Central Nervous System Cystic Echinococcosis: A Systematic Review

Abstract

Central nervous system (CNS) cystic echinococcosis (CE) is a rare disease caused by Echinococcus which especially exists in agricultural endemic areas. This condition is more frequent in the pediatric and adolescent population and it can be associated with hydatid cyst in other localizations. A literature search was conducted up to 28 April 2021 by two independent reviewers. This study focused on clinical, imaging, therapeutic features as well as on complications of CNS CE among children and adults. Fifteen studies from seven different countries were included. A significant prevalence in males (ranging from 51% to 100%) was observed with an average rate of 60%. CNS CE was mainly single and located in the parietal region. The predominant symptoms were those of increased intracranial pressure. All patients were treated surgically, and the most common post-surgical complication was cyst rupture (prevalence: [3.3–37.5%], average: 12.9%). Furthermore, the outcomes were worse amongst patients with cyst ruptures and multiple recurrences. The average proportion of deaths due to CNS CE was 5.6% (range: 2.5–14.8%). This review highlights the necessity of including CNS CE in the differential diagnosis of patients with cystic lesions, especially in those residing in endemic areas. Early gross total cyst removal is the mainstay of treatment yielding the best outcomes.

Introduction

Although cystic echinococcosis (CE) of the central nervous system (CNS) is rare, it is posing significant challenges for diagnosis and treatment in infested regions [1,2]. Causes of the disease include the Echinococcus granulosus, which causes the cystic hydatid disease, Echinococcus multilocularis, which causes the alveolar hydatid disease, Echinococcus vogeli, which causes the polycystic disease, and Echinococcus oligarthrus. Echinococcus granulosus and Echinococcus multilocularis have the major clinical importance for humans [3]. CNS CE is far more common in pediatric and adolescent populations, where it accounts for 50–75% of all CNS hydatid cases [4,5]. In these age groups, CNS CE may solely occur in the CNS or be associated with involvement of other systems [6,7]. In particular, larvae that overcome the filtering barrier systems in the liver and lung can thereafter enter the systemic circulation and invade the CNS [2,8,9]. Once the hexacanth larvae has reached the target organ, a hydatid cyst will be formed where conditions for growth will be ideal [10]. Previous studies have reported that hydatid disease is located in the intracranial cavity in only 0.5-3% of patients with CE [4,11,12,13,14].

Children with CNS CE are common clinical cases for neurosurgeons and pediatric neurologists, particularly in agricultural endemic regions, where sheep and cattle raising is a common practice [9,14]. Previous comprehensive reviews have mainly focused on countries where the disease is endemic, such as Turkey, providing useful diagnostic and therapeutic guidelines [15,16,17]. However, there is still a need for a thorough systematic review of the existing literature, so that firmer conclusions will be drawn.

We have systematically reviewed the existing literature published during the last 25 years focusing on the clinical, imaging, and therapeutic features of CNS CE in both children and adults.

Methods

Search Strategy and Study Selection

Two independent and blinded to each other reviewers systematically searched Medline database through PubMed from January 1 1995 up to April 28 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary

Table 1. Descriptive characteristics and main findings of eligible studies.

) [18]. The following algorithm was implemented: (echinococcosis OR Echinococcus OR (hydatid AND cyst) OR echinococcal) AND ((brain OR (central AND nervous AND system))). The reference lists of reviews and eligible studies were also searched for potentially eligible articles (“snowball”). Studies were eligible if they evaluated the prevalence and clinical presentation of CNS cystic echinococcosis during the last 25 years. No language or other restrictions were applied. Case reports, case series with less than 10 participants, experimental or animal studies were excluded. Systematic reviews and meta-analyses were also excluded.

Duplicate studies were removed and the remaining articles were independently screened by two reviewers to identify those that met the predetermined inclusion criteria. Disagreements in the selection of studies or snowball procedure were resolved by team consensus. In articles with overlapping populations, the most recent or most complete publication was considered eligible.

Data Extraction

For each eligible study, the data extraction included the following variables: year of publication, study area, design and period, sample size, age, and male proportion. In addition, information about the localization of hydatid cyst(s), the most common clinical findings, the treatment and complications during the follow-up period was extracted. Two reviewers performed the data extraction; any disagreements were resolved by team consensus.

A qualitative (narrative) synthesis of the results of the eligible studies was thereafter performed as shown in Table 1.

Results

Study Characteristics

The flow chart of the literature search and selection process is shown in Figure 1. The initial literature search yielded 584 potentially eligible studies, without any additional articles identified through the snowball procedure. Following the initial screening (“titles and abstract”), 501 studies were excluded. Of the remaining publications, 68 studies were excluded due to specific reasons, such as case series with less than 10 participants, studies on other than CNS cystic echinococcosis, reviews, animal or experimental studies. Finally, 15 eligible studies were included in the present review [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33].

Table 1 presents the characteristics of the included studies, all of which were cross-sectional yielding a total sample of 592 patients with CNS CE. Five of the eligible studies were conducted in Turkey, while the remaining studies were based in Romania, Tunisia, Libya, Pakistan, India and China. Seven studies included only children aged 0-18 years, whereas the remaining studies included both children and adults (age range: 0-68 years) with CNS CE. All but two studies showed a significant prevalence of CNS CE in males, ranging from 51% to 100%, with an average prevalence of 60%.

Localization and Clinical Presentation

The most common site of CNS CE was the parietal region, followed by the frontal, temporal and occipital regions. Few studies (n=2) reported CNS hydatid cysts located in the cerebellar hemisphere. The hydatid cysts were single in the majority of studies, whereas multiple lesions were more rarely presented.

In all studies, the predominant symptoms of patients with CNS CE were those of increased intracranial pressure, namely headache and nausea or vomiting. Among clinical signs, papilledema, slight to moderate hemiparesis and visual symptoms were frequently reported. Seizures were less common among patients with CNS CE, although two studies showed a prevalence of 36% for seizures in patients with CE; however, the small number of study subjects should be acknowledged.

Treatment and Complications

All patients with CNS CE were treated surgically. Different surgical techniques were implemented across the different study groups, such as the Dowling’s technique, the method of Arana-Iniguez and the peri cystic hydraulic method. In case of cyst rupture, recurrence and systemic hydatid disease, treatment further included antiparasitic medication, such as albendazole or mebendazole.

The most common intra-surgical complication was cyst rupture with a prevalence ranging from 3.3% to 37.5% (average: 12.9%). Other complications included recurrence of the cyst, transient hemiparesis, epilepsy, hydrocephalus, porencephalic cysts, and deep venous thrombosis. The outcomes were worse amongst patients with cyst rupture and consequent multiple recurrences. The average proportion of deaths due to CNS hydatid cyst was 5.6% across the identified studies (range: 2.5–14.8%).

Discussion

Main Findings

The present systematic review included approximately 600 patients with CNS cystic echinococcosis stemming from 15 studies published during the last 25 years. Due to the rarity of the disease, literature is scarce and is mainly based on studies conducted in endemic in sheep and cattle-raising areas, especially in Mediterranean countries, such as Turkey and Syria. Indeed, about one third of the eligible studies identified through our literature search were conducted in Turkey (n = 5). The parietal lobe was most commonly affected in both children and adults with CNS CE. The clinical presentation of the disease is largely non-specific mainly including symptoms and signs of intracranial hypertension. Treatment is primarily surgical, whereas complications during or after surgery included cyst rupture and recurrences, which both affected the prognosis of patients.

Interpretation of Findings

Central nervous system cystic echinococcosis is scarce and accounts for 2–3% of all CE worldwide. The disease is due to the cestode Echinococcus, presenting with a global prevalence, but being endemic in regions with high prevalence of sheep and cattle raising, such as Latin America, Australia, Mediterranean countries, the Middle East, and India. The present review showed a high prevalence of CE among males; a potential explanation is that males work more in agriculture, which enhances the spread of the disease. Moreover, due to activities such as hunting, males appear to get in contact more often with canines, such as dogs, wolves, and foxes, which are the definitive hosts for Echinococcus.

Hydatid disease is spread through contaminated food ingestion. The human intestine is invaded by oncospheres formed by the viable parasite eggs, which subsequently penetrate the mucosa, reaching hematogenously the liver (75%), lung (15%), and CNS (2%) [17,34]. Cerebral involvement is scarce, with the majority of cases occurring in children [35]. Indeed, about half of the identified studies in our review included only children with CNS hydatid disease, while the remaining studies included both children and adults. Cysts are usually single, unilocular, and located in the distribution of the middle cerebral artery, but they may also occur infratentorially [36,37]. The parietal lobe is primarily affected, followed by the frontal and temporal lobes, as shown in the present study.

The clinical presentation of CNS hydatid disease is not specific, and depends on the location and size of the cyst [38]. Consistent with the existing literature, our review showed that the clinical findings of increased intracranial pressure, such as headache, nausea/vomiting, papilledema and focal neurological deficits are the most commonly reported. Seizures are less commonly presented, although two studies of small sample size showed a prevalence of about 36% of patients presenting with seizures due to CNS hydatid disease. Despite the non-specific clinical presentation of CNS CE, imaging techniques, including CT scan and MRI, are highly accurate to establish the diagnosis, when history (residency in endemic area) and clinical findings are indicative of CNS CE [39]. The sensitivity of serological tests is low in CNS hydatid disease; thus, even if serological tests are negative, the characteristic imaging findings still support the diagnosis [40].

Surgical treatment remains the milestone of treatment for CNS hydatid disease [41]. Anti-helminthic medications, such as benzimidazole, are complimentarily used in case of systemic disease, recurrence, or cyst rupture [41]. The primary aim of surgery is the intact cyst removal without spillage of the contents. Dowling’s technique was the most commonly used method across the eligible studies identified herein, and remains a popular method of “in toto” cyst extirpation using hydrostatic dissection to define the plane between the cyst wall and the brain [42,43,44].

Cyst rupture during surgery was the most frequently reported complication accounting for 13% of patients, and in all cases was inevitably associated with recurrence. Indeed, previous studies report that cyst rupture is an indication for use of anti-helminthic treatment [42]. Usually, the brain re-expands to a remarkable extent within months. However, occasional postoperative complications, such as subdural collections or porencephalic cysts, seizures, and transient neurological deficits may occur [43,44,45,46,47]. The prognosis of patients may be affected by such complications. In our review, about 6% of patients died, the majority of them due to large hydatid cysts, cyst rupture, multiple recurrences or other post-operative complications.

Strengths and Limitations

The results of the present systematic review should be interpreted with caution in view of limitations inherent to data availability. Owing to the rarity of the disease, all identified studies were case series with 11-40 patients, except for two larger series in Turkey (n=140) and Tunisia (n=155). A quantitative synthesis of the results was thus non-feasible due to the study design of existing evidence. Moreover, most studies did not include detailed information on diagnosis or treatment options, i.e., a detailed description of the surgery performed. Thus, we could not expand on our narrative review on such data, which need to be further explored in future studies.

Beyond these limitations, we performed a systematic literature search based on predefined guidelines, which yielded a large sample size of approximately 600 patients, mainly children, with CNS CE focusing on the localization, clinical presentation, treatment and complications of this disease, which may be useful as basis for future longitudinal research on this field.

Conclusions

Despite the scarce literature regarding CNS CE, the present review confirmed the high prevalence of the disease in children residing in Mediterranean regions, the Middle East, and India. CE should be thus considered part of the differential diagnosis in patients with CNS cystic lesions, especially in endemic regions. Early surgical intact cyst removal is the mainstay of treatment yielding the best outcomes. Gross total resection without cyst rupture is challenging, but optimal treatment remains an active nationwide prevention.