Clin. exp. Immunol. (1976) 23, 451-455.

Transient appearance of oligoclonal immunoglobulins and measles virus antibodies in the cerebrospinal fluid in a case of acute measles encephalitis BIRGIT SKOLDENBERG, ANDERS CARLSTROM, MARIANNE FORSGREN & ER LING NO RRBY Departments of Infectious Diseases and Clinical Chemistry, Danderyd Hospital, Virus Department, Microbiological Central Laboratory of Stockholm County, and Department of Virology, Karolinska Institutet, School of Medicine, Stockholm, Sweden (Received 24 July 1975)

SUMMARY

Acute measles encephalitis with severe sequelae in a 25-year-old man was studied. A transient appearance of oligoclonal IgG in cerebrospinal fluid and of intrathecally produced measles antibodies was found during 2 months after the onset of the disease. On the basis of this finding of local hyperimmunization it is proposed that in the case studied the measles virus infection may have been directly responsible for the disease process in the central nervous system.

INTRODUCTION Acute encephalitis is a frightening complication of primary measles virus infection with an estimated approximative incidence of 1: 1000 (Miller, Slanton & Gibbons, 1956). Besides this, post-infectious encephalitis measles virus is also responsible for subacute sclerosing panencephalitis (SSPE), a late sequelae of the acute infection (ter Meulen, Katz & MUller, 1 972b). Patients with SSPE have high titres of measles antibodies in serum and cerebrospinal fluid (CSF). A local production of measles virus antibodies in the central nervous system (CNS) of patients with SSPE has been shown (Salmi, Norrby & Panelius, 1972) by means of analysis of the ratios of serum: CSF measles antibody titres as compared with the corresponding ratios of reference antibody titres. Local hyperimmunization with production of immunoglobulin G (IgG) has been linked to the presence of measles virus antigen. The virus isolated from cases of SSPE is immunologically indistinguishable from regular measles virus (Payne, Baublis & Itabashi, 1969). In certain cases of multiple sclerosis (MS) the situation is somewhat similar. Persistent intrathecal production of measles virus antibodies has also been demonstrated in more than half of the cases (Norrby, Link & Olsson, 1974; Salmi et al., 1972). However, there is no direct evidence for the presence of measles virus antigen in the CNS of MS patients. In contrast to MS and SSPE the immunology of acute measles encephalitis has been very poorly analysed. It is known that in most cases there is an increase in the protein content of the CSF (Miller et al., 1956). Whether this is due to damage to the blood-brain barrier or possibly to a local production in the CNS of antibodies against the virus has not been investigated. Correspondence: Professor Erling Norrby, Department of Virology, Karolinska Institutet, SBL, 105 21 Stockholm 1, Sweden.

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Here we present a case of acute measles encephalitis with a local and transient hyperimmunization in the CNS reflected in a concomitant occurrence of locally produced measles virus antibodies and oligoclonal IgG.

MATERIALS AND METHODS Immunochemical methods. Electrophoresis of CSF was performed in agarose gel as described by Johansson (1972). Prior to the electrophoretic separation, the CSF was concentrated 100 times using Minicon B 15 cells (Amicon, Netherlands). Immunoglobulin G, A, and M as well as albumin in CSF and in serum were determined by the method of electro-immunoassay described by Laurell (1972). Before the determinations the immunoglobulins were carbamylated according to the method of Weeke (1969), with some modifications (Carlstrom et al., in preparation). Total protein concentration in CSF was determined by Lowry's method as described by Eggstein & Kreutz (1955). Serological tests. Measles virus haemagglutination-inhibiting (HI), haemolysin-inhibiting (HLI) and nucleocapsid complement-fixing (NC-CF) antibody titres were determined as described previously (Norrby & Gollmar, 1972; Norrby et al., 1974). The Edmonston A strain propagated in Vero cells and treated with polysorbate 80 and ether was used as antigen in HI tests. Products of the SSPE-measles virus strain LEC were used as antigen in HLI and NC-CF tests. There were no differences in the antibody titres recorded when virus material of the other strains was used in any of the tests. Group-specific adenovirus penton haemagglutination-enhancement (HE) antibodies and poliovirus neutralizing antibodies were determined as described previously (Norrby et al., 1974).

RESULTS Case report The patient was a 25-year-old man, previously in good health with no history of measles and no known exposure to measles. He fell ill on 9 May 1974, with rhinitis, an increasing hacking cough, and fever. On 10 May a confluent papular exanthem developed on his face and spread over his body during the following 2 days. On 12 May he suddenly became unconscious and had prolonged convulsions. On admission to hospital the patient was unconscious, had tonic spasms of the extensor muscles with rigidity of all extremities, superficial breathing, a temperature of 40.90 C and haemorrhagic exanthem on his chest, trunk and thighs. He was given intensive therapy, including treatment in a respirator with positive pressure. The degree of wakefulness increased slowly and the respirator treatment was gradually reduced until mid-July. A duodenal tube was used for feeding until mid-August; the tracheal tube was removed in mid-September. In December, 7 months after the onset of the symptoms, the patient was transferred to the rehabilitation ward. By then he had slight dysarthria and answered adequately without latency. He was dysphoric; the function of cranial nerves was normal; he had slight tetraparesis with fairly marked spasticity, moderate intention tremor, and ataxia. Psychological testing in January 1975 revealed a reduction of the patient's general intellectual level to one slightly below average with a very even test profile.

Electroencephalography In mid-May severe diffuse functional disturbances without focal or epileptogenic findings were found. A gradual improvement of the EEG changes occurred, but the pattern was not normalized until December. Leucocytes and immunoglobulin abnormalities in CSF Determinations of the ratios between the albumin concentration in CSF and serum and the corresponding ratios of immunoglobulins G, A and M (Delpech & Lichtblau, 1972; Ganrot & Laurell, 1974) indicated that there was an intrathecal production of immuno-

Oligoclonal IgG-acute measles encephalitis

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TABLE 1. CSF contents of leucocytes, total protein concentration, bands of oligoclonal Ig and indications of intrathecal IgG and IgM production in a patient with acute measles encephalitis (onset of encephalitic signs on 12 May)

Date 12 May 16 May 24 May 17 June 18 July 29 October 9 December

Leucocytes per mm3

Protein concentration (mg/100 ml)

Intrathecal IgG production*

Intrathecal IgM production*

Oligoclonal Ig bands

0 28 0 0 0 6 1

103 126 137 100 80 82 56

n.i. + +

n.i.

-

-

n.i. + + (+) -

-

-

+ -

-

-

n.i. = Not investigated. * For criteria of intrathecal IgG and IgM production see Delpech & Lichtblau (1972), Ganrot & Laurell (1974).

globulins G and M in the early stage of the illness. During approximately the same period oligoclonal immunoglobulin bands were observed in the electrophoretic patterns on concentrated CSF (Table 1). No oligoclonal immunoglobulin bands were seen in serum.

Antibody titres in serum and cerebrospinalfluid Comparison of measles CF antibody titres in sera collected on 13 May and 20 May demonstrated a significant rise in antibody titre. Serum titres of antibodies against different measles virus antigens decreased with time from May and onwards in a manner normal for measles (Table 2). Titres of antibodies against adenovirus and poliovirus did not show significant changes. TABLE 2. Antibody titres (reciprocals) in serum and CSF samples from a patient with acute measles encephalitis (onset of encephalitic signs on 12 May)

Antibodies to measles virus* Date of sampling 16 May

Sample HI

Serum CSF

24 May 17 June

18 July 29 October

10 December

Antibodies to reference virus*

Serum CSF Serum CSF Serum CSF Serum CSF Serum CSF

160

lot

16

160 16 80 2 20

Transient appearance of oligoclonal immunoglobulins and measles virus antibodies in the cerebrospinal fluid in a case of acute measles encephalitis.

Clin. exp. Immunol. (1976) 23, 451-455. Transient appearance of oligoclonal immunoglobulins and measles virus antibodies in the cerebrospinal fluid i...
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