My name is Ariane Lewis. I'm the Director of Neurocritical Care at NYU Langone Medical Center in New York. I'm going to be speaking about neuro-oncology. I have no disclosures. During this talk, we'll improve knowledge about the epidemiology, imaging findings, and treatment options for primary brain tumors and brain metastases, review the etiologies for spinal cord tumors, review the diagnosis and treatment of carcinomatous meningitis, review paraneoplastic syndromes, assess complications of radiation therapy, and finally, assess complications of chemotherapy. The first primary brain tumor that we'll be speaking about is the meningioma. Here you can see three different scans which show meningiomas in different locations. The meningioma is a homogeneously enhancing lesion. It's dural based. You can see that this can be infertentorial or supertentorial and that in some cases you can see bifrontal lesions which cause brain compression. Meningiomas can occur in a wide range of different locations throughout the brain including the cerebral hemispheres, the optic nerve sheath, the cavernous sinus, the nasal cavity, spinal cord, cerebellal pontine angle, the ventricles, and the pituitary gland. Thus, there's a wide range of differential diagnoses in each of these locations for lesions and in some cases it's not obvious that the lesion is a meningioma until pathology is obtained. They can be confused for other primary brain tumors or metastatic brain tumors. In some cases, they can appear similar to inflammation or demyelination or infection. Meningioma is the most common primary brain tumor in adults and comprises one-third of intracranial neoplasms. They're more common in women than in men at a ratio of three to one. The incidence increases in age with a median age of diagnosis of 65 years. Meningiomas are composed of arachnoid cells. They can be seen in syndromic presentations, particularly NF2 and Cowden syndrome, but also Gorlin syndrome. Patients with meningiomas present with headaches, seizure, or focal deficits. In some cases, they have genetic mutations on 22q12. In terms of pathology, patients can have a whorl formation or somoma bodies. The natural history of meningioma is very good, as this is a benign lesion. The five-year survival is greater than 80% for patients who have WHO grade one meningiomas. Meningiomas are usually treated with surgery. However, in some cases, they can be monitored on serial imaging. Additional treatment can include radiation in the setting of anaplastic, atypical, recurrent, or surgically inaccessible meningiomas, or in some cases, VEGF inhibitors are considered. Second type of primary brain tumor, which we'll be speaking about, is glioma. Here you can see that there are a number of different presentations of glioma. You can see a butterfly glioma that impacts the corpus callosum. You also can see supertentorial and infertentorial presentations of gliomas, and in some cases, gliomas present at multiple foci. Like meningiomas, gliomas present with headaches, seizures, and focal deficits. These lesions are composed of astrocytes and or oligodendrocytes. Higher grade lesions, glioblastoma multiforme, present with atypia, hypercellularity, increased mitotic rate, increased vascularity, and necrosis in their lesions. The IDH mutant type tumors have a better prognosis than the IDH wild type type tumors. MGMT promoter methylation is also associated with a better prognosis, as is younger age and lower grade. In terms of treatment, patients can be treated with surgery, radiation, and temozolomide, but a wide range of other types of chemotherapy have been used in trials to assess improvement for patients with gliomas. The third type of primary brain tumor is primary CNS lymphoma. As you can see on these imaging studies here, CNS lymphoma can appear in a wide range of different presentations on imaging. Like gliomas, it can impact the corpus callosum, but you can also see periventricular lesions, and you can see lesions that are further out in the brain. These lesions present with changes often on diffusion-weighted imaging, and there can be patchy enhancement on post-contrast imaging as well. Primary CNS lymphoma is responsible for four percent of newly diagnosed brain tumors. The incidence increases with age, with a median age of diagnosis in the 60s to 70s. CNS lymphoma can present in patients who are immunocompromised, as well as those who are immunocompetent. The clinical history of presentation prior to primary CNS lymphoma diagnosis includes neurocognitive or neuropsychiatric symptoms, focal deficits, and headaches. While the final diagnosis of primary CNS lymphoma can be made by biopsying a lesion, additional testing should be performed prior to proceeding with biopsy. A lumbar puncture should be performed to assess for cytology and flow cytometry. Ophthalmology should perform a slit lamp evaluation to look to see if there's evidence of lymphoma in the eye. A PET scan, testicular ultrasound, and bone marrow biopsy can assess for lymphoma in other systemic sites. It's important to be aware that steroids can obscure the diagnosis of primary CNS lymphoma. As a result, if primary CNS lymphoma is in the differential diagnosis, steroids should be avoided unless there is a high degree of brain edema or brain compression, which appears to be life-threatening. In terms of the natural history of primary CNS lymphoma, the five-year survival is 30 to 70 percent depending on the subtype. Treatment for primary CNS lymphoma includes methotrexate, chemotherapy, and consideration of autologous stem cell treatment. Here we have a 50-year-old woman with a recently diagnosed bifrontal GBM whose two-week status post debulking of the left frontal tumor and now comes in with two days of acute on subacute progression of aphasia, lethargy, and right-sided weakness. On this MRI, we see that she has had recurrence and growth of the left frontal lesion despite her debulking, and we also see evidence of the right frontal lesion, which had not been addressed previously. This scan shows us that there's concern for edema, brain compression, and progression of disease. As a result, in order to deal with the edema, we wish to increase her dose of steroids and start her on some hypertonic saline to be able to decrease intracranial pressure. One could consider surgery again here, but it's obvious that she had progression of disease in a very short period of time such that it's not beneficial to proceed with surgery in this setting. Additionally, she could begin with whole-brain radiation and plan for future chemotherapy, but it's also important to have a goals of care discussion here given the fact that her tumor progressed in just a few weeks. Lastly, one can't rule out seizures as contributing to her aphasia, so it's important to do an EEG to rule out seizures. Next, we move on to talk about metastatic brain tumors. Here, we can see that we have three different types of presentations of metastatic brain tumors. Metastatic brain tumors can occur in isolation or can occur with numerous METs at the same time. Metastatic brain tumors are 10 times more common than primary brain tumors. Any systemic tumor can metastasize to the brain, but the ones that most commonly go to the brain include breast cancer, lung cancer, and melanoma. 30% of adults with cancer develop metastatic brain tumors. These patients present with seizures, focal deficits, and headaches. Metastatic brain tumors are located at the gray-white junction. In terms of treatment, one could consider surgery if there's a dominant symptomatic lesion or if there's up to three brain metastases. Radiation is another therapy that could be employed for metastatic brain tumors, and if there are multiple lesions, whole-brain radiation should be considered rather than focal radiation. Steroids can address brain edema in the setting of metastatic brain tumors. In terms of chemotherapy, consideration of agents which have CNS penetration is important. Here, you can see a number of different agents which are described which can have CNS penetration for systemic tumors such as methotrexate, thiotopa, and temozolomide. Immunotherapy can also be considered for these patients. Patients who have brain tumors are at risk for seizures, so it's necessary to consider if the patient needs to be on an antiepileptic agent. However, it's important to be aware that patients who are on chemotherapy should not be on enzyme-inducing antiepileptic agents. So levotriacetam, leucosamide, and zonisamide are the appropriate agents for seizure treatment in this patient population. In terms of the natural history, patients who have metastatic brain tumors have a mean survival of four to six months, with a better survival in younger patients who have good functional status and patients who have solitary metastases. The risk of local recurrence post-resection is 50%. There are three different locations that spinal cord tumors can occur, intradural extramedullary, intradural intramedullary, and extradural tumors. Intradural extramedullary tumors include meningioma and nerve sheath tumors. Intradural intramedullary tumors include ependymoma and astrocytoma. Extradural tumors include metastases, chordoma, Ewing sarcoma or osteosarcoma, and lymphoma. Spinal cord tumors can cause cord compression and lead to myelopathy. In terms of the types of spinal cord tumors, they're both benign and malignant lesions. Benign spinal cord tumors include meningiomas and nerve sheath tumors such as schwannoma, neurofibroma, ganglioneuroma. This is the most common intradural extramedullary lesion. Malignant spinal cord tumors include gliomas. Ependymoma is more common than astrocytoma, and this comprises most of the intramedullary lesions. Spinal column tumors are also another type of spinal tumor. There can be both benign or malignant spinal column tumors. Benign lesions include hemangiomas, osteoid osteoma, and osteoblastoma, whereas malignant lesions include chordoma, chondrosarcoma, Ewing sarcoma, lymphoma, or metastasis, which is the most common spinal cord tumor. When thinking about how to manage spinal cord tumors, it's important to identify whether or not there are neurologic deficits and subsequently to identify whether or not it is appropriate for the lesion to be treated with radiation or with chemotherapy, depending upon whether the lesion would be resistant to this type of therapy. Carcinomatous meningitis can present on imaging or can be found on lumbar puncture. Here you can see three different presentations of carcinomatous meningitis. In the first image here, we can see dural enhancement. In the second image here, we can see that there is enhancement within the meninges in the posterior fossa. And in the third image here, we can see that there is enhancement around the brainstem. Patients with carcinomatous meningitis have cranial or radicular nerve deficits, change in mental status, or headache. The diagnosis of carcinomatous meningitis can be made by CSF or neuroimaging. In terms of CSF, the sensitivity is poor. As a result, it can be necessary to conduct three lumbar punctures before the diagnosis is made or before carcinomatous meningitis is effectively ruled out. An MRI brain and an MRI total spine, with and without contrast, can also be used to make the diagnosis of carcinomatous meningitis. The imaging of the brain in the setting of carcinomatous meningitis shows linear enhancing deposits in the cerebellar folia, the cortical sulci, or along the cranial nerves. And on the spine, you can see nodular enhancement of the cauda equina or coating of the spinal cord. Patients with carcinomatous meningitis have a mean survival of less than six months. This can be treated using whole-brain radiation therapy or craniospinal radiation in order to be able to ameliorate symptoms and to try and prolong survival for a brief period. Systemic chemotherapy with agents that have good CNS penetration can also be utilized. In some cases, intrathecal chemotherapy is utilized, and patients have an OMAYA placed in order to be able to deliver that intrathecal chemotherapy, or these agents can be introduced with serial lumbar punctures. Some patients develop hydrocephalus secondary to carcinomatous meningitis and require a palliative shunt. Here we have a 40-year-old woman with a history of breast cancer who presented with left face numbness and was found to have leptomeningeal disease. After whole-brain radiation was initiated, she became somnolent. We can see on the MRI here that she's got significant evidence of carcinomatous meningitis in her cerebellar folia. While her initial presentation just involved left face numbness, and you can see that there's evidence of enhancement at the fifth cranial nerve on the left side, the disease was obviously much more extensive than that. When radiation began, she had increased swelling and brainstem compression, which is what led to her change in mental status. Steroids, hypertonic saline, and mannitol were initiated in order to address the edema and brainstem compression. While suboccipital craniotomy and EBD were considered to address the increase in intracranial pressure, these were not offered on account of the fact that this would not affect her underlying disease. Radiation was continued, and intrathecal chemotherapy and systemic chemotherapy were considered, but not given at this point in time. Goals of care discussion was also conducted as, of course, she had had significant advancement in her disease here and was at high risk for progression of herniation and death. We now transition to talking about perineoplastic syndromes. There are a number of different types of perineoplastic syndromes, including limbic encephalitis, encephalomyelitis, perineoplastic syndromes that affect the basal ganglia or movement disorders, such as opsochlonous or myoclonus, perineoplastic syndromes that affect the cerebellum, including progressive cerebellar degeneration. There are also perineoplastic syndromes that can affect the spinal cord, such as stiff person syndrome. The peripheral nervous system also can be involved by perineoplastic syndromes, leading to a sensory neuronopathy. Neuromuscular junction also can be involved, leading to myasthenia or Lambert-Eaton. Muscle can be involved in perineoplastic syndrome, as patients can present with dermatomyositis, and the visual system can be involved, leading to a cancer-associated retinopathy. There are a number of different antibodies, which are responsible for perineoplastic syndromes. These antibodies can be to the cell surface or synaptic antigens, or antibodies to intracellular antigens. Here you can see a list of a variety of different antibodies and the clinical clues, which can allow you to identify the type of antibody that may be associated with the given patient's presentation. Sending off a perineoplastic panel from the serum and the CSF allows for identification of an antibody. However, it's important to be aware that we are constantly identifying new antibodies for perineoplastic syndromes, and so in some cases, patients have a presentation which clearly appears consistent with a perineoplastic syndrome, but no antibody is identified. This does not rule out a perineoplastic syndrome as being responsible for the patient's presentation. Some pitfalls and principles to consider when dealing with perineoplastic syndromes. First, it's important to perform antibody testing before initiating immunosuppressive treatments, as treatments could lead to a false negative diagnosis. Second, testing serum and CSF for neural autoantibodies is optimal, particularly when suspicion is high. Sending a panel of antibodies is particularly optimal, as this allows for an assessment of multiple different types of antibodies rather than just a singular antibody. Confirmation of antibody positivity using two separate assay techniques is beneficial and yields higher specificity. If commercial testing is negative, then as I mentioned, one could consider sending to a research lab to assess for antibodies not commercially available or for which the antigen has yet to be determined. In terms of pitfalls, it's important to be aware that older techniques can sometimes yield positive results in a proportion of healthy controls, but with newer techniques, this is much lower. Serial testing for neural antibodies and following titers is not useful, and so follow-up treatment decisions should be made based on clinical status rather than serologic status. And as I mentioned, a negative antibody result does not exclude a perineoplastic neurologic disorder, and screening for cancer in suspicious cases when antibody testing is negative is still appropriate. So it's important to be aware that while a perineoplastic syndrome can be diagnosed in a patient who has known cancer, sometimes a perineoplastic syndrome is the first presentation of cancer. In terms of treatment for perineoplastic syndromes, first, as I mentioned, you want to identify and treat any underlying cancer. Second, initiation of steroids using methylprednisolone one gram daily for five days followed by a taper is appropriate. IVIG or plasmapheresis can be considered. And then as a last line intervention, one could consider rituximab and or cyclophosphone. Patients with cancer often are treated with radiation, and there's a number of different complications of radiation therapy which affects the nervous system. Acute complications which occur days to weeks after radiation include presentation of altered mental status, fatigue, and worsening of preexisting neurologic deficits, which can be treated with steroids. The mechanism behind this is the development of cerebral edema, neuroinflammation, vascular toxicity, or transient disruption of the blood-brain barrier. In terms of the prognosis associated with these types of complications, symptoms usually resolve after treatment with steroids. The second type of complication after radiation therapy is early delayed complications. This occurs between weeks and six months after radiation. Patients can present with cognitive symptoms, fatigue, headache, nausea, and lethargy. The mechanism that is proposed for this is transient demyelination. And the third type of complication that can occur after treatment with radiation therapy is the late delayed type of complication. This occurs between months and years after radiation. These symptoms can include cognitive decline, which is developed in 80% of patients after whole brain radiation therapy, and in some cases there can be focal findings. The radiographical and pathological findings associated with late delayed radiation therapy complications include leukoencephalopathy, which can be present in 5 to 30% of cases, tissue necrosis, which could actually mimic tumor recurrence, and this presents in 5 to 50% of cases. There can be atrophy of the brain, secondary tumors such as a meningioma, and also vasculopathy, which can lead to ischemia or hemorrhage. The mechanisms behind this is direct cytotoxic effects on various neural cells and their progenitors, but also chronic inflammation and neurovascular injury. Treatments for this type of complication includes neurostimulants, and in some cases a shunt can be beneficial. Here we have a 60-year-old woman with a history of breast cancer complicated by intraparenchymal and leptomeningeal metastasis who came in with encephalopathy, headache, and nausea two days after completing craniospinal radiotherapy. Her labs were notable for hyponatremia with a sodium of 124, mild leukocytosis with a white count of 11, and thrombocytopenia with platelet count of 88. She also had a respiratory acidosis with a pH of 7.24 and a PaCO2 of 73. She was started on noninvasive mechanical ventilation, 3% hypertonic saline, and an increased dose of levotriazetam out of concern for seizures. Also, her dexamethasone dose was increased due to concern for brain edema, and she was put on empiric broad-spectrum meningoencephalitis coverage with vancomycin, cefepime, and acyclovir. She was hooked up to EEG, which demonstrated right frontotemporal intermittent rhythmic delta activity, which was initially attributed to her prior metastasis, but she had no evidence of subclinical seizures. A brain MRI was performed and demonstrated new diffusion restriction in the right insula. She also had a lumbar puncture, which showed that she had a slightly elevated pressure, and she also had a red blood cell count of seven, a white blood cell count of four, a protein of 114, and a glucose of 71. Her meningoencephalitis panel was positive for HSV1. Here, you can see the area of hyperintensity on her diffusion-weighted imaging in the right insula, and on her EEG, you can see that there's evidence of abnormality on the right side in comparison to the left side. A key takeaway here is that HSV encephalitis has a higher incidence in cancer patients undergoing whole-brain radiation than in the general population. Four out of 1,000 patients who have cancer and undergoing whole-brain radiation in comparison to two to four out of one million patients in the general population. So HSV encephalitis should always be considered in patients with cancer who are undergoing radiation and present with encephalopathy, and these patients should be treated empirically. Chemotherapy can have a number of different toxic effects on the central nervous system, including acute encephalopathy, subacute encephalopathy, chronic encephalopathy, PRESS, multifocal leukoencephalopathy, thrombotic microandriopathy, strokes, cortical blindness, optic neuropathy, other visual disturbances, pseudotumor, cerebral venous sinus thrombosis, cerebellar dysfunction, seizures, and aseptic meningitis. When evaluating a patient with cancer who's been receiving chemotherapy for new-onset neurologic symptoms, it's important to review their chemotherapy history and become aware of the different side effects associated with these agents, as chemotherapy itself could be responsible for the patient's symptoms rather than a neurologic manifestation of the cancer. Chemotherapy can also cause toxic effects on the peripheral nervous system. The agents most commonly associated with that include platinum compounds, vinca alkaloids, taxanes, bortezomib, thalidomide, and suramin. Here we have a 50-year-old man with systemic lymphoma being treated with CAR T-cell therapy, who presents with fever, encephalopathy, and aphasia. His inflammatory markers are elevated. His MRI brain is normal, but his EEG shows evidence of statics epilepticus. In addition to initiation of anti-epileptics, he's treated with hydosteroids, which led to gradual improvement. It's important to be aware that CAR T-cell therapy can lead to a cytokine release syndrome, similar to what we've seen in many patients with severe COVID-19 infection. This inflammation can develop three to 10 days after administration of CAR T-cell therapy. Patients can develop neurosymptoms ranging from encephalopathy, behavioral changes, headaches, tremors, seizures, and even coma. Patients can also develop cerebral edema. Steroids and supportive care are the only treatment for this presentation. It's important to be aware that tocolizumab can improve cytokine release syndrome, but it's not going to impact the neurotoxicity. Key takeaways associated with this presentation on neuro-oncology is that cancer can directly or indirectly impact any part of the nervous system. A thorough history of chemotherapy, radiation treatment needs to be obtained when evaluating a patient with cancer who has neurological signs and symptoms, as chemotherapy and radiation can have complications that lead to neurologic signs and symptoms. It should not be assumed that neurological signs and symptoms in patients with cancer are the result of progression of disease, but this should always be in the differential diagnosis. Unless CNS lymphoma is on the differential, empiric treatment with steroids should be considered in patients with cancer who have neurological signs and symptoms. Lastly, goals of care discussions and involvement of palliative care should be considered in patients with cancer who have neurological signs and symptoms. Thank you very much.

neuro-oncology

primary brain tumors

radiation therapy complications

chemotherapy toxicities

new-onset neurological symptoms

palliative care