α-Interferon and isoprinosine in adult-onset subacute sclerosing panencephalitis

Journal of the Neurological Sciences 162 (1999) 62–64

a-Interferon and isoprinosine in adult-onset subacute sclerosing panencephalitis Zeki Gokcil*, Zeki Odabasi, Seref Demirkaya, Erdal Eroglu, Okay Vural Department of Neurology, Gulhane Medical School, Ankara, Turkey Received 14 May 1998; received in revised form 14 October 1998; accepted 16 October 1998

Abstract We report eight patients with adult-onset subacute sclerosing panencephalitis (SSPE), of which, four were treated with oral isoprinosine and four with intraventricular a-interferon plus oral isoprinosine. One of the four patients treated with oral isoprinosine died within two months, and the disease progressed in three patients. Of the four patients treated with oral isoprinosine plus intraventricular a-interferon, one showed mild progression, one remission, and the remaining two showed stabilization. The group of patients is relatively small, but our results suggest that treatment with oral isoprinosine plus a-interferon is effective for SSPE.  1999 Elsevier Science B.V. All rights reserved. Keywords: Subacute sclerosing panencephalitis (SSPE); Adult-onset; a-Interferon; Isoprinosine

1. Introduction Subacute sclerosing panencephalitis (SSPE) is a rare, slow viral infection caused by defective measles virus. SSPE follows measles infection by several months to several years, and usually affects children or young adults. It has a gradual, progressive course, leading to death within a few years, although spontaneous improvement or stabilization has been seen in a small number of patients [9–11]. In about 10% of all cases, the disease can progress more rapidly and lead to death within a few months [6,7]. Affected patients usually have behavioral changes, myoclonus, mental deterioration, seizure, extrapyramidal dysfunction and visual disturbance [10,11]. The diagnosis is based upon the characteristic clinical and electroencephalographic findings and demonstration of elevated antibody titers against measles in the plasma and cerebrospinal fluid. This report concerns the long-term follow-up of eight *Corresponding author. Tel.: 190-312-321-0491; fax: 190-312-3217778; e-mail: [email protected]

patients with adult-onset SSPE, of which, four were treated with oral isoprinosine and four with intraventricular ainterferon plus oral isoprinosine.

2. Materials and methods Eight consecutive patients (all males, ranging in age from 18 to 22; mean, 20.4 years) with adult-onset SSPE were prospectively studied in the period 1992–1998. One case (Case 2) was previously reported [7]. Diagnosis was based on clinical manifestations, electroencephalogram (EEG) findings, and elevated titers of measles antibody. Cranial magnetic resonance images (MRIs) were obtained in all patients except one. The patients were subdivided into three stages according to the system of Risk and Haddad [9]. Our patients started to receive the treatment in the early phase of the disease, i.e. at stages I, IIA or IIB. Four patients were treated with intraventricular a-interferon and oral isoprinosine. The treatment regimen consisted of six-week courses of a-

0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00302-5

Z. Gokcil et al. / Journal of the Neurological Sciences 162 (1999) 62 – 64

interferon, started as 1310 5 U / m 2 and increased to 1310 6 U / m 2 body area per day, five days / week, given through an Ommaya reservoir. The course was repeated at two to six-month intervals, up to six times. These patients were also given oral isoprinosine, 50 to 100 mg / kg / daily. Four patients were treated with oral isoprinosine alone, 50 to 100 mg / kg / daily. Follow-up continued for three to four years, except in one, rapidly fatal, case.

3. Results Clinical and laboratory findings are summarized in Table 1. Four patients treated with combined therapy (intraventricular a-interferon plus oral isoprinosine) are still alive. One patient improved, one mildly progressed, and the other two stabilized. Two patients showed fever and headache at the beginning of treatment. The patients treated with oral isoprinosine alone showed clinical progression. However, one died two months after onset of the disease, despite therapy. The disease continued its progressive course after oral isoprinosine treatment in the other three patients.

63

4. Discussion SSPE is relatively rare in the Western world, while the incidence is still high in developing and underdeveloped countries such as India and the Middle East [5,9,10]. Although most studies report the onset of SSPE between the ages of five and fifteen, adult-onset cases have been reported sporadically in the literature. Recently, the age of onset of SSPE has become higher and the incubation period from measles to SSPE onset has become more prolonged [10]. The reason for this increase in measles-toSSPE latency remains unexplained. SSPE has a culminating fatal course, leading to death within one to three years. Rarely, spontaneous remissions, which may last for seven to ten years, have been seen [1,6]. The pathophysiology of remissions and relapses in SSPE is unknown. The duration of remissions or improvements induced by therapy is unclear. Treatment for SSPE is still undetermined. Antiviral agents, such as amantadine, or immunomodulators, such as isoprinosine, a-interferon, immunoglobulin and corticosteroids, have been used [3,5]. Dyken et al. [3] have reported improvement or stabilization in ten of fifteen patients treated with isoprinosine.

Table 1 Clinical and laboratory findings for SSPE patients Case number

Age at onset/sex

Initial symptoms

EEG findings

Measles antibodies

Clinical stage a

PGC

Serum

CSF

Before treatment

After treatment

1

22/M

Ataxia, dysphasia, myoclonus

1

1

1

IIB

2

21/M

Hemianopia, behavioral changes, myoclonus

1

1

1

3

18/M

Ataxia, behavioral changes, myoclonus

1

1

4

21/M

Ataxia, behavioral changes, visual hallucination

1

5

21/M

Behavioral changes, myoclonus

6

20/M

Blurred vision, behavioral changes, myoclonus

7

18/M

Behavioral changes, myoclonus

8

22/M

Behavioral changes, myoclonus

a

MRI findings

Treatment

Duration of follow-up

IIIA

Multiple hyperintense lesions in the left nucleus lentiformis, nucleus caudatus and corpus callosum

Isoprinosine

5 years

IIA

IIIC

Bilateral occipital hyperintense lesions

Isoprinosine

2 months (exitus)

1

IIB

IIC

Minimal cortical atrophy

Isoprinosine

4 years

1

2

IIB

IIC

Multiple periventricular hyperintense lesions

Isoprinosine

4 years

1

1

1

IIA

IIB

Not performed

Isoprinosine, a-interferon

3 years

1

1

1

IIB

IIB

Multiple hyperintense lesions in the left nucleus lentiformis and bilateral occipital lobes

Isoprinosine, a-interferon

3 years

1

1

1

IIA

I

Multiple hyperintense lesions in periventricular areas and nucleus caudatus

Isoprinosine, a-interferon

4 years (remission)

1

1

1

IIA

IIA

Multiple hyperintense lesions in the periventricular areas

Isoprinosine, a-interferon

4 years

PGFW

Stage I, psycho-intellectual changes; stage IIA, stereotyped attacks, but the patient can walk independently; stage IIB, patient falls from attacks and walks with support; stage IIC, bedridden state; stage IIIA, no purposeful but some spontaneous movements, some responses to other than noxious stimuli; stage IIIB, vegetative responses to noxious stimuli; stage IIIC, deep coma and death. PGC, periodic generalized complexes; PGFW, periodic generalized fast waves.

64

Z. Gokcil et al. / Journal of the Neurological Sciences 162 (1999) 62 – 64

Improvement has also been reported in some cases who treated with trihexyphenidyl and isoprinosine [8]. At present, combined treatment of oral isoprinosine and intraventricular a-interferon appears to be an effective treatment for SSPE. To our knowledge, 53 cases have been treated by intraventricular a-interferon with or without oral isoprinosine, 30 (59%) of which showed stabilization or improvement [1,2,4,5]. Although most patients have not shown severe side effects, in some patients treated with intraventricular a-interferon, upper and lower motor neuron pathology and ventriculitis have been observed [2,4]. In our study, one of the four patients treated with oral isoprinosine died within two months, and the disease progressed in three patients. One of the four patients treated with oral isoprinosine plus a-interferon had a mild progression from stage IIA to stage IIB. One patient in this group had a remission, and the other two stabilized. In conclusion, adult-onset SSPE should be considered in the differential diagnosis of demyelinating disease and viral encephalitis since it is still seen in developing and underdeveloped countries. Treatment should be started as soon as the diagnosis is made. Ours is a small group of patients, but our results suggest that treatment with oral isoprinosine plus a-interferon is effective for SSPE. However, further multicenter collaborative controlled studies are needed to determine the efficacy of a-interferon or combined therapy in the treatment of SSPE.

References [1] Anlar B, Yalaz K, Oktem F, Kose G. Long-term follow-up of patients with subacute sclerosing panencephalitis treated with intraventricular a-interferon. Neurology 1997;48:526–8.

[2] Cianchetti C, Marrosu MG, Muntoni F, Fratta AL, Zuddas A. Intraventricular alpha-interferon in subacute sclerosing panencephalitis. Neurology 1998;50(1):315–6. [3] Dyken PR, Swift A, DuRant HR. Log-term follow-up of patients with subacute sclerosing panencephalitis treated with inosiplex. Ann Neurol 1982;11:359–64. [4] Fayad MN, Yamout BI, Mroueh S. alpha-Interferon in the treatment of subacute sclerosing panencephalitis. J Child Neurol 1997;12(8):486–8. [5] Gascon G, Yamanis S, Crowell J, Stigsby B, Nester M, Kanaan I, Jallu A. Combined oral isoprinosine-intraventricular alpha-interferon therapy for subacute sclerosing panencephalitis. Brain Dev 1993;15:346–55. [6] Gilden DH, Rorke LB, Tanaka R. Acute SSPE. Arch Neurol 1975;32:644–6. [7] Gokcil Z, Odabasi Z, Aksu A, Vural O, Yardim M. Acute fulminant SSPE: clinical and EEG features. Clin Electroencephalogr 1998;29(1):43–8. [8] Nunes ML, da Costa JC, da Silva LF. Trihexyphenidyl and isoprinosine in the treatment of subacute sclerosing panencephalitis. Pediatr Neurol 1995;13(2):153–6. [9] Risk WS, Haddad FS. The variable natural history of subacute sclerosing panencephalitis: a study of 118 cases from the Middle East. Arch Neurol 1979;36:610–4. [10] Singer C, Lang AE, Suchowersky O. Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 1997;12(3):342–53. [11] Yaqub BA. Subacute sclerosing panencephalitis (SSPE): early diagnosis, prognostic factors and natural history. J Neurol Sci 1996;39:227–34.