Intraventricular Neurocysticercosis: Comparative Analysis of Different Localizations. Clinical Course and Treatment. A Systematic Review

Background Neurocysticercosis is significant due to its high prevalence and considerable morbidity and mortality. The intraventricular form of NCC is less common than parenchymal, may have a rapidly progressive course and it requires a corresponding therapeutic response. Despite the extensive literature dealing with NCC and intraventricular cystic lesions, no systematic reviews have addressed similar work related to the clinical course and treatment of the infestation. Our main objective was to analyze the clinical type of the disease and the management for each ventricle separately on the basis of case reports or series of patients with individual data on the course of the disease and its treatment. As a control group, we used data on signs&symptoms and treatment of patients from published series on intraventricular neurocysticercosis. Method We performed a search in the Medline database. Google Scholar was also randomly searched. We extracted the following data from the eligible case/series: age and gender, symptoms, clinical signs, diagnostic examinations and findings, localization, treatment, follow-up period, outcome, and publication year. All data are presented in the form of absolute and relative numbers. The frequency of signs and symptoms, treatment and outcomes of the observed groups were checked by the Chi-square test and Fisher's test. The hypothesis was tested with p <0.05 as statistical significance. Results We selected 160 cases of intraventricular neurocysticercosis (IVNCC) and divided them according to their localization into five categories. Hydrocephalus was recognized in 134 cases (83.4%). Patients with isolated IVNCCare are younger (P=.0264) and have a higher percentage of vesicular cysts (p <.00001). In mixed IVNCC, degenerative and multiple confluent cysts predominate (p = 0.00068). Individuals carrying fourth + third ventricular cysts (potentially obstructive form) are younger than individuals with lateral ventricles (potentially less obstructive forme) (p = .0083). The majority of patients had individual symptoms for a longer period before the acute onset of the disease (p <.00001). The predominant clinical manifestation is headache (88.7%); the proportion within the groups ranged from 100% to 75% without statistical significance (p.074214). The same was true for patients with symptoms of vomiting or nausea, who had a lower and roughly balanced percentage of 67.7% to 44.4% (p.34702). Altered level of consciousness (ranging from 21% to 60%) and focal neurological deficit (from 51.2% to 15%) are the only clinical category with statistical significance (p <0.001 and p.023948 ). Other signs and symptoms were less frequent and statistically irrelevant. Surgical resection of the parasite was the predominant type of treatment, varying from 55.5% to 87.5% (p- .02395); endoscopy (48.2%) and craniotomy (24.4%), each individually, showed statistical significance (.00001 and .000073, respectively). The difference was also relevant among patients who had CSF diversion performance with/without medical treatment (p-.002312. Postoperatively, 31.8% of patients received anthelmintics with/without anti-inflammatory or other drugs. Endoscopy, open surgery, and postoperative antiparasitic therapy showed statistical differences (p < 0.001). Favorable outcomes or regression of symptoms were recorded in 83.7%, mortality 7.5%. In the case series, the clinical signs&symptoms were as follows: headache-64%, nausea and vomiting 48.4%, focal neurological deficit 33.6% and altered level of consciousness 25%. Open surgery was the predominant form of intervention (craniotomy (57.6% or endoscopy 31.8%); with statistical significance between them (p< .00001). Conclusion. Ventricular neurocysticercosis is an alarming clinical condition. Hydrocephalus is the dominant diagnostic sign. Isolated IVNCC patients were recognized at a younger age than Mix.IVNCC individuals; poeple with cysts in the fourth and third ventricles (as a potentially more occlusive type of disease), presented their symptoms at a younger age than individuals with LVNCC. The majority of patients had long-term signs and symptoms before the acute onset of the disease. Headache, nausea& vomiting are the most common symptoms of infestation accompanied by altered sensorium and focal neurological deficits. Surgery is the best treatment option. A sudden increase in ICP due to cerebrospinal fluid obstruction with a successive cerebral hernia is the leading cause of fatal outcomes.

Despite the extensive literature dealing with NCC and intraventricular cystic lesions, no systematic reviews have addressed similar work related to the clinical course and treatment of the infestation. We did not nd a prospective, randomized, double-blind study that supports proper clinical-surgical decisions in daily medical practice. Heterogeneous signs and symptoms were reported in available IVNCC or extra parenchymal neurocysticercosis publications [(4, 7, 10,23, 38, 41 ,44, 48 ]. Ventricular NCC might be potentially severe; it requires a corresponding therapeutic response. A few clinicians presented their results with medical therapy, most of them as case reports [(19,-22, 24,41]). Others have published their surgical experiences applying the same treatment to all patients or did not specify which type of surgery was used [4,14,23,25,26,41].
Our idea was to analyze the clinical type of the disease and the management for each ventricle separately based on case reports or series of patients with individual data on the course of the disease and its treatment. As a control group, we used data on signs&symptoms and treatment of patients from published series on intraventricular neurocysticercosis.
Lifecycle of the parasite Taenia (T.) solium has an indirect life cycle that requires two different hosts for species to survive in the wild. It includes man as the nal host where the tapeworm parasitizes in its adult form, and pigs and human beings as an intermediate host in which the development of the larva in the body occurs. People become infected by eating raw and/or dried pork that contains cysts, a larval form. After swallowing the larva-form ( Cysticercus), the released scolex from the cysticercus, straights, attaches to the jejunum´s mucosa, growth, and develops into a mature adult tapeworm. The adult stage secretes eggs through the genital pores in the proglottids from the intestinal lumen into the environment through feces. Poor sanitation conditions favor pig access to human feces that potentially contain T solium eggs. The embryos, released from eggs, cross intestinal mucosa, enter the bloodstream and disseminate into any organ or tissue where they develop into cysts. The life cycle is completed after a person eats such infected meat [ (17]. Infection may occur when a person eats eggs that are usually in improperly cleaned food (vegetables/fruits) or are on contaminated hands and objects (fecal-oral route) or even by regurgitation of eggs [55]. Person-to-person infection is more common than contamination that comes from eating undercooked pork infected with cysts [35,40.].

Material And Method
Using the keywords 'Intraventricular neurocysticercosis' 'Brain ventricle cyst' Cysticercus cyst in brain ventricles' 'Intraventricular cystic brain lesion' 'Intraventricular cysticercosis' 'Neuroendoscopy, we conducted a search of the English literature in the Medline database without restrictions on the date ranges of published articles. Google Scholar was also randomly searched.

Data collection and analysis
The document was read and reviewed by two investigators. In the rst step, titles and abstracts were screened by one reviewer (SM) and by the second reviewer if the rst one was uncertain about the eligibility of the case/series (ZM).
Joanna Briggs Institute Critical Appraisal Tool: Checklist for Case Reports (REF) [ 28)] assessed case reports and case series for methodological quality. The aim of the quality assessment tool was not to eliminate articles with poor methodological quality. The objective was to stress the potential bias of selected cases/series. The searches performed are presented in Table 1 and the Supplementary tables containing the papers of the reported cases. We excluded cases-series without an individual case description from the examination ( Figure 1). As a control group, we compared our ndings with a case series of patients with IVNCC regardless of topics (neurocysticercosis, extraventricular neurocysticercosis, or intraventricular cysticercosis) (Fig 2).
All data are presented in the form of absolute and relative numbers. The frequency of signs and symptoms, treatment and outcomes between the examined groups were checked by the Chi-square test and the Fisher test. The hypothesis was assessed with a p<0,05. as statistical signi cance. Statistical data processing was performed in Open Epi Info Version 7.2.2.6 (CDC, US).
Isolated ventricular cases were divided into four categories: fourth ventricular neurocysticercosis (FV-NCC), lateral ventricular neurocysticercosis (LV-NCC), third-ventricle neurocysticercosis (TV -NCC), and migratory ventricular cysts (Mig. -IVNCC); the last group consisted of individuals with mixed intraventricular neurocysticercosis (Mix. IVNCC), involving the brain parenchyma, subarachnoid space, and ventricles. The following data were extracted from the eligible case/series: age and gender, symptoms, clinical signs, diagnostic examinations and ndings, localization, treatment (with histological con rmation of cysticercosis in the operative group of patients), follow-up period, outcome, and publication year. The lifetime of the patients was classi ed into six groups: under 16 years old, between 17-30 years old, 31-40 years old,41-50 years old,51-60 years old, and above 60 years old.
The diagnosis of NCC was established by a combination of Computed Tomography (CT) Scan and/or Magnetic resonance imaging (MRI) (except in one case) with new acquisition techniques ( CISS, FlAR, SWAN, ESTA), serological test, and in most cases by histologic con rmation of cysticerci. The imaging ndings of NCC cysts were de ned according to the neuroimaging de nition [11]. We also adopted a set of revised criteria and degrees of diagnostic certainty to con rm the de nite and probable diagnosis of

Results
Out of 121 articles that dealt with various problems related to intraventricular cysticercosis, we singled out 158 cases that met the inclusion criteria. The most common localization of the cysticerci was FV -NCC -44 (28. The gender ratio was practically equal: 78(49.7%) males and 79(50.3% ) females(one data was missing); noticeable in favor of women between isolated IVNCC vs Mix.IVNCC(65:14) but without statistical signi cance ( p= .1660.) (Table 2a) . Age ranged from 6 to77 (30.42 ±2.16); the average age ratio between isolated IVNCC and Mix IVNCC was 28.73 ±2.28 (median 28) vs 36.83 ± 4.99(median 35). (Fig 3). In Mix. IVNCC the predominant cases fell between 31 and 40 years old (25.75%); in the isolated form of IVNCC, the most common prevalence was identi ed in the group of 21 to 30 years old (46.7%), with statistical signi cance within the group (P=.02646). Similarly, patients who had cysts in the fourth and third ventricles (potentially obstructive form) were younger than persons with LV NCC (possibly less obstructive form) (median 45:14; p =.0083) (Table 2b and  Hydrocephalus was recognized in 133 (84.2%) patients with a prevalence in Mix. IVNCC (94.3%), FV-NCC (88.4%), less in LV-NCC 72.3%, but without statistical signi cance (p= .137949) ( Symptoms in most patients lasted from several years to more than seven days 73(71.6%), and only 28(27.7%) had an acute onset at admission (p < .00001). Data were missing for 59 people.
No symptomatology data were available in 9(5.7%) patients; two individuals had asymptomatic cysts. Four cases had signs and symptoms of elevated intracranial pressure (  All treated cases met favorable outcomes or regression of symptomatology; not a report on the failure of the VP shunt (Table 5).
Twelve persons (7.6%) had a fatal outcome. Eight patients died due to obstruction of cerebrospinal uid ow and consequent cerebral hernia and brain stem compression; two cases suffered a severe chest infection and postoperative cardiac arrest. One patient, a 77-year-old man, had a decrease in the "immune response and resistance to applicable therapy." The last patient to experience a rupture of a giant basilar aneurysm harbored an asymptomatic cyst con rmed at autopsy. The follow-up (FU) was recorded in 65 (41.1%) patients, ranging from 17 days to 5 years (average days360 ±243.54); no mention of FU in 93(58.9%) subjects ( Table 5).
The published case-control series on IVNCC had 16 publications with 286 individuals with the clinical course and treatment method. Clinical manifestations were heterogeneous: headache -64.4%, nausea and vomiting 48.4%, focal neurological de cit 33.6%, and altered level of consciousness 25%.
Hydrocephalus was present in 68.3%. In several cases, symptomatology was described as a syndrome of increased intracranial pressure (1.6%). The ndings were statistically signi cant with Yates correction only in the frequency of headaches and altered level of consciousness (p<0.00001 and p=0.00 respectively) as well as hydrocephalus (p<0.00001) ( Table 6).
Surgical excision of cysts was the dominant form of treatment (craniotomy (57.6% or endoscopy 31.8%); a smaller number of patients had different types of CSF diversion (17.8%), or only medical treatment (2.8%). The ratio of craniotomy and endoscopy was statistically signi cant (p< .00001). In most individuals, the outcome was satisfactory ( Table 5). The statistical signi cance was a rmative in relation to endoscopy and the craniotomy between "our clinical materials" and patients with case series((P-value = .000266 and P-value = .00001). This was not the case with CSF diversion (P-value = .2139) or with only drug therapy (P-value = .3768. The majority of patients had involvement of the fourth ventricle with NCC (44.7%), and a smaller number of individuals had parasites in the lateral ventricle, the third ventricle, and mixed IVNCC in total (30.4%); for fty patients there were no precise descriptions of localization (Table 7).

Discussion
In "our study group " the gender ratio is slightly in favor of women, and the nding does not differ much from other available clinical materials [26., 38., 23) ].Patients with isolated IVNCC are younger than those with Mic.IVNCC. Symptomatology of patients with cysts in the fourth and third ventricles occurs at a younger age than those with LVNCC It is postulated that the parasites in the subarachnoid compartment have more room to increase their dimensions before they come into contact with the cerebral tissue [38]. A similar explanation can be for cysts in the lateral ventricles.
Intracranial hypertension and focal neurological de cit were the dominant clinical features in the present collection of patients. A focal neurological de cit occurs due to compression of local brain tissue (corticospinal tract, visual pathways, periaqueductal gray matter, our IV) by the parasite [16]); while direct pressure on the brain cysticerci le cerebellar structures due to the increased dimension of the fourth ventricle can cause neurological loss, gait ataxia, dysmetria, and diplopia [13,15] On the other hand, migratory cysticerci due to their small size move freely through the ventricular system and do not exert local pressure on the tissue.
Symptoms lasted from several years to more than seven days; a small percentage had an acute onset of the disease. The duration of clinical signs before the diagnosis can vary signi cantly, depending on the cyst's location or its evolution. A growing cyst that interferes with CSF ow manifests its symptomatology more quickly; in ammation is a slow-developing process, and signs and symptoms can appear several years after infection [2] A higher percentage of vesicular cysts was observed in isolated IVNCC than in the mixed form of NCC; the proportion of degenerative and multiple con uent cysts was more common in Mix.IVNCC than in the isolated form of IVNCC. By invading the ventricle, viable parasites initiate evasion of the immune response through negligible in ammation, allowing them to persist in the host for long periods, sometimes years [54 ]. Active, oating cysts are asymptomatic and can freely migrate within the ventricular system. Clinical manifestations can occur if the cyst blocks the ventricular openings, causing disruption of cerebrospinal uid ow with consequent acute hydrocephalus [5,24 ]. Gravity and changes in CSF pressure are provoking mechanisms of cyst migration. In the degenerative stage, the cyst releases antigenic substances that cause an in ammatory reaction; the capsule becomes attached to the ventricular wall with brous adhesions, which may give rise to ependymitis, ventriculitis, scars, and obstruction of CSF ow. The outcome may be lethal [43]. If in ammation involves meninges, the symptoms of meningeal irritation become manifest (fever, change of consciousness, nuchal rigidity [29]. Post-in ammatory sequelae cause mental deterioration, blindness, quadriparesis, and ataxia [ 22,24,29 ]. Surgery is the best treatment option for IVNCC. The main goal is to eliminate the symptoms of elevated ICP and to resect the cyst in the same setting. Sudden obstruction of the cerebrospinal uid ow requires immediate operative intervention. In patients with a cyst in the involutional or granular phase, surgical resection of the cyst may be di cult, can initiate damage to the surrounding structures, and cause ventricular bleeding. If the lesion is not amenable to complete excision, the primary goal is to treat hydrocephalus with or without partial resection of the cyst [14,26,30,52]. Partial cyst removal does not appear to cause recurrence [23,26,47]. Cyst rupture during surgery has been reported harmless and without complications [26,30]. Cyst removal sometimes requires a permanent shunt due to chronic in ammation caused by cysticerci [9 ]. Unfortunately, VP shunt failure has proven to be a frequent complication with its tendency to infection, occlusion of the system (by cyst-associated gelatinous material or high CSF protein), and cyst migration [3,14,32]. External ventricular drainage is still warranted in cases with severe infection and ependymitis [27]. Surgical removal of a single cyst is considered the end of treatment. Any suspicion of the existence of multiple cysts requires antihelminthic therapy [ 53]. It is not recommended to install antiparasitic drugs before surgery because they lead to parasite disruption, which may be accompanied by an in ammatory response of the adjacent tissue and compromise of surgical removal of the cyst [52)]. This therapy is also not recommended in patients with increased ICP [51].
The endoscopic transventricular-transforaminal approach seems appropriate to solve problems for cysts in the lateral and third ventricles. Endoscopic management of the fourth ventricle may be challenging.
However, endoscopy is not without risks. Intraventricular bleeding, memory loss, hemiparesis, mutism, ventricular entrapment, and aphasia have been reported [39,41]. The common approaches in open surgery are transcortical (lateral ventricular cyst); transcallosal or transcortical (lateral or third ventricle) and suboccipital midbrain (fourth ventricle) [4,31,33]. [4,31,33]. Open surgery has drawbacks: craniotomy, blood loss, possibly delayed hydrocephalus, withdrawal of brain invasion with the potential risk of damage to the vital structure, periventricular edema, and ventricular entrapment [23,26,46]. Controversy exists between 'our clinical material' and the collective case-series regarding the type of surgical treatment. While the percentage of endoscopically treated patients in' our series' is higher than patients with open surgery, in the case-series patient the situation is the opposite. The explanation may lie in the fact that the number of NCC cases involving LV, T V, and mixed forms of IVNCC were more numerous than the number of patients with parasites in the fourth ventricles; in the case series, the sum of individuals with the fourth ventricle's infestation was higher than in the other three compartments. According to Clinical Practice Guidelines, neuroendoscopy is recommended as the rst option in the treatment of cysts in LV-NCC or TV-NCC, and surgical resection of fourth ventricular cysts by suboccipital approach [52].
Hydrocephalus, a common clinical sign, was treated surgically in most cases with endoscopy, ETV, EVD, and VP/VA shunt [10,14,23,26 ]. Unilateral hydrocephalus occurs as a result of unilateral obstruction of the openings of Monro; clinical manifestations are usually slowly progressive and less dramatic [20].
Anti-helminthic treatment, as the only therapy, was applied to seven individuals(4.4%) with favorable outcomes. Several authors witnessed satisfying results with the absence of cysts on imaging outcomes after the single use of the medication [19,24].
The limitation of the study is the modest number of IVNCCs, because the survey includes only case reports and case series with individual reports published in English. In general, publication bias is a limitation of systematic reviews, especially for case/case reports, as each has its subject of interest that might neglect another area of research. Searching a single database, such as Medline, brings about the possibility that the analysis does not cover all individual cases. Language bias is another limitation since a number of IVNCC patients were published in other languages.
In conclusion: Ventricular neurocysticercosis is an alarming clinical condition. Hydrocephalus is the dominant diagnostic sign. Isolated IVNCC patients were recognized at a younger age than Mix.IVNCC individuals; with cysts in the fourth and third ventricles (as a potentially more occlusive type of disease), presented their symptoms at a younger age than individuals with LVNCC. The parasites in its vesicular stage are located predominantly in isolated IVNCC, while degenerative and multiple con uent cysts are the main feature of Mix.IVNCC. Most patients had long-term signs and symptoms before the acute onset of the disease. Headache, nausea& vomiting are the most common symptoms of infestation accompanied by altered sensorium and focal neurological de cits. Surgery is the best treatment option. A sudden increase in ICP due to cerebrospinal uid obstruction with a successive cerebral hernia is the leading cause of fatal outcomes.  Tables   Tables 1 to 7 are available in the Supplementary Files section   Supplementary Tables   The Supplementary Tables are not available   In Mix. IVNCC the predominant cases fell between 31 and 40 years old (25.75%, median 28); in the isolated form of IVNCC, the most common prevalence was identi ed in the group of 21 to 30 years old (46.7%, median 35), with statistical signi cance within the group (P=.02646).