CASES OF THE MONTH

A NOVEL SMALL DELETION IN PMP22 CAUSES A MILD HEREDITARYNEUROPATHY WITH LIABILITY TO PRESSURE PALSIES PHENOTYPECARLOS CASASNOVAS, MD, PhD,1 ISABEL BANCHS, BHSc,2 LAURA DE JORGE, BPharm,2

MARIA ANTONIA ALBERTI, MD,1 YOLANDA MARTINEZ–CAMPO, AST,1 MONICA POVEDANO, MD,1

JORDI MONTERO, MD, PhD,1 and VICTOR VOLPINI, MD, PhD2

1Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, c/ Feixa Llarga s/n, 08907 L’Hospitalet deLlobregat, Barcelona, Spain

2Molecular Genetic Diagnosis Center, Institut de Investigacion Biomedica de Bellvitge, Barcelona, Spain

Accepted 9 June 2011

ABSTRACT: Introduction: In this study we examined a familywith electrophysiological findings of hereditary neuropathy withliability to pressure palsies (HNPP) and a mild clinical presenta-tion. Methods: Four members of a family were referred for diag-nosis of HNPP. Electrophysiological studies included motor andsensory nerve conduction studies in the upper and lowerextremities. Investigations of microsatellites, using polymorphicrepeat markers flanking the gene, and multiplex ligation-de-pendent probe amplification (MLPA) were performed for molec-ular studies. Results: The initial study of microsatellites did notdetect any change, but MLPA demonstrated a small deletion ofexon 5 in the PMP22 gene. Conclusion: Our findings demon-strate the important role of small deletions in the PMP22 genein the etiology of HNPP with a normal microsatellite study.

Muscle Nerve 45: 135–138, 2012

Hereditary neuropathy with liability to pressure pal-sies (HNPP) is an autosomal dominantly inheriteddisease. Motor and sensory nerve dysfunction due tocompression at common entrapment sites is thecharacteristic clinical presentation of this disease,even though there is a wide clinical spectrum of pre-sentation, including asymptomatic individuals.1 Ithas been reported that electrophysiological findingsin HNPP show a distinctive background polyneurop-athy independent of superimposed entrapment neu-ropathy. The condition is characterized by diffusesensory nerve conduction velocity (SNCV) slowingand prolongation of distal motor latencies with a rel-atively infrequent, minor reduction of motor nerveconduction velocities. This is interpreted to showdisproportionate distal conduction slowing in thedisorder.2,3 It has been suggested that this electro-physiological pattern in HNPP is due to predisposi-tion to pressure palsies and does not reflect a distalmyelinopathy.4

Up to 84% of HNPP cases are due to the 1.5-Mb deletion at 17p11.2-12 containing the periph-eral myelin protein 22 (PMP22) gene.5 This genecodes for the membrane glycoprotein PMP22,which plays an important role in the formationand maintenance of compact myelin in the periph-eral nervous system. Point mutations in the PMP22gene, causing a loss of function in the PMP22 pro-tein through premature termination of translationor aberrant gene splicing, explain some of thecases that lack a deletion at PMP22.6–8 In addition,point mutations at myelin protein 0 (MPZ) havebeen reported to cause HNPP.9

In this study we report the clinical and electro-physiological findings of a family with a mild HNPPphenotype with a novel small deletion of exon 5 ofthe PMP22 gene. In this family, microsatellite analy-sis did not reveal any pathological change. However,multiplex ligation-dependent probe amplification(MLPA) studies revealed the presence of a small de-letion of exon 5 in PMP22. Thus, we confirm theusefulness of MLPA in the study of HNPP patients,especially in those whose microsatellite studies donot detect the typical 1.5-Mb deletion.

METHODS

Patients. The study patients were referred to theneuromuscular unit of our hospital for diagnosis.

Electrophysiological Methods. Electrophysiologicalstudies were carried out by the same investigator(C.C.) on a Synergy (CareFusion, San Diego, Cali-fornia) electromyography machine. Skin tempera-ture was >32�C in all patients. Motor nerve con-duction (MNC) studies were performed on themedian, ulnar, and fibular nerves, with supramaxi-mal stimulation and surface electrodes. Sensorynerve conduction was studied with surface electro-des, using antidromic techniques on median, ul-nar, and sural nerves. Needle electromyographywas performed with a concentric needle in at leastone muscle of the lower and upper limbs. A valuewas defined as abnormal if it fell outside our labo-ratory range of normal, corrected for age.

Abbreviations: CMAP, compound muscle action potential; EMG, electro-myography; HNPP, hereditary neuropathy with liability to pressure palsies;MLPA, multiplex ligation-dependent probe amplification; MNC, motornerve conduction; MNCV, motor nerve conduction velocity; MPZ, myelinprotein 0; SNAP, sensory nerve action potential; SNCV, sensory nerveconduction velocity

Correspondence to: C. Casasnovas; e-mail: carloscasasnovas@bellvitgehospital.cat

VC 2011 Wiley Periodicals, Inc.Published online in Wiley Online Library (wileyonlinelibrary.com).DOI 10.1002/mus.22201

Key words: hereditary neuropathy with liability to pressure palsies; HNPP;novel mutation; MLPA, PMP22 deletion

Small PMP22 Deletion in HNPP MUSCLE & NERVE January 2012 135

Molecular Methods. Genomic DNA was extractedfrom peripheral blood lymphocytes of 4 membersof the family after informed consent was obtained.Chromosome 17p11.2-12 polymorphic (CA)nrepeat markers, D17S921, D17S955, D17S1358,D17S839, D17S1356, D17S1357, and D17S261,within the 1.5-Mb region that contains the PMP22gene, were amplified by polymerase chain reaction(PCR) using primers reported prior to sequenceanalysis (ABI Prism 3130 XL Genetic Analyzer; LifeTechnologies) and subsequent interpretation withGenMapper.1,2,4 The same samples were also ana-lyzed by MLPA, using a commercial MLPA kit(SALSA P033B CMT1/HNPP region; MRC-Hol-land, Amsterdam, The Netherlands), according tothe manufacturer’s instructions. The PCR resultsthen underwent sequence analysis (ABI Prism 3130XL). Excel software recorded the peak areas forthe signal of each probe. To produce normalizedratios reflecting the relative probe dose, each peakarea was divided by the sum of all peaks. Expectednormalized values were 1.0 in absence of anychange and 0.5 in case of a heterozygousdeletion.10,11

RESULTS

Clinical Findings. Patient II.2. A 54-year-old Span-ish man (Fig. 1) was referred to our electromyogra-phy (EMG) laboratory with suspected L5 radicu-lopathy. He complained of >10 years of nocturnalhand paresthesias and numbness. Neurological ex-amination did not reveal any abnormality.

Patient III.2. A 27-year-old man, son of patientII.2 (Fig. 1), complained of occasional nocturnalnumbness and paresthesias in both hands. Neuro-logical examination did not reveal any abnormality.

Electrophysiological Findings. The findings aresummarized in Table 1. Patients II.2 and III.2 had

the usual HNPP electrophysiological findings char-acterized by diffuse SNCV slowing and prolonga-tion of distal motor latencies with minor reduc-tions of MNC velocities.

Molecular Findings. Chromosome 17p11.2-12 poly-morphic (CA)n repeat markers did not reveal anyabnormality. MLPA studies revealed the presenceof a deletion in exon 5 (Fig. 2). This finding wasonly present in the affected family members andnot in the healthy ones. It was also not found in100 alleles from 50 healthy controls.

FIGURE 1. Summary of affected individuals in the family. There

is dominant inheritance with male-to-male transmission.

Table 1. Summary of electrophysiological findings.

Patient II-2 Patient III-2

Sensory NCSRight suralSNAP (lV) 5.4 (>15) 4.8 (>11)Latency (ms) 4.3 (<2.9) 3.4 (<2.9)NCV (m/s) 32.6 (>42) 38.1 (>42)Duration (m/s) 1.65 (<1.7) 2.5 (<1.6)

Left suralSNAP 5.2 (>15) 2.5 (>11)Latency 4.8 (<2.9) 3.5 (<2.9)SNCV 29.2 (>42) 38.0 (>42)Duration 1.95 (<1.7) 2.0 (<1.6)

Right median (second finger)SNAP 3.1 (>15) 15.3 (>25)Latency 5.6 (<3) 4.1 (<3)SNCV 26.9 (>42) 34 (>42)Duration 2.4 (<1.9) 3.5 (<1.9)

Right ulnar (fifth finger)SNAP 11.2 (>12) 10.0 (>18)Latency 3.85 (<2.7) 3.3 (<2.7)SNCV 31.2 (>42) 36.4 (>42)Duration 2.5 (<1.2) 2.9 (<1.2)

Motor NCSRight fibular (extensor digitorum brevis)CMAP (mV) NR (>2) 5.9 (>2)Distal latency (ms) NR (<5.5) 6.2 (<5.5)MNCV (m/s) NR (>42) 40.1 (>42)

Right fibular (tibialis anterior)CMAP 5.1 (>2) NPDistal latency 3.8 (<5.5) NPMNCV 51.6 (>42) NP

Right tibialCMAP 5.4 (>3) NPDistal latency 5.1 (<6) NPMNCV 49.9 (>38) NP

Right medianCMAP 2.3 (>6) 7.4 (>6)Distal latency 6.7 (<3.9) 5.3 (<3.9)MNCV 51.1 (>54) 58.1 (>54)

Right ulnarCMAP 7.1 (>5) 10.7 (>5)Distal latency 4.5 (<3.3) 3.3 (<3.3)MNVC 51.9 (>48) 49.4 (>48)

Summary of electrophysiological findings in affected family members. Aprimary demyelinating sensory and motor neuropathy suggesting HNPPwas found. NR, not recordable; NP, not performed; SNCV, sensorynerve conduction velocity; MNCV, motor nerve conduction velocity;CMAP, compound muscle action potential; SNAP, sensory nerve actionpotential. In parentheses: normal ranges used in our EMG laboratory(adjusted for patient’s age).

136 Small PMP22 Deletion in HNPP MUSCLE & NERVE January 2012

DISCUSSION

HNPP is a focal and recurrent sensory and motorneuropathy inherited as a dominant trait. In mostcases, it occurs because of a 1.5-Mb deletion onchromosome 17 that includes this gene.5 Pointmutations in this gene cause a loss of function,6–8

and the involvement of other genes has also beenreported to cause the HNPP phenotype.9 The clas-sical clinical manifestation of HNPP is recurrentpainless mononeuropathies. However, other atypi-cal manifestations have been reported.12 Electro-physiological examination plays a central role inthe diagnosis of this disease.2,3

We have reported a family with a mild HNPPphenotype without recurrent palsies. Mutations inthe PMP22 gene producing HNPP without recur-rent palsies have been described elsewhere.13 Infact, in the family reported herein, the proposituswas referred to our electrodiagnostic laboratorywith symptoms of mild carpal tunnel syndromeand no suspicion of HNPP. A family with HNPPand only carpal tunnel syndrome was alsodescribed elsewhere.14 The electrophysiologicalfindings revealed diffuse SNCV slowing and pro-longation of distal motor latencies. Significantslowing of motor nerve conduction velocities wasnot found, supporting the typical disproportion of

the conduction slowing in distal and proximal seg-ments that has been reported as electrophysiologi-cal findings in HNPP.2–4 Molecular study revealedthe presence of a small deletion of exon 5 ofPMP22 in the affected individuals, which had notbeen described previously. Regular chromosome17p11.2-12 polymorphic (CA)n repeat markerscould not detect the change. This is because thesemarkers are located in the duplicated region ofthe chromosome and not within the PMP22 gene(Fig. 2). MLPA was used to detect the change (Fig.3). Previous studies reported the presence of smalldeletions or duplications in PMP22 that were de-tectable by MLPA, one of which also showed clini-cal evidence of carpal tunnel syndrome.15–17

Although no study has demonstrated the func-tional consequences of such a change, the trun-cated PMP22 product is expected to be unstableand degraded. The presence of characteristic elec-trophysiological findings in the affected individualsstrongly suggests that this small deletion has identi-cal consequences to the common 1.5-Mb deletion.This hypothesis and the fact that the change isfound only in clinically and electrophysiologicallyaffected family members (Table 1), and not inhealthy family members (data not shown) andhealthy controls, are the reasons why we consider

FIGURE 2. Various chromosome 17p11.2-12 polymorphic (CA)n repeat markers are seen outside the deleted region (exon 5) as well

as the different MLPA probes, including the coding regions of PMP22. [Color figure can be viewed in the online issue, which is avail-

able at wileyonlinelibrary.com.]

FIGURE 3. Results of MLPA study in one of the affected individuals. An exon 5 deletion at PMP22 was found. [Color figure can be

viewed in the online issue, which is available at wileyonlinelibrary.com.]

Small PMP22 Deletion in HNPP MUSCLE & NERVE January 2012 137

this change pathologic. Future functional studiescould confirm whether the mild clinical conditionfound in the affected individuals in this family isbecause of the heterogeneity of the disease or isspecifically related to this change. In fact, otherreported HNPP patients with small deletions inPMP22 also presented with mild clinical findings.15

This study has confirmed the important role ofother diagnostic techniques, such as MLPA, in the di-agnosis of HNPP. Population studies are needed todetermine whether small deletions in PMP22 are morefrequent than point mutations in HNPP patients.These future studies could support the inclusion ofMLPA studies in the diagnostic algorithm of HNPP.

This work was supported by the Hospital Intensification Programof the Centro de Investigacion Biomedica en Red de Enferme-dades Degenerativas (CIBERNED).

REFERENCES

1. Mouton P, Tardieu S, Gouider R, Birouk N, Maisonobe T, Dubourg O,et al. Spectrum of clinical and electrophysiologic features in HNPPpatients with the 17p11.2 deletion. Neurology 1999;22;52:1440–1446.

2. Andersson PB, Yuen E, Parko K, So YT. Electrodiagnostic features ofhereditary neuropathy with liability to pressure palsies. Neurology2000;54:40–44.

3. Li J, Krajewski K, Shy ME, Lewis RA. Hereditary neuropathy withliability to pressure palsy: the electrophysiology fits the name. Neu-rology 2002;25;58:1769–73.

4. Hong YH, Kim M, Kim HJ, Sung JJ, Kim SH, Lee KW. Clinical andelectrophysiologic features of HNPP patients with 17p11.2 deletion.Acta Neurol Scand 2003;108:352–358.

5. Nelis E, van Broeckhoven C, de Jonghe P, Lofgren A, VandenbergheA, Latour P, Le Guern E, et al. Estimation of the mutation frequen-cies in Charcot–Marie–Tooth disease type 1 and hereditary neuropa-thy with liability to pressure palsies: a European collaborative study.Eur J Hum Genet 1996;4:25–33.

6. Meuleman J, Pou-Serradell A, Lofgren A, Ceuterick C, MartinJJ, Timmerman V, et al. A novel 30-splice site mutation in

peripheral myelin protein 22 causing hereditary neuropathy withliability to pressure palsies. Neuromuscul Disord 2001;11:400–403.

7. Nicholson GA, Valentijn LJ, Cherryson AK, Kennerson ML, BraggTL, DeKroon RM, et al. A frame shift mutation in the PMP22 genein hereditary neuropathy with liability to pressure palsies. Nat Genet1994;6:263–266. [Erratum: Nat Genet 1994;7:113]

8. Young P, Wiebusch H, Stogbauer F, Ringelstein B, Assmann G,Funke H. A novel frameshift mutation in PMP22 accounts for hered-itary neuropathy with liability to pressure palsies. Neurology 1997;48:450–452.

9. Magot A, Latour P, Mussini JM, Mourtada R, Guiheneuc P, PereonY. A new MPZ mutation associated with a mild CMT1 phenotype pre-senting with recurrent nerve compression. Muscle Nerve 2008;38:1055–1059.

10. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F,Pals G. Relative quantification of 40 nucleic acid sequences by multi-plex ligation-dependent probe amplification. Nucleic Acids Res2002;30:e57.

11. Stangler Herodez S, Zagradisnik B, Erjavec Skerget A, Zagorac A,Kokalj Vokac N. Molecular diagnosis of PMP22 gene duplicationsand deletions: comparison of different methods. J Int Med Res 2009;37:1626–1631.

12. Pareyson D, Scaioli V, Taroni F, Botti S, Lorenzetti D, Solari A, et al.Phenotypic heterogeneity in hereditary neuropathy with liability topressure palsies associated with chromosome 17p11.2–12 deletion.Neurology 1996;46:1133–1137.

13. Luigetti M, Conte A, Madia F, Mereu ML, Zollino M, Marangi G,et al. A new single-nucleotide deletion of PMP22 in an HNPP familywithout recurrent palsies. Muscle Nerve 2008;38:1060–1064.

14. Del Colle R, Fabrizi GM, Turazzini M, Cavallaro T, Silvestri M,Rizzuto N. Hereditary neuropathy with liability to pressure palsies:electrophysiological and genetic study of a family with carpaltunnel syndrome as only clinical manifestation. Neurol Sci 2003;24:57–60.

15. Sutton IJ, Mocroft AP, Lindley VH, Barber RM, Bryon RJ, Winer JB,et al. Application of multiplex ligation-dependent probe analysis todefine a small deletion encompassing PMP22 exons 4 and 5 in he-reditary neuropathy with liability to pressure palsies. NeuromusculDisord 2004;14:804–809.

16. Stangler Herodez S, Zagradisnik B, Erjavec Skerget A, Zagorac A,Kokalj Vokac N. Molecular diagnosis of PMP22 gene duplicationsand deletions: comparison of different methods. J Int Med Res 2009;37:1626–1631.

17. van de Wetering RA, Gabreels-Festen AA, Timmerman V, PadbergGM, Gabreels FJ, Mariman EC. Hereditary neuropathy with liabilityto pressure palsies with a small deletion interrupting the PMP22gene. Neuromuscul Disord 2002;12:651–655.

DIFFUSE LARGE B-CELL LYMPHOMA PRESENTING AS MILLER FISHERSYNDROMENIDA USMANI, MD,1 RITA BHATIA, MD,2 OFFIONG F. IKPATT, MD, PhD,3 and KHEMA R. SHARMA, MD1

1Department of Neurology, Miller School of Medicine (M740), University of Miami, 1150 NW 14th Street,Room 609, Miami, Florida 33136, USA

2Department of Radiology, Miller School of Medicine, University of Miami, Miami, Florida, USA3Department of Hematopathology, Miller School of Medicine, University of Miami, Miami, Florida, USA

Accepted 27 June 2011

ABSTRACT: We report a patient with diffuse large B-celllymphoma (DLBCL) who initially presented as Miller Fishersyndrome (MFS) responsive to high-dose immunoglobulin treat-ment. Detailed investigations for the recurrence of neurological

symptoms revealed DLBCL that was responsive to chemother-apy. DLBCL should be considered in the differential diagnosisof patients with MFS who have worsening of their neurologicalcondition after initial improvement with conventional therapy.

Muscle Nerve 45: 138–143, 2012

Peripheral nervous system involvement occurs in5% of patients with lymphoma.1 The syndromescommonly occur by direct infiltration or compres-sion of nerves, as a side effect of chemotherapy orradiotherapy, infectious processes, direct infiltrationof vessels supplying the nerves, or paraneoplasticmechanisms. We report a patient who initially pre-sented with acute onset of multiple cranial nervepalsies, ataxia, and areflexia, with significant

Abbreviations: BL, Burkitt lymphoma; CHOP, cyclophosphamide, doxoru-bicin, vincristine, prednisone; CMAP, compound muscle action potentials;CSF, cerebrospinal fluid; DLBCL, diffuse large B-cell lymphoma; EMG, elec-tromyography; GBS, Guillain–Barre syndrome; ILCL, intravascular large-celllymphoma; IVIg, intravenous immunoglobulin; MFS, Miller Fisher syndrome;MRC, Medical Research Council; MRI, magnetic resonance imaging; MUAP,motor unit action potential; SNAP, sensory nerve action potential; SF, superfi-cial fibular nerve; TRF, treatment-related fluctuationKey Words: chemotherapy; demyelinating neuropathy; diffuse large B-celllymphoma; intravenous immunoglobulin; Miller Fisher syndromeCorrespondence to: K.R. Sharma; e-mail: ksharma@med.miami.edu

VC 2011 Wiley Periodicals, Inc.Published online in Wiley Online Library (wileyonlinelibrary.com).DOI 10.1002/mus.22223

138 DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012

improvement with high-dose immunoglobulin treat-ment. The initial diagnosis was Miller Fisher syn-drome (MFS).2 However, detailed investigation aftera recurrence of neurological symptoms revealed dif-fuse large B-cell lymphoma (DLBCL), which was re-sponsive to chemotherapy. We suggest consideringthe possibility of DLBCL in those patients with MFSwho have worsening of their neurological conditionafter initial improvement with conventionaltherapy.

CASE REPORT

A 61-year-old male office worker, with no historyof viral infection, vaccination, or travel abroad,developed acute onset of diplopia, right-side facialweakness, and dysphagia. In the following week hebecame ataxic and had frequent falls. He hadessential hypertension of 5-years duration, whichwas controlled with metoprolol. He occasionallysmoked cigars and drank socially. A neurologistevaluated the patient, and the examination was re-markable for weakness of the muscles innervatedby the oculomotor nerves and facial nerves bilater-ally, diminished muscle stretch reflexes, and ataxicgait with ability to take only a few steps with assis-tance. He was diagnosed with MFS and received in-travenous immunoglobulin (IVIg) treatment 400mg/kg/day for 5 days, followed by physicaltherapy.

Magnetic resonance imaging (MRI) of thebrain without contrast was normal. Endoscopic ex-amination of the upper gastrointestinal tract forevaluation of dysphagia was also normal. Cerebro-spinal fluid (CSF) examination was abnormal (pro-tein 78 mg/dl; glucose 85 mg/dl, with concurrentserum glucose of 92 mg/dl; white blood cells 6/ll,all monocytes). Nerve conduction studies were

suggestive of an early demyelinating peripheralsensory motor polyradiculoneuropathy (Table 1;first study). There were significant functionalimprovements in his ability to perform activities ofdaily living after the IVIg therapy and 2 weeks ofin-patient rehabilitation. These included resolutionof diplopia only in primary gaze (elimination ofthe need for an eye patch to prevent diplopia onprimary gaze), improvement in dysphagia (fromfrequent choking and requiring changes in thedietary consistency to occasional choking with solidfood), improvement in facial muscle function(complete resolution of excessive drooling of salivaand food, and need for eye patches during sleepfor prevention of corneal trauma), and ability towalk with a walker for >10 meters.

In the following 2 weeks, the patient noted re-currence of weakness of cranial nerve innervatedmuscles and new neurological symptoms. Theseincluded impaired sensation distally in the handsand feet, weakness in limb and axial musclesrequiring a wheelchair for ambulation, painfulexposure keratitis of the right eye, and bilateralimpaired hearing. Because of his deterioring con-dition, at week 6 after initial onset of symptoms hewas transferred to our institution for further care.

On admission, his vital signs were normal (tem-perature 98�F; pulse 74; respirations 22; bloodpressure 112/74 mm Hg). Neurological examina-tion revealed that cognitive function and languagewere intact. Cranial nerve examination was remark-able for bilateral lower motor neuron extraocularmuscle and facial weakness and bilateral impairedhearing (left side more than right). The right eyewas congested and had corneal haziness, but cor-neal sensitivity to light touch, visual acuity, visualfields, and pupillary reactions were normal. Both

Table 1. Nerve conduction studies.

DML (ms) AMP (mV) CV (m/s) Minimum F-wave (ms)

Nerve tested First study Second study First study Second study First study Second study First study Second study

Motor Median R 4.8 5.6 6.9/5.4* 4.5/3.3* 48.6 45.1 37.2 46.5Ulnar R 3.6 3.7 12.9/9.6* 10.3/3.9* 51.2 54.5 35.6 44.6Fibular L/R 5.2 4.7 4.5/2.9* 0.5/0.4* 37.2 40.8 63.9 NRTibial R 5.7 6.2 8.9/6.8* 4.2/0.5* 33.8 32.4 59.2 65.4Facial R/L ND NR ND

Sensory†

Sural R/L NA NA 7.3 NR 34.6 NRSF R/L NA NA ND NR NDMedian R NA NA 15.9 3.1 lV 47.8 46.4Ulnar R NA NA 10.2 7.1 lV 42.3 39.5

Abnormal values are shown in bold; normal values for our laboratory presented in the study by Sharma et al.3 DML, distal motor latency; AMP, amplitudeof motor compound action potential and sensory nerve action potential; CV, conduction velocity; R, right; L, left; NR, no response; NA, not applicable; SF,superficial fibular.*Expressed as distal compound muscle action potential amplitude/proximal.†Antidromic studies for sural and superficial fibular nerves, and orthodromic studies for median and ulnar sensory nerves. First study performed on day 8from the onset of the initial symptoms. Second study performed during recurrence of the neurological symptoms at day 43 after initial symptoms.

DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012 139

muscle bulk and strength of pharyngeal, laryngeal,and tongue muscles were normal. Neck, axial, andlimb muscle strength examination revealed diffuseweakness in a proximal–distal gradient affectinglower extremities more than upper extremities. Inthe upper extremities, proximal strength was 4þ/5on the Medical Research Council (MRC) scale,and distal strength was 4/5. In the lower limbs,proximal strength was 3/5 and distal strength was2/5. The axial muscles were also weak, as heneeded help in sitting from the supine position.The general motor examination showed no musclewasting or fasciculation. Muscle tone was normalin the upper limbs and diminished in the lowerlimbs. Coordination was normal in the upper limbsand impaired in the lower limbs. Even with supporthe could not stand. Sensory examination revealedimpaired light touch and pin-prick sensation distallyin the feet and hands and impaired vibration andproprioception in the great toes. Muscle stretchreflex examination revealed normal jaw reflex,decreased reflexes in the upper limbs, and absent

reflexes in the lower limbs. The plantar responseswere flexor bilaterally.

The general physical examination was remark-able for a left groin lymph node, 0.5–1 cm in di-ameter, and a right axillary node, 1–2 cm in diam-eter. No other lymphadenopathy or organomegalycould be detected.

MRI of the brain (Fig. 1A–D) showed contrastenhancement of the third (Fig. 1A), seventh, andeighth cranial nerves (intracanalicular portions)bilaterally (Fig. 1B), along with subependymal(Fig. 1C), cerebellar (Fig. 1D), and pachymenin-geal enhancement in the left temporal and parie-tal regions (not included in Fig. 1).

Nerve conduction studies (Table 1 and Fig. 2;second study) and needle electromyography(EMG) showed: (1) prolonged distal motor latency(right median, ulnar, and tibial motor nerves); (2)decreased amplitudes of compound muscle actionpotentials (CMAPs, left fibular motor) or noobtainable CMAPs (bilateral facial motor nerves);(3) slowed motor nerve conduction velocity (right

FIGURE 1. Magnetic resonance imaging of brain with gadolinium contrast showing selected axial and coronal T1 images. (A) Bilateral

third cranial nerve enhancement (arrows). (B) Bilateral seventh nerve enhancement (arrow heads), right eighth cranial nerve enhance-

ment (arrow), and left seventh and eighth cranial nerve complex enhancement (arrow with small head). (C) Enhancement of the sub-

ependymal region of lateral ventricles (arrows). (D) Left cerebellar enhancing lesion (arrow).

140 DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012

median and tibial motor nerves); (4) motor nerveconduction block [right ulnar motor nerve in theforearm with no evidence for anomalous commu-nication from median to ulnar nerves in theforearm (Fig. 2), and right tibial motor in the legusing near-nerve needle electrode stimulationtechnique3]; (5) prolonged minimum F-wave laten-cies (right median, ulnar, and tibial nerves) orabsent F-waves (left fibular nerve); (6) abnormalsensory nerve conduction studies [no obtainablesensory nerve action potential (SNAP) amplitudesfrom sural and superficial fibular nerves bilater-ally], decreased right median SNAP amplitude,and slowed right ulnar nerve conduction velocity;and (7) fibrillation potentials, increased size ofmotor unit action potentials (MUAPs), anddecreased recruitment of MUAPs or no MUAP

activation (bilateral facial nerve innervated musclesand distal leg muscles) during voluntary contrac-tion of muscles. Overall, the studies were consist-ent with peripheral sensorimotor demyelinatingpolyradiculoneuropathy.3

CSF studies revealed an opening pressure of17 cm H2O (horizontal position, normal 7–20), whiteblood cell count of 177/ll (normal 0–5) with pre-dominant lymphocytes (99%) and multiple atypicallymphocytes, protein 682 mg/dl (normal 15–45), andglucose 16 mg/dl (normal 40–70 mg/dl, serum glu-cose 91 mg/dl). The CSF cultures were negative.

Computed tomography scan with intravenouscontrast of chest, abdomen, and pelvis revealedmultiple bilateral axillary, mediastinal, hilar, retro-peritoneal, inguinal, and iliac lymph nodes of vari-able size (0.6–3.5 cm).

FIGURE 2. Ulnar motor nerve conduction studies show evidence of conduction block in the forearm and across the elbow. The upper

trace represents the distal CMAP of the abductor digiti minimi with supramaximal ulnar nerve stimulation nerve at the wrist. The middle

trace represents supramaximal stimulation of the ulnar nerve below the elbow. There is 58.8% reduction of the area of the CMAP

compared with the distal CMAP. The bottom trace represents supramaximal stimulation of the ulnar nerve above the elbow. There is

59.4% reduction of the area of the CMAP compared with the below-elbow CMAP. Also shown is the scale for an amplifier gain of

5 mV/division and a sweep speed of 30 ms (3 ms/division).

DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012 141

A 2.6-cm right axillary lymph node was biop-sied. Grossly it appeared tan and fleshy. Micro-scopic examination showed diffuse effacement ofthe nodal architecture by tumor cells. The tumorconsisted predominantly of centroblasts, medium-to large-sized cells with vesicular nuclei, and cen-tral nucleoli. Immunohistochemical studies showedthat the tumor cells were positive for leukocytecommon antigen (CD45) and B-cell antigen(CD20). They were also positive for Bcl-2, Bcl-6,and immunoglobulin kappa light chain, and Ki-67expression was present in 90% of the cells. Thecells were negative for CD3, CD10, CD5, Mum-1,CD30, and cytokeratin. Whereas no rearrangementfor the IgH/BCL2 genes was detected, additionalsignals for the IGH gene in the 14q32 region (69%of cells examined) and missing signal of the BCL2gene in the 18q21 region (48.5% of cells exam-ined) were seen. Rearrangement of the c-MYCgene in the 8q24 region was observed in 48.5%of cells, suggestive of biological aggressiveness ofthe tumor. These findings are consistent with adiagnosis of DLBCL with origin in germinal centerB-cells.4

The blood work-up revealed a moderate nor-mocytic anemia (hemoglobin 11.2 mg/dl, hemato-crit 34.6%), and mild to moderately elevated he-patic enzymes (aspartate aminotransferase 101 U/L, alanine aminotransferase 59 U/L, lactatedehydrogenase 860 U/L). Metabolic, endocrine,infectious (including human immunodeficiencyvirus and tuberculosis), collagen vascular diseaseand plasma cell dyscrasia (antinuclear antibody,double-stranded DNA, anti-SSA/SSB antibodies,cytoplasmic and perinuclear staining–antineutro-phil cytoplasmic antibodies, serum electrophoresiswith immunofixation, sedimentation rate, cryoglo-bulins, and rheumatoid factor), and sarcoidosis(serum angiotensin-converting enzyme) evaluationswere unrevealing. Serologies for anti-Hu, anti-Yo,anti-CV2, anti-GQ1b, and anti-GD1a antibodieswere negative.

The patient was treated with the standardchemotherapy that included cyclophosphamide,doxorubicin, vincristine, prednisone (CHOP), rit-uximab and intrathecal methotrexate, and cytara-bine. After the second of the six cycles of chemo-therapy and in-patient rehabilitation, his conditionimproved. The cranial neuropathies improved sig-nificantly (bilateral facial strength 4�/5 andimproved ability to swallow liquids and solids).Similarly, strength improved significantly in theupper limbs (proximally 5/5, distally 4/5) andlower limbs (able stand up with help and take afew steps with a walker). Unfortunately, after thesixth treatment cycle, he had a massive pulmonaryembolism and died. The family declined autopsy.

DISCUSSION

We describe a patient with DLBCL who had anunusual initial neurological manifestation thatmimicked MFS. He had significant improvementof the neurological deficit initially with the use ofIVIg therapy and, subsequently, with standardchemotherapy during a neurological recurrence. AGuillain–Barre syndrome (GBS) or GBS-like pre-sentation may occur in Hodgkin disease5 and disse-minated intravascular large cell lymphoma.6 Therehas also been a case report of MFS with Burkittlymphoma (BL).7 However, there were significantdifferences in the findings of that case7 when com-pared with ours. First, electrodiagnostic studiesrevealed diffuse axonal neuropathy, but withoutevidence of demyelination as was observed in ourcase (Table 1 and Fig. 2). Second, the conditionoccurred in a renal transplant recipient who wastreated with an immunosuppressant (cyclosporine100 mg/day for 7 years). Third, IVIg therapy wasineffective in their patient, unlike our patient.These findings suggest that the altered immunesystem in patients with non-Hodgkin lymphoma,similar to that of patients with Hodgkin lym-phoma,5 plays a significant role in the pathogene-sis of GBS or MFS associated with BL,7 intra-vascular large-cell lymphoma (ILCL),6 and DLBCL(our case).

Several explanations for the pathogenesis ofneuropathy associated with lymphoma have beensuggested. These include: direct invasion of lym-phoma cells; metabolic and infectious processes;vascular impairment; and immunological mecha-nisms, including paraneoplastic neuropathy.1,8,9 Inour case, the most likely pathogenetic factors wereimmunological/paraneoplastic and direct invasionof lymphoma cells, as stated previously. This is fur-ther supported by additional observations: First,there was significant recovery of the neurologicaldeficit with the use of IVIg therapy initially andsubsequent significant improvement with the useof chemotherapy for the recurrence of the syn-drome. Second, there was abnormal gadoliniumenhancement of the cranial nerves (Fig. 1A andB), similar to that of previous reports in MFS.10

This reflects a breakdown of the blood–nervebarrier associated with immune-mediated inflam-mation11 or direct infiltration of the cranial/peripheral nerves (see later).8 However, the likelyantibodies derived from molecular mimicrydirected at antigens in lymphoma cells or accom-panying viral infections, which are observed insome of the paraneoplastic neuropathies, wereabsent in our patient.12,13

The other likely pathogenic risk factor, inaddition to paraneoplastic disease, was directinfiltration of peripheral nerves by lymphoma

142 DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012

cells.8 Direct infiltration of the central nervoussystem, spinal roots, or peripheral nerves bylymphocytic cells commonly occurs in malignantlymphomas.9,14,15 When these malignant cellsinvade the brain and leptomeninges, there is anincrease in lymphocytes and protein levels in theCSF,16 and there is enhancement of cranial nerves,meninges, subependyma, and cerebellum on brainMRI, as seen in our case, similar to that of previ-ous reports.8,15,17 Similarly, when these malignantcells invade peripheral nerves beyond the duralsleeve, there are pathologic changes of segmentaldemyelination and axonal degeneration.9,15,16 Thiscorrelates with the significant reduction of SNAPand CMAP, slowing of motor and sensory nerveconduction, and conduction block, as seen in ourcase (Fig. 2).

Finally, vasculopathic processes such as vasculi-tis are a recognized association with lymphoma,but the mechanism and the frequency of thisassociation are not known.1,6,18,19 The clinical pre-sentation with a sudden, painful, asymmetric onsetof peripheral neuropathy (mononeuritis multi-plex) associated with paraneoplastic vasculitis issimilar to that of conventional idiopathic vasculitis.Nerve biopsy is required to confirm this diagnosis,but this was not done in our patient. However, theclinical presentation of painless, diffuse, symmetri-cal weakness, along with the findings of segmentaldemyelination (conduction block) would make avasculitis less likely. Because nerve biopsy was notdone in our patient, the possible role of vasculitiscould not be ruled out.

In 5–16% of patients with GBS, there is deterio-ration after initial improvement or stabilization fol-lowing IVIg therapy or plasma exchange, calledtreatment-related fluctuations (TRFs).20 Althoughin our patient recurrence of the neurologicaldeficit occurred 2 weeks after completion of IVIgtherapy, it is unlikely that this was a TRF, given theresponse to the chemotherapy and the presence ofthe atypical lymphocytic cells in the CSF.

In conclusion, we have described a case ofDLBCL with an unusual initial neurological mani-festation that mimicked MFS and had a significantimprovement in the neurological deficit initiallywith the use of IVIg therapy and subsequentstandard chemotherapy during a recurrence of the

neurological disorder. We suggest consideringDLBCL in those patients with MFS who haveneurological worsening after initial improvementwith conventional therapy.

The authors thank Michael Benatar, MD, for the critical review ofthe manuscript, and Regina Menendez-Choy for help in manu-script preparation.

REFERENCES

1. Hughes RA, Britton T, Richards M. Effects of lymphoma on theperipheral nervous system. J R Soc Med 1994;87:526–530.

2. Fisher M. An unusual variant of acute idiopathic polyneuritis(syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med1956;255:57–65.

3. Sharma KR, Cross J, Ferronay O, Ayyar DR, Shebert RT, Bradley WG.Demyelinating neuropathy in diabetes mellitus. Arch Neurol 2002;59:758–765.

4. Zhao XF. Pitfalls in hematopathology—part II. Int J Clin Exp Pathol2010;3:39–46

5. Lisak RP, Mitchell M, Zweiman B, Orrechio E, Asbury AK. Guillain–Barre syndrome and Hodgkin’s disease: three cases with immunolog-ical studies. Ann Neurol 1977;1:72–78.

6. Jiang QL, Pytel P, Rowin J. Disseminated intravascular large-cell lym-phoma with initial presentation mimicking Guillain–Barre syndrome.Muscle Nerve 2010;42:133–135.

7. Gentile S, Messina M, Rainero I, Lo Giudice R, De Martino P, PinessiL. Miller Fisher syndrome associated with Burkitt’s lymphoma. Eur JNeurol 2006;13:430.

8. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clini-cal review. Muscle Nerve 2005;31:301–313.

9. Vallat J, De Mascarel H, Bordessoule D, Jauberteau M, Tabaraud F,Gelot A, et al. Non-Hodgkin malignant lymphomas and peripheralneuropathies—13 cases. Brain 1995;118:1233–1245.

10. Ito M, Kuwabara S, Odaka M, Misawa S, Koga M, Hirata K, et al.Bickerstaff’s brain encephalitis and Fisher syndrome form a contin-uous spectrum: clinical analysis of 581 cases. J Neurol 2008;255:674–682.

11. Perry JR, Fung A, Poon P, Bayer N. Magnetic resonance imaging ofnerve root inflammation in the Guillain–Barre syndrome. Neuroradi-ology 1994;36:139–140.

12. Noguchi M, Mori K, Yamazaki S, Suda K, Sato N, Oshimi K. Multifo-cal motor neuropathy caused by a B-cell lymphoma producing amonoclonal IgM autoantibody against peripheral nerve myelin glyco-lipids GM1 and GD1b. Br J Haematol 2003;123:600–605.

13. Psimaras D, Carpentier AF, Rossi C, the PNS Euronetwork. Cerebro-spinal fluid study in paraneoplastic syndromes. J Neurol NeurosurgPsychiatry 2010;81:42–45.

14. Jellinger K, Radiaszkiewicz T. Involvement of the central nervous sys-tem in malignant lymphomas. Virchows Arch 1976:370:345–362.

15. Baering J, Damek D, Martin E, Betensky R, Hochberg F. Neurolym-phomatosis. Neuro-Oncology 2003;5:104–115.

16. Ince P, Shaw P, Fawcett P, Bates D. Demyelinating neuropathy dueto primary IgM kappa B cell lymphoma of peripheral nerve. Neurol-ogy 1987;37:1231–1235.

17. DeAngelis LM, Boutros D. Leptomeningeal metastasis. Cancer Invest2005;23:145–154.

18. Creange A, Theodorou I, Sabourin J, Vital C, Farcet J, Gherardi R.Inflammatory neuromuscular disorders associated with chroniclymphoid leukemia: evidence for clonal B cells within muscle andnerve. J Neurol Sci 1996;137:35–41.

19. Wooten M, Jasin H. Vasculitis and lymphoproliferative diseases.Semin Arthritis Rheum 1996;26:564–574.

20. Ruts L, van Koningsveld R, van Dooran PA. Distinguishing acute-onset CIDP from Guillain–Barre syndrome with treatment relatedfluctuations. Neurology 2005;65:138–140.

DLBCL: Miller Fisher Syndrome MUSCLE & NERVE January 2012 143

SKIN BIOPSY–PROVEN FLECAINIDE-INDUCED NEUROPATHYAHMET Z. BURAKGAZI, MD,1 MICHAEL POLYDEFKIS, MD, MPH,2 and AHMET HOKE, MD, PhD2

1Department of Neurology, George Washington University, Washington, DC, USA2Department of Neurology, The Johns Hopkins School of Medicine, 855 North Wolfe Street, Rangos 248, Baltimore,Maryland 21205, USA

Accepted 11 July 2011

ABSTRACT: Flecainide acetate is a classic Ic antiarrhythmicagent used to treat a variety of cardiac arrhythmias. Non-car-diac side effects usually affect the central nervous system. Fewcase reports of possible flecainide-induced peripheral neuropa-thy have been reported. We report this unique case in that fle-cainide-induced sensory neuropathy was confirmed with skinbiopsy, and subsequent improvement of neuropathy was docu-mented with assessment of intraepidermal nerve fiber densityin a repeat nerve biopsy.

Muscle Nerve 45: 144–146, 2011

Flecainide acetate is a class Ic antiarrhythmicagent used to treat a variety of cardiac arrhythmias,including paroxysmal atrial fibrillation, paroxysmalsupraventricular tachycardia (PSVT), and ventricu-lar tachycardia.1 Flecainide blocks sodium channelsin the heart, causing prolongation of the cardiacaction potential.2 Use of flecainide has been lim-ited to certain forms of ventricular tachycardiabecause of its side effects. It increases the risk of afatal arrhythmia in patients who have structuralheart disease.3 Non-cardiac side effects of flecai-nide mainly affect the central nervous system andcause symptoms such as dizziness, visual disturban-ces, headache, fatigue, tremor, and nervousness.4

There have been a few case reports of possible fle-cainide-induced peripheral neuropathy, but theylack pathologic confirmation.5,6 Here we report fle-cainide-induced neuropathy proven with skinbiopsy.

CASE REPORT

A 66-year-old man presented with gradual onset ofnumbness in his feet for about 1 year. Hedescribed this sensation as if his feet were‘‘encased’’ in foam. His feet tended to becomecold quickly and had a tingling sensation withtouch. He felt as if he were wearing tight boots tojust below the knees. He did not describe any sig-nificant pain or motor symptoms in his lower

extremities. He did not have similar symptoms inthe hands at the onset, but in the recent fewmonths he had noticed unusual sensations in hisfingers. He denied any autonomic symptoms suchas persistent nausea, vomiting, diarrhea, constipa-tion, urinary or fecal incontinence, sweating abnor-malities, or orthostatic hypotension. His past medi-cal history was significant for hypertension as wellas cardiac arrhythmias with intermittent paroxys-mal supraventricular tachycardia that rarely wentinto atrial fibrillation. His medications includedflecainide 100 mg twice daily, bisoprolol 2.5 mgtwice daily, hydrochlorothiazide 6.25 mg oncedaily, and irbesartan 10 mg every day. He hadbeen using flecainide for about 7 years. Social his-tory and family history were non-contributory. Onneurological examination, his mental status andcranial nerves were normal. His muscle bulk, tone,and strength were normal. Deep tendon reflexeswere normal and symmetrical, including theankles. Plantar responses were flexor. He haddecreased pinprick sensation in a stocking-and-glove distribution up to the metacarpophalangealjoints in both hands and decreased pinprick andtemperature sensation up to the knees. Vibrationsensation was intact in the upper extremities,absent in the toes, and reduced at the ankles. Hiscoordination on finger–nose–finger testing wasnormal, and he did not have a Romberg sign. Hisgait was normal except for minimal difficulty withtandem walking. An extensive blood work-up,including a comprehensive metabolic panel, anoral glucose tolerance test, vitamin B12, folate,Sjogren serology, serum and urine protein electro-phoresis with immunofixation, and anti-Hu anti-bodies, was negative or normal. Nerve conductionstudies of sural sensory and fibular motor nervesand needle electromyography of the right legmuscles were normal.

A skin biopsy showed a length-dependent neurop-athy affecting small sensory nerve fibers. The densityof intraepidermal nerve fibers was reduced at 1 or 2fibers per millimeter at the distal leg (Fig. 1A). At thedistal thigh, the biopsy showed mildly reduced densityof intraepidermal nerve fibers with patchy distribu-tion, and the proximal thigh site showed only mildmorphological abnormalities, such as swellings of theintraepidermal nerve fibers without a reduction indensity (not shown).

Abbreviations: NCS, nerve conduction studies; PSVT, paroxysmal supra-ventricular tachycardia

Correspondence to: A. Hoke; e-mail: ahoke@jhmi.edu

VC 2011 Wiley Periodicals, Inc.Published online in Wiley Online Library (wileyonlinelibrary.com).DOI 10.1002/mus.22239

Key words: flecainide; peripheral neuropathy; skin biopsy; toxicneuropathy; potassium channelA.Z.B. is currently affiliated with Virginia Tech Carilion School of Medicine,Roanoke, Virginia

144 Flecainide-Induced Neuropathy MUSCLE & NERVE January 2012

Because there was no other obvious etiology forhis neuropathy, the possibility of flecainide-induced toxic neuropathy was considered. He wasswitched to another agent, propafenone, for his ar-rhythmia. Within 3 months, he noticed significantimprovement in his symptoms and has since con-tinued to improve. Neurological examination atthe second visit (16 months after stopping flecai-nide) was unremarkable, except for moderatelyreduced vibration perception in his big toes.Repeat skin biopsy at the second visit showed animprovement of intraepidermal nerve density (3 or4 fibers per millimeter) that was consistent with hisclinical improvement (Fig. 1B).

DISCUSSION

There have been a few case reports of possible fle-cainide-induced peripheral neuropathy in the liter-ature.5,6 Palace et al. reported a 51-year-old manwith paroxysmal supraventricular tachycardia whoreceived flecainide 100 mg three times daily for2.5 years and presented with progressive paresthe-sias of the hands and feet.5 His nerve conductionstudy showed sensory polyneuropathy. After discon-tinuation of flecainide, his symptoms mostlyresolved within 3 months. In addition, Maleskeret al. reported a 78-year-old woman who receivedlong-term flecainide treatment (for 10 years) anddeveloped significant peripheral neuropathy.6 Shedeveloped progressive lower extremity weaknessand gait disturbance that started to resolve within

6 weeks after discontinuation of flecainide. Besidethese 2 case reports, the Committee on Safety ofMedicines received 4 other reports of new-onsetperipheral neuropathy possibly associated with fle-cainide, and 3 other patients who had pre-existingneuropathy that was exacerbated by flecainide.5

No obvious age-, gender-, or dose-related predispo-sition was detected, and the onset of symptomsranged from 3 days to 12 months after starting fle-cainide. The neuropathy did not resolve in allcases.5 The Collaborative Group for the Study ofPolyneuropathy7 assessed the prevalence and speci-ficity of polyneuropathy in patients on long-termantiarrhythmic drugs using standard clinical andelectrophysiological techniques. In their studygroup, 20 subjects were on flecainide, 1 of whomhad clinical polyneuropathy and 5 of whom hadelectrophysiological polyneuropathy. Their com-plaints were not severe enough to cause a discon-tinuation of flecainide.7 Our patient had predomi-nantly sensory symptoms that resolved afterdiscontinuation of flecainide.

Flecainide-induced neuropathy seems to affectsmall and large fibers. In the previous 2 casereports, the first patient5 had abnormal nerve con-duction studies (NCS) that were consistent withaxonal sensory–motor neuropathy, and the secondpatient6 presented with weakness and gait disturb-ance. Our patient had a predominantly small-fibersensory neuropathy; however, the absence of vibra-tion sensation in the feet and decreased vibrationsensation at the ankle were most likely related tolarge fiber involvement, even if the NCS were nor-mal. All 3 patients had significant clinical improve-ment after the discontinuation of flecainide. Palaceet al. also showed an improvement in both sensoryand motor action potential amplitudes.5 In ourpatient, the evoked amplitudes were within normallimits initially and were not repeated at the follow-up assessment. However, repeat skin biopsy showeda clear improvement in morphological changes anddensity of intraepidermal nerve fibers. The unequiv-ocal improvement in epidermal nerve fiber densityin this toxic neuropathy with normal nerve conduc-tion studies highlights the potential utility of skinbiopsy as a progression and outcome measure.

Our case is unique in that reversibility of patho-logic changes in distal axons was demonstrated inthis presumed toxic neuropathy. The mechanismof toxicity is unknown, but rare central nervous sys-tem toxicity has been observed both with normallevels8 and high levels9 of flecainide due to renalinsufficiency. Flecainide is an inhibitor of voltage-gated Kv2.1 potassium channels, which are respon-sible for delayed rectifier currents in dorsal rootganglion sensory neurons.10 Because mutations inKv2.1 channels underlie responsiveness to

FIGURE 1. Standard skin biopsies were done at the distal leg

site 2 inches above the lateral malleolus at the time of initial

diagnosis (A) and 18 months after stopping flecainide (B). In

the initial biopsy the epidermis (black arrow) was virtually

devoid of any innervation, but at the second biopsy there was a

return of epidermal innervation (white arrows).

Flecainide-Induced Neuropathy MUSCLE & NERVE January 2012 145

flecainide in Anderson syndrome,11 it is possiblethat polymorphisms in the Kv2.1 channel subunitsmay result in altered membrane potential in sen-sory axons and put them at risk for distal axonaldegeneration. It is of interest to note that, in dia-betic rats, there was a reduction in voltage-gatedpotassium channels, including Kv2.1, and this ob-servation correlated with axonal degeneration.12

In conclusion, a detailed medication history iscrucial for evaluation of neuropathy. Flecainide-induced peripheral neuropathy is a rare, but clini-cally significant complication that should be con-sidered when other more common causes of pe-ripheral neuropathy are not identified.

REFERENCES

1. Flecainide for supraventricular tachyarrhythmias. Med Lett DrugsTher 1992;34:71–72.

2. Aoike F, Takahashi MP, Sakoda S. Class Ic antiarrhythmics blockhuman skeletal muscle Na channel during myotonia-like stimulation.Eur J Pharmacol 2006;532:24–31.

3. Antiarrhythmic Drug Evaluation Group (A.D.E.G.). A multi-centre, randomized trial on the benefit/risk profile of amioda-rone, flecainide and propafenone in patients with cardiacdisease and complex ventricular arrhythmias. Eur Heart J 1992;13:1251–1258.

4. Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide.Am J Cardiol 1984;53:101B–105B.

5. Palace J, Shah R, Clough C. Flecainide induced peripheral neuropa-thy. BMJ 1992;305:810.

6. Malesker MA, Sojka SG, Fagan NL. Flecainide-induced neuropathy.Ann Pharmacother 2005;39:1580.

7. The Collaborative Group for the Study of Polyneuropathy. Antiar-rhythmic drugs and polyneuropathy. J Neurol Neurosurg Psychiatry1994;57:340–343.

8. Bennett MI. Paranoid psychosis due to flecainide toxicity in malig-nant neuropathic pain. Pain 1997;70:93–94.

9. Ting SM, Lee D, Maclean D, Sheerin NS. Paranoid psychosis andmyoclonus: flecainide toxicity in renal failure. Cardiology 2008;111:83–86.

10. Bocksteins E, Raes AL, van de Vijver G, Bruyns T, van Bogaert PP,Snyders DJ. Kv2.1 and silent Kv subunits underlie the delayed recti-fier Kþ current in cultured small mouse DRG neurons. Am J PhysiolCell Physiol 2009;296:C1271–C1278.

11. Caballero R, Dolz-Gaiton P, Gomez R, Amoros I, Barana A, Gonzalezde la Fuente M, et al. Flecainide increases Kir2.1 currents by inter-acting with cysteine 311, decreasing the polyamine-induced rectifica-tion. Proc Natl Acad Sci USA 2010;107:15631–15636.

12. Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated Kþ channel activity in primary sensory neurons in painful dia-betic neuropathy: role of brain-derived neurotrophic factor. J Neuro-chem 2010;114:1460–1475.

146 Flecainide-Induced Neuropathy MUSCLE & NERVE January 2012