2025/05/29 by Kevin A. Smith, Monica M. Diaz, Christine L. Heumann · 1 voice
Psychology · #Migration, Health and Trauma
paper · pdf · doi:10.1093/cid/ciaf282
A 31-year-old previously healthy female presented to the emergency department with new-onset seizure just before arrival. She had left leg pain and cramping but denied other symptoms. She was found to have 2 hypodense cortical lesions with surrounding edema on noncontrasted computed tomography (CT) scan of the head (Figure 1). Axial images of initial computed tomography scan of the head that show 2 hypodense lesions with surrounding edema. The arrow indicates the presence of a possible scolex. This patient is presenting with new-onset seizure and 2 cystic-appearing lesions with perilesional edema. In an immunocompetent patient, etiologies of a brain cyst would include a central nervous system (CNS) bacterial or fungal abscess, CNS amoebiasis, tuberculoma, echinococcosis, neurocysticercosis (NCC), and noninfectious etiologies such as brain metastases, low-grade glioma, CNS lymphoma, and neurosarcoidosis. Other autoimmune etiologies are unlikely to present with a cystic lesion. On closer inspection of the CT images, the more superior cystic lesion contains what appears to be a scolex, which has a more limited differential diagnosis, and specifically increases my concern for NCC. The lack of calcifications on CT does not rule out NCC, as she may only have lesions in the cystic phase. Additional information about her travel history or birthplace would be relevant as Taenia solium is endemic to sub-Saharan Africa, South and Central America, and southeast Asia. If she has not been to an area endemic with NCC, then contrasted brain magnetic resonance imaging (MRI) with and without contrast may provide evidence indicating another etiology such as toxoplasmosis, cryptococcomas (especially if CD4 count is below 100 cells/mm3 in the case of human immunodeficiency virus [HIV] infection or other immunosuppression such as organ transplant), bacterial or fungal abscess, tuberculoma, and CNS malignancies. I would recommend obtaining a brain MRI scan with and without contrast if possible and starting antiseizure medications to prevent further seizure activity. She reported no medication or supplement use and no surgical history. The patient prepared food at a local restaurant. She was originally from Haiti, moved to Chile 6 years ago, then moved to the United States 1 year prior to presentation. Her social history was otherwise unremarkable. On physical examination, her vital signs were within normal limits. She had decreased strength on left hip flexion and left foot dorsiflexion. She had no skin lesions or rashes and there were no murmurs on heart auscultation. The examination was otherwise normal. Laboratory testing revealed a white blood cell count of 10.6 k/mm3 with a normal differential. Complete blood count and comprehensive metabolic panel were otherwise normal. A combined antigen/antibody HIV screening test was negative. The patient is from a region where neurocysticercosis and tuberculosis are endemic. Opportunistic infections, such as cryptococcoma, are much less likely given she is HIV negative and presumed immunocompetent. The patient's occupation is also relevant, given she works in food preparation and ingestion of food contaminated with Taenia solium eggs could lead to cysticercosis. Other etiologies, such as brucellosis, from ingestion or handling of unpasteurized milk products can be considered. However, CNS brucellosis is not known to cause cystic brain lesions. Given that the patient was afebrile and had a normal white blood cell count, a CNS bacterial abscess is less likely, but this is consistent with the leading differential of NCC, which is indolent. The left lower extremity weakness localizes to the right frontal lobe, where 1 cyst is located. The next steps in the patient's management would be to obtain a brain MRI scan with and without contrast and a fundoscopic examination assessing for ocular cysticerci. In addition, based on the results of the MRI scan, a lumbar puncture could be considered to work-up etiologies other than NCC. The patient's ophthalmologic examination was normal. A brain MRI scan with contrast was performed (Figure 2) and revealed 3 cystic lesions with peripheral enhancement and surrounding edema that measured 2 cm in the right paracentral lobule, 2 cm in the right occipital lobe, and 0.8 cm in the posteromedial left parietal lobe. There were 2 additional small subarachnoid lesions, 1 in the left central sulcus and 1 in the right quadrigeminal plate cistern. Additionally, an interferon gamma release assay for tuberculosis was negative and a Strongyloides immunoglobulin G antibody by enzyme-linked immunosorbent assay (ELISA) was 0.5 (normal ≤0.9). The initial brain magnetic resonance imaging scan with contrast axial fluid-attenuated inversion recovery (FLAIR) images with small arrows indicating subarachnoid cysticerci and a wide arrow indicating a parenchymal cysticercus. The lesion in the right occipital lobe demonstrates what appears to be a scolex which is very characteristic of NCC. The subarachnoid lesions are also characteristic of neurocysticercosis. Given the subarachnoid lesions are small and not obstructing the 4th ventricle, it is reasonable to obtain a lumbar puncture to check for T. solium antibodies in the cerebrospinal fluid (CSF). Eosinophilia in the CSF could also point toward a parasitic infection. If a lumbar puncture is unable to be obtained (in the case of obstructive hydrocephalus, or if there were midline shift from edema), I think there is sufficient evidence to begin treatment of NCC. Per the IDSA guidelines for management of NCC, combination praziquantel and albendazole with adjunct dexamethasone are recommended in the setting of subarachnoid NCC [1]. A minimum duration of 10–14 days is recommended for NCC but may need to be extended for subarachnoid neurocysticercosis. Given there is perilesional edema, dexamethasone should be started at least 1 day before initiation of anthelmintic therapy, and antiseizure medications should be initiated to prevent further seizures. Dexamethasone or a steroid-sparing immunosuppressant is recommended for the duration of anthelmintic therapy and is usually tapered over months after completion of therapy. Strongyloides serology and latent tuberculosis testing is crucial prior to beginning long-term steroids or immunosuppression given Strongyloides stercoralis hyperinfection or latent tuberculosis reactivation may occur. Based on characteristic imaging findings, diagnoses of parenchymal and subarachnoid neurocysticercosis were made and treatment was initiated with dexamethasone and levetiracetam followed the next day by combination praziquantel and albendazole. Given the presence of subarachnoid lesions, she was also initiated on vitamin D and pantoprazole in anticipation of a prolonged course of corticosteroids. She was advised on pregnancy-related adverse effects of dexamethasone and opted to start an oral contraceptive. The patient was discharged from the hospital. Upon 2-week outpatient follow-up, a serum cysticercosis immunoglobulin G antibody by ELISA sent to Associated Regional and University Pathologists laboratory from her hospitalization returned at 5 U (<9 U negative). Based on her clinical presentation and imaging findings, the patient has a provisional diagnosis of NCC. The imaging findings (scolex within a cystic lesion) have high sensitivity and high specificity for NCC [2], which is sufficient to begin NCC therapy without the use of serological testing if suspicion is high. Serological testing for NCC is imperfect. ELISA kits have poor sensitivity and often lead to cross-reactions, with sensitivities of 44.4% and 22.2% from 2 different assays for detecting antibodies in patients with viable NCC [3]. In contrast, the Centers for Disease Control's enzyme-linked immunoelectrotransfer blot (EITB) assay, using lentil lectin-bound glycoproteins from T. solium cysticerci, achieves 99% sensitivity and specificity, and 100% sensitivity with 99% specificity when 2 or more intracranial cysts are present [4]. Given the low sensitivity of ELISA, a negative result does not rule out NCC, and the presumptive diagnosis of NCC should remain. Current anthelmintic and adjunct immunosuppressive treatment should be maintained. Reimaging in 4–6 weeks to determine cyst response should be pursued. A follow-up MRI scan with contrast was performed 4 weeks into treatment and shows resolution of edema and reduction in size of parenchymal cysts (Figure 3A). The subarachnoid lesions had decreased in size slightly and showed reduced enhancement. EITB antibody testing was not pursued. To assess response to therapy, serum and CSF T. solium antigen and quantitative polymerase chain reaction (qPCR) tests were sent to the National Institutes of Allergy and Infectious Diseases’ Laboratory of Parasitic Diseases at the National Institutes of Health. A, The axial FLAIR images from repeat brain MRI at 4 wk demonstrate subarachnoid cysticerci that have become less prominent. The parenchymal lesions no longer have surrounding edema and have decreased in size. B, The axial FLAIR images from a repeat brain MRI at 8 m demonstrate subarachnoid cysticerci that progressed to the granular nodular stage and are even smaller in size. The parenchymal lesions have nearly completely resolved. Abbreviations: FLAIR, axial fluid-attenuated inversion recovery; MRI, magnetic resonance imaging. The MRI scan shows a good therapeutic response. Serum and CSF T. Solium antigen and qPCR testing can help determine length of treatment. While not always necessary, these tests can function as a surrogate for the burden of disease. It is prudent to also repeat a brain MRI to guide the length of treatment. Therapy should be continued until there is complete resolution of viable cysticerci on MRI, as this would suggest elimination of the parasite. The patient should be maintained on a steroid course but could begin to taper every 2–4 weeks, now that edema is resolving, maintaining a dose of at least 6 mg of dexamethasone daily until MRI is repeated, possibly in 6–8 weeks. If it is not possible to obtain MRI, then using CSF and serum T. solium antigen and PCR can be a surrogate for visualizing the lesions on MRI. If the patient begins to have adverse effects from steroid use, then you could consider a steroid-sparing agent such as methotrexate. After 2 months of therapy, her serum antigen and qPCR testing returned negative. Subsequently, the patient underwent lumbar puncture and CSF testing for T. solium antigen and qPCR, and both returned negative. Due to significant delays in collection and processing, these had not resulted until the seventh month of therapy. In the interim, she developed some abdominal striae and mild moon facies. Her hemoglobin A1c was 5.7%. The appropriate duration of therapy for NCC—specifically subarachnoid NCC—is challenging to define. Data that can help guide this decision include serial imaging studies, antigen testing, and qPCR testing. In this case, the patient has had 1 repeat MRI that showed significant, but not total, improvement of abnormalities, and a negative serum antigen and qPCR test after 2 months of anti-helminthic therapy. The natural history of NCC cysts on imaging typically progresses through several stages in response to therapy. Initially, cysts appear as vesicular lesions with clear fluid and a visible scolex. As treatment with antiparasitic therapy progresses, the cysts transition to a colloidal stage, characterized by increased inflammation and edema around the cysts. Eventually, the cysts may calcify, appearing as small, dense nodules on imaging. This calcification indicates the death of the parasite and resolution of active infection. These can still be associated with residual inflammation and seizures, which is why it is crucial to continue anti-inflammatory and anti-seizure medications during treatment. Quantitative qPCR levels decrease in response to treatment with a reduction in detectable DNA from T. solium in both plasma and CSF as the infection resolves. qPCR is highly sensitive and specific, making it a valuable tool for monitoring treatment response and confirming the cure of NCC. In 1 study, qPCR in CSF was able to distinguish 94.4% of all patients with cured subarachnoid NCC [5]. Both imaging and qPCR should be used together to make a clinical decision on whether to stop treatment. If qPCR is not available, imaging is an excellent marker of treatment response. Given the serum antigen and qPCR testing has come back as negative, it would be reasonable to stop albendazole and praziquantel treatment if the patient is reimaged and the cystic lesions and edema are reduced compared to prior imaging. Corticosteroids should have started being tapered once MRI showed reduction in edema. Given serum antigen and qPCR testing are negative, it is reasonable to start tapering down steroids. Retreatment should be completed with antiparasitic treatment for any parenchymal cysts that persist for 6 months after stopping the initial course of treatment. MRI scans should be repeated at least every 6 months until all resolution of cysts per IDSA guidelines [1]. After the CSF testing returned negative, albendazole and praziquantel were discontinued. A slow dexamethasone taper was completed over many weeks. A brain MRI scan was performed soon after the discontinuation of her anthelmintics (Figure 3B). Her parenchymal cysts nearly resolved and based on neuroradiology evaluation the subarachnoid cysts appeared to be in the granular nodular stage and thus were nonviable. The patient denied recurrence of symptoms at her 6-month follow-up from completion of therapy. Subarachnoid neurocysticercosis is an uncommon complication of a globally prevalent disease [6]. The lack of controlled trials makes treating this entity challenging. Patients with extraparenchymal neurocysticercosis have a variable response to treatment following standard short courses of anthelmintics [7]. Additionally, cases of recurrence after total MRI resolution have been reported [8]. Current guidelines do not directly address this gap in subarachnoid neurocysticercosis care and do not address the diagnostic uncertainty demonstrated by this case [1]. Despite the negative serology, antigen, and PCR test results from serum or CSF, the diagnosis carried high certainty based on established diagnostic and radiographic criteria. The evidence which ruled strongly in favor of the diagnosis included the presence of a scolex on MRI, her presenting symptoms, and social history. These findings were sufficient to warrant treatment for neurocysticercosis. Finally, in hindsight, her response to treatment also supports the diagnosis. The most readily available commercial laboratory test for neurocysticercosis in the United States is the cysticercosis immunoglobulin G antibody by ELISA in serum and CSF. As pointed out by the discussant, ELISA has relatively poor performance characteristics in NCC [3, 9, 10]. The EITB test is both more sensitive and specific [4, 9, 10]. Cysticercosis antibody testing by ELISA is not sufficiently sensitive to rule out disease nor is it specific for active neurocysticercosis, and the limited availability of EITB hinders its utility. Considering this, the treating clinicians had high enough diagnostic certainty to forego additional antibody testing in the follow-up period, interpreting the result as a false negative. In this case, antigen and PCR testing were performed many weeks into therapy. There may be some utility in performing these tests earlier in the course to confirm disease, but the limited published clinical experience with these tests does not clearly indicate whether a downward trend of antigen or PCR values is beneficial. This patient's test results were interpreted as indicating the resolution of her subarachnoid neurocysticercosis. The discussant's recommendation to use imaging results to determine disease resolution and treatment duration represents the historically established standard of care. The use of PCR and antigen testing to determine treatment duration has not been evaluated in any controlled trials, but this approach was used in a case series by Nash et al and demonstrated a sustained response to therapy following a negative CSF antigen test [8], and also a negative qPCR predicted durable response in 95% of patients when used as a test of cure [5]. In these cases, anthelmintics were continued until testing became negative, which is consistent with current expert recommendations and is the reason this approach was chosen [11]. The management of this case of subarachnoid NCC emphasized many uncertainties encountered when caring for patients with infectious diseases. Given a lack of controlled trials, decisions rely heavily on expert consensus documents, published case series, and anecdotal experience. This case demonstrates how these resources support treating clinicians when forming a diagnosis and treatment plan. Furthermore, it highlights the frequent challenge of making management decisions when the diagnostic data are incomplete, discordant with the clinical diagnosis, and how therapeutic trials serve as an important mechanism by which infectious disease clinicians refine their clinical gestalt for future undifferentiated cases. The patient has made a full recovery and, to our knowledge, continues to do well. Acknowledgments. The authors thank Dr. Daniel Minter and Dr. Varun Phadke for their guidance during the presubmission process. We also acknowledge Dr. A. Clinton White for his guidance on this case and Dr. Elise O’Connell's laboratory for conducting the tests necessary in this patient's care. Financial support. No source of funding was associated with this publication. Blind Respondent. Dr. Monica M Diaz.