Prior studies have shown that parenchymal or brain metastases are less common than leptomeningeal metastases from NHL, accounting for 16% of CNS involvement. However, more recent studies have demonstrated that 50–75% of the patients with CNS involvement develop brain relapse only [18–20, 46]. Signs and symptoms may be focal or generalized depending on the site and number of lesions. Patients may develop progressive focal motor or sensory symptoms, gait abnormalities, mental status changes, or symptoms and signs of raised intracranial pressure. Cranial nerve deficits are often seen. Seizures and headaches are less common, but can occur. Involvement of the brain by intravascular lymphoma can lead to strokes.

Gadolinium-enhanced MRI of the brain is the optimal imaging for the CNS. Brain metastases can occur anywhere within the brain and appear as single or multiple, homogenously enhancing lesions on T1 post-contrast sequences of MRI. See Fig. 31.2a, b. There is associated surrounding edema as evidenced by T2 hyperintensity. The appearance is radiographically similar to primary CNS lymphoma (PCNSL) with a common site being deep gray matter. The differential includes primary brain malignancy such as glioma or other neurologic disorders, such as infectious, vascular, inflammatory, demyelinating, or autoimmune conditions. Diagnosis is made by evaluation of CSF or by brain biopsy for pathologic confirmation.

Systemic chemotherapy with high-dose methotrexate (HD-MTX) is the standard treatment for lymphoma in the brain parenchyma [47–49]. This is associated with high response rates that are typically not durable. Addition of high-dose cytarabine and rituximab, which are used in treatment of PCNSL, may be considered [50, 51]. Some studies have combined HD-MTX with ifosfamide or procarbazine. More recently, studies with high-dose chemotherapy followed by autologous stem cell rescue have shown improved survival in patients with CNS involvement by NHL [41–44]. Intrathecal chemotherapy may be considered in combination with systemic chemotherapy especially in patients with CSF involvement, but by itself it is not recommended due to inadequate brain penetration. Radiation is typically used for palliative treatment in secondary CNS lymphoma, particularly in those who do not respond to or are not candidates for systemic chemotherapy. Whole brain radiation may be considered for brain involvement. Involved field radiation is typically not recommended in CNS lymphoma due to its invasiveness and extent of disease, but may be considered for palliation and symptom management. While craniospinal radiation would treat the full extent of disease particularly in leptomeningeal metastases or disease with brain and spinal cord involvement, it is associated with significant morbidity including neurologic side effects, fatigue, and bone marrow toxicity.

Corticosteroids can help with symptom management by reducing tumor burden and associated edema. They also have direct lymphocytolytic effects, and so should be held prior to obtaining pathologic diagnosis.

Intramedullary spinal cord metastases from NHL are rare [52]. Often, spinal cord involvement is a result of epidural disease or in conjunction with leptomeningeal metastases. Patients may present with signs and symptoms of a myelopathy such as weakness, sensory level, spasticity, and bladder/bowel dysfunction. Spinal cord lesions may be present at multiple levels.

Total spine MRI with and without gadolinium contrast is optimal for evaluation of spinal cord metastases, which typically show intramedullary contrast-enhancing lesions with associated cord edema. There may be involvement of the cauda equina associated with intradural lesions or leptomeningeal enhancement along the cord and nerve roots. Spinal cord biopsies are typically not performed due to the risk of permanent neurologic deficits and reserved for cases in which CSF is negative and the clinical and radiographic picture are not suggestive of lymphoma.

For acute onset and progressive myelopathy, corticosteroids are helpful with symptom management, followed by focal radiation. Chemotherapy is considered when neurologic symptoms are mild.

Dural and epidural metastases typically occur in the spine as a result of vertebral body, intervertebral foramina or paraspinal muscle involvement of NHL [52]. Patients typically present with signs and symptoms of cord compression or cauda equina syndrome depending on the location in the spine. Patients may present with back pain or weakness. Back pain in a patient with systemic NHL particularly with known bony involvement should raise the suspicion for epidural spinal cord compression.

Dural metastases in the brain are less common and cause symptoms from compression of the brain and mass effect. Patients may present with headache, seizures, or focal deficits based on the location and size of the lesion.

Spine and brain MRI are useful for diagnosis. Occasionally, leptomeningeal metastases may also be present. Biopsy may be considered in patients without a known diagnosis of NHL.

Cord compression is a neurosurgical emergency, and surgery and decompression may be necessary in unstable cases. High-dose corticosteroids, such as dexamethasone, are used for acute management. NHL is radiosensitive and in patients with a known diagnosis emergent radiation is preferred. Chemotherapy is typically not preferred in patients with cord compression as neurologic and radiographic response is slower than with radiation.

Direct compression or infiltration by NHL can lead to plexopathies. Symptoms include severe pain in addition to weakness and sensory loss in the distribution of the involved levels of the plexus. The differential includes radiation induced plexopathy and paraneoplastic plexopathy, both which may be seen as indirect complications of NHL. The distinguishing feature is pain, which typically indicates lymphomatous plexopathy.

Imaging with MRI demonstrates enhancement of the involved plexus (Fig. 31.3). Rarely, biopsy is employed for diagnosis.

Focal radiation or chemotherapy is used for treatment of lymphomatous plexopathy. Radiation also helps with quicker pain relief.

Neurolymphomatosis or lymphomatous involvement of nerve roots and peripheral nerves is a rare complication of NHL [53, 54]. Patients typically present with a painful peripheral neuropathy or radiculopathy. Mononeuropathies of the sciatic, median or radial nerves may be seen. Occasional cranial nerves are also involved. Motor or sensory nerves can be involved. This may also be seen in association with plexopathies. Pain is absent in 25–50% of the cases.

PET imaging is helpful in diagnosis of neurolymphomatosis. The involved areas show increased uptake. MRI is also useful when the involved segment of nerve is imaged.

Chemotherapy and focal radiation are the modalities of treatment.

Chemotherapy-induced and paraneoplastic peripheral neuropathy are described in detail in other chapters.

Lymphomatous involvement of the muscle is rare. The most common form of muscle involvement in NHL is related to corticosteroid induced proximal myopathy, which is discussed in Chap. 19. The muscle (dermatomyositis and polymyositis) and neuromuscular junction may be involved in paraneoplastic syndromes from NHL (later in this chapter and reviewed in Chap. 13 in detail).

Classic paraneoplastic neurologic syndromes are rare in lymphomas and different from those seen in association with solid tumors. The incidence of paraneoplastic syndromes is higher in HL, and the type and frequency differ between NHL and HL [58]. Onconeural antibodies are often absent except with paraneoplastic cerebellar degeneration (more common in HL). Dermatomyositis, polymyositis, and sensorimotor neuropathies are seen in association with NHL. Brainstem and limbic encephalitis, neuromyotonia, and motor neuron disease have also been reported [58, 59]. A detailed description of paraneoplastic neurologic syndrome is available in Chap. 13.

Neurologic complications can result from the various treatment modalities for NHL including chemotherapy, radiation, autologous stem cell transplant, and allogeneic transplant. Please refer to Chaps. 14–20 for specific treatment-related complications.

Radiographic evaluation by spine MRI with and without gadolinium is optimal, followed by CSF or tissue analysis, although spinal cord biopsy is rarely performed.

Spinal HL responds well to radiation and/or chemotherapy. Surgery is reserved for patients with spinal instability and progressive neurologic deficits [73]. The degree of motor deficits remains the single most important prognostic factor for outcome and recovery of function after treatment.

Cerebrospinal fluid (CSF) studies generally reveal elevated protein and lymphocytic pleocytosis. The identification of Reed-Sternberg cells in the CSF cytology is a definitive indicator of HL-related leptomeningeal metastases [76]. Additionally, if eosinophilic pleocytosis is identified, one should consider HL-related leptomeningeal metastases [74].

No standard treatment exists for HL-related leptomeningeal disease, but intrathecal chemotherapy may play a role in these patients. If untreated, patients die from their disease within weeks to months.

The diagnosis of primary angiitis of the CNS and HL is often made simultaneously or closely correlated in time [77]. The diagnosis is challenging because there exist no specific findings on MRI, CSF analysis, or cerebral angiography; in fact, these results can appear normal [83]. One should be suspicious of this entity if the cerebral angiography identifies multifocal and segmental narrowing of blood vessels, or microaneurysm formation. Ultimately, the diagnosis requires a biopsy of the leptomeninges or brain parenchyma demonstrating focal and segmental non-necrotizing granulomatous inflammation of small vessels. Other conditions associated with primary angiitis of the CNS include herpes zoster, HIV, and Sjögren syndrome.

No evidence-based treatment strategies are available for the treatment of primary angiitis of the CNS associated with HL, but the combination of corticosteroids and immunosuppression with specific treatment of HL should be initiated. Unfortunately, results are usually disappointing.