Exploring the frequency and clinical background of the “zebra sign” in amyotrophic lateral sclerosis and multiple system atrophy

Published:April 24, 2019DOI:https://doi.org/10.1016/j.jns.2019.04.032


      • In half of ALS patients, the “zebra sign” on PADRE images was observed.
      • The “zebra sign” has high specificity for differentiating ALS from healthy subjects.
      • The “zebra sign” might reflect degeneration of the UMN within the motor cortex.
      • The “zebra sign” was observed in some MSA patients and not specific to ALS.


      In amyotrophic lateral sclerosis (ALS), the “zebra sign” in the precentral gyrus on phase difference enhanced magnetic resonance imaging (PADRE) recently has been reported as a possible imaging biomarker for upper motor neuron (UMN) involvement. A previous study has shown that the “zebra sign” allowed us to differentiate patients with ALS from healthy subjects with excellent accuracy. We validated the usefulness of the sign for differentiating patients with ALS from healthy subjects and investigated whether the “zebra sign” can be observed other neurodegenerative disorders with UMN involvement. The “zebra sign” on PADRE was assessed in 26 patients with ALS, 26 with multiple system atrophy (MSA) and 26 healthy controls, and the sign was observed in 50%, 23%, and no subjects, respectively. ALS patients with the “zebra sign” demonstrated a higher UMN burden score than those without the sign. The “zebra sign” on PADRE is not specific to ALS, also present in MSA, but might reflect the degeneration of the UMN within the motor cortex in neurodegenerative disorders.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brooks B.R.
        • Miller R.G.
        • Swash M.
        • Munsat T.L.
        El Esocorial rivisted: revised criteria for the diagnosis of amyotrophic lateral sclerosis.
        Amyotroph. Lateral Scler. 2000; 1: 293-299
        • de Carvalho M.
        • Dengler R.
        • Eisen A.
        • et al.
        Electrodiagnostic criteria for diagnosis of ALS.
        Clin. Neurophysiol. 2008; 119: 497-503
        • Zoccolella S.
        • Beghi E.
        • Palagano G.
        • et al.
        Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients: a population-based study.
        J. Neurol. Sci. 2006; 250: 45-49
        • Al-Chalabi A.
        • Hardiman O.
        • Kiernan M.C.
        • et al.
        Amyotrophic lateral sclerosis: moving towards a new classification system.
        Lancet Neurol. 2016; 15: 1182-1194
        • Kakeda S.
        • Yoneda T.
        • Ide S.
        • et al.
        Zebra sign of precentral gyri in amyotrophic lateral sclerosis: a novel finding using phase difference enhanced (PADRE) imaging-initial results.
        Eur. Radiol. 2016; 26: 4173-4183
        • Quinn N.P.
        • Marsden C.D.
        The motor disorder of multiple system atrophy.
        J. Neurol. Neurosurg. Psychiatry. 1993; 56: 1239-1242
        • Köllensperger M.
        • Geser F.
        • Ndayisaba J.P.
        • et al.
        Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry.
        Mov. Disord. 2010; 25: 2604-2612
        • da Rocha A.J.
        • Maia Jr., A.C.
        • da Silva C.J.
        • et al.
        Pyramidal tract degeneration in multiple system atrophy: the relevance of magnetization transfer imaging.
        Mov. Disord. 2007; 22: 238-244
        • Muayqil T.
        • Chan K.M.
        • Camicioli R.
        • et al.
        Motor cortex and spinal degeneration in multisystem atrophy: a multimodal study.
        Can J Neurol Sci. 2008; 35: 658-660
        • Gilman S.
        • Wennin G.K.
        • Low P.A.
        • et al.
        Second consensus statement on the diagnosis of multiple system atrophy.
        Neurology. 2008; 71: 670-676
        • Balendra R.
        • Jones A.
        • Jivraj N.
        • et al.
        Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials.
        J. Neurol. Neurosurg. Psychiatry. 2015; 86: 45-49
        • Alshikho M.J.
        • Zürcher N.R.
        • Loggia M.L.
        • et al.
        Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis.
        Neurology. 2016; 87: 2554-2561
        • Kakeda S.
        • Korogi Y.
        • Yoneda T.
        • et al.
        A novel tract imaging technique of the brainstem using phase difference enhanced imaging: normal anatomy and initial experience in multiple system atrophy.
        Eur. Radiol. 2011; 21: 2202-2210
        • Sugiyama A.
        • Sato N.
        • Kimura Y.
        • et al.
        MR findings in the substantia nigra on phase difference enhanced imaging in neurodegenerative parkinsonism.
        Parkinsonism Relat. Disord. 2018; 48: 10-16
        • Kakeda S.
        • Korogi Y.
        • Yoneda T.
        • et al.
        Pakinson's disease: diagnostic potential of high-resolution phase difference enhanced MR imaging at 3 T.
        Eur. Radiol. 2013; 23: 1102-1111
        • Kwan J.Y.
        • Jeong S.Y.
        • Gelderen P.V.
        • et al.
        Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology.
        PLoS ONE. 2012; 7e35241
        • Adachi Y.
        • Sato N.
        • Saito Y.
        • et al.
        Usefulness of SWI for the detection of iron in the motor cortex in amyotrophic lateral sclerosis.
        J. Neuroimaging. 2015; 25: 443-451
        • Cosottini M.
        • Donatelli G.
        • Costagli M.
        • et al.
        High-resolution 7T MR imaging of the motor cortex in amyotrophic lateral sclerosis.
        Am. J. Neuroradiol. 2016; 37: 455-461
        • Costagli M.
        • Donatelli G.
        • Biagi L.
        • et al.
        Magnetic susceptibility in the deep layers of the primary motor cortex in amyotrophic lateral sclerosis.
        NeuroImage. 2016; 12: 965-969
        • Endo H.
        • Sekiguchi K.
        • Shimada H.
        • et al.
        Low signal intensity in motor cortex on susceptibility-weighted MR imaging is correlated with clinical signs of amyotrophic lateral sclerosis: a pilot study.
        J. Neurol. 2018; 265: 552-561
        • Kakeda S.
        • Yoneda T.
        • Ide S.
        • et al.
        Signal intensity of superficial white matter on phase difference enhanced imaging as a landmark of the perirolandic cortex.
        Acta Radiol. 2016; 57: 1380-1386
        • Kakeda S.
        • Korogi Y.
        • Kamada K.
        • et al.
        Signal intensity of the motor cortex on phase-weighted imaging at 3T.
        Am. J. Neuroradiol. 2008; 29: 1171-1175
        • Papp M.I.
        • Kahn J.E.
        • Lantos P.L.
        Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and shy-Drager syndrome).
        J. Neurol. Sci. 1989; 94: 79-100
        • Papp M.I.
        • Lantos P.L.
        The distribution of oligodenderoglial inclusions in multiple system atrophy and its relevance to clinical symptomatology.
        Brain. 1994; 117: 235-243
        • Fujita T.
        • Doi M.
        • Ogata T.
        • et al.
        Cerebral cortical pathology of sporadic olivopontocerebellar atrophy.
        J. Neurol. Sci. 1993; 116: 41-46
        • Wakabayashi K.
        • Ikeuchi T.
        • Ishikawa A.
        • et al.
        Multiple system atrophy with severe involvement of the motor cortical areas and cerebral white matter.
        J. Neurol. Sci. 1998; 156: 114-117
        • Konagaya M.
        • Sakai M.
        • Matsuoka Y.
        • et al.
        Multiple system atrophy with remarkable frontal lobe atrophy.
        Acta Neuropathol. 1999; 97: 423-428
        • Tsuchiya K.
        • Ozawa E.
        • Haga C.
        • et al.
        Constant involvement of the Betz cells and pyramidal tract in multiple system atrophy: a clinicopathological study of seven autopsy cases.
        Acta Neuropathol. 2000; 99: 628-636
        • Su M.
        • Yoshida Y.
        • Hirata Y.
        • et al.
        Primary involvement of the motor area in association with the nigrostriatal pathway in multiple system atrophy: neuropathological and morphometric evaluations.
        Acta Neuropathol. 2001; 101: 57-64
        • Matsusue E.
        • Fujii S.
        • Kanasaki Y.
        • et al.
        Putaminal lesion in multiple system atrophy: Postmortem MR-pathological correlations.
        Neuroradiology. 2008; 50: 559-567
        • Matsusue E.
        • Fujii S.
        • Kanasaki Y.
        • et al.
        Cerebellar lesions in multiple system atrophy: Postmortem MR imaging-pathologic correlations.
        Am. J. Neuroradiol. 2009; 30: 1725-1730
        • Visanji N.P.
        • Collingwood J.F.
        • Finnegan M.E.
        • et al.
        Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson's disease and multiple system atrophy.
        J. Park. Dis. 2013; 3: 523-537
        • Kaindlstorfer C.
        • Jellinger K.A.
        • Eschlböck S.
        • et al.
        The relevance of iron in the pathogenesis of multiple system atrophy: a viewpoint.
        J. Alzheimers Dis. 2018; 61: 1253-1273
        • Miwa H.
        • Kajimoto Y.
        • Nakanishi I.
        • et al.
        T2-low signal intensity in the cortex in multiple system atrophy.
        J. Neurol. Sci. 2003; 211: 85-88
        • Braak H.
        • Rüb U.
        • Schultz C.
        • Del Tredici K.
        Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases.
        J. Alzheimers Dis. 2006; 9: 35-44
        • Wakabayashi K.
        • Mori F.
        • Oyama Y.
        • et al.
        Lewy bodies in Betz cells of the motor cortex in a patient with Parkinson's disease.
        Acta Neuropathol. 2003; 105: 189-192
        • Kasanuki K.
        • Josephs K.A.
        • Ferman T.J.
        • et al.
        Diffuse Lewy Body Disease Manifesting as Corticobasal Syndrome.
        vol. 91. 2018: e268-e279
        • Marchese R.
        • Trompetto C.
        • Buccolieri A.
        • et al.
        Abnormalities of motor cortical excitability are not correlated with clinical features in atypical parkinsonism.
        Mov. Disord. 2000; 15: 1210-1214
        • Eusebio A.
        • Azulay J.P.
        • Witjas T.
        • et al.
        Assessment of cortico-spinal tract impairment in multiple system atrophy using transcranial magnetic stimulation.
        Clin. Neurophysiol. 2007; 118: 615-823
        • Low P.A.
        • Reich S.G.
        • Jankovic J.
        • et al.
        Natural history of multiple system atrophy in North America: a prospective cohort study.
        Lancet Neurol. 2015; 15: 710-719