International 2015; volume 7:5885

Amyotrophic lateral sclerosis: Introduction Correspondence: Marco Orsini, Programa de Pós- new perpectives and update Graduação em Ciências da Reabilitação, Praça The technological breakthrough in the field das Nações, 34, Bonsucesso, Rio de Janeiro, CEP: Marco Orsini,1,2 Acary Bulle Oliveira 3 of neurolog /neuroscience, with modern imag- 21041021, Brasil. Osvaldo J.M. Nascimento,1 , ing and genetic studies, may, sometimes, E-mail: [email protected] Carlos Henrique Melo Reis 1 make the neurologist stay away from indispen- Key words: Amyotrophic lateral sclerosis; neu- Marco Antonio Araujo Leite, 1 sable propaedeutic techniques for the correct rodegenerative diseases; diagnosis; treatment; 1 1 Jano Alves de Souza Camila, Pupe diagnosis of amyotrophic lateral sclerosis rehabilitation. Olivia Gameiro de Souza, 1 , (ALS). ALS is without doubt a disease of the Victor Hugo Bastos 4 , central (CNS), which its natu- Contributions: the authors contributed equally. Marcos R.G. de Freitas, 1 Silmar Teixeira 4 ral history is one of the darkest in neurology. A progressive, devastating and inexorable dis- Carlos Bruno 1 Eduardo, Davidovich 1 , Conflict of interest: the authors declare no poten- ease, commonly leads to death by respiratory tial conflict of interest. Benny Smidt3, , failure a few years after onset of first symp- 1Neurology Department, Universidade toms. Rowland,1 centuries ago, defines its nat- Received for publication: 25 February 2015. Federal Fluminense, Rio de Janeiro; ural history well by stating that any notifica- Accepted for publication: 15 June 2015. 2Programa de Mestrado em Ciências da tion of improvement in patients with this dis- This work is licensed under a Creative Commons ease deserves careful review, because probably Reabiitação – UNISUAM, Rio de Janeiro; Attribution NonCommercial 3.0 License (CC BY- 3Neurology Department, Universidade it is not a case of ALS. Prompt diagnosis, sen- NC 3.0). Federal de São Paulo – UNIFESP, São sitive communication of the diagnosis, the involvement of the patient and their family, Paulo; 4Neuroscience Department, ©Copyright M. Orsini et al., 2015 and a positive care plan are pre requisites for Licensee PAGEPress, Italy Universidade Federal do Piaiu, Parnaiba, good clinical management. While ALS is an Neurology International 2015; 7:5885 Brazil incurable disease, many symptoms are doi:10.4081/ni.2015.5885 amenable to supportive and adjunctive thera- only pies, some of which may even improve the dis- U.S. alone.6 A high prevalence of ALS cases is ease course.2 Nowadays, ALS is considered a reported in certain geographical areas, for Abstract multisystemic disease with broad pathophysio- example the Pacific island of Guam (50 times logical framework and numerous theoriesuse that that of ALS in western countries), leading to Amyotrophic lateral sclerosis (ALS), surround it, hampering a unique therapeutic speculation about environmental and genetic target.3 These pathophysiological mechanisms Charcot’s disease or Lou Gehrig’s disease, is a factors as potential triggers for ALS. People include oxidative stress, mitochondrial impair- term used to cover the spetrum of syndromes over fifty are the most affected. Men are affect- ment, protein aggregation, cytoskeletal disrup- caracterized by progressive degeneration of ed nearly twice as often as women, with no motor neurons, a paralytic disorder caused by tion, glutamate and neuronal cytotoxicity, altered regulation of gene expression, inflam- racial differences. motor neuron degeneration. Currently, there 7 mation, and apoptotic cell death. An under- A study by Orsini et al., that aimed to delin- are approximately 25,000 patients with ALS in eate the clinical and functional profile of the USA, with an average age of onset of 55 standing of how these potential therapeutic patients with ALS in Brazil and compare with years. The incidence and prevalence of ALS are targets interrelate will provide direction both other regions of the world, identified a rapid 1-2 and 4-6 per 100,000 each year, respectively, in the development of a pharmacotherapy and 4 depletion of functional capacity, muscle with a lifetime ALS risk of 1/600 to 1/1000. It in the design of clinical trials. Countless experts in the field, for example, the group strength, swallowing and breathing pattern. In causes progressive and cumulative physical conducted by Oliveira and Pereira,5 consider that study, the onset of ALS is often insidious disabilities, and leads to eventual death due to that a combination of drugs focused on more and can manifest by unexplained trip or motor respiratory muscle failure. ALS is diverse in its than one pathogenic pathway may slow dis- disabilities, usually in the distal arm. Some presentation, course, and progression. We do ease progression in an additive or synergistic not yet fully understand the causes of the dis- patients with bulbar onset have difficulty in Non-commercialfashion. It is noteworthy that such combina- ease, nor the mechanisms for its progression; swallowing and changes in voice tonality. The tion therapy has been successful in oncology, thus, we lack effective means for treating this time between the onset of first symptoms and though multiple drug interactions and seeking care services was 11.6±12.4 months. disease. In this chapter, we will discuss the increased incidence of drug side effects should diagnosis, treatment, and how to cope with The time between the first symptoms and the be considered. The risk for benefit ratio should diagnosis was 20.5±8.4 months. The author impaired function and end of life based on of also be considered. demonstrates that the findings related to ALS our experience, guidelines, and clinical trials. Histopathological findings reveal an impair- presentation in the subgroup of European Nowadays ALS seems to be a more complex ment of the motor neurons of the pyramidal countries (Italy, Germany, Spain) have some disease than it did two decades – or even one beam, the and in varying decade – ago, but new insights have been plen- degrees. Although ALS are readily recognized similarity with the characteristics of other tiful. Clinical trials should be seen more as by neurologists, about 10% of patients are mis- industrialized countries as, for example, in experiments on pathogenic mechanisms. A diagnosed, and delays in diagnosis are com- Brazil. To sum up, ALS is part of the so-called medication or combination of medications that mon.5 (MND) disease, along targets more than one pathogenic pathway The disease has several features in the dif- with progressive spinal amyotrophy (PSA) and may slow disease progression in an additive or ferent presentation forms, course and progres- primary lateral sclerosis. The progressive bul- synergistic fashion. sion. The incidence is approximately two cases bar palsy (PBP), does not fail to take part in per 100,000 inhabitants, which represents the spectrum of presentation of classical ALS, approximately 5000 patients per year in the so, it should be studied together.8

[Neurology International 2015; 7:5885] [page 39] Review

anterograde and retrograde axonal transport, onset is slow and progressive, alveolar Classification and microglial activation, , and hypoventilation typically goes undiagnosed physiopathogenesis growth factor deficiency. and untreated until an episode of acute respi- Several factors are proposed to instigate ratory failure occurs. This episode of decom- The ALS cases can be classified into spo- these phenomena, including latent infections pensation is frequently seen during common radic, familial, and from the western Pacific by viral and non-viral agents, toxins (for exam- upper airway infections, and it results from (ALS and - Complex), ple, insecticides and pesticides) and autoim- patient incapacity to eliminate secretions. At 9 the latter very common in Chamorro people of mune reactions. Genetic factors, changes in the moment that the ventilatory muscles are Guam and Marianas island, the Kii peninsula intracellular calcium levels in motor neurons, compromised, individuals present pulmonary of Honshu Island, and the Auyu and Jakai peo- and programmed cell death (apoptosis) have restrictions, characterized by reduced vital 12,13 ple of south west New Guinea. In around 5-10% also been linked to the development of ALS. capacity (VC) and tidal volume (TV) with con- there is evidence of family history (familial sequently chronic respiratory failure. ALS), and, approximately 20% of these variants Atelectasis, pneumonia and respiratory failure, are linked to the gene encoding the enzyme initially during sleep and later on even during copper-zinc superoxide dismutase (Cu-Zn Clinical profile wakefulness, are the complications expected 21 SOD1), and 2-5% have mutations of TARDBP in this situation. (TDP-43) gene. The clinical presentations of patients do not ALS can produce sleep alterations, since Commonly these cases show Mendelian follow a pattern, although some initial mani- alveolar hypoventilation is more intense dur- autosomal dominant inheritance. However, festations are present in most cases. ing sleep. The worsening of alveolar air autosomal recessive patterns have also been Unexplained tripping (slight foot drop) with or exchange presents subtle symptoms that can identified.8 Investigations of mutant SOD1 without episodes of falls in addition to impair- pass unnoticed if not directly analyzed. have illuminated crucial components of the ment of dexterity in distal crural are usually Hypoventilation during sleep can initially man- death process including: a propensity for recounted by patients. This situation trans- ifest as a progressively increasing number of mutant SOD1 to be unstable; a multiplicity of lates into an involvement of the motor cells of nighttime awakenings, fatigue, daytime 22 mitochondrial defects that predict cellular the anterior horn in L4 and C8-T1 segments sleepinessonly and morning . In ALS, energy failure, enhanced glutamate sensitivity respectively. Unfortunately, when muscle 30% of patients begin with bulbar symptoms and activation of the machinery of pro- weakness becomes noticeable, patients have including dysphagia, dysarthria, dyspnea and grammed cell death; and a role for non-neu- lost about 80% of the motor neurons in the cor- changes in phonation. It is unclear whether ronal cells as modulators of neuron death.9 responding myotomes. the bulbar involvement implies the simultane- Recently a mutation in the gene coding for the The degree of involvement of the pyramidaluseous deterioration of the four functions or if protein VAPB (vesicle-associated membrane beam and the ventral horn is variable and non- they may have an independent evolution. protein-associated protein B), mapped at standardized. However, the fact of muscles that Among these, dysphagia is one of the most 20q13.3, was reported in a large white control eye movements and the urinary sphinc- important problems faced in ALS, not uncom- Brazilian family with ALS cases and traced to a ters are spared. Cramps and fasciculations are mon as the initial symptom. The presence of common ancestor from the time of contact frequent. Before long, the triad of cadaveric dysphagia and the aspiration pneumonia with Portugal.5 Recently mutations in the gene hands (atrophic weakness), hyperreflexia and report are usually the biggest damages to the FUS with involvement of TDP-43 and FUS pro- spasticity – usually in absence of sensory quality of patients’ life, in addition to the risk teins have been described. These cases are changes – leaves little doubt as to diagnosis. It of malnutrition and dehydration, occurring usually associated with frontotemporal atro- Is worth mentioning that although dominated particularly in elderly.23 To sum up, the majori- phy. Sporadic ALS differs from familial ALS in by motor dysfunction, there is increasing evi- ty (65%) of patients present limb symptoms, some aspects. In sporadic ALS symptoms onset dence that ALS is a multisystem disorder in while 30% present symptoms of bulbar dys- usually occur around the age of 55-65 years, which the autonomic system, spinocerebellar function in the form of dysarthria or dyspha- with a mean of 64 years old; it is more preva- tracts, dorsal columns, basal ganglia and gia. 5% of patients have respiratory-onset dis- lent in men than in women (1.5:1), probably extramotor cortex may also be affected.14-17 ease. Initial symptoms of weight loss and iso- due to a hormonal protection in women and a The occurrence of cognitive decline in ALS, lated emotional lability have also been report- greater exposure among men to supposedNon-commercial risk especially in the form of frontotemporal ed.24 In some cases of ALS, the characteristic factors; it also presents a mortality of 1.84 per dementia (FTD), notably with the behavioural combination of upper motor neuron and lower 100,000 inhabitants. Differently, in familial variant FTD, has been described previously. motor neuron abnormalities may be absent, ALS the age of onset of symptoms varies Recent molecular biology and histopathology leading to diagnostic uncertainty for months or between 45-55 years, and the prevalence is data suggest that both ALS and FTD may share years.25 It was not found in the literature a similar between men and women, with a lower common pathological pathways and may pres- work that addressed all major emergency care life expectancy. Both forms of the disease are ent two phenotypes of the same proteinopathy. in ALS for professionals in the health field. The similar in clinical and pathological presenta- Cognitive decline in ALS is characterised by Canadian Society has created a guideline for tion.10 As stated previously, endogenous and personality change, irritability, obsessions, ALS patients living with ALS, which contains environmental factors appear to be interrelate poor insight, and pervasive deficits in frontal explanations of the disease, where to find and contribute to the development and evolu- executive tests.18,19 help, signs and symptoms, mobility and inde- tion of the disease neurotoxicity that ultimate- The association between neuropathy and pendence, among other items geared to the ly culminates with the depletion of motor neu- ALS has been reported rarely and the line dis- patient and caregivers not portraying there- rons.11 Amongst others these include: oxida- tinguishing from motor neuropathies is some- fore, conducts to be taken by professionals in tive stress, excitotoxicity mediated by gluta- times blurred. Among MND (Motor Neuron the health field in cases of emergency.26,27 mate, toxic effects caused by the mutation of Diseases), the Patrikio’s pseudopolyneuritic super oxide dismutase (SOD1), inclusion of form of ALS strictly mimics a kind of neuropa- Progressive muscular amyotrophy the abnormal protein aggregation, intermedi- thy.17,20 Neuromuscular diseases, as seem in Progressive muscular amyotrophy (PMA) is aries filaments disorganization, changing the ALS, lead to alveolar hypoventilation. When the a heterogeneous syndrome that overlaps with

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ALS. Although it is considered to carry a better emotional lability and early evolution of the prognosis than typical ALS, approximately 30% respiratory muscles progressing to death Routine investigation of patients with PMA develop upper motor neu- around 6 months to 3 years of age.8,33,34 ron signs within 18 months, and progress to a Routine investigation of a patient with diagnosis of ALS. Corticospinal tract involve- apparently typical ALS should include meas- ment is demonstrated on autopsy in up to 50% urement of erythrocyte sedimentation rate, of patients with an initial diagnosis of PMA.28 Diagnostic criteria serum and urine protein electrophoresis, thy- Clinical manifestation is characterized by the roid function tests, serum calcium and phos- involvement of lower motor neurons. It is There is no definitive diagnostic test for phate measurements, and genetically determined, with the absence or ALS. The combination of suggestive clinical analysis. Infection-related tests: syphilis; mutation of the survival motor neuron 1 signs with negative laboratory tests and imag- Lyme; HIV; HTLV-1 and 2; hepatitis B and C are (SMN1) as a hallmark. A similar copy of the ing studies for other pathologies supports the necessary; muscle enzymes: CK; ALT; AST; SMN1, named SMN2, modulates the severity of diagnosis, although disease progression is a LDH.5 Image evaluation is composed by: mag- the disease. Several types of the disease have pre requisite. The two conditions most com- netic resonance investigation (brain and been described along with several classifica- monly mistaken for ALS are multifocal motor spine); DNA evaluation (SOD1, VAPB, tion systems based either on the age at onset neuropathy with conduction block, and cervical Kennedy’s disease – expansion of trinu- of symptoms or on the maximum function spondylotic . Differentiating multi- cleotídeo GCC on chromosome X). A heavy achieved. PMS presents itself in a wide clinical focal motor neuropathy from ALS is especially metal screen should be performed in individu- spectrum ranging from death in infancy (PMA important, as patients with this neuropathy als with a potential history of exposure. -hex- type I) to a natural history characterized by may benefit from intravenous immunoglobulin osaminidase deficiency (Tay-Sachs disease) is only slight muscle weakness, with survival to treatment. Generally, patients with common common in some ethnic groups, and can adulthood (PMA adult onset). Currently, facing mimic syndromes do not progress as rapidly as mimic ALS. -hexosaminidase subunits and a phenotype suggestive, genetic study is per- those with ALS, and tend to survive for longer activity should be tested in patients of formed to detect homozygous deletion of exons periods. Spinobulbar muscular atrophy Ashkenazi Jewish extraction.5 7 and 8 of SMN1 gene, with a sensitivity of (Kennedy disease) is also often misdiagnosed Electrodiagnostic studies are the most criti- about 95% and 100% specificity in the diagno- as ALS. Kennedy disease is an X-linked disor- calonly ancillary tool in the investigation of ALS. sis of PMA.29,30 Araújo described the clinical der associated with an expansion of trinu- Electromyography can identify loss of lower findings of patients with spinal muscular atro- cleotide repeats in the androgen receptor motor neurons, the hallmark of ALS, and it is phy (SMA) with survival motor neuron (SMN) gene. The clinical features of this condition particularly useful in clinically unaffected gene deletion.31 All of the 22 included patients include slowly progressive lower motoruse neuron regions. The most frequently recognized had symmetrical muscle weakness, which was signs in the bulbar region and proximal limbs, abnormalities observed on electromyography diffuse in those with onset of symptoms up to and 50% of affected patients have gynecomas- are fasciculation, spontaneous denervation 6 months of age (75%), and either proximal or tia. A pure lower motor neuron syndrome with discharges (fibrillation potentials and positive predominant in lower limbs in the remaining a family history demonstrating no male-to- sharp waves) indicative of ongoing motor neu- group (67%). Fasciculations and atrophy were male inheritance should, therefore, alert the ron loss, and polyphasic units indicative of both frequent findings (82%). Laboratory tests physician to this possible diagnosis.35-37 reinnervation.The measurement of central findings were variable, with positivity of 57% Several diagnostic criteria for ALS exist, motor conduction has been refined and may, for electrophysiology and of 58% for muscle namely, El Escorial criteria revised and today, through transcranial electrical stimula- biopsy. Lambert criteria, however, these criteria may tion of the motor area, verify the slow transi- not be useful in early diagnosis. In December tion through the I motor neuron. This exam Primary lateral sclerosis 2006, researchers around the globe met in can be useful in cases that the suffering from Upper motor neuron involvement predomi- Awaji Island, Japan to discuss about proposing pyramidal tract is not clinically evident.40 nates clinically in patients with PLS, although, a recent rationalisation of the El Escorial crite- in some cases, slight lower motor neuron ria (the Awaji consensus) to facilitate detec- symptoms may be present. Clinical features tion of ALS in an early stage.36 The Awaji- include severe spasticity with slight weakness Shima criteria was introduced in 2008, use of Differential diagnosis in the lower limbs and eventually Non-commercialpseudobulbar which improved diagnostic sensitivity without symptoms (dysarthria and compulsive laugh- increasing false-positive rates (Table 1).38 In patients diagnosed with ALS, theabsence ing or crying). The course of the disease is Carvalho have tested the sensitivity of a of disease progression, the presence of an atypi- slowly progressive. Pathologically, a selective recently published approach to combining clin- cal history, or the presence of unusual symp- involvement of the motor cortex is seen with ical and EMG data in the research diagnosis of toms should trigger a search for mimic syn- degeneration of the Betz cells and demyelina- ALS, in 55 consecutive patients clinically diag- dromes. Generally, patients with common tion of the descending motor tracts. Primary nosed with ALS.39 The application of this Awaji mimic syndromes do not progress as rapidly as lateral sclerosis can be distinguished from ALS algorithm to the revised El Escorial diagnostic those with ALS, and tend to survive for longer by the long duration of the disease, the exten- criteria for diagnosis of ALS, achieved a diag- periods.41 sive cortical atrophy and the considerable pro- nostic sensitivity of 95% for definite ALS com- Considering the clinical and laboratory find- longing of the motor evoked potential (MEP). pared with 18% using the clinical El Escorial ings, the motor neuron diseases have been Motor nerve conduction velocity in PLS is nor- criteria and 53% when the EMG criteria as classified as ALS/DNM (sporadic cases, family mal or prolonged.32 defined in the El Escorial criteria. This or genetically determined), ALS-plus syn- increased sensitivity was particularly relevant dromes (multisystem neurodegenerative dis- Progressive for bulbar onset patients (sensitivity improved ease affecting motor neurons), the ALS-related We consider ASL and progressive bulbar from 38% to 87%) and for patients with El syndromes (represent symptomatic or second- palsy the same pathological entity. PBP pre- Escorial clinically possible ALS (from 50% to ary forms of motor neuron disease, with a dominates in females being characterized by 86%). known associated condition that may be caus-

[Neurology International 2015; 7:5885] [page 41] Review ing the disease) and the ALS variants (are Clinical treatment: therapeutic tar- uncommon unless the patient lives in particu- gets and control-submitted symp- Management of respiratory lar geographic locations) (Table 2).41-44 Some problems clinical features are inconsistent with the tomatology diagnosis of ALS, although still possible, they We reinforce that although ALS has no cure. The indication of NIV (non-invasive ventila- are: anterior visual pathway abnormalities, Symptom control and anticipation of clinical tion) in ALS patients has been recommended autonomic nervous system dysfunction; cogni- problems are extremely important for this when there is a reduction of 50% of the pre- tive abnormalities associated with Alzheimer’s clientele. Many doctors believe that even today dicted value for forced vital capacity (FVC), disease; movement abnormalities associated the provision of an early diagnosis does not and/or a decrease of SpO below 88% for more with Parkinson’s disease; sensory disturbance; change the patient’s history as far as the dis- 2 sphincter abnormalities. As mentioned previ- ease goes. Fortunately, this fact is not true, than five consecutive minutes during the night ously, recent studies suggest that the patho- since there is strong evidence that early detec- and/or increased partial pressure of oxygen in genic processes of ALS LS are more extensive, tion prolongs survival of patients.45 Other pro- arterial blood (PaCO2) greater than 45 mmHg involving dysfunction of cortical grey and fessionals still wonder if such survival is with and/or increase in maximal inspiratory pres- white matter with clinical correlates of impair- good quality of life. Unfortunately our role is to sure of inspiratory muscles (MIPIM) above ment in cognition and language. In reality, at provide the best in the treatment and con- −60 cm H2O. Besides these, there are indica- least a subgroup of ALS LS patients experience tribute to mitigating their pain. Considering tions related to possible signs and symptoms personality changes and cognitive problems the quality of life, it is variable and changeable such as: dyspnea, fatigue, morning , consistent with fronto-temporal dementia between ALS patients during the natural histo- aggravated sleepiness among others. (ALS LS-FTD).5 Reports suggest that in some ry of the disease. Respiratory failure and pulmonary complica- specific settings (especially in monomelic A good doctor monitors the patient towards tions of bulbar paralysis (i.e. aspiration pneu- forms, ALS syndrome and some neuropathies), their difficulties. Unfortunately, riluzole monia) are the most common causes of death a search for HIV infection is warranted, espe- remains the only evidence-based disease-mod- in ALS.47,48 cially in young individuals.44 ifying drug for ALS.46 Despite being a palliative care, the applica- tion ofonly NIV in ALS patients can improve quality use

Table 1. El Escorial and Awaji-Shima criteria. Criteria Definite ALS Probable ALS Possible ALS Suspected ALS El Escorial Upper and lower motor Upper and lower motor neuron signs Upper and lower motor neuron Lower motor neuron neuron signs in 3 regions in at least 2 regions, with upper motor signs in 1 region, upper motor signs only, in 2 neuron signs rostral to lower motor neuron signs alone in 2 or more regions neuron signs or more regions, or lower motor neuron rostral to upper neuron signs Awaji-Shima Clinical or electrophysiological Clinical or electrophysiological evidence, Clinical or electrophysiological NA evidence, demonstrated by the emonstrated by upper and lower signs of upper and lower motor presence of upper and lower dmotor neuron signs in at least 2 neuron dysfunction in only 1 region, motor neuron signs in the spinal regions, with some upper or upper motor neuron signs alone bulbar region and at least motor neuron signs necessarily in 2 or more regions, or lower motor 2 spinal regions, rostral to the lower motor neuron signs neuron signs rostral to upper motor or the presence of upper neuron signs and lower motor neuron signs in 3 spinal regionsNon-commercial ALS, amyotrophic lateral sclerosis; NA, not available.

Table 2. Differential diagnoses of amyotrophic lateral sclerosis. Hereditary conditions Spinobular muscular atrophy (Kennedy disease); hereditary spastic paraparesis; acid maltase deficiency; facioscapulohumeral muscular dystrophy; adrenomyeloneuropathy; Huntington disease; hexosaminidase deficiency Metabolic conditions and toxic effects Hyperthyroidism; hyperparathyroidism; heavy metal intoxication; lathyrism; organophosphate toxic effects Immune and/or inflammatory conditions Multifocal motor neuropathy with conduction block; chronic inflammatory demyelinating polyneuropathy; myasthenia gravis; inclusion body myositis; polymyositis; ; paraneoplastic disorders Structural disorders Cervical spondylotic myelopathy; or syringobulbia; postirradiation myelopathy and/or plexopathy; tumor - Other neurodegenerative diseases Corticobasal degeneration; ; progressive supranuclear palsy; Parkinson disease; Huntington disease Other motor neuron diseases Primary lateral sclerosis; progressive muscular atrophy; ; post- spinal muscle atrophy; benign fasciculation syndrome; Hirayama disease Infections diseases HIV; HTLV; Lyme disease; Syphilis

[page 42] [Neurology International 2015; 7:5885] Review of life and prolong survival in some cases, in demonstrates the need for early and specific course of ALS, but this treatment achieves only more than 12 months in patients with impair- nutritional care at every stage of the disease. It a modest improvement in survival (3-6 ment of respiratory function. Eventually, when is possible to do body energy reserve in months). The recommended dosage of the the need for HMV exceeds 16-20/24 hours, patients with ALS by minimizing significant drug is 100 mg/day, split into two dosages of 12 some centers would consider a change to inva- loss of lean body mass and total body fat.49 hrs/day. This drug seems to be well tolerated, sive ventilation. Tracheostomies hinder the Nutritional support comprises the early although it has some side effects such as: normal defense mechanisms of the trachea, detection of the decrease in food intake, par- asthenia, nausea, vomiting, dizziness, drowsi- increase secretion, rapidly colonize with diffi- ticularly in kilocalories, the change in the con- ness and perioral paresthesia. Cases of pneu- cult to control germs, impede swallowing and sistency of the diet and the early indication of monitis have been reported following the use impair speech.22 A more proactive attitude to alternative feeding ways. The alternative feed- of the drug. Patients may show an increase of treat respiratory infections, avoiding broncho- ing ways of patients with ALS include gastros- hepatic markers, therefore, a control of liver pneumonia and/or pneumonia conditions, tomy or jejunostomy. The advantages of gas- function in an average period of three months could have a significant impact on survival. trostomy include improved nutrition, although is necessary. In case of significant increase, Patients should also participate in the annual evidence to support a substantial effect on sur- the drug should be discontinued. After demon- vaccination campaign against influenza and vival remains to be firmly established.50 strating of decline in mortality, Riluzole, most other infectious agents (Table 3). The guidelines for nutrition as well as the likely related to its anti-excitotoxic properties, directives for implementation of enteral nutri- was approved by the United States food and tion/parenteral follow in Table 4.51,52 Drug Administration in December, 1997. Later meta-analysis indicates that the effect was Dysphagia management and Speech management real, and that there may have been a small support in amyotrophic lateral When speech can no longer be understood, effect on function (Table 5).55,56 sclerosis nutrition adaptive strategies such as sign language, mime, posture and alternative communication Drugs used for control of symp- by computer systems, may be used by patients toms Drooling, dehydration, malnutrition with with ALS. Most devices now offer a range of weight loss and aspiration are all associated onlyWe alert that the therapeutic options for the access methods, starting with keyboards, management of clinical problems presented by with dysphagia.5 ALS patients, especially with touch screens, a head mouse, and Morse patients with ALS is wide, therefore, we men- bulbar involvement, demonstrate more severe code.53,54 problems swallowing (such as aspiration). tion just a couple of drugs that can attenuate 57 Early leak is more common with thin liquids use them (Table 6). and a major cause of tracheal aspiration, even Emergency situations in amy- at early stages of the disease and mild abnor- Therapeutic trials in amy- malities of the oral musculature. Swallowing otrophic lateral sclerosis alterations occur due to the inefficiency of oral otrophic lateral sclerosis In cases of respiratory failure, it is common transit, the reduction of the movement of the Riluzole in ALS patients to arrive at emergency depart- tongue base, laryngeal elevation and anterior- ments where healthcare professionals ignor- ization reduction and pharyngeal contrac- Riluzole is a benzothiazole derivative that ing the concept of ventilation failure, treat the tion.49 The loss of body weight associated with modulates glutamatergic activity, thereby sup- symptoms with the administration of oxygen. bulbar disorders (dysphagia and breathing), pressing excitotoxicity. This drug modifies the This leads to an exacerbation of hypoventila-

Table 3. Respiratory guidelines. Respiratory function Indications for non-invasive ventilation and tracheostomy Non-invasive ventilation Reduction of 50% of the predicted value for forced vital capacity; decrease of SpO2 below 88% for more than five consecutive minutes during night; increased partial pressure of oxygen in arterial blood greater than 45 mmHg; Non-commercial increase in maximal inspiratory pressure of inspiratory muscles above −60 cm H2O. Dyspnea, fatigue, morning headache, aggravated sleepiness among others. Tracheostomy When the need for home mechanical ventilation exceeds 16-20/24 hours Respiratory therapy The selection of physical therapy techniques , the work at submaximal limits, the variation in time of application, in addition to particular features of the patients are essential Vaccination schedule Influenza and Pneumococcal must be performed (unless there are specific contraindications).

Table 4. Guidelines for nutrition and directives for implementation of enteral nutrition/parentera. General guidelines Patients that feed or are fed quickly, are more susceptible to episodes of bronchial aspiration. Food should be well cut. Nutritional supplementation is necessary. ALS patients may have increased nutritional requirements, since they have loss of total body mass, even in the presence of adequate protein-calorie intake. To offer powder supplementing diluted in whole milk, or adding fruit in its preparation seem to be good strategies. For patients with frequent gagging, thickeners should be introduced in liquids. Soft food is easier to swallow and should be encouraged. Offer food in small amounts at regular intervals. Percutaneous endoscopic gastrostomy Such procedure should be considered when weight loss of over 10%; severe dysphagia; inadequate energy intake; functional vital capacity of less than 50% of predicted; history of aspiration and a body mass index of less than 20 Speech therapy Early detection of these disorders allows speech therapists to objectively evaluate functional impairment and set realistic goals of rehabilitation

[Neurology International 2015; 7:5885] [page 43] Review tion and sudden failure with subsequent need ment and prevention of breast carcinoma its ability to inhibit protein kinase C, which for intubation (rarely necessary for these dependent of hormonal regulation, because it mediates inflammation in spinal cords of patients) or even death. In these cases one is a selective estrogen-receptor modulator patients with ALS.59 The serendipitly way, in a should remember that the important thing is (SERM). Despite its effectiveness depend on patient with breast cancer and ALS who was to ventilate and not oxygenate the patient. Also the metabolic activation of this prodrug, pre- treated with tamoxifen experienced marked it is emphasized the importance of manual and dominantly via cytochrome P450 2D6, the slowing in progression of the ALS. The drug mechanical aid to the cough through the air- active metabolite endoxifen and 4-hydroxyta- was well tolerated in both sexes and data from stacking, abdominal press or cough assist moxifen. Tamoxifen has an anti-estrogen an extended follow-up period, suggested that (auxiliary cough) made by health profession- action by binding to the first receptor of estro- patients receiving 20 to 40 mg per day may als when patient does not reach the minimum gen than estrogen, the level of the tumor cell have longer survival compared to patients flow of cough: 160l/min or 2.7 l/sec.26 itself. If we are considering an estrogen- receiving only 10 mg per day (Dr. Ben Brooks, dependent tumor, tamoxifen will prevent the reported at the 15th International ALS/MND binding of estrogen and, consequently, the Symposium, Philadelphia, 2004).56 tumor is decreasing. It is also believed that Study medications for patients tamoxifen affects the most important factor in with amyotrophic lateral scle- the regulation of angiogenesis is vascular endothelial growth factor (VEGF). Therefore, it Stem cells in patients with rosis: tamoxifen is considered that the drug prevents tumor- amyotrophic lateral sclerosis induced angiogenesis.58 On the other hand, Tamoxifen is an important drug in the treat- propably has neuroprotective action because of The relentless pursuit of treatment for this

Table 5. Medications and therapeutic targets. Medicamento Mechanism of action Posology Side effects Target Riluzole* Modulates glutamatergic activity 100 mg/day in 2 dosages of 50 mg Conditions of elevated liveronly enzymes, Alleviate neuronal death suppressing excitotoxicity and pneumonitis are the most serious side effects Lithium** Activation of autophagy and na Daily doses, leading to plasma levels Acne, itching, confusion, dry mouth, Increased autophagy of increase in the number of the ranging from 0.4 to 0.8 mEq/liter, memory problem, loss of apetite, abnormal cellular mitochondria in motor neurons delay disease progression in human Delirium,use siarrhoea components and potentiation and suppressed reactive patients affected by ALS of mitochondrial activity astrogliosis *The only drug that modifies the course of ALS, increasing survival in a short period of time. **Despite its use in animal models have been successful, the risk-benefit ratio in humans is still not satisfying.

Table 6. Therapeutic options for the management of clinical problems presented by patients with amyotrophic lateral sclerosis. Clinical problems Drug and/or guidelines Sialorrhea Botulinum toxin type B; Tricyclic antidepressants (Amitriptyline) Pain (commonly triggered by contractures, Non-narcotic analgesics, and antispasticity agents (baclofen) for initial treatment. immobility or associated with spasticity) Administer opioids liberally, following the WHO HO guidelines, when non-narcotic analgesics fail. Physiotherapy is also necessary for management of conditions (stretching, passive mobilisations and Transcutaneous Electrical Neurostimulation) in some cases Bowel function (commonly is not affected in ALS, Increased Hydro Intake, Increased Intake of Dietary Fiber or even use of compost (sachet) Fibers. however paresis of the abdominal muscles, on the part of patients) Fasciculations (do not harm patients functionally, Gabapentin; other drugs used are also phenytoin and pregabalin. however they are subject of and irritability There comes a moment that fasciculations cease in patients with ALS, on the part of patients) Non-commercial because they are due the frustrated attempt of reinnervation. When the muscles become totally denervated, such mechanism does not happen. Excessive and strenuous physical activities in patients with ALS may potentiate deflagrate fasciculations Fatigue (several mechanisms are associated with Amantadine is an example of medicine for this purpose. Antidepressants such as venlafaxine are fatigue in patients with motor neurone disease, also used. Other strategies for easing of fatigue are quality and duration of sleep. Also, to avoid which can be of central or peripheral origin) exhaustive and strenuous physical activities during rehabilitation and rest periods during the day are needed, saving energy for priority activities Depression (by the tragic outcome of ALS, Despite existing several medications for this purpose, we chose to mention the SSRI e Tricyclic it is common for many patients to have antidepressants. Patients may also experience emotional lability, most often controled with the use episodes of depression) of SSRIs. We emphasize that psychotherapy is also extremely important for this clientele. Families and caregivers should, if possible, actively participate in this process. Cramps (patients with ALS may present episodes Vitamin E and diazepam are widely used drugs for this purpose. Other medications may also be used, of cramps or rest or when performing for example clonazepam. Stretching and massage therapy can also be performed by the functional activities) physiotherapist Spasticity (patients with spastic muscle groups The use of Baclofen has been proved to be effective in the management of spasticity in some cases. can experience pain and myo-joint contracturesin When patients have severe contractures and severe spasticity uncontrolled by the use of oral addition to loss in performing basic and instrumental medications, botulinum toxin type A may be an alternative treatment. The physiotherapist plays an activities of daily living) important role in the management of spasticity through stretching, weight transfer and other manual. 10-60 mg TID

[page 44] [Neurology International 2015; 7:5885] Review inexorable condition has been based on solid spinal fluid of patients with ALS without evi- 2007;6:913-25. principles related to probable multiple and cer- dence of clinical improvement, nevertheless 3. Goodall EF, Morrison KE. Amyotrophic lat- tainly not mutually exclusive physiopathologic consider the procedure safe.65 Within this line eral sclerosis (motor neuron disease): pro- mechanisms, the complex interaction of of conduct the use of stem cells in the setting posed mechanisms and pathways to treat- genetic, epigenetic, metabolic and pathophysi- of ALS has at least two well-established theo- ment. Expert Rev Mol Med 2006;8:1-22. ological factors that can initiate or propagate retical principles. The differentiating cells in 4. Ciesler J, Sari Y. 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only use

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