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Single-enhancing CT lesions in Indian patients with seizures: a review
Epilepsy Research 38 (2000) 91 – 104 www.elsevier.com/locate/epilepsyres
Single-enhancing CT lesions in Indian patients with seizures: a review Ravindra Kumar Garg *, Manish Kumar Singh, Surendra Misra Department of Neurology, Institute of Medical Sciences, Banaras Hindu Uni6ersity, Varanasi-221 005, India Received 13 April 1999; received in revised form 13 July 1999; accepted 5 August 1999
Abstract Single enhancing CT lesions are the commonest radiological abnormality in Indian patients with new-onset partial seizures. In few patients the lesions may be ‘tuberculoma’ (especially in presence of evidence of tuberculosis elsewhere). However, histopathological studies have proved that neurocysticercosis is the most frequent cause for these lesions. Acute inflammation in and around the cerebral lesions of cysticercosis manifests as acute seizure disorder. These cysticercal granulomas represent ‘colloidal’ and ‘nodular-granular’ stages of Escobar’s pathological classification of natural evolution of a parenchymal cysticercus cyst. In 8 – 12 weeks time majority of these lesions spontaneously disappear, few may calcify. As albendazole therapy is of controversial value, these patients, possibly, need to be treated only with antiepileptic drugs. Associated seizure disorder is also benign in nature and remit in majority within 6–8 months, recurrences are usually infrequent. Antiepileptic drug may be withdrawn once follow-up CT scan shows resolution of the lesion. If seizures recur after resolution of the lesion, CT lesion persists or CT lesion calcified, a long-term (2–3 years) antiepileptic therapy may be required. The single enhancing CT lesions which persist despite anticysticercal or antituberculous therapy may need histopathological evaluation to establish the correct diagnosis. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Single enhancing CT lesion; Cysticercosis; Epilepsy; Neurocysticercosis; Tuberculoma; Seizures in Indian patients
1. Introduction Single enhancing computed tomographic (CT) lesions are the commonest imaging abnormality in Indian patients with new-onset seizures (Fig. 1). These lesions were first reported by Tandon and Bhargava (1980), at that time these CT lesions were presumed to be tuberculomas. Histo-
* Corresponding author.
pathological studies, subsequently, had suggested that single enhancing CT lesions often represented dying cysticerci (larval stage of tapeworm Taenia solium). These lesions are usually benign and tend to resolve spontaneously. Conflicting results were obtained regarding early resolution of CT lesions following anticysticercal therapy. So, precise management of these lesions is still uncertain. This article reviews the substantial new information that has appeared in recent past.
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2. Incidence Initially it was thought that these lesions are seen only in Indian subcontinent, later similar lesions have been reported from other parts of the world. In Latin-American countries single enhancing CT lesions are frequently seen and these are considered as cysticercus granuloma (Del Brutto, 1993). Similar lesions are also reported from developed countries like Australia, United
Fig. 2. Cranial computed tomography showing: (a) a ring enhancing lesion; (b) complete disappearance of the lesion after 8 weeks.
Fig. 1. Plain and contrast cranial computed tomographic scans showing a cystic lesion along with scolex in plain scan. After contrast administration whole structure has enhanced.
Kingdom, United States of America, (Minguetti and Ferriera 1983; Kennedy and Schon 1991; Stamos et al., 1996) and other parts of Asia like Thailand (Bhoopat et al., 1989). The exact incidence in Indian population is not known, most of the data are from hospital-based studies. Wadia et al. (1987) investigated 150 patients with simple partial seizures and observed that these CT lesions were present in approximately 26% of the patients. The incidence of single enhancing CT lesions was higher among children as 40% of patients were below 15 years of age. Murthy et al. (1998) in a recent study, reported these single CT lesions in 23.4% of 2531 patients with all types of epilepsies. Garg and Nag (1997) observed a higher incidence of single ring enhancing CT lesions in children and adolescents (72%), when CT scans
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were performed after the first seizure. Chopra et al. (1992) also observed that 78% of 122 patients in their series were between 11 and 20 years of age. Why this lesion is common in children and patients of younger age group is not clear. As these lesions most often have cysticercal etiology, possibly poor hygienic conditions prevailing around children make them more susceptible to infection than adults (Cao et al., 1997).
3. Imaging features The characteristic ring or disk enhancing CT lesions are seen after intravenous contrast administration. Plain CT scans also, however frequently, show some abnormality. The commonest abnormality in plain CT scan is irregular low attenuation areas in cerebral hemispheres. In the series by Chopra et al. (1992), low attenuation areas were seen in all patients, in two patients a tiny speck of calcification was also present within the hypodense areas. With higher performance CT machines, it is not uncommon to see a cystic lesion with an eccentric nodule (features consistent with
Fig. 3. Cranial computed tomographic scan showing a disk enhancing lesion.
Fig. 4. Cranial computed tomography showing: (a) a ring enhancing lesion; (b) CT scan after 2 years showing calcification of the lesion.
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the structure of cysticercus larva) (Garg et al., 1999) (Fig. 1). Plain CT scan, at times, may not reveal any abnormality (Rajshekhar 1991). In a recent study, Garg and Nag (1998) observed abnormalities in plain CT scan in 66% of 101 patients. Focal hypodensity was present in 49% of patients, and 17% of patients had cystic lesions with eccentric dot. After contrast administration, there is a ring (Fig. 2) or homogenous disk (Fig. 3) like enhancement within the region of hypodensity. The enhancing lesions are usually less than 20 mm in diameter surrounded by mild to moderate perifocal oedema. The oedema may occasionally be severe enough to produce a mid-line shift, this feature frequently suggests non-cysticercal pathologies especially tuberculoma. An enhancing
Fig. 6. Cranial computed tomography showing a persisting CT lesion: (a) initial scan; (b) scan after 18 months.
Fig. 5. MR images showing a single cysticercus granuloma. (a) T1-weighted image; (b) T2-weighted image.
or a calcified eccentric dot (presumed to be the scolex of cysticercus larva) can be seen within the ring lesion. Chopra et al. (1992) observed a ring lesion with an enhancing eccentric dot (target lesions) in only three of 122 cases. In the study by Garg and Nag (1998) enhancing eccentric dot was observed in approximately half of 101 patients. Single CT lesions can be seen throughout the cerebral hemispheres. Lesions are situated superficially in the gray matter or at the junction of gray and white matter. parietal lobes are the commonest location for these lesions. Frontal lobe and occipital lobe are next common sites. In few patients the ring or disk lesion may be seen in the parasagittal areas (Chopra et al. 1992; Garg and Nag 1997). These CT lesions are uncommon in temporal lobes where they are frequently missed in CT scans. Such lesions may be discovered with the help of magnetic resonance (MR) imaging.
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4. Disappearance of the CT lesions The outstanding feature of single CT lesions in patients with epilepsy is the complete spontaneous disappearance in the majority, and significant reduction in the size of the lesions in a few other patients (Fig. 2). In the study by Chopra et al., (1992) follow-up CT scans (usually within 6 – 12 weeks) were available in 78 patients (out of 122 patients). The CT lesions completely disappeared in 47 patients, reduction in the size of lesion and surrounding oedema was seen in 24 cases. Further follow-up of later cases showed complete disappearance in another 14 patients. In only seven cases the CT lesions persisted for longer duration. An almost similar radiological course was observed in previous studies also (Jaya Kumar et al., 1985; Sethi, et al. 1985). The time for spontaneous resolution of these lesions was variable and varied from as early as 6 weeks to as long as 75 weeks. Even longer persistence of CT lesions can be observed (Sawhney et al., 1999). The oedema around the lesion is usually first to resolve. Later on, the lesion may either disappear completely without any residue or it may leave a tiny speck of calcification at the site of original lesion. In few patients the granulomatous lesion is replaced by a calcified lesion (Rajshekhar, 1991; Garg and Nag, 1998) (Fig. 4).
5. Etiopathogenesis Since these lesions had been described their precise etiology remained controversial (Goulatia et al., 1987; Ahuja et al., 1989; Bansal et al., 1989; Rajshekhar, 1991). Until recently, the main point of controversy was whether these lesions were the cause or effect of the associated seizure disorder. Various biochemical and physiological changes do occur at the site of abnormal neuronal activity during or following seizures. These changes are noted in neurons, blood vessels and the blood – brain barrier, so enhancing CT lesions were considered by various authors as secondary phenomenon due to disruption of blood – brain barrier induced by seizures (Jaya Kumar et al., 1985; Goulatia et al., 1987). Demonstration of
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cysticercus larva in plain CT scan and healing of few of these lesions with calcification are some evidences, which are against the hypothesis of ‘post-ictal phenomenon’. Tandon and Bhargava (1980) reported these lesions as ‘tuberculomas’ because of various presumptive reasons. Firstly, intracranial tuberculomas were common intracranial masses in India and were seen in : 10–20% of all intracranial space occupying lesions. Secondly, these enhancing lesions were frequently seen in patients with tuberculous meningitis, and in association with tuberculosis affecting other systems of the body. A favorable response to empirical antituberculous therapy provided additional support for tuberculous etiology (Tandon and Bhargava, 1985; Kumar et al., 1990). Furthermore, tuberculosis is a highly endemic disease in India. Rajshekhar et al. (1993) performed CT guidedstereotactic biopsies of these lesions. The histopathological examination of tissues obtained after brain biopsy revealed cysticercus granuloma in majority of the patients (25 out of 51 patients), only in six patients a definite tuberculoma was demonstrated. Of remaining 20 patients, 12 patients had parasitic granuloma (cysticercal lesion was not definite), six patients had non-specific inflammation and one patient each had dystrophic calcification and secondary metastasis. In another study Kumar et al., (1995) performed excisional biopsy in 18 patients, and observed that cysticercosis was the most frequent cause for single enhancing CT lesions. A cysticercal lesion was seen in seven patients, in rest of the patients histopathological diagnosis included tumors (four patients), abscesses (three patients), and in one patient each due to infarction and gliosis. Tuberculomas were present in three patients. In a study Rajshekhar et al., (1995) tried to demonstrate presence of a viable parasite within single enhancing CT lesions. Histopathological examination of brain tissues revealed cystic lesions containing parts of an intact or degenerated cysticecus larva in 22 patients, inflammatory cavitary lesions without parasite in 13 patients, and non-cavitary hyalinized fibrous nodules with inflammation in eight patients. Of the 22 specimens with definite evidence of cysticercosis only two
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patients had entire parasite within the lesions, and it was not possible to predict presence of intact parasite in the granuloma on the basis of clinical or radiological features. The reason why most of the patients of neurocysticercosis, present with single rather than multiple lesions, is not clear. In order to find out answer to this question Thussu et al. (1997) evaluated immunological parameters in patients with single and multiple cysticercal lesions. The study pointed out that among patients of neurocysticercosis only those with multiple enhancing CT lesions have defective functions of neutrophils and T-lymphocytes.
5.1. Genetic link Recently, hereditary factors have been suggested in the etiopathogenesis of single enhancing CT lesions. Jain et al. (1997) observed that a very high percentage (25%) of probands with single enhancing CT lesions had a family history of seizures. Generalized epilepsy was the most common type of epileptic syndrome among relatives of patients with single enhancing CT lesions. Seven percent of relatives had single enhancing CT lesions, besides other relatives with different other epilepsy syndromes. These authors suggest that the syndrome of single enhancing CT lesions possibly occur in population that is genetically predisposed to seizures. In a more recent study Jain et al. (1999) studied HLA class II antigens using polymerase chain reaction amplified DNA and sequence specific oligonucleotide probe hybridization technique. They observed a positive association of HLADRB1*13 with this syndrome, further suggesting a genetic susceptibility to this disorder.
6. Clinical features These patients usually have partial seizures with or without secondary generalization irrespective of cerebral location of the lesion (Garg and Nag, 1998). With occipital lobe lesions frequently there is preceding visual aura and with
frontal lobe lesions adversive seizures are frequently seen, rarely complex partial seizures are encountered. Few patient may present with partial status-epilepticus. The seizures are almost always acutely developed. Usually, several episodes of seizures occur in cluster within a span of 2–3 days, and may not recur in near future. Sethi et al. (1994) in a series of 186 patients reported that 53% of the patients had a history of seizures for less than 3 months, 30% had seizures for more than 6 months and only 17% for more than one year. With disappearance of CT lesions, the risk of seizure recurrence is greatly reduced. In acute stage intense diffuse bursting headache may occasionally be associated. Usually, there is no history of preceding illness in form of fever, exanthema or any other systemic infection. There may be associated transient focal neurological deficit which is more common with parasagittal lesions, and weakness is usually more marked in lower limbs. Electroencephalographic (EEG) abnormalities are present in about 35% to 57% of the cases, usually in form of focal slowing, focal epileptiform activity may be rarely seen. After disappearance of the CT lesion, focal EEG abnormalities also resolve (Sethi et al., 1994).
7. Serological studies In several series, immunological tests have been used for the diagnosis of neurocysticercosis and intracranial tuberculous lesions. Enzymelinked immunosorbent assays (ELISA) were employed for the diagnosis of both these diseases in patients with single enhancing CT lesions. Ahuja et al. (1989) observed a positive reaction in serum for tuberculosis in only 5% of patients while a significantly higher number (30%) of patients were positive for cysticercosis. Subsequent studies employing ELISA and enzyme-linked immunotransfer blot assay showed low sensitivity of serological tests in the diagnosis of single cystiercus granuloma. Less than one-third of patients showed cysticercus antibodies in their
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serum. The poor results could be due to weak antibody response to the antigenic load from a single lesion. So, these tests are of limited value in this setup (Rajshekhar et al., 1991; Rajshekhar and Oommen, 1997).
8. Cysticercus granuloma versus tuberculoma An attempt had been made by Rajshekhar et al. (1993) to differentiate cysticercus granuloma from tuberculoma in patients with new-onset seizures and single enhancing CT lesions. They compared the clinical features and radiological characteristics of histopathologically proven cases of tuberculoma and cysticercus granuloma. Among clinical features presence of raised intracranial tension (papilloedema) and a focal neurological deficit pointed towards tuberculoma. Radiologically all tuberculomas were greater than 20 mm in size and the lesions were having irregular outline, whereas, all cysticercus granulomas were less than 20 mm in size and had a regular ring. Only tuberculomas were associated with midline shift (suggestive of severe brain edema) on CT, in patients of cysticercus granuloma perifocal oedema was either mild (localized to same lobe) or moderate (spread to adjacent lobe of same cerebral hemisphere). In this set-up ‘target lesions’ (central nidus of calcification or central enhancement surrounded by a ring of enhancement) is frequently encountered. Target lesions were initially considered a pathognomonic finding of CNS tuberculomas (Bargallo et al., 1996). Del Brutto et al. (1996) reported that visualization of an enhancing eccentric dot represent the scolex of cysticercus larva and can be considered a definite diagnostic feature in favour of cysticercus etiology. Histopathological evaluation of target lesions is not available. Furthermore, no effort has been made to note any difference in the natural courses of various types of single CT lesions (for example, lesion less than 20 mm versus lesion greater then 20 mm, and lesion with eccentric dot versus lesion without dot). So clinical importance of all these imaging features in Indian patients with single enhancing CT lesions is uncertain.
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9. Other differential diagnosis Various other presumptive diagnoses such as glioma, larva migrans infection, microabscesses, secondaries, small infarcts, transient focal viral encephalitis and arteriovenous malformation have been suggested but none of them could consistently been demonstrated in histopathological studies (Rajshekhar, 1991). However, it is important to look for a systemic disease such as tuberculosis, malignancy or a source of bacterial infection. In presence of these factors single enhancing CT lesions should not be considered as ‘cysticercus granuloma’ until CT lesion disappears spontaneously (Rajshekhar and Chandy, 1997). Enlargement of these CT lesions in follow-up scans is not necessarily indicative of neoplastic nature as small but significant number of single cysticercus granuloma may show paradoxical enlargement (exceeding 20 mm in diameter) after treatment with anticysticercal drugs (Rajshekhar and Chandy, 1994). On slightest suspicion (e.g. history of sexual contact with high risk persons) serological tests for human immunodeficiency virus (HIV) should be performed as toxoplasmosis, primary CNS lymphoma and various fungal granulomas may present with single enhancing CT lesions along with seizures in patients of acquired immunodeficiency syndrome.
10. Neurocysticercosis and single enhancing CT lesion: natural course A parenchymal cysticercus cyst of the brain passes through four stages in its natural evolution. The initial phase is the ‘‘vesicular phase’’, which represents the viable and live larvae of cysticercus cellulose. In this stage larva lives inside a translucent liquid-filled cystic structure surrounded by a thin membrane, where it can remain viable from a few months to several years. These vesicular lesions appear as ‘circumscribed’ hypodense unenhanced cystic lesions on CT scan. The second stage is ‘colloidal stage’. In this stage the cystic lesions are attacked by host’s immune defense mechanisms and inflammatory changes develop in the cyst wall and surrounding brain parenchyma.
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The parasite begins to show degenerative changes, the vesicular fluid becomes gelatinous and the wall of cyst thickens. On CT these lesions appear in ‘ring enhancing’ pattern. The third stage, ‘granular-nodular’ stage refers to dying larva in advanced stage of inflammation and destruction. The vesicle tends to shrink, content becomes semisolid as it is progressively replaced by granulomatous tissue, on CT these lesions appear as homogenous disk enhancement. The fourth stage is the ‘calcific’ stage, formed by calcification of the gliotic scar that replaces the dead parasite. The first stage, which is considered live form of neurocysticercosis, the patient may remain asymptomatic. In patients with new-onset seizures these unenhanced cystic lesions have never been demonstrated. Second and third stages, which represent dying stages of cysticercus larva, are seen in CT scans of Indian patients with epilepsy. Acute development of inflammation, and surrounding cerebral oedema is responsible for new-onset seizures in these patients. Because of intense inflammation in and around the parasite, in acute stage patients experience cluster of seizures. With eventual resolution of inflammatory phase the risk of subsequent seizure progressively decreases. Calcified lesions though represent a ‘dead’ parasite has potential for producing chronic epilepsy. This process of involution of parasite usually begins spontaneously with the disintegration of the outer vesicular membrane and discoloration of the fluid content (Escobar, 1983; Del Brutto and Sotelo, 1988; Rajshekhar et al., 1995; Carpio et al., 1998).
eral enhancement and a central low signal area. MR imaging is, frequently not helpful in determining the etiology of granuloma. CT has an advantage over MR studies, as calcified lesions are better seen with CT scans (Rajshekhar and Chandy, 1996).
12. Management Until recently there was no consensus about the etiology of single enhancing CT lesions in Indian patients with epilepsy, a uniform treatment protocol was not practiced and had been treated differently by different workers.
12.1. Antituberculous treatment In earlier studies these patients were treated with antituberculous treatment (Kumar et al., 1990). Wadia et al. (1987) observed that at least one third of the patients had some systemic evidence of tuberculosis. Out of 39 patients with systemic evidences of tuberculosis, ten patients had active pulmonary tuberculosis. These authors suggested that antituberculous treatment is justified in all patients with single enhancing CT lesions. After histopathological demonstration of tuberculous etiology only in minority of patients, and because of spontaneous resolution of CT lesions, antituberculous treatment is now infrequently used.
12.2. Anticysticercal treatment 11. MR features MR imaging is frequently performed with the objective of differentiating cysticercus granuloma and tuberculoma. MR pictures of both these conditions are exceedingly similar. T1-weighted images usually show a low-signal center with isointense periphery. The granulomas are better visualized in T2-weighted images where low-signal ring and a high signal center are characteristic features (Fig. 5). Surrounding oedema is also best seen in T2-weighted images. In contrast-enhanced MR studies the granuloma shows marked periph-
After availability of reports indicating that majority of these lesions are inflammatory stage of parenchymal neurocysticercosis, anticysticercal drugs are increasingly being employed. Del Brutto, (1993) reported early resolution of lesions following albendazole therapy in Latin-American patients with similar CT lesions. There have been several studies trying to prove the efficacy of anticysticercal treatment in Indian patients with single enhancing CT lesion, however, with conflicting results. Padma et al. (1994) in a controlled study observed that, seven days treatment with albendazole did not hasten the resolution of these
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CT lesions. However, in a recent double-blind study Baranwal et al. (1998) observed a significantly faster and higher incidence of complete lesion disappearance in children who received albendazole. In this study 63 pediatric patients were randomly assigned to receive either albendazole (15 mg/kg per day) or placebo for 4 weeks and follow-up CT scans were performed at 1 month and 3 months. After 3 months 64.5% of patients who received albendazole and 37.5% of placebo-treated patients showed resolution of the CT lesions. Published dosage regimens of albendazole in patients of neurocysticercosis have varied from 15 mg/kg per day for 7 days to up to 30 days. Cruz et al. (1995) demonstrated the effectiveness, in clinical and radiological terms, of albendazole 800 mg/day for 8 days for the majority of patients affected with cystic or encephalitic parenchymatous cysticercosis. They concluded that there was no apparent advantage of continuation of treatment for 15 or 30 days in this series. However, 7 days albendazole therapy was not found effective in Indian patients with single cysticercus granuloma. So, comparative study using short (7 or 8 days) and long term (30 days) treatment is required to resolve the issues related to the effectiveness of albendazole in patients with single enhancing CT lesions. Administration of albendazole in these patients may lead to an enhanced inflammatory reaction around the cyst consequent to the death of parasite, and patient may experience recurrence of seizures, headache and vomiting. These side effects are infrequently reported, because parasitic load is limited to a single lesion and secondly majority of cysticercus granulomas contain only degenerated larva (Rajshekhar et al., 1995). Whenever side-effects of albendazole therapy in patients with single granulomatous lesion is present indicate cysticercal nature of the lesion (Rajshekhar, 1998). Del Brutto and Quintero (1995) observed that even early resolution of single enhancing lesion following empirical albendazole therapy indicated cysticercal nature of the lesion in a patient having a CT lesion mimicking brain tumor.
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12.3. Antiepileptic treatment only Chopra et al. (1992) suggested that because of benign nature of CT lesions these patients needed treatment only with antiepileptic drugs, as irrespective of etiology (tuberculoma or cysticercus granuloma) the CT lesions resolved spontaneously. Another important aspect about the management of these patients is how long antiepileptic treatment be given. Murthy et al. (1998) followed 262 patients with single CT lesions and observed that seizures did not recur in 62% of patients after commencement of antiepileptic drugs during mean follow-up time of 31.4 months (range 14–73 months). Seventyfour (28%) patients continued to have seizures for some time (median, 2 months). The remaining 26 (10%) patients continued to have seizures (median 8 months), and observed seizure remission following cysticidal therapy. Antiepileptic drugs were stopped after a seizure-free period of two or more than 2 years. In the study by Chopra et al., (1992) antiepileptic therapy was tapered off after at least three years of seizure-free period. The prognosis of associated epileptic disorder in majority of patients with single enhancing CT lesions seems to be different than in patients with other forms of parenchymal neurocysticercosis where there is a high rate of recurrence after withdrawal of antiepileptic drugs. Several workers now believe that most of these patients do not require conventional prolonged treatment with antiepileptic drugs (Srinivas, 1992; Garg, 1995; Rajshekhar and Chandy, 1995). Murthy and Subba Reddy (1998) in a recent study demonstrated that the seizures ceased to recur once the CT lesion resolved. This retrospective study included 102 patients with single enhancing CT lesions with seizures. Antiepileptic drug therapy was started in all these patients. Seizures did not recur in 68 (63%) of patients after starting antiepileptic drugs. Twenty-eight (27.5%) patients had recurrence of seizures for a median period of 2 months before remission was achieved. In the remaining 10% of patients seizures remitted after albendazole therapy, me-
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dian period of seizure recurrence was 8 months. The antiepileptic drugs were withdrawn once the follow-up CT scan showed complete resolution of the lesion. Only one patient experienced seizure recurrence during mean follow-up period of 45 months (range 19–101 months). In this patient follow-up CT scan showed gliotic scar at the site of previous lesion. Carpio et al. (1998) also, in a recent review, suggested that seizures in patients with single enhancing lesions should be considered acute symptomatic seizures. These patients need treatment with antiepileptic drugs for the duration of the acute condition perhaps several months during which the inflammatory response is active. Once the lesion has disappeared antiepileptic drugs may be gradually withdrawn. If seizures recur, antiepileptic drugs should be restarted and then patient may be treated for 2 – 3 years. If lesion has calcified again antiepileptic drugs should be given for longer period (at least for 2 – 3 years) before being tapered off. In a few patients the epilepsy is difficult to control and may even be intractable. Persistence of a CT lesion or gliotic changes in the cerebral parenchyma, secondary to intense granulomatous inflammation, may account for uncontrolled seizures (Garg and Nag, 1998). Calcified lesions, because of their epileptogenic potential, act as source of chronic epilepsy, and seizures can recur even after stopping antiepileptic treatment (Garg et al., 1997).
13. Persistence of CT lesions CT lesions with similar clinical and radiological characteristics if do not disappear or regress in 8–12 weeks time (Fig. 6), whether do they represent other disease? Chopra et al. (1992) reported five such patients in a series of 78 patients and reported a very good response to antituberculous treatment. In another study Rajshekhar (1993) reported excellent response to albendazole in patients with persisting CT lesions with epilepsy. He reported that albendazole produced complete resolution or regression in all 11 patients who were studied. The exact incidence of single enhancing CT lesions persisting for long duration or being calcified is not known. In a retrospective analysis Garg and Nag (1998) observed that 16% of 101 patients the lesions did not disappeared nor regressed even after prolonged follow-up (\ 6 months). Subsequent follow-up of these patients with persisting CT lesions revealed that in four patients the lesions eventually calcified, in four patients the ring lesions changed to a disk lesion and in the remaining eight patients the lesion persisted unchanged. In patients with uncontrolled seizures, progressive focal neurological deficit and appearance of raised intracranial tension the persisting CT lesions may be subjected to brain biopsy to establish the correct diagnosis (Rajshekhar and Chandy, 1994).
14. Future research
12.4. Follow-up CT scan There are no definite guidelines to suggest the need for repeat CT scan. Sawhney et al. (1999), on the basis of their experience, recommend that first repeat CT scan should be done after 12 weeks if patient is symptom free and neurological examination is normal. It may be done early if new sign or symptom appear. A third CT scan may be required where second scan has not shown any resolution of lesion, seizures are uncontrolled, progressive neurological deficit appears, or patient has been treated with albendazole or antituberculous drugs.
Despite several advances in etiology and pathogenesis and management of single enhancing CT lesions, there are several issues, which need to be addressed. Why these lesions are common only in Indian subcontinent is still not clear. Whether genetic factor is responsible need to be explored. The early evidences in this regard are already available. Immunological factors responsible in the etiopathogenesis of these lesions should be examined. The role of corticosteroids in the management of single enhancing CT lesions needs to be explored. Our unexamined observations suggest that a short course of oral corticosteroids helps in early resolution of lesions and helps in
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Fig. 7. Treatment algorithm for patients with single enhancing CT lesions.
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better control of seizures. Immunological tests available for diagnosis of neurocysticercosis as a cause of single enhancing CT lesions are unreliable. In future there is a need to develop better investigative modalities like polymerase chain reaction to detect even minimal parasitic antigen load. Conflicting reports are available about efficacy of anticysticercal treatment. What should be appropriate dosage schedule of albendazole? A comparative study is needed to evaluate 7 or 8 days course of albendazole with a 30 days course. A controlled multicentric study with prolonged prospective follow-up will help in establishing benefits of albendazole in the long-term management of these patients. In one unreported study we observed that patients treated with albendazole CT lesions are less likely to be calcified, hence, patients are less likely to experience seizure in future. This observation needs to be verified. The seizures in these patients are less likely when lesion has resolved, a prospective study using shorter courses of antiepileptic therapy need to be done. Histopathological evaluation of CT lesions, which persist despite all efforts, is required to establish the nature of persisting lesions. Some of these patients may have different etiology. Studies are needed to establish precisely the role of MRI and follow-up CT scans so that the cost of treatment can be reduced to a minimum.
15. Conclusion Controversies about etiology and management of single enhancing CT lesions in Indian patients with seizures persist even nearly two decades after when these lesions were first reported. Initially, these lesions were presumed as tuberculoma and were treated empirically with antituberculous drugs. Later, histopathological examination of tissues obtained after stereotactic brain biopsies revealed that the majority of these lesions were inflamed cysts of cysticercus larva. The clinical criteria suggestive of single cysticercus granuloma are seizures as the initial symptom with no evidence of persistent raised intracranial pressure, no progressive neurological deficit and no active systemic disease. The CT diagnostic criteria are evi-
dence of a single contrast-enhancing lesion measuring 5 20 mm, without a shift of midline structures due to surrounding oedema. Irrespective of etiology these lesions tend to resolve spontaneously. Role of anticysticercal treatment is still controversial. However, the best way to manage patients with these CT lesions is that the granuloma should be allowed to resolve in its natural course even if it takes several months, meanwhile, to prevent the seizure recurrence antiepileptic drugs should be employed. Antiepileptic drugs may be tapered off once CT lesion has disappeared. Brain biopsy should be considered in patients in whom lesion is persisting or increasing in size (even after empirical trial of albendazole or antituberculous therapy) and producing uncontrolled seizures or progressive focal neurological deficit (Fig. 7). References Ahuja, G.K., Behari, M., Goulatia, R.K., Jailkhani, B.L., 1989. Disappearing CT lesions in epilepsy: is tuberculosis or cysticercosis the cause? J. Neurol. Neurosurg. Psychiatry 59, 915 – 916. Bansal, B.C., Dua, A., Gupta, R., Gupta, M.S., 1989. Appearing and disappearing CT scan abnormalities in epilepsy in India — an enigma. J. Neurol. Neurosurg. Psychiatry 52, 1185 – 1187. Baranwal, A.K., Singhi, P.D., Khandelwal, N., Singhi, S.C., 1998. Albendazole therapy in children with focal seizures and single small enhancing computerized tomographic lesions: a randomised placebo-controlled double blind trial. Pediatr. Infect. Dis. J. 17, 696 – 700. Bargallo, J., Berenguer, J., Garcia-Barrionuevo, J., Ubeda, B., Bargallo, N., Cardenal, C., Mercader, J.M., 1996. The ‘target sign’: it is a specific sign of CNS tuberculoma? Neuroradiology 38, 547 – 550. Bhoopat, W., Poungwarin, N., Issaragrisil, R., Sughiponchai, S., Khanyanasthiti, P., 1989. CT diagnosis of cerebral cysticercosis. J. Med. Assoc. Thai 72, 673 – 681. Cao, W., Van-der Ploeg, C.P., Xu, J., Gao, C., Ge, L., Habbema, J.D., 1997. Risk factors for human cysticercosis morbidity: a population-based case-control study. Epidemiol. Infect. 119, 231 – 235. Carpio, A., Escobar, A., Hauser, W.A., 1998. Cysticercosis and epilepsy: a critical review. Epilepsia 39, 1025 – 1040. Chopra, J.S., Sawhney, I.M.S., Suresh, N., Prabhakar, S., Dhand, U.K., Suri, S., 1992. Vanishing CT lesions in epilepsy. J. Neurol. Sci. 107, 40 – 49. Cruz, I., Cruz, M.E., Carrasco, F., Horton, J., 1995. Neurocysticercosis: optimal dose treatment with albendazole. J. Neurol. Sci. 133, 152 – 154.
R.K. Garg et al. / Epilepsy Research 38 (2000) 91–104 Del Brutto, O.H., Sotelo, J., 1988. Neurocysticercosis: an update. Rev. Infect. Dis. 10, 1075–1087. Del Brutto, O.H., 1993. The use of albendazole in patients with single lesions enhanced on contrast CT (letter). New Engl. J. Med. 328, 356–357. Del Brutto, O.H., Quintero, L.A., 1995. Cysticercosis mimicking brain tumor: the role of albendazole as a diagnostic tool. Clin. Neurol. Neurosurg. 97, 256–258. Del Brutto, O.H., Wadia, N.H., Dumas, M., Cruz, M., Tsang, V.C.W., Schantz, P.M., 1996. Proposal of diagnostic crieteria for human cysticercosis and neurocysti-cercosis. J. Neurol. Sci. 142, 1 – 6. Escobar, A., 1983. In: Palacio, E., Rodriguez-Carbazal, J., Taveras, J.M. (Eds.), The Pathology of Neurocysticercosis Cysticercosis of the Central Nervous System. Thomas, CC, Springfield, IL, pp. 27–54. Garg, R.K., 1995. Solitary cysticercus granuloma (letter). J. Neurosurg. 82, 911. Garg, R.K., Kar, A.M., Nag, D., Shukla, R, Agrawal, A., 1997. Recurrent simple partial status and intractable epilepsy in patients with single small CT (ring) lesions and effect of albendazole therapy: case reports. J. Assoc. Physicians India 44, 960 (abstract). Garg, R.K., Nag, D., 1997. Single ring or disk enhancing computed tomographic lesion in Indian children and adolescents after first seizures (letter). Arch. Pediatr. Adolesc. Med. 157, 632 – 634. Garg, R.K., Nag, D., 1998. Single enhancing CT lesions in Indian patients with seizures: clinical and radiological evaluation, and follow-up. J. Trop. Pediatr. 44, 204–210. Garg, R.K., Karak, B., Sharma, A.M., Ojha, R., Misra, S., 1999. Single CT (ring) lesion in epilepsy patients: a new observation (letter). Indian J. Pediatr. 66, 155–157. Goulatia, R.K., Verma, A., Misra, N.K., Ahuja, G.K., 1987. Disappearing CT lesions in epilepsy. Epilepsia 28, 523– 527. Jain, S., Padma, M.V., Puri, A., Jyoti, Maheshwari, M.C., 1997. Occurrence of epilepsies in family members of Indian probands with different epileptic syndromes. Epilepsia 38, 237 – 244. Jain, S., Padma, M.V., Kanga, U., Mehra, N.K., Maheshwari, M.C., 1999. Family studies and human leukocyte antigen class II typing in Indian probands with seizures in association with single small enhancing computed tomography lesions. Epilepsia 40, 232–238. Jaya Kumar, P.N., Taly, A.B., Mohan, P.K., 1985. Transient computerized tomographic (CT) abnormalities following partial seizures. Acta Neurol. Scand. 72, 26–29. Kennedy, A., Schon, F., 1991. Epilepsy: disappearing lesions appearing in United Kingdom. Br. Med. J. 302, 933–935. Kumar, N., Narayanaswamy, A.S., Singh, K.K., 1995. Ring enhancing CT lesion — a diagnostic dilemma. J. Assoc. Physicians India 43, 391–393. Kumar, R., Kumar, A., Kohli, N., Pant, M.C., Govil, Y.C., Sharma, B., 1990. Ring or disc like enhancing lesions in partial epilepsy in India. J. Trop. Pediatr. 36, 131–134.
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Minguetti, S., Ferriera, M.V.C., 1983. Computed tomography in neurocysticercosis. J. Neurol. Neurosurg. Psychiatry 46, 936 – 942. Murthy, J.M.K., Yangala, R., Srinivas, M., 1998. The syndromic classification of the International League against Epilepsy: a hospital-based study from South India. Epilepsia 38, 48 – 54. Murthy, J.M.K., Subba Reddy, Y.V., 1998. Prognosis of epilepsy associated with single CT enhancing lesion: a long term follow-up study. J. Neurol. Sci. 159, 151 – 155. Padma, M.V., Behari, M., Misra, N.K., Ahuja, G.K., 1994. Albendazole in single CT ring lesions in epilepsy. Neurology 44, 1344 – 1346. Rajshekhar, V., 1991. Etiology and management of single small CT lesions in patients with seizures: understanding a controversy. Acta Neurol. Scand. 84, 465 – 470. Rajshekhar, V., Wilson, M., Schantz, P.M., 1991. cysticercus immunoblot assay in Indian patients with single enhancing small CT lesions (letter). J. Neurol. Neurosurg. Psychiatry 54, 561 – 562. Rajshekhar, V., Haran, R.P., Prakash, G.S., Chandy, M.J., 1993. Differentiating solitary small cysticercus granuloma and tuberculoma in patients with epilepsy: clinical and computerised tomographic criteria. J. Neurosurg. 78, 402 – 407. Rajshekhar, V., 1993. Albendazole therapy of persistent, solitary cysticercus granulomas in patients with seizures. Neurology 43, 1238 – 1240. Rajshekhar, V., Chandy, M.J., 1994. Enlarging cysticercus granuloma. J. Neurosurg. 80, 840 – 843. Rajshekhar, V., Chacko, G., Haran, R.P., Chandy, M.J., Chandi, S.M., 1995. Clinicoradio-logical and pathological correlations is patients with solitary cysticercus granuloma and epilepsy focus on presence of the parasite and oedema formation. J. Neurol. Neurosurg. Psychiatry 59, 284 – 286. Rajshekhar, V., Chandy, M., 1995. Solitary cysticercus granuloma (letter). J. Neurosurg. 82, 911 – 912. Rajshekhar, V., Chandy, M.J., 1996. Comparative study of CT and MRI in patients with seizures and a solitary cerebral cysticercus granuloma. Neuroradiology 58, 542 – 546. Rajshekhar, V., Chandy, M.J., 1997. Validation of diagnostic crieteria for solitary cerebral cysticercus granuloma in patients presenting with seizures. Acta. Neurol. Scand. 96, 76 – 81. Rajshekhar, V., Oommen, A., 1997. Serological studies using ELISA and EITB in patients with solitary cysticercus granuloma and seizures. Neurol. Infect. Epidemiol. 2, 177 – 180. Rajshekhar, V., 1998. Incidence and significance of adverse effects of albendazole therapy in patients with a persistent solitary cysticercus granuloma. Acta Neurol. Scand. 98, 121 – 123. Sawhney, I.M.S., Thussu, A., Chopra, J.S., 1999. Single small enhancing CT lesions in epilepsy. In: Chopra, J.S., Sawhney, I.M.S. (Eds.), Neurology in Tropics. B.I. Churchill Livingstone, New Delhi, pp. 532 – 541.
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R.K. Garg et al. / Epilepsy Research 38 (2000) 91–104 Tandon, P.N., Bhargava, S., 1980. CNS tuberculosis: lessons learnt from CT studies. Neurol. India 28, 225 – 230. Tandon, P.N., Bhargava, S., 1985. Effect of medical treatment on intracranial tuberculoma — a CT study. Tubercle 66, 85 – 87. Thussu, A., Sehgal, S., Sharma, M., Lal, V., Sawhney, I.M.S., Prabhakar, S., 1997. Comparison of cellular responses in single and multiple lesion neurocysticercosis. Ann. Trop. Med. Parasitol. 91, 627 – 632. Wadia, R.S., Makhale, C.N., Kelkar, A.V., Grant, K.B., 1987. Focal epilepsy in India with special reference to lesions showing ring or disc like enhancement on contrast computed tomography. J. Neurol. Neurosurg. Psychiatry 50, 1298 – 1301.
Sethi, P.K., Kumar, B.R., Madan, V.S., Mohan, V., 1985. Appearing and disappearing CT scan abnormalities and seizures. J. Neurol. Neurosurg. Psychiatry 48, 866– 869. Sethi, P.P., Wadia, R.S., Kiyawat, D.P., Ichaporia, N.R., Kothari, S.S., Sangle, S.A., Wadhwa, P., 1994. Ring or disc enhancing lesions in epilepsy in India. J. Trop. Med. Hyg. 97, 347 – 353. Srinivas, H.V., 1992. Disappearing CT lesions — clinical features. J. Trop. Geograph. Neurol. 2, 88–91. Stamos, J.K., Hahn, Y.S., Chadwick, E.G., Schantz, P.M., 1996. Neurocysticercosis: report of unusual pediatric cases. Pediatrics, 98, 974–977.
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Single-enhancing CT lesions in Indian patients with seizures: a review Ravindra Kumar Garg *, Manish Kumar Singh, Surendra Misra Department of Neurology, Institute of Medical Sciences, Banaras Hindu Uni6ersity, Varanasi-221 005, India Received 13 April 1999; received in revised form 13 July 1999; accepted 5 August 1999
Abstract Single enhancing CT lesions are the commonest radiological abnormality in Indian patients with new-onset partial seizures. In few patients the lesions may be ‘tuberculoma’ (especially in presence of evidence of tuberculosis elsewhere). However, histopathological studies have proved that neurocysticercosis is the most frequent cause for these lesions. Acute inflammation in and around the cerebral lesions of cysticercosis manifests as acute seizure disorder. These cysticercal granulomas represent ‘colloidal’ and ‘nodular-granular’ stages of Escobar’s pathological classification of natural evolution of a parenchymal cysticercus cyst. In 8 – 12 weeks time majority of these lesions spontaneously disappear, few may calcify. As albendazole therapy is of controversial value, these patients, possibly, need to be treated only with antiepileptic drugs. Associated seizure disorder is also benign in nature and remit in majority within 6–8 months, recurrences are usually infrequent. Antiepileptic drug may be withdrawn once follow-up CT scan shows resolution of the lesion. If seizures recur after resolution of the lesion, CT lesion persists or CT lesion calcified, a long-term (2–3 years) antiepileptic therapy may be required. The single enhancing CT lesions which persist despite anticysticercal or antituberculous therapy may need histopathological evaluation to establish the correct diagnosis. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Single enhancing CT lesion; Cysticercosis; Epilepsy; Neurocysticercosis; Tuberculoma; Seizures in Indian patients
1. Introduction Single enhancing computed tomographic (CT) lesions are the commonest imaging abnormality in Indian patients with new-onset seizures (Fig. 1). These lesions were first reported by Tandon and Bhargava (1980), at that time these CT lesions were presumed to be tuberculomas. Histo-
* Corresponding author.
pathological studies, subsequently, had suggested that single enhancing CT lesions often represented dying cysticerci (larval stage of tapeworm Taenia solium). These lesions are usually benign and tend to resolve spontaneously. Conflicting results were obtained regarding early resolution of CT lesions following anticysticercal therapy. So, precise management of these lesions is still uncertain. This article reviews the substantial new information that has appeared in recent past.
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2. Incidence Initially it was thought that these lesions are seen only in Indian subcontinent, later similar lesions have been reported from other parts of the world. In Latin-American countries single enhancing CT lesions are frequently seen and these are considered as cysticercus granuloma (Del Brutto, 1993). Similar lesions are also reported from developed countries like Australia, United
Fig. 2. Cranial computed tomography showing: (a) a ring enhancing lesion; (b) complete disappearance of the lesion after 8 weeks.
Fig. 1. Plain and contrast cranial computed tomographic scans showing a cystic lesion along with scolex in plain scan. After contrast administration whole structure has enhanced.
Kingdom, United States of America, (Minguetti and Ferriera 1983; Kennedy and Schon 1991; Stamos et al., 1996) and other parts of Asia like Thailand (Bhoopat et al., 1989). The exact incidence in Indian population is not known, most of the data are from hospital-based studies. Wadia et al. (1987) investigated 150 patients with simple partial seizures and observed that these CT lesions were present in approximately 26% of the patients. The incidence of single enhancing CT lesions was higher among children as 40% of patients were below 15 years of age. Murthy et al. (1998) in a recent study, reported these single CT lesions in 23.4% of 2531 patients with all types of epilepsies. Garg and Nag (1997) observed a higher incidence of single ring enhancing CT lesions in children and adolescents (72%), when CT scans
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were performed after the first seizure. Chopra et al. (1992) also observed that 78% of 122 patients in their series were between 11 and 20 years of age. Why this lesion is common in children and patients of younger age group is not clear. As these lesions most often have cysticercal etiology, possibly poor hygienic conditions prevailing around children make them more susceptible to infection than adults (Cao et al., 1997).
3. Imaging features The characteristic ring or disk enhancing CT lesions are seen after intravenous contrast administration. Plain CT scans also, however frequently, show some abnormality. The commonest abnormality in plain CT scan is irregular low attenuation areas in cerebral hemispheres. In the series by Chopra et al. (1992), low attenuation areas were seen in all patients, in two patients a tiny speck of calcification was also present within the hypodense areas. With higher performance CT machines, it is not uncommon to see a cystic lesion with an eccentric nodule (features consistent with
Fig. 3. Cranial computed tomographic scan showing a disk enhancing lesion.
Fig. 4. Cranial computed tomography showing: (a) a ring enhancing lesion; (b) CT scan after 2 years showing calcification of the lesion.
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the structure of cysticercus larva) (Garg et al., 1999) (Fig. 1). Plain CT scan, at times, may not reveal any abnormality (Rajshekhar 1991). In a recent study, Garg and Nag (1998) observed abnormalities in plain CT scan in 66% of 101 patients. Focal hypodensity was present in 49% of patients, and 17% of patients had cystic lesions with eccentric dot. After contrast administration, there is a ring (Fig. 2) or homogenous disk (Fig. 3) like enhancement within the region of hypodensity. The enhancing lesions are usually less than 20 mm in diameter surrounded by mild to moderate perifocal oedema. The oedema may occasionally be severe enough to produce a mid-line shift, this feature frequently suggests non-cysticercal pathologies especially tuberculoma. An enhancing
Fig. 6. Cranial computed tomography showing a persisting CT lesion: (a) initial scan; (b) scan after 18 months.
Fig. 5. MR images showing a single cysticercus granuloma. (a) T1-weighted image; (b) T2-weighted image.
or a calcified eccentric dot (presumed to be the scolex of cysticercus larva) can be seen within the ring lesion. Chopra et al. (1992) observed a ring lesion with an enhancing eccentric dot (target lesions) in only three of 122 cases. In the study by Garg and Nag (1998) enhancing eccentric dot was observed in approximately half of 101 patients. Single CT lesions can be seen throughout the cerebral hemispheres. Lesions are situated superficially in the gray matter or at the junction of gray and white matter. parietal lobes are the commonest location for these lesions. Frontal lobe and occipital lobe are next common sites. In few patients the ring or disk lesion may be seen in the parasagittal areas (Chopra et al. 1992; Garg and Nag 1997). These CT lesions are uncommon in temporal lobes where they are frequently missed in CT scans. Such lesions may be discovered with the help of magnetic resonance (MR) imaging.
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4. Disappearance of the CT lesions The outstanding feature of single CT lesions in patients with epilepsy is the complete spontaneous disappearance in the majority, and significant reduction in the size of the lesions in a few other patients (Fig. 2). In the study by Chopra et al., (1992) follow-up CT scans (usually within 6 – 12 weeks) were available in 78 patients (out of 122 patients). The CT lesions completely disappeared in 47 patients, reduction in the size of lesion and surrounding oedema was seen in 24 cases. Further follow-up of later cases showed complete disappearance in another 14 patients. In only seven cases the CT lesions persisted for longer duration. An almost similar radiological course was observed in previous studies also (Jaya Kumar et al., 1985; Sethi, et al. 1985). The time for spontaneous resolution of these lesions was variable and varied from as early as 6 weeks to as long as 75 weeks. Even longer persistence of CT lesions can be observed (Sawhney et al., 1999). The oedema around the lesion is usually first to resolve. Later on, the lesion may either disappear completely without any residue or it may leave a tiny speck of calcification at the site of original lesion. In few patients the granulomatous lesion is replaced by a calcified lesion (Rajshekhar, 1991; Garg and Nag, 1998) (Fig. 4).
5. Etiopathogenesis Since these lesions had been described their precise etiology remained controversial (Goulatia et al., 1987; Ahuja et al., 1989; Bansal et al., 1989; Rajshekhar, 1991). Until recently, the main point of controversy was whether these lesions were the cause or effect of the associated seizure disorder. Various biochemical and physiological changes do occur at the site of abnormal neuronal activity during or following seizures. These changes are noted in neurons, blood vessels and the blood – brain barrier, so enhancing CT lesions were considered by various authors as secondary phenomenon due to disruption of blood – brain barrier induced by seizures (Jaya Kumar et al., 1985; Goulatia et al., 1987). Demonstration of
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cysticercus larva in plain CT scan and healing of few of these lesions with calcification are some evidences, which are against the hypothesis of ‘post-ictal phenomenon’. Tandon and Bhargava (1980) reported these lesions as ‘tuberculomas’ because of various presumptive reasons. Firstly, intracranial tuberculomas were common intracranial masses in India and were seen in : 10–20% of all intracranial space occupying lesions. Secondly, these enhancing lesions were frequently seen in patients with tuberculous meningitis, and in association with tuberculosis affecting other systems of the body. A favorable response to empirical antituberculous therapy provided additional support for tuberculous etiology (Tandon and Bhargava, 1985; Kumar et al., 1990). Furthermore, tuberculosis is a highly endemic disease in India. Rajshekhar et al. (1993) performed CT guidedstereotactic biopsies of these lesions. The histopathological examination of tissues obtained after brain biopsy revealed cysticercus granuloma in majority of the patients (25 out of 51 patients), only in six patients a definite tuberculoma was demonstrated. Of remaining 20 patients, 12 patients had parasitic granuloma (cysticercal lesion was not definite), six patients had non-specific inflammation and one patient each had dystrophic calcification and secondary metastasis. In another study Kumar et al., (1995) performed excisional biopsy in 18 patients, and observed that cysticercosis was the most frequent cause for single enhancing CT lesions. A cysticercal lesion was seen in seven patients, in rest of the patients histopathological diagnosis included tumors (four patients), abscesses (three patients), and in one patient each due to infarction and gliosis. Tuberculomas were present in three patients. In a study Rajshekhar et al., (1995) tried to demonstrate presence of a viable parasite within single enhancing CT lesions. Histopathological examination of brain tissues revealed cystic lesions containing parts of an intact or degenerated cysticecus larva in 22 patients, inflammatory cavitary lesions without parasite in 13 patients, and non-cavitary hyalinized fibrous nodules with inflammation in eight patients. Of the 22 specimens with definite evidence of cysticercosis only two
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patients had entire parasite within the lesions, and it was not possible to predict presence of intact parasite in the granuloma on the basis of clinical or radiological features. The reason why most of the patients of neurocysticercosis, present with single rather than multiple lesions, is not clear. In order to find out answer to this question Thussu et al. (1997) evaluated immunological parameters in patients with single and multiple cysticercal lesions. The study pointed out that among patients of neurocysticercosis only those with multiple enhancing CT lesions have defective functions of neutrophils and T-lymphocytes.
5.1. Genetic link Recently, hereditary factors have been suggested in the etiopathogenesis of single enhancing CT lesions. Jain et al. (1997) observed that a very high percentage (25%) of probands with single enhancing CT lesions had a family history of seizures. Generalized epilepsy was the most common type of epileptic syndrome among relatives of patients with single enhancing CT lesions. Seven percent of relatives had single enhancing CT lesions, besides other relatives with different other epilepsy syndromes. These authors suggest that the syndrome of single enhancing CT lesions possibly occur in population that is genetically predisposed to seizures. In a more recent study Jain et al. (1999) studied HLA class II antigens using polymerase chain reaction amplified DNA and sequence specific oligonucleotide probe hybridization technique. They observed a positive association of HLADRB1*13 with this syndrome, further suggesting a genetic susceptibility to this disorder.
6. Clinical features These patients usually have partial seizures with or without secondary generalization irrespective of cerebral location of the lesion (Garg and Nag, 1998). With occipital lobe lesions frequently there is preceding visual aura and with
frontal lobe lesions adversive seizures are frequently seen, rarely complex partial seizures are encountered. Few patient may present with partial status-epilepticus. The seizures are almost always acutely developed. Usually, several episodes of seizures occur in cluster within a span of 2–3 days, and may not recur in near future. Sethi et al. (1994) in a series of 186 patients reported that 53% of the patients had a history of seizures for less than 3 months, 30% had seizures for more than 6 months and only 17% for more than one year. With disappearance of CT lesions, the risk of seizure recurrence is greatly reduced. In acute stage intense diffuse bursting headache may occasionally be associated. Usually, there is no history of preceding illness in form of fever, exanthema or any other systemic infection. There may be associated transient focal neurological deficit which is more common with parasagittal lesions, and weakness is usually more marked in lower limbs. Electroencephalographic (EEG) abnormalities are present in about 35% to 57% of the cases, usually in form of focal slowing, focal epileptiform activity may be rarely seen. After disappearance of the CT lesion, focal EEG abnormalities also resolve (Sethi et al., 1994).
7. Serological studies In several series, immunological tests have been used for the diagnosis of neurocysticercosis and intracranial tuberculous lesions. Enzymelinked immunosorbent assays (ELISA) were employed for the diagnosis of both these diseases in patients with single enhancing CT lesions. Ahuja et al. (1989) observed a positive reaction in serum for tuberculosis in only 5% of patients while a significantly higher number (30%) of patients were positive for cysticercosis. Subsequent studies employing ELISA and enzyme-linked immunotransfer blot assay showed low sensitivity of serological tests in the diagnosis of single cystiercus granuloma. Less than one-third of patients showed cysticercus antibodies in their
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serum. The poor results could be due to weak antibody response to the antigenic load from a single lesion. So, these tests are of limited value in this setup (Rajshekhar et al., 1991; Rajshekhar and Oommen, 1997).
8. Cysticercus granuloma versus tuberculoma An attempt had been made by Rajshekhar et al. (1993) to differentiate cysticercus granuloma from tuberculoma in patients with new-onset seizures and single enhancing CT lesions. They compared the clinical features and radiological characteristics of histopathologically proven cases of tuberculoma and cysticercus granuloma. Among clinical features presence of raised intracranial tension (papilloedema) and a focal neurological deficit pointed towards tuberculoma. Radiologically all tuberculomas were greater than 20 mm in size and the lesions were having irregular outline, whereas, all cysticercus granulomas were less than 20 mm in size and had a regular ring. Only tuberculomas were associated with midline shift (suggestive of severe brain edema) on CT, in patients of cysticercus granuloma perifocal oedema was either mild (localized to same lobe) or moderate (spread to adjacent lobe of same cerebral hemisphere). In this set-up ‘target lesions’ (central nidus of calcification or central enhancement surrounded by a ring of enhancement) is frequently encountered. Target lesions were initially considered a pathognomonic finding of CNS tuberculomas (Bargallo et al., 1996). Del Brutto et al. (1996) reported that visualization of an enhancing eccentric dot represent the scolex of cysticercus larva and can be considered a definite diagnostic feature in favour of cysticercus etiology. Histopathological evaluation of target lesions is not available. Furthermore, no effort has been made to note any difference in the natural courses of various types of single CT lesions (for example, lesion less than 20 mm versus lesion greater then 20 mm, and lesion with eccentric dot versus lesion without dot). So clinical importance of all these imaging features in Indian patients with single enhancing CT lesions is uncertain.
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9. Other differential diagnosis Various other presumptive diagnoses such as glioma, larva migrans infection, microabscesses, secondaries, small infarcts, transient focal viral encephalitis and arteriovenous malformation have been suggested but none of them could consistently been demonstrated in histopathological studies (Rajshekhar, 1991). However, it is important to look for a systemic disease such as tuberculosis, malignancy or a source of bacterial infection. In presence of these factors single enhancing CT lesions should not be considered as ‘cysticercus granuloma’ until CT lesion disappears spontaneously (Rajshekhar and Chandy, 1997). Enlargement of these CT lesions in follow-up scans is not necessarily indicative of neoplastic nature as small but significant number of single cysticercus granuloma may show paradoxical enlargement (exceeding 20 mm in diameter) after treatment with anticysticercal drugs (Rajshekhar and Chandy, 1994). On slightest suspicion (e.g. history of sexual contact with high risk persons) serological tests for human immunodeficiency virus (HIV) should be performed as toxoplasmosis, primary CNS lymphoma and various fungal granulomas may present with single enhancing CT lesions along with seizures in patients of acquired immunodeficiency syndrome.
10. Neurocysticercosis and single enhancing CT lesion: natural course A parenchymal cysticercus cyst of the brain passes through four stages in its natural evolution. The initial phase is the ‘‘vesicular phase’’, which represents the viable and live larvae of cysticercus cellulose. In this stage larva lives inside a translucent liquid-filled cystic structure surrounded by a thin membrane, where it can remain viable from a few months to several years. These vesicular lesions appear as ‘circumscribed’ hypodense unenhanced cystic lesions on CT scan. The second stage is ‘colloidal stage’. In this stage the cystic lesions are attacked by host’s immune defense mechanisms and inflammatory changes develop in the cyst wall and surrounding brain parenchyma.
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The parasite begins to show degenerative changes, the vesicular fluid becomes gelatinous and the wall of cyst thickens. On CT these lesions appear in ‘ring enhancing’ pattern. The third stage, ‘granular-nodular’ stage refers to dying larva in advanced stage of inflammation and destruction. The vesicle tends to shrink, content becomes semisolid as it is progressively replaced by granulomatous tissue, on CT these lesions appear as homogenous disk enhancement. The fourth stage is the ‘calcific’ stage, formed by calcification of the gliotic scar that replaces the dead parasite. The first stage, which is considered live form of neurocysticercosis, the patient may remain asymptomatic. In patients with new-onset seizures these unenhanced cystic lesions have never been demonstrated. Second and third stages, which represent dying stages of cysticercus larva, are seen in CT scans of Indian patients with epilepsy. Acute development of inflammation, and surrounding cerebral oedema is responsible for new-onset seizures in these patients. Because of intense inflammation in and around the parasite, in acute stage patients experience cluster of seizures. With eventual resolution of inflammatory phase the risk of subsequent seizure progressively decreases. Calcified lesions though represent a ‘dead’ parasite has potential for producing chronic epilepsy. This process of involution of parasite usually begins spontaneously with the disintegration of the outer vesicular membrane and discoloration of the fluid content (Escobar, 1983; Del Brutto and Sotelo, 1988; Rajshekhar et al., 1995; Carpio et al., 1998).
eral enhancement and a central low signal area. MR imaging is, frequently not helpful in determining the etiology of granuloma. CT has an advantage over MR studies, as calcified lesions are better seen with CT scans (Rajshekhar and Chandy, 1996).
12. Management Until recently there was no consensus about the etiology of single enhancing CT lesions in Indian patients with epilepsy, a uniform treatment protocol was not practiced and had been treated differently by different workers.
12.1. Antituberculous treatment In earlier studies these patients were treated with antituberculous treatment (Kumar et al., 1990). Wadia et al. (1987) observed that at least one third of the patients had some systemic evidence of tuberculosis. Out of 39 patients with systemic evidences of tuberculosis, ten patients had active pulmonary tuberculosis. These authors suggested that antituberculous treatment is justified in all patients with single enhancing CT lesions. After histopathological demonstration of tuberculous etiology only in minority of patients, and because of spontaneous resolution of CT lesions, antituberculous treatment is now infrequently used.
12.2. Anticysticercal treatment 11. MR features MR imaging is frequently performed with the objective of differentiating cysticercus granuloma and tuberculoma. MR pictures of both these conditions are exceedingly similar. T1-weighted images usually show a low-signal center with isointense periphery. The granulomas are better visualized in T2-weighted images where low-signal ring and a high signal center are characteristic features (Fig. 5). Surrounding oedema is also best seen in T2-weighted images. In contrast-enhanced MR studies the granuloma shows marked periph-
After availability of reports indicating that majority of these lesions are inflammatory stage of parenchymal neurocysticercosis, anticysticercal drugs are increasingly being employed. Del Brutto, (1993) reported early resolution of lesions following albendazole therapy in Latin-American patients with similar CT lesions. There have been several studies trying to prove the efficacy of anticysticercal treatment in Indian patients with single enhancing CT lesion, however, with conflicting results. Padma et al. (1994) in a controlled study observed that, seven days treatment with albendazole did not hasten the resolution of these
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CT lesions. However, in a recent double-blind study Baranwal et al. (1998) observed a significantly faster and higher incidence of complete lesion disappearance in children who received albendazole. In this study 63 pediatric patients were randomly assigned to receive either albendazole (15 mg/kg per day) or placebo for 4 weeks and follow-up CT scans were performed at 1 month and 3 months. After 3 months 64.5% of patients who received albendazole and 37.5% of placebo-treated patients showed resolution of the CT lesions. Published dosage regimens of albendazole in patients of neurocysticercosis have varied from 15 mg/kg per day for 7 days to up to 30 days. Cruz et al. (1995) demonstrated the effectiveness, in clinical and radiological terms, of albendazole 800 mg/day for 8 days for the majority of patients affected with cystic or encephalitic parenchymatous cysticercosis. They concluded that there was no apparent advantage of continuation of treatment for 15 or 30 days in this series. However, 7 days albendazole therapy was not found effective in Indian patients with single cysticercus granuloma. So, comparative study using short (7 or 8 days) and long term (30 days) treatment is required to resolve the issues related to the effectiveness of albendazole in patients with single enhancing CT lesions. Administration of albendazole in these patients may lead to an enhanced inflammatory reaction around the cyst consequent to the death of parasite, and patient may experience recurrence of seizures, headache and vomiting. These side effects are infrequently reported, because parasitic load is limited to a single lesion and secondly majority of cysticercus granulomas contain only degenerated larva (Rajshekhar et al., 1995). Whenever side-effects of albendazole therapy in patients with single granulomatous lesion is present indicate cysticercal nature of the lesion (Rajshekhar, 1998). Del Brutto and Quintero (1995) observed that even early resolution of single enhancing lesion following empirical albendazole therapy indicated cysticercal nature of the lesion in a patient having a CT lesion mimicking brain tumor.
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12.3. Antiepileptic treatment only Chopra et al. (1992) suggested that because of benign nature of CT lesions these patients needed treatment only with antiepileptic drugs, as irrespective of etiology (tuberculoma or cysticercus granuloma) the CT lesions resolved spontaneously. Another important aspect about the management of these patients is how long antiepileptic treatment be given. Murthy et al. (1998) followed 262 patients with single CT lesions and observed that seizures did not recur in 62% of patients after commencement of antiepileptic drugs during mean follow-up time of 31.4 months (range 14–73 months). Seventyfour (28%) patients continued to have seizures for some time (median, 2 months). The remaining 26 (10%) patients continued to have seizures (median 8 months), and observed seizure remission following cysticidal therapy. Antiepileptic drugs were stopped after a seizure-free period of two or more than 2 years. In the study by Chopra et al., (1992) antiepileptic therapy was tapered off after at least three years of seizure-free period. The prognosis of associated epileptic disorder in majority of patients with single enhancing CT lesions seems to be different than in patients with other forms of parenchymal neurocysticercosis where there is a high rate of recurrence after withdrawal of antiepileptic drugs. Several workers now believe that most of these patients do not require conventional prolonged treatment with antiepileptic drugs (Srinivas, 1992; Garg, 1995; Rajshekhar and Chandy, 1995). Murthy and Subba Reddy (1998) in a recent study demonstrated that the seizures ceased to recur once the CT lesion resolved. This retrospective study included 102 patients with single enhancing CT lesions with seizures. Antiepileptic drug therapy was started in all these patients. Seizures did not recur in 68 (63%) of patients after starting antiepileptic drugs. Twenty-eight (27.5%) patients had recurrence of seizures for a median period of 2 months before remission was achieved. In the remaining 10% of patients seizures remitted after albendazole therapy, me-
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dian period of seizure recurrence was 8 months. The antiepileptic drugs were withdrawn once the follow-up CT scan showed complete resolution of the lesion. Only one patient experienced seizure recurrence during mean follow-up period of 45 months (range 19–101 months). In this patient follow-up CT scan showed gliotic scar at the site of previous lesion. Carpio et al. (1998) also, in a recent review, suggested that seizures in patients with single enhancing lesions should be considered acute symptomatic seizures. These patients need treatment with antiepileptic drugs for the duration of the acute condition perhaps several months during which the inflammatory response is active. Once the lesion has disappeared antiepileptic drugs may be gradually withdrawn. If seizures recur, antiepileptic drugs should be restarted and then patient may be treated for 2 – 3 years. If lesion has calcified again antiepileptic drugs should be given for longer period (at least for 2 – 3 years) before being tapered off. In a few patients the epilepsy is difficult to control and may even be intractable. Persistence of a CT lesion or gliotic changes in the cerebral parenchyma, secondary to intense granulomatous inflammation, may account for uncontrolled seizures (Garg and Nag, 1998). Calcified lesions, because of their epileptogenic potential, act as source of chronic epilepsy, and seizures can recur even after stopping antiepileptic treatment (Garg et al., 1997).
13. Persistence of CT lesions CT lesions with similar clinical and radiological characteristics if do not disappear or regress in 8–12 weeks time (Fig. 6), whether do they represent other disease? Chopra et al. (1992) reported five such patients in a series of 78 patients and reported a very good response to antituberculous treatment. In another study Rajshekhar (1993) reported excellent response to albendazole in patients with persisting CT lesions with epilepsy. He reported that albendazole produced complete resolution or regression in all 11 patients who were studied. The exact incidence of single enhancing CT lesions persisting for long duration or being calcified is not known. In a retrospective analysis Garg and Nag (1998) observed that 16% of 101 patients the lesions did not disappeared nor regressed even after prolonged follow-up (\ 6 months). Subsequent follow-up of these patients with persisting CT lesions revealed that in four patients the lesions eventually calcified, in four patients the ring lesions changed to a disk lesion and in the remaining eight patients the lesion persisted unchanged. In patients with uncontrolled seizures, progressive focal neurological deficit and appearance of raised intracranial tension the persisting CT lesions may be subjected to brain biopsy to establish the correct diagnosis (Rajshekhar and Chandy, 1994).
14. Future research
12.4. Follow-up CT scan There are no definite guidelines to suggest the need for repeat CT scan. Sawhney et al. (1999), on the basis of their experience, recommend that first repeat CT scan should be done after 12 weeks if patient is symptom free and neurological examination is normal. It may be done early if new sign or symptom appear. A third CT scan may be required where second scan has not shown any resolution of lesion, seizures are uncontrolled, progressive neurological deficit appears, or patient has been treated with albendazole or antituberculous drugs.
Despite several advances in etiology and pathogenesis and management of single enhancing CT lesions, there are several issues, which need to be addressed. Why these lesions are common only in Indian subcontinent is still not clear. Whether genetic factor is responsible need to be explored. The early evidences in this regard are already available. Immunological factors responsible in the etiopathogenesis of these lesions should be examined. The role of corticosteroids in the management of single enhancing CT lesions needs to be explored. Our unexamined observations suggest that a short course of oral corticosteroids helps in early resolution of lesions and helps in
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Fig. 7. Treatment algorithm for patients with single enhancing CT lesions.
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better control of seizures. Immunological tests available for diagnosis of neurocysticercosis as a cause of single enhancing CT lesions are unreliable. In future there is a need to develop better investigative modalities like polymerase chain reaction to detect even minimal parasitic antigen load. Conflicting reports are available about efficacy of anticysticercal treatment. What should be appropriate dosage schedule of albendazole? A comparative study is needed to evaluate 7 or 8 days course of albendazole with a 30 days course. A controlled multicentric study with prolonged prospective follow-up will help in establishing benefits of albendazole in the long-term management of these patients. In one unreported study we observed that patients treated with albendazole CT lesions are less likely to be calcified, hence, patients are less likely to experience seizure in future. This observation needs to be verified. The seizures in these patients are less likely when lesion has resolved, a prospective study using shorter courses of antiepileptic therapy need to be done. Histopathological evaluation of CT lesions, which persist despite all efforts, is required to establish the nature of persisting lesions. Some of these patients may have different etiology. Studies are needed to establish precisely the role of MRI and follow-up CT scans so that the cost of treatment can be reduced to a minimum.
15. Conclusion Controversies about etiology and management of single enhancing CT lesions in Indian patients with seizures persist even nearly two decades after when these lesions were first reported. Initially, these lesions were presumed as tuberculoma and were treated empirically with antituberculous drugs. Later, histopathological examination of tissues obtained after stereotactic brain biopsies revealed that the majority of these lesions were inflamed cysts of cysticercus larva. The clinical criteria suggestive of single cysticercus granuloma are seizures as the initial symptom with no evidence of persistent raised intracranial pressure, no progressive neurological deficit and no active systemic disease. The CT diagnostic criteria are evi-
dence of a single contrast-enhancing lesion measuring 5 20 mm, without a shift of midline structures due to surrounding oedema. Irrespective of etiology these lesions tend to resolve spontaneously. Role of anticysticercal treatment is still controversial. However, the best way to manage patients with these CT lesions is that the granuloma should be allowed to resolve in its natural course even if it takes several months, meanwhile, to prevent the seizure recurrence antiepileptic drugs should be employed. Antiepileptic drugs may be tapered off once CT lesion has disappeared. Brain biopsy should be considered in patients in whom lesion is persisting or increasing in size (even after empirical trial of albendazole or antituberculous therapy) and producing uncontrolled seizures or progressive focal neurological deficit (Fig. 7). References Ahuja, G.K., Behari, M., Goulatia, R.K., Jailkhani, B.L., 1989. Disappearing CT lesions in epilepsy: is tuberculosis or cysticercosis the cause? J. Neurol. Neurosurg. Psychiatry 59, 915 – 916. Bansal, B.C., Dua, A., Gupta, R., Gupta, M.S., 1989. Appearing and disappearing CT scan abnormalities in epilepsy in India — an enigma. J. Neurol. Neurosurg. Psychiatry 52, 1185 – 1187. Baranwal, A.K., Singhi, P.D., Khandelwal, N., Singhi, S.C., 1998. Albendazole therapy in children with focal seizures and single small enhancing computerized tomographic lesions: a randomised placebo-controlled double blind trial. Pediatr. Infect. Dis. J. 17, 696 – 700. Bargallo, J., Berenguer, J., Garcia-Barrionuevo, J., Ubeda, B., Bargallo, N., Cardenal, C., Mercader, J.M., 1996. The ‘target sign’: it is a specific sign of CNS tuberculoma? Neuroradiology 38, 547 – 550. Bhoopat, W., Poungwarin, N., Issaragrisil, R., Sughiponchai, S., Khanyanasthiti, P., 1989. CT diagnosis of cerebral cysticercosis. J. Med. Assoc. Thai 72, 673 – 681. Cao, W., Van-der Ploeg, C.P., Xu, J., Gao, C., Ge, L., Habbema, J.D., 1997. Risk factors for human cysticercosis morbidity: a population-based case-control study. Epidemiol. Infect. 119, 231 – 235. Carpio, A., Escobar, A., Hauser, W.A., 1998. Cysticercosis and epilepsy: a critical review. Epilepsia 39, 1025 – 1040. Chopra, J.S., Sawhney, I.M.S., Suresh, N., Prabhakar, S., Dhand, U.K., Suri, S., 1992. Vanishing CT lesions in epilepsy. J. Neurol. Sci. 107, 40 – 49. Cruz, I., Cruz, M.E., Carrasco, F., Horton, J., 1995. Neurocysticercosis: optimal dose treatment with albendazole. J. Neurol. Sci. 133, 152 – 154.
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