Anti-N-methyl-D-aspartate Receptor Encephalitis with Positive Serum Antithyroid Antibodies, IgM Antibodies Against Mycoplasma pneumoniae and Human Herpesvirus 7 PCR in the CSF

Abstract

Abstract:We report the case of a boy with an encephalopathy associated with extrapyramidal and psychiatric symptoms and anti-N-methyl-D-aspartate receptor antibodies. He had positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and human herpesvirus 7 polymerase chain reaction in the cerebrospinal fluid. He was successfully treated with rituximab, after steroids, intravenous immunoglobulin and plasma exchange. The pathophysiology of this disorder may be post-infectious and autoimmune. The diagnosis is based on the clinical course and, in addition, on the demonstration of anti-NMDAR antibodies in the serum and cerebrospinal fluid (CSF).In patients with a tumor, predominantly an ovarian teratoma, the condition is treated by tumor removal, whereas first-line immunotherapy [corticosteroids plus intravenous immunoglobulin (IVIg) or plasma exchange] has been proposed in previous reports. 2When no response is seen second-line immunotherapy (rituximab and/or cyclophosphamide) should be considered. 4-6The pathogenesis of anti-NMDAR encephalitis is unclear. Although recent studies showed that a few patients with non-tumorassociated anti-NMDAR encephalitis have elevated antithyroid peroxidase (anti-TPO) antibodies, 5-7 the combined occurrence of anti-NMDAR and anti-TPO antibodies was not followed up in detail in the literature.Neurologic disease associated with Mycoplasma pneumonia and Human herpesvirus 7 (HHV-7) infections have been described rarely contrasting with the occurrence of nearly universal primary infection in early childhood. 8 We report an anti-NMDAR encephalitis in a 9-year-old boy, not associated with malignancy, with positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and HHV-7 polymerase chain reaction (PCR) in the CSF that showed significant improvement after administration of rituximab. CASE PRESENTATIONA 9-year-old boy initially had upper respiratory symptoms and low-grade fever. One week later, he progressively developed limb muscle weakness, fatigue, waddling gait, refusal to walk, changes of mood and self-injurious behavior. He was seen at a local hospital with a severe headache and vomiting. CT-scan was normal and the symptoms improved. Two weeks later, he manifested incoherent delirious and obsessive thoughts, slurred speech and a mild motor incoordination. He was fully awake, with periods of agitation. Neurologic examination did not indicate any other abnormalities. Extensive investigations for metabolic, infectious, toxic, autoimmune and central nervous system disorders were performed. CSF cyto and biochemical analyses were normal. Brain magnetic resonance imaging fluid-attenuated inversion recovery showed bilateral medial temporal lobe hyperintensities, predominantly involving the left hippocampus. Electroencephalogram demonstrated right-sided, fronto-temporal slowing without epileptiform discharges. Considering encephalitis, he was treated with acyclovir, ceftriaxone and ciprofloxacin.Further CSF analysis showed elevated IgG and IgM...

Herpes simplex virus‐induced anti‐N‐methyl‐d‐aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases

“…Supporting these findings, an interesting recent work focused on the frequency of coexisting herpes viruses and autoantibodies in patients with encephalitis (herpes or autoimmune) in clinical laboratory service, disclosing that autoantibodies and herpes virus DNA frequently coexist in encephalitic CSF . In this study, as well as in other case reports, other types of herpes viruses beside HSV have been found in association with anti‐NMDAR antibodies, including Epstein–Barr virus, human herpesvirus 6 and 7, and varicella zoster virus . However, other autoantibodies to neuronal surface antigens, in particular anti‐dopamine‐2 receptor, anti‐ γ ‐aminobutyric acid A receptor antibodies and antibodies against unknown neuronal cell surface proteins, have also been detected in patients with immune‐mediated encephalitis (with negative CSF HSV PCR) occurring after HSE, suggesting that other antibodies may also be produced in this syndrome.…”

“…56 In this study, as well as in other case reports, other types of herpes viruses beside HSV have been found in association with anti-NMDAR antibodies, including Epstein-Barr virus, human herpesvirus 6 and 7, and varicella zoster virus. [56][57][58][59][60] However, other autoantibodies to neuronal surface antigens, in particular anti-dopamine-2 receptor, 20 anti-c-aminobutyric acid A receptor antibodies and antibodies against unknown neuronal cell surface proteins, 27 have also been detected in patients with immune-mediated encephalitis (with negative CSF HSV PCR) occurring after HSE, 16,27 suggesting that other antibodies may also be produced in this syndrome. In these cases, similarly to what is suggested for anti-NMDAR antibodies, it may be hypothesized more broadly that autoantibody production is triggered by herpes viruses infection, but further study for novel autoantibodies is required.…”

Insights into the pathogenesis of Mycoplasma pneumoniae

“…In addition, in the acute phase and recovery phase of mycoplasma pneumonia, the contents of IgG, IgM, IgA and immune complex in the serum increase significantly, particularly in severely affected patients (50). Following M. pneumoniae infection, the IgM level has been shown to markedly increase in normal children, which usually occurred 7–14 days following infection, peaked in weeks 3–4 and persisted for months (51). M. pneumoniae infection can cause an increase in the level of total IgE in the serum, whereas delayed-type and anaphylactic-type allergic reactions induce asthma as an immediate reaction and delayed-phase reaction or a dual-phase reaction, which induce the IgE-mediated airway inflammation and airway hyper-reactivity (52).…”

Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals

“…Encephalitis in immunocompetent children due to primary HHV-7 infection is rare. An acute HHV-7 infection in the CSF might be accompanied by severe neurological and generalized symptoms, including encephalitis, meningoencephalitis, encephalopathy, facial palsy, vestibular neuritis, febrile or focal seizures, severe headache, somnolence, fatigue, nausea, vomiting, fever up to 39.8 °C, photosensitivity, lethargy, impaired orientation, difficulties in walking, tendency to fall to one side (straddle gait), tiredness, sudden onset of dizziness, and comatous state (Chan et al 2002 ; Ward 2005 ; Epstein et al 2012 ; Pohl-Koppe et al 2001 ; Venancio et al 2014 ). Delayed primary HHV-7 infection in older children and adolescents can cause more serious neurological complications.…”

“…In adults, primary HHV-7 infection-associated encephalitis is rare but is concomitant with severe generalized symptoms, such as urinary retention, respiratory failure, and flaccid paralysis of the limbs progressing to quadriplegia (Miranda et al 2011 ; Schwartz et al 2014 ; Ward 2005 ; Ward et al 2005 ). Recently, the combination of a genetic disorder (anti-N-methyl-D-aspartate receptor dysfunction) and HHV-7 DNA positivity in the CSF has been described in a 9-year-old boy with typical neurological symptoms (Venancio et al 2014 ).…”