6. Nowak KJ, Ravenscroft G, Laing NG. Skeletal muscle a-actin diseases (actinopathies): pathology and mechanisms. Acta Neuropathol 2013; 125:19–32. 7. Kornblum C, Lutterbey G, Bogdanow M, Kesper K, Schild H, Schr€ oder R, et al. Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2: a whole body highfield MRI study. J Neurol 2006;253:753–761. 8. Ladha S, Coons S, Johnsen S, Sambuughin N, Bien-Wilner R, Sivakumar K. Histopathologic progression and a novel mutation in a child with nemaline myopathy. J Child Neurol 2008;23:813–817. 9. Ravenscroft G, Wilmshurst JM, Pillay K, Sivadorai P, Wallefeld W, Nowak KJ, et al. A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance. Neuromuscul Disord 2011;21:31–36. 10. Tajsharghi H, Ohlsson M, Palm L, Oldfors A. Myopathies associated with b- tropomyosin mutations. Neuromuscul Disord 2012;22:923–933. 11. Maggi L, Scoto M, Cirak S, Robb SA, Klein A, Lillis S, et al. Congenital myopathies—clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord 2013;23:195–205. 12. Yoshimura T, Motomura M, Tsujihata M. Histochemical findings of and fine structural changes in motor endplates in diseases with neuromuscular transmission abnormalities. Brain Nerve 2011;63:719–727. 13. Clarke NF, North KN. Congenital fiber type disproportion—30 years on. J Neuropathol Exp Neurol 2003;62:977–989. 14. Waddell LB, Kreissl M, Kornberg A, Kennedy P, McLean C, LabarreVila A, et al. Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3. Neuromuscul Disord 2010;20:464–466. 15. Agrawal PB, Strickland CD, Midgett C, Morales A, Newburger DE, Poulos MA, et al. Heterogeneity of nemaline myopathy cases with

16. 17. 18. 19.

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23. 24.

skeletal muscle alpha-actin gene mutations. Ann Neurol 2004;56:86– 96. Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, et al. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 2003;60:665–673. Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, et al. Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Disord 2004;14:779–784. Quijano-Roy S, Carlier RY, Fischer D. Muscle imaging in congenital myopathies. Semin Pediatr Neurol 2011;18:221–229. Quijano-Roy S, Avila-Smirnow D, Carlier RY; WB-MRI muscle study group. Whole body muscle MRI protocol: pattern recognition in early onset NM disorders. Neuromuscul Disord 2012;22(suppl 2):S68– 84. Bianco F, Leone A, Pane M, Vasco G, Colosimo C, Mercuri E. Muscle MRI: out of the tunnel. Neuromuscul Disord 2011;21:501–502. Mercuri E, Clements E, Offiah A, Pichiecchio A, Vasco G, Bianco F, et al. Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine. Ann Neurol 2010;67:201–208. Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, et al. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 1999;23:208–212. Feng JJ, Marston S. Genotype–phenotype correlations in ACTA1 mutations that cause congenital myopathies. Neuromuscul Disord 2009;19:6–16. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007;39:1488–1493.

PRIMARY MULTIFOCAL LYMPHOMA OF PERIPHERAL NERVOUS SYSTEM: CASE REPORT AND REVIEW OF THE LITERATURE ALESSANDRA DEL GRANDE, MD,1 MARIO SABATELLI, MD,1 MARCO LUIGETTI, MD, PhD,1 AMELIA CONTE, MD,1 GIUSEPPE GRANATA, MD,1 VITTORIA RUFINI, MD,2 ANNEMILIA DEL CIELLO, MD,2 SIMONA GAUDINO, MD,3 EDUARDO FERNANDEZ, MD,4 STEFAN HOHAUS, MD,5 ANTONELLA COLI, MD,6 and LIBERO LAURIOLA, MD6 1 Institute of Neurology, Catholic University of Sacred Heart, Largo F. Vito 1, 00168, Rome, Italy 2 Institute of Nuclear Medicine, Catholic University of Sacred Heart, Rome, Italy 3 Institute of Radiology, Catholic University of Sacred Heart, Rome, Italy 4 Institute of Neurosurgery, Catholic University of Sacred Heart, Rome, Italy 5 Institute of Haematology, Catholic University of Sacred Heart, Rome, Italy 6 Institute of Pathology, Catholic University of Sacred Heart, Rome, Italy Accepted 29 July 2014 ABSTRACT: Introduction: Primary lymphomas of peripheral nerves are extremely rare, and only a few cases have been reported. Methods: We describe the clinical, neurophysiological, radiological, and pathological findings in a 61-year-old woman affected by primary multifocal lymphoma of the peripheral nervous system without systemic involvement. Results: Fascicular left femoral nerve biopsy was decisive for the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Magnetic resonance

imaging, fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography, and nerve ultrasound contributed to the diagnosis. Conclusions: Primary lymphoma of peripheral nerves (PLPNs) is a rare but potentially treatable condition, which is frequently misdiagnosed. In the literature, there are very few descriptions of PLPNs, most of which are mononeuropathies. The possibility of a neuropathy associated with lymphoma should be considered in patients with poor response to treatment and severe pain symptoms. Muscle Nerve 50:1016–1022, 2014

Abbreviations: 18F-FDG PET-CT, fluorine-18 fluorodeoxyglucose positron emission tomography–computed tomography; CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; CSA, cross-sectional area; CT, computed tomography; EBV, Epstein–Barr virus; ELISA, enzyme-linked immunosorbent assay; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; MRC, Medical Research Council; NHL, non-Hodgkin lymphoma; NL, neurolymphomatosis; PLPNs, primary lymphomas of peripheral nerves; PNS, peripheral nervous system; R-ProMACE-MTX, rituximab, cyclophosphamide, adriablastin, etoposide, methotrexate; US, ultrasound; VZV, varicella zoster virus Keywords: FDG PET-CT; nerve biopsy; nerve ultrasound; neurolymphomatosis; primary lymphoma of peripheral nerves Additional Supporting Information may be found in the online version of this article. Correspondence to: A. Del Grande; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V

Published online 1 August 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24354


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Peripheral nervous system (PNS) disease occurs in about 5% of patients with lymphoma1 and may originate from compression by the lymphomatous process or invasion by lymphoma cells into the nerve; immune-mediated, metabolic, toxic, and infectious mechanisms leading to nerve damage may also be implicated, including side effects of drugs. Infiltration by lymphomatous cells of nerve trunks, nerve roots, plexi, and cranial nerves in the setting of a hematological malignancy is a distinct clinical entity called “neurolymphomatosis” (NL).2 NL is a rare complication of non-Hodgkin MUSCLE & NERVE

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FIGURE 1. MR images. (a, b) Coronal T1 fat-saturation (Fsat) imaging after gadolinium. Spinal lumbosacral MR images show enlarged enhancing left L3–S1 nerve roots (arrows). (c, d) Follow-up coronal T1-Fsat imaging after gadolinium. Spinal lumbosacral MR images also show swollen and enhancing right L3–S1 nerve roots [arrows in (c)] and further enlargement of the left nerve roots [arrows in (d)].

lymphoma (NHL) and leukemia, but its incidence is poorly defined.2 When NL is the first manifestation of the hematological malignancy, the condition is defined as primary NL.2 In a subset of primary NL, lymphoma cells are found uniquely in the PNS, and this disorder is designated as primary lymphoma of peripheral nerves (PLPNs). As far as we know, only 15 cases of PLPNs have been Muscle MRI in ACTA1 NM

described to date (see Table S1, available online).3–15 We report the case of a woman affected by PLPN with progressive multifocal nerve involvement. A fascicular nerve biopsy was performed, which showed infiltration by B-cell lymphoma. There were no symptoms of systemic disease. Despite chemotherapy, the patient died 19 months after onset of symptoms. MUSCLE & NERVE

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FIGURE 2. Coronal total-body PET-CT (upper row) and axial PET-CT image at the level of the mid-lumbar spine and cervical spine (lower rows) before (a–c) and after (d–f) chemotherapy. (a–c) Increased FDG uptake is seen in the left lumbosacral plexus and lumbar nerve roots (long arrows). Increased FDG uptake is seen also in the right brachial plexus (short arrows). (d–f) There is partial resolution of the FDG uptake in the previously described areas (long arrows), but new FDG uptake appears in the right C6 nerve root (short arrows).


A 61-year-old woman presented with painful dysesthesias in the L3–4 dermatome of her left leg. Three weeks later she developed progressive wasting and weakness of the proximal left leg muscles, associated with burning pain. Her past medical history was negative for autoimmune disorders, use of immunosuppressive medications, or infections. She 1018

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underwent MRI of the spine at another institution, which showed marked thickening of the left L3–4 nerve roots, and total-body fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography– computed tomography (PET-CT) showed uptake of 18F-FDG only in the left L3–5 nerve roots. At admission to our department 5 months after symptom onset, neurological examination showed MUSCLE & NERVE

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FIGURE 3. Ultrasound evaluation. (a, b) Nerve US evaluation of the radial nerve shows an increase of the cross-sectional area (CSA) from the distal third of the arm to the axilla (CSA 5 29 mm2) with respect to the contralateral radial nerve (CSA 5 7 mm2). (c, d) Nerve US evaluation of the femoral nerve shows an increase of the CSA between the anterosuperior iliac spine and the inguinal region (CSA 5 29 mm2) with respect to the contralateral nerve (CSA 5 15 mm2).

severe weakness and wasting of the left rectus femoris and iliopsoas muscles, graded 1/5 on the Medical Research Council (MRC) scale. There was less severe weakness in the left tibialis anterior (4/5 on MRC scale). Tendon reflexes were absent in the left leg, yet they were normal in the other limbs. Plantar responses were flexor bilaterally. Hypoesthesia in an L4–5 distribution was detected in her left lower limb. The patient continued to complain of severe pain in the left leg. The following investigations were normal: complete blood count; erythrocyte sedimentation rate; plasma urea and electrolytes; liver function tests; thyroid function; angiotensin-converting enzyme; autoantibody screening; immunofixation electrophoresis; tumor markers; serologic tests for hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), Epstein–Barr virus (EBV), herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV); chest radiograph; and electrocardiogram. Anti-nerve autoantibodies (anti-GM1, anti-GD1a, and anti–myelin-associated glycoprotein), tested with enzyme-linked immunosorbent assay (ELISA), were negative. Electromyographic examination of lower limb muscles showed denervation changes (fibrillation potentials and positive sharp waves) only in the left iliopsoas, rectus femoris, and tibialis anterior muscles. Motor and sensory nerve conduction studies of fibular, tibial, and sural nerves bilaterally, and F-wave latencies from tibial nerve bilaterally were normal. Cerebrospinal fluid (CSF) revealed an increased protein level (146 mg/dl), with normal glucose level and absence of cells. Muscle MRI in ACTA1 NM

CSF microbiological (serology for HIV, EBV, HSV 1 and 2, VZV, and CMV; polymerase chain reaction for HSV, EBV, VZV, and CMV) and immunological (oligoclonal bands) tests were negative. Serial blood glucose testing revealed the presence of previously undiagnosed type 2 diabetes mellitus. A total-body contrast-enhanced CT scan confirmed that the left lumbar roots were thickened, and there was no lymphadenopathy or other masses. Cranial MRI was normal; spinal lumbosacral MRI showed swollen left L3–S1 nerve roots with hyperintense signal in T2-weighted fat-saturated images and enhancement after gadolinium that extended to the lumbar and sacral plexus regions (Fig. 1a and b). The clinical history and laboratory findings led us to hypothesize that the patient had diabetic radiculoplexopathy, and she was treated with intravenous high dose corticosteroids for 1 week. For 2 weeks after this treatment, her symptoms improved, but 1 month later she developed weakness and paresthesia in the right upper limb. Neurological examination revealed 3/5 MRC strength of the right triceps, extensor carpi radialis and ulnaris, extensor digitorum, and extensor indicis proprius. The right triceps reflex was absent. Weakness and wasting of the left lower limb muscles was unchanged. An 18F-FDG PET-CT scan showed increased metabolic activity in the left lumbosacral plexus and right brachial plexus (Fig. 2a– c). A new lumbosacral spinal MRI showed increased enlargement of the left roots and involvement of the contralateral lumbosacral roots (Fig. 1c and d). Neurophysiological examination MUSCLE & NERVE

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FIGURE 4. Histopathology. (a, b) Fascicular biopsy of the left femoral nerve stained with hematoxylin and eosin shows diffuse infiltration by a population of large and pleiomorphic cells. (c) By immunohistochemistry, the neoplastic cells show diffuse cytoplasmic reactivity for CD20 (brown). (d) Immunostaining for neurofilaments (brown) demonstrates few residual nerve fibers. (e, f) Immunohistochemistry with anti-CD20 (green) and DAPI (blue) (e) and anti-CD20 (green) (f) confirms diffuse positivity of the endoneural infiltrate.

of right upper limb revealed conduction block in the radial nerve with axillary stimulation. Nerve conduction studies of the other right upper limb nerves were unremarkable. Electromyographic examination of right triceps, extensor carpi ulnaris, and extensor digitorum muscles showed reduced recruitment in all muscles without abnormal spontaneous activity. Nerve ultrasound (US) evaluation of bilateral median, ulnar, radial, femoral, fibular, tibial, and sural nerves and brachial plexus was performed, as described previously.16 Nerve US detected increased cross-sectional area of 1020

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right radial nerve, left femoral nerve, right brachial plexus, and cervical roots from C5 to C8. The right radial nerve was involved from the distal third of the arm to the axilla (Fig. 3a and b). The right brachial plexus and cervical roots were swollen along the entire course detectable with ultrasound, from the foramina to the clavicle. The left femoral nerve was damaged between the anterosuperior iliac spine and the inguinal region (Fig. 3c and d). The fascicular echotexture was partially preserved for the radial nerve and the brachial plexus, but fascicles were enlarged. The femoral nerve MUSCLE & NERVE

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appeared completely hypoechoic in the proximal part, whereas distally the fascicular structure was partially preserved. Other examined nerves were normal in size and echotexture. We suspected an immune-mediated neuropathy, and the patient was treated with intravenous immunoglobulin and steroids, but without any significant improvement. A fascicular biopsy of the left femoral nerve was carried out. Hematoxylinand-eosin–stained sections showed infiltration of nerve fascicles and perineural connective tissue by a population of large, pleiomorphic, mitotically active lymphoid cells that showed diffuse cytoplasmic immunostaining for CD20 and nuclear immunostaining for PAX5, indicating a B-lymphocyte immunophenotype (Fig. 4a–f). A diffuse large Bcell non-Hodgkin lymphoma was the final diagnosis. The patient was referred to the Department of Hematology for staging and therapy. Bone marrow examination revealed no abnormalities. A second lumbar puncture revealed 34 cells/mm2, with cell typing showing the same lymphocyte subtypes detected on nerve biopsy (CD20-positive and PAX5-positive), with normal glucose and protein level. This was consistent with meningeal lymphoma. Contrast-enhanced brain and spine MRI did not reveal evidence of CNS parenchymal involvement. Total body contrast-enhanced CT scan did not show evidence of lymphoma in other organs. The patient was treated with 6 cycles of systemic chemotherapy with a modified R-ProMACEMTX regimen [rituximab, cyclophosphamide, adriablastin, etoposide on day 1 and high-dose systemic methotrexate (3.5 g/m2) on day 8 with leukovorin rescue] combined with 6 cycles of intrathecal chemotherapy (methotrexate 12 mg, liposomal aracytin 50 mg, and methotrexate 12 mg with aracytin 40 mg, twice each). After this treatment, repeat staging studies, including a further biopsy of the bone marrow, were negative for systemic lymphoma. Follow-up CSF analysis was negative for malignant cells. Her neurological examination showed global improvement with disappearance of right arm weakness. MRI showed a reduction of left lumbosacral and cervical plexus involvement, but contrast enhancement was still present. Therefore, the patient underwent highdose aracytin (2 g/m2 every 12 h for 2 days) therapy with subsequent collection of peripheral blood stem cells for autologous transplantation. Unfortunately, 2 months after the end of the chemotherapy cycle, she developed dysesthesias and weakness of her left arm. Neurophysiological evaluation of left upper limb showed the presence of a left brachial plexopathy with predominant involvement of the middle and lower trunks. A third 18F-FDG Muscle MRI in ACTA1 NM

PET-CT scan revealed reduction of the previously described lesions, but there was now 18F-FDG uptake in the right C6 nerve root (Fig. 2d–f). Because the clinical findings suggested a left brachial plexopathy, the patient underwent radiotherapy at this site for 2 months. The evidence of the tumor progression in the peripheral nervous system (PNS) prompted plans for further treatment, but the patient died of sepsis about 19 months after the onset of symptoms. DISCUSSION

We describe a case of PLPNs with multifocal peripheral nervous system involvement. The majority of patients with PLPNs described to date presented as mononeuropathy cases (see Table S1 online). Notably, 10 cases involved the sciatic nerve3–5,7,8,10–14; the remaining cases included involvement of the radial nerve in 2,11,15 1 in the median nerve9 and 1 in the ulnar nerve.6 In 1 case the lymphoma was confined to the sympathetic chain and T2 spinal nerve (Table S1).11 Thirteen cases were found to be of B-cell lineage,3–6,8,10–15 and only 2 of T-cell lineage (Table S1).7,9 In our patient, the disease presented as subacute left lumbosacral radiculoplexopathy, with spread to several other nerve trunks, including right brachial and lumbosacral plexus and left brachial plexus, thus constituting multifocal PLPNs. In the first stages of the disease the diagnosis was challenging, as the presence of diabetes mellitus and the negativity of all examinations for a malignancy prompted us to make a diagnosis of diabetic radiculoplexopathy or inflammatory neuropathy. The poor response to anti-inflammatory therapies and the presence of painful symptoms brought us to investigate further, leading to a fascicular femoral biopsy that revealed nerve infiltration by a diffuse large B-cell lymphoma. The peculiarity of our patient was that, until the end, lymphomatous infiltration involved only the peripheral nervous system, mainly in the proximal portions, without evidence of systemic diffusion. The last PET-CT scan, in fact, showed uptake of the 18F-FDG only in the PNS, and the total-body CT scan did not reveal lymphadenopathy or neoplasms. The difficulty in making a diagnosis of primary NL and PLPNs is due to the scarcity of specific laboratory and radiological findings and also to the presence of misleading signs, including demyelinating features on electrophysiological study and partial response to immunomodulating therapies. In fact, although FDG PET scan is the most sensitive imaging technique available in patients with lymphoma, its specificity in the diagnosis of NL has not yet been established. In certain cases it does not MUSCLE & NERVE

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allow differentiation between NL and chronic inflammatory demyelinating polyneuropathy.17 Early diagnosis of lymphoma is important in order to initiate timely targeted therapy. Some clinical characteristics, such as severe pain, asymmetric distribution, or rapid evolution, are suggestive of NL rather than inflammatory neuropathy.18 If lymphoma is suspected, fascicular nerve biopsy can diagnose the disease definitively. Unfortunately, the prognosis in patients affected by neuropathy associated with lymphoma is poorer than in those affected by only systemic lymphoma. In our patient the response to chemotherapy was poor, as the disease relapsed after only 6 months to involve other PNS sites. The general outcome of PLPNs is not well defined, because, in the majority of cases described, the follow-up was too brief (

Primary multifocal lymphoma of peripheral nervous system: case report and review of the literature.

Primary lymphomas of peripheral nerves are extremely rare, and only a few cases have been reported...
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