The Anti-NMDA Receptor Encephalitis Foundation Newsletter

World Encephalitis Day 2020 Encephalitis Conference. Encephalitis Global has been proud to offer an annual Encephalitis Conference welcoming survivors and caregivers to spend the weekend in a venue where everyone understood the life-altering impact of encephalitis.

 




Abstract Background Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. Methods In a 1-year, multice…

 




Young and healthy, this woman suddenly was suffering hallucinations and seizures; her brain was under attack from her own body.

 




In October 2016, I had just begun my third and final year of university, happily planning my Halloween costume with my housemates, attending freshers’ events and lectures, when suddenly and unexpectedly, my whole life changed forever.

 




Acute encephalopathy is a common clinical presentation for hospital admissions. Autoimmune encephalitis is a rare cause of encephalopathy which has increasingly been recognized over the last decade. The detection of various neuronal antibodies has helped diagnose these syndromes, but they have…

 




Abstract Objective To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. Methods Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. Results Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. Conclusions Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies. Glossary BBB=blood-brain barrier; BCR=B-cell receptor; cDNA=complementary DNA; DIRS=deep B-cell immune repertoire sequencing; IgD=immunoglobulin D; IgG=immunoglobulin G; IgM=immunoglobulin M; LGI1=leucine-rich, glioma-inactivated 1; NMDAR=NMDA receptor; PB=peripheral blood; SHM=somatic hypermutation; SM=switched memory; UCSF=University of California, San Francisco; VH=heavy chain variable region Leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis is characterized by rapidly progressive cognitive impairment, frequent seizures, most characteristically faciobrachial dystonic seizures, psychiatric disturbances, and sleep alterations.1,2 These distinctive clinical features, alongside in vitro and in vivo studies,3,4 and the often rapid response of seizures to immunotherapies all strongly suggest that LGI1 antibodies are pathogenic.2 However, LGI1 antibody encephalitis can often result in residual cognitive impairment and neurologic disability: this represents an unmet medical need.2,5 Although CSF LGI1 antibodies are detected in around 90% of cases, this condition is infrequently associated with CSF lymphocytosis or oligoclonal bands.2,6,7 Therefore, the CSF B-cell response has received limited consideration as contributor to pathogenesis or as a potential therapeutic target. Indeed, very little is known about B cells that participate in the autoimmune response against LGI1, either in the periphery or CSF. Here, we applied deep B-cell immune repertoire sequencing (DIRS) on sorted peripheral blood (PB) B-cell subsets and CSF and found strong evidence for intrathecal antigen-driven immune responses in patients with LGI1 antibody encephalitis. These observations inform disease biology and suggest CNS B cells as a candidate therapeutic target in these patients. Methods Patient samples Six patients with LGI1 antibody encephalitis from the University of California, San Francisco (UCSF) Autoimmune Encephalopathy Clinic underwent collection of paired PB (40 mL) and 10–25 mL of CSF. B-cell subsets were isolated as described previously.8 As controls, 2 patients with other noninflammatory neurologic diseases from the same center were included in the study and their PB and CSF samples collected accordingly. Standard protocol approvals, registrations, and patient consents The study was approved by the Institutional Review Board of the UCSF. Written informed consent was obtained from all participants in the study. Cell staining and sorting Ficoll-density separated peripheral blood mononuclear cells were stained with the following antibodies: CD19 (APC Cy7), immunoglobulin D (IgD) (PE Cy7), CD27 (Qdot605), CD38 (PerCP Cy5.5), and CD3 (Pacific blue) as previously described.8 B-cell subsets were sorted using a FACS Aria III (BD Biosciences, Franklin Lakes, NJ) into naive (CD19+IgD+CD27−), unswitched memory (CD19+IgD+CD27+), switched memory (CD19+IgD−CD27+CD38−), double negative (CD19+IgD−CD27−), and plasmablasts/plasma cells (CD19+IgD−CD27hiCD38hi). Sorted cells were immediately lyzed in RLT buffer (RNeasy kit; Qiagen, Hilden, Germany) and stored at −80°C. To preserve the far lower CSF lymphocyte frequencies, unfractionated pelleted CSF cells were studied. Immunoglobulin messenger RNA amplification and immunoglobulin repertoire sequencing Sequencing work flow was performed as previously described,9 with modifications to sequence human samples. In brief, total RNA was isolated from CSF cells and PB B-cell subsets, followed by reverse transcription into complementary DNA (cDNA). Next, immunoglobulin G (IgG) heavy chain variable region (VH) and immunoglobulin M (IgM) VH were amplified by PCR using the following primers: IgG 3′ primer: 5′-GGGAAGACSGATGGGCCCTTGGTGG-3′; IgM 3′ primer: 5′-GCTCGTATCCGACGGG-3′; an equimolar mix of 7 VH family 5′ primers: VH1: 5′-GAARRTYTCCTGCAAGGYWTC-3′; VH2: 5′-CACRCTGACCTGCACCKTCTC-3′; VH3: 5′-KARACTCTCCTGTRCAGCCTB-3′; VH4: 5′-GTCCCTCACCTGCRCTGTCTM-3′; VH5: 5′-GARGATCTCCTGTAAGGGTTC-3′; VH6: 5′-CTCACTCACCTGTGCCATCTC-3′; VH7: 5′-GAAGGTTTCCTGCAAGGCTTC-3′. PCR conditions were (1) 95°C, 60 seconds; (2) 95°C, 30 seconds; 66.6°C, 30 seconds; 72°C, 60 seconds (33 or 45 cycles); and (3) 72°C, 7 minutes. Specific PCR products were gel purified and mixed to create 15 pM cDNA libraries, which were analyzed by Ion Torrent semiconductor sequencing. Sequence analysis IGHV and IGHJ gene segment usage, complementarity determining region (CDR)1-3 amino acid sequence, and number of somatic hypermutation (SHM) events were determined as previously described.8,9 Briefly, CDR3 amino acid sequences were determined using a custom-made pipeline adapted from the AbMining tool,10 and identified CDR3 regions were related to IGHV and IGHJ germline genes using IgBlast. To calculate SHM profiles, sequencing reads with identical CDR1 to CDR3 nucleotide sequences were grouped as nonredundant (unique) reads, and SHMs were quantified for this entire region based on the alignment of reads with germline gene segments. Compartmental connectivity via bicompartmental clustering of IgM-VH or IgG-VH from CSF and PB B-cell subsets was performed as previously described.8 Briefly, clonally related Ig-VH sequences were identified based on H-CDR3 similarity (hamming distance of H-CDR3 amino acid sequence less than 2) and usage of identical Ig germline segments. For lineage analysis, only Ig-VH sequences with in-frame H-CDR3 and which spanned at least from the 5′ end of H-CDR1 to the 3′ end of H-CDR3 with a contiguous reading frame were used; IgTree11 (kindly provided by Dr. Ramit Mehr, Bar-Ilan University, Ramat-Gan, Israel) was used to map the lineage.8 Putative germline nodes are inferred, and lineage intermediates not found by DIRS were calculated by IgTree. Data availability All next-generation sequencing data and computer code other than software packages are available from the corresponding author on reasonable request. Results Serum LGI1 antibodies titers were on average 127-fold higher than CSF LGI1 antibody titers by live cell–based assay using a membrane-tethered LGI1 construct in all 6 patients with LGI1 antibody encephalitis (table), none of whom were asymptomatic at follow-up.12 None of the 6 patients showed a CSF lymphocytosis or oligoclonal bands on routine CSF analysis. There was no abnormal enhancement on brain MRI in any of the patients following the administration of gadolinium, consistent with no substantial blood-brain barrier (BBB) opening. DIRS of IgG-VH and IgM-VH was performed from paired CSF and B-cell subsets sorted from peripheral blood mononuclear cell samples of the 6 LGI1 antibody encephalitis patients, and a median of 600,707 sequences per sample (range 165,369–1,586,974) were generated. As expected, circulating naive B cells had limited somatic mutations and as cells acquired the postgerminal center marker CD27, and class-switched to IgG, mutations accumulated (figure 1A). These findings are a validation that DIRS reliably reflects the conventional B-cell maturation stages and suggests that CSF B cells in LGI1 encephalitis have undergone antigen-driven maturation (figure 1A). View inline View popup Table Patient characteristics of 6 patients with LGI1 encephalitis and 2 controls (bottom 2 rows) Figure 1 In patients with leucine-rich, glioma-inactivated 1 antibody encephalitis, deep immune repertoire sequencing of the immunoglobulin heavy chain variable region (Ig-VH) shows connectivity of class-switched mature peripheral blood (PB) B cells to clonally expanded CSF B cells/clusters One representative patient of 6 patients is shown in A–D. (A) Cumulative number of somatic mutations (x-axis) in the IGHV gene nucleic acid sequence excluding the CDR3 region in nonredundant sequences (count; y-axis) of sorted PB B-cell subsets and CSF B cells are shown for IgM (left panels) and IgG (right panels). (B) Connectivity of the various PB and CSF B-cell compartments based on clonal relationship is illustrated. While the size of the boxes correlates with the number of reads in each compartment, the thickness of the connecting line correlates with the number of related sequences between the 2 compartments it connects. For better display, all lines connecting to the CSF IgG compartment are depicted in red, whereas all others are in black. IgG = immunoglobulin G; IgM = immunoglobulin M; N = naive; PC = plasmablast/plasma cell; SM = switched memory; USM = unswitched memory. (C) All clusters of clonally related Ig-VH that have at least 1 sequence in one of the PB compartments and 1 in the CSF compartments (shared PB and CSF clusters) are depicted with their respective size (number of nonredundant sequences) on the y-axis. (D) Frequency of used IGHV genes in the IgG CSF, PB plasmablast/plasma cell, and PB SM cell subsets. Overall, across all 6 patients, all B-cell subsets of IgG and IgM isotypes showed high degrees of sequence connectivity in both PB and CSF compartments (figure 1B). A striking link existed between PB IgG-expressing SM cells/plasmablasts/plasma cells and the IgG-expressing CSF B cells, suggesting that class-switched mature B-cell compartments are consistently connected across the BBB. The CSF B cells often represented a discrete number of highly expanded clusters (figure 1C). Indeed, this restriction of the CSF B-cell repertoire was also evident at the level of the heavy V gene family usage. In contrast to the peripheral SM and plasmablast/plasma cell IgG compartments, which were diverse and highly comparable, the CSF IgG repertoire was distinct and restricted (figure 1D). Next, clusters shared between the CSF and PB were examined more closely. These shared CSF/PB clusters on average had 990.3 (range 110–1,749) unique sequences. In this analysis, each unique sequence was represented by a dot and a line joining neighboring sequences represented a mutational (Hamming) distance of 1 in their CDR3 region (figure 2A). By definition, there is at least 1 PB (red) and 1 CSF (blue) sequence in each cluster. Many shared clusters were dominated by peripheral B cells and were related to only a small number of CSF B cells. Also, of interest, several clusters highly dominated by CSF sequences were apparent and often showed a PB sequence in the center, representing a more proximal sequence with fewer mutations from which surrounding CSF sequences may have descended. More detailed analysis of Ig lineage trees from clonally related CSF IgG-VH demonstrated intensive mutational activity, again suggesting intrathecal SHM (figure 2B). Figure 2 Intrathecal somatic hypermutation in patients with leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis (A) Data from 1 representative patient of 6 LGI1 patients showing all clusters of clonally related immunoglobulin heavy chain variable region, which are shared between peripheral blood (PB) and CSF B cells. Each red dot represents ≥1 identical PB sequence, and each blue dot ≥1 identical CSF sequence. Two dots connected by a line differ from each other by a Hamming distance of 1 in their CDR3 region on the nucleotide sequence level. Clusters of related sequences are grouped together. (B) Two Ig lineage trees of CSF B cells from 1 patient are shown. Each dot represents 1 sequence, and its size correlates with the number of times this sequence could be found. Two dots connected by a line differ from each other by 1 nucleotide in the CDR3 region unless marked otherwise. Putative germline nodes are labeled; lineage intermediates not found in the sequencing data were calculated and are labeled in gray. In contrast to all LGI1 antibody encephalitis cases, 2 patients ultimately diagnosed with noninflammatory neurologic diseases (1 with headache and 1 with chronic migraine), which were analyzed following the same protocol, did not show comparable intrathecal B-cell activity. In 1 of the 2 controls, we were unable to amplify enough CSF IgG RNA for sequencing, indicating very few CSF IgG transcripts; in the other, we were able to detect 43 unique sequences in the CSF, which were parts of shared CSF/PB clusters compared with 990.3 (mean; range 110–1,749) in LGI1 antibody encephalitis. Shared clusters in the control were overwhelmingly PB dominated and had on average 1.2 CSF IgG sequences (range 1–3), whereas shared clusters in patients with LGI1 antibody encephalitis had larger CSF fractions with a mean of 8.1 CSF IgG sequences (range: mean value per patient 3.4–11.9; minimum/maximum value per patient across all 6 patients 1/465). Taken together, DIRS demonstrated high sensitivity in detecting an intrathecal B-cell response and marked interconnectivity between the PB and CSF compartments in LGI1 antibody encephalitis, particularly of the more mature B-cell subsets. However, the antigen specificity of the clonally expanded intrathecal B cells remains unclear. Peripheral B-cell expansions infrequently reached the CSF, but those which did commonly lead to intrathecal B-cell expansions, consistent with secondary intrathecal B-cell receptor (BCR) diversification in LGI1 antibody encephalitis but not in noninflammatory controls. Discussion Here, we examined the potential paradox between the limited detectable CSF activity in routine clinical assessments (e.g., CSF cell count and oligoclonal bands), alongside the presence of pathogenic CNS-active autoantibodies in patients with LGI1 antibody encephalitis. For the first time, using DIRS, we demonstrate highly active intrathecal B-cell activity in LGI1 antibody patients and show that B-cell repertoires, particularly from postgerminal center B cells on both sides of the BBB, may actively mutate and mature in patients with LGI1 antibody encephalitis. Because, for methodological reasons, our study could not address the antigen specificity of the intrathecal B-cell response, it remains to be determined whether these expanded clones recognize LGI1-specific epitopes, and it is likely that some of these represent non–LGI1-specific B cells. LGI1-specific CSF B cells are more likely to exist in the patients in which intrathecal LGI1 antibodies were detectable. However, it cannot be excluded that LGI1 antibodies have passively diffused to the CSF. In our studies, we found PB plasmablast/plasma cell IgG-VHs, which underwent SHM and were related to expanded clusters of CSF B cells. This pattern closely resembles findings in MS, suggesting that it may be a generic mechanism across CNS autoimmune conditions,8,9,13 and accordingly, we did not observe this phenomenon in noninflammatory controls. Yet, these observations appear different to the more limited intrathecal expansions observed in neuromyelitis optica spectrum disorder and the very low mutational load in CSF B cells from patients with NMDA receptor (NMDAR) antibody encephalitis.14,15 Hence, it may be that several different immunologic mechanisms operate across these autoantibody-mediated conditions. Our study did not aim to examine the antigen-specific population or correlate intrathecal B-cell responses with clinical outcome. Of interest, it has recently been observed that intrathecal LGI1 antibody synthesis correlates with a poorer prognosis.16 However, the lack of CSF LGI1 antibodies in some of our patients with striking intrathecal SHM may suggest that DIRS provides a more sensitive measure of B-cell activity. In general, the majority of autoimmune encephalitis syndromes are considered to be IgG mediated.2,7,16,17 However, we also found evidence for extensively activated IgM-expressing peripheral B cells, which share similar or identical BCR heavy chains to intrathecal IgG-expressing B cells. The immunopathologic relevance of this IgM response is unknown, but may indicate an ongoing germinal center reaction-mediated stimulation of B cells as has been proposed in patients with NMDAR antibody encephalitis, where IgM NMDAR-reactive autoantibodies can be detected.18,19 A major question is whether interrupting these responses could potentially mitigate disease activity, prevent relapses, and improve long-term cognitive outcomes. Yet, only a subset of patients with LGI1 antibody encephalitis have been reported to respond favorably to rituximab, which targets—mainly peripheral—CD20-expressing B cells and has little effect on LGI1 antibody production.20 Our findings suggest that plasmablasts and plasma cells (which do not express CD20) are active in the CSF, and therefore, novel drugs that actively target these prolific protein synthesizers in the CNS compartment might be more effective than selective anti-CD20 treatments. Conversely, given that affinity maturation is an ongoing process in LGI1 antibody encephalitis and could result in increasingly efficient pathogenic antibodies, therapeutic depletion of CD20-expressing B-cell populations early in this disease might prevent development of chronic or progressive clinical phenotypes. Accordingly, early diagnosis of intrathecal immune activation in patients with mild clinical signs would be highly desirable. Study funding The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Disclosure K.L.-H. has received research support (to TUM) from Novartis, honoraria from Novartis and F. Hoffmann-La Roche, and compensation for travel expenses from Merck Serono. S.R.I. is a coapplicant and receives royalties on patent application WO/2010/046716 (U.K. patent no., PCT/GB2009/051441) entitled “Neurological Autoimmune Disorders.” The patent has been licensed for the development of assays for LGI1 and other VGKC complex antibodies. S.W., S.J., R.D., G.L., and S.M. have nothing to report. A.P. is a current employee of Janssen Inc. A.L.G. reports a patent for Method for High Percentage Recovery of Rare Cells (European application 18185007.4; US, Japan, and Chinese patents pending). J.M.G. received consulting fees from Biogen and Alexion, research support (to UCSF) from Genentech and previous research support to UCSF from Quest Diagnostics, service contract support (to UCSF) from MedDay, honoraria for editorial work from DynaMed Plus, and personal compensation for medical-legal consulting. M.D.G. reports grants and personal fees from Quest Diagnostics, Inc., grant support from the NIH, personal fees from Adept Field Consulting, Gerson Lehrman Group, Guidepoint Global, InThought, Best Doctors, Market Plus, and Advance Medical, speaker/teaching fees from the American Academy of Neurology Oakstone Publishing, and personal fees from medical-legal consulting. M.R.W. has received research support from Roche and Genentech. S.S.Z. is Deputy Editor of Neurology® Neuroimmunology & Neuroinflammation and is a member of the advisory board for the International Society of Neuroimmunology. He has served as a consultant and received honoraria from Biogen Idec, EMD Serono, Genzyme, Novartis, Roche/Genentech, and Teva Pharmaceuticals, Inc., and has served or serves on Data Safety Monitoring Boards for Lilly, BioMS, Teva, and Opexa Therapeutics. Currently, he receives research grant support from the NIH, the NMSS, the Maisin Foundation, Biogen, and Celgene. H.-C.v.B. is an employee of F. Hoffmann-La Roche, Basel, Switzerland. He has received compensation for consulting activities from Roche, Novartis, and Genzyme and research funding from Roche, Genentech, and Pfizer. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors express their gratitude to the patients who agreed to participate in this research study. K.L.-H. received fellowship grants from the Deutsche Forschungsgemeinschaft (LE 3079/1-1) and the US National Multiple Sclerosis Society (NMSS) (FG 2067-A-1; G-1508-07064) and research support from the Munich Cluster for Systems Neurology (SyNergy), the Deutsche Forschungsgemeinschaft (SFB-TR-128), and the Hertie Foundation (MyLab program). S.R.I. is supported by the Wellcome (104079/Z/14/Z), BMA Research Grants-Vera Down Grant (2013) and Margaret Temple (2017), and by the Fulbright UK-US commission (MS-SOCIETY research AWARD). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health). A.L.G was supported by the NMSS Clinician-Scientist Development Award Kathleen C. Moore postdoctoral fellowship. M.D.G. was supported by the NIH, National Institute of Aging (R01 AG031189), and the Michael J. Homer Family Fund. Support was provided to S.S.Z. by the NIH (1 RO1 AI131624-01-A1; 1 R21 NS108150-01; 1 R21 AI142186-01), National Multiple Sclerosis Society (RG 1701-26628, RG 1807-31679 and RG 1801-29861), Maisin Foundation, and Guthy-Jackson Charitable Foundation. This study was supported by grants from the NIH/NINDS (K02NS072288 to H.-C.v.B., R01NS092835 initially to H.-C.v.B., transferred to Stephen L. Hauser). H.-C.v.B. was also supported by an endowment from the Rachleff Family Foundation. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. ↵* These authors contributed equally to the manuscript. The Article Processing Charge was funded by UCSF. Received September 5, 2019. Accepted in final form December 23, 2019. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. References 1.↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.OpenUrlCrossRefPubMed 2.↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–356.OpenUrlCrossRef 3.↵Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161–18174. 4.↵Petit-Pedrol M, Sell J, Planaguma J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144–3159.OpenUrl 5.↵Finke C, Prüss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74:50–59.OpenUrl 6.↵Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013;136:3151–3162.OpenUrlCrossRefPubMed 7.↵van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 2016;87:1449–1456.OpenUrl 8.↵Palanichamy A, Apeltsin L, Kuo TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 2014;6:248ra106. 9.↵Lehmann-Horn K, Wang SZ, Sagan SA, Zamvil SS, von Budingen HC. B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. JCI Insight 2016;1:e87234.OpenUrl 10.↵D’Angelo S, Glanville J, Ferrara F, et al. The antibody mining toolbox: an open source tool for the rapid analysis of antibody repertoires. MAbs 2014;6:160–172.OpenUrlCrossRefPubMed 11.↵Barak M, Zuckerman NS, Edelman H, Unger R, Mehr R. IgTree: creating immunoglobulin variable region gene lineage trees. J Immunol Methods 2008;338:67–74.OpenUrlCrossRefPubMed 12.↵Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 2010;133:2734–2748.OpenUrlCrossRefPubMed 13.↵von Büdingen HC, Kuo TC, Sirota M, et al. B cell exchange across the blood-brain barrier in multiple sclerosis. J Clin Invest 2012;122:4533–4543.OpenUrlCrossRefPubMed 14.↵Kowarik MC, Astling D, Gasperi C, et al. CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. Ann Clin Transl Neurol 2017;4:369–380.OpenUrl 15.↵Kreye J, Wenke NK, Chayka M, et al. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 2016;139:2641–2652.OpenUrlCrossRefPubMed 16.↵Gadoth A, Zekeridou A, Klein CJ, et al. Elevated LGI1-IgG CSF index predicts worse neurological outcome. Ann Clin Transl Neurol 2018;5:646–650.OpenUrl 17.↵Varley J, Taylor J, Irani SR. Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy. Neuropharmacology 2018;132:71–82.OpenUrl 18.↵Makuch M, Wilson R, Al-Diwani A, et al. N-methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–561.OpenUrl 19.↵Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012;72:902–911.OpenUrlCrossRefPubMed 20.↵Irani SR, Gelfand JM, Bettcher BM, Singhal NS, Geschwind MD. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy. JAMA Neurol 2014;71:896–900.OpenUrl

 




Unexpected outcome (positive or negative) including adverse drug reactions Case report Complete cognitive recovery in a severe case of anti-N-methyl-d-aspartate receptor encephalitis treated with electroconvulsive therapy Cæcilie Leding1, Lisbet Marstrand2 and Anders Jorgensen1,3 Psychiatric Center Copenhagen, Rigshospitalet, Mental health services in the Capital Region of Denmark, Copenhagen, Denmark Department of Neurology, Rigshospitalet, Copenhagen, Denmark Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Correspondence to Dr Anders Jorgensen; anders.01.joergensen{at}regionh.dk Abstract Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis usually presents with prominent neuropsychiatric symptoms and many patients experience cognitive sequelae. Electroconvulsive therapy (ECT) has been suggested as a part of the treatment, particularly for catatonia, but concerns that ECT may worsen the cognitive function and long-term outcome may limit its use. We present a case of anti-NMDA receptor encephalitis with severe neuropsychiatric manifestations including refractory catatonia and behavioural change. A pre-ECT neuropsychological assessment revealed dysfunction in multiple cognitive domains in spite of intensive pharmacological treatment. Twenty days after the ninth and last ECT treatment, the patient underwent the same neuropsychological tests, which showed normalised test results within all cognitive domains and no need of rehabilitation. The case demonstrates that the use of ECT in anti-NMDA receptor encephalitis with severe pretreatment cognitive dysfunction can be associated with a highly favourable cognitive outcome. View Full Text Statistics from Altmetric.com View Full Text Footnotes Contributors CL wrote the first draft of the paper. LM cowrote the paper and performed the neuropsychological tests. AJ wrote the final version of the paper. All authors have contributed to and approved the final version of the paper. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Obtained. Provenance and peer review Not commissioned; externally peer reviewed. Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Copyright information: © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ. Read the full text or download the PDF: Subscribe Log in

 




This JAMA Patient Page describes different possible causes of memory loss, including neurodegenerative dementias and other conditions that may be reversible or…

 




Autoimmune encephalitis and myelitis is increasingly recognized as a cause of CNS disease in children and teens. Andrew McKeon, M.B., B.Ch., M.D, gives an overview of this test available through Mayo Clinic Laboratories.

 




Introduction We, as the neurologists, have all been asked to see ‘unresponsive’ patients immobile in bed, on a ventilator, doing nothing, with no movement, no grimace except for an occasional twitch and, when eyes are opened, a blank stare. What do we say? What can we say? We do not want to ‘write the obituary’ for a patient who might be sitting in a chair the next day. (‘Have you seen Mr. Taylor? You won’t believe it!’) We do not want to tell families not to lose hope (or worse, that ‘time will tell’) when we are pretty convinced that the status will not change for the better. We cannot (and should not) provide escalating intensive care to a patient who, because of a significant injury, is in devastatingly poor shape or even imminently close to brain death. Any neurologist will approach these patients with trepidation because we seldom know enough about their circumstances; their hospital course has been long and complicated, and prior (sometimes critically essential) details are hard to find in the records. Prognostication of coma is difficult; truly it is. Algorithms are inherently artificial, lack the necessary precision and performance and never account for all those confounders (drugs, drugs, drugs) and medical illness, either present or intercurrent. Many new guidelines are derivatives of older ones and the parameters have not changed, only their interpretation. This review is an amalgamation of literature review and opinions, as well as an attempt to establish some procedure to address the questions. The neurologist’s prognostications are not scientific instruments. Neurology is not like that. Definition of coma A traditional, but simple and useful distinction, is to separate states by the degrees of wakefulness and awareness (figure 1). This distinction allows us to separate coma from a persistent vegetative state (and severe forms of minimally conscious state, MCS). Coma denotes being unaware and not awake. Clinicians have gone farther in describing a comatose patient, and this includes descriptions of eye movements (absent fixation or finger tracking), motor responses (absent localisation or reflexive movements) and no verbal output but of no significance in many instances, because comatose patients are intubated to protect the airway. Attempts to categorise coma into several grades of severity have proven futile unless the evaluation takes into account the absence of one or more brainstem reflexes. An important clinical fact is that most patients in coma recover and become more awake. Prolonged disorders of consciousness, such as a vegetative state or MCS, are, therefore, rarely seen after the first year of the injury. It is also a real possibility that patients were misdiagnosed and misclassified after being admitted to neurorehabilitation centres or nursing homes.1 Researchers have subclassified MCSs into those with (MCS+) or without language (MCS–); those with language are more likely to improve further. The classification becomes less articulate since functional MR scan-based categorisation has identified a patient subset fulfilling all vegetative state criteria but in whom functional MR showed a command-following response. Doing or asking something to the patient creates brain activation maps. Another patient subset, higher order cortex motor dissociation, shows a cortical response to the auditory stimuli, again without evident awareness.2 Similar observations have been made with EEG power spectral analysis both early3 and late4 in the clinical course. EEG responses to spoken simple one-task commands were variable among the small group of patients who responded. Responses on EEG spectra and MR cannot (yet) be seen as proof of awareness and may cause considerable disquiet if deciding family members interpret them as such. More importantly, neurologists do not seem to know how to channel these research observations into the practice of prognostication. Figure 1 Definition of coma and vegetative state. Once coma is diagnosed, any clinician will seek an explanation, and in most cases, the explanation can be found through neuroimaging, electrophysiology or cerebrospinal fluid evaluation. It is uncommon to still have a patient with an unexplained coma 24 hours after the admission. When confronted with such an unresolved situation, the neurologist should seek a less common cause, such as an undetected toxin or prolonged, unrecorded hypoglycaemia or anoxia. Emergency departments, worldwide, see coma from opioids, anoxic–ischaemic injury after cardiopulmonary resuscitation, traumatic brain injury, status epilepticus, acute central nervous system (CNS) infections and rapid multiorgan failure. Psychiatric causes for coma do exist, but they are not of long duration. They are quite rare, declare themselves quickly and are not further considered. Extreme forms of catatonia (previously known as lethal catatonia) require a careful assessment and often a search for autoimmune encephalitis. We can safely say that most comas originate from neuronal depression due to intoxication, acute metabolic or endocrine derangement or a lesion in crucially important brain structures. In the case of a structural brain injury, the affected structures are the bilateral cortex or white-matter connections to the cortex, thalamus, dorsal pons and midbrain containing the fibres of the ascending reticular activating system. Acute coma will involve each of these structures. Deepening or emerging coma from a lesser state of impaired consciousness can result from a unilateral lesion displacing other structures from mass effect and causing those structures to become dysfunctional, either from a pressure effect or through ischaemia when the feeding arteries are threatened. Neuroimaging, frequently just a CT scan by itself, often establishes the cause. MRI becomes exceedingly important in the workup of a patient when the cause cannot be established. For example, it may show posterior reversible encephalopathy syndrome not clearly imaged on CT scan and any of the more severe leucoencephalopathies associated with illicit drug use. Patients rarely go into non-convulsive status epilepticus ‘out of the blue’; usually, there are clinical signs pointing to it (blinking, eye deviation and jaw twitching). In any patient in whom the EEG shows epileptiform activity, further monitoring might be necessary. We all think of it, hoping that it is the cause, but we very rarely diagnose non-convulsive status epilepticus clinically or electrographically—despite consulting on a large volume of patients admitted to medical or surgical intensive care units with no prior neurological injury. Other studies have claimed higher percentages (still less than 10%) in comatose patients treated for a critical illness but without a proven effect on outcome after treatment. Transformation of generalised convulsive status epilepticus to non-convulsive status epilepticus is far more common and eminently treatable.5 Before we can prognosticate, we must diagnose the condition. Wrong diagnoses lead to incorrect prognoses (but not always). Much may be said for experience. Indeed, some studies suggest that seniority of staff boosts chances of survival, but careful assessment of all possible variables remains key.6 7 Additionally, before we prognosticate, we must consider all potential (including aggressive) treatments. No neurologist should entertain an outcome prediction if the results of a medical or surgical treatment are not yet known. An additional important, seldom mentioned or acknowledged factor is the early recognition of the cause of coma. Outcome has to be linked to time of intervention and acting quickly. Untreated hydrocephalus, prolonged pressure effect from a mass, untreated large-vessel occlusion and untreated (or inadequately treated) seizures or infection can all impede recovery. There are several situations where timely and aggressive treatment may lead to substantial recoveries. These recoveries may surprise the uninitiated but should not surprise the experienced neurologist (box 1). Box 1 Ten ‘surprising’ coma recoveries Acute meningitis (treated). Acute subdural haematoma (evacuated). Acute hydrocephalus (drained). Intoxications (antidotes). Non-convulsive status epilepticus (antiepileptic medications). Uraemic encephalopathy (dialysis). Posterior reversible encephalopathy syndrome (lowered blood pressure). Myxoedema coma (thyroid supplement). Basilar artery embolus (clot retrieval). Accidental hypothermia (warming). Principles of prognostication in coma Accurate prognostication is based on good judgement, and the key to good judgement is good evaluation of all the information. In some situations, it is coming to terms with it; in others, it is better to deflect a request to make a final decision. The main principles in assessing the patient in prolonged (>24 hours) coma are (1) to examine and identify what counts; (2) to review neuroimaging and know what matters; (3) to evaluate laboratory tests and ancillary tests to see what is missing; (4) to find confounders and consider contributing factors that might have been forgotten; (5) to decide and acknowledge inevitable uncertainties; (6) to factor in the bigger picture (ie, the patient’s previously stated wishes regarding independence and comorbidity); (7) to refrain from predictions if all too confusing; (8) to proceed with a brain-death examination to declare a patient brain dead (the deceased have no prognoses); (9) to speak candidly with family members in a scheduled conference with all medical stakeholders and (10) to proceed with an agreed-on de-escalation plan or withdrawal of support when the best time has been identified. This may help to answer the most commonly asked questions (ie, what is the likelihood that patients will die or remain in an absolutely hopeless condition whatever we do? How far should treatment go?) Prognosis by disease categories It is important to confirm the manner in which the brain has been injured and to identify important and clinical and laboratory data specific to certain disorders. These prime indicators of outcome are critical to an accurate prognosis. Neurologists are often (and undeservedly) mislabelled as harbingers of doom or nihilists, but our goal is to distinguish between the situations that are futile and situations in which the patient has a ‘fighting chance’ (often, when others are ready to give up) and may gain some state of self-reliance. But prognostication for full recovery after a major neurological injury leading to coma continues to elude us. Coma and traumatic brain injury In the elderly, any major traumatic brain injury resulting in coma generally has a poor outcome. Age remains the most important determinant and most indicative variable.8–10 Prognostication in the case of a young adult with a traumatic brain injury is difficult.11 Traumatic brain injury in younger persons (<40 years) remains a ‘roll of the dice’ probability in any multicentre, large-database model.10 While many awaken, survive and improve to the point of walking, talking and taking care of basic needs, their recovery is often accompanied by depression, new addictions, epilepsy and emotional instability. Certain variables, including prolonged severe hypotension and anoxia during injury or during transport to hospital, light-fixed pupils or extensor motor responses, move the needle somewhat but not enough to claim these models as clinical bedside aids. Neuroimaging is seldom definitive, but the presence of primary traumatic brainstem lesions on neuroimaging consistently indicates a poor prognosis12 (figure 2). Similarly, MR-confirmed lesions of the genu of corpus callosum correlate with severe disability. Each of these lesions represents major flexion–extension tearing injuries to the parenchymal structures. Figure 2 Primary brainstem trauma with basal ganglia contusion. Another determinant is sustained, increased intracranial pressure, and we can expect this to lead to a shift of the brain tissue, displacement of the thalamus and midbrain, and a change in pupil size and light responses. Decompressive hemicraniectomy as a treatment for intractable increased intracranial pressure results in a 6-month postoperative mortality rate around 30% but with no measurable effect on the severity of morbidity.13 14 Traumatic brain injury with evacuation of a contusion or epidural or subdural haematoma may lead to protracted recovery. Despite adequate removal of the subdural hematoma, patients may take weeks to improve, and many need close EEG monitoring for seizures.15 In any patient with traumatic brain injury, physicians should watch for the presence of paroxysmal sympathetic hyperactivity. Physicians unfamiliar with this complication may consider these manifestations a mere epiphenomenon of severe brain injury. Paroxysmal sympathetic hyperactivity (‘storming’) after traumatic brain injury is often associated with a worse neurological outcome with longer rehabilitation stays and more cognitive impairment. Paroxysmal sympathetic hyperactivities are rapid and episodic manifestations of excessive sympathetic activity (tachycardia; hypertension with increased pulse pressure, tachypnoea, fever spike and diaphoresis; and increased muscle tone assuming extensor or dystonic postures). An effective treatment is intravenous morphine, scheduled doses of clonidine and increasing doses of gabapentin. It is very uncertain whether aggressive early treatment of these storming episodes affects long-term outcome. Coma and anoxia Coma after resumption of circulation following cardiopulmonary resuscitation has been associated with and explained by severe anoxic–ischaemic injury to the cortical mantle, thalamus, striatum and globus pallidus. Outcome predictions were, for many years, based on a prospective study of the findings on neurological examination and, more importantly, improvement over time.16 17 The distinctions proposed by Levy et al were too clinically useful to dismiss and shifted the conversation.16 Suddenly, 3 days seemed enough (and could be enough) to ascertain whether the patient had a chance to improve. However, a later study found less certainty with this time interval.18 The American Academy of Neurology practice parameter identified poor prognostication but only in a small group of patients.19 We hope no physicians consider employing the 3-day cut-off in these patients without persistent loss of brainstem reflexes or other very good reasons that lead them to doubt the possibility of improvement. Prognostication in coma after cardiopulmonary resuscitation has been studied extensively in recent years and led to the 2014 European Resuscitation Council/European Society of Intensive Care Medicine Guideline.20 Several factors clearly determine a poor prognosis. These include early anoxic brain swelling, an indication of severity (figure 3); diffuse cortical restriction on diffusion-weighted MR scan of brain; absent cortical somatosensory evoked potentials; rising serum neurone-specific enolase21; unreactive and burst–suppression EEG patterns or marked suppression to less than 20 µV,22 burst–suppression EEG time locked with myoclonus status and refractory status epilepticus after CPR (with or without clinical manifestations and with or without myoclonus status). Figure 3 Brain oedema after severe anoxia. There are exceptions, and there are late recoveries with variable outcomes.23–25 However, these occur too infrequently to affect decision-making in this category of patient. Prognostication was perhaps ‘simpler‘ in earlier days of examining patients after a successful cardiopulmonary resuscitation—now, confounders (mostly hypothermia but also a slew of intravenous drugs to support the intervention) are very significant. Drug washout in a severely afflicted patient with associated kidney and liver injury during cardiopulmonary resuscitation remains very difficult to assess and cannot be predicted. Conspicuously lacking in many studies on outcome is information about the neurological examination, use of sedation, neuroimaging and postresuscitation haemodynamic and organ function, which many of us consider crucial in deciphering these patients’ prognoses. Caution is key, and the decision to address the level of care (and what can help the patient) may still have to wait or be regularly revisited. Coma and stroke Both haemorrhagic stroke and ischaemic stroke are heterogeneous disorders, and thus, prognosis is very disease specific.26–28 Coma after a parenchymal (lobar or deep ganglionic) haemorrhage denotes shift from a large-volume destruction of the thalamus or trapping of the ventricle causing obstructive hydrocephalus. Another factor influencing prognosis is the expansion of the clot volume due to anticoagulation. Prognosis in a patient with a deteriorating lobar haematoma depends on whether evacuation is entertained, feasible or delayed. Rapid improvement with resolution of shift attests to that observation. Deep-seated haematomas (putamen and caudate thalamus) cannot be reached surgically, and even placement of a ventricular drain with use of thrombolytic drugs does not improve outcome.29 Haemorrhage in the cerebellum or pons is much less common. Cerebellar haemorrhage with CT evidence of a tight posterior fossa (obliteration of cisterns, tissue displacement upward or downward and tonsillar herniation) will lead to rapid loss of brainstem reflexes without emergent evacuation. Once evaluated, the outcome can be quite good because stance and gait are more affected by injury to efferent fibres than cerebellar structures. Pontine haemorrhages causing coma rarely (if ever) resolve to improvement in functional status and most certainly when they additionally damage the thalamus due to upward extension.30 Coma from ischaemic stroke is based on similar principles. Shift from oedema will not be tolerated unless relieved by a decompression. Haemorrhagic conversion of a large ischaemic stroke does increase mass effect and is a major additional determinant in outcome (figure 4). In a haemispheric stroke (ie, middle cerebral artery), outcome is poor when a decompressive craniectomy is not considered or when performed in the elderly (>60 years).31 32 Early versus late decompressive surgery also influences outcome, and the preponderance of evidence suggests that early decompression before the patient develops clinical signs of deterioration from brainstem involvement will help more. Bithalamic infarcts (from the top-of-the-basilar artery clot) are associated with coma at presentation, but patients may awaken, often after a period of marked fluctuation in alertness. An acute embolus to the basilar artery is devastating (causing infarction of the pons, midbrain and cerebellar haemispheres). Endovascular retrieval of a clot has a high success rate if the admission CT scan is normal. An embolus in the basilar artery that causes coma or locked-in syndrome (caveat non-neurologist) is associated with high mortality and no functional recovery, but there is a chance for substantial recovery if the clot is retrieved. Figure 4 Haemorrhagic infarct with mass effect. Prognostication in aneurysmal subarchnoid hemorrhage is largely unreliable – even in patients who appear moribund soon after the rupture. A comatose patient with aneurysmal subarachnoid haemorrhage can improve rapidly within hours after placement of a ventriculostomy and removal of a temporal lobe clot associated with middle cerebral artery aneurysm. However, if upper brainstem reflexes remain lost after this ‘cerebral resuscitation’, recovery rarely occurs. In many cases, patients presenting with coma have large ventricles filled with blood, and many have rebleeding—the overwhelmingly critical factor in outcome of aneurysmal subarachnoid haemorrhage. The development of later cerebral ischaemia from cerebral vasospasm and inability to control it medically are the major factors in poorer outcomes.33 Older age greatly influences outcome, and in patients over age 80 years, the likelihood of meaningful survival is low.33 34 Nonetheless caution is important because poor grade patients may become good grade patients after active interventions. Coma and CNS infections The outcome for patients with an infection-induced coma (bacterial or viral) depends on the degree of coma and ‘FOUR Score’ on admission. No patient with a ‘FOUR score’ of less than 3 will survive meningitis.35 Causes for this poor prognosis are cerebral oedema, secondary cerebral infarcts (possibly from associated cerebral venous thrombophlebitis and thrombosis) and hydrocephalus. Time to antibiotic treatment36 is a critical determinant, with delay reducing the likelihood of a good functional outcome. Associated sepsis and septic shock, which can result from late recognition and insufficient aggressive intervention, can also worsen the outcome.37 Likely complications include seizures, acute hydrocephalus and septic cerebral infarctions, all of which affect morbidity. Multiorgan failure and septic shock may be the first presentation in a patient with bacterial meningitis. The most important factor associated with poor outcome in bacterial meningitis is systemic illness that manifests itself by tachycardia, hypotension, positive blood cultures, increased erythrocyte sedimentation rate and thrombocytopaenia.38 39 The underlying cause is important, and the odds of an unfavourable outcome are six times higher in patients infected with Streptococcus pneumoniae when compared with patients infected with Neisseria meningitidis. A CT scan of head showing ventriculomegaly or diffuse brain oedema denotes a poor prognosis. Outcome of encephalitis remains indeterminate. The variables include age, duration of disease and level of consciousness. Patients younger than 30 years of age who remain largely alert have a much higher chance of returning to preinfection normal life than older patients with altered consciousness. Encephalitis leading to coma is associated with poor outcome, largely because the available treatments are ineffective.40 41 A small proportion will awaken, and an even smaller proportion will regain independent status. Some encephalitides have no effective treatment and hence a poor outcome. These include rabies encephalitis, many of the fungal infections and, more recently, West Nile virus encephalitis. Many patients with fever or meningitis recover fully, but the more invasive neurological form can cause flaccid paralysis and marked changes in basal ganglia, thalami and brainstem. In general, West Nile virus encephalitis has a 20% mortality rate and acute West Nile virus encephalitis myelitis has a 10%–15% mortality rate (and higher in the elderly). A patient who is comatose from West Nile virus encephalitis has a high risk of mortality. Patients requiring mechanical ventilation may seem to have a poor prognosis, but many can show substantial recovery over a number of years.40 41 These recoveries cannot be adequately predicted. Prognostication in most infectious encephalitides likely should be avoided. Coma and immune-mediated encephalitis There is increasing evidence that, in a large proportion of patients, encephalitis has an autoimmune origin. Patients often present with worsening encephalopathy and status epilepticus. N-methyl-d-aspartate-receptor encephalitis often results in coma from new-onset refractory epilepsy (NORSE), and there is an emerging consensus that patients with NORSE also require immunotherapy. A recent study warned that dyskinetic and stereotypical movements might have been misdiagnosed and overtreated as status epilepticus.42 First-line immunotherapy includes corticosteroids, intravenous immunoglobulin or plasma exchange, with several more options for second-line immune therapies. The outcome in this patient population is always uncertain, and aggressive escalation of therapy with multiple antiepileptic drugs eventually may lead to months of stay in an intensive care unit and protracted improvement. None of the intuitive poor prognostic indicators (MR brain scan abnormalities, refractory status epilepticus and mechanical ventilation for coma) panned out.43 Some patients may develop severe catatonia.44 Coma and neurotoxicity Several types of intoxication and medication overdoses are immediately problematic and may lead to permanent neurological deficits. In many instances, clinical presentation is not easily attributed to a single known toxin. In today’s world, we are confronted with drug abusers, intentional poisoners and, in nearly epidemic proportions, the synthetic opioids. In addition, there is another whole world out there of inhalants containing brain-damaging substances such as aerosols and dry-cleaning fluids. Opioid toxicity—mostly through heroin injection or the use of oxycodone for chronic pain management—can cause permanent injury through anoxic–ischaemic injury. There is a known methadone leucoencephalopathy associated with abnormalities on MR brain imaging that spares the subcortical U-fibres. Usually, this pattern is seen with methadone intoxication.45 Heroin users can remain comatose for weeks with severe white-matter change but sparing of cortex (figure 5). There are a couple extremely important questions that the consulting neurologist should ask. Are there elements of permanent injury, particularly anoxic–ischaemic injury? Do patients need continuous electroencephalography (EEG) monitoring to recognise and manage ongoing seizures? Awakening does occur despite severe white-matter disease on MRI, and even cognition can substantially improve. Nevertheless, prolonged stays in an intensive care unit with tracheostomy and gastrostomy and prolonged gait rehabilitation are common.46 47 Atypical alcohol ingestion (ie, methanol found in commercial products such as windshield washer fluids, deicers, antifreeze, paints, wood stains and glass cleaners) is very problematic and often lethal. Unfortunate cases of survival of intentional carbon monoxide intoxication are occasionally seen. The earliest signs of carbon monoxide poisoning are personality changes with loss of orderliness, snapping at people and outbursts of anxiety but also profound headache and coma when carboxyhaemoglobin concentration increases. Diffuse, haemispheric white-matter involvement on CT scan often develops in comatose patients and patients with long exposure and predicts poor outcome. Figure 5 Heroin-associated leucoencephalopathy. Coma and the unknown There are several circumstances when we do not know (and will never fully know) due to their rarity. These are patients with environmental injuries (eg, electrocution, lightning strikes) and rare disorders such as severe acute metabolic derangements, including hypoglycaemia, leading to permanent coma. In other situations, patients have been found unconscious, and the circumstances cannot be retraced. The best approach remains serial clinical examination and using MR brain imaging to find structural injury and then interpret the severity of injury. A discussion with the family Skilful communication about coma and its consequences is just as important as anything else we do in neurology. This needs a complex core team of nurses, clergy and palliative care professionals with experience in mediating differences of opinion. Fortunately, in many cases—after an adequate explanation—common sense prevails, and consensus between families and the healthcare team can be achieved. Again, prognosis is certainly poor in several conditions (box 2).48 49 Box 2 When the prognosis is certainly poor Massive haemispheric swelling (any cause). Deterioration and sequential loss of brainstem reflexes (any cause). Traumatic brain injury (with primary brainstem and corpus callosum lesions). Pontine haemorrhage with thalamic extension. Embolus to basilar artery (with no reopening). The term ‘futility’ has important connotations, but definitions of medical futility can easily become ‘gobbledy-gook’, and families may wish to continue care even with a very low likelihood of improvement (as long as continuing care does not harm the patient). The quality of the information provided is decisive for many family members. Families may not be fully able to judge the long-term effects of a major neurological injury, and explanations about quality of life should follow. Neurological disability is difficult to describe, and it is even more difficult to know whether the patient can handle these deficits. Just as we would be under similar circumstances, the patient’s family is notoriously unprepared for these situations; the onus is on the experienced neurologist to explain what neurological morbidity and disability entail. Families should clearly understand what we mean by ‘palliative care’, and we should carefully re-explain anything that seems unclear. In general, the aim of palliative care is to reduce suffering and promote comfort resulting in a peaceful and natural death. Conversations should typically occur after 2 weeks have passed or when the patient needs a tracheostomy and gastrostomy. This fork in the road will often lead to reassessment: either support in the hope of improvement or de-escalation to palliative care. We should provide sufficient details about what can be expected for both options. This may be harsh news for the families to absorb: death in a number of days versus prolonged weaning off the ventilator, treatment of multiple complications associated with immobilisation and nursing home placement. The practising neurologist should actively participate in these discussions and develop a rapport with family members. A final word The overall lesson is that we rarely should be surprised by the actual outcome if we take all predictive factors into account. If identified, we should ‘Venn diagram’ the comatose patient with a multitude of serious and often obvious medical conditions. Whether all of this will improve our prediction is uncertain. And then there is the unknown. Reawakening is, of course, not the same as recovery, and long convalescence may reveal pervasive major deficits; for many, traits and skills will never return. We will never have an early, reliable prediction for the previously young and healthy comatose patient with a likely structural injury but no convincing abnormality on MR or other poor clinical indicators. We have limited understanding of the outcome in many patients, and we always will. Machine learning will introduce itself in the coming decade, but machines depend on the questions we pose, and even then it may not be enough.50 Prognostication in coma is not a just fallacy of predetermined outcome or in the eye in the beholder and requires a careful evaluation and some observation time to put the deficit into sharp focus. That is why it is important to acknowledge the neurologist who works beyond simple coma scales or scores. Key points Prognostication in coma can only proceed with full understanding of its cause. Prognostication is not improved using major statistical models. Prognostication works best in identifying the extremes of injury. 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