Amyotrophic lateral sclerosis

Non-pharmacologic aspects of ALS: correlation of higher BMI with greater survival, beneficial use of cannabidiol, respiratory evaluation, exercise and anesthetic considerations 

Virginia Thornley, M.D., Neurologist, Epileptologist

March 4, 2018

ALS is a progressive neurodegenerative illness which affects the lower motor neurons causing progressive weakness and eventually respiratory failure. There are currently only 2 prescription agents available for slowing the progression of the disease. Management is largely symptomatic treatment of debilitating symptoms.  Much consideration is being directed towards alternative treatments such as dietary considerations and use of cannabidiol.

ALS and supplements and BMI

Based on one large review of studies, there was not enough evidence to support recommendations of Vitamin A, and C or Coenzyme Q10. For Vitamin B complex, Homocysteine, Vitamin D, there is limited data which is not enough to support or refute recommendation, more clinical trials are needed. Vitamin E may be beneficial in preclinical patients with a familial tendency. Omega-3 was found to accelerate disease progression with increased vacuolization of anterior horn cells and are deleterious in presymptomatic patients. L-Carnitine may increase survival time with a slower ALSFRS or ALS functional revised score and greater FVC volumes but more trials are needed (1). Body mass index of less than 18.5kg/m is found with less survival time, while those with a higher BMI have greater survival time. One small study suggested a high calorie, hypercaloric enteral diet was tolerable in patients but unclear if associated with better outcome in terms of survival time.

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Cannabidiol as a novel therapeutic agent

Cannabidiol is known in animal models to be anti-inflammatory and anti-oxidant. In the G93A SOD-1 mouse model, it was found to slow progression of the disease and increase survival time. In a study of 13 patients, it reduced drooling, loss of appetite, pain, and spasticity.

In one study, cannabidiol was used in human gingiva-derived mesenchymal stromal cells. The transcriptomic sequence in the next generation shows a change in gene expression in ALS related genes. There was a change in the genes connected to ALS regarding oxidative stress, mitochondrial dysfunction and excitotoxicity in the human gingiva-derived mesenchymal stromal cells when treated with cannabidiol. This suggests that cannabidiol may serve as a modulatory role in the early pathogenesis of ALS (2).

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Other aspects of ALS

Exercise 

Studies regarding exercise showed flaws in methodology or were in small numbers. Therefore, based on available studies it is unclear if exercise benefits a patient’s long-term outcome.

 

Sialorrhea

Sialorrhea should be addressed. Aside from conventional medications, other options include botulinum toxin and small doses of radiation therapy delivered to the salivary glands.

Anesthesia 

Anesthetic agents such as neuromuscular blockers are contraindicated in patients with ALS due to the risk of increased potassium release. In one study of 51 patients with ALS, general anesthesia was safely administered.

Pulmonary function 

Pulmonary function tests are monitored every few months depending on the rapidity of the progression of the disease. Non-invasive positive pressure ventilation is used in patients with ALS with an oral or nasal mask. As force vital capacity (FVC) declines, it may be administered through a bi-level positive airway ventilation machine continuously at night(1).

Introduction/Disclaimer

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References

1. Karam, et al, “Palliative care issues in amyotrophic lateral sclerosis: an evidence-based review,” American Journal of Palliative Care, 2016, Feb., 33(1):84-92.

2. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.

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Amyotrophic lateral sclerosis

Pluripotent stem cell research and amyotrophic lateral sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2108

Introduction

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease resulting in muscle weakness and respiratory failure. The mechanisms still remain unclear and there is no cure. Recent interest is growing in stem cell research as a novel treatment for ALS.

Stem cells and ALS

Induced pluripotent stem cells have been studied to identify the mechanism underlying ALS and develop treatments using these models. Using stem cells it is possible to grow a disease in a dish and study the mechanisms. The cells are generated from healthy subjects and patients with neurodegenerative disorders cultivating them to produce different types of neurons. CNS neurons are separated from peripheral neurons. Neurotrophins and other factors are used to accomplish this. It is important that these neurons can produce synaptic connections. In some studies, only a low number will differentiate into the neurons with the desired morphologic features and have the desired physiologic functions. The use of pluripotent stem cells is an important landmark in research because it allows researchers to study the disease of ALS with pluripotent cells capable of differentiating into different types of neurons including upper motor neuron, lower motor neuron cells, astrocytes, oligodendrocytes and allows researchers to understand the different dynamics between the cells in the diseased state (2).

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Potential mechanisms of stem cell treatment in ALS

One mechanism is by changing the somatic cells into neuron-like cells. There are now established ways of forcing transcription factors into changing somatic cells into neuron-like cells expressing neuron-specific proteins. The majority studied had excitatory traits. The most important feature is being able to propagate action potentials and developing dendrites.There are some reports of fibroblasts transforming into GABAergic cells using neurotrophins. Reprogrammed cells could convert into neurons, astrocytes and oligodendrocytes. Some cells cannot convert using genomic insertion which may be a barrier.

Induced pluripotent stem cells can be produced from the patient’s own stem cells. Direct conversion of somatic cells into neural cells is an alternative (1).

Introduction/Disclaimer

References

  1. Csobonyeiova, et al, “Induced Pluripotent Stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis, ” Journal of Physiology and Pharmacology, 2017, 68(5):649-657.
  2. Guo, et al, “Current advances and limitations in modeling ALS/FTD in a dish using induced pluripotent stem cells,” front. Neuroscience, 2017, Dec., https://doi.org/10.3389/fnin.2017.00671
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Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis: how diet may be associated with better outcome and management

Virginia Thornley, M.D., Neurologist, Epileptologist

February 27, 2018

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder resulting in muscle weakness, atrophy and eventual respiratory failure. It involves mitochondrial dysfunction, oxidative stress, apoptosis, neural inflammation, metallic accumulation, decreased trophic factors, glutamate activation, and superoxide dismutase-1. There is a growing interest in the role of diet in the natural progression and treatment. Risk of ALS may increase with increased intake of macronutrients such as carbohydrates, glutamate, and fat and a reduced intake of micronutrients such as carotenoids, fruits and vegetables, polyunsaturated fatty acids and Vitamin E. Oxidative stress may also increase the risk of ALS.

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Good food versus bad food in ALS

In one study of 306 patients in over 16 ALS centers, milk and lunchmeat seemed to correlate with a negative ALS function using the ALSFRS score (ALS functional rating score) or the percentage FVC (forced vital capacity) for the outcome. Milk and lunchmeat are associated with higher fat and potentially promote oxidative stress. It studied foods that were considered good (calcium, iron, potassium, iron, thiamine, riboflavin, niacin, zinc, selenium, vitamins C, D, E, K, and B6, magnesium, and glutathione) versus bad(phosphorus, caffeine, food-producing high glycolic index). The components of the good food groups had eggs, poultry, fish, beneficial oils and vegetables and are often associated with anti-oxidants and a healthy diet. The study only provides an association not a causation of good food towards a better outcome. Food high in fiber, carotenoids, and antioxidants provided a better outcome(1).

Another study noted that patients with the lowest score of ALSFRS appear in those with the lowest intake of vegetables, grains, oils, and seasonings (3).

Novel treatments using diet

In one study using a high caloric diet and an MAO-inhibitor/iron-chelating compound  M30 in the superoxide dismutase-1 mouse model, results showed neuroprotection involving motor function and increased survival in the SOD-1 G93A transgenic mouse model. The M3 and CED (high caloric diet) resulted in increased mitochondrial biogenesis and metabolic regulators. A combination of novel approaches may help treat this condition (2).

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1. Nieves, et al, “Association between dietary intake and function in Amyotrophic lateral sclerosis, ” 2016, Dec., 73 (12)1425-1432.

2. Golko-Perez, et al, “Additive Neuroprotective effects of the multifunctional iron chelator M30 with enriched diet in a mouse model of amyotrophic lateral sclerosis,” Neurotoxicity Research, 2016, Feb., 29(2):208-217.

3. Park, et al, “Association between nutritional status and disease severity using amyotrophic lateral sclerosis (ALS) functioning rating scale in ALS patients”Nutrition, 2015, Nov.-Dec., 31(11-12):1362-7.

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