Polineuropathy due to chronic use of statins

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Rev Bras Neurol. 51(3):61, 2015

Editorial

Professor Helcio Alvarenga

Em 29 de agosto faleceu o Professor Helcio Alva-renga, perdendo a Neurologia brasileira um dos seus integrantes mais exemplares. Conheci-o na década de 1960, jovem cheio de vigor, com expressivo conhe-cimento em clínica neurológica e em clínica médica. Destemido, cuidava de Enfermarias e de um concor-rido Ambulatório do então Instituto de Neurologia da Universidade do Brasil. Amigo dos residentes e dos médicos jovens, foi capaz de viajar comigo de automóvel, um Fusca, para Ribeirão Preto, em 1964, a fim de assistir ao primeiro Congresso Brasileiro de Neurologia. Viajando para Paris em 1965 a fim de estagiar na Salpêtrière, foi novamente generoso, permitindo que o substituísse no Ambulatório de Neurologia do Instituto de Aposentadoria e Pensões dos Bancários, uma entidade pública de alto nível de atendimento médico. Cumpriu um fantástico está-gio em Paris, em Neurologia e em Neuropediatria, e, com suas anotações e sua prodigiosa memória, delei-tava os amigos e os residentes com a expressão de seu conhecimento e seu humor, algumas vezes crítico, mas sempre não rancoroso. Fez teses brilhantes, com pioneirismo, como a da Síndrome de Hakim-Adams, com prefácio do próprio Prof. Hakim e comentários do Prof. Adams, e também mais tarde a tese para Professor Titular, sobre o tema ataxia-telangiectasia,

a Doença de Louis Bar. Ao início do processo elei-toral para escolha de dirigentes na UFRJ, ao final da década de 1980, tornou-se Diretor do Instituto de Neurologia Deolindo Couto (INDC) da UFRJ, participando de sua administração e condução aca-dêmica. Nas sessões clínicas das sextas-feiras, além das magistrais conclusões dos casos, entremeava com expressões humoradas e questionamentos de com-portamentos sociais então nascedouros na socieda-de brasileira. Alvarenga foi sempre um Professor na acepção mais correta e adequada da palavra. Dedica-va muito de seu tempo à leitura e atualização de seus conhecimentos. Seu casamento com Regina, após se conhecerem no INDC, foi a amálgama para o desen-volvimento de uma família com três filhos dedica-dos à Saúde, todos com alta qualificação profissional, dois dos quais neurologistas de sucesso. Perdemos todos: a família, a Neurologia, as escolas e as socieda-des de Medicina das quais fez parte, e eu, que perdi um amigo, que embora afastado nos últimos anos, sempre foi uma pessoa de minha admiração e a qual tenho muita gratidão.

José Luiz de Sá CavalcantiDiretor do INDC

62Revista Brasileira de Neurologia » Volume 51 » Nº 3 » jul - ago - set 2015

Rev Bras Neurol. 51(3):62-8, 2015

1 Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.2 Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil.

Address for correspondence: Dra. Gisele Schenkel de Moura Leite Neves. Programa de Epilepsia do Instituto de Neurologia Deolindo Couto da Universidade Federal do Rio de Janeiro (UFRJ). Av. Venceslau Braz, 95, Botafogo – 22290-140 – Rio de Janeiro, RJ, Brazil. E-mail: [email protected]

Insomnia current diagnosis: an appraisal

Diagnóstico atual de insônia: uma apreciação

Philippe Joaquim Oliveira Menezes Macêdo1, Gisele Schenkel de Moura Leite Neves1, Dalva Lucia Rollemberg Poyares2, Marleide da Mota Gomes1

RESUMOA insônia crônica é o transtorno do sono mais comum em adultos, e seu diagnóstico é fundamental para o manejo clínico adequado. O principal objetivo deste trabalho é apresentar, em relação à insô-nia, as definições publicadas recentemente segundo as novas classi-ficações internacionais, como a Classificação Internacional de Distúr-bios do Sono – Terceira Edição e o Manual Diagnóstico e Estatístico de Transtornos Mentais – Quinta Edição. Pela primeira vez, essas classificações são congruentes a respeito de seus critérios diagnós-ticos, pois ambas apresentam a insônia como uma doença em si e a dividem em aguda, crônica e outras. Isso enfatiza a necessidade de uma abordagem específica da insônia. Além do mais, é necessá-rio reconhecer os insones com estado fisiológico de hiperalerta que podem ser identificados por medidas objetivas (tempo total de sono curto, por exemplo). Esses pacientes podem ter pior prognóstico, por causa do maior risco de desenvolver condições cardiometabólicas e comprometimento neurocognitivo. O diagnóstico da insônia é feito principalmente com base em dados clínicos (anamnese e exame fí-sico), e o uso de diário de sono e questionários (tais como o Índice de Gravidade de Insônia) pode ajudar na avaliação desses pacientes. Análises objetivas, como aquelas obtidas pela polissonografia, não são rotineiramente necessárias na maioria dos casos, exceto quando há a suspeita de outro distúrbio do sono.

Palavras-chave: Insônia, insônia comórbida, sono de duração curta.

ABSTRACTChronic insomnia is the most common sleep disorder in adults and its diagnosis is fundamental for adequate clinical management. The aim of this paper is to present recently published definitions of in-somnia according to current international classifications, such as the International Classification of Sleep Disorders – Third Edition and the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition. For the first time, these classifications are congruent related to their diagnostic criteria; both present insomnia as a distinct disorder and divide it into acute, chronic and other. This emphasizes the necessi-ty of a specific insomnia approach. Furthermore, it is necessary to recognize those insomniacs with physiological hyperarousal, which may be identified by objective measures (short total sleep time, for instance). These patients may have poorer outcome, as they are at higher risk of developing cardiometabolic conditions and neuro-cognitive impairment. Diagnosis is primarily made on a clinical ba-sis (anamnesis and physical examination), while sleep diaries and questionnaires (such as Insomnia Severity Index) can help evaluate these patients. Objective measures, such as polysomnography, are not required in most cases, except when suspicion of another sleep disorder arises.

Keywords: Insomnia, comorbid insomnia, short sleep duration.


INTRODUCTION

The adverse consequences of sleep disruption on hu-man physiology are well known as they compromise the individual’s health and well-being. Short sleep has been linked to obesity, hypertension, altered metabolic/endocrine profile (such as diabetes), coronary heart disease and increased mortality risk.1 Furthermore, many studies demonstrate an associa-tion between untreated or underlying sleep disorder with daytime dysfunction, cognitive impairment, metabolic disorders, stroke, sudden death during sleep and higher risk of fatal and nonfatal cardiovas-cular diseases.2-8 Insomnia is the most prevalent sleep disorder in the general population.9 It is currently defined, according to the International Classifica-tion of Sleep Disorders – Third Edition (ICSD-3) criteria, as persistent difficulty with sleep initiation, duration, consolidation or quality that occurs despite the opportunity and circumstances for sleep, which results in some type of disability during the day.10 Despite the relevance of insomnia in clinical prac-tice, it is undervalued by most health professionals and patients. Additionally, due to the wide variety of definitions used in scientific papers, it is difficult to compare outcomes and risk factors in a meaning-ful way.11 Nevertheless, as a symptom, syndrome or disease, it has a significant negative impact on social life, task performance and daytime functioning with higher odds of errors or accidents.12,13 Therefore, the objective of this paper is to appraise the most recent international insomnia classifications and raise some issues regarding insomnia diagnosis.

PREVALENCE OF INSOMNIA COMPLAINTS, SYMPTOMS, SYNDROME AND DISORDER

Ohayon and Reynolds12 assessed the prevalence of insomnia according to various definitions in a Euro-pean population aged 15-years or older. They found that one-third (34.5%) of individuals had at least one symptom of insomnia: 23.1% experienced difficulty maintaining sleep (the most common symptom), whilst 10.9%, 12.3% and 11.1% experienced diffi-culty initiating sleep, early morning awakening and non-restorative sleep, respectively. When applying DSM-IV criteria, 9.8% were found to have insomnia disorder, and after exclusion of other clinical and psy-chiatric conditions, 3% were diagnosed with primary

insomnia.12 In a study evaluating 1,042 subjects in Brazil, 15% were found to have insomnia based on DSM-IV criteria, while 32% were found to experi-ence insomnia using objective measures.14 Objective insomnia was defined as meeting one of the follow-ing criteria: sleep onset latency > 30 minutes (sleep initiating insomnia), wake after sleep onset lasting > 30 minutes (sleep maintenance insomnia), total sleep time < 360 minutes and a terminal wakefulness > 30 minutes (insomnia with too short duration of sleep or early morning awakening), or a combination of the previous quantitative criteria (mixed disorder).

CORRELATES OF INSOMNIA, COSTS AND QUALITY OF LIFEThe isolated occurrence of insomnia disorder in the general population is an uncommon event. It is typi-cally followed by multiple, recurrent and persistent health problems, which increase demand for health care and raise direct and indirect costs related to insomnia management.3,4,11,15 Considering the high prevalence of this sleep disturbance and its burden on public health, the consequences of untreated dis-ease for both the individual and society can be disas-trous. Untreated disease can lead to increased work absenteeism related to all causes of illness (clinical and psychiatric), lower task performance and higher odds of accidents.4,5,16 The risk of non-intentional fatal injuries increases in individuals who experience difficulty falling asleep, maintaining sleep or non-restorative sleep, and also increases when there is an association of two or more of these symptoms.17

According to social and demographic data, insom-nia is usually more common in women than men, with a woman/man ratio of 1.4 for insomnia symptoms (1.7 after 45 years of age), and of 2.0 for insomnia diagnosis.6,11 Old individuals have also higher odds of developing insomnia,18 as well as those with impaired marital status (widow, divorced, separated), unemplo-yed or retired.11 When considering only newly diagno-sed patients, Singareddy et al.6 found that the incidence of insomnia was higher in younger individuals. Quality of life of insomniacs is significantly impaired, affecting their overall subjective sense of physical well-being. This is probably secondary to psychiatric or physical di-sorders, medications and psychosocial issues, with some studies showing a positive effect of insomnia treatment and management of comorbidities on quality of life.19

Insomnia current diagnosis


Insomnia disorder and insomnia symptoms are commonly related to neuropsychiatric illness, es-pecially mood disorders.11 The majority of subjects with major depression (80%) develop insomnia symptoms in the course of their disease, exhibiting a four-fold risk when compared with the general population.11,12 Anxiety disorder is also more com-mon in insomniacs, while insomnia can facilitate or trigger anxiety and depressive disorder.11,12 Smoking positively correlates with difficulty in achieving sleep initiation and maintenance and may lead to short sleep duration (< 6 hours).11 Alcohol consumption may at first accelerate sleep onset, but chronic use will likely increase sleep disruption and abolish its effect on sleep initiation.11

It is possible to define two subgroups of insomnia patients with the presence or absence of physiologi-cal hyperarousal, which can be identified by objective measures, as short sleep duration and mean latency > 8 minutes on Multiple Latency Sleep Test (MLST).7,8 Patients with hyperarousal/hyperalert state express a higher risk of cardiometabolic conditions, such as hypertension, impaired heart rate variability and pre-ejection period and type 2 diabetes – all of which in-crease mortality in these individuals.1,7 Furthermore, these patients are more likely to develop neurocog-nitive impairment, poorer psychiatric comorbidity and a more severe phenotype of insomnia.7 While evaluating the performance of insomniacs and nor-mal sleepers using computer-administered reaction time tasks, Edinger et al.8 demonstrated that those with insomnia and physiological hyperarousal (defi-ned by mean latency on MLST > 8 minutes) had lower performance on tasks requiring attention. This was evidenced by higher error rate, showing cogni-tive deficit.8

CURRENT CLASSIFICATIONS

International Classification of Sleep Disorders – Third Edition (ICSD-3, tables 1 and 2)10

The last update of the ICSD occurred in 2014 and its content revisions were in line with the DSM-V. One of the major changes includes a sin-gle entry for the disorders of insomnia called “in-somnia disorder”. Compared to ICSD-2, ICSD-3 has a less extensive diagnostic subtyping, which

applies to patients with and without comorbidities, regardless of the disruptive potential of the comor-bidities. Among adults with insomnia, sleep com-plaints typically include more difficulty in initiating or maintaining sleep. Concerns over long periods of nocturnal wakefulness, insufficient amounts of night-time sleep or poor quality of sleep often ac-company these complaints. In children, this sleep disorder is frequently reported by caregivers and characterized by resistance to sleep, frequent noc-turnal awakenings, and/or an inability to sleep in-dependently.

Daytime consequences are reported by these sub-jects, presumably caused by reduced nocturnal sleep or by some other common mechanism. Daytime symptoms often include fatigue, decreased mood or irritability, malaise and cognitive impairment. Among adults, chronic insomnia can impair social or occupational functioning and reduce quality of life. In children, it can lead to poor school performan-ce, impaired attention and behavior disorders. It is not unusual for some patients to experience physical symptoms such as muscle tension, palpitations and headache. Despite daytime impairment, these pa-tients usually don’t complain of excessive somnolen-ce or report a high occurrence of naps.

ICSD-3 includes three diagnostic categories for insomnia: chronic insomnia disorder (Table 1), di-sorder of short-term insomnia (Table 2) and ano-ther insomnia disorder. Chronic insomnia disorder is characterized by difficulty falling asleep and/or complaints of sleep maintenance associated with daytime impairment for at least three months. It is reserved for individuals whose sleep difficulties ex-ceed frequency limits (at least three times per week) and minimum length to be associated with clinically significant morbidity. Of note, former chronic pri-mary insomnia criteria (DSM IV) included symp-toms occurring for at least one month. Short-term insomnia has a similar definition and is applied when the complaints or symptoms last less than three mon-ths; when neither criterion is fulfilled, a definition of other insomnia disorder is used.

Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-V, table 3)20,21

DSM-V was launched in 2013 and is much like ICSD-3. Compared with DSM-IV-TR, DSM-V

Macêdo PJOM et al.



Table 1. Chronic insomnia disorder (ICSD-3)

Diagnostic Criteria

Criteria A-F must be met A. The patient reports, or the patient’s parent or caregiver observes, one or more of the following:

1. Difficulty initiating sleep.

2. Difficulty maintaining sleep.

3. Waking up earlier than desired.

4. Resistance to going to bed on appropriate schedule.

5. Difficulty sleeping without parent or caregiver intervention.

B. The patient reports, or the patient’s parent or caregiver observes, one or more of the following related to the night-time sleep difficulty:

1. Fatigue/malaise.

2. Attention, concentration or memory impairment.

3. Impaired social, family, occupational or academic performance.

4. Mood disturbance/irritability.

5. Daytime sleepiness.

6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression).

7. Reduced motivation/energy/initiative.

8. Proneness for errors/accidents.

9. Concerns about or dissatisfaction with sleep.

C. The reported sleep/wake complaints cannot be explained purely by inadequate opportunity (i.e., enough time is allotted for sleep) or inadequate circumstances (i.e., the environment is safe, dark, quiet and comfortable) for sleep.

D. The sleep disturbance and associated daytime symptoms occur at least three times per week.

E. The sleep disturbance and associated daytime symptoms have been present for at least three months.

F. The sleep/wake difficulty is not better explained by another sleep disorder.

Table 2. Short-term insomnia disorder (ICSD-3)

Diagnostic Criteria

Criteria A-E must be metA. The patient reports, or the patient’s parent or caregiver observes, one or more of the following:

1. Difficulty initiating sleep.

2. Difficulty maintaining sleep.

3. Waking up earlier than desired.

4. Resistance to going to bed on appropriate schedule.

5. Difficulty sleeping without parent or caregiver intervention.

B. The patient reports, or the patient’s parent or caregiver observes, one or more of the following related to the night-time sleep difficulty:

1. Fatigue/malaise.

2. Attention, concentration or memory impairment.

3. Impaired social, family, vocational or academic performance.

4. Mood disturbance/irritability.

5. Daytime sleepiness.

6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression).

7. Reduced motivation/energy/initiative.

8. Proneness for errors/accidents.

9. Concerns about or dissatisfaction with sleep.

C. The reported sleep/wake complaints cannot be explained purely by inadequate opportunity (i.e., enough time is allotted for sleep) or inadequate circumstances (i.e., the environment is safe, dark, quiet and comfortable) for sleep.

D. The sleep disturbance and associated daytime symptoms have been present for less than three months.

E. The sleep/wake difficulty is not better explained by another sleep disorder.

mandates concurrent specification of coexisting con-ditions and acknowledges the bidirectional and in-teractive effects between sleep disorder and coexist-ing medical and mental disorders. This is a paradigm shift widely accepted in the field of sleep medicine,

moving away from causal attributions between co-existing disturbances. The diagnosis of primary in-somnia disorder was replaced for insomnia disorder (Table 3), avoiding the differentiation between pri-mary and secondary insomnia.


International Classification of Diseases (ICD-10, Table 4)22

The latest edition of the International Classifica-tion of Diseases assesses insomnia in a symptomatic definition with no considerations for daytime impair-ment. It is considered among mental disorders (non-organic insomnia, ICD-10 F.51.0) and neurological conditions (disorder of initiating sleep and maintain-ing sleep – insomnia, ICD-10 G.47.0). According to the World Health Organization, the next revision of this classification is due in 2017.

criteria (ICSD-3 and DSM-V) rather than relying on laboratory or polysomnographic findings. Consider-ing the ethiopathogenics, this sleep disorder can be biological, environmental, behavioral or psychologi-cal in nature. Therefore, it is important to perform a systematic search for predisposing and perpetuat-ing factors, such as stress, clinical and mental con-ditions (Table 5), inadequate sleep hygiene, use of substances/medications (caffeine, alcohol or drugs), circadian unsuitability (“jet lag”, shift work), sleep rumination, family history of insomnia or other sleep disturbance.9,13,23

Systematic sleep history helps to assess sleep-wake patterns over a period of weeks or months; charac-terization of the premorbid baseline sleep patterns helps to establish a clinical relevance for insomnia complaints. Questions concerning chronotype and nocturnal sleep characteristics (e.g., sleep latency af-ter lights out, occurrence and number of nocturnal awake during the night, rough time awake after sleep onset and what time the patient gets out of bed) are relevant to establish whether insomnia symptoms are present. The presence of mood changes, irritability, poor memory, fatigue, drowsiness, lack of energy, ge-neral malaise and work or social impairment display the occurrence of daytime dysfunction. When related with insomnia complaints, the diagnosis of insomnia disorder is supported. Complete medical history is necessary to help identify medical and mental condi-tions that can be the source or a secondary effect of this sleep disorder.13,23,24

Although it is not mandatory for insomnia diag-nosis, instruments can be used to help identify other comorbidities, measure severity of sleep complaints and as a comparison tool for treatment response. For example, the Insomnia Severity Index (ISI) is a subjective scale that assesses the intensity of insom-nia symptoms. It has proven valuable for the diag-nosis of this sleep disorder.25 The ISI contains seven questions, each one scoring a value between 0 and 4 points, and the summation gives a total score ranging from 0 to 28. When the sum is higher than 14, cli-nical insomnia can be defined with great specificity.26 Assessment of sleep quality and daytime sleepiness is possible by using the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale, respectively. There are many questionnaires that can assess depression and anxiety symptoms, such as Beck Depression In-ventory and Beck Anxiety Inventory, among others.

Table 3. Insomnia disorder criteria (DSM-V)

Criteria A-H must be met

A. A predominant complaint of dissatisfaction with sleep quantity or quality, associated with one or more of the following symptoms:

1. Difficulty initiating sleep (in children, this may manifest as difficulty initiating sleep without a caregiver intervention).

2. Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings (in children, this may manifest as difficulty returning to sleep without a caregiver intervention).

3. Early morning awakening with inability to return to sleep.

B. The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral or other important areas of functioning.

C. The sleep difficulty occurs at least three nights per week.

D. The sleep difficulty is present for at least three months.

E. The sleep difficulty occurs despite adequate opportunity for sleep.

F. The insomnia is not better explained by and does not occur exclusively during the course of another sleep disorder (e.g., narcolepsy, a breathing related sleep disorder, a circadian rhythm sleep-wake disorder, parasomnias).

G. The insomnia is not attributable to the psychological effects of a substance (e.g., drug abuse or a medication.)

H. Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia.

Table 4. Nonorganic insomnia (ICD-10)

A. A complaint of difficulty falling asleep, maintaining sleep or non-refreshing sleep.

B. The sleep disturbance occurs at least three times per week for at least one month.

C. The sleep disturbance results in marked personal distress or interference with personal functioning in daily living.

D. Absence of any known causative organic factor, such as a neurological or other medical condition, psychoactive substance use disorder or a medication.

HOW TO DIAGNOSE INSOMNIA

Insomnia diagnosis is based on clinical features pro-vided by complete medical history, assessment of subjective sleep parameters, comprehensive physical examination and application of current classifications

Macêdo PJOM et al.


Quality of life is frequently impaired in these pa-tients, and surveys that assess this parameter are very interesting, especially for treatment evaluation.24

Patients with insomnia disorder are dissatisfied with sleep quantity or quality. This generally leads to overestimation of their sleep difficulty and unde-restimation of actual sleep time, which can also lead to anticipatory anxiety and fear of not sleeping at all. For better elucidation of actual sleep pattern, a sle-ep log prior to and during treatment must be con-sidered. It is a descriptive subjective report of sleep, evaluating bedtime, sleep latency, number of awake-nings, time awake after sleep onset, time in bed, total sleep time, sleep efficiency, nap times and medication use.24 There is a modest correlation between sleep logs and objective measures, with a tendency to un-derestimate total sleep time and overestimate sleep latency. Nevertheless, it is still useful as an indicator

of the patient’s sleep perception.15 If for some reason these individuals show difficulty completing the sleep log or great sleep misperception, actigraphy can be used as an objective measure.23,24

Polysomnography is not routinely indicated for insomnia diagnosis, except when there is suspicion of other sleep disorders, such as sleep apnea, perio-dic limb movement disorder and restless leg syndro-me or former paradoxical insomnia.23,24 However, recent data suggest that insomniacs with objective hyperalert state might have a more severe insom-nia phenotype, with a more chronic and progressive course. This could become a prognostic biomarker for clinical decision-making and therefore define a formal indication for standard sleep study in these patients.7 Nevertheless, there are not enough data to support routine polysomnography in patients with insomnia.

CONCLUSION

Insomnia is a clinical condition that presents as per-sistent difficulty in sleep initiation or sleep mainte-nance or not feeling refreshed upon waking, with impaired social or occupational functioning. It is a prevalent sleep disorder in general population and may lead to serious repercussions to personal and social health. Current classifications (ICSD-3 and DSM-V) are highly similar and lessen confusion re-garding insomnia definition, facilitating comparison of insomnia outcomes in future research endeavours. Special attention must be given for those insomni-acs with hyperaroused state, who present more se-vere cardiovascular and neuropsychiatric outcomes, therefore requiring closer assessment.

PARTICIPATION

Philippe Joaquim Oliveira Menezes Macêdo – text writing; Gisele S. M. Leite Neves – review and text writing; Dalva Lucia Rollemberg Poyares – out-line reappraisal and text writing; Marleide da Mota Gomes – objective proposal and outline.

Conflict of interest

The authors declare that there is no conflict of inter-ests regarding the publication of this paper.

Table 5. Comorbid clinical and mental conditions of insomnia (adapted from Schutte-Rodin et al., 2008)24

Neurological: Stroke, dementia, Parkinson’s disease, seizure disorders, headache disorders, traumatic brain injury, peripheral neuropathy, chronic pain disorders, neuromuscular disorders

Cardiovascular: Angina, congestive heart failure, dyspnoea, dysrhythmias

Pulmonary: COPD, emphysema, asthma, laryngospasm

Digestive: Reflux, peptic ulcer disease, cholelithiasis, colitis, irritable bowel syndrome

Genitourinary: Incontinence, benign prostatic hypertrophy, nocturia, enuresis, interstitial cystitis

Endocrine: Hypothyroidism, hyperthyroidism, diabetes mellitus

Musculoeskeletal: Rheumatoid arthritis, osteoarthritis, fibromyalgia, Sjögren syndrome, kyphosis

Reproductive: Pregnancy, menopause, menstrual cycle variations

Sleep disorders: Obstructive sleep apnea, central sleep apnea, restless leg syndrome, periodic limb movement disorder, circadian rhythm sleep disorders, parasomnias, bruxism

Mental: Depression, anxiety, psychotic disorders, attention deficit disorder, personality disorder

Substance use/abuse/withdrawal: Anxiolytics and antidepressants: SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine), venlafaxine, duloxetine, monoamine oxidase inhibitors

Stimulants: Caffeine, methylphenidate, amphetamine derivatives, ephedrine and derivatives, cocaine

Descongestants: Pseudoephedrine, phenylephrine, phenylpropanolamine

Narcotic: Oxycodone, codeine, propoxyphene

Cardiovascular: β-Blockers, α-receptor agonists and antagonists, diuretics, lipid-lowering agents

Pulmonary: Theophylline, albuterol

Alcohol

Other: Allergies, rhinitis, sinusites



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Rev Bras Neurol. 51(3):69-72, 2015

Short communication

Effects of aerobic physical exercise on cognition

Efeitos da atividade física aeróbica na cognição

Fábio Henrique de Gobbi Porto1, Jano Alves de Souza2, Sara Lucia Silveira de Menezes3, Marco Antonio Araujo Leite2, Vilma Duarte Câmara2, Marco Orsini3

1 Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) – Department of Neurology and Cognitive Disorders Reference Center (CEREDIC), São Paulo, SP, Brazil.2 Hospital Universitário Antônio Pedro (HUAP) – Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil. 3 Centro Universitário Augusto Motta (UNISUAM) – Programa de Mestrado em Ciências da Reabilitação, Rio de Janeiro, RJ, Brazil; HUAP-UFF, Niterói, RJ, Brazil.

Address for correspondence: Dr. Marco Orsini. Programa de Mestrado/Doutorado em Ciências da Reabilitação. Av. Paris, 72, Bonsucesso – 21041-020 – Rio de Janeiro, RJ, Brazil. E-mail: [email protected]

ABSTRACTIntroduction: The increasing prevalence of cognitive impairment in older adults is a major concern nowadays. Interventions able to change the natural history of the most common cause of cognitive impairment in older adults, Alzheimer’s disease (AD), are needed. Physical inactivity is considered one of the most important modifia-ble risk factors for AD. Objective: To review recent evidence on the role of physical exercise (PE) in the older adults cognition. Method: The authors reviewed recent papers about PE and cognition in older adults. Conclusion: Current data indicate that PE is a promising in-tervention to decrease the risk of cognitive impairment in cognitively normal older subjects and in those with Mild Cognitive Impairment. Controversy still remains about the effect of PE in demented patients, but more recent data is pointing towards a positive effect.

Keywords: Cognition, physical exercise, rehabilitation.

RESUMOIntrodução: A prevalência crescente de comprometimento cogni-tivo em adultos mais idosos é uma grande preocupação atual. Inter-venções capazes de alterar a história natural da causa mais frequente de comprometimento cognitivo em adultos mais idosos, a doença de Alzheimer (DA), são necessárias. A inatividade física é considerada um dos fatores de risco modificáveis mais importantes na DA. Ob-jetivo: Rever evidências recentes no papel do exercício físico (EF) na cognição de adultos mais idosos. Método: Os autores fizeram uma revisão dos artigos recentes sobre EF e cognição em adultos mais idosos. Conclusão: Dados correntes indicam que o EF é uma intervenção promissora para diminuir o risco de comprometimen-to cognitivo em indivíduos mais idosos cognitivamente normais e naqueles com Comprometimento Cognitivo Leve. Ainda permane-cem controvérsias quanto ao efeito do EF em pacientes demencia-dos, porém dados mais recentes apontam para um efeito positivo.

Palavras-chave: Cognição, exercício físico, reabilitação.


As life-expectancy increased in the last half of the last century, a growing concern is the increasing preva-lence of cognitive impairment in older adults.1 Cur-rent numbers indicate that approximately 13% of the population over 65 years has some cognitive impair-ment, the most common cause being Alzheimer’s disease (AD).2 AD is estimated to affect 1% of the older adult population, and its incidence duplicates every 5 years. The prevalence of cognitive impair-ment is expected to triplicate by 2050, if no inter-vention that changes the natural history of AD is de-veloped. These numbers are actually worst for Latin America countries, where due to several factor, the prevalence of dementia may be possible bigger.3,4 The financial burden of cognitive impairment in old-er adults is enormous. The direct costs of dementia are expected to exponentially increase in the future, with the frightening figure of 1% of the gross do-mestic product by 2050.5 Also, the emotional impact of AD and other dementias in the families, and the indirect cost for the caregivers, are both important questions for the future. As developing countries are more susceptible to the economic burden of demen-tia care, this is an emerging public-health issue. In the view of the epidemic proportions of dementia in the future, there has been an extensive search for in-terventions that reduce the progression of cognitive decline in older subjects.

Physical inactivity is considerate one of the most important modifiable risk factors for AD.1 In a re-cent meta-analysis of the population-attributable risk for AD, physical inactivity was one of the greatest modifiable risk factors.6 The risk attributed to physi-cal inactivity was 21% (95% CI, 95% CI 5.8-36.6) for the American population. This risk is comparable to the risk attributed to low educational attainment of 19.1% (95% CI 12.3-25.6), a well-known risk factor for AD.1 In contrast, physical exercise (PE) is asso-ciated with a decreased risk of dementia in normal older adults.7,8 A meta-analysis has shown the protec-tive effects PE in cognitively normal older adults.9 However, data is not so encouraging when subjects with established dementia are studied. Despite some studies have shown benefits,10,11 a meta-analysis dem-onstrated absence of benefit of PE on cognition, in subjects with dementia.12 However, more recent data is challenging this statement,13 and this question is definitely still open. Current evidence is stronger for a preventive role of PE on cognition. In 2010,

the NIH state-of-the-science conference statement about prevention of AD and cognitive impairment concluded that there was not enough evidence to conclude that PE decreases the risk of cognitive im-pairment.14 Despite that, several critics were drawn about the conclusion, which were too conservative.15 The effects of PE on cognitive functions are still an outstanding question. Several biological mechanisms have been implicated in the protective effects of PE, including improved neurogenesis, angiogenesis, and synaptic plasticity as well as a decrease in vascular risk factors, insulin resistance, and normal aging-related brain atrophy.16,17 These protective effects are based in the concept of cognitive reserve.18 Ac-cording to this theory, an increased brain resiliency to AD pathology would delay the clinical symptoms, even with the accumulation of brain pathology. Al-ternatively, PE may also decrease brain deposition of amyloid β (Aβ) protein, one of the hallmarks features of AD pathology. Aβ protein is currently thought to be the initial event in a cascade of events leading to neurodegeneration.19 Although data regarding this effect are conflicting, this effects may be implicate in the lower risk of dementia in subjects who were ac-tive through their lives.20,21

The potential benefits of PE on cognitive func-tion have been supported by studies showing that physically active subjects during adulthood have a decreased risk of cognitive impairment during later life.22-26 PE has been shown to improve cognition in cognitively normal older adults, to reduce age-rela-ted hippocampal atrophy and general brain tissue loss, to improve vascular function, and to interact with genetic risk factor for AD, such as APOE.24-27 The current evidence is strongest for benefic cog-nitive effects of PE for normal older adults without cognitive impairment. A 2008 Cochrane Database states: “there is evidence that aerobic physical activi-ties, which improve cardiorespiratory fitness, are ben-eficial for cognitive function in healthy older adults, with effects observed for motor function, cognitive speed, delayed memory functions and auditory and visual attention”.9

An important question is if PE may still ben-efit subjects with increased risk of cognitive decline compared with the normal elderly population, such as subjects with mild cognitive impairment (MCI). MCI is a heterogeneous condition characterized by cognitive decline that is not severe enough to cause

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Effects of aerobic physical exercise on cognition

functional impairment, and meet the threshold of de-mentia.28 It is a major risk factor for dementia, with an annual conversion rate to dementia of 5%-15% (as compared to a 1% rate in cognitively normal older adults).29 Recent studies have demonstrated that PE may improve cognition in subjects with MCI. Data from randomized controlled trials with PE have in-dicated improvements in global cognitive function, memory, and executive function.30-36 A recent meta-analysis showed strong evidence of benefits for glo-bal cognitive function.37 Furthermore, some stu dies revealed changes in biomarkers: decreased brain atrophy rate,35 and improved brain efficiency38,39 in subjects with MCI who performed PE.

In conclusion, current data indicate that PE is a promising intervention to decrease the risk of cogni-tive impairment in cognitively normal older subjects and in those with MCI. Controversy still remains for dementia, but more recent data is pointing towards a positive effect. Further studies are necessary to better understand the mechanisms implicated in the effects of PE on brain functions. Despite some gaps in the current knowledge, there is enough evidence to sup-port the PE as an intervention to generally prevent cognitive impairment.

REfEREnCES1. Ferri CP, Prince M, Brayne C, et al.; Alzheimer’s Disease

International. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366(9503):2112-7.

2. Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep. 2009;57(14):1-134.

3. Ferri C. Population ageing in Latin America: dementia and related disorders. Rev Bras Psiquiatr. 2012;34(4).

4. Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr. 2009;21(4):622-30.

5. Ferri C, Chisholm D, Van Ommeren M, Prince M. Resource utilisation for neuropsychiatric disorders in developing countries: a multinational Delphi consensus study. Soc Psychiatry Psychiatr Epidemiol. 2004;39(3):218-27.

6. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-94.

7. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-84.

8. Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med. 2009;39(1):3-11.

9. Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2008;(2):CD005381.

10. Arcoverde C, Deslandes A, Moraes H, et al. Treadmill training as an augmentation treatment for Alzheimer’s disease: a pilot randomized controlled study. Arq Neuropsiquiatr. 2014;72(3):190-6.

11. Deslandes AC. Exercise and mental health: what did we learn in the last 20 years? Front Psychiatry. 2014; 5: 66.

12. Forbes D, Forbes S, Morgan DG, Markle-Reid M, Wood J, Culum I. Physical activity programs for persons with dementia. Cochrane Database Syst Rev. 2008;(3):CD006489.

13. Forbes D, Thiessen EJ, Blake CM, Forbes SC, Forbes S. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2013;12:CD006489.

14. Daviglus ML, Bell CC, Berrettini W, et al. NIH state-of-the-science conference statement: preventing Alzheimer’s disease and cognitive decline. NIH Consens State Sci Statements. 2010;27(4):1-30.

15. Qiu C, Kivipelto M, Fratiglioni L. Preventing Alzheimer disease and cognitive decline. Ann Intern Med. 2011. Available at: <http://www.ncbi.nlm.nih.gov/pubmed/21282705>.

16. Barber SE, Clegg AP, Young JB. Is there a role for physical activity in preventing cognitive decline in people with mild cognitive impairment? Age Ageing. 2012;41:5-8.

17. Cadar, Dorina, Pikhart, Hynek, Mishra, Gita, Kuh, Diana and Richards, Marcus. Is there a role for physical activity in preventing cognitive decline?. In: 8th World Congress on Aging and Physical Activity, Glasgow, Scotland, (S34-S34). 13-17 August 2012.

18. Barulli D, Stern Y. Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn Sci. 2013;17(10):502-9.

19. Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-16.

20. Vemuri P, Lesnick TG, Przybelski SA, et al. Effect of lifestyle activities on Alzheimer disease biomarkers and cognition. Ann Neurol. 2012;72(5):730-8.

21. Liang KY, Mintun MA, Fagan AM, et al. Exercise and Alzheimer’s disease biomarkers in cognitively normal older adults. Ann Neurol. 2010;68(3):311-8.

22. Dik M, Deeg DJ, Visser M, Jonker C. Early life physical activity and cognition at old age. J Clin Exp Neuropsychol. 2003;25(5):643-53.

23. Buchman AS, Yu L, Boyle PA, Shah RC, Bennett DA. Total daily physical activity and longevity in old age. Arch Intern Med. 2012;172(5):444-6.

24. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003;14(2):125-30.

25. Kramer AF, Colcombe SJ, McAuley E, Scalf PE, Erickson KI. Fitness, aging and neurocognitive function. Neurobiol Aging. 2005;26 Suppl 1:124-7.

26. Colcombe SJ, Kramer AF, Erickson KI, et al. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A. 2004;101(9):3316-21.

27. Okonkwo OC, Schultz SA, Oh JM, et al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology. 2014;83(19):1753-60.

28. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58(12):1985-92.

29. Petersen RC, Roberts RO, Knopman DS, et al. Mild cognitive impairment: ten years later. Arch Neurol. 2009;66(12):1447-55.

30. Lam LC, Chan WC, Leung T, Fung AW, Leung EM. Would older adults with mild cognitive impairment adhere to and benefit from a structured lifestyle activity intervention to enhance cognition?: a cluster randomized controlled trial. PLoS One. 2015;10(3):e0118173.


31. Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008;300(9):1027-37.

32. Nagamatsu LS, Chan A, Davis JC, et al. Physical activity improves verbal and spatial memory in older adults with probable mild cognitive impairment: a 6-month randomized controlled trial. J Aging Res. 2013;2013:861893.

33. van Uffelen JG, Chinapaw MJ, van Mechelen W, Hopman-Rock M. Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sports Med. 2008;42(5):344-51.

34. Baker LD, Frank LL, Foster-Schubert K, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67(1):71-9.

35. Suzuki T, Shimada H, Makizako H, et al. A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS One. 2013;8(4):e61483.

36. Suzuki T, Shimada H, Makizako H, et al. Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 2012;12:128.

37. Wang C, Yu JT, Wang HF, Tan CC, Meng XF, Tan L. Non-pharmacological interventions for patients with mild cognitive impairment: a meta-analysis of randomized controlled trials of cognition-based and exercise interventions. J Alzheimers Dis. 2014;42(2):663-78.

38. Smith JC, Nielson KA, Antuono P, et al. Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. J Alzheimers Dis. 2013;37(1):197-215.

39. Porto FH, Coutinho AM, Pinto AL, et al. Effects of aerobic training on cognition and brain glucose metabolism in subjects with mild cognitive impairment. 2015. Available at: <http://www.researchgate.net/profile/Fabio_Porto2/publication/274396614_Effects_of_Aerobic_Training_on_Cognition_and_Brain_Glucose_Metabolism_in_Subjects_with_Mild_Cognitive_Impairment/links/5522f0ec0cf2f9c130544b25.pdf>.

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Metabolismo da homocisteína em doenças neurológicas

Homocysteine metabolism in neurologic disorders

Celmir de Oliveira Vilaça1,2, Marcos Raimundo Gomes de Freitas2, Osvaldo José Moreira do Nascimento2, Marco Orsini2, Marco Antônio Araujo Leite2, Jano Alves de Souza¹

1 Instituto Nacional de Traumatologia e Ortopedia (INTO), Rio de Janeiro, RJ, Brasil.2 Universidade Federal Fluminense (UFF), Departamento de Medicina Clínica - Neuro - UPC (Unidade de Pesquisa Clínica). Divisão de Neurologia, Hospital Universitário Antônio Pedro (HUAP), Programa de Pós-Graduação em Neurologia/Neurociências, Niterói, RJ, Brasil.

Endereço para correspondência: Dr. Marco Antonio Araujo Leite. Rua Tavares de Macedo, 95/902, Icaraí – 24220-215 – Niterói, RJ, Brasil. E-mail: [email protected]

RESUMOObjetivo: Realizar uma revisão sobre o metabolismo do aminoá-cido sulfurado homocisteína, analisando como elevações de seus níveis séricos se correlacionam com a fisiopatologia das mais diver-sas doenças neurológicas, assim como sobre o tratamento da hiper--homocisteinemia. Método: Revisão não sistemática de artigos que abordassem o papel da homocisteína associado a doenças neuro-lógicas. Foi priorizada a utilização de artigos que apresentassem no título as palavras-chave “homocisteína” ou “hiper-homocisteinemia”, associadas a palavras-chave contendo as enfermidades neurológi-cas de maior prevalência como acidente vascular cerebral, doença de Alzheimer, doença de Parkinson e outras. Foram utilizadas as bases de dados do PubMed, Lilacs e Google Scholar. Resultados: Foram utilizados 35 artigos em inglês e 2 artigos em português para a confecção desta revisão. Conclusão: A homocisteína se encontra elevada em associação com as mais diversas doenças neurológicas. Contudo, em muitas delas não está estabelecido se esse aumento é um achado secundário ou se representa um papel da homocisteína na patogênese dessas enfermidades. Mais estudos são necessários para estabelecer o papel da homocisteína em situações neurológi-cas. O tratamento da hiper-homocisteinemia é fácil, sendo feito com reposição de vitamina B12 e, principalmente, de folatos.

Palavras-chave: Homocisteína, S-adenosil-homocisteína, metioni-na, doenças neurológicas.

ABSTRACTObjective: Review the metabolism of sulfur amino acid homocystei-ne and how elevation of its serum levels is correlated with the patho-physiology of several neurological diseases, as well as the treatment of hyperhomocysteinemia. Method: A non-systematic review of articles discussing the role of homocysteine associated with neuro-logical diseases was performed. The use of articles that presented in the title the keywords “homocysteine” or “hyperhomocysteinemia” associated with keywords containing the most prevalent neurologi-cal disorders such as stroke, Alzheimer’s disease, Parkinson’s dise-ase and others were preferred. The search was underdone through PubMed, Google Scholar and Lilacs databases. Results: There were selected 35 articles in English and 2 articles in Portuguese in this this review. Conclusion: High levels of homocysteine are associated with various neurological disorders. However, in many of these are not established whether this increase is a consequence of these di-sorders or if homocysteine plays a role in the pathogenesis of these diseases. More studies are needed to establish the participation of homocysteine in neurological disorders. The treatment of hyperho-mocysteinemia is easy, being done with replacement of vitamin B12 and especially folate.

Keywords: Homocysteine, S-adenosyl-homocysteine, methionine, neurologic disorders.


INTRODUÇÃO

A homocisteína (HCT) é um aminoácido sulfurado (contém grupamento tiol ou -SH) não participante da constituição das proteínas corporais. Não é direta-mente obtida pela dieta, sendo derivada do metabo-lismo do aminoácido metionina, principalmente no fígado.1

O metabolismo da HCT envolve a participação de reações de remetilação para metionina por meio da enzima metilenotetrahidrofolato redutase (MTFH), utilizando folato como cofator. Também participa do processo de remetilação a enzima metionina sin-tase (MS), esta usando a vitamina B12 como cofator. Alternativamente, a HCT é eliminada mediante rea-ções de transulfuração com a participação da enzima cistationina β-sintase (CBS), utilizando-se da vitami-na B6 com a produção de cistationina2-4 (Figura 1).

A avaliação laboratorial dos níveis séricos de HCT envolve a dosagem de sua quantidade total no plas-ma. Desse total, 70% a 80% representam a quantida-de de HCT ligada a proteínas, 25% correspondem à quantidade encontrada sob a forma de dímeros de homocisteína/homocistina ou dímeros de homocis-teína-cisteína. Os 5% restantes representam a forma livre de HCT.1,6

A dosagem de HCT geralmente é realizada em jejum e muitos pacientes, embora apresentem níveis de HCT séricos normais durante o jejum, apresen-tam níveis elevados após teste de sobrecarga de me-tionina.1,3

A hiper-HCT pode ser classificada em moderada, quando os níveis séricos se encontram na faixa de 15 a 30 µmol/l, intermediária, com valores de 30 a 100 µmol/l e severa, com níveis acima de 100 µmol/l.5

O objetivo do presente artigo foi realizar uma revisão não sistemática sobre os níveis de HCT nas doenças neurológicas de maior prevalência. Deu-se ênfase em como a elevação da HCT pode estar re-lacionada à fisiopatologia dessas enfermidades. Dis-cute-se também o tratamento da hiper-HCT com reposição de vitamina B12 e folatos.

MÉTODO

Para a realização da presente atualização, foram uti-lizadas as bases de dados PubMed, Lilacs e Google Scholar, no período compreendido entre janeiro de 1997 e dezembro de 2014. Realizou-se revisão não sistemática de artigos, considerando artigos origi-nais, descritivos ou experimentais, assim como ar-tigos de revisão e opiniões de experts, excluindo-se artigos contendo apenas relatos de casos. Foram uti-lizadas para a busca as palavras-chave “homocisteína” e “hiper-homocisteinemia”, associadas a doenças de maior prevalência neurológica, como acidente vascu-lar cerebral (AVC), epilepsia, doença de Alzheimer, doença de Parkinson (DP) e outras. Artigos que con-tivessem a associação de homocisteína/hiper-homo-cisteinemia com cada doença neurológica em uniter-mos no título, tanto em inglês como em português, foram priorizados. Alguns artigos foram escolhidos com base no número de citações e pela relevância na discussão dos mecanismos relacionando HCT ou hiper-homocisteinemia na fisiopatologia das afecções neurológicas mais frequentes, não sendo adotado ne-

MS: metionina sintase; SAM: S-adenosil metionina; SAH: S-adenosil- -homocisteína; CBS: cistationina β-sintase; MTHFR: metiltetrahidrofolato redutase.

Figura 1. Metabolismo da homocisteína.2-4

Síntese de ácidos nucleicos Proteínas da dieta

Metionina

5,10-metileno-THF MSVitamina B12

Metil-THFMTHFR

Homocisteína

SAM

Purinas

THF

CBSSerina

Vitamina B6

Vitamina B6α-cetobutirato + NH4+

Cistationina

Cisteína

Glutationa

SAH

R (Aceptor deradical metil)

Proteínas (mielina); DNA;RNA; catecolaminas

R-CH3 (Aceptor metilado)

Aumento dos níveis plasmáticos de homocisteína e sua relação com doenças neurológicas foi primeiro aventado, em 1969, por McCully. Ele observou, na autópsia de uma criança, acelerado processo de ate-rogênese associado a altos níveis de HCT.5 Os acha-dos se assimilavam aos encontrados em crianças com homocistinúria, doença caracterizada por presença de disfunção intelectual, crises convulsivas, atrofia cerebral e doença aterosclerótica precoce em decor-rência da disfunção da CBS e hiper-homocisteinemia (hiper-HCT).3

Posteriormente, ao longo das últimas quatro dé-cadas e, principalmente, a partir dos anos 1990, a HCT foi associada a outras doenças neurológicas além da doença vascular.

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Homocisteína em doenças neurológicas

nhum critério específico para exclusão dos artigos. O estudo foi realizado no Serviço de Pós-graduação em Neurologia/Neurociências da Universidade Federal Fluminense (UFF).

RESULTADOS E DISCUSSÃO

Foram escolhidos 35 artigos em língua inglesa e 2 artigos em português, que a seguir serão analisados e discutidos.

HOMOCISTEÍNA E DOENÇA CEREBROVASCULAR

Entre todas as patologias neurológicas, a relação en-tre HCT e doença vascular é a mais estabelecida. A doença aterosclerótica é a principal causa de morte em países desenvolvidos, quando se associam o AVC e o infarto agudo do miocárdio (IAM).7 Pacientes com hiper-HCT severa (acima de 100 µmol/l) cos-tumam apresentar evento vascular antes dos 30 anos, como nos casos descritos de homocistinúria.7 É inte-ressante notar que tanto a hiper-HCT de jejum como a de pós-sobrecarga de metionina durante alimenta-ção rica em proteínas estão associadas ao aumento de risco de doença cerebrovascular.3

A hiper-HCT pode estar mais associada à doença cerebrovascular em comparação com a doença car-diovascular ou vascular periférica.8 A HCT, assim como seu metabólito ácido homocisteico (HCA), atua como agonista glutamatérgico dos receptores NMDA (N-metil-D-aspartato) cerebrais. A hiperes-timulação desses receptores ocasiona aumento da ex-citotoxicidade cerebral glutamatérgica por meio do influxo de cálcio e apoptose neuronal.8

A HCT diminui o transporte de arginina para as plaquetas. Esse processo é necessário para a produ-ção de óxido nítrico (NO), que atua como relaxante vascular e diminui a agregação plaquetária.9

A elevação dos níveis de HCT também favore-ce a agregação plaquetária mediante o aumento da síntese plaquetária de tromboxano A2. Concomitan-temente, a HCT apresenta capacidade de ativar subs-tâncias pró-coagulantes da circulação, como o fator V, e de inibir a atividade de substâncias anticoagulan-tes naturais, como a proteína C e a trombomodulina, aumentando a formação de trombina.10

O aumento da HCT acarreta a produção de es-pécies reativas de oxigênio, possivelmente por meio

da auto-oxidação com outra molécula de HCT. Esse processo leva à formação de espécies reativas de oxi-gênio e à peroxidação de moléculas de LDL-coles-terol, promovendo lesão endotelial e proliferação da musculatura lisa vascular. Todos esses eventos cola-boram para o processo de aterogênese.7,11

A hiper-HCT também provoca desvio do meta-bolismo HCT para a formação de S-adenosil-homo-cisteína (SAH), acarretando diminuição das reservas de adenosina intracelular. A adenosina é uma purina que atua na diminuição da reatividade plaquetária e risco vascular.12

HOMOCISTEÍNA E EPILEPSIA

A maioria das medicações anticonvulsivantes reduz a quantidade de folato sérico, levando à hiper-HCT. Isso pode colocar pacientes em uso de anticonvulsivantes durante décadas em maior risco de evento vascular na senescência.4 Os defeitos do tubo neural encontrados em recém-nascidos de gestantes sob terapia anticon-vulsivante e atribuídos à carência de folato podem re-presentar, na verdade, um papel nocivo da homociste-ína nessas gestações. Nesse contexto, há aumento nos níveis de HCT sérica e no líquido amniótico em mães de recém-nascidos com defeitos do tubo neural.3

HOMOCISTEÍNA E TRANSTORNOS COGNITIVOS

Idosos com aumento dos níveis de HCT apresentam quadro de atrofia hipocampal independentemente da presença de critérios para doença de Alzheimer (DA). Também apresentam maior risco de evolução para DA no futuro. Admite-se que a HCT é mais tó-xica para neurônios hipocampais em relação a outros neurônios corticais.13

Pacientes com DA podem apresentar pior evolu-ção clínica em casos de aumento da HCT.14 O au-mento da HCT provocaria elevação nos níveis da proteína amiloide e aumentaria a sua toxicidade nas placas senis, assim como promoveria hiperfosforila-ção da proteína Tau.15 Somado a isso, altos níveis de HCT promoveriam estresse oxidativo por geração de radicais superóxido a partir de seu grupo tiol após oxidação. Além disso, a HCT provoca estresse na função de síntese do retículo endoplasmático, acar-retando ativação de vias celulares e caspases e levando à apoptose neuronal.15


HOMOCISTEÍNA E TRANSTORNOS DO MOVIMENTO

Durante o metabolismo da levodopa pela catecol--O-metiltransferase (COMT), há produção de 3-O--metildopa (3-OMD). A COMT utiliza a SAM como doadora de radical metil. A SAM origina SAH, e esta última, por meio de hidrólise, origina HCT.16 Rati-ficam-se tais achados pela capacidade do inibidor da COMT entacapona em reduzir os níveis de HCT em pacientes com DP em tratamento com levodopa.2,17 O aumento nos níveis de HCT provoca sensibiliza-ção de neurônios dopaminérgicos a danos induzidos por íons de ferro na substância negra do mesencéfalo, podendo acelerar a evolução da DP.18,19 Além disso, a SAM é o principal doador de radicais metil para di-versas reações intracerebrais. Alterações de metilação no DNA neuronal decorrentes de hiper-HCT provo-cam acúmulo de SAH e inibem a produção de SAM, ocasionando variações na expressão gênica. Isso pode resultar em morte neuronal, também contribuindo para progressão da DP.18 O aumento de HCT tam-bém poderia colaborar para o aumento do risco car-diovascular em pacientes com DP,20 assim como ace-lerar o surgimento da demência associada à DP.2

Níveis de HCT aumentados também são encon-trados em pacientes com doença de Huntington.17 Tal fato pode ser consequência da capacidade da pro-teína hungtintina em interagir com a CBS, causan-do níveis elevados de HCT. A HCT ocasionaria seus efeitos neurotóxicos em locais onde há alta densida-de de receptores NMDA, como no corpo estriado. Esse local é onde se localizam os neurônios espinhais médios do caudado, sítio anatômico preferencial de início do processo degenerativo da doença.21

HOMOCISTEÍNA E DOENÇA DO NEURÔNIO MOTOR

Estudos indicam aumento da HCT em pacientes com esclerose lateral amiotrófica (ELA).22,23 Esse aumento pode se correlacionar com a progressão da doença, sendo independente dos níveis de folato ou vitamina B12.

23 A HCT é capaz de causar a morte do neurônio motor por excitotoxicidade glutamatérgica com influxo de cálcio.24 Ademais, neurônios motores com mutação da SOD (superóxido dismutase), res-ponsável pela forma mais comum de ELA familiar, parecem ser mais suscetíveis ao dano causado por al-tos níveis de HCT.23

HOMOCISTEÍNA E NEUROPATIAS PERIFÉRICAS

Níveis elevados de HCT são um achado secundário em doenças causadoras tanto de neuropatia como de hiper-HCT. Exemplos são: hipotireoidismo, diabe-tes, etilismo e insuficiência renal ou baixos níveis de folato e vitamina B12.

17 Contudo, um único trabalho demonstrou a existência de aumento da HCT em pacientes com neuropatia periférica, independente-mente de qualquer outra etiologia. Embora não se saiba como elevações da HCT sérica sozinhas pos-sam originar uma neuropatia, esse achado pode ser relevante em casos de neuropatias de causa desco-nhecida.25

HOMOCISTEÍNA E DOENÇA DESMIELINIZANTE

A SAM é o principal doador de radical metil para vá-rias reações no sistema nervoso central (SNC), como a síntese de ácidos nucleicos, neurotransmissores e lipídios, entre esses os componentes da mielina18,26. A hipometilação da proteína básica da mielina torna a mielina menos hidrofóbica, mais instável e susce-tível a dano oxidativo e inflamatório27. Estudos de metanálise mostram aumento dos níveis de HCT em pacientes com esclerose múltipla (EM), podendo ser esse mais um evento na fisiopatologia da EM27,28. Como nas outras doenças degenerativas já aborda-das, também ocorreria hiperativação da NMDA em pacientes com EM e hiper-HCT29. Um único traba-lho também demonstra elevação dos níveis de HCT em pacientes com neuromielite óptica, contudo esse aumento não foi relacionado à progressão da neuro-mielite, sendo considerado um achado secundário ao processo inflamatório decorrente da doença.30

HOMOCISTEÍNA E DEPENDÊNCIA QUÍMICA

Em pacientes etilistas, o álcool, mediante a formação de acetaldeído, é inibidor da MS, com diminuição da remetilação da HCT para produção de metionina.31 A hiper-HCT também está associada à ocorrência de crises convulsivas durante períodos de abstinência do álcool. A hiperestimulação de receptores NMDA pela HCT e de seus produtos de oxidação, como HCA, sem o efeito inibitório do álcool sobre os recepto-res de ácido gama-aminobutírico (GABA) durante a abstinência, ocasionaria hiperexcitação cortical e crises convulsivas.6 Alternativamente, a hiper-HCT

Vilaça CO et al.


provoca a formação de SAH, consumindo as reservas de adenosina, uma purina com efeito anticonvulsi-vante, além do já descrito efeito de proteção vascu-lar.12 O aumento dos níveis de HCT também pode colaborar para o déficit cognitivo e atrofia cerebral em pacientes com histórico de etilismo.32

O cigarro também causa hiper-HCT e este pode contribuir para o aumento do risco vascular relacio-nado ao tabagismo. O tabaco diminui as reservas de piridoxal fosfato, a forma ativa da vitamina B6. A pi-ridoxina (B6) é um cofator da enzima CBS, portanto sua inativação inibe a via de transulfuração da HCT, acarretando hiper-HCT.5 Alternativamente, o tabaco promove a liberação de substâncias tóxicas nitroge-nadas, causando a inativação da vitamina B12 e dimi-nuindo a função de remetilação da HCT pela MS.33

Poucos estudos avaliaram correlação da cocaína e seus derivados como o crack com níveis de HCT. Es-ses estudos mostram evidência de elevação da HCT ou aumento da reatividade da HCT sob a ação da co-caína. Isso está em concordância com a possibilidade de a hiper-HCT estar envolvida no risco vascular e de crises convulsivas em usuários de cocaína.34,35

TRATAMENTO DA HIPER-HOMOCISTEINEMIA

O tratamento da hiper-homocisteinemia engloba a reposição de vitamina B12 e folatos, com o objetivo de favorecer a remetilação da HCT para a formação de metionina. Esse tratamento é barato e de baixo risco. Embora a reposição de folato apresente maior impac-to na redução da hiper-HCT, em comparação com a reposição de vitamina B12, a deficiência da última é a principal causa de elevação de HCT na população.5 Sempre existe a preocupação de a terapia com folatos mascarar um quadro de déficit de vitamina B12 pree-xistente, resultando em piora do quadro neurológi-co.36 Recomenda-se, portanto, a reposição associada de ambos os elementos. Houve desânimo sobre o tratamento da hiper-HCT após o estudo multicêntri-co VITATOPS não mostrar utilidade na reposição de vitamina B12 e folato na profilaxia secundária do AVC e do acidente isquêmico transitório (AIT). Contu-do, o estudo não avaliou o efeito da diminuição da hiper-HCT em outras enfermidades neurológicas em que pode ocorrer participação da HCT.37 Uma das explicações para o insucesso do tratamento é a possibilidade, discutida anteriormente, de altos ní-

veis de HCT acarretarem elevação da SAH. A SAH inibe a produção da SAM necessária para a metilação de diversas reações vitais ao pleno funcionamento do SNC. A SAH não é difusível através das membranas celulares e não sofreria interferência com a reposição de vitamina B12 ou folatos.15

CONCLUSÃO

A homocisteína se encontra elevada em associação com as mais diversas doenças neurológicas, contudo em muitas delas não está estabelecido se esse aumen-to representa uma causa ou se é secundário a outros fatores ligados à fisiopatologia dessas enfermidades. Destaca-se o papel da hiper-homocisteinemia na ex-citotoxicidade neuronal, por meio dos receptores NMDA com influxo de cálcio e apoptose neuronal, como sendo o mecanismo implicado na maioria des-sas entidades. Mais estudos são necessários para esta-belecer o papel da homocisteína nas doenças neuro-lógicas. O tratamento de seus elevados níveis séricos é fácil, sendo feito com a reposição de vitamina B12

e folatos.

REFERÊNCIAS1. Neves LB, Macedo DM, Lopes AC. Homocisteína. J Bras Patol

Med Lab. 2004;40(5):311-20.

2. Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology. 2004;63(5):886-91.

3. Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol. 2000;57(10):1422-7.

4. Sachdev P. Homocisteína e transtornos psiquiátricos. Rev Bras Psiquiatr. 2004;26(1):50-6.

5. Badawy AA. Moderate alcohol consumption as a cardiovascular risk factor: the role of homocysteine and the need to re-explain the ‘French Paradox’. Alcohol Alcohol. 2001;36(3):185-8.

6. Bleich S, Degner D, Sperling W, Bönsch D, Thürauf N, Kornhuber J. Homocysteine as a neurotoxin in chronic alcoholism. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):453-64.

7. Wang H, Tan H, Yang F. Mechanisms in homocysteine-induced vascular disease. Drug Discov Today Dis Mech. 2005;2(1):25-31.

8. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94(11):5923-8.

9. Boldyrev AA. Why homocysteine is a risk factor of neurodegenerative diseases mini review. Neurochem J. 2007;1(1):14-20.

10. Haynes WG. Hyperhomocysteinemia, vascular function and atherosclerosis: effects of vitamins. Cardiovasc Drugs Ther. 2002;16(5):391-9.

11. Garcia A, Zanibbi K. Homocysteine and cognitive function in elderly people. CMAJ. 2004;171(8):897-904.

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12. Deussen A. Adenosine-the missing link to understanding homocysteine pathogenicity or more smoke on the horizon? Cardiovasc Res. 2003;59(2):259-61.

13. den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126(Pt 1):170-5.

14. Morris MS. Homocysteine and Alzheimer’s disease. Lancet Neurol. 2003;2(7):425-8.

15. Zhuo JM, Wang H, Praticò D. Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci. 2011;32(9):562-71.

16. Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Müller T. Hyperhomocysteinaemia in Parkinson’s disease. J Neurol. 1998;245(12):811-2.

17. Zoccolella S, Martino D, Defazio G, Lamberti P, Livrea P. Hyperhomocysteinemia in movement disorders: current evidence and hypotheses. Curr Vasc Pharmacol. 2006;4(3):237-43.

18. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 2003;26(3):137-46.

19. Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem. 2002;80(1):101-10.

20. Müller T, Muhlack S. Peripheral COMT inhibition prevents levodopa associated homocysteine increase. J Neural Transm. 2009;116(10):1253-6.

21. Boutell JM, Wood JD, Harper PS, Jones AL. Huntingtin interacts with cystathionine beta-synthase. Hum Mol Genet. 1998;7(3):371-8.

22. Levin J, Bötzel K, Giese A, Vogeser M, Lorenzl S. Elevated levels of methylmalonate and homocysteine in Parkinson’s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. Dement Geriatr Cogn Disord. 2010;29(6):553-9.

23. Zoccolella S, Simone IL, Lamberti P, et al. Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis. Neurology. 2008;70(3):222-5.

24. Orrell RW. What is the clinical significance of SOD1 mutations in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2010;81(5):473.

25. Luo JJ, Sivaraaman K, Nouh A, Dun NJ. Elevated plasma level of homocysteine is an independent risk factor for peripheral neuropathy. Br J Med Med Res. 2014;4(1):161-9.

26. Hooshmand B, Solomon A, Kåreholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology. 2010;75(16):1408-14.

27. Zoccolella S, Tortorella C, Iaffaldano P, et al. Elevated plasma homocysteine levels in patients with multiple sclerosis are associated with male gender. J Neurol. 2012;259(10):2105-10.

28. Ramsaransing GS, Fokkema MR, Teelken A, Arutjunyan AV, Koch M, De Keyser J. Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77(2):189-9.

29. Ashtari F, Abari SS, ShayganNejad V. Serum homocysteine level in patients with multiple sclerosis. J Res Med Sci. 2005;10(5): 302-4.

30. Zhang L, Shu Y, Sun S, et al. Plasma homocysteine levels in neuromyelitis optica. Int J Neurol Neurother. 2014;1(10).

31. Bleich S, Carl M, Bayerlein K, et al. Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS). Alcohol Clin Exp Res. 2005;29(3):334-6.

32. Bleich S, Bandelow B, Javaheripour K, et al. Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism. Neurosci Lett. 2003;335(3):179-82.

33. Sobczak AJ. The effects of tobacco smoke on the homocysteine level – a risk factor of atherosclerosis. Addict Biol. 2003;8(2):147-58.

34. Williams RH, Maggiore JA, Shah SM, Erickson TE, Negrusz A. Effects of cocaine abuse on plasma homocysteine and related thiols. Ther Drug Monit. 1999;21(4):471.

35. Kowalczyk-Pachel D, Chwatko G, Iciek M, et al. The effects of cocaine on different redox forms of cysteine and homocysteine, and on labile, reduced sulfur in the rat plasma following active versus passive drug injections. Neurotox Res. 2013;24(3):377-92.

36. Johnson MA. If high folic acid aggravates vitamin B12 deficiency what should be done about it? Nutr Rev. 2007;65(10):451-8.

37. VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010;9(9):855-65.

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Rev Bras Neurol. 51(3):79-83, 2015

Polineuropatia secundária ao uso crônico de estatinas

Polineuropathy due to chronic use of statins

Karina Magalhães de Castro Henriques1, Jackeline Moreira Campos Pereira2, Marco Orsini3, Marcos Raimundo Gomes de Freitas4

1 Residente do Setor de Doenças Neuromusculares, Serviço de Neurologia do Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil.2 Especializanda do Setor de Doenças Neuromusculares, Serviço de Neurologia do HUAP, UFF, Niterói, RJ, Brasil.3 Professor do Programa de Mestrado/Doutorado em Neurologia/Neurociências do Setor de Doenças Neuromusculares, Serviço de Neurologia do HUAP, UFF, Niterói, RJ, Brasil.4 Professor titular e chefe do Setor de Doenças Neuromusculares, Serviço de Neurologia do HUAP, UFF, Niterói, RJ, Brasil.

Endereço para correspondência: Dra. Karina Magalhães de Castro Henriques. Rua Doutor Tavares de Macedo, 136/1801, bloco B, Icaraí – 24220-211 – Niterói, RJ, Brasil. E-mail: [email protected]

RESUMOOs inibidores da 3-hidroxi-3-metilglutaryl coenzima-A (HMG-CoA) redutase têm eficácia comprovada em reduzir os níveis de colesterol e prevenir a inflamação do endotélio coronariano, cerebral e perifé-rico. Os efeitos adversos devem ser conhecidos, pois sua suspensão pode levar à completa reversibilidade dos sintomas. São descritas complicações musculares, entre elas, mialgia, miosite e rabdomió-lise, além de complicações hepáticas, neuropatias e outras. Foram revistos 1 estudo experimental, 6 estudos populacionais, 25 relatos de casos e 2 revisões sobre o tema, a maioria apontando para a real existência dessa complicação. A neuropatia induzida por estatinas tem incidência aproximada de 12 por 100.000 pessoas-ano. Apresen-ta-se mais comumente como polineuropatia sensitivo-motora axo-nal de predomínio sensitivo. Em alguns casos, agravam neuropatias periféricas preexistentes. A fisiopatologia parece convergir para o comprometimento da cadeia respiratória mitocondrial. O diagnósti-co baseia-se na relação temporal entre o uso ou suspensão da droga e o surgimento ou melhora dos sinais e sintomas. Os exames labora-toriais são fundamentais para excluir causas de neuropatias periféri-cas bem estabelecidas. O prognóstico relaciona-se com o momento de suspensão da droga, com relatos desde melhora completa até irreversibilidade.

Palavras-chave: Polineuropatia, estatinas, neuropatia periférica.

ABSTRACTInhibitors of coenzyme A 3-hydroxy-3-metilglutaryl (HMG-CoA) re-ductase inhibitors have proven to reduce cholesterol levels and prevent inflammation of the coronary, cerebral and peripheral en-dothelium. Adverse effects should be known, for its suspension can lead to complete reversibility of symptoms. Muscle complications are described, among them, myalgia, myositis and rhabdomyolysis, besides hepatic, neuropathies, and others. One experimental study and 6 population studies, 25 cases reports, and other 2 reviews were reviewed, most pointing to the actual existence of this complication. Statin induced neuropathy has an approximate incidence of 12 per 100,000 persons-year. It most commonly is presented as a sensori-motor axonal polyneuropathy predominantly sensory. In some cases it aggravates pre-existing peripheral neuropathies. The pathophy-siology seems to converge to impairment of the mitochondrial res-piratory chain. The diagnosis is based on the temporal relationship between the use or discontinuation of the drug and the emergence or improvement of signs and symptoms. Laboratory tests are essential to exclude well established causes of peripheral neuropathies. The prognosis is related to the moment of drug suspension, with reports from complete recovery to irreversibility.

Keywords: Polineuropathy, statins, peripheral neuropathy.


ESTATinAS

Os inibidores da 3-hidroxi-3-metilglutaryl coenzi-ma-A (HMG-CoA) redutase, comumente conheci-dos como estatinas, constituem uma notável classe de medicamentos hipolipemiantes empregados na atualidade. A eficácia na prevenção primária e secundária de eventos cardiovasculares e cerebrovas-culares, além da segurança na administração das es-tatinas comprovados em estudos (4S, CARE, HPS, LIPID, WOSCOPS, SPARCLE),15 tornou-as os principais hipolipemiantes.

Atualmente, sete estatinas são empregadas cli-nicamente: lovastatina (Mevacor®), pravastatina (Pravachol®), sinvastatina (Zocor®), derivado semis-sintético, e fluvastatina (Lescol®), primeiro agente totalmente sintético, derivado de mevalonolactona, produzido na forma racêmica. A nova geração de es-tatinas sintéticas, puras, é representada por atorvasta-tina (Lipitor®), rosuvastatina (Crestor®) e pitavastati-na (Livalo®).8,16

As estatinas atuam primariamente no fígado, onde um sistema especial de transporte permite sua incorporação ao tecido hepático para biotransforma-ção, com ampla variação tanto no seu sítio metabóli-co como na formação de metabólitos ativos, até sua eliminação pela bile. Alguns polimorfismos genéticos e a interação com alguns fármacos podem determi-nar dificuldade na sua captação, metabolização e eli-minação.3 O mecanismo de ação das estatinas para obtenção da redução do colesterol se deve à inibição reversível e competitiva da enzima HMG-CoA redu-tase, na conversão para mevalonato, um precursor do colesterol, por meio de uma afinidade desses fárma-cos com o sítio ativo da enzima. A principal indica-ção para uso das estatinas é o tratamento da hiper-colesterolemia, que se refere aos níveis aumentados de colesterol na corrente sanguínea. Condições com elevadas concentrações de partículas LDL oxidadas, especialmente partículas LDL pequenas, estão asso-ciadas com a aterosclerose, que é a principal causa de doença arterial coronariana (DAC). Em contraste, as partículas de HDL têm sido identificadas como me-canismo pelo qual o colesterol e mediadores inflama-tórios podem ser removidos da placa de ateroma. As taxas aumentadas de HDL estão relacionadas a taxas menores de progressão e até mesmo regressão dos ateromas. Os efeitos colaterais relacionados à medi-cação são principalmente hepáticos e musculares, e recentemente foi relatada neuropatia periférica.7,27,29

nEUROPATiA PERiFÉRiCA inDUZiDA POR ESTATinAS

São descritas complicações musculares, entre elas, mialgia, miosite e rabdomiólise, além de complica-ções hepáticas, neuropatias e outras relacionadas a estatinas. Foram revistos 1 estudo experimental, 6 es-tudos populacionais, 25 relatos de casos e 2 revisões sobre a existência de neuropatias periféricas relacio-nadas a estatinas.1-34,39

inCiDÊnCiA

Os dados disponíveis atualmente não são conclusivos para determinar a incidência. No entanto, uma revisão sistemática22 de 2006, com um total de 16 relatos de casos publicados e quatro estudos de coorte, mostrou heterogeneidade entre eles. A estimativa combinada de risco relativo foi de 1,8 (95% IC 1,1-3,0). Os resul-tados indicam incidência de 12 por 100.000 pessoas- -ano ou prevalência de 6 em 10.000 pessoas, ou 1 em 10.000 pacientes tratados por um ano.22

Existem várias hipóteses acerca de como as esta-tinas levam à neuropatia periférica. De acordo com os relatos de casos e estudos disponíveis até o mo-mento, o risco desse efeito colateral parece aumentar com o tempo de uso e a dose total do medicamento. Teorias sugerem diversas causas: a própria redução nos níveis de colesterol; a inibição de ubiquinona; o bloqueio da síntese de dolicolfosfato; ou a inibição da isopentenilação de selenocisteína tRNA; e a inibi-ção de remielinização4,22 (Figura 1).

(Adaptada de: Bhalla et al.5)

Figura 1. Provável mecanismo causador de polineuropatia secundária ao uso de estatinas.

HMG-CoA Mevalonato

Estatinas

Colesterol

Farnesilpirofosfato

Síntese de Co-Q10

Atividade antioxidante

Ação antioxidante

Polineuropatiasecundária às estatinas

Produção de mielina

Formação de sinapse

Dano na transmissão neuronal

Henriques KMC et al.


Polineuropatia e estatinas

Coulson11 refere que a polineuropatia (PNP) se-cundária a estatinas se relaciona com o tempo de uso, além de estar mais relacionada às estatinas lipofílicas como a sinvastatina e a lovastatina. Além disso, a neuropatia parece ser dose-dependente e estar rela-cionada com o maior tempo de exposição.10

Apesar dessas teorias, há ainda alguns autores, como Shi et al.,35 que defendem o efeito benéfico das estatinas nas neuropatias periféricas atuando na redução da resposta inflamatória, por meio da dimi-nuição da produção de citocinas.

QUADRO CLÍniCO

Substâncias, quando administradas, promovem efei-tos sistêmicos e, portanto, quando acometem o sis-tema nervoso periférico, fazem-no de forma difusa. Sendo assim, o quadro clínico de polineuropatia é mais provável do que o de mononeuropatias ou mo-noneuropatias múltiplas.

Os pacientes apresentam-se com quadro de poli-neuropatia insidiosa, de predomínio distal, em geral sensitivo, com abolição de reflexos, mas pode haver sintomas motores ou autonômicos. São descritos, porém, casos de neuropatias agudas ou subagudas.15

Existem casos atípicos relatados. Scola et al.,33 Ra-jabally et al.,31 Vaughan e Bell39 e Sasson e Pesach32

referem o uso de estatinas predispondo a neuropa-tias como mononeuropatia múltipla, síndrome de Guillain-Barré, neuropatia diabética autoimune com sintomas autonômicos e meralgia parestésica, respec-tivamente.

ELETROnEUROMiOGRAFiA

Entre os casos relatados, 21 pacientes realizaram ele-troneuromiografia (ENMG), e o acometimento axo-nal foi observado em 12 dos casos apresentados, 4 tinham comprometimento apenas de fibras finas, ha-via disfunção sensitiva isolada em 2 casos e 1 paciente teve PNP sensitivo-motora, sem referência de ser por acometimento axonal ou desmielinizante.6,11,21,30-33

OUTROS EXAMES

Como sugerido por Boger et al.,6 podem ser neces-sários novos estudos eletrofisiológicos que envolvam

avaliação de fibras finas, somáticas ou autonômicas, entre eles o QSART (Quantitative Sudomotor Axon Reflex Test), o CPT (Current Perception Threshold Testing), o LEP (Laser-Evoked Potentials), o CHEPs (Contact Heat-Evoked Potential Stimulators), o Mi-croneurografic C-fiber Recordings, o SSR (Sympa-thetic Skin Response), o Skin Vasomotor Temperature Testing, o LDF (Laser Doppler Flowmetry), o Car-diovascular Reflex Testing, Metaiodobenzylguanidine (123I-MIBG) Scintigraphy ou, mais recentemente, a biópsia de pele.

ASSOCiAÇÃO COM MiOPATiAS

Na maioria dos estudos, os grupos placebo e estuda-do apresentam entre 1% e 5% de complicações mus-culares.10 Nos pacientes com neuropatia causada por estatina que apresentam dor generalizada, deve-se fazer eletromiografia para verificar a coexistência de miopatia.15

Os autores consideraram importante investigar, ainda, miopatias em todos os pacientes que desenvol-vessem alterações musculares ou elevação nos níveis de CK em vigência do uso de estatinas.31,32,39

DiAGnÓSTiCO DiFEREnCiAL

O diagnóstico da PNP induzida por estatinas se dá principalmente por exclusão de outras PNP. A into-lerância à glicose foi relacionada como responsável por muitas das PNP antes diagnosticadas como PNP idiopáticas por Singleton et al.,36 em 2005, o que pode invalidar alguns estudos antigos, que relacio-naram o uso de estatinas ao surgimento da doença e não consideraram a intolerância à glicose como cri-tério de exclusão.

TRATAMEnTO

Interromper a terapia com estatinas e observar a me-lhora potencial é a conduta ideal até o momento e também é a chave do diagnóstico da PNP induzida por estatinas, após a exclusão de causas bem estabe-lecidas. Coulson,11 após suspender o uso de estatinas, prescreveu ezetimiba 10 mg/dia ou niacina 2g diá-rios, o que pode ser considerado uma opção terapêu-tica para a hipercolesterolemia.


Um caso isolado foi reportado, em que o pacien-te recebeu ubiquinona (coenzima Q10) 30 mg/dia, cursando com melhora da neuropatia induzida pela lovastatina.13

COMORBiDADES

Estudo populacional de Corrao et al.10 parece não comprovar que o risco de neuropatia periférica entre os pacientes com comorbidades seja maior. Os resul-tados sugerem que a associação entre agentes hipoli-pemiantes e PNP ocorre de forma independente da presença de comorbidades (doenças da tireoide, ane-mia, diabetes, insuficiência renal crônica e doenças do tecido conectivo). No entanto, ainda permanece in-certa a necessidade de suspender ou evitar a terapia com estatinas nos pacientes que já apresentam com-prometimento do sistema nervoso periférico ou que possuem doenças que predispõem ao seu surgimento.

PROGnÓSTiCO

O prognóstico parece relacionar-se com o tempo de uso das estatinas e com o tempo entre o início dos sintomas e a suspensão da droga. Estudos sugerem que os pacientes que tiveram suspeita de PNP rela-cionada a estatinas, logo em seguida ao início dos sintomas, quando descontinuada a terapia, mostra-ram reversibilidade parcial ou completa do quadro.6

COMEnTÁRiOS

Após análise dos dados fornecidos, algumas ques-tões podem ser discutidas. Os estudos populacionais apontam para a real existência de uma neuropatia pe-riférica induzida por uso de estatinas, não conseguin-do excluir essa possibilidade. Eles evidenciam que a PNP ocorre de forma independente da presença de comorbidades. A média de idade entre os relatos de casos encontrados foi de 56,25 anos (variando de 18 a 68 anos). O tempo médio de recuperação parcial ou completa após qualquer retirada da droga foi de 61 dias (variando de duas semanas a nove meses).12-18

A variabilidade genética entre indivíduos parece in-fluenciar na resposta hipolipemiante das estatinas, na possibilidade de surgirem efeitos colaterais e na forma como estes se apresentam. Esse fator, além de outros,

como presença de comorbidades, interações medica-mentosas, particularidades da estatina, dose e tempo de uso, pode ser responsável pela variabilidade de apre-sentações discutidas nos relatos de casos. O novo con-senso da Academia Americana de Cardiologia,37 com a proposta de expansão da indicação das estatinas, torna a discussão acerca dos efeitos colaterais cada vez mais relevante. Assim, novos estudos devem ser elaborados para melhores esclarecimentos sobre o tema.

COnCLUSÃO

Considerando os dados observados, as estatinas su-peram em benefícios no que se refere à proteção contra eventos vasculares cardíacos, em relação aos efeitos adversos no sistema nervoso periférico. A evi-dência da ação em afecções que possam levar a várias oclusões arteriais e a rigidez de metas estabelecidas na terapia hipolipemiante (colesterol LDL < 70 mg/dl), além dos efeitos pleiotrópicos, tornam o uso dessas drogas extremamente necessário.

Assim como todos os medicamentos usados em grande proporção, os raros efeitos colaterais tornam--se situações de grande importância para conheci-mento dos médicos.

A fisiopatologia por inibição na produção de ubi-quinona parece ser a teoria mais aceita. O quadro clínico leva a crer que o acometimento do sistema nervoso periférico tem forma difusa, levando à PNP. O processo por si só pode ter sido iniciado com comprometimento predominante de fibras finas, o que justifica os casos relatados em que os exames de ENMG estavam normais.

O tratamento se dá com a suspensão da droga e a substituição por outra classe de hipolipemiantes, sempre associado à terapia dietética. Não está claro se a redução da dose pode ser suficiente. Deve ser lembrado que a neuropatia periférica pode não ser o ponto principal de atenção necessária ao paciente, já que muitos usuários de estatinas estão sob risco de eventos vasculares, o que implica maior morbidade e mortalidade. O prognóstico parece ser bom quando a droga é suspensa no início da sintomatologia.

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Henriques KMC et al.


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3. Anderson JL, Muhlestein JB, Bair TL, et al. Do statins increase the risk of idiopathic polyneuropathy? Am J Cardiol. 2005;95(9):1097-9.

4. Backes JM, Howard PA. Association of HMG-CoA reductase inhibitors with neuropathy. Ann Pharmacother. 2003;37(2):274-8.

5. Bhalla S, Singh N, Jaggi AS. Statins: do they aggravate or ameliorate neuropathic pain? J Pain. 2014;15(11):1069-80.

6. Boger MS, Hulgan T, Donofrio P, Peltier AC. QSART for diagnosis of statin-associated polyneuropathy. Muscle Nerve. 2011;43(2):295-6

7. Brass LM, Alberts MJ, Sparks L; National Lipid Association Statin Safety Task Force Neurology Expert Panel. An assessment of statin safety by neurologists. Am J Cardiol. 2006;97(8A):86C-88C.

8. Campo VL, Carvalho I. Estatinas hipolipêmicas e novas tendências terapêuticas. Quim. Nova 2007;30(2):425-30.

9. Chazerain P, Hayem G, Hamza S, Best C, Ziza JM. Four cases of tendinopathy in patients on statin therapy. Joint Bone Spine. 2001;68(5):430-3.

10. Corrao G, Zambon A, Bertù L, Botteri E, Leoni O, Contiero P. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases. J Epidemiol Community Health. 2004;58(12):1047-51.

11. Coulson WF. Statin Neuropathy. J Farm Pract. 2011;60(4):182-4.

12. de Langen JJ, van Puijenbroek EP. HMG-CoA-reductase inhibitors and neuropathy: reports to the Netherlands Pharmacovigilance Centre. Neth J Med. 2006;64(9):334-8.

13. Drory VE, Groozman GB, Rubinstein A, Korczyn AD. Hypertriglyceridemia may cause a subclinical peripheral neuropathy. Electromyogr Clin Neurophysiol. 1999;39(1):39-41.

14. Durrieu G, Lacroix I, Olivier P, Sommet A, Sénard JM, Montastruc JL. Neuropathies médicamenteuses: analyse de la Banque française de pharmacovigilance de 1995 à 2005. Presse Med. 2008;37:935-42.

15. Fenoll LT, Pascual JM, Estefânia CM. Estatinas y patologia neuromuscular. Rev Neurol. 2008;47:46-51.

16. Fonseca FAH. Farmacocinética das estatinas. Arq Bras Cardiol. 2005;85 (5):9-14.

17. Gaist D, García Rodríguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol. 2001;56(12):931-3.

18. Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58(9):1333-7.

19. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs. 2008;8(6):373-418.

20. Jacobs MB. HMG-CoA reductase inhibitor therapy and peripheral neuropathy. Ann Intern Med. 1994;120(11):970.

21. Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol. 1999;54(11):835-8.

22. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C-60C.

23. Leis AA, Stokic DS, Olivier J. Statins and polyneuropathy: setting the record straight. Muscle Nerve. 2005;32(4):428-30.

24. Ii M, Nishimura H, Kusano KF, et al. Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy. Circulation. 2005;112(1):93-102.

25. Lo YL, Leoh TH, Loh LM, Tan CE. Statin therapy and small fibre neuropathy: a serial electrophysiological study. J Neurol Sci. 2003;208(1-2):105-8.

26. Mangravite LM, Krauss RM. Pharmacogenomics of statin response. Curr Curr Opin Lipidol. 2007;18(4):409-14.

27. McManis PG, Windebank AJ, Kiziltan M. Neuropathy associated with hyperlipidemia. Neurology. 1994;44(11):2185-6 .

28. Otruba P, Kanovsky P, Hlustik P .Treatment with statins and involvement of peripheral nervous system: results of a prospective clinical and neurophysiological follow–up.2007Neuro Endocrinol Lett. 2011;32(5):688-690.

29. Pasternak RC, Smith SC, Merz CNB, Grundy SM, Cleeman JL, Lenfant C. ACC∕AHA∕NHLBI clinical advisory on the use and safety of statins. Stroke. 2002;33:2337-41.

30. Phan T, McLeod JG, Pollard JD, Peiris O, Rohan A, Halpern JP. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatr. 1995;58(5):625-8.

31. Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain-Barré syndrome on initiation of statin therapy. Muscle Nerve. 2004;30(5):663-6.

32. Sasson M, Pesach S. Simvastatin-induced meralgia paresthetica. J Am Board Fam Med. 2011;24(4):469-73.

33. Scola RH, Trentin AP, Germiniani FM, Piovesan EJ, Werneck LC. Simvastatin-induced mononeuropathy multiplex: case report. Arq Neuropsiquiatr. 2004;62(2B):540-2.

34. Seehusen DA, Asplund CA, Johnson DR, Horde KA. Primary evaluation and management of statin therapy complications. South Med J. 2006;99(3):250-6.

35. Shi XQ, Lim TK, Lee S, Zhao YQ, Zhang J. Statins alleviate experimental nerve injury-induced neuropathic pain. Pain. 2011;152(5):1033-43.

36. Singleton JR, Smith AG, Russell J, Feldman EL. Polyneuropathy with impaired glucose tolerance: implications for diagnosis and therapy. Curr Treat Options Neurol. 2005;7(1):33-42.

37. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-S45.

38. Tsivgoulis G, Spengos K, Karandreas N, Panas M, Kladi A, Manta P. Presymptomatic neuromuscular disorders disclosed following statin treatment. Arch Intern Med. 2006;166(14):1519-24.

39. Vaughan TB, Bell DSH. Statin neuropathy masquerading as diabetic autoimmune polyneuropathy. Diabetes Care. 2005;28(8):2082.

40. Ziajka PE, Wehmeier T. Peripheral neuropathy and lipid-lowering therapy. South Med J. 1998;91(7):667-8 .

Polineuropatia e estatinas


Rev Bras Neurol. 51(3):84-8, 2015

Charcot and aphasia: contributions of his assistants

Charcot e afasia: contribuições de seus assistentes

Eliasz Engelhardt1, Marleide da Mota Gomes2

1 Neurologist, full professor (retired), Cognitive and Behavioral Neurology Unit, Institute of Neurology Deolindo Couto, Alzheimer’s Disease Center, Institute of Psychiatry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.2 Neurologist, associate professor, Epilepsy Program, Institute of Neurology Deolindo Couto, School of Medicine, UFRJ, Rio de Janeiro, RJ, Brazil.

Address for correspondence: Dr. Eliasz Engelhardt. E-mail: [email protected]

ABSTRACTThe ideas and concepts regarding language and its disorders have a longstanding history. However, it was possible to consider the 19th century as the period when the main milestones on the subject be-gun to be settled, with Paul Broca’s and Carl Wernicke’s pivotal fin-dings. Albeit language disorders (aphasia) were not, apparently, his preferential interest, Charcot engaged himself in the issue, and after thorough studies delivered a series of lectures on this theme at the Salpêtrière Hospital, transcribed by two of his assistants, Charles Féré and Gaetano Rummo, and then published. Other three assis-tants, inspired in Charcot’s teachings, Désiré Bernard, Gilbert Ballet and Pierre Marie, contributed independently with papers or books. The lectures and the contributions of those collaborators were par-tially incorporated in the Oeuvres Complètes published by Charcot.

Keywords: Language disorders, aphasia, Charcot, Féré, Rummo, Bernard, Ballet, Marie.

RESUMOAs ideias e os conceitos sobre a linguagem e suas desordens pos-suem uma história de longa duração. Entretanto, é possível conside-rar o século XIX como o período no qual os principais marcos sobre o tema começaram a ser estabelecidos, com os achados fulcrais de Paul Broca e Carl Wernicke. Embora desordens da linguagem (afasia) não tenham sido, aparentemente, seu interesse predileto, Charcot se envolveu no assunto e, depois de aprofundados estudos, ministrou uma série de lições sobre o tema no Hospital da Salpêtrière, trans-critas por dois de seus assistentes, Charles Féré e Gaetano Rummo, sendo publicados em seguida. Outros três assistentes, inspirados nos ensinamentos de Charcot, Désiré Bernard, Gilbert Ballet e Pierre Marie, contribuíram de modo independente com artigos ou livros. As lições e as contribuições desses colaboradores foram parcialmente incorporadas nas Oeuvres Complètes publicadas por Charcot.

Palavras-chave: Desordens da linguagem, afasia, Charcot, Féré, Rummo, Bernard, Ballet, Marie.


INTRODUCTION

The ideas and concepts regarding language and its disorders have a longstanding history. However, it is possible to circumscribe to the 19th century the uncovering of the main milestones about the sub-ject.1 Modern studies, apparently, begun with Franz Joseph Gall (1758-1828), with his phrenological approach, which included memory for words and the sense of the language faculty (1808). Follow-ing, Jean-Baptiste Bouillaud (1796-1881) localized the language center in the “anterior lobe” [frontal lobe] (1825), and Marc Dax (1771-1837) located “the forgetfulness of the signs of the thought” in the left hemisphere (presented in 1836, published only in 1865). More precise and consistent studies of language-brain relationships were inaugurated by Paul Broca (1824-1880), who described a le-sion in the posterior part of the 3rd left frontal gy-rus associated to a disorder of ‘‘motor’’ language (speech) he named “aphemia” (1861). Soon, Ar-mand Trousseau (1801-1867) introduced the term “aphasia” (1864) in substitution of Broca’s designation. Later, Carl Wernicke (1848-1905) described a ‘‘sensory’’ form of language disor-der (1874) due to a lesion in the posterior part of the 1st left temporal gyrus.1,2 Further observations identified other language centers – “center for vi-sual memory” (1869) [Henry Charlton Bastian (1837-1915)], “center for ideation” (1872) [Wil-liam Henry Broadbent (1835-1907)], and “center for writing” (1881) [Siegmund Exner Ritter von Ewarten (1846-1926)].2,3

Broca’s and Wernicke’s findings raised a “local-izationistic” theory, initially with centers for expres-sion (“motor aphasia”) and for reception (“sensory aphasia”). However, some neurologists acknowl-edged the weight of connections between the cen-ters, an “information processing model”. Wernicke was the first of them, proposing such interconnec-tions, and predicting “conduction aphasia” (1874), soon followed by (1877) Adolph Kussmaul (1822-1902), Jean-Martin Charcot (1825-1893) [“The bell diagram” (1884)], and by Ludwig Lichtheim (1845-1928) [“Lichtheim’s House” (1885)], among others, giving way to an “associationist” or “connectionist” theory.2-4 The prestigious Eng-lish neurologist Henry Head (1861-1940) came

to dismiss the latter models, labeling those illustri-ous authors as “diagram makers”, in a depreciative manner.4 Other authors, like Pierre Marie, based on his clinicopathological studies, contested both theories, arguing misinterpretation of the available data.5 Finally, “holistic” models were also proposed, as by Sigmund Freud (1856-1939) and Constantin von Monakow (1853-1930), the latter adding his concepts of “diaschisis” and “plasticity” to explain symptoms and recovery of language disorders after brain lesions.5,6

CHARCOT AND APHASIA

Aphasia was not, apparently, Charcot’s preferential interest. However, he studied in depth the subject and delivered a series of Lessons (lectures) on the theme at the Salpêtrière Hospital. Transcribed by one of his assistants, Charles Féré (1852-1907), they were published in Le Progrès Médicale (1883) in five consecutive numbers7. These lectures, unfolded in nine chapters, apparently the only complete ver-sion of the originally delivered, were transcribed and translated to Italian by Gaetano Rummo (1852-1917), who attended Charcot’s clinic, and pub-lished (1884), the Differenti forme d’afasia: lezioni fatte nella Salpetriere nel semestre d’estate dell’anno 1883, as a book with many figures.8,9 Charcot was identified as a connectionist (diagram-maker), and authored one of the known schemata, “The bell dia-gram”, that appeared for the 1st time in his Italian translated conferences.3,8

CHARCOT’S ASSISTANTS AND THEIR STUDIES ON APHASIA

The Salpêtrière School produced important con-tributions to aphasia, not only by Charcot himself, with his memorable lectures, but also by his assis-tants, who worked, in different moments, at the Salpêtrière Hospital.10 Besides Féré and Rummo who transcribed Charcot’s lectures, Désiré-An-toine-François Bernard (1853-1888) (Box 1), Gil-bert Ballet (1853-1916) (Box 2), and Pierre Marie (1853-1940) (Box 3) must be cited for their impor-tant contributions.

Aphasia and Charcot’s assistants


Box 1. Contribution of Désiré Bernard (with condensed excerpts)

Désiré Bernard, one of Charcot’s Interne (House Officer) (1883), remained relatively unkown.10

Bernard approached his studies on aphasia after deeply immersing in Charcot’s teachings, and stated that without those it would not be possible to escape of getting lost in the maze of information accumulated since 1861 (year of Broca’s finding).3 He defended his inaugural thesis De l’aphasie et de ses diverses formes (1885), published as a commercial book in the same year,10,11 soon followed by a new edition (1889), considering its positive reception, with the collaboration of Féré. The book comprised definition and history, relation of language and aphasia, anatomical localizations, the several language disorders (verbal blindness, verbal deafness, aphemia, agraphia, complex aphasias, and forensic medicine) known at the time, anatomical and pathological drawings. Charcot’s bell diagram, already presented in his thesis, is displayed in Chapter III (Le langage et l’aphasie) (Figure 1). Apparently, it was published there for the 1st time in French. He sustained that the diagram easied the understanding of the mechanisms of language and their changes and degradations that occurred in aphasia. The convexity of the left hemisphere with the localization of the language centers was also displayed (Figure 2). Bernard explained that he made nothing else than to implement Charcot’s notes, including the diagram that the master kindly permitted to be published.11

Désiré Bernard, in his short time of life, was an important contributor to the development of knowledge on aphasia of the Salpêtrière School.

The bell (cloche) rings, it is heard and seen. The centers were defined by clinicopathological analysis. Input – auditory input: CAC: center of shared hearing, and CAM: auditory center for words; visual input: CVC: center of shared vision, and CVM: visual center for words. Output – spoken output: CLA: center of articulated language; written output: CLE: center of written language. IC: ideation center. Arrows show the direction of the nervous paths connecting the centers.

Figure 1. Charcot´s bell diagram, in Bernard’s book.11

[1] Sylvius fissure; [2] Rolando sulcus; [3] interparietale sulcus; [4] parallel [1st temporal] sulcus; [5] external perpendicular fissure.

[F1] 1st frontal gyrus; [F2] 2nd frontal gyrus; [F3] 3rd frontal gyrus; [Fa] ascending frontal gyrus; [Pa] ascending parietal gyrus; [Ps] superior parietal lobule; [Pi] inferior parietal lobule; Pc, angular gyrus [lobule du pli courbe]; [T1] 1st temporal gyrus; [T2] 2nd temporal gyrus; [T3] 3rd temporal gyrus; [O1] 1st occipital gyrus; [O2] 2nd occipital gyrus; [O3] 3rd occipital gyrus.

[F2] Agraphy; [F3] Motor aphasia (Bouillaud-Broca type); [T1] Verbal deafness; [Pi] Verbal blindness.

Figure 2. Left hemisphere convexity and the localization of the language centers, in Bernard’s book (after Dr. P. Richer’s autopsy sheets).11

Box 2. Contribution of Gilbert Ballet (with condensed excerpts)

Gilbert Ballet was one of Charcot’s Interne (1880) and Chef de Clinique (Head of Clinic) (1882).10

The book Le langage intérieur et les diverses formes de l’aphasie was his main contribution to the theme (1886).12 He discussed the development of language since infancy. To understand the mental operations for the acquisition of understanding and speaking he reminded two laws of thought, sensation (visual, auditory, etc.) and association (sensations and the derived ideas). He stated that words, spoken or written, were ancillary to ideas, not inseparable – the idea may exist without the representative word, and might be formed without or before the word. Charcot’s bell diagram was utilized for better explaining the matter. He considered the word as constituted by the association of four kinds of images – auditory (heard word), visual (read word), motor of articulation (spoken word) and motor graphic (written word), interplaying internally. Such images emerge during ones reflection (thinking), constituting an internal phenomenon, a veritable “interior language”. Ballet intended to show that aphasia was an incomplete or complete deterioration of one or several modalities of the interior language. Further, he discussed aphasia in general, examined the known forms (verbal blindness, verbal deafness, motor aphasia, agraphia, combined aphasias, and conduction aphasia), and localized the centers of language, similar to Bernard’s, and concluded with diagnostic considerations of the different forms of aphasia.12

Gilbert Ballet’s “interior language” concept was a major contribution to aphasia studies of the Salpêtrière School.

Engelhardt E, Gomes MM


Aphasia and Charcot’s assistants

Box 3. Contribution of Pierre Marie (with condensed excerpts)

Pierre Marie was Charcot’s Interne (1882) and Chef de Clinique (1883-1884), and later his successor.9,10

He published a review on aphasia (1883) and then the paper De l’Aphasie en general et de l’Agraphie en particulier d’aprés l’enseignement de M. le professeur Charcot (1888),14 where he reported a case of a female who, after a stroke, presented incapacity to write, despite able to hold a pen, and knowing what she wanted to write. However, “the scheme of the characters did not come back” – she forgot their form. The abilities to read and to speak were maintained. After three more strokes she lost her speech. There was not verbal deafness or blindness, she was able to draw named or written objects, copy characters and numbers, staying unable to write spontaneously or on command. Thus, she retained the visual and auditory images, and possibly the motor image of articulation, but has lost the mechanism to express herself by written language – a true agraphia. Marie discussed the condition, reminding that the term was introduced (1869) by John William Ogle (1824-1905). He described and draw a schema of the paths related to written language (Figure 3) implemented from Charcot’s diagram, as he specified, and explained the consequences after lesions, always citing Charcot’s ideas.13

However, his concepts on aphasia, diametrically opposed to those of Broca and Wernicke, were only disclosed in 1906, raising polemics (“Marie the Iconoclast”, according Head).14 Developments on this issue might deserve, in another opportunity, further consideration.

Pierre Marie was one of the main contributors on aphasia of the Salpêtrière School, and also one of the most outstanding neurologist of his time.

CVC: center of shared vision; CVM: visual center for words; CAC: center of shared hearing; CAM: auditory center for words; CLA: center of articulated language; CLE: motor center for written language.

Figure 3. Pierre Marie’s diagram displaying the language centers, and the inputs (visual, auditory) and outputs (spoken, written).13 (Arrows show the direction of the nervous pathways).

COMMENTARIES

The historical thoughts regarding language and its disorders paved the way to the modern concepts, which emerged in the 19th century, when the main milestones begun to be settled, between 1861 and 1881, initially with Broca’s and Wernicke’s findings, soon followed by Bastian’s, Broadbent’s, and Exner’s contributions, who established the localization of specific language “centers”. The initial concepts of centers, favored by the “localizationists”, were com-plemented by the acknowledgement of the value of their interconnections, privileged by the “asso-ciationists” or “connexionnists”, represented mainly by Wernicke, Lichtheim, and Kussmaul. The latter were depreciated by Head, labeling these authors as “diagram makers”, followed by Marie, who criticized both models, and then Freud and von Monakow, who proposed, alternatively, a “holistic” model.

In such a scenario stepped in Charcot. Albeit lan-guage disorders (aphasia) were not, apparently, his preferential interest, he engaged himself in the issue, and after thorough studies delivered a series of lec-tures on this theme at the Salpêtrière Hospital, tran-scribed by two of his assistants, Féré and Rummo, and then published. Other three assistants, Bernard, Ballet and Marie contributed independently with pa-pers or books, inspired in Charcot’s teachings. It is worthwhile to remind that the master’s lectures to-gether with contributions of his collaborators, who worked on this theme, were partially incorporated in Charcot’s Oeuvres completes, volume III (pp 154-192, 513-523) of the 1890 edition,15 transcribed and published by Babinski, Bernard, Féré, Guinon, Marie and Gilles de la Tourette, his close assistants.

Conflict of interest

None for this paper.

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Engelhardt E, Gomes MM

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