Journal of
J. Neurol. 221,269-278 (1979)
Neurology © by Springer-Verlag 1979
Unusual Features in a Case Diagnosed as Subacute Sclerosing Panencephalitis (SSPE) K. A. FRigel, A. Barocka, and H. Woelk Universit~its-Nervenklinik mit Poliklinik Erlangen (Direktor: Prof. Dr. H. H. Wieck), im Kopfklinikum, Schwabachanlage 6, D-8520 Erlangen, Federal Republic of Germany
Summary. SSPE is characterised by progressive mental deterioration, myoclonic 'and similar motor disorders and final severe comatose states, increase of immunoglobuline G in the CSF, strongly elevated antibody titers to measles virus in serum and CSF and typical periodic K-complexes in the EEG. The disease appears commonly in childhood and has a fatal course. Cases with atypical signs have occasionally been reported. The case described in this paper shows a number of uncommon features: late onset, partial remission and stationary course, increased antibody titers to measles virus but relatively low in comparison to others, dissociation of cytoplasmic and nuclear fluorescent antibodies against SSPE brain tissue and an initial increase of antibodies against rubella virus. The patient was treated with isoprinosine. Improvement was observed before the start of this therapy and stabilized while treatment was being continued. Key words: Subacute sclerosing panencephalitis - Remitting course - Antibody titers - Uncommon features of SSPE.
Zusammenfassung. Die SSPE ist durch folgende diagnostische Kriterien charakterisiert: bestimmte klinische Erscheinungen einschlieBlich progredienter psychopathologischer Symptome bis zum finalen Koma, Myoklonien und andere extrapyramidale Bewegungsst6rungen, erh6hte ImmunglobulinG-Fraktion im Liquor, stark erh6hte Masernantik6rpertiter im Serum und Liquor sowie typische periodische (alle 5--7 Sec) K-Komplexe im EEG. Die Krankheit tritt in der Kindheit auf und nimmt in der Regel einen t6dlichen Verlauf. Wiederholt sind Krankheitsf~lle mit Abweichungen vom typischen Verlauf oder mit atypischen Befunden beschrieben worden. Der hier dargestellte Fall weist folgende ungew6hnliche Merkmale auf: sp~ter Beginn, partielle Remission und Stillstand im Verlauf, verh~iltnismfil3ig wenig stark erh6hte Masernantik6rpertiter im Vergleich mit den meisten 0340-5354/79/0221/0269/$2.00
270
K.A. Flügel et al. SSPE-Fällen, dissoziiertes Verhalten der cytoplasmatischen und nukleären Fluoreszenzantikörper gegen Hirngewebe von SSPE-Kranken und initial erhöhte Antikörper gegen Rötelnvirus. Die Patientin wurde mit Isoprinosine behandelt. Die klinische Besserung was bereits vor Therapiebeginn zu erkennen, doch wurde während der Behandlung eine weitere Remission und Stabilisierung beobachtet.
SSPE is generally considered to be the prototype of a slow virus disease of the central nervous system. D a w s o n was the first to indicate viral infection as the possible cause, discovering eosinophilic and cytoplasmatic inclusion bodies in brain sections o f SSPE patients [10]. Following Schilder [37], Bodechtel and G u t t m a n n [3] and van Bogaert [41] several others have described the clinicopathological findings in subacute encephalitis affecting gray or white matter or both gray and white cerebral tissue [7, 13, 28, 34]. In the clinical course three [15] or four stages [19] are distinguished rather arbitrarilly. In the first stage psychic and mental disorders predominate, with deterioration of school performance or emotional disorders which m a y sometimes be very mild and often are recognized only retrospectively. In the second stage m o t o r dysfunction appears, especially myoclonic twitching, choreiform movements, athetosis or dystoaaic spasms. Frequently there are cerebral seizures, macular degeneration develops, and mental disorders become progressive. In the third stage we find s y m p t o m s of decortication and the final cornatose state is described as the fourth stage. A relation between SSPE and measles has been discussed for some time. There are great similarities between masles and SSPE viruses as has been f o u n d with the electron microscope [4] and biochemically [18]. Antibodies against measles virus are increased in the serum and CSF of SSPE patients [9, 14, 27, 31], most of w h o m have a history of measles infection [11]. However, in spite of the frequency of measles, SSPE is a rare disease. SSPE is estimated to occur once in a million in Europe and N o r t h America. The question is unsolved as to which specific immunological constellation causes manifestation of SSPE on an average of 7 years following measles infection. F o r this purpose it appears justified to study every case accurately, especially cases with an unusual course.
Case Report Elfriede L., born in 1951, was healthy up to her 25th year of life. She is the seventh of nine children and grew up in a rural district. She claims that she had measles between the second and fourth year without complications. There had been no vaccination except for smallpox when she was one and four years old. She married 1974 and has borne two children, one is alive and the other child died a few days after birth. In the autumn of 1975 she developed visual disorders of her left eye. Ophthalmological examination disclosed papilledema, hemorrhages and vascular proliferation in the left eye and chorioretinitis was diagnosed. Since February 1976 the patient has lost spontaneity and is markedly slower. Because of psychic disorders combined with dizziness and clumsiness she was brought to the outpatient
Subacute Sclerosing Panencephalitis (SSPE)
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Fig. 3. Antibody titers against measles virus in serum (S) and CSF (C)
Fig. 4. Antibodies against rubella virus in serum (S) and CSF (C). Initially increased titers
neurological department where the following findings were recorded: gross speech disorder, pale optic papillae, visual deficit, left hemiparesis accentuated in the arm and pyramidal signs. Cerebrospinal fluid (CSF) examination demonstrated greatly increased gamma globulin. The EEG showed diffuse slow activity and periodically recurrent sharp complexes on the right side. The patient was transferred to our department in April 1976 with a diagnosis of encephalitis. At that time she was markedly lacking in spontaneity, speech was dysarthric and her verbal utterances were scarce. There was beginning optic nerve atrophy left more than right, spastic left hemiparesis, increased muscle tone in all extremities and rhythmic myoclonic twitchings. Myoclonia was pronounced on the left side of the body and appeared synchronously with sharp complexes in the EEG (Fig. 1). The diagnosis of SSPE was furthermore based upon increased titers of antibodies to measles virus in blood and CSF and the establishment of cytoplasmic and nuclear antibodies against SSPE I. The myoclonic jerks transiently showed some recovery but since June 1976 there was further progression even spreading to the right side. General rigidity also increased. The patient could hardly be induced to move about and was not able to hold her head upright. She was suffering from circulatory dysregulation and lost weight increasingly. At the beginning of 1977 1 Determinations were performed by the Institute of Virology, University of Wiirzburg. We want to thank Prof. Dr. V. ter Meulen for his assistance
SSPE-factor in serum and CSF FA-(cytopl) 1:
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Fig. 6 a--f. CT findings in the course of SSPE. (a) and (b) recorded 20.7.77, (e) and (d) 5.5.78, (e) and (f) 18.12.78. Marked enlargement of subarachnoid space, right more than left, and dilation of right lateral ventricle. Structure of low density in right parieto-occipital area
Subacute Sclerosing Panencephalitis (SSPE)
275
Table 1. Activities of phospholipase A~ and plasmalogenase in CSF during acute stage of SSPE and after partial remission. Control values of normal CSF Enzyme activity in CSF
Acute stage (Oct. 76)
Remission (June 78)
Control value
Phospholipase A~ (nmol/ml)
37.1
14.6
12.4
Plasmalogenase
40.6
12.4
9.8
(nmol/ml)
progression slowed down and some improvement was observed. Myoclonic jerks became less and even ceased. Later she was able to perform physical exercises. At the beginning of 1978 further improvement took place, so she could sit freely without support, raise her head and hold objects in each hand. There were no more myoclonic jerks, but the spastic hemiplegia persisted. Surgical prolongation of the triceps surae tendon was performed in July 1978 because of spastic contracture with drop foot with good result. During the following months the patient learned to walk again, at last without support, At the time of her discharge at the end of 1978 both optic nerve discs were pale. Vision had improved although visual deficits were still present. A very impressive improvement has taken place with the mental state. Persisting neuropsychological disturbances include agraphia and constructive apraxia. Corresponding with the clinical improvement the EEG tended to become normal. Periodic transients have disappeared, but a right hemisphere focus is still present (Fig. 2). The CSF cell count and protein content were normal, but immunoglobulin G was always distinctly increased. Accordingly the colloid curve showed a constant left drop-out. Measles antibodies in serum and CSF remained increased during the entire course independent of the remission of clinical findings (Fig. 3). However, titers were not as high as have been described in other cases of SSPE [1]. Initially elevated titers have been found for antibodies to rubella virus (Fig. 4). They may be of special interest in respect to the hypothesis of double infection in the pathogenesis of SSPE. Fluorescent antibody (FA) test revealed elevated titers both for cytoplasmatic and intranuclear fluorescence. In the later course antibodies to cytoplasmic fluorescence remained constantly high whereas antibodies to nuclear factor decreased in both serum and CSF and finally failed completely (Fig. 5). Computed tomography revealed lowered density in the right paraventricular area and an extension of the subarachnoid space, pronounced on the right. A progression of brain atrophy was demonstrable between June 1976 and May 1978 (Fig. 6). Phospholipase A~ and plasmalogenase, both enzymes that split lipids, were found increased in the CSF (Table 1). In cases of SSPE the enzymes have been found increased in brain tissue [21 ]. This finding is regarded as an expression of demyelination, which may be variably distinct in SSPE according to the pathological findings. Phospholipase A~ and plasmalogenase concentrations of CSF were three times as high as normal in the acute stage of the disease (Sept. 1976) and were markedly decreased in the stage of remission (June 1978). Following antecedant corticosteroid treatment the patient, since December 1977, received isoprinosine, a purine derivative, which has been given in several instances of SSPE since 1974 and which is supposed to have antiviral and immunosupportive effects [29, 39].
Discussion In r e c e n t y e a r s d e v i a t i n g c o u r s e s o f S S P E h a v e b e e n o b s e r v e d in a n u m b e r o f cases. T h e y c o n c e r n the speed, o u t c o m e a n d c o u r s e o f the disease as weil as a t y p i c a l s y m p t o m s o r m o r p h o l o g i c a l f i n d i n g s ( T a b l e 2).
276
K. A, Flügel et al.
Table 2. Variants of unusual features in SSPE Atypical features in SSPE
1. Unusually acute (rnalignant) course [30] 2. Unusually chronic (benign) course with relapses, long-lasting remissions or recovery [8, 12, 25, 35] 3. Courses with late onset [6] 4. Atypical anatomical findings [38]
Diagnosis is mainly based on the combination of rnyoclonic jerks, Radermecker complexes in the EEG, increased IgG fraction of gammaglobulins in the CSF and increased antibody titers against measles virus in serum and CSF. In our case, moreover, antibodies to SSPE brain tissue were present in the patient's serum. In the aspect of epidemiology the patient's origin from a rural district may be worth mentioning [20]. Instances of spontaneous improvement of SSPE have been observed repeatedly [35]. It is, however, important to distinguish between actual remissions and stationary phases [8]. In our patient the start of improvement can be regarded as spontaneous, even if the most impressive phase of clinical remission was coincident with isoprinosine treatment. Apart from the favorable course there are still other remarkable features. Though a case has been reported in which the disease began at the age of 32 years [6], our patient, aged 25, was relatively old at the onset of her disease in comparison to the majority of SSPE cases. There was an uncommonly long interval of 21 years between the measles infection and the outbreak of SSPE. Another atypical feature is that the antibodies to measles virus were--though elevated--lying below the titers generally reported in SSPE [1]. Moreover, antibodies marked by fluorescence also showed some peculiarity. The method of indirect immunofluorescence for the detection of antibodies against cultures of SSPE brain tissue has been refined by the differentiation between cytoplasmic and nuclear fluorescence [32]. It could be demonstrated that sera of SSPE patients behaved differently from sera of patients with acute or previous measles infection. In SSPE sera there is always cytoplasmic as well as nuclear fluorescence. The same is true of acute measles though with lower titers. Sera that are investigated 5 months or even later after measles infection, show merely cytoplasmic fluorescence [27]. Therefore, the findings in our patient, who exhibited initially both nuclear and cytoplasmic fluorescence and later cytoplasmatic fluorescence only, are atypical for SSPE. High antibody titers to rubella virus have been seen in SSPE before [16]. As an answer to the essential question what kind of immunological costellation taust be present in patients with measles that years later are followed by SSPE in comparison to those with c o m m o n uncomplicated measles, a theory has been developed concerning a second virus infection [5]. The second virus is supposed to cause the disease in combination with the persisting paramyxovirus. Papova-like viruses [26], papova virus [2], varicella virus [11], Epstein-Barr virus [22] and rubella virus have been incriminated.
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277
Cases o f p a n e n c e p h a l i t i s occuring years after c o n g e n i t a l rubella infection have been d e s c r i b e d [40]. H a l l a n d ter Meulen [18] f o u n d 90% h o m o l o g y in a sequential c o m p a r i s o n between measles virus a n d SSPE virus b e l o n g i n g to the stems Lec a n d Jec. SSPE virus contains the c o m p l e t e sequence o f bases o f the measles virus b u t a d d i t i o n a l ly some p a r t s that are n o t present in measles virus. The a u t h o r s discuss the origin o f the a d d i t i o n a l R N A f r o m the h y p o t h e t i c a l second virus. A n o t h e r q u e s t i o n arising in this context is whether a f a v o r a b l e course with remission m a y be i n d u c e d b y a s e c o n d virus infection. Z e m a n [42] m e n t i o n e d a case with a transient remission for m o r e t h a n 3 years f r o m stage 3 following an a d d i t i o n a l r u b e l l a infection. In s u m m a r y it m a y be stated that cases like the one r e p o r t e d in this p a p e r take up an e x c e p t i o n a l p o s i t i o n within SSPE which for its p a r t represents a special v a r i a n t o f measles infection.
References 1. Adels, B. R., Gajdusek, D. C., Gibbs, C. J., Albrecht, P., Rogers, N. G.: Attempts to transmit subacute sclerosing encephalitis and isolate a measles-related agent, with a study of the immune response in patients and experimental animals. Neurology (Minneap.) 18, 30--51 (1968) 2. Baguly, D. M., Glasgow, G. L.: Subacute sclerosing panencephalitis and Salk vaccine. Lancet 1973 II, 763--765 3. Bodechtel, G., Guttmann, E.: Diffuse Encephalitis mit sklerosierender Entzündung des Hemisphärenmarkes. Z. ges. Neurol. Psychiat. 133, 601--619 (1931) 4. Bouteille, M., Fontaine, C., Vedrenne, C., Delarue, J.: Sur un cas d'encéphalite subaigue ä inclusions. Etude anatomoclinique et ultrastructurale. Rev. Neurol. 113, 454--458 (1965) 5. Brody, J. A., Detels, R.: Subacute sclerosing panencephalitis. A zoonosis following aberrant measles. Lancet 197011, 500--501 6. Cape, C. A., Martinez, A. J., Robertson, J. T., Hamilton, R., Jabbour, J. T.: Adult onset of subacute sclerosing panencephalitis. Arch. Neurol. 28, 124--127 (1973) 7. Clark, N. S., Best, P. V.: Subacute sclerosing (inclusion body) encephalitis. Arch. Dis. Child. 39, 356--362 (1964) 8. Cobb, W. A., Morgan-Hughes, J. A.: Non-fatal subacute sclerosing panencephalitis. J. Neurosurg. Psychiat. 31, 115--123 (1968) 9. Conolly, J. H., Allen, I. V., Hurwitz, L. J., Millar, J. H. D.: Measles-virus antibody and antigen in subacute sclerosing panencephalitis. Lancet 19671, 542--544 10. Dawson, J. R. Jr.: Cellular inclusions in cerebral lesions of lethargic encephalitis. Am. J. Path. 9, 7--15 (1933) 11. Detels, R., Brody, J. A., Mac New, J., Edgar, H. A.: Further epidemiological studies of subacute sclerosing panencephalitis. Lancet 197311, 11--14 12. Donner, M., Waltimo, O., Porras, J., Forsius, H., Saukkonen, A.-L.: Subacute sclerosing panencephalitis as a cause of chronic dementia and relapsing brain disorder. J. Neurol. Neurosurg. Psychiat. 35, 180--185 (1972) 13. Foley, J., Williams, D.: Inclusion encephalitis and its relation to subacute sclerosing leucoencephalitis. Quart. J. Med. 22, 157--196 (1953) 14. Freeman, J. M., Magoffin, R. L., Lanette, L. H., Herndon, R. M.: Additional evidence of the relation between subacute inclusion-body encephalitis and measles virus. Lancet 196711, 129--131 15. Freeman, J. M.: The clinical spectrum and early diagnosis of Dawson's encephalitis. J. Pediatr. 75, 590--603 (1969)
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16. Gerson, K. L., Haslam, R. H. A.: Subtle immunologic abnormalities in four boys with subacute sclerosing panencephalitis. N. Engl. J. Med. 285, 78--82 (1971) 17. Glasner, H., Kirsch, W.: Ätiopathogenetische und therapeutische Aspekte der subakuten sklerosierenden Encephalitis. Arch. Psychiat. Nervenkr. 221, 29--38 (1975) 18. Hall, W. W., ter Meulen, V.: RNA homology between subacute sclerosing panencephalitis and measles virus. Nature 264, 474--477 (1976) 19. Jabbour, J. T., Garcia, J. H., Lemmi, H., Ragland, J., Duenas, D., Sever, J. L.: SSPE: multidisciplinary study of eight cases. JAMA 220, 2248--2254 (1969) 20. Jabbour, J. R, Duenas, D. A., Sever, J. L., Krebs, H. M., Horta-Barbosa, L.: Epidemiology of subacute sclerosing panencephalitis. JAMA 220, 959--962 (1972) 21. Jakumeit-Morgott, U~, Woelk, H.: On the effect of brain phospholipase A1 on specifically labelled glycerophospholipids in the course of subacute sclerosing panencephalitis. J. Neurol. 209, 37--44 (1975) 22. Joncas, J., Geoffroy, G., McLaughlin, B., Lapointe, N., David, P., Granger-Julien, M.: Subacute sclerosing panencephalitis. Elevated Epstein-Barr virus antibody titers and failure of amantadine therapy. J. Neurol. Sci. 21, 381--390 (1974) 23. Katz, M.: Subacut¢ sclerosing panencephalitis. In: Slow virus infections of the central nervous system, V. ter Meulen and M. Katz (eds.). Berlin-Heidelberg-New York: Springer 1977 24. Katz, M., Ter Meulen, V., Leonard, L., Koprowski, H.: SSPE: A new serological test in the diagnosis of the disease. Pediat. Res. 4, 482 (1970) 25. Kennedy, C.: A ten-year-experience with subacute sclerosing panencephalitis. Neurology (Minneap.) lg, 58--59 (1968) 26. Koprowski, H., Barbanti-Brodano, G., Katz, M.: Interaction between papova-like virus and paramyxovirus in human brain cells: a hypothesis. Nature (London) 225, 1045--1047 (1970) 27. Legg, N. J.: Virus antibodies in subacute sclerosing encephalitis: a study of 22 patients. Br. Med. J. 3, 350--352 (1967) 28. Malamud, N., Haymaker, W., Pinkerton, H.: Inclusion encephalitis with a clinico-pathological report of three cases. J. Path. 26, 133--145 (1950) 29. Mattson, R.: Isoprinosine therapy in subacute sclerosing panencephalitis. Presented at the Ann. Meeting of the Amer. Academ. of Neurology, San Francisco 1974 30. Nrhei, K., Kamoshita, S., Mizutani, H., Kitayama, R., Nishimura, H.: Atypical subacute sclerosing panencephalitis. Acta Neuropath. 38, 163--166 (1977) 31. Meulen, V. ter, Joppich C.: Fluorescence microscopy studies of brain tissue from a case of subacute progressive panencephalitis. Germ. Med. Mth. 12, 438--441 (1967) 32. Meulen, V. ter, Katz, M., Oyanagi, S.: Differences in intracellular antigen distribution between SSPE (subacute sclerosing panencephalitis)viruses and measles. (Abstract.) Fed. Proc. 29, 436 (1970) 33. Osetowska, E.: The distribution of telencephalic lesions in subacute sclerosing leucoencephalitis (pathological examination of 50 cases). In: Encephalitides: Proceedings of a symposium, Antwerp 1959, L. van Bogaert, J. Radermecker, J. Hozay, A. Lowenthal (eds.), pp. 414--469. Amsterdam: Elsevier 1961 34. Pette, H., Döhring, G.: Über eine einheitliche Panencephalomyelitis vom Charakter der Encephalitis japonica. Dtsch. Z. Nervenheilk. 149, 7--44 (1939) 35. Resnick, J. S., Engel, W. K., Sever, J. L.: Subacute sclerosing panencephalitis. Spontaneous improvement in a patient with elevated measles antibody in blood and spinal fluid. N. Engl. J. Med. 279, 126--129 (1968) 36. Risk, W. S., Haddad, F. S., Chemali, R.: Substantial spontaneous long-term improvement in subacute sclerosing panencephalitis. Arch. Neurol. 35, 499--502 (1978) 37. Schilder, P.: Die Encephalitis periaxialis diffusa. Arch. Psychiat. 71, 327--356 (1924) 38. Schubert, P.: Atypischer Fall einer subakuten sklerosierenden Leukoencephalitis (van Bogaert). Acta Neuropathol. 6, 93--97 (1966) 39. Streletz, L. J., Cracco, J.: The effect of isoprinosine in subacute sclerosing panencephalitis (SSPE). Ann. Neurol. 1, 183--184 (1977) 40. Townsend, J. J., Baringer, R., Wolinski, J. S., Mednick, J. P., Panitch, H. S., Scott, R. A. T., Oshiro, L. S., Cremer, N. E.: Progressive rubella panencephalitis. Late onset after congenital rubella. N. Engl. J. Med. 292, 990--993 (1975) 41. Van Bogaert, L.: Une leuco-encéphalite sclérosante subaigue. J. Neurol. Neurosurg. Psychiat. 8, 101--120 (1945)
J. Neurol. 221,269-278 (1979)
Neurology © by Springer-Verlag 1979
Unusual Features in a Case Diagnosed as Subacute Sclerosing Panencephalitis (SSPE) K. A. FRigel, A. Barocka, and H. Woelk Universit~its-Nervenklinik mit Poliklinik Erlangen (Direktor: Prof. Dr. H. H. Wieck), im Kopfklinikum, Schwabachanlage 6, D-8520 Erlangen, Federal Republic of Germany
Summary. SSPE is characterised by progressive mental deterioration, myoclonic 'and similar motor disorders and final severe comatose states, increase of immunoglobuline G in the CSF, strongly elevated antibody titers to measles virus in serum and CSF and typical periodic K-complexes in the EEG. The disease appears commonly in childhood and has a fatal course. Cases with atypical signs have occasionally been reported. The case described in this paper shows a number of uncommon features: late onset, partial remission and stationary course, increased antibody titers to measles virus but relatively low in comparison to others, dissociation of cytoplasmic and nuclear fluorescent antibodies against SSPE brain tissue and an initial increase of antibodies against rubella virus. The patient was treated with isoprinosine. Improvement was observed before the start of this therapy and stabilized while treatment was being continued. Key words: Subacute sclerosing panencephalitis - Remitting course - Antibody titers - Uncommon features of SSPE.
Zusammenfassung. Die SSPE ist durch folgende diagnostische Kriterien charakterisiert: bestimmte klinische Erscheinungen einschlieBlich progredienter psychopathologischer Symptome bis zum finalen Koma, Myoklonien und andere extrapyramidale Bewegungsst6rungen, erh6hte ImmunglobulinG-Fraktion im Liquor, stark erh6hte Masernantik6rpertiter im Serum und Liquor sowie typische periodische (alle 5--7 Sec) K-Komplexe im EEG. Die Krankheit tritt in der Kindheit auf und nimmt in der Regel einen t6dlichen Verlauf. Wiederholt sind Krankheitsf~lle mit Abweichungen vom typischen Verlauf oder mit atypischen Befunden beschrieben worden. Der hier dargestellte Fall weist folgende ungew6hnliche Merkmale auf: sp~ter Beginn, partielle Remission und Stillstand im Verlauf, verh~iltnismfil3ig wenig stark erh6hte Masernantik6rpertiter im Vergleich mit den meisten 0340-5354/79/0221/0269/$2.00
270
K.A. Flügel et al. SSPE-Fällen, dissoziiertes Verhalten der cytoplasmatischen und nukleären Fluoreszenzantikörper gegen Hirngewebe von SSPE-Kranken und initial erhöhte Antikörper gegen Rötelnvirus. Die Patientin wurde mit Isoprinosine behandelt. Die klinische Besserung was bereits vor Therapiebeginn zu erkennen, doch wurde während der Behandlung eine weitere Remission und Stabilisierung beobachtet.
SSPE is generally considered to be the prototype of a slow virus disease of the central nervous system. D a w s o n was the first to indicate viral infection as the possible cause, discovering eosinophilic and cytoplasmatic inclusion bodies in brain sections o f SSPE patients [10]. Following Schilder [37], Bodechtel and G u t t m a n n [3] and van Bogaert [41] several others have described the clinicopathological findings in subacute encephalitis affecting gray or white matter or both gray and white cerebral tissue [7, 13, 28, 34]. In the clinical course three [15] or four stages [19] are distinguished rather arbitrarilly. In the first stage psychic and mental disorders predominate, with deterioration of school performance or emotional disorders which m a y sometimes be very mild and often are recognized only retrospectively. In the second stage m o t o r dysfunction appears, especially myoclonic twitching, choreiform movements, athetosis or dystoaaic spasms. Frequently there are cerebral seizures, macular degeneration develops, and mental disorders become progressive. In the third stage we find s y m p t o m s of decortication and the final cornatose state is described as the fourth stage. A relation between SSPE and measles has been discussed for some time. There are great similarities between masles and SSPE viruses as has been f o u n d with the electron microscope [4] and biochemically [18]. Antibodies against measles virus are increased in the serum and CSF of SSPE patients [9, 14, 27, 31], most of w h o m have a history of measles infection [11]. However, in spite of the frequency of measles, SSPE is a rare disease. SSPE is estimated to occur once in a million in Europe and N o r t h America. The question is unsolved as to which specific immunological constellation causes manifestation of SSPE on an average of 7 years following measles infection. F o r this purpose it appears justified to study every case accurately, especially cases with an unusual course.
Case Report Elfriede L., born in 1951, was healthy up to her 25th year of life. She is the seventh of nine children and grew up in a rural district. She claims that she had measles between the second and fourth year without complications. There had been no vaccination except for smallpox when she was one and four years old. She married 1974 and has borne two children, one is alive and the other child died a few days after birth. In the autumn of 1975 she developed visual disorders of her left eye. Ophthalmological examination disclosed papilledema, hemorrhages and vascular proliferation in the left eye and chorioretinitis was diagnosed. Since February 1976 the patient has lost spontaneity and is markedly slower. Because of psychic disorders combined with dizziness and clumsiness she was brought to the outpatient
Subacute Sclerosing Panencephalitis (SSPE)
271
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Subacute Sclerosing Panencephalitis (SSPE)
273
Fig. 3. Antibody titers against measles virus in serum (S) and CSF (C)
Fig. 4. Antibodies against rubella virus in serum (S) and CSF (C). Initially increased titers
neurological department where the following findings were recorded: gross speech disorder, pale optic papillae, visual deficit, left hemiparesis accentuated in the arm and pyramidal signs. Cerebrospinal fluid (CSF) examination demonstrated greatly increased gamma globulin. The EEG showed diffuse slow activity and periodically recurrent sharp complexes on the right side. The patient was transferred to our department in April 1976 with a diagnosis of encephalitis. At that time she was markedly lacking in spontaneity, speech was dysarthric and her verbal utterances were scarce. There was beginning optic nerve atrophy left more than right, spastic left hemiparesis, increased muscle tone in all extremities and rhythmic myoclonic twitchings. Myoclonia was pronounced on the left side of the body and appeared synchronously with sharp complexes in the EEG (Fig. 1). The diagnosis of SSPE was furthermore based upon increased titers of antibodies to measles virus in blood and CSF and the establishment of cytoplasmic and nuclear antibodies against SSPE I. The myoclonic jerks transiently showed some recovery but since June 1976 there was further progression even spreading to the right side. General rigidity also increased. The patient could hardly be induced to move about and was not able to hold her head upright. She was suffering from circulatory dysregulation and lost weight increasingly. At the beginning of 1977 1 Determinations were performed by the Institute of Virology, University of Wiirzburg. We want to thank Prof. Dr. V. ter Meulen for his assistance
SSPE-factor in serum and CSF FA-(cytopl) 1:
SSPE-factor in serum and CSF FA- (nucl) 1:104
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8 [~ ~ ~ b 1976 1977 1978 Fig. S.(a) SSPEfactor (FA cytoplasm.) in serum and CSF (b) SSPE factor (FA nuclear) in serum and CSF
Fig. 6 a--f. CT findings in the course of SSPE. (a) and (b) recorded 20.7.77, (e) and (d) 5.5.78, (e) and (f) 18.12.78. Marked enlargement of subarachnoid space, right more than left, and dilation of right lateral ventricle. Structure of low density in right parieto-occipital area
Subacute Sclerosing Panencephalitis (SSPE)
275
Table 1. Activities of phospholipase A~ and plasmalogenase in CSF during acute stage of SSPE and after partial remission. Control values of normal CSF Enzyme activity in CSF
Acute stage (Oct. 76)
Remission (June 78)
Control value
Phospholipase A~ (nmol/ml)
37.1
14.6
12.4
Plasmalogenase
40.6
12.4
9.8
(nmol/ml)
progression slowed down and some improvement was observed. Myoclonic jerks became less and even ceased. Later she was able to perform physical exercises. At the beginning of 1978 further improvement took place, so she could sit freely without support, raise her head and hold objects in each hand. There were no more myoclonic jerks, but the spastic hemiplegia persisted. Surgical prolongation of the triceps surae tendon was performed in July 1978 because of spastic contracture with drop foot with good result. During the following months the patient learned to walk again, at last without support, At the time of her discharge at the end of 1978 both optic nerve discs were pale. Vision had improved although visual deficits were still present. A very impressive improvement has taken place with the mental state. Persisting neuropsychological disturbances include agraphia and constructive apraxia. Corresponding with the clinical improvement the EEG tended to become normal. Periodic transients have disappeared, but a right hemisphere focus is still present (Fig. 2). The CSF cell count and protein content were normal, but immunoglobulin G was always distinctly increased. Accordingly the colloid curve showed a constant left drop-out. Measles antibodies in serum and CSF remained increased during the entire course independent of the remission of clinical findings (Fig. 3). However, titers were not as high as have been described in other cases of SSPE [1]. Initially elevated titers have been found for antibodies to rubella virus (Fig. 4). They may be of special interest in respect to the hypothesis of double infection in the pathogenesis of SSPE. Fluorescent antibody (FA) test revealed elevated titers both for cytoplasmatic and intranuclear fluorescence. In the later course antibodies to cytoplasmic fluorescence remained constantly high whereas antibodies to nuclear factor decreased in both serum and CSF and finally failed completely (Fig. 5). Computed tomography revealed lowered density in the right paraventricular area and an extension of the subarachnoid space, pronounced on the right. A progression of brain atrophy was demonstrable between June 1976 and May 1978 (Fig. 6). Phospholipase A~ and plasmalogenase, both enzymes that split lipids, were found increased in the CSF (Table 1). In cases of SSPE the enzymes have been found increased in brain tissue [21 ]. This finding is regarded as an expression of demyelination, which may be variably distinct in SSPE according to the pathological findings. Phospholipase A~ and plasmalogenase concentrations of CSF were three times as high as normal in the acute stage of the disease (Sept. 1976) and were markedly decreased in the stage of remission (June 1978). Following antecedant corticosteroid treatment the patient, since December 1977, received isoprinosine, a purine derivative, which has been given in several instances of SSPE since 1974 and which is supposed to have antiviral and immunosupportive effects [29, 39].
Discussion In r e c e n t y e a r s d e v i a t i n g c o u r s e s o f S S P E h a v e b e e n o b s e r v e d in a n u m b e r o f cases. T h e y c o n c e r n the speed, o u t c o m e a n d c o u r s e o f the disease as weil as a t y p i c a l s y m p t o m s o r m o r p h o l o g i c a l f i n d i n g s ( T a b l e 2).
276
K. A, Flügel et al.
Table 2. Variants of unusual features in SSPE Atypical features in SSPE
1. Unusually acute (rnalignant) course [30] 2. Unusually chronic (benign) course with relapses, long-lasting remissions or recovery [8, 12, 25, 35] 3. Courses with late onset [6] 4. Atypical anatomical findings [38]
Diagnosis is mainly based on the combination of rnyoclonic jerks, Radermecker complexes in the EEG, increased IgG fraction of gammaglobulins in the CSF and increased antibody titers against measles virus in serum and CSF. In our case, moreover, antibodies to SSPE brain tissue were present in the patient's serum. In the aspect of epidemiology the patient's origin from a rural district may be worth mentioning [20]. Instances of spontaneous improvement of SSPE have been observed repeatedly [35]. It is, however, important to distinguish between actual remissions and stationary phases [8]. In our patient the start of improvement can be regarded as spontaneous, even if the most impressive phase of clinical remission was coincident with isoprinosine treatment. Apart from the favorable course there are still other remarkable features. Though a case has been reported in which the disease began at the age of 32 years [6], our patient, aged 25, was relatively old at the onset of her disease in comparison to the majority of SSPE cases. There was an uncommonly long interval of 21 years between the measles infection and the outbreak of SSPE. Another atypical feature is that the antibodies to measles virus were--though elevated--lying below the titers generally reported in SSPE [1]. Moreover, antibodies marked by fluorescence also showed some peculiarity. The method of indirect immunofluorescence for the detection of antibodies against cultures of SSPE brain tissue has been refined by the differentiation between cytoplasmic and nuclear fluorescence [32]. It could be demonstrated that sera of SSPE patients behaved differently from sera of patients with acute or previous measles infection. In SSPE sera there is always cytoplasmic as well as nuclear fluorescence. The same is true of acute measles though with lower titers. Sera that are investigated 5 months or even later after measles infection, show merely cytoplasmic fluorescence [27]. Therefore, the findings in our patient, who exhibited initially both nuclear and cytoplasmic fluorescence and later cytoplasmatic fluorescence only, are atypical for SSPE. High antibody titers to rubella virus have been seen in SSPE before [16]. As an answer to the essential question what kind of immunological costellation taust be present in patients with measles that years later are followed by SSPE in comparison to those with c o m m o n uncomplicated measles, a theory has been developed concerning a second virus infection [5]. The second virus is supposed to cause the disease in combination with the persisting paramyxovirus. Papova-like viruses [26], papova virus [2], varicella virus [11], Epstein-Barr virus [22] and rubella virus have been incriminated.
Subacute Sclerosing Panencephalitis (SSPE)
277
Cases o f p a n e n c e p h a l i t i s occuring years after c o n g e n i t a l rubella infection have been d e s c r i b e d [40]. H a l l a n d ter Meulen [18] f o u n d 90% h o m o l o g y in a sequential c o m p a r i s o n between measles virus a n d SSPE virus b e l o n g i n g to the stems Lec a n d Jec. SSPE virus contains the c o m p l e t e sequence o f bases o f the measles virus b u t a d d i t i o n a l ly some p a r t s that are n o t present in measles virus. The a u t h o r s discuss the origin o f the a d d i t i o n a l R N A f r o m the h y p o t h e t i c a l second virus. A n o t h e r q u e s t i o n arising in this context is whether a f a v o r a b l e course with remission m a y be i n d u c e d b y a s e c o n d virus infection. Z e m a n [42] m e n t i o n e d a case with a transient remission for m o r e t h a n 3 years f r o m stage 3 following an a d d i t i o n a l r u b e l l a infection. In s u m m a r y it m a y be stated that cases like the one r e p o r t e d in this p a p e r take up an e x c e p t i o n a l p o s i t i o n within SSPE which for its p a r t represents a special v a r i a n t o f measles infection.
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