Abstract
Paraneoplastic Limbic Encephalitis (PLE) is a neurocognitive condition caused by an immune response to neuronal proteins linked to malignancy, such as testicular cancer. We report a 25-year-old male with cognitive and personality changes. His initial MRI showed vasogenic edema. A subsequent CT scan revealed bilateral hydroceles, and a follow-up scrotal US uncovered a right testicular mass, leading to a radical orchiectomy that confirmed a Sertoli cell tumor. Following orchiectomy and immunomodulating therapy, the patient's symptoms showed near-complete resolution within a year. This is the first documented case of PLE resulting from a non-germ cell testicular tumor.
1. Introduction
Although initially thought to be a rare condition, paraneoplastic limbic encephalitis (PLE) is now a relatively frequent autoimmune disorder often associated with small cell lung carcinoma, ovarian malignancies, Hodgkin's lymphoma, and testicular germ cell tumors.1,2 Proposed etiologies to the disorder include immune cross-reactivity against tumor antigens that have structural similarity to neurologic antigens, mounting a T-cell mediated response at a site distant from the cancer.2 Advancement in the detection of paraneoplastic and anti-neuronal antibodies has led to greater identification of PLE. Known associations exist between certain antibodies and specific cancers, such as anti-Hu and small cell lung carcinoma or anti-Ma2 and testicular germ cell tumors.1 As such, early identification of paraneoplastic antibodies can help identify the primary malignancy causing PLE. In fact, 90 % of patients with paraneoplastic neurologic diseases will have their cancer diagnosed within a year of presentation, underscoring the potential opportunity to identify and treat a previously undiagnosed malignancy in these patients.
Symptoms of PLE include short-term memory loss, personality change, and seizures with symptom severity proportional to the degree of inflammation and edema.2 In a recent systematic review by Deol et al., 96 cases of paraneoplastic encephalitis secondary to testicular tumors were identified. Notably, all cases were associated with germ cell tumors. PLE secondary to germ cell testicular tumors is well documented and associated with a variety of autoantibodies such as anti-Ma1/2, anti-KLHL11, and anti-TA.3 Using both PubMed and Ovid MEDLINE, we searched the keywords “Sertoli cell tumor,” “non-germ cell tumor,” and “paraneoplastic limbic encephalitis” to assess previous cases examining the association between PLE and non-germ cell tumors. Our search included the time frame from January 1st, 1946 to February 14th, 2025 and included all forms of publication types. To date, there has not been a reported case of PLE secondary to a non-germ cell testicular tumor. Here, we present the first description of PLE secondary to a non-germ cell tumor, specifically a Seritoli cell tumor.
1.1. Case presentation
A 25-year-old male with a past medical history significant for Bell's Palsy presented to the ED with a one-month history of syncope, short-term memory loss including an inability to recognize family, personality changes, irritability, and aphasia. The patient had a baseline degree of mental disability of unknown origin but was able to live and work independently prior to symptom onset. He was initially seen at an outside hospital, where he received a course of empiric antibiotics and steroids with no immediate improvement in his neurological symptoms.
At presentation, the patient reported intermittent headaches and neck stiffness concerning for meningitis. An infectious workup, which included testing for HIV, syphilis, COVID-19, and HSV-1 & 2, was negative. Routine blood work revealed no metabolic source of his encephalopathy. The differential diagnosis was broadened with further testing revealing normal vitamin B12 and folate levels, mildly increased inflammatory markers including ESR and CK. Initial MRI revealed nonspecific vasogenic edema in the medial temporal and occipital lobe with the left side worse than the right (Fig. 1), new from prior imaging 3 weeks earlier at the outside hospital. As his symptoms continued to progress and without a clear etiology, the patient was started on quetiapine for significant agitation and valproate for seizure prophylaxis.
Fig. 1.
MRI without contrast on 07/25/2021 showing edema within the left temporal lobe (yellow arrow) and anterior medial left occipital lobe (red arrow) (T2). Findings are consistent with Encephalitis.
As his initial workup was non-contributory, his workup continued with an EEG, which revealed generalized delta and theta slowing indicating diffuse cerebral dysfunction, however, no epileptiform activity was seen. A lumbar puncture was performed and showed lymphocytosis, oligoclonal bands, and elevated protein. Complete infectious testing of the CSF was altogether negative and included: Cryptococcus, CMV, HSV, Enterovirus, E coli K1, Haemophilus influenzae, HIV, Leptospira, Neisseria gonorrhoeae, Listeria, GBS, Streptococcus Pneumoniae, and Varicella. Additionally, a bacterial culture of the CSF showed no growth. A comprehensive paraneoplastic and infectious disease panel was negative.
In an effort to further assess for a source of the patient's encephalopathy, a CT scan of the chest, abdomen, and pelvis was ordered to assess for malignancy. While no acute malignant changes were identified, bilateral hydroceles were visible and prompted a testicular ultrasound, which revealed a 1.5 cm by 1.1 cm by 1.5 cm right testicular mass (Fig. 2). At this point, the patient was urgently referred to urology, and a comprehensive genitourinary physical exam showed a right-sided posterior testicular mass, confirming the scrotal ultrasound findings. A more focused review of his CT did not reveal evidence of metastasis including no retroperitoneal lymphadenopathy and tumor markers AFP, LDH, and b-hCG were all within normal range. Three days later, an uncomplicated right radical orchiectomy with right testicular implant was performed under general anesthesia, and pathology characterized the mass as a sclerosing Sertoli cell tumor with negative margins. Immunohistochemistry was positive for vimentin, beta-catenin, and synaptophysin, which was further suggestive of a neoplasm of Sertoli cell origin.
Fig. 2.
Scrotal Ultrasound on 07/27/2021, which shows a 1.5 cm × 1.0 cm x 1.5 cm oval heterogenous intratesticular mass with irregular margins and internal vascularity. Findings concerning for testicular cancer.
Following the discovery of the testicular tumor, a paraneoplastic syndrome was considered based on the patient's subacute change in mental status, working memory deficits, and personality changes, along with MRI features consistent with encephalitis. Postoperatively, the patient was further treated with IVIG 2 mg/kg for 5 days and IV solumedrol 1 g for 5 days. The patient remained agitated and altered while hospitalized and was discharged on hospital day 26. He continued to follow up with the neurology team every 2 months and demonstrated continued improvement in orientation, recall, and memory testing as he became more capable of performing activities of daily living independently. A repeat MRI performed 4 months after discharge showed near complete resolution of the inflammatory changes and vasogenic edema seen in the medial temporal and occipital lobes (Fig. 3). At follow-up with urology, a CT scan of the abdomen and pelvis confirmed localized disease without extra-testicular progression. The patient has since returned to full independence including returning to work and no longer requires family support for activities of daily living.
Fig. 3.
MRI without contrast on 12/17/2021 showing resolution of the inflammatory changes previously seen in the temporal (yellow arrow) and occipital lobes (red arrow) (T2 FLAIR).
2. Discussion
PLE, a paraneoplastic neurological syndrome, is an increasingly recognized disorder that can be caused by a number of malignancies, including testicular tumors. To date, only testicular germ cell tumors have been reported in association with PLE.3 Based on our PubMed and Ovid MEDLINE search criteria mentioned previously, our report is the first of its kind to discuss PLE resulting from a non-germ cell tumor, specifically one derived from Sertoli cells. The recommended treatment for PLE involves both oncological and immunomodulating therapies.4 In this report, the patient underwent a radical orchiectomy followed by immunotherapy. His neuropsychiatric disturbances gradually improved following treatment, leading to a near complete recovery and return to baseline in under a year. Previous studies have indicated that early initiation of immunotherapies is particularly crucial in improving long-term outcomes.5,6 In fact, immunomodulating therapies should be promptly initiated once diagnostic criteria for PLE are met, which include subacute changes in neuropsychiatric status, a timeframe of less than 4 years between the development of neurological symptoms and identification of associated tumor, MRI imaging demonstrating features consistent with encephalitis, and exclusion of alternate causes.7,8 The patient described here was originally treated for his neurological symptoms with a 5-day course of steroids at an outside institution before presenting to our ED. This initial steroid regimen as well as postoperative steroid therapy may have contributed to our patient's drastic improvement following tumor resection and subsequent immune-targeting medications. Ultimately, our study reinforces the benefit of the dual treatment approach to PLE as it relates to a non-germ cell testicular tumor.
In nearly 80 % of paraneoplastic encephalitis cases, neurological symptoms predate malignancy identification by weeks to months. The onset of these symptoms tend to be acute or subacute in nature rather than insidious.9 In the case described above, our patient presented with neurological symptoms consistent with PLE – inability to remember family members, headaches, confusion, and agitation – over one month prior to being diagnosed with a Sertoli cell tumor. Neuronal destruction typically progresses at a rapid pace in paraneoplastic neurological syndromes, and delayed treatment increases the risk of irreversible damage.10 As such, symptoms consistent with PLE without an identifiable cause on initial workup should warrant an immediate oncological workup. This may lead to earlier diagnosis of a malignancy and reduce the time to appropriate treatment, ultimately improving outcomes. Through our report, we demonstrate that non-germ cell tumors such as Sertoli cell tumors should be added to the differential when considering potential etiologies of PLE.
The relationship between germ cell testicular tumors and PLE has been well documented, specifically as it pertains to the associated neuronal antibodies.11 Anti-Ma1/Ma2, anti-KLHL11, and anti-NMDA antibodies have all been linked to germ cell tumors in relation to PLE.9,12 PLE resulting from germ cell tumors has also shown to be independent of known antibody markers.3 In this case of PLE associated with a Sertoli cell tumor, the patient's immunological workup did not test for the antibodies traditionally linked to PLE. Moving forward, the relationship between non-germ cell tumor antibodies and PLE should be further investigated. Common antibodies related to Sertoli cell tumors include, but are not limited to, anti-inhibin, anti-Vimentin, anti-cytokeratin, and anti-S10013. As such, patients should undergo complete antibody panel testing to determine any similarities or differences between germ cell and non-germ cell tumors with respect to the development of PLE.
Additionally, it would be interesting to explore whether specific tumors and their accompanying antibodies target distinct regions of the brain in PLE. While temporal lobe involvement is classically associated with PLE, regardless of the type of neoplasm, the case described here also demonstrated significant occipital lobe involvement. Furthermore, though specific neoplasm type and related antibodies have been established as major risk factors for developing PLE, other characteristics, such as baseline cognitive function, have not been well explored.14 While our patient presented with a pre-existing mental disability, mental disability itself has not been identified or specifically investigated as a potential risk factor for the development of PLE. Future research could investigate any potential correlations between tumor type, antibody profile, and the specific regions of the brain impacted in PLE, as well as how cognitive vulnerabilities may influence the development or presentation of the syndrome.
3. Conclusion
Paraneoplastic Limbic Encephalitis is a rare complication of testicular malignancies, historically shown to be associated with germ cell tumors. To our knowledge, this is the first description of PLE resulting from a Sertoli cell tumor, a type of non germ cell tumor. This case demonstrates that early detection and treatment with immunomodulatory and oncologic therapies are effective in addressing the neuropsychiatric symptoms of this condition. Further investigation is needed to examine the relationship between non-germ cell tumors and PLE, specifically the neuronal antibodies that may contribute to this syndrome.
CRediT authorship contribution statement
Dar Yoffe: Writing – original draft, Data curation, Conceptualization. Joseph GR. Paturzo: Writing – original draft, Data curation, Conceptualization. Alexandra Payne: Writing – original draft, Data curation, Conceptualization. Erin Hays: Writing – review & editing, Supervision, Project administration. Michael Markel: Writing – review & editing, Supervision, Project administration. Gaurav Bandi: Writing – review & editing.
Informed consent
Informed consent was obtained from the patient for this publication and any accompanying images.
Funding sources
None.
References
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