KETOCONAZOLE IN THE TREATMENT OF CRYPTOCOCCOSIS
OF THE CENTRAL NERVOUS SYSTEM
P. C. TREVISOL-BITTENCOURT * — J. W. A. S. SANDER ** — C. S. SILVADO *** E. O. WITTIG ***
S U M M A R Y — T w o p a t i e n t s w i t h c r y p t o c o c c o s i s o f t h e C N S w e r e t r e a t e d w i t h k e t o c o n a z o l e ( K T Z ) , a n i m i d a z o l e d e r i v a t i v e w i t h f u n g i s t a t i c p r o p e r t i e s ; t h e y h a d e i t h e r f a i l e d s t a n d a r d t h e r a p y ( A m p h o t e r i c i n - B + 5 - F l u r o c y t o s i n e ) o r s u f f r e d i n t o l e r a b l e s i d e - e f f e c t s t o it. B o t h p a t i e n t s w e r e a d m i n i s t e r e d K T Z 800 m g / d a y a s m o n o t h e r a p y f o r s i x m o n t h s w i t h o u t i n t e r r u p -t i o n a n d b o -t h r e s p o n d e d . O n e m o n -t h a f -t e r K T Z -t h e r a p y w a s w i -t h d r a w n , h o w e v e r , a r e l a p s e o f t h e i n f e c t i o n w a s s e e n i n o n e c a s e . S i d e - e f f e c t s w e r e m i n i m a l d u r i n g t h e trial o f t r e a t m e n t . K T Z c o u l d b e a u s e f u l d r u g i n s o m e c a s e s o f n e u r o c r y p t o c o c c o s i s .
Ketoconazole no tratamento da neurocriptococose
R E S U M O — D o i s p a c i e n t e s c o m n e u r o c r i p t o c o c o s e f o r a m t r a t a d o s c o m k e t o c o n a z o l e ( K T Z ) , u m d e r i v a d o i m i d a z ó l i c o d e p r o p r i e d a d e s f u n g o s t á t i c a s . A m b o s f o r a m t r a t a d o s i n i c i a l m e n t e c o m o e s q u e m a t e r a p ê u t i c o t r a d i c i o n a l ( a n f o t e r i c i n a - B + 5 - f l u r o c i t o s i n a ) p o r é m e m u m d o s c a s o s p a r a - e f e i t o s i n t o l e r á v e i s o b r i g a r a m a s u s p e n s ã o d o t r a t a m e n t o e , n o o u t r o c a s o , n ã o h o u v e r e s p o s t a a o e s q u e m a t e r a p ê u t i c o . K T Z f o i a d m i n i s t r a d o r e g u l a r m e n t e p o r v i a o r a l e m r e g i m e d e m o n o t e r a p i a n a d o s e d e 8 0 0 m g d i á r i a s d u r a n t e 6 m e s e s c o m ó t i m o s r e s u l t a d o s . T o d a v i a , u m m ê s a p ó s a s u s p e n s ã o d o t r a t a m e n t o , h o u v e r e c o r r ê n c i a d a i n f e c ç ã o e m u m p a c i e n t e . E f e i -t o s c o l a -t e r a i s f o r a m m í n i m o s d u r a n -t e o c u r s o d o -t r a -t a m e n -t o . K T Z p o d e s e r ú -t i l n o -tra-ta- trata-m e n t o d e a l g u n s c a s o s d e n e u r o c r i p t o c o c o s e .
Ketoconazole no tratamento da neurocriptococose
R E S U M O — Dois pacientes com neurocriptococose foram tratados com ketoconazole ( K T Z ) , um derivado imidazólico de propriedades fun gosta ticas. A m b o s foram tratados inicialmente com o esquema terapêutico tradicional (lanfotericina-B + 5-flurocitosina) porém em um dos casos para-efeitos intoleráveis obrigaram a suspensão do tratamento e, no outro caso, não houve resposta ao esquema terapêutico. K T Z foi administrado regularmente por via oral em regime de monotempia na dose de 80Omg diárias durante 6 meses com ótimos resultados. Todavia, um mês após a suspensão do tratamento, houve recorrência da infecção em um paciente. Efei-tos colaterais foram mínimos durante o curso do tratamento. K T Z pode ser útil no trata-mento de alguns casos de neurocriptococose.
Cryptococcosis is a rare but grievous affliction caused by the fungus Crypto-coccus neoformans, an agent which in humans exhibits a special tropism for the central nervous system ( C N S ) . In nearly 5 0 % of patients affected there is an underlying immunological deficiency ( A I D S , diabetes mellitus, hematopoietic diseases, leprosy, neoplasias, prolonged steroid therapy or other immunosupressive agents). It is generally accepted that the simultaneous use of amphotericin-B ( A B )
intrave-nously and of 5-flurocytosine ( 5 F C ) orally is the treatment of choice 5,6. This regimen, however, is far from ideal; almost one third of patients do not respond to the combi-nation of A B + 5 F C and there is a high incidence of side effects that sometimes leads to the temporary or permanent interruption of the therapy. The pursuit for a less toxic and more efficacious drug as an alternative treatment is thus a necessity. Ketoconazole ( K T Z ) is an imidazole derivative with fungistatic properties, which is effective in the treatment of systemic mycosis and other fungal infection of the C N S . In addition, K T Z seems to be less toxic than the standard therapy with A B + 5 F C 1.2,4, despite its potentiality to provoke liver damage 3 and inhibit steroid synthesis 7. We treated two patients suffering from cryptococcosis of the C N S with K T Z at a dose of 8 0 0 m g / d a y orally for six months uninterrupted and the results obtained are pre-sented here.
D e p a r t a m e n t o d e C l í n i c a M é d i c a , H o s p i t a l d e C l í n i c a s , U n i v e r s i d a d e F e d e r a l d o P a r a n á , ( U F P R ) C u r i t i b a : * N e u r o l o g i s t , U n i v e r s i d a d e F e d e r a l d e S a n t a C a t a r i n a ( U F S C ) ; * * N e u r o l o g i s t , I n s t i t u t e o f N e u r o l o g y , Q u e e n S q u a r e ( L o n d o n W C 1 N 3 B G , U K ) ; *** N e u r o l o g i s t , A s s o -c i a t e P r o f e s s o r , U F P R .
CASE R E P O R T S
T w o male inpatients of the neurological department of Hospital de Clinicas, Universi-dade Federal do Parana, Curitiba, in w h o m a diagnosis of cryptococcal meningitis was made, were treated with K T Z for six months. Both received 800 m g / d a y orally (400 mg b d . ) and were assessed on a monthly basis.
Patient 1 — OB, a 50 year old farmer, with tuberculoid leprosy, presented with) reduced visual acuity in the right eye, headache, fever, vomiting and weakness in his left arm and leg. These symptoms had commenced 30 days before and had been gradually increasing in severity. The neurological examination on admission demonstrated signs of meningeal irrita-tion, left hemiplegia and right optic nerve atrophy. Cerebral angiography indicated occlusion of rigth middle cerebral artery ( R M C A ) ; CT scan displayed an ischemic infarction in the territory of the R M C A ; cerebrospinal fluid (CSF) examination showed a lymphocytic pleocy-tosis (148 cells/mm3), low glucoce (19mg%) and raised protein (295mg%); Cryptocoecus neo-formans in Indian ink preparations w a s positive and the culture was also positive. The patient w a s treated with systemic AB (0.3 m g / K g per d a y ) and 5FC (150 m g / K g / d a y ) . Due to the perseverance of symptoms, after a cumulative dose of 4.6 grams of AB intravenously was reached, the administration of AB intrathecally was instituted, with 0.5 mg being given every 2 days. T h i s therapy, however, was abandoned after a cumulative dose of 10 mg, be-cause of the development of urinary retention! land diffuse pain in both legs. An Omaya servoir was then inserted for the intraventricular administration of AB and the patient re-ceived 0.5 mg every other day to a cumulative dose of 15 m g . Despite improvement in CSF parameters treatment w a s discontinued due to transitory and bilateral oculomotor palsies after each application and the occurrence of a tonic-clonic seizure of few seconds after the last dose. In spite of the treatment, the patient presented continuous evidence of active fungal infection and complained of fierce headache. Consequently, due to the failure of the conventional treat-ment, a K T Z trial w a s started with a daily dosage of 800 mg. Clinical improvement was noticed during the follow up period. The symptoms gradually lessened and simultaneously CSF examination showed progressive normalisation and after 6 month of treatment K T Z was tapered off. Recurrence of the clinical symptoms and a positive microscopy were seen a month after the suspension of K T Z therapy. Treatment was restarted and his condition stea-dily improved from then on. The patient remained well for a further 9 months when he was lost to follow-up having moved to another State.
Patient 2 — M L F , a 66 year o l d cabinet maker, with 3 year history of diabetes mellitus treated with chlorpropamide, presented with frontal headache and brief episodes of diplopia. Clinical examination on admission recordedi paresis of the right lateral rectus muscle, absence of ankles reflexes and a background diabetic retinopathy. CT scan was normal and the CSF indicated a lymphocytic pleocytosis (129 cells/mm3), l o w glucose (46 m g % ) , and raised protein
(190 m g % ) . T h e Indian ink preparation revealed Crytococcus neformans and the culture was positive. A course with systemic AB (0.3mg/Kg/da,y) combined with 5FC (150mg/Kg/day)
was started. After a cumulative dose of 1.6 grams of A B , a persistent and progressive im-pairment of renal function was noticed, requiring the withdrawal of the drug in spite of the clear-cut clinical improvement. T h e patient was asymptomatic and the CSF examination showed 18 cells/mm3, glucoses 65 mg% (blood 148 m g % ) , protein 78 m g % . Cryptocoecus neoformans was seen on microscopy but the culture was negative. No further medication was prescribed and the patient w a s re-evaluated monthly. After a 5 months follow up period in which no symptoms were noted, the patient started again to complain of frontal headache and episodic diplopia. T h e clinical examination w a s unchanged. The CSF analysis at this occasion revealed 26 cells/mm3, glucose 55mg% ( b l o o d 132mg%), protein 93mg%. Cryptocoecus neoformans was seen on microscopy but culture w a s again negative. In spite of the culture result, his symp-toms w e r e suggestive of a reactivation of the fungal infection and a trial of K T Z was there-fore initiated. There was progressive clinical improvement and the patient became
asympto-matic after 2 months from commencing K T Z therapy. Treatment was withdrawn after 6 months and recurrence was not observed during a 3 year follow up period.
COMMENTS
This was construed as a consequence of the fungistatic action of K T Z and this may necessitate the administration of the drug for an indefinite period of time.
Patient 2 was given K T Z on clinical grounds alone having a relapse of his symptoms 5 months after the cessation of A B + 5 F C therapy. T h e C S F examination before the initiation of K T Z showed similar changes to those noticed when the A B + 5 F C treatment w a s interrupted and the Indian ink test w a s postive but culture was negative. As this diabetic patient already presented signs ot peripheral neuro-pathy (absence of Achilles reflexes), the visual complaint due to paresis of right lateral rectus muscle could also be interpreted as an aftermath of a diabetic VI nerve palsy. This, however, would not account for the prevailing symptom of headache and it w a s felt that both symptoms were brought about by the reactivation of the fungal infection. T h e disappearance of these symptoms and the normalisation of the CSF during the therapy with K T Z further supports this hypothesis. It cannot be certain that the cure was effected by the drug, because the microscopy for
Crypto-coccus neoformans in the Indian ink test was positive but the cultures were negative
from the commencement.
Only patient 2 suffered any side effects. He complained of nausea during the first two weeks of his treatment, however, this did not require the reduction or suspension of the drug. Monthly liver function tests were within normal parameters in both patients.
On the basis of our experience we suggest that K T Z could be useful in C N S cryptococcosis in the event of either failure of the standard therapy or when intole-rable toxic side effects do not allow the continuation of conventional treatment. Its fungistatic action, however, may render the administration of the drug imperative for an indefinite period of time.
This was construed as a consequence of the fungistatic action of K T Z and this may necessitate the administration of the drug for an indefinite period of time.
Patient 2 was given K T Z on clinical grounds alone having a relapse of his symptoms 5 months after the cessation of A B + 5 F C therapy. T h e C S F examination before the initiation of K T Z showed similar changes to those noticed when the A B + 5 F C treatment w a s interrupted and the Indian ink test w a s postive but culture was negative. As this diabetic patient already presented signs ot peripheral neuro-pathy (absence of Achilles reflexes), the visual complaint due to paresis of right lateral rectus muscle could also be interpreted as an aftermath of a diabetic VI nerve palsy. This, however, would not account for the prevailing symptom of headache and it w a s felt that both symptoms were brought about by the reactivation of the fungal infection. T h e disappearance of these symptoms and the normalisation of the CSF during the therapy with K T Z further supports this hypothesis. It cannot be certain that the cure was effected by the drug, because the microscopy for
Crypto-coccus neoformans in the Indian ink test was positive but the cultures were negative
from the commencement.
Only patient 2 suffered any side effects. He complained of nausea during the first two weeks of his treatment, however, this did not require the reduction or suspension of the drug. Monthly liver function tests were within normal parameters in both patients.
On the basis of our experience we suggest that K T Z could be useful in C N S cryptococcosis in the event of either failure of the standard therapy or when intole-rable toxic side effects do not allow the continuation of conventional treatment. Its fungistatic action, however, may render the administration of the drug imperative for an indefinite period of time.
REFERENCES
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3. Goldberg A. Oral ketoconazole and liver damage. L o n d o n : HMSO - Comittee on Safety of Medicine, 1985, Adverse Reaction Series 19.
4. Graybill JR, Drutz DJ. Ketoconazole: a major innovation for treatment of fungal disease. Ann Intern Med 1980, 93:921-923.
5. Tija T L , Y e o w Y K , Tan CB. Cryptococcal meningitis. J Neurol Neurosurg Psychiat 1985, 48:853-858.
