Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 73

Neurologic aspects of plasma cell disorders URSZULA SOBOL* AND PATRICK STIFF Department of Hematology and Oncology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Plasma cell disorders, also known as plasma cell dyscrasias, are a group of malignant diseases arising from proliferation of a single clone of plasma cells which often produce a homogenous (monoclonal) immunoglobulin protein (M protein) (Drappatz and Batchelor, 2004). This M protein can be easily identified as a spike on serum and/or urine protein electrophoresis (SPEP, UPEP, respectively) and further characterized by immunofixation as immunoglobulin (Ig) G, IgA, IgM, IgD, which represents the two heavy chains of the immunoglobulin, and k (kappa) or l (lambda), which represents the type of light chain. The secreted immunoglobulin can react with or deposit in various tissues resulting in organ dysfunction and damage. Plasma cells disorders cover a wide spectrum of clinical manifestations, ranging from clinically aggressive and treatment requiring to more indolent and benign illnesses that can be monitored. Plasma cell disorders include: monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenstr€ om macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma), solitary plasmacytoma, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), immunoglobulin-related amyloidosis and immunoglobulin-related cryoglobulinemia. Within this group, multiple myeloma can be further subclassified into symptomatic MM requiring treatment due to associated end organ damage and smoldering (asymptomatic) MM with no associated end organ damage and not requiring treatment. Rarely MM can be nonsecretory, where neoplastic plasma cells do not secrete the monoclonal immunoglobulin.

Neurologic complications arising from these plasma cell disorders primarily affect the peripheral nervous system, with peripheral neuropathy (PN) being the predominant manifestation of the underlying disease or its treatment. The central nervous system (CNS) is less likely to be affected but clinically more significant. Tables 73.1 and 73.2 summarize the major neurologic complications of plasma cell disorders. A detailed discussion of the various plasma cell disorders and their specific neurologic implications follows below.

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE The majority, 50–75%, of all monoclonal immunoglobulins (monoclonal gammopathy) fall into the category of monoclonal gammopathy of undetermined significance (MGUS) (Kyle et al., 2006). MGUS is more common in men and can be identified in 1–3% of the population over the age of 50 years and 3–5% over the age of 70 years (Kyle et al., 2006). The diagnosis of MGUS is defined by the presence of serum M protein of less than 3 g/ dL (as detected by SPEP), with less than 10% plasma cells on bone marrow examination, and no related organ or tissue impairment (Table 73.3) (International Myeloma Working Group, 2003). MGUS is a premalignant state and can progress to MM, with a risk of progression of 1% per year (Kyle et al., 2002). MGUS can also progress to other related plasma cell disorder (WM or amyloidosis) (Fig. 73.1). Main risk factors for progression include concentration of serum M protein > 1.5 g/dL and an abnormal serum free light chain ratio (k:l light chain ratio). Also, patients with IgM and IgA are at higher risk as compared to patients with IgG gammopathy (Kyle et al., 2002). MGUS does not require treatment

*Correspondence to: Urszula Sobol, M.D., Loyola University Medical Center, Cardinal Bernardin Cancer Center, Department of Hematology/Oncology, 2160 S. First Ave., Maywood, IL 60153, USA. Tel: þ1-708-327-1248, Fax: þ1-708-216-3319, E-mail: [email protected]

Table 73.1 Plasma cell disorders and peripheral neuropathy Peripheral neuropathy

Associated disease

Ig

Incidence of PN

Symptoms

Treatment

Sensory > motor demyelinating neuropathy

MGUS – anti-MAG positive WM – anti-MAG positive

IgM

8–37% in MGUS 5–10% in WM

MGUS – anti-MAG negative

IgG, IgA

Observation/supportive; in severe cases steroids, plasma exchange, chemotherapy, IVIg, rituximab can be considered Supportive

WM – anti-MAG negative Cryoglobulinemia

IgM

Slowly progressive gait ataxia, tremor, loss of joint position, Romberg sign. Usually men > 50 years, favorable course Chronic, symmetric, progressive, distal sensory or sensorimotor (CIDP-like) CIDP-like

IgG (or IgM)

70%

Plasma exchange, steroids, cyclophosphamide

Treatment-related

n/a

40–75%

Painful, progressive, symmetric distal sensorimotor,  multiple mononeuritis Primarily sensory neuropathy

MM

IgG (or IgM)

5–50%

CIDP-like

POEMS

IgG, IgA

>90%

Amyloidosis

IgG, IgA

15–20%

Proximal and distal senosorimotor, loss of vibration and proprioception Painful, progressive, symmetric distal sensorimotor. Autonomic dysfunction with orthostatic hypotension, bladder or bowel dysfunction

Sensory > motor axonal neuropathy

Motor > sensory demyelinating neuropathy

Sensory > motor neuropathy  autonomic dysfunction

Treat underlying disorder

Drug holiday, complete cessation or dose reduction MM therapy, which may actually exacerbate PN Treat the underlying disorder

Treat the underlying disorder but PN may not improve

MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; WM, Waldenstr€om macroglobulinemia; Ig, immunoglobulin; PN, peripheral neuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy. (Modified from Drappatz and Batchelor, 2004.)

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS

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Table 73.2 Plasma cell disorders and central nervous system Pathology

Plasma cell disorder

Symptoms

Spinal cord compression

MM/pathologic fracture Plasmacytoma

Leptomeningeal Infiltration Hyperviscosity syndrome

MM

Back pain, paralysis, sensory loss, loss of bowel and bladder function, Lerhmitte’s sign Multiple cranial neuropathies, HA, confusion, obstructive hydrocephalus HA, vertigo, ataxia, confusion, hearing loss, strokes Leukoencephalopathy with seizures, altered mental status, paralysis HA, weakness, seizures, lethargy, confusion, coma Cognitive decline, dementia CVA, symptoms due to mass effect Cognitive decline, dementia, CVA, hemorrhage

Bing–Neel syndrome

WM MM WM

Hypercalcemia

MM

Amyloidoma Cerebral amyloid angiopathy

AL amyloidosis AL amyloidosis

MM, multiple myeloma; WM, Waldenstr€om macroglobulinemia; HA, headache; CVA, cerebrovascular accident (Modified from Drappatz and Batchelor, 2004.).

but does require indefinite monitoring at periodic intervals for evidence of progression to a malignant condition.

MGUS and peripheral neuropathy Peripheral neuropathy (PN) is the only clinically significant neurologic complication of MGUS. It can be seen in 8–37% of MGUS patients and is often the only clinical manifestation of the underlying hematologic process (Vrethem et al., 1993). Of all patients with idiopathic neuropathy approximately 10% have an underlying monoclonal gammopathy, prevalence six to ten times that in the general population (Kelly et al., 1981). The most common type of MGUS is IgG; however, it is IgM gammopathy that is responsible for most cases of symptomatic neuropathy (typically with k light chain). This is likely due to the fact that IgM is the most likely antibody to cross-react with neural antigens (60%), followed by IgG (30%), and IgA (10%) (Yeung et al., 1991). In general, PN due to MGUS appears insidiously and progresses slowly over months to years. Most common presentation is distal, symmetric, sensorimotor neuropathy. Less frequent presentation is predominantly sensory neuropathy, about 20% of patients (Katirji and Koontz, 2012). Lower extremities are affected earlier and to a greater extent than upper extremities. Muscle stretch reflexes are universally decreased or absent. Electrodiagnostic studies commonly show evidence of both demyelination and axonal degeneration. Sural nerve biopsies show nerve fiber loss, segmental

demyelination, and axonal atrophy and degeneration (Katirji and Koontz, 2012). There are several distinct groups that patients with M protein-associated PN may be categorized into based on unique clinical features, type of immunoglobulin, and the underlying disease process (Table 73.1).

IGM-RELATED PERIPHERAL NEUROPATHY, ANTI-MAG POSITIVE IgM MGUS neuropathy represents a distinct homogenous group. Approximately 50% of patients with IgM gammopathy and PN will have detectable IgM autoantibodies directed at myelin-associated glycoprotein (MAG) (Silberman and Lonial, 2008). MAG acts as an adhesion molecule for Schwann cells and axons, and the intercalation of anti-MAG antibodies between layers of myelin appears to explain the wide spacing between myelin lamellae (as seen on peripheral nerve biopsies) and consequent demyelination (Ritz et al., 1999; Vital, 2001). This immune-mediated destruction of nerve fibers may be the pathogenesis of neuropathy yet there has been a lack of correlation between the deposition of anti-MAG and amount of M protein with the degree of pathologic nerve damage (Katirji and Koontz, 2012). Patients with high anti-MAG antibodies are clinically unique, typically men in their sixties to seventies, with slowly progressive sensory gait ataxia, with loss of proprioception, vibration, and Romberg’s sign (features of large-fiber sensory dysfunction) (Drappatz and Batchelor, 2004). Tremor and paresthesias may be prominent. Patients have absent deep tendon reflexes and little

Table 73.3 Diagnostic criteria for common plasma cell disorders*

Bone marrow plasma cells (%) Serum monoclonal protein (M protein, g/dL) Clinical manifestations

MGUS

Smoldering MM

MM

Nonsecretory MM

Waldenstr€ om macroglobulinemia

10%{

and 10% lymphoplasmacytic cells. MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; HSM, hepatosplenomegaly; LAD, lymphadenopathy.

Anemia, constitutional symptoms, hyperviscosity, LAD, HSM

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS

1087

Fig. 73.1. Overlap and relationship of the different plasma cell disorders. MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; POEMS syndrome, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes; Cryo, cryoglobulinemia.

to no weakness. Fortunately the majority of patients have a favorable course with respect to neuropathy-related disability. A number of therapies directed at the underlying IgM monoclonal gammopathy have been investigated: plasma exchange (Gertz, 2006), steroids, chemotherapy (Blume et al., 1995; Notermans et al., 1996), intravenous immunoglobulins (IVIg) (Lunn and Nobile-Orazio, 2006) and rituximab (Benedetti et al., 2008; Dalakas et al., 2009; Leger et al., 2010). However, due to very mixed and transient responses along with substantial side-effects of such therapies, treatment of the underlying hematologic condition cannot be routinely recommended and has to be considered on a case by case basis. Severity and rate of objective functional decline should guide any attempts at treatment and consideration of treatment should be given only to patients with progressive deficits. Patients with mild deficits should be observed. This is especially important as patients with anti-MAG neuropathy typically have a benign course with long-term favorable prognosis and little functional deterioration.

IGM-RELATED PERIPHERAL NEUROPATHY, ANTI-MAG NEGATIVE AND/OR NO DETECTABLE AUTOANTIBODY Additional antineuronal antibodies have been identified, although they are less common than anti-MAG antibodies (of all patients with detectable antibodies, 70% have anti-MAG antibodies and 30% have other

antibodies) (Silberman and Lonial, 2008). They include antibodies against sulfate-3-glucuronyl paragloboside (SGPG), sulfoglucuronyl lactosaminyl paragloboside, neurofilaments, sufatides, gangliosides (anti GM1, GD1a, GD1b, GM2, GQ1b), P0 (a myelin-associated protein), and chondroitin sulfate (Drappatz and Batchelor, 2004). The specific antimyelin or other nerve component antibodies can produce distinct clinical syndromes. For example, the antiganglioside antibody GM1 tends to be purely motor neuropathy (known as multifocal motor neuropathy, with clinical symptoms similar to ALS but without upper motor neuron findings), while the antiganglioside antibody GD1b and GQ1b tends to be purely sensory neuropathy (Sadiq et al., 1990). Lastly, patients who have disialosyl-ganglioside antibodies present with a rare clinical syndrome, CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM monoclonal protein, cold agglutinins, and disialosyl antibodies) (Willison et al., 2001; Arbogast et al., 2007). It is important to note that anti-MAG antibodies can cross-react with some of these neural components as well (P0 for example) (Katirji and Koontz, 2012). The clinical implications of detecting these antibodies remain controversial as no clear prognostic or therapeutic value has been identified (Eurelings et al., 2001); nevertheless, some argue that the more favorable disease course in anti-MAG PN justifies its identification. About one-third of IgM MGUS and two-thirds of WM patients will not have identifiable antineural

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U. SOBOL AND P. STIFF

antibodies (Silberman and Lonial, 2008). Proposed pathogenesis in these cases includes direct infiltration of nerves, microangiopathy, hyperviscosity, and vascular precipitation of immunoglobulins. Clinical manifestations may vary from mononeuropathy and mononeuritis multiplex to symmetric polyneuropathy.

IGG- AND IGA-RELATED NEUROPATHY PN associated with IgG or IgA gammopathies are less common and not well described. The underlying diseases may include not only MGUS but also MM, POEMS syndrome, amyloidosis and cryoglobulinemia. The majority of patients with IgG gammopathy do not have symptoms of neuropathy, even in circumstances where an antineural antibody is detected (Hadden et al., 2010). However, if neuropathy is present it can be sensory, motor, or mixed. Patients with IgG gammopathy and rarely IgA or IgM gammopathy can present with polyradiculoneuropathy that closely resembles chronic inflammatory demyelinating polyneuropathy (CIDP). CIDP is an autoimmune inflammatory disorder of the peripheral nerves with demyelination resulting in proximal and distal symmetric muscle weakness, typically with motor greater than sensory symptoms. Although weakness is a characteristic feature of CIDP, and not MGUS neuropathy, a primary sensory variant of CIDP has been recognized, making the distinction rather difficult (Simmons and Tivakaran, 1996). Patients with MGUS and symptoms of CIDP tend to be older and have worse long-term functional outcome than patients with CIDP without MGUS (Simmons et al., 1995). Treatment of IgG or IgA neuropathy is not routinely recommended, similarly to IgM PN. If it is treated it tends to respond better than IgM-driven neuropathy. Also, the closer it resembles CIDP the better, as patients are more likely to respond to immunomodulatory treatments (IVIg, plasma exchange, steroids). In fact, patients with IgG MGUS resembling CIDP should be treated like patients with CIDP without the gammopathy (Katirji and Koontz, 2012). Nevertheless, the distinction between the two (CIDP with or without M protein) is important as the underlying hematologic condition, if present, requires appropriate diagnostic evaluation and indefinite monitoring.

SMOLDERING MULTIPLE MYELOMA As stated above, MM can be divided into smoldering (asymptomatic, with no associated end organ damage) or symptomatic MM due to end organ dysfunction (Table 73.3). End organ damage is defined as presence of any one or more of the following features: hypercalcemia, renal failure, anemia, and lytic bone lesions (which can be diagnosed on bone radiographs). Without the associated end organ damage smoldering MM, just like MGUS, does not require treatment but can progress to symptomatic MM, with a higher progression risk than in MGUS (1% per year in MGUS versus 10% per year for the first 5 years in smoldering MM) and a median time to progression of 2–3 years (Kyle et al., 2007). Randomized clinical trials are ongoing to determine if early institution of therapy can delay progression, and until the results are known, the standard of care remains observation alone with close follow-up. Neurologic complications of smoldering MM, if any, are similar to those of MM and described in the following section.

MULTIPLE MYELOMA Monoclonal gammopathy with > 10% plasma cells in the bone marrow along with associated end organ dysfunction is diagnostic of symptomatic MM (Table 73.3). Median age at diagnosis is 70 years (Altekruse et al., 2007). MM is the second most prevalent hematologic neoplasm, with a higher incidence in men and African Americans (Altekruse et al., 2007). With autologous stem cell transplantation, availability of immunomodulatory agents (lenolidomide, thalidomide) and proteasome inhibitors (bortezomib, carfilzomib) survival is increasing but cure has not been realized. Patients with MM are staged using the International Staging System, which takes into account levels of b2-microglobulin and albumin (Table 73.4). Prognosis and risk can be further classified with chromosomal assessment using cytogenetic and FISH (fluorescent in situ hybridization) data (Table 73.5) (Kyle and Rajkumar, 2009). Treatment of MM consists of induction therapy, intensification with autologous stem cell transplantation Table 73.4 International staging system for multiple myeloma Stage

b2-microglobulin

Albumin

1 2

5.5 mg/dL

>3.5 g/dL

MGUS and the central nervous system MGUS does not have any clinical manifestation in the central nervous system but cerebral spinal fluid (CSF) protein elevation (>100 mg/dL) can be seen in 80% of cases (Yeung et al., 1991; Rajabally, 2011). Cellularity is normal.

3

(Modified from Kyle and Rajkumar, 2009.)

Any

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS Table 73.5 Classification of active multiple myeloma based on cytogenetic abnormalities High risk

Intermediate risk

Standard risk

Deletion 17p t(14;16) t(14;20)

t(4;14) Hypodiploidy Deletion 13

t(11;14) t(6;14) Hyperdiploidy

(Modified from Rajkumar, 2012.)

in transplant-eligible patients, followed by consolidation and maintenance therapy in the majority of patients. After this prolonged treatment, if and when relapse occurs additional active therapy is indicated. The various agents used at different times during MM therapy typically include cytotoxic chemotherapy such as melphalan, cyclophosphamide, and doxorubicin (liposomal) as well as newer agents, such as lenolidomide, thalidomide, bortezomib and carfilzomid. These drugs are typically given with dexamethasone to form two or three drug combinations which can be administered together. Neurologic complications can stem from MM itself or its therapy. Both peripheral and central nervous systems can be affected.

Multiple myeloma and peripheral neuropathy Incidence of PN and untreated MM can be variable, with estimates ranging from 5% (Katirji and Koontz, 2012) to 50% (Silberman and Lonial, 2008). Neuropathy in these patients can be clinically heterogeneous but most patients present with mild distal sensorimotor polyneuropathy. Pure sensory neuropathy is possible but not as frequent. Pathogenesis is thought to be due to perineurial or perivascular IgG (and IgM k) deposition (Ramchandren and Lewis, 2012), due to nutritional and metabolic factors, and/or due to treatment-related toxicity. Patients may also have symptoms of radiculopathy, sometimes associated with myelopathy, due to epidural spinal compression. Electrophysiology reveals axonal damage but sural nerve biopsies can show demyelination as well (Katirji and Koontz, 2012; Ramchandren and Lewis, 2012). Unfortunately treatment of MM does not reverse the neuropathy and can actually cause or exacerbate existing PN. About 30–40% of MM patients have related AL amyloidosis with amyloid deposits consisting of light or heavy chain immunoglobulins (Drapppatz and Batchelor, 2004). In these patients the sensorimotor neuropathy tends to be more painful and severe with an overall poor prognosis. This is discussed in greater detail below under AL amyloidosis.

1089

Multiple myeloma and treatment-related neuropathy Treatment emergent PN and exacerbation of existing PN is a real concern in MM treatment. About 30–75% of patients experience treatment-related PN (O’Connor et al., 2009; Richardson et al., 2012). The incidence, symptoms, reversibility and etiology varies across the MM treatment spectrum. Treatment-related PN can be sensory, motor, sensorimotor, and autonomic. Clinical assessment by a neurologist may be helpful in distinguishing between MM-related and treatmentrelated PN. Electomyogram (EMG) may help, as MMassociated PN is primarily demyelinating while treatment-related PN is largely axonal (Richardson et al., 2012). Also, treatment-related PN needs to be distinguished from myopathy, which can be steroidinduced in many MM patients. Medications most likely to cause neuropathy include bortezomib, thalidomide, vinca alkaloids (vincristine), and cisplatin. Bortezomib-induced peripheral neuropathy (BiPN) preferentially induces sensory neuropathy, typically mild (Sonneveld and Jongen, 2010). Bortezomib is a reversible proteasome inhibitor which prevents degradation of ubiquitinated proteins (Orlowski and Kuhn, 2008). Potential mechanisms for BiPN include: (1) accumulation of proteins in neuronal (dorsal root ganglia) and supportive cells; (2) mitochondrial-mediated neural apoptosis (as seen in in vitro studies when bortezomib was combined with calcium modulators); (3) blockade of transcription (of nerve growth factor); (4) increased tubulin polymerization and microtubule stabilization (Landowski et al., 2005; Poruchynsky et al., 2008). Incidence of BiPN can range between 44% and 70% (Jagannath et al., 2004; Richardson et al., 2012). Early recognition is of the greatest importance, with appropriate dose modification to prevent progression and severe symptoms. Symptomatic neuropathy, once present, can improve or completely resolve, in about 60–64% of patients, after completion or interruption in bortezomib therapy (Richardson et al., 2009b; Dimopoulos et al., 2011). Bortezomib administration via subcutaneous route (as opposed to intravenous) results in a significantly lower rate of BiPN with no loss in efficacy (Moreau et al., 2011). Weekly as opposed to twice-weekly bortezomib also results in significantly decreased rates of PN with equal efficacy (Bringhen et al., 2010). A newer, irreversible proteasome inhibitor, carfilzomib, was recently (July 2012) FDA approved for patients with relapsed MM. The incidence of PN with carfilzomib appears to be lower than in bortezomib-treated patients, estimated at 10–15% (in contrast to 44–70% with bortezomib), with only 1.1% being grade 3 or higher (O’Connor et al., 2009; Siegel et al., 2012). Another similar agent in

1090

U. SOBOL AND P. STIFF

development, marizomib, is also showing promising low incidences of PN (Richardson et al., 2009a). Thalidomide, as described above, is an immunomodulatory agent used in the treatment of MM with neuropathy being a major side-effect. Incidence of thalidomide-induced peripheral neuropathy (TiPN) increases with duration of therapy, with an overall estimate of 40–75% (Richardson et al., 2012). Pathogenesis has been proposed to include dorsal root ganglia degeneration, wallerian degeneration and demyelination through downregulation of tumor necrosis factor-a (TNF-a) (Chaudhry et al., 2002; Giannini et al., 2003). Neuropathy is sensorimotor with preferential degeneration of the longest axons. Unlike BiPN, TiPN can be permanent and emerge even after therapy has been stopped. Newer agents in this class, lenalidomide (FDA approved) and pomalidomide (not yet FDA approved) have been associated with substantially lower rates and much less severe PN (Richardson et al., 2012). Cisplatin and vincristine are other agents that are occasionally used in MM treatment. The neuropathy with these agents tends to be distal symmetric sensorimotor. About 10–13% of MM patients develop PN with vincristine but no specific data on cisplatin and MM patients are available; in other malignancies cisplatin has been shown to cause long-term peripheral sensory nerve damage (Cavaletti et al., 1994; Dimopoulos et al., 2003). Careful monitoring for treatment-related PN, early recognition of symptoms, and early intervention are necessary to prevent progression to more severe, debilitating, neuropathy. Appropriate guideline-driven dose adjustment and discontinuation of the offending medication(s) is indicated. Early dose modification may allow for ongoing use of the drug and its therapeutic effect, while possibly improving existing neurologic symptoms and more importantly preventing further damage. If needed, symptomatic treatment with antiepileptics, antidepressants, calcium channel a2-d ligands (gabapentin, pregabalin), and opioids can be tried, as long as the underlying cause of neuropathy has been addressed. a-Lipoic acid and antidepressant venlafaxine have appeared promising in patients with colorectal cancer and treatment-related neuropathy (Gedlicka et al., 2002; Barton et al., 2011). Other agents including acetyl-L-carnitine, topical baclofen, amitriptyline, ketamine, and topical methanol creams appear effective as well (Richardson et al., 2012). Unfortunately there is no proven porphylaxis for treatment-related PN but multivitamis (vitamins B, E, B12, folic acid), magnesium, amino acid, omega-3 fatty acids and fish oil supplements can be tried; however, this is based on anecdotal evidence alone (Richardson et al., 2012). Of note, pre-existing neuropathy or the use of combination therapy with both

drugs being neurotoxic (e.g., bortezomib-thalidomide), are not contraindications to initiation (or retreatment) with bortezomib-containing regimens, but more vigilant monitoring is required in such instances.

Multiple myeloma and the central nervous system EPIDURAL DISEASE IN MULTIPLE MYELOMA Spinal cord compression occurs in approximately 20% of patients with MM (Colak et al., 1989). Most commonly it results from vertebral body collapse due to myeloma bone involvement (Byrne, 1992) (Fig. 73.2). Less frequently, plasma cell tumors (also known as plasmacytoma(s)) can extend into the epidural space causing spinal cord compression (Blumenthal and Glenn, 2002) (Fig. 73.3). A majority (60%) of epidural metastases arise in the thoracic spine while 30% arise in the lumbosacral spine (Drappatz and Batchelor, 2004). Symptoms of spinal cord compression can include back pain, weakness (present in 60–85% of patients), sensory deficits (with a sensory level usually 1–5 segments below the anatomic level of cord compression), Lhermitte’s sign (characterized by electric shock-like sensation upon neck flexion), as well as bowel and bladder disturbances (which tend to occur late in the disease process) (Drappatz and Batchelor, 2004). Early recognition of these symptoms is important as neurologic status

Fig. 73.2. MRI showing pathological fracture at the L5 vertebral body with retropulsion of the bony fragments causing central canal stenosis and mass effect on the lumbar nerve roots. Pathology confirmed plasma cell infiltration (plasmacytoma). (Figure courtesy of Edward Melian, M.D., Loyola University Medical Center.)

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS

1091

shows plasma cells within the CSF, significantly increased protein with detectable M protein on protein electrophoresis of the CSF. Treatment of leptomeningeal disease includes intrathecal chemotherapy, systemic chemotherapy, and cranial irradiation (Mendez et al., 2010). Prognosis is poor with a median survival of only 1.5–3 months (Mendez et al., 2010).

INTRACRANIAL PLASMACYTOMA

Fig. 73.3. MRI showing a large mass with significant retrolisthesis of L4 and L5 with almost complete destruction of the L4 and L5 vertebral bodies and posterior elements. There is near complete effacement of the central spinal canal. Mass was biopsy proven plasmacytoma. (Figure courtesy of Edward Melian, M.D., Loyola University Medical Center.)

at the time of diagnosis predicts outcome after treatment (Maranzano and Latini, 1995). Spinal cord compression requires immediate diagnosis and appropriate emergent treatment to prevent permanent motor and sensory damage. Corticosteroids with urgent radiation therapy are appropriate. Occasionally decompressive surgery is required, especially when the diagnosis is uncertain, the bulk of tumor is located posteriorly, or there is associated spine instability. Bisphosphonate therapy in MM can reduce pain associated with lytic lesions and significantly reduce skeletal-related events (such as vertebral pathologic fractures) (Morgan et al., 2010).

LEPTOMENINGEAL INVOLVEMENT Involvement of leptomeninges by clonal plasma cells of MM is very rare, estimated at about 1% (Mendez et al., 2010). Pathogenesis is thought to be due to hematogenous spread (as opposed to direct extension from bone). Leptomeningeal infiltration can be focal, multifocal, or diffuse. Diffuse involvement of the leptomeninges is also referred to as CNS myelomatosis (Mendez et al., 2010). Patients can present with cranial nerve palsies, paraparesis, seizures, or confusion. Obstructive hydrocephalus from leptomeningeal infiltration has been described (Dennis and Chu, 2000). Primary dural involvement is rare but has been described primarily in case reports (Mendez et al., 2010). Cerebrospinal fluid (CSF) analysis in patients with meningeal involvement

Plasmacytomas can be found in the vertebral column, as described above, as well as intracranially. Solitary intracranial plasmacytomas have been described in the pituitary, typically with preserved pituitary function and associated cranial nerve neuropathies (McLaughlin et al., 2004). They have also been described to involve the orbit and base of skull with involvement of the neural foramina or distortion of nerves by tumor masses (Cerase et al., 2008). Metastatic involvement of the mandible can lead to unilateral chin hypoesthesia (“numb chin syndrome”), which can be present in about 10– 15% of MM patients (Hogan et al., 2002). Treatment for intracranial plasmacytomas is typically surgery followed by radiation therapy, or radiation therapy alone if the tumor is unresectable (Cerase et al., 2008). Solitary plasmacytomas (outside of the CNS) are described in greater detail below.

METABOLIC DISTURBANCES Encephalopathy and cranial nerve palsies can also result from metabolic derangements including hypercalcemia, uremia, and hyperviscosity. Hypercalcemia of malignancy is common in MM patients, estimated to occur in about 30% of MM patients at some point during the course of the disease (Mundy, 1998) and in 13% of newly diagnosed patients (Kyle et al., 2003). Hypercalcemia is caused by increased bone resorption by osteoclasts which is driven by a variety of mediators including interleukin (IL)-6, IL-1, tumor necrosis factor-b and macrophage inflammatory protein (Drappatz and Batchelor, 2004). Increased bone resorption can be appreciated as lytic lesions on plain radiographs. Neurologic symptoms of hypercalcemia include weakness, confusion, headache, even coma and seizures. Other symptoms include nausea, vomiting, anorexia, constipation, abdominal pain, increased thirst and urination (from hypercalcemiainduced nephrogenic diabetes insipidus). Treatment consists of immediate lowering of the serum calcium with aggressive hydration (with or without loop diuretics) or hemodialysis in severe cases or in patients who cannot tolerate hydration. Equally important is decreasing bone resorption and calcium release into the bloodstream by

1092

U. SOBOL AND P. STIFF

inhibiting osteoclast activity with bisophosphonates (and/ or calcitonin). Hyperviscosity due to hypergammaglobulinemia can occur in MM; however, it is much more common in Waldenstr€ om macroglobulinemia (10–30% in WM and 2–6% in MM) (Mehta and Singhal, 2003). Hyperviscosity syndrome is discussed in greater detail below under Waldenstr€ om macroglobulinemia.

which tend to occur in late stages of the disease and in high-risk MM (as defined by Table 73.5). Radiation therapy alone may be a treatment option for solitary plasmacytoma but systemic therapy is indicated in patients with multiple plasmacytomas and MM. Neurologic complications from plasmacytomas can vary depending on the location of mass effect (spinal cord versus intracranial), as described above.

NONSECRETORY MYELOMA Rarely, patients with symptomatic MM do not have a detectable M protein in the serum or urine (Table 73.3). These patients are categorized as having nonsecretory MM, estimated to occur in only 3% of MM patients (International Myeloma Working Group, 2003). With more sensitive testing, including free light chain assays (to identify patients with light chain only MM) the incidence of true nonsecretory MM may actually be lower. Renal insufficiency is less common in these patients. Neurologic complications in patients with nonsecretory MM have not been well described, likely due to the rarity of the disorder. Treatment and prognosis of nonsecretory MM are similar to symptomatic MM.

SOLITARY PLASMACYTOMA Solitary plasmacytoma (plasma cell tumor) is the only known potentially curable plasma cell disorder. It can arise in bone or soft tissue. When it is confined to bone it is categorized as solitary bone plasmacytoma (also known as intramedullary plasmacytoma or osteosclerotic myeloma); when it occurs in soft tissue sites (most commonly the upper respiratory tract but also CNS, gastrointestinal tract, bladder, thyroid, breast, testes, parotid gland, and lymph nodes) it is called extramedullary plasmacytoma (Rajkumar et al., 2006). In patients with plasma cell disorders, the incidence of solitary plasmacytoma is only 3–5% (International Myeloma Working Group, 2003). The diagnosis is confirmed by biopsy-proven solitary lesion of bone or soft tissue with clonal plasma cells but normal bone marrow with no clonal plasma cells, normal skeletal survey, and MRI of spine/pelvis and no evidence of end organ damage (anemia, hypercalcemia, renal failure, or additional lytic bone lesion) (Rajkumar et al., 2006). Patients with solitary plasmacytoma are at risk of progression to multiple myeloma (with higher progression rate in patients with solitary bone plasmacytoma as opposed to extramedullary plasmacytoma). Patients with solitary bone plasmacytomas may also have systemic manifestations such as POEMS syndrome (described below). Solitary plasmacytoma, a potentially curable plasma cell disorder, is in contrast to multiple plasmacytomas,

POEMS SYNDROME POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder (Dispenzieri, 2012). POEMS syndrome can have multisystem manifestations as represented by the acronym, which refers to the constellation of salient signs and symptoms: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. It is also known as osteosclerotic myeloma, Crow–Fukase syndrome and Takatsuki syndrome (Rajkumar et al., 2006). Diagnostic criteria required for POEMS syndrome are listed in Table 73.6. Patients with Table 73.6 POEMS syndrome diagnostic criteria Mandatory major criteria (both required): 1. Monoclonal plasma cell disorder 2. Peripheral neuropathy Other major criteria (at least one is required): 1. Sclerotic bone lesions (single or multiple plasmacytoma(s)) 2. Castleman disease (angiofollicular lymph node hyperplasia) 3. Vascular endothelial growth factor (VEGF) elevation Minor criteria (at least one is required): 1. Organomegaly (hepatomegaly, splenomegaly, lymphadenopathy) 2. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic){ 3. Edema (anasarca, pleural effusion, ascities) 4. Typical skin changes (hyperpigmentation, hypertrichpsis, plethora, hemangioma, white nails, acrocyanosis, thickening) 5. Papilledema 6. Thrombocytosis/erythrocytosis Other signs and symptoms: Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/ restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values Note: not every patient who meets these criteria will have POEMS syndrome; features should be in temporal relationship with no other attributable cause. Absence of osteoclerotic lesions or Castleman disease should make the diagnosis suspect. Elevations in plasma or serum levels of VEGF (vascular endothelial growth factor) and thrombocytosis are commonly present and may help with the diagnosis. { Hypothyroidism and diabetes mellitus alone are not sufficient to meet this criteria. (Modified from Rajkumar, 2012.)

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS POEMS syndrome tend to be younger (median 51 years), usually men, and can have an indolent or a fulminant disease course (Rajkumar et al., 2006). Typical monoclonal protein is IgG or IgA with almost exclusively l light chain restriction (Katirji and Koontz, 2012). The prognosis for patients with POEMS syndrome is poor but clinical improvement can occur after the disappearance of the monoclonal protein. If a solitary bone plasmacytoma or < 3 plasmacytomas are detected in a patient with POEMS syndrome, treatment with radiation therapy may be effective in controlling the symptoms (Dispenzieri, 2012). Patients with more diffuse bone lesions or clonal plasma cells on bone marrow biopsies should be treated with systemic chemotherapy, resembling that of MM and light chain amyloidosis.

POEMS syndrome and peripheral neuropathy Neuropathy is the main feature in these patients and actually a requirement for the diagnosis of POEMS syndrome (Table 73.6). Patients have symmetric distal, ascending, motor neuropathy with variable sensory loss (Katirji and Koontz, 2012). Neuropathy can be progressive, debilitating, and painful. Electrophysiologic testing reveals demyelinating neuropathy with superimposed or secondary axonal loss (Ramchandren and Lewis, 2012; Rajabally, 2011). Nerve biopsy can show endoneurial deposits and uncompacted myelin lamellae (Vital, 2001). Neuropathy may improve (although slowly) with successful treatment of the underlying plasma cell disorder.

€ MACROGLOBULINEMIA WALDENSTROM Waldenstr€ om macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a low-grade IgM producing lymphoid and plasma cell disorder. Median age at diagnosis is 65 years with a slight male predominance (Rajkumar et al., 2006). Diagnosis is confirmed by the presence of monoclonal IgM, >10% bone marrow lymphoplasmacytic infiltration with a characteristic immunophenotype (Rajkumar et al., 2006). Treatment for patients with WM is indicated if they have diseaseassociated anemia, thrombocytopenia, constitutional symptoms (weakness/fatigue, weight loss, night sweats), hyperviscosity, symptomatic cryoglobulinemia, significant hepatosplenomegaly, or lymphadenopathy.

Waldenstr€ om macroglobulinemia and peripheral neuropathy PN occurs in about one-third of patients with WM (Katirji and Koontz, 2012). Typically it is chronic, symmetric, predominantly sensory neuropathy, similar to IgM-MGUS

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PN. Anti-MAG antibodies can be found in about 50% of WM patients (Katirji and Koontz, 2012). Electrophysiologic studies demonstrate demyelination, similar to IgM-MGUS. Treatment is geared at the underlying disease process with some responses in neuropathy symptoms. WM can also produce cryoglobulinemia (described below), which may manifest with an immune-mediated vasculitis, leading to painful, distal symmetric sensorimotor neuropathy (Drappatz and Batchelor, 2004).

Waldenstr€om macroglobulinemia and the central nervous system HYPERVISCOSITY SYNDROME The IgM antibody that is secreted by the malignant lymphoplasmacytic cells is a multivalent molecule that has the tendency to aggregate, leading to slowing of the cerebral and retinal circulation resulting in symptoms due to transient ischemia (Drappatz and Batchelor, 2004). Symptoms usually occur when IgM levels are > 3 g/dL and/or serum viscosity is  4.0 centipoise (normal 1.4–1.8 centipoise), although this may vary among individual patients (Mehta and Singhal, 2003). The clinical triad of hyperviscosity syndrome includes neurologic symptoms, vision changes, and mucosal bleeding (Ghobrial et al., 2003). Neurologic symptoms include dizziness, headache, vertigo, ataxia, confusion, syncope, and stroke. Vision changes include blurry vision and diplopia with fundoscopic examination revealing papilledema, tortuosity of veins and thrombosis (Ghobrial et al., 2003). Mucosal bleeding in the oropharynx, gastrointestinal tract, ureter, or vagina can occur as the monoclonal IgM interferes with platelet function. Rarely patients can have retinal and intracranial hemorrhage. As a result of increased plasma volume patients may experience dyspnea, chest pain, pulmonary edema, or congestive heart failure. Treatment is aimed at emergently decreasing the IgM level in order to provide rapid relief of symptoms and avoid long-term complications. In severe situations this can be quickly achieved with aggressive intravenous hydration and plasmapheresis. Long-term management consists of systemic chemotherapy in order to decrease the IgM production. Much less frequently, MM can result in hyperviscosity syndrome. This can be seen when IgG levels are > 4 g/ dL and IgA levels > 6 g/dL along with increased serum viscosity (Mehta and Singhal, 2003).

BING–NEEL SYNDROME Bing–Neel syndrome is an extremely rare neurologic complication of WM and usually presents late in the disease course. It occurs when the neoplastic lymphoplasmacytic or plasma cells infiltrate the perivascular

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spaces, leptomeninges, and/or brain parenchyma in the CNS. These infiltrates can be found in other organs as well, including bone marrow, lymph nodes, spleen, and liver. The infiltrate may be diffuse in the CNS, causing symptoms of confusion and lethargy. Alternatively, the cells may coalesce into tumors with symptoms mainly from mass effect including paralysis and seizures (Malkani et al., 2009). Additional symptoms can include headache, blurry vision, psychiatric manifestations, numbness, paresthesias, hearing loss, and weakness. CSF analysis can show leukocytosis (WBC 100–500 cells/mm3), elevated total protein (>100 mg/ dL), normal or decreased glucose, and hypergammaglobulinemia with detectable M protein on protein electrophoresis and IgM confirmation on immunofixation of the CSF (Malkani et al., 2009). These CSF abnormalities are more common in diffuse rather than coalescent CNS disease. Brain imaging can be normal or show regions of enhancement on T2-weighted MRI images and occasionally tumoral or nodular masses on CT scans (Grewal et al., 2009). Treatment includes intrathecal chemotherapy and radiation therapy (focal or cariospinal radiation therapy),

along with systemic chemotherapy. Preliminary data suggest a role for intrathecal rituximab; however, additional studies are needed to evaluate dosing and potential toxicities before it can be recommended as a treatment option (Rubenstein et al., 2007). Due to the rarity of the disease, randomized controlled studies which establish the treatment recommendations in this disease have been difficult to do and will continue to be a challenge. Fortunately, with treatment, patients can have an improvement in their quality of life and remission can be achieved, with some patients having a sustained, long-lasting remission (Grewal et al., 2009).

AL AMYLOIDOSIS (IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS) Amyloidosis refers to the deposition of insoluble fibrillar proteins in various tissues (Kyle et al., 2005). The deposited protein is detected by Congo red staining based on characteristic apple-green birefringence under polarized light (Gertz et al., 2005). Amyloidosis consists of several distinct types, based on the protein composition of the amyloid fibril, as seen in Table 73.7. Only one

Table 73.7 Classification of amyloidosis Type of amyloidosis

Precursor protein component

Symptoms

AL amyloidosis*

l or k immunoglobulin light chain (l is more common; l to k ratio, 3:1)

AA amyloidosis{

Serum amyloid A protein

Systemic: nephrotic syndrome, restrictive cardiomyopathy, neuropathy Localized: isolated organ involvement (e.g., carpal tunnel syndrome, isolated lesions in ureter, urethra, bladder, lung, bronchus or trachea) Renal presentation most common, associated with chronic inflammatory conditions

ATTR amyloidosis Mutant TTR{

Mutated transthyretin

Normal TTR{

Normal transthyretin

b2-microglobulin amyloidosis Ab amyloidosis Other hereditary amyloidosis A fibrinogen Lysozyme Apolipoprotein A-I

b2-microglobulin Ab protein precursor

Fibrinogen a-chain Lysozyme Apolipoprotein A-I

Hereditary; peripheral neuropathy and/or cardiomyopathy (commonly referred to as familial amyloid polyneuropathy) Restrictive cardiomyopathy; carpal tunnel syndrome (commonly referred to as senile amyloidosis) Carpal tunnel syndrome (associated with long-term dialysis) Alzheimer’s syndrome

Renal presentation (also called familial renal amyloidosis) Renal presentation most common Renal presentation most common

*Previously referred to as primary amyloidosis; the only amyloidosis secondary to a plasma cell disorder. { Previously referred to as secondary amyloidosis. { TTR, transthyretin (prealbumin). (Modified from Rajkumar et al., 2006.)

NEUROLOGIC ASPECTS OF PLASMA CELL DISORDERS form of amyloidosis is secondary to a clonal plasma cell disorder, AL amyloidosis (also referred to as immunoglobulin light chain amyloidosis and previously known as primary systemic amyloidosis). Diagnostic criteria for AL amyloidosis are listed in Table 73.8. Potential areas to biopsy for tissue confirmation of amyloid deposition include the affected organ (e.g., heart, kidney, peripheral nerve, rectum), bone marrow, or abdominal fat. In clinical practice the diagnosis can be quite challenging and often delayed given the vague constellation of symptoms, which mimic more common diseases. AL amyloidosis may be localized or systemic. Localized AL amyloidosis is often benign, can affect isolated organ systems (e.g., carpal tunnel syndrome) and treatment consists primarily of symptom relief. Systemic AL amyloidosis, on the other hand, can have profound multisystem involvement and requires treatment with chemotherapy and stem cell transplantation in transplant-eligible patients. Presentation may be variable depending on dominant organ involvement, with nephrotic syndrome, restrictive cardiomyopathy, peripheral and autonomic neuropathy being most common. Patients may also have macroglossia, carpal tunnel syndrome, organomegaly, weight loss, and periorbital and face purpura (“raccoon eyes sign”) (Rajkumar et al., 2006). AL amyloidosis can coexist with MM in 10% of patients but typically one of the two disorders dominates the clinical picture (Rajkumar et al., 2006). Improvement in organ dysfunction can be seen in about 50% of responding patients and prolonged organ remission can be achieved with stem cell transplantation (Rajkumar et al., 2006). Overall prognosis is poor but improving over the years thanks to the advances in therapy, stem cell transplantation and supportive care. Patients with confirmed amyloidosis need to be referred Table 73.8 Diagnostic criteria for AL amyloidosis Diagnosis (all four required)

Signs and symptoms

1. Amyloid related systemic syndrome* 2. Positive Congo red staining in any tissue 3. Light chain confirmation{ 4. Clonal plasma cell disorder{

Fatigue, weight loss, proteinuria (nephrotic range), CHF, hepatomegaly, peripheral and autonomic neuropathy

*Nephrotic syndrome, restrictive cardiomyopathy, hepatomegaly, malabsorption, peripheral or autonomic neuropathy (axonal neuropathy). { By direct examination of the amyloid using mass spectrometry. { M-protein, abnormal free light chain ratio, or clonal plasma cells. CHF, congestive heart failure. (Modified from Rajkumar, 2012.)

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to tertiary medical center for a thorough evaluation and appropriate management.

AL amyloidosis and peripheral neuropathy Amyloid neuropathy can be present in about 17–35% of patients with AL amyloidosis and is the presenting manifestation in 10% (Kyle and Gertz, 1995; Matsuda et al., 2011). It is a progressive, usually painful sensory polyneuropathy, with or without autonomic dysfunction. Neuropathy may be asymmetric, worse distally than proximal, with lower limbs being affected earlier than upper limbs (i.e., length-dependent neuropathy). Pain and temperature sensation are lost before light touch or vibratory sense and motor neuropathy tends to appear after sensory loss (Drappatz and Batchelor, 2004). Patients typically complain of burning, painful electrical sensations as well as symptoms of carpal tunnel syndrome, which may be present in up to 25% of patients and is due to amyloid deposition in the flexor retinaculum (Katirji and Koontz, 2012). Electrophysiologic studies show an axonal, sensory greater than motor neuropathy (Ramchandren and Lewis, 2012). Nerve biopsy can confirm the diagnosis by identifying endoneurial amyloid deposits. This direct toxin effect and amyloid-induced vascular insufficiency have been proposed as possible mechanisms in the pathogenesis of neuropathy. Unfortunately there is no clear evidence that treatment directed at the underlying plasma cell disorder improves symptoms of PN. Autonomic neuropathy is frequently present. It may present with symptoms due to orthostatic hypotension, impotence, bladder dysfunction, or gastrointestinal dysfunction. Symptomatic treatment with elastic stockings, fluorinated steroids, or dihydroergotamine may be helpful in patients with orthostatic hypotension.

AL amyloidosis and the central nervous system A subset of amyloid fibrils can deposit in the CNS; examples include amyloid b (Ab, responsible for some cases of Alzheimer’s disease), transthyretin (TTR), and British amyloid protein (BR12) (Lee and Picken, 2012). Common symptoms include cognitive decline, dementia, stroke, and less frequently, symptoms due to mass effect. AL amyloidosis is extremely rare in the CNS but has been reported in the literature with clinical manifestations related to amyloidoma and leptomeningeal cerebral amyloid angiopathy. CNS amyloidoma contains light chain amyloid which can form nodules or space-occupying lesions within the brain parenchyma or vertebral spinal axis (Tabatabai et al., 2005; Lee and Picken, 2012). CNS amyloidoma can occur in patients with or without evidence of

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systemic amyloidosis or plasma cell dyscrasia. Leptomeningeal cerebral amyloid angiopathy occurs when light chain amyloid fibrils deposit in small- and medium-sized blood vessels, similarly to the more common amyloid angiopathy in Alzheimer’s disease with amyloid b deposition (Lee and Picken, 2012). Focal intracranial hemorrhages have been reported as a complication of amyloid angiopathy. Unfortunately there is no effective treatment for this complication; supportive care and symptom relief are recommended.

CRYOGLOBULINEMIA Cryoglobulins are immunoglobulins that precipitate when cooled and dissolve when heated. Cryoglobulins are classified into three types: type I is monoclonal, type II is mixed (one monoclonal immunoglobulin the other polyclonal, most commonly associated with hepatitis C infection), and type III is strictly polyclonal (without monoclonal immunoglobulins). Type I cryoglobulinemia is most commonly of the IgM or IgG class and is associated with Waldenstr€ om macroglobulinemia, MM, or MGUS (Drappatz and Batchelor, 2004). It is estimated that 5–7% of patients with MM and 20% of patients with WM have an associated cryoglobulinemia (Bloch and Franklin, 1982). Patients with cryoglobulinemia can be asymptomatic or can present with Raynaud’s phenomenon, purpura, acrocyanosis, and skin ulceration. Other manifestations can include arthralgias, renal disease, and neuropathy. Treatment usually consists of rewarming and decreasing the immunoglobulin concentration by plasma exchange, with systemic chemotherapy if cryoglobulinemia is driven by underlying MM or WM (type I cryoglobulinemia). Therapy in type II should be directed at the underlying hepatitis C infection, if present.

Cryoglobulinemia and peripheral neuropathy Peripheral neuropathy has been reported in 17–56% of patients with cryoglobulinemia (Hoffman-Snyder and Smith, 2008). Neuropathy in type I (monoclonal) cryoglobulinemia is infrequent but a lot more common in type II and III cryoglobulinemia. Presentations of neuropathy can range from subacute mononeuritis multiplex to a chronic distal symmetric sensorimotor polyneuropathy, with sensory symptoms usually preceding motor dysfunction (Garcia-Bragado et al., 1988). Neuropathy is most often characterized by axonal degeneration with some reports of demyelination, either primary demyelination or secondary to axonal damage (Ropper and Gorson, 1998). Nerve biopsy can show epineurial vasculitis and epineurial cryoglobulin deposits (which have been described in MM and WM) (Vital

et al., 1991). Improvement in symptoms of neuropathy, even with treatment of the underlying cause, may be slow and very limited.

CONCLUSION Plasma cell disorders range from benign and indolent to malignant and aggressive disease processes. Clinical manifestations are variable and an array of neurologic complications can be present. Although the impact on the peripheral central nervous system is far more common, the clinical implications are typically greater with central nervous system involvement. Peripheral neuropathy is the most common complication and symptoms may vary from mild to debilitating, pure sensory to sensorimotor. Treatment of the underlying plasma cell disorder is often ineffective at controlling or improving neuropathy and, in fact, treatment of the underlying malignancy may cause or exacerbate the neuropathy. Symptomatic relief is necessary, though not always successful or adequate. Central nervous system involvement is rare, can have variable etiologies and symptoms, and usually carries a poor prognosis with limited treatment options. Recognition of the underlying plasma cell disorder is of great importance as it requires a proper diagnostic evaluation, surveillance, and treatment, if indicated.

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