Autoantibodies to N-methyl-D-aspartate Receptor Found in Some Adults with Herpes Simplex Encephalitis: Are They Significant?

Abstract & Commentary

By Bianca D. Santomasso, MD, PhD, and Matthew E. Fink, MD

Dr. Santomasso is Chief Resident in Neurology, and Dr. Fink is Professor and Chairman, Department of Neurology, Weill Cornell Medical College

Dr. Santomasso reports no financial relationships relevant to this field of study.

Synopsis: Some patients with herpes simplex encephalitis develop autoantibodies against N-methyl-D-aspartate receptors. Sera from these patients cause a downregulation of neuronal synaptic markers in vitro, suggesting a potential pathogenic disease-modifying effect.

Source: Pruss H, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012;72:902-911.

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic fatal viral encephalitis. Although the mortality and morbidity of HSE has been significantly reduced due to early antiviral therapy, even after treatment, about 35% of patients have severe neurological sequelae or even death. It is possible that not all symptoms of HSE result from a direct effect of viral invasion and neuronal cell lysis, but that a secondary autoimmune mechanism may be at play. This is suggested by three points that the authors mention: 1) combining acyclovir with corticosteroids may improve clinical outcome of HSE, 2) the disease course may be more severe in immunocompetent as compared to immunocompromised patients, and 3) some patients who experience clinical relapses of HSE after viral clearance are found to have proinflammatory profiles in their cerebrospinal fluid (CSF), suggesting that immunologically mediated pathogenicity may be at play.

In the current study, the authors set out to investigate the question of whether HSE patients might have pathogenic antibodies against neuronal cell antigens. They performed a blinded, retrospective analysis of 44 consecutive patients with polymerase chain reaction (PCR)-proven HSE, examining the serum and CSF for the presence of antineuronal antibodies by recombinant immunofluorescence or immunoblot assay. Among the 44 HSE patients tested, 13 (30%) were found to have IgG, IgM, or IgA antibodies against N-methyl-D-aspartate receptor (NMDAR). HSE cases were associated with anti-NMDAR but not with a large panel of other onconeuronal antibodies (i.e., anti-Hu, -Yo, -Ri, -Ma, -CV2, -amphiphysin) nor with antibodies against other specific synaptic proteins (AMPA receptor, GABAb-receptor or VGKC-complex). These anti- NMDAR antibodies were specific to samples from HSE patients; none were present in the serum or CSF of 20 control patients with either PCR-confirmed enterovirus or VZV encephalitis.

The authors emphasize that the presence of anti- NMDAR antibodies is not equivalent to the diagnosis of anti-NMDA receptor encephalitis, a distinct disorder affecting primarily young women with or without tumor association (usually teratoma of the ovary). Anti-NMDAR encephalitis is characterized by acute psychiatric manifestations, seizures, dyskinesias, hypoventilation, and autonomic instability, and is generally responsive to immunotherapy. The median age of most patients with anti-NMDAR encephalitis is ~20 years and most have normal or only mild abnormalities on MRI brain, moderate CSF pleocytosis, and normal or mildly increased CSF protein concentration. In contrast, the patients with HSE and NMDAR antibodies in this study were generally older and had higher levels of CSF pleocytosis and protein concentration, suggesting a more intense inflammatory response. Patients with anti-NMDAR encephalitis almost always have CSF antibodies, whereas some of the HSE patients in this study had NMDAR antibody only in serum. A subset of HSE patients in this study had evidence of intrathecal production of IgG antibodies directed against NR1a subunit of the NMDA receptor (similar to classical anti-NMDAR encephalitis); however, the majority of the anti-NMDAR antibodies found in HSE were either a different antibody class (IgA or IgM) or were specific for a different epitope of NMDAR.

Although the pathogenic role for NMDAR antibodies is well established for antibodies of the IgG classes, IgM antibodies had not been previously observed and their significance is unclear. The authors demonstrated that IgM antibody positive sera from patients, but not negative control sera, can downregulate NMDAR and synaptic proteins when co-cultured with mouse primary hippocampal cell cultures. These results are similar to the functional effect on hippocampal cultures previously shown for anti-NMDAR IgG from NMDAR encephalitis patients. This suggests that the anti-NMDAR antibodies in patients with HSE could be pathogenic.

Commentary

A coincidence of HSE and anti-NMDAR encephalitis in these patients is theoretically possible but appears unlikely given the low incidence of both diseases and the clinical differences between anti-NMDAR encephalitis and HSE mentioned above. It seems more likely that viral infection causes destruction of neurons initiating a primary autoimmune response against NMDAR in some patients. This might occur by a mechanism involving release and presentation of tissue that is normally shielded by the immune privilege of the central nervous system.

A key question is whether the anti-NMDA antibodies detected in HSE are clinically significant or simply bystander markers of tissue destruction and immune activation. The clinical characteristics of antibody-negative vs antibody-positive patients were examined in this study and no statistically significant difference was found between the two groups regarding response to treatment with acyclovir, the presence of seizures, or neuropsychological or psychiatric symptoms. The only difference found was a significantly longer time between prodromal signs and clinical admission (P < 0.05) in the antibody-positive cohort. Unfortunately, this retrospective study was limited by small sample size and lack of long-term follow-up, so no conclusions could be made beyond the acute phase of encephalitis. To elucidate whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy, prospective studies with longer follow-up during the time after viral clearance has been achieved are needed. These studies should include screening of all antibody classes.

Stroke Alert: A Review of Current Clinical Stroke Literature

By Matthew E. Fink, MD, Professor and Chairman, Department of Neurology, Weill Cornell Medical College, and Neurologist-in-Chief, New York Presbyterian Hospital

Special Report from the International Stroke Conference: Current Endovascular Interventions for Acute Ischemic Stroke Do Not Result in Better Clinical Outcomes than Intravenous Thrombolysis

Attendees of the international stroke meeting in Hawaii, in February 2013, were astonished by three reports of long-awaited trials comparing endovascular therapies with intravenous thrombolysis — IMS III,1 SYNTHESIS,2 and MR RESCUE.3 In all three studies, the clinical outcomes were not statistically different between the intra-arterial interventional groups and the intravenous-medical groups.

In IMS III, the study was stopped, for futility, after 656 patients with moderate-to-severe ischemic stroke were randomized to either intravenous tPA alone or endovascular therapy after IV tPA. The primary outcome measure, a modified Rankin score of 2 or less at 90 days, did not differ significantly between the two groups (40.8% for endovascular and 38.7% with intravenous tPA), and there were no subgroups based on clinical severity that showed any differences in outcome. Mortality was similar between the groups (19.1% vs 21.6%) as was symptomatic intracerebral hemorrhage (6.2% vs 5.9%). The trial showed similar safety profiles and outcomes. Of note, there was variability in the devices used for endovascular therapy at the discretion of the operators — Merci retreiver, Penumbra system, Solitaire device, or intra-arterial tPA. Angiography had to begin within 5 hours of symptom onset and be completed within 7 hours.

In the SYNTHESIS trial, 362 patients with acute ischemic stroke were randomly assigned, within 4.5 hours of symptom onset, to intravenous thrombolysis with tPA or intra-arterial endovascular therapy using a combination of thrombolysis or clot retrieval, or both. The median time from stroke onset to start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous tPA. The primary outcome was survival free of disability (Rankin score of 0 or 1) at 3 months, and there was no significant difference between the groups (30.4% for endovascular and 34.8% for intravenous). Odds ratios were adjusted for age, sex, stroke severity, and atrial fibrillation at baseline. Symptomatic intracranial hemorrhage occurred in 6% of each group and there were no significant differences in other serious adverse events or death rates.

The MR RESCUE trial used imaging in an attempt to select patients for treatment and predict outcome based on CT or MR measurements of potentially reversible ischemic penumbra. The study randomly assigned 118 eligible patients within 8 hours after onset of large-vessel, anterior-circulation ischemic strokes to undergo mechanical embolectomy with Merci retriever or Penumbra system, or receive standard care, which might include intravenous tPA. All patients underwent CT or MRI studies to determine infarct core and penumbra, and were stratified to favorable penumbra group or a non-penumbra pattern. For all patients, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbra pattern. Revascularization was successful in 67% of the embolectomy group. Mortality at 90 days was 21%, and the rate of symptomatic hemorrhage was 4%, without any significant differences between the two groups. Mean scores in the modified Rankin score did not differ between the groups, and there were no differences between the favorable penumbra pattern or the nonpenumbral pattern group. A favorable penumbra pattern did not predict a better outcome, and there was no difference between embolectomy vs standard care.

We congratulate the investigators of all three of these studies for their herculean efforts to complete this work, but we are disappointed by the results. How can we explain the findings, and what should be our next steps?

First, the methodology for clot extraction in all three studies used a first generation of devices, and the newer devices that are becoming available are technically superior at performing clot extraction. So, it is expected that use of these newer devices will result in better outcomes. But second and more importantly, the time windows allowed for these studies had a negative impact on the results. The IMS III study allowed angiography to begin as long as 5 hours after onset of symptoms and was completed by 7 hours. In the SYNTHESIS trial, the intravenous tPA group was treated on average 1 hour faster than the endovascular intervention group. In MR RESCUE, mean time to enrollment was 5.5 hours and extended up to 8 hours.

We know from experimental studies in animals as well as humans that speed and time to revascularization has a profound impact on outcome. We constantly state that “time is brain” and urge our physicians to institute thrombolysis as fast as possible. Yet, these studies all had delays in the institution of treatment, often due to the extensive diagnostic studies that were part of the protocols. In this situation “perfect is the enemy of good.” The future studies must have protocols that limit the diagnostic studies to only what is absolutely necessary to make a triage decision — intravenous thrombolysis or intra-arterial clot extraction. Then we will need to repeat these studies using the newest devices in the shortest time window possible. Imaging studies will have to follow treatment and not delay it. Time is still the enemy, and remains the single most important variable that influences the results of therapies. Although it is certainly important and intellectually interesting to evaluate the penumbra and the collaterals, we cannot allow those studies to slow us down in our attempts to treat patients. New trials must reflect real-world practice issues, or we will not make the progress we are seeking. I would propose a simple clinical scale and rapid CT or MRI as we are currently performing it, and then an immediate decision to go to the angiography suite for interventional clot retrieval or standard therapy. Any further delays will result in worse outcomes. I am optimistic that future studies, if properly designed, will show that new interventional techniques will improve the clinical outcomes for patients with acute ischemic stroke.

References

  1. Broderick JP, et al, for the IMS III Investigators. Endovascular therapy after intravenous versus tPA alone for stroke. N Engl J Med 2013; [Epub ahead of print] DOI: 10.1056/NEJMoa1214300.
  2. Ciccine A, et al, for the SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; DOI: 10.1056/NEJMoa1213701.
  3. Kidwell CS, et al, for the MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; [Epub ahead of print] DOI: 10.1056/NEJMoa1212793.
  4. Chimowitz M. Endovascular treatment for acute ischemic stroke — Still unproven. N Engl J Med 2013; [Epub ahead of print].