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anniversary article

Two Centuries of Neurology and Psychiatry in the Journal

Allan H. Ropper, M.D.
From Brigham and Womens Hospital and Harvard Medical School, Boston. Address reprint requests to Dr. Ropper at the Department of Neurology, Brigham and Womens Hospital, 75 Francis St., Boston, MA 02115, or at aropper@partners.org.
N Engl J Med 2012;367:58-65. DOI: 10.1056/NEJMra1104781
Copyright 2012 Massachusetts Medical Society.

ifty years ago, when the curator of the Boston Medical Library, Henry Viets, collated a score of the most important articles that had been published in the first century and a half of the New England Journal of Medicine, 10 of the 20 related to neurologic conditions.1 On the occasion of its 200th anniversary, one might ask why so many articles on neurologic and psychiatric diseases have been published in the Journal and what impact these pieces have had on their respective fields. Although the Journal is replete with reports of neurologic conditions that have entered the canon of medicine, it has been the large number and the breadth of clinical trials that have redefined neurology and psychiatry as active, therapeutic specialties. This article reviews the evolution of our understanding of neurologic and psychiatric conditions during the past two centuries.

Emergence of Speci a lt ie s of the Br a in

The origin of the Journal 200 years ago coincided with the deduction that lesions of the nervous system cause predictable signs and symptoms. Early issues of the Boston Medical and Surgical Journal (BMSJ), the predecessor of the current Journal, were already modern in featuring the work of one of the most colorful, innovative, and productive figures that neurology has known, C.E. Brown-Squard. Although his late career was tainted by a preoccupation with the rejuvenating effects of monkey and calf testicles (that nonetheless propelled the field of hormone-replacement therapy), he was imported to Boston to introduce the scientific European style of physiology to American medicine. The articles he published in BMSJ over a period of 25 years initiated an expansion of the Journal from a local to an international organ. In addition to his eponymic hemispinal cord syndrome,2 Brown-Squards experimental investigations of the sensory pathways in the spinal cord contravened the dogma of the day,3,4 and his extensive work on epilepsy has endured.5 His admonition to avoid asphyxia during a seizure at all costs and his instructions for 1st, dashing very cold water on the face; 2d, the inhalation of chloroform were prescient.5 An 1872 lecture reported in BMSJ6 was the only documentation that Brown-Squard was physically present in Boston. Many of his original syntheses, particularly his emphasis on the electrical properties of the nervous system, and his commitment to experimental observation have been recurrent themes in subsequent generations of the Journal. Modern scientific neurology, based on neuropathology and neurophysiology, began after World War II. By 1952, patients with tabes dorsalis and general paresis had practically disappeared from hospital wards. Antimicrobial agents had changed the course of bacterial and tuberculous meningitis, but poliomyelitis was still a nemesis. Denny-Browns Shattuck Lecture on the state of neurology that year in the Journal pronounced that, freed from its preoccupation with syphilology and now

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Neurology and Psychiatry in the Journal

separating itself from internal medicine and psychiatry, neurology had entered on an extremely productive and virile phase.7 Denny-Brown emphasized recent contributions on the neurologic aspects of liver failure, the recognition that transient ischemic attacks were due to occlusion of the carotid artery, and the emerging understanding of increased intracranial pressure. There was little question at the time that neurologic and psychiatric diseases both acted on the same brain, but Denny-Browns position in his Shattuck Lecture marked the emergence of American neurology, pointedly disengaging it from the popular practice of neuropsychiatry and aligning it with internal medicine. He provided a modern manifesto for neurology, which nonetheless remained largely an elegant diagnostic specialty.

It is also notable that the Journal published reports on several neurology trials that failed to verify the results of studies published earlier in the Journal. Clotting factors to improve the outcome in cerebral hemorrhage53 and neuroprotective agents for stroke54 led initially to great optimism, only to be supplanted by larger, negative trials performed by the same investigators.55,56 However, a negative trial of streptokinase for acute stroke acted as a brake on the use of the drug at a time when the results of three concurrent trials led to a different conclusion.57 For closed head injury, uncomfortably negative results from studies of hypothermia and bilateral decompressive craniectomy had as much effect on practice as positive trials did (Table 1).27,28

From a n Observat iona l t o a Ther a peu t ic Speci a lt y

Articles published in the pages of the Journal over the subsequent 50 years have thrust neurology, to paraphrase Denny-Brown, into an age of aggressive therapeutics (Table 1). Consider the numerous trials that have become the basis of established medical practice for stroke prevention and treatment trials of endarterectomy to prevent stroke,10 warfarin to reduce the risk of stroke due to atrial fibrillation,13 tissue plasminogen activator for the treatment of acute stroke,8 hypothermia to reduce cerebral damage after cardiac arrest,30,31 and other trials listed in Table 1. Similarly influential contributions have appeared regarding the treatment of multiple sclerosis from interferon18 to oral medications that free patients from the need for frequent self-injection23 and the other potent treatments listed in Table 1. The Journal debuted reports on treatment with adenine arabinoside for herpes encephalitis,39 medication that alters the course of glioblastoma (temozolomide),24 relief of migraine with a new class of drugs represented by sumatriptan,44 lorazepam for halting status epilepticus,45 and perhaps the most influential of all, the demonstration of the short-term and long-term effects of L-dopa in Parkinsons disease by Cotzias and colleagues.47,48 Even a venerable practice was proved correct with a randomized trial that validated magnesium for eclampsia.46 Neurology has been transformed by these articles.

The L eg ac y of Cl inic a l De scr ip t ion

Although many an established treatment falls into obscurity after the results of a new clinical trial are published, descriptive medical firsts are less ephemeral; most, of course, are pseudofirsts, having been described a generation earlier and usually in French or German. Essential clinical observations in neurology have appeared in abundance in the Journal. Censoriously called anecdotal, the descriptions of these diseases simply did not exist in the collective consciousness of general medicine until their publication (Table 2). Original articles introduced normal-pressure hydrocephalus,58 carotid sinus syncope,70 the subclavian steal syndrome,59 vertigo from a vascular loop,79 an ataxicophthalmoplegic form of the GuillainBarr syndrome,75 patent foramen ovale in cerebral embolus in young adults,83 prions in CreutzfeldtJakob disease,68 cryptococcal meningitis in the acquired immunodeficiency syndrome,81 and the reversible posterior leukoencephalopathy syndrome.82 In the emerging field of functional imaging and consciousness, there has been the extraordinary demonstration that some patients in a vegetative or minimally conscious state are able to communicate by activating portions of their brains.33 These descriptive articles have had a disproportionate effect on neurology and psychiatry because the specialties are entirely dependent on

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accurate interpretation of the patients history and the findings on physical examination for the treatment of all manner of psychic experiences, odd movements, paralysis, pain, sensations, visual difficulties, dizziness, and trouble with walking and speech. Although clinical observa-

tions that synthesize a new disorder are understandably more durable than clinical trials are, we may have seen the last of such broad-gauge descriptive articles in major publications. On the other hand, the current fetishization of imaging in neurology has been balanced by articles in the

Table 1. Pivotal Articles in the Journal Concerning the Treatment of Neurologic Diseases. Stroke Tissue plasminogen activator for acute stroke8 and extension of its use to 4.5 hours after onset of stroke9 Carotid endarterectomy for prevention of transient ischemic attack and stroke10 Calcium-channel blockers to reduce the risk of ischemic stroke after subarachnoid hemorrhage11 Proton-beam therapy for arteriovenous malformation in the brain12 Warfarin for atrial fibrillation13 Aspirin to reduce the risk of stroke from intracranial atherosclerosis14 Surgery for and natural history of cerebral aneurysms15 Multiple sclerosis Glucocorticoids for acute optic neuritis16 Cyclophosphamide17 Interferon-beta18 Copolymer19 Natalizumab20 Rituximab21 Alemtuzumab22 Oral fingolimod23 Brain tumor Temozolomide for prolonging survival with glioblastoma24 Localization of lesions by electroencephalography25 Traumatic brain and spinal injury Superiority of saline over albumin for resuscitation in closed head injury26 Failure of hypothermia therapy in children27 Limitations of bilateral decompressive craniectomy28 High-dose glucocorticoids for acute spinal trauma29 Coma Hypothermia for cardiac arrest in adults30,31 Hypothermia for hypoxicischemic encephalopathy in neonates32 Functional-imaging demonstration of awareness in vegetative and minimally conscious states33 Midline shift and level of consciousness34 Cerebral edema of diabetic ketoacidosis35 Successful treatment of transtentorial herniation36 Neuromuscular disease Intravenous immune globulin for dermatomyositis37 Autoantibodies against glutamic acid decarboxylase in the stiff-man syndrome38

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Neurology and Psychiatry in the Journal

Table 1. (Continued.) Infections of the nervous system Acyclovir for herpes encephalitis39 Glucocorticoids for acute bacterial meningitis in children40 Praziquantel for seizure reduction in cysticercosis brain abscess41 Induction of coma for prolonged survival in rabies42 Deleterious effects of dexamethasone in cerebral malaria43 Headache Subcutaneous sumatriptan for migraine44 Epilepsy Lorazepam for status epilepticus45 Magnesium for prevention of eclampsia46 Parkinsons disease and movement disorders L-dopa for Parkinsons disease47,48 Thalamotomy for torticollis49 Deep-brain stimulation for Parkinsons disease50 Deep-brain stimulation for focal51 and generalized52 dystonia

Journal that demonstrate how frequently a mag- ty of the Case Records featuring neurologists netic resonance imaging scan of the brain is clut- has influenced the teaching of the subject to residents and still informs the highest levels of tered with incidental findings.84 clinical practice.

A V ehicl e for Neurol o gy

The published Case Records of the Massachusetts General Hospital, long a staple of the Journal under the series name Clinicopathological Conferences, have particularly showcased Boston and American neurology and neurologists.85 Neurologic cases are the ones that are often most suitable for the purpose of clinicopathological correlation, and they have been disproportionately represented in these exercises, accounting on average for 14% of the Cabot Cases (as the series was known in the early 20th century) from 1975 to the present. In some years, neurologic cases constituted one in five Case Records. Their main theme, promulgated by the eminent neurologist, Raymond D. Adams, a frequent discussant, was the correlation of clinical signs with a special approach to neuropathology that emphasized not just the loci of lesions but the particular manner in which processes such as inflammation, trauma, infection, and ische mia affected nervous tissue. The populari-

T wo Influen t i a l A r t icl e s
A seemingly mundane clinical neurology article in the pages of the Journal had a highly felicitous effect on the relief of human suffering by addressing the problem of sciatica. That 1934 report by Mixter and Barr61 established intervertebral disk rupture with nerve-root compression as the mechanism and also provided a remarkably sophisticated analysis of cervical-disk herniation and cord compression. It presented detailed instructions for the cure in both instances, laminectomy. Twelve terse pages provided meticulous clinical descriptions and drawings of the corrective operation (Fig. 1). The enduring impact of that article, as well as the continuity of attention to this topic in the Journal, was affirmed by a 2007 report on a clinical trial that showed the superiority of surgery over conservative management.86 The excess of ill-advised laminectomies for back pain that followed Mixter and Barrs article was not their doing; in a less frequently cited but more

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Table 2. Neurologic and Psychiatric Conditions First Described or Synthesized in the Journal.* Normal-pressure hydrocephalus58 Subclavian steal syndrome59 Aortic-arch atherosclerosis as a risk factor for stroke60 Lumbar-disk sciatica61,62 Eastern equine encephalitis63 Progressive multifocal leukoencephalopathy,64 its association with natalizu mab for multiple sclerosis,65,66 and its treatment67 Prions as the cause of CreutzfeldtJakob disease68 Pseudotumor cerebri from hypertension69 Carotid sinus syncope70 Hysteria in men71 Epidemic hysteria (insanity by contagion)72 Fatal familial insomnia73 Dialysis-associated encephalopathy and aluminum74 Miller Fisher syndrome (ataxia, ophthalmoplegia, and areflexia)75 Cerebral form of poliomyelitis76 Vacuolar myelopathy of the acquired immunodeficiency syndrome77 Parkinsonism induced by MPTP78 Recurrent vertigo from a vascular-loop anomaly79 SOD1 mutation in familial amyotrophic lateral sclerosis80 Cryptococcal meningitis in the acquired immunodeficiency Reversible posterior leukoencephalopathy syndrome82 Patent foramen ovale as a cause of embolic stroke in young adults83 * MPTP denotes 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. syndrome81

American disease by the illustrious French neurologist, J.-M. Charcot, who took it up for study as a strictly neurologic condition. By medicalizing the misfortunes of life, for which care is still so frequently sought, physicians became comfortable invoking a patients constitutional makeup, as if it were a physical entity, as the substrate for exhaustion, melancholia, depression, discouragement, weakness, and headache. Beards observations led to the personalization of medicine well before the modern use of the term personalized medicine but avoided any implication that patients were culpable for their symptoms. The distinction between asthenia as a neurologic illness and as a psychiatric illness is still unclear. Beard suggested electrization when medication failed and endorsed the application of electricity from proprietary boxes directed to various body parts, entirely in the service of improving sleep, appetite, rest, and muscular exercise. Twenty of his 30 patients were cured or had great improvement in symptoms.

The R ise of Biol o gic Ps ychi at r y

Some topics in every field turn out to be fraught with specious ideas, and neurology and psychiatry have grappled with many of them. We cannot know whether the absence of articles on phrenology in BMSJ was an implicit message or whether it was a reflection of Bostons medical orthodoxy. Many positive reports of magnetism applied to nervous conditions and endorsements of autointoxication as the cause of mental diseases were, however, published in the Journal.88 Most of these quaint notions simply reflected the medical ideologies of the time. For an example of early continuity of subject matter regarding the nerves that has appeared in the Journal one has only to look at Brown-Squards work on electrical activity of the nervous system and J.C. Warrens derisive article Animal Magnetism, stating that the concept, which some thirty years ago excited great attention . . . has since been viewed as one of the remarkable impositions on the credulity of mankind.89 But the use of electricity for brain disorders is now again invoked through the technology of deep-brain stimulation. Escaping from the stigma of psychosurgery, articles in the Journal have

detailed contribution published in the Journal 6 years after their first report, they state, We wish to emphasize at this point that a large proportion of the cases of sciatica resolve spontaneously or under conservative orthopedic treatment.62 An influential article in psychiatry from the New England Journal of Medicine with vast secular influence was Neurasthenia, or Nervous Exhaustion by George Beard, published in 1869.87 He spoke of a condition of the system that is, perhaps, more frequently than any other in our time at least, the cause and effect of disease. . . . Both anemia and neurasthenia are most frequently met with in civilized intellectual communities. They are part of the compensation for our progress and refinement.87 The use of the label neurasthenia, and probably its reported incidence, expanded greatly after Beards article appeared. It was called the

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expanded the application of deep-brain stimulation well beyond its usual use in Parkinsons disease and found substantiation for its use in intractable obsessivecompulsive disorder90 and in dystonia.51,52 When psychodynamic systems that attributed mental diseases to unconscious conflicts were popularized in the mid-20th century, there was a conspicuous absence of articles about them in the Journal. The exception was psychosomatic medicine. In a 1948 article in the Journal, A.O. Ludwig wrote that emotional influences acting over longer or shorter periods result at first in disturbed physiology and eventually in structural change. Peptic ulcer is the simplest example . . . [u]lcerative colitis . . . asthma, hay fever and urticaria, certain skin diseases, such as eczema and neurodermatitis, migraine, possibly certain cases of epilepsy; hypertension and rheumatoid arthritis.91 Concerning much of 20thcentury psychiatry, including psychoanalysis, however, the Journal spoke through its silence. With the ascent of biologic psychiatry in the first decade of the 21st century, large pragmatic efficacy trials identified by their acronyms have appeared in the pages of the Journal for depression (STAR*D),92 psychosis (CATIE),93 and dementia (CATIE-AD).94 These studies affirm the value but expose the shortcomings and risks of medical treatment for mental conditions and suggest that the field may have moved a bit too far, as in a quip by the late Leon Eisenberg, from brainlessness to mindlessness.95 These articles about psychiatry published in the Journal are influencing that field, as other articles have in neurology and neurosurgery, bringing the study of mental life and its diseases back into contemporary medicine and thereby rejoining the specialties of the brain. For 200 years, the Journal has seen neurology and psychiatry evolve from a European to an international scope, from an emphasis on diagnosis to an emphasis on treatment, and has published many of the fundamental descriptions of nervous and mental diseases while cultivating a new and potent therapeutic course. One would expect the next 100 years to bring a new outlook on diseases of the nervous system that is based on fundamental biology, but the need for keen observation of the individual patient is not likely to be supplanted.

Figure 1. Mixter and Barrs Descriptions and Operation for Disk Rupture. Panel A shows the specimens removed during the operation61 Panel B shows the configurations of lumbar-disk rupture and ligamentous thickening with nerve-root distortion.62 Panel C shows a laminectomy being performed.62

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