Introduction to supplement: the current status of treatment for ALS

Abstract

ALS is a lethal neurodegenerative disease wherein the diagnosis is often delayed. Our understanding of the pathobiology is slowly expanding, and the number of new genes is rapidly increasing. The development of potential treatments targeting specific mechanisms is beginning to offer hope. Evidence-based treatments and the development of quality measures have raised the standard of care. The current status of treatment for ALS includes one drug riluzole that slows progression modestly, and another drug edaravone that was recently approved by FDA to slow ALS progression. Multidisciplinary clinics and symptomatic treatments ease the burden of ALS and prolong life. An overview of these treatments is provided here.

Keywords:

• Treatment
• clinical trials
• amyotrohpic lateral sclerosis
• practice parameters
• multidisciplinary clinics
• quality measures

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron cell death and progressive paralysis. Most patients die within 3–5 years of symptom onset, usually of respiratory failure (1). Although considered rare (1.5 new cases annually per 100,000 population) (2), the lifetime risk of developing ALS is 1 in 400 (3), comparable to the risk of multiple sclerosis. At this time it is estimated that approximately 30,000 Americans (5 per 100,000) are struggling with the disease (4).

The diagnosis of ALS depends primarily on clinical features of the medical history and neurological examination, which include the presence of both upper motor neuron and lower motor neuron signs and evidence of progressive weakness (5). Conditions such as spinal bulbar muscular atrophy, inclusion body myositis, cervical spondylotic radiculomyelopathy, and multifocal motor neuropathy can mimic ALS and must be thoroughly evaluated and excluded. This usually requires imaging, blood studies, EMG and nerve conduction tests, and in some cases cerebrospinal fluid analysis and muscle biopsy. There is at this time no single diagnostic test that establishes the diagnosis of ALS with certainty.

The diagnostic process is time-consuming and usually delayed until the patient is beyond the time-frame when early treatment and entry into clinical trials might be most beneficial. The average time from onset of first symptom of weakness until diagnosis is 12 months, a figure that has not changed significantly over the past decade (6–9). Sources of delay include patient reluctance to seek medical help, delay in getting appointments and awaiting testing, inappropriate treatments including surgery for mistaken diagnoses, and a lengthy interval before referral to a neurologist. In addition, due to the devastating nature of the diagnosis, and the lack of effective treatment, there has been a reluctance by many clinicians to make the diagnosis.

Great progress has been made in elucidating the pathogenesis of motor neuron injury in ALS patients, largely due to the discovery of more than 30 genes that cause the ALS phenotype (10), and the ability to develop rodent models based on these mutations (11). The first such gene discovered was mutant superoxide dismutase (SOD) which is responsible for 25% of familial ALS. More recently an expansion mutation in the C9orf72 gene was discovered and is responsible for up to 40% of familial and up to 10% of sporadic ALS (12).

Free radical stress and mitochondrial dysfunction are prominent intrinsic motor neuron deficits as are misfolded proteins, impaired axonal transport, autophagy, and RNA dysfunction (13). Pathology of the lower motor neuron may appear distally with ‘dying back’ as evidenced by alterations at the neuromuscular junction at an early stage of disease (14).

ALS can be divided into intrinsic cell-autonomous injury of the motor neuron, and propagation of the injury by a non-cell autonomous process involving microglia, astrocytes, and immune system reactivity (15). There is definite evidence of systemic inflammation with activated pro-inflammatory circulating macrophages and dysfunctional protective suppressive regulatory T-lymphocytes.

The current treatment for ALS includes one drug riluzole that slows progression modestly (16), and another drug edaravone that was recently approved by FDA to slow ALS progression (17). The field is desperate for more effective treatment for this disease.

Novel therapeutic approaches are being developed especially for patients with FALS employing gene silencing with antisense oligonucleotides. Studies of mutant SOD1 in transgenic mice and ALS patients document the feasibility of knocking out the protein product of the mutation with antisense oligonucleotides (18) and a further dose-finding study is now underway. These new approaches to treatment, which involve newly identified targets that, if responsive to therapy, will be a welcome step forward in the battle against ALS.

Recently we completed a clinical trial of a novel anti-inflammatory agent (NP001, Neuraltus Pharmaceuticals, Inc.) that blocks monocyte and macrophage activation (19). A subset of patients in the study who had evidence of systemic inflammation showed no progression of ALS during six months of treatment, prompting a larger follow-up study (NCT02794857) which is underway to seek to confirm these findings.

Oxidative stress also appears to be important in ALS and a new antioxidant, edaravone, has been licenced in Japan, and very recently approved by the FDA for use in the United States, on the basis of slowing the functional decline of ALS (17). Much of the clinical trial data forms the basis for this supplement.

A very innovative approach to treating ALS is being pioneered by a biotech company in South San Francisco, Cytokinetics. This agent, tirasemtiv increases force production in fast skeletal muscle by increasing the sensitivity to calcium in the troponin complex. A large trial recently showed significant slowing of the decline in respiratory and limb muscle function in patients with ALS (20). A pivotal trial VITALITY-ALS is underway, and results eagerly awaited.

There has also been progress in symptomatic therapy for ALS. Muscle cramps are very bothersome for patients with ALS and there has been no effective therapy, but recent studies have demonstrated a significant reduction in cramps with mexilitene (21). Treatment of pseudobulbar affect, which consists of episodic outbursts of emotion in patients with pseudobulbar palsy, is now treatable with a combination of dextromethorphan and low dose quinidine. The drug, Nuedexta, was approved by the FDA on the basis of two controlled trials showing more than a 90% reduction in emotional outbursts (22,23). Sialorrhoea is frustrating and embarrassing and when oral agents become ineffective, botulinum toxin injection into salivary glands is usually effective (24). Emerging evidence suggests that radiotherapy of the salivary glands may be an effective alternative (25). Effective treatment for respiratory insufficiency with non-invasive ventilation at night extends life, improves sleep, quality of life and alleviates dyspnoea (26). Dysphagia and weight loss shorten life for these patients, but a percutaneous gastrostomy (PEG) stabilises weight and improves nutrition (27,28).

Systematic reviews of the evidence-based management of ALS were undertaken to help clinicians and patients make good decisions about therapeutics and to guide practice (16,28,29). More high quality studies are needed and the practice parameters point the way to future research.

Three studies showed that multidisciplinary clinics specialising in ALS care improved quality of life and lengthened survival through preventing problems by increased use of adaptive equipment, increased utilisation of riluzole, PEG, and non-invasive ventilation (30–32). In specialised multidisciplinary clinics, patients with ALS receive comprehensive care from a neurologist, respiratory physician, gastroenterologist, rehabilitation medicine physician, social worker, occupational therapist, speech therapist, respiratory therapist, specialised nurse case manager, physical therapist, dietitian, psychologist, and palliative care expert (29). The whole spectrum of care is available from a team of experts, with ‘one stop shopping’. Specialized clinics coordinate care and interface with a primary care physician, local neurologist and community-based services.

Recently, a task force was convened by the American Academy of Neurology to develop quality measures in ALS in order to allow measurement of quality of care, and to guide management. It has been shown that quality measures can improve patient outcomes (33). Third party payers and major health systems have adopted quality measures that are also being adopted in other neurologic diseases (33). A quality measure must be evidence-based, cost-effective, address a gap in care, be relevant to patients and improve health or quality of life. Table 1 lists the 11 quality measures for ALS (33).

Table 1. Quality Measures in ALS.

Multidisciplinary Care Plan Developed or Updated

Disease Modifying Pharmacotherapy Discussed

Cognitive and Behavioral Impairment Screening

Symptomatic Therapy Offered

Respiratory Insufficiency Querying and Testing

Non-invasive Ventilation for Respiratory Insufficiency

Screening Dysphagia, Weight Loss and poor Nutrition

Nutritional Support Offered

Communication Support Referral

End of Life Planning Assistance

Falls Querying

Thus, while we await more definitive disease modifying therapy for ALS, we are able to utilise a variety of treatments to ease the burden of this terrible disease. The evidence based practice parameters, the emerging use of quality measures, and the increasing use of multidisciplinary clinics will improve care and close some of the existing gaps to enhance quality of life for patients battling ALS.

Declaration of interest

Dr Miller has been a consultant to Cytokinetics, Neuraltus, and Mitsubishi Tanabe Pharma America, Inc. Dr Appel is a scientific adviser for Neuraltus and Mitsubishi Tanabe Pharma America, Inc., and a member of the Speaker's Bureau for Avanir.

Open access publication of this article was funded by Mitsubishi Tanabe Pharma America, Inc.