The philosopher of the nervous systemIn 1898, aged 63 and already retired, John Hughlings Jackson delivered the first of the eponymous lectures named in his honour by the Neurological Society of the United Kingdom (previously, of London).His aim was to summarize ideas on organization of the brain developed over the previous four decades and set down in his writings from 1861.Jackson's audience was told that the nervous system is an organ for the coordination of impressions and movements.Evolution has resulted in three hierarchical layers organized around physiological systems.Each level adds complexity in rearranging a lower evolutionary system.The layers have anatomical substrates but without abrupt topographical localization.Ideation and will are represented as movements; some are voluntary, others automatic.Physical and psychical events occur independently but in parallel, through 'concomitance'.Lesions result in loss of the most evolved functions and release of more primitive activities.The clinical features of focal lesions are stereotyped but do not indicate restricted localization of normal functions.Whether the audience was able to appreciate the profundity of these insights is unclear for there was a problem with Jackson.His modest and unassuming demeanour, the unparalleled reputation he had acquired as an intellectual giant in Victorian medicine and the complexity and prolixity of his expositions led to a heady mix of affection, admiration and incomprehension.Those who may have listened and felt that the ideas could be appreciated at leisure by reading Jackson's writings on the nervous system were destined for disappointment.Nor has posterity fared much better.Many of Jackson's writings were published in obscure journals, the archives of which are not easily found.Some were privately printed in a limited edition for distribution to friends.Jackson tended to write what he thought with much repetition, in sesquipedalian prose and with little attempt at organizing the flight of ideas.Many of his fuller explanations were embedded in footnotes which sought, but rarely added, clarity.Not unreasonably, his ideas changed over time.Although Jackson started two books on epilepsy, published as a series of chapters 'to be continued', in the event neither was completed.His intention to write a monograph organized around physiology and levels rather than anatomical regions also never materialized.Now, more than 100 years later, the difficulty of appreciating the writings has changed with the publication of John Hughlings Jackson.Clinical neurology, evolution, and Victorian brain science (2022).

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing–remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN–alemtuzumab), followed by additional, as-needed, alemtuzumab. Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN–alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN–alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. ClinicalTrials.gov identifiers: NCT00530348; NCT00548405; NCT00930553

On the quatercentenary of his birth, it is appropriate to celebrate the writings and discoveries of the British neuroanatomist Thomas Willis (1621–75) about the cerebral cortex and its connections. 1 Compston A ‘All manner of ingenuity and industry’. A bio-bibliography of Thomas Willis 1621–1675. Oxford University Press, Oxford, UK2021 Google Scholar Willis observed that complexity in the convoluted surface of the cerebrum, with continuity of the underlying structures, accounts for differences in memory, imagination, and intelligence among species. In mammals and fishes that act mainly by instinct, the convolutions of the cerebral cortex are relatively under-developed. The corpus callosum acts as a “market place” so that “every impression coming this or that way, becomes still one and the same”. 2 Willis T [translated by Samuel Pordage] ‘The anatomy of the brain’. In: The remaining medical works of that famous and renowned Dr Thomas Willis. London, UK. Printed for Dring T, Harper C, Leigh J, Martyn S, 1681. Google Scholar Willis also noticed that the internal capsule is atrophied in people who have been long paralysed. He saw the decussation of motor tracts in the medulla and named the pyramids through which the fibres of the pyramidal tract, originating in the motor cortex, pass. Three centuries later, Cajal beautifully drew the pyramidal cortical cells (appendix).

Chapter 7: ‘A certain physiologie and pathology of the brain and nervous stock: Pathologiæ cerebri (1667–1678)’ provides a detailed bibliography, using the system described in chapter 4, of seven copies of Willis’s third published book in which are included two treatises: 6. De morbis convulsivis; and 7. De scorbuto. It is the first publication which includes the portrait of Willis, aged 45, engraved by David Loggan on which formed all subsequent images were based. These descriptions are preceded by a narrative highlighting the main bibliographic issues that characterize the various editions, states, and issues of these copies. Of these, some are already known but others newly identified. {107 words}

2021 marks the quatercentenary of the birth of Thomas Willis on 27 January 1621. As a physician in Oxford, Willis's work in the 1650s provides an example of rural medical practice in early modern England. As a member of the Oxford Philosophical Club that met from the 1640s, he was central to the move from classical scholasticism to accounts of anatomy and physiology based on observation and experiment. As Sedleian Professor of Natural Philosophy in Oxford, the surviving records of his lectures from the 1660s provide an example of pedagogy in medicine at that time. And, after moving to London in 1667, Willis continued to interact with a community of scientists and physicians who transformed ideas on respiration, muscular movement, and the nervous system. Despite a busy clinical practice, Willis found time to write fourteen treatises on anatomy and physiology, clinical medicine, and therapeutics. These were published between 1659 and 1675, the year in which he died. Willis's method was to replace dogma with empirical evidence: 'I determined to believe Nature and ocular demonstrations [and] did chiefly inquire into the offices and uses of the Brain and its nervous Appendix. I addicted myself to the opening of Heads on which a more certain Physiologie [and] Pathologie of the Brain and nervous stock, might be built'. This celebratory lecture will set Willis's ideas in the context of the times in which he worked and assess their legacy for the subsequent accumulation of knowledge relating to the nervous system.

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10–24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.

At various times in history, technology has led to abrupt and far-reaching changes in how societies communicate: printing with moveable type in the 15th century; broadcasting in the 19th century and early 20th century; electronic transfer of information in the late 20th century; and machine learning with robotic systems in the 21st century. In that context, it is timely to reflect on the past, present and future trajectory of knowledge relating to medicine and what might be lost and gained as science and society increasingly enter the digital age. Here, the topic of interest is multiple sclerosis.Broad consensus on the pathogenesis of multiple sclerosis was reached in the late 1980s, the application of which has since yielded significant advances in therapy. In 2020, a reasonable formulation would consider multiple sclerosis to involve a distinct geographical distribution resulting from the interplay of environmental and genetic aetiological factors; inflammatory and degenerative disease mechanisms working in sequence or in parallel expressed as an evolving phenotype characterised by intermittent and then progressive symptoms and signs leading to gradual accumulation of disability; clinical features and their pathological substrate represented by various surrogate laboratory biomarkers; the availability of therapies that modify the course of the illness but varying in their risks and benefits making for complex prescribing algorithms; and, underpinning the whole scientific endeavour, the wish to settle the hopes and fears for their future of affected individuals.Digital technology uses binary rather than continuous analogue variables to detect patterns in large datasets, far outstripping the capacity of human agency for memory and analysis. Artificial intelligence develops systems that function according to preset rules but, primed by training datasets, generate their own information, learn from experience and adapt in order to achieve goals through deep learning. The boundaries of artificial intelligence are provisionally mapped in …

Background In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing–remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656). Methods In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies. Results Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7–12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases. Conclusions Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.

BACKGROUND:Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS:We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS:As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION:Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

‘Neuron’ or ‘neurone’? While it is often assumed that these different spellings reflect usage of American versus British English, there are also inconsistencies within these cultural boundaries. Mehta et al. review historical, etymological and linguistic evidence concerning the spelling of ‘neuron(e)’ and conclude that the only correct spelling is ‘neuron’.

At various times in history, technology has led to abrupt and far-reaching changes in how societies communicate: printing with moveable type in the 15th century; broadcasting in the 19th century and early 20th century; electronic transfer of information in the late 20th century; and machine learning with robotic systems in the 21st century. In that context, it is timely to reflect on the past, present and future trajectory of knowledge relating to medicine and what might be lost and gained as science and society increasingly enter the digital age. Here, the topic of interest is multiple sclerosis.\n\nBroad consensus on the pathogenesis of multiple sclerosis was reached in the late 1980s, the application of which has since yielded significant advances in therapy. In 2020, a reasonable formulation would consider multiple sclerosis to involve a distinct geographical distribution resulting from the interplay of environmental and genetic aetiological factors; inflammatory and degenerative disease mechanisms working in sequence or in parallel expressed as an evolving phenotype characterised by intermittent and then progressive symptoms and signs leading to gradual accumulation of disability; clinical features and their pathological substrate represented by various surrogate laboratory biomarkers; the availability of therapies that modify the course of the illness but varying in their risks and benefits making for complex prescribing algorithms; and, underpinning the whole scientific endeavour, the wish to settle the hopes and fears for their future of affected individuals.\n\nDigital technology uses binary rather than continuous analogue variables to detect patterns in large datasets, far outstripping the capacity of human agency for memory and analysis. Artificial intelligence develops systems that function according to preset rules but, primed by training datasets, generate their own information, learn from experience and adapt in order to achieve goals through deep learning. The boundaries of artificial intelligence are provisionally mapped in …