Acta Neurol. Scandinav. 56, 177-180, 1977
S H O R T COMMUNICATIONS
Departments of Neurology, Neurosurgery, and Virology, University of Turku, Turku, Finland. ANTIBODIES AGAINST HERPES SIMPLEX VIRUS TYPE 1 SUBUNIT ANTIGENS IN PATIENTS WITH TRIGEMINAL NEURALGIA AND CONTROLS
Reijo J . Marttila, Harry Frey, Kirsti 0 . K . Kalimo, Ilkka Rautakorpi and Tapio T o r m a
ABSTRACT Serum IgG antibody levels against herpes simplex virus (HSV) type 1 subunit (capsid, envelope, and excreted) antigens detected with radioimmunoassay were compared in 25 patients with trigeminal neuralgia and their age- and sex-matched controls. No significant differences were found between the patients and controls, either in the distribution of the antibody titers o r in the mean titers against any of the subunit antigens tested. In 6 patients HSV antibody titers were tested before and after trigeminal root section; no significant changes were observed. Herpes simplex virus is known to reside in a latent form in human trigeminal ganglia (Bastian et al. 1972, Baringer h Swoueland 1973). Reactivation takes place after various stimuli, most consistently after trigeminal sensory root section (Carton & Kilbourne 1952) and t h e virus travels probably along axons (Kristensson 1970) into the skin or mucous membranes causing a typical recurrent HSV infection, a cold sore. Shortly before recrudescence, neuralgic pains are sometimes observed in thc trigeminal area (Behrman & Knight 1954, Constantine et al. 1968). In addition to acute and recurrent infections, HSV is suspected to be involved in oncogencsis of the cervical carcinoma ( R a w l s et al. 1973) and some preliminary data suggest t h a t HSV might have connections with certain chronic brain diseases (Halonen et al. 1974, Lycke et al. 1974, Marttila et al. 1977). Furthermore, HSV might have etiological importance in some cases of facial pain and trigeminal sensory neumpathy (Krohel et al. 1976). Since the peculiar interaction of HSV and nervous tissue is not fully known, a possibility remained that due t o the close relationship of HSV with t h e trigeminal ganglion, the HSV infection and trigeminal neuralgia could be linked with each other. Accordingly, the present study was carried out to investigate the antibody response against HSV i n patients with trigeminal neuralgia in comparison with age- and sex-matched controls.
Patients and Methods Patients. Twenty-five patients with trigeminal neuralgia attending the Department of Neurology o r t h e Department of Neurosurgery of the University Central
Capsid patients controls Envelope patients controls Excreted patients controls 1 2 1
12 12
24 25
24 25
< 11.0
24 25
No positive Titer (log,)
2 2
3 4
6 7
3 7
5
3
-
5 2
13.0-13.9
8 G
12.0-12.9
3 3
11.0-11.9
-
1
9 12
4
3
2 15.0
-
6 3
4 8
14.0-14.9
10.9 & 1.7 10.9 f 1.6
14.3 f 1.8 14.6 f 1.4
13.1 & 1.6 13.4 & 1.6
Mean -t SD
Table 1. Serum ZgG antibodies against HSV subunit antigens in 25 patients with trigeminal neuralgia and 25 controls.
4
c.r 00
179 Hospital i n Turku were included i n the study. The diagnosis was based o n the occurrence of typical, temporary, short-lasting pains in the trigeminal area without neurological findings. The patients consisted of 10 men and 15 women. The mean age of the patients was 58.4 years with a range from 37 to 76. The mean duration of t h e disease was 5.9 years, range 1-13. Five patients had previously undergone a trigeminal root section and the operation was carried out i n 6 further patients during this study. Controls. Control persons, matched i n sex and age for each patient, were selected from among the persons attending a general health examination in southwest Finland. Serum specimens. Both the patient and control sera were collected in March-May, 1976. except f o r 6 patients from whom a serum sample was obtained before a trigeminal root section and a second sample 1 to 4 wccks after the operation. Thc sera were stored a t - 20" C until tested. Serological technique. A solid-phase radioimmunoassay method, developed to demonstrate class specific HSV antibodies (Kalimo et al. 1977 a ) and further applied to the detection of antibodies against HSV capsid, envelope, and excreted antigens, was used as previously described in detail (Kalimo et al. 1977 b). HSV capsid and envelope antigens were prepared according to Martin e t al. (1972), and excreted antigen as described by Kaplan e t 01. (1975). Only IgG antibodies were tested.
Results When the history of occurrence of recurrent orofacial HSV infections was taken, only three patients and three controls reported previous cold sores. The results of the antibody tests are shown i n t h e Table. A cornparison of the distribution of the antibody titers to different subunit antigens did not show any significant differences between the patients and controls (p 0.05; Chi-square test). The HSV antibody titers did not differ significantly between the patients and controls ( p 0.05; Mann-Whitney's U test). Furthermore, no significant changes were found i n the antibody titers to HSV subunit antigens i n t h e sera taken after t h e trigeminal root section compared with the preoperative sera of the same patients. In no patient was a n immediate HSV recurrence observed after t h e operation.
>
>
Discussion Based on antibody studies, the HSV might be linked with several chronic disorders. Increased HSV type 2 antibody response is found among patients with cervical carcinoma (Rawls e t al. 1973). A higher HSV antibody level, i n comparison with controls, is observed in patients with certain chronic brain diseases, namely psychotic depression (Halonen et al. 1974), dementia (Lycke et al. 1974), and Parkinson's disease (Marttila et al. 1977). However, a t present, the significance of these findings still remains unknown b u t nevertheless they suggest a potential linkage of HSV with chronic disorders of the nervous system. A theoretically interesting possibility of connecting HSV with trigeminal neuralgia was a n indication for us to carry out this comparative serological study. The newly developed, highly sensitive and specific radioimmunoassay of antibodies against HSV subunit antigens (Kalimo et al. 1977 b ) was adopted to achieve as high a discrimination of antibody titers as possible. Furthermore, t h e antibody response to HSV subunit antigens is known to depend on the type of HSV infection, i.e. primary, latent, or recurrent (Martin et al. 1972, Back h Schmidt 1974, Kalimo et al. 1977 b).
180 The results of the study, however, showed a similar occurrence and level of antibodies against different HSV subunit antigens i n the patients with trigeminal neuralgia and their controls. Consequently, it seems that the patients with trigeminal neuralgia harbour latent HSV as often as do the controls, and that the humoral immune response against virus is analogous in both groups. Thus, no support was gained for the contribution of HSV to the ctiopathogenesis of trigeminal neuralgia.
Acknowledgements This study was supported by the Academy of Finland, Medical Research Council. Marjut Kallila and Marita Maaronen provided excellent technical assistance. References Back, A. F. & N. J. Schmidt (1974): Reactivity of envelope, capsid, and soluble antigens of herpesvirus hominis types 1 and 2 in the indirect hemagglutination test. Infect. Immun. 10, 102-106.-Baringer, J. R. & P. Swoveland (1973): Recovery of herpes simplex virus from human trigeminal ganglions. New Engl. J. Med. 288, 648-650.-Bastian, F. O., A. S. Rabson, C. L. Yee & T. S. Tralka (1972) : Herpesvirus hominis : isolation from human trigeminal ganglion. Science 178, 306-307.-Behrman, S. & G. Knight (1954) : Herpes simplex associated with trigeminal neuralgia. Neurology 4, 525-530.--Carton, C. A. & E. D. Kilbourne (1952) : Activation of latent herpes simplex by trigeminal sensory-root section. New Engl. J. Med. 256, 172-176.Constantine, V. S., R. D. Francis & L. F. Montes (1968): Association of recurrent herpes simplex with neuralgia. J A M A 05, 181-183.-Halonen, P. E., R. Rimon, K. Arohonka & V. Jiintti (1974) : Antibody levels to herpes simplex type 1, measles and rubella viruses i n psychiatric patients. Br. J. Psychiat. 125, 461-465.--Kalimo, K. 0. K., B. 2. Ziola, M. K. Viljanen, K. Granfors & P. Toivanen (1977 a) : Solid-phase radioimmunoassay of herpes simplex virus IgG and IgM antibodies. J. Immunol. Methods 14, 183-195.--Kalimo, K. 0. K., R. J. Marttila, K. Granfors & M. K.Viljanen (1977 b) : Solid-phase radioimmunoassay of human IgM and IgG antibodies against herpes simplex virus type 1 capsid, envelope, and excreted antigens. Infect. Immun. (in press).-Kaplan, A. S., J. S. Erickson & T. Ben-Porat (1975): Synthesis of proteins in cells infected with herpesvirus. X. Proteins excreted by cells infected with herpes simplex virus types 1 and 2. Virology 64, 132-143.-Kristensson, K. (1970) : Morphological studies of the neural spread of herpes simplex virus to the central ncrvous system. Acta Neuropath. 16, 5&63.--Krohel, G. B., J. R. Richardson & D. F. Farrell (1976) : Herpes simplex neuropathy. Neurology 26, 596-597.-Lycke, E., R. Norrby & B. E. Roos (1974): A serological study o n mentally ill patients. Br. J. Psychiat. 124, 273-279.-Martin, M. L., E. L. Palmer & R. E. Kissling (1972): Complement-fixing antigens of herpes simplex virus types 1 and 2: reactivity of capsid, envelope, and soluble antigens. Infect. Immun. 5, 248-254.--Marttila, R. J., P. Arstila, J. Nikoskelainen, P. E. Halonen & U. K. Rinne (1977) : Viral antibodies in the sera from patients with Parkinson disease. Eur. Neurol. 15, 25-33.-Rawls. W.E.,E. Adam & J. L. Melnick (1973) : An analysis of seroepidemiological studies herpesvirus type 2 and carcinoma of the cervix. Cancer Rcs. 33, 1477-1482. Received January 31, accepted March 8, 1977.
R . Marttila, M.D. Department of Neurology University of Turku SF-20520 Turku 52 Finland
S H O R T COMMUNICATIONS
Departments of Neurology, Neurosurgery, and Virology, University of Turku, Turku, Finland. ANTIBODIES AGAINST HERPES SIMPLEX VIRUS TYPE 1 SUBUNIT ANTIGENS IN PATIENTS WITH TRIGEMINAL NEURALGIA AND CONTROLS
Reijo J . Marttila, Harry Frey, Kirsti 0 . K . Kalimo, Ilkka Rautakorpi and Tapio T o r m a
ABSTRACT Serum IgG antibody levels against herpes simplex virus (HSV) type 1 subunit (capsid, envelope, and excreted) antigens detected with radioimmunoassay were compared in 25 patients with trigeminal neuralgia and their age- and sex-matched controls. No significant differences were found between the patients and controls, either in the distribution of the antibody titers o r in the mean titers against any of the subunit antigens tested. In 6 patients HSV antibody titers were tested before and after trigeminal root section; no significant changes were observed. Herpes simplex virus is known to reside in a latent form in human trigeminal ganglia (Bastian et al. 1972, Baringer h Swoueland 1973). Reactivation takes place after various stimuli, most consistently after trigeminal sensory root section (Carton & Kilbourne 1952) and t h e virus travels probably along axons (Kristensson 1970) into the skin or mucous membranes causing a typical recurrent HSV infection, a cold sore. Shortly before recrudescence, neuralgic pains are sometimes observed in thc trigeminal area (Behrman & Knight 1954, Constantine et al. 1968). In addition to acute and recurrent infections, HSV is suspected to be involved in oncogencsis of the cervical carcinoma ( R a w l s et al. 1973) and some preliminary data suggest t h a t HSV might have connections with certain chronic brain diseases (Halonen et al. 1974, Lycke et al. 1974, Marttila et al. 1977). Furthermore, HSV might have etiological importance in some cases of facial pain and trigeminal sensory neumpathy (Krohel et al. 1976). Since the peculiar interaction of HSV and nervous tissue is not fully known, a possibility remained that due t o the close relationship of HSV with t h e trigeminal ganglion, the HSV infection and trigeminal neuralgia could be linked with each other. Accordingly, the present study was carried out to investigate the antibody response against HSV i n patients with trigeminal neuralgia in comparison with age- and sex-matched controls.
Patients and Methods Patients. Twenty-five patients with trigeminal neuralgia attending the Department of Neurology o r t h e Department of Neurosurgery of the University Central
Capsid patients controls Envelope patients controls Excreted patients controls 1 2 1
12 12
24 25
24 25
< 11.0
24 25
No positive Titer (log,)
2 2
3 4
6 7
3 7
5
3
-
5 2
13.0-13.9
8 G
12.0-12.9
3 3
11.0-11.9
-
1
9 12
4
3
2 15.0
-
6 3
4 8
14.0-14.9
10.9 & 1.7 10.9 f 1.6
14.3 f 1.8 14.6 f 1.4
13.1 & 1.6 13.4 & 1.6
Mean -t SD
Table 1. Serum ZgG antibodies against HSV subunit antigens in 25 patients with trigeminal neuralgia and 25 controls.
4
c.r 00
179 Hospital i n Turku were included i n the study. The diagnosis was based o n the occurrence of typical, temporary, short-lasting pains in the trigeminal area without neurological findings. The patients consisted of 10 men and 15 women. The mean age of the patients was 58.4 years with a range from 37 to 76. The mean duration of t h e disease was 5.9 years, range 1-13. Five patients had previously undergone a trigeminal root section and the operation was carried out i n 6 further patients during this study. Controls. Control persons, matched i n sex and age for each patient, were selected from among the persons attending a general health examination in southwest Finland. Serum specimens. Both the patient and control sera were collected in March-May, 1976. except f o r 6 patients from whom a serum sample was obtained before a trigeminal root section and a second sample 1 to 4 wccks after the operation. Thc sera were stored a t - 20" C until tested. Serological technique. A solid-phase radioimmunoassay method, developed to demonstrate class specific HSV antibodies (Kalimo et al. 1977 a ) and further applied to the detection of antibodies against HSV capsid, envelope, and excreted antigens, was used as previously described in detail (Kalimo et al. 1977 b). HSV capsid and envelope antigens were prepared according to Martin e t al. (1972), and excreted antigen as described by Kaplan e t 01. (1975). Only IgG antibodies were tested.
Results When the history of occurrence of recurrent orofacial HSV infections was taken, only three patients and three controls reported previous cold sores. The results of the antibody tests are shown i n t h e Table. A cornparison of the distribution of the antibody titers to different subunit antigens did not show any significant differences between the patients and controls (p 0.05; Chi-square test). The HSV antibody titers did not differ significantly between the patients and controls ( p 0.05; Mann-Whitney's U test). Furthermore, no significant changes were found i n the antibody titers to HSV subunit antigens i n t h e sera taken after t h e trigeminal root section compared with the preoperative sera of the same patients. In no patient was a n immediate HSV recurrence observed after t h e operation.
>
>
Discussion Based on antibody studies, the HSV might be linked with several chronic disorders. Increased HSV type 2 antibody response is found among patients with cervical carcinoma (Rawls e t al. 1973). A higher HSV antibody level, i n comparison with controls, is observed in patients with certain chronic brain diseases, namely psychotic depression (Halonen et al. 1974), dementia (Lycke et al. 1974), and Parkinson's disease (Marttila et al. 1977). However, a t present, the significance of these findings still remains unknown b u t nevertheless they suggest a potential linkage of HSV with chronic disorders of the nervous system. A theoretically interesting possibility of connecting HSV with trigeminal neuralgia was a n indication for us to carry out this comparative serological study. The newly developed, highly sensitive and specific radioimmunoassay of antibodies against HSV subunit antigens (Kalimo et al. 1977 b ) was adopted to achieve as high a discrimination of antibody titers as possible. Furthermore, t h e antibody response to HSV subunit antigens is known to depend on the type of HSV infection, i.e. primary, latent, or recurrent (Martin et al. 1972, Back h Schmidt 1974, Kalimo et al. 1977 b).
180 The results of the study, however, showed a similar occurrence and level of antibodies against different HSV subunit antigens i n the patients with trigeminal neuralgia and their controls. Consequently, it seems that the patients with trigeminal neuralgia harbour latent HSV as often as do the controls, and that the humoral immune response against virus is analogous in both groups. Thus, no support was gained for the contribution of HSV to the ctiopathogenesis of trigeminal neuralgia.
Acknowledgements This study was supported by the Academy of Finland, Medical Research Council. Marjut Kallila and Marita Maaronen provided excellent technical assistance. References Back, A. F. & N. J. Schmidt (1974): Reactivity of envelope, capsid, and soluble antigens of herpesvirus hominis types 1 and 2 in the indirect hemagglutination test. Infect. Immun. 10, 102-106.-Baringer, J. R. & P. Swoveland (1973): Recovery of herpes simplex virus from human trigeminal ganglions. New Engl. J. Med. 288, 648-650.-Bastian, F. O., A. S. Rabson, C. L. Yee & T. S. Tralka (1972) : Herpesvirus hominis : isolation from human trigeminal ganglion. Science 178, 306-307.-Behrman, S. & G. Knight (1954) : Herpes simplex associated with trigeminal neuralgia. Neurology 4, 525-530.--Carton, C. A. & E. D. Kilbourne (1952) : Activation of latent herpes simplex by trigeminal sensory-root section. New Engl. J. Med. 256, 172-176.Constantine, V. S., R. D. Francis & L. F. Montes (1968): Association of recurrent herpes simplex with neuralgia. J A M A 05, 181-183.-Halonen, P. E., R. Rimon, K. Arohonka & V. Jiintti (1974) : Antibody levels to herpes simplex type 1, measles and rubella viruses i n psychiatric patients. Br. J. Psychiat. 125, 461-465.--Kalimo, K. 0. K., B. 2. Ziola, M. K. Viljanen, K. Granfors & P. Toivanen (1977 a) : Solid-phase radioimmunoassay of herpes simplex virus IgG and IgM antibodies. J. Immunol. Methods 14, 183-195.--Kalimo, K. 0. K., R. J. Marttila, K. Granfors & M. K.Viljanen (1977 b) : Solid-phase radioimmunoassay of human IgM and IgG antibodies against herpes simplex virus type 1 capsid, envelope, and excreted antigens. Infect. Immun. (in press).-Kaplan, A. S., J. S. Erickson & T. Ben-Porat (1975): Synthesis of proteins in cells infected with herpesvirus. X. Proteins excreted by cells infected with herpes simplex virus types 1 and 2. Virology 64, 132-143.-Kristensson, K. (1970) : Morphological studies of the neural spread of herpes simplex virus to the central ncrvous system. Acta Neuropath. 16, 5&63.--Krohel, G. B., J. R. Richardson & D. F. Farrell (1976) : Herpes simplex neuropathy. Neurology 26, 596-597.-Lycke, E., R. Norrby & B. E. Roos (1974): A serological study o n mentally ill patients. Br. J. Psychiat. 124, 273-279.-Martin, M. L., E. L. Palmer & R. E. Kissling (1972): Complement-fixing antigens of herpes simplex virus types 1 and 2: reactivity of capsid, envelope, and soluble antigens. Infect. Immun. 5, 248-254.--Marttila, R. J., P. Arstila, J. Nikoskelainen, P. E. Halonen & U. K. Rinne (1977) : Viral antibodies in the sera from patients with Parkinson disease. Eur. Neurol. 15, 25-33.-Rawls. W.E.,E. Adam & J. L. Melnick (1973) : An analysis of seroepidemiological studies herpesvirus type 2 and carcinoma of the cervix. Cancer Rcs. 33, 1477-1482. Received January 31, accepted March 8, 1977.
R . Marttila, M.D. Department of Neurology University of Turku SF-20520 Turku 52 Finland
