Brain metastases from gastric cancer are very rare and have been reported in less than 1% of cases. York and coworkers identified only 24 brain metastasis patients (0.7%) of the 3320 gastric cancer patients treated at MD Anderson Cancer Center 1957–1997 [59]. There was a greater incidence of brain metastases from primary tumors originating in the proximal stomach, and all 24 patients had concurrent systemic metastatic disease (most commonly bone, liver, and lung). Mean interval from gastrectomy to the diagnosis of brain metastasis was 9 months. Median survival was only 2.4 months.

Kasakura et al. [60] reported brain metastasis in only 11 of 2322 (0.47%) of Japanese patients treated between 1980 and 1998. They noted median survival of 24 weeks in patients who had surgical resection, compared with 10.8 weeks with WBRT and 54 weeks for those who had both surgery and WBRT.

Oh and colleagues reported 54 cases of cytologically confirmed leptomeningeal metastasis from gastric adenocarcinoma at four institutions in Korea from 1994 to 2007 [61]. The most common presenting symptoms were headache and nausea or vomiting. Opening pressure on lumbar puncture was elevated in 29 patients (58%), and MRI demonstrated leptomeningeal enhancement in 45 (82%). The median interval from diagnosis of the primary gastric cancer to the diagnosis of leptomeningeal disease was 6.3 months. Thirty-six patients received intrathecal chemotherapy with methotrexate alone or in combination with hydrocortisone or cytarabine. Twenty of these patients also received chemotherapy or radiation. Median overall survival was dismal at 6.7 weeks, and only conversion to negative cytology was predictive of relatively longer survival duration (14.6 weeks) on multivariate analysis. Other smaller series similarly suggest extremely poor prognosis as well as a possible modest benefit of intrathecal treatment [50, 62–66]. Leptomeningeal metastasis has also been reported as the presenting manifestation of gastric malignancy in several cases [67–71].

Two patients with gastric adenocarcinoma were reported to have paraneoplastic cerebellar degeneration associated with anti-Yo antibody; titers dropped in one patient after resection of the tumor [72, 73]. Another patient with paraneoplastic cerebellar degeneration due to anti-Ri antibody had a mixed tumor of neuroendocrine (reactive part of tumor) and adenocarcinoma [74]. Other cases include a sensorimotor neuropathy and encephalopathy with an antibody to alpha-enolase [75], peripheral neuropathy with arteritis of the sciatic nerve [76], and opsoclonus–myoclonus syndrome [77].

Earlier retrospective studies have reported an incidence of brain metastases in 0.2–2.2% of HCC patients [80–83]. However, a more recent review by Shao and colleagues identified brain metastases in 11 (7%) of 158 advanced HCC cases [84], which may be related to improved survival in the setting of new molecular targeted agents such as sorafenib. Median overall survival was poor at 4.6 months. Lim and colleagues reviewed 118 patients with HCC-brain metastases to develop an HCC-specific graded prognostic assessment (GPA) [85]. Patients with a single brain metastasis, Child–Pugh grade of A, and AFP less than 400 had the best prognosis with a median survival of 27 weeks. Sixty-five (55.1%) had associated brain hemorrhage and 101 (85.6%) had extracranial metastases. Studies suggest that treatment with surgery or radiation does improve survival [86]. Xu et al. [87] reported a median survival time of 5.0 months in 14 patients treated with gamma knife radiosurgery. However, Han et al. [88] noted better survival with surgical resection (with or without WBRT) compared to patients who received just stereotactic radiosurgery and or WBRT on analysis of 33 HCC-brain metastasis cases.

Leptomeningeal disease with HCC is rare. One woman with HCC and headaches, hoarseness, dysphagia, and vomiting was diagnosed with leptomeningeal metastasis by CSF cytology in the setting of concomitant systemic and parenchymal brain metastases [89]. Her symptoms improved with intrathecal methotrexate and WBRT, but she passed away four months after diagnosis.

Several patients with demyelinating neuropathy have been reported [90–93]. In addition, there have been cases of motor neuronopathy, polymyositis, and cancer-associated retinopathy [94–97].

Large series have described the incidence of brain metastasis to be less than 0.5% of gallbladder cancer patients [99]. Few cases of brain metastasis in gallbladder cancer or cholangiocarcinoma have been reported [100–102].

Although generally more rare than BM, several cases of leptomeningeal metastasis have been published. One patient with gallbladder cancer presented with psychosis [103], while others presented with headaches and cranial neuropathies [104, 105] and a meningitic picture [106]. Two patients with cholangiocarcinoma and LM have been described [107, 108].

One case of Guillain–Barré syndrome that may have been paraneoplastic has been described in association with gallbladder cancer; patients with polymyositis and opsoclonus have also been reported [109–111]. Another patient was diagnosed with an anti-Hu paraneoplastic sensory neuropathy related to small cell carcinoma of the gallbladder [112].

Pancreatic metastases to the brain are very rare (reported incidence of 0.33–0.57%) potentially related to poor overall survival [20, 115]. Kumar et al. [116] reported eight cases of CNS involvement with pancreatic adenocarcinoma at Johns Hopkins between 2004 and 2012. Six of the eight had other systemic metastases, and median time to diagnosis of brain metastasis was 29 months. Lemke et al. [117] retrospectively analyzed 12 patients with pancreatic cancer brain metastases reported in the literature. They identified two patients who underwent pancreatectomy with curative intent who developed solitary brain metastases (one 11 months and the other 6 years after initial diagnosis). These were surgically resected with subsequent extended survival (5 years and 4 years from diagnosis of the brain metastasis, respectively).

As with brain metastases, leptomeningeal disease from pancreatic cancer is exceedingly rare. Several cases have been reported with poor survival [50, 118–121].

One patient with encephalomyelitis was found to have anti-GAD antibodies and another with small cell pancreatic cancer who presented with PCD and later polyneuropathy had anti-Hu antibodies [122, 123].

Intravenous fluorouracil (5-FU) can rarely be associated with acute and chronic neurotoxicities. The acute toxicities have two clinical presentations: the acute cerebellar syndrome characterized by ataxia, confusion, drowsiness, disorientation, euphoria, headache, nystagmus, and visual disturbances or an encephalopathy with the notable biochemical changes: hyperammonemia and lactic acidosis [14]. These toxicities usually develop shortly after therapy and persist for 48–72 h after therapy has stopped. Dihydropyrimidine dehydrogenase (DPD), which is necessary in clearing 5-FU, is deficient in 2.4% of cancer patients; its absence has been linked to an increase in neurotoxicity [127].

In early studies combining levamisole and 5-FU in the treatment of metastatic colorectal cancer, some patients developed a subacute multifocal leukoencephalopathy manifested as cognitive abnormalities, disturbances of consciousness, dysarthria, focal extremity weakness, and gait and limb ataxia 3–5 months post-therapy [128, 129]. Brain MRI revealed multifocal enhancing white matter lesions, which were both supra and infratentorial. Discontinuation of levamisole generally results in improvement.

Other reported side effects include ophthalmoplegia, optic neuropathy, encephalopathy, focal dystonias, and parkinsonism [28].

Bevacizumab is a monoclonal antibody against VEGF. It has been associated with reversible posterior leukoencephalopathy syndrome (RPLS) , which may present with varied neurologic symptoms including headaches, seizures, lethargy, confusion, blindness, or other visual disturbances. Hypertension may precede the symptoms but is not necessary for diagnosis. Magnetic resonance imaging is used to confirm the diagnosis based on characteristic findings. The incidence is less than 0.1% [130]. Bevacizumab increases the risk of arterial thromboembolic events including stroke, transient ischemic attacks, and myocardial infarctions. Although less common than venous thrombotic disease in general, the morbidity associated with arterial events can be quite significant. The bevacizumab study AVF2107 g reported 13 (3.3%) events compared to 5 (1.3%) when treated with and without bevacizumab [131]. Similarly, AVF2192 g reported an absolute doubling of the rate of arterial thrombotic events when bevacizumab was used (10 vs. 4.8%). Of note, the study population had median age of 70 years [87]. In practice, clinicians must exercise caution in prescribing bevacizumab for patients with risk factors for or with known vascular disease. Intratumoral bleeding is another side effect that may occur in tumors; for intracranial tumors, this could be fatal.

Oxaliplatin is a third-generation platinum compound that causes acute and chronic peripheral neuropathies. The acute neurotoxicity may occur during, shortly after, or 1–2 days postinfusion of the drug and is associated with paresthesias, hypesthesias, and dysesthesias. These usually begin in the hands or feet, but may occur around the mouth or in the throat as well. Acute side effects occur at a dose of about 130 mg/m² [132]. Patients may also have a sense of dyspnea or dysphagia without bronchospasm, wheezing, stridor, or laryngospasm. Patients have described an unusual sensation in the tongue, jaw spasms, eye pain, and muscle spasms or cramps, which are sometimes described as stiffness in the hands or feet or an inability to release grip. Cold temperature may exacerbate symptoms, and patients are educated to avoid cold drinks, wear gloves when handling refrigerated items, and avoid inhaling cold air. Symptoms usually last only a few days post-therapy [133].

One suggestion for the mechanism by which oxaliplatin causes an acute neurotoxicity has been coined “channelopathy.” Oxaliplatin has been shown to be associated with the prolonged opening of sodium-gated channels on peripheral nerves that leads to hyperexcitability [134–136]. Whether this is a direct effect or not is unclear but may be related to the sequestration of calcium by the oxaliplatin–oxalate metabolite.

There are little published data on how to prevent and treat the acute neurotoxicity associated with oxaliplatin. Using a lower dose or increasing the infusion time has been thought to lessen the occurrence of these symptoms [137]. Administering calcium and magnesium salts like calcium gluconate and magnesium chloride has reportedly decreased the occurrence of pharyngolaryngeal dysesthesia (1.6 vs. 26%) [132, 138], although subsequent studies did not confirm this. Amifostine has also been studied as a preventative measure in reducing acute oxaliplatin-induced neuropathy. Patients receiving oxaliplatin, 5-FU, and leucovorin (a common first- or second-line therapy for metastatic colon cancer) in addition to amifostine reported less cold-induced sensitivity. However, there are significant toxicities associated with the administration of intravenous amifostine including hypotension, nausea, and vomiting that may limit its practical use; therefore, a subcutaneous preparation is recommended [139].

Symptoms associated with a more prolonged administration of oxaliplatin (total doses of ≥540–850 mg/m²) include paresthesia, hypesthesia, dysesthesia, and changes in proprioception that do not resolve between cycles. Proprioceptive dysfunction may present with difficulties in fine motor coordination required for writing, holding objects, picking up coins, and buttoning shirts. The chronic neuropathy is cumulative with a reported incidence of grade 3 toxicity occurring in 10% after nine cycles and in roughly 50% after 12–14 cycles (based on oxaliplatin doses of 85 mg/m² infused over 2 h every 14 days) [140, 141]. Lhermitte’s phenomenon, an electric sensation experienced with neck flexion, has also been reported as a manifestation of chronic oxaliplatin-induced neuropathy [142]. Other central neuropathic symptoms such as urinary retention have also been reported less commonly. Symptoms usually last months with most resolving completely or to grade 1–2 toxicity within 12 months [143]. Rare symptoms include optic neuritis and visual field deficits [144].

Preventive strategies such as those outlined above (e.g., longer infusion time) have some reported efficacy in helping to prevent or at least minimize the chronic neuropathic effects of oxaliplatin. Gabapentin has also been shown to reduce the acute neuropathic toxicity but also prevents the chronic form as well.

Capecitabine is a prodrug metabolized to 5-FU by thymidine phosphorylase. Neurologic toxicity is rare and limited to one case of peripheral neuropathy and several cases of encephalopathy. The latter is different from that seen with 5-FU/levamisole, as this is a reversible process with diffusion-restricted changes that do not enhance on brain MRI. This process starts earlier than that of 5-FU/levamisole [145, 146]. Capecitabine can cause an erythpalmar dysesthia that may mimic symptoms of neuropathy or give a sense that an underlying neuropathy is worsening.

Gemcitabine is a deoxycytidine analogue with minimal CNS effects. About 1% of patients complain of mild paresthesias and rare autonomic neuropathy is reported [147]. It may increase neurotoxicity when given after WBRT [148].

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies. Neither carries significant neurologic toxicity, but both have been noted to cause headache in recent trials with metastatic colorectal cancer [149].