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LETTERS TO THE EDITORPARASPINAL MYOPATHY WITH NOVELSHARD-LIKE COMPACT AGGREGATES OFTHIN FILAMENTSAn 83-year-old woman developed dropped head and pos-terior neck pain over 6 weeks while denying other neu-rological symptoms. Neurological examination showedisolated mild weakness of neck extensor muscles butwas otherwise normal. Magnetic resonance imaging ofthe cervical spine was normal, electrophysiological studieswere consistent with a myopathic process isolated to theneck extensors, and creatine kinase was 80 IU/L. A diag-nosis of isolated neck extensor myopathy was made. Myas-thenia gravis (MG) was ruled out by physical examinationand negative anti-acetylcholine receptor antibodies, andamyotrophic lateral sclerosis (ALS) was ruled out withphysical examination and electrophysiological studies.Paraspinal muscle biopsy showed rare interstitial mono-nuclear inammation, groups of atrophic bers and inter-nalized myonuclei (Fig. 1A), and scattered rimmed vacuoles(Fig. 1B), reminiscent of inclusion-body myositis (IBM).Sections treated with Congo red stain highlighted sarcoplas-mic inclusions. On ultrastructural examination there werecompact, elliptical inclusions comprised of thin, 4-nm-diam-eter laments with periodicity (Fig. 1C and D) lacking cross-linkage. No intranuclear inclusions were found.Over the next year she was stable and was treatedonly with a neck brace and analgesics.Numerous conditions are associated with droppedhead syndrome. The majority of cases occur in ALS andMG. Approximately 2% of ALS patients13 and 3% ofMG4 patients have head drop as the initial disease mani-festation. Head drop as the primary manifestation ofmyopathy is rarer. Although it can be part of the clinicalspectrum of adult-onset nemaline myopathy,5 carnitinedeciency,6,7 and adult acid maltase deciency,8 it is usu-ally accompanied by generalized weakness. A literaturereview yielded 4 cases of IBM with isolated head drop.912All had a consistent clinical phenotype of an elderly per-son with relatively normal creatine kinase whose headdrop was unresponsive to treatment. The skeletal musclehistology often included brosis, atrophy, and variablenumbers of rimmed vacuoles. When electron microscopywas undertaken, unlike our case, typical intranuclear la-mentous inclusions of IBM were found.The paraspinal muscles are uncommonly biopsied,but two small studies suggested their normal histologycan include type I predominance, type II atrophy,ragged red bers, and myonecrosis.13,14No reports of normal or diseased paraspinal muscleshave described inclusions resembling those seen in this case.Despite their reactivity for Congo red stain, the ultrastruc-ture of these inclusions diverges from amyloid, as they havea shard-like arrangement and a smaller diameter (4-nm la-ment vs. the 7.510-nm amyloid lament). They bear someresemblance to Hirano bodies, which have been describedrarely in skeletal muscle,15 but these laments are thinnerand lack cross-bridging and actin immunopositivity.In conclusion, our case of an elderly woman with iso-lated neck extensor myopathy and light-microscopic fea-tures of IBM demonstrated unique sarcoplasmic inclu-sions on ultrastructural examination, which we havetermed shard-like compact aggregates of thin la-ments. In recognition of the paucity of investigationinto this uncommonly biopsied muscle, it is possible thatthese inclusions are a normal or possibly age-relateddegenerative nding of the paraspinal muscles, or a hith-erto undescribed form of isolated paraspinal myopathy.Julia Lee Keith, MD, FRCPC1Lorne Zinman, MS, MD, FRCPC, MSc2Sandra Cohen, RT3Beverly Young, MLT, BAS1Juan Bilbao, MD, FRCPC11Department of Anatomical Pathology, Sunnybrook HealthSciences Centre, University of Toronto, Toronto, Ontario, Canada2Department of Internal Medicine, Division of Neurology,Sunnybrook Health Sciences Centre, University of Toronto,Toronto, Ontario, Canada3Electron Microscopy, St. Michaels Hospital, University ofToronto, Toronto, Ontario, Canada1. Katz JS, Wolfe GI, Burns DK, Bryan WW, Fleckenstein JL, Barohn RJ.Isolated neck extensor myopathy: a common cause of dropped headsyndrome. Neurology 1996;46:917921.2. Grob D, Brunner NG, Namba T. The natural course of myastheniagravis and effect of therapeutic measures. Ann NY Acad Sci 1981;377:652669.3. Jokelainen M. Amyotrophic lateral sclerosis in Finland. Acta NeurolScand 1977;56:194204.4. Wolfe GI, Bank WJ. Pseudokyphosis in motor neuron disease cor-rected by the pocket sign [abstract]. Muscle Nerve 1994;17:1091.5. Lomen-Hoerth C, Simmons ML, Dearmond SJ, Layzer RB. Adultonset nemaline myopathy: another cause of dropped head. MuscleNerve 1999;22:11461150.VC 2011 Wiley Periodicals, Inc.Letters to the Editor MUSCLE & NERVE July 2011 1456. Karpati G, Carpenter S, Engel AG. The syndrome of systemic carni-tine deciency: clinical, morphologic, biochemical, and pathophysio-logic features. Neurology 1975;25:1624.7. Vandyke DH, Griggs RC, Markesbery W, Dimauro S. Hereditary car-nitine deciency of muscle. Neurology 1975;25:154159.8. Trend PJ, Wiles CM, Spencer GT, Morgan-Hughes JA, Lake BD, Pat-rick AD. Acid maltase deciency in adults: diagnosis and manage-ment in ve cases. Brain 1985;108:845860.9. Luque FA, Rosenkilde CE, Valsamis M, Danon MJ. Inclusion bodymyositis presenting as the dropped head syndrome. Brain Pathol1994;4:568.10. Hund E, Heckl R, Goebel HH, Menck HM. Inclusion body myositispresenting as isolated erector spinae paresis. Neurology 1995;45:993994.11. Oerlemans WGH, de Visser H. Dropped head syndrome and bent spinesyndrome: two separate clinical entities or different manifestations ofaxial myopathy? J Neurol Neurosurg Psychiatry 1998;65:258259.12. Suarez GA, Kelly JJ. The dropped head syndrome. Neurology 1992;42:16251627.13. Wharton SB, Chan KK, Pickard JD. Paravertebral muscles in disease ofthe cervical spine. J Neurol Neurosurg Psychiatry 1996;61:461465.14. Laroche M, Delisle MB, Aziza R, Lagarrigue J, Mazieres B. Is campto-cormia a primary muscular disease? Spine 1995;20:10111016.15. Fernandez R et al. Adult glycogenosis II with paracrystalline mito-chondrial inclusions and Hirano bodies in skeletal muscle. Neuro-muscul Disord 1999;9:136143.Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22093---------------------------------------------------------MYASTHENIA GRAVIS EXACERBATIONAFTER CETIRIZINE ADMINISTRATIONA 22-year-old woman presented with a 6-month historyof proximal muscle weakness, dysphagia, and weaknessof jaw closure in December 1992. Neurological exami-nation revealed nasal speech, weakness of proximalmuscles of upper and lower limbs (4/5), and bilateralBell sign. Ptosis and diplopia were apparent after afatigability test. The serum acetylcholine receptorbinding antibody titer was elevated. Repetitive nervestimulation at 3 HZ with recording from abductor dig-iti minimi and nasalis induced decremental responsesof 18% and 31%, respectively. Chest tomographyshowed both enlarged and small nodular lesions with-out contrast enhancement in the thymus gland. Thepatient had symptomatic improvement in response totreatment with pyridostigmine (60 mg every 8 h) overthe next 10 days. At the time of discharge, she wasasymptomatic. The thymus gland was removed 20 dayslater and was found to have follicular hyperplasia.This patient would be classied as IIIb according tothe Myasthenia Gravis Foundation of America (MGFA)clinical classication. The patient was in completeFIGURE 1. (A) Hematoxylin and eosinstained section (original magnification 4) showing groups of atrophic fibers and myopathicabnormalities with foci of mononuclear inflammation (inset, original magnification 10). (B) Rimmed vacuoles on modified Gomori tri-chrome stain (original magnification 40). (C, D) Ultrastructural examination yielded novel shard-like compact aggregates of thin, 4-nmfilaments with periodicity (indicated by arrows). [Color figure can be viewed in the online issue, which is available]146 Letters to the Editor MUSCLE & NERVE July 2011stable remission (CSR) according to the MGFA post-intervention status for the next 18 years of follow-up.In May 2010 she was treated with cetirizine 10 mg/dayfor allergic sinusitis (AS), which had been present for7 days. No other medications were added. Within 24hours of the initial dose, she developed diplopia, fa-cial weakness, nasal voice, dysphagia, and weakness ofjaw closure. Cetirizine was discontinued at 48 h, andher symptoms improved progressively over the next 2days. Five days after starting cetirizine the patient hadminimal manifestations, and pyridostigmine wasrestarted. She became asymptomatic 10 days later. Thepyridostigmine was discontinued 3 weeks later, with nosubsequent exacerbation of MG.A wide variety of drugs have been associated withclinical deterioration of MG.1 Antihistamines are struc-turally similar to histamine, and mainly they are competi-tive blockers of histamine receptors.2 Cetirizine, a non-sedating, second-generation H1 receptor antagonist, hasa relative incidence of adverse anticholinergic and cen-tral nervous system effects similar to that produced byplacebo.3 Our patient developed ocularfacialbulbarsymptoms within the rst 24 hours after starting cetiri-zine. The main argument implicating cetirizine in thedeterioration of MG is the time interval between admin-istration and onset of symptoms, which coincides withthe drugs time to peak plasma concentration (around 1hour). Furthermore, this hypothesis is supported by theprompt recovery after withdrawal of the drug (steady-state plasma levels were reached by the second day) andthe absence of other medications added.4 The AS is lesslikely to have been the cause of the MG exacerbation,because no deterioration of MG was documented duringthe 7 days from clinical onset to the start of cetirizine.We are unaware of other reports of deterioration of MGafter administration of antihistamines. We believe thatantihistamines, especially cetirizine, may be detrimentalin patients with MG, and they should only be adminis-tered with caution in patients known to have thisdisease.Alvaro Cobo Calvo, MD1Maria Anto`nia Albert Aguilo, MD1Carlos Casasnovas Pons, MD, PhD1,21Neuromuscular Unit, Neurology Department2Centro de Investigacion Biomedica en Red de EnfermedadesNeurodegenerativas IDIBELL, Hospital Universitari de Bellvitge,LHospitalet de Llobregat, Barcelona, Spain1. Eric TW. Drugs and myasthenia gravis, an update. Arch Intern Med1997;157:399408.2. Pearlman DS. Antihistamines: pharmacology and clinical use. Drugs1976;12:258273.3. Simons FE. New H1 receptor antagonist: clinical pharmacology. ClinExp Allergy 1990;20(suppl 2):1924.4. Molimard M, Diquet B, Benedetti MS. Comparison of pharmacoki-netics and metabolism of desloratadine, fexofenadine, levocetirizineand mizolastine in humans. Fundam Clin Pharmacol 2004;18:399411.Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22096---------------------------------------------------------DEMYELINATING SYMMETRIC MOTORPOLYNEUROPATHY WITH HIGH ANTI-GM1ANTIBODY TITER: DO WE NEED TO SPLIT?Multifocal motor neuropathy (MMN) is characterized bystepwise or progressive muscle weakness with wasting andfasciculations.14 Characteristic features include a ndingindicative of demyelination, motor conduction block(CB) outside of sites of nerve compression.4 Although CBremains the hallmark of MMN, it was not consideredessential for diagnosis.5 OFerrall et al. reported a patientwith progressive motor demyelinating neuropathy associ-ated with elevated titers of antibodies against the ganglio-side GM1.6 The patient had mostly distal weakness andnormal sensory examination; over 5 years, his disorderremained symmetric and conned to the motor system.Treatment with intravenous immunoglobulins (IVIg),oral prednisone, methylprednisolone, and cyclophospha-mide had questionable benet. The patient6 had demyeli-nating features in the motor nerves, including prolongeddistal latencies, conduction slowing, prominent temporaldispersion, and CBs.14 The investigators6 concluded thatthe extent of ndings was far beyond those expected fromreported series of MMN patients.15 The electrophysiolog-ical abnormalities spared the sensory bers, which demon-strated selectivity of this condition for motor axons anddifferentiated it from chronic inammatory demyelinat-ing polyneuropathy (CIDP).4,5 The patients serum con-tained elevated titers of IgM antibodies to GM1.Among a cohort of 29 MMN patients followed at ourinstitution since 1993, we identied 4 males affected byrelentless disease that began in both hands and progressedsymmetrically to the lower limbs. The age of onset wasbetween 25 and 50 years. The proximal power in upperand lower extremities remained almost intact over 1517years, whereas distal muscle strength (hand grip, ngerextension, and foot dorsiexion) was graded 12/5 on theMedical Research Council scale after 813 years of illness.Sensation to light touch, pin-prick, and vibration was intact,but deep tendon reexes were diminished throughout. Allpatients had anti-GM1 antibody titers 5060 times greaterthan the mean value of controls on enzyme-linked immu-nosorbent assay.3 Spinal uid examination was normal.Genetic testing for peripheral myelin protein 22 or P0mutations was negative. On serial electrophysiology, CBswere found in at least three motor nerves, and there wereprolonged distal latencies and delayed or absent F-waves.14Reduced distal CMAP amplitudes observed during diseaseprogression were related to axon loss.14,7 All patientsreceived IVIg (0.41.0 g/kg body weight) every 68 weeks.We agree with OFerrall et al.6 that their patient didnot demonstrate clinically what is usually expected inMMN.15 However, the motor conduction abnormalitiesin their patient were asymmetric from initial presenta-tion; in addition, his gait was unsteady, which can beseen in MMN.3 Twenty-two percent of the patientsreported by Taylor et al.7 exhibited a symmetrical neu-ropathy, and 4 of the patients observed by Kinsellaet al.8 had a symmetric lower motor neuron disorderand high-titer anti-GM1 antibodies. Kimura et al.9reported 5 patients with motor-dominant relapsingremitting CIDP with predominant upper limb weakness;Letters to the Editor MUSCLE & NERVE July 2011 147none had detectable autoantibodies in serum, as did thevan der Berg-Vos et al.10 patients, who had a multifocalinammatory demyelinating neuropathy with features incommon with MMN and CIDP.The pathogenesis of MMN remains largely elusive;sera from a substantial subgroup of patients contain IgMantibodies against GM1, which is abundantly expressedin motor axons and Schwann cell surfaces.13,5,11 Catset al.3 studied a large cohort of MMN patients and con-cluded that anti-GM1 IgM antibody screening is themost efcient diagnostic marker. Patients with anti-GM1IgM antibodies had lower Medical Research Council(MRC) sum scores compared to those without antibod-ies.3 Recently, Yuki et al.12 described binding of patho-genic anti-GM1 autoantibodies to the target antigenGM1 in vitro and suggested that a similar effect occursduring MMN progression. Anti-GM1 antibodies arethought to cause weakness by interfering with motornerve conduction at the nodes of Ranvier.1,3,11,12 IVIgcounteracts complement-mediated tissue damage activa-tion leading to improvement of muscle strength.12We believe that the OFerrall et al.6 patient wasaffected by symmetrically progressive MMN, conrmingthat the pathogenic mechanism can be length-depend-ent.1,3,7,8 It cannot be determined whether this distalsymmetric form represents a disease entity or a variant,but it should be recognized as a clinical entity.Giuliana Galassi, MDDepartment of Neurology, University of Modena & Reggio Emilia,Modena, Italy1. Cats EA, van der Pol WL, Piepers S, Franssen H, Jacobs BC, van denBerg-Vos RM, et al. Correlates of outcome and response to IVIg in 88patients with multifocal motor neuropathy. Neurology 2010;75:818825.2. Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: the diagnos-tic spectrum and response to treatment. Neurology 2007;69:16801687.3. Cats EA, Jacobs BC, Yuki N, Tio-Gillen AP, Piepers S, Franssen H,et al. Multifocal motor neuropathy: association of anti GM1 IgM withclinical features. Neurology 2010;75:19611967.4. van Schaik IN, Bouche P, Illac I, Leger J-M, van den Bergh P, Corn-blath D, et al. European Federation of Neurological Societies/Pe-ripheral Nerve Societies guidelines on management of multifocalmotor neuropathy. Eur J Neurol 2006;13:802808.5. Katz JS, Barohn RJ, Kojan S, Wolfe GI, Nations SP, Saperstein DS,et al. Axonal multifocal motor neuropathy without conduction blockor other features of demyelination. Neurology 2002;58:615620.6. OFerrall EK, White CM, Zochodne DW. Demyelinating symmetricmotor polyneuropathy with high titers of anti-GM1 antibodies. Mus-cle Nerve 2010;42:604608.7. Taylor BV, Wright AR, Harper MC, Dyck PJ. Natural history of 46patients with multifocal motor neuropathy with conduction block.Muscle Nerve 2000;23:900908.8. Kinsella LJ, Lange DJ, Trojaborg W, Sadiq SA, Younger DS, Latov N.Clinical and electrophysiologic correlates of elevated anti-GM1 anti-body titers. Neurology 1994;44:12781282.9. Kimura A, Sakurai T, Koumura A, Yamada M, Hayashi Y, Tanaka Y,et al. Motor-dominant chronic inammatory demyelinating polyneu-ropathy. J Neurol 2010;257:621629.10. van den Berg-Vos RM, van den Berg LH, Franssen H, Vermeulen M,Witkamp TD, Jansen GH, et al. Multifocal demyelinating neuropa-thy: a distinct clinical entity? Neurology 2000;54:2632.11. Kaji R. Physiology of conduction block in multifocal motor neuropathyand other demyelinating neuropathies. Muscle Nerve 2003;27:285286.12. Yuki N, Watanabe H, Nakajima P, Spath PJ. IVIG blocks complementdeposition mediated by anti-GM1 antibodies in multifocal motorneuropathy. J Neurol Neurosurg Psychiatry 2011;82:8791.Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22106---------------------------------------------------------REPLYWe appreciate the comments by Dr. Galassi regarding ourreport.1 We were interested to nd that she has observedadditional cases with a similar phenotype to our patient.Among her cohort of 29 patients with multifocal motorneuropathy, Dr. Galassi reported 4 male patients who weresimilar to our patient in that they had progressive diseasewith onset in the hands but with spread to the lower limbs.Proximal strength was relatively preserved, and sensationwas intact. Similar to our patient, all patients had high anti-GM1 antibody levels (5060 times greater than the mean ofcontrols). The occurrence of this clinical phenotype (distalsymmetric motor weakness) with high titers of anti-GM1antibodies could be interpreted in two ways: (1) it couldrepresent a new phenotype (i.e., a distinct entity) associ-ated with anti-GM1 antibodies; or (2) it could represent avariant of multifocal motor neuropathy (MMN).The patients described by Dr. Galassi and ourselves dif-fer from those with typical MMN in that their phenotypewas symmetric. In addition, our patients had diffuse sym-metric weakness during the initial weeks, and this was citedas an exclusion criterion by the guidelines of the EuropeanFederation of Neurological Societies/Peripheral Nerve So-ciety.2 The response in terms of disability or musclestrength to immunomodulatory treatment is consideredsupportive in the criteria. Our patient did not respond.We would be interested to know how Dr. Galassis patientsresponded to intravenous immunoglobulin (IVIg).On the other hand, there are several similaritiesbetween MMN patients and the patients we and Dr.Galassi have described. These include motor involve-ment with sparing of sensory bers even in contiguousnerve segments tested simultaneously, presence of anti-GM1 antibodies, and sparing of cranial nerves. Webelieve that gait unsteadiness is too nonspecic a ndingto differentiate MMN from other neuropathies.We also believe that the report of the 4 patients of Dr.Galassi, when considered in conjunction with our patient,contributes to the phenotypic spectrum associated withhigh anti-GM1 titers. She has quite correctly pointed outthat the controversy as to whether this distal symmetricphenotype represents a variant of MMN or a distinct dis-ease entity cannot be denitively resolved at present, butwe suggest the label of multifocal would be difcult toapply. We thank Dr. Galassi for sharing her experience.Erin K. OFerrall, MD, FRCPCChristopher M. White, MD, FRCPCDouglas W. Zochodne, MD, FRCPCDepartment of Clinical Neurosciences, University of Calgary,Calgary, Alberta, Canada1. OFerrall EK, White CM, Zochodne DW. Demyelinating symmetricmotor polyneuropathy with high titers of anti-GM1 antibodies. Mus-cle Nerve 2010;42:604608.2. Joint task force of the EFNS and the PNS. European Federation ofNeurological Societies/Peripheral Nerve Society guideline on manage-ment of multifocal motor neuropathy. Report of a joint task force ofthe European Federation of Neurological Societies and the PeripheralNerve Societyrst revision. J Peripher Nerv Syst 2010;15:295301Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22105---------------------------------------------------------148 Letters to the Editor MUSCLE & NERVE July 2011TOO MUCH, TOO SOON?We read with interest the article by Chio` et al.1 on theuse of granulocyte colony stimulating factor (G-CSF) inthe treatment of amyotrophic lateral sclerosis (ALS).ALS is a devastating disease with a signicant clinicaland caregiver burden. The only FDA-approved treat-ment, riluzole, increases the life expectancy by a coupleof months.2 New therapies would be welcomed by clini-cians, patients, and caregivers alike. In our enthusiasmto welcome new therapies, however, we must beextremely cautious of their potential adverse effects.G-CSF is known to be associated with respiratorycomplications ranging from simple cough, dyspnea, tointerstitial or alveolar pulmonary inltration, and evenadult respiratory distress syndrome (ARDS).3,4 There are3 case reports, 2 in healthy donors5,6 and the other in apatient with chronic anemia,7 who developed ARDS afterG-CSF infusion, 1 of whom died.7 Even among pulmo-nologists the general consensus is that the pulmonarycomplications of G-CSF are underreported.2Chio` et al.1 reported 4 deaths in a span of 1 year: 3patients died due to respiratory failure of unknown causesand 1 patient died from gastric aspiration. In addition, 2patients required tracheotomy. Readers may get the impres-sion that the investigators did not pursue this further andthe deaths were presumed to be due to respiratory failurefrom ALS. We do agree that given the severity of ALS in thepopulation selected these may represent the natural courseof the illness. However, with the known respiratory compli-cations of G-CSF, especially ARDS, more data regarding thecause and type of respiratory failure should be acquired.Crucial data, such as the presence or absence of concomi-tant pneumonia, and imaging studies of the chest, if avail-able, need to be forthcoming. Further, it is unfortunatethat no autopsy data were available, as more informationmay have been provided as to cause of death.We recognize the limitations of an intent-to-treatstudy design, but everyone involved in the evaluationand treatment of patients with ALS cannot presumesome of these novel therapies are free of severe sideeffects as implied by Chio` and colleagues.Caution must be exercised when using G-CSF, partic-ularly in ALS patients, because respiratory complicationsare the leading cause of death in these patients and thedrugs side effects may just help exacerbate rather thanalleviate the treatment efforts.Raghav Govindarajan, MDNestor Galvez-Jimenez, MDDepartment of Neurology, Cleveland Clinic, Weston, Florida1. Chio` A, Mora G, Bella VL, Caponnetto C, Mancardi G, Sabatelli M,et al. Repeated courses of granulocyte colony stimulating factor inamyotrophic lateral sclerosis: clinical and biological results from aprospective multicenter study. Muscle Nerve 2011;43:189195.2. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotro-phic lateral sclerosis (ALS)/motor neuron disease (MND). CochraneDatabase Syst Rev 2007;24:CD001447.3. Azoulay E, Attalah H, Harf A, Schlemmer B, Delclaux C. Granulocytecolony-stimulating factor or neutrophil-induced pulmonary toxicity:myth or reality? Systematic review of clinical case reports and experi-mental data. Chest 2001;120:16951701.4. Tigue CC, McKoy JM, Evens AM, Trilio SM, Tallman MS, BennettCL. Granulocyte-colony stimulating factor administration to healthyindividuals and persons with chronic neutropenia or cancer: an over-view of safety considerations from the Research on Adverse DrugEvents and Reports project. Bone Marrow Transplant 2007;40:185192.5. Ruiz-Arguelles GJ, Arizpe-Bravo D, Sanchez-Sosa S, Rojas-Ortega S,Moreno-Ford V, Ruiz-Arguellas A. Fatal G-CSF-induced pulmonarytoxicity [letter]. Am J Hematol 1999;60:8283.6. Arimura K, Inoue H, Kukita T, Matsushita K, Akimot M, KawamataN, et al. Acute lung injury in a healthy donor during mobilization ofperipheral blood stem cells using granulocyte-colony stimulating fac-tor alone. Haematologica 2005;90:ECR10.7. Kitamura S, Kinouchi K, Fukumitsu K, Takeuchi M, Matsuyama M,Miyamoto Y, et al. A risk of pulmonary edema associated with G-CSFpretreatment [in Japanese]. Masui 1997;46:946950.Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22108---------------------------------------------------------REPLYWe thank Drs. Govindarajan and Galvez-Jimenez fortheir comments on our article in which we reported theresults of our G-CSF trial in ALS.1 Their comments allowus to discuss in depth the issues of the safety of G-CSFin ALS. Based on a few case reports, Drs. Govindarajanand Galvez-Jimenez argue that G-CSF is known to beassociated with respiratory complications. Thus, theyraise the possibility that G-CSF could have been responsi-ble for the respiratory distress observed in our ALSpatients. In fact, 4 of the patients in our trial died, and2 underwent tracheostomy. Our response to their letterincludes the following points:1. The death rate of 25% at 2 years from diseaseonset reported in our trial is in line with theexpected mortality rate2 and is similar to thatobserved in other recent clinical trials3,4; thisargues against the possibility that G-CSF mighthave adversely affected the life expectancy ofour ALS patients. Moreover, not all patientsdied from respiratory failure.2. The supposed respiratory side effects of G-CSFare based on only a few cases out of presumablyhundreds of thousands who have received G-CSF without major drug-related side effects.According to the most recent systematic reviewsof the literature, referring to thousands of sub-jects treated with G-CSF, the risk of respiratorydisturbances is extremely low, even in patientswith chronic neutropenia and cancer.5,6 Arecent nationwide study among 3264 normaldonors who received G-CSF for mobilizationpurposes indicates that the incidence of allacute and severe side effects, including intersti-tial pneumonitis and angina, was 0.58% amongdonors, without any mortality within 30 days ofdonation.7 This conrms the extremely lowoccurrence rate of acute respiratory complica-tions in subjects undergoing hematopoieticstem cell (HSC) mobilization and collectionwho received G-CSF at comparable or evenhigher doses than those used in our trial.Letters to the Editor MUSCLE & NERVE July 2011 1493. The possible, although rare, respiratory sideeffects of G-CSF have been described as acutecomplications occurring during administrationof the drug. This was not the case in our patients.Their respiratory distress did not occur during thetreatment with G-CSF, but instead was seen 12months after G-CSF. This makes any correlationwith the administered drug quite unlikely.4. Concerning the possibility of a specic G-CSFrisk related to ALS, three other phase I studieshave been performed with G-CSF in ALS, andno cases of respiratory failure have beenreported to be related to the study drug.810Thus, the concern of Govindarajan and Galvez-Jime-nez that G-CSF in ALS may just help exacerbate ratherthan alleviate efforts of treatment seems quite specula-tive and in any case unrelated to the acute side effectsknown to be associated infrequently with G-CSF. Indeed,G-CSF represents an interesting mode of treatment ofneurodegenerative disorders, particularly ALS, because itcan act on various pathways in the degenerative pro-cesseither directly on motor neuron survival, or indi-rectly to restore the imbalance of microglial function11and block apoptotic death. Moreover, the induction oftransient mobilization of bone marrow cells (BMCs) tothe peripheral blood may contribute to brain repair.Only a phase II, placebo-controlled trial will allow us todetermine whether this treatment is truly effective inthis inevitably fatal disorder.Adriano Chio, MD1Corrado Tarella, MD21ALS Center, Department of Neuroscience, University of Torino,Torino, Italy1Corrado Tarella, Hematology and Cell Therapy Unit, A.O.O.Mauriziano and University of Torino, Torino, Italy1. Chio A, Mora G, Bella VL, Caponnetto C, Mancardi G, SabatelliM, et al. Repeated courses of granulocyte colony stimulating fac-tor in amyotrophic lateral sclerosis: clinical and biological resultsfrom a prospective multicenter study. Muscle Nerve 2011;43:18995.2. Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, BeghiE, et al. Prognostic factors in ALS: a critical review. Amyotroph Lat-eral Scler 2009;10:310323.3. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH,Armon C, et al. Subcutaneous IGF-1 is not benecial in 2-year ALStrial. Neurology 2008;71:17701775.4. Piepers S, Veldink JH, de Jong SW, van der Tweel I, van derPol WL, Uijtendaal EV, et al. Randomized sequential trial of val-proic acid in amyotrophic lateral sclerosis. Ann Neurol 2009;66:227234.5. Tigue CC, McKoy JM, Evens AM, Trilio SM, Tallman MS, BennettCL. Granulocyte-colony stimulating factor administration to healthyindividuals and persons with chronic neutropenia or cancer: an over-view of safety considerations from the Research on Adverse DrugEvents and Reports project. Bone Marrow Transplant 2007;40:185192.6. Anderlini P. Effects and safety of granulocyte colony-stimulating fac-tor in healthy volunteers. Curr Opin Hematol 2009;16:3540.7. Kodera Y, Yamamoto K, Kato S, Harada M, Kanda Y, Hamajima N,et al. Safety and risk of allogeneic peripheral blood stem cell dona-tion: the comprehensive report of the Nation-Wide ConsecutivelyPre-Registered 3,264 Family Donor Survey in 10 Years Project by theJapan Society for Hematopoietic Cell Transplantation. American So-ciety of Hematology, 52nd Annual Meeting, Blood 2010, 116 (21),Abstract # 1180.8. Cashman N, Tan LY, Krieger C, Madler B, Mackay A, Mackenzie I,et al. Pilot study of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells in amyotrophic lateral sclero-sis (ALS). Muscle Nerve 2008;37:620625.9. Zhang Y, Wang L, Fu Y, Song H, Zhao H, Deng M, et al. Preliminaryinvestigation of effect of granulocyte colony stimulating factor onamyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009;10:430431.10. Nefussy B, Artamonov I, Deutsch V, Naparstek E, Nagler A, DroryVE. Recombinant human granulocyte-colony stimulating factoradministration for treating amyotrophic lateral sclerosis: a pilotstudy. Amyotroph Lateral Scler 2010;11:187193.11. Yamasaki R, Tanaka M, Fukunaga M, Tateishi T, Kikuchi H, Moto-mura K, et al. Restoration of microglial function by granulocyte-col-ony stimulating factor in ALS model mice. J Neuroimmunol 2010;229:5162.Published online 15 June 2011 in Wiley Online Library( DOI 10.1002/mus.22107---------------------------------------------------------150 Letters to the Editor MUSCLE & NERVE July 2011