Paraneoplastic Neurological Syndromes: Transitioning Between the Old and the New.

PURPOSE OF REVIEW: Paraneoplastic neurological syndromes (PNS) are caused by nervous system-targeting aberrant anti-tumoral immune responses. We review the updated criteria for PNS diagnosis, incorporating novel information on clinical phenotypes, neuronal autoantibodies (Nabs), and tumors. The impact of the oncologic use of immune checkpoint inhibitors (ICI) on PNS occurrence is also addressed. RECENT FINDINGS: Clinical phenotypes and Nabs are redefined as "high/intermediate/low" risk, following the frequency of cancer association. Nabs, the diagnostic hallmark of PNS, can target intracellular or surface neuronal proteins, with important prognostic and pathogenic implications. Many novel assays have been incorporated into laboratory diagnostics, that is becoming increasingly complex. ICI fight tumors, but favor autoimmunity, thus increasing the incidence of PNS-like disorders. Overcoming the old PNS criteria, the new ones are centered around the presence of tumor. Clinical presentation, Nabs, and tumor findings are translated in diagnostic scores, providing a useful tool for PNS diagnosis and management.

A multimodal imaging approach to foreign accent syndrome. A case report.

This article describes a case of Foreign accent syndrome (FAS) in an Italian woman who developed a Canadian-like foreign accent without brain damage (functional FAS). The patient underwent an in-depth neuroimaging and (neuro)psychological evaluation. Language networks in the frontotemporal-parietal areas were typically activated bilaterally through fMRI and MEG assessments based on task-based data. Resting-state fMRI showed preserved connectivity between language areas. An obsessive-compulsive personality profile and mild anxiety were found, suggesting psychological and psychiatric factors may be relevant. Accordingly with our findings, multimodal imaging is beneficial to understand FAS neurological and functional etiologies.

Camillo Negro (1861-1927) and the "bulbo-palpebral hyperkinetic phenomenon" in peripheral facial palsy.

Camillo Negro (1861-1927) was a leading Italian neurologist and neuropathologist between the nineteenth and twentieth centuries. He is best known for describing the cogwheel sign in Parkinson disease. In an article published in 1906, Camillo Negro described the "bulbo-palpebral hyperkinetic phenomenon": in peripheral facial paralysis, if the patient is asked to look up, the eyeball deviates outwards and elevates farther on the affected side. Negro thoroughly investigated the neuroanatomic and neurophysiological basis of this phenomenon that gained a certain popularity and was reported in several articles and textbooks. This sign retains some utility in peripheral facial palsy to identify a doubtful or very slight impairment of the upper face muscles, which may otherwise go unnoticed. The interest towards the semiology of peripheral facial palsy was shared by Negro's assistant Giuseppe Roasenda (1879-1959), who in 1933 described the incomplete convergence of the eyeballs in this condition.

Adolph Seeligmüller (1837-1912) and the first graphic illustration of the "toe phenomenon" (later called "Babinski sign") in the medical literature.

The "toe phenomenon" refers to the extension (dorsiflexion) of the great toe, which occurs instead of the normal flexion following stimulation of the foot sole. Its clinical significance was not fully appreciated until Joseph Jules François Félix Babinski (1857-1932) described it in 1896. In 1881, Ernst Strümpell (1853-1925) had described a continuous (tonic) extension of the big toe, a finding that years later the French neurologist Jean-Athanase Sicard (1872-1929) recognized as an equivalent of the "toe phenomenon", also indicating pyramidal tract dysfunction. Previously, this phenomenon had been mentioned in patients only passingly and without providing a picture of it. In 1887, the German neurologist Adolph Seeligmüller (1837-1912) mentioned the tonic extension of the big toe among the characteristic clinical features of spastic infantile hemiplegia-a condition first described by the Austrian physician Moritz Benedikt (1835-1920) in 1868. Seeligmüller incorrectly attributed the tonic extension of the big toe to spastic contracture of the extensor hallucis longus muscle. However, he put great emphasis on this sign and considered it worth being illustrated. Adolph Seeligmüller therefore provided the very first graphic illustration of the (tonic) "toe phenomenon" in the medical literature. Of note, the first photographic illustration of this sign made by Babinski appeared only in 1900, when it had already been adopted by neurologists all over the world.

Camillo Negro (1861-1927) and his method for eliciting the extensor toe sign.

The "toe phenomenon", or extensor toe sign, is characterized by the extension (dorsiflexion) of the great toe elicited by plantar stimulation, and indicates pyramidal tract dysfunction. This phenomenon was first extensively described and studied by Joseph Jules François Félix Babinski (1857-1932), who introduced it in clinical practice. In 1912, the famous Italian neurologist Camillo Negro (1861-1927) proposed a new method of eliciting the extensor toe sign by inviting the patient, lying in bed in dorsal decubitus position, to raise the paretic limb with the leg extended on the thigh. This sign appeared during voluntary effort and could not be elicited by raising the unaffected lower limb. Negro was also the first to investigate the influence of cold upon the appearance of the "toe phenomenon" and to propose the use of (faradic) electrical stimulation to evoke it.

Jean-Martin Charcot (1825-1893) and the "Alice in Wonderland syndrome".

The "Alice in Wonderland syndrome" (AIWS) is a neurological disorder characterized by altered body schema perception, visual, or somesthetic symptoms, which is frequently associated with migraine. In this article, we present the earliest known description of symptoms attributable to AIWS in the medical literature. During a lecture held on November 22, 1887, at the Salpêtrière, Jean-Martin Charcot (1825-1893) examined a patient with somesthetic symptoms (partial macrosomatognosia) in the context of migraine with aura. Although this condition was not known at the time, Charcot tried to provide an accurate semiological and nosographic framework of this case, attributing the complex of symptoms to migraine with aura and epilepsy with sensory symptoms. With intellectual honesty and clinical prudence, Charcot correctly pointed to a disturbance in the excitability of cortical areas responsible for processing and perceiving sensory stimuli.

Vincenzo Neri (1880-1960) and his sign to detect leg weakness due to corticospinal tract injury.

The Italian neurologist Vincenzo Neri (1880-1960), a pupil of Joseph Babinski (1857-1932), greatly contributed to refining the semiotics of neurological examination and was a pioneer in medical cinematography. In 1909, Neri proposed a sign to diagnose leg paresis due to a pyramidal tract lesion. According to Neri, if a patient standing with the legs apart and the arms crossed on the chest bends the trunk of the pelvis, when the trunk has almost reached the horizontal line, the leg on the paralyzed side flexes, whereas the unaffected leg remains extended. This sign reflects a spinal hyperfunctioning emerging after a pyramidal lesion, and should be interpreted as a part of a triple flexion reflex. Beyond the acute stage, it could reflect an unusual pattern of flexor spasticity involving the lower limb due to corticospinal tract injury. The sign described by Neri retains its validity in identifying this organic leg weakness due to pyramidal lesions, particularly when it is mild or in its early stages.

Cognitive and behavioral involvement in ALS has been known for more than a century.

BACKGROUND: Among clinicians and researchers, it is common knowledge that, in ALS, cognitive and behavioral involvement within the spectrum of frontotemporal degenerations (FTDs) begun to be regarded as a fact in the late 1990s of the twentieth century. By contrast, a considerable body of evidence on cognitive/behavioral changes in ALS can be traced in the literature dating from the late nineteenth century. METHODS: Worldwide reports on cognitive/behavioral involvement in ALS dating from 1886 to 1981 were retrieved thanks to Biblioteca di Area Medica "Adolfo Ferrate," Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy and qualitatively synthetized. RESULTS: One-hundred and seventy-four cases of ALS with co-occurring FTD-like cognitive/behavioral changes, described in Europe, America, and Asia, were detected. Neuropsychological phenotypes were consistent with the revised Strong et al.'s consensus criteria. Clinical observations were not infrequently supported by histopathological, post-mortem verifications of extra-motor, cortical/sub-cortical alterations, as well as by in vivo instrumental exams-i.e., assessments of brain morphology/physiology and psychometric testing. In this regard, as earlier as 1907, the notion of motor and cognitive/behavioral features in ALS yielding from the same underlying pathology was acknowledged. Hereditary occurrences of ALS with cognitive/behavioral dysfunctions were reported, as well as familial associations with ALS-unrelated brain disorders. Neuropsychological symptoms often occurred before motor ones. Bulbar involvement was at times acknowledged as a risk factor for cognitive/behavioral changes in ALS. DISCUSSION: Historical observations herewith delivered can be regarded as the antecedents of current knowledge on cognitive/behavioral impairment in the ALS-FTD spectrum.

Camillo Negro (1861-1927) and Antonio Carle (1854-1927): Pioneers of non-resective surgical approach to epilepsy treatment.

Epilepsy surgery developed following the clinical and experimental demonstration of the existence of the primary motor cortex in animals and humans. The first epilepsy surgery procedures were mainly performed to treat focal motor (Jacksonian) epilepsy, as the seizure semiology precisely pointed to the contralateral motor cortex (epileptogenic zone), guiding the surgical removal of the visible lesion found in that region. However, mainly in the absence of any visible alteration of brain tissue, the removal of the portion of the cortex supposed to be responsible for the seizures carried the risk of injuring healthy areas of the brain, often resulting in permanent neurological deficits. In 1891, the prominent Italian neurologist Camillo Negro (1861-1927) described a new technique to treat focal epilepsy using galvanic electrical stimulation of the motor cortex to induce selective cortical destruction. The procedure of "cortical electrolysis", initially performed by prof. Antonio Carle (1854-1927), chief surgeon at the Mauriziano Hospital of Turin, aimed at avoiding the risk of hemorrhage and neurological deficits due to the resective surgical procedures, without compromising asepsis. Camillo Negro deserves to be credited as the first to have envisioned a non-resective surgical approach to the treatment of epilepsy, which in its conceptual basis appears nowadays as extraordinarily modern and pioneering. Recent neurosurgical procedures, such as stereoelectroencephalography-guided radiofrequency thermocoagulation and MRI-guided laser-induced interstitial thermal ablation, although based on different technologies, share the same rationale, using minimally invasive epilepsy surgery to reduce tissue disruption and thus morbidity.

"You Are Older, although You Do Not Know That": Time, Consciousness, and Memory in "A Kind of Alaska" by Harold Pinter (1930-2008).

"A Kind of Alaska" is a one-act play by the British playwright and Nobel Prize winner Harold Pinter (1930-2008), based on the book Awakenings by the neurologist Oliver Sacks (1933-2015). This play, first performed in 1982, is centered around the character of Deborah, a middle-aged woman, struck by encephalitis lethargica ("sleeping sickness") at the age of 16, who wakes up after 29 years of apparent sleep following the injection of an unnamed drug. This article analyzes how Pinter's drama investigated the mysterious and fascinating relationship between time, memory, and consciousness. The term "awakenings," chosen by Sacks himself, clearly refers to the restoration of voluntary motor function in patients with postencephalitic parkinsonism who responded to levodopa. However, it also suggests that these patients had an impairment of awareness. Actually, beyond the acute phase, subjects with postencephalitic parkinsonism were not sleeping but severely akinetic and therefore probably aware of the passage of time. Oliver Sacks probably did not entirely recognize the intrinsic contradiction between prolonged sleep (with consequent impairment of awareness and subjective "time gap") of the acute lethargic phase and the severe akinesia with preserved awareness of the time-passing characteristic of postencephalitic parkinsonism. This confusion was further compounded by Harold Pinter in his play.

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe.

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.

Occupational medicine and occupational psychology: a rendezvous in Milan after World War II.

BACKGROUND: In the 1950s, occupational medicine and occupational psychology found a common field of action in the Clinica del Lavoro in Milan. OBJECTIVES This study aims to analyze and document how this encounter took place and, in particular, the contribution of the Clinica del Lavoro to the development of occupational psychology in Italy. METHODS: Historical sources of that period were investigated. RESULTS: Before the 1950s, experimental psychology was only taught at the Catholic University of the Sacred Heart in Milan. The first professor of clinical psychology in the School of Medicine at the State University of Milan, was Marcello Cesa-Bianchi (1926-2018). He collaborated with the graphic, textile and pharmaceutical industries for the personnel training and management, and carried out important research in occupational psychology on behalf of the European Coal and Steel Community. The Chair of Clinical Psychology was initially located in the Clinica del Lavoro and the activity of the team of Cesa-Bianchi was oriented towards the elaboration of professional profiles and job analysis. In those years Cesa-Bianchi also conducted pioneering research in the field of psycho-gerontology. CONCLUSIONS: The historical experience that integrated psychology and occupational medicine in the scientific context of Milan contains a series of values, useful to today's reflection and practice. Our work also undelines the importance of preserving historical documents: only a better knowledge of history can guarantee a better destiny.

Neuroscience without borders: Preserving the history of neuroscience.

Over the last 50 years, neuroscience has enjoyed a spectacular development, with many discoveries greatly expanding our knowledge of brain function. Despite this progress, there has been a disregard for preserving the history of these discoveries. In many European countries, historic objects, instruments, and archives are neglected, while libraries and museums specifically focusing on neuroscience have been closed or drastically cut back. To reverse this trend, the Federation of European Neuroscience Societies (FENS) has organized a number of projects, including (a) the History of Neuroscience online projects, (b) the European Brain Museum Project (EBM), (c) the History online library, (d) the FENS meeting History Corner, (e) history lectures in historic venues, and (f) a series of history seminars in various European venues. These projects aim to stimulate research in, and increase awareness of, the history of European neuroscience. Our seminars have attracted large audiences of students, researchers, and the general public, who have supported our initiatives for the preservation of the history of neuroscience for future generations and for the promotion of interest in the history of neuroscience. It is therefore urgent to develop new methods for preserving our history, not only in Europe but also in the rest of the world, and to increase greatly teaching and research in this important aspect of our scientific and cultural legacy.

[Mobile miniature X-ray evaluation and pneumoconiosis: the role of the Clinica del Lavoro in Milan (1941-1948)]. / La valutazione schermografica delle pneumoconiosis (1941-1948): il ruolo della Clinica del Lavoro di Milano.

Since the end of the 19th century, X-rays have been used to detect lung diseases. In Italy, 207,096 miniature chest radiographs were taken from 1941 to 1948. Traditional radiographs gave better results, but miniature chest radiographs were useful for screening. Indeed, the development of mobile miniature chest radiography units resulted in an improvement in mass X-rays screening for the detection of penumoconiosis. These mobile miniature units were mounted on a bus chassis, a solution that allowed to easily reach workers. The authors analyze some models of X-ray wagon units used by the "Clinica del Lavoro" in Milan in the 1950s. From the point of view of medical museology, the preservation of these devices requires appropriate spaces.

Work and health care in Milan, 1864-1874. / Lavoro e assistenza sanitaria a Milano, 1864-1874.

In 1864 in Milan, Giovanni Rosmini (1832-1896) opened an ophthalmic dispensary for workers. In 1874 this dispensary was transformed into the first ophthalmic hospital of the city. This hospital still exists today. The authors analyze a document that belonged to the lawyer Enrico Rosmini (1828-1898), brother of Giovanni, which helps to piece together the early years of the dispensary, where about 4,000 surgeries were carried out in the first four years of activity. This historical document is valuable as it sheds light on one of the first healthcare institution for workers in Milan.

Between Bouillaud and Broca: An unknown Italian debate on cerebral localization of language.

From 1825 onward, Bouillaud began gathering clinical evidence to support the hypothesis that speech is located in the cerebral frontal lobes. His aim was to provide empirical proof to Gall's theory of a specific substratum of speech in the anterior region of the brain. A well-known discussion ensued inside the French school among supporters and detractors that went far beyond Broca's first report in 1861. Unknown is that Bouillaud's investigations on localization of articulated language also gave rise to a discussion in Italy in the same period. In particular, speech localization formed a central topic in the mid-19th century in Northern Italy mainly thanks to four physicians, Michelangelo Asson, Mosè Rizzi, Gaetano Strambio and Filippo Lussana, who reported on language-impaired patients and approached these cases in the light of Bouillaud's claims. Similarly to the French debate, the Italian medical community also included attacks and advocacies of the hypothesis of a precise localization of articulated language in the frontal lobes. However, they were mainly interested in investigating the anatomo-clinical relationships rather than in supporting Gall's organology. This Italian debate appears to be the first to have developed in the mid-19th century outside that of the French community.

The Neurologist in Dante's Inferno.

The year 2015 marks the 750th birth anniversary of the Italian poet Dante Alighieri (1265-1321). It is less known that Dante had a sound level of medical knowledge, probably derived by his academic studies. In his works, medieval notions of neuroanatomy and neurophysiology (e.g. the connection between brain and spinal cord, function of optic nerve and peripheral nerves, knowledge of vegetative nervous system) and descriptions of neurological disorders (e.g. epileptic seizures, effects on nervous system by metal intoxication, and narcolepsy) may be found, specially in the Inferno, the first part of his masterpiece, the Divine Comedy. These accurate descriptions have led some authors to believe that the poet himself may have suffered from a neurological disease (epilepsy or hypersomnia). Damned souls of the Inferno seem to be also afflicted by psychiatric disorders, such as melancholia and depression. The analysis of Dante's works confirms that poetry - as well as literature in general - may be an important source of information for historians of neurology.

[Industrial first aid equipment: a historical analysis (1840-1914) ]. / Gli strumenti di pronto soccorso in azienda: un'analisi storica (1840-1914).

Even if references to the tools required to intervene after an accident can be found in the works of Bernardino Ramazzini (1633-1714) or Johann Peter Frank (1745-1821), it was only with the development of industrial manufacturing that the need to study means to prevent and intervene in cases of accident became evident. In October 1894 the III Congrés International des Accidents du Travail et des Assurances Sociales was held in Milan. The following year, the Milanese trade union movement acknowledged the necessity to address the problem of industrial accidents. In 1896 the Association for Medical Assistance in  Industrial Accidents was founded in Milan. A specific medical institute was set up, appropriate first aid tools were collected and first aid rooms in the main Milanese factories were inaugurated. Nevertheless, few data seem to be available regarding the manufacture and use of this equipment in industry. We analyzed more than fifty catalogs of European industrial products, between 1843 and 1914, to study the evolution of first aid equipment for industrial use. They reflect and attest to the evolution of medicine and surgery, although some models seem to be related to certain industrial categories (railways, electrical appliances), some were similar to ordinary first aid boxes, others were strictly related to surgery; some could only be used by physicians, and others only by workers. Identification, conservation, and reappraisal of these tools is essential for historians of occupational health because these objects were normally not preserved. The catalogues of industrial production are also precious sources, since they are rarely preserved in public libraries and deserve to be used for historical studies.