The Japanese Journal of Psychiatry and Neurology, Vol. 46, No. 3, 1992

An Autopsied Case of Interferon Encephalopathy Yoshio Mitsuyama, M.D., Hiroyuki Hashiguchi, M.D., Toshihiko Murayama, M.D., * Masashi Koono, M.D. and Shohei Nishi, M.D.** Department of Psychiatry, Miyazaki Medical College, Miyazaki *Department of Pathology, Miyozaki Medical College, Miyazaki **Department of Urology, Miyazaki Medical College, Miyazaki

Abstract: A 78-year-old male with renal carcinoma was treated with a high dose infusion of interferon-alpha (IFN-alpha) for eight months. The patient had evidence of organlc brain syndrome such 88 dysfunction of memory, slowing of behavior, and development of mental confusion that appeared eight months after the treatment. MRI at the time of mental confusion revealed difise white matter lesions. Neuropathologic findings were compatible to Binswanger’s disease and Senile Dementia of Alzheimer Type (SDAT), Preexisting neurologic abnormalities including intracerebral arteriosclerosis and cerebral atrophy may increase susceptibility to unacceptably severe IFN neurotoxicity. Key Words: white matter disease, interferon encephalopathy Jpn J Peychiatr Neurol46: 741-748,1992

INTRODUCTION

Interferon (IFN) is currently being evaluated in the treatment of various viral and malignant diseases. The side effects of a high dose IFN treatment include pyrexia, fatigue, general malaise, fever, shaking, muscle pain, confusion, drowsiness, leukopenia, and EEG abnormalities, including difise slowing of background activity and intermittent frontally dominant delta activity.” l4 l7 specific psychiatric syndromes have been described as “Interferon Encephalopathy,” including a disorder of higher mental functions manifested by psychomotor slowing, disReceived for publication on Oct. 7, 1991. Mailing address: Yoshio Mitsuyama, M.D., Department of Psychiatry, Miyazaki Medical. College, 5,200 Kihara, Kiyotake, Miyazaki 889-16, Japan.

turbed motivation, attentional deficits, and cognitive impairment.’ l4 Hallucination and abnormal mood states have also been reported.I4 In general, the acute neurobehavioral side effects of IFN-alpha have been reported to disappear within several days to two weeks after cessation of treatment. In some cases the psychiatric symptoms were severe enough to need urgent psychiatric attention. There are no reports of neuropathological changes attributable to IFN-alpha therapy. We have encountered an autopsied case who had received IFN-alpha for the treatment of cancer and developed severe and global organic mental disorders while receiving the high dose intramuscular infusion of IFN-alpha. This paper describes the clinico-pathological Andings in a patient who demonstrated neurobehavioral side effects while receiving the high dose of IFN-alpha.

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CASE REPORT

A 78-year-old farmer had been well until he had a right nephrectomy for renal carcinoma at the age of 77. There was no family or past history of dementing illness of hypertensive disorders. After the surgery, he was treated with IFN-alpha as a continuous intramuscular infusion. The treatment protocol specified daily doses of 900 million IU, three times a week. Informed consent was obtained

from the patient and his family, and the treatment was approved by the Kyushu Urology Association in Japan. He received the total doses of 14,400 million IU from September 1989 to October 1989 and discharged with unremarkable side effects. There was no change in the blood pressure or other vital signs during the administration of IFN-alpha. MRI of the head studied after two months with the IFN-alpha treatment (November 1989) revealed periventricular high intensity

Fig. 1 : Followup study of CT and MRI revealed increased periventricular high intensity areas and white matter lesions, prominent in the frontal lobes.

An Autopsied Case of Interferon Encephalopathy

areas with TZweighted imaging (Fig. 1). After discharge, the IFN-alpha of 900 million IU was given intramuscularly three times a week. Clinical toxicity was assessed by observation of the general demeanor of the patient and direct questioning aimed at eliciting any intellectual impairment. Formal psychiatric testing was not undertaken. Eight months after the beginning of the IFN-alpha treatment, he developed a respiratory distress state and he was readmitted to the Urology Department of Miyazaki Medical College Hospital. On admission, he was disoriented to time and place in spite of familiarity with the ward. He developed profound confusion, loss of concentration and appeared anxious, and consequently refused to take any form of nourishment. The IFN-alpha treatment was discontinued and his respiratory distressing condition disappeared with-

Fig. 2a

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in a few days. His behavior increasingly deteriorated and he was transferred to the Psychiatric Department. Evidence of hepatic dysfunction was not observed. No electrolyte disturbances were observed except for a temporarily increased BUN (87.1 mg/dl). Soon after admission to the Psychiatric Department, he became increasingly agitated with unintelligible speech. He appeared to be fearful and visually hallucinating. He whispered answers and frequently looked away, as if distracted. BUN was decreased to 3 1.1 mg/dl three days after admission. He showed nocturnal confusion and bewilderment. Although metabolic and toxic etiologies could be considered, he appeared to be suffering from a delirium secondary to IFN-alpha administration. He was treated with haloperidol for sedation in a low dosage. This reduced his confusion and he became less agitated and

Fig. 2b

Figs. 2a and b: Diffuse pallor of myelin sheath and lacuna with subcortical gliosis (a: KliiverBarrera stain; b: Holzer stain).

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Fig. 3 : Sclerotic changes of small arteries in the deep white matter (H=E. X 396).

Fig. 4: Lacuna in the frontal white matter (H-E. X 396).

more oriented temporarily, but he remained withdrawn and required nasogastric tube feeding. He showed a progressive downhill course. Neuropsychological testing was not performed because he was too confused and could not cooperate. No focal neurological signs were elicited. Follow-up CT and MRI (Fig. 1) studies revealed increased periventricular high intensity areas and white matter lesions in the frontal lobes compared to the previous studies. An EEG was not

obtained prior to or following IFN therapy. He expired at the age of 78, 10 months after beginning of the IFN-alpha treatment. General pathology revealed aspiration pneumonia as an immediate cause of death. There was no metastasis at postmortem examination. The heart weight was 360 g. The brain weighed 1,320 g and had a normal external appearance except for a slight diffuse cortical atrophy. The Circle of Willis showed moderate arteriosclerotic

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Fig. 5 : Senile plafrontal cortex (Methenamine-Bodian stain, X 396).

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Fig. 6: Alzheimer’s neurofibrillary tangles in the parafiPpoc=Pal gyms (Methenamine-Bodian stain, X 792).

changes without any occlusion. On sectioning, there was a slight dilation of the ventricular system without any focal lesion. Microscopically, cytoarchitecture in the cerebral cortices was well preserved. There were diffuse areas of demyelination sparing the subcortical U-fibers and subcortical gliosis (Figs. 2a, b), arteriosclerosis of the penetrating blood vessels (Fig. 3), and lacunae in the subcortical white matter (Fig. 4). Numerous senile plaques were present throughout the

cerebral cortex and basal ganglia, and many of neurofibrillary tangles were observed in the hippocampal formation (Figs. 5, 6 ) . Congophilic angiopathy was not seen. Calcifications of the basal ganglia were not found. No inflammatory changes were seen. DISCUSSION

The coexistence of a diffuse ischemic loss of myelin in the hemispheric white matter with

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subcortical gliosis and arteriosclerotic changes of penetrating arteries, and numerous senile plaques throughout the CNS is compatible to the mixed type of Binswanger's disease and SDAT. It is of critical importance to rule out iatrogenesis in patients with the IFN administration who display psychiatric symptoms. This patient developed clinical evidence of CNS disturbance during the course of the IFN infusion and the neurotoxic symptoms did not appear to be attributable to other therapy or changes in the disease status. IFN encephalopathy of this patient may due to direct effects of this substance on the brain. The study by McDonald et al." has shown a rise in psychiatric symptoms among those on IFN treatment compared with the matched control. The clinical findings of CNS toxicity with a high dose IFN have been reported and most of the side effects of the high dose IFN treatment is reversible and recovery is almost complete in the report by Iivanainen et aL6 However, there is a report of persistent neurotoxicity attributable to IFN-alpha therapy.I3Meyer et al.I3 reported that there was a strong relationship between the dose and schedule of IFN-alpha treatment and the severity of persistent neurobehavioral symptoms. From the neuropsychological studies of patients with the high dose IFN treatment, Iivanainen et aL6 concluded that the effect of IFN on the brain was selective and involves the frontal and basal areas most intensively. Previous studies have shown that IFN does not cross the blood-brain barrier and cannot be identified in CSF, even in the presence of high circulating blood concentrations.' Recently, Wiranowska et al." analyzed the IFN content of homogenized cerebral hemispheres and acknowledged that IFN might enter the brain at low levels through circumventricular organs, such as the area postrema, median eminence, and infundibular recess. CT/MRI abnormality has been reported in the case of IFN encephalopathy." Meyers et al.j 3 described that imaging and physiologic studies did not contribute much information

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regarding the pathophysiology of IFN-alpha neurotoxicity. The correlation between CT/ MRI abnormality and the neuropathological finding has not been confirmed. The diffuse loss of myelin with white matter infarction associated with arteriosclerotic changes of small penetrating arteries and reactive gliosis are prominent histopathological findings in this patient. Although hypertensive conditions had not been observed in this patient, these findings are compatible to Binswanger's disease. Pathological studies of patients with white matter lesions and the clinical features of Binswanger's disease indicate that hypertensive changes are frequently seen in small penetrating arteries.24 Is The correlation between the incidence of hypertension and the white matter lesions has also been reported in an uncontrolled series of patients with cranial CT-scans.*lo I' 'I From the study of a progressive familial encephalopathy associated with calcification of the basal ganglia and hypodensities with CT-scans, with special reference to the detection of IFN-alpha in the sera, the presence of IFN-alpha in the CSF and sera has suggested the possibility of a viral infection and association between the IFN-alpha and white matter lesions has been reported.' However, the diffuse white matter lesions similar to Binswanger's disease have not been described in the case of IFN encephalopathy. Whether arteriosclerotic subcortical encephalopathy in this patient could be attributed to the IFNalpha administration or not remains uncertain and the underlying mechanism of interferon encephalopathy is not definitive. The role of intracerebral arteriosclerosis in the development of neurotoxicity is also unclear, and presence of intracerebral arteriosclerosis may provide a condition of diminished functional reserves. The patient received no chemotherapy or X-radiation in addition to IFN. We can only speculate about the possible mechanisms for persisting neurotoxicity of IFN-alpha and the IFN-alpha administration could be one of the possible causes in the development of white matter lesions in this

An Autopsied Case of Interferon Encephalopathy patient, because of the subacute onset of his clinical symptomatology during the IFNalpha administration. We speculate that the IFN-alpha contributed to the progression of subclinical white matter lesions that are common findings in older persons and develop t o diffuse subcortical encephalopathy. The presence of numerous senile plaques throughout the CNS in this patient was compatible to a diagnosis of SDAT. This patient did not show any dementia symptoms before the IFN-alpha administration. The presence of subclinical dementia can be drawn from the pathological findings, and the dissociation between the pathological findings and clinical symptoms is also seen infrequently. The role of IFN contributing to the development of these lesions is unclear. The possibility that the IFN-alpha administration hastened or even induced an inevitable formation of senile plaques in a predisposed brain is speculative at best. Slowing of the dominant alpha rhythm in EEG has been reported in patients receiving conventional cytotoxic agents.’ Although the mechanism accounting for the CNS effects by I F N is unclear, the possibility of viral infection for the cytotoxic effect from the IFNalpha administration should not be discarded without extensive virological investigations. More cases are necessary to investigate this possibility. REFERENCES 1. Adams, F., Quesada, J.R. and Gutterman, J.

U.: Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA 252: 938-941, 1984. 2. Caplan, L.R. and Schoene, W.C.: Clinical fea-

tures of subcortical arteriosclerotic encephalopathy (Binswanger disease). Neurology 28: 1206-1215, 1987. 3. Garcia-Albea, E., Cabello, A. and Franch, 0.: Subcortical arteriosclerotic encephalopathy (Binswanger’s disease): A report of five patients. Acta Neurol Scand 75: 295-303, 1987. 4. Goto, K., Ishii, N. and Fukosawa, H.: Diffuse

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white matter disease in the geriatric population. Radiology 141: 687-695, 198 1. 5. Horning, S., Levine, J., Miller, R., Rosenberg, S. and Merigan, T.: Clinical immunologic effects of recombinant leukocyte. An interferon in patients with advanced cancer. JAMA 247: 1718-1722, 1982. 6. Iivanainen, M., Laaksonen, R., Niemi, M.L., Faerkkilae, M., Bergstroem, L., Mattson, K., Niilanen, A. and Cantell, K.: Memory and psychomotor impairment following highdose interferon treatment in amyotrophic lateral sclerosis. Acta Neurol Scand 72: 475-480, 1985. 7. Itil, T.M. and Itil, K.Z.: The establishment of

CNS toxicity of drugs. In: Herrmann, W.M. (Ed.), Electroencephalography in drug research. Gustav Fischer, Stuttgart, New York, pp 23-29, 1982. 8. Kinkel, W.R., Jacobs, L., Polachini, I., Bates, V. and Heffner, R.R. Jr.: Subcortical arteriosclerotic encephalopathy (Binswanger’s disease). Computed tomographic, nuclear magnetic resonance and clinical correlations. Arch Neurol42: 951-959, 1985. 9. Lebon, P., Badoual, J., Ponsot, G., Goutieres, F., Hemeury-Cukier, F. and Aicardi, J.: Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 8 4 201-209, 1988. 10. Loizou, L.A., Kendall, B.E. and Marshall, J.: Subcortical arteriosclerotic encephalopathy. A clinical and radiological investigation. J Neurol Neurosurg Psychiat 44: 294-304, 1981. 11. Mattson, K., Niiranen, A., Iivanainen, M.,

Faerkkilae, M., Bergstroem, I., Hosti, L.R. and Cantell, K.: Neurotoxicity of interferon. Cancer Treat Rep 67: 958-961, 1983. 12. McDonald, E.M., Mann, A.H. and Thomas, H.C.:Interferons as mediators of psychiatric morbidity. Lancet 2: 1175-1 177, 1987. 13. Meyers, C.A., Scheibel, R.S.and Forman, A. D.: Persistent neurotoxicity of systematically administered interferon-alpha. Neurology 41: 672-676, 199 1. 14. Rohatiner, A.Z.S., Prior, P.F., Burton, A.C.,

Smith, A.T., Balkwill, F.R. and Lister, T.A.: Central nervous system toxicity of interferon. Br J Cancer 47: 419-422, 1983. 15. Rosenberg, G.A., Kornfeld, M., Stovring, J., Bicknell, J.M.: Subcortical arterioscleroticen-

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cephalopathy (Binswanger): Computed tomography. Neurology 2 9 1102-1 106, 1979. 16. Smeldy, H., Katrak, M., Sikora, K. and Wheeler, T.: Neurological effects of recombinant human interferon. Br Med J 286 262-264, 1983. 17. Sutter,

C.C., Westmoreland, B.F. and Hermann, R.C.: Electroencephalographic abnormalities in interferon encephalopathy: A preliminary report. Mayo Clin Proc 5 9 847-

850, 1984. 18. Takahashi, T., Ichimiya, Y.and Iizuka, R.: A

case of interferon encephalopathy. Seishin Igaku 32: 93-95, 1990 (in Japanese).

19. Valentine, A.R., Moseley, I.F. and Kendall,

B.E.: White matter abnormality in cerebral atrophy: Clinicoradiographic correlations. J Neurol Neurosurg Psychiat 43: 139-142, 1980. 20. Wiranowska, M., Wilson T.C., Thompson, K.

and Prockop, L.D.:Cerebral interferon entry in mice after osmotic alteration of blood-brain barrier. J Interferon Res 9 353-362, 1989. 21. Zeumer, H., Schonsky, B. and Strum, K.W.: Predominant white matter involvement in subcortical arterioschlerotic encephalopathy (Binswanger disease). J Comput Assist Tomogr 4 14-19, 1980.