2. The Era of Charcot and Contemporary Clinicians

Not Just Charcot—A Leader but also a Team

«Il y a un affaiblissement marqué de la mémoire; les conceptions sont lentes; les facultés intellectuelles et affective émoussées dans leur ensemble. Ce qui paraît dominer chez les malades, c’est une sorte d’indifférence presque stupide à l’égard de toutes choses. Il n’est pas rare de les voir tantôt rire niaisement, sans aucun motif, et tantôt, au contraire, fondre en larmes sans plus de raison.–Il n’est pas rare non plus de voir éclater, au milieu de cet état de dépression mentale, des troubles psychiques qui revêtent l’une ou l’autre des formes classiques de l’aliénation mentale»

Charcot’s role in defining the fundamental characteristics of MS has been emphasized so clearly and frequently that there is no need to reiterate it. Regarding his identification of the presence of cognitive disorders, many the recent reports on this aspect of MS begin with the recognition of what Charcot established, based on clinical evaluation alone, more than 150 years ago [26,27]^[19][20]. It is relevant to underline the role of Charcot’s lifelong friend, Edmè Felix Alfred Vulpian (1826–1887) [28^[21][22],29], in the development of the anatomo-clinical correlation method that led to the separation of MS from other diseases of the central nervous system, particularly from Parkinson’s disease [30]^[23]. Between 1865 and 1866, Charcot and Vulpian took turns describing various aspects of the “new” pathological entity. According to Bourneville and Guérard [31]^[24], Charcot and Vulpian were aware of the descriptions made by Turck, Rokitansky, Frerichs, Valentiner, and others. Regarding Valentiner, Charcot emphasized the lack of a rigorous approach to grouping cases. It can also be said that Vulpian contributed, on par with Charcot, to identifying cognitive disturbances as one of the hallmarks of the disease. As reported by Ross [32]^[25] who, in turn, cites Ballet [33]^[26], Vulpian seemed to have understood that the mental symptoms were inconstant, irregular, and polymorphic, as were the lesions, which were found in autopsies at the time and are identified today using MRI. Charcot’s description evidently spread rapidly: as soon as 1870, in the United States, Clymer [34]^[27] published a long report on the “new” disease. He adhered to the subdivision of MS into cerebral, spinal, and cerebro-spinal forms, believing that memory and intelligence problems occurred as the disease progressed in the cerebro-spinal cases, up to the loss of the latter. He also affirmed that an intellectual weakening could already be present at an early stage. However, Clymer’s report could have had a scarce diffusion; the uncertain place of mental disorders caused by diseases such as MS, of proven “organic” origin [35]^[28] in the American medical world, could also have had a role. Another pioneer of the recognition of MS as a specific disease in the USA was Edward Seguin (1878), who is also credited with the first use of the name “multiple sclerosis” [36,37]^[29][30]. Moreover, as reported by Butler et al. [35]^[28], various prominent English clinicians, such as Wilks [38]^[31], Gowers [39]^[32], and Bury [40]^[33], in a period of about 30 years, placed the mental disorders of MS in a secondary position. In England, in a first-described case [41]^[34], Moxon reported “a weakened intellect”. In his subsequent descriptions of MS cases [42]^[35], mention is also made of possible cognitive deficits. Once again, however, it is not easy to establish whether these are the aspects that we currently consider cognitive or not, or whether they were the emotional and affective disorders that emerged more sensationally. Clymer [34,42]^[27][35] is positioned in the conceptual line that considered affective and cognitive disorders together (according to Richardson et al. [5]^[1]).

3. From Charcot to the 1980s

The Alternation of Points of View

At the beginning of the twentieth century, the vision of the exceptional nature of cognitive disorders in MS patients does not seem to change substantially. The reports of MS cases insisted on atypicality or exceptionality or hypothesized the superimposition of other pathological conditions to explain the occurrence of mental symptoms. For example, Cestan and Philippe, as reported by Walusinski [43]^[36], considered cognitive disturbances (the impairment of memory and intellectual abilities) to be frequent only in the advanced stages of the disease; rather, they emphasized euphoria and the pseudobulbar affect. The report by Ross [32]^[25] in The Review of Neurology and Psychiatry is quite representative of the opinions of most contemporary clinicians regarding “mental” disorders in MS. In the introduction, Ross reported that the “occasional presence of mental symptoms in disseminated sclerosis is recognized by all authorities”, even if there was no agreement on their frequency. Charcot, Raecke, and Seiffer are cited as supporters of a high percentage of occurrence. Ross then illustrated 5 cases identified at the Royal Edinburgh Mental Hospital as the only 5 among the 750 hospitalized. This confirms other reports of the rarity in of the mental symptoms that would have led to hospitalization in an asylum in MS. Of the five cases described, only one showed a clear and relevant impairment of cognitive functioning, including a working memory deficit (arithmetic calculation). Two had mild cognitive impairment. However, psychiatric disorders prevailed, and this justified the admission to the Mental Hospital. This report from a small cohort is additionally useful because it re-proposes the inclusion, without any distinction, of psychiatric disorders and cognitive deficits in an indistinct group of mental disorders. In the discussion, Ross focuses, above all, on aspects such as sclerotic euphoria and on what we currently call pseudobulbar affect. Ross states that other authors had underlined the presence of cognitive impairments. Following Oppenheim’s Textbook on Nervous Diseases, it is mentioned that Seiffer and Daunenberger attributed a peculiarity, calling it “polysclerotic dementia”, to the cognitive and behavioral impairment found in MS patients. Another interesting quote made by Ross is that Seiffer attributed the mental disorders to the pathological (brain sclerotic) process caused by the disease. In the period between the end of the 19th century and the First World War, considering also the descriptions of Wilks [38]^[31], Bury [40]^[33], and Gowers [39,44]^[32][37] as well as that of Ross [26]^[19], the following can be said about cognitive disturbances: (1) they were considered mild and rare or unusual by the majority, or frequent by a minority; (2) some considered cognitive disorders a reaction to the disease; (3) in the advanced forms, the mental deterioration could be severe; and (4) the conjunction between affective–emotional disturbances and cognitive disturbances persists. In the years following the end of the First World War, greater attention to cognitive impairments in MS seemed to emerge: Jeliffe [45]^[38] identified frequent difficulties in formulating thought, attentional processes, and memory; Sachs and Friedman [46]^[39] established, using a statistical approach, that 15.6% of a sample of 141 cases had mental changes. As highlighted by Butler et al. [35]^[28], the vagueness of the term “mental changes”, together with other limitations, did not allow for any generalizations. Brown and Davis [47]^[40] believed that cognitive impairments (mental deterioration) may or may not have occurred and were, for the most part, mild; they believed that these impairments would progress to varying degrees from case to case and, even in the advanced stages of the disease, severe deterioration was occasional. Bohmig [48]^[41] examined a large sample of patients (318) with MS and carried out a statistical analysis of their characteristics, finding psychological problems in only 14 subjects. Two reports published 1926 and 1929, respectively, represented a relevant methodological progress but, paradoxically, they hold two essentially opposite points of view. Cottrell and Wilson [49]^[42] concluded, on the basis of the collected data, that affective disorders had such a significant frequency that they should be considered even more pathognomonic than the symptoms of Charcot’s triad. On the contrary, more strictly cognitive disorders should be considered very rare. The study has undoubted merits: it was the fruit of a close cooperation between a neurologist and a psychiatrist, and it was the first systematic examination of a large sample, enrolled according to random criteria, to use a formal questionnaire. A summary of previous studies reveals that some argued for a high [45,50,51]^[38][43][44] and others for a low frequency of cognitive disorders [47,48,52,53]^{[40][41][45][46]}. Additionally, there was one study that did not distinguish between cognitive deficits and mental disorders [54]^[47]. The study obviously has weaknesses when evaluated with current parameters. The questionnaire used did not contain questions on cognitive state (memory, attention, etc.) and, as it was based on self-reporting, suffered from the inadequate awareness of some deficits by the patients themselves. The affirmation of the rarity of cognitive disorders (only two cases), apart from being inaccurate (the authors wrote that, in a small number of cases, attention was below normal levels), seems to have been based on a clinical evaluation rather than on collected data, as in the case of psychic and affective alterations. In any case, Cottrell and Wilson’s work had a significant influence over the following decades and was substantially replicated by Sugar and Nadell [55]^[48]. The second study is that of Ombredane [56]^[49]. It is considered by many to be the forerunner of the methodologically modern evaluation of cognitive and affective status of MS patients. Another advancement was the attempt to exclude, with the methods available at the time, possible diagnostic confusion with neurolue. Berrios and Quemada [57]^[50] highlighted the limits and merits of Ombredane’s work on the basis of current diagnostic criteria and with the aid of a statistical approach. On one hand, the limits include the questionable location of some symptoms (fatigue among cognitive disorders and fatalism among affective ones) and the inconsistency of the conclusions with the data as such. On the other hand, the merits include the identification of a category of variables that correspond to what are now considered cognitive disorders, having brought cognitive disorders out of the grouping with affective-emotional disorders, and to have excluded their reactive nature. The favor Ombredane’s work met in France, and possibly throughout Europe, brings us back to what has already been stated about other studies: hypotheses and data receive a different reception based on the predisposition of the scientific and social environment in which they are presented. As mentioned above, the study of Sugar & Nadell [55]^[48] represented a verification of the work of Cottrell and Wilson with a very similar conceptual approach, even if the semi-structured interview method was not used. Notwithstanding the differences in the frequency of the various disorders between Sugar and Nadell and Cottrell and Wilson, the overall picture speaks in favor of a considerable frequency of affective disorders. The differences are an increase in optimism and an increase in pessimism, moving in the opposite direction in the two surveys, and the loss of emotional control, which was much higher in the Cottrell and Wilson study than in the Sugar and Nadel study. The first discrepancy is attributed to the different durations of the illness or different frequencies in the feeling of well-being between the two samples. A work by Canter [58]^[51], which is perhaps not quoted often enough, presented several interesting points. There was a definition of psychological deficit, derived from a direct comparison between a previous performance and the current one. In Canter’s study, this comparison was possible for 23 of the 47 enrolled subjects, thanks to the availability of an examination with the same instrument, made years before (the Army General Classification Test-AGCT). In addition, all 47 subjects included in the study were subjected, 6 months apart, to two assessments with the Wechsler–Bellevue Intelligence Scale. For the latter scale, the deterioration index was calculated. This index, and the difference in the scores of the two evaluations with the AGCT, were considered direct measures of the presence of a psychological deficit. The subjects were also evaluated with other instruments, and their results were considered indirect measures of the occurrence of psychological deficits. In addition to the group of MS patients, a group of 38 healthy control subjects underwent evaluations. Based on the results, some aspects were considered which would receive attention many years later: that (a) psychological (cognitive) deficits tend to progress over time; (b) the time interval required to highlight the aforementioned progression is years, while for shorter intervals (e.g., 6 months), there is substantial stability in cognitive performance; (c) deficits can be brought to light with the use of various tools; (d) statistical analyses and, therefore, the use of group studies (also considering a control group), allows the acquisition of more informative data than the evaluation of individual cases; and (e) on the basis of the data obtained in the sub-tests of the batteries used, the possibility that there are deficits in specific aspects of cognitive functioning is taken into consideration; some of these features correspond to deficits currently considered to be prevalent in people with MS. Canter’s study certainly had limitations. These include, first, the use of tools that have been replaced by others considered more specific in relation to the potential deficits of MS patients. Another limitation is that all patients, except one, were male (as much more recent studies have shown, MS male patients have a higher risk of cognitive impairment) [59]^[52]. The work of Jambor [60]^[53] can be considered a further advance. It was published in the same issue of the British Journal of Psychiatry, which also contained Surridge’s paper [61]^[54] and was dedicated to the evaluation of psycho-affective disorders. This work was a further index of the awareness that cognitive and affective–emotional disorders could and should be separated. The aims of Jambor’s study were to assess whether there were impairments in intellectual efficiency in MS patients, to what extent these impairments existed, and with what pattern they presented (the latter aspect was, perhaps, proposed for the first time in these terms). A series of tools were used. These were divided by cognitive areas, with coverage of the main ones. The evaluation of signs indicative of organic involvement was also proposed. In addition to MS patients (divided between patients without (77) and with (26) mood disturbance, for a total of 103 patients), three control groups were examined (79 healthy subjects, 35 patients with psychiatric disorders (mood disorders), and 37 patients with muscular dystrophy). These choices were justified by the impossibility of identifying a single group that would allow for the control of the organic and functional aspects of MS and those that could affect cognitive performance. The statistical approach appeared adequate to the objectives of the study. The results of the study supported the hypothesis that MS patients have a significantly lower intellectual efficiency than control subjects, with worse performance in several domains: in particular, memory and non-verbal conceptualization and, to a lesser extent, spatial ability and speech functions. It is surprising that MS patients without depression have a greater impairment compared to those with depression. The author, also based on the performance of psychiatric patients, supported the independence of cognitive deficits from mood disorders. A comparison with patients with muscular dystrophy confirmed that cognitive deficits are due to central nervous system damage. It emerged that the impairment affects various and different cognitive areas. The attribution of memory deficits to the prevalent localization of focal lesions in the periventricular regions is interesting. The author pointed out the evidence of the differentiation between verbal and non-verbal conceptualization as a striking result. More recent studies (see [26]^[19], for a summary) have not confirmed some of the findings obtained by Jambor (e.g., the absence of influence of mood disorders on cognitive performance) and the relative conclusions reached by the author; other results have been confirmed and expanded. The merit remains of having conducted a study with specific purposes, of having examined a sample of significant size with a methodology ahead of its time, and of having considered the need for comparable control groups for one or another aspect of MS. Eighteen years elapsed between Canter’s and Jambor’s papers. Afterwards, in the 1970s, the frequency of studies specifically investigating cognitive disorders in MS slowly grew. Only six papers can be found by searching PubMed for publications whose title and/or abstract contains the terms “multiple sclerosis” and “cognitive,” in the interval of 1970, January/1980, December. Three of these papers can be considered specific. Another paper can be found using the words “neuropsychological” and “multiple sclerosis”. In order of time, Matthews et al. [62]^[55] compared the performance of MS patients on cognitive, sensory–motor tasks and personality tests with the performance of patients with other neurological conditions. The results showed that MS patients differ from those with other neurological pathologies only in tests of motor speed, steadiness, and fine coordination; for cognitive performances, deficits in non-verbal, conceptual abstraction, attention, and speech-perception tasks were identified, but no significant differences were found between the MS patients and neurological patients. Reitan et al. [63]^[56] investigated the respective roles of motor and cognitive deficits in 30 individuals with MS, noting the prevalence of motor versus cognitive impairments. Beatty and Gange [64]^[57] highlighted the presence of memory deficits and put forward hypotheses, both on the most affected stage of the memorization process and on the relationship between cognitive deficits and motor deficits. Peyser et al. [65]^[58] aimed to establish whether the evaluation of cognitive functions using specific tests could have a diagnostic value, and to establish the independence of cognitive deficits from physical impairment, the degree of neurological involvement, and depression; the clinical evaluation proved decidedly imprecise. One peculiar aspect of this study is the hypothesis that cognitive deficits are the consequence of focal lesions of the subcortical white matter. These works, therefore, begin to pose specific questions. The limited number of subjects examined does not allow us to establish the frequency of impairments and advises caution in generalizing the conclusions. Using the same search strategy for the period 1981–1990, 56 papers are found. Of these, 15 articles were published in 1990 and 1989, while the other 26 were published between 1984 and 1988. The end of the decade seems to have been characterized by a significant increase in interest in the cognitive function of people with MS. Moreover, as previously mentioned, in 1991, we entered the current situation for research on MS and cognitive disorders with the studies of Rao et al. [66]^[59]. The most significant works of the 1981–1990 period are: a study by Rao et al. [67]^[60], which evaluated memory impairment in patients with chronic–progressive forms of MS; a review, also by Rao [68]^[61], on the neuropsychology of MS; the studies by Rao and Hammeke [69]^[62], Kaplan [70]^[63], Peyser [71]^[64], and Medaer et al. [72]^[65], who examined, from various viewpoints, the problems of assessing cognitive functioning in patients with MS; the study by Heaton et al. [73]^[66], which compared the performance of patients with relapsing–remitting courses and progressive courses, identifying a significantly greater impairment in the latter group; the studies of Lyon-Caen et al. [74]^[67] and van der Burg et al. [75]^[68], who evaluated cognitive functioning in patients with recent onset of MS or with clinically isolated syndromes: these studies showed that some cognitive impairments may occur already in the early stages of the disease; the study by Rao et al. [76]^[69], focusing on the nature of memory impairment, which suggested a prevalent impairment in accessing the information stored in memory as opposed to encoding difficulties and limitations in storage capacity. This hypothesis was questioned by subsequent research, which seems to support the hypothesis of encoding difficulties [77]^[70]; early work attempting to correlate cognitive impairments with CT or MRI lesion locations [78,79,80,81,82,83]^{[71][72][73][74][75][76]}; yet another study by Rao et al. [84]^[77] that evaluated information-processing speed; the papers of Beatty et al. [85,86,87,88]^{[78][79][80][81]} and of Jennekens-Schinkel et al. [89,90,91,92,93,94]^{[82][83][84][85][86][87]}; and the paper by Minden et al. [95]^[88] that again investigated the nature of memory impairments and their relationship with demographic and clinical variables. Finally, there were neuropsychological research guidelines by Peyser et al. [96]^[89]. Two aspects can be underlined based on the works of the 1980s: the refinement of the methodology due to an ever-greater reference to the dictates of clinical and experimental neuropsychology, with the consequent proposal of increasingly targeted questions; and the arrival of neuroimaging, with investigative possibilities that were unimaginable only a few years earlier.