key: cord-0009293-u3oqaem7
authors: Vaheri, Antti; Julkunen, Ilkka; Koskiniemi, Marja-Leena
title: CHRONIC ENCEPHALOMYELITIS WITH SPECIFIC INCREASE IN INTRATHECAL MUMPS ANTIBODIES
date: 1982-09-25
journal: Lancet
DOI: 10.1016/s0140-6736(82)90713-9
sha: 8a6d8754a8f644b6decc50b0ea53493105d21ac5
doc_id: 9293
cord_uid: u3oqaem7

Symptoms of severe encephalomyelitis developed in a 31-year-old man in 1967. He had a high serum antibody titre to mumps virus associated with a polymorphic cell reaction and an increased protein concentration in cerebrospinal fluid (CSF). He recovered considerably within a year and was able to resume work. In 1975 his condition deteriorated again; it improved during the following few years, but a further deterioration then occurred. In March, 1981, the complement-fixing antibody titre to mumps virus was 1/32 in the serum and 1/4 in the CSF. In November, 1981, the CSF IgG index was increased and the altered serum/CSF antibody ratio persisted. The specificity of the altered antibody ratio was confirmed by the single radial haemolysis test and an immunoassay specific for mumps virus. Antibodies against the mumps virus envelope glycoprotein, M-protein, and nucleoprotein could be demonstrated by immunoprecipitation and the antibody patterns in serum and CSF were similar. Antibodies against other microorganisms were not detected in the patient's CSF, and mumps antibodies were not found in the CSF specimens of 57 control patients. This case may be an example of a new disease—chronic mumps virus infection in the central nervous system.

Agarose gel electrophoresis of plasmid DNA extracted from Pseudomonas aeruginosa strains from various sources: A=unopened gallon iodophor container from ward 2; B and E = peritoneal fluid from two separate patients; C = iodophor bottle from room 2 of dialysis area; D=molecular weight control plasmids: 2457 0 s(r) (140 and 105 megadalton), Rl(62 megadalton), RP4(34 megadalton); and

F=culture from infection at catheter insertion site. these products, and our finding of two of eight containers of the same lot number positive in widely varying concentrations echoes this problem. We need to determine factors that permit survival of bacteria in iodophors, and whether the containers used for the solution can affect antimicrobial efficacy. We need to determine a measure of iodophor potency that correlates well with bactericidal activity. Most important is the need to reassess the guidelines for use of these agents as disinfectants and antiseptics.11

Iodophors are widely used and recommended for rhis purpose by hospitals today, and guidelines for these uses should take into account the possibility of microbial contamination. This may be an especially important issue when these agents are considered as an antiseptic for use before surgery; before they are thus used it may be necessary to define a standard of sterility for the product.

We thank Dr Ruth Berkelman for her helpful advice and Dr Roger Anderson and Anita Highsmith for confirming the isolation of and serotyping the bacterial strains. Symptoms of severe encephalomyelitis developed in a 31-year-old man in 1967. He had a high serum antibody titre to mumps virus associated with a polymorphic cell reaction and an increased protein concentration in cerebrospinal fluid (CSF). He recovered considerably within a year and was able to resume work. In 1975 his condition deteriorated again; it improved during the following few years, but a further deterioration then occurred. In March, 1981, the complement-fixing antibody titre to mumps virus was 1/32 in the serum and 1/4 in the CSF. In November, 1981, the CSF IgG index was increased and the altered serum/CSF antibody ratio persisted. The specificity of the altered antibody ratio was confirmed by the single radial haemolysis test and an immunoassay specific for mumps virus. Antibodies against the mumps virus envelope glycoprotein, M-protein, and nucleoprotein could be demonstrated by immunoprecipitation and the antibody patterns in serum and CSF were similar. Antibodies against other microorganisms were not detected in the patient's CSF, and mumps antibodies were not found in the CSF specimens of 57 control patients. This case may be an example of a new disease—chronic mumps virus infection in the central nervous system. We report a patient with chronic encephalomyelitis with a specific increase in intrathecal antibodies to mumps virus.

The complement fixation (CF) test was used to assay antibodies to adenovirus, corona virus, Coxsackie B5, cytomegalovirus, hepatitis B, herpes simplex, influenza A and B, measles, mumps, parainfluenza 1 and 3, polio, respiratory syncytial, rotavirus, and varicella viruses and to Chlamydia group antigen, Mycoplasma pneumoniae, and Toxoplasma gondii. Single radial haemolysis (SRH) tests ('Orivir', Orion Diagnostica, Helsinki, Finland) were used to detect mumps, rubella, and influenza A (Victoria strain) viruseslo-II and solid-phase enzyme-immunoassays (EIA) for mumps and cytomegalovirus antibodies. [12] [13] [14] In addition, patient's CSF (100 µl)was absorbed with 50 pg of mumps virus for 4 h at 4°C and the virus was pelleted (100 000 g, 30 min), and mumps antibodies were sought by an SRH test of the supernatant.

Serum and CSF concentrations of IgG and albumin were simultaneously measured by automated fluoronephelometry (Technicon 'AutoAnalyzer'). The IgG index (CSF IgG/serum IgG x serum albumin/CSF albumin) was calculated according to Delpech and Lichtblauls and de novo IgG synthesis in the CNS according to Tourtellotte et al.I6 Oligoclonal bands were determined as described.12 *Present address: Department of Paediatrics, University of Helsinki.

Purified mumps virus (Enders strain; 1 mg) grown in chickens' eggs was radiolabelled with 1251 (0 -5 mCi) by the chloramine T method of Krohn et Sweden) in phosphate buffered saline was added for 1 h at 37°C. Sepharose was washed twice with the triton/saline liquid and once with sodium dodecyl sulphate (SDS) depleted electrophoretic buffer, always pelleting with an Eppendorf microcentrifuge between washings. Sepharose-bound proteins were solubilised in 50 J..Il of electrophoretic buffer in the presence of 10% mercaptoethanol and boiled for 3 min. The supernatant was run in polyacrylamide (10%) gel electrophoresis in the presence of SDS (SDS-PAGE), dried, and the precipitated virus proteins were detected as bands by autoradiography.

Case-report In February, 1967, a 31-year-old, previously healthy man developed fever, headache, and vomiting followed by paraesthesia, muscular weakness, disturbances of micturition, and diplopia. Three weeks after the onset of symptoms spastic paresis of the legs, distal weakness of the arms, and vague sensory disturbances in the legs were noted. A positive Babinski sign appeared bilaterally, tendon stretch reflexes were brisk, and abdominal reflexes were absent. In addition nystagmus, intention tremor and dysarthria were present and the patient seemed euphoric. In April his legs were paralysed. An electroencephalogram (EEG), first obtained in April, 1967, was normal, brain scan was also normal. An electroneuromyogram (ENMG) revealed marked denervation in the legs suggesting an anterior-horn lesion similar to that in poliomyelitis. The patient was treated in hospital until October, 1967, and diagnosed as having acute encephalomyelitis. He was rehabilitated, was able to walk in a year, received professional training as a technician, and worked until 1975. His condition deteriorated in 1975 and he had difficulty in walking and some spasticity. After a period of improvement lasting some years his symptoms increased again early in 1980, with positive Babinski sign, ankle clonus, and neuropsychological deficiences. His condition has remained poor and he is unable to work. There has been a further deterioration since 1980. Both EEG and computed tomography were normal in 1981. An ENMG showed a chronic neurogenic lesion without active denervation.

Hospital records showed that in 1967 serum mumps CF titre was high (1:128) without evidence of clinical parotitis or previous mumps vaccination. At that time the CSF was not tested for antibody and no virus was detected. CSF contained 321 leucocytes per µl, total protein was raised (1500 mg/1 [normal range 150-450 mg/1), and glucose concentration was normal. Serum mumps CF titre remained high and titres of 1:128, 1:64, and 1:64 were later recorded in 1967.

In March, 1981, mumps CF titre was 1:32 in serum and 1:4 in CSF and no other antibodies were detected in CSF.

Thus the serum/CSF antibody ratio was 8, while the serum/CSF ratio for total IgG was normal at 252 (normal range 200-300). At this time total protein concentration in CSF was normal (353 mg/1) and there were no cells. This was also the situation in November, 1981. However, CSF IgG was slightly raised as was the IgG/albumin ratio ( (table II) .

Since oligoclonal CSF IgG bands have been described in acute as well as in chronic infections of the central nervous system, 7,16,19 the patient's CSF specimen was further analysed by the SDS-PAGE procedure.l' We found a moderate increase in the IgG region ( fig. 1 ).

The patient's antibody response to mumps virion proteins was investigated by immunoprecipitation. The precipitated protein bands indicate the presence of antibodies. We found antibodies to envelope glycoproteins haemagglutininneuraminidase (HN, 75K), fusion protein (Fl, 58K), viral membrane protein (M, 39K), and various nucleocapsid proteins (200K, 68K, 45K and 42K) (fig. 2 ).20 Our lysis buffer leaves the nucleocapsid intact and possibly different nucleocapsid proteins are precipitated together. The antibody patterns in serum and CSF were. similar and resemble the antibody response in serum of patients with acute mumps infection (Julkunen I, unpublished observations). Control sera and CSF with no mumps antibodies did not precipitate any virion proteins ( fig. 2 ).

This patient had chronic encephalomyelitis with a slowly progressive course and a specific increase in mumps antibodies in the CSF and intrathecal IgG production with an oligoclonal pattern. Intrathecal antibody production has been reported in chronic CNS infections caused by measles8 and rubella,5 and probably herpes viruses.21 In acute mumps virus meningitis CNS antibody production has been detected. 13 Vandvik et al.22 reported prolonged pleocytosis in CSF as late as a year after mumps meningitis, suggesting persistence of virus infection in the CNS. An earlier paper23 reported a case of aqueductal stenosis two years after mumps encephalitis but with no serological follow-up in the CSF or other evidence of ongoing mumps infection. We know of no other reports of prolonged disease or antibody production caused by mumps virus. Mumps virus can cause spinal-cord as well as pontine and cerebellar lesions. 24,25 Our patient displayed these features but a chronic progressive course also developed. In addition, some cerebral signs such as neuropsychological deficiences were observed.

Increased titres to measles virus and to several other viruses including mumps virus have been found in multiple sclerosis without evidence of viral antigen in CNS.19 It has been suggested that the broad-spectrum viral antibody response in the CNS in this disorder results from a polyclonal B cell activation. In the present case only antibodies to mumps virus were increased in the CSF, and we were able to absorb the antibodies with purified mumps virus.

By immunoprecipitation we demonstrated that the antibody response to mumps virus was similar in the patient's serum and CSF and was directed against nearly all structural proteins including M-protein. In chronic measles-virus encephalitis a lack of antibodies against M-protein has been detected and the possibility of defective viral protein synthesis has been discussed, 26, 27 The present case could represent a chronic form of mumps virus infection in the CNS. This can only be confirmed by virus isolation or demonstration of antigen within brain tissue. Mumps virus has a remarkable tendency to produce chronic infections in cell cultures,28 but has not previously been associated with chronic human infection.

We thank Dr M. Kaste for serum and CSF specimens, Dr J. Suni for performing the cytomegalovirus EIA, and Mrs Liisa Pitkanen for expert technical assistance. This work was supported by the Association of Finnish Life Assurance Companies.

Correspondence should be addressed to A. V., Department of Virology, University of Helsinki, Haartmarinkatu 3, 00290 Helsinki 29, Finland.

Pseudomonas aeruginosa is a common respiratory pathogen in cystic fibrosis (CF) patients. Where patients acquire their infecting strains from is unclear. Some workers believe that cross-infection contributes to the frequent isolation of Ps. aeruginosa. 1,2 If cross-infection did occur, clearly it would be important to attempt to separate CF patients from each other socially and during hospital attendances. We tried to determine the extent of pseudomonas cross-infection by investigating the types of respiratory isolates and relating them to the degree of contact that patients had with each other.-The study was based on the premise that the greater the degree of contact that patients had with each other, the more likely it was for cross-infection to occur. It did not dismiss the possibility that infection could be acquired from the environement.

Patients were grouped according to the degree of contact they were likely to have had with each other. _ Group A (low-contact) consisted of 26 unrelated adolescent CF patients (mean age 17 -15 years) who attended a general respiratory outpatient clinic in St Vincent's Hospital, Elm Park, Dublin. Here, generally only 2-3 CF patients attend the same outpatient session, and only rarely are there more than 2 CF inpatients at any one time.

Group B (medium contact) consisted of 26 unrelated paediatric CF patients (mean age 6 -5 years) who attended a special CF outpatient clinic at Our Lady's Hospital for Sick Children, Crumlin, Dublin. Here there are generally 12-18 CF patients at each outpatient session, and there are likely to be more than one CF inpatient at any one time.

Group C (close contact) consisted of 14 pairs of CF siblings.

Patients usually attended as outpatients every 3-4 months, and sputum samples, or occasionally throat swabs, were taken at each outpatient visit over the course of a year. The samples were plated on blood agar, cystine lactose electrolyte deficient agar (CLED), and cetrimide agar ('Pseudosel' agar, BBL).

Antibiotic susceptibility testing by a single disk method

Simple agarose gel electrophoresis method for the identification and characterization of plasmid deoxyribonucleic acid

A rapid alkaline extraction procedure for screening recombinant plasmid

Serological characteristics of P. aeruginosa

Centers for Disease Control Epidemiologic notes and reports: Pseudomonas aeruginosa peritonitis attributed to a contaminated iodophor solution—Georgia

Subacute sclerosing panencephalitis: isolation of measles from a brain biopsy

Subacute sclerosing panencephalitis: a review

Non-congenital rubella encephalitis

Progressive rubella panencephalitis. Late onset after congenital rubella

Chronic progressive panencephalitis due to rubella virus simulating subacute sclerosing panencephalitis

Comparison of antibodies against different viruses in cerebrospinal fluid and serum samples from patients with multiple sclerosis

Oligoclonal IgG antibody response in the central nervous system to different measles virus antigens in subacute sclerosing panencephalitis

Quantification of de novo central nervous system IgG measles antibody synthesis in SSPE

Central nervous system syndromes of "viral" etiology

Determination of mumps and influenza antibodies by haemolysis-in-gel

Haemolysis-in-gel test in immunity surveys and diagnosis of rubella

semiautomated enzyme-linked immunosorbent assay for viral antibodies

Local production of mumps IgG and IgM antibodies in the cerebrospinal fluid of meningitis patients

Solid-phase enzyme immunoassay for immunoglobulin M antibodies to cytomegalovirus

Étude quantitative des immunoglobulines G et de l'albumine du liquide cephalo-rachidien

Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate

Micromethod for detection of oligoclonal IgG in unconcentrated CSF by polyacrylamide gel elctrophoresis

Studies of radioiodinated fibrinogen I. Physiocochemical properties of the ICI, chloramine-T and electrolytic reaction products

Antibodies to viral and nonviral antigens in subacute sclerosing panencephalitis and multiple sclerosis demonstrated by thin-layer polyacrylamide gel isoelectric focusing, antigen immunofixation and autoradiography

A comparison of the structural polypeptides of five strains of mumps virus

Diagnostic value of cerebrospinal fluid antibodies in herpes simplex virus encephalitis

Mumps meningitis: prolonged pleocytosis and occurrence of mumps virus-specific oligoclonal IgG in the cerebrospinal fluid

Aqueductal stenosis and hydrocephalus after mumps encephalitis

Mumps virus infection simulating paralytic poliomyelitis

Sequelae of mumps-meningoencephalitis

The functions and inhibition ofthe membrane glycoproteins of paramyxoviruses and myxoviruses and the role of the measles virus M protein in subacute sclerosing panencephalitis

Antibody response to structural proteins of measles virus in patients with natural measles and subacute sclerosing panencephalitis

A persistent infection of Vero cells by eggadapted mumps virus

Our Lady's Hospital for Sick Children, Crumlin; and Department of Clinical Microbiology, St. James's Hospital, James's St