Neuropathies associated with lymphoma

Abstract

Neuropathy occurs with various manifestations as a consequence of lymphoma, and an understanding of the etiology is necessary for proper treatment. Advances in medical imaging have improved the detection of peripheral nerve involvement in lymphoma, yet tissue diagnosis is often equally important. The neoplastic involvement of the peripheral nervous system (PNS) in lymphoma can occur within the cerebrospinal fluid (CSF), inside the dura, or outside of the CSF space, affecting nerve root plexuses and peripheral nerves. The infiltration of either cranial or peripheral nerves in lymphoma is termed neurolymphomatosis (NL). These infiltrations can occur as mononeuropathy, multifocal neuropathy, symmetric neuropathies, or plexopathies. In rare cases, intravascular lymphoma (IL) can affect the PNS and an even rarer condition is the combination of NL and IL. Immune-mediated and paraneoplastic neuropathies are important considerations when treating patients with lymphoma. Demyelinating neuropathies, such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, occur more frequently in non-Hodgkin's lymphoma than in Hodgkin's disease. Paraproteinemic neuropathies can be associated with lymphoma and paraneoplastic neuropathies are rare. While the treatment of lymphomas has improved, a knowledge of neurotoxic, radiotherapy, neoplastic, immune-mediated and paraneoplastic effects are important for patient care.

Peripheral neuropathies occur in patients with lymphoma at different stages of the disease and under various conditions. Cranial nerve (CN) lesions, mononeuropathies, and polyneuropathies can be the presenting signs in patients with lymphoma, or appear during treatment or late in the course of the disease. A wide spectrum of causal mechanisms, such as a neoplastic involvement of CN and peripheral nerves, toxic effects, and immune-mediated and paraneoplastic syndromes, have been reported, as have other less specific causes, such as infection, the effects of weight loss, and local mechanical lesions.

In clinical practice, following the neurological examination, electrophysiology is often the first investigation helping to identify nerve lesions. Increasingly, imaging is becoming one of the most important tools for investigating cancerous nerve lesions. In addition to MR, CT, and PET, the use of ultrasound for this purpose has been increasing. Once the cause of the lesions has been identified, therapy can be initiated.

This review presents the mechanisms that result in nerve damage in cases of lymphoma along with diagnostic methods, such as electrophysiology and imaging.

General Aspects of Lymphomas

Lymphomas are malignant hematological neoplasms of lymphocytic origin. The current standard classification of malignant lymphomas, established by the World Health Organization in 2008,¹ lists more than eighty unique entities, characterized by distinct genetic abnormalities, immune phenotypes, histology, clinical characteristics, and outcomes. This classification includes Hodgkin and non-Hodgkin lymphomas (NHL), but also includes lymphoid leukemia, meaning leukemia that affects circulating lymphocyte cells, and myelomas, which are tumors arising from plasma cells. These two latter entities will not be considered in this review.

Lymphomas may arise in all body organs and at all ages, with a slight male predominance and slight increase with age. Lymphomas represent 3.4% of all cancer cases worldwide.¹ The incidence of NHL increased steadily by 3% to 4% per year from the 1970s until the 1990s, after which they showed a decrease of 1% to 2% per year.² In 2014, there were 70 800 new cases diagnosed in the United States. More than 500 000 people are currently estimated to be living with lymphoma in the United States.

The incidence rate of NHL varies geographically, with the highest rates in the United States: 16.27 per 100 000 men and 11.46 per 100 000 women, according to world standard population,³ as compared with the rural Chinese population that has an incidence of 2.52 per 100 000 men and 1.66 per 100 000 women. Interestingly, the incidence of lymphomas shows a striking correspondence to income and lifestyle. The highest incidences occur in industrialized countries, including the United States, Canada, Australia, Europe, and Japan, and lower incidences occur in less wealthy countries whose people lead a less sedentary lifestyle and have shorter life expectancy. Many causal factors have been identified for lymphoma, including genetic predisposition, environmental toxins, agents that cause chronic immune stimulation, weakening of the immune system due to infection, and viruses with lymphocyte-transforming properties.²

Lymphomas were among the first cancers known to be responsive to radiation and chemotherapy. In the last decade, the therapy of lymphomas has been improved through the introduction of targeted therapies and adoptive immunotherapy, such as anti CD 20 antibodies in NHL of B cell origin.⁴

Approach to the Patient With Lymphoma and Neuropathy

Generalized neuropathies (polyneuropathies) may appear in several circumstances connected with lymphoma.^5–8 Most frequently, toxic neuropathies have to be considered in these cases. Neoplastic neuropathies, inflammatory and paraneoplastic neuropathies are less frequently observed. Generalized neuropathies can be divided into axonal and demyelinating lesions as well as symmetric and asymmetric types. Axonal types of neuropathy are the most frequent type and are often due to chemotherapy. Demyelinating neuropathies are rare but point towards an association with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or a paraproteinemia. These types of neuropathies are depicted in Scheme 1, Figure 1 and Table 1.

Scheme 1.

Approach to the patient with lymphoma and neuropathy.

Fig. 1.

Cranial nerve infiltration. Brain MRI of a 48-year-old woman affected with Burkitt's lymphoma and presenting with acute left trigeminal neuralgia (mandibular branch). (A and B) Contiguous coronal contrast-enhanced, T1-weighted images showing the lymphoma infiltrating the dura of the left cavernous sinus and the floor of the middle cranial fossa (white arrows); the ipsilateral foramen ovale is slightly enlarged (black arrowheads) and tumor tissue spreads within the contiguous extracranial soft tissues. (C) Sagittal contrast-enhanced, T1-weighted image showing the spread of the tumor (white arrows) through the foramen ovale (black arrowheads) with likely involvement of the mandibular branch of the trigeminal nerve. Courtesy of Renzo Manara.

Table 1.

Electrophysiology in different types of neuropathies

Electro-physiology	Root Pathology	Focal Nerve Lesions	Polyneuro-pathies Symmetric	Polyneuro-pathies Asymmetric
NCV		+	Axonal demyelinating	+
EMG	+	+		+
Small fiber			+
Autonomic			+

Electrophysiology is helpful in investigating lesions in the peripheral nervous system. Table 1 suggests the use of NCV, EMG, small fiber and autonomic testing in focal nerve lesions and in neuropathies. In neuropathies, the distinction between axonal and demyelinating lesions helps to identify the cause. All of these tests are nonspecific for lymphoma.

NCV: nerve conduction velocities; EMG: electromyography

Neuropathies Appearing Before or at the Presentation of Lymphoma

Neuropathies of various types, such as sensorimotor, motor, and multiplex types, can be the presenting sign of lymphoma. Asymmetric neuropathies should raise a suspicion of vasculitis or neoplastic involvement. An association with a CN lesion makes meningeal involvement more likely.

Neuropathies Appearing During the Course of the Disease

For those patients already suffering from lymphoma, there are four main paradigms:

1. Axonal symmetric sensorimotor neuropathies: consider toxicity of treatment.

2. Asymmetric neuropathies: consider vasculitis and neoplastic involvement.

3. Asymmetric neuropathies with CN lesions: consider meningeal involvement.

4. Demyelinating neuropathy, such as the acute Guillain-Barré syndrome (GBS) and CIDP: consider immune and paraneoplastic causes and also consider that, in rare cases, neurolymphomatosis can mimic CIDP.

Investigative Steps

1. Classify the neuropathy.

2. Use electrophysiology to determine the type (axonal/ demyelinating) and the distribution (symmetry or asymmetry).

3. In cases of focal nerve lesions, use imaging, including MR, MR/CT/PET or, if the site is easily accessible, nerve ultrasound.

4. In cases of suspected neoplastic lesions, confirm by biopsy, including CSF if necessary.

Treatment

1. Toxic neuropathies: consider changing the treatment regimen.

2. Neoplastic involvement: consider using chemotherapy or, if needed, focal radiotherapy.

3. Immune mediated: use steroids, immune-modulation/suppression.

Methods of Investigation

Patients with lymphoma-correlated symptoms of cranial and other peripheral nerves need a spectrum of diagnostic tools, including imaging, electrophysiology, CSF analysis, and tissue confirmation with immunohistochemistry. Neuroimaging is increasingly capable of demonstrating peripheral nerve and plexus involvement and can not only identify the site of lesions, but also give clues as to the pathogenesis.

Electrophysiology and Nerve Conduction Studies

Electrophysiology with nerve conduction velocities (NCV) and electromyography (EMG) gives the clinician the ability not only to localize lesions, but also to distinguish between axonal and demyelinating neuropathies, which can be helpful in finding the etiology of a peripheral nerve lesion.

Focal nerve lesions can be localized using NCV and EMG, however the results of these studies for focal nerve lesions are not specific. Examples of focal nerve lesions can be mononeuropathies, nerve plexus lesions, and, rarely, focal lymphomas presenting as nerve tumors.^9–19 The issue of an asymmetric neuropathy resembling a multiplex or multifocal type has been pointed out by Tomita et al²⁰ and indicates a vasculitic or neoplastic cause.

EMG can also be used to identify normal muscle de- and re-innervation and is helpful for characterizing focal nerve lesions by the distribution of the affected muscles.

Imaging

Magnetic resonance imaging (MRI) is the primary imaging modality for investigating leptomeningeal, plexus, and nerve metastases. With the application of gadolinium contrast media, leptomeningeal metastases can be visualized with a typical linear and nodular enhancement.²¹ Masses surrounding or infiltrating a plexus, as well as a mass within a plexus, can also be easily depicted with MRI.²² Metastases can be shown in MRI as focally thickened nerves, optionally with focal contrast enhancement Figure 2.²³

Fig. 2.

Non-Hodgkin lymphoma infiltration of the brachial plexus. (A) High-resolution ultrasound of the brachial plexus in a coronal plane. Note the thickening of all trunci of the brachial plexus (arrows). (B) T1-weighted MRI scan with fat saturation and contrast enhancement of the same patient. Note the thickening of the brachial plexus (arrows), especially in comparison with the contralateral side.

The application of gadolinium contrast media not only facilitates the detection of metastases within the peripheral nervous system, but also allows monitoring of the tumor's response to therapy.²⁴ MRI can also be used to assess a possible plexopathy that is secondary to the application of radiation therapy. However, stronger contrast enhancement, as well as focal thickening of the nerve structures, is not specific for neurolymphomatosis (NL) and can occur with other diseases. NL lesions might have a patchy distribution and can easily be overseen in a scanning protocol with thick scan slices. A combination of F-fluoro-2-deoxy-D-glucose (FDG) scans using PET with CT (FDG/PET-CT) can be useful for diagnosing NL. Recently, the application of whole-body diffusion weighted sequences has been advocated for staging malignant lymphoma.^25–28 With a specificity and sensitivity comparable to PET/CT but far better availability, this technique could overcome the above mentioned flaws of MRI. However, large prospective studies are still necessary.

FDG/PET-CT allows the evaluation of the peripheral nerve system with respect to the distribution of lymphoma-affected regions and treatment responses.^29,30 Combining the PET signal with CT improves the spatial assignment. FDG-PET/CT has a high sensitivity but may also show nonspecific enhancement in surrounding muscles, soft tissue, and blood vessels. While MRI and PET/CT are established modalities for depicting leptomeningeal and plexuses lesions, they have also proved useful in the visualization of more peripheral regions of the nerves.^23,31,32

In contrast to MRI and PET/CT, ultrasound of the peripheral nervous system is not an established imaging modality in the assessment of NL. Besides commonly understood limitations, such as obstructions of the scan range due to gas and bone, there are no large prospective studies comparing ultrasound to other techniques. If the region of the peripheral nerve can be visualized by ultrasound, this technique should allow the examination of nerves with very high spatial resolution. Thus, focal thickening of the nerve or of some individual fascicles within the nerve or infiltration of the nerve by a surrounding mass might be depicted and subsequently could lead to more focused nerve biopsy. In light of some promising case reports, larger clinical studies with this technique should be initiated Figure 3.^33,34

Fig. 3.

Non-Hodgkin lymphoma infiltration of the femoral nerve. High-resolution ultrasound scan in a longitudinal scan plane. Note the fusiform enlargement of the nerve (arrowheads) and the continuous transition from the infiltration site to the unaffected femoral nerve (arrows).

CSF Analysis

If meningeal or meningo-radicular involvement is suspected, a CSF analysis with cytology, immunohistochemistry, and flow cytometry would be warranted. Diagnostically, such patients usually have a characteristic CSF cytology, which is conventionally needed for confirmation of malignant involvement. Flow cytometry is helpful for identifying neoplastic cells.^35–37

Tissue Biopsy

Tissue from peripheral nerves can be obtained by nerve biopsy (often the sural nerve) or by biopsy of locally enlarged nerves. This is typically easy in limbs, but can be a difficult task for proximal nerves, such as the plexus. A search and precise determination through imaging, in particular ultrasound, would be helpful. Neuropathological staining techniques will allow a precise characterization of neoplastic cells by immunohistochemistry.

Mechanisms of Nerve Damage

In the course of lymphoma, the peripheral nervous system may be involved in different sites (roots, meninges, plexuses, peripheral nerves), and peripheral neuropathies may often represent the first symptom of an underlying lymphoproliferative disease.

The pathogenic mechanisms of peripheral nervous system involvement in lymphoma include direct infiltration of peripheral nerves from the lymphomatous cells, hematogenous spread (as demonstrated by epineurial B cell infiltration in nerve biopsy specimen), amyloid or immunoglobulin deposition, and intravascular proliferation. Iatrogenic neuropathies, both chemotherapy-induced and radiation-induced, are also common.

Viala et al³⁸ described patients with neuropathy in lymphoma and tried to correlate the pattern of neuropathy with the type of lymphoma and prognosis. The authors showed that half of lymphoma-associated neuropathies were demyelinating, and that one quarter of radiculopathies or multiplex neuropathies were caused either by neoplastic changes or by microvasculitis. Neuropathy either precedes or is the initial symptom of lymphoma.

Diagnostic indicators include rapid progression with early axonal involvement, poor response to therapy in demyelinating neuropathies, and an asymmetric pattern of pain in radiculopathies. In all cases, CSF analysis can be informative (see Methods of Investigation). Nerve biopsy may be useful in general, but is essential for vasculitic neuropathies and in cases of neoplastic neuropathy.

Neoplastic Neuropathies

Although neoplastic neuropathies rarely accompany lymphoma, their detection is important since treatment would potentially be available.

Meningeal Lymphomatosis

Lymphoma and meningeal lymphomatosis have been extensively reviewed.^30,39–42 The most frequent neoplastic cause of CN and root involvement is leptomeningeal spread. Multiradicular distribution or cauda equina infiltration can mimic neuropathy. The clinical triad of CNS involvement, CN lesions, and spinal/radicular symptoms/signs usually indicates leptomeningeal carcinomatosis.

Focal Lymphoma

Focal lymphoma can damage CN,⁴³ but can also appear isolated in nerve roots, nerve plexuses, and individual nerves. The clinical appearance is similar to a plexopathy or mononeuropathy.^44,45 In rare cases, a focal lymphoma can mimic an entrapment syndrome, such as carpal tunnel syndrome.⁴⁶ Inflammatory nerve lesions and local amyloidomas have similar presentation so must also be considered in a differential diagnosis.

Neurolymphomatosis

NL is usually a diffuse infiltration of the peripheral nervous system. Reviews of NL by Baehring et al³⁹ and Grisariu et al³⁰ describe this condition in more detail. Histologically, descriptions of NL are not uniform and vary from local tumors to intra -, extra- and pan-fascicular as well as perivascular infiltration of the peripheral nerve Figure 4.

Fig. 4.

Patterns of lymphoma invasion in nerve roots and peripheral nerves. (A) Patchy lymphoma infiltrate between fascicles, which themselves seem to be only slightly affected. (B) Peripheral nerve, perifascicular infiltrate. (C) Nerve root, reticular-like perifascicular lymphoma spread. (D) Nerve root, dense lymphomatous infiltrate within few individual remaining myelinated nerve fibers.

Several types of NL neuropathy occur, including symmetric types, multiplex types, and CIDP-like manifestations. The presentation of NL can also be the first sign of lymphoma⁴⁷ or of a relapse.⁴⁸ Tomita et al²⁰ observed a number of instances of focal and multifocal nerve damage in a small selected series. The diagnosis in suspected cases of NL needs to be histologically confirmed by biopsy. Ultrasound and MRI can be helpful in detecting nerve thickening. Several reports describe successful treatment in individual cases of NL but no standardized treatment is available.

Intravascular Lymphoma

The occurrence of intravascular lymphoma (IL) is even rarer than NL, primarily manifesting itself in the central nervous system, although radiculopathies, nerve plexus, and individual nerves lesions have also been observed.^44,49–52 Generalized neuropathy caused by IL is rare.⁵³ A combination of NL occurring with IL has been described,⁴⁵ but is probably indistinguishable clinically.

Other Types of Infiltration

Several other types of neoplastic infiltration of the peripheral nerves, such as infiltration of dorsal root ganglia and dural infiltration with polyradicular distribution, have been described.^54,55 The infiltration of the dorsal root ganglia is a rare and perhaps underdiagnosed neoplastic condition, which lacks a precise clinical correlate Figure 5.^56–58

Fig. 5.

Dorsal root ganglia (DRG) infiltration in lymphoma. (A) DRG with diffuse patchy lymphomatous infiltrates (arrows). (B and C) Enlarged.

The clinical characteristics of spinal dural lymphoma are not well characterized^54,55,59,60 and may not be distinguishable from meningoradicular spread.

Toxic Neuropathies

Toxic neuropathies are usually characterized by a length-dependent and symmetric neuropathy of axonal type. Chemotherapy-induced neurotoxicity is a frequent cause of peripheral nerve lesions that result in generalized neuropathy. The mechanisms underlying chemotherapeutic neurotoxicity vary and are often dose-dependent or the result of cumulative toxicity. Both conventional drugs, specifically vinca alkaloids, procarbazine, MTX, doxorubicine, dacarbazine, cylophosphamide, chlorambucile and bleomycine,^5,61 and new agents, such as vincristine sulfate liposome, bortezomib,⁶² brentuximab vedotin, nelarabine⁶³ and lenalidomide,⁶⁴ have been implicated.

Nelarabine, which is a purine nucleoside analogue that has been used in T-cell leukemia and in lymphoblastic T-cell lymphoma, can cause severe neurotoxicity with a GBS-like neuropathy,⁶³ especially when applied intrathecally. Brentuximab vedotin (SGN-35; Adcetris^®) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the anti-microtubule agent monomethyl auristatin E.⁶⁵ The antitubulin agent auristatin E causes neurotoxicity. Thalidomide, which has been widely used to treat multiple myeloma, has also been used in some types of lymphoma, such as mantle cell lymphoma, indolent lymphoma, and aggressive lymphoma. Several reviews have described thalidomide-related peripheral neurotoxicity.⁶⁶ Lenalidomide and pomalidomide, which were developed as analogs of thalidomide with fewer side effects, are less neurotoxic.

The proteasome inhibitors bortezomib and carfilzomib have also been used primarily in multiple myeloma, but several reports describe their use in cases of lymphoma.⁶⁷ The neurotoxic effects of these inhibitors seem to be reduced by subcutaneous injection.^68,69

Hand-foot syndrome, also called palmar-plantar erythrodysesthesia, is a side effect of some types of chemotherapy,⁷⁰ specifically connected with 5-fluorouracil, capecitabine doxorubicin, cytarabine, cyclophosphamide, vinorelbine, docetaxel, and some multikinase inhibitors. The sensory and painful sensations can misleadingly cause a suspicion of neuropathy. Pyridoxine is not preventive.⁷¹

Radiotherapy (RT) can induce acute, delayed, and late neurotoxicity on peripheral nerves and muscles.^72,73 Radiation injury often occasionally occurs in the focal treatment of nerve and plexus lesions.^74–76 Vulnerable structures at the base of the skull, such as the optic nerves and other cranial nerves, can be damaged by RT. Skeletal muscle can also be affected by RT-induced local fibrosis (e.g. Hodgkin's disease and mantle field radiation)⁷⁷ and, rarely, a radiation recall syndrome may be observed.^78,79 Secondary nerve tumors have been described as resulting from RT.⁸⁰

Paraneoplastic Neuropathy

Paraneoplastic syndromes are thought to be caused by an autoimmune response to protein (onconeural antigens) shared by the cancer and the central or peripheral nervous system.⁶ Lymphoma-associated paraneoplastic neurological syndromes can manifest themselves in both the central and peripheral nervous systems; however, peripheral nervous system involvement is more prevalent in NHL, especially of B cell type, than in Hodgkin's lymphoma (HL). Recommended diagnostic criteria have been developed based on the presence or absence of an identifiable tumor, clinical presentation (classic or not classic), and the presence or absence of serum antibodies to onconeural proteins.⁸¹

Lymphoma-associated paraneoplastic neuropathy is rare. In a study of 899 patients suffering from paraneoplastic neurological syndromes entered in the Euronetwork database, lymphomas represented only 6.4% of the tumors (68 lymphomas).⁶ In a study of 974 patients with paraneoplastic syndromes (PNS-EURONET group database), Briani et al⁷ found that only 53 cases were associated with lymphoma (24 HL, 29 NHL). Only four of the 24 HL patients suffered from neuropathies. In 62% (18/29) of the NHL patients neuropathy was found. Nine patients had either acute (2 patients) or chronic (7 patients) demyelinating polyradiculoneuropathies, the latter antedating the detection of NHL in 6 of 7 patients. Five patients had a sensory-motor neuropathy and 2 patients a sensory-motor neuronopathy.

Immune-mediated Neuropathies

Vasculitic neuropathies are painful sensory and motor neuropathies that are secondary to the inflammatory destruction of nerve blood vessels and subsequent ischemic injury.⁸²

Secondary vasculitic neuropathies may occur in association with solid tumors, but these are more common in hematologic malignancies.⁸³ In a series by Tomita,²⁰ out of 32 cases with a multiple-mononeuropathy type, 57% suffered from NL and in these cases only nerve biopsy was diagnostic. Lymphomas can also be associated with paraproteinemias,⁸⁴ which can subsequently damage the peripheral nervous system.^85–89 Cryoglobulinemia can also be associated with lymphoma.⁹⁰

Lymphoproliferative diseases are associated with an immune system derangement that likely favors the occurrence of immune-mediated neuropathies, namely acute (GBS) or CIDP. GBS was reported to be more frequent in Hodgkin's disease,^74,91 but results from the largest sample with paraneoplastic syndromes and lymphoma did not confirm this conclusion.⁷

CIDP is more common in NHL and should be considered in a differential diagnosis with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome and NL.²⁰

Lymphoma-associated demyelinating neuropathies can be associated in 55% of the cases with IgM monoclonal gammopathies.³⁸ A prompt and correct diagnosis is crucial to achieve a proper therapy.⁹² Additional mechanisms of inflammation affecting peripheral nerves have been described.⁹³

Motor Neuropathy

Pure motor neuropathies, in the sense of a lower motor neuron disease, have been observed infrequently in conjunction with lymphoma.^94–96 The original description by Schold⁹⁷ showed autoptically a loss of motor neurons, as did a later observation.⁹⁸

Amyloid-induced neuropathy

Amyloid depositions in the peripheral nerves and muscle have been observed in association with lymphoma, causing CN damage or focal damage to peripheral nerves.⁹⁹ Focal amyloidomas¹⁰⁰ damaging peripheral nerves are rare.

Miscellaneous

Generalized sensorimotor neuropathies can appear following weight loss and malnutrition. Also, intensive care treatments complicated by infections and sepsis can cause neuropathy in critical illness. Lymphoma can result in weight loss and cachexia.

Infection is frequently observed concurrently with lymphoma or as an antecedent of the disease. The presence of neurotropic Herpes virus has been considered to be a risk factor for the development of lymphoma¹⁰¹ and is also frequently observed in conjunction with overt lymphoma.¹⁰² Infections with cytomegalovirus only occur rarely with lymphoma and appear to be associated with lymphoma connected with HIV. Isolated or focal nerve damage in conventional sites appearing in a mononeuritic pattern can be caused by an inadvertent IV drip complication, entrapment, malpositioning, surgical procedures, and other nonlymphoma-related causes.

Lesions of the Peripheral Nervous System

Cranial Nerves

CN lesions can be the initial sign of lymphoma or appear during its course. The most common cause of these lesions is meningeal spread, typically involving the optomotor and facial nerves. The optic nerve can be affected in isolation^103–106 or in conjunction with CNS infiltration.^104,107 Usually, the optomotor nerves, the trigeminal nerve, and the facial nerve are bilaterally involved. Caudal CN lesions are less frequently described.^108,109 Lymphoma can also affect various parts of the eye, including the retina, which can cause various types of loss of vision.^110,111 Lymphoproliferative diseases can also cause numb chin syndrome, which affects the inferior alveolar nerve. This may be the result of leptomeningeal tumor spread, bone metastases, or mental nerve infiltration.^112,113

In rare cases, cranial nerve lesions may be caused by primary leptomeningeal lymphoma.^49,114–116 Lymphoma can also appear at different sites of the skull and head, such as the dura, the pituitary gland,¹¹⁷ the cavernous sinus, the clivus,¹¹⁸ the nasal cavities,^119,120 the orbit, the base of the skull,^121,122 and multilocally in the head and neck region involving individual nerves.^123–125 Outside of the cranial vault, the CN consist of a network of anastomoses,¹²⁶ in particular between the Vth and VIIth nerves, but also between the caudal CN and the cervical plexus. The CN and their wide anastomoses can be the site of anterograde and retrograde spread of lymphoma.¹²⁷

Nerve Roots and Nerve Plexus

Lymphoma can affect the nerve roots, proximal parts of the peripheral nerves, and nerve plexuses. Lesions in these areas are most frequently caused by meningeal spread and often associated with additional involvement of the CSF. However, isolated infiltration of the cauda equina has also been described.^128,129 Bulky disease can result in additional spinal cord compression. Infiltration of the nerve roots can be diagnosed and evaluated with functional imaging and on MRI.^130,131 Neoplastic infiltration can also cause vagal nerve¹³² and brachial plexus lesions.^133,134

Radiation therapy can also affect the nerve roots and nerve plexus, but symptoms generally occur later in the course of the disease and rarely do patients have acute or subacute symptoms Figure 6.

Fig. 6.

Lymphoma of cauda equina. (A) MR scan of the lumbar spine shows a mass in the cauda equina (dotted arrow). Distinction of individual nerve roots is impossible. The CSF (T 2) can be seen above the level of vertebrum 1 (small arrow). (B) Autopsy, massively enlarged cauda equina nerve roots (arrow). (C1) Cauda equina (HE staining). The spinal cord parenchyma is invaded by lymphoma via the blood vessels (arrow). The intrinsic parenchyma is spared. Also, the anterior horn cells (C2) are not affected. (D) Nerve root (HE staining) with lymphomatous infiltration.

The cervical plexus is often neglected in neurological assessments, but local radiation therapy can cause dropped head¹³⁵ as well as phrenic nerve lesions,¹³⁶ which may also be caused by vincristine treatment.¹³⁷

The lumbo-sacral plexus

The clinical term “lumbo-sacral plexopathy” is problematic because it is used to describe symptoms involving both the lumbar plexus and the sacral plexus at the same time, despite the two distinct anatomical locations.

The clinical discrimination of symptoms and signs caused by radiculopathies, plexopathies, and individual nerves in the lumbo-sacral region is not precise and symptoms often cannot be exactly allocated to individual nervous structures. Imaging studies are helpful to discriminate the site of the lesion.

Summary

Neuropathies can appear along with an initial presentation of lymphoma or during the course of the disease. They appear with a variety of clinical presentations, are caused by multiple mechanisms, and require unique therapeutic strategies. The most common lymphoma-associated neuropathies are toxic neuropathies, followed by immune- or paraneoplastic neuropathies. Neoplastic neuropathies occur less frequently, may mimic other types of neuropathy, and are potentially more treatable. The direct involvement of the peripheral nervous system in such cases, including but not limited to meningeal involvement, can result in cranial nerve lesions and radiculopathies, both inside and outside of the meningeal space. This direct involvement of peripheral nerves can further be subclassified into NL, IL or combinations, or focal lymphoma situated in peripheral nerves.

In recent years, there have been greater numbers of reported case observations and small series involving NL and IL, either as a result of an increase in the occurrence of these diseases or, more likely, as a consequence of the greater availability of imaging (MR, ultrasound, and PET). Furthermore, the improved survival of lymphoma patients may increase the likelihood of eventual spread to the peripheral nervous system.

Funding

None.

Conflict of interest statement. The authors declare no conflict of interest.