CONACyT Vol. 18, núm. 6 (noviembre-diciembre de 2017)
Rev Mex Neuroci ahora en Revista Mexicana de Neurociencia Publicación oficial de la Academia Mexicana de Neurología A.C. Revista Mexicana de Neurociencia; 18,6 (2017):1-103 Mexicana Revista
Órgano Oficial de Difusión de la AMN Academia Mexicana de www.revmexneuroci.com / ISSN 1665-5044 Neurología, A.C. Editorial committee 2017
Chief editor: Dr. en C. Ildefonso Rodríguez Leyva [email protected] Co-editors: M.C. Carolina León Jimenez Dr. en C. Antonio Arauz Góngora [email protected] Founding editor: Dra. Lilia Núñez Orozco Emeritus editor: Dr. en C. Carlos Cantú Brito
National editorial comitee
Dr. Sergio de Jesús Aguilar Castillo Dr. Rubén Haro Silva Dra. Mayela Rodríguez Violante Dr. Marco Antonio Alegría Loyola Dr. Juan Calixto Hernández Aguilar Dr. Leopoldo Rivera Castaño Dra. Alma Yolanda Alvarado Dr. Héctor Gerardo Hernández Dr. Ulises Rodríguez Ortiz Gutierrez Rodríguez Dr. Francisco Rogel Ortiz Dr. Carlos Gabriel Ascanio Rodríguez Dr. Jesús Higuera Calleja Dr. Luis Ángel Ruano Calderón Dra. Catherine Boll Woehrlen Dr. Javier Jaramillo de la Torre Dra. Angélica Ruiz-Franco Dr. Antonio Bravo Oro Dr. Humberto Juárez Jiménez Dr. José Luis Ruiz-Sandoval Dr. Jorge Burgos Centeno Dr. Rubén Martínez Hernández Dr. José Manuel Sandoval Rivera Dra. Graciela Cárdenas Hernández Dra. Iris E. Martínez Juárez Dr. Daniel San Juan Dr. Paul Carrillo Mora Dra. Adriana Martínez Mayorga Dr. Horacio Sentíes Madrid Dra. Teresa Corona Vázquez Dr. Francisco Mena-Barranco Dra. Mónica Sierra del Rio Dra. Beatriz Chavez Dra. Roxana Millán Cepeda Dra. Ana Luisa Sosa Ortiz Dr. Bruno Estañol Vidal Dra. Rebeca Millán Guerrero Dr. José Luis Soto-Hernández Dra. Agnes Fleury Dr. Alberto Mimenza Alvarado Dr. Gersain Trujillo Alonso Dr. José Flores Rivera Dra. Leticia Munive Baez Dr. Steven Vargas Cañas Dra. Silvia García Dr. Luis Manuel Murillo Bonilla Dr. Rubén Darío Vargas García Dr. Fernando Góngora Rivera Dr. Alfredo Ponce de León Dra. Karina Vélez Jiménez Dra. Margarita González Cruz Dr. Guillermo Punzo Bravo Dr. Marco Zenteno Castellanos Dra. Alejandra González-Duarte Dra. Sandra Quiñones Aguilar Dr. Oscar González-Vargas Dra. María Teresa Reyes
International editorial comitee Dr. Anthony Amato Dr. José Obeso Dr. José Biller Dr. Julio Pascual Dr. Andre Kanner Dr. Marc Patterson Dra. Farrah Mateen Dr. Eduardo Tolosa Dr. José Merino Dr. Samuel Wiebe
Statistical Advisor Héctor Gerardo Hernández Rodríguez Style corrector Maestro Alejandro García Translator Rebeca Barroso Design Design Cortex Contenidos Contents
GUÍAS DE PRÁCTICA CLÍNICA CLINICAL PRACTICE GUIDELINES • Recomendaciones sobre el diagnóstico • Recommendations on the diagnosis y tratamiento de la polineuropatía and treatment of chronic inflammatory desmielinizante inflamatoria crónica demyelinating polyneuropathy
CONTRIBUCIONES ORIGINALES ORIGINAL CONTRIBUTIONS • Quejas subjetivas de memoria en población • Memory subjective complaints in geriatric geriátrica y sus factores asociados: estudio population and its related factors: a pilot study piloto en población mexicana in Mexican population • Funciones ejecutivas y conducta de • Executive functions and behavior of estudiantes secundarios ecuatorianos ecuadorian high school students • Desarrollo y salud en el diagnóstico • Development and health in the diagnosis in en trastorno por déficit de atención / attention-deficit / hyperactivity disorde hiperactividad REVIEWS • Falta título REVISIONES • Basal Ganglia and Behavior • Cefaleas por esfuerzo • Infectios of the Central Nervous System, part • Ganglios Basales y Conducta 2: neuroinfections in patients with Infection by • Infecciones del Sistema Nervioso Central, Human Immunodeficiency Virus parte 2: neuroinfecciones en pacientes con Infección por Virus de Inmunodeficiencia Humana CASE REPORTS • Marchiafava-Bignami: case report REPORTES DE CASO • Marchiafava bignami: reporte de un caso y EDITORIAL revisión de la literatura • Editorial Letter by Ildefonso Rodríguez Leyva
EDITORIAL • Carta Editorial por Ildefonso Rodríguez Leyva 2 Systemic review Clinical practice guide Management of chronic inflammatory demyelinating polyneuropathy
Clinical practice guide
Edwin Steven Vargas-Cañas,1 Recommendations for the diagnosis Erwin Chiquete,2 Luis A. and treatment of chronic inflammatory Ruano-Calderón,3 Elizabeth León-Manríquez,1 Mónica demyelinating polyneuropathy Edith Salmerón-Mercado,1 Noel Isaías Plascencia-Álvarez,4 Recomendaciones sobre el diagnóstico y tratamiento de la Gabriela Madrigal-Salas,2 polineuropatía desmielinizante inflamatoria crónica David Gilberto Zúñiga-García,1 Humberto Juárez-Jiménez,5 Abstract Raúl Carrera-Pineda6
Chronic inflammatory demyelinating 1 Neuromuscular Diseases Clinic, Introduction. National Institute of Neurology polyneuropathy (or polyradiculoneuropathy, CIDP) is an uncommon and Neurosurgery “Manuel Velasco entity of very heterogeneous clinical behavior, but susceptible to Suárez,” Mexico City, Mexico. treatment. Several proposals on electrophysiological diagnostic 2Neuromuscular Diseases Clinic, criteria exist as well as numerous studies on the response to Department of Neurology and immunomodulatory treatments. The general consensus about its Psychiatry, National Institute of diagnosis and management, however, has not been reached in Mexico Medical Science and Nutrition through its major health institutions. “Salvador Zubiran,” Mexico City, Mexico. To develop a guideline on definition, diagnosis and 3Department of Neurology, Durango Objective. General Hospital, Durango, Mexico. treatment of the CIDP by using the best existing scientific evidence 4Department of Neurology, ISSSTE and when not available, the consensus of experts. National Medical Center “20 de Noviembre,” Mexico City, Mexico . Methods. A group of neurologists of Mexican institutions pertaining 5Department of Neurology, General to the Study Group of Neuromuscular Diseases of the Mexican Hospital “Doctor Gaudencio González Academy of Neurology carried out a MEDLINE and Cochrane Garza” at the IMSS National Medical systematic reviews search, selecting the best available evidence and Center “La Raza,” Mexico City, Mexico. qualifying the recommendations according to the GRADE 6 (Grading Department of Neurology, IMSS of Recommendations Assessment, Development and Evaluation) system. National Medical Center “Siglo XXI,” The recommendations are organized into short statements that are Mexico City, Mexico. supported by a brief dissertation on the scientific evidence of which the statements derived.
Recommendations. This panel recommends testing and diagnostic criteria proposed by the EFNS/PNS (European Federation of Neurological Societies / Peripheral Nerve Society) that are described in the present document. For treatment aspects, this panel recommends intravenous immunoglobulin or steroids as first line treatment for the classical sensorimotor forms of CIDP, immunoglobulin exclusively for pure motor forms and plasma exchange in case of treatment failure
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or incomplete response to immunoglobulin or steroids. In case of inappropriate response or required high doses or long periods of Keywords first-line drugs, immunomodulatory adjuvant therapy should be Clinical practice guideline, considered alone or in combination. chronic inflammatory demyelinating polyradiculoneuropathy, definition, diagnosis, management, treatment. Resumen
Introducción. La polineuropatía (o también Evaluation). Las recomendaciones se organizan en polirradiculoneuropatía) desmielinizante enunciados breves que son sustentados por una inflamatoria crónica (PDIC) es una entidad breve disertación sobre la evidencia científica de la infrecuente, de comportamiento clínico muy que derivaron. heterogéneo, pero susceptible de tratamiento. Existen varias propuestas sobre los criterios de Recomendaciones. Este panel recomienda diagnóstico electrofisiológico, así como numerosos utilizar las pruebas y criterios diagnósticos estudios sobre la respuesta a tratamientos propuestos por la EFNS/PNS (European Federation inmunomoduladores. El consenso general sobre of Neurological Societies/ Peripheral Nerve Society), su diagnóstico y manejo, sin embargo, no se ha mismos que son expuestos en este documento. El alcanzado en México a través de sus principales panel recomienda la inmunoglobulina humana o instituciones sanitarias. esteroides como primera línea de tratamiento para las formas sensitivo-motoras clásicas de la PIDC, Objetivo. Elaborar una guía sobre definición, exclusivamente inmunoglobulina para la PDIC diagnóstico y tratamiento de la PDIC utilizando la motora pura y en caso de falla a inmunoglobulina mejor evidencia científica existente y cuando no o esteroide debe ser considerado el recambio esté disponible, el consenso de expertos. plasmático. Si la respuesta es inapropiada o se requieren dosis altas o largos periodos con los medicamentos de primera línea, debe ser Métodos. Un grupo de neurólogos de considerada la terapia coadyuvante sola o instituciones mexicanas y pertenecientes al grupo combinada con inmunomoduladores. de estudio de Enfermedades Neuromusculares de la Academia Mexicana de Neurología realizó una búsqueda en MEDLINE y revisiones sistemáticas Cochrane, seleccionando la mejor evidencia Palabras clave disponible clasificando la recomendación Definición, diagnóstico, guía de práctica clínica, de acuerdo al sistema GRADE (Grading of tratamiento, polineuropatía desmielinizante Recommendations Assessment, Development and inflamatoria crónica.
Corresponding Author: ≠Dr. Edwin Steven Vargas-Cañas. Clínica de Enfermedades Neuromusculares. Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”. Insurgentes Sur, 3877. Col. La Fama. CP 14269. Tlalpan, México DF, México. Fax: +52-51710890. E-mail: [email protected]
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Introduction in subjects with diabetes mellitus can often go unnoticed because it is thought to be a diabetic Chronic inflammatory demyelinating polyneuropathy neuropathy, whose pathogenic base is essentially (CIDP—also known as chronic inflammatory toxic-metabolic.4 It is possible that in certain demyelinating polyradiculoneuropathy) is the most populations, like in Mexico, many patients with common of chronic autoimmune neuropathies.1 It is a CIDP are misdiagnosed with diabetic neuropathy. group of acquired disorders of the peripheral nerves However, this has not been adequately addressed and nerve roots that converge in a pathogenesis in quality observational studies. common to all of them: the immune-mediated demyelination of the peripheral nerve.1,2 For many Whether CIDP is a disease or a syndrome continues decades there have been descriptions of patients to be controversial. Independently of this, currently with disorders that would today be considered CIDP. we recognize clinical variants of CIDP that have The reader should be aware, however, that clinical chronicity, demyelination, inflammation, or immune descriptors are evolving as new scientific evidence mediation in common:1-4 Lewis-Sumner syndrome accumulates, so the CIDP concept is now considered or multifocal acquired demyelinating sensory an “umbrella” descriptor that groups conditions and motor neuropathy (MADSAM), pure motor with shared pathogenesis, but whose clinical CIDP, sensory-predominant CIDP, focal CIDP, presentation, subtype of immunopathogenesis, acute-onset CIDP, chronic autoimmune sensory prognosis, and response to treatments is actually polyneuropathy, distal acquired demyelinating very heterogeneous.1-3 symmetric neuropathy (DADS), and demyelinating neuropathy associated with demyelination of The estimated prevalence of CIDP in the different the central nervous system. In contrast, most populations of the world is as wide as 0.8 to 8.9 per authors currently consider the following as 100,000 inhabitants.1 These estimates are derived separate syndromes (non-variants of CIDP) of from developed countries and, notably, in Mexico, chronic demyelination of the peripheral nervous there are no estimates or direct measurements of system (PNS): multifocal motor neuropathy, distal the health burden of this entity. CIDP can affect demyelinating neuropathy with paraprotein IgM all ages but is more common in men over 40 years with or without anti-MAG (myelin-associated old. It is believed that progressive forms are more glycoprotein), demyelinating neuropathy with common in older subjects, while recurrent forms paraprotein IgG or IgA (monoclonal gammopathy are seen more in younger patients.3 The classic, of undetermined significance or MGUS), POEMS pure course with relapses and remissions occurs syndrome (Polyneuropathy, Organomegaly, in a third of patients and the rest is thought to Endocrinopathy, Monoclonal protein, Skin have a single-phase progressive course. However, changes) and demyelinating neuropathies it is possible that this classification might be associated with systemic diseases (e.g. hepatitis B reductionist and does not capture the essence or C, HIV, lymphoma, diabetes mellitus, systemic of the temporary clinical behavior of CIDP, since lupus erythematosus and other collagenopathies, perhaps the majority of patients considered with dysthyroidism, bone marrow transplant, nephrotic “pure” progressive forms have a superimposed syndrome, and inflammatory bowel disease). course of relapses over a behavior of progression The classification of inflammatory demyelinating (mixed or recurrent-progressive forms).2,3 neuropathies will continue to evolve as specific immune mechanisms are clarified. No specific predisposing factors for CIDP have been identified, although about 50% of patients This document aims to describe the results of a have diabetes mellitus or carbohydrate intolerance systematic review of diagnosis and management of (prediabetes states), but this, of course, is not CIDP, to serve as the scientific basis for the shaping specific to CIDP and the diagnosis of this entity of recommendations on these topics.
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Methods
A working group formed by clinical neurologists and costs of interventions, as well as the values with knowledge and interest in neuromuscular and preferences of patients. diseases was convened. Questions and topics about the diagnosis and treatment of CIDP were MEDLINE and PubMed were searched for articles posited and an agreement was reached. This on CIDP with specific keywords and MeSH terms produced an agenda for a 12-hour face-to-face in English related to the design of the study, session distributed over a day and a half. Prior treatment, and disease, as follows: to the meeting, the topics and clinical questions were distributed among the participating #1. Chronic inflammatory demyelinating clinicians for response and development in two polyneuropathy groups of panelists. The members of the working #2. CIDP group systematically formulated the pertinent #3. Long-term answers to the questions posed according to #4. Diagnosis the recommendations of the GRADE system #5. Treatment (Grading of Recommendations Assessment, #6. Therapy Development and Evaluation)(Table 1).5,6 Briefly, #7. Trial this system is mainly a series of steps to organize #8. Clinical trial the systematized answer of clinical questions of #9. Controlled trial interest, particularly with respect to diagnosis and #10. Randomized clinical trial treatment. It focuses mainly (but not exclusively) #11. Guideline on qualifying the quality of the evidence and thus #12. Open-label study formulating a recommendation structured in a #13. Observational study concise statement, which is properly the answer #14. #1 AND #2 to the clinical question posed. #15. #2 AND #3 #16. #1 AND #4 The workgroup agreed to use the GRADE system #17. #3 AND #4 in order to systematize the development of the #18. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 document and to evaluate the evidence, in order #19. #8 OR #9 OR #10 OR #11 OR #12 to offer the user of the guide certainty about the #20. #13 OR #14 OR #15 knowledge that supports each recommendation. #21. #16 AND #17 AND #18 The workgroup, however, is aware that there is no system for classifying the evidence that is perfect No date restrictions were applied to the searches. and that none of them have been scientifically Additionally, reference lists of the selected proven in a proper way to support its use over relevant articles were searched manually. The the other systems. That is to say, so far we cannot evidence and recommendations were classified know which system is the best; nevertheless, this according to the GRADE system (Table 1).5 When method was chosen because it is widely used today only very low quality evidence was found (opinions and because it has the strength to provide texts of other expert panels, clinical anecdotes, or that are easy to understand without excessive use the working group’s own experience), the team of technicalities. The working group formulated made an attempt to reach a consensus and the recommendations for clinical practice based recommendations were classified as “good on evidence that provides a systematic review, practice points.” with which semi-axiomatic principles on health care were formulated, considering equally the The statements were reviewed one by one by judgments about the perceived risk-benefit ratio all the members of the working group and were
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Table 2. Currently recognized clinical variants of chronic inflammatory demyelinating polyradiculopathy (CIDP).
inica arian recuenc inica eno e Typical CIDP Sensorimotor, distal and proximal, symmetric, evolution weeks. Sensory CIDP Sensory predominant, it can develop minor motor symptoms, distal and proximal, symmetrical, evolution weeks. DADS 2 Sensory predominant, it can develop minor motor symptoms, distal, symmetrical, evolution weeks. Acute onset CIDP 2 Sensorimotor, distal and proximal, symmetrical, evolution weeks. ewis Sumner syndrome ADSA Sensorimotor, fre uent onset in upper extremities, asymmetrical, evolution weeks. Chronic autoimmune sensitive polyneuropathy 2 Sensory ataxia, distal and proximal, symmetrical, evolution weeks. otor CIDP Predominantly motor, distal and proximal, symmetrical, evolution weeks. Focal CIDP Sensorimotor, focal, can progress to diffuse form with time, asymmetrical, evolution weeks.
The percentages do not necessarily add up to due to the variability of the distribution of the variants among the different populations. DADS: distal acquired demyelinating symmetric neuropathy. MADSAM: multifocal acquired demyelinating sensory and motor neuropathy.
Are there other useful neurophysiological tests to Is the repetition of the neurophysiological protocol establish the diagnosis of CIDP? valid when there is a high clinical suspicion which This panel suggests performing somatosensory evoked did not meet the criteria proposed by the EFNS/ potentials (SEPs) especially in patients with the variant PNS for CIDP in the initial evaluation? of sensory CIDP or atypical clinical presentations. This panel suggests repeating the neurophysiological (Good practice point) evaluation proposed by the EFNS/EPN, in case of not Somatosensory evoked potentials may be useful meeting the criteria for definitive CIDP in the initial to demonstrate alteration of proximal sensory evaluation. (Weak recommendation, low quality of conduction, particularly in sensory CIDP18,19 and evidence: 2C) may contribute to the diagnosis of CIDP when If the electrodiagnostic criteria are not initially neuroconduction studies result insufficient to met for definitive CIDP, repetition of the study at detect peripheral demyelination.20 a later date should be considered. This can avoid false negatives and could narrow the differential diagnosis.10
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onset forms. The latter ones are challenging to motor nerves in suspicion of CIDP distinguish from Guillain-Barré syndrome (GBS).1 This panel recommends performing neuroconduction tests to explore at least four motor nerves, using the The mechanism of injury is undoubtedly immune- demyelination diagnostic criteria proposed by the mediated. The experimental models of allergic EFNS/PNS. (Strong recommendation, high quality of neuritis and the histopathological similarities evidence: 1A) with GBS support this premise; however, the The criteria of the European Federation of immunopathogenesis remains imprecise. To Neurological Societies and Peripheral Nerve date, no triggering event has been identified, the Society (EFNS/PNS)3 have a sensitivity of 81% exposure of individuals genetically susceptible to and specificity of 96% to establish the diagnosis of various environmental or infectious agents has CIDP, compared to the original criteria proposed by been proposed on multiple occasions without the American Academy of Neurology (AAN) (100% being able to firmly establish the association.1 specificity and 45% sensitivity).7-12 According to the Recently, autoantibodies against the paranodal criteria met, the diagnosis of definitive, probable, proteins contactin-1 (CNTN1) and NF155 have or possible CIDP can be established (Table 3). The been described in a small subgroup of patients sensitivity of electrodiagnostic criteria for motor with CIDP with a homogeneous clinical pattern. nerves can be improved by examining more than Outside of these associations, pathogenic four nerves, including proximal stimulation in the autoantibodies or specific antigens are unknown upper limb13,14 and examining sensory nerves.15,16 in the PNS.4 Isolated reports of CIDP associated with tumors (melanoma) or post-vaccination To apply these criteria, evaluate the nerves suggest that molecular mimicry could be involved median, ulnar (stimulus below the elbow), peroneal in the pathogenesis.1-3 (stimulus under the fibular head), and tibial on just one side. If the criteria are not met, the same The diagnostic suspicion is established based on nerves are evaluated contralaterally and/or the suggestive clinical manifestations. The typical median and ulnar nerves are stimulated bilaterally CIDP (which is not precisely the most common) in the armpit and Erb’s point. The blockage of the presents with at least eight weeks of evolution of motor conduction is not considered in the ulnar distal paresthesias with stocking/glove distribution, nerve in its passage through the elbow and there symmetric, with progressive distal paresis and must be at least 50% reduction in the amplitude eventual involvement of shoulder girdle and pelvic between Erb’s point and the wrist to consider girdle, which can progress to loss of autonomic a probable conduction block. The temperature ambulation and the appearance of atrophy. Still, this should be maintained at least 33°C in the palm and is not the only clinical presentation of CIDP, which 30°C in the external malleolus.3 has led to the recognition of clinical variants (Table 2). Usefulness of neurophysiological evaluation of Diagnostic criteria sensory nerves in suspicion of CIDP Given the wide phenotypic variability (50% of This panel recommends conducting sensory cases), the protocol of diagnostic auxiliaries neuroconduction to patients with clinical suspicion of becomes relevant to confirm the diagnostic typical or atypical CIDP. (Weak recommendation, low certainty and reasonably exclude differential quality of evidence: 2C) diagnoses. In this vein, the pertinence of lumbar The sensitivity of the electrodiagnostic criteria for punctures, electrophysiology studies, magnetic motor nerves can be improved by examining more resonances, and peripheral nerve biopsies will be than four nerves, including proximal stimulation weighted according to the best evidence available in the upper limb,13,14 and there are reports of in the body of this document. cases where atypical CIDP was suspected where Electrophysiological criteria the examination of sensory nerves increased the Usefulness of neurophysiological evaluation of diagnostic certainty.15,16
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Table 2. Currently recognized clinical variants of chronic inflammatory demyelinating polyradiculopathy (CIDP).
inica arian recuencia eno i o c nico ypical C Sens rim t r distal and pr imal symmetric ev luti n wee s Sens ry C Sens ry pred minant it can devel p min r m t r sympt ms distal and pr imal symmetrical ev luti n wee s S Sens ry pred minant it can devel p min r m t r sympt ms distal symmetrical ev luti n wee s cute nset C Sens rim t r distal and pr imal symmetrical ev luti n wee s ewis Sumner syndr me S Sens rim t r re uent nset in upper e tremities asymmetrical ev luti n wee s C r nic aut immune sensitive p lyneur pat y Sens ry ata ia distal and pr imal symmetrical ev luti n wee s t r C red minantly m t r distal and pr imal symmetrical ev luti n wee s cal C Sens rim t r cal can pr gress t di use rm wit time asymmetrical ev luti n wee s
The percentages do not necessarily add up to 100 due to the variability of the distribution of the variants among the different populations. distal acquired demyelinating symmetric neuropathy. M M multifocal acquired demyelinating sensory and motor neuropathy.
Are there other useful neurophysiological tests to Is the repetition of the neurophysiological protocol establish the diagnosis of CIDP? valid when there is a high clinical suspicion which This panel suggests performing somatosensory evoked did not meet the criteria proposed by the EFNS/ potentials (SEPs) especially in patients with the variant PNS for CIDP in the initial evaluation? of sensory CIDP or atypical clinical presentations. This panel suggests repeating the neurophysiological (Good practice point) evaluation proposed by the EFNS/EPN, in case of not Somatosensory evoked potentials may be useful meeting the criteria for definitive CIDP in the initial to demonstrate alteration of proximal sensory evaluation. (Weak recommendation, low quality of conduction, particularly in sensory CIDP18,19 and evidence: 2C) may contribute to the diagnosis of CIDP when If the electrodiagnostic criteria are not initially neuroconduction studies result insufficient to met for definitive CIDP, repetition of the study at detect peripheral demyelination.20 a later date should be considered. This can avoid false negatives and could narrow the differential diagnosis.10
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Table 3. Electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculopathy (CIDP).
e ini i e a ea one o e o o in A. Prolonged distal motor latency ≥50% above the ULN in two nerves (excluding carpal tunnel syndrome), or B. Reduction of the CV ≥30% under the LLN in two nerves, or C. F waves with prolonged latency ≥30% of the ULN in two nerves (≥50% if the amplitude of the negative peak CMAP is <80% of the LLN), or D. Absence of F waves in two nerves, if those nerves have amplitudes of distal negative peak CMAP ≥20% of the LLN + at least some other demyelination parameter in at least some other nerve (a), or E. Partial blockage of motor conduction: reduction ≥ 50% of amplitude of proximal negative peak CMAP in relation to distal, if distal negative peak CMAP is ≥20% of the LLN in two nerves; or in one nerve + at least some other demyelination parameter in at least some other nerve (a), or F. Abnormal temporal dispersion (>30% increase in duration between proximal and distal negative peak CMAP) in at least two nerves, or G. Duration of distal CMAP (interval between the beginning of the first negative peak and the return to baseline of the last negative peak) increased in at least one nerve (median 6.6 ms, ulnar 6.7 ms, peroneal 7.6 ms, tibial 8.8 ms) (b) + at least some other demyelination parameter in at least some other nerve (a)
ro a e ≥30% reduction of the amplitude of the proximal negative peak CMAP in relation to the distal, excluding the posterior tibial nerve, if the distal negative peak is ≥20% of the LLN in two nerves, or in one nerve + at least some other parameter of demyelination in at least some other nerve.
o i e Like "1" but in just one nerve
Conduction Velocity M Compound Muscle Action Potential N pper Limits Normal N Lower Limits Normal
a Any other nerve that meets any of the A-G criteria Isose S. et al.15 Lumbar puncture practice for patients with clinical important piece of information in the CSF analysis. suspicion of CIDP Although its usefulness is reported in some This panel recommends that in the event of clinical studies, the determination of oligoclonal bands for suspicion of CIDP, a lumbar puncture be performed for cases without demyelination of the CNS is, in fact, routine cytological and cytochemical analysis. (Strong debatable and of limited utility.23 recommendation, high quality of evidence: 1A) The presence of hyperproteinorrachia in patients Nerve biopsy practice in patients with suspicion of with CIDP occurs between 76 and 90% of CIDP patients, where a protein level is demonstrated This panel suggests performing a sural nerve biopsy >45 mg/dL.9,21-22 Normally no pleocytosis should when the clinical, neurophysiological, and CSF elements be observed in the CSF; if observed, it usually are insufficient to support the diagnosis of CIDP or in suggests coexisting infection, for example by selected cases of atypical clinical presentations. (Weak HIV.23 Cyto-protein dissociation is the most recommendation, low quality of evidence: 2C)
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The nerve biopsy can provide evidence to support cervical cord have been described in isolation, but the diagnosis of CIDP when the results of other the clinical and prognostic significance of these diagnostic tests are inconclusive.22 However, the findings is still controversial.27-31 histopathological findings are not specific and their absence does not exclude the diagnosis. The Chemical and/or immunological analysis in the biopsy of the sural nerve is preferred because patient diagnosed with CIDP of its easy access and fewer adverse events. The This panel suggests carrying out the necessary one that is clinically and/or electrophysiologically investigations to search for other concomitant most affected should be chosen. Other options diseases in the patient diagnosed with possible, are the superficial peroneal or superficial radial probable, or definite CIDP, based on a detailed clinical nerves. Histopathological findings of CIDP history. (Good practice point) include the inflammatory reaction associated Mainly based on case reports, numerous diseases with macrophages, onion bulb formations have been associated with CIDP.12 These include (demyelination-remyelination), endoneurial diabetes mellitus, monoclonal gammopathies IgG edema, mononuclear infiltration in endoneurium or IgA, monoclonal gammopathy by IgM without and variations between the fascicles.12,25 antibodies against myelin-associated glycoprotein, HIV infection, chronic active hepatitis, systemic Nuclear magnetic resonance (NMR) study of lupus erythematosus or other connective plexuses and spinal roots in the diagnosis of CIDP tissue diseases, sarcoidosis, thyroid disease, and its variants inflammatory bowel disease,32 membranous This group suggests conducting NMR imaging of glomerulonephritis,33 and transplantation of bone roots and spinal plexuses as a diagnostic aid for marrow or solid organs.34 There is insufficient CIDP of initial atypical presentation and in which the evidence to consider a direct association neurophysiological and CSF evaluation has not allowed between CIDP and these diseases, however, to establish a definitive diagnosis. (Good practice point) consider the necessary investigations to rule out In some patients with atypical CIDP, alterations concomitant diseases. Perhaps, over time, some in NMR have been demonstrated, such as of these systemic diseases causing demyelinating hypertrophy of the brachial or lumbar plexus and/ neuropathies may be considered forms of CIDP of or extraforaminal roots with gadolinium uptake, determinate cause. which denotes inflammation with vascular leakage. These alterations are mostly asymmetrical and are Treatment more frequently observed in the brachial plexus Oral steroids for the treatment of CIDP than in the lumbar.12,24 This panel recommends prednisone as a first-line treatment for patients with sensory-motor CIDP. NMR of the spinal cord and/or brain in the (Strong recommendation, high quality of evidence: 1A) diagnosis of CIDP and its variants There is only one multicenter, randomized, and This panel does not suggest carrying out routine NMR controlled study with prednisone at a dose of imaging studies of the spinal cord and/or brain in patients 60 mg daily that proved superior against not with suspected CIDP, except in cases in which the physical receiving treatment.33 However, there are many examination indicates involvement of the CNS. (Weak observational studies that indicate the efficacy recommendation, low quality of evidence: 2C) of prednisone in CIDP, except for pure motor Some studies have looked for the presence of CIDP, whose use could even lead to clinical concomitant alterations in the CNS in patients deterioration.12 There is no consensus on which with CIDP. There are only small series of patients is the best prednisone administration scheme subjected to this type of research and the number of considering daily regimens, on alternate days, patients in whom this type of alterations have been or intermittent monthly.12 This panel suggests corroborated has been a minority.26 White matter prednisone 60 mg daily or on alternate days for hyperintensities in T2 sequences and atrophy of at least a month or until reaching a symptoms
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stabilization phase, then start a gradual reduction In the case that the patient requires sustained full scheme of 10 mg per month until reaching 5 mg doses of IVIG to maintain stability, it is suggested daily or every other day and complete two years to add oral steroids or immunomodulatory drugs. of treatment at this dosage, at the end of which, (Good practice point) if the patient is asymptomatic or only minor sensory symptoms persist, prednisone may be Plasmatic exchange for the treatment of CIDP discontinued and the patient kept under medical This panel recommends the use of plasma exchange observation 1 to 2 times per year for 3 years.35-38 in patients with CIDP refractory to steroids and IVIG (Good practice point.) in the induction phase. (Strong recommendation, high quality of evidence: 1A) Intravenous steroids for the treatment of CIDP In randomized, controlled, and double-blind This panel recommends methylprednisolone as a first- studies, the manifestations of CIDP have shown line treatment for patients with sensory-motor CIDP. short-term benefits with plasma exchange. It is (Strong recommendation, low quality of evidence: 1C) suggested to be administered 2 to 3 times a week. In some observational studies and clinical trials, However, a rapid deterioration after the procedure intravenous methylprednisolone 1 g has been is reported, so the use of other treatment measures evaluated for 3 to 5 days, followed by 1 g monthly is recommended for stabilization in the medium for 6 months, which has been shown to be as and long term.45,46 effective as oral steroids at 6 months of follow-up, however, it requires more long-term studies.39,40 General therapeutic recommendations Polyvalent human immunoglobulin for the Induction treatment treatment of CIDP 1. IVIG and steroids are considered first-line This panel recommends the use of human treatments in patients with CIDP, except for pure immunoglobulin as the first line of treatment for adult motor CIDP, where steroids could cause clinical patients with CIDP. (Strong recommendation, high deterioration and IVIG should be considered as the quality of evidence: 1A) first-choice treatment. (Good practice point) A meta-analysis that included four randomized, double-blind studies, two of them controlled by 2. The presence of relative contraindications placebo, demonstrated the efficacy and safety of for each of the drugs can influence the therapy intravenous immunoglobulin (IVIG) in patients decision-making. In either case, the advantages and with CIDP and its clinical variants.41-44 Given the disadvantages of both options should be discussed short half-life of IVIG, it should be administered at with the patients to involve them in making the regular intervals and at individualized frequency. decision. (Good practice point) Crossover studies have shown no difference in efficacy when comparing IVIG against plasma 3. For refractory forms of CIDP that do not respond exchange, nor IVIG against prednisolone. A total to steroids or IVIG, plasma exchange should be induction dose of 2 g/kg fractionated in 2 to 5 days considered as the second line of treatment. (Good is recommended, followed by a maintenance dose practice point) of 1 to 2 g/kg fractionated in 2 to 5 days every 2 to 6 weeks.41-44 Maintenance treatment 1. In case of effectiveness during the induction The scheme should be sustained until a symptom phase, the treatment must be maintained until stabilization phase is observed, then it is clinical stability is reached and then gradually recommended to reduce the dose of IVIG (10 reduce the dose. (Good practice point) to 15%) before extending the administration 2. For patients under treatment with IVIG intervals. (Good practice point) at high doses and short intervals, steroids or
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immunosuppressive drugs should be considered as for 6 months was effective in the treatment of adjuvant therapy. (Good clinical practice point) CIDP cases that did not respond to steroids, human immunoglobulin, or plasma exchange.49
Immunomodulatory drugs Mycophenolate mofetil This panel suggests the use of mycophenolate mofetil No randomized, controlled study has been at a dose of 2 g/day for the treatment of sensorimotor conducted to demonstrate the efficacy and CIDP. (Weak recommendation, moderate quality of tolerance of any immunomodulatory drug in the evidence: 2B) treatment of CIDP other than azathioprine. Its use One retrospective study evaluated the efficacy is reserved only during the maintenance phase or of mycophenolate mofetil at a dose of 2 g/day in cases refractory to conventional treatment. in patients with CIDP, without demonstrating a difference in strength, sensitivity, or modified Azathioprine Rankin scale before and after treatment. A second This panel suggests the use of azathioprine at doses study, also retrospective, suggested efficacy in the .50,51 of 100 to 200 mg/day as treatment for sensorimotor treatment of this condition CIDP. The use of this immunomodulator is as a steroid- sparing agent and usually in concomitance with Interferon beta prednisone. (Weak recommendation, low quality of This panel does not recommend the use of interferon evidence: 2C) beta in patients with CIDP. (Strong recommendation, There is only one randomized study with high quality of evidence: 1B) azathioprine in patients with CIDP that did not A prospective, randomized, double-blind, placebo- demonstrate efficacy when used concomitantly controlled study that used interferon beta 1a at a with prednisone; however, the study included a dose of 30 or 60µg twice a week for 4 months small number of patients, the follow-up was short, showed no benefit in symptom control or reduced and the dose used was suboptimal.47 IVIG dosage compared against placebo. In this case, the evidence, although not completely Methotrexate conclusive, is considered of sufficient quality to This panel suggests the use of methotrexate at a dose recommend against the use of interferon beta in 52 of 15 mg/week for the treatment of CIDP. The use of cases with CIDP. this immunomodulator is as a steroid-sparing agent and usually in concomitance with prednisone. (Weak Monoclonal antibodies recommendation, low quality of evidence: 2C) There is only one randomized, double-blind, Rituximab placebo-controlled study that used methotrexate This panel suggests the use of rituximab at a dose of at a dose of 15 mg/week in patients with CIDP 375 mg/m2, one cycle every week for four weeks in but showed no benefit over placebo. However, adult patients with CIDP with IgG4 anti-CNTN1/ the study suffered from severe limitations in NF155 or hematological diseases antibodies. (Weak its design, so its benefit for patients with CIDP recommendation, low quality of evidence: 2C). remains uncertain.48 A report of two cases of CIDP associated with IgG4 anti-CNTN1/NF155 antibodies Cyclophosphamide resistant to conventional therapy showed a This panel suggests the use of intravenous significant improvement or CIDP associated cyclophosphamide at a dose of 1 g/m2 monthly for 6 to with hematological pathology or coexisting with 12 months to treat for CIDP. (Weak recommendation, another autoimmune disease.53 low quality of evidence: 2C) An open non-controlled study with Alemtuzumab cyclophosphamide at a dose of 1 g/m2 per month This panel suggests the use of alemtuzumab in
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selected patients with CIDP resistant to conventional treatment. (Weak recommendation, low quality of This guide in perspective evidence: 2C) A case report that included seven patients with CIDP resistant to conventional therapy treated This is, to the best of our knowledge, the first with alemtuzumab showed prolonged remission clinical practice guide on diagnosis and treatment in two of them, partial improvement in two, and of CIDP using a system of evaluation for the three had no benefit.54 quality of evidence and grading the strength of the recommendations with the participation Natalizumab of members of diverse Mexican institutions. Its This panel suggests the use of natalizumab in selected text gathers, orders, summarizes, and combines patients with CIDP resistant to conventional therapy. the best available evidence in a clear and simple (Weak recommendation, low quality of evidence: 2C) format in order to reduce the variability of clinical A report of three cases of patients with CIDP practices in the management of CIDP. Its original resistant to conventional therapy who were design weighs equally the diagnosis and treatment, treated with natalizumab reported sustained fostering, on one hand, the encounter between improvement in one, dramatic improvement in research and clinical practice by reporting the another, and stabilization in the third. Other quality of the available evidence in the statements, studies have not been consistent in their results.55 and, on the other hand, improving the quality of health service management. Physical therapy and rehabilitation
This panel suggests counseling patients regarding lifestyle changes including a balanced diet, regular physical activity, special dedication to foot care, physical rehabilitation (stretching exercises, strengthening, and Research occupational therapy) and, depending on the needs of the patients, psychological support. (Good practice recommendations point)
There are no observational or intervention The high variability of treatments, doses, studies that show, with traditional objective schedules, and routes of administration makes outcomes, the effectiveness of different physical standardization and comparison with different therapy schemes. This is an area of opportunity therapeutic maneuvers complex and laborious, for research. In our experience, almost any partly explained by the heterogeneous nature regime that provides regular use of facilities and of the disease discussed. This opens areas of therapist services is associated with greater opportunity to design multicenter studies that patient satisfaction, but with minimal effects in provide the best level of evidence in terms of the improvement of independence, autonomous diagnosis and treatment as well as explore new ambulation, or reversal of the physical limitations diagnostic tools for atypical forms. There should imposed by the disease. Nevertheless, this must be be an evaluation of the role of rescue therapies and demonstrated with scientific rigor in the future. second-line therapies, as well as different physical therapy techniques and multimodal treatments with different traditional objective outcomes (or added) to the overall satisfaction of the patient.
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Guide synopsis possible, probable, or definite CIDP, based on a detailed clinical history. (Good practice point) Diagnosis Treatment 1. This panel recommends performing neuroconduction tests by exploring at least 1. This panel recommends prednisone as first- four motor nerves using the diagnostic line treatment for patients with sensorimotor demyelination criteria proposed by EFNS/ CIDP. (Strong recommendation, high quality of PNS. (Strong recommendation, high quality of evidence: 1A) evidence: 1A) 2. This panel recommends methylprednisolone 2. This panel suggests performing sensory as first-line treatment for patients with neuroconduction in patients with clinical sensorimotor CIDP. (Strong recommendation, suspicion of typical or atypical CIDP. (Weak high quality of evidence: 1C) recommendation, low quality of evidence: 2C) 3. This panel recommends the use of human 3. This panel suggests performing somatosensory immunoglobulin as first-line treatment for adult evoked potentials (SEPs) in patients with patients with CIDP. (Strong recommendation, sensory variant CIDP or atypical clinical high quality of evidence: 1A) presentation. (Good practice point) 4. This panel recommends the use of plasma 4. This panel suggests repeating the exchange in patients with steroid-refractory neurophysiological evaluation proposed by CIDP and IVIG in the induction phase. (Strong EFNS/EPN in case of not meeting the criteria recommendation, high quality of evidence: 1A) for definitive CIDP in the initial evaluation. 5. This panel suggests the use of azathioprine at (Weak recommendation, low quality of doses of 100 to 200 mg/day as treatment for evidence: 2C) sensorimotor CIDP. (Weak recommendation, 5. Recommendation: This panel recommends, in low quality of evidence: 2C) the event of clinical suspicion of CIDP, lumbar 6. This panel suggests the use of methotrexate puncture. (Strong recommendation, high at a dose of 15 mg/week for the treatment of quality of evidence: 1A) CIDP. (Weak recommendation, low quality of 6. This panel suggests performing a sural nerve evidence: 2C) biopsy when the clinical, neurophysiological, 7. This panel suggests the use of intravenous and CSF elements are insufficient to support cyclophosphamide at a dose of 1 g/m2 monthly the diagnosis of CIDP, or when faced with for 6 to 12 months for the treatment of atypical clinical presentations. (Weak CIDP. (Weak recommendation, low quality of recommendation, low quality of evidence: 2C) evidence: 2C) 7. This group suggests carrying out NMR imaging 8. This panel suggests the use of mycophenolate of spinal roots and plexuses as a diagnostic mofetil at a dose of 2 gr/day for the treatment aid for CIDP of initial atypical presentation of sensorimotor CIDP. (Weak recommendation, and when the neurophysiological and CSF low quality of evidence: 2B) evaluation have not allowed establishing a 9. This panel does not recommend the use of definitive diagnosis. (Good practice point) interferon B1 in patients with CIDP. (Strong 8. This panel does not suggest performing spinal recommendation, high quality of evidence: 1B) and/or brain NMR imaging studies in patients 10. This panel suggests the use of rituximab at with suspected CIDP. (Weak recommendation, a dose of 375 mg/m2, one cycle every week low quality of evidence: 2C) for four weeks in adult patients with CIDP 9. This panel suggests conducting the necessary associated with IgG4 anti-CNTN1/NF155 investigations to search for other concomitant or hematological diseases antibodies. (Weak diseases in the patient with a diagnosis of recommendation, low quality of evidence: 2C)
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11. This panel suggests the use of alemtuzumab in patients with CIDP resistant to conventional treatment. (Weak recommendation, low quality of evidence: 2C) 12. Recommendation: This panel suggests the use of natalizumab in patients with CIDP resistant to conventional therapy. (Weak recommendation, low quality of evidence: 2C) 13. This panel suggests advising patients on lifestyle changes that include a balanced diet, regular physical activity, extreme foot care, physical rehabilitation (stretching exercises, strengthening, and occupationa occupational therapy), and, depending on the patient’s need, psychological support. (Good practice point)
Acknowledgments
The authors express their gratitude to Innovare S.A. de C.V. and LFB France for the support received for the meeting of experts to take place in an academic environment and without pressure or coercion of any kind.
Conflicts of interest Funding sources There are no potential conflicts of interest for This work received logistic support partially any of the authors in this scientific report. funded by Innovare S.A. de C.V. and LFB France. The pharmaceutical companies did not participate, directly or indirectly, in the design of the project, selection of the information, analysis, synthesis of the data, in the elaboration of this article, nor in its publishing.
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39. Machkhas H, Harati Y. Pulse intravenous methylprednisolone (IVMP) in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurology. 1997;48 Suppl:A87–8. 40. Lopate A, Pestronk A, Al-Lozi M. Treatment of chronic inflammatory demyelinating polyneuropathy with high- dose intermittent intravenous methylprednisolone. Arch Neurol. 2005;62(2):249–54. 41. Börü ÜT, Erdoğan H, Alp R, Taşdemir M, Yıldırım S, Bilgiç A, Duman A, Arslan A. Treatment of chronic inflammatory demyelinating polyneuropathy with high dose intravenous methylprednisolone monthly for five years: 10-Year follow up.Clin Neurol Neurosurg. 2014;118:89- 93. 42. van Doorn PA, Brand A, Strengers PF, Meulstee J, Vermeulen M (1990). High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study. Neurology. 40:209–212. 43. Vermeulen M, van Doorn PA, Brand A, Strengers PFW, Jennekens FGI, Busch HFM. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry.1993;56:36–39. 44. Mendell JR, Barohn RJ, Freimer ML, Kissel JT, King W, Nagaraja HN, Rice R, Campbell WW, Donofrio PD, Jackson CE, Lewis RA, Shy M, Simpson DM, Parry GJ, Rivner MH, Thornton CA, Bromberg MB, Tandan R, Harati Y, Giuliani MJ. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.Neurology. 2001;56:445–449. 45. Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2013;(12):CD001797.. 46. Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev. 2017;1:CD010369. 47. Dyck PJ, O’Brien P, Swanson C, Low P, Daube J. Combined azathioprine and prednisone in chronic inflammatory- demyelinating polyneuropathy.Neurology. 1985;35:1173–1176. 48. RMC Trial Group. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol. 2009;8(2):158-64. 49. Good JL, Chehrenama M, Mayer RF, Koski CL. Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy.Neurology. 1998;51(6):1735-1738. 50. Gorson KC, Amato AA, Ropper AH. Efficacy of mycophenolate mofetil in patients with chronic immune demyelinating polyneuropathy. Neurology. 2004;63(4):715-7. 51. Bedi G, Brown A, Tong T, Sharma KR. Chronic inflammatory demyelinating polyneuropathy responsive to mycophenolate mofetil therapy. J Neurol Neurosurg Psychiatry. 2010;81(6):634-6. 52. Hughes RA, Gorson KC, Cros D, Griffin J, Pollard J, Vallat JM, Maurer SL, Riester K, Davar G, Dawson K, Sandrock A; Avonex CIDP Study Group. Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy.Neurology. 2010;74(8):651-7. 53. Querol L, Rojas-García R, Diaz-Manera J, Barcena J, Pardo J, Ortega-Moreno A, Sedano MJ, Seró- Ballesteros L, Carvajal A, Ortiz N, Gallardo E, Illa I. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm. 2015;2(5):e149. 54. Marsh EA, Hirst CL, Llewelyn JG, Cossburn MD, Reilly MM, Krishnan A, Doran M, Ryan AM, Coles AJ, Jones JL, Robertson NP. Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy.J Neurol. 2010;257(6):913-9. 55. Vallat JM, Mathis s, Ghorab K, Milor MA, Richard L, Magy L. Natalizumab as a Disease-Modifying Theraphy in Chronic Inflammatory Demyelinating Polyneuropathy – A Report of three cases.Eur Neurol. 2015;73(5-6):294-302.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):1-18 Original contribution 19 Subjective memory complaints in Mexico
Original contribution
Paul Carrillo-Mora,1 Brenda Subjective memory complaints in the geriatric García-Juárez,2 Yesenia Lugo- population and related factors: a pilot study in Rodríguez,2 Elena del Pilar Moreno-Méndez,2 Leonardo Mexican population Cruz-Alcalá 3 Quejas subjetivas de memoria en población geriátrica y sus factores asociados: Estudio piloto en población mexicana 1 Department of Neurosciences/ Neurobiology Subdivision. National Institute of Rehabilitation “Luis Guillermo Ibarra Ibarra.” Abstract Coordinator of the Dementia Study Group, AMN. Subjective Memory Complaints (SMC) represent 2 Faculty of Psychology, UNAM Introduction. the individual’s perception of a change in their memory. In the elderly 3 Department of Clinics, University Center at Los Altos, University of population, a variable frequency of 10 to 90% has been reported. The Guadalajara. significance of SMC is still controversial in the geriatric population and there are no studies that have explored the frequency of SMC and their associated factors in Mexico.
Objective. To identify the frequency of SMC using a structured questionnaire, as well as to identify the associated factors in the elderly population.
Methods. A clinical pilot, observational, cross-sectional study of individuals over 60 years old of both sexes. Exclusion criteria: diagnosis of cognitive impairment, dementia or delirium, other neurodegenerative or psychiatric diseases, history of traumatic brain injury, or stroke in the previous six months. Instruments: the Spanish version of the Subjective Memory Complaints Questionnaire (SMCQ), the Folstein Mini-Mental State Examination (MMSE), the Hospital Anxiety and Depression Scale (HADS), and a questionnaire of interest variables were applied.
Results. A total of 100 patients were included: 77 women and 23 men with a mean age of 72.8 years; 96% of the individuals reported at least one SMC, and 53% had significant SMC (>5). There was no observed association between SMC and the MMSE, only a significant correlation with the anxiety and depression scores (HADS) was shown. In addition, elevated education levels, reading habits, and exercise were associated with a lower number of SMC.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 20 Original contribution Subjective memory complaints in Mexico
Conclusions: A high frequency of SMC (>90%) was found, and these were related to the symptoms of anxiety and depression. Keywords There was no association with cognitive performance and it was Subjective memory complaints, evidenced that education, reading habits, and regular exercise cognitive impairment, positively modulate the number of SMC. depression, anxiety, México.
Resumen
Introducción. Las Quejas Subjetivas de Memoria Resultados. Se incluyó un total de 100 pacientes: (QSM) representan la percepción del individuo a 77 mujeres y 23 hombres con un promedio de cerca de un cambio en su memoria. En población edad de 72.8 años. Se encontró que el 96% de adulta mayor se ha reportado una frecuencia los individuos referían al menos una QSM, y el variable de entre 10 al 90%. El significado de las 53% presentaban QSM significativas (>5). No se QSM aún resulta controversial en la población observó asociación entre QSM y el MMSE, y solo geriátrica y en nuestro país no existen estudios se demostró una correlación significativa con las previos que hayan explorado la frecuencia de QSM puntuaciones de la escala de ansiedad y depresión y sus factores asociados. (HADS). Además, la escolaridad elevada, el hábito de lectura y el ejercicio se asociaron con un menor Objetivo. Conocer la frecuencia de QSM usando número de QSM. un cuestionario estructurado, así como conocer cuáles son sus factores asociados en población Conclusiones: Se encontró una elevada adulta mayor. frecuencia de QSM (>90%), y éstas se relacionaron con los síntomas de ansiedad y depresión. No se Métodos. Se realizó un estudio clínico piloto, observó asociación con el rendimiento cognitivo y observacional, transversal. Se incluyó a individuos se evidenció que la escolaridad, el hábito de lectura > 60 años de ambos sexos. Criterios de exclusión: y el ejercicio regular modulan positivamente el diagnostico de deterioro cognitivo, demencia o número de QSM. delirium, otras enfermedades neurodegenerativas o psiquiátricas, antecedente de trauma craneal o enfermedad vascular cerebral en los 6 meses previos. Se aplicó la versión en español del Subjective Memory Complaints Questionnaire, el Mini Palabras clave mental de Folstein (MMSE), la Escala de Ansiedad Quejas subjetivas de memoria, deterioro cognitivo, y Depresión Hospitalaria (HADS) y un cuestionario depresión, ansiedad, México. de variables de interés.
Correspondence: Dr. en C. Paul Carrillo-Mora. Instituto Nacional de Rehabilitación. Calz. México-Xochimilco No. 289 Col. Arenal de Guadalupe, México D.F., 14389, México. Tel.(+52-55) 5999-1000 Ext. 19204. Fax.(+52-55) 5603-9138. Correo electrónico: [email protected]
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 Original contribution 21 Subjective memory complaints in Mexico
Introduction Methods
Subjective Memory Complaints (SMC) represent A clinical, observational, cross-sectional, an individual’s perceived change in the state that descriptive and analytical study was designed maintains their mnesic abilities (with respect to and participants were selected from the different a previous state). Even though SMC can present external consultation areas of the National at any age, those occurring in individuals over 60 Institute of Rehabilitation “Luis Guillermo Ibarra years old have recently become relevant.1 Ibarra” (INR-LGII). A sample size calculation was not performed since it was an exploratory study, SMC are one of the main reasons for consultation in so it was done for convenience. It included all the elderly population; however, in clinical studies, patients over 60 years old, of both sexes, who the prevalence varies from 12% to 90% of cases.2,3 agreed to participate through informed consent. This variance can be related to issues such as study The following were considered exclusion criteria: design, type of population studied, age groups, previous or current diagnosis of cognitive etc., but one of the most important factors is that impairment, dementia or delirium, other there is still no universally accepted and validated neurodegenerative or psychiatric diseases, history questionnaire to measure SMC.4 of cranial trauma or cerebrovascular disease in the past 6 months, and current consumption of drugs The relevance of SMC lies not only in their frequency affecting cognitive performance (anticholinergics, but also in their meaning. There are two positions benzodiazepines, neuroleptics, etc.). Patients in the literature with regards to this. On one hand, who did not adequately complete all of their some studies suggest that such complaints are evaluations were removed from the study. The associated with a lower cognitive performance Spanish version of the Subjective Memory and indicate an increased risk of developing mild Complaints Questionnaire (SMCQ) was applied cognitive impairment or dementia in the future.5,6 to assess SMC.9 It is a short questionnaire (15 On the other hand, there is the suggestion that items) which in previous studies has demonstrated SMC are the manifestation of an altered mood, adequate reliability (α Cronbach: 0.86) and a since in some studies they are only related to the good correlation with the neuropsychological presence and severity of anxiety and depression evaluations, plus it can be self-applied when a symptoms.7,8 For this reason, the meaning of SMC reliable informant does not exist (Appendix 1). is still controversial, which is why it is important to In addition, a cognitive screening was applied carry out more studies to try to understand their through Folstein’s Mini-Mental State Examination significance and causal factors. To date, there are (MMSE), the Hospital Anxiety and Depression very few studies conducted in Latin America, and Scale (HADS),10 and a survey of sociodemographic to our knowledge, there are no previous studies variables of interest: age, schooling, comorbidities, on SMC performed in the Mexican population; body mass index (BMI), sleep quality, drug use, therefore, this study aims to learn the frequency of etc. Statistical analysis was performed using the SMC and its associated factors in a sample of older statistical program GraphPad Prism version 5.0 adults in Mexico. using measures of central tendency and dispersion, associations between variables were performed with a Spearman correlation, and categorical variables were analyzed using an X2 or Fisher’s exact test.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 22 Original contribution Subjective memory complaints in Mexico
Results
A total of 100 patients participated in the study: in relation to the number of SMC. Taking into 77 women and 23 men, with an average age of consideration the cut-off point suggested by the 72.8 years (SD: 6.3, range 60-89 years) and an authors of the SMCQ (5 points), we found that average schooling of 9.08 years (SD: 5.5, range 53% of the cases had significant SMC. In regards 0-20 years). The average BMI was 26.28 (SD: 4.2, to cognitive evaluation, the average obtained in range 17-38). Considering this BMI, only 36% of the MMSE was 18.5 points (SD: 9.3). Considering the subjects had a normal weight, whereas 64% the cut-off point of 23 points, it was observed that had some degree of overweight or obesity. In 15% of the cases presented a score that suggests terms of marital status, 46% of the subjects were some degree of cognitive deterioration. The married and the other 54% had no partner for average in the total HADS score was 5.3 points various reasons (widowed, separated, divorced, (SD: 3.4) and considering the cutoff point of >15 or single). Regarding current work, only 37% had points for the total HADS, a frequency of 21% of some paid activity. As for other activities, 41% significant anxiety and depression was attained. exercised regularly (at least three times a week) It is important to note that patients who scored and 63% had a regular reading habit. Concerning high on the HADS scale or low on the MMSE the subjective quality of sleep, an average score were channeled for psychiatric or neurological of 7.2 was reported (SD: 2), a score of 4.4 in assessments, respectively. presence of daytime hypersomnia (maximum 10), and an average of 5.7 hours (SD: 1.9) of nocturnal When trying to relate the number of SMC to sleep. Regarding the presence of comorbidities different variables, we found the following: First, (hypertension, diabetes, dyslipidemia, cancer, a correlation analysis was performed between heart disease, etc.), only nine patients had none the total number of SMC and the variables (age, while the average was 2.5 comorbidities per schooling, BMI, weight, number of comorbidities, individual (range 0-7). As for SMC, only 4% did subjective sleep quality, hours of nocturnal sleep, not report any, while 96% reported at least one, daytime sleepiness, MMSE score, and HADS and the average was 5.2 SMC per individual (SD: scores) and only a significant correlation was 3.4). Figure 1 shows the distribution of cases obtained with the different HADS scores. See
Figure 1. Frequency of cases in relation to the number of SMC.
ases
M
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 Original contribution 23 Subjective memory complaints in Mexico
Table 1 and Figure 2. Additionally, a significant or without regular exercise and reading habits. positive correlation was observed between See Figures 3 and 4. In addition, a significant the MMSE score and the individuals’ schooling difference was also observed between the groups (Spearman’s r=0.3126, p=0.0015). of individuals with low schooling (<6 years) and high schooling (>9 years), with a higher number of Then, an association analysis was performed SMC in the low schooling group (figure 5). When between the number of SMC and the different we sectioned them into three age groups (60-69, categorical variables: sex, occupation, marital 70-79 and 80+), there was a tendency to present status, obesity or overweight, with or without a higher number of SMC as age increased, but this comorbidities, and we did not observe any difference was not significant (p=0.7010). Finally, significant differences. Some significant when patients were divided into MMSE scores of differences were found, however, when comparing more or less than 23 points, this did not have an the number of SMC in the groups of patients with association with the number of SMC.
Table 1. Significant correlations with the number of SMC.
aria e a ue e ear an r 0 12 0 3 9 to 0 6 73 0 0001 0 93 0 3231 to 0 6321 0 2 0 2 39 to 0 77
Figure 2. Correlation between the SMC number and the HADS scale scores.
c e
M
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 24 Original contribution Subjective memory complaints in Mexico
Figure 3. Number of SMC in relation to regular exercise. The bars represent the average SME * p=0.0315, Mann- Whitney U.
*
M
it it t
Figure 4. Number of SMC in relation to reading habits. The bars represent the average SME * p=0.0230, Mann- Whitney U
*
M
Figure 5. Number of SMC in relation to low/high schooling. The bars represent the average SME * p=0.0471, Mann-Whitney U.
M
a i a
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 Original contribution 25 Subjective memory complaints in Mexico
be related to the low level of schooling of the Discussion patients included, since it has been shown that the educational level has a strong influence on the performance shown in the MMSE.16 On the other The clinical significance of SMC in the elderly is hand, the observed frequency of 15% of patients still a matter of debate. As previously mentioned, with probable cognitive deterioration is high if we there is as much evidence suggesting it may be take into account that previous studies carried out 11 an indicator of cognitive decline or a risk factor in our country have observed a frequency of 7% of 12 for the development of cognitive impairment, as cognitive impairment in people over 65 years old.17 there is proposing that it is only an alteration of This may be due to the fact that the present study self-perception of the cognitive state caused by involved a hospital population with low schooling 13 mood disorders (anxiety and depression). and a high frequency of SMC which may affect the incidence of cognitive impairment observed. In To our knowledge, the present pilot study addition, it should be considered that the cognitive represents the first research of this type in the evaluation used (MMSE) does not really allow to Mexican population. We consider that some diagnose cognitive deterioration with certainty of the main characteristics of the population since it is only a cognitive screening instrument, so included in this study are representative of the it is possible that some of these patients may have Mexican population in this age stratum: a female undiagnosed dementia. predominance (77%), a low schooling average (9 years), a high incidence of overweight and obesity Regarding the frequency of SMC, this study (64%), high number of comorbidities (91%, average: observed that 96% of individuals referred at least 14 2.5), and a low frequency of paid work (37%). one, the average was 5.2 per person (maximum Regarding their exercise habits, the proportion 15), and over 50% of the individuals reported of regular exercise was found at 41%, which we significant complaints (>5 SMC). These figures are considered to be high; a previous study carried out similar to those obtained by Slavin et al. in 2010, in Mexico, however, reports a frequency of regular who found that 95.5% of their sample of 1,037 15 exercise in this age group of up to 70%, though this individuals reported some cognitive problem; in divergence may be due to the definition of regular that study, however, a different questionnaire was exercise used in each study. Regarding reading used to search for cognitive complaints, and the habits, which were reported in 63% of the cases, age group was older (>70 years).18 The frequency we did not find figures in the national literature of SMC reported in the literature varies greatly with which to compare it, although we estimate from less than 10% to more than 90% of cases; that it is perhaps a high figure notwithstanding the the are various reasons for this wide variability, low level of schooling of the sample. It is important perhaps related to the methodological differences to note that our sample of patients was obtained of the studies and their populations: population from an outpatient hospital population (external surveys, memory clinics, hospital population, consultation) which may affect the frequency of retirement homes, nursing homes, women-only comorbidities and pharmacological treatment, samples, and even telephone interviews.19 Another as well as other factors which may not be fully important source of discrepancy is the instrument representative of the general population. used to search for cognitive complaints. Since there is no universally accepted or standardized Another important data to consider is that in questionnaire, some studies are based only on our sample the average obtained in the cognitive one or two non-specific questions about the screening performed with the MMSE was 18.5 opinion of the state of their memory, and others points, in addition to the 15% of the individuals use structured questionnaires with dichotomous who obtained a score suggestive of some degree (yes/no) responses, or even Likert-like scores4,18,19 of cognitive impairment (<23 points). This may which undoubtedly greatly affects the frequency
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of SMC reported in each study. Furthermore, and symptoms of anxiety and depression, different although some questionnaires explore several hypotheses have been proposed. The most common cognitive domains, most focus on aspects related is that SMC is actually an altered perception of the to memory, so it is debatable to say we’re talking cognitive state caused by the coexisting symptoms about cognitive complaints when in reality it is of anxiety and depression—that is, that the older only memory complaints. In this study, we used the adult patient with anxiety and depression may pay Spanish version of the SMCQ (Appendix 1), which is more attention or magnify some cognitive errors a brief self-application tool that has demonstrated that are not really significant.4 This might lead us adequate internal consistency and a significant to assume that depressive symptoms should also correlation with neuropsychological performance affect the performance of individuals in cognitive in patients with cognitive impairment. Additionally, assessments; however, at least in our study, this instrument contains questions that, in addition there was no significant correlation between the to exploring possible flaws in different aspects of HADS scale score and the score obtained by the memory in the daily environment, also allows us to MMSE (p=0.1942), even when only patients with estimate the degree of functional impact that these more severity in their emotional symptoms were complaints have on the patient’s life.9 However, we considered (HADS >15) this association was not must consider that when applying an instrument observed (p=0.1421). In other words, anxiety and that intentionally interrogates the state of memory depression appear to have no significant influence of individuals, this can increase the frequency on cognitive performance. of reports of complaints when compared with spontaneous complaints that the patient could It is important to note that in our study there was offer—something which has, incidentally, already no association between the current cognitive been investigated and demonstrated in recent performance and the number of SMC. A studies.20 relationship was found only between the level of schooling and the number of SMC, with a greater Another of the main objectives of this study was number of complaints in the low schooling group to try to identify the factors associated with (<9 years). This, together with the observation that the presence and the number of SMC. In the regular physical activity, as well as a reading habit, correlation analysis, a significant association seems to decrease the number of SMC suggests of the number of SMC was observed only with that all these factors may generate a greater the severity of the symptoms of anxiety and cognitive reserve in these patients, thus reducing depression that the HADS scale measures. This the number of SMC, as has been widely reported association was most significant in the test’s total before.25,26 It cannot be ruled out completely, score, followed by the anxiety score, and finally in though, that factors such as exercise and reading the depression score. These findings coincide with may also have an effect by decreasing anxiety and those extensively described in other literature on depression in these patients. cognitive complaints, especially in cross-sectional studies.13,18,21 It is important to note here that It is also relevant to note that the presence of the frequency of anxiety-depressive symptoms depression in itself (regardless of cognitive observed in this study (21%) coincides with complaints) is considered an important risk factor that reported in the international literature22,23 for the development of cognitive impairment although there is also great variability in these or dementia, so that depressive symptoms may figures—for instance, a study in the Mexican actually be an indicator of early neurochemical geriatric population observed the incidence of dysfunction predisposing them in some way to depression was over 41%,24 which suggests that it cognitive deterioration, in this group of patients.27 is a prevalent disorder in this age group. Although the relationship between SMC and In order to explain this association between SMC cognitive performance is obviously very complex,
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it is interesting to remark that some studies, Finally, it should be pointed out that due to the especially longitudinal studies and studies in limitations of our study, because it was a pilot which some biomarkers (amyloid beta) have study, the sample was very small, and a broader been measured, do suggest that SMC appear to neuropsychological evaluation was not performed, raise the risk of cognitive impairment.28,29 Recent nor were functional scales used to distinguish studies show that cognitive complaints reported patients with functional impairment associated by an informant seem to be more closely related with cognitive impairment. Therefore, more to cognitive performance and to the risk of future studies will be required in the future—especially cognitive impairment.30 This difference between longitudinal studies using broad and standardized the cross-sectional and longitudinal studies neuropsychological batteries that consider both suggests that perhaps the cognitive changes spontaneous complaints as well as complaints that occur in patients with SMC are actually very recalled by memory, and take the point of view of an dynamic and highly dependent on each individual, external informant to improve the methodological so that only the long-term and serial evaluations quality of the studies and to be able to know with allow us to notice changes in the cognitive status greater certainty the implications of SMC in this that cross-sectional studies cannot demonstrate. age group.
Appendix 1.Spanish Version of the Subjective Memory Complaints Questionnaire.9
ue ion e No 1 Do ou t in ou ave a roblem it our memor 2 Do ou t in t at our memor i or e no t an it a 10 ear ago 3 Do ou t in t at our memor i or e t an t at o ot er eo le our ame age Do ou eel t at our ail li e i more com licate no becau e our memor a imini e 5. Have you had difficulties remembering a recent event? 6. Have you had difficulties remembering a conversation you had a few days ago? 7. Have you had difficulties remembering a commitment you made a few days ago? 8. Are you experiencing difficulty recognizing the faces of people close to you? 9. Are you having difficulty remembering where you have left things? 10 ave ou lo t t ing more re uentl no 11 ave ou got lo t or gone a tra ome ere out i e our ome 12 ave ou a trouble remembering to get t o or t ree article en ou go o ing or grocerie 13 Do ou ave trouble remembering to turn o t e tove or t e lig t in our ou e 1 Do ou ave trouble remembering t e one number o our c il ren 15. Do you think these memory problems have interfered significantly in your daily life?
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 28 Original contribution Subjective memory complaints in Mexico
Conclusions
In this pilot study, a high frequency of SMC (>90%) was found, and these were mainly associated with the symptoms of anxiety and depression. No association was observed with cognitive performance and it was also evidenced that factors such as schooling, reading habits, and regular exercise seem to modulate positively the number of SMC in this sample of patients. More extensive and longitudinal studies will be necessary in order to be able to know more precisely the meaning of SMC in the elderly population.
Conflict of interest statement Funding The authors declare there are no relevant There was no particular source of funding for conflicts of interest in this study. this scientific report.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 Original contribution 29 Subjective memory complaints in Mexico
References
1. Schultz SA, Oh JM, Koscik RL, Dowling NM, Gallagher C L, Carlsson CM, et al. Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-age adults at risk of AD. Alzheimer’s & Dementia. 2015; 1: 33-40. 2. Sachdev PS, Brodaty H, Reppermund S, Kochan NA, Trollor JN, Draper B, et al. The Sydney Memory and Ageing Study (MAS): Methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of australians aged 70-90 years. Int Psychogeriatr. 2010; 22:1248-64. 3. Paradise MB, Glozier NS, Naismith SL, Davenport TA, Hickie IB. Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study. BMC Psychiatry. 2011;11:108. 4. Garcia-Ptacek S, Eriksdotter M, Jelic V, Porta-Etessam J, Kåreholt I, Manzano-Palomo S. Subjective cognitive impairment: Towards early identification of Alzheimer disease.Neurologia. 2016; 31:562- 71. 5. Reid LM, MacLullich AM. Subjective memory complaints and cognitive impairment in older people. Dement Geriatr Cogn Disord. 2006; 22:471–85. 6. Reisberg B, Shulman M, Torossin C, Leng L, Zhu W. Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alzheimers Dement. 2010; 6:11–24. 7. Reisberg B, Gauthier S. Current evidence for subjective cognitive impairment (SCI) as the pre-mild cognitive impairment (MCI) stage of subsequently manifest Alzheimer’s disease. Int Psychogeriatr. 2008; 20:1-16 8. Buckley R, Saling MM, Ames D, Rowe CC, Lautenschlager NT, Macaulay S, et al. Factors affecting subjective memory complaints in the AIBL aging study: biomarkers, memory, affect, and age. Int Psychogeriatr. 2013; 25: 1307-15. 9. Youn JC, Kim KW, Lee DY, Jhoo JH, Lee SB, Park JH, et al. Development of the Subjective Memory Complaints Questionnaire. Dementia Geriatr Cogn Disord. 2009; 27:310-7. 10. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002; 52 :69-77. 11. Crumley JJ, Stetler CA, Horhota M. Examining the relationship between subjective and objective memory performance in older adults: a meta-analysis. Psychol Aging. 2014; 29:250-63. 12. Mitchell AJ. The clinical significance of subjective memory complaints in the diagnosis of mild cognitive impairment and dementia: a meta-analysis. Int J Geriatr Psychiatry. 2008;23:1191-202. 13. Zlatar ZZ, Moore RC, Palmer BW, Thompson WK, Jeste DV. Cognitive complaints correlate with depression rather than concurrent objective cognitive impairment in the successful aging evaluation baseline sample. J Geriatr Psychiatry Neurol. 2014;27:181-7. 14. Wong R, Espinoza M, Palloni A. Mexican older adults with a wide socioeconomic perspective: health and aging. Salud Publica Mex. 2007;49 suppl 4: S436-S447. 15. Wilson-Escalante LK, Sanchez-Rodriguez MA, Mendoza-Nuñez VM. Sedentarismo como factor de riesgo de trastornos depresivos en adultos mayores. Un estudio exploratorio. Rev Fac Med UNAM. 2009; 52:244-247. 16. Carnero Pardo C. Should the mini-mental state examination be retired? Neurologia. 2014; 29 :473- 81. 17. Mejía-Arango S, Miguel-Jaimes A, Villa A, Ruiz-Arregui L, Gutiérrez-Robledo LM. Deterioro cognoscitivo y factores asociados en adultos mayores en México. Salud Pública Méx. 2007; 49( Suppl 4 ): s475-s481. 18. Slavin MJ, Brodaty H, Kochan NA, Crawford JD, Trollor JN, Draper B, et al. Prevalence and predictors of “subjective cognitive complaints” in the Sydney Memory and Ageing Study. Am J Geriatr Psychiatry. 2010;18: 701-10. 19. Rabin LA, Smart CM, Crane PK, Amariglio RE, Berman LM, Boada M, et al. Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies. J Alzheimers Dis. 2015;48 Suppl 1:S63-86. 20. Burmester B, Leathem J, Merrick P. Assessing subjective memory complaints: a comparison of spontaneous reports and structured questionnaire methods. Int Psychogeriatr. 2015; 27:61-77. 21. Minett TS, Da Silva RV, Ortiz KZ, Bertolucci PH. Subjective memory complaints in an elderly sample: a cross-sectional study. Int J Geriatr Psychiatry. 2008;23 :49-54.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 30 Original contribution Subjective memory complaints in Mexico
22. Seitz D, Purandare N, Conn D. Prevalence of psychiatric disorders among older adults in long-term care homes: a systematic review. Int Psychogeriatr. 2010; 22:1025-39. 23. Creighton AS, Davison TE, Kissane DW. The prevalence of anxiety among older adults in nursing homes and other residential aged care facilities: a systematic review. Int J Geriatr Psychiatry. 2016;31:555-66. 24. Castro-Lizarraga M, Ramirez-Zamora S, Aguilar-Morales LV, Diaz de Anda VM. Factores de riesgo asociados a la depresión del Adulto Mayor. Rev Neurol Neurocir Psiquiatria. 2006; 39:132-37. 25. Barulli D, Stern Y. Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn Sci. 2013;17:502-9. 26. Young J, Angevaren M, Rusted J, Tabet N.Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2015;(4):CD005381. 27. Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011; 7:323-31. 28. Gallassi R, Oppi F, Poda R, Scortichini S, Stanzani Maserati M, Marano G, et al. Are subjective cognitive complaints a risk factor for dementia? Neurol Sci. 2010;31:327-36. 29. Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, Sperling RA, Johnson KA, Rentz DM. Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia. 2012; 50: 2880-6. 30. Slavin MJ, Sachdev PS, Kochan NA, Woolf C, Crawford JD, Giskes K, et al. Predicting cognitive, functional, and diagnostic change over 4 years using baseline subjective cognitive complaints in the Sydney Memory and Ageing Study. Am J Geriatr Psychiatry. 2015;23:906-14.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):19-30 Original contribution 31 Executive functions and behavior
Original contribution
Carlos Ramos-Galarza,1 Janio Executive functions and behavior in Jadán-Guerrero,2 Lorena Paredes-Núñez,3 Mónica Ecuadorian high-school students Bolaños-Pasquel,4 Washington Santillán-Marroquín,3 Claudia Funciones ejecutivas y conducta de estudiantes secundarios Pérez-Salas5 ecuatorianos
1 Facultad de Psicología. Pontificia Universidad Católica del Ecuador. Abstract 2 Centro de Investigación MIST. Universidad Tecnológica Indoamérica. Quito, Ecuador. INTRODUCTION: Executive functions are a set of mental skills 3 Escuela de Psicología. Universidad that allow students to self-regulate their behavior and cognition. Internacional SEK Ecuador. 4 Centro de Investigación en OBJECTIVE: To analyze the relationship between executive Neuropsicología del Ecuador. Quito, functions and behavior of high school students. Ecuador. 5 Escuela de Psicología. Universidad de Concepción de Chile. METHOD: The sample consisted of 250 Ecuadorian students between 12 and 18 years old. The measures were the EFECO rating and the behavior and academic performance grades of the school year 2015. The data analyses instruments used were the Pearson correlation and one-way ANOVA.
RESULTS: The executive functions of inhibitory control (r=0.15, p=0.01), organization of material (r=0.22, p=0.01), monitoring (r=0.25, p=0.01), initiative (r=0.21, p=0.01), working memory (r=0.21, p=0.01), and planning (r=0.24, p=0.01) are related to the behavior of high school students. Keywords executive functions, behavior, CONCLUSIONS: The results regarding the role of executive academic achievement. functions in behavioral control and academic performance of high school students in Ecuador are discussed.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 32 Original contribution Executive functions and behavior
Resumen
INTRODUCCIÓN: Las funciones ejecutivas son un conjunto de habilidades mentales que permiten a un estudiante auto-regular el comportamiento y la cognición.
OBJETIVO: Analizar la relación entre las funciones ejecutivas y la conducta de estudiantes secundarios.
MÉTODO: La muestra se conformó de 250 estudiantes ecuatorianos entre 12 y 18 años de edad. Se utilizaron como medidas el instrumento EFECO, la calificación de la conducta y rendimiento académico del año lectivo 2015. En el análisis de datos se utilizó correlación de Pearson y ANOVA de una vía.
RESULTADOS: Se encontró que las funciones ejecutivas: control inhibitorio (r=0,15, p=0,01), organización de materiales (r=0,22, p=0,01), monitorización (r=0,25, p=0,01), iniciativa (r=0,21, p=0,01), memoria de trabajo (r=0,21, p=0,01), y planificación (r=0,24, p=0,01), se relacionan con la conducta del estudiante secundario. Palabras clave CONCLUSIONES: Se discuten los resultados en torno al papel de las funciones ejecutivas en el control conductual y desempeño funciones ejecutivas, conducta, académico de los estudiantes secundarios de Ecuador. rendimiento académico.
Corresponding Author: Dr. Carlos Alberto Ramos Galarza. Profesor Principal de la Facultad de Psicología. Pontificia Universidad Católica del Ecuador. Quito, Ecuador. Calle Fernández Salvador OE489 y Av. La Prensa. E-mail: [email protected]
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 Original contribution 33 Executive functions and behavior
The executive functions have been reported as Introduction important for the regulation of student behavior in the educational context, where these mental skills have a leading role in the achievement of The executive functions are a set of cognitive educational success from pre-school to university.5 abilities the human being possesses, which are Ramos and Lozada submitted an investigation involved in the organization and planning of a task, asserting that executive function monitoring plays a the planning of strategies for the achievement role in academic performance.6 The study mentions of goals or objectives, development of organized that students with low levels of monitoring present plans, inhibition of distractions to be able to difficulties in performing adequate supervision of comply with proposed goals, and the ability to their behavior in the educational context, where react appropriately to certain situations. They they demonstrate behaviors such as acting without make use of highly complex mental processes such full awareness of the consequences of their actions, as self-regulation, working memory, organization leaving aside activities that may influence the of materials, and planning, which are the main accomplishment of their tasks, submit homework requirements for solving problems in everyday without adequate verification of its quality, and life.1-2 skip classes to perform activities with immediate gratification, among others. Executive functions play an important role in the academic life of a teenager since they undertake a As described, executive functions are core skills transcendental role in the consideration of short in educational and social success in general. For or long-term objectives, in problem-solving, and example, inhibitory control allows the student in developing effective strategies to achieve to regulate a response or immediate reaction, established goals. These executive capacities letting them wait or execute a more prudent increase from childhood to adolescence, response, delaying gratification, inhibiting their contributing to improve the resolution of first impulsive reaction, or replacing it with a more problems as development progresses. Rosselli, appropriate response.5 Jurado, and Matute assert that from birth to the adolescent stage the performance of tasks Furthermore, inhibitory control allows the student that involve executive functions gets gradually to keep at school tasks, finish the work although better.3 it may be tedious or highly complex, inhibit the temptation to do something more fun, and sustain From a neurophysiological perspective, executive their attention in a task for a long time without functions are located in the frontal lobe and being distracted—even when the activity may be are performed mainly by the prefrontal cortex, little motivating or useless.5 which is recognized as the most evolved part of the human brain and gives us the characteristic Another executive function with important influence of being rational individuals, setting us apart on the student’s behavior is the operative memory. from the rest of the animal kingdom. It is known This ability allows keeping information in mind that the dorsolateral portion is associated with while performing an activity.7 In order for a student metacognitive processes such as planning, working to maintain adequate behavior in an educational memory, verbal and design fluency, solving environment, it is necessary to keep in line with the complex problems, cognitive flexibility, generation informative content of the social norms of behavior. of hypotheses, work strategies, seriation, and When this function is weakened, it is likely that the sequencing; the orbitofrontal portion is related to student’s behavior will be characterized as one functions regulating behavior, inhibitory control, that does not follow instructions, meets only some and adaptation of behavior to social norms; and the elements of a sequence of phases in an activity, or medial portion of the anterior cingulate is related leaves tasks unfinished, etc.8 to the regulation of motivation.4
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 34 Original contribution Executive functions and behavior
Cognitive flexibility allows the student to explore different behavioral responses and decisions on Methods how to act in any given situation.9 According to Anderson, this executive function allows students to quickly change from one response to another Participants using alternative strategies.10 This involves We worked with a non-probability sample of 250 habitually analyzing the consequences of their own students in the educational system in the city behavior and learning from their mistakes. of Quito, Ecuador. The distribution according to gender was 120 men (48%) and 130 women Regarding the rest of the executive functions, (52%). Their ages ranged between 12 and 18 years the organization of materials is an executive (M=16.26, SD=1.56). The socioeconomic level function that allows the student to efficiently of the participants was middle class. We got an make use of the different elements that will be informed consent of voluntary participation in the used in the learning process. Monitoring provides study from all subjects; additionally, the principles the possibility of supervising the adequate of research ethics declared in Helsinki were performance in academic tasks and in behavior. respected at all times.12 Planning allows the elaboration of a sequential action scheme. Emotional regulation consists in Research Design the adequate control of emotional expressions in It is a study with nonexperimental quantitative different situations. And, initiative provides the methodology, transversal temporality, and possibility for the student to act without needing correlational scope. an external motivator to activate the behavior.11 Measurement Tools Within the proposed context, a research question The deferred observation procedure was used as a emerges: What is the relationship between student measure of executive functions, using a behavioral behavior and executive functions? As previously report scale with great ecological validity, unlike described, theoretically there is an interesting logic classical laboratory tests.18-19 We used the which invites an approach to answer the question EFECO scale (Evaluation of Executive Functions since the association that exists between both in Childhood through a Behavioral Observation variables is clear; however, as a contribution to the Questionnaire) in a self-report version,13 which line of investigation regarding executive functions, consists of 67 items that allow us to assess the in the present study we propose to report empirical executive functions: (a) inhibitory control, (b) evidence of this relationship. A significant aspect cognitive flexibility, (c) emotional control, (d) that must be underlined is that, in the Ecuadorian organization of materials, (e) monitoring, (f) context, after having reviewed the main databases initiative, (g) working memory, and (h) planning. As (Scopus, Web of Science and Latindex), no previous a measure of academic performance and behavior, studies on the topic of interest of this article have we used the grades obtained by the participants been found, therefore, this research constitutes during the 2015 school year. the first empirical contribution in this line of research in Ecuador. Data Analysis In the statistical analysis, we used descriptive techniques of central tendency and dispersion. To analyze the relationship between executive functions and student behavior, the Pearson correlation procedure was used. To analyze the differences in academic performance considering as a factor the students’ behavior, the one-way ANOVA was used.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 Original contribution 35 Executive functions and behavior
Procedure was found that there are statistically significant We began by requesting the voluntary participation differences in the executive functions of inhibitory of the students. The instrument was applied control F(3.226)=2.91, p=0.03, organization of massively in groups of around 30 participants. materials F(3.226)=4.37, p=0.005, monitoring The academic performance and behavior grades F(3.226)=7.24, p=0.001, initiative F(3.226)=3.76, were obtained from the database records of the p=0.01, working memory F(3.226)=5.19, p=0.002, educational institutions to which the students and planning F(3.226)=7.18, p=0.001. Whereas, belong. Subsequently, the data was entered into in cognitive flexibility F(3.226)=1.66, p=0.17, the statistical package SPSS14 to perform the and emotional control F(3.226)=1.33, p=0.26, no statistical analyses. differences were found, according to the behavior factor analyzed. In all the comparisons made, it was observed that the greater the behavioral difficulty, the greater the deficit of the executive functions of Results the students. Table 1 shows the descriptive values of the executive functions. First, the reliability parameters of the instrument used were evaluated with the Cronbach’s alpha. In the comparison of academic performance, we The [internal consistency] coefficients found considered the behavior grade as an independent variable with four sublevels: very satisfactory, were: inhibitory control α=0.76, flexibility α=0.64, satisfactory, unsatisfactory, and improvable. The emotional control α=0.83, planning α=0.73, comparison of the academic performance through organization of materials α=0.78, monitoring the behavior factors presented a statistically α=0.72, initiative α=0.77, and working memory significant difference F(3.226)=4.88, p=0.003. α=0.82. When analyzing whether it would be necessary to eliminate an item to improve the Figure 1 shows the average academic performance coefficient of its corresponding scale we found according to the level of behavior presented by that it was not useful to perform this procedure, students. therefore, all the items on the scale were worked with.
In the relationship between the executive functions and the student’s behavior grade, we saw that inhibitory control (r=0.15, p=0.01), organization of materials (r=0.22, p=0.01), monitoring (r=0.25, p=0.01), initiative (r=0.21, p=0.01), working memory (r=0.21, p=0.01), and planning (r=0.24, p=0.01), are significantly related to the behavior that students present in their educational institution. The rest of the executive functions (cognitive flexibility and emotional control) did not present statistically significant relationships.
To contrast the executive functioning of the students according to the type of behavior, four groups of student behavior were organized (very satisfactory, satisfactory, unsatisfactory, and improvable), which were considered as factors in the ANOVA analysis. In the results it
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 36 Original contribution Executive functions and behavior
Table 1. Descriptives of executive functions.
ini u a i u e ian an ar e r ur o i ica ica rror rror n i i or on ro 0 2 8 33 3 683 1 71 307 o ni i e e i i i 0 13 1 2 832 6 1 - 093 307 o iona on ro 0 21 7 82 797 8 1 - 30 307 r ani a ion o a eria 0 19 6 29 3 967 777 1 76 307 oni orin 0 18 88 2 99 1 128 1 1 6 8 307 ni ia i e 0 23 7 2 13 83 1 1 2 307 or in e or 0 26 8 09 9 97 1 1 672 307 annin 0 18 6 29 3 37 8 3 1 1 3 8 308
IC = inhibitory control, CF = cognitive flexibility, EC = emotional control, OM = organization of materials, M = monitoring, I = initiative, WM = working memory, P = planning, BF = behavioral factor, Md = median, SD = standard deviation, VS = very satisfactory, S = satisfactory, US = unsatisfactory. *. The comparison made in ANOVA is significant at 0.05.
Figure 1. Academic performance of the participants according to their type of behavior.
ca e ic er or ance e ian er or ance ca e ic
: ver ati actor : ati actor : un ati actor D: im rovable e a ior
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 Original contribution 37 Executive functions and behavior
Discussion
In this article, we have reported an investigation one of the most influential factors in educational that aimed to analyze the relationship between success is executive functioning.5 executive functions and the behavior of Ecuadorian high school students. As the main result, we This relates to the findings by Reyes, Barreyro, found that the inhibitory control, organization of and Injoque-Ricle16 and Berninger, Abbott, Cook, materials, monitoring, initiative, work memory, and Nagy17 who described that the executive and planning are related to the behavior of the functions have an important incidence in academic student. This relationship suggests that the greater performance mentioning working memory, verbal the deficit in executive functions, the greater the fluency, regulation of attention, and planning as student’s behavior difficulties. the executive functions with the greatest impact on student academic performance. This result confirms the findings in the study conducted by Arango, Puerta, and Pineda, where As it has been described throughout the article, the they describe that executive functions would act executive functions have a significant impact on in concert to effectively guide and supervise the student behavior, which delineates possible future behavior and responses set to achieve a goal, fulfill research where longitudinal experimental studies a task, or self-regulate behavior, according to what of intervention in the executive functions can be the environment demands from the individual, just carried out to improve the behavior of high-school as it happens with the students who get a better students. grade in the educational context.15 Finally, as a limitation in the present study, we Considering the executive functions as responsible must mention the implicit subjective character for behavioral supervision invites reflection on the of self-reporting as an assessment instrument role they have for the student to control impulsive of executive functions. It could bias the results responses, moving from one activity to another described previously, since the makeup of without difficulties in its correct execution, and individual behavior may be different for each regulation of responses of the emotional type student. Another limitation that must be kept in (crying, anger, frustration, or aggression) in the mind is the local character of the sample, which pursuit of educational objectives—in short, to belongs to a specific city in Ecuador, and means present a behavior within socially accepted that the results cannot be generalized to the entire standards.15 population of the country. However, this situation is a motivation that invites us to continue in this In addition, we analyzed the influence of behavior line of investigation with a study with a greater on academic performance and found there is a scope at a national level. significant association between these variables. The students with the best academic performance presented a better behavioral score while the students with low academic performance presented worse behavioral score. This suggests that, although executive functions have an influence on student behavior, they would also have an influence on the student’s academic performance, which would allow us to ratify what was mentioned by Diamond, who affirmed that
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 38 Original contribution Executive functions and behavior
Conclusiones
Faltan las conclusiones
Conflict of interest statement Funding The authors declare there are no relevant There was no particular source of funding for conflicts of interest in this study. this scientific report.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 Original contribution 39 Executive functions and behavior
References
1. Slachevsky, A., & Núñez-Huasaf, J. Procesos Ejecutivos y Adaptación del Comportamiento. In J. Lavados, & A. Slachevsky, Neuropsicología de los Procesos Mentales. Santiago, Chile: Editorial Mediterráneo, 2013, pp. 189-209. 2. Soprano, M. Evaluación de las Funciones Ejecutivas en el Niño. Revista de Neurología. 2003,44-50. 3. Rosselli, M., Jurado, M., & Matute, E. Las Funciones Ejecutivas a través de la Vida. Neuropsicología, Neuropsiquiatría y Neurociencias. 2008, 8 (1), 23-46. 4. Stuss, D., & Alexander, M. Executive functions and the frontal lobes: a conceptual view. Psychological Research. 2000, 63, 289-298. 5. Diamond, A. Why Improving and Assesing Executive Functions Early in Life is Critical. In J. Grifin, P. McCardle, & L. Freund, Executive Function in Preschool-Age Children: Integrating Measurement, Neurodevelopment, and Translational Research. Washington: American Psychological Association, 2016, pp. 11-43. 6. Ramos, C., & Lozada, J. ¿Los estudiantes universitarios tienen dificultades neuropsicológicas en el control de impulsos o en su monitorización? CienciAmérica. 2015, 4, 13-24. 7. Baddeley, A. Working memory: Theories, Models, and Controversies. Annual Review of Psychology. 2012, 63, 1-29. 8. Servera-Barceló, M. Modelo de autorregulación de Barkley aplicado al Trastorno por Déficit de Atención con Hiperactividad: una revisión. Revista de Neurología. 2005, 40 (6), 358-368. 9. Morash, K., Raj, V., & Bell, M. The development of cognitive control from infancy through childhood. In D. Resiberg, Oxford Handbook of cognitive psychology. New York: Oxford University Press, 2013, pp. 989-999. 10. Anderson, P. Assessment and development of executive function during childhood. Child Neuropsychology: A Journal on Normal and Abnormal Development in Childhood and Adolescence. 2002, 8 (2), 71-82. 11. Gioia, G., Isquith, P., Retzlaff, P., & Espy, K. Confirmatory Factor Analysis of the Behavior Rating Inventory of Executive Function (BRIEF) in a Clinical Sample. Child Neuropsychology. 2002, 8 (4), 249-257. 12. Williams, J. Revising the declaration oh Helsinki. World medical journal. 2008, 54 (4), 120-122. 13. Ramos-Galarza, C., Jadán-Guerrero, J., García-Gómez, A., & Paredes, L. Propuesta de la escala EFECO para evaluar las funciones ejecutivas en formato de auto-reporte. CienciAmérica. 2016, 5 (1), 104-109. 14. IBM. SPSS Statistics. IBM Corp, 2011. 15. Arango, O., Puerta, I., & Pineda, D. Estructura Factorial de la Función Ejecutiva desde el Dominio Conductual. Revista Diversitas - Perspectivas en Psicología. 2008, 63-77. 16. Reyes, S., Barreyro, J., & Injoque-Ricle, I. El rol de la función ejecutiva en el rendimiento académico en niños de 9 años. Revista Neuropsicología Latinoamericana. 2015, 7 (2), 42-72. 17. Berninger, V., Abbott, R., Cook, C., & Nagy, W. Relationships of Attention and Executive Functions to Oral Language, Reading, and Writing Skills and Systems in Middle Childhood and Early Adolescence. Journal of Learning Disabilities. 2016, 8, 1-16. 18. García-Gómez, A. Desarrollo y validación de un cuestionario de observación para la evaluación de las funciones ejecutivas en la infancia. Revista Intercontinental de Psicología y Educación. 2015, 17 (1), 141-162. 19. Pérez-Salas, C., Ramos, C., Oliva, K., & Ortega, A. Bifactor Modeling of the Behavior Rating Inventory of Executive Function (BRIEF) in a Chilean Sample. Perceptual and Motor Skills. 2016, 122 (3), 757-776.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):31-39 40 Original contribution Neonatal seizures and electroencephalogram
Original contribution
Liane Aguilar-Fabré,1 René Neonatal Seizures: etiology, Francisco Rodríguez-Valdés,1 Libertad Rivera-Alés,2 Lídice electroencephalographic patterns, and Galán-García,3 Luena Cárdenas outcome González,2 Kenia Aguilar- 4 Fabré, Hebert Luis Hernández- Convulsiones neonatales: etiología, patrones electroencefalográficos 1 Montiel. y evolución.
1 Nervous System Clinic. Department of Biomedical Research. School of Medicine. Autonomous University of Querétaro. Mexico. Abstract 2 Neonatology Care Unit. Juan Manuel Márquez Pediatric Teaching Hospital. Havana. Cuba. Introduction: Neonatal seizures (NS) constitute the clinical 3 Department of Neuroinformatics. expression par excellence of a dysfunction in the Central Nervous Cuban Neuroscience Center. Havana. System and present a high incidence. Cuba. 4 Gynecology Service. National Objective: To review etiology, electroencephalographic patterns, Institute of Oncology and and the outcome of neonatal seizures, as well as to seek associations Radiobiology. Havana. Cuba. between NS and other neurological risk factors.
Methods: We studied 22 patients with NS. Pre-, peri-, and postnatal antecedents were collected. Electroencephalogram (EEG) was performed, classifying the results into normal, mild, moderate and severe alterations. A general linear model was used to demonstrate possible associations between seizures and other neurological risk factors.
Results: Hypoxic-ischemic encephalopathy was the most frequent etiology, approximately 40% of the subjects showed a good outcome, and the most frequent sequel was epilepsy (40.9%). EEG was normal only in 13.63% of patients. The analysis of possible statistical associations showed statistically significant associations between the EEG outcome and the patient’s outcome (p=0.015), between gestational age and outcome (p=0.003) as well as between birth weight and outcome (p=0.003).
Keywords Conclusions: The prediction of morbid damage has made it necessary to search for biochemical, neurophysiological, and neonatal seizures, etiology, neuroimaging indicators in order to identify early lesions that electroencephalographic threaten the satisfactory evolution of children due to morphological patterns, and evolution. and functional alterations.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 Original contribution 41 Neonatal seizures and electroencephalogram
Resumen
Introducción: Las convulsiones neonatales (CN) constituyen la expresión clínica por excelencia de una disfunción en el Sistema Nervioso Central y presentan una elevada incidencia.
Objetivo: Revisar la etiología, los patrones electroencefalográficos y la evolución de las convulsiones neonatales, así mismo se intentará buscar asociaciones entre las CN y otros factores de riesgo neurológico.
Métodos: Se estudiaron 22 pacientes con CN. Se recogieron antecedentes pre, peri y post natales. Se realizó estudio electroencefalograma (EEG), clasificando los resultados en normal, alteraciones ligeras, moderadas y graves. Se utilizó un modelo lineal general para demostrar las posibles asociaciones entre las convulsiones y otros factores de riesgo neurológico.
Resultados: La encefalopatía hipóxico isquémica fue la etiología más frecuente, aproximadamente el 40% de los sujetos mostraron una buena evolución y la secuela más frecuentes fue la epilepsia (40.9%). El EEG fue normal sólo en el 13.63% de los pacientes. The analysis of the possible statistical associations showed statistically significant associations between the EEG result and the outcome of the patient (p=0.015), between gestational age and outcome (p=0.003), and between birth weight and outcome (p=0.003). Palabras clave Conclusiones: La predicción de daños mórbidos ha hecho necesaria la búsqueda de indicadores bioquímicos, neurofisiológicos convulsiones neonatales, y de neuroimágenes con la finalidad de identificar tempranamente etiología, patrones lesiones que amenacen la evolución satisfactoria de los niños, por electroencefalográficos, alteraciones morfológicas y funcionales. evolución.
Corresponding author: René Francisco Rodríguez-Valdés. Nervous System Clinic. Department of Biomedical Research. School of Medicine. Autonomous University of Querétaro Address: Calle Clavel No. 200. Col Prados de la Capilla. Querétaro. Qro. México. Código Postal 76170. Tel: (442) 192-1200 ext: 6252 E-mail: [email protected]
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 42 Original contribution Neonatal seizures and electroencephalogram
Introduction Methods
Seizures in the neonatal period (NS) constitute the Twenty-two newborns admitted to the Neonatal characteristic clinical expression of a dysfunction of Care Unit of the Juan Manuel Márquez Pediatric the Central Nervous System (CNS).1 The incidence Teaching Hospital with the diagnosis of neonatal of NS is 0.15-1.4% of newborns.2 seizures were studied. We collected pre-, peri-, and postnatal antecedents, gestational It is not always easy to recognize them and they age, and birth weight. The patients attended can go unnoticed, especially in the preterm neurodevelopment consultations for periodic newborn—this is related to the anatomical, evaluations for at least 12 months. biochemical, and physiological development of the CNS during the perinatal period.1 The clinical and Electroencephalographic evaluation electroencephalographic manifestations differ The electroencephalographic record was obtained from those of a newborn with greater neurological in spontaneous sleep with an approximate maturity, reflecting functional differences due to a duration of 60 minutes. For the monitoring of lower degree of myelination.3 other polygraphic variables (electrooculogram, electromyogram, and oxygen saturation) we The occurrence of seizures in the newborn is of used the digital electroencephalographic system great importance because of its association with MEDICID-5 (Neuronic SA) with amplifiers with high rates of neurological morbidity and mortality; a gain of 10,000, sampling frequency of 200 Hz, furthermore, they require urgent diagnosis and and filters with a 0.5-30 Hz bandwidth. We used treatment to prevent the aggravation of underlying 19 surface electrodes placed according to the brain lesions.4,5 international 10-20 system. Shorted electrodes located on both earlobes were used as reference. The electroencephalogram is not only one of the The visual inspection of the EEG was done offline few methods that allow a functional study of the by two experts independently. CNS, but it also has the advantages of being safe and of low economic cost in comparison with the The electroencephalographic studies were neuroimaging techniques—such as tomography and classified as normal, with minimal alterations magnetic resonance imaging—which are structural (immaturity of base rhythms, interhemispheric methods that allow us to visualize the lesion but asynchrony, decreased voltage), moderate do not inform us about the pathophysiological alterations (persistent focal or generalized process. acute spikes and waves), critical tracing (with patterns of focal disturbances during crises, The aim of this study is to review the etiology, focal or multifocal monorhythmic discharges the electroencephalographic patterns, and the during crises), and severe alterations (presence outcome of seizures in the prenatal period, as well of isoelectric tracing or with a burst-suppression as to establish possible associations between NS pattern).6 and other neurological risk factors. Death or manifestations of serious sequelae (epilepsy, psychomotor development retardation, infantile cerebral palsy) were considered “unfavorable outcome.”
Statistical Analysis We calculated the mean and the standard
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 Original contribution 43 Neonatal seizures and electroencephalogram
deviation as well as the distribution of risk factor in 9.09% (2/22), psychomotor development frequencies. A general linear model was applied retardation plus epilepsy in 4.54% (1/22), and an for the statistical analysis of the data, accepting infant cerebral palsy plus epilepsy in the remaining p<0.05 as statistically significant. subject.
Ethical Considerations The analysis of the possible statistical associations The research was approved by the Research showed statistically significant associations Ethics Committee of the Juan Manuel Márquez between the EEG result and the outcome of the Pediatric Teaching Hospital and met the ethical patient (p=0.015), between gestational age and guidelines of the Declaration of Helsinki. outcome (p=0.003), and between birth weight and outcome (p=0.003).
Seizures occurred in isolation (as the only risk Results factor) in 27.2%, associated with another risk factor in 18.1%, and with more than two risk factors in 53.7%. Characteristics of the sample We studied 22 newborns with NS, 11 of which were male (50%). The mean gestational age was 37.98 weeks (SD 2.35, range 32.6-42), with four subjects Discussion (18.18%) premature (gestational age less than 37 weeks). The average birth weight was 2924 g (SD In the study, the most frequent cause of NS was 582.68, interval 1802-3850), there were no cases hypoxic-ischemic encephalopathy coinciding with with birth weight under 1500 g. the results of other investigations.2,7-10 In relation to the etiology of seizures and the time of onset, There were 12 eutocic births (54.54%), six some authors report that the majority of seizures cesarean sections (27.27%), and four deliveries that occur before the fifth day of life are usually due with instruments (18.18%). The Apgar score at five to hypoxic-ischemic encephalopathy, intracranial minutes of life was less than 4 in two cases (9.09%). hemorrhage, metabolic disorders, CNS infection, or by the direct effect of drugs.2,11-13 Ninety Etiological Diagnosis percent of the seizures that appear in the course of Table 1 shows the distribution of neonatal seizures hypoxia-ischemia occur within the first 48 hours of according to etiology. life. Seizures that manifest between 24-72 hours of life are due to CNS infections, drug withdrawal, hemorrhage, the onset of congenital errors in the Electroencephalographic evaluations metabolism, or brain malformations.2,8,14,15 The EEG behaved in the following way: 13.63% had normal EEG, 9.09% presented minimal In this work, it is striking that the majority of NS alterations, 59.09% had moderate alterations, and occurred in full-term newborns (81.82%). A study 18.18% had serious alterations. Figure 1 shows the by Sheth et al. analyzing the relationship between electroencephalographic tracing of a patient who these two conditions found a parabolic distribution presented neonatal seizures before 24 hours of with a lower incidence between 30-36 weeks age. (4.8%) compared to the term group (11.9%).10
Outcome Moreover, the electroencephalographic alterations There were no deaths. In 40.9% (9/22) of the described in the group of patients who presented patients, a good outcome was observed. In the rest neonatal seizures in this study are similar to those of the patients: epilepsy occurred in 40.9% (9/22), reported by other authors2,6 highlighting that most a delay in psychomotor development presented of the patients presented moderate and severe
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 44 Original contribution Neonatal seizures and electroencephalogram
Table 1. Etiology of neonatal seizures
io o N 10 4 4 4 18 18 N mal ormation 1 4 4 etabolic 2 0 N in ection 22 72
HIE: Hypoxic-Ischemic Encephalopath, ICH: Intracranial Hemorrhage, CNS: Central Nervous System
Figure 1. Pattern of surge suppression in newborn that begins with tonic spasms at 23 hours of birth.
alterations. Alcover also found that the recording of a is associated with normal results or with minor pathological EEG (critical or with severe alterations) neurological alterations.16 is associated with an unfavorable outcome in most cases.6 A more accurate prognosis in these patients The study by Jiménez et al. lists the presence can be attained from the etiology of neonatal seizures of clinical neurological alterations during the and electroencephalographic patterns.4 first week of life, the presence of seizures, anda pathological EEG, as the main prognostic factors in The persistence of pathological records beyond perinatal asphyxia.17 72 hours of birth is invariably associated with death or serious neurological sequelae, while Preterm children with an intercritical EEG within early recovery—before 12 or at least 36 hours— normality generally have a good prognosis, whereas
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 Original contribution 45 Neonatal seizures and electroencephalogram
the EEG tracing of a “burst-suppression” in the The association between gestational age and neonatal period translates into a poor prognosis birth weight is well known. Preterm newborns except when said tracing is of pharmacological constitute a vulnerable population with a high risk origin.18 of suffering medical problems and neurobehavioral disabilities20,21 including poor cognitive The EEG is very useful to confirm suspicions; performance and greater learning difficulties, as however, it is not definitive for the diagnosis of NS. well as an elevated risk of presenting behavioral Conventional electroencephalography has a series disorders. of limitations in the study of these patients, among which are: a) difficulties in prolonged monitoring, Of the total number of premature children, up to b) excessive number of electrodes, c) electrical 47% of them present cerebral palsy, 27% show interference by surrounding equipment, d) important cognitive disorders, and 23-37% have difficulties in interpretation of the study requiring sensory disorders.22,23 a staff trained in clinical neurophysiology, e) brief records (45-60 minutes) that even with periodic A study conducted by Salinas-Álvarez noticed evaluations can lose information on the outcome that approximately three-quarters of their sample of the alterations of the base activity, sleep states, presented an overlap of risk factors. Their study of and sporadic seizures. The incorporation of the patients with high neurological risk describes that amplitude-integrated EEG, a safe method for on a scale of one to ten risk factors, their sample cerebral function monitoring, is a simple method of had an average of 4.1.24 It has been described that continuous recording of cortical electrical activity these cases are more likely to develop a disability allowing to predict the final neurological outcome and that the accumulation of risks is not equivalent in as short a time as the first 6 hours of life.16,19 to a sum but that they are potentiated.
Conclusions
In patients with neonatal seizures, the etiology should be determined and confirmed by electroencephalographic evaluation; in turn, the result of the EEG could provide elements in the neurological prognosis of these children.
Conflicts of interest Funding The authors of the research state there are no This research did not have any financing sources. conflicts of interest in this study.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 46 Original contribution Neonatal seizures and electroencephalogram
References
1. Volpe JJ. Neurology of the newborn (3a ed). Philadelphia, WB Saunders, 1995. 2. Campistol J, de Jaro P, Póo P, Kraurel J, Fernández-Álvarez E. Convulsiones neonatales. Formas de presentación y evolución. Rev Neurol. 1994; 22: 171-175. 3. Caro Castellar I. Crisis neonatales. Acta Neurol Colomb. 2008; 24: 25-33. 4. Lombroso CT. Neonatal sizures: a clinician´s overview. Brain Dev. 1996;18: 1-28. 5. Stafstrom CE. Neonatal seizures. Pediatr Rev. 1195; 16: 248-56. 6. Alcover-Bloch E, Campistol J, Iriondo-Sanz M. Convulsiones neonatales, experiencia en la unidad. Revista de Neurología. 2004; 38(9):808-812. 7. Campistol J. Convulsiones y síndromes epilépticos del recién nacido. Formas de presentación, protocolo de estudio y tratamiento. Rev Neurol. 2000;31(7):624-631. 8. Mizrahi E.M., Kellaway P. Characterization and classification of neonatal seizures.Neurology. 1987; 37: 1837-44. 9. Volpe J. Neonatal seizures: current concepts and revised classification.Pediatrics. 1989; 84: 422-8. 10. Sheth RD, Hobbs GR, Mullett M. Neonatal Seizures: incidence, onset and etiology by gestional age. J. Perinatol. 1999;19:40-3. 11. Bergman I, Painter MJ, Hirsch RP, et al. Outcome in neonates treated in an intensive care unit. Ann Neurol. 1983;14: 642-8. 12. Holmes G. Convulsiones neonatales.- Acta Neuropediatr. 1995; 1: 240-51. 13. Levene MI, Traura JQ. Causes of neonatal convulsions. Arch Dis Child. 1986; 61: 78-9. 14. Andre M, Matisse N, Vert P, Debrouille CH. Neonatal seizures. Recent aspects. Neuropediatrics. 1988;19:201-7. 15. Rodríguez Barrionuevo AC, Bauzano Poley E, Tosina García E. Guía práctica de neurología neonatal. Correlación clínico-EEG. Barcelona: César Viguera, editor; 1997. 16. Protocolos Diagnóstico Terapéuticos de la AEP: Neonatología. Asociación Española de Pediatría. 2008 www.aeped.es/protocolos/ 17. Jiménez R, Figueras J, Cañadell D, Botet F, Cruz M. Factores pronósticos en la encefalopatía hipóxico isquémicas del recién nacido a término. An Esp Pediatr. 1989; 31:189-195. 18. Campistol J. Convulsiones Neonatales. Asociación Española de Pediatría. 2008 www.aeped.es/ protocoloes/ 19. Rakshasbhuvankar A, Paul S, Nagarajan L, Ghosh S, Rao S. Amplitude-integrated EEG for detection of neonatal seizures: a systematic review. Seizure 2015; DOI of original article: http://dx.doi. org/10.1016/j.seizure.2015.09.014 20. Clark C, Woodward L. Neonatal cerebral abnormalities and later verbal and visuospatial working memory abilities of children born very preterm. Dev Neuropsychol. 2010;35: 622–42. 21. Taylor HG, Klein N, Minich NM, Hack M. Middle–school–age outcomes in children with very low birth weight. Child Dev. 2000;71(6):1495–511. 22. Peterson B, Anderson AW, Ehrenkranz R, Staib LH, Tageldin M, Colson E, et al. Regional brain volumes and their later neurodevelopmental correlate in term and preterm infants. Pediatrics. 2003; 111(5):939–48. 23. Fraello D, Maller–Kesselman J, Vohr B, Katz KH, Kesler S, Schneider K, et al. Consequence of preterm birth in early adolescence: the role of language on auditory short–term memory. J Child Neurol. 2011;26: 738–42. 24. Poo P, Campistol J, Iriondo M, Recién nacido de riesgo neurológico en el año 2000. Recomendaciones para el seguimiento, incorporación de nuevos instrumentos. Rev Neurol. 2000; 31:645-652.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):40-46 Original contribution 47 Health in ADHD
Original contribution
Development and health in the diagnosis of Denise Medici, Pilar Codoñer Franch, María Morales Suárez attention-deficit/hyperactivity disorder Varela1 Desarrollo y Salud en el diagnóstico en Trastorno por Déficit de Atención/Hiperactividad 1 Pediatrics Service Dr. Peset University Hospital Preventive Medicine and Public Health Bromatology, Toxicology and Legal Medicine, University of Valencia Abstract
Introduction: The purpose of the study was to describe the health status in children diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD), to know possible diseases and the clinical interdisciplinary intervention.
Method: This retrospective cohort study included 297 medical histories of patients from both genders diagnosed with ADHD (DSM IV) meeting the clinical criteria previously established in a public hospital of the Community of Valencia.
Results: The otorhinolaryngology, ophthalmology, and allergology results in children diagnosed with ADHD and those obtained by several previous studies were statistically significant, except in obesity at 16 years of age for Khalife, in diabetes mellitus and in asthma for Guerro-Prado, and in asthma for Calam.
Conclusions: The general health difficulties for patients diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) can be treated, and there is a significant correlation in the remission of symptoms after treatment. Finally, it will be interesting to develop Keywords further research on whether the optimization in the management ADHD, Pediatric, ORL, OPD, of these processes influences or not the evolution of the ADHD- ALG. diagnosed child.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):47-57 48 Original contribution Health in ADHD
Resumen
Introducción: El propósito del estudio fue describir la salud en los niños con diagnóstico en Trastorno por Déficit de Atención/ Hiperactividad (TDAH), conocer posibles enfermedades y su intervención clínica interdisciplinaria.
Método: Estudio cohorte retrospectivo de 297 historias clínicas (HC) de pacientes de ambos géneros con diagnóstico en Trastorno por Déficit de Atención/Hiperactividad (TDAH) en un Servicio de Pediatría en un hospital público de la Comunidad de Valencia.
Resultados: Los resultados en Otorrinolaringología (ORL), Oftalmología (OFT) y Alergología (ALG) en los niños diagnosticados TDAH y en los obtenidos por diversos estudios previos, fueron estadísticamente significativos, exceptuando en obesidad a los 16 años de edad por Khalife, en Diabetes Mellitus y en asma por Guerro- Prado y en asma por Calam.
Conclusiones: Las dificultades generales en la salud en los pacientes con diagnóstico en Trastorno por Déficit de Atención/Hiperactividad (TDAH) del estudio son atendidos por los demás servicios médicos del hospital (ORL, OFT, ALG) comprobándose una correlación significativa en la remisión de los síntomas luego de su tratamiento. Palabras clave Finalmente, será interesante desarrollar más investigaciones sobre si la optimización en el manejo de estos procesos influye o no en la TDAH, Pediatría, ORL, OFT, evolución del niño con diagnóstico en TDAH. ALG.
Correspondence: Denise Medici Correo electrónico: [email protected]
Revista Mexicana de Neurociencia November-December, 2017; 18(6):47-57 Original contribution 49 Health in ADHD
Introduction Methods
According to the epidemiological studies of the During the first semester of 2015, one researcher American Academy of Pediatrics, Attention- made a cohort study of retrospective analysis Deficit/Hyperactivity Disorder (ADHD) is the most of 1,049 clinical histories (CH) of children and frequently diagnosed neurobiological disorder adolescents diagnosed with ADHD according in childhood and adolescence.1 The scientific to the criteria of DSM-IV (Diagnostic and literature has studied the common pathologies at a Statistical Manual of Mental Disorders) in the pediatric age in ADHD and they confirm there has Pediatric Service of the Dr. Peset University been an increase in recent decades in prevalence Hospital, selecting and analyzing the clinical data and burden of atopic diseases such as eczema, statistically. The search and statistical analysis of atopic dermatitis, rhinitis, and asthma accompanied personal and clinical data of children diagnosed by a global increase in diagnosis of ADHD.2-7 One with ADHD who met the previously-established of the most studied medical conditions is allergy in clinical criteria was performed. The profiles of ADHD. the children with the CH included in the study did not present significant differences in terms of A recent study conducted by the National Health clinical, psychological, or social variables. Based Insurance Research Database (NHIRD) showed on the homogeneity present in all participants, that pediatric patients with allergic disorders 297 CH were selected (79 girls and 218 boys) had a substantial increase in odds of developing with Spanish nationality aged ≥6 to ≤16 years ADHD. Eczema and asthma are diagnosed more old (mean age in years: 09.10), meeting the frequently in children with ADHD than in children established clinical criteria. without diagnosis of ADHD—however, asthma does not represent a greater risk for ADHD.8 Description of the selection of the study Furthermore, ADHD-diagnosed children in the subjects: following consultations report: dysphonia and laryngeal nodules in the Otorhinolaryngology department,9 hyperopia, myopia, strabismus, o a e c u e and amblyopia (“lazy eye”) in Ophthalmology,10,11 226 orn bet een 1 0 an 1 8 headaches and febrile seizures in Neurology,10-14 7 ere not iagno e in an inter i ci linar a and in Pediatric Nephrology, nocturnal enuresis— 14 re ente D which causes a great problem in emotional 47 re ente a reviou l - iagno e neurological behavior.15-18 Cardiology has reported the presence at olog comorbi D D (e g , e ile , , ) of congenital heart murmurs and heart disease,19 0 re ente iagno e genetic n rome (e g , and Endocrinology reports the existence of eletion ) overweight and obesity in children and adolescents 26 ere a o te at t e national or international level, with ADHD, which, similarly to nocturnal enuresis, in o ter care an or born in ain rom arent o brings with it important affective consequences, oreign origin and, if compounded by academic difficulties, results re ente neuro iological tu ie but ere no 20,21 in an even more complex situation. longer atient o t e e iatric ervice o t e o ital 12 nacce ible ata High-quality interdisciplinary prospective research N should continue to advance to better understand N 2 7 met t e clinical criteria the mechanisms underlying these diseases and ADHD and to establish prevention and treatment strategies directed at ADHD.21
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Selection criteria Results Inclusion criteria: 1- patients of either gender born with a diagnosis of ADHD, aged between ≥6 and ≤16 years old, with an IQ over 80, and Development and general health history. Regarding born and raised in Spain by Spanish parents; general health history in children diagnosed with 2- patients who met the requirements of the ADHD, statistically significant results were obtained previous point and have attended pediatric in all the types analyzed (p≤0.001). Table 1. check-ups correctly; 3- patients who met both previous requirements and who have complied In the general health history in children diagnosed with the pertinent medical indications. with ADHD studied by the authors, the results are statistically significant in headaches/migraines Exclusion criteria: 1- patients of either gender (p≤0.001) from Guerro-Prado,39 Arruda,13 and diagnosed with ADHD aged ≥6 to ≤16 years old, Genizi,14 and from Khalife40 in obesity/overweight, born and raised in Spain by parents with IQ under except for obesity at 16 years of age (p=0.146) which 80 and/or illiteracy; 2- patients of either gender coincides with our total data, as well as with the data diagnosed with ADHD, aged between ≥6 and ≤16 obtained by Guerro-Prado in asthma (p=0.705) and years old, born in Spain but brought up abroad, diabetes mellitus (p=0.889). Table 1 (a). or brought up by foreign parents, or adopted regardless of being reared inside or outside of Otorhinolaryngology history. Regarding the ENT Spain; 3- patients of either gender diagnosed history in children diagnosed with ADHD, the with ADHD, aged ≥6 to ≤16 years old, with no results are statistically significant in all the clinical attendance at pediatric check-ups, failure to aspects analyzed (p≤0.001). Table 2. Six pathologies comply with the pertinent medical indications, have χ² values of p≤0.001. or diagnosed with ADHD after acquired brain damage, surgeries, and/or neurological disease. In the ENT history of laryngeal nodules = dysphonia in children diagnosed with ADHD, the results The study was carried out without financial of Barona-Lleo9 are statistically significant with funding and was approved by the Ethics respect to the present study (p≤0.001). Table 2 (a). Committee for Clinical Research of the Dr. Peset Ophthalmology history. Regarding the University Hospital in the city of Valencia. The ophthalmology history of children diagnosed with records related to the children were gathered in ADHD, the results are statistically significant in all a confidential database, for the sole and exclusive the clinical aspects analyzed (p≤0.001) as well as use in the project. The data related to the among the five diagnoses χ( ² p=0.003). Table 3. diagnosis of each child, treatments, and personal circumstances, as well as those that refer to their In the ophthalmology medical history of children evolution, were collected according to the Law diagnosed with ADHD studied by the authors, the 15/99 on Protection of Personal Data. results are statistically significant with the present study in all the clinical aspects analyzed (p≤0.001). For the descriptive data, dispersion measures Table 3 (a). were used in order to evaluate the extent to which the data differed from each other by Allergology history. In the allergology history of establishing frequencies (FR), percentages (%), children diagnosed with ADHD, the results are and p value, to indicate the significant statistical statistically significant in all the clinical aspects level, considering >0.05 not significant and analyzed (p≤0.001). Table 4. ≤0.001 statistically significant. In bivariate analysis of the quantitative variables, Pearson’s In the allergology history of children diagnosed with test (χ²) was used. ADHD obtained by the authors, the results have been statistically significant in atopy (p=0.002) and
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Table 1. Development and Health. aria e re ent ealt i tor 127 42.76 37.09-48.61 Deficits in motor development 7 12.46 9.02-16.88 <0.001 Bronchospasms in childhood 6 2.02 0.82-4.56 <0.001 Resp. insufficiency upper airways 1 10.43 7.30-14.62 <0.001 Febrile convulsions in childhood 4 1.34 0.42-3.64 <0.001 Primary nocturnal enuresis 15 5.05 2.95-8.36 <0.001 Pneumonia 4 1.34 0.42-3.64 <0.001 Cryptorchidism 4 1.34 0.11-2.67 <0.001 Juvenile idiopathic arthritis 1 0.33 0.01-2.15 Childhood viral meningitis 1 0.33 0.01-2.15 Headaches/Migraines 24 8.08 5.35-11.93 Asthma 3.03 1.48-5.87 Obesity/Overweight 6 2.02 0.82-4.56 Diabetes Mellitus 2 0.67 0.11-2.67
Table 1a. ADHD child’s health according to previous studies.
aria e ea ac e igraine 2 0 5 0 08-1 86 0 001 uerro- ra o D 2014 ea ac e igraine 21 1 80 22 26-46 44 0 00 eni i 201 ea ac e igraine 114 4 80 7-5 7 0 015 rru a 2010 t ma 11 2 68 1 5-4 67 0 705 uerro- ra o D 2014 Over eig t at 8 o 16 1 20 10 6 -12 01 0 001 ali e N 2014 Over eig t at 16 o 288 4 10 16- 8 0 07 Obe it at 8 o 787 11 80 0 -10 7 0 001 Obe it at 16 o 2 8 60 2 58- 0 146 Diabete ellitu 2 0 50 0 08-1 86 0 88 uerro- ra o D 2014
RF: Relative frequency. %: proportion, CI 95%: Confidence interval 95%, p: Fisher values *39, 14, 13, 40.
Table 2. ENT History of the ADHD child.
aria e re ent i tor otal 77 26 21 11- 1 7 on il a enoi ectom 4 12 10 8 16-15 76 0 001 Otiti 1 2 4 1 40 0 42- 64 0 001 ecurrent lar ngiti 10 50 1 72-6 2 0 001 Otiti recurrent lar ngiti 2 0 70 0 11-2 67 0 001 inu iti 1 0 0 0 01-2 15 0 001 ar ngeal no ule onia 26 8 75 5 0-12 71 0 001
Table 2a. ENT history of the ADHD child according to previous studies.
aria e ar ngeal no ule onia 25 78 12 5 55- 0 05 0 001 arona- leo 2015 RF: relative frequency, %: proportion, CI 95%: Confidence interval 95%, p: Fisher values. χ²= Pearson’s test *9.
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Table 3. Ophthalmology History of the ADHD child.
aria e re ent i tor otal 7 12 45 0 -16 88 o ia 21 7 07 4 5 -10 76 0 026 tigmati m 4 1 40 0 42- 64 0 001 trabi mu 7 2 5 1 0 -5 00 0 00 ero ia 1 01 0 26- 17 0 001 tigmati m ero ia 2 0 67 0 11-2 67 0 001
Table 3a. Ophthalmology history of the ADHD child according to previous studies.
aria e o ia 22 4 00 2 62-57 67 0 001 e er 2012 o ia 8 1 00 14- 4 62 0 021 r nlun tigmati m 10 1 60 10 28- 54 0 001 2007 tigmati m 10 24 00 12 58- 80 0 001 e er 2012 trabi mu 5 88 1 5 -17 22 0 001 r nlun trabi mu 10 24 00 12 58- 80 0 001 2007 ero ia 10 1 60 10 28- 54 0 001 e er 2012 ero ia 10 24 00 12 58- 80 0 001 r nlun
RF: relative frequency, %: proportion, CI 95%: Confidence interval 95%, p: Fisher values. χ²= Pearson’s test *10, 11.
Table 4. Allergology History of the ADHD child.
aria e re ent i tor otal 48 16 16 12 26-20 5 to 2 7 74 5 07-11 54 0 001 t ma 6 2 02 0 82-4 56 0 001 initi 7 2 6 1 0 -5 00 0 001 nver e oria i 2 0 67 0 11-2 67 0 001 oo allerg 6 2 02 0 82-4 56 0 001 ariou allergie 1 01 0 26- 17 0 001
Table 4a. Allergology history of the ADHD child according to previous studies.
aria e to -10 ear 7 15 08 12 07-18 65 0 002 c mitt 2010 to 4 0 7 0 1-2 65 0 002 uerro- ra o D 2014 t ma 11 2 68 1 41-4 8 0 6 uerro- ra o D 2014 t ma 1 28 2 80-8 60 0 001 ie erman 1 5 t ma 0 2 00 1 7-2 87 0 70 alam 2005 t ma 5 0 22 0 08-0 54 0 007 ecni 2005
RF: relative frequency, %: proportion, CI 95%: Confidence interval 95%, p: Fisher values. *8 Biederman J and Secnik K according to a review by Schmitt J, 2. *animals/grasses/olives/mites.
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in asthma by Biederman (p=≤0.001) and by Secnik and frequency of headaches are contradictory (p=0.007), while the results in asthma by Guerro- data, both create difficulties in concentration, Prado (p=0.633) and by Calam (p=0.970) correspond hyperactivity, behavior, and in the family and/ to those obtained in the present study. Table 4 (a). or school environment.26,27 In summary, frequent headaches can increase distraction28 and 13 Discussion deteriorate school learning. Regarding 5.05% of primary nocturnal enuresis (PNE) in the clinical histories of the study, it The study highlights the conditions of represents a valid clinical datum within the psychophysical development and general health anamnesis that should be evaluated considering in children diagnosed with ADHD. A percentage of the psychological problems reported by the 12.46 observed difficulties in motor development parents of these children, compared to those was reported, which was clinically corroborated who do not present enuresis.29 A study with with the detection of limited fine and gross motor functional magnetic resonance imaging (fMRI) in skills and a poor manual and exploratory game. working memory with children with PNE showed a During childhood, movement experiences are significant reduction of activity in the left posterior essential because they provide opportunities cerebellum compared to controls.30 Another for learning and promoting the development of fMRI study showed a low activation in the right important everyday skills such as the correct use prefrontal cortex and an increase in activity in the of cutlery, drawing, and playing with toys and left hemisphere in children with PNE compared games. The recognition of the importance of the to healthy controls during the inhibition of motor evolution of motor competence for social and response, indicating an abnormal network in these emotional development is also increasing due areas of the brain during the inhibition response to the numerous studies that show a significant in children with PNE.31 In another investigation in relationship between these domains.22 In addition, children with PNE, they detected that the results the hypothesis arising is that psychosocial problems in the latency measurements were prolonged or are secondary consequences of problems in motor the amplitude was reduced in the parietal area (Pz) development,23 and these deficits tend to appear in the neurophysiological studies called Cognitive increasingly highlighted for the child through Evoked Potentials (p300)32,33 providing evidence social demands and classmates in school years.24 of deficit in the uniform maturation of cortical Problems in the social domain in children with structures mainly in the motor cortex circuit.34 motor difficulties have also been communicated by the parents, and the deficit in the level of skill With regard to Otorhinolaryngology history, there is verified in the clinic.25 Nowadays, if cognitive is 10.43% of respiratory failure due to obstruction difficulties presented by children with ADHD are of the upper airways and 12.10% of tonsillectomy added to disability in sports and/or games, these and/or adenoidectomy. This represents interesting can trigger emotional consequences. Therefore, it data considering that a previous investigation is vital to evaluate, guide, and encourage physical reported a decrease in ADHD symptoms 2-13 activity and/or playfulness, as they are essential to months after surgery to remove tonsils and improve the motor skills, in general, and to develop adenoids, suggesting that the improvement post- positive emotions resulting from both activities, in adenotonsillectomy indicates that the symptoms particular. of ADHD are also related to sleep disturbances due to breathing difficulties.35 Another health condition for children with ADHD is the presence of headaches in 8.08%. Although Regarding Ophthalmology history, 12.45% the prevalence of headaches in children with of the ADHD-diagnosed children have ocular ADHD, as well as its association with the duration convergence failure, a relevant result because it
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shows that ocular deficits often accompany poor reading skills and poor school performance, both of which exist in the clinical histories of analyzed ADHD-diagnosed children. It has even been postulated that the treatment of an insufficient and/or underlying anomaly in ocular convergence could improve the functioning of children diagnosed with ADHD.11 Although the range and spectrum of ocular alterations vary substantially between studies, their existence together with other neurological and behavioral difficulties may hinder the overall development of children with ADHD. Since ametropia and heterotropia can be easily treated to potentially improve the functioning of these children, it is advisable to perform an ophthalmological examination as part of the routine evaluation.10
Finally, 16.16% of allergic pathologies were reported in children with ADHD, 7.74% of which were characterized by the presence of atopies, diseases which, together with asthma, have been associated with ADHD, although their underlying mechanisms require greater clarification.7 Eczema and asthma are diagnosed more frequently in children with ADHD than in children without ADHD, though asthma does not represent an increased risk for ADHD.8 Recent studies have provided some possible explanations for the association between asthma and ADHD. First, inflammatory cytokines released during atopy can pass the blood-brain barrier36 and activate neuro- immune mechanisms that involve the brain circuits of ADHD-related behavior and emotions.37 Images in fMRI show that the anterior cingulate cortex and the insula are involved in the evaluation of sensory affective stimulation, in the regulation of homeostatic responses, and in visceral perception. In people with asthma and other stress-related conditions, these regions of the brain may be hypersensitive to the afferent emotional and physiological signals specific to the disease, which may contribute to the deregulation of peripheral processes, as occurs during atopic episodes.38
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Conclusions
Regarding general health in children diagnosed with ADHD, the results are statistically significant by themselves as well as compared to the results obtained by Guerro-Prado in Spain, Genizi in Israel, Arruda in Brazil, and Khalife in Finland, the ENT results by Barona-Light in Spain, the Ophthalmological results by Mezer in Israel and Grönlund in Sweden, and the Allergy results from Schmitt in Germany, Biederman and Secnik in the USA, and Calam in the United Kingdom.
In short, the rapid detection of health problems in children diagnosed with ADHD after a successful pediatric examination and its subsequent referral to specialist clinicians (ENT, Ophthalmologist, Allergologist), not only represents the cure of the ailment or malaise, but also a positive change in the psychosocial behavior of the child in the school and family environment, aspects which are essential to correct in order to avoid aggravating the symptoms of ADHD. Finally, it will be interesting to develop more research on whether optimization in the management of these processes influences or not the evolution of the patient with ADHD.
Conflicts of interest Funding The authors of the research state there are no This research did not have any financing sources. conflicts of interest in this study.
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References
1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and meta-regression analysis. Am J Psychiatry. 2007;164(6):942–94. 2. Calam R, Gregg L, Goodman R. Psychological adjustment and asthma in children and adolescents: the UK Nationwide Mental Health Survey. Psychosom Med. 2005 Jan-Feb;67(1):105-10. 3. Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Bai YM. Asthma and attention- deficit/hyperactivity disorder: a nationwide population-based prospective cohort study.J Child Psychol Psychiatry. 2013; 54: 1208-14. 4. Yang MT, Lee WT, Liang JS, Lin YJ, Fu WM, Chen CC. Hyperactivity and Impulsivity in Children with Untreated Allergic Rhinitis: Corroborated by Rating Scale and Continuous Performance Test. Pediatr 256- Neonatol. 2014 Jun;55(3):168-74. 5. Suwan P, Akaramethathip D, Noipayak P. Association between Allergic Sensitization and Attention Deficit Hyperactivity Disorder (ADHD). Asian Pac J Allergy Immunol. 2011 Mar;29(1):57-65. 6. Pelsser LM, Buitelaar JK, Savelkoul HF. ADHD as a (non) allergic hypersensitivity disorder: A hypothesis. Pediatr Allergy Immunol. 2009 Mar;20(2):107-12. 7. Tsai MC, Lin HK, Lin CH, Fu LS. Prevalence of attention deficit/hyperactivity disorder in pediatric allergic rhinitis: a nationwide population-based study. Allergy Asthma Proc. 2011; 32: 41-6. 8. Schmitt J, Buske-Kirschbaum A, Roessner V. Is atopic disease a risk factor for attention deficit / hyperactivity disorder? A systematic review. Allergy. 2010; 65: 1506-24. 9. Barona-Lleo L, Fernandez S. Hyperfunctional Voice Disorder in Children With Attention Deficit Hyperactivity Disorder (ADHD). A Phenotypic Characteristic? J Voice. 2015 Apr 7. 10. Mezer E, Wygnanski-Jaffe T. Do children and adolescents with attention deficit hyperactivity disorder have ocular abnormalities? Eur J Ophthalmol. 2012 Apr 2:0. 11. Grönlund MA, Aring E, Landgren M, Hellström A. Visual function and ocular features in children and adolescents with attention deficit hyperactivity disorder, with and without treatment with stimulants. Eye (Lond). 2007 Apr;21(4):494-502. 12. Parisi P, Verrotti A, Paolino MC, Ferretti A, Raucci U, Moavero R, Villa MP, Curatolo P. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014; 32: 72-5. 13. Arruda MA, Guidetti V, Galli F, Albuquerque RC, Bigal ME. Migraine, tension-type headache, and attention-deficit/hyperactivity disorder in childhood: a population-based study.Postgrad Med. 2010 Sep;122(5):18-26. 14. Genizi J, Gordon S, Kerem NC, Srugo I, Shahar E, Ravid S. Primary headaches, attention deficit disorder and learning disabilities in children and adolescents. J Headache Pain. 2013 Jun 27;14:54. 15. Park S, Kim BN, Kim JW, Hong SB, Shin MS, Yoo HJ, et al. Nocturnal enuresis is associated with attention deficithyperactivity disorder and conduct problems.Psychiatry Investig. 2013; 10: 253-8. 16. Mellon MW, Natchev BE, Katusic SK, Colligan RC, Weaver AL, Voigt RG, Barbaresi WJ. Incidence of enuresis and encopresis among children with attention deficit/hyperactivity disorder in a population-based birth cohort. Acad Pediatr. 2013; 13: 322-7. 17. Shreeram S, He JP, Kalaydjian A, Brothers S, Merikangas KR. Prevalence of Enuresis and Its Association With Attention-Deficit/Hyperactivity Disorder Among U.S. Children: Results From a Nationally Representative Study. J Am Acad Child Adolesc Psychiatry. 2009 Jan;48(1):35-41. 18. Park S, Kim BN, Kim JW, Hong SB, Shin MS, Yoo HJ, Cho SC. Nocturnal Enuresis Is Associated with Attention Deficit Hyperactivity Disorder and Conduct Problems.Psychiatry Investig. 2013 Sep;10(3):253-8. 19. Hansen E, Poole TA, Nguyen V, Lerner M, Wigal T, Shannon K, Wigal SB, Batra AS.. Prevalence of ADHD symptoms in patients with congenital heart disease. Pediatr Int. 2012; 54: 838-43. 20. Cortese S, Castellanos FX. The relationship between ADHD and obesity: implications for therapy. Expert Rev Neurother. 2014 May;14(5):473-9. 21. Cook BG, Li D, Heinrich KM. Obesity, Physical Activity, and Sedentary Behavior of Youth With Learning Disabilities and ADHD. J Learn Disabil. 2014 Jan 21. 22. Goulardins JB, Rigoli D, Loh PR, Kane R, Licari M, Hands B, Oliveira JA, Piek J. The Relationship Between Motor Skills, Social Problems, and ADHD Symptomatology: Does It Vary According to Parent and Teacher Report? J Atten Disord. 2015 Apr 10. pii: 1087054715580394.
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23. Cairney, Rigoli, D, Piek, J. Developmental coordination disorder and internalizing problems in children: The environmental stress hypothesis elaborated. Developmental Review. 2013 , 33, 224- 238. 24. Piek, JP, Bradbury GS, Elsley SC. Motor coordination and social–emotional behaviour in preschool- aged children. International Journal of Disability, Development and Education. 2008, 55, 143-151 25. Cummins A, Piek J.P, Dyck MJ. Motor coordination, empathy and social behaviour in school-aged children. Developmental Medicine & Child Neurology. 2005, 47, 437-442 26. Aromaa M, Rautava P, Helenius H, Sillanpaa ML. Factors of early life as predictors of headache in children at school entry. Headache. 1998;38(1):23–30. 27. Parisi P, Verrotti A, Paolino MC, Ferretti A, Raucci U, Moavero R, Villa MP, Curatolo P. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014; 32: 72-5. 28. Virtanen R, Aromaa M, Koskenvuo M, Sillanpää M, Pulkkinen L, Metsähonkala L, et al. Externalizing problem behaviors and headache: a follow-up study of adolescent Finnish twins. Pediatrics. 2004;114:981–7. 29. von Gontard A, Equit M. Comorbidity of ADHD and incontinence in children. Eur Child Adolesc Psychiatry. 2015 Feb;24(2):127-40. 30. Yu B, Guo Q, Fan G, Ma H, Wang L, Liu N. Evaluation of working memory impairment in children with primary nocturnal enuresis: evidence from event-related functional magnetic resonance imaging. J Paediatr Child Health. 2011; 47:429–435 31. Lei D, Ma J, Du X, Shen G, Tian M, Li G (2012) Altered brain activation during response inhibition in children with primary nocturnal enuresis: an fMRI study. Hum Brain Mapp. 33:2913–2919 32. Freitag CM, Rohling D, Seifen S, Pukrop R, von Gontard A. Neurophysiology of nocturnal enuresis: evoked potentials and prepulse inhibition of the startle reflex.Dev Med Child Neurol. 2006; 48:278– 284. 33. Iscan A, Ozkul Y, Unal D, Soran M, Kati M, Bozlar S, Karazeybek AH. Abnormalities in event-related potential and brainstem auditory evoked response in children with nocturnal enuresis. Brain Dev. 2002; 24:681–687. 34. Karlidag R, Ozisik HI, Soylu A, Kizkin S, Sipahi B, Unal S, Ozcan. Topographic abnormalities in event- related potentials in children with monosyptomatic nocturnal enuresis. Neurourol Urodyn. 2004. 23:237–240. 35. Sedky K, Bennett DS, Carvalho KS. Attention deficit hyperactivity disorder and sleep disordered breathing in pediatric populations: a meta-analysis. Sleep Med Rev. 2014 Aug;18(4):349-56 36. Yarlagadda A, Alfson E, Clayton AH. The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry. (Edgmont). 2009;6:18-22. 37. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24-31. 38. Rosenkranz MA, Busse WW, Johnstone T, Swenson CA, Crisafi GM, Jackson MM, Bosch JA, Sheridan JF, Davidson RJ. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci. USA. 2005;102:13319-13324. 39. Guerro-Prado D, Mardomingo-Sanz ML, Ortiz-Guerra JJ, García-García P, Soler-López B. Evolución del estrés familiar en niños con trastorno por déficit de atención con hiperactividad. doi:10.1016/j. anpedi. 2014.12.004. 40. Khalife N, Kantomaa M, Glover V, Tammelin T, Laitinen J, Ebeling H, Hurtig T, Jarvelin MR, Rodriguez A. Childhood attention-deficit/hyperactivity disorder symptoms are risk factors for obesity and physical inactivity in adolescence. J Am Acad Child Adolesc Psychiatry. 2014 Apr;53(4):425-36.
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Revision
Julio Pascual1 Exertion headaches
Cefaleas por esfuerzo 1 University Hospital Marqués de Valdecilla and IDIVAL, Santander, Spain. Abstract
Introduction: Headaches related to exertion include headaches precipitated by coughing or other Valsalva maneuvers, headaches brought on by prolonged physical exercise, and sexual headaches.
Objetive: To analyze and actualize the clinical characteristics of headaches related to exertion.
Methods: We have revised publications, both in PubMed and in the main textbooks, on the different headaches brought on by physical exercise.
Results: Headaches related to exertion include mainly three entities: cough headaches, exercise headaches, and sexual headaches. These three varieties of exertional headaches can be primary or secondary. The treatment of primary varieties (indomethacin for cough headaches, beta-blockers for exercise and sexual headaches) and etiologies for secondary varieties (mainly Chiari type I malformation for cough headaches, vascular malformations for exercise and sexual headaches) are different for cough versus exercise and sexual headaches.
Keywords Conclusions: : In contrast to classical works, cough headaches are clearly a separate entity from headaches related to prolonged Cough headache, exercise exercise and, in general, sexual headaches, and these two latter headache, sexual headache. conditions share many aspects.
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Resumen
Introducción: La cefaleas en relación con esfuerzo físico incluyen la cefalea desencadenada por la tos u otras maniobras de Valsalva, la cefalea desencadenada por ejercicio físico prolongado y la cefalea sexual.
Objetivo: Analizar y actualizar las características clínicas de las cefaleas en relación con esfuerzo físico.
Métodos: : Revisión de la publicaciones, tanto en PubMed como en los principales libros de texto, referentes a las diferentes cefaleas desencadenadas por esfuerzo físico.
Resultados: Las cefaleas en relación con el ejercicio o cefaleas de esfuerzo comprenden fundamentalmente tres grandes entidades, la cefalea tusígena, la cefalea de esfuerzo prolongado (que en la nueva versión se llamará cefalea por ejercicio) y la cefalea orgásmica o sexual. Las tres variedades pueden a su vez ser primarias o sintomáticas. El tratamiento de las variantes primarias (indometacina para la cefalea tusígena y beta-bloqueantes para cefaleas por ejercicio y sexual) y las etiologías para las variantes secundarias (fundamentalmente malformación de Chiari tipo I para la cefalea tusígena y malformaciones vasculares para cefaleas por ejercicio y sexual) difieren para cefalea tusígena y cefaleas por ejercicio y sexual.
Palabras clave Conclusiones: En contra de la concepción de los trabajos clásicos, la cefalea tusígena es una entidad claramente separada clínicamente Cefalea tusígena, cefalea de de la cefalea de esfuerzo prolongado y, en general, de la cefalea sexual, esfuerzo, cefalea sexual. condiciones que comparten a su vez muchos aspectos comunes.
Correspondence: Dr. Julio Pascual Servicio de Neurología Hospital Universitario Central de Asturias Calle Celestino Villamil s/n 33006, Oviedo, España. Correo electrónico: [email protected]
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The relationship between these three headaches Introduction is uncertain. In Lance’s experience, for instance, the relationship between sexual headache and Headaches induced by coughing, prolonged headache from prolonged physical exercise is non- physical exercise, and sexual activity may be existent.6,7 In contrast, Silbert et al. found that 40% secondary to an intracranial structural injury of patients with sexual headaches also experienced or an annoying but unimportant picture. Until headaches from prolonged physical exercise.8 relatively recently, these headaches have been poorly cataloged and defined in the literature. In Thus, in 1996 we published our retrospective 1932, Tinel was the first to publish about several experience with the 72 patients who had patients with intermittent, paroxysmal headaches consulted in our Neurology Service due to related to exercise or maneuvers that increased triggered headaches.9 Irrespective of the different intrathoracic pressure.1 Subsequently, Sir Charles precipitants, we were able to clinically separate Symonds published about 27 patients with short- the three types of headaches. In addition, and even term headaches caused by Valsalva maneuvers: when sharing precipitants, we verified that the coughs, laughter, defecation, or abrupt postural clinical characteristics of benign headaches for the changes. This author subdivided these patients three varieties were clearly different from those into two groups. The first group consisted of six of secondary headaches, which made it possible to cases in which he could demonstrate intracranial suspect an etiological diagnosis based on clinical structural damage. The second group contained parameters. Finally, our data coincided with that the remaining 21 patients, in whom he could not of Silbert’s findings, that headaches due to physical find a space-occupying intracranial lesion. Symonds exercise and sexual headaches were conceptually was, therefore, the first author to consider cough similar entities.8 The emergence of our work headaches “benign,” that is, not secondary to an made it possible for the International Headache intracranial lesion.2 Despite this, the first large Society in its new Classification of Headaches series of exertion-triggered headaches published and Facial Neuralgias to clearly differentiate by Rooke in 1968 still encompassed all headaches between a cough headache, a headache from produced by coughing, prolonged physical exercise, prolonged exercise, and a headache attributed and sexual arousal within the umbrella of “exertion to sexual activity, and within the three consider headaches.”3 Rooke’s influence remained until the varieties as primary (idiopathic) or secondary the 1990s. In 1991, Sands et al. grouped together (symptomatic) to structural intracranial injury.10 An 219 cases of headaches caused by coughing and important limiting factor of our work was that the physical exercise.4 In this study, they found one in data collection was retrospective and that many of five cases was secondary to intracranial structural the patients in the series had not been studied with pathology—primarily posterior fossa lesions. modern magnetic resonance techniques, with all that the diagnostic elaboration in an entity such as Stemming from the initial descriptions, the “benign” a cough headache—in which detailed study of the sexual headache became a well-defined entity. The posterior fossa is essential—entails. first classification of the International Headache Society has already described three types of Today we know, and this is reflected in the new headaches related to sexual activity. Type 1 mimics a headache version of the International Headache tension headache, and type 3 is actually a headache Society, that headaches in relation to exercise of hypotension due to leaking of cerebrospinal or exertion headaches basically comprise three fluid, secondary to a burst of the dura, related to major entities: cough headaches, prolonged effort the exertion of intercourse.5 The most common headaches (in the new version will be called exercise sexual headache, also known as type 2 or vascular headaches), and orgasmic or sexual headaches. sexual headache, occurs abruptly during orgasm All three can be either primary or symptomatic. and is probably related to hemodynamic changes. Contrary to the conception of the classic works,
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the cough headache is clearly separated from the Pathophysiology headache of prolonged exercise and, in general, The pathophysiology of a cough headache of the orgasmic headache, and the latter two secondary to a Chiari malformation type I is share many common aspects. In this chapter, we simple to understand. The headache is secondary will review the different varieties of exertion to the temporal impact of the cerebellar tonsils headaches, and provide recent data to clarify some below the foramen magnum, which conditions a 11,12 of the statements we have just posed. dissociation of craniospinal pressure evidenced during coughing or other Valsalva maneuvers.19-22 The fact that a decompressive suboccipital Cough headaches craniectomy cures cough headaches confirms this pathophysiological proposal.9 There is a significant relationship between cough headaches and the Definition extent of tonsillar descent, and Cine MRI has shown A cough headache is considered to be induced, not this abnormal pulsation of the cerebellar tonsils aggravated, by coughing or other abrupt Valsalva specific to patients with Chiari type I and capable of maneuvers such as laughter, sneezing, defecation, interrupting the circulation of cerebrospinal fluid sudden incorporation, weightlifting, etc.10 from the cranial cavity to the spinal subarachnoid space (Figure 1). The onset of cough headaches Epidemiology was correlated with the degree of collapse of the Cough headaches are considered an infrequent subarachnoid space.23,24 entity. The published data put the prevalence of triggered headaches in between 0 and 2% of The pathophysiology of primary cough headaches the general population.13,14 They are, therefore, remains unknown and must be different from very uncommon headaches when compared to, that of secondary cough headaches, as there is for instance, migraines, whose prevalence in the no involvement of the posterior fossa and there general population is closer to 20%.13 Our data is a selective response to indomethacin.9,11,25 confirm that these headaches are rare, accounting Other factors can be involved, such as a transient for about 1.5% of headache consultations in a hypersensitivity reaction to a previous viral Neurology Service (93 patients out of a total of infection in the foramen magnum area receptors. 6412 patients who had consulted for headache in Recently, a somewhat reduced size of posterior 10 years). 11 If we consider that headaches account fossa structures in these patients has been for almost 25% of neurological consultations in our described in relation to controls, which could country, then a simple calculation indicates that contribute to the development of this headache.26 one out of 250-300 patients seeking a neurology A novel finding, of undoubted practical interest, consultation will do so due to a triggered headache. has been the detection of a large number of At least in terms of consultation, however, cough patients with cough headaches whose triggers headaches are the most frequent, accounting for have been ACE inhibitor drugs which are capable 75% of triggered headaches.9,11 Indeed, in our series, of inducing cough as a side effect.11,17 These 1% of the patients who consulted for headache did drugs undoubtedly revealed cough headaches in so for cough headaches (64 patients with cough predisposed patients but were not causal factors. headaches out of the total 6,412 patients with In any case, it is important to take this information headaches). Cough headaches may be benign/ into consideration when questioning and managing primary or secondary to intracranial structural these patients, since it is usually sufficient to pathology. Following the availability of modern withdraw the cough-inducing drug in these cases. neuroradiological techniques, fundamentally in this case MRI, it has been shown that at least half Diagnosis and differential diagnosis the cough headache cases are symptomatic of a The new diagnostic criteria for benign or primary posterior fossa lesion.9,11,15-18
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Figure 1. MRI and Cine MRI of a patient with cough headaches and Chiari malformation in which the cerebrospinal fluid has difficulty flowing anteriorly and posteriorly in the region of the amenfor magnum.
cough headaches are listed in Table 1.10 40% of cases, while one in 10 patients said it lasted over a patients with cough headaches have primary minute. As for the precipitants, in our experience, cough headaches, i.e. without underlying structural 100% of the patients reported their headache was pathology.9,11,17,18 The picture of a primary cough triggered by coughing, 56% by abrupt postural headache is very characteristic, which allows its changes, 39% by weightlifting, 33% by laughter, differentiation from secondary cases from a clinical and 22% by defecation. In most patients, and this is point of view on many occasions. a relevant aspect, there are no other accompanying symptoms. About 10% report a non-specific Primary cough headache is a typical entity of feeling of dizziness. There are cases of headache elderly men. The mean age at onset is 60 years and in patients taking Captopril or derivatives, drugs approximately 60-80% of the patients who consult whose side effects include coughing. The intake of about it are men, though in the most recent data the these drugs is, therefore, a question that we have male predominance is no longer so clear. Primary to ask every patient with cough headaches.9,11,15-18 cough headaches are an episodic disorder with a duration that usually ranges from two months to Thanks to magnetic resonance techniques we know two years (the mean duration in our series was that approximately 50-60% of the patients who 11 months). The pain begins immediately after consult for cough headaches have a demonstrable a coughing fit or any other Valsalva maneuver underlying intracranial structural pathology. These (and not of prolonged exercise) and is moderate- data clearly differ from previous series. Only intense. As for its location, pain is predominantly 10% of Rooke’s patients and 22% of Symonds’ hemicranial in half of the cases, bilateral in 40%, had intracranial structural lesions.2,3 In our first and occipital-suboccipital in the remaining 10%. series9, in which not all patients could be studied The quality of the pain is variable. In our series, with resonance, the proportion of symptomatic 22% of the cases described it as stabbing, 17% cases was lower, demonstrating the importance of as explosive, 17% as oppressive, and 44% as a the MRI study in the cataloging of these patients mixture of all of them. The typical duration of the and in their differential diagnosis. As for the pain is mere seconds for more than 75% of the etiology, more than 80% of cases of symptomatic
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Table 1. ICHD-III diagnostic criteria for primary cough headache.10
e s o e iso es mee e -D cri eri reci i e n occ rrin on in ssoci ion i co in or o er s v m ne vers en onse D D r ion be een 1 secon n 2 o rs No rib b e o no er D- i nosis cough headache have a type I Chiari malformation, to posterior fossa lesions. Patients with secondary while the rest have other space-occupying lesions headaches report a long history of headache (the in the posterior fossa and, more specifically, in mean is five years), compared to primary cases the foramen magnum region.9,11,27 The mean age (mean is 11 months). In addition, while patients of onset of symptomatic cough headaches is 44 with cough headaches did not present other years (range 21-60). The predominant localization accompanying symptoms/signs, 85% of cases of pain in the cases in our series is 72% occipital- of secondary cough headache had semiology of suboccipital, 14% hemicranial, and 14% bilateral. posterior fossa. Another diagnostic possibility The quality of the pain is very variable: oppressive that we have to consider with a cough headache in 31% of cases, explosive in 21%, stabbing in 21%, patient is a reversible tonsillar descent secondary and a mixture of all of them for 24%. The duration to a cerebrospinal fluid hypopressive syndrome, of the pain lasted mere seconds for fewer than 50% spontaneous or secondary to dural puncture of the cases. In our series, the duration of the pain (Figure 2). These patients worsen with standing episode at the time of diagnosis averaged 5 years (“orthostatic headache”) and improve with bed (maximum 30 years). As for the precipitants, 72% rest.28 had it triggered by coughing fits, 41% by abrupt postural movements, 33% by laughter, and 17% Treatment by defecation. More than 80% of the patients Primary cough headaches respond well to have subjective or objective semiologic findings, indomethacin, administered prophylactically at in this order: dizziness, instability, paresthesia doses of 25 to 150 mg daily with the corresponding in the face or upper limbs, vertigo, syncope, and gastric protection.9,11,24,29,30 The mechanism of action miscellaneous.9,11,12,15-18,27 of indomethacin is unknown, although it is thought that it may decrease intracranial pressure, which Clinical data allow in most cases to differentiate may explain why some patients also improve with between primary and secondary headaches. In lumbar punctures31 or acetazolamide.32,33 For some fact, unlike the primary variety, secondary cough patients, withdrawal of cough-inducing drugs may headaches are predominantly posterior, have a be sufficient to control the clinical picture. more irregular and prolonged duration (more than 50% of patients have episodes lasting at least one Patients with symptomatic cough headaches do minute) and are not precipitated by coughing but not respond to indomethacin and require specific by other Valsalva maneuvers in almost a third of surgical treatment. Indications for surgery would the cases. Secondary cough headaches begin an be incapacitating headache or the occurrence of average of 16 years earlier than primary headaches, posterior fossa semiology or the development so we have to suspect a primary cough headache if of syringomyelia (Figure 3). In our experience, it’s an elderly patient and the secondary variant if approximately one-third of patients with secondary we are treating a young patient. Gender does not cough headaches require surgical treatment. seem to be clearly clinically useful in the etiological It has been consistently demonstrated that diagnosis. There are other clinical data that help decompressive suboccipital craniectomy with a us to differentiate between a primary cough successful reconstruction of the posterior fossa headache and a secondary cough headache due eliminates cough headaches. 9,11,27
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Figure 2. A: Tonsillar descent in a patient with cough headaches and orthostatic headache after a lumbar puncture. B: Disappearance of the tonsillar descent after an epidural patch of autologous blood.
Figure 3. A: MRI in which typical tonsillar descending of Chiari type I malformation (arrow) is observed in a 34-year-old patient who consulted for cough headaches. B: MRI of the same patient, already asymptomatic, after reconstruction of the posterior fossa. Note the appearance of the cisterna magna after surgery.
physical exercise is unknown, although it has been Headaches due to estimated at approximately 1% of the general population.12 In terms of medical consultation, prolonged exercise or headaches due to prolonged physical exercise are clearly less frequent than cough headaches, exertion headaches with approximately one patient consulting for this headache for every six patients consulting Definition for cough headaches.8,11 As we will see later, most Exertion headache or exercise headache is a cases are primary and occur in middle-aged males. headache triggered by prolonged physical exercise, such as running, cycling, etc., but not in relation to Pathophysiology sudden Valsalva maneuvers, such as coughing. The pathophysiology of primary exercise headache Like cough headaches, exercise headaches may be is speculative. It has been linked to the development benign/primary or symptomatic/secondary.8,9,11,34,35 of cerebral vasodilation. Patients with primary exercise headache have a higher frequency than the Epidemiology expected migraine and orgasmic headache, so it is The prevalence of headaches due to prolonged logical to assume that they share pathophysiological
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mechanisms. The fact that patients with primary from a vascular malformation (Figure 4). Rarely, exercise headaches tend to suffer crises on hot exercise headaches may be secondary to cranial days and after prolonged exercise suggests a arterial dissection or pheochromocytoma.37 In vasodilation component in their pathophysiology, patients who report a “thunderclap” component, although we do not have objective evidence to it is necessary to exclude reversible cerebral confirm this point. The pathophysiology of the angiopathy syndrome.38 Today, therefore, MRI and symptomatic exercise headache is specific to the MR angiography are indicated. In doubtful cases, causative process of the headache.17,18 lumbar puncture is necessary (Figure 5).
Diagnosis and differential diagnosis There is also a variant of exercise headache in The new diagnostic criteria for primary exercise relation to coronary ischemia (“cardiac cephalgia”). headaches are listed in Table 2.10 Unlike primary Their new diagnostic criteria are listed in Table 10 cough headaches, primary stress headaches affect 3. In those patients with exertion headaches and younger people, with a mean age at onset of 40 history of ischemic heart disease or atherosclerosis, years (with a range of 10 to 48 years in our series). it is necessary to request an electrocardiogram Primary exercise headaches are more common and determine cardiac enzymes. The diagnosis of in males (90%) than in females. A good number this condition is not trivial since the anti-migraine of cases have a personal and family history of drugs (ergot, triptan) are formally contraindicated 39-41 migraines. Heat, humidity, barometric changes, in these patients. altitude, caffeine, hypoglycemia, and alcohol have been described as predisposing factors in these Some of these patients with cardiac cephalgia also patients. This headache can be triggered by any have episodes of headache in relation to angina at type of prolonged physical exercise, although rest. There are three proposed pathophysiological the exercise needs to double the basal heart rate explanations for cardiac cephalgia: 1) that it is a for at least 10 seconds (and usually minutes or pain referred at a distance, similar to right shoulder hours). The headache appears in the acme of pain in subphrenic lesions; 2) that it results from the exercise and usually disappears if physical activity release of algogenic peptides, such as the peptide ceases, although it may persist for one to four days in relation to the calcitonin gene or the vasoactive (median duration four hours). It’s usually bilateral intestinal peptide, by the ischemic zone; and 3) that and accompanied by migraine characteristics such it is secondary to transient stasis due to momentary as pulsatile quality, nausea, vomiting, photophobia, heart failure in relation to coronary ischemia. Be and sonophobia.8,11,34-36 that as it may, we should suspect the diagnosis of cardiac cephalgia in those episodic headaches of Diagnosis of primary exertion headache requires recent onset in elderly people with a history of thorough investigation, although, unlike cough ischemic heart disease, and especially if the pain 39-41 headaches, less than 20% of patients will have subsides after administration of nitrites. the secondary variant. In typical patients (middle- aged/young men and normal examination) it is Treatment mandatory to exclude any type of intracranial For those patients with non-disabling primary space-occupying lesion and sentinel hemorrhage exertion headache or with a low frequency of
Table 2. ICHD-III diagnostic criteria for primary exercise headache.10
e s o e iso es mee in cri eri n reci i e b , n occ rrin on rin or er in ense sic e ercise D r ion ess n 8 o rs D No rib b e o no er D- i nosis
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physical exercise, temporary abstinence or moderation may suffice. In these cases, treatment Sexual headaches with NSAIDs or triptans immediately prior to physical exercise may also be tested. If necessary, beta-blockers used in migraine prevention such Definition as propranolol or nadolol, for example, are usually Classically, three types of headaches have been effective, although they may reduce exercise described in relation to sexual activity. The first tolerance (Figure 5).42 For those patients who do of the varieties is the sexual headache by muscle not tolerate beta-blockers or in whom they are contraction and it would actually be a tension contraindicated, indomethacin at a dose of 25 to headache triggered by the sexual act. This headache 150 mg/day has been shown to be effective.43,44 is similar to tension headache. The second subtype There is no consensus regarding the duration of or “postural” headache is actually a headache due background treatment in these patients. Primary to cerebrospinal fluid hypotension, which would be exertion headache is a transient condition that secondary to a small burst of the dura as a result of usually lasts less than three months and rarely the effort in the sexual act.9 These two headaches more than six months; therefore, common sense do not occur in the acme of sexual activity, but as a indicates that preventive treatment should be consequence of it, and are clearly separated from withdrawn three to six months after initiation to the actual sexual headache, now also known as see if it continues to be necessary.18 orgasmic headache. The true orgasmic headache occurs in relation to the orgasm and is the most Treatment of secondary exertion headache is common type of headache in relation to sexual specific to its underlying process. activity.9,42-45
Pathophysiology The pathophysiology of primary orgasmic headache is superimposable to that of primary exertion headache. In fact, sexual activity is still a “prolonged” Figure 4. CT angiogram in which a fusiform aneurysm physical exercise, so everything said for exercise of the vertebral artery was observed in a patient who headaches is valid for orgasmic headaches. Many consulted for episodes of headaches due to physical patients suffer exertion and orgasmic headaches exertion and sexual intercourse. together, whereas there is a minority of patients with orgasmic headaches and cough headaches. Undoubtedly, this is a consequence of the Valsalva that also takes place in the acme of the sexual act and explains that the orgasmic headache is a headache that we could determine as intermediate between cough headache and exercise headache.
Some authors have suggested that the sexual headache is due to poor brain self-regulation, as dysregulation of cerebral vasodilation has been demonstrated in these patients compared to patients with migraines or healthy subjects.46,47 Hypertension as such does not seem to play a definitive role since the percentage of hypertensive patients with sexual headaches does not exceed that expected for the general population, although it has been shown that these patients experience a
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Figure 5. Differential diagnosis, protocol of complementary studies, and treatment scheme of headaches related to physical exertion. SAH=subarachnoid hemorrhage. SOL=space-occupying lesion. See text for additional information.
ea ac e re a e o e er ion
ea ac e ri ere e er ion ea ac e a ra a e e er ion
cou or o er ro on e ica e ua oun an e a a a a a e erci e arou a nor a e oca i
e er o an oun o er a e o er neuroi a in a e ear a e ear
a ne ic re onance n io ea an nec n io u ar unc ure
unci n u ar
ri ar iari ri ar ri ar i raine in racrania cou e e erci e e ua e an i e ea ac e ea ac e ea ac e roce
n o e acin ur er ro rano o ur er ro rano o ur er
Table 3. ICHD-III diagnostic criteria for cardiac cephalalgia.10
. n e c e mee s cri erion . c e m oc r i isc emi emons r e C. vi ence o c s ion emons r e b e s o o e o o in : 1 e c e s eve o e in em or re ion i e onse o c e m oc r i isc emi 2 ne or bo o e o o in : a. The headache has worsened significantly in parallel with the worsening of the myocardial ischemia b e e c e s im rove or s been reso ve in r e i e reso ion o e m oc r i isc emi e e c e s e s o o e o o in o r c r c eris ics: o er e-severe in ensi b ccom nie b n se c No ccom nie b o o obi or sono obi r v e b e er ion . No rib b e o no er D- i nosis
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greater increase in blood pressure under conditions intracranial expansive process. Unlike cough of physical stress.44 headaches, approximately 10% of the patients who consult for sexual headaches are diagnosed Diagnosis and differential diagnosis with symptomatic headaches. As with headaches The diagnostic criteria for orgasmic headaches are due to prolonged physical exercise, neuroimaging listed in Table 4. Similar to headaches of prolonged studies (CT or MRI with angio-resonance or CT- physical effort, primary orgasmic headaches are angiography) are necessary for the investigation more frequent in males (80%). The mean age of onset of these headaches. Conventional angiography is 40 years (limits 19-58 years) and coincides with and lumbar puncture are indicated only in specific the time of greater sexual activity of individuals. cases of high clinical suspicion of subarachnoid Type 2 or true orgasmic headache occurs at the time bleeding despite a negative angio-resonance and/ of, or just before, orgasm (either as a result of coitus or CT angiography, but never routinely (Figure or through masturbation). Its location is bilateral 5). On the one hand, it has been shown that the “at the temples” in three out of four patients and sensitivity of angio-resonance and CT angiography hemicranial in the remaining patient. The duration for the screening of intracranial aneurysms is very of sexual headaches ranges from one minute to six high and, on the other hand, we have already seen days (median, in our experience, is 10 minutes). It that the percentage of secondary cases for these may be accompanied by migraine-like symptoms headaches is really low. such as nausea or sonophobia/photophobia and is described as an intense and usually pulsatile Treatment pain. The mean duration of the symptomatic The management of true orgasmic headache period is three months (minimum two days and is schematized in Figure 5 and is similar maximum six years) and the number of headaches to that developed for prolonged exercise in the symptomatic period is very variable since headache.9,11,41,44,47 There are no controlled it depends on sexual activity, generally ranging studies in the management of this entity, so the between a minimum of one and a maximum of 50. recommendations are based on clinical series. It is The typical trigger (94% of cases) is intercourse, important to explain to the patient the benignity of followed by masturbation. Patients with a sexual the process and its excellent prognosis. Since the headache exclusively caused by masturbation are risk of recurrence of this headache is high the days very rare. The rate of incidence does not vary with immediately following one of the attacks of pain, a change of partner. Approximately 40% of the it seems reasonable to advise sexual abstinence patients manage to make the headache go away by if possible for several weeks. In the case of ceasing sexual activity and, in more than half, the intercourse, it is advisable to play a role as passive headache is not invalidating at all if they adopt a as possible. Non-steroidal anti-inflammatory passive role during the sexual act.9,11,41,43,47 drugs (see symptomatic treatment of migraines) or triptans can be used immediately before the Usually, patients with sexual headaches are middle- sexual act although we do not know their real aged and healthy males. Approximately two-thirds effectiveness. meet criteria for other headaches, such as episodic tension headache (35%), primary prolonged If changes in sexual habits are not sufficient or are not exercise headache (35%), migraine headache (25%) possible and the patient is symptomatic, preventive and chronic tension headache (10%). treatment is advisable. Short guidelines have been tested with non-steroidal anti-inflammatories, The etiologies for secondary orgasmic headache triptans, and even benzodiazepines, with poor are the same as those discussed for secondary results. The preventive treatment of choice for exertion headache, essentially subarachnoid sexual headaches are the beta-blocking drugs hemorrhage sentinel cephalea (Figure 4), reversible we have already mentioned for headaches due to cerebral vasoconstriction syndrome, and broad prolonged physical exercise, which are effective in
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about 80% of the cases. For resistant cases or with contraindications to treatment with beta-blockers we can use indomethacin at doses of 50-150 mg/ day. Given the usual duration of the symptomatic period, it is advisable to try to withdraw the preventive treatment after three months of initiation.
Table 4. ICHD-III diagnostic criteria for primary sexual headache.10
. e s o e iso es o e n or nec in mee e -D cri eri . reci i e b n occ rrin on er se c ivi C. ne or o o e o o in : 1 ncre se in ensi b incre sin se ro s 2 br , e osive in ensi s be ore or rin or sm . No rib b e o no er D- i nosis
Conclusions
Faltan conclusiones
Conflict of interest statement Funding The authors declare there are no relevant There was no particular source of funding for conflicts of interest in this study. this scientific report.
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References
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29. Dodick DW. Indomethacin responsive headache syndromes. Curr Pain Headache Reports. 2004; 8: 19-28. 30. Mathew NT. Indomethacin responsive headache syndromes. Headache. 1981; 21:147-150. 31. Raskin NH. The cough headache syndrome: treatment. Neurology. 1995; 45:1784. 32. Chalaupka FD. Therapeutic effectiveness of acetazolamide in hindbrain hernia headache. Neurol Sci. 2000; 21. 117-119. 33. Wang SJ, Fuh JL, Lu SR. Benign cough headache is responsive to acetazolamide. Neurology. 2000; 55:149-150. 34. Chen SP, Fuh JL, Lu SR, Wang SJ. Exertional headache. a survey of 1963 adolescents. Cephalalgia. 2009b;29:401-7. 35. Halker RB, Vargas BB. Primary exertional headache: updates in the literature. Curr Pain Headache Rep. 2013; 17: 337-40. 36. Diamond S. Prolonged benign exertional headache: its clinical characteristics and response to indomethacin. Headache. 1982; 22:96-98. 37. Adams C, Trevenen C. Middle cerebral artery dissection. Neuropediatrics. 1996;27:331-332. 38. Wang SJ, Fuh JL. The “other” headaches: primary cough, exertion, sex, and primary headaches. Curr Pain Headache Rep. 2010; 14: 41-46. 39. Lipton RB, Lowenkopf T, Bajwa ZH, Leckie RS, Ribeiro S, Newman LC, et al. Cardiac cephalgia: a treatable form of exertional headache. Neurology. 1997;49:813-816. 40. Gutiérrez-Morlote J, Pascual J. Cardiac cephalgia is not necessarily an exertional headache. Cephalalgia. 2002;22:765-766. 41. Chen YY, Lirng JF, Yu WC, Wang SJ. Cardiac cephalgia. Case report and review of the literature with new ICHD-II criteria revisited. Eur Neurol. 2004; 51: 221-226. 42. Diamond S. Benign exertional headaches. Postgrad Med J. 1982;71:244-245. 43. Evers S, Lance JW. Primary headache attributed to sexual activity. In: Olesen J, Goadsby PJ, Tfelt- Hansen P, Welch KMA (Eds). The Headaches, 3rd edition. Philadelphia, Lippincott Williams & Wilkins, 2006: pp. 841-845. 44. Frese A, Eikermann A, Frese K, Schwaag S, Husstedt IW, Evers S. Headache associated with sexual activity: demographics, clinical features, and comorbidity. Neurology. 2003; 23:796-800. 45. Yeh YC, Fuh JL, Chen SP, Wang SJ. Clinical features, imaging findings and outcomes of headache associated with sexual activity. Cephalalgia. 2010; 30: 1329-35. 46. Evers S, Schmidt O, Frese A, Husstedt IW, Ringelstein EB. The cerebral hemodynamics of headache associated with sexual activity. Pain. 2003;102:73-800. 47. Evans RW, Pascual J. Orgasmic headaches: clinical features, diagnosis and management. Headache. 2000;40:491-4.
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Revision
Basal Ganglia and Behavior Natalia Ospina-García,1 Christian Pérez-Lohman,1 Juan Diego Vargas-Jaramillo,1 Amin Ganglios basales y conducta Cervantes-Arriaga, 1,2 Mayela Rodríguez-Violante.1,2
1 Movement Disorders Clinic, Abstract National Institute of Neurology and Neurosurgery, Mexico City, Mexico. Historically, the function of the basal ganglia has been a subject 2Clinical Laboratory of Neurodegenerative Diseases, of debate and study. Initially it was proposed that these structures National Institute of Neurology and participated exclusively in the motor behavior; however, the current Neurosurgery, Mexico City, Mexico. body of knowledge and science progress allows us to understand that these structures and their connections determine not only motor behavior, but also cognition and emotions. The present review Keywords describes the neuroanatomic and functional basis of the basal ganglia, emphasizing both the traditional schemes and the most recent models Basal ganglia, behavior, including sensorimotor, associative, and limbic circuits, along with the cognition, emotion, reward. relevance of reward systems.
Resumen
Históricamente la función de los ganglios basales ha sido motivo de debate y de estudio. Inicialmente se consideró que estas estructuras participaban exclusivamente en la conducta motora; sin embargo, el conocimiento que se tiene hoy en día, permite entender que estas estructuras y sus conexiones son determinantes no solamente en la conducta motora, sino también en la cognición, aprendizaje y las emociones. En la presente revisión se describen las bases Palabras clave neuroanatómicas y funcionales de los ganglios bases, enfatizando tanto en los esquemas tradicionales como en los modelos más Ganglios basales, conducta, recientes incluyendo los circuitos sensorimotor, asociativo y límbico, recompensa, sistema límbico. así como la relevancia de los sistemas de recompensa.
Corresponding author: Rodríguez-Violante Mayela Clínica de Trastornos del Movimiento. Instituto Nacional de Neurología y Neurocirugía. Insurgentes Sur #3877 Col. La Fama 14269 México City, México. Tel. +52 5556063822 Ext. 5018 Fax +52 55 51716456 e-mail: [email protected]
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include the substantia innominate (SI), the nucleus Introduction basalis of Meynert, and the nucleus accumbens (NAc). The latter is subdivided in the central zone The role of the basal ganglia has traditionally been (Core) of the nucleus accumbens (NAcC) and the focused on the planning, integration, and control of cortical zone (Shell) of the accumbens (NAcS). motor movement, as well as emotional behavior and reward systems. Functional models have changed Moreover, given the interconnections and circuits over time. About three decades have elapsed to be described below, it is relevant to identify since David Marsden described “the mysterious the structures involved in the limbic circuit and function of basal ganglia” and concluded that they reward system. The limbic system is a group are involved in automatic behaviors and motor of cortical interconnections and subcortical learning.1 Later, the first descriptions of functional structures dedicated to linking visceral and circuits were made by DeLong, which described emotional states with the cognitive and behavioral 8 their function through a direct pathway to facilitate parts. There is no universal agreement on the movement and an indirect pathway to inhibit it.2,3 structures that comprise the limbic system. There is some consensus, however, that the cerebral 9 Thus, basal ganglia were initially related only to regions that constitute the limbic system include: motor functions; however, they are now known to limbic cortex, cingulate gyrus, parahippocampal play an important role, not only in motor behavior, gyrus, hippocampal formation, dentate gyrus, but also in cognition, emotions, and learning.4-6 hippocampus, subicular complex, amygdala, Advances in science have made it possible to reveal septal area, hypothalamus, and habenula. The profound changes in the initial model, broadening term “extended amygdala” includes the nucleus the knowledge and understanding of the role that of the amygdala and the bed nucleus of the stria this group of structures plays in behavior. In this terminalis. review, we consider the components of the basal ganglia, the neurotransmitters involved, the way II. Neurotransmitters involved in basal these interact, and their functions. ganglia physiology
I. Components of the basal ganglia The final function of each nucleus depends on the neurotransmitter used. Table 1 summarizes the The basal ganglia are a group of deep nuclear main neurotransmitters used by each nucleus. structures which are well-defined both In general, it can be considered that there are anatomically and functionally. They are located excitatory nuclei and inhibitory nuclei. It is within the telencephalon, diencephalon, and important to consider that the basal ganglia do not mesencephalon. The structures that are included use various neurotransmitters, and they also have within the basal ganglia vary according to different different receptors. authors; however, it is classically considered to be neostriatum or striatum (caudate and putamen), The striatum does not express only receptors globus pallidus, substantia nigra, and subthalamic for dopamine; it also has receptors for nucleus.7 glutamate, acetylcholine, γ-aminobutyric acid (GABA), adenosine, histamine, neuropeptide Y, From the anatomical point of view, they can be somatostatin and nitric oxide, among others. All subdivided into dorsal and ventral. The nuclei of these neurotransmitters interact to modulate the dorsal portion include the striatum, external the final inhibitory response of the striatum; for globus pallidus (GPe), internal globus pallidus example, adenosine type 2A receptors bind to (GPi), subthalamic nucleus (STN), and substantia dopamine receptors type D2 and antagonize the nigra (SN) with its pars compacta (SNc) and pars function of the latter.10 Likewise, γ-aminobutyric reticulata (SNr). The nuclei of the ventral portion acid (GABA) is not the only neurotransmitter
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Table 1. Major efferent neurotransmitters in basal ganglia.
Neuro ran i er unc ion Nuc ei γ- minob ric ci ( ) n ibi or ri m n ern ob s i s ( i) ern ob s i s ( e) bs n i Ni r rs re ic ( Nr) m e ci or b mic n c e s ( N) Do mine De en en on e bs n i Ni r rs com c e o rece or en r e men re released by the striatum. It is known that this area (PM), the somatosensory cortex, and frontal nucleus expresses endocannabinoids, which eye field (FEF).14-15 These cortical afferents synapse interact in neuronal plasticity and help to modulate with the main population of striatum neurons: the excitatory messages from the cortex.11 Dopamine medium spiny neurons (MSNs)—named after the synthesized in the SNc of the mesencephalon is thorn-like ramifications seen in their dendrites. the neurotransmitter best represented in the MSNs are the only projection neurons of the physiology of the base ganglia. Different types of striatum and communicate with the intrinsic and dopamine receptors may increase or reduce the output nuclei through γ-aminobutyric acid function of the base ganglia. (GABA).15,16
The known five types of dopamine receptors (D1, There are two distinct types of MSNs which differ in D2, D3, D4, and D5) are divided into two large their projection target, expressed neuropeptides, families: D1-like receptors (which include types D1 excitability, and main subtype of dopamine and and D5, and are bound to stimulatory G proteins), acetylcholine receptors. Table 2 shows the main and D2-like receptors (which include types D2, D3, characteristics of each type of MSNs. and D4, and are bound to G protein inhibitors).12 The different interactions between each of the In basal conditions, the output nuclei are found to elements mentioned are described in more detail generate tonic inhibition of the Ventral Anterior in the following sections. (VA) and Ventral Lateral (VL) nuclei of the thalamus through GABA and, therefore, the thalamus is III. Intrinsic and extrinsic interactions of unable to excite the cortex.14,15 The end result of these actions is inhibition of movement. the basal ganglia a. Traditional functional model • Direct pathway The traditional functional model of the basal ganglia At the moment when the execution of a voluntary was formulated in the early 1990s and consists of movement is planned, the cortex sends information two antagonistic pathways; the direct pathway that of the desired movement to the striatum. The direct facilitates movement and the indirect pathway that pathway MSNs inhibit the GPi and SNr, which were inhibits movement.2,7 In this model, the different inhibiting the thalamus, releasing it so that this nuclei of the basal ganglia can be categorized as 1. structure can excite the cortex and, finally, the Input nucleus (striatum), 2. Output nuclei (GPi and desired movement is executed via the corticospinal SNr), and 3. Intrinsic nuclei (GPe and STN).13 tract.16,17
The striatum receives excitatory afferents via • Indirect pathway glutamate of the primary motor cortex (M1), the The indirect pathway MSNs send inhibitory supplementary motor area (SMA), the premotor afferents to the GPe, which is tonically inhibiting
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Table 2. Characteristics of the different types of medium spiny neurons (MSNs).
irec a a N n irec a a N ro ec ion r e i Nr e Ne ro e i es bs nce n D nor in n e in ci bi i inor or Do miner ic rece or D1 ( ci er) D2 ( n ibi or) o iner ic rece or 2 ( n ibi or) 1 ( ci er)
MSNs - Medium spiny neurons, GPi - Internal globus pallidus, SNr - Substantia Nigra pars reticulata GPe - External globus pallidus the STN; once the latter is released it is able to send b. Recent models excitatory afferents to the GPi and SNr, causing More recent studies have allowed the proposition greater inhibition on the thalamus, resulting in of a model in which the PFC and the different motor the inhibition of movements antagonistic to those areas communicate and maintain a “dialogue” with desired.16,17 the striatum through different types of neurons with a different excitability pattern. Thus the The correct function of both pathways is facilitated information of the different cortical areas reaches by the dopamine present in the neurons of the SNc the striatum through two types of neurons: located in the mesencephalon. The direct pathway intratelencephalic (IT) and pyramidal neurons MSNs express D1-dopaminergic receptors, which, (PN). IT neurons carry information from the PM, upon binding to dopamine, activate stimulatory the SMA and the somatosensory cortex areas, are G proteins and, through the cascade of second primarily involved with planning movement, and messengers, promote the function of the direct communicate primarily with direct pathway MSNs. pathway. On the other hand, the indirect pathway Meanwhile, PNs carry information from the cortex MSNs express dopamine receptors type D2, M1 to the motor neurons of the corticospinal tract, which when they bind to dopamine they activate and at the same time to the indirect pathway MSNs inhibitory G proteins, finally resulting in the and the STN; the final result is the transmission inhibition of the indirect pathway.18 The net result of a copy of the movements in execution to of the dopaminergic action is the facilitation of the striatum, which results in the inhibition of movement. undesired movements.15,20
• Hyperdirect pathway c. Other nuclei involved At the beginning of the millennium, the so-called There are other important nuclei, such as the hyperdirect pathway was described. In this centromedian (CM) and parafascicular (Pf) nuclei pathway, the information of the different cortical of the thalamus. These nuclei send excitatory areas arrives directly at the STN, without passing signals to the cholinergic interneurons of the through the striatum. That is, the STN ceased to be striatum to “warn” about relevant sensory considered a relay station for the indirect pathway. stimuli. In addition, these nuclei send projections The net result is the rapid excitation of GPi and directly to the SNc and the ventral tegmental SNr, with subsequent inhibition of movement.19 area (VTA) to facilitate the release of dopamine. We currently know that the traditional model and In addition, other brainstem nuclei such as the its unidirectional flow represents a simplification superior colliculus (SC), the red nucleus (RN), of the motor functions of the basal ganglia, and the pedunculopontine nucleus (PPN), have nevertheless, understanding it is fundamental connections to the striatum directly and through for the study of Parkinson’s disease and other the thalamus, to modulate movement.21 Finally, movement disorders. there are intrinsic connections; these microcircuits
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between the different nuclei have the function To understand these circuits it is important of obtaining feedback and a constant evaluation to consider that there are two types of motor that keeps each part of the circuit informed, thus responses: a goal-directed response, which implies 15,21 avoiding unnecessary responses. an explicit or conscious processing with a high attentional demand; and a habitual or automatic IV. Functional circuits in the basal ganglia behavior that involves implicit, parallel, and rapid processing.17,24 Depending on the required motor In addition to the connections explained responses, the sensory-motor circuit will be active above, such as direct, indirect, and hyperdirect for quick responses and previously-acquired pathways, research using micro-stimulation, motor behaviors such as walking or blinking, and microregistration, and functional images has the associative circuit will, if the motor behaviors demonstrated the existence of regions in the basal required are the result of previous deliberation ganglia with functional implications. As already and decision-making in a continuous dialogue with mentioned, basal ganglia are composed of closed the cortex. circuits that originate in the cerebral cortex, which later pass through the basal ganglia, pass b. Sensory-motor circuit through the thalamus, and finally return to the As previously mentioned, the sensory-motor circuit frontal cortex.22,23 Accordingly, three functional has a dorsolateral location. It originates in the M1 circuits have been described according to their cortex, SMA, PM area, and FEF, then goes in the site of origin: 1. Sensory-motor circuit (motor), dorsolateral region of the striatum, especially the 2. Associative circuit (cognitive), and 3. Limbic posterior putamen, traverses the STN and output circuit (motivational and emotional). The sensory- nuclei in its dorsolateral portion, and finally to the motor circuit has a dorsolateral localization, it is thalamic nuclei VA, VL and CM, which connect related to habitual or automatic behaviors. The again with the M1, SMA, and PM area, completing associative circuit is dorsomedial, it is related to a closed circuit. This circuit is involved in the the goal-directed, decision-making, and planning selection of habitual or automatic behaviors.17,25 behaviors. The limbic circuit, which is rostroventral, is related to behaviors guided by emotions and c. Associative circuit motivation.17,23 Next, we will briefly describe each On the other hand, the associative circuit is of the circuits. dorsomedial, its origin is in the dorsolateral prefrontal cortex (DLPFC) and medial and lateral Figure 1 shows the nuclei, afferences, efferences, orbitofrontal cortex (OFC), then it has connections and main neurotransmitters involved in the with the dorsomedial region of the striatum, functional circuits of the basal ganglia. especially with the caudate nucleus, crossing the STN and output nuclei, and finally, in the thalamus a. Motor Behaviors in the VA, VL, and Pf nuclei. This circuit is related Basal ganglia and their connections are involved to goal-directed behaviors, decision making, and in the selection of habitual or goal-directed motor planning.17,25 behaviors according to the needs and responses of the external and internal environment.17 Figure d. Role of dopamine 2 summarizes the types of motor behaviors. Dopamine, as in the modulation of direct, indirect, Evolution has led to a specialization within the and hyperdirect pathways, which in turn are basal ganglia structures so that the response part of the sensory-motor, associative, and systems can be carried out quickly and with less limbic functional circuits, has a determining role. computational demand. In this way, it is possible Dopamine is key in the selection, execution, and to obtain effective motor responses that allow change of motor behaviors, as well as for learning survival and appropriate interactions with the by reinforcing new behaviors, for motivation, and environment. in the reward system. At baseline, dopaminergic
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Figure 1. Functional circuits of the basal ganglia.
Main nuclei, afferents, efferents, and neurotransmitters of the functional circuits of the basal ganglia. Detailed description in the text. ACh = Acetylcholine (Cholinergic Interneuron). SMA = Supplementary Motor Area. VTA = Ventral Tegmental Area. CM = Centromedian Nucleus. SC = Superior Colliculus. PFC = Prefrontal Cortex. OFC = Orbitofrontal Cortex. FEF = Frontal Eye Field. GPe = External Globus Pallidus. GPi = Internal Globus Pallidus. MSNs D = Direct pathway Medium Spiny Neurons. MSNs I = Indirect pathway Medium Spiny Neurons. RN = Red Nucleus. STN = Subthalamic Nucleus. PPN = Pedunculopontine Nucleus. PFN = Parafascicular Nucleus. SNc = Substantia Nigra pars compacta. SNr = Substantia Nigra pars reticulata. VA = Ventral Anterior Nucleus. VL = Ventral Lateral Nucleus. neurons in the SNc have a tonic firing frequency changing their tonic activity to a phasic activity. On of 2-10 Hz, while the output nuclei fire at a tonic the other hand, the cholinergic interneurons that frequency of 60 to 80 Hz. When there is a salient are tonically active respond by means of a pause stimulus in the environment or a deliberation in our that allows a stop in the motor act, followed by an frontal cortex, the dopaminergic neurons in the SNc excitatory response. These changes in the firing respond by changing their tonic activity to a phasic patterns allow the direct pathway to be stimulated activity composed of bursts of high frequency firing, and the indirect pathway inhibited, allowing the up to 80 Hz in humans, that stimulate the direct selection of a new motor act, usually automatic pathway through D1 receptors and inhibit the when rapid responses are required—in this case, indirect pathway through D2 receptors, facilitating a saccadic eye movement towards the outward a change in previously established behavior and visual stimulus.28 Following the selection of the the selection of a new motor pattern.17,26 most relevant motor pattern, the motor cortex constantly excites the striatum and STN through By way of example, we will use a salient visual the indirect and hyperdirect pathways respectively, stimulus. In this case, a visual stimulus arrives so that through the output nuclei the unwanted through the optic tract to SC, which in turn sends motor patterns are inhibited and the chosen motor an excitatory signal to the CM and Pf thalamic pattern is maintained. This processing occurs in nuclei, which send projections to the SNc and parallel.28,29 the cholinergic interneurons in the striatum.27,28 The dopaminergic neurons of the SNc respond by In contrast, when there is a deliberation in the
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Figure 2. Types of Motor Behaviors.
a di ected t atic e avi a it a e avi
e es nse aste es nse se entia n a a e
ttenti na de and ivided attenti n
e ecti n
ea nin M t es nse
Basal ganglia and their connections are involved in the selection of daily motor behavior or goal-directed motor behavior. These behaviors differ in response speed and need for attention.
PFC to carry out a goal-directed behavior, a e. Limbic Circuit dialogue occurs between the PFC, the PM area, Behavior can be considered as a mechanism where the SMA, and the basal ganglia to select the most the brain manages the input of information and appropriate response according to the desires, immediately generates an output order that allows memories, emotions, and context. Subsequently, a the organism to adapt to the circumstances of the response is produced that is again facilitated by a environment.31 The information received through phasic dopamine discharge that allows the change the senses is translated mainly inside the cerebral and the selection of a new motor behavior. When a cortex and this directs an output behavior. To new motor pattern is efficient, dopamine performs process the information coming from the senses a positive reinforcement, so that by means of long- and to allow a behavior to be performed, regulatory term potentiation mechanisms (LTP) new motor levels are required. The highest level is integrated acts are learned. These new motor acts can be by the cerebral cortex; the second level is made selected in the future more quickly and without up of the basal ganglia, including the extended attentional demand as habitual behaviors.29 amygdala; the third level is the mesencephalon; and, finally, a fourth level is regulated by the By means of electrophysiological experiments habenula. with field potentials measurement, this variability in the dopamine-guided responses has been demonstrated by the registration of high 1) First level of regulatory behavior frequencies, usually in the gamma band (>60Hz), as The first regulatory level is the cerebral cortex. well as desynchronization in these potentials. The The limbic system receives three main sources of aforementioned reflects the diversity of responses input: a) from the posterior association cortex, the and changes in the firing rate of dopaminergic cingulate gyrus, the insula, the hippocampus, and neurons that modulate circuits and, consequently, the fornix, which in turn connect the hippocampus the selection and changes in motor behavior.30 with the mammillary bodies in the posterior
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hypothalamus; b) the inferior temporal cortex, via a large part of this circuit has connections that the entorhinal cortex; c) the PFC. Each of these are directed towards the brainstem where they input sources provides information from the synapse with nuclei of the autonomic nervous association cortex and provides the limbic system system, to produce the visceral responses involved with highly processed information about the with the emotions. Through these connections, environment.31 the amygdala affects motor output signals, guiding behaviors driven by emotions, as well as impulses Within the PFC, a similar information flow occurs, needed for survival such as seeking food, warmth, which leads to the activation of specific regions, comfort, escaping pain, quenching thirst, and for example, the M1 cortex and other more distant fleeing danger, among others.31 regions. Each neuronal connection is able to learn through glutamatergic transmission—which increases In a very general way, sensory-motor and associative or decreases the sensitivity of the connecting circuits regulate rational behavior, while the limbic synapses by inducing LTP or long-term depression circuit regulates emotional behaviors.36,37 The two (LTD). Through these mechanisms, the cortex can systems can be inhibited or activated, depending “learn” to transmit detailed sensory information to on the situation, even in parallel. The dorsolateral a specific output unit through a “preferred” cortical PFC is important in particular to control the goal- tract. Consequently, the cerebral cortex and the directed responses while the medial PFC controls networks it integrates interpret sensory information the emotional responses. Within the medial PFC, and produce a specific behavioral response through the OFC is essential to regulate the direction of networks that in turn connect with deep structures the motivation.32 This motivation requires the such as the basal ganglia.32,33 participation of two specific structures in the nucleus accumbens: the NAcC and the NAcS.38-40 2) Second level of regulatory behavior The processing units in the cerebral cortex send 3) Third level of regulatory behavior information to the basal ganglia.34,35 The route The NAcC motivates the individual towards a through the basal ganglia and the thalamus is behavior that can lead to a feeling of reward, directed to the corresponding processing units while the NAcS motivates the individual towards in the anterior cortex. This parallel circuit, as behaviors that can lead to escape a feeling of 41 previously mentioned, has stimulatory pathways misery. The activities of the NAcC and the (direct pathway) and inhibitory pathways (indirect NAcS are controlled by monoaminergic nuclei pathway), and its glutamatergic synapses can within the mesencephalon. These nuclei transmit also induce LTP and LTD. Therefore, this parallel signals through dopaminergic (VTA), adrenergic pathway through the basal ganglia allows the (norepinephrine, locus coeruleus), and serotonergic 40,41 brain to correct and guide the information as (5-hydroxytryptamine, raphe nuclei) pathways. well as select the motor behavior to give it a final destination.31 4) Fourth level of regulatory behavior The fourth level of regulation is given by the The amygdaloid complex, formed by the basolateral coupling between the cerebral cortex and the and centromedial (or nuclear) region, together mesencephalon. Here, a very old structure within with its connections constitutes the main pathway the diencephalon stands out: the lateral habenula to regulate behaviors guided by emotions. The (LHb)—located in the dorsomedial portion of 33 basolateral region can be considered as a receptor the thalamus. The dopaminergic neurons that area; on the other hand, the centromedial region project from the VTA to the NAc are activated (ganglionar or nuclear) functions as an emitting by an unexpected reward (or stimuli predicting or output area.35 The terminal stria connects the a reward), and inhibited by the omission of the nuclear amygdala with the diencephalon and with expected rewards. This inhibition seems to depend 33,42 the anterior dorsomedial frontal areas; additionally, on the contributions from the LHb.
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f. Reward system The NAc receives projections from the lateral Reward systems are centers in the central hypothalamus (LH), PFC, dorsomedial thalamus nervous system that obey specific and natural (DMT), hippocampus (HC), and VTA. The NAc, stimuli, allowing the individual to develop learned in turn, sends projections to the VTA and the LH behaviors that respond to pleasant or unpleasant while the VTA sends and receives projections events. Figure 3 describes in a simplified way from the PFC and the LH. We should mention the the main nuclei, afferents and efferents in the cerebellum, which allows the control of muscular reward system. functions, and the pituitary gland, which is responsible for pain relief and establishing Activation of the NAc by the release of positive bonds, among others. These structures dopamine from the VTA occurs in the presence form the reward system, which is also called the of natural (e.g. food, water, sex) or artificial limbic-motor circuit. This entire circuit is in turn (e.g. psychoactive drug substances) boosters. modulated by the amygdala.
Figure 3. Reward System. isce a and end c ine e nta ate a in ati n Re a d s ste i ca s c tex t a a s
s edia c e s cc ens a ine ent a e enta t a a s ea
d ate ex
s c active s stances
it ita da a and e e e
Reward system’s main nuclei, afferents and efferents. Detailed description in the text.
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Table 3. Clinical correlation and alterations in circuits and neurotransmitters of the basal ganglia.
i ea e o or e a iora an ain ircui or a ec e ain o c ia ric ruc ure Neuro ran i er o in o e r inson s r inesi , oss o o miner ic Do mine Dise se s i ness, De ression ne rons in s bs n i ni r ce c o ine remor res , n ie Ni ros ri ero onin c n es in ec ive er ion, in e Nor ren ine os re n s nc ion sensor -mo or, ssoci ive, enosine i er ions in n imbic circ i s or in Direc n in irec memor er ion, res in in m se ers im ion o on ro s b mic n c e s n Disor er er ic e i n c ei ( i n Nr) e nc o on ine n c e s n n c e s b s is o e ner er ion Re r circ i er ion
n in on s ore , De ression, Ne ron oss in c e, ise se ics, rri bi i , men, re ron cor e , m e D s oni , m sivi , cin e n m n e in r inesi , D s ori , i re in e in irec Do mine Ri i i n ie , n in e bs nce ni , in ibi or ro e o e b s , n i s c osis, er ion o e me i ec ive orbi o ron cor ic D s nc ion circ i er ion o e ron os ri circ i
ener i e D s oni De ression, oss o n r cor ic rim r n ie , n ibi ion n ncre se ce c o ine D s oni m sivi r in s ici Do mine ere sensorimo or in e r ion i re in in ibi ion ro n cessive irec c ivi , Decre se in irec c ivi Decre se e n i c ivi Decre se s b mic n c e s c ivi ver c ivi o re ron cor e rin movemen
GPi - Internal globus pallidus SNr - Substantia Nigra pars reticulata GABA - γ-aminobutyric acid GPe - External globus pallidus
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Conclusions
Basal ganglia and their connections are determinant in the selection, execution, and learning of new behaviors that have their expression through motor acts, thoughts, and emotions. These connections allow to act according to internal and external environment requirements. According to these requirements, the answers can be automatic, goal-directed, or guided by our emotions. Table 3 summarizes the clinical and anatomo-functional correlations of some of the most common basal ganglia diseases to illustrate the relevance of these circuits and their neurotransmitters.
Although science has allowed a better understanding of the functioning and integration of these structures, it would be pretentious to ensure that everything has been explained because some of these are theoretical models. In addition, there are still gaps in knowledge that do not allow a complete understanding of their functionality and their relation to a concept as complex and broad as behavior. However, the advances made today highlight the importance not only of their individual components but also of their connections, that is, neural networks, neurotransmitters, and functional circuits. The aforementioned allows an understanding of the behaviors from a pragmatic point of view and helps us comprehend not only their normal functioning but also a wide variety of neurological syndromes that carry motor and neuropsychiatric symptoms derived from their alterations.
Conflict of interest statement Funding The authors declare there are no relevant There was no particular source of funding for conflicts of interest in this study. this scientific report.
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30. Brown P. Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson’s disease. Mov Disord. 2003;18(4):357-363. 31. Loonen AJ, Ivanova SA. Circuits regulating pleasure and happiness: The evolution of the amygdalar- hippocampal-habenular connectivity in vertebrates. Front Neurosci. 2016;10(539):1-17. 32. Loonen AJ, Ivanova SA. New insights into the mechanism of drug-induced dyskinesia. CNS Spectr. 2013;18(1)15-20. 33. Heimer L. A new anatomical framework for neuropsychiatric disorders and drug abuse. Am J Psychiatry. 2003;160(10):1726-1739. 34. Groenewegen HJ. The basal ganglia and motor control. Neural Plast. 2003;10(1-2):107-120. 35. Benarroch EE. Habenula: recently recognized functions and potential clinical relevance. Neurology. 2015;85(11):992-1000. 36. Cassell MD, Freedman LJ, Shi C. The intrinsic organization of the central extended amygdala. Ann NY Acad Sci. 1999;877:217-241. 37. Heimer L, Van Hoesen GW. The limbic lobe and its output channels: implications for emotional functions and adaptive behavior. Neurosci Biobehav Rev. 2006;30(2):126-147. 38. Groenewegen HJ, Trimble M. The ventral striatum as an interface between the limbic and motor systems. CNS Spectr. 2007;12(12):887-892. 39. Dalley JW, Mar AC, Economidou D, Robbins TW. Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry. Pharmacol Biochem Behav. 2008;90(2):250- 260. 40. Stahl SM, Loonen AJ. The mechanism of drug-induced akathisia. CNS Spectr. 2011;16(1):7-10. 41. Loonen AJ, Ivanova SA. Circuits regulating pleasure and happiness in major depression. Med Hypotheses. 2016;87:14-21. 42. Ortega LA, Solano JL, Torres C, Papini MR. Reward loss and addiction: Opportunities for cross- pollination. Pharmacol Biochem Behav. 2017;154:39-52.
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Revision
MA Valle-Murillo1, ME Central nervous system infections, part 2: Amparo-Carrillo2 Neuroinfections in patients with human immunodeficiency virus infection 1Department of Neurology and Psychiatry. National Institute of Medical Science and Nutrition Infecciones del Sistema Nervioso Central, parte 2: Neuroinfecciones “Salvador Zubiran.” en pacientes con Infección por Virus de Inmunodeficiencia Humana 2Mexican Social Security Institute, Family Medicine Unit #58
Abstract
Since the first reports of Human Immunodeficiency Virus (HIV) infection, the field of infectology has changed in a vertiginous way resulting in the appearance of two new subspecialties: HIV infectology and neuroHIV—the latter focused in the nervous system complications caused by the virus or its treatment.
About 50-70% of patients with HIV infection have or will develop a symptom or neurologic syndrome at some point during the course of their illness, either caused by the virus, an opportunistic infection, or as a complication of the drugs. Among the most common Neurological issues are peripheric neuropathies, neuropsychiatric manifestations, and aseptic meningitis. However, the most challenging and complex aspect by far is the approach to the patient with a suspected neuroinfection in the context of HIV infection, because the immune system has been compromised and its response might not be the one expected in an immunocompetent patient. That’s why a special algorithm must be designed for the diagnosis and management of this population.
Keywords Neuroinfections, meningitis,hiv, toxoplasma encephalitis, cryptococcal meningitis.
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Resumen
Desde la aparición de los primeros casos con infección por el virus de inmunodeficiencia humana (VIH) la infectología se ha revolucionado de una forma vertiginosa de tal forma que actualmente existen subespecialidades dentro de la infectología que se dedican al estudio de pacientes con VIH y dentro de la neurología que se enfocan en las complicaciones en el sistema nervioso causadas por el virus o su tratamiento.
Se estima que entre el 50-70% de los pacientes con infección por VIH tienen o tendrán en algún momento un síntoma o síndrome neurológico ya sea causado directamente por el virus, por un oportunismo o como complicación del tratamiento. Dentro de las complicaciones más comunes se encuentran las neuropatías periféricas, cambios neuropsiquiátricos y la meningitis aséptica, sin embargo definitivamente el aspecto más complejo es el abordaje de un paciente con sospecha de neuroinfección en el contexto de VIH ya que el sistema inmunológico se encuentra alterado y la respuesta puede no ser la misma que en el caso de una persona inmunocompetente por lo que se requiere de un algoritmo especial para el diagnóstico y manejo de esta población.
Palabras clave Neuroinfecciones, vih, meningitis, toxoplasmosis, criptococosis.
Corresponding Author: Dr. Miguel Angel Valle Murillo. Vasco de Quiroga 15, Colonia Belisario Domínguez Sección XVI, Tlalpan C.P.14080, Ciudad de México, D.F. E-mail: [email protected]
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I.- Approach to the patient with suspected Introduction neuroinfection in hiv
Facing a neurological case in the context of As we mentioned in the first part of this series a patient living with HIV is very particular on neuroinfections, a classification by clinical and requires all the skills and knowledge of syndromes is very useful because it allows us to the internist, infectious disease specialist, or reduce the diagnostic possibilities and we can neurologist managing the case. We know the follow a diagnostic and therapeutic algorithm immune response is compromised and therefore focused on the most probable cause. Unlike some manifestations derived from it such as fever, an immunocompetent patient, in the case of a pleocytosis, hyperproteinorraquia, or intracranial patient with HIV, in addition to considering the hypertension may be barely present or not found predominant clinical presentation, we need to at all. In these cases, it is of vital importance to also take into account the CD4 cell count, the consider the CD4+ cell count as well as the use adherence to antiretrovirals if they are taken, the of antiretroviral drugs and chemoprophylaxis for use of prophylaxis, and specific risk factors such opportunism. We can also find the case of a patient as visit to caves, consumption of undercooked with a high CD4+ count who is on antiretrovirals, foods, etc.1,2 presenting with a rare picture of neuroinfection which may be due to immune reconstitution or Table 1 describes the characteristics of the the rare syndrome of viral escape in cerebrospinal CSF cytochemistry in the different entities of fluid (CSF).1 infectious processes without clinical focalization.
Neuroinfections in the patient with HIV The meningeal syndrome, as already described, infection is mainly accompanied by meningism, Kerning’s sign, and Brudzinski’s signs. The non-focal The neurology of patients with HIV infection syndrome includes diffuse symptoms such as has currently grown in importance since it is encephalopathy syndrome, gait disorder, etc. The known that more than 50% of them have a focal syndrome includes sensory-motor deficits, neurological syndrome either due to the virus dysphasia, etc. Figure 1 describes the causes to be itself, which is neurotropic, or opportunism considered depending on the clinical syndrome due to immunosuppression or derived from that predominates. In the case of patients with the antiretroviral treatment. This topic is HIV and encephalopathy syndrome with or very extensive and, in this section, only the without focal symptoms, it is essential to obtain infectious neurological syndromes derived from CSF for cultures and special studies depending on opportunism in HIV patients will be addressed.1 the case, without forgetting that HIV infection is an absolute indication to perform neuroimaging
Tablet 1. CSF profile in different entities.
enin re ure eu o ce N ro ein uco e c 100-10,000 80 100-500 10 N o 20 5-1,000 60 50-250 10- 5 N 5-100 60 5-100 10- 5 N 25-1000 60 50-1500 10- 5 N o 20
The findings of the analysis of cerebrospinal fluid (CSF) in the main neuroinfections are shown. ABM = acute bacterial meningitis. AM = aseptic meningitis. AE = acute encephalitis. TBM = tuberculous meningitis.
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Figure 1. A neuroinfection approach and its differential diagnosis depending on the clinical syndrome in a patient with HIV infection. HIV = human immunodeficiency virus. CMV = cytomegalovirus. CNS = central nervous system. PML = progressive multifocal leukoencephalopathy.
t c cc sis Menin ea s nd e e c s enin itis e s i is
ass ciated de entia n ca s nd e M ence a itis
x as sis e c a ca s nd e i a a M prior to performing a lumbar punction (LP) approach is neuroimaging either by tomography or independently of the CD4 count.3 cranial magnetic resonance imaging. This way, we can divide it into four radiological presentations. The CSF cytochemistry is usually very similar to that of immunocompetent patients but we * Group 1: Normal image or with diffuse must always consider that the inflammatory meningeal enhancement suggests bacterial or response may be lower. Although the possibility fungal meningitis as first possibilities and MTB of neuroinfection due to opportunism must or neurosyphilis as second options. For this always be kept in mind, the possibility of acute group, request bacterial cultures, mycobacteria, bacterial meningitis (ABM) should not be ruled cryptococcal antigen, adenosine deaminase (ADA) out, so empirical management for ABM is and VDRL. Empirical treatment should include recommended unless there is a very clear cause antibiotic for ABM and consider amphotericin B in from the beginning—for example, in the case of case of cryptococcal antigen and anti-tuberculosis a patient with hemiparesis and neuroimaging drugs in case of ADA>10. compatible with toxoplasmic encephalitis, coverage for ABM would not be necessary in the * Group 2: Basal enhancement. There may be absence of meningeal syndrome. Whenever a LP multiple differential diagnoses but, in this context, is performed in this context, CSF cultures should the main suspect is tuberculous meningitis (TBM) be requested for aerobic bacteria, anaerobes, so an ADA>10 or some other finding compatible mycobacteria, bacterial antigens, India ink stain, with TBM suggests initiation of anti-tuberculosis cryptococcal antigen, venereal disease research drugs. laboratory (VDRL) and protein chain reaction (PCR) for herpes simplex virus (HSV), varicella * Group 3: focal lesion either in basal or zoster, and cytomegalovirus (CMV). In blood, subcortical gray nuclei. Stronger alternatives VDRL, toxoplasma IgG, and blood culture should such as toxoplasmosis should be considered, be requested.3 especially if there is ring enhancement. For its approach, serotype IgG for toxoplasmosis is The next step in the diagnostic-therapeutic recommended and consider a brain SPECT (Single
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Photon Emission Computed Tomography). The empirical treatment is the same as described in therapeutic approach, in this case, is to start Figure 4.5 treatment for toxoplasmic encephalitis even if the toxoplasmosis IgG is negative. If it fails, then treat III. Central nervous system tuberculosis as possible lymphoma. This topic will be discussed in more detail in a *Group 4. Diffuse lesions in white matter. They special section; however, it is important to mention comprise many etiologies, but the more important in this article because the risk of tuberculosis are progressive multifocal leukoencephalopathy in HIV is 1 in 3. Twenty percent of all cases are (PML) and HSV or HIV encephalitis. The diagnostic associated with HIV and it’s currently the most approach in this group should include CSF with common cause of death in the AIDS population.6 bacterial cultures, HSV PCR, VZV, CMV, and JC The most common form of infection in the CNS virus. Acyclovir can be initiated empirically if is TBM. TBM can occur simultaneously with the clinic suggests viral encephalitis, pending the the primary infection, which happens mainly results of other studies. See Table 2.4 in children, but in adults it is usually due to reactivation of a previous infection. Transmission The most important infectious syndromes are is through the inhalation of drops. During primary briefly discussed below. infection, it germinates in the brain, spinal cord, and meninges forming the “Rich focus” which II.- Bacterial meningitis can break into the subarachnoid space where it produces inflammatory exudates that favor the 6,7 This topic was already addressed in the previous development of meningitis. article, but we must emphasize the fact that in the context of HIV the meningeal signs are Clinically, in an immunocompetent patient, it presents absent and suspicion should remain high in case with a prodrome. Like many neuroinfections, it of headache and fever without clear explanation. is accompanied by nonspecific symptoms such The CSF is usually very similar to that of its as fever, headache, malaise, and nausea. Unlike immunocompetent counterpart. The etiologies bacterial meningitis, which is characterized by an are usually the same although L. monocytogenes acute picture of days of evolution, TBM presents as is slightly more prevalent in this group of patients, a subacute or chronic meningitis that develops over 6,7 so empirical coverage is recommended for it. The a period of two to eight weeks.
Table 2. Approach to neuroinfection in HIV by neuroimaging.
rou Norm im e or i se menin e c eri menin i is, menin e en ncemen cr ococcosis, menin e berc osis, ne ros i is rou s eve en ncemen berc o s menin i is rou oc esion i e em in e b s or o o sm ence i is, rim r s bcor ic r n c ei N m om rou Di se esions in i e m er , ence i is, -6 or ence i is, in ec io s v sc o Depending on the neuroimaging findings, the picture of a neuroinfection in a patient with HIV can be divided into four groups and this reduces the differential diagnoses as shown in the table. CNS = central nervous system. PML = progressive multifocal leukoencephalopathy. HIV = human immunodeficiency virus. HHV = human herpesvirus. CMV = cytomegalovirus.
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The clinical presentation in the patient with HIV patients with HIV. It usually occurs with <100 is very similar, but the alteration of the early CD4.10 warning state is more prevalent. The CSF is reported with little cellularity and predominance The most common presentation is meningeal of mononuclear cells. Microscopy has a very cryptococcosis. It presents as subacute-chronic variable sensitivity of 25-50% but increases up meningitis with insidious onset, fever, headache, to 80% with large samples 20ml and repeated. nausea, vomiting, and cognitive deterioration The culture has 50% sensitivity. Currently, the followed by an altered state of alertness. preferred technique for detection of TB in CSF Ophthalmoparesis, alterations in the visual field, is GeneXpert—with a sensitivity of 80% and and papilledema are frequent findings in the specificity of 97%, it is positioning itself as the neurological examination due to the subacute preferred diagnostic method from the start.8,9 intracranial hypertension they develop.10
By image, meningeal enhancement is usually Meningeal syndrome might be found, though it’s observed at the basal level delimiting the arteries often absent in the context of HIV. In the suspicion of the circle of Willis, although less intense than of meningeal cryptococcosis, it is recommended in the immunocompetent, and there may be to obtain neuroimaging, as indicated in all HIV hydrocephalus which progresses insidiously. patients with neuroinfection, before performing Figure 2. Mortality at 6-9 months is 24-60% vs a LP. The cytochemistry is similar to that found in 0-30% of the immunocompetent.6 viral encephalitis or aseptic meningitis. India ink is reported in a few hours and can be useful for The treatment in all forms of TB requires a an early start of treatment, but its sensitivity is combination of the four classic anti-tuberculosis low <50%. The opening pressure is usually high. drugs: rifampicin, isoniazid, pyrazinamide, and ethambutol. The addition of pyridoxine to avoid toxicity is very important. In addition, it should Figure 2. Magnetic resonance imaging of a case be considered that the prevalence of multidrug of tuberculous meningitis. A basal arachnoiditis is resistance is greater (13-40%) than that of the observed, affecting most of the circle of Willis. immunocompetent (2-5%) and taking into account that the penetration of anti-tuberculosis drugs to the CNS could be poor, it is suggested to consider the addition of secondary anti-tuberculosis drugs. There are some complications observed mainly in the patient with HIV, such as a decrease in the plasmatic levels of rifamycin by HIV itself or by drug interaction. Immune reconstitution inflammatory syndrome (IRIS) in two forms: 1) IRIS with TBM unmasked - new diagnosis of TBM in patient without previous TB; 2) paradoxical IRIS - new signs of TBM, tuberculoma or complications due to TBM in a patient with a previous diagnosis of TBM.6,7
IV.- Cns cryptococcosis
An infection by Cryptococcus neoformans, an encapsulated yeast transmitted via respiratory airways, is the most common fungal infection in
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The antigen in CSF has a sensitivity of 91% and a Because intracranial hypertension develops specificity of 95%.10 chronically, the patients, despite having papilledema and ophthalmological alterations, do The definitive diagnosis is made by CSF culture, not usually show signs of instability if they receive which has a sensitivity of 70-95%. The tomography treatment.10,11 and MR are usually normal, occasionally showing meningeal enhancement and pseudocystic lesions V.- Toxoplasmic encephalitis in deep perivascular spaces such as the territory of lenticulostriate or cryptococcoma.10,11 Toxoplasmic encephalitis (TE) is the inflammation of the cerebral parenchyma secondary to The management recommended by IDSA infection by T. gondii. It is the most common cause guidelines is amphotericin B 0.7mg-1mg/kg/day of focal brain syndrome in a patient with HIV. The + flucytosine 100mg/kg/day; however, in Mexico, prevalence of T. gondii infection in Latin America the latter is not available, so fluconazole 800mg reaches 70%. It may present as cerebritis, abscess, per day is used as an alternative. The induction diffuse encephalitis and usually appears with therapy described must be continued for at CD4<100 cells. Due to reactivation of previous least two weeks. If the induction therapy was exposure, the clinical picture is established satisfactory (defined as clinical improvement insidiously and progressively in the course of and negative CSF culture), consolidation can be weeks to months. About 50% have fever and initiated and, finally, maintenance therapy. It is headache, and TE has tropism for gray nuclei, so important to consider that the CSF cytochemistry movement disorders—mainly focal chorea and in cases of meningeal cryptococcus may have ballism—are not rare. Table 3.10,11 minor changes after the induction phase, so it should NOT be considered a treatment failure if Diagnosis is usually relatively simple since the the cell count, protein, or glucose ratio does not picture is typical: patient with HIV—or suspicion change significantly since this can happen in most of it due to risk factors—without antiretrovirals, chronic meningitis.10,11 presents with a neurological focal syndrome, plus frequent hemiparesis and dysphasia. Imaging In case of intracranial pressure >25cm H2O it is finds multiple lesions (60-70%), hypodense on CT, recommended to decrease the pressure through hypointense on T1, iso- or hypointense on T2, with draining liquids by 50% or else 20-30 ml. The gadolinium ring enhancement, and localization measurement and drainage must be done—every at the supratentorial gray nuclei, thalamus, and day, if necessary—until it is normal. Steroids or corticomedullary junction. Figure 3.10,11,12 acetazolamide are not useful in these cases. If the punctures need to be frequent, external lumbar The serology for toxoplasma IgG is present in drainage can be done and, in select cases, surgical >90% of the cases and its absence must force a drainage.10 reconsideration of the diagnosis; however, it is
Table 3. Signs and symptoms of toxoplasmic encephalitis. i n o re uenc bcor ic or cerebe r - i isor er 51 oc -cor ic - mono resis emi resis 65 oc -cor ic - s si si 55 Di se - e c e 61
The frequency of the signs and symptoms of toxoplasmic encephalitis is shown depending on the tomography of the lesion.
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Figure 3. Magnetic resonance imaging of a case of toxoplasmic encephalitis. The left side (A) is prior to treatment and the right side (B) after treatment.
not used as diagnostic method, only suggestive case of significant mass effect that conditions of it. The definitive diagnosis is made by biopsy imminent herniation or important neurological but it is rarely considered if there is no treatment deterioration; otherwise, it is recommended to failure. The most important differential diagnosis avoid or discontinue their use as soon as possible is with primary central nervous system lymphoma since they do not allow an objective evaluation of (PCNSL) which presents in a very similar way, the response to treatment. The recommendation both clinically and by imaging. In case of focal is dexamethasone 4-8 mg IV every 6 hours.10,12 lesion with edema, it is always handled initially as TE and if the treatment fails then it is approached To interpret the response to treatment, a scale has as PCNSL. If, however, from the beginning there is been proposed where the clinical manifestations data suggestive of PCNSL or serology absent for T. are graded by category. Table 4.12,13,14 gondii, then an early SPECT is recommended. The SPECT is performed with thallium 201, comparing Neurological response is defined as improvement the lesion against a healthy hemisphere or uptake of at least 50% in at least one clinical category, ratio. The increase in uptake is compatible with without worsening in some other category, and lymphoma. In TE cases there is no increase—there without the appearance of new symptoms in might even be a decrease in uptake. Its sensitivity another category. The neurological response is 92% and specificity 89%, though lesions <1cm or occurs in 50% at three days, 86% at day seven, with necrotic areas interfere with sensitivity.10,11,12 and 90% at 14 days. At seven days, 70% of the cases had at least 50% improvement. The cut to * Management: it was already mentioned that any evaluate response is at 14 days, and the scale focal lesion with edema should be treated as TE. must be repeated.14 The treatment recommended by the IDSA and the DHHS guidelines for opportunistic management is The imaging response is divided into categories: pyrimethamine with a loading dose of 100-200mg Complete: study of image without injuries; Good: and then 75-100 mg a day, always accompanied by decrease of >50% of the lesions, without new folic acid + sulfadiazine 6-8 gr a day or clindamycin lesions or worsening of others; Partial: decrease IV 900 mg every six hours for at least six weeks. of <50% of a lesion, without increase in size or appearance of new lesions; Mixed: any decrease Steroids: the use of steroids deserves special in size with increase or appearance of others.14 mention because its administration is often abused with TE. The indication for steroids use is only in
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Table 4. Systems to be evaluated in the clinical evolution of CNS toxoplasmosis.
a e or i n o Di se cor ic or m i oc er ness, memor , evoc ion, n orien ion No oc or e c e, sei res bcor ic or cerebe r nce, i , sensi ive, c ore oc cor ic Visual fields, language, language fluency, comprehension, repetition, MT force, MP force, global force. n r en ori Facial paralysis, diplopia, ophthalmoparesis, sphincter control.
For clinical follow-up and to determine the response to treatment in toxoplasmic encephalitis, the clinical categories shown in the table should be evaluated. CNS = central nervous system.
Figure 4. Algorithm for management of a patient with HIV and focal brain injury. HIV = human immunodeficiency virus. CT = computed tomography. TC + c = contrast tomography. TE = toxoplasmic encephalitis. MR = magnetic resonance. SPECT = single-photon emission computed tomography. PET = positron emission tomography.
ca ain esi n c inica and
c
t s estive e ative estive se MR
sitive sitive i s se se MR
e ative c inica se i ica x es nse
nside
* Multiple lesions less than 3cm, with ring enhancement, in basal ganglia, thalamus, or corticomedullary junction. ** Improvement >50% in at least one clinical category without worsening or appearance of lesions in other categories.
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Conclusions
The approach to the patient with an infection in the central nervous system requires a multidisciplinary team and it is important to always consider there are no rigid protocols because the clinical presentations can be very variable. Initially, therapeutics should be guided by the characteristics of the patient such as age, gender, co-morbidities, immunosuppression status, and risk factors such as travel, immunizations, previous use of antibiotics, etc. The rapid establishment of adequate therapy offers the opportunity for a good outcome with little or no long-term disability as well as a lower rate of morbidity and mortality.
Conflicts of interest Funding sources There are no potential conflicts of interest for The authors have not declared any source of any of the authors in this scientific report. funding for this scientific report.
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References
1. Corral I, Quereda, Carmen. The Neurological spectrum of HIV infection. In: García.Moncó JC. CNS Infections, a clinical approach. Vizcaya, España. Springer. 2014:229-239 2. Verma A, Berger J. Neurological manifestations of Human Immunodeficiency virus infection. In: Daroff R. Bradley’s Neurology in clinical practice. Philadelphia. Elsevier. 2012: 1211-1230 3. Marra C. Infections of the central nervous system in patients with human immunodeficiency virus. Continuum. 2006. 4. Tan I, Smith B, von Geldern G, Mateen F, McArthur J. HIV-associated opportunistic infections of the CNS. Lancet Neurol. 2012; 11: 605-17 5. Fitch M, van de Beek D. Emergency diagnosis and treatment of adult meningitis. Lancet Infect Dis. 2007;7:191-200. 6. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British infection society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Journal of infection. 2009. 59,167-187. 7. Thwaites G, Hien T. Tuberculous meningitis: many questions, too few answers. Lancet Neurol. 2005; 4:;160-70 8. Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A et al. Tuberculos mengitis in patients infected with the human immunodeficiency virus.Nejm. 1992. 326: 10; 668-672- 9. Dekinger C, Schumacher S, Boehme C, Dendukuri N, Madhukar P, Steingart K et al. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Euro Resp J. 2014: 44; 435-446. 10. Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 May;58(9):1308-11 11. Avindra N. Neurologic complications of human immunodeficiency virus infection.Continuum. (Minneap Minn) 2015; 21: 1557-1576. 12. Berger J. Pearls: Neurologic complications of HIV/AIDS. Semin Neurol. 2010. 30 (1) 66-70. 13. Soto J. Toxoplasmosis cerebral en pacientes con infección por VIH-SIDA. Enf Infec y Microbiol. 199; 19:10-7. 14. Luft B, Hafner R, Korzun A, Leport C, Antoniskis D, Bosler E z. Toxoplasmis encephalitis in patients with the acquired immunodeficiency syndrome.Nejm. 1993. 329; 14: 995-1000
Revista Mexicana de Neurociencia November-December, 2017; 18(6):85-95 96 Case report Marchiafava-Bignami disease
Case report
Marchiafava-bignami disease: case report Gabriel Miranda-Nava,1 Martha Guadalupe García-Toribio2 and review of the literature
Marchiafava bignami: reporte de un caso y revisión de la literatura 1Clinical Neurologist and Neurophysiologist, Neurophysiology department, ABC Medical Center. 2Neurologist and second-year resident of the subspecialty of Clinical Abstract Neurophysiology, ABC Medical Center. INTRODUCTION: Marchiafava-Bignami (MB) is a rare disease characterized by the primary degeneration of the corpus callosum mainly associated with chronic consumption of alcohol. However, this condition can be mistaken for many other diseases which cause lesions of the corpus callosum. Even though it’s been said Carducci was the first to report a case of MB in 1898, this disease was named in honor of two Italian pathologists in 1903, Ettore Marchiafava and Amico Bignami, who described the symptoms of an Italian male with excessive consumption of red wine.1 The majority of patients are male, aged between 40 to 60 years old, with a history of chronic alcoholism and malnutrition. In these cases, morbidity and mortality rates are relatively high. In 2004, there were approximately 250 patients reported, 200 of them died, 30 were diagnosed with severe dementia, and just 20 patients had a positive outcome.2
The treatment for MB is still controversial and shows changing outcomes. Some authors have proposed benefits following the administration of vitamin B, corticosteroids and amantadine.
CASE REPORT: A 41-year-old male with a history of 15 years of chronic alcohol abuse drinking whiskey and rum presents disorientation and minor psychomotor agitation. During physical examination the patient presents dysarthria and ataxy. A family member reports that Keywords the patient has presented frequent forgetfulness which has caused Marchiafava, Bignami, him work problems. Nuclear magnetic resonance FLAIR images reveal demyelination. the presence of demyelination of the corpus callosum, such as a little alteration of the white matter of the brain.
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Resumen
INTRODUCCION: Marchiafava-Bignami (MB) en una enfermedad rara caracterizada por degeneración primaria del cuerpo calloso principalmente asociada con consumo crónico de alcohol. Sin embargo, puede ser mimetizada por muchas otras enfermedades que causan lesiones en el cuerpo calloso. Aunque se ha dicho que Carducci fue el primero en reportar un caso de en 1898, esta patología fue originalmente acuñada en honor a los dos patólogos italianos, Ettore Machiafava y Amico Bignami en 1903, quienes describen los síntomas de un hombre italiano con alto consumo de vino tinto.
La gran mayoría de los pacientes son varones, entre 40 y 60 años de edad, con historia de alcoholismo crónico y desnutrición. En estos casos la morbilidad y mortalidad son relativamente altos. En 2004 aproximadamente se habían descrito 250 pacientes, de los cuales 200 habían muerto, 30 sufrieron demencia severa y sólo 20 pacientes tuvieron resultados positivos. El tratamiento de MB es aún controversial y muestra resultados variables. Algunos autores han propuesto cierto beneficio con el reemplazo con vitamina B, corticoesteroides y amantadina.
REPORTE DE CASO: Se trata de paciente masculino de 41 años de edad que tiene el antecedente de 15 años de ingesta crónica de alcohol en su modalidad de whisky y ron, llegando a la embriaguez de forma constante; se presenta en el servicio con desorientación, agitación psicomotriz; en la exploración cursa con disartria escandida, así como ataxia y alteraciones a la marcha (en estrella). Al interrogatorio indirecto refiere el familiar que ha presentado olvidos frecuentes que incluso le han ocasionado una problemática laboral y en el manejo de dinero. Se realiza estudio clínico que incluye un minimental test, así como el apoyo de neuroimágen a través de resonancia magnética nuclear de encéfalo, donde se muestran imágenes en FLAIR donde resalta la presencia de desmielinización del cuerpo calloso, así como una discreta afección a Palabras clave sustancia blanca contigua, los estudios de laboratorio son normales y no se detecta otra patología agregada, resaltando incluso la normalidad Marchiafava, Bignami, de las pruebas de funcionamiento hepático o electrolitos séricos. desmielinización.
Correspondence: Dr. Gabriel Miranda Nava. Neurólogo y Neurofisiólogo Clínico adscrito al servicio de Neurofisiología del Centro Médico ABC. E-mail: [email protected]
Revista Mexicana de Neurociencia November-December, 2017; 18(6):96-101 98 Case report Marchiafava-Bignami disease
Introduction Clinical case
Marchiafava-Bignami disease is characterized An interconsultation was requested by the by demyelination of the corpus callosum. The emergency department for a 41-year-old male most frequent clinical features are dementia, patient presenting a state of neurological attention deficit, walking difficulty, dysarthria, deterioration consisting of chronic disorientation and interhemispheric disconnection syndrome. of the three mental spheres, dysarthria, and a Pathologically it is characterized by the production constant ataxic or star-shaped gait. An indirect of corpus callosum necrosis affecting it locally or interrogation through his companion reported totally, and a progressive demyelination of the these symptoms have been present for more than 2-4 nearby white matter. a year. The scan revealed pancerebellar syndrome. The Mini-Mental test scored 18 points out of 30. A nuclear magnetic resonance of the brain was indicated and lesions by demyelination in the Objetives corpus callosum were observed. Figures 1 and 2.
The knowledge of this disease as one of many related to the use and abuse of alcohol, as well as its clinical correlation and neuroimaging study.
Figures 1 y2. Nuclear magnetic resonance FLAIR imaging shows the demyelination of the corpus callosum.
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Etiology and Differential diagnosis pathogenesis We must consider a recurrent artery of Heubner The main hypothesis is a deficiency of the vitamin infarct, neoplastic diseases such as astrocytoma B complex and many patients improve after or lymphoma, demyelinating diseases such administration of these components. Other as multiple sclerosis, progressive multifocal nutritional and toxic etiologies have also been leukoencephalopathy, or acute disseminated considered and some studies have concluded a racial encephalomyelitis.9,10 susceptibility to this disease. Patients without alcohol consumption with MB are mostly younger and are more likely to be female.5-8 Clinical picture Treatment
Patients related to chronic alcoholism (often the The etiology of MB is unknown, therefore specific habit of consumption is a daily and continuous therapy cannot be recommended. Treatment with pattern), malnutrition, anorexia, cachexia, or thiamine and other B vitamins, including vitamin decreased food intake in previous days. Within the B-12 and folic acid, has shown recovery in some clinical manifestations they may present alterations patients; however, therapy failure is not infrequent, of the mental state (including confusion, delirium, even if treatment is initiated at the onset of some degree of alertness decrease, memory symptoms. Thiamine has become a treatment impairment and/or disorientation), deterioration option because an association between MB and of gait, dysarthria, mutism, signs or syndromes of Wernicke’s Disease has been observed in up to 15 disconnection (typical clinical characteristic of the to 20% of patients. Patients treated with thiamine disease), pyramidal signs, primitive reflexes, stiffness, in the acute phase have better results than those incontinence, sensory symptoms, paralysis of the gaze treated in the chronic phase.9,10 or diplopia, hemi- or tetraparesis, and nystagmus.9 Comorbidities include neuroinfections and Given the time of clinical evolution, phases have epileptic states, among others, which are been proposed: acute when the time of evolution potentially treatable. is less than two weeks, subacute when it is greater than two weeks, and chronic when it is greater than Corticosteroids may decrease cerebral edema, three months. Diagnosis is based on clinical findings suppress demyelination, stabilize the blood- in combination with imaging features. In computed brain barrier, and reduce inflammation. Some tomography, the corpus callosum appears hypo- publications have reported cases with improvement attenuated, with the exception of the case that is after the administration of steroid treatment; characterized by subacute bleeding, in which the despite this, there are other studies in which no net lesion is shown iso- or hyper-attenuated. During positive effect was observed. the acute phase, the corpus callosum appears hyperintense in T2 and hypointense in T1. In the Better results have been observed in patients subacute phase, the patient may develop cystic who are treated with parenteral thiamine within lesions and small foci in T2, commonly due to the first two weeks of symptom onset, whereas hemosiderin deposits. In chronic stages, alterations delayed treatment has been a significant risk factor of the signal intensity are less evident but a residual with poor outcome.9-11 atrophy is seen surrounding the structure.6,9,10
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Follow-up Conclusion
Acute or subacute MB patients who survive suffer MB disease presents a great variety of neurological subsequent dementia, though occasionally they signs and symptoms. Disconnection syndrome is may recover partially or completely. Patients who a cardinal point for the clinical suspicion of this survive the disease should stop drinking alcohol, pathology, as well as the relevance of antecedents of undergo rehabilitation therapy, and receive alcoholism, malnutrition, and other comorbidities nutritional advice. Recovery should be followed by with neuropsychiatric symptoms. These should repeated neuropsychological examinations, as well guide the clinician who, aided by imaging studies, as magnetic resonance control studies, preferably will arrive at a timely diagnosis for the immediate using image diffusion tensor.12 establishment of the therapeutics suggested by the literature, which will give the patient greater opportunities for recovery or at least limit the damage. Prognosis
A good response is not always observed despite the suggested therapeutics. Some factors that worsen the prognosis are a history of alcoholism and delay initiating thiamine treatment.
The prognosis may also be influenced by the location of the lesion, as solitary splenius lesions are associated with better results compared to lesions located elsewhere or completely crossing the corpus callosum.9,10
Conflict of interest statement Funding The authors declare there are no relevant There was no particular source of funding for conflicts of interest in this study. this scientific report.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):96-101 Case report 101 Marchiafava-Bignami disease
References
1. Navarro JF, Noriega S. Enfermedad de Marchiafava Bignami. Rev Neurol. 1999; 28: 519-523. 2. Marchiafava E, Bignami A. Sopra una alterazione del corpo calloso osservata in soggeti alcolisti. Riv Pat Nerv Ment. 1903; 8:544-9. 3. Gervith RS, Mendizábal RG. Enfermedad de Marchiafava-Bignami. Arch Neurocien. (Mex) Vol. 13, No. 2: 138-142; 2008. 4. Yongjian C, Lei Z, Xiaoli W, Weiwen Z et al. Marchiafava-Bignami disease with rare etiology: A case report, Experimental and Therapeutic Medicine. 2015; 9: 1515-1517. 5. Samine B, Sirous N, Farrokh ST, Hossein R-D et al. Marchiafava-Bignami and Alcohol Related Acute Polyneuropathy: The Cooccurrence of Two Rare Entities, Case Reports in Neurological Medicine. 2016. 6. Sunil K, Rimiki C, Naveen J, Jatishwor S. Marchiafava - Bignami disease: Review of Imaging Features & Case Report, Journal of Clinical and Diagnostic Research. 2014; Vol-8(8): RD01-RD02 7. Wenz H, Eisele P, Artemis D, Förster A et al. Acute Marchiafava-Bignami Disease with Extensive Diffusion Restriction and Early Recovery: Case Report and Review of the Literature, Journal of Neuroimaging. 2014; Vol 24 No 4. 8. Tekwani PH. Marchiafava-Bignami disease in chronic alcoholic patient. Radiology Case Reports II. (2016); 234-237 9. Caulo M, Briganti C, Notturno F, Committeri G et al. Non-Alcoholic Partially Reversible Marchiafava-Bignami Disease: Review and Relation with Reversible Splenial Lesions A Case Report and Literature Review. The Neuroradiology Journal. 2009; 22: 35-40. 10. 2 Hillbom M, Saloheimo P, Fujioka S, Wszolek ZK et al. Diagnosis and management of Marchiafava- Bignami Disease: A review of CT/MRI confirmed cases.J Neurol Neurosurg Psychiatry. 2014; 85(2): 168–173. 11. 1 Mestrinelli PE, Marques dos Santos MB, Piasecki L, Cezar JA. Marchiafava-Bignami disease: a rare entity with a poor outcome. Rev Bras Ter Intensiva. 2013; 25(1):68-72. 12. Tavares L, Freua F, Kok F. Chronic stage of Marchiafava –Bignami disease. Images in Neurology. 2015. 13. Namekawa M, Nakamura Y, Nakano I. Cortical Involvement in Marchiafava-Bignami Disease Can Be a Predictor of a Poor Prognosis: A Case Report and Review of the Literature. 2013; Intern Med. 52: 811-813. 14. Augusto L, Figueiredo R, Costa H, Reis C. Marchiafava-Bignami disease as a cause of visual hallucinations. Rev Bras Psiquiatr. 2015; 37:82–83. 15. Yadala S, Luo JJ. Marchiafava-Bignami Disease in a Nonalcoholic Diabetic Patient. Case Reports in Neurological Medicine. 2013. 16. Furukawa K, Maeshima E, Maeshima S, Ichinose M. Multiple symptoms of higher brain dysfunction caused by Marchiafava–Bignami disease in a patient with dermatomyositis. Rheumatol Int. 2011; 31:109–112. 17. Hoshino Y, Ueno Y, Shimura H, Miyamoto N et al. Marchiafava-Bignami disease mimics motor neuron disease: case report. BMC Neurology. 2013; 13:208. 18. Rickert CH, Karger B, Varchmin-Schultheiß K, Brinkmann B, Paulus W. Neglect-associated fatal Marchiafava-Bignami disease in a non-alcoholic woman. Int J Legal Med. 2001; 115: 90–93. 19. Consoli A, Pirritano D, Bosco D, Postorino P et al. Corticosteroid treatment in a patient with Marchiafava–Bignami disease. Neurol Sci. 2014; 35:1143–1145. 20. Kinno R, Yamamoto M, Yamazaki T, Owan Y et al. Cerebral microhemorrhage in Marchiafava– Bignami disease detected by susceptibility-weighted imaging. Neurol Sci. 2013; 34:545–548. 21. Heinrich A, Runge U, Khaw AV. Clinicoradiologic subtypes of Marchiafava-Bignami disease. J Neurol. 2004; 251 : 1050–1059. 22. Clavier E, Thiebot J, Delangre T, Hannequin D et al. Marchiafava-Bignami disease A case studied by CT and MR imaging. Neuroradiology. 1986; 28:376.
Revista Mexicana de Neurociencia November-December, 2017; 18(6):96-101 102 Editorial
Editorial
REVISTA MEXICANA DE NEUROCIENCIA NOVEMBER 2017
Dear Readers:
It is a pleasure to present this issue, in which you will find works showcasing the richness of Neurology. We have excellent contributions that make this edition especially important. We are also proud to share with you the news that Dr. Steven L. Lewis, Editor-in-Chief of Continuum Neurology® the most widely-read continuing education publication in the world, and Dr. Grisold Wolfgang, General Secretary of the World Federation of Neurology, have joined our Editorial Committee adding to the extraordinary group of international editors who are increasing the prestige of this publication.
In this edition, we present the clinical practice guidelines for the diagnosis and management of chronic inflammatory demyelinating polyneuropathy, developed by the neuromuscular diseases study group, led by Dr. Edwin Steven Vargas-Cañas and Dr. Erwin Chiquete. Their recommendations update us on adequate diagnostic and therapeutic approaches that best benefit the patient suffering from this painful condition—such as when to use steroids, human immunoglobulin, or plasmapheresis— and reports on the level of evidence of different options for immunomodulation from monoclonal to azathioprine.
Dr. Paul Carrillo-Mora and his collaborators present us with a very topical matter: subjective memory complaints and their associated factors in the geriatric population in Mexico. It shows us how mood—for instance, anxiety or depression—, low schooling, overweight, obesity, and other comorbidities favor amnesia while regular exercise and reading habits can prevent it.
Another original contribution is from Dr. Ramos-Galarza and collaborators on the executive and behavioral functions of high-school students in Ecuador, presenting the relationship with school performance. Dr. Aguilar-Fabre and her colleagues present a correlation between the electroencephalographic pattern, the etiology, and the outcome of neonatal epileptic seizures. Dr. Denise Medici and her colleagues review the state of
Revista Mexicana de Neurociencia November-December, 2017; 18(6):102-103 Editorial 103
health in children suffering from attention deficit hyperactivity disorder in relation to ophthalmological, otorhinolaryngological, metabolic, and respiratory aspects. It’s very interesting that those suffering from this problem may have comorbidities that must be addressed to avoid aggravating the problem and influencing their development.
We are honored to have in this issue the revision of exertion headaches by Dr. Julio Pascual from Santander, Spain. He is one of the experts in the field worldwide and we pride ourselves to have him as a distinguished member of this magazine’s International Editorial Committee.
A very attractive and educational review is presented by Dr. Ospina-García of the Movement Disorders Clinic led by Dr. Rodríguez-Violante. It transports us with a review of basal nuclei physiology and behavior exploring the fascinating tasks of sensory-motor, associative, and limbic circuits, the neurotransmitters involved in their functioning, and how they are modified by disease. We also have in this issue the second part of the review on infections affecting the nervous system by Dr. Valle-Murillo and Dr. Amparo-Carrillo, dedicated to the different aggregate infections suffered by the patient with acquired immunodeficiency. Finally, Dr. Miranda-Nava and colleagues present a case of an intriguing pathology affecting the corpus callosum due to wine consumption described at the beginning of the 20th century by Drs. Marchiafava and Bignami in Italy.
I am sure that this number will appeal to our readers. With it, we close a year in which the problems of the world have continued to grow and many people still suffer from disease and injustice, but medicine keeps looking for an opportunity to serve those in need of it and make a difference in the life of the patients and their families. Let us wish for a better year, and finish this one with the satisfaction of having fulfilled our duty and with the hope to do our best in the years to come.
Ildefonso Rodriguez-Leyva November 2017
Revista Mexicana de Neurociencia November-December, 2017; 18(6):102-103 e i a e icana e Neurociencia Publicación oficial de la Academia Mexicana de Neurología A.C.
Estimado Académico:
Por medio de la presente, es un gusto saludarle y extenderle la más cordial invitación a colaborar con la publicación de artículos de investigación original; básica, tradicional o aplicada, casos clínicos o artículos de revisión en la Revista Mexicana de Neurociencia, órgano oficial de difusión científica de la Academia Mexicana de Neurología.
Esta Revista ha sido incluida recientemente en el índice de revistas de CONACyT, y estamos trabajando para que pronto esté disponible en las plataformas OVID y SciELO, especialmente en PubMed.
Estamos seguros que su trayectoria académica le permitirá participar e invitar a colaborar a sus distinguidos colegas, que con su participación enriquecerán nuestra revista.
El Comité Editorial está formado por investigadores de diversas instituciones de nuestro país y del extranjero, que cuentan con reconocida calidad académica.
Esperamos que usted y cada integrante de la Academia Mexicana de Neurología se sientan parte y sumamente orgullosos de la Revista Mexicana de Neurociencia.
Reciba un cordial saludo. Atentamente,
Dra. Carolina León Dr. Ildefonso Rodríguez Dr. Antonio Arauz Co-Editor Editor Co-Editor Revista Mexicana de Neurociencia
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