Diagnostic reference value of antibody levels measured using enzyme immunoassay for subacute sclerosing panencephalitis.

High measles-specific antibody titers in the cerebrospinal fluid (CSF) have important diagnostic significance for subacute sclerosing panencephalitis (SSPE), a progressive neurological disorder caused by measles virus variants. However, the diagnostic reference value of antibody levels and the usefulness of the CSF/serum ratio measured using enzyme immunoassays (EIAs) for SSPE diagnosis remain unclear. To facilitate SSPE diagnosis using EIAs, measles immunoglobulin G (IgG) titers in the CSF and serum of patients with and without SSPE were measured and their CSF/serum antibody ratios evaluated. Serum and CSF antibody levels were compared among three patients with SSPE (59 paired samples), 37 non-SSPE patients, and 2618 patients of unknown backgrounds. Of the 59 paired samples from three patients with SSPE, 56 paired samples (94.9%) showed CSF measles IgG levels ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, whereas non-SSPE cases showed CSF measles IgG levels <0.1 IU/mL and a CSF/serum ratio <0.03. Of the 2618 CSF samples with unknown backgrounds, 951 showed measurable IgG levels with EIA, with a CSF/serum ratio peak of 0.005-0.02, with a 90th percentile of 0.05. Assuming the SSPE criteria as CSF measles IgG ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, only 20 samples (0.8%) with unknown backgrounds were categorized as having SSPE. Conversely, assuming the non-SSPE criteria as CSF measles IgG <0.1 IU/mL and a CSF/serum ratio <0.03, 2403 samples (92%) with unknown backgrounds were categorized as not having SSPE. In conclusion, high CSF/serum ratios (≥0.05) and high measles CSF IgG levels (≥0.5 IU/mL) may be useful for diagnosing SSPE.

Measles Virus and Subacute Sclerosing Panencephalitis.

BACKGROUND: Subacute Sclerosing Panencephalitis (SSPE) mainly affects children and young people. It is a rare, chronic progressive degenerative form of cerebral inflammation with various infectious noxa, which develops for years after a primary, uncomplicated infection, and the highest percentage can be caused by measles virus and in rare cases by rubella. The aim of the present study is to investigate in the laboratory the role of measles virus in the development of neurological symptoms and diseases of the CNS. METHODS: A total of 46 clinical materials (23 sera samples and 23 CSF) obtained from 23 patients with neurological symptoms and diagnoses: "SSPE" (in 10 patients) and "Encephalitis" (in 13 patients), in the period January 2011 - December 2020 were tested in the National Reference Laboratory (NRL) "Measles, mumps and rubella" at National Centre of Infectious and Parasitic Diseases (NCIPD), Sofia, Bulgaria. Serological (indirect ELISA test for the detection of specific measles IgG/IgM antibodies in serum samples and cerebrospinal fluid) and molecular (RT-PCR for the demonstration of viral RNA) methods were used. RESULTS: The study was performed by parallel testing of serum samples and CSF from each patient. Positive results for measles IgG antibodies in sera were found in 21 patients. Presence of measles IgG antibodies in CSF was demonstrated in four children with diagnosis SSPE (two children at 4 years, one child at 4 years and 6 months, and one at 11 years old). All children with positive laboratory results for SSPE had evidence of MeV infection before 2 years of age. The patients with SSPE had high antibody titers (CSF > 230 U/mL) in their CSF. Patients with positive anti-Measles IgG in the CSF were also found to have positive results for protective measles IgG in the serum samples and their IgG titers were nearly twice as high compared to other patients' sera. The presence of specific measles IgM antibodies was not demonstrated in the tested specimens. RT-PCR test was performed for all samples, and the presence of viral RNA was not detected. CONCLUSIONS: The measles infection can be a reason for developing serious complications affecting CNS in all age groups. SSPE itself is extremely difficult to diagnose, which is why laboratory confirmation of any clinical case is a necessary condition for effective disease surveillance.

Utility of enzyme immunoassays for diagnosis of subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a progressive neurologic disorder caused by the measles virus (MV) and is identified by positive MV-specific antibody titers, detected mainly by hemagglutination inhibition (HI) tests in the cerebrospinal fluid (CSF). However, an alternative method, the enzyme immunoassay (EIA), has increasingly become a preferred method for detecting MV antibodies. To establish the index for SSPE diagnosis using EIA, we investigated the correlation between HI and EIA titers of MV antibodies in SSPE patients. METHODS: Data on MV antibody titers and measurement methods at the time of diagnosis in 89 Japanese SSPE cases diagnosed between 1979 and 2006 were obtained by a survey. We also assessed the serum and CSF MV antibody titers in three patients with SSPE and serum MV antibody titers in 38 healthy adults using immunoglobulin G (IgG)-EIA and HI. RESULTS: In all cases diagnosed as SSPE, IgG-EIA titers in the CSF were ≥0.49 IU/mL. There was a positive correlation between serum antibody values in the controls measured by IgG-EIA and HI. In patients with SSPE, both serum and CSF antibody values, measured by IgG-EIA, and HI, were positively correlated, and a positive correlation was found between the serum and CSF MV antibody titers as measured by IgG-EIA. The serum/CSF MV antibody titer ratios determined by IgG-EIA were <20 in most SSPE patients. CONCLUSIONS: Immunoglobulin G-EIA may be a suitable alternative method for SSPE diagnosis; however, its potential utility and the cut-off point of ≥0.49 IU/mL should be tested with additional patient cohorts.

Subacute Sclerosing Panencephalitis: The Devastating Measles Complication That Might Be More Common Than Previously Estimated.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a fatal complication of measles. We reviewed California cases from 1998-2015 to understand risk factors for SPPE and estimate incidence. METHODS: SSPE cases had clinically compatible symptoms and measles antibody detection in cerebrospinal fluid (CSF) or medical record documentation of SSPE. Cases were identified though a state death certificate search, Centers for Disease Control and Prevention reports, or investigations for undiagnosed neurologic disease. Measles detection in CSF was performed by serology at the California Department of Public Health or at clinical laboratories. RESULTS: Seventeen SSPE cases were identified. Males outnumbered females 2.4:1. Twelve (71%) cases had a history of measles-like illness; all 12 had illness prior to 15 months of age. Eight (67%) children were exposed to measles in California. SSPE was diagnosed at a median age of 12 years (3-35 years), with a latency period of 9.5 years (2.5-34 years). Among measles cases reported to CDPH during 1988-1991, the incidence of SSPE was 1:1367 for children <5 years, and 1:609 for children <12 months at time of measles disease. CONCLUSIONS: SSPE cases in California occurred at a high rate among unvaccinated children, particularly those infected during infancy. Protection of unvaccinated infants requires avoidance of travel to endemic areas, or early vaccination prior to travel at age 6-11 months. Clinicians should be aware of SSPE in patients with compatible symptoms, even in older patients with no specific history of measles infection. SSPE demonstrates the high human cost of "natural" measles immunity.

[Subacute sclerosing panencephalitis cases diagnosed by increased CSF/serum measles antibody indices]. / Yüksek BOS/Serum Kizamik Antikor Indeksi ile Tanimlanan Subakut Sklerozan Panensefalit Olgulari

Subacute sclerosing panencephalitis (SSPE) caused by persistent defective measles virus strains, is a progressive neurological disorder of children and adolescents. The aim of this letter was to share the data from SSPE-suspected cases who were definitely diagnosed by the detection of increased antibody index in serum and cerebrospinal fluid (CSF) samples. A total of 11 patients (mean age: 14.3 years) with suspected SSPE between February 2006 to August 2008, were included in the study. Simultaneously obtained serum and CSF samples from patients were analyzed in terms of albumin, total IgG and measles-specific IgG levels (Measles Virus IgG ELISA for CSF Diagnostics, Euroimmun, Germany). The value of CSQrel (relative CSF/serum quotient) ≥ 1.5 was accepted indicative for intrathecal measles antibody synthesis. Seven (63.6%) of the 11 patients' diagnosis were confirmed with the demonstration of elevated CSF/serum indices (CSQrel range: 2.3-36.9; mean: 12.9). Mean age of those seven cases was 12.3 years (age range: 7-21) and four of them were male. The history of patients with high antibody indices indicated that three of four patients who had measles infection had not been vaccinated against measles. These three unvaccinated patients had measles infection at 3rd, 8th and 30th months of age, respectively, and the period of SSPE development were 15, 6 and 4.5 years, respectively. With this letter we would like to emphasize once more that effective measles vaccination is the only way for the prevention of measles and SSPE and the demonstration of increased measles antibody index in simultaneously obtained serum and CSF samples is crucial for the diagnosis of SSPE.

Challenges in diagnosing SSPE.

PURPOSE: The typical clinical presentation of subacute sclerosing panencephalitis (SSPE) includes behavioral and intellectual changes followed by myoclonia. However, there are a considerable number of SSPE cases which present with distinct clinical features that can lead to a diagnostic difficulty. In this report, we summarize the clinical features of patients with SSPE who have uncommon presentations or features of the disease or coexisting medical conditions which may lead to diagnostic difficulties. METHODS: We studied 173 patients, all under the age of 17. Patients were included in the study group according to following criteria: onset of the disease before age 2 years, seizures occurring before the onset of myoclonia and/or behavioral symptoms, extrapyramidal or cerebellar signs and ocular manifestations as initial presenting symptoms, fulminant course including coma or death within 6 months. Additionally, patients with onset of SSPE at the setting of a known neurological disorder are defined as another group in the study. RESULTS: Out of 173 patients with SSPE who were followed in two neurology centers, 31 (17.9%) met our criteria. CONCLUSIONS: We found a relative high frequency of these clinical features. Our findings suggest that clinicians should be aware of this clinical characteristics and rule out the disease in cases were other common causes have been excluded, especially in countries with insufficient measles immunization.

Functional gamma chain-associated T cell receptors on cerebrospinal fluid-derived natural killer-like T cell clones.

We have derived 33 independent T cell clones from the cerebrospinal fluid (CSF) of a patient with subacute sclerosing panencephalitis using a single T cell cloning method. 6% (2 of 33) of these clones express the T cell receptor gamma (TCR-gamma) protein and are called CSF TCR-gamma clones. Phenotypic analyses of the CSF TCR-gamma clones indicate that they are WT-31-, CD3+, CD4-, and CD8-. The TCR-gamma protein exists on the cell surface as part of an 85-kD disulphide-linked dimer noncovalently associated with the CD3 polypeptides. The CSF TCR-gamma clones have NK-like activity that can be inhibited by anti-CD3 mAbs. Both CSF TCR-gamma clones proliferated in response to anti-CD3 mAbs coupled to Sepharose beads and/or IL-2. Furthermore, stimulation of one of these clones with anti-CD3 mAbs results in a rapid rise in intracellular calcium. These data suggest that T cells bearing the CD3-TCR-gamma protein complex are functional and play a role in the human immune response.

Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis.

We have investigated the T cell populations in the cerebrospinal fluid (CSF) of chronic progressive multiple sclerosis (MS) patients. Individual T cells from the CSF and blood were cloned before expansion and their clonotypes were defined by analysis of rearranged T cell receptor beta chain and gamma chain genes. 87 T cell clones from blood and CSF of two patients with chronic progressive MS were examined for common TCR gene rearrangement patterns. In one patient, 18 of 28 CSF-derived T cell clones demonstrated common TCR gene rearrangements indicating oligoclonal T cell populations; in the blood, two patterns were found twice among 26 T cell clones. In another patient, 5 of 27 CSF-derived clones had common TCR gene rearrangement patterns. In contrast, no common beta chain rearrangement pattern was found among 67 T cell clones derived from the blood or CSF of a patient with subacute sclerosing panencephalitis, among 20 clones from the CSF of a patient with herpes zoster meningoencephalitis, or among 66 clones from a normal subject. A subject with atypical, fatal MS of 8-mo duration was also studied and did not have oligoclonal T cells in the CSF or blood. These results demonstrate that distinct oligoclonal T cell populations can be found in the CSF immune compartment of subjects with nonmalignant inflammatory disease and they can create a new avenue for the investigation of the specificity of the T cell response within the central nervous system.

Demonstration of a blocking factor in the plasma and spinal fluid of patients with subacute sclerosing panencephalitis. I. Partial characterization.

Conflicting reports on the immune responsiveness of patients with subacute sclerosing panencephalitis (SSPE) have been reported. This report shows that the leucocytes from four SSPE patients exhibited strong sensitivity to both measles and SSPE virus preparations as measured by the macrophage migration inhibition test, mixed lymphocyte virus infected cell culture test, and the lymphotoxin assay. Earlier suggestions that a factor may be operating to suppress cellular reactivity are confirmed by the demonstration that the response of lymphocytes from SSPE patients could be blocked by the addition of SSPE spinal fluid or plasma. It was determined that the blocking factor was stable at -20 degrees C, heat labile at 56 degrees C for 30 minutes, trypsin and neuraminadase sensitive, and had a mol wt greater than 150,000 as determined by Sephadex G-200 gel chromatography. The blocking factor appeared to be specific for SSPE virus and did not block the response of lymphocytes to nonspecific mitogenic agents and other viral and bacterial agents.

Subacute sclerosing panencephalitis: an update.

Subacute sclerosing panencephalitis (SSPE) is a chronic encephalitis occurring after infection with measles virus. The prevalence of the disease varies depending on uptake of measles vaccination, with the virus disproportionally affecting regions with low vaccination rates. The physiopathology of the disease is not fully understood; however, there is evidence that it involves factors that favour humoral over cellular immune response against the virus. As a result, the virus is able to infect the neurons and to survive in a latent form for years. The clinical manifestations occur, on average, 6 years after measles virus infection. The onset of SSPE is insidious, and psychiatric manifestations are prominent. Subsequently, myoclonic seizures usually lead to a final stage of akinetic mutism. The diagnosis is clinical, supported by periodic complexes on electroencephalography, brain imaging suggestive of demyelination, and immunological evidence of measles infection. Management of the disease includes seizure control and avoidance of secondary complications associated with the progressive disability. Trials of treatment with interferon, ribavirin, and isoprinosine using different methodologies have reported beneficial results. However, the disease shows relentless progression; only 5% of individuals with SSPE undergo spontaneous remission, with the remaining 95% dying within 5 years of diagnosis.

Elevated quinolinic acid levels in cerebrospinal fluid in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a rare neurodegenerative disorder caused by a persistent infection with aberrant measles virus. Indoleamine-2, 3-dioxygenase (IDO) initiates the increased production of kynurenine pathway (KP) metabolites quinolinic acid (QUIN), which has an excitotoxic effect for neurons. We measured serum IDO activity and cerebrospinal fluid (CSF) levels of QUIN. The CSF QUIN levels were significantly higher in SSPE patients than in controls, and increased according as neurological disability in a patient studied. Elevation of CSF QUIN and progression of SSPE indicate a pathological role of KP metabolism in the inflammatory neurodestruction.

CSF neurofilament and soluble TNF receptor 1 levels in subacute sclerosing panencephalitis.

Neurofilament (NF) is one of the major cytoskeleton proteins of neurons and sTNFR1 is thought to reflect the true biological activity of TNF-alpha. To evaluate the levels of the heavy subunit of neurofilament (NF-H) and soluble TNF receptor 1 (sTNFR1) in cerebrospinal fluid (CSF) as biomarkers of clinical severity of subacute sclerosing panencephalitis (SSPE), concentrations of NF-H and sTNFR1 in CSF of 34 patients with SSPE and in control subjects were measured by ELISA. The CSF NF-H levels were significantly higher in patients with SSPE than in controls (p<0.0001), and those in patients in Jabbour stage III were significantly higher than in patients in stage II (p=0.015). The CSF sTNFR1 levels in SSPE patients were significantly higher than those in controls (p=0.004), but there were no significant differences in CSF sTNFR1 levels between patients in Jabbour stages II and III. There was a significant correlation between CSF NF-H and sTNFR1 levels in patients with SSPE (p=0.011). We suggest that CSF NF-H levels can be used as a marker of development of neuronal degeneration in SSPE, and that TNF-alpha modifies the neurodestructive pathogenesis in SSPE.

Long-term follow-up of patients with adult-onset subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a rare infectious central nervous system disease with a poor prognosis. Nineteen patients, 18 males and one female, ranging in age from 18 to 22, mean 19.6+/-1.5 years with SSPE were evaluated. We treated 9 patients with oral isoprinosine and 10 patients with alpha-interferon plus oral isoprinosine and followed up for 16 to 160 months. Of the 9 patients treated with oral isoprinosine, 7 (77.7%) died, one stabilized, and one showed progression. Seven (70%) of 10 patients treated with alpha-interferon plus oral isoprinosine died, one showed progression, and stabilization was observed in two patients. Thus, we suggest that isoprinosine alone or in combination with intraventricular interferon did not change the prognosis in long-term follow-up periods.

Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response.

The detection of intrathecal antibody synthesis by qualitative methods or the Antibody-Index (AI) is a relevant tool for diagnosis of inflammatory neurological diseases. An increased AI can be observed for a causative antigen as well as part of a polyspecific immune response. The quantitation of the intrathecal antibody fraction in cerebrospinal fluid (CSF), F(S), helps to discriminate both cases. In contrast to AI, F(S) needs an absolute antibody concentration detected in the ELISA in mg/L. The intrathecally synthesized, "local" antibody concentration in CSF (AB(Loc)) is expressed as the specific fraction of the intrathecally synthesized total IgG (IgG(Loc)) in CSF with F(S)=AB(Loc)/IgG(Loc) x 100 in %. F(S) for HSV or measles has about 20- to 60-fold higher values in virus-caused antibody synthesis in acute herpes simplex encephalitis (mean HSV-F(S)=8.9%) or subacute sclerosing panencephalitis (mean measles-F(S)=18.8%) compared to the polyspecific immune response against these antigens e.g., in multiple sclerosis (0.14% or 0.52%, correspondingly). F(S) helps also to avoid misinterpretations of an increasing AI in cases of therapy control, and allows direct comparison of relative antibody concentrations (R(S)) in blood and intrathecally synthesized fractions in CSF (F(S)): In multiple sclerosis patients F(S):R(S) has a mean ratio of about 3 for the measles, rubella and VZV antibodies. Together with the large variability we find by ranking that about two third of MS patients have no direct correlation of the relative concentrations in serum and intrathecal synthesis. So this concept gains increasingly relevance for analysis of the polyspecific immune response in brain.

Cerebrospinal fluid pressures in subacute sclerosing panencephalitis.

Increased intracranial pressure can rarely be the initial symptom in subacute sclerosing panencephalitis (SSPE). We examined cerebrospinal fluid (CSF) pressures and their correlation with clinical features in 58 patients with SSPE. CSF pressure varied between 50 and 500 mmH2O, mean 210.9+/-103.7 mmH2O. Twenty-five (42%) patients had pressures above 200 mmH2O and 15/58 (25%), above 250 mmH2O. There was no correlation between CSF pressure and neurological disability, spasticity, or clinical stage. Frequent myoclonia and shorter interval between measles and onset of SSPE were associated with CSF pressure >200 mmH2O (p=0.035). The causes of high pressure in certain SSPE patients is unknown but may include the effect of myoclonic jerks or inflammatory reaction. Because these patients may be unable to express symptoms, increased intracranial pressure should be considered in the presence of irritability or frequent myoclonia.

Increased insulin-like growth factor-1 levels in cerebrospinal fluid of advanced subacute sclerosing panencephalitis patients.

PURPOSE: Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients. METHODS AND RESULTS: In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG. CONCLUSIONS: The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways.

Changing trend of SSPE over a period of ten years.

Sub acute sclerosing pan-encephalitis (SSPE) is a slowly progressive inflammatory disorder of the central nervous system. A decline in frequency has been noticed in most of the developed countries, whereas it continues to be high in developing countries. Though a number of studies have been carried out, the exact trend of SSPE is still not clear. Hence the present study was carried out to analyze the trend of SSPE over the past ten years in and around Chandigarh. A total of 205 patients with clinical features suggestive of SSPE were enrolled for the study during Jan'92 to Dec. 2001. Measles specific antibodies were detected in blood and CSF by HAI method. 114 patients were found to be positive for measles specific HAI antibody with a male preponderance. The number of SSPE cases were found to be more during the period 1992-95 in comparison to the next 6 years (p < 0.05). The high incidence of SSPE in our country could be due to improper vaccine coverage, poor cold chain maintenance or circulation of atypical measles virus strain.

CSF oligoclonal bands, immunoglobulins, and viral antibodies in progressive myoclonus epilepsy.

We studied CSF and serum samples from 16 patients with progressive myoclonus epilepsy (PME). These patients had juvenile-onset PME with evidence of autosomal recessive inheritance and no Lafora bodies. Twelve of the 16 patients with PME had immunologic abnormalities. Oligoclonal gamma bands were seen in six of the eight patients from whom sufficient CSF was available. The CSF albumin and serum/CSF albumin ratios were normal in all 16 patients, indicating the presence of intact blood-brain barriers. Six of the 16 patients showed increased CSF IgG levels and five had an increased CNS IgG synthesis. All patients had normal serum and CSF IgM and IgA levels. Three patients, all with bands, had reduced measles and/or vaccinia serum/CSF antibody ratios. The findings suggest altered immune response of the CNS of some patients with PME apparently caused by nonspecific immunostimulation.

Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man.

CONTEXT: Subacute sclerosing panencephalitis (SSPE) is a rare, slow viral infection caused by a defective measles virus. It is characterized by progressive mental deterioration associated with motor impairment and prominent myoclonus. In about 10% of all cases, the disease can progress rapidly and lead to death within a few months. The oldest previously reported fulminating case was in a 25-year-old man. OBJECTIVE: To emphasize the relationship between retinal involvement and acute SSPE by reporting the case of a 49-year-old man with clinical, laboratory, and pathological evidence of acute SSPE. SETTING: Hôpital de l'Enfant-Jésus, Quebec, Quebec. REPORT OF A CASE: This man was referred to the Department of Neurological Sciences on March 21, 2001, because of recent behavioral changes and progressive cognitive impairment over the past few months. Medical history was unremarkable except for an episode of measles in his childhood. Neurological examination showed bilateral myoclonic jerks. Ophthalmic examination revealed bilateral macular swelling and papilledema. Electroencephalography showed periodic sharp and slow-wave discharges. Magnetic resonance imaging showed bilateral diffuse T2-signal hyperintensities in both periventricular and subcortical white matter. Cerebrospinal fluid antimeasles antibody titers were highly positive. An Omaya reservoir was inserted and therapy using a combination of high-dose intrathecal interferon alfa and oral isoprinosine were administered for 6 weeks. Despite transient subjective improvement in the patient's condition, it continued to deteriorate, he became bedridden, and he died on June 26, 2001. CONCLUSION: To our knowledge, this patient is the oldest case of SSPE reported in the literature. This patient and other patients with acute SSPE associated with bilateral macular swelling described in the literature raised the possibility of measles virus-acquired virulent neurotropism in the retina before invading the central nervous system.