General Child Neurology
May. 31, 2021
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This article includes discussion of neurolymphomatosis, Marek disease, peripheral lymphomatosis, and reticulosis of nervous system. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The term neurolymphomatosis is used to describe peripheral nervous system or spinal root disease resulting from infiltration by malignant lymphoma cells (14; 30). This phenomenon was originally recognized by Marek, who observed a neuropathy in 4 chickens and found demyelination and lymphomatous nerve infiltrates with sparing of internal organs in 1 autopsy (46). Now referred to as Marek disease, it is recognized as a T-cell lymphoma in fowl associated with a Herpes virus (42). Pappenheimer and colleagues attempted to reproduce this condition in experimental chickens in order to identify its etiology; they coined the term “neurolymphomatosis gallinarum” (53). Association with leukemia was described in a report of a young man who died 1 month after presenting with sensorimotor polyneuropathy, anemia, and splenomegaly; autopsy showed leukemic involvement of nerves, liver, kidney, and spleen (26). The term "peripheral lymphomatosis" was proposed by Lhermitte and Trelles for the case of 67-year-old woman with malignant neuropathy and lymphoid nerve infiltrates but no systemic or brain involvement (43).
A histologically similar case of multiple relapsing-progressive mononeuropathies was described by Garcin and colleagues (19). They report that an autopsy 7 months after onset demonstrated generalized nerve enlargement and diffuse lymphomatous infiltration of essentially all nerves, dural spaces, and central nervous system with sparing of internal organs. Radnai and Takacs Nagy described a 36-year-old woman with multiple mononeuropathies and lymphomatous involvement of the brain and peripheral nervous system but not the spinal cord, and of internal organs but not lymphoid organs (57).
Allison and Gordon used the term "reticulosis of nervous system" for the case of a 56-year-old woman with progressive sensorimotor peripheral and cranial neuropathies, characterized by lymphomatous nerve infiltrates (03). Barron and colleagues described a case associated with Hodgkin disease (07). Gherardi and colleagues presented 2 patients with T cell lymphomatous infiltrates (20). Diaz-Arrastia and colleagues presented a literature review dedicated to neurolymphomatosis (14). Vital and colleagues detected retrovirus-like particles consistent with HTLV-1 on electron microscopy of peripheral nerves with T-cell lymphomatous infiltrates (77). Abad and colleagues described 4 cases of neurolymphomatosis with malignant infiltration in Waldenstrom macroglobulinemia (01).
Peripheral neurolymphomatosis is a rare neurologic manifestation of non-Hodgkin lymphoma in which peripheral nerve infiltration of lymphoma cells is a dominant feature both clinically and pathologically. It can be difficult to distinguish from leptomeningeal lymphoma (31), as these patients can present with signs and symptoms attributable to involvement of the peripheral nerves, which include radicular pain, cranial nerve deficits, lower motor neuron disease, or cauda equina syndrome (06).
The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients over a 16-year period (25). Neurolymphomatosis was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It was the initial manifestation of malignancy in 26% of cases. Affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%), with multiple site involvement in 58%. Neurolymphomatosis was also reported as a relapse of intravascular large B cell lymphoma (47).
When peripheral nerves are primarily involved, a variety of neurologic syndromes occurs. The most common syndrome is a progressive sensorimotor polyneuropathy (69; 14). These patients typically present with asymmetric painful neuropathy or paresthesias of the distal extremities with progression to weakness of the proximal or distal extremities over weeks to months. They can develop hyporeflexia, fasciculations, lancinating pain, or diminished cutaneous sensation in a stocking and glove distribution. In addition to polyneuropathy, mononeuropathies occur; these include sciatic neuropathy (79), median neuropathy (35), radial neuropathy (66), and peroneal neuropathy (22). Other syndromes described are mononeuritis multiplex (78), including multiple cranial neuropathies (36), cauda equina syndrome (Abuzinadah and Almalik 2012), plexopathy (55; 51), polyradiculopathy (74), complex regional pain syndrome (38), pseudodiabetic syndrome (ataxia, areflexia, and Argyll-Robertson pupils) due do infiltration of the ciliary nerves and ganglion (41), or nerve root involvement (50).
Aside from the typical course, fulminant courses have been described that resemble acute inflammatory demyelinating polyneuropathy (62; 71; 11). There was 1 case of relapsing-remitting polyneuropathy; exacerbations were associated with infections, fatigue, or surgical procedures (09).
The prognosis of neurolymphomatosis is difficult to separate from that of the underlying malignancy. In an International Primary CNS Lymphoma Collaborative Group report, response to treatment was observed in 46% (25). Median overall survival was 10 months, with 12- and 36-month survival rates of 46% and 24%, respectively. Patients will relapse solely with neurolymphomatosis, despite ongoing complete remission at sites outside the nervous system. Prognosis of these patients is poor.
Excluding neurolymphomatosis, the cure rate for Hodgkin disease stages IA and IIA after radiation therapy is 90% and 70%, respectively. Patients with low-grade non-Hodgkin lymphoma live an average of 10 years after diagnosis, until the malignancy transforms to higher grade. Of those with high-grade non-Hodgkin lymphoma, only 35% are disease-free at 5 years; patients with disease relapses have a worse prognosis, with a 5-year survival of less than 10% (45). Diaz-Arrastia and colleagues found that 36 out of 40 patients had their outcome described (14). They were followed for 3 months to 7 years, with a 75% mortality rate. There was occasional improvement with prednisone, chemotherapy, radiation, or surgery. Instances of systemic spread of lymphoma in patients with solitary peripheral neurolymphomatosis as late as 3 years after treatment emphasize the need for close follow-up (56).
A 79-year-old woman was in good health until 1 year prior to admission, when she developed numbness and tingling in both feet and later in the hands (69). In the 6 months before admission she lost 12 pounds of weight, developed difficulty walking, and fell frequently because of unsteadiness and pain in the soles of her feet. She admitted to moderate alcohol abuse over several years. On examination she had mild lymphadenopathy. Muscle power was generally reduced to 4/5 (British Medical Research Council Classification); knee and ankle reflexes were absent; and plantars were flexor. There was panmodal sensory loss in the legs and a wide based, ataxic gait; a Romberg sign was present. The patient ambulated with a walker. Laboratory data were remarkable for a white blood cell count of 31,000, a hematocrit of 45, and a platelet count of 270,000. Serum protein electrophoresis, quantitative immunoglobulins, folate, and B12 levels were all normal. Cerebrospinal fluid analysis showed a lymphocytic pleocytosis without atypical cells. Glucose was 63 mg/100 ml, total protein was 32 mg/100 ml, and oligoclonal bands were absent. EMG and nerve conduction studies revealed a demyelinating neuropathy with sensorimotor involvement. Motor nerve conduction velocities were reduced: left median 36.3 m/s (normal 49), left ulnar 33.3 m/s (normal 48), left peroneal 25 m/s (normal 44), and left posterior tibial 23 m/s (normal 43). Sensory nerve conduction velocities were also reduced: left median 35.4 m/s (normal 54) and left sural 35 m/s (normal 43). The response after proximal stimulation of the posterior tibial nerve was 30% of the amplitude of the distal response consistent with a 70% conduction block. There was no denervation. A myelogram was noncontributory. Cell marker analysis of peripheral blood lymphocytes revealed a monoclonal B cell population with CD20+, CD5- lymphocytes that expressed HLA-DR and moderately high-density surface immunoglobulins of the gamma-IgM and gamma-IgD isotypes. Light microscopy of a sural nerve biopsy showed moderate reduction of myelinated fibers and a moderate number of myelin ovoids.
The epineurium showed several perivascular foci of monomorphic small lymphoid cells. Scattered small lymphoid cells were located in the endoneurium of 1 fascicle. The lymphoid cells in the epineurium were CD22+ and CD5-. No CD22+ cells were encountered in the endoneurium. The hematopathologic and immunophenotypic findings were consistent with a small lymphocytic lymphoma. Treatment began with prednisone 50 mg orally per day for 5 days and cyclophosphamide 1 g intravenously every 3 weeks. She was then maintained on chlorambucil 2 to 4 mg orally per day. She stopped drinking alcohol. Although her white cell count normalized, the neuropathy did not improve but progressed slowly for 6 months. In this case, the chronic neuropathy was the presenting feature leading to the diagnosis of a lymphoproliferative disorder characterized by CD5- B cells. Even though the nerve conduction study documented segmental demyelination, the neuropathological findings were consistent with axonal degeneration, as the segmental demyelination was not included in the tissue sampled for biopsy.
Malignant lymphomas are divided into non-Hodgkin lymphoma and Hodgkin disease. Non-Hodgkin lymphoma is subdivided into B-cell and T-cell types, with B-cell types comprising approximately 90% of the cases. In a review by Diaz-Arrastia and colleagues, 39 of 40 patients had non-Hodgkin lymphoma, and the other had Hodgkin disease. Among the non-Hodgkin lymphoma cases, 9 were B-cell types (14). Isotypes include IgM, IgA combined IgM and IgD, and both kappa and lambda light chains (28; 70; 69; 14; 23; 01; 39; 51).
Diaz-Arrastia and colleagues suggested that the neuropathy and lymphoma may be caused by a virus with neurotropic properties (14). Kuroda and colleagues presented the case of a HTLV-1 seropositive patient with T-cell neurolymphomatosis (40). Vital and colleagues described retrovirus-like particles in lymphomatous T cells infiltrating nerves (77). Polymerase chain reaction analysis detected sequences resembling the HTLV-1 Tax gene, suggesting that the lymphoma was caused by HTLV-1. In analogy to Marek disease (42), other viruses have been considered. Pietrangeli presented a patient who had negative polymerase chain reaction studies for Epstein-Barr virus and human Herpes virus type 8 (55).
The exact mechanism of how the malignant cells penetrate the peripheral nervous system has yet to be understood. Possible mechanisms are direct neuronal invasion after binding to vascular cell adhesion molecules (34), hematogenous metastasis, or penetration of the CSF space along spinal roots (49). In addition, extranodal lymphoma restricted to the peripheral nervous system may spread systemically (56; 28; 17; 67; 50). Solitary extranodal lymphoma may result from malignant transformation of cells located in intraneural lymphatic channels (49).
Much like the brain, which has a blood-brain barrier to limit access of many compounds into the central nervous system, the peripheral nervous system has a blood-nerve barrier composed of tight capillary endothelial junctions, which accounts for relative resistance to hematogenous spread of tumoral cells (49). Zimmermann reviewed the pathology of 7000 cases of lymphomas involving neural structures and found 10 with peripheral nerve involvement (80). All had extension of malignant cells along blood vessels or invasion between myelin sheaths resulting in destruction of myelin sheaths and axons. A hematogenous mechanism is supported by perineurial location of large atypical lymphoid cells in the perivascular space leading into the nerve bundle (56; 04); however, this is not always present (62; 69; 64; 14; 23), which naturally may represent sampling bias.
Lymphomatous cells may bypass the blood-nerve barrier via several mechanisms. They can access the peripheral nervous system through direct penetration from the leptomeninges, dorsal root ganglia, or spinal roots (where the blood nerve barriers is less tight) traveling in the CSF space along nerve fibers (14; 49), or they can bind to cell adhesion molecules on peripheral nerves. Neural cell adhesion molecules contain homophilic properties found in variable amounts in the brain, meninges, peripheral nervous system, muscle, and certain CD56+ T-cell lymphoma cells, suggesting that these T cells may be able to bind to NCAM+ neuronal cells or processes (34). Kim and colleagues presented a patient with CD56+ T cell lymphoma and infiltration of the sciatic nerve (35). Other pathomechanisms exist, as Misdraji and colleagues presented 4 cases of CD56- lymphoma with peripheral nervous system involvement (50). Thomas and colleagues reported a patient with CD5+ and CD22+ cells in the endoneurium (which have the capacity of producing antibodies) and proposed that a neuropathy in this setting may be caused by local production of antibodies that would have easy access to antigenic sites on neuronal structures (69).
The incidence of lymphoma in the general population is 11/100,000 people annually, whereas neurolymphomatosis is much more rare (27). Camerlingo and colleagues observed 363 consecutive patients with sensory polyneuropathy and found 3 with non-Hodgkin lymphoma infiltrating the peripheral nervous system (10). In 7000 autopsied cases of lymphoma with nervous system involvement, Zimmermann found only 10 with lymphomatous peripheral nervous system infiltration.
In a review, 60% of peripheral neurolymphomatosis patients were men; 75% of all patients in the study were older than 50 years of age (52). However, peripheral neurolymphomatosis has been described at 7 years of age (24).
Neurolymphomatosis should be considered in all patients with unexplained polyneuropathy, mononeuropathy, or mononeuropathy multiplex (78). Patients with lymphoma and recent-onset neurologic presentations must be evaluated for the same etiologies as someone without lymphoma before a definitive diagnosis of neurolymphomatosis is made. As many lymphoma patients are multimorbid, multiple possible causes will coexist. Such causes include diabetes mellitus; neurotoxic drugs; substance abuse and nutritional deficiency as well as other hematologic, neoplastic, and paraneoplastic conditions (27); vasculitides; connective tissue disorders; porphyria; infectious polyneuritis (03); nerve compression (12; 67); schwannoma (23); neurosarcoidosis; Lyme and Whipple diseases (04); and amyloidosis (13).
Physical findings in patients with neuropathy (whether mimicking acute inflammatory demyelinating polyneuropathy or more slowly progressive neuropathies) that should raise suspicion for neurolymphomatosis include new-onset dementia, cranial neuropathies (07), early severe neuropathic pain (75), and asymmetric features.
In patients with known lymphoma, it can be difficult to distinguish intercurrent neuropathies, including acute inflammatory demyelinating polyneuropathy, from rapidly progressive neurolymphomatosis. However, an acute inflammatory demyelinating polyneuropathy diagnosis becomes more likely if neurologic signs improve while the systemic lymphoma progresses (58).
Consultations between neurologists and internists are desirable in the care of patients with neurolymphomatosis. Some 50% of patients are only diagnosed at autopsy (14), which illustrates how difficult the diagnosis can be. Neurophysiological, laboratory, and imaging studies as well as lumbar puncture are best used in combination.
Several laboratory tests serve to identify other or coexisting causes of neuropathy. The physical exam and anatomical structures involved can influence the choice of tests. B12 folate, thyroid stimulating hormone, HgA1C, rapid plasma reagin, antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, c-reactive protein, and renal panel are often indicated, as well as serum and urine protein electrophoresis, for which immunofixation is much more sensitive than traditional methods. Depending on the features, myelin associated glycoprotein, GM 1 ganglioside, Yo, Hu and sulfatide antibodies as well as cryoglobulins, heavy metals, and Vitamin E levels should be assayed.
Neurophysiological studies not only define the type of nerve damage but also identify candidate nerves for biopsy. Diaz-Arrastia and colleagues found that sensorimotor axonal neuropathy was the most common finding on nerve conduction study followed by mixed axonal or demyelinating neuropathy, motor axonal neuropathy, and sensorimotor demyelinating neuropathy (14).
Partial conduction block is an early nerve conduction study abnormality in neurolymphomatosis (54).
All patients with suspected neurolymphomatosis should undergo a lumbar puncture to evaluate for leptomeningeal spread. This is typified by positive cytology. In 1 case, CSF cytology was normal with a traditional filter preparation, but was positive with a cytocentrifuge preparation (48). Diaz-Arrastia and colleagues studied lumbar puncture results for 30 patients with neurolymphomatosis and found that 19 had elevated protein and 21 had elevated cell counts (14). If leptomeningeal spread is a strong concern, repeat and high volume CSF analyses increase the yield because CSF cytology is frequently false negative (05).
Typical magnetic resonance imaging findings are enlarged nerves or masses that are isodense on T1-weighted images, hyperintense on T2-weighted images, and enhance with gadolinium (23; 76). In cases of inconclusive MRIs, MR neurography may be another option. MR neurography uses high resolution T1-weighted images to delineate anatomic structures and fat-suppressed T2-weighted images to detect abnormal water content in the nerves (51). In neurolymphomatosis we see the disruption of the normal fascicular morphology on T1-weighted images and hyperintensities on T2 images (51). A gallium-67 citrate scan can detect lymphomatous involvement of the brachial plexus and peripheral nerves and is used to monitor patient response to therapy (44; 32; 78). Fusion PET-CT has proven to be a powerful imaging tool for diagnosis and staging of NHL. The combined test is more accurate than either of its components and is particularly useful when a biopsy cannot be performed or the results are inconclusive or negative. Limitations include a lack of specificity because infection or inflammation can also produce a positive result. PET-CT has shown lesions along the peripheral nerves (72; 65), cranial nerves (36), and the brachial and lumbosacral plexus (08; 33; 61). PET combined with MRI and EMG proved helpful in a patient with a cervical radiculoplexopathy from a large B-cell non-Hodgkin lymphoma (59).
A nerve biopsy allows for direct visualization and characterization of the malignant cells, which may be located in the perineurium, epineurium, and endoneurium (69; 64; 14). F-18 FDG-PET/CT is a sensitive modality that can suggest the presence of malignancy and identify appropriate places for diagnostic biopsies. It is especially useful when combined with Gd-enhanced MRI (37).
There occasionally is an association with perivascular infiltrates (56; 04). Nerves involved clinically and electrophysiologically are preferable. Most commonly, the sural nerve is used; however, there are falsely negative biopsies that fail to show lymphomatous infiltrates (74; 68; 76; 55). Semithin sections provide evidence of demyelination or axonal damage (14). Cell marker studies serve to differentiate and characterize polyclonal and monoclonal infiltrates (69).
The treatment is aimed at both symptoms and the underlying malignancy. The latter is the domain of the internist or oncologist. Response of non-Hodgkin lymphoma to therapy is influenced by age, histologic grade, concomitant diseases, and patient’s wishes (45). For low-grade non-Hodgkin lymphoma, radiotherapy is used for localized stage I disease, and chemotherapy is used for diffuse disease. With high-grade non-Hodgkin lymphoma the mainstay for treatment is chemotherapy, whereas radiotherapy is reserved for localized masses, compressive lesions, or lesions in the neuraxis (45). Intrathecal therapy should be considered for suspected or proven leptomeningeal involvement. Combination therapy with rituximab and chemotherapy has been shown to be superior to chemotherapy alone in other forms of non-Hodgkin lymphoma; this benefit does not appear to be the case in patients with neurolymphomatosis (18). Bendamustine, an alkylating agent, has been effective in a case of neurolymphomatosis from follicular lymphoma (73). Autologous stem cell transplantation may also be of benefit (47).
Treatment modalities for Hodgkin disease include radiotherapy, chemotherapy, or both in combination. Indications for radiotherapy are stage I disease and stage IIA disease with 3 or fewer areas of involvement after chemotherapy. Indications for chemotherapy are all patients with stage B disease, stage II disease with 3 or more areas of involvement, stage III disease, and stage IV disease (45).
Symptomatic treatment may involve ankle-foot orthoses for foot drop and splinting or elbow pads for pressure or entrapment neuropathies. If the neuropathy is severe and the patient has limited mobility, contractures must be prevented with range of motion exercises, whereas frequent turning and appropriate mattresses can prevent skin breakdown. Deconditioning can be addressed with strength and endurance exercises. Ataxia can be treated with a cane, walker, or wheelchair.
Part of the scientific evidence regarding neuropathic pain treatment comes from diabetes, AIDS, cancer, trigeminal neuralgia, and shingles patients. Anticonvulsants (ie, gabapentin) and antidepressants in particular tricyclics have the best efficacy. Although gabapentin is often better tolerated, tricyclics have the advantage of once-daily dosing.
Tricyclic antidepressants are effective for lancinating or steady pain (63) and are usually given at hour of sleep. Use is limited by sedation, anticholinergic effects, erectile dysfunction, weight gain, and cardiac conduction abnormalities. The specific choice is often dictated by the need for nighttime sedation and the risk of daytime sedation. Doxepin and amitriptyline are the most sedative, whereas nortriptyline and desipramine are the least; their efficacy and dosage are similar. No benefit of doses above 125 mg has been documented. Initial dosing should be at 10 to 25 mg, with increases every 3 to 7 days until benefit or side effects occur. The authors obtain EKG for dose increases above 75 mg to rule out abnormal cardiac conduction. The selective serotonin reuptake inhibitors appear to be less effective that the tricyclics; this is believed to be due to the lack of noradrenalin reuptake inhibition (63). Typical doses used are fluoxetine 20 mg daily and paroxetine 20 to 40 mg daily.
Several antiepileptics are available for use including gabapentin, carbamazepine, lamotrigine, topiramate, and oxcarbazepine. Of these, gabapentin is the best tolerated, with a similar efficacy as tricyclic antidepressants. The dose of gabapentin used in neuropathic pain studies was 600 mg every 8 hours up to 3600 mg per day; carbamazepine doses ranged from 200 mg per day to 200 mg every 8 hours. Gabapentin is the authors’ preferred antiepileptic due to its generally high tolerability in the elderly as well as its wide range of effective dosage. Typically we start outpatients on 100 mg on day 1, 100 mg twice a day on day 2, 100 mg 3 times a day on day 3, 400 mg per day for the next 4 days, 400 mg twice a day for the second week, then 400 mg 3 times a day, and then slowly titrate upwards until pain is well controlled or side effects occur. Topiramate was studied in pain control starting at 25 mg per day and titrating by 25 to 50 mg per day over an 8-week period (21). Impaired cognition, drowsiness, and weight loss are not uncommon. Lamotrigine was studied starting at 25 mg per day and titrating slowly over 6 weeks to a maximum of 400 mg per day (16). Lamotrigine is associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, among others.
Multiple opioid medications are available. Most physicians reserve these for severe refractory pain. Relative contraindications include a history of substance abuse, severe depression, and poor compliance. Long-acting opioids are preferred, as the steady blood levels are associated with a lower incidence of opioid “high” and constipation.
For highly localized pain, topical drugs such as lidocaine creams and transdermal patches and capsaicin cream (63) are available. Although often not providing complete pain relief, they may reduce pain significantly and, thus, reduce the required dose of other analgesics.
For patients with refractory pain, epidural morphine, clonidine, and ketamine should be considered (15; 60; 29).
Niranjan N Singh MD
Dr. Singh of the University of Missouri, Columbia received honorariums from AbbVie for speaking engagements.See Profile
Florian P Thomas MD MA PhD MS
Dr. Thomas of Hackensack University Medical Center, Hackensack Meridian School of Medicine, has received honorariums from Acceleron and Pharnext for consulting work.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
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