RESIDENT & FELLOW SECTION Clinical Reasoning:

Section Editor A 45-year-old man with acute onset of Mitchell S.V. Elkind, MD, MS multifocal weakness and paresthesias

Jose Montes-Rivera, MD SECTION 1 pattern. Motor examination revealed normal tone Sarah Zubkov, MD A 45-year-old man with epilepsy and immunoglobulin and strength except for profound weakness (Medical Rajeev Motiwala, MD G(IgG)k multiple myeloma (MM) diagnosed a year Research Council [MRC] 2/5) in the muscles inner- Susan C. Shin, MD ago presented to the neurology clinic with right hand vated by the left C5-6 myotomes and weakness weakness and paresthesias, painless proximal left arm (MRC 4/5) in the muscles innervated by the right weakness, and paresthesias in the right foot. Symptoms ulnar nerve. Reflexes were 11 throughout except Correspondence to began acutely over a 2-week period in the setting of a for absent left biceps and brachioradialis. Plantar Dr. Shin: [email protected] diffuse nonpruritic rash. The patient had undergone an reflexes were flexor. Pinprick was diminished in allogenic hematopoietic stem cell transplant (HSCT) a the right fourth and fifth digits, and lateral aspect month prior due to suboptimal response to bortezomib, of the right foot. The rest of his neurologic exami- cyclophosphamide, etoposide, cisplatin, carfilzomib, nation was unremarkable. and autologous stem cell transplant. He denied head- Questions for consideration: aches, neck pain, radicular symptoms, bladder or bowel dysfunction, or gait imbalance. 1. What is the differential diagnosis for multifocal Examination revealed normal vital signs, mental sta- motor and sensory deficits? tus, and cranial nerves. A maculopapular rash was seen 2. What are some diagnostic considerations to over the trunk and extremities, without a dermatomal include with the presence of the skin rash?

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From Mount Sinai Medical Center, New York, NY. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. e186 © 2015 American Academy of Neurology ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 2 zoster and vasculitic neuropathy were considered to be Multifocal sensorimotor deficits can occur from cen- improbable based on the appearance of the rash and lack tral or peripheral processes. Central causes can of pain. include demyelination, metastatic disease, multifocal infarctions, abscesses, or granulomas. Peripheral pro- Questions for consideration: cesses can result in involvement of multiple nerve 1. Which tests would you order at this junction? roots, brachial or lumbar plexus, or individual nerves. 2. What is the relationship between MM and periph- The patient’s clinical presentation resulted from eral neuropathy? involvement of right ulnar and sural nerves, and left C5–6 nerve roots vs upper trunk of the brachial Nerve conduction study (NCS) and EMG can help plexus. Interestingly, there was no pain or sensory localize the lesions and distinguish between axonal and findings in the left arm. Of note, the patient lacked demyelinating neuropathies. Demyelination points symptoms of neuropathy or risk factors for neuropa- toward immune-mediated mechanisms whereas most thy like diabetes, vitamin deficiencies, or alcohol other neuropathies show length-dependent axonal pat- abuse prior to this presentation. The asymmetric tern. The patient’s electrodiagnostic study revealed a sensory-motor deficits in discrete nerve distributions right ulnar mononeuropathy with conduction block combined with lower motor neuron signs (absent across the forearm, prolonged ulnar F-responses, and reflexes in the left upper extremity) were most con- an absent ulnar sensory response. The left axillary and sistent with a diagnosis of mononeuropathy multi- suprascapular compound muscle action potentials plex. Mononeuropathy multiplex can be caused by (CMAP) were at the low end of normal but could a variety of diseases like diabetes mellitus, immune- not be compared to the right side due to the patient’s mediated demyelination, or vasculitis, infections such chemotherapy port. There was slight asymmetry in the as Lyme and herpes zoster, and multiple compressive lateral antebrachial cutaneous sensory responses, lesions including hereditary neuropathy with liability ;25% smaller on the left. Sural sensory responses were to pressure palsies. Direct spread of myeloma into the normal, as were the rest of the NCS of the right lower left brachial plexus or cervical nerve roots was thought and bilateral upper extremities. EMG revealed no unlikely due to the lack of pain. spontaneous activity in select muscles of the right The concomitant rash along with neurologic symp- and left upper extremities including the corresponding toms is an important finding in a patient who has cervical paraspinal muscles. Reduced recruitment with received a HSCT. Skin biopsy confirmed the rash normal motor unit morphology was seen in the left was due to graft-versus-host disease (GVHD). Neuro- deltoid, infraspinatus, biceps, and right ulnar- logic manifestations of GVHD can result from involve- innervated muscles. The presence of conduction block ment of the CNS (encephalitis, myelitis) or the PNS seen in the right ulnar nerve and relatively preserved (acute or chronic demyelinating neuropathy, myositis).1 CMAP amplitudes in the left axillary and suprascapular Our patient’s neurologic symptoms were thought to be nerves, absence of abnormal spontaneous activity, and due to an immune-mediated neuropathy, another com- marked reduction in motor unit recruitment suggested plication of his GVHD. Other conditions like herpes the presence of demyelinating lesions involving the

Figure Neuromuscular ultrasound, C1 sagittal T1, and axial T2 fluid-attenuated inversion recovery

(A) Neuromuscular ultrasound demonstrates focal enlargement of the right ulnar nerve in the mid-forearm (12.5 cm distal to the elbow). Cross-sectional area (CSA) right 17 mm2, left 6 mm2 (normal CSA 6.3 6 1.0 mm2).9 (B) C 1 Sagittal T1 demonstrates stippled enhancement along the superior cerebellar folia and fissures. (C) Axial T2 fluid-attenuated inversion recovery demonstrates a hyperintense lesion in the hand motor area of the left precentral gyrus.

Neurology 84 June 2, 2015 e187 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. upper trunk of the left brachial plexus and the right were negative. These findings were consistent with ulnar nerve. Normal right sural response despite abnor- CNS myelomatous spread. mal pinprick in the lateral foot may have been due to a Polyneuropathies can occur in MM by a variety demyelinating lesion proximal to the site of stimulation of mechanisms. The plasma cell dyscrasia itself can in this clinical context. cause a neuropathy, as seen in POEMS syndrome Ultrasound showed a focal area of enlargement in (polyneuropathy, organomegaly, endocrinopathy, the right ulnar nerve that corresponded to the region M-protein, and skin changes). Other causes of conduction block in the mid-forearm (figure, A), include amyloidosis by way of light chain deposits, which provided further support of a demyelinating cryoglobulinemia, direct infiltration of the nerves process. MRI of the cervical spine with gadolinium by plasma cells, and nerve root compression by did not show any nerve root enhancement or neuro- vertebral body lesions.2,3 Treatment-related neu- foraminal compression. ropathy can be caused by platinum-containing Bloodwork searching for common causes of neurop- chemotherapy agents, bortezomib, and thalido- athy was unremarkable except for the known IgG k mide.4,5 No effective treatment has been estab- monoclonal gammopathy. Ganglioside markers (GM1, lished with polyneuropathy associated with MM, Gd1b, Gq1b, Gd1a, sulfatide, and MAG), reported in with some reports indicating that treating the MM cases of Guillain-Barré syndrome after allogenic HSCT1 may worsen the neuropathy.6 Attempts at neuro- were negative. protection during chemotherapy with vitamin B Although the cervical spine MRI did not reveal and antioxidants are largely based on theoretical root involvement with myeloma, it did show lepto- models and have no efficacy data based on clinical meningeal enhancement around the cerebellum. trials. Supplements should be used cautiously Brain MRI with gadolinium was significant for a left since some may interfere with certain chemothera- precentral gyrus enhancing lesion corresponding to pies. Dose reduction and prolonging dose inter- the hand motor area (figure, B and C). vals may prevent treatment-induced neuropathy.5 Spinal fluid revealed protein of 1,104 mg/dL (15–45 Neuropathic pain can be treated with anticonvul- mg/dL), leukocytes of 231 (0–5/mL), erythrocytes of sants and antidepressants. m – 2(0/ L), and glucose of 157 mg/mL (40 80 mg/dL). Questions for consideration: CSF immunofixation revealed IgG monoclonal protein. Abnormal plasma cells were confirmed with cytology 1. How is immune-mediated neuropathy treated? and flow cytometry. Cytomegalovirus, herpes simplex 2. How common is CNS involvement in MM? virus, Epstein-Barr virus, and varicella-zoster virus PCR 3. How is CNS MM treated?

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e188 Neurology 84 June 2, 2015 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 3 resurgence of seizures. The patient was transferred to Immune-mediated neuropathies can be treated with cor- thepalliativecareunit,wherehediedonhospitalday29. ticosteroids, IV immunoglobulin, plasma exchange, and CNS involvement of MM is rare, making up only other immunomodulatory therapies. The patient was 1% of cases. MM can spread to the leptomeninges, admitted and treated with high-dose IV methylprednis- infiltrate the nerve roots or nerves, or penetrate the olone for his immune-mediated neuropathy and brain or spinal cord. Survival is poor (median 2–6 GVHD. His skin rash and paresthesias improved but months)7,8 but may be increased with combination his motor deficits did not. Intrathecal methotrexate was intrathecal chemotherapy and radiation treatment.8 initiated for the CNS myeloma. Whole-brain radiation was considered; however, the patient clinically deterio- DISCUSSION This case illustrates how MM and its rated and developed status epilepticus. Although his seiz- treatment can cause serious neurologic consequences ures had previously been well-controlled, the progression in the peripheral nervous system and CNS (table). of malignancy to involve CNS structures likely led to Our patient had 2 rare causes for his neurologic

Table Neurologic complications of multiple myeloma

CNS Peripheral nervous system

Disease-related complications Disease-related complications

Spinal cord Neuropathy

Extradural spinal cord compression Paraproteinemic demyelinating or axonal neuropathy (IgG-, IgM-related)

Vertebral body pathologic fractures Amyloidosis

Lytic bone lesions Microangiopathy

Plasmacytomas Hyperviscosity

Paraneoplastic necrotizing myelopathy

Cerebral infarction due to hyperviscosity Radiculopathy

Neuroforaminal narrowing due to lytic bone lesions or pathologic fractures

Myelomatous nerve root infiltration

Leptomeningeal carcinomatosis Plexopathy

Direct spread of myeloma

Demyelinating

Parenchymal metastasis Myopathy

Amyloid deposition in muscle

Treatment-related complications Treatment-related complications

Allogeneic HSCT GVHD complications Allogeneic HSCT GVHD complications

Cerebral vasculitis Polyneuropathy (GBS, CIDP)

Demyelination Myasthenia gravis

Immune-mediated encephalitis Myositis

Myelitis

Progressive multifocal leukoencephalopathy Treatment-induced neuropathy: immune-mediated

Case reports after high-dose chemotherapy Polyneuropathy and autologous SCT

Mononeuritis multiplex

Bortezomib: sensory . sensorimotor

Myelopathy Treatment-induced neuropathy: toxic

Postradiation Thalidomide: length-dependent axonal sensory/sensorimotor neuropathy

Vincristine: axonal sensorimotor neuropathy

Platinum-containing agents

Lenalidomide (rare)

Abbreviations: CIDP 5 chronic inflammatory demyelinating polyradiculoneuropathy; GBS 5 Guillain-Barré syndrome; GVHD 5 graft-versus-host disease; HSCT 5 hematopoietic stem cell transplant; IgG 5 immunoglobulin G; IgM 5 immunoglobulin M.

Neurology 84 June 2, 2015 e189 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. symptoms: (1) immune-mediated demyelinating DISCLOSURE neuropathy due to GVHD and (2) CNS involvement The authors report no disclosures relevant to the manuscript. Go to of the myeloma. The neuropathy was thought to be Neurology.org for full disclosures.

immune-mediated because of its simultaneous REFERENCES presentation with the skin rash, multifocal nature 1. Grauer O, Wolff D, Bertz H, et al. Neurological manifes- of the sensorimotor deficits, as well as demyelination tations of chronic graft-versus-host disease after allogenic noted in the right ulnar nerve. Immune-mediated haematopoietic stem cell transplantation: report from the neuropathy related to bortezomib4 was thought Consensus Conference on Clinical Practice in chronic – unlikely due to the time course. Although MRI of graft-versus-host disease. Brain 2010;133:2852 2865. 2. Dispenzieri A, Kyle R. Neurological aspects of multiple the brachial plexus could have helped in localization, myeloma and related disorders. Best Pract Res Clin Hem- we chose not to order additional tests once the atol 2005;18:673–688. myelomatous meningitis became evident. CNS 3. Joint Task Force of the EFNS and the PNS. European involvement due to direct spread of the MM was Federation of Neurological Societies/Peripheral Nerve Soci- documented by MRI (parenchymal, leptomeningeal ety Guideline on management of paraproteinemic demye- lesions) and by spinal fluid analysis. Interestingly, the linating neuropathies: report of a Joint Task Force of the European Federation of Neurological Societies and the patient’s initial right hand weakness appeared to be Peripheral Nerve Society: first revision, J Peripher Nerv Syst due to an ulnar neuropathy; however, as his disease 2010;15:185–195. progressed, he developed poor dexterity, likely due to 4. Ravaglia S, Corso A, Piccolo G, et al. Immune-mediated the left precentral gyrus lesion. The patient’s history of neuropathies in myeloma patients treated with bortezomib. epilepsy and CNS MM likely contributed to the Clin Neurophysiol 2008;119:2507–2512. development of status epilepticus. Although MM 5. Delforge M, Bladé J, Dimopoulos MA, et al. Treatment- was the unifying diagnosis, the mechanisms of how related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 2010;11:1086–1095. the central and peripheral nervous systems were 6. Silberman J, Lonial S. Review of peripheral neuropathy in affected were different. plasma cell disorders. Hematol Oncol 2008;26:55–65. 7. Gangatharan S, Carney DA, Prince HM, et al. Emergence AUTHOR CONTRIBUTIONS of central nervous system myeloma in the era of novel Jose Montes-Rivera: study concept/design, analysis and interpretation of data, agents. Hematol Oncol 2012;30:170–174. literature review, manuscript drafting/revision. Sarah Zubkov: study concept/ 8. Chen C, Masih-Khan E, Jiang H, et al. Central nervous design, literature review, manuscript drafting/revision. Rajeev Motiwala: critical system involvement with multiple myeloma: long term sur- revision of the manuscript for important intellectual content, analysis and interpretation of data, study supervision. Susan C. Shin: critical revision of vival can be achieved with radiation, intrathecal chemother- the manuscript for important intellectual content, contribution of ultrasound apy, and immunomodulatory agents. Br J Haematol 2013; data, analysis and interpretation of data, study supervision. 162:483–488. 9. Cartwright MS, Shin HW, Passmore LV, Walker FO. STUDY FUNDING Ultrasonographic findings of the normal ulnar nerve in No targeted funding reported. adults. Arch Phys Med Rehabil 2007;88:394–396.

e190 Neurology 84 June 2, 2015 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Clinical Reasoning: A 45-year-old man with acute onset of multifocal weakness and paresthesias Jose Montes-Rivera, Sarah Zubkov, Rajeev Motiwala, et al. Neurology 2015;84;e186-e190 DOI 10.1212/WNL.0000000000001647

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