Treatments in Neurology: The Winding Road from 1897 to 2022.

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).

Beasts and Gods: Hippocampal quarrels before memory.

The first description and naming of the hippocampus is usually credited to Arantius (c. 1530 - 1589), whose comparison of the swelling inside the temporal horn of the lateral ventricle to a seahorse (hippocampus) or silkworm (bombyx) was published in the 1587 edition of the Anatomicarum Observationum Liber. However, in the 17th century, the term hippocampus was rarely used and its precise anatomy remained a mystery. The 18th century saw the hippocampus referred to as a wide range of animals and divinities. These terminological issues provoked heated discussions in the French Académie Royale des Sciences, culminating in the seminal description of the hippocampus in the 1780s by Félix Vicq d'Azyr (1748-1794). However, it is striking that no hypothesis concerning the function of the hippocampus was proposed, and its link with memory was not established until the mid-20th century.

Charcot, Janet, and French Models of Psychopathology.

Jean-Martin Charcot (1825-1893), thanks to his insight as a clinician can be said to be one of the precursors of scientific psychology. Charcot's 30 years of activity at La Salpêtrière hospital display an intellectual trajectory that decisively changed the idea of human psychology by favouring the emergence of two concepts: the subconscious and the unconscious. It was his collaboration with Pierre Janet (1859-1947), a philosopher turned physician, that led to this evolution, relying on the search for hysteria's aetiology, using hypnosis as a method of exploration. Focusing on clinical psychology that was experimental and observational, Janet built a theory of psychic automatism, "the involuntary exercise of memory and intelligence" leading to "independence of the faculties, freed from personal power." From all that came the idea of the subconscious, a functioning as a passive mental mechanism, resulting from a more or less temporary dissociation of previously associated mental content.

The Merging Tracks of Anosognosia and Neglect.

Anosognosia and hemineglect are among the most startling neurological phenomena identified during the 20th century. Though both are associated with right hemisphere cerebral dysfunction, notably stroke, each disorder had its own distinct literature. Anosognosia, as coined by Babinski in 1914, describes patients who seem to have no idea of their paralysis, despite general cognitive preservation. Certain patients seem more than unaware, with apparent resistance to awareness. More extreme, and qualitatively distinct, is denial of hemiplegia. Various interpretations of pathogenesis are still deliberated. As accounts of its captivating manifestations grew, anosognosia was established as a prominent symbol of neurological and psychic disturbance accompanying (right-hemisphere) stroke. Although reports of specific neglect-related symptomatology appeared earlier, not until nearly 2 decades after anosognosia's inaugural definition was neglect formally defined by Brain, paving a path spanning some years, to depict a class of disorder with heterogeneous variants. Disordered awareness of body and extrapersonal space with right parietal lesions, and other symptom variations, were gathered under the canopy of neglect. Viewed as a disorder of corporeal awareness, explanatory interpretations involve mechanisms of extinction and perceptual processing, disturbance of spatial attention, and others. Odd alterations involving apparent concern, attitudes, or belief characterize many right hemisphere conditions. Anosognosia and neglect are re-examined, from the perspective of unawareness, the nature of belief, and its baffling distortions. Conceptual parallels between these 2 distinct disorders emerge, as the major role of the right hemisphere in mental representation of self is highlighted by its most fascinating syndromes of altered awareness.

Cerebral Hyperperfusion Syndrome and Related Conditions.

Cerebral vasoconstriction is a normal physiological response under determined conditions to preserve a normal cerebral blood flow. However, there are several syndromes, with impaired cerebral autoregulation and cerebral vasoconstriction, not related with infection or inflammation, which share the same radiological and clinical presentation. We review here the cerebral hyperperfusion syndrome and related conditions such as hypertensive encephalopathy, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome. These syndromes might share the same pathophysiological mechanism with endothelial damage, cerebral vasoconstriction, blood-brain barrier disturbance, cerebral edema, and, occasionally, intracerebral hemorrhage, with fatal cases described in all. Despite knowledge of these syndromes, they still remain unknown to us. Why these entities present in some patients and not in others goes further than the actual understanding of these diseases. We have to consider that a genetic susceptibility and molecular disturbances may be involved. Thus, more studies are needed in order to better characterize such syndromes.

The mysteries of hysteria: a historical perspective.

Jean-Martin Charcot started his main work on hysteria around 1870, until his death in 1893. Désiré Bourneville had triggered Charcot's interest in hysteria during his stay as an interne in his department, while Charles Richet's 1875 article on somnambulism was the trigger for Charcot to develop hypnotism. Charcot's collaborators Paul Richer, Georges Gilles de la Tourette, Paul Sollier, Joseph Babinski, Sigmund Freud and Pierre Janet subsequently became most famous in hysteria. In 1908, a "quarrel of hysteria" opposed several of Charcot's pupils, from which Babinski, who had developed the concept of "pithiatism", was considered victorious against Charcot's first successor Fulgence Raymond. There was a surge of interest in hysteria associated with war psycho-neuroses in 1914-1918, and Babinski's pupil Clovis Vincent developed a treatment called torpillage (torpedoing) against war hysteria, associating painful galvanic current discharges with "persuasion". After World War I, the neurological and psychiatric interest in hysteria again faded away, before a renewed interest at the turn of the last century. Contrary to a common view, the modernity of several of Charcot's concepts in hysteria is remarkable, still today, mainly for: (1) his traumatic theory, which encompassed psychological and certain sexual factors several years before Freud; (2) his personal evolution towards the role of emotional factors, which opened the way to Janet and Freud; (3) his claim of specific differences vs. similarities in mental states such as hypnotism, hysteria, and simulation, which has recently been confirmed by functional imaging; and (4) his "dynamic lesion" theory, which now correlates well with recently established neurophysiological mechanisms.

Édouard Manet's Tabes Dorsalis: From Painful Ataxia to Phantom Limb.

Édouard Manet (1832-1883) is considered the 'father' of Impressionism and even of XXth century modern art. Manet's genius involved getting away from the classical narrative or historical topics and replacing them by the banality of daily life. Technically, he erased volumes into flat two-dimensional coloured planes, and distorted conventional perspective with often gross brushstrokes intentionally giving an 'unfinished' aspect to the work. It is little known that Manet had a very painful second part of his life, due to excruciating limb and chest pains, which developed in parallel with proprioceptive ataxia and gait imbalance. Manet always remained discreet about his private life, and we mainly know that his future wife was his family piano teacher, with whom he had a liaison already at age 17. Later, the great but platonic passion of his life was the painter Berthe Morisot (1841-1895), who got married to Manet's brother Eugène. In fact, we do not know whether he had any mistress at all, although he had several elegant 'flirts' in the mundane and artistic milieu. Thus, while Manet's progressive painful ataxia from age 40 yields little doubt on its tabetic origin, how he contracted syphilis at least 15-20 years before will probably remain a mystery. It is fascinating that Manet's daily struggle against pain and poor coordination may have led his art to become one of the most significant of modern times, opening the way to XXth century avant-gardes, along with another victim of syphilis, Paul Gauguin (1848-1903). Manet never showed any sign of General Paresis, and like his contemporary the writer Alphonse Daudet, his clinical picture remained dominated by paroxysmal pain and walking impairment. Difficult hand coordination made him quit watercolor painting, and during the last 2 years of his life, he had to focus on small format oil works, whose subject was nearly limited to modest bunches of fresh flowers, now often considered to be his maturity masterpieces. Having become bedridden, he had to be amputated of one leg, which was developing gangrene probably associated with ergot overuse. While he died shortly thereafter, we have some witness anecdotes suggesting that he experienced a phantom limb: when Claude Monet (1840-1926) visited him and sat down on his bed, Manet violently shouted at him that he was just sitting on his (absent) leg, which provoked terrible pains. With its facts and mysteries, the subtle interaction between Manet's illness and his work output remains one of the most intriguing stories in neurology of art.

Antithrombotic therapy in carotid artery stenosis: an update.

Carotid stenosis is generally associated with high risks of stroke and vascular events. In asymptomatic and symptomatic patients, with or without revascularization, optimal managements of carotid artery stenosis require the use of medications or lifestyle modifications (stopping smoking and monitoring hypertension, hyperlipidemia, and diabetes) to control the processes associated with atheroma to reduce the risk of embolic events. Moreover, antiplatelet therapy should be considered. There is little evidence that antiplatelet therapy is beneficial in preventing stroke or the progression of stenosis in asymptomatic patients, whereas, evidence of a benefit from antiplatelet therapy for secondary prevention of recurrent stroke in symptomatic patients with carotid atherosclerosis is more robust. Also, in patients undergoing carotid endarterectomy, perioperative antithrombotic therapy should include aspirin, while the addition of clopidogrel should be decided case-by-case. Furthermore, perioperative antithrombotic therapy in patients undergoing carotid stenting should consist a combination of aspirin plus clopidogrel.

Post-stroke fatigue: epidemiology, clinical characteristics and treatment.

Fatigue is a disabling and persistent symptom affecting many stroke survivors and is a predictor for death after stroke onset. Post-stroke fatigue is a multidimensional motor-perceptive, emotional and cognitive experience that has become of interest for stroke researchers only in the recent past. More studies are still needed to understand the pathophysiology, clinical characteristics, associated factors and best treatment strategy. The aim of this narrative review was to provide a comprehensive knowledge, from current literature, regarding the epidemiology, clinical characteristics and treatment of fatigue in order to provide physicians with better tools for treating this debilitating symptom that worsens outcome.

Charcot's international visitors and pupils from Europe, the United States, and Russia.

The foundation by Jean-Martin Charcot (1825-1893) of the Salpêtrière School in Paris had an influential role in the development of neurology during the late-nineteenth century. The international aura of Charcot attracted neurologists from all parts of the world. We here present the most representative European, American, and Russian young physicians who learned from Charcot during their tutoring or visit in Paris or Charcot's travels outside France. These include neurologists from Great Britain and Ireland, the United States, Germany and Austria, Switzerland, Russia, Italy, Spain, Belgium and the Netherlands, Scandinavia and Finland, Poland, Bohemia, Hungary, and Romania. Particularly emblematic among the renowned foreign scientists who met and/or learned from Charcot were Charles-Edouard Brown-Séquard, who had interactions with Paris University and contributed to the early development of British and American neurological schools; John Hughlings Jackson, who was admired by Charcot and influenced French neurology similarly as Charcot did on British neurology; Silas Weir Mitchell, the pioneer in American neurology; Sigmund Freud, who was trained by Charcot to study patients with hysteria and then, back in Vienna, founded a new discipline called psychoanalysis; Aleksej Yakovlevich Kozhevnikov and almost all the founders of the Russian institutes of neurology who were instructed in Paris; and Georges Marinesco, who established the Romanian school of neurology and did major contributions thanks to his valuable relation with Charcot and French neurology.

Effectiveness, Safety and Patients' Satisfaction of Nabiximols (Sativex®) on Multiple Sclerosis Spasticity and Related Symptoms in a Swiss Multicenter Study.

Background: Cannabinoid oro-mucosal spray nabiximols is approved for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other antispastic medications. Few real-world data are available on the effectiveness, safety and patients' satisfaction in MS patients treated with nabiximols as monotherapy. Methods: To investigate the effectiveness, tolerability and satisfaction of nabiximols in a real-life multicentric Swiss cohort as monotherapy or with stable doses of other antispastic medications, and explore clinical features which may predict treatment response. The following data were collected at treatment start (baseline) and 12 weeks thereafter: Modified Ashworth scale (MAS), scores at numerical rating scales ranging from 0 (absent) to 10 (considerable) for effect on spasticity (sNRS), pain (pNRS), gait (gNRS), urinary symptoms (uNRS), tolerability (tNRS) as assessed by the treating neurologist, and overall treatment satisfaction (TsNRS) and tolerability (tNRS) as assessed by the patient. Results: Ninety-five patients (44 relapsing remitting, 37 secondary progressive and 14 primary progressive MS; median age = 53 (IQR 45-62); female 70%; median EDSS 6 (IQR 4-6), concomitant antispastic treatments in 54% of patients) were included. From baseline to week 12, median MAS score decreased from 3.0 to 2.0 (p < 0.001). Median scores of the each NRS also significantly decreased (p < 0.001 for all comparisons). At week 12, the median TsNRS and tTS scores were 8/10 (IQR: 6-9) and 9/10 (IQR: 7-10), respectively, and 93.7% of patients continued to use nabiximols at the average dose of six sprays/day. No clinical factors, including use of nabiximols as add on vs. monotherapy, were associated with responder status. Conclusions: Our first Swiss, multicentric, observational, real-life study supports and enhances previous finding of nabiximols as monotherapy and as add-on therapy, being an effective, safe and well-tolerated treatment option for resistant MS spasticity and spasticity-related symptoms (pain, bladder dysfunction and gait).

Neurology and surrealism: André Breton and Joseph Babinski.

Before he became the initiator of the surrealist movement, André Breton (1896-1966) studied medicine and worked as a student in several hospitals and as a stretcher bearer at the front during World War I. There he became interested in psychiatric diseases such as hysteria and psychosis, which later served as a source of inspiration for his surrealist writings and thoughts, in particular on automatic writing. Breton worked under Joseph Babinski at La Pitié, nearby La Salpêtrière, and became impressed by the 'sacred fever' of the famous neurologist. In this article, we describe the relationship between Breton and Babinski and try to trace back whether not only Breton's psychiatric, but also his neurological experiences, have influenced surrealism. We hypothesize that Breton left medicine in 1920 partly as a consequence of his stay with Babinski.

Stroke and patent foramen ovale in young individuals.

The importance of patent foramen ovale (PFO) has long been discussed in the literature in relation to different coexisting medical conditions. Many researchers focused on the occurrence of PFO in ischemic stroke patients, especially in the subgroup of young patients with a recurrent event. Unfortunately, before establishing a clear significance of PFO and right-to-left shunting (RLS) in pathogenesis of cerebrovascular disorders, multiple interventional trials have been launched, aimed at PFO closure in heterogeneous populations of patients. Moreover, some closure devices were granted at least partial approval by regulatory agencies for this indication. There is a need for large and unbiased epidemiological studies assessing the role of RLS through the PFO in ischemic stroke. All patients with recurrent ischemic events and PFO should be assessed by multidisciplinary teams, including a stroke neurologist, and all potential and rare causes of stroke should be considered before any decision for closure is made.

'Distorteidolias' - fantastic perceptive distortion. A new, pure dorsomedial thalamic syndrome.

The role of the thalamus in the pathogenesis of the visual and auditory hallucinations has been reported under the name of peduncular hallucinosis, usually with coexisting midbrain involvement. These hallucinations typically take the form of dreamy de novo productions (phanteidolias), less often that of transformations of perceptions into new items (such as seeing faces in clouds) called pareidolias. However, hallucinations taking the form of a complex distortion of perception is a different phenomenon, which to our knowledge has not been reported. We studied 2 patients with complex, 'fantastic', perceptive distortion involving the visual and auditory systems after thalamic stroke limited to the region of the dorsomedial nucleus, sparing the intralaminar nuclei and the midbrain (explaining the lack of disorders of consciousness and confusional state). Our patients reported the modification of usual stimuli (face, body, voices) into unreal, fantastically distorted perceptions (monstrous change of shapes or sounds without appearance of new items). While the exact mechanism leading to such perceptive distortions remains unknown, a release phenomenon due to damage to the dorsomedial thalamus (probably affecting cholinergic system) responsible for a disinhibition of cortical function involved in familiarity of perception seems likely. We suggest that these hallucinations should be called 'distorteidolias'.

Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial.

INTRODUCTION: Patients with unknown stroke onset are generally excluded from acute recanalisation treatments. We designed a pilot study to assess feasibility of a trial of perfusion computed tomography (PCT)-guided thrombolysis in patients with ischemic tissue at risk of infarction and unknown stroke onset. METHODS: Patients with a supratentorial stroke of unknown onset in the middle cerebral artery territory and significant volume of at-risk tissue on PCT were randomized to intravenous thrombolysis with alteplase (0.9 mg/kg) or placebo. Feasibility endpoints were randomization and blinded treatment of patients within 2 h after hospital arrival, and the correct application (estimation) of the perfusion imaging criteria. RESULTS: At baseline, there was a trend towards older age [69.5 (57-78) vs. 49 (44-78) years] in the thrombolysis group (n = 6) compared to placebo (n = 6). Regarding feasibility, hospital arrival to treatment delay was above the allowed 2 h in three patients (25%). There were two protocol violations (17%) regarding PCT, both underestimating the predicted infarct in patients randomized in the placebo group. No symptomatic hemorrhage or death occurred during the first 7 days. Three of the four (75%) and one of the five (20%) patients were recanalized in the thrombolysis and placebo group respectively. The volume of non-infarcted at-risk tissue was 84 (44-206) cm(3) in the treatment arm and 29 (8-105) cm(3) in the placebo arm. CONCLUSIONS: This pilot study shows that a randomized PCT-guided thrombolysis trial in patients with stroke of unknown onset may be feasible if issues such as treatment delays and reliable identification of tissue at risk of infarction tissue are resolved. Safety and efficiency of such an approach need to be established.