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.

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.

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.

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.

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.

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.

Oxidant and antioxidant status in children with subacute sclerosing panencephalitis.

We analyzed serum alpha-tocopherol, beta-carotene, retinol, and ascorbic acid levels and malondialdehyde and reduced glutathione concentrations on erythrocyte and cerebrospinal fluid in 30 patients with subacute sclerosing panencephalitis to evaluate oxidant and antioxidant status. Serum alpha-tocopherol, beta-carotene, retinol, ascorbic acid levels, and erythrocyte and cerebrospinal fluid reduced glutathione concentrations were decreased; however, erythrocyte and cerebrospinal fluid malondialdehyde levels were increased in the patients. Cerebrospinal fluid malondialdehyde levels were different between clinical stages of the disease (P < .05). Higher cerebrospinal fluid malondialdehyde level was associated with the more severe clinical stage. A positive correlation was found between cerebrospinal fluid malondialdehyde level and clinical stages (r = 0.42; P < .05) and between erythrocyte malondialdehyde level and clinical stages (r = 0.40; P < .05). Our findings showed presence of oxidative damage in subacute sclerosing panencephalitis and that antioxidants were increased as defense mechanisms of the organism against oxidative damage.

A close look at EEG in subacute sclerosing panencephalitis.

PURPOSE: To define atypical clinical and EEG features of patients with subacute sclerosing panencephalitis that may require an overview of differential diagnosis. METHODS: A total of 66 EEGs belonging to 53 (17 females and 36 males) consecutive patients with serologically confirmed subacute sclerosing panencephalitis were included in this study. Patient files and EEG data were evaluated retrospectively. EEGs included in the study were sleep-waking EEGs and/or sleep-waking video-EEG records with at least 2 hours duration. Cranial MRIs of the patients taken 2 months before or after the EEG records were included. RESULTS: Age range at the onset of the disease was 15 to 192 months (mean age: 80.02 months). Epilepsy was diagnosed in 21 (43%) patients. Among epileptic seizures excluding myoclonic jerks, generalized tonic-clonic type constituted the majority (58%). Tonic seizures were documented during the video-EEG recordings in four patients. Epileptogenic activities were found in 56 (83%) EEG recordings. They were localized mainly in frontal (58%), posterior temporal, parietal, occipital (26%), and centrotemporal (8%) regions. Multiple foci were detected in 26 recordings (39%). Epileptiform activities in the 39 (59%) EEGs appeared as unilateral or bilateral diffuse paroxysmal discharges. CONCLUSIONS: Recognition of uncommon clinical and EEG findings of subacute sclerosing panencephalitis, especially in countries where subacute sclerosing panencephalitis has not been eliminated yet, could be helpful in prevention of misdiagnosis and delay in the management of improvable conditions.

Subacute sclerosing panencephalitis presenting as neuromyelitis optica.

Subacute sclerosing panencephalitis (SSPE) is a slowly progressing inflammatory and degenerative disorder of the brain caused by a mutant measles virus. The diagnosis of SSPE is based on characteristic clinical and EEG findings (periodic complexes) and demonstration of elevated antibody titres against measles in cerebrospinal fluid. SSPE can have atypical clinical features at the onset. The authors here report a case of a 3-year-old child who presented with vision loss followed 15 months later by quadriparesis with bladder involvement. These clinical features resembled that of neuromyelitis optica. However, as the disease progressed, appearance of myoclonic jerks, periodic discharges on EEG and positive cerebrospinal fluid serology for measles led to the final diagnosis of SSPE.

[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.

Cerebrospinal fluid apolipoprotein E levels in subacute sclerosing panencephalitis.

Neurofibrillary tangles (NFTs) have been shown in 20% of subacute sclerosing panencephalitis (SSPE) cases. NFTs contain paired helical filaments formed by hyperphosphorylated tau. The intraneuronal tau metabolism and the rate of formation of paired helical filaments can be regulated by interactions between tau and isoforms of Apolipoprotein E (Apo E). Tau binds in vitro to Apo E3, interferes with the hyperphosphorylation of tau and may reduce the formation of NFTs. We investigated cerebrospinal fluid (CSF) Apo E levels in SSPE (n=37) and age-matched control (n=38) groups. The median level of total Apo E and Apo E4 were lower in the SSPE than the control group (p<0.001 and p=0.002). On the other hand, median Apo E3 level (0.28±0.23 µg/ml) was higher in the SSPE group (p<0.001). Such elevated levels of ApoE3 might play a role in controlling the formation of NFTs in SSPE. Because NFT-associated neurodegeneration is a slow process, comparison of the long-term clinical course of SSPE cases with high and low Apo E3 levels might provide further understanding or the role of these molecules in this disease, and help the planning of neuroprotective treatment.

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.

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.

Tau proteins in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis.

Neurodegenerative diseases characterized by cytoskeletal deformation and neurofibrillary tangles are associated with altered levels of tau and related proteins in cerebrospinal fluid (CSF). Neuronal or glial fibrillary tangles have been shown in 20% of subacute sclerosing panencephalitis (SSPE) patients. We therefore investigated CSF samples from 60 newly diagnosed SSPE and 31 neurological control patients for total tau (t-tau), phosphorylated tau (p-tau), and S100-B levels by ELISA. There was no difference between patient and control groups in t-tau and S100-B levels. p-Tau was lower in the SSPE group (p=0.009). Past history of measles infection, measles immunization status, latent period between measles and onset of SSPE, duration of symptoms, frequency of myoclonia, neurological deficit index, stage and progression rate of the disease, CSF glucose levels and cell counts, CSF and serum measles IgG titer, distribution of lesions on brain magnetic resonance imaging were not related to t-tau, p-tau and S100-B levels. Mental status and age were negatively correlated with t-tau, and male gender and EEG abnormalities were associated with higher t-tau levels. The levels of tau proteins in our patients suggest there is no, or only scarce and immature, neurofibrillary tangle formation in SSPE. Autopsy studies showing neurofibrillary tangles might have examined older patients with longer disease and more parenchymal involvement.

Serum and cerebrospinal fluid cytokine concentrations in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disease due to persistent measles virus infection. Its immunopathogenesis is unknown. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-6, IL-10 and IL-4 concentrations were measured in cerebrospinal fluid (CSF) and serum samples from 30 SSPE patients and 19 control subjects by cytometric bead array. CSF and serum IFN-gamma, IL-12 and IL-18 levels were measured in 18 SSPE patients by ELISA. Serum IL-4 and IL-10 (p<0.001), CSF IL-4 (p<0.001) and IL-6 (p=0.049) concentrations were lower, and serum IL-2 concentrations, higher (p=0.001) in SSPE patients. Serum TNF-alpha and IL-6, CSF TNF-alpha, IL-10, and IL-2 concentrations were not different between SSPE and control groups. Serum IFN-gamma levels were higher in stage I and II than stage III patients (p<0.05), whereas there was no difference between stages in terms of other cytokines. The levels of Th2-type cytokines: IL-4, IL-6 and IL-10 were suppressed in our SSPE cases. This finding, along with relatively elevated IFN-gamma and IL-2 levels, may suggest more active effector T cells compared to regulatory T cells (Treg), especially induced Treg, in early disease. High serum IL-2 concentrations might indicate peripheral Th1 activation. Discrepancies between various reports in the literature should be examined in view of the ages, stage and treatments of the patients studied. The interplay of various cytokines or cellular systems which may vary over time and between patients. Studies of treatment measures favoring the preservation of the early inflammatory response may be of interest in SSPE.

Cerebrospinal fluid nitric oxide levels in subacute sclerosing panencephalitis.

Oxidative damage plays a role in neurodegenerative diseases. Levels of cerebrospinal fluid nitrite and nitrate levels (oxidation products that provide an indirect estimation of nitric oxide) were investigated in relation to clinical and laboratory features in subacute sclerosing panencephalitis (n = 47) and age-matched control (n = 43) groups. Significantly decreased levels of nitrite (median, 4.91 micromol/L) and nitrate (median, 6.14 micromol/L) were found in the patients. Nitrite and nitrate levels did not correlate with clinical or laboratory findings, except for presence of myoclonus. Cerebrospinal fluid nitrite levels of subacute sclerosing panencephalitis patients without myoclonic jerks were significantly higher than in those with myoclonus (median, 15.63 vs 4.34 micromol/L, respectively). The higher levels of nitrite in these patients can be explained by short disease duration and early stages of disease. Nitrate levels in subacute sclerosing panencephalitis patients with myoclonus (median, 9.26 micromol/L) were higher than in those without myoclonus (median, 4.25 micromol/L). Microbleeding resulting in conversion of nitrite to nitrate and increased production of superoxide can be suggested as possible mechanisms underlying these findings.

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.