Classification of glioblastoma

• i.
  

  Microvascular proliferation and pseudopalisading necrosis are pathologic hallmarks of glioblastoma (GBM) and, when present, establish the diagnosis of GBM.

  
  
• ii.
  

  IDH1/2 gene mutation is rare in GBM; EGFR amplification and MGMT promoter methylation are observed in approximately 40% of GBMs.

Classification of low-grade oligodendroglioma

• i.
  

  When molecular profiling of a brain tumor reveals the presence of 1p/19q co-deletion and IDH1/2 mutation, a diagnosis of oligodendroglioma is made.

  
  
• ii.
  

  Histologically, oligodendrogliomas are characterized by the presence of round nuclei and perinuclear halo that has a “fried egg” appearance.

  
  
• iii.
  

  Grading of oligodendrogliomas is restricted to grade II and III tumors; there is no grade I or IV oligodendroglioma; oligodendrogliomas with necrosis and microvascular proliferation are grade III.

Classification of low-grade astrocytoma

• i.
  

  Grade I gliomas are generally well circumscribed, whereas grades II–IV are diffusely infiltrating.

  
  
• ii.
  

  Low-grade diffusely infiltrating gliomas that lack co-deletion of chromosomes 1p and 19q are molecularly defined as astrocytomas.

  
  
• iii.
  

  While IDH1/2 gene mutation is common in low-grade diffuse astrocytomas, this is not a molecularly defining event and IDH wild-type low-grade diffuse astrocytomas also occur.

  
  
• iv.
  

  Low-grade gliomas (LGGs) can progress to higher-grade neoplasms and, when they recur as GBM, are considered “secondary” GBMs.

Classification of anaplastic astrocytoma

• i.
  

  The presence of mitoses (a marker of cell division) in a diffuse glioma warrants upgrading to an anaplastic glioma (grade III).

  
  
• ii.
  

  The presence of chromosome 10q loss combined with polysomy of chromosome 7 favors a molecular diagnosis of a higher-grade glioma.

Classification of meningioma

• i.
  

  Meningiomas are the most common primary brain tumor and appear as dural-based lesions often with an area of adjacent thickened dura, termed a dural “tail.”

  
  
• ii.
  

  Up to 95% of meningiomas are benign WHO grade I lesions, but rarely grade II and grade III tumors can present and require additional treatment.

Surgical management of posterior fossa lesions and increased intracranial pressure

• i.
  

  Clinicians must be aware of symptoms of increased intracranial pressure (ICP) including early morning headache, unexplained nausea, vision changes, bilateral cranial nerve VI palsies, and papilledema.

  
  
• ii.
  

  Obstructive hydrocephalus from a posterior fossa mass requires urgent or emergent surgical evaluation for resection or ventricular decompression.

  
  
• iii.
  

  Children with posterior fossa pilocytic astrocytomas generally have excellent outcomes, particularly when gross total resection (GTR) is achieved.

Surgical management of resectable brain lesions

• i.
  

  Gross or near GTR with >90% of tumor resected is consistently associated with improved outcomes in uncontrolled studies of glioma.

  
  
• ii.
  

  In general, surgery plays three roles in the management of glioma patients including: (1) tissue diagnosis, (2) cytoreduction of tumor, and (3) symptom relief from cerebral edema.

Surgical management of unresectable brain lesions

• i.
  

  Tumors in deep locations, adjacent to eloquent structures, or crossing the midline may not be amenable to open resection.

  
  
• ii.
  

  In selected cases, laser interstitial thermal therapy (LITT) is a surgical option for tissue ablation and can be performed at the time of tissue biopsy.

Surgical management of spinal cord lesions

• i.
  

  GTR is consistently associated with improved outcomes for patients with ependymoma and should be pursued aggressively.

  
  
• ii.
  

  Extramedullary tumors such as metastases, meningiomas, and schwannomas carry a different surgical risk from intramedullary lesions such as astrocytomas or ependymomas.

Surgical management of brain metastasis

• i.
  

  When evaluating a patient with a known cancer diagnosis and multiple brain lesions, surgery may be beneficial when there is a single, large (>3 cm) lesion with symptomatic cerebral edema.

Surgical management of meningioma

• i.
  

  For meningiomas that cannot be observed, surgical resection should be considered, particularly when there is brain infiltration, mass effect, or clinical symptoms.

  
  
• ii.
  

  Extent of surgical resection for WHO grade 1 meningiomas is guided by the Simpson grade scale where greater extent of resection predicts lower rates of tumor recurrence.

Surgical management of epidural spinal cord compression

• i.
  

  Management of patients with osseous metastasis to the spinal cord should include assessment of new neurological symptoms, degree of spinal cord compression on axial T2-weighted MRI images at the point of greatest compression, and treatment responsiveness of the tumor type.

  
  
• ii.
  

  Spinal cord decompression improves neurological outcomes for patients with new deficits including paralysis, bowel or bladder dysfunction, or sensory loss that have been present for no more than 48 hours from onset.

Radiation therapy for high-grade glioma (HGG)

• i.
  

  The standard of care for HGG is maximal safe resection followed by combined modality therapy consisting of adjuvant radiation therapy and temozolomide. The typical radiation regimen is 60 Gy in 30 fractions (2 Gy per fraction) delivered over 6 weeks.

  
  
• ii.
  

  Among the elderly or those with poor performance status, hypofractionated radiation therapy (for example, 40.05 Gy in 15 fractions delivered over 3 weeks) with temozolomide, radiation therapy alone, or temozolomide alone may be appropriate in certain patients. This decision is often guided by MGMT methylation status.

  
  
• iii.
  

  External beam radiotherapy for HGG may be planned and delivered with 3D-conformal radiotherapy, intensity-modulated radiotherapy, or volumetric-modulated arc radiotherapy.

  
  
• iv.
  

  Imaging follow-up should occur 1 month after completion of radiation therapy to establish a new baseline prior to continuation of additional adjuvant chemotherapy. The possibility of pseudoprogression instead of early disease progression should be considered, particularly in patients treated with concurrent temozolomide.

Stereotactic radiosurgery (SRS) for brain metastasis

• i.
  

  Among patients with a limited number of brain metastases and good prognosis, SRS is preferred over whole brain radiation therapy (WBRT). SRS achieves high rates of local control and is associated with improved cognitive function and quality of life compared to WBRT.

  
  
• ii.
  

  Because of the risk of developing new brain metastases after SRS, patients should have routine surveillance imaging every 2–3 months following treatment and with longer intervals with longer time of central nervous system disease stability.

  
  
• iii.
  

  Radiation necrosis is a late toxicity of SRS that develops months to years after treatment and is most commonly asymptomatic but can have associated symptoms ranging from focal neurologic deficits to generalized cognitive symptoms depending upon the location. Steroids, bevacizumab, or surgical resection are used to treat symptomatic radiation necrosis.

  
  
• iv.
  

  The risk of radiation necrosis is associated with brain metastasis size and radiation dose. Fractionated radiation therapy should be considered for high-risk lesions. Alternatively, SRS can be delivered with a reduced dose or in few fractions (between two and five) to reduce risk of toxicity.

Whole Brain Radiation Therapy (WBRT) for Brain Metastasis

• i.
  

  WBRT is generally recommended for patients with diffuse brain metastases and reduces the risk of new brain metastases compared to management by SRS.

  
  
• ii.
  

  WBRT improves survival for only limited sets of patients. Patients who are elderly, debilitated, or with a very poor prognosis may not benefit from WBRT in terms of survival or quality of life. Best supportive care is a reasonable alternative for these groups of patients.

  
  
• iii.
  

  WBRT is most commonly delivered as 30 Gy in 10 fractions over 2 weeks.

  
  
• iv.
  

  WBRT harbors significant risk of toxicity, the most severe of which is irreversible cognitive decline that may occur months to years after treatment.

  
  
• v.
  

  Delivery of WBRT with intensity-modulated radiotherapy and/or volumetric-modulated arc radiotherapy allows dose adjustment to specific intracranial structures, including dose reduction to the hippocampus. This approach is termed hippocampal avoidance whole brain radiation therapy (HA-WBRT) and may reduce cognitive decline following treatment.

Radiation therapy for spinal cord tumors

• i.
  

  Radiation therapy for intramedullary spinal cord tumors is standard after surgery or at the time of progressive disease.

  
  
• ii.
  

  Patients are most commonly treated with a dose between 45 to 54 Gy in 1.8 Gy daily fractions over the course of 5–6 weeks.

  
  
• iii.
  

  Chronic progressive myelopathy is the most serious complication of spinal cord irradiation. It results in permanent and often progressive neurologic deficits, ranging from minor sensory and motor deficits to complete paraplegia in severe cases. There are no proven effective treatments.

  
  
• iv.
  

  Proton therapy for intramedullary spinal cord tumors may be considered in some clinical scenarios, particularly for children who are at highest risk of long-term treatment-associated toxicity.

General principles of chemotherapy for gliomas

• i.
  

  In general, chemotherapy has been use as a neoadjuvant, adjuvant, or concurrent treatment defined as: neoadjuvant chemotherapy is administered prior to the main or definitive treatment which is usually surgery (i.e., before surgery); adjuvant chemotherapy is administered after the main or definitive treatment; concurrent chemotherapy may be administered simultaneously with radiation therapy.

  
  
• ii.
  

  Temozolomide (TMZ) is used commonly in many central nervous system (CNS) regimens due to its many favorable characteristics including good oral bioavailability, limited binding protein, and good CNS penetration with measurable levels being achieved in the cerebrospinal fluid (CSF) and in brain parenchyma following oral administration.

  
  
• iii.
  

  The most frequent side effects of TMZ are nausea/vomiting and fatigue. However, approximately 20% of patients discontinue TMZ due to myelosuppression, in particular for thrombocytopenia (<100,000/mm ³ ).

  
  
• iv.
  

  Procarbazine (PC), lomustine (CCNU), and vincristine (PCV) is a combined therapy used frequently to treat patients with oligodendrogliomas including both low-grade and anaplastic.

Chemotherapy for co-deleted anaplastic oligodendrogliomas

• i.
  

  IDH mutant, 1p19q co-deleted oligodendrogliomas are among the most chemosensitivity gliomas with several clinical trials having demonstrated prolonged median survival of more than 10 years by adding PCV chemotherapy to radiotherapy (RT).

  
  
• ii.
  

  Clinicians should be aware of the risk of a tyramine reaction in patients taking procarbazine (included in the PCV chemotherapy regimen). This catecholamine-like reaction can occur in patients who ingest or consume tyramine-containing foods or pharmacologic agents while taking procarbazine.

Chemotherapy for non–co-deleted anaplastic gliomas

• i.
  

  The standard of care for 1p/19q non–co-deleted anaplastic gliomas includes maximal safe resection, RT, and TMZ-based chemotherapy.

  
  
• ii.
  

  To date, data show that a trend toward a benefit of concomitant chemoradiation is observed in IDH mutated tumors, but not in IDH wild-type tumors.

Chemotherapy for low-grade gliomas

• i.
  

  LGGs are a heterogeneous group of tumors that include pure oligodendrogliomas, IDH mutant astrocytomas, and IDH wild-type astrocytomas.

  
  
• ii.
  

  Selected LGGs are chemosensitive to alkylating therapy with recent clinical trials showing favorable outcomes in patients with 1p19q co-deleted oligodendrogliomas and frequently for IDH mutant astrocytomas, compared to IDH wild-type LGGs, which have largely not been responsive to chemotherapy.

Chemotherapy for glioblastoma

• i.
  

  Standard of care for patients with GBM includes concurrent chemotherapy followed by six cycles of adjuvant temozolomide chemotherapy and tumor treating field therapy.

  
  
• ii.
  

  Methylation of the MGMT gene promoter is both prognostic of improved survival as well as predictive of a more favorable response to chemotherapy.

Chemotherapy for recurrent gliomas

• i.
  

  Treatment options for patients with recurrent gliomas are limited and generally include temozolomide, nitrosoureas, and bevacizumab.

Clinical pearls for evaluating dural-based lesions

• i.
  

  Most are T1 iso-hypointense on MRI. If they are T1 hyperintense, consider etiologies that contain methemoglobin (subacute hemorrhage), high protein, fat, melanin, or calcium.

  
  
• ii.
  

  Some dural-based lesions are T2 hyperintense due to high water content. Others are T2 hypointense due to their high cellularity (particularly if the tumor cells have a high nuclear-to-cytoplasmic ratio, such as lymphoma). Some meningiomas can be fibrous and these have lower T2 signal.

  
  
• iii.
  

  Diffusion restriction in dural-based lesions is variable. Diffusion restriction is an evaluation of how freely water molecules can move in a given medium. If restricted diffusion is present, then consider highly cellular tumors, such as lymphoma, cellular meningiomas, or metastases.

  
  
• iv.
  

  Enhancement is a product of disruption of the blood-brain barrier. Extraaxial lesions do not have a blood-brain barrier and most avidly enhance. Meningiomas, the most common dural-based neoplasm, typically diffusely and homogeneously enhance. They often have adjacent dural enhancement/thickening that is referred to as a “dural tail.” Most other dural-based neoplasms also avidly enhance, so the presence of enhancement does not exclude more aggressive neoplasms. If the enhancement pattern is heterogenous, a low-grade meningioma is less likely.

  
  
• v.
  

  Evaluate the relationship of the dural-based lesion with the brain. To establish the lesion is truly extraaxial, look for CSF between the margins of the tumor and the adjacent brain parenchyma (also called a CSF cleft). If there is an indistinct interface between the dural-based mass and the brain or if there is a large amount of edema in the brain, there is a higher likelihood that the mass will be a higher meningioma grade or a more aggressive neoplasm.

Imaging features of supratentorial GBM

• i.
  

  The imaging differential for a single ring-enhancing supratentorial lesion includes HGG, solitary brain metastasis, cerebral abscess, tumefactive demyelination, and subacute stroke.

  
  
• ii.
  

  For such a lesion, surgical consultation and evaluation is required to establish a tissue diagnosis and guide treatment decisions.

Imaging features of supratentorial low-grade glioma

• i.
  

  The differential diagnosis of a non-enhancing supratentorial lesion on MRI includes LGG and subacute ischemia, cerebritis, an arteriovenous malformation, or herpes encephalitis

Imaging features of CNS lymphoma

• i.
  

  The imaging differential diagnosis for an enhancing lesion consistent with CNS lymphoma includes CNS lymphoma, GBM, infections (i.e., abscess, toxoplasmosis), progressive multifocal leukoencephalopathy (PML), demyelinating disorders, or metastases.

  
  
• ii.
  

  Compared to malignant glioma, treatment response is considerable higher for patients with CNS lymphoma even without cytoreduction. Thus, stereotactic biopsy is favored.

Imaging features of brain metastasis

• i.
  

  The imaging differential for multifocal brain metastasis includes multifocal GBM, abscess, demyelinating disease, or CNS lymphoma (in immunocompromised patients).

  
  
• ii.
  

  Multidisciplinary evaluation including radiology, neurosurgery, radiation oncology, medical oncology, and neuro-oncology help determine an optimal treatment plan.

General tips for imaging of the posterior fossa

• i.
  

  MRI offers higher soft-tissue resolution with more qualitative data on posterior fossa lesions, though it is not available at all centers, requires a degree of technical expertise, is slower, may necessitate sedation for younger and unstable patients, and is more expensive than CT.

  
  
• ii.
  

  CT is fast, less expensive, and more widely available than MRI, and offers insights into calcifications and boney involvement of lesions though with limited resolution and narrow lesion characteristics. Additionally, CT can be used to rapidly assess potentially life-threatening complications of posterior fossa masses, including hydrocephalus, acute hemorrhage, or pending herniation.

  
  
• iii.
  

  In pediatric patients with space-occupying posterior fossa lesions, a primary brain tumor is by far the most likely diagnosis, with metastatic lesions in this population being exceedingly rare.

  
  
• iv.
  

  In older adults, a space-occupying lesion in the posterior fossa is more likely to be a metastatic tumor or acute hemorrhage, and should prompt a comprehensive history and physical examination and consideration of additional body imaging to evaluate for a primary tumor or risk factors for stroke.

  
  
• v.
  

  Location and characteristics of pediatric tumors can guide the clinician regarding a most likely diagnosis, which may include LGG, HGG, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor, or others.

Differential diagnosis of a midline fourth ventricular lesion

• i.
  

  The imaging differential of a midline posterior fossa lesion in a child should include medulloblastoma (e.g., “M” for midline) and ependymoma. Pilocytic astrocytomas tend to occur in the lateral cerebellum.

Differential diagnosis of a lateral cerebellar lesion

• i.
  

  Lateral cerebellar cystic lesion with a mural nodule should raise suspicion for a pilocytic astrocytoma in children and for a cerebellar hemangioblastoma in adults.

Differential diagnosis of a non-enhancing pontine lesion

• i.
  

  The imaging differential diagnosis for an intrinsic pontine brainstem glioma should include causes of rhombencephalitis (e.g., infectious, inflammatory, paraneoplastic) including Listeria infection, enterovirus, other viral encephalitis (e.g., herpes simplex virus, Epstein-Barr virus [EBV], human herpesvirus 6), Behcet disease, Erdheim-Chester disease, or other etiologies.

  
  
• ii.
  

  Pontine gliomas are typically expansile with enlargement of the central pons, often with the basilar artery displaced anteriorly or with the tumor appearing to engulf the artery.

Differential diagnosis of an enhancing cerebellar lesion

• i.
  

  The cerebellum is the second most common parenchymal location for brain metastasis.

  
  
• ii.
  

  Management of cerebellar metastasis should include definitive tumor treatment as well as a consideration for reducing brainstem compression, maintaining CSF flow, and providing a tissue diagnosis when there is no contributory systemic malignancy present.

Differential diagnosis of a non-enhancing cerebellar lesion

• i.
  

  Acute cerebellitis is a heterogeneous clinical syndrome characterized by cerebellar ataxia or dysfunction that is attributable to a recent or concurrent infection, a recent vaccination, or an ingestion of medication.

  
  
• ii.
  

  MRI imaging of typical acute bilateral cerebellitis includes metabolic diseases, demyelinative disorders, and meningitis.

  
  
• iii.
  

  In cases of hemicerebellitis when imaging findings are asymmetric, the imaging differential includes dysplastic cerebellar gangliocytoma (Lhermitte-Duclos), vasculitis, and inflammatory processes related to cytarabine or other toxicities.

Imaging findings of spinal cord astrocytoma

• i.
  

  Intramedullary spinal cord tumors account for ∼10% of primary spinal cord tumors and are most often ependymomas, which are slightly favored over astrocytomas.

  
  
• ii.
  

  Most intramedullary WHO grade 1 pilocytic astrocytomas enhance on neuroimaging and may be confused with higher-grade lesions without a tissue diagnosis.

Imaging findings of spinal cord ependymoma

• i.
  

  Enhancing spinal cord tumors can mimic inflammatory and infectious lesions in the spinal cord including transverse myelitis, multiple sclerosis, neuromyelitis optic spectrum disorder, infectious myelitis, and other related conditions.

Imaging findings of spinal cord hemangioblastoma

• i.
  

  Spinal hemangioblastomas are the prototypical tumor associated with von Hippel Lindau (vHL) disease.

  
  
• ii.
  

  Hemangioblastomas associated with vHL have earlier onset of disease, and are often solitary but can be multiple, including the cerebellum.

Imaging findings of peripheral nerve sheath tumors

• i.
  

  Schwannomas and neurofibromas account for up to one-third of intradural spinal cord tumors and appear as homogeneously enhancing extramedullary masses.

Imaging findings of a solitary neurofibroma

• i.
  

  The vast majority of neurofibromas are sporadic and not associated with neurofibromatosis type 1 (NF1).

  
  
• ii.
  

  Characteristic MRI features include heterogeneous enhancement on T1-weighted post-contrast and hyperintensity on T2-weighted and short tau inversion recovery (STIR) sequences. A target and/or split-fat sign may be seen.

  
  
• iii.
  

  The main differential diagnosis for a neurofibroma is schwannoma, and these two entities may be difficult to distinguish based on MRI alone.

Imaging findings of plexiform neurofibromas in NF1

• i.
  

  Plexiform neurofibromas (pNFs) affect up to 60% of patients with NF1.

  
  
• ii.
  

  Although histologically benign and typically slow growing, pNFs can cause significant morbidity due to local mass effect and infiltration of vital anatomic structures. A small proportion of pNFs can transform into malignant peripheral nerve sheath tumors.

  
  
• iii.
  

  A regional MRI with contrast-enhanced and STIR sequences of the affected region should be obtained. Whole-body MRI may be useful to assess a patient’s baseline tumor burden.

Imaging findings of malignant peripheral nerve sheath tumors (MPNSTs)

• i.
  

  Rapid development or changes of symptoms (e.g., tumor growth, pain, or neurologic dysfunction) in a patient with NF1 should prompt evaluation for MPNST.

  
  
• ii.
  

  Initial workup should include a contrast-enhanced regional MRI of the affected body region. Diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping may aid in the detection of malignant foci. If the history or MRI is suggestive of malignancy, an ¹⁸ F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT should be obtained to identify metabolically active areas suitable for biopsy and histologic confirmation of malignancy.

  
  
• iii.
  

  Patients should be referred to a surgeon for an image-guided biopsy and managed by an experienced multidisciplinary team including a surgeon, radiation oncologist, and medical oncologist.

  
  
• iv.
  

  Prognosis is poor even with treatment, particularly for patients with advanced or metastatic disease.

Diffuse lumbosacral nerve root thickening

• i.
  

  The etiology of nerve root thickening and enhancement on spine MRI includes inflammatory/autoimmune, hereditary, infectious, and neoplastic causes.

  
  
• ii.
  

  The degree of thickening, presence of significant nodularity, and degree of enhancement, and clinical and family history can help narrow down the differential diagnosis.

  
  
• iii.
  

  Additional studies should be patient-specific and may include brain MRI, systemic body imaging, electromyography/nerve conduction studies, and CSF analysis.

Non-vestibular schwannomas in NF2

• i.
  

  Most schwannomas are solitary and occur sporadically. The presence of multiple schwannomas should prompt evaluation for an underlying genetic syndrome such as NF2 or schwannomatosis (SWN).

  
  
• ii.
  

  A contrast-enhanced MRI of the entire brain and with thin cuts through the internal auditory canals to evaluate for vestibular schwannomas should be obtained. Similarly, a spine MRI with and without contrast is required to assess for the presence of spinal schwannomas, ependymomas, and meningiomas.

  
  
• iii.
  

  Non-vestibular schwannomas may be difficult to distinguish from neurofibromas on MRI but the patient’s history and examination can help establish the diagnosis.

Schwannomas in schwannomatosis

• i.
  

  Schwannomas in SWN patients most commonly involve the spinal and peripheral nerves.

  
  
• ii.
  

  Evaluation of a patient presenting with possible NF2 or SWN should include a brain MRI with thin cuts through the internal auditory canal to exclude the presence of bilateral vestibular schwannomas as well as a spine MRI.

  
  
• iii.
  

  Benign schwannomas can display FDG avidity on PET/CT and mimic malignancy.

  
  
• iv.
  

  Genetic testing for mutations in the NF2 , SMARCB1 , and LZTR1 genes is recommended given the significant phenotypic overlap between NF2 and SWN.

  
  
• v.
  

  Management should focus on pharmacologic and non-pharmacologic treatment of pain, and if medically refractory, surgical resection of symptomatic or compressive tumors.

Approach to patients without a tissue diagnosis

• i.
  

  The decision for observation or surgery of a meningioma should be made on an individual basis after discussions with the patient, taking into account the patient’s clinical presentation, imaging characteristics, tumor growth patterns, and other medical history and comorbidities.

  
  
• ii.
  

  In symptomatic patients or patients with rapidly enlarging tumors without tissue diagnosis, surgery is the main treatment modality for both symptomatic relief and pathologic diagnosis.

Approach to WHO grade I meningioma

• i.
  

  GTR is the goal of any meningioma surgery.

  
  
• ii.
  

  Extent of resection after meningioma surgery is determined by the Simpson grading scale with Simpson grades I–III indicating total/near total resection of tumor and Simpson grades IV–V indicating partial/minimal resection of tumor.

  
  
• iii.
  

  For WHO grade I meningiomas, tumors can be monitored with serial imaging after GTR if the patient remains asymptomatic.

Approach to WHO grade II meningioma

• i.
  

  Evidence supports safe GTR of WHO grade II meningiomas as the first-line treatment for surgically resectable lesions.

  
  
• ii.
  

  Retrospective data supports a trend toward adjuvant radiation following resection of WHO grade II meningiomas in favorable locations; however, the strength of radiation as an effective adjuvant therapy in these patients is still unclear.

  
  
• iii.
  

  At 5 years, 60–90% of patients will be free of meningioma recurrence after GTR and 30–70% of patients will be recurrence free after subtotal resection.

  
  
• iv.
  

  If GTR is not feasible for a WHO grade II meningioma, subtotal resection with adjuvant RT should be considered.

Approach to WHO grade III meningioma

• i.
  

  WHO grade III meningiomas are aggressive malignant neoplasms.

  
  
• ii.
  

  Safe maximal resection should be pursued for WHO grade III meningiomas followed by RT.

  
  
• iii.
  

  Even with maximal aggressive therapy, rates of recurrence are as high as 60–90%.

Approach to Recurrent Meningioma

• i.
  

  If recurrent meningioma is detected that poses a significant risk to neighboring brain structures or patient quality of life, the patient and clinician can choose between repeated surgery or radiation therapy.

  
  
• ii.
  

  Systemic therapies have not been shown to improve outcomes in newly diagnosed meningiomas but are often considered in multiply recurrent, treatment-refractory, or metastatic meningiomas.

  
  
• iii.
  

  In recent years, several clinical trials of systemic therapies have become available for patients with grade II and III meningiomas refractory to surgery and radiation.

Classification of low-grade gliomas

• i.
  

  Most diffuse LGGs can be separated into three molecularly, prognostically, and clinically distinct groups: 1p/19q co-deleted, IDH mutant, and IDH wild-type gliomas.

Timing of treatment for low-grade gliomas

• i.
  

  Observation of low-risk asymptomatic patients, including patients with controlled seizures, is reasonable and typically includes MRI every 3 months, which is gradually lengthened in patients whose gliomas show stability.

  
  
• ii.
  

  High-risk features in LGG patients include age >40 years, subtotal resection and, in some cases, tumor-related symptoms, poor performance status, preoperative tumor size (worse if ≥5 cm), astrocytic histology, and high proliferative index (poor if MIB-1 is >3%).

Approaches to treatment protocols for low-grade gliomas

• i.
  

  For low-grade 1p/19q co-deleted oligodendrogliomas, evidence-based treatment is radiation plus PCV.

  
  
• ii.
  

  For low-grade IDH -mutant non–co-deleted astrocytomas, the optimal treatment regimen is not as clear but some clinicians will add temozolomide to radiation therapy either concurrently and/or adjuvantly.

  
  
• iii.
  

  Despite their low-grade, IDH -wild type gliomas follow an aggressive clinical course and patients tend to have worse outcomes with poorer response to chemotherapy.

Approach to anaplastic oligodendroglioma

• i.
  

  Oligodendrogliomas are defined by co-deletion of chromosomes 1p/19q and respond well to radiation and PCV chemotherapy.

  
  
• ii.
  

  Maximum safe resection may prolong survival but is never curative and may not be feasible in deeply infiltrative lesions that cross the midline or are adjacent to eloquent structures.

  
  
• iii.
  

  New or worsening seizures are an indicator of tumor progression in HGGs and should be evaluated with contrast-enhanced MRI and, if necessary, biopsy or resection.

  
  
• iv.
  

  Besides antiepileptic drugs (AEDs), antineoplastic therapy may help improve seizure control.

Approach to anaplastic astrocytoma

• i.
  

  High-grade astrocytomas are treated with RT with concurrent and adjuvant temozolomide chemotherapy.

  
  
• ii.
  

  IDH mutant astrocytomas have a more favorable prognosis and response to treatment than those with wild-type IDH.

Approach to glioblastoma

• i.
  

  High-grade diffuse gliomas include GBMs, anaplastic astrocytomas, and oligodendrogliomas.

  
  
• ii.
  

  Diagnosis of a HGG begins with histologic assessment and integrates molecular alterations to identify HGG subgroups that have distinct prognoses and therapy responses.

  
  
• iii.
  

  MGMT promoter methylation predicts favorable response to temozolomide in IDH wild-type astrocytomas.

Approach to neurological complications of high-grade glioma

• i.
  

  Multidisciplinary symptom-oriented care may provide improved quality-of-care in complex cases.

  
  
• ii.
  

  Corticosteroids are used to manage symptoms caused by tumor-induced edema.

  
  
• iii.
  

  Corticosteroids can be effectively administered in one or two doses a day and evening doses should be avoided to minimize steroid-related insomnia.

  
  
• iv.
  

  Bevacizumab can be utilized as a steroid-sparing agent in select cases.

Approach to non-neurological complications of HGG

• i.
  

  Thirty percent of patients with IDH wild-type gliomas develop venous thromboembolisms (VTEs).

  
  
• ii.
  

  Anticoagulation is safe in most glioma patients with VTE.

  
  
• iii.
  

  Lymphopenia is a common complication of chemoradiation and is associated with shorter survival and increased risk for infection.

  
  
• iv.
  

  Pneumocystis jirovecii pneumonia prophylaxis is recommended in lymphopenic patients.

Approach to imaging surveillance and recurrence in HGG

• i.
  

  Guidelines recommend surveillance imaging of a HGG every 2–4 months for the first 3 years and these recommendations are often individualized based on prognostic factors and risk of early recurrence.

  
  
• ii.
  

  Virtually all HGGs will recur, at which time repeat surgery, radiation, salvage chemotherapy, or clinical trials are considered.

  
  
• iii.
  

  There is currently no known second-line systemic therapy that prolongs overall survival for GBM.

  
  
• iv.
  

  Palliative care is optimally integrated into the management of HGGs early and contemporaneously with aggressive tumor-directed therapy, particularly once these tumors recur.

Approach to the diagnosis of CNS lymphoma

• i.
  

  Immunosuppression and older age are the major risk factors for the development of primary central nervous system lymphoma (PCNSL).

  
  
• ii.
  

  The typical clinical presentation of PCNSL involves progressive and relatively rapid focal neurological symptoms associated with the neuroanatomic localization of the tumor.

  
  
• iii.
  

  Treatment with corticosteroids should be deferred until pathologic confirmation.

Differentiating primary and secondary CNS lymphoma

• i.
  

  Ninety to ninety-five percent of cases of PCNSL are classified histologically as diffuse large B-cell lymphoma (DLBCL).

  
  
• ii.
  

  MRI with contrast is the most sensitive imaging modality for the detection of PCNSL.

  
  
• iii.
  

  Diagnosis and staging require a HIV serology, full body CT or PET-CT; detailed ophthalmologic examination, lumbar puncture, and, in older males, a testicular ultrasound.

Treatment of primary CNS lymphoma

• i.
  

  High-dose methotrexate is the single most important treatment agent for PCNSL. Current therapy consists of a methotrexate-based combination chemotherapy with rituximab for B-cell lymphomas. Intrathecal therapy may be considered in patients with evidence of leptomeningeal involvement.

  
  
• ii.
  

  In patients who achieve a complete response to induction therapy, high-dose chemotherapy with autologous stem cell rescue should be offered as consolidation to fit patients.

  
  
• iii.
  

  In patients who achieve a complete response to induction therapy and are not candidates for autologous stem cell rescue, consolidation chemotherapy is considered or in some cases clinicians may consider WBRT.

Approach to PCNSL in immunocompromised patients

• i.
  

  Patients with AIDS-related PCNSL require highly active antiretroviral therapy and chemotherapy.

  
  
• ii.
  

  An elevated CSF EBV polymerase chain reaction in the setting of a typical brain lesion on MRI or FDG-avid CNS lesion on PET is highly specific for primary CNS lymphoma and may justify treatment initiation.

Posttransplant lymphoproliferative disease (PTLD)

• i.
  

  Patients with PTLD and PCNSL require reduction in immunosuppression and chemotherapy.

Approach to recurrent primary CNS lymphoma

• i.
  

  More than half of PCNSL patients who respond to treatment suffer from relapse. PCNSL relapse is treated with chemotherapy, immunotherapy, or WBRT.

Bing-Neel syndrome

• i.
  

  Bing-Neel syndrome is a rare and slowly progressing complication of Waldenström macroglobulinemia whereby malignant lymphoplasmacytic cells invade the CNS.

  
  
• ii.
  

  Treatment of Bing-Neel syndrome aims at treating neurological symptoms of the disease.

Primary T-cell lymphoma

• i.
  

  T-cell primary CNS lymphoma (TPCNSL) is a rare form of PCNSL. The clinical picture and treatment modalities for TPCNSL are similar to DLBCL with similar agents used in treatment.

Diagnosis and management of neurological complications of PCNSL treatment

• i.
  

  Treatment related neurotoxicity including neurocognitive dysfunction after WBRT, delayed-onset leukoencephalopathy after methotrexate, or progressive multifocal leukoencephalopathy are major complications of PCNSL treatment and require frequent follow-up after treatment.

Fundamentals of brain metastasis

• i.
  

  Brain metastases are the most common CNS malignancy with approximately 160,000 new cases per year.

  
  
• ii.
  

  Patients who experience a seizure due to brain metastases should be managed with brain metastases and advised to not drive an automobile for at least 6 months after last seizure.

Craniotomy for brain metastasis

• i.
  

  Craniotomy is indicated for patients with large, symptomatic lesions or those without a known diagnosis of cancer.

  
  
• ii.
  

  Cavity-directed SRS is indicated to reduce the risk of recurrence after craniotomy for brain metastases.

Radiosurgery for brain metastasis

• i.
  

  SRS for intact brain metastases is preferred for treatment of a limited number of brain metastases, as it preserves quality of life and neuro-cognition.

  
  
• ii.
  

  Patients who are managed with SRS are more likely to develop new brain metastases than those with WBRT, but these can be managed with a second session of SRS.

WBRT for brain metastasis

• i.
  

  WBRT is useful for patients with too many brain metastases to effectively treat with SRS.

  
  
• ii.
  

  WBRT contributes to decline in quality of life and neurocognitive decline, and is avoided when possible due to side effects.

Neurological complications of brain metastasis treatment

• i.
  

  Follow-up for brain metastases with MRI is critical in order to detect new brain metastases prior to developing symptoms and to detect radiation necrosis after SRS.

  
  
• ii.
  

  Neurocognitive dysfunction is common after WBRT with up to 90% of patients developing a decline in neurocognitive testing after WBRT.

  
  
• iii.
  

  In patients who do undergo WBRT, clinicians may consider strategies to avoid long-term neurocognitive dysfunction including hippocampal avoidance and prophylactic pharmacologic therapy (e.g., memantine, donepezil), though the benefits of these interventions have not been confirmed in large, randomized phase III studies.

The role of spinal tap in the diagnosis and management of leptomeningeal disease (LMD)

• i.
  

  CSF cytology is the gold standard for diagnosing LMD.

  
  
• ii.
  

  Common solid tumors that metastasize to the leptomeninges include melanoma, breast cancer, small-cell lung cancer, and non–small-cell lung cancer.

  
  
• iii.
  

  CSF cytology has a high false negative rate; in patients with a high index of suspicion for LMD, a second or third dural puncture may be needed if CSF cytology is negative after the first spinal tap.

  
  
• iv.
  

  In patients with suspected LMD, CSF studies should include cell count, glucose, protein, and cytology.

  
  
• v.
  

  In patients with known or suspected hematologic malignancies, CSF flow cytometry should be performed as it is two to three times more sensitive than cytology for the detection of leukemic or lymphomatous meningitis.

The role of neuroimaging in the diagnosis and management of LMD

• i.
  

  The most frequent MRI findings of LMD are focal or diffuse enhancement of leptomeninges along the sulci, cranial nerves, and spinal nerve roots, linear or nodular enhancement of the cord, and thickening of lumbosacral roots.

  
  
• ii.
  

  Neuroimaging also helps define the extent of disease and the presence of bulky/nodular disease that may require radiation or selected high-dose systemic therapies.

Approach to the treatment for LMD

• i.
  

  Cancer-directed treatment is individualized based on various factors including the type of malignancy (e.g., solid versus hematologic malignancy), performance status, type and state of systemic cancer, burden of LMD, and clinical symptoms.

  
  
• ii.
  

  Symptomatic treatments include management of elevated ICP seizure treatment, supportive care for cranial neuropathies, and pain control.

  
  
• iii.
  

  WBRT is used for treating diffuse LMD in patients with symptoms of high ICP to improve CSF flow.

  
  
• iv.
  

  Focal conformal radiation therapy or SRS are used for treating bulky lesions that impair CSF flow (noncommunicating hydrocephalus) or symptomatic nodules that result in impaired neurological function.

  
  
• v.
  

  In LMD patients with active systemic therapy, clinicians should explore systemic chemotherapy or targeted therapies with favorable blood-brain barrier penetrating properties.

  
  
• vi.
  

  In LMD patients without bulky, nodular disease, intrathecal chemotherapy is a treatment consideration, particularly for patients without active systemicdisease.

  
  
• vii.
  

  Intrathecal chemotherapy is administered either by lumbar puncture or intraventricular administration via a surgically implanted Ommaya reservoir.

  
  
• viii.
  

  Intrathecal chemotherapy is generally well tolerated, though up to 20% of patients will develop aseptic meningitis and present with abrupt onset of headache, stiff neck, nausea, vomiting, lethargy, and fever several hours after the injection.

Approach to NF1 associated plexiform neurofibroma

• i.
  

  Clinically, changes in the severity or nature of pain or rapid growth warrants evaluation for possible malignant conversion with imaging and biopsy.

  
  
• ii.
  

  Currently, in a person with NF1 with a growing plexiform neurofibroma that is increasingly symptomatic and has findings that could be consistent with malignant degeneration based on a distinct nodular appearance on anatomic MRI, low ADC on functional MRI, and elevated standardized uptake value maximum on FDG-PET, biopsy of the most atypical region on imaging should be pursued if feasible.

  
  
• iii.
  

  It is important to distinguish plexiform neurofibro-ma from cutaneous and subcutaneous neurofibromas that can involve the skin; cutaneous neurofibromas do not require regular surveillance.

  
  
• iv.
  

  Increasingly good medical options are available for both adults and children with plexiform neurofibroma.

Approach to NF1 associated optic pathway glioma

• i.
  

  Optic pathway gliomas (OPGs) are seen in 15–20% of NF1 patients.

  
  
• ii.
  

  Vision should be followed with yearly eye examination in all NF1 children and, if deficits are observed, MRI and regular ophthalmology examination should be performed to follow patients found to have an OPG.

  
  
• iii.
  

  Symptoms and signs that warrant treatment include vision loss, proptosis, or endocrinopathy.

Approach to brainstem or cerebellar glioma in NF1

• i.
  

  Three imaging characteristics favor that a brain lesion in an NF1 patient is LGG and not a benign focal area of signal abnormality (FASI) including: contrast enhancement, mass effect on surrounding tissue, or T1-weighted hypointensity relative to gray matter.

  
  
• ii.
  

  Lesions concerning for tumor should be followed by an oncologist familiar with NF1.

  
  
• iii.
  

  For NF1-associated LGG, surgical resection is the mainstay of therapy. Tumors that have been completely or nearly resected often require no further therapy. Subtotally resected or recurrent tumors are treated with chemotherapy or targeted systemic therapies.

Management of vestibular schwannomas in NF2

• i.
  

  Bilateral vestibular schwannomas (VS) are pathognomonic for NF2. VSs present with hearing loss, tinnitus, and balance difficulty. Vertigo is rare.

  
  
• ii.
  

  NF2 patients should be monitored with neuroimaging of suspicious lesions and audiometry initially at 6-month intervals to determine tumor growth rate and hearing.

  
  
• iii.
  

  Removal of every tumor in NF2 is usually not feasible or necessary. Treatment focuses on preserving hearing, maintaining function, and maximizing quality of life.

  
  
• iv.
  

  Bevacizumab has been studied at multiple dose schedules, each showing a hearing improvement rate of around 40–50% and radiographic response rate of 30–50% in NF2 patients.

Diagnosis of schwannomatosis

• i.
  

  SWN is characterized by germline pathogenic variants in SMARCB1 or LZTR1 genes and likely additional unidentified genes.

  
  
• ii.
  

  Tumor formation in SWN is caused by mutational inactivation of two genes including the NF2 gene as well as either SMARCB1 or LZTR1.

Management of pain in schwannomatosis

• i.
  

  Chronic pain is the most common symptom reported by over 65% of patients with SWN.

  
  
• ii.
  

  Managing chronic pain is challenging in SWN as no class of pain medication has been associated with consistent benefit.

  
  
• iii.
  

  Referral to pain specialists may be helpful for comprehensive pain management. Treatment of concomitant anxiety and depression is strongly recommended.

Diagnosis of tuberous sclerosis

• i.
  

  Cutaneous findings are present in approximately 90% of tuberous sclerosis complex (TSC) patients.

  
  
• ii.
  

  The first cutaneous sign is often hypopigmented macules called Ash leaf spots that are first apparent in infancy.

  
  
• iii.
  

  Between 10% and 25% of patients who fulfill the clinical criteria for TSC will have no identified mutation on genetic testing.

  
  
• iv.
  

  Several important TSC findings manifest later in life including pulmonary lymphangioleiomyomatosis, which occurs more commonly in adult women.

TSC-associated epilepsy

• i.
  

  Seizures occur in approximately 85% of TSC patients, often beginning as infantile spasms and progressing to include multiple seizures types.

  
  
• ii.
  

  Vigabatrin is the only AED with TSC-specific data supporting its efficacy in TSC.

  
  
• iii.
  

  In the EXIST-3 study, treatment with the oral mTOR inhibitor everolimus resulted in improvement in seizures in 50% of patients at 2 years.

Brain MRI findings in TSC

• i.
  

  Cortical tubers occur in 90% of TSC patients, have no malignant potential, but can contribute to epilepsy.

  
  
• ii.
  

  Subependymal nodules are hyperintense lesions adjacent to the ventricular surface that do not enhance with gadolinium contrast.

  
  
• iii.
  

  Subependymal giant cell astrocytomas (SEGAs) are a WHO grade 1 glioma that occur within the ventricular system often around the foramen of Munro and enhance with gadolinium contrast.

Renal angiomyolipomas in TSC

• i.
  

  Angiomyolipomas (AMLs) are benign kidney tumors that are present in up to 80% of patients with TSC.

  
  
• ii.
  

  AMLs rarely develop into renal cell carcinoma but can be complicated by renal hemorrhage, which is rare.

  
  
• iii.
  

  When treatment of an AML is indicated, mTOR inhibitors (e.g., everolimus) are first-line therapy, with an overall response rate of 58%.

von Hippel Lindau

• i.
  

  vHL is tumor-predisposition syndrome characterized by neoplasms of the nervous system, kidneys, and other organs.

  
  
• ii.
  

  Cerebellar, spinal, and retinal hemangioblastomas are the most common nervous system manifestations.

  
  
• iii.
  

  Cerebellar hemangioblastomas are benign, slow-growing, highly vascular, cystic WHO grade I neoplasms.

Cowden syndrome

• i.
  

  Cowden syndrome is a rare autosomal dominant disorder that results from germline mutation in the phosphatase and tensin homolog ( PTEN ) gene.

  
  
• ii.
  

  Neurologic manifestations in Cowden syndrome frequently include benign CNS tumors such as meningiomas, macrocephaly, heterotopias, vascular abnormalities, and developmental delay.

  
  
• iii.
  

  The most common CNS neoplasm is the dysplastic gangliocytoma of the cerebellum which, when present, is known as Lhermitte-Duclos disease (LDD). In adults, LDD is pathognomonic for Cowden syndrome.

Li-Fraumeni syndrome

• i.
  

  Li-Fraumeni is a rare autosomal dominant disease that results from inactivating mutation in the TP53 gene which predisposes patients to a wide array of neoplasms.

  
  
• ii.
  

  CNS neoplasms occur in approximately 10% of patients with Li-Fraumeni syndrome and include supratentorial tumors, neuroectodermal tumors, choroid plexus carcinomas, and medulloblastoma.

Lynch syndrome

• i.
  

  Lynch syndrome (e.g., hereditary nonpolyposis colorectal cancer syndrome) is a multi-tumor syndrome caused by germline mutation in DNA mismatch repair genes.

  
  
• ii.
  

  Lynch syndrome is characterized by a significantly increased risk of colorectal and endometrial cancer along with a fourfold higher risk of GBM.

Neurological side effects of brain tumors

• i.
  

  Dexamethasone is the preferred corticosteroid for treating cerebral edema. Treatment decisions should be based on the degree of neurologic symptoms and not on imaging findings.

  
  
• ii.
  

  Patients should be managed on the lowest dose of dexamethasone that controls their symptoms. Given the long-term side effects, efforts should continually be made to taper or discontinue corticosteroids when symptomatically possible.

  
  
• iii.
  

  Brain tumor patients presenting with a seizure should be treated with an antiepileptic medication. Enzyme-inducing AEDs should be avoided due to interactions with chemotherapy and corticosteroids.

  
  
• iv.
  

  There is no evidence to support the use of prophylactic anticonvulsants in brain tumor patients.

  
  
• v.
  

  Brain tumor patients are at increased risk for hemorrhagic and ischemic stroke. Patients with acute onset of neurologic symptoms should be urgently evaluated for stroke.

  
  
• vi.
  

  Endocrinologic complications are common in brain tumor patients and can present with variable symptoms. Hypopituitarism and syndrome of inappropriate antidiuretic hormone should be considered in the differential of fatigue and encephalopathy.

Non-neurological side effects in brain tumor patients

• i.
  

  Venous thromboembolism is common in brain tumor patients. Patients with new lower extremity swelling, shortness of breath, or hypoxia should be urgently evaluated for deep venous thrombosis or pulmonary embolism with lower extremity ultrasound or CT angiogram of the chest.

  
  
• ii.
  

  Prophylactic anticoagulation is only indicated for brain tumor patients in the perioperative setting.

  
  
• iii.
  

  Therapeutic anticoagulation with low-molecular-weight heparin is preferred for prevention of recurrent venous thromboembolism in cancer patients.

  
  
• iv.
  

  The etiology of fatigue and cognitive dysfunction in brain tumor patients is multifactorial. Assessment includes evaluation of antitumor treatments, supportive care medications, metabolic and endocrine abnormalities, mood disturbance, and sleep dysregulation.

  
  
• v.
  

  All patients should be screened for depression throughout their disease course and treated when appropriate.

Broadly, paraneoplastic neurologic disorder (PND) syndromes can be classified by whether the target is an intracellular antigen (e.g., anti-Hu, anti-Yo, anti-CV2, anti-Ri, anti-Ma, and others) or a neuronal cell surface antigen (e.g., anti-NMDA receptor, anti-VGCC, and others).

PND may manifest in typical ways such as encephalitis, myelitis, cerebellar degeneration, neuropathy, myoclonus/opsoclonus, Lambert-Eaton myasthenic syndrome, and dermatomyositis.

Typical findings in PND involving the CNS include CSF pleocytosis, elevated CSF protein, increased CSF immunoglobulin synthesis and presence of oligoclonal bands.

The first approach to PND should be source control with tumor treatment as appropriate for the given malignancy.

First-line immunotherapies include corticosteroids, intravenous immunoglobulins, and plasma exchange. Second-line immunosuppressant medications include rituximab, cyclophosphamide, azathioprine, and mycophenolate.

General principles of perineural invasion

• i.
  

  Perineural invasion (PNI) refers to a rare type of contiguous spread of neoplastic cells from their primary site along the potential space between or beneath the layers of perineurium.

  
  
• ii.
  

  PNI can be broadly divided into microscopic PNI and clinical PNI.

  
  
• iii.
  

  Classically, PNI presents in a patient with a history of head and neck cancer who develops cranial neuropathy, with cranial nerve V and VII being the most commonly affected.

Brachial plexus invasion of malignancy

• i.
  

  Contrast-enhanced MRI is the gold standard for establishing an imaging diagnosis of PNI but false-negative rates are high and may fail to demonstrate active disease in at least 45% of patients.

  
  
• ii.
  

  A combination of CT and MRI with selected use of FDG-PET may increase the detection rate and improve the understanding of disease extent.

  
  
• iii.
  

  The differential diagnosis of a new-onset brachial plexopathy in a cancer patient includes perineural spread and radiation-induced brachial plexopathy.

  
  
• iv.
  

  For these patients, the presence of pain should favor perineural spread or locoregional cancer recurrence, while the absence of pain should favor radiation-induced brachial plexopathy.

Perineural cranial neuropathy

• i.
  

  Early diagnosis of PNI is critical for prompt initiation of treatment as neurological deficits are poorly rescued once significant dysfunction has developed.

  
  
• ii.
  

  Surgical resection with the goal of clear margins must be balanced against the risk of postoperative morbidity from neurological insult.

  
  
• iii.
  

  Five-year survival in patients treated with surgical resection and adjuvant RT is 55% for patients with microscopic PNI and 50% for symptomatic patients.

Neoplastic brachial plexopathy

• i.
  

  The presentation of a neoplastic brachial plexopathy is frequently in the form of worsening pain in the neck, shoulder, or arm over the span of weeks to months.

  
  
• ii.
  

  In such cases, Horner syndrome may be present, especially with the involvement of the lower trunk.

  
  
• iii.
  

  The lower plexus is most often involved in cancer-related brachial plexopathies and electrodiagnostic studies can be helpful to confirm localization.

  
  
• iv.
  

  MRI images of the cervical spine and plexus are required to assess for bulky locoregional disease that may be amenable to treatment with surgery or radiation therapy.

Radiation-induced brachial plexopathy (RIBP)

• i.
  

  RIBP can occur years following the initial course of radiation therapy.

  
  
• ii.
  

  The progression of symptoms may occur in an indolent fashion over months and even years and is typically in the form of sensory symptoms, pain, and worsening weakness and atrophy.

  
  
• iii.
  

  Although classically thought to involve the upper plexus, RIBP can also involve the lower plexus or entire plexus, as is the case in this scenario.

  
  
• iv.
  

  Imaging of the brachial plexus may reveal RT-related changes in other adjacent anatomic structures such as the lung, bones, and connective tissue.

Lumbosacral plexopathy

• i.
  

  A prior history of a pelvic floor tumor and new lower extremity symptoms should raise the concern for a lumbosacral plexopathy related to local disease recurrence or metastasis.

  
  
• ii.
  

  Electrodiagnostic studies are not required to confirm localization if the imaging findings can account for the localization suggested by the clinical examination.

Lymphomatous meningitis

• i.
  

  Lymphomatous infiltration of the leptomeninges is the most common neurologic complication of non-Hodgkin lymphoma (NHL).

  
  
• ii.
  

  The clinical presentation of leptomeningeal metastases is characterized by multifocal neurological signs and symptoms affecting the brain, cranial nerves, spinal cord, and exiting nerve roots. It may also cause obstructive hydrocephalus.

  
  
• iii.
  

  MRI demonstrating leptomeningeal enhancement and CSF analysis including cytology and flow cytometry are typically needed for diagnosis of leptomeningeal involvement.

  
  
• iv.
  

  Treatment strategies for leptomeningeal disease typically include a combination of intrathecal and systemic chemotherapy.

CNS recurrence of systemic lymphoma

• i.
  

  Parenchymal metastases are less common than leptomeningeal disease in secondary CNS lymphoma, with the exception of DLBCL.

  
  
• ii.
  

  Treatment of secondary CNS lymphoma with parenchymal disease is similar to that of primary CNS lymphoma, including systemic high-dose methotrexate, rituximab, and temozolomide as primary treatment options. Emerging treatment agents include lenalidomide, ibrutinib, and immune therapies.

Epidural spinal cord compression

• i.
  

  Red flag symptoms of spinal cord compression in a patient with known cancer such as back pain, lower extremity weakness, incontinence, and gait instability should prompt urgent neurologic evaluation and spinal MR imaging.

  
  
• ii.
  

  Initial treatment includes intravenous dexamethasone 10 mg IV followed by 4 mg every 6 hours to reduce vasogenic edema with close monitoring of patient’s symptoms and neurological examination.

  
  
• iii.
  

  Hematologic malignancies are radiosensitive and urgent treatment should be provided to reduce the risk of permanent neurological injury.

Neurolymphomatosis

• i.
  

  Neurolymphomatosis is a rare manifestation of lymphoma, and may manifest as a painful radiculopathy, cranial neuropathy, painless polyneuropathy, or mononeuropathy.

  
  
• ii.
  

  MR imaging is useful for diagnosis; however, nerve biopsy is the gold standard of diagnosis and will show lymphomatous cell infiltration in the perineurium and endoneurium.

  
  
• iii.
  

  Treatment of neurolymphomatosis involves high-dose IV methotrexate with ibrutinib and lenalidomide as possible options for refractory cases.

CNS prophylaxis for high-risk systemic lymphoma

• i.
  

  The prevalence of CNS involvement in acute lymphoblastic leukemia is sufficiently high that all patients should routinely receive CNS prophylaxis.

  
  
• ii.
  

  CNS prophylaxis in DLBCL is reserved for high-risk patients.

  
  
• iii.
  

  The best prophylactic strategy is yet to be determined, but regimens typically include intrathecal chemotherapy in combination with systemic chemotherapy. Ommaya reservoir placement for intrathecal therapy may be desirable in some patients due to the need of frequent injections and superior distribution of the drug after intraventricular administration.

Paraneoplastic disorders in hematologic malignancies

• i.
  

  Paraneoplastic syndromes are rarely associated with Hodgkin and non-Hodgkin lymphoma and most cases have negative onconeural antibodies.

  
  
• ii.
  

  Patients with low-grade lymphomas may have accompanying devastating paraneoplastic neurological disorders. Some of these patients respond to immunotherapy.

  
  
• iii.
  

  PCA-Tr, mGluR1, and mGluR5 are well-recognized biomarkers of paraneoplastic neurological syndromes associated with Hodgkin lymphoma.

  
  
• iv.
  

  Granulomatous angiitis is a unique paraneoplastic syndrome associated with Hodgkin lymphoma.

Pseudoprogression in glioma

• i.
  

  Pseudoprogression is an earlier and reversible form of radiation necrosis that typically occurs within 3 months of chemoradiotherapy for glioma and resolves spontaneously.

  
  
• ii.
  

  Although there is no imaging modality proven to provide accurate diagnosis of radiation necrosis, MR perfusion, MR spectroscopy, or PET may be considered to help supplement the diagnostic workup.

Radiation necrosis in glioma

• i.
  

  Delayed radiation necrosis can occur months or years after fractionated RT and can continue to wax and wane even after surgical resection.

  
  
• ii.
  

  Surgical resection or prolonged follow-up of clinical course remains the best way to establish the diagnosis of radiation necrosis at the current time.

  
  
• iii.
  

  In cases of suspected radiation necrosis, early involvement of a multidisciplinary team that includes neurosurgeons, radiation oncologists, and neuro-oncologists is recommended.

  
  
• iv.
  

  Asymptomatic cases should be initially observed with close monitoring.

  
  
• v.
  

  For symptomatic cases, corticosteroids are the initial mainstay of treatment.

  
  
• vi.
  

  Additional treatment options for mild cases include Vitamin E and pentoxifylline; for more severe cases, surgery, interstitial laser ablation, bevacizumab, or hyperbaric oxygen may be considered.

Neurocognitive dysfunction from radiation (beamo- brain)

• i.
  

  The neuropsychologic evaluation should include an assessment of fatigue and depression as both occur at high rates within the brain tumor patient population and can impact cognitive functioning.

  
  
• ii.
  

  Neuropsychologic evaluation should be performed by a board-certified neuropsychologist who is experienced in working with brain tumor patients.

  
  
• iii.
  

  Neurologists and neuro-oncologists should use the neuropsychology report to guide treatment interventions that can include pharmacologic and non-pharmacologic interventions.

  
  
• iv.
  

  Cognitive impairment can indicate disease recurrence or progression so imaging should be obtained if a patient has a significant and sudden decline in cognitive performance.

  
  
• v.
  

  However, cognitive impairment often increases over time after treatment for brain tumors in the absence of disease progression as a result of treatment-related damage to neural circuitry.

  
  
• vi.
  

  Shortened neuropsychologic examinations may be appropriate for brain tumor patients who are older or have poorer performance status as they may not have the stamina to complete a full evaluation.

  
  
• vii.
  

  Patients with severe cognitive impairment may not be capable of living independently. Consideration should be given in these cases to home safety evaluations or assisted living should be discussed with the patient’s family.

  
  
• viii.
  

  Preventive strategies are an area of very active research and include radioprotective agents, use of radiosurgery, and hippocampal-avoidance.

Radiation myelitis

• i.
  

  Radiation myelitis is the most common of the rare complications of spinal cord irradiation and can present as a transient early or irreversible late reaction.

  
  
• ii.
  

  Other rare complications include paralysis secondary to ischemia, hemorrhage, and lower motor neuron syndrome.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome

• i.
  

  SMART syndrome is a delayed complication of brain irradiation characterized by recurrent episodes of complicated migraines.

  
  
• ii.
  

  This is a rare entity with approximately 40 reported cases.

  
  
• iii.
  

  Time to onset in these cases ranges from 1–35 years with a median of 14 years post-irradiation.

  
  
• iv.
  

  Common symptoms include headache, seizure, hemianopsia, hemiparesis, and aphasia.

  
  
• v.
  

  Symptoms are often recurrent over a period of hours to weeks but generally considered reversible, although incomplete neurologic recovery has been reported.

Hypothalamic dysfunction

• i.
  

  Dysfunction of the hypothalamus most often involves the hypothalamic-pituitary axis but can also be limited to the hypothalamus alone.

  
  
• ii.
  

  The hypothalamus is located in the ventral brain above the pituitary gland and may fall within the radiation field during cranial irradiation for numerous indications including prophylactic irradiation (≤30 Gy), total-body irradiation (10–14 Gy), and treatment of primary brain, nasopharyngeal, sinonasal, skull base, and metastatic lesions (≤60 Gy).

  
  
• iii.
  

  The hypothalamus releases hormones that act on the pituitary gland, forming the hypothalamic-pituitary axis to regulate multiple endocrine systems and is also involved in nonendocrine functions of temperature, appetite, and autonomic nervous system regulation.

  
  
• iv.
  

  Disruptions of either the hypothalamic or pituitary component of the axis can lead to endocrine dysfunction, both of which require care coordination with endocrinology, with a focus on managing hormonal derangements.

Post-radiation vasculopathy and stroke

• i.
  

  Post-radiation vasculopathy is a late-onset complication potentially manifesting as ischemic or hemorrhagic cerebrovascular accidents (CVA), vascular occlusive disease, vascular malformations, or intracranial hemorrhage.

  
  
• ii.
  

  Incidence is higher among those who received radiation as children compared to adults.

  
  
• iii.
  

  The pathophysiology of radiation-induced vascular injury is complex and attributed to multiple changes including progressive endothelial loss, disruption of the blood-brain barrier, inflammation, vasogenic edema, and thrombosis, followed by long-term effects on vascular remodeling including atheroma formation, endothelial proliferation, adventitial fibrosis, basement membrane thickening, and eventual vessel dilation.

Radiation-induced meningioma

• i.
  

  Meningiomas are tumors arising from the meninges surrounding the brain and spinal cord and are the most common primary CNS tumors, accounting for approximately one-third of cases.

  
  
• ii.
  

  While the vast majority of meningiomas arise spontaneously, prior exposure to ionizing radiation is an established acquired risk factor for development of meningioma, and meningiomas are in fact the most common secondary CNS tumors following cranial RT.

Radiation-induced glioblastoma

• i.
  

  Radiation-induced gliomas (RIG) are a rare but known entity following cranial irradiation, second to radiation-induced meningiomas.

  
  
• ii.
  

  Criteria for RIG are similar to those for other secondary neoplasms per modified Cahan criteria, including occurrence within the irradiated field, sufficient latency between radiation and new neoplasm development, distinct tumor histology compared to the primary lesion, and absence of genetic predisposition to tumor development.

Posttreatment PML

• i.
  

  The risk for infection continues well beyond the active treatment period.

  
  
• ii.
  

  CSF can be negative for John Cunningham (JC) virus when tested by commercially available methods.

  
  
• iii.
  

  CSF formulas in immunocompromised patients can fail to reflect inflammation in the presence of cytopenias or impaired immune response.

  
  
• iv.
  

  PML can have variable appearances with or without contrast enhancement.

  
  
• v.
  

  Immunocompromised patients should have screening CT/MRI before lumbar puncture.

  
  
• vi.
  

  There is no established therapy for PML, but pembrolizumab is being investigated.

Posttreatment meningoencephalitis

• i.
  

  Up to 15% of leukemia and lymphoma patients will have symptomatic dermatomal varicella zoster virus infection. Post-herpetic neuralgia is more than three times as frequent in cancer patients as in those without cancer who develop shingles.

  
  
• ii.
  

  Systemic neurologic syndromes from zoster include the well-known dermatomal or disseminated skin lesions, focal segmental weakness, acute encephalitis or myelitis, vasculopathy with large and small vessel arteritis—40% of whom have no history of rash and up to one-third who have no CSF pleocytosis.

  
  
• iii.
  

  Ocular manifestations of varicella zoster virus include Ramsay-Hunt syndrome, pontine myelitis infarction of one or more cranial nerves, acute monocular visual loss with temporal arteritis-like presentation, and acute outer retinal necrosis.

  
  
• iv.
  

  The new varicella zoster virus subunit vaccine (Shingrix) is appropriate for immunocompromised patients.

Chemo brain

• i.
  

  Radiation in childhood leads to many long-term sequelae including endocrinopathies, vasculopathy, neurocognitive dysfunction, and risk of second malignancy among others. The patient (in Case 27.3) did not have cavernous angiomata or communicating hydrocephalus and had no evidence of a secondary neoplasm, both differential considerations in this situation.

  
  
• ii.
  

  Superficial siderosis is a syndrome usually appearing many years after cranial surgery or traumatic brain injury, particularly in the posterior fossa. The pathophysiology is deposition of hemosiderin around the brainstem and cerebellar folia; the MRI signature is a rim of hypointensity around the basal cisterns and in the cerebellum.

  
  
• iii.
  

  Differential diagnosis of late-onset cognitive change after cancer treatment, as in this patient, should include interrogation of endocrine status for further discussion of evaluating patients with treatment-induced neurocognitive dysfunction.

  
  
• iv.
  

  Chronic cytopenias raise the risk of a myelodysplastic syndrome and such patients require lifelong surveillance.

  
  
• v.
  

  Chemo brain is not explained exclusively by affective disorder or post-traumatic stress disorder.

  
  
• vi.
  

  Early detection of cerebral micro-hemorrhages requires attention to specific susceptibility-weighted imaging MRI sequences and may represent an opportunity to adjust therapeutic strategies before cognitive impairment becomes clinically detectable.

  
  
• vii.
  

  Specific attention to rigorous hypertension and other vascular risk factor treatment is indicated.

Delayed posttreatment leukoencephalopathy

• i.
  

  Delayed leukoencephalopathy has been seen in transplant recipients receiving cyclosporine or tacrolimus.

  
  
• ii.
  

  There is emerging clinical experience with some patients who are receiving immune checkpoint inhibitors who may experience accelerated cognitive decline with immune-mediated encephalitis as the underlying pathophysiology and often a limbic encephalitis pattern on MRI.

Posttreatment stroke

• i.
  

  Posterior reversible encephalopathy syndrome should be considered in many clinical settings, the common denominator often being elevated blood pressure and usually involves CT/MRI evidence of vasogenic edema predominantly in the posterior cerebral hemispheres.

  
  
• ii.
  

  Bevacizumab has been associated with both thrombotic and hemorrhagic events. Individualized decisions must be made about the risk/benefit of continuing this drug in the presence of arterial or venous thrombosis.

  
  
• iii.
  

  There are multiple mechanisms of hemorrhagic and ischemic stroke in cancer patients whose presentation may appear to be more of a mental status change than the onset of a focal deficit.

  
  
• iv.
  

  There are no firm guidelines for the use of direct oral anticoagulants in cancer patients with brain metastases or primary brain tumors.

  
  
• v.
  

  Bevacizumab has been associated with both thrombotic and hemorrhagic cerebral events as well as venous thromboembolism.

Treatment-induced malignancies

• i.
  

  Lifelong monitoring includes attention to vascular, endocrinologic, dermatologic, dental, cardiac, and pulmonary function.

  
  
• ii.
  

  Neurological monitoring should include inquiry about both central (cognitive, vascular) and peripheral (peripheral neuropathy, pain) nervous system problems.

  
  
• iii.
  

  Psychosocial problems can be addressed with appropriate neuropsychologic testing and education plans.

  
  
• iv.
  

  Secondary cancers include both primary brain tumors and systemic neoplasms that can be related both to prior radiation therapy and to antecedent chemotherapy.

Taxane-induced chemotherapy-induced peripheral neuropathy (CIPN)

• i.
  

  Taxanes, including paclitaxel, docetaxel, and cabazitaxel, have been used for nearly 30 years to treat a variety of cancers including breast, ovarian, non–small-cell lung cancer, and prostate cancer.

  
  
• ii.
  

  Skin biopsy is another technique that allows for objective quantification of intraepidermal nerve fiber density in small fiber sensory neuropathies like CIPN.

Oxaliplatin-induced CIPN

• i.
  

  Acute oxaliplatin neuropathy is an infusional hyperexcitability that results in cold allodynia and paresthesias of the hands and feet precipitated by cold exposure within 24 hours of the oxaliplatin infusion.

  
  
• ii.
  

  Chronic oxaliplatin-induced CIPN is characterized by a pure sensory, axonopathy that develops in a stocking-and-glove distribution.

  
  
• iii.
  

  Venlafaxine was shown to relieve the acute neuropathy from oxaliplatin when given 1 hour prior to the infusion.

  
  
• iv.
  

  Duloxetine is an American Society of Clinical Oncology (ASCO) recommended therapy for patients with established CIPN based on results of a phase III, randomized, double-blind, placebo-controlled crossover study where 231 patients were randomized to receive duloxetine at a target dose of 60 mg daily or placebo for six weeks.

CIPN in hematologic malignancies

• i.
  

  Peripheral neuropathy is most commonly associated with vincristine but can be seen to a lesser degree with the other vinca alkaloids.

  
  
• ii.
  

  Brentuximab is a CD30-specific antibody-drug conjugate that has activity in relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Peripheral neuropathy is one of the most common treatment-related adverse events of this agent.

  
  
• iii.
  

  There are two main goals when managing CIPN: the first is to prevent CIPN before it occurs; the second is to relieve symptoms once CIPN has set in.

Bortezomib-induced peripheral neuropathy

• i.
  

  Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and mantle cell non-Hodgkin lymphoma.

  
  
• ii.
  

  The neurotoxicity is dose-dependent and the duration is variable; the painful peripheral neuropathy has resolved in some patients within weeks, and in other patients it has persisted for years.

  
  
• iii.
  

  Paraproteinemic neuropathy refers to a heterogeneous set of neuropathies associated with the presence of a clonal proliferation of immunoglobulin in the serum.

  
  
• iv.
  

  Neuropathic pain typically presents as a length-dependent axonal sensorimotor polyneuropathy resulting in numbness, paresthesias, allodynia, cramping, or mild distal motor weakness.

Serious neurologic immune-related adverse events (IRAEs) have been shown to occur in up to 1% of patients receiving immune checkpoint inhibitors (ICIs).

In general, IRAEs have been shown to be more common and more severe in patients receiving combination therapy.

Neurologic IRAEs from ICIs are idiosyncratic and can occur at any point during treatment.

Neurologic IRAEs are highly variable and have been shown to occur throughout the nervous system, with presentations including encephalitis, meningitis, myelitis, meningoradiculitis, myasthenic syndrome, Guillain–Barre-like syndrome, and peripheral neuropathy.

The differential diagnosis in a patient receiving ICIs and presenting with a new neurologic syndrome includes infection, tumor progression, primary neurologic syndrome and neurologic IRAE. Infection and tumor progression in particular must be ruled out as part of the workup for a neurologic IRAE, often requiring neuroimaging and lumbar puncture.

The treatment of neurologic IRAEs varies by the grade of adverse event, but for IRAEs of grade 2 or higher, will typically require oral or intravenous corticosteroids and delay in, or discontinuation of, immunotherapy.

Fatal neurotoxicity has been described in clinical studies of chimeric antigen receptor (CAR) T-cell therapies.

Neurotoxicity from CAR T-cells is highly correlated with manifestation of cytokine release syndrome (CRS), and neurologic symptoms are preceded by fever in most patients.

Common signs and symptoms of CAR T-cell–associated neurotoxicity include lethargy, somnolence, impaired attention, headache, tremor, dysgraphia, aphasia, focal weakness, seizures, and elevated ICP. Of these signs and symptoms, only expressive aphasia is highly specific for neurotoxicity from CAR T-cells, often manifesting as an awake patient who is mute and does not respond verbally or physically to an examiner.

Neuroimaging is frequently unrevealing in patients with neurotoxicity from CAR T-cells, but may reveal nonspecific T2/fluid attenuated inversion recovery (FLAIR) signal abnormality and/or cerebral edema in severe cases. Serum levels of inflammatory markers may correlate with severity.

CAR T-cell–associated neurotoxicity is graded based on assessing multiple neurologic domains that span the constellation of signs and symptoms associated with this phenomenon; CARTOX and the American Society for Blood and Marrow Transplantation (ASBMT) immune effector-cell associated neurotoxicity syndrome (ICANS) Consensus Grading systems are the most commonly utilized.

Management of neurotoxicity from CAR T-cell therapy is primarily supportive in nature and is based on the toxicity grade. Anti-IL-6 therapy is recommended for patients with grade ≥1 neurotoxicity with concurrent CRS; if not associated with CRS, corticosteroids are the preferred treatment for grade ≥2 neurotoxicity, and can be tapered after improvement of ICANS to grade 1.

Both seizure-like activity and non-epileptic myoclonus are common in patients with neurotoxicity from CAR T-cells, and EEG typically demonstrates diffuse background slowing. For patients who progress to non-convulsive or convulsive status epilepticus, benzodiazepines and levetiracetam are preferred; phenobarbital is added if seizures persist.

CAR T-cell–associated neurotoxicity with raised ICP should be managed promptly with corticosteroids and acetazolamide; patients who develop grade 4 neurotoxicity with cerebral edema should also receive hyperventilation and hyperosmolar therapy.

Patients who receive CAR T cell therapy are often heavily pre-treated for their malignancies and may have significant medical comorbidities. Therefore, it is critical that a broad differential diagnosis is considered beyond CAR T-cell–related neurotoxicity is considered when neurologic symptoms are encountered in these patients. Diagnostic considerations include but are not limited to intracranial bleeding in the setting of thrombocytopenia, opportunistic infections, and CNS involvement of the patient’s tumor.