Andrea Cordaro

Harry R. Haynes

Marcus Likeman

Patrick J. Gallagher

Seth Love

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Forensic Science Medicine and Pathology

A case of chronic asymptomatic central pontine myelinolysis with histological evidence of remyelination

Central pontine myelinolysis (CPM) is a neurological demyelinating disease of the pons. Although usually associated with rapid correction of hyponatremia, CPM may occur despite normonatremia, is often associated with chronic alcoholism and may be asymptomatic. Histological confirmation of asymptomatic CPM is rare. We describe an unusual post-mortem case of extensive but asymptomatic CPM in a chronic alcoholic patient with normonatremia. The affected part of the pons contained thinly myelinated axons with appearances supporting remyelination. We suggest that remyelination may account for the subclinical nature of this patient's CPM.</p

Haynes, Harry R

Cordaro, Andrea

Likeman, Marcus

Love, Seth

Explore Bristol Research

                          Haynes, H. R., Cordaro, A., Likeman, M., & Love, S. (2017). A case ofchronic asymptomatic central pontine myelinolysis with histologicalevidence of remyelination. Forensic Science, Medicine, and Pathology.https://doi.org/10.1007/s12024-017-9933-yPublisher's PDF, also known as Version of recordLicense (if available):CC BYLink to published version (if available):10.1007/s12024-017-9933-yLink to publication record in Explore Bristol ResearchPDF-documentThis is the final published version of the article (version of record). It first appeared online via SPRINGER athttps://link.springer.com/article/10.1007%2Fs12024-017-9933-y#copyrightInformation. Please refer to anyapplicable terms of use of the publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only the publishedversion using the reference above. Full terms of use are available:http://www.bristol.ac.uk/pure/about/ebr-termsCASE REPORTA case of chronic asymptomatic central pontine myelinolysiswith histological evidence of remyelinationHarry R. Haynes1 & Patrick J. Gallagher2 & Andrea Cordaro2 & Marcus Likeman3 &Seth Love4Accepted: 24 October 2017# The Author(s) 2017. This article is an open access publicationAbstractCentral pontine myelinolysis (CPM) is a neurological demyelinating disease of the pons. Although usually associated with rapidcorrection of hyponatremia, CPM may occur despite normonatremia, is often associated with chronic alcoholism and may beasymptomatic. Histological confirmation of asymptomatic CPM is rare. We describe an unusual post-mortem case of extensivebut asymptomatic CPM in a chronic alcoholic patient with normonatremia. The affected part of the pons contained thinlymyelinated axons with appearances supporting remyelination. We suggest that remyelination may account for the subclinicalnature of this patient's CPM.Keywords Central pontine myelinolysis . Remyelination . Post-mortem . Alcohol . AsymptomaticIntroductionCentral pontine myelinolysis (CPM) is a non-inflammatorydemyelinating disease of the pons, first described in1959 [1]. Extrapontine myelinolysis may additionallyoccur in the basal ganglia or cerebellum. Macroscopically,bilateral symmetrical softening and discoloration is seenin the base of the pons. Histology reveals loss of mye-lin and oligodendroglia with relative sparing of axonsand neurons [2]. The clinical severity ranges from anasymptomatic finding on neuroimaging to locked-in syn-drome, coma and death [2]. CPM may present withdysarthria, dysphagia, hyperreflexia or paralysis. Theextent of the demyelination has not been found to correlatewith the symptoms.Clinical summaryA 47-year-old chronic alcoholic self-discharged from hospitalwhere he was being treated for alcohol withdrawal. No focalneurological abnormalities had been noted on examinationand serum electrolytes were within normal limits. 72 h laterhe was found deceased in a wooded area, partially undressed.At autopsy, the stomach lining contained numerousblack areas (‘Wischnewski spots’), supportive of a diag-nosis of fatal hypothermia. The ‘paradoxical undressing’described above is a well-recognized feature of deaths second-ary to hypothermia (defined by a fall in core body temperatureto below 35 °C).Examination of the brain revealed a symmetrical, centralregion of discoloration and partial cavitation within thepons, up to 25 mm across (Fig. 1a). A correspondinglesion had been seen on an ante-mortem MRI scan twoyears previously (Fig. 1b & c). No further white matterchanges were seen macroscopically, including within thecorona radiata, internal capsule, basal ganglia or cere-bellar white matter.Pathological findingsHistology showed demyelination with astrocytosis and infil-tration by lymphocytes and macrophages (Fig. 1d). Staining* Andrea Cordaroac12370@my.bristol.ac.uk1 Department of Cellular Pathology, North Bristol NHS Trust,Bristol, UK2 University of Bristol Medical School, Bristol, UK3 Department of Neuroradiology, North Bristol NHS Trust,Bristol, UK4 Department of Neuropathology, North Bristol NHS Trust,Bristol, UKForensic Science, Medicine and Pathologyhttps://doi.org/10.1007/s12024-017-9933-ywith luxol fast blue and cresyl violet revealed a sharply de-marcated region of demyelination in the central part of thebase of the pons, with good preservation of neurons(Fig. 1e). Anti-myelin PLP1 immunohistochemistry (IHC)confirmed the loss of myelin (Fig. 1f & g).The appear-ance was typical of central pontine myelinolyis (CPM).However, included within the region of demyelinationwere many thin myelin sheaths that were weakly butconvincingly immunopositive for PLP1. This pattern ofimmunopositivity suggested reparative myelination hadoccurred (Fig. 1h).DiscussionThe main cause of CPM is the rapid correction ofhyponatremia [3] exposing pontine oligodendrocytes to os-motic stress [4]. This most often occurs in the context of al-coholic liver disease. It has been proposed that osmotic injuryto vascular endothelial cells after the rapid reversal ofhyponatremia releases myelinotoxic factors [5]. This causesvasogenic edema and demyelination at highly vascular grey-white matter interfaces such as the pons [5]. CPM also occursin normonatremia, with the majority of cases associated withadg he fb cFig. 1 a Post-mortem image of the fresh pons and medulla, openedsagitally from the ventral aspect. A red, central, triangular region ofsoftening is seen with preservation of the surrounding parenchyma. bSagittal T1 and (c) Axial T2 ante-mortem MRI sequences. The ponsincludes a trident-shaped focus of high T2 signal. Cerebellar atrophy isalso noted, in keeping with the history of alcoholism. d Hypercellularpontine tissue, reflecting astrocytic gliosis and perivascular andparenchymal accumulation of chronic inflammatory cells (scale bar =200 μm). e Staining with luxol fast blue and cresyl violet revealed asharply demarcated region of reduced staining of myelin in the centralpart of the base of the pons, with good preservation of neurons (scalebar = 200 μm). f & g There was reduced labelling of myelin with anti-PLP1 in the affected region of pons (scale bar = 200μm). h Includedwithin this region were many large-caliber but thinly myelinated axons(blue arrowhead), in contrast to the normally myelinated, large-caliberfibers in the adjacent pons (green arrowhead) (scale bar = 50μm)Forensic Sci Med Patholchronic alcoholism. Alcoholism may deplete intracellular glu-cose and glycogen, resulting in metabolic stress and a pro-apoptotic milieu, in which excess production of free radicalsand nitric oxide leads to myelin injury [6].In this case, serum sodium was normal ante-mortem and thepatient was asymptomatic with no previous history of neuro-logical disease. An autopsy series of over 3000 patients found15 cases of CPM, all of which were asymptomatic (12 out ofthe 15 were associated with alcoholism). The majority of activelesions were associated with a rapid reversal of hyponatremia[7]. Asymptomatic CPM has been reported in the absence ofdocumented electrolyte disturbance [8], although histologicalconfirmation of the lesion, as seen in this case, is extremely rare.It is increasingly recognized that functional neurologicalrecovery is possible after a diagnosis of CPM [9]. Althoughserial MRI studies have shown that radiological resolutiondoes occur [10], the temporal evolution of radiological fea-tures is not considered to have prognostic value in predictingclinical outcome [11]. In this case, histological features ofremyelination were seen within the lesion which, to the au-thors’ knowledge, have not previously been demonstrated.Remyelination is likely to underpin neurological and radiolog-ical improvement after acute osmotic demyelination, and wesuggest that remyelination could explain why the present pa-tient was asymptomatic prior to his death. Improved under-standing of the process of remyelination after CPM may helpto identify radiological markers that better predict clinical out-come and guide the development of therapies.Key points1. Chronic alcohol abuse is a risk factor for the developmentof CPM, which may occur with normonatremia.2. Neurological recovery has been reported after CPM andwe postulate that remyelination may account for this.3. Further research into the histological and radiologicalmarkers of remyelination in CPM is needed.Author contributionsH.R.H performed the post-mortem, reviewed the histology and wrote themanuscript.P.J.G reviewed the histology and wrote the manuscript.A.C wrote the manuscript.M.L reviewed the radiological scans.S.L reviewed the histology and corrected the manuscript.All authors approved the final version of the manuscript.Compliance with ethical standards The use of this case is in accordancewith the requirements of the UK Human Tissue Act 2004.Conflicts of interest None.Informed consent Written informed consent was obtained from the pa-tient’s next of kin for publication of this case report and any accompany-ing images.Declaration of interest The Authors declare no sources of funding, di-rect or indirect, and any connection of any of the researchers with thetobacco, alcohol, pharmaceutical or gaming industries or anybody sub-stantially funded by one of these organizations. The Authors declare alsothat there are no contractual constraints on publishing imposed by anyfunder.Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.References1. Adams RD, Victor M, Mancall EL. Central pontinemyelinolysis: a hitherto undescribed disease occurring in al-coholic and malnourished patients. AMA Arch NeurolPsychiatry. 1959;81:154–72.2. Hurley RA, Filley CM, Taber KH. Central pontine myelinolysis: ametabolic disorder of myelin. J Neuropsychiatry Clin Neurosci.2011;23:369–74.3. Kleinschmidt-DeMasters BK, Norenberg MD. Rapid correction ofhyponatremia causes demyelination: relation to central pontinemyelinolysis. Science. 1981;6:1068–70.4. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581–9.5. NorenbergMD. A hypothesis of osmotic endothelial injury. A path-ogenetic mechanism in central pontine myelinolysis. Arch Neurol.1983;40:66–9.6. Ashrafian H, Davey P. A review of the causes of central pontinemyelinosis: yet another apoptotic illness? Eur J Neurol. 2001;8:103–9.7. Newell KL, Kleinschmidt-DeMasters BK. Central pontinemyelinolysis at autopsy; a twelve year retrospective analysis. JNeurol Sci. 1996;142:134–9.8. Razvi SS, Leach JP. Asymptomatic pontine myelinolysis. Eur JNeurol. 2006;13:1261–3.9. Louis G, Megarbane B, Lavoué S, Lassalle V, Argaud L, PousselJF, et al. Long-term outcome of patients hospitalized in intensivecare units with central or extrapontine myelinolysis. Crit Care Med.2012;40:970–2.10. Buis C. Serial magnetic resonance imaging of central pontinemyelinolysis. Liver Transplant. 2002;8:643–5.11. Beh SC. Temporal evolution of the trident and piglet signsof osmotic demyelination syndrome. J Neurol Sci. 2017;373:268–73.Forensic Sci Med Pathol

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A case of chronic asymptomatic central pontine myelinolysis with histological evidence of remyelination

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