PNS are seen in patients with malignant tumors and are exclusive of tumor invasion and metastasis, nutritional and metabolic disturbances, and side effects of antitumor drugs. PNS are stated to be “remote effects of cancer on the nervous system” [2]. Broadly, PNS refer to the remote effects of malignancy on organs and tissues other than the primary tumor site. However, in a narrower sense, the syndromes do not include metabolic conditions, such as hypercalcemia associated with malignancy. Rather, only immune-mediated neurological disorders are included. Among patients with malignant tumors, PNS are more common in those with small cell carcinoma of the lung; the incidence in other solid tumors is much lower than 1%, and it is considered a rare condition [3]. PNS can present with the following neurological manifestations: encephalomyelitis, limbic encephalitis, paraneoplastic cerebellar degeneration, opsoclonus/myoclonus, sensory neuropathy, chronic intestinal pseudo-obstruction, and Lambert–Eaton myasthenic syndrome (LEMS), and are called "classical syndromes" which have a robust association with tumors [4, 5]. In the current case, the patient had muscle weakness and decreased deep tendon reflexes in the lower extremities, suggesting Lambert–Eaton myasthenic syndrome. Lambert–Eaton myasthenic syndrome is often associated with small cell carcinoma of the lung but is also seen in patients with gastric cancer and thymoma [6]. Antibodies against P/Q-type voltage-gated calcium channels (VGCCs) and other voltage-gated calcium channels are common [7]; however, antibodies against synaptotagmin [8], amphiphysin [9], and CRMP-5 [3] have also been reported. These antibodies were not detected in this case.
Approximately two-thirds of patients suspected of having PNS have neurological symptoms, but no diagnosis of cancer [10]. In a review of 10 patients with PNS, Taketa et al. reported that, on average, neurological symptoms were present approximately 6 months before the diagnosis of cancer [11]. If PNS is suspected in such patients, it is necessary to measure PNS-related antibodies and search for cancer. Although the presence of PNS-related antibodies is highly suggestive of the presence of tumors, the positivity rate is less than 1% [12, 13]. Therefore, even if the test is negative, the patient should be retested at 3 and 6 months. In addition, the European Federation of Neurological Societies (EFNS) Task Force recommends periodic searches every 6 months for 4 years [14]. When a patient diagnosed with cancer develops neurological symptoms, the diagnosis of PNS is made after ruling out metastasis to the central nervous system via imaging and CSF studies. There are three main groups of PNS-associated antibodies: "well-characterized onconeural antibodies," such as anti-Hu and anti-Yo antibodies, in which neurological symptoms are strongly considered paraneoplastic and are strongly associated with certain cancers; a group that is not necessarily associated with the presence of cancer; and a group known as "partially-characterized onconeural antibodies," in which significance as markers of PNS has been confirmed, although the characteristics of the corresponding antigen are not precise [4]. In the current case, neurological symptoms preceded the disease. However, anemia was also observed in blood tests, which led to upper gastrointestinal endoscopy and early diagnosis. Although specific antibodies were negative, metastasis to the central nervous system was ruled out, leading to an early diagnosis of PNS.
The EFNS Task Force considers the search for and treatment of malignancy, immunosuppression, and symptom control as the mainstays of therapy [14]. Resection of malignant tumors is the most effective treatment to control the progression of neurological symptoms and, in particular, to restore function [10, 15, 16]. Immunosuppressive treatment includes plasma exchange and large doses of immunoglobulins, corticosteroids, rituximab, and tacrolimus [17]. PNS often lead to irreversible neurological damage by the time of therapeutic intervention, and the treatment prognosis is generally poor. In several reports, PNS have been caused by gastric cancer, including our case (Table 1). Taketa et al. [10] reported the following characteristics of gastric cancer associated with PNS: first, approximately half of the cases are neuroendocrine tumors (NET) or undifferentiated carcinomas, such as signet ring cell carcinoma derived from neuroendocrine tumors. In the present case, postoperative pathological examination revealed the presence of poorly differentiated adenocarcinoma, which is consistent with previous reports. Second, although NET is usually considered to have a poor prognosis, when accompanied by PNS, the prognosis is relatively good, with an excellent response to treatment. This is due to the expression of major histocompatibility complex (MHC) class 1 and non-amplification of the myc gene. To date, the current case is under observation without recurrence. The third point is that it takes an average time of 5.8 months from the onset of symptoms to diagnosis. However, in the present case, gastric cancer was diagnosed within approximately 1 month from the onset of symptoms, and we were able to intervene early with treatment. In addition to surgical intervention, there are many reports of patients being treated with chemotherapy and immunosuppressive agents that have shown therapeutic efficacy. However, although there are few case reports of complete response, in the current case, early diagnosis and resection of the primary lesion, followed by prompt introduction of immunosuppressive agents, may have contributed to the disappearance of neurological symptoms. Conversely, considering approximately 2 years of oral immunosuppressive medication was necessary to achieve complete resolution of symptoms, the importance of early diagnosis is apparent. When PNS is suspected, early diagnosis, early surgery, and immunosuppressive therapy are considered necessary.
