Review
Clinical management of neurocysticercosis Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by National University of Singapore on 06/03/14 For personal use only.
Expert Rev. Neurother. 14(4), 389–396 (2014)
Oscar H Del Brutto School of Medicine, Universidad Espiritu Santo – Ecuador, Guayaquil, Ecuador Air Center 3542, P.O. Box 522970, Miami, FL 33152-2970, USA [email protected]
Neurocysticercosis is the most common helminthic disease of the nervous system and a leading cause of acquired epilepsy worldwide. Differences in the number and location of lesions as well as in the severity of the immune response against the parasites, makes neurocysticercosis a complex disease. Therefore, a single therapeutic approach is not expected to be useful in every patient. Introduction of cysticidal drugs – praziquantel and albendazole – have changed the prognosis of thousands of patients with neurocysticercosis. While pioneer trials of therapy were flawed by a poor design, recent studies have shown that cysticidal drugs results in disappearance of lesions and clinical improvement in most cases. Nevertheless, some patients with parenchymal neurocysticercosis may be left with remaining cysts and may develop recurrent seizures after therapy, and many patients with subarachnoid cysts may need repeated courses of therapy. In addition, not all forms of the disease benefit from cysticidal drugs. KEYWORDS: albendazole • cysticercosis • cysticidal drugs • epilepsy • neurocysticercosis • parasitic diseases • praziquantel • seizures • Taenia solium
Neurocysticercosis is defined as the infection of the CNS and its coverings by the larval stage of Taenia solium, the pork tapeworm. The disease occurs when humans become intermediate hosts of this cestode after ingesting its eggs directly from an asymptomatic Taenia carrier or, less often, from the environment through contaminated food or water. Neurocysticercosis is a pleomorphic disease, mainly related to individual differences in the number and location of lesions as well as in the severity of the host’s immune response to the parasites. Cysticerci may lodge at any part of the nervous system, causing a myriad of pathological lesions that range from a single cyst to massive infections with involvement of the brain parenchyma, the subarachnoid space, the ventricular system or the spinal cord [1]. Epileptic seizures are the most common – and often the single – form of presentation of the disease, occurring in about 70% of cases [2]. Other patients may present with a combination of intellectual decline, focal neurological signs or increased intracranial pressure. Finally, neuroimaging studies performed in otherwise healthy patients evaluated for a head trauma or other unrelated medical conditions have shown that a sizable percentage of neurocysticercosis infections may be asymptomatic [3]. informahealthcare.com
10.1586/14737175.2014.890892
Differences in the clinical presentation of neurocysticercosis, together with the lack of specificity of the most common neuroimaging findings and the poor reliability of some tests used for detection of anticysticercal antibodies or antigens in blood, make the diagnosis of this parasitic disease a real challenge. A set of diagnostic criteria was proposed in 2001 to avoid the over diagnosis of neurocysticercosis that often occurs in population-based surveys and to help clinicians evaluate patients with suspected disease in the hospital setting. The set included four categories of criteria – absolute, major, minor and epidemiologic – which were stratified according to their diagnostic strength, and interpretation of these criteria permits two degrees of diagnostic certainty, definitive and probable [4]. This set of diagnostic criteria has been widely adopted by the medical community and is currently considered by many as the gold standard for the diagnosis of neurocysticercosis. Neurocysticercosis was considered for centuries as a disease that could only be amenable to surgical management, either for resection of large cysts or for placement of ventricular shunts in patients with hydrocephalus. The introduction of cysticidal drugs early in the 1980s spurred a substantial interest in the disease as – for the very first time – parasites
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could be destroyed and the disease could be cured without the need of invasive interventions. However, the anecdotal nature of pioneer studies on medical management of neurocysticercosis created controversies and skepticisms on their efficacy. It was not until recently that the actual role of cysticidal drugs has been relatively well established, and nowadays thousands of patients with neurocysticercosis are benefited from the use of these drugs. It must be kept in mind, however, that the first line of management of neurocysticercosis should always target the clinical manifestations of a given patient and the pathogenetic mechanisms involved in their occurrence [5]. Therefore, proper institution and optimization of symptomatic therapy should always precede the use of cysticidal drugs. This concept is important since during the first days or weeks after the onset of cysticidal therapy, symptoms will not improve and could even get worse; this may be dangerous in a given patient with poorly controlled seizures or intracranial hypertension. Moreover, a unique therapeutic scheme cannot be useful in every patient and proper characterization of the disease is important before planning therapy. Finally, there are no data to base treatment decisions in asymptomatic individuals when neurocysticercosis is fortuitously discovered by the time neuroimaging studies are performed for unrelated reasons. Risks and benefits of any symptomatic or specific treatment should then be weighted in the context of the individual infection type and parasite burden. Cysticidal drugs can trigger seizures or may lead to intracranial hypertension in patients with massive infections or large cysts. On the other hand, there are some forms of neurocysticercosis that are progressive and eventually lethal; therefore, the use of cysticidal drugs – even at an asymptomatic stage – should be considered. Symptomatic clinical management
Neurocysticercosis-related seizures often respond well to a firstline antiepileptic drug (AED), and refractory seizures are rare [6]. In a recent study, it was found that up to 40% of patients with cysticercosis-related medically intractable epilepsy had parenchymal brain calcifications associated with ipsilateral hippocampal sclerosis, suggesting that the occurrence of this dual pathology may be responsible for AED-resistant epilepsy in these cases [7]. The most frequently used AEDs in patients with neurocysticercosis have been carbamazepine, phenytoin and valproate. Before choosing the AED, it must be remembered that some patients with cysticercus granuloma may develop cutaneous reactions with the use of phenytoin, probably related to mechanisms involved in the immune-mediated response of the host to the parasite [8]. There is no consensus on the required length of AED treatment in patients with neurocysticercosis. It has been suggested that short courses (3–6 months) of therapy may be enough. However, there is no controlled evidence to support this assertion and standard guidelines on the use of AEDs should be followed, which requires that the patient be at least 2 years free of seizures before AED withdrawal. Even after seizure remission and proper AED tapering, still half the patients will present further 390
seizures and require reinstalment of AEDs for much longer time [9]. There is evidence favoring the concept that patients who develop calcifications and those who had multiple seizures before achieving control are those that will need longer courses of AED therapy to reduce the risk of relapses [10]. Also, a large prospective study with long-term follow-up showed that neurocysticercosis patients who had more than two seizures before achieving control, as well as those who experience breakthrough seizures and in those with residual calcifications, have more risk to develop recurrent seizures after withdrawal of AEDs [11]. Headache, another common clinical manifestation of neurocysticercosis, also requires symptomatic therapy. If no signs of increased intracranial pressure exist, then common analgesics or anti-inflammatory agents should be used. Acute antiinflammatory therapy in neurocysticercosis is primarily directed to reduce edema and local inflammation. Corticosteroids remain the first line of therapy for these patients, and the length of therapy varies according to the size of the lesions and the extent of the resulting inflammatory reaction. In many cases, the use of corticosteroids should be sustained for weeks or months (more markedly so in patients with multiple parenchymal brain or extraparenchymal cysts). As long-term corticosteroid use may be associated with unpleasant and sometimes deleterious side effects, the use of methotrexate has been proposed as a corticosteroid-sparing agent in some cases [12]. Attention should be given to the occurrence of intracranial hypertension, and cysticidal drugs must not be initiated if intracranial pressure is increased as patients may worsen in the short term. Corticosteroids must be given as the first line of therapy in these cases. While the choice of a particular corticoid agent and the regimen of therapy are not based on controlled data, most experts recommend the use of dexamethasone at doses ranging from 8 to 32 mg/day. Using this approach, a rapid response is obtained and most patients improve their condition in a few days. However, symptom relapses may occur when corticosteroids are withdrawn, so gradual tapering of these drugs is recommended [13]. If ventricular cysts or hydrocephalus are present, a neurosurgeon should be consulted as shunt placement or resection of lesions may be required. Cysticidal drugs
Over the past four decades, a number of antiparasitic drugs have been claimed to be cysticidals. Of these, only praziquantel and albendazole have shown potent effects in humans and are still used nowadays. Other agents, such as metrifonate and flubendazole, have been tried in patients with neurocysticercosis, but their use has been abandoned due to adverse side effects or lack of efficacy. There is also a single study showing that ivermectin may be effective in selected neurocysticercosis patients [14]. Oxfendazole is a benzimidazole compound with documented efficacy in swine cysticercosis; if this drug proves to be safe in humans, it may be a therapeutic alternative to currently used cysticidal drugs [15]. Praziquantel is a pyrazino-isoquinoline derivative with broad antihelminthic activity. While its mechanism of action is not Expert Rev. Neurother. 14(4), (2014)
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fully known, it seems that the drug affects calcium channels in the surface of the adult parasite, causing muscle contractions and paralysis. It is well absorbed after oral administration, particularly if given with grapefruit juice or a high carbohydrate meal. Peak serum levels are obtained 1.5–2 h after administration and drop rapidly thereafter. Praziquantel is metabolized in the liver, and its plasma concentration is modified by drugs acting on the cytochrome P450 microsomal system. As known, concomitant use of cimetidine increases, and dexamethasone and some AEDs reduce plasma concentration of praziquantel [16]. Side effects are often mild and include gastric disturbances, dizziness, drowsiness, fever, headache, increased sweating and, less often, allergic reactions. For treatment of neurocysticercosis, praziquantel is often given at daily doses of 50 mg/kg for 2 weeks, although other regimens – ranging from 10 to 100 mg/kg per day from 3 to 21 days – have been proposed. In all these studies, praziquantel has been administered every 8 h, and it seems that the cysticidal effect has been reached by exposing the parasites to intermittent peaks of the drug. A single-day course of 75–100 mg/kg divided in three doses given every 2 h has also been described, but it seems to be more effective in patients with a single parenchymal brain lesion than in those with multiple cysts [17]. Albendazole is a benzimidazole compound. It causes degeneration of parasite cytoplasmic microtubules impairing glucose intake, which lead to energy depletion and parasite starvation. Albendazole is rapidly and well absorbed after oral administration, particularly if given with a fatty meal. Then, it is metabolized in the liver and transformed into albendazole sulfoxide, the active molecule of this drug. The half-life is up to 15 h, which allows an easy administration schedule of two-times per day. Contrary to what has been reported with praziquantel, plasma levels of albendazole increase when dexamethasone is given simultaneously, so no concern on its therapeutic efficacy exists when corticosteroids have to be used for therapy of adverse reactions related to destruction of intracranial cysticerci [16]. Side effects are mostly related to liver toxicity, hematological effects, hair loss and gastrointestinal symptoms. For therapy of neurocysticercosis, albendazole is usually given at daily doses of 15 mg/kg for 1–4 weeks, with a maximum dose of 800–1200 mg/day in adults. Pioneer trials of cysticidal drugs
The first patient treated with cysticidal drugs was a Mexican boy whose computed tomography showed degenerating cysts in the brain parenchyma that disappeared after a course with praziquantel [18]. This report prompted neurologists to treat neurocysticercosis medically, and small case series and uncontrolled or quasi-controlled studies showing efficacy of praziquantel in different forms of the disease were published [19–21]. Thereafter, the other cysticidal drugs – albendazole – were tested in Mexico and then in other countries, and proved effective for destroying parenchymal brain cysticerci, with the advantage of being somewhat more effective than praziquantel [22–25]. Pioneer studies showed that praziquantel destroys about 60% while albendazole destroys 70% of lesions. Approximately 50% informahealthcare.com
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of patients treated with praziquantel and 55% of those receiving albendazole were free of lesions after therapy. In these studies, efficacy of cysticidal drugs was measured by counting the number of intracranial cysts on CT scans performed before and 3–6 months after therapy, and little attention was paid to the clinical course of the disease. After the very first study, it was noticed that a sizable proportion of patients develop headache, nausea and vomiting a few days after the onset of therapy. Even seizures or other severe adverse effects including intracranial hypertension or death occurred in some cases [26]. This, together with the finding that some cysticerci may disappear without therapy, challenged the efficacy of cysticidal drugs and prompted some physicians to conclude that there was no benefit of specific therapy for neurocysticercosis [27]. Following a long discussion in the literature, two studies published in the 1990s showed an association between the use of cysticidal drugs and fewer seizures in patients with neurocysticercosis at follow-up [28,29]. Nevertheless, these findings were also questioned based on the uncontrolled design of these studies, as well as on the variable clinical expression of neurocysticercosis. Contemporary trials of drug therapy
To better understand discrepancies in the results of therapeutic trials, we need to put them in the context of the pleomorphism of neurocysticercosis. First of all, cysticidal drugs are not antiepileptics and the prognosis of neurocysticercosis-related seizures also depend on a proper management of the seizure disorder. Second, most adverse reactions are not related to drug toxicity but to destruction of parasites and can be avoided with symptomatic management. Finally, the clinical evolution of patients with a single cysticercus granuloma is different from that of those with multiple parenchymal-viable cysts or with extraparenchymal (subarachnoid and ventricular) neurocysticercosis and the results of different trials cannot be pulled together. Cysticidals for patients with a single cysticercal granuloma
One of the most common forms of neurocysticercosis is the socalled ‘single cysticercal granuloma’ in which one (or sometimes two) degenerating brain parasite appearing in the form of ringor nodular-enhancing lesions is visible in neuroimaging studies of patients with a recent-onset seizure disorder [30]. This type of neurocysticercosis most often affects children and young adults [31] and is highly prevalent in disease-endemic areas of the Indian Subcontinent and Latin America, as well as in residents of nonendemic countries who get exposed to the parasite while traveling or due to sporadic contact with an asymptomatic T. solium carrier [32,33]. It has been suggested that these lesions represent an early stage of the disease in which metacestodes – soon after entering the brain parenchyma – go directly to the granular stage without going through the vesicular and colloidal stages [34]. Due to the benign nature of this form of the disease, some authors have questioned the benefits of cysticidal drug therapy. Indeed, the risk for recurrent seizures in patients with a single cysticercus granuloma seems to be below 30%, strongly 391
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associated to cases where a calcification is left instead of total disappearance of the lesion [35]. Despite this belief and the conflicting findings of a poor-quality trial [36], other double-blind trials showed that the prognosis is better when patients receive cysticidal drugs than when they were left untreated [37,38]. In addition, the first meta-analysis on controlled trials conducted in patients with this form of neurocysticercosis showed significant benefits of albendazole for both resolution of the granuloma (odds ratio [OR]: 1.9; 95% CI: 1.2–3.1) and reduction in seizures recurrence (OR: 0.4; 95% CI: 0.2–0.6) [39]. A more recent meta-analysis reviewed 10 controlled trials comparing resolution of single cysticercal granuloma and rates of seizure freedom in patients receiving cysticidal drugs versus those that were only treated with AEDs, and it was found that the use of albendazole improved the rate of seizure-free persons (OR: 2.5; 95% CI: 1.5–4) and hastens the resolution of the granuloma (OR: 2.1; 95% CI: 1.4–3) compared with no treatment [40]. In the same meta-analysis, it was shown that the use of corticosteroids alone did not modify the natural history of these lesions or the risk of seizure recurrences. The main problem with published evidence on the management of patients with single cysticercal granuloma is the short time of follow-up (6 months to 1 year). Therefore, there is no firm evidence on the prognosis of treated versus nontreated patients on the long term [41]. Cysticidals for patients with viable parenchymal brain cysts
This type of lesions will not resolve by itself and are likely to continue causing symptoms for years [42]. Clinicians familiar with this form of neurocysticercosis know about the benefits of destroying all cysts under controlled conditions and most of them support the routine use of cysticidal drugs [43,44]. Despite the large number of case series and open randomized trials – most of them showing a beneficial effect of cysticidal drugs – double-blind trials comparing cysticidal drugs versus placebo in patients with parenchymal cysts in the vesicular stage are scarce. The first of these trials (a poorly conducted study according to most experts) showed no benefit of albendazole over placebo in 29 patients with multiple cysts [45]. More recently, two larger – and better conducted – studies showed that albendazole therapy was associated with a significant reduction in both the number of parenchymal brain cysts and in the percentage of patients free of cysts compared with placebo (p < 0.001 in both studies) [46,47]. In one of these studies, intervention reduced the rate of recurrence for partial seizures by 41% and that of seizures with generalization by 67%; only the latter was statistically significant [46]. In the other study, using Kaplan–Meier survival analysis, the authors found no significant difference in the proportion of patients with seizures before therapy who were free of seizures by the end of the follow-up (0.62 in the albendazole group vs 0.52 in the placebo group, p = 0.274) [47]. From these studies, it was clear that a sizable proportion of patients were left with some residual cysts after therapy and that, in many of them, the course of the disease remained unchanged. So, there is an urgent need 392
for either the introduction of a more potent drug or the modification of current regimens of therapy if we want to cure patients with this form of neurocysticercosis. Pending further evidence, there seems to be no reason to leave viable parenchymal brain cysts untreated as the use of cysticidal drugs was not associated with significant detrimental effects in such studies. Cysticidals for patients with extraparenchymal cysticerci
Patients with cysticerci located in the subarachnoid cisterns at the base of the brain often develop protracted courses and poor prognoses. In these cases – and only after hydrocephalus and intracranial hypertension have been managed and solved – cysticidal drugs may be given until no evidence of living parasites exists [48–51]. Due to its better penetrance in the subarachnoid space, albendazole is the preferred drug in this setting although not all patients respond to medical treatment [52]. According to uncontrolled evidence, treatment of giant cysts located inside subarachnoid cisterns often requires higher doses of albendazole (30 mg/kg/day), prolonged courses of therapy (more than 1 month) or even repeated cycles [49–51]. Control neuroimaging studies and circulating antigen monitoring are of particular importance in these cases. Caution should be taken in these patients because treatment may result in sudden intracranial hypertension or stroke. However, under appropriate corticosteroids coverage, these events are rare and the benefits of treatment outweigh the risk of disease progression [53]. Some studies have shown that albendazole may destroy ventricular cysticerci [54]; however, endoscopic resection of the lesion seems to be the safest and most effective approach for this kind of lesions [55]. What is not known is whether these patients should receive cysticidal drugs after resection of ventricular cysts [56]. If those cysts were entirely removed, there should be no reason for further medical treatment. However, there is no certainty that other small lesions may had been missed by neuroimaging studies, particularly if located in the ventricles or subarachnoid cisterns at the base of the brain. Persistence of viable cysts or membrane remnants could lead to further clinical manifestations. Use of circulating antigen detection assays could orientate the use of cysticidal drug therapy in such patients [57]. In any case, neuroimaging and serological monitoring of these patients should be maintained for years. Expert commentary
Owing to the pathological and clinical pleomorphism of neurocysticercosis, characterization of the disease according to the viability of cysts, severity of the host’s immune response and location of lesions, is the first and most important step for planning a rational therapy. It must also be remembered that general guidelines of therapy may need to be modified when different forms of the disease coexist in the same patient [43,44]. Parenchymal brain cysticercosis
Vesicular cysts located in the brain parenchyma have reached a state of immune tolerance with the host and may remain unchanged for years. The use of cysticidal drugs results in Expert Rev. Neurother. 14(4), (2014)
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resolution of lesions in most of these cases [46,47]. Nevertheless, the clinical course of the seizure disorder may not be modified by this intervention, and most patients will need to be treated with AEDs for years to reduce the risk of seizure recurrences. Colloidal and granular cysticerci are degenerating parasites, and the natural history of most of these lesions would be to disappear or to end up as a calcified nodule. Despite this presumable benign natural course, a number of double-blind trials have favored the use of cysticidal drugs in these kind of lesions as their use not only result in more expedite resolution of lesions but also in the reduction of the risk of seizure recurrence in most patients [40]. The initial regimen of therapy depends on the burden of infection. Most experts favor the use of albendazole for 3 days or a single-day course of praziquantel for patients with a single cyst and albendazole for 1 week or praziquantel for 15 days for those with mild-to-moderate infections. Repeated courses of therapy may be needed when neuroimaging studies show persistence of some lesions. Treatment of patients with massive nonencephalitic infections of the brain parenchyma needs to be individualized, always weighting the benefits versus the risks associated with the use of cysticidal drugs. In contrast, cysticidals must not be used in patients with cysticercotic encephalitis since these drugs may exacerbate the inflammatory response that occurs during the acute phase of this severe form of the disease. In such cases, corticosteroids and osmotic diuretics are advised as the first therapeutic measures to reduce the severity of brain edema, and refractory cases should undergo decompressive craniotomy to avoid the life-threatening risk of uncontrolled increased intracranial pressure [43]. Calcified cysticerci represent sequelae of previous infections and should not receive cysticidal drugs, but the use of AEDs is recommended when these lesions are associated with seizures. Recent evidence suggests that calcified cysticerci are permanent epileptogenic foci susceptible to reactivation [58–60]. Therefore, a seizure-free state without medication seems to be difficult to achieve in a sizable percentage of patients with this kind of lesions. Subarachnoid cysticercosis
Therapy of patients with small subarachnoid cysts over the convexity of cerebral hemispheres is similar to that described for parenchymal brain cysts, as the percentage of small subarachnoid cysts disappearing after the use of cysticidal drugs is comparable to that reported for parenchymal brain cysts. In contrast, treatment of giant cysts located inside cerebrospinal fluid cisterns is controversial. It has been suggested that medical therapy may be equally effective but less aggressive than surgical resection. Higher doses of albendazole, more prolonged courses of therapy or even repeated cycles may be needed for therapy of patients with racemose cysticercus [49–51]. Due to the vicinity with subarachnoid blood vessels, the inflammatory reaction that follows destruction of cysts may enhance a process of endarteritis resulting in a cerebral infarction. Corticosteroids are mandatory to avoid this hazard and must be given before the informahealthcare.com
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administration of albendazole, and their use should be prolonged for several days after the trial has been completed. Severity of inflammation, assessed on serial MRIs – or eventually by evaluating changes in the cytochemical analysis of cerebrospinal fluid – will determine the length of corticosteroid treatment. Patients with cysticercotic arachnoditis require a different approach that often includes a ventricular shunt for the relief of hydrocephalus and continuous administration of prednisone to reduce the risk of shunt dysfunction in the long term [61]. There is no evidence supporting the value of cysticidal drugs in these cases. Ventricular cysticercosis
Intraventricular cysticerci may be treated by surgery or cysticidal drugs. While some reports suggest that albendazole destroy ventricular cysts, an expert consensus recommended endoscopical resection of most of these lesions with the possible exception of small cysts located in the lateral ventricle [43]. These thoughts have been more recently supported in a comprehensive review of the subject [55]. The surgeon must always consider the possibility of cyst migration within the ventricular system and it should be a routine practice to get a control neuroimaging study immediately before surgery to avoid an unnecessary procedure. Spinal cysticercosis
Surgical resection is the most accepted form of therapy for cysts located in the spinal subarachnoid space or the spinal cord parenchyma. However, a recent review showed that cysticidal drugs have been successfully used in a number of patients with intramedullary cysticerci [62]. More experience is needed before a recommendation can be made for either surgical or medical approach to these lesions. Five-year view
As previously noticed, most of our current knowledge on medical management of neurocysticercosis comes from studies conducted during the last decade of the 20th century and the first lustrum of the new Millennium. Nevertheless, important pieces of evidence-based medicine regarding the efficacy of cysticidal drugs have been published during the past 5 years. Among these, stand out a meta-analysis showing that albendazole therapy is associated with improved control of seizures and faster resolution of single cysticercus granulomas [40] and a controlled study showing that 1 week of albendazole is equally effective as a 4-week course for therapy of patients with a single-enhancing cysticercus [63]. Also, a recent consensus report from the American Academy of Neurology concluded that the use of albendazole plus corticosteroids reduced the number of viable lesions on control neuroimaging studies and the long-term risk of seizure recurrence in patients with parenchymal brain cysts [64]. A preliminary report on the use of combination therapy with albendazole plus praziquantel for neurocysticercosis showed a nonsignificant trend for a better efficacy when both drugs were given [65]. This is possible since both cysticidals have different 393
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mechanisms of action and their combined use may provide better clearance of cysticerci [66]. Some recent research has also focused on the mechanisms of epileptogenesis in calcified cysticerci and the optimal management of these patients, which often require long-term AED administration to avoid relapses [59,60]. With the exception of seizures occurring in the context of a patient with a single cysticercal granuloma that completely disappears in the follow-up, neurocysticercosis-related seizures should not be defined as ‘acute symptomatic seizures’. There is increasing evidence favoring an active role of parenchymal brain calcifications as responsible for
symptoms in a sizable proportion of neurocysticercosis patients and calcifications should no longer be seen as inert lesions. Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Neurocysticercosis is a pleomorphic parasitic disease causing different pathological lesions and clinical syndromes. Therefore, a single therapeutic approach should not be expected to be useful in every patient. • Proper characterization of neurocysticercosis according to the viability of cysts, severity of the host’s immune response and location of lesions, is of paramount importance for a rational therapy. • The first line of management of neurocysticercosis should be directed to control the clinical manifestations of a given patient and the pathogenetic mechanisms involved in their occurrence. • Two drugs, praziquantel and albendazole, have been shown to have potent cysticidal effects and have improved the prognosis of thousands of patients with neurocysticercosis. • The anecdotal nature of pioneer trials on cysticidal drugs created concern and it was postulated that these drugs do not modify the natural course of the disease. • More recently, a number of double-blind, placebo-controlled studies have shown that the use of cysticidal drugs is associated with resolution of lesions and clinical improvement in most patients with parenchymal brain cysticercosis. • Treatment of extraparenchymal neurocysticercosis is more complicated and many patients do not respond to medical treatment. In these cases, repeated trials of cysticidal drugs (or even surgical interventions) are often needed. • Some forms of neurocysticercosis, like cysticercotic encephalitis, must not be treated with cysticidal drugs as their use exacerbates the inflammatory reaction against parasites and may cause seizures or intracranial hypertension. • Calcifications should not be seen as inert lesions, as they represent permanent epileptogenic foci that may reactivate causing recurrent seizures. Long-term therapy with antiepileptic drugs is needed in most of these cases.
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Kramer LD. Medical treatment of cysticercosis – ineffective. Arch Neurol 1995;52(1):101-2 Del Brutto OH, Santiba´n˜ez R, Noboa CA, et al. Epilepsy due to neurocysticercosis: analysis of 203 patients. Neurology 1992; 42(2):389-92 Vazquez V, Sotelo J. The course of seizures after treatment for cerebral cysticercosis. N Engl J Med 1992;327(10):696-701 Garcia HH, Gonzalez AE, Rodriguez S, et al. Neurocysticercosis: unraveling the nature of the single cysticercal granuloma. Neurology 2010;75(7):654-8 Del Brutto OH. Neurocysticercosis in infants and toddlers. Report of seven cases and review of published patients. Pediatr Neurol 2013;48(6):432-5
Del Brutto VJ, Del Brutto OH, Ochoa E, Garcia HH. Single parenchymal brain cysticercus: relationship between age of patients and evolutive stage of parasites. Neurol Res 2012;34(10):967-70 Verma A, Misra S. Outcome of short-term antiepileptic treatment in patients with solitary cerebral cysticercus granuloma. Acta Neurol Scand 2006;113(3):174-7 Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in single CT ring lesions in epilepsy. Neurology 1994;44(7): 1344-6 Baranwal AK, Singhi PD, Khandelwal N, Singhi SC. Albendazole therapy in children with focal seizures and single small enhancing computerized tomographic lesions: a randomized, placebo-controlled double-blind trial. Pediatr Infect Dis 1998; 17(8):696-700 Gogia S, Talkdar B, Choudhury V, Arora BS. Neurocysticercosis in children: clinical findings and response to albendazole therapy in a randomized, double-blind,
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Expert Rev. Neurother. 14(4), (2014)
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Expert Rev. Neurother. 14(4), 389–396 (2014)
Oscar H Del Brutto School of Medicine, Universidad Espiritu Santo – Ecuador, Guayaquil, Ecuador Air Center 3542, P.O. Box 522970, Miami, FL 33152-2970, USA [email protected]
Neurocysticercosis is the most common helminthic disease of the nervous system and a leading cause of acquired epilepsy worldwide. Differences in the number and location of lesions as well as in the severity of the immune response against the parasites, makes neurocysticercosis a complex disease. Therefore, a single therapeutic approach is not expected to be useful in every patient. Introduction of cysticidal drugs – praziquantel and albendazole – have changed the prognosis of thousands of patients with neurocysticercosis. While pioneer trials of therapy were flawed by a poor design, recent studies have shown that cysticidal drugs results in disappearance of lesions and clinical improvement in most cases. Nevertheless, some patients with parenchymal neurocysticercosis may be left with remaining cysts and may develop recurrent seizures after therapy, and many patients with subarachnoid cysts may need repeated courses of therapy. In addition, not all forms of the disease benefit from cysticidal drugs. KEYWORDS: albendazole • cysticercosis • cysticidal drugs • epilepsy • neurocysticercosis • parasitic diseases • praziquantel • seizures • Taenia solium
Neurocysticercosis is defined as the infection of the CNS and its coverings by the larval stage of Taenia solium, the pork tapeworm. The disease occurs when humans become intermediate hosts of this cestode after ingesting its eggs directly from an asymptomatic Taenia carrier or, less often, from the environment through contaminated food or water. Neurocysticercosis is a pleomorphic disease, mainly related to individual differences in the number and location of lesions as well as in the severity of the host’s immune response to the parasites. Cysticerci may lodge at any part of the nervous system, causing a myriad of pathological lesions that range from a single cyst to massive infections with involvement of the brain parenchyma, the subarachnoid space, the ventricular system or the spinal cord [1]. Epileptic seizures are the most common – and often the single – form of presentation of the disease, occurring in about 70% of cases [2]. Other patients may present with a combination of intellectual decline, focal neurological signs or increased intracranial pressure. Finally, neuroimaging studies performed in otherwise healthy patients evaluated for a head trauma or other unrelated medical conditions have shown that a sizable percentage of neurocysticercosis infections may be asymptomatic [3]. informahealthcare.com
10.1586/14737175.2014.890892
Differences in the clinical presentation of neurocysticercosis, together with the lack of specificity of the most common neuroimaging findings and the poor reliability of some tests used for detection of anticysticercal antibodies or antigens in blood, make the diagnosis of this parasitic disease a real challenge. A set of diagnostic criteria was proposed in 2001 to avoid the over diagnosis of neurocysticercosis that often occurs in population-based surveys and to help clinicians evaluate patients with suspected disease in the hospital setting. The set included four categories of criteria – absolute, major, minor and epidemiologic – which were stratified according to their diagnostic strength, and interpretation of these criteria permits two degrees of diagnostic certainty, definitive and probable [4]. This set of diagnostic criteria has been widely adopted by the medical community and is currently considered by many as the gold standard for the diagnosis of neurocysticercosis. Neurocysticercosis was considered for centuries as a disease that could only be amenable to surgical management, either for resection of large cysts or for placement of ventricular shunts in patients with hydrocephalus. The introduction of cysticidal drugs early in the 1980s spurred a substantial interest in the disease as – for the very first time – parasites
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could be destroyed and the disease could be cured without the need of invasive interventions. However, the anecdotal nature of pioneer studies on medical management of neurocysticercosis created controversies and skepticisms on their efficacy. It was not until recently that the actual role of cysticidal drugs has been relatively well established, and nowadays thousands of patients with neurocysticercosis are benefited from the use of these drugs. It must be kept in mind, however, that the first line of management of neurocysticercosis should always target the clinical manifestations of a given patient and the pathogenetic mechanisms involved in their occurrence [5]. Therefore, proper institution and optimization of symptomatic therapy should always precede the use of cysticidal drugs. This concept is important since during the first days or weeks after the onset of cysticidal therapy, symptoms will not improve and could even get worse; this may be dangerous in a given patient with poorly controlled seizures or intracranial hypertension. Moreover, a unique therapeutic scheme cannot be useful in every patient and proper characterization of the disease is important before planning therapy. Finally, there are no data to base treatment decisions in asymptomatic individuals when neurocysticercosis is fortuitously discovered by the time neuroimaging studies are performed for unrelated reasons. Risks and benefits of any symptomatic or specific treatment should then be weighted in the context of the individual infection type and parasite burden. Cysticidal drugs can trigger seizures or may lead to intracranial hypertension in patients with massive infections or large cysts. On the other hand, there are some forms of neurocysticercosis that are progressive and eventually lethal; therefore, the use of cysticidal drugs – even at an asymptomatic stage – should be considered. Symptomatic clinical management
Neurocysticercosis-related seizures often respond well to a firstline antiepileptic drug (AED), and refractory seizures are rare [6]. In a recent study, it was found that up to 40% of patients with cysticercosis-related medically intractable epilepsy had parenchymal brain calcifications associated with ipsilateral hippocampal sclerosis, suggesting that the occurrence of this dual pathology may be responsible for AED-resistant epilepsy in these cases [7]. The most frequently used AEDs in patients with neurocysticercosis have been carbamazepine, phenytoin and valproate. Before choosing the AED, it must be remembered that some patients with cysticercus granuloma may develop cutaneous reactions with the use of phenytoin, probably related to mechanisms involved in the immune-mediated response of the host to the parasite [8]. There is no consensus on the required length of AED treatment in patients with neurocysticercosis. It has been suggested that short courses (3–6 months) of therapy may be enough. However, there is no controlled evidence to support this assertion and standard guidelines on the use of AEDs should be followed, which requires that the patient be at least 2 years free of seizures before AED withdrawal. Even after seizure remission and proper AED tapering, still half the patients will present further 390
seizures and require reinstalment of AEDs for much longer time [9]. There is evidence favoring the concept that patients who develop calcifications and those who had multiple seizures before achieving control are those that will need longer courses of AED therapy to reduce the risk of relapses [10]. Also, a large prospective study with long-term follow-up showed that neurocysticercosis patients who had more than two seizures before achieving control, as well as those who experience breakthrough seizures and in those with residual calcifications, have more risk to develop recurrent seizures after withdrawal of AEDs [11]. Headache, another common clinical manifestation of neurocysticercosis, also requires symptomatic therapy. If no signs of increased intracranial pressure exist, then common analgesics or anti-inflammatory agents should be used. Acute antiinflammatory therapy in neurocysticercosis is primarily directed to reduce edema and local inflammation. Corticosteroids remain the first line of therapy for these patients, and the length of therapy varies according to the size of the lesions and the extent of the resulting inflammatory reaction. In many cases, the use of corticosteroids should be sustained for weeks or months (more markedly so in patients with multiple parenchymal brain or extraparenchymal cysts). As long-term corticosteroid use may be associated with unpleasant and sometimes deleterious side effects, the use of methotrexate has been proposed as a corticosteroid-sparing agent in some cases [12]. Attention should be given to the occurrence of intracranial hypertension, and cysticidal drugs must not be initiated if intracranial pressure is increased as patients may worsen in the short term. Corticosteroids must be given as the first line of therapy in these cases. While the choice of a particular corticoid agent and the regimen of therapy are not based on controlled data, most experts recommend the use of dexamethasone at doses ranging from 8 to 32 mg/day. Using this approach, a rapid response is obtained and most patients improve their condition in a few days. However, symptom relapses may occur when corticosteroids are withdrawn, so gradual tapering of these drugs is recommended [13]. If ventricular cysts or hydrocephalus are present, a neurosurgeon should be consulted as shunt placement or resection of lesions may be required. Cysticidal drugs
Over the past four decades, a number of antiparasitic drugs have been claimed to be cysticidals. Of these, only praziquantel and albendazole have shown potent effects in humans and are still used nowadays. Other agents, such as metrifonate and flubendazole, have been tried in patients with neurocysticercosis, but their use has been abandoned due to adverse side effects or lack of efficacy. There is also a single study showing that ivermectin may be effective in selected neurocysticercosis patients [14]. Oxfendazole is a benzimidazole compound with documented efficacy in swine cysticercosis; if this drug proves to be safe in humans, it may be a therapeutic alternative to currently used cysticidal drugs [15]. Praziquantel is a pyrazino-isoquinoline derivative with broad antihelminthic activity. While its mechanism of action is not Expert Rev. Neurother. 14(4), (2014)
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fully known, it seems that the drug affects calcium channels in the surface of the adult parasite, causing muscle contractions and paralysis. It is well absorbed after oral administration, particularly if given with grapefruit juice or a high carbohydrate meal. Peak serum levels are obtained 1.5–2 h after administration and drop rapidly thereafter. Praziquantel is metabolized in the liver, and its plasma concentration is modified by drugs acting on the cytochrome P450 microsomal system. As known, concomitant use of cimetidine increases, and dexamethasone and some AEDs reduce plasma concentration of praziquantel [16]. Side effects are often mild and include gastric disturbances, dizziness, drowsiness, fever, headache, increased sweating and, less often, allergic reactions. For treatment of neurocysticercosis, praziquantel is often given at daily doses of 50 mg/kg for 2 weeks, although other regimens – ranging from 10 to 100 mg/kg per day from 3 to 21 days – have been proposed. In all these studies, praziquantel has been administered every 8 h, and it seems that the cysticidal effect has been reached by exposing the parasites to intermittent peaks of the drug. A single-day course of 75–100 mg/kg divided in three doses given every 2 h has also been described, but it seems to be more effective in patients with a single parenchymal brain lesion than in those with multiple cysts [17]. Albendazole is a benzimidazole compound. It causes degeneration of parasite cytoplasmic microtubules impairing glucose intake, which lead to energy depletion and parasite starvation. Albendazole is rapidly and well absorbed after oral administration, particularly if given with a fatty meal. Then, it is metabolized in the liver and transformed into albendazole sulfoxide, the active molecule of this drug. The half-life is up to 15 h, which allows an easy administration schedule of two-times per day. Contrary to what has been reported with praziquantel, plasma levels of albendazole increase when dexamethasone is given simultaneously, so no concern on its therapeutic efficacy exists when corticosteroids have to be used for therapy of adverse reactions related to destruction of intracranial cysticerci [16]. Side effects are mostly related to liver toxicity, hematological effects, hair loss and gastrointestinal symptoms. For therapy of neurocysticercosis, albendazole is usually given at daily doses of 15 mg/kg for 1–4 weeks, with a maximum dose of 800–1200 mg/day in adults. Pioneer trials of cysticidal drugs
The first patient treated with cysticidal drugs was a Mexican boy whose computed tomography showed degenerating cysts in the brain parenchyma that disappeared after a course with praziquantel [18]. This report prompted neurologists to treat neurocysticercosis medically, and small case series and uncontrolled or quasi-controlled studies showing efficacy of praziquantel in different forms of the disease were published [19–21]. Thereafter, the other cysticidal drugs – albendazole – were tested in Mexico and then in other countries, and proved effective for destroying parenchymal brain cysticerci, with the advantage of being somewhat more effective than praziquantel [22–25]. Pioneer studies showed that praziquantel destroys about 60% while albendazole destroys 70% of lesions. Approximately 50% informahealthcare.com
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of patients treated with praziquantel and 55% of those receiving albendazole were free of lesions after therapy. In these studies, efficacy of cysticidal drugs was measured by counting the number of intracranial cysts on CT scans performed before and 3–6 months after therapy, and little attention was paid to the clinical course of the disease. After the very first study, it was noticed that a sizable proportion of patients develop headache, nausea and vomiting a few days after the onset of therapy. Even seizures or other severe adverse effects including intracranial hypertension or death occurred in some cases [26]. This, together with the finding that some cysticerci may disappear without therapy, challenged the efficacy of cysticidal drugs and prompted some physicians to conclude that there was no benefit of specific therapy for neurocysticercosis [27]. Following a long discussion in the literature, two studies published in the 1990s showed an association between the use of cysticidal drugs and fewer seizures in patients with neurocysticercosis at follow-up [28,29]. Nevertheless, these findings were also questioned based on the uncontrolled design of these studies, as well as on the variable clinical expression of neurocysticercosis. Contemporary trials of drug therapy
To better understand discrepancies in the results of therapeutic trials, we need to put them in the context of the pleomorphism of neurocysticercosis. First of all, cysticidal drugs are not antiepileptics and the prognosis of neurocysticercosis-related seizures also depend on a proper management of the seizure disorder. Second, most adverse reactions are not related to drug toxicity but to destruction of parasites and can be avoided with symptomatic management. Finally, the clinical evolution of patients with a single cysticercus granuloma is different from that of those with multiple parenchymal-viable cysts or with extraparenchymal (subarachnoid and ventricular) neurocysticercosis and the results of different trials cannot be pulled together. Cysticidals for patients with a single cysticercal granuloma
One of the most common forms of neurocysticercosis is the socalled ‘single cysticercal granuloma’ in which one (or sometimes two) degenerating brain parasite appearing in the form of ringor nodular-enhancing lesions is visible in neuroimaging studies of patients with a recent-onset seizure disorder [30]. This type of neurocysticercosis most often affects children and young adults [31] and is highly prevalent in disease-endemic areas of the Indian Subcontinent and Latin America, as well as in residents of nonendemic countries who get exposed to the parasite while traveling or due to sporadic contact with an asymptomatic T. solium carrier [32,33]. It has been suggested that these lesions represent an early stage of the disease in which metacestodes – soon after entering the brain parenchyma – go directly to the granular stage without going through the vesicular and colloidal stages [34]. Due to the benign nature of this form of the disease, some authors have questioned the benefits of cysticidal drug therapy. Indeed, the risk for recurrent seizures in patients with a single cysticercus granuloma seems to be below 30%, strongly 391
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associated to cases where a calcification is left instead of total disappearance of the lesion [35]. Despite this belief and the conflicting findings of a poor-quality trial [36], other double-blind trials showed that the prognosis is better when patients receive cysticidal drugs than when they were left untreated [37,38]. In addition, the first meta-analysis on controlled trials conducted in patients with this form of neurocysticercosis showed significant benefits of albendazole for both resolution of the granuloma (odds ratio [OR]: 1.9; 95% CI: 1.2–3.1) and reduction in seizures recurrence (OR: 0.4; 95% CI: 0.2–0.6) [39]. A more recent meta-analysis reviewed 10 controlled trials comparing resolution of single cysticercal granuloma and rates of seizure freedom in patients receiving cysticidal drugs versus those that were only treated with AEDs, and it was found that the use of albendazole improved the rate of seizure-free persons (OR: 2.5; 95% CI: 1.5–4) and hastens the resolution of the granuloma (OR: 2.1; 95% CI: 1.4–3) compared with no treatment [40]. In the same meta-analysis, it was shown that the use of corticosteroids alone did not modify the natural history of these lesions or the risk of seizure recurrences. The main problem with published evidence on the management of patients with single cysticercal granuloma is the short time of follow-up (6 months to 1 year). Therefore, there is no firm evidence on the prognosis of treated versus nontreated patients on the long term [41]. Cysticidals for patients with viable parenchymal brain cysts
This type of lesions will not resolve by itself and are likely to continue causing symptoms for years [42]. Clinicians familiar with this form of neurocysticercosis know about the benefits of destroying all cysts under controlled conditions and most of them support the routine use of cysticidal drugs [43,44]. Despite the large number of case series and open randomized trials – most of them showing a beneficial effect of cysticidal drugs – double-blind trials comparing cysticidal drugs versus placebo in patients with parenchymal cysts in the vesicular stage are scarce. The first of these trials (a poorly conducted study according to most experts) showed no benefit of albendazole over placebo in 29 patients with multiple cysts [45]. More recently, two larger – and better conducted – studies showed that albendazole therapy was associated with a significant reduction in both the number of parenchymal brain cysts and in the percentage of patients free of cysts compared with placebo (p < 0.001 in both studies) [46,47]. In one of these studies, intervention reduced the rate of recurrence for partial seizures by 41% and that of seizures with generalization by 67%; only the latter was statistically significant [46]. In the other study, using Kaplan–Meier survival analysis, the authors found no significant difference in the proportion of patients with seizures before therapy who were free of seizures by the end of the follow-up (0.62 in the albendazole group vs 0.52 in the placebo group, p = 0.274) [47]. From these studies, it was clear that a sizable proportion of patients were left with some residual cysts after therapy and that, in many of them, the course of the disease remained unchanged. So, there is an urgent need 392
for either the introduction of a more potent drug or the modification of current regimens of therapy if we want to cure patients with this form of neurocysticercosis. Pending further evidence, there seems to be no reason to leave viable parenchymal brain cysts untreated as the use of cysticidal drugs was not associated with significant detrimental effects in such studies. Cysticidals for patients with extraparenchymal cysticerci
Patients with cysticerci located in the subarachnoid cisterns at the base of the brain often develop protracted courses and poor prognoses. In these cases – and only after hydrocephalus and intracranial hypertension have been managed and solved – cysticidal drugs may be given until no evidence of living parasites exists [48–51]. Due to its better penetrance in the subarachnoid space, albendazole is the preferred drug in this setting although not all patients respond to medical treatment [52]. According to uncontrolled evidence, treatment of giant cysts located inside subarachnoid cisterns often requires higher doses of albendazole (30 mg/kg/day), prolonged courses of therapy (more than 1 month) or even repeated cycles [49–51]. Control neuroimaging studies and circulating antigen monitoring are of particular importance in these cases. Caution should be taken in these patients because treatment may result in sudden intracranial hypertension or stroke. However, under appropriate corticosteroids coverage, these events are rare and the benefits of treatment outweigh the risk of disease progression [53]. Some studies have shown that albendazole may destroy ventricular cysticerci [54]; however, endoscopic resection of the lesion seems to be the safest and most effective approach for this kind of lesions [55]. What is not known is whether these patients should receive cysticidal drugs after resection of ventricular cysts [56]. If those cysts were entirely removed, there should be no reason for further medical treatment. However, there is no certainty that other small lesions may had been missed by neuroimaging studies, particularly if located in the ventricles or subarachnoid cisterns at the base of the brain. Persistence of viable cysts or membrane remnants could lead to further clinical manifestations. Use of circulating antigen detection assays could orientate the use of cysticidal drug therapy in such patients [57]. In any case, neuroimaging and serological monitoring of these patients should be maintained for years. Expert commentary
Owing to the pathological and clinical pleomorphism of neurocysticercosis, characterization of the disease according to the viability of cysts, severity of the host’s immune response and location of lesions, is the first and most important step for planning a rational therapy. It must also be remembered that general guidelines of therapy may need to be modified when different forms of the disease coexist in the same patient [43,44]. Parenchymal brain cysticercosis
Vesicular cysts located in the brain parenchyma have reached a state of immune tolerance with the host and may remain unchanged for years. The use of cysticidal drugs results in Expert Rev. Neurother. 14(4), (2014)
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resolution of lesions in most of these cases [46,47]. Nevertheless, the clinical course of the seizure disorder may not be modified by this intervention, and most patients will need to be treated with AEDs for years to reduce the risk of seizure recurrences. Colloidal and granular cysticerci are degenerating parasites, and the natural history of most of these lesions would be to disappear or to end up as a calcified nodule. Despite this presumable benign natural course, a number of double-blind trials have favored the use of cysticidal drugs in these kind of lesions as their use not only result in more expedite resolution of lesions but also in the reduction of the risk of seizure recurrence in most patients [40]. The initial regimen of therapy depends on the burden of infection. Most experts favor the use of albendazole for 3 days or a single-day course of praziquantel for patients with a single cyst and albendazole for 1 week or praziquantel for 15 days for those with mild-to-moderate infections. Repeated courses of therapy may be needed when neuroimaging studies show persistence of some lesions. Treatment of patients with massive nonencephalitic infections of the brain parenchyma needs to be individualized, always weighting the benefits versus the risks associated with the use of cysticidal drugs. In contrast, cysticidals must not be used in patients with cysticercotic encephalitis since these drugs may exacerbate the inflammatory response that occurs during the acute phase of this severe form of the disease. In such cases, corticosteroids and osmotic diuretics are advised as the first therapeutic measures to reduce the severity of brain edema, and refractory cases should undergo decompressive craniotomy to avoid the life-threatening risk of uncontrolled increased intracranial pressure [43]. Calcified cysticerci represent sequelae of previous infections and should not receive cysticidal drugs, but the use of AEDs is recommended when these lesions are associated with seizures. Recent evidence suggests that calcified cysticerci are permanent epileptogenic foci susceptible to reactivation [58–60]. Therefore, a seizure-free state without medication seems to be difficult to achieve in a sizable percentage of patients with this kind of lesions. Subarachnoid cysticercosis
Therapy of patients with small subarachnoid cysts over the convexity of cerebral hemispheres is similar to that described for parenchymal brain cysts, as the percentage of small subarachnoid cysts disappearing after the use of cysticidal drugs is comparable to that reported for parenchymal brain cysts. In contrast, treatment of giant cysts located inside cerebrospinal fluid cisterns is controversial. It has been suggested that medical therapy may be equally effective but less aggressive than surgical resection. Higher doses of albendazole, more prolonged courses of therapy or even repeated cycles may be needed for therapy of patients with racemose cysticercus [49–51]. Due to the vicinity with subarachnoid blood vessels, the inflammatory reaction that follows destruction of cysts may enhance a process of endarteritis resulting in a cerebral infarction. Corticosteroids are mandatory to avoid this hazard and must be given before the informahealthcare.com
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administration of albendazole, and their use should be prolonged for several days after the trial has been completed. Severity of inflammation, assessed on serial MRIs – or eventually by evaluating changes in the cytochemical analysis of cerebrospinal fluid – will determine the length of corticosteroid treatment. Patients with cysticercotic arachnoditis require a different approach that often includes a ventricular shunt for the relief of hydrocephalus and continuous administration of prednisone to reduce the risk of shunt dysfunction in the long term [61]. There is no evidence supporting the value of cysticidal drugs in these cases. Ventricular cysticercosis
Intraventricular cysticerci may be treated by surgery or cysticidal drugs. While some reports suggest that albendazole destroy ventricular cysts, an expert consensus recommended endoscopical resection of most of these lesions with the possible exception of small cysts located in the lateral ventricle [43]. These thoughts have been more recently supported in a comprehensive review of the subject [55]. The surgeon must always consider the possibility of cyst migration within the ventricular system and it should be a routine practice to get a control neuroimaging study immediately before surgery to avoid an unnecessary procedure. Spinal cysticercosis
Surgical resection is the most accepted form of therapy for cysts located in the spinal subarachnoid space or the spinal cord parenchyma. However, a recent review showed that cysticidal drugs have been successfully used in a number of patients with intramedullary cysticerci [62]. More experience is needed before a recommendation can be made for either surgical or medical approach to these lesions. Five-year view
As previously noticed, most of our current knowledge on medical management of neurocysticercosis comes from studies conducted during the last decade of the 20th century and the first lustrum of the new Millennium. Nevertheless, important pieces of evidence-based medicine regarding the efficacy of cysticidal drugs have been published during the past 5 years. Among these, stand out a meta-analysis showing that albendazole therapy is associated with improved control of seizures and faster resolution of single cysticercus granulomas [40] and a controlled study showing that 1 week of albendazole is equally effective as a 4-week course for therapy of patients with a single-enhancing cysticercus [63]. Also, a recent consensus report from the American Academy of Neurology concluded that the use of albendazole plus corticosteroids reduced the number of viable lesions on control neuroimaging studies and the long-term risk of seizure recurrence in patients with parenchymal brain cysts [64]. A preliminary report on the use of combination therapy with albendazole plus praziquantel for neurocysticercosis showed a nonsignificant trend for a better efficacy when both drugs were given [65]. This is possible since both cysticidals have different 393
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Del Brutto
mechanisms of action and their combined use may provide better clearance of cysticerci [66]. Some recent research has also focused on the mechanisms of epileptogenesis in calcified cysticerci and the optimal management of these patients, which often require long-term AED administration to avoid relapses [59,60]. With the exception of seizures occurring in the context of a patient with a single cysticercal granuloma that completely disappears in the follow-up, neurocysticercosis-related seizures should not be defined as ‘acute symptomatic seizures’. There is increasing evidence favoring an active role of parenchymal brain calcifications as responsible for
symptoms in a sizable proportion of neurocysticercosis patients and calcifications should no longer be seen as inert lesions. Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Neurocysticercosis is a pleomorphic parasitic disease causing different pathological lesions and clinical syndromes. Therefore, a single therapeutic approach should not be expected to be useful in every patient. • Proper characterization of neurocysticercosis according to the viability of cysts, severity of the host’s immune response and location of lesions, is of paramount importance for a rational therapy. • The first line of management of neurocysticercosis should be directed to control the clinical manifestations of a given patient and the pathogenetic mechanisms involved in their occurrence. • Two drugs, praziquantel and albendazole, have been shown to have potent cysticidal effects and have improved the prognosis of thousands of patients with neurocysticercosis. • The anecdotal nature of pioneer trials on cysticidal drugs created concern and it was postulated that these drugs do not modify the natural course of the disease. • More recently, a number of double-blind, placebo-controlled studies have shown that the use of cysticidal drugs is associated with resolution of lesions and clinical improvement in most patients with parenchymal brain cysticercosis. • Treatment of extraparenchymal neurocysticercosis is more complicated and many patients do not respond to medical treatment. In these cases, repeated trials of cysticidal drugs (or even surgical interventions) are often needed. • Some forms of neurocysticercosis, like cysticercotic encephalitis, must not be treated with cysticidal drugs as their use exacerbates the inflammatory reaction against parasites and may cause seizures or intracranial hypertension. • Calcifications should not be seen as inert lesions, as they represent permanent epileptogenic foci that may reactivate causing recurrent seizures. Long-term therapy with antiepileptic drugs is needed in most of these cases.
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