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Journal of Neurology Research

Review

Volume 3, Number 1, February 2013, pages 1-11

Patient Care and Treatment in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons in the cerebral cortex, brainstem and spinal cord, leading to limb paralysis and respiratory failure. Patient care and therapy of ALS has considerably amended over the past two decades. Recently, three effective treatments have been recommended for prolonging survival in ALS patients: multidisciplinary team care, mechanical ventilation and gastrostomy tubes [1, 2]. Although ALS is considered as an incurable disease, many symptoms occurring during the disease course are treatable. All efforts should be made to improve quality of life and to assist in keeping the patient’s autonomy. Advanced directives on end of life care, respiratory and nutritional management during late stages of life are important issues. ALS patients and their relatives need to discuss at the earliest opportunity that they are willing to do those management. They often suffer from depression, feelings of hopelessness and anxiety regarding end-of-life problems following the diagnosis of ALS or with the disease progresses [3, 4]. Therefore, psychological counsel and palliative care should be offered to the patients and relatives early [1, 2, 5, 6]. This review introduces current treatment in ALS patients at the following four divisions: symptomatic treatment; ventilation; nutrition; and disease modifying medication.

ALS patients develop numerous manifestations and problems during the disease course. Symptomatic treatment aims to improve quality of life in ALS patients and their caregivers. Main symptoms of ALS patients and those medications are summarized in Table 1. Physicians need to monitor and care for these symptoms from the early stage of ALS.

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Table 1. Symptomatic Treatments in ALS Patients

Respiratory insufficiency occurs commonly in ALS patients and it is a major cause of mortality. Clinical symptoms due to respiratory muscle weakness include dyspnoea on exertion or talking, orthopnea, disturbed sleep, excessive daytime somnolence, morning headaches, fatigue, anorexia, depression, poor concentration, vivid nightmares and nocturia. Clinical examination reveals tachypnea, use of accessory breathing muscles, paradoxical movement of the abdomen, weak cough and rarely papilledema [5, 7]. The forced vital capacity (FVC) is the most widely used for measurement of respiratory function in ALS [8], and it was a significant predictor of survival [9]. Measurement of the Sniff nasal inspiratory pressure (SNIP) is a useful parameter for the diaphragmatic strength. SNIP is probably more accurate than vital capacity, although both measurements are unable to estimate respiratory function accurately in patients with bulbar palsy. Published guidelines for respiratory care were based on clinical experience, expert opinion, and observational research [7, 10, 11]. Recently, the American Academy of Neurology (AAN) ALS Practice Parameter recommends consideration of noninvasive ventilation (NIV) when patients have orthopnea, SNIP < 40 cm or maximal inspiratory pressure < -60 cm, abnormal nocturnal oximetry or FVC < 50% (Fig. 1) [1]. Otherwise, patients with FVC ≥ 70% occasionally develop respiratory failure. Therefore, FVC ≤ 75% is probably more appropriate for earlier monitoring of respiratory symptoms [2-14]. SNIP < 25 cm H₂O is highly predictive of respiratory failure [15]. Overnight oximetry can detect episodes of nocturnal hypoventilation [16]. Ventilator support is usually provided by NIV without tracheostomy. Bi-level positive pressure devices are commonly used in NIV, whereas continuous positive pressure ventilation is not usually helpful [17]. NIV initially applied for intermittent nocturnal support to alleviate symptoms due to nocturnal hypoventilation. When respiratory function worsens, patients tend to require daytime support and eventually continuous support. Observational studies and a recent randomised controlled trial involving 92 ALS patients show that NIV improves survival and quality of life [18, 19]. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage [19]. Finally, AAN Practice Parameter of ALS care recommends that NIV should be considered to treat respiratory insufficiency in ALS patients for lengthening survival and slowing FVC decline rate [1].

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Figure 1. Respiratory management algorithm by AAN ALS Practice Parameter [1]. PFT: pulmonary function tests. PCEF: peak cough expiratory flow. NIV: noninvasive ventilation. SNP: sniff nasal pressure. MIP: maximal inspiratory pressure. FVC: forced vital capacity (supine or erect). Abnl. nocturnal oximetry =pO2 < 4% from baseline. *Symptoms suggestive of nocturnal hypoventilation: frequent arousals, morning headaches, excessive daytime sleepiness, vivid dreams. †If NIV is not tolerated or accepted in the setting of advancing respiratory compromise, consider invasive ventilation or referral to hospice.

In ALS patients, adequate nutrition is restricted insidiously and nutritional conditions worsen progressively. Dysphagia is a usual symptom of ALS and leads to increased risk of aspiration, malnutrition, weight loss and dehydration. Malnutrition and dehydration can also occur in patients with severe upper limb weakness because they have difficulties in meal preparation or prolonged meal times. ALS patients are reported to have a hypermetabolic state. They require increased calorie intake [20, 21]. Early management of dysphagia contains dietary advice, modification of food consistency (blending solid, adding thickening agents to liquids) and patient education on special swallowing techniques, such as supraglottic swallowing and postural changes (‘Chin tuck maneuver’) [5, 22]. Most guidelines address that supplementary enteral feeding should be considered when body weight loss (BMI) > 10% of the pre-diagnostic or baseline weight [5, 22]. Available enteric feedings include percutaneous endoscopic gastrostomy (PEG), percutaneous radiologic gastrostomy (PRG), radiologically inserted gastrostomy (RIG), and nasogastric tube (NGT). For therapeutic strategies to keep oral nutritional intake, PEG or RIG may be needed as an alternative route for delivering nutrition (Fig. 2). Physicians should emphasize to patients that PEG does not eliminate oral feeding. PEG is a convenient method for administering medication and fluid, and stabilizing body weight [23]. PEG is the standard procedure for enteral feeding, although the procedure requires mild sedation and has inference in patients with respiratory disturbance. To lower the risk, several studies recommend that PEG should be performed at VC > 50% [1, 5, 24]. Although it may be possible to insert PEG with NIV assistance, PRG/RIG insertion is a better alternative in these patients [25-27]. NGT is a relatively non-invasive option, but its long-term use is limited by discomfort and frequent replacement. Therefore, NGT should only be considered in patients who cannot undergo PEG or RIG insertion.

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Figure 2. Nutrition management algorithm by AAN ALS Practice Parameter [1]. *e.g., Bulbar questions in the Amyotrophic Lateral Sclerosis Functional Rating Scale, or other instrument.†Prolonged meal time; ending meal prematurely because of fatigue; accelerated weight loss due to poor caloric intake; family concern about feeding difficulties. ‡Percutaneous endoscopic gastrostomy: rule out contraindication.

Despite many clinical trials and various advances in the understanding of ALS, there has been little successful treatment for disease modifying or neuroprotective agents. Riluzole is the only approved drug that has been shown to have a modest effect on prolonging survival in ALS patients [28-33]. The mechanism of riluzole is though to include interference with N-methyl-D-aspartate receptors, stabilization of the inactivated state of voltage-dependent sodium channels, inhibition of glutamate release from presynaptic terminals and increasing of extracellular glutamate uptake [34]. The AAN practice advisory recommended riluzole at 100 mg/day to extend survival in ALS patients clinically probable or definite El Escorial ALS who had symptoms less than 5 years, FVC > 60% and non-tracheostomy [35]. Cochrane Collaboration meta-analysis showed that the absolute risk reduction with the 100 mg dose at 12 months was 9%, with the numbers needed-to treat to delay one death after 12 months is 11 [36]. The drug is generally well tolerated and the most common side effects contain asthenia, nausea, gastrointestinal upset and liver dysfunction. Therefore liver function should be regularly monitored during therapy [37].

Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western and Japanese patients with ALS. The main previous studies of lipid, urate and ferritin levels in blood samples of ALS patients are summarized in Table 2.

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Table 2. Main Previous Linked Studies Between Disease Progression and Lipid, Urate and Ferritin in Sera or Plasma of ALS Patients

Four large European studies showed that serum lipid levels were related to better respiratory function or longer survival in ALS patients [38-41]. In a recent cross-sectional study, baseline serum levels of total cholesterol and low-density lipoprotein-cholesterol were independent predictors for rapid worsening of ALS-Functional Rating Scale-Revised (ALS-FRS) and FVC in Japanese patients [42]. In contrast, two studies showed no significant longer survival in ALS patients with hyperlipidemia [43, 44].

Otherwise, there is no consensus of statin use. Lipid-lowering treatment has been debated in occurrence and survival of ALS patients. Some database studies showed an apparent increased developmental risk of ALS for patients taking statins, whereas others suggested no association between ALS onset and statin use [45]. Some cohort studies exhibited an increased progression rate in ALS patients taking statins [46]. In contrast, others described that statins had no significant effects on survival [47]. At least, statins may be used in ALS patients with slowly progression and multiple cardiovascular disease risk factors.

A previous Israeli study described lower urate levels in sera of ALS patients compared to controls matched for age, sex and body mass index. The univariate analysis showed that relative reduction of serum urate levels was inversely correlated with ALS-FRS decline rate [48]. A recent Italian study described decreased levels of urate in sera of ALS patients [49]. ALS patients with long disease duration had significantly lower serum urate levels compared to controls. Greater reductions of serum urate levels were observed in patients with bulbar onset compared to patients with limb onset [49]. Our previous study indicated that baseline serum urate levels were an independent factor for rapid worsening of ALS-FRS or FVC [42]. Thus, higher urate levels could have favorable effects on both nutrition and disease progression in ALS patients.

Serum ferritin levels are well known as a marker for iron storage in humans. In a previous study, increased serum ferritin levels over one year were correlated with rapid progression of muscle weakness and shorter survival [50]. Another study also suggested higher serum ferritin levels in ALS patients, and a significant association between serum ferritin levels and rapid worsening of ALS-FRS and FVC [42].

Metabolic and nutritional conditions of lipid, urate, iron and BMI could contribute to disease progression in ALS patients [38-43, 48-50]. Finally, further studies investigating high nutrition diets and iron chelating are warranted for the treatment of ALS.

More than 100 neuroprotective or neurotrophic agents have been treated in ALS patients [51-75]. Main phase II or III human clinical trials are listed in Table 3. Most of those clinical trials have shown inconclusive evidence or demonstrate no beneficial effects on routine clinical practice.

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Table 3. Main Previous Clinical Trials of Phase II or III in ALS Patients

As gene therapy approach to deliver neurotrophic factors directly to motor neurons, genetically engineered adeno-associated viruses (AAV) expressing neurotrophic factor genes was applied. Those AAV evaluated in mutant superoxide dismutase 1-transgenic mice and some promising results were reported [76]. However, human clinical studies are not yet underway. Another novel approach is the use of autologous stem cell transplantation. So far there have been no convincing results in human studies [77, 78]. Recent discovery show that induced pluripotent stem (iPS) cells generated from ALS patients are differentiated into motor neurons [79]. Production and therapeutic application of ALS-targeted iPS cells are strongly expected in the near future.

As multidisciplinary care in the United States of America, ALS patients are cured by their neurologist together with a team of therapists, usually including speech therapists, physical and occupational therapists, respiratory therapists, a nutritionist and a social worker [1, 2]. Cooperation between physicians and medical experts is required for better management and medication in ALS patients. According to the medical insurance system and national circumstances in each country, medical and social supports are needed for care of ALS patients.

Conflict of Interest

The authors state that they have no conflict of interest (COI).

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