Barp A

Ciscato P

Lunetta C

Sansone VA

Velardo D

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AIR Universita degli studi di Milano

COVID-19Anti-HMGCR myopathy misdiagnosed as motor neuron diseaseand complicated with COVID-19 infectionAndrea Barp1 & Daniele Velardo2 & Patrizia Ciscato2 & Valeria Ada Sansone1 & Christian Lunetta1,3Received: 3 January 2021 /Accepted: 22 February 2021# Fondazione Società Italiana di Neurologia 2021Dear Editor-in-Chief,Inflammatory myopathy (IIMs) are a large group of poten-tially treatable myopathies in children and adults; necrotizingautoimmune myopathy is a distinct clinicopathologic entity,accounting for up to 19% of all IIM, and it is clinically charac-terized by proximalmuscle weakness of acute or subacute onsetand high creatine kinase levels (CK) [1]. Most patients withnecrotizing autoimmune myopathy have antibodies against sig-nal recognition particle (SRP) or against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) [2].The severe acute respiratory syndrome-correlated new co-ronavirus (SARS-CoV-2) is spreading worldwide since thebeginning of 2020. The major clinical manifestations of theSARS-Cov-2 infection are due to pulmonary complications,and although most have mild symptoms, such as fever, head-ache, cough, dyspnea, myalgia, and anosmia, some developacute respiratory distress syndrome that can result in death.Several neuromuscular symptoms were identified as part ofthe COVID-19 spectrum, and myalgias are reported in up to ahalf of patients with SARS-CoV-2 infection; instead, CK ele-vations depend on the disease severity, ranging from mild tosevere rhabdomyolysis. Even if electromyography, muscleimaging, and muscle histopathology are not available to date,coronavirus infections may cause an IIM; few cases [3, 4]have described myositis triggered by SARS-CoV-2, and todate little is known [5] about the role of SARS-CoV-2 infec-tion to determine relapse in previously affected patients.Here we present a case of a patient who was firstly diag-nosed with a “lower motor neuron disease”, in which furtherassessment revealed the presence of necrotizing autoimmunemyopathy. After a few weeks on steroid treatment, symptomsworsened and only subsequently this was proved to be a re-lapse triggered by SARS-CoV-2 infection.The patient is a 64-year-old male who came to our attentionfor a rehabilitation program due to a recent diagnosis of “low-er motor neuron disease”. His first symptoms started 6 monthsbefore admission to our Centre, and they were characterizedby a progressive weakness in his lower limbs with difficultyclimbing stairs and walking for long distances, along withdifficulty raising his arms over his head. He did not complainof any cramps or myalgias. No sensory or autonomic symp-toms were reported. Three months after the onset of symp-toms, the patient was admitted to a Neurology Clinic where heunderwent several assessments including an EMG test whichshowed a diffuse increased spontaneous activity at rest; duringvoluntary contraction, polyphasic motor unit action potentials(MUAPs), with normal amplitude, duration and pattern ofrecruitment, were registered. CK level was> 4000–5000 U/Lin three serial blood draws. Brain and spinal MRIs were allunremarkable. He was discharged with a diagnosis of “atypi-cal motor neuron disease with predominant involvement oflower motor neuron”. The patient was started on riluzole.When the patient was admitted to our Centre for aneurorehabilitation program, neurological examination re-vealed a normal muscle bulk and tone without any fascicula-tions. He was unable to raise his arms above his head, and herequired to push himself out of a chair using both hands andwith a widened base. Gait was pretty stable. On manualstrength testing, a significant symmetric loss of strength inhis proximal muscles in both upper (UL) and lower limbs(LL) was evident. Specifically, according to the MedicalResearch Council (MRC) Scale, deltoid was 2+, biceps andtriceps brachii 4+, iliopsoas 2+, hamstrings 4−, quadriceps 4+and gluteus maximus 2+ bilaterally. Sensory and cerebellarsystems were within normal limits. Deep tendon reflexes* Andrea Barpandrea.barp1985@libero.it1 Neurorehabilitation Unit, NeMO Clinical Center, University ofMilano, Piazza Ospedale Maggiore 3, 20162 Milano, Italy2 Neuromuscular and Rare Diseases Unit, Department ofNeuroscience, Foundation IRCCS Ca’ Granda Ospedale MaggiorePoliclinico, Via Francesco Sforza 35, 20122 Milano, Italy3 NeMO LAB S.r.l., Piazza Ospedale Maggiore 3, Milano 20162, ItalyNeurological Scienceshttps://doi.org/10.1007/s10072-021-05146-w(DTRs) were diffusely reduced. Cranial nerves were apparent-ly intact. General examination did not reveal any rash or der-matitis, especially over face, neck or hands. His past medicalhistory was remarkable for benign prostatic hypertrophy andfor a perivascular dermatitis of trunk and neck which occurredabout 3 months before the onset of motor symptoms (andwhich had regressed with a few weeks of oral steroid treat-ment). The patient was on tamsulosin and had apparently nev-er been exposed to statins.Blood tests were normal except for CK levels which werestill significantly elevated (4890 U/L). Routine screening forSARS-CoV-2 with a nasopharyngeal swab was negative.Spirometry and transthoracic echocardiography were normal.Results of a new EMG test showed the presence of spontaneousactivity characterized by fibrillations and positive sharp waveswhich were evident mostly in proximal muscles both in the ULsand LLs, also involving paraspinal muscles and tongue. Duringvoluntary contraction small, short and polyphasic MUAPs weredetected in the same muscles, with an early recruitment. Thepatient underwent a muscle MRI with STIR sequences whichrevealed the presence of a hyperintense signal in the thighs,especially in the adductor muscles and hamstrings. A musclebiopsy was performed on the left deltoid (Fig. 1). Several fibralsplittings, scattered necrotic fibres, macrophagic infiltration andmild increase of connective tissue were observed. To exclude aparaneoplastic aetiology, a PET of the whole body was per-formed, which did not identify any suspected mass; a diffusehypercaptation of F18-fluorodeoxyglucose was observed in allmuscles of the trunk and girdles (Fig. 2). Serological tests forcommon antibodies associated to inflammatory myopathies re-vealed the presence of anti-3-hydroxy-3-methyl-glutaryl-coen-zyme A reductase antibodies. (anti-HMGCR). So a final diag-nosis of necrotizing autoimmune myopathy with anti-HMGCRantibodies was made.Based on these findings, steroid therapy with high dose ofmethylprednisolone was initiated (1 g/day) with a gradualimprovement of muscle strength; after 5 days of intravenoussteroids, the therapy was shifted to oral steroid (prednisone 1mg/kg/day). At discharge, the patient had regained a goodmotor function; he was independent in walking, climbingstairs and getting from supine to seated, and from seated tostanding. However, after 14 days from discharge the patientstarted presenting a rapid worsening of his muscle strengthwith difficulty walking and getting up from sitting; he alsoreported marked asthenia along with occasional difficulty inswallowing and dry cough; no fever or other signs of respira-tory infection were present. A possible inflammatory relapsewas considered, and the patient was readmitted at our site torevisit treatment options. Neurological examination showed adecrease in muscle strength in all the muscles, especially in theproximal ones (deltoid 2, biceps and triceps 3, iliopsoas 2,quadriceps 3); the patient was not able to stand or walk with-out support, and he required assistance to get from supine toseated. CK level was >8000 U/L.Routine screening for SARS-CoV-2with a nasopharyngealswab proved to be positive. A CT scan of the chest revealed aFig. 1 Muscle histology(magnification ×200, scale bar 50μm). a Gomori trichrome stainshowing increased fibre diametervariability, mild endomysialconnective tissue increase,numerous splitting fibres(asterisks), pale degeneratingfibres (arrows), phagocyteinvasion, and replacement ofnecrotic fibres (arrowheads). bAcid phosphatase stain showingphagocytes invadingdegenerating fibres (asterisks) andendomysial inflammatory cells(arrowheads). c ATPase pH 4.6stain showing the normal check-erboard pattern of type 1 (dark)and type 2 (2a pale; 2b brownish)fibres. d MHC-1 immunofluores-cence showing cytoplasmic andsarcolemmal positivity in somenecrotic fibres (asterisks) andmembrane staining of inflamma-tory cells (arrow)Neurol Scibilateral interstitial pneumonia (Fig. 3). The patient was trans-ferred to the infectious disease department where he continuedhis ongoing steroid therapy at the same dosage (1 mg/kg/day)along with prophylactic anticoagulation. During his stay, thevital signs remained within normal limits, including oxygensaturation. A few days after admission, muscle strength startedto improve gradually along with CK levels which dropped to800 U/L; 2 weeks later, the patient was discharged (after twonegative nasopharyngeal swabs for SARS-CoV-2).Neurological evaluation at discharge revealed a marked im-provement of muscle strength; gait was stable, and the patientdid not require any assistance to stand or getting seated fromsupine.Inflammatory myopathies are rare diseases, occurring at arate of 9 to 14 cases per 100,000 people. They were firstrecognized in adults, but childhood onsets have been alsodescribed [6]. Anti-HMGCR myopathy is a subtype of IIM.What distinguishes anti-HMGCR myopathy from other IIMsubtypes is the presence of anti-HMGCR autoantibodies and astrong association with statin use. Almost 90% of patientswere exposed to statins [7]. Considering that statins can befound in foods and supplements, such as red yeast rice, it isconceivable that some statin-naïve patients may have un-knowingly been exposed to statins [8].Neurological practice is affected by the COVID-19 pan-demic in several key ways. Patients with neuromuscular dis-orders may be particularly susceptible to SARS-CoV-2 infec-tion and its complications, and this pandemic has forced arapid reorganization of clinical care delivery, including tele-medicine and telephonic contacts. A recent meta-analysisshowed that the pooled percentage for having a pre-existingneurological disease in patients with severe COVID-19 was8% [9]. Moreover, many patients with neurological autoim-mune disease, such as inflammatory myopathies, are on awide variety of immunosuppressive therapies, which canmask (as it happened in the patient presented above) symp-toms related to a viral infection.It might be prudent for such patients to take extra precau-tions to prevent exposure to the virus and in selected instancesto revaluate the dosages of the medications. Holding orsuspending oral corticosteroids or subcutaneous immunoglob-ulins is not routinely recommended; on the contrary, they cancontribute to reduce cytokine’s damaging effects by limitingthe formation of cytokine [10].In conclusion, COVID infectionmust be taken into accountas a possible trigger for relapse of an inflammatory myopathy(especially in this pandemic period); prompt recognition ofinfection may be delayed due to ongoing immunosuppressivetherapies; holding or suspending oral corticosteroids is usuallynot recommended; and the resolution of the viral infectionseems to result in a spontaneous patient recovery without ad-justments of the ongoing steroid therapy.Fig. 2 Whole-body PET-CT scanwith F18-fluorodeoxyglucose(F18-FDG). A significanthypercaptation (white arrow) isevident at scapular and deltoidmuscles bilaterally (a) at musclesbelonging to anterior compart-ment of arms (b), at paraspinalmuscles (c), and thighs, especiallyposterior compartment (d)Fig. 3 Chest CT scan. Small ground glass opacities (white arrows) areevident at posterior level of the inferior lobesNeurol SciAbbreviations ALS, amyotrophic lateral sclerosis; CK, creatine kinase;COVID-19, coronavirus disease 19; CT, computed tomography; DTRs,deep tendon reflexes; EMG, electromyography; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; IIM, inflammatory myopathies;MRC, Medical Research Council; MRI, magnetic resonance imaging;MUAPs, motor unit action potentials; LLs, lower limbs; PET, positronemission tomography; SRP, signal recognition particle; STIR, short tauinversion recovery; ULs, upper limbsAcknowledgements We would like to thank the patient and his family.Author contribution DV and PC participated in the acquisition and anal-ysis of data, and in the critical revision; AB, VAS, and CL participated inthe acquisition and analysis of data, in the conception of the manuscript,in drafting the manuscript or figures, and in the critical revision.Data availability Not applicable.Code Availability Not applicable.DeclarationsEthics approval This case report is in accordance with the ethical stan-dards laid down in the declaration of Helsinki and its later amendments.Consent to participate Not applicable.Consent for publication The participant has consented to the submis-sion of the case report to the journal.Conflict of interest CL received compensation for occasional scientificconsulting from Neuraltus, Cytokinetics, Mitsubishi Tanabe PharmaEurope, and Italfarmaco and has received funds from ARISLA andItalian Ministry of Health. VAS participates in Advisory Boards orTeaching activities for Biogen, Roche, Avexis, PTC, Santhera, Sarepta,and Dyne. The remaining authors have nothing to declare.References1. van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, vanVenrooij WJ, Voskuyl AE et al (2003) Polymyositis: anoverdiagnosed entity. Neurology 61(3):316–321. https://doi.org/10.1212/wnl.61.3.3162. Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A,Doering KR et al (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63(3):713–721. https://doi.org/10.1002/art.301563. Beydon M, Chevalier K, Al Tabaa O, Hamroun S, Delettre AS,Thomas M et al (2020) Myositis as a manifestation of SARS-CoV-2. Ann Rheum Dis annrheumdis-2020-217573. https://doi.org/10.1136/annrheumdis-2020-2175734. 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Anti-HMGCR myopathy misdiagnosed as motor neuron disease and complicated with COVID-19 infection

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Anti-HMGCR myopathy misdiagnosed as motor neuron disease and complicated with COVID-19 infection

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