroids are controversial, and the prognosis of neurological sequelae is largely unknown.

Background

The prevalence of neurological symptoms in immunocompetent patients with infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) is between 0.37% and 7.3%.^{1 2} It is presumably higher in immunocompromised patients.^{3 4} A broad spectrum of neurological manifestations has been reported in immunocompetent patients with a primary EBV infection, involving mononeuropathy, mononeuritis multiplex, polyneuropathy, polyradiculitis, anterior horn syndrome, myelitis, cranial nerve palsies, meningitis and encephalitis.^{5 6} Meningitis is most commonly reported and myelitis is the rarest manifestation.^{5 6} Often, there is overlap in neurological symptoms, but they can also occur isolated. We reported two cases of immunocompetent patients with neurological manifestations of a primary EBV infection. The first patient had acute transverse myelitis and the second patient had a combination of polyradiculitis and anterior horn syndrome.

Case presentation

First case

A 50-year-old immunocompetent male presented with a 1-day history of urinary retention, after several days of polyuria and dysuria. The night before presentation, he had back pain without radiation to the legs and hyperesthesia of the ventral side of upper legs and the dorsal side of the lower legs. No weakness was found. His medical and family history (in particular for immune disorders) were unremarkable. His last intercontinental travel was seven years ago (in 2010), when he travelled to Africa. He was fully vaccinated according to the National Immunisation Programme in the Netherlands (which includes polio vaccine). History of exposure to animal bites was negative and there were no affected family members. Two weeks before, the patient had general malaise, fever and cervical lymphadenopathy. He was clinically diagnosed with IM.

On examination, the patient was vitally stable, without fever. No signs of pharyngitis and no enlarged liver or spleen were found. Initial neurological examination showed decreased vibration at both toes, but normal proprioception. No weakness of the extremities was found and normal triceps, biceps, patellar, ankle and anal reflexes were found. There was no saddle anaesthesia.

Laboratory investigations on admission showed normal values for erythrocyte sedimentation rate (ESR), platelet count, serum electrolytes. Initially low haemoglobin recovered during the hospital stay without intervention. Normal leucocyte count with normal neutrophils, but increased lymphocytes (5×10⁹/L) with atypical lymphocytes. Alkaline phosphatase (153 (ref: <115) U/L), gamma-glutamyl transpeptidase (78 (ref: <55) U/L), alanine aminotransferase (129 (ref: <45) U/L) and aspartate aminotransferase (88 (ref: <35) U/L) were slightly elevated. Urine tests, including dipstick test were negative. A traumatic lumbar puncture was performed. Cerebrospinal fluid (CSF) analysis revealed 76×10⁶/L white cell count of which 88% mononuclear cells and 12% polymorphonuclear leucocytes, 125 mg/dL protein and 3.1 mmol/L glucose and erythrocytes 26 000×10⁶/L.

Serology for EBV showed positive immunoglobulin (Ig)G and IgM antibodies against EBV viral capsid antigen (VCA) in serum, whereas IgG antibodies against EB nuclear antigen (EBNA) were negative. The EBV-polymerase chain reaction (PCR) in CSF (Abbott RealTime EBV PCR assay) was positive with 1200 IU/mL. Serological tests for cytomegalovirus (CMV), human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus, hepatitis C virus, Treponema pallidum, and Borrelia were negative, and PCRs for herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), enteroviruses, parechoviruses, and Borrelia in CSF were negative. Abdominal echo revealed no enlarged spleen nor liver.

After 3 days, the patient noticed that cold water felt warm on both legs and he developed faecal incontinence. Non-contrast enhanced MR images of the cervical, thoracic and lumbar spine demonstrated diffuse increased intramedullary signal and no signs of compression of the spine cord or spinal nerve roots.^{1 7–9} (figure 1). After 5 days, the patient developed progressive weakness of the proximal muscles of both legs with normal strength of the distal muscles, decreased sensibility below level of Th-5, high patellar and ankle reflexes at both legs, absent anal reflex and bilaterally positive Babinski signs. The patient was diagnosed with acute inflammatory longitudinally extensive transverse myelitis as manifestation of a recent primary EBV infection.^{10 11}

Figure 1.

T2-weighted image of the MRI of patient 1 revealed high-signal intensity lesions and a widened spinal cord from T9 to T12 on the sagittal image (A) and the transversal image of T10 (B). Even though the sagittal image might give the impression of L4/L5 intervertebral disc protrusion, the transverse image at that level showed no signs of spinal nerve root compression.

Second case

The second case is an 18-year-old immunocompetent male who presented with progressive and constantly present tingling of both feet for 10 days and both hands for 4 days. He noticed mild problems with his balance, especially while climbing stairs. Next to that, he had a sore throat, general malaise, stuffy nose, a cold and cervical lymphadenopathy for 4 days. He was diagnosed with IM by his general practitioner. His medical history revealed coarctectomy and closure of the ductus arteriosus at the age of 7 months. He was fully vaccinated according to the National Immunisation Programme in the Netherlands, and his family history (in particular for immune disorders) was unremarkable.

On examination, we found an elevated blood pressure (150/127 mm Hg) and heart rate (109/min), but further normal vital signs, without fever. Cervical lymphadenopathy and pharyngitis were present; liver and spleen were not enlarged. Initial neurological examination showed absent patellar and ankle reflexes and very low biceps and triceps reflexes. Negative Babinski sign bilaterally. Mild problems with his balance were found but the Romberg’s test was negative.

Laboratory investigations on admission showed normal haemoglobin, platelet count and normal serum electrolytes. ESR was slightly elevated (19 (ref <15) mm/hour) and leucocytose of 13.1 (ref: 4.0–11.0)×10⁹/L with normal neutrophils and elevated lymphocytes of 8.5 (ref: 1.0–4.0)×10⁹/L and atypical lymphocytes. Alkaline phosphatase (140 (ref: <115) U/L), gamma-glutamyl transpeptidase (258 (ref: <55) U/L), alanine aminotransferase (693 (ref: <45) U/L) and aspartate aminotransferase (395 (ref: <35) U/L) were elevated. CSF analysis revealed 24×10⁶/L white cell count of which 100% mononuclear cells and 0% polymorphonuclear leukocytes, 122 mg/dL protein and 2.6 mmol/L glucose.

Serology for EBV showed positive IgG and IgM antibodies against EBV VCA in serum, whereas IgG antibodies against EBNA were negative. The EBV-PCR in CSF (Abbott RealTime EBV PCR assay) was positive with 500 IU/mL. Serological tests for CMV IgM, HIV-1, HIV-2, hepatitis B virus were negative. Hepatitis A virus IgG was positive after vaccination, CMV IgG was positive, Borrelia IgG and HSV IgG were negative, but Borrelia IgM was equivocal and HSV IgM was positive. The last two findings were interpreted as cross-reactivity due to primary EBV infection. More specific, HSV-1 or HSV-2 as cause of the neurological symptoms were ruled out by negative HSV-1 and HSV-2 PCR on CSF. Also, PCRs for VZV, enteroviruses (including polioviruses), parechoviruses and Borrelia in CSF were negative. No abdominal echo or MR imaging of the spinal cord was performed.

During the hospital stay, the patient developed paresis of ankle dorsiflexors at both legs and the imbalance increased. The patient was diagnosed with acute flaccid weakness, a combination of polyradiculitis and anterior horn syndrome. No disabilities with breathing or speaking were found, and a problem with swallowing did not require medical intervention.

Outcome and follow-up

The first patient was treated with methylprednisolone 1000 mg once a day for 5 days. After 7 days, the patient slowly recovered with no muscle weakness at discharge at day 15. At discharge, normal sensibility and reflexes, including anal reflex, were found. The patient was still unable to urinate for which he was treated with intermittent self-catheterisation. At follow-up, he regained strength and coordination in both legs. After 4 months, he still performed clean intermittent self-catheterisation occasionally. The EBNA IgG was positive at that time. After 1 year of follow-up, his bladder function was fully recovered, but mild balance and sensory disturbances at both legs remained.

No treatment was given to the second patient. After 7 days, the neurological condition of the patient improved: the weakness and imbalance resolved and the tingling disappeared. After 1 month, the liver function tests normalised. After 6 weeks at the outpatient department, the patient had complete recovery of weakness and sensory impairment. After 6 months, the EBNA IgG was positive.

Discussion

The role of EBV as the most frequent aetiological agent causing IM was established in 1968.^{12 13} IM is characterised by the classic triad of symptoms: fever, pharyngitis and cervical lymphadenopathy, often in combination with lymphocytosis and atypical lymphocytes in the blood slide. The diagnosis of a primary EBV infection is based on serological testing. A positive heterophil antibody test (the monospot has replaced the classical Paul-Bunnell test) confirms the clinical diagnosis of IM.^14–16 Definite diagnosis of primary EBV infection is established by the combination of antibodies directed against EB VCA, followed by the development of antibodies against EBNA. It is reported that detectable virus by PCR in serum correlates with lymphadenopathy and lymphocytes characteristics.¹⁷ In CSF, pleiocytosis is often found with increased ratio of mononuclear leucocytes compared with granulocytes, as was the case in our patients. The diagnostic validity of detection of EBV by PCR in CSF has been reported.^{17 18} Some authors suggest its usefulness in terms of specificity, based on the detection of viral DNA copies in seven of nine patients with a variety of central nervous symptoms.¹⁹ In both our patients, EBV-DNA was detected in the CSF, supporting the aetiological role of EBV in their neurological manifestations. Although EBV, as a member of the Herpesviridae, is a well-known neurotropic virus, neurological manifestations in a primary EBV-infection are relatively rare.^{1 2} Other viruses, among which HSV-1, HSV-2, VZV, CMV, human herpes virus (HHV)-6, HHV-7 (as a cause of acute transverse myelitis), enteroviruses (among which polioviruses as a cause of acute flaccid weakness) and HIV should be in the differential diagnosis when searching for a viral aetiology of acute transverse myelitis and acute flaccid weakness.²⁰

In patients with acute transverse myelitis, in general, it is important that the occurrence of an infection does not implicate that multiple sclerosis or neuromyelitis optica are ruled out, especially since infections causing acute transverse myelitis are known to announce those conditions.

The neurological deficit and concomitant primary EBV infection in the second patient might suggest that the EBV infection directly involved the nerve roots and the anterior horn cells.²¹ In patients with involvement of the anterior horn cells, the term poliomyelitis-like syndrome was coined.²² The postinfectious neurological complication Guillain-Barré syndrome is more often described as neurological manifestation. In clinical practice, it can be difficult to distinguish the primary infection from its concurrent immune response,²³ even though this might have important therapeutic consequences. The role of steroids (in addition to intravenous immunoglobulin), used for their anti-inflammatory effect, in Guillain-Barré syndrome is well established, but the onset of a new neurological manifestation has been described after treatment with steroids in a patient with EBV infection.²⁴ In patients with acute transverse myelitis, steroids could be considered with the aim to decrease swelling of the spinal cord.

The role of antiviral treatment for IM without neurological manifestations is not well established^{25 26} and treatment is therefore mainly supportive.²⁷ The evidence for the treatment of IM with neurological manifestations is based on case reports and response to treatments is mixed, therefore no evidence-based recommendations can be formulated about the best treatment strategies. Treatment decisions should therefore be made on an individual basis. Whereas IM is considered a self-limiting disease with generally a good prognosis, less is known about the long-term outcome of the neurological sequelae.

Learning points.

• Neurological manifestations of primary Epstein-Barr virus (EBV) infection are relatively uncommon.

• Primary EBV infection with neurological manifestations should be considered in immunocompetent patients of all ages.

• Neurological manifestations of primary EBV infection include acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome.

• Treatment decisions should be made on an individual basis since no evidence-based recommendations are available.