Background: For many years, neurology was seen as a purely observational discipline, focused on pathology and with little interest in treatments. Summary: From the creation in 1897 of Monatsschrift für Psychiatrie und Neurologie, the forebear of European Neurology, to nowadays, there have been great changes in the paradigms and concepts of treatments in neurology. We present an overview of the evolution of neurological treatments from 1897 to 2022. Key Messages: However, the last 125 years have not consisted of constant progress. The exceptional advances made in some diseases (multiple sclerosis or surgical treatment of Parkinson’s disease) cannot hide the stagnation in others (certain brain tumors or amyotrophic lateral sclerosis).

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Introduction

The term neurology was coined in the second part of the 17th century by Thomas Willis (1621–1675), but the discipline itself was not born until the last quarter of the 19th century, spearheaded by Jean-Martin Charcot (1825–1893) at La Salpêtrière hospital in Paris. For many years, neurology was an observational discipline, prioritizing semiology and pathology over treatments, and this clinicopathologic approach remained dominant until the mid-20th century and the emergence of the first effective therapeutics.

Monatsschrift für Psychiatrie und Neurologie, the forebear of European Neurology, was first published in 1897. At that time, neurology was still a young discipline whose borders with psychiatry and alienism were yet to be clearly defined. Although Charcot had died 4 years earlier, neuropathology remained the key focus of research. A glance into the medical journals of this era, including the first issue of Monatsschrift für Psychiatrie und Neurologie, confirms that therapy was not the major concern of the time. However, hysteria, which had changed the landscape of the field of neurology, had led to the development of electrotherapy and hypnosis. Additionally, some neurologists were performing unusual and unexpected procedures, such as stretching therapy or opotherapy to treat patients suffering from tabes dorsalis.

The paradigms and concepts of treatments in neurology have changed since the journal’s creation, but progress over the last 125 years has not been consistent. The exceptional advancement made in some diseases, such as multiple sclerosis or the surgical treatment of Parkinson’s disease, cannot hide the stagnation in others, such as the field of brain tumors or amyotrophic lateral sclerosis.

The Eternal Flame of Electrotherapy

Neurology and electricity have always been closely linked, particularly in the use of electromyography and electroencephalography for neurological diagnosis. The seminal textbook by the German neurologist Erb [1] (1840–1921) firmly placed electrotherapy at the center of neurological therapies. Often regarded as a versatile and miraculous treatment, electrotherapy regularly reappears through the years as a neurological therapy. However, exploitative uses of this technique on soldiers by famous neurologists during WW1 led to severe criticism [2]. Nevertheless, its use has endured through the decades and has led to many applications, including improvements in neurorehabilitation. Electrotherapy strongly re-emerged in the late 1980s in the therapeutic context of deep brain stimulation (DBS). This innovative technique, developed by Benabid et al. [3], transformed Parkinson’s disease treatment. DBS is nowadays widely used for numerous indications, including tremor and other movement disorders, drug-resistant epilepsy, or psychiatric disorders [4]. Another therapeutic form of electric current, used less frequently than DBS, is transcranial direct current stimulation, which reappeared in a modern form in 1998 for the treatment of some neurological and psychiatric disorders [5]. Additionally, repetitive transcranial magnetic stimulation (rTMS), introduced in 1985, has been adapted into a treatment for neurogenic pain [6]. DBS, transcranial direct current stimulation, and rTMS have highlighted the therapeutic role of electrical stimulation (or inhibition) of the nervous system. The nervous system should not, however, be reduced to a purely electrical model.

Wars as Catalysts for Progress

What drove the progress in neurological treatments? In the 20th century, world wars acted as a catalyst for advancements in neurological therapy. From among the abhorrent pseudo-medical abuses of these conflicts emerged undisputed progress. For example, in WW1, the extreme medical practices and inappropriate therapies used by some neurologists to treat psychological trauma finally led to the definition of posttraumatic stress disorder [7]. The thousands of soldiers with nerve injuries in WW1 led to major developments in nerve surgery. Neurorehabilitation procedures, regarded nowadays as a key therapeutic tool, also saw major improvements after the world wars [8]. The global deviance of Nazi medicine during WW2 included neurological and anatomopathological research conducted without moral boundaries, leading to new data for some disorders [9]. While trying to weaponize toxins during WW2, British and the US military researchers provided useful data for the first steps of the therapeutic use of botulinum toxin (purification, production of toxoid, etc.) [10]. A few years later, Scott [11] (1932–2021), while looking for drugs to paralyze oculomotor muscles to treat strabismus, used botulinum toxin in animals and then in patients. Since the 1980s, botulinum toxin has become an efficient treatment for movement disorders and poststroke spasticity and is nowadays used in multiple indications in other medical specialties (ENT, dermatology, urology, etc.).

Trial and Error, Serendipity, and Pharmacological Renaissance

After the mid-20th century and the decline of pathology in neurology, neuropharmacology became a major focus of research. The history of use of L-Dopa in neurology is an interesting example of this major change [12]. The long and sometimes serendipitous development of antiepileptic drugs is also a good demonstration of the important place occupied by neuropharmacology in this pathology [13]. A chemical conceptualization of the nervous system was developed in parallel to the electrical model of the brain. Many molecules were tested using trial and error, usually based on similarities between the diseases. For example, in 1934, Walker [14] (1888–1974) was the first to try physostigmine in treating patients with myasthenia gravis, based on the fact that the clinical signs of the disease were close to those of curare poisoning. Therapeutic research in neuroscience has also not been exempt from chance, as is frequently the case in medicine and biology. Among other examples, valproate was used only as a solvent until a pharmaceutical company found that all tested agents dissolved in valproate had antiepileptic properties [15]. Another constant in neuropharmacology is the reuse of old drugs in a modified form. The saga of the use of urokinase/streptokinase drugs in stroke treatment between the 1930s and 1990s is a demonstration of this pharmacological “renaissance” [16].

Neurology, Neurosurgery, and Neuroradiology: New Therapeutic Borders

In recent decades, neurosurgery, born in the first third of 20th century, has progressively taken on a new role in the therapeutic arsenal. During a brief period (1930–1950), neurosurgery focused on psychosurgery, with a Nobel Prize awarded to Egas Moniz (1874–1955), who had developed cerebral angiography a few years earlier [17]. Neurosurgery subsequently returned to more conventional aspects and progressively turned to functional surgery, awake brain surgery, and stereotactic surgery. Some specific surgical procedures were developed for the treatment of resistant epilepsy [18].

New 3D-guidance tools, neuronavigation systems, and virtual reality technology have allowed this progressive change and have already transformed many neurosurgical procedures into minimally invasive surgical interventions. Interventional radiology, which has greatly expanded in recent years, has modified the role of neurosurgery in the management of intracranial aneurysms. These paradigm shifts make close collaboration between neurosurgeons, neurologists, and neuroradiologists more necessary than ever. Stroke management using new procedures, such as thrombectomy and intra-arterial thrombolysis, has placed neurologists firmly in the neuroradiology field. Change is on the way. Stroke specialists are now neurologists involved in treating very acute disease with interventional procedures, and the new generations of stroke specialists are now trained in neuroradiological procedures for therapeutic purposes.

The Biotherapy and Oligonucleotide (R)evolution

In neurology, as is often the case in other medical disciplines, there is a gap between the discoveries made in basic research and their clinical applications. Neural transplants and stem cell therapy are prime examples of this. At the turn of the 21st century, hopes of such therapies for patients with Parkinson’s disease have been dashed. Research concerning neurodegenerative disorders and spinal cord injury has been reduced to basic research, with clinical human applications seeming distant. However, in recent decades, the emergence of biotherapies has transformed the field of neurological therapy. The first step toward this kind of therapy was the effective use of intravenous immunoglobulins in treating patients with neuropathies (acute or chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, etc.). Monoclonal antibodies (anti-TNF, natalizumab, rituximab, etc.) have transformed the management of immune-mediated neurological diseases such as multiple sclerosis or myasthenia gravis. Recent pathologic entities, such as autoimmune encephalitis, can also be treated with such therapies.

Some of these new treatments are regarded as near-miraculous drugs [19]. This is also the case for oligonucleotide therapies, which have more recently been used in spinal muscular atrophy [20].

Conclusion

Genetics is now a key to neurological diagnosis and to choosing, for instance, the best therapies in some forms of epilepsy. However, neurologists are not magicians and must keep things in perspective, bearing in mind certain tumors and degenerative diseases for which no effective treatment yet exists. This ineffectiveness is mainly due to a lack of understanding in the pathophysiology of these serious diseases. Some of these uncertainties take us back to the seminal descriptions of Jean-Martin Charcot (1825–1893), who was already questioning the mechanisms of these intractable pathologies.

Acknowledgments

We would like to thank Jennifer Dobson for proofreading this manuscript. Published in Celebration of the 125th Anniversary of the inception of European Neurology 1897–2022.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was obtained for this study.

Author Contributions

Laurent Tatu: design, literature search, and writing of the manuscript. Julien Bogousslavsky: design and supervision of the manuscript.

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