Managing a patient with ALS (Amyotrophic Lateral Sclerosis) Presented by: John Sugrue

Objectives Provide an example of a patient with ALS Discuss pathophysiology of ALS and its progression Identify proven drug therapy as well as some potential drugs to aid in symptom management Analyze the example patient’s medication list to optimize therapy

Patient Case JD is a 56 year old female presenting to the ED with increasing lethargy and altered mental status. Past Medical History: ALS DVT PE s/p IVC filter Dyslipidemia Iron-deficiency anemia Chronic lymphedema GERD Nephrolithiasis Single kidney Recurrent UTI

Patient Case Social History: lives at home, VNA comes to house. No smoking, alcohol, or other drug abuse. Family History: Non-contributory Review of Systems (pertinent positives): GI – positive for abdominal pain MS – positive for muscle pain from spasms in lower limb. Neuro – altered mental status Allergies: Oxycodone, Percocet, codeine

Patient Case Home Medications Baclofen 20 mg 2 tablets PO AM, 3 PO PM Docusate 100 mg capsule PO BID PRN Mirtazapine 15 mg tablet PO at bedtime Morphine 30 mg tablet PO TID Nystatin topical powder, apply topically three times daily to affected areas

Patient Case Medications continued: Omeprazole 40 mg capsule PO QD Riluzole 50 mg tablet PO Q12H Senna 8.6 mg 2 tablets PO QD PRN Simvastatin 20 mg tablet PO at bedtime Sucralfate 1 g tablet PO TID before meals and bedtime Venlafaxine 100 mg tablet PO TID

Patient Case Vitals upon admission T – 97.6 F HR – 92 RR – 22 BP – 122/71 O2 sat- 100% Height – 156 cm Weight – 84.4 kg Pertinent Labs WBC’s urine - >182/HPF RBC’s urine – 52/ HPF Chem 7 WNL

About ALS Often developed between ages of 40-75. Affected Patients: 60% - male, 93% - Caucasian. Approximately 6,000 new diagnoses every year in the US Estimated 20,000 people living with ALS in US. Life expectancy once diagnosed is an average of 3 years 10% live with disease for 10 years 5% live with disease for 20 years Military veterans are twice as likely to develop ALS What is ALS? [Internet]. Washington DC: The ALS Association; 2016 [cited 2016 Dec 1] Available from: http://www.alsa.org/about-als/what-is-als.html

Pathophysiology Progressive degeneration of motor neurons Motor neurons are then unable to send a signal to voluntary muscles to contract Muscles atrophy and harden (sclerosis) Image from: http://www-personal.umich.edu/~sbarmada/Images/Research/ALS_2.jpg What is ALS? [Internet]. Washington DC: The ALS Association; 2016 [cited 2016 Dec 1] Available from: http://www.alsa.org/about-als/what-is-als.html

Progression Gradual onset Progressive painless muscle weakness Hands Voice Swallowing Uncontrolled expression of emotion (laughing/crying) Dyspnea

Rilutek® (riluzole) Only drug FDA approved to prolong life/slow disease progression in patients with ALS. MOA: unknown, however there are some hypotheses Inhibition of glutamate release Inactivates sodium gated channels Interference with excitatory amino acid receptors Major side effect = fatigue and nausea. HTN, dizziness, ↑ LFT’s, ↓ lung function Image from: http://image.ec21.com/image/hkhiqueen/OF0010137647_1/Sell_Rilutek.jpg Lexicomp. Rilizole. [online] 1 December 2016

Rilutek® (riluzole) Dosed at 50 mg tablet by mouth twice daily Considerations Severe neutropenia has been reported within the first 2 months of treatment May cause hepatic injury Major CYP1A2 substrate When taking riluzole with high fat meals, the level in the blood is reduced by about half. Lexicomp. Rilizole. [online] 1 December 2016

Clinical Trials A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. Purpose: to evaluate the efficacy and safety of riluzole in patients with ALS. Setting: Hôpital de la Pitié-Salpêtrière, Paris, France, 1994. Methods: double blind, placebo-controlled trial in 155 patients with ALS Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group [abstract]. N. Engl. J. Med. 1994 March; 330(9): 585-91.

Clinical Trials Primary Endpoints: survival and rates of change in functional status Results: after 12 months, 58% still alive in placebo, 74% still alive in riluzole group (p=0.014). Deterioration of muscles was significantly slower in riluzole group when compared to placebo group (p=0.046). Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group [abstract]. N. Engl. J. Med. 1994 March; 330(9): 585-91.

Clinical Trials Set the bar for studies to come The US guidelines mention 4 class I studies supporting the safety and efficacy of riluzole for its indication of slowing disease progression of ALS and increasing survival time. Miller R.G., Jackson C.E., Kasarskis E.J., et al. The care of the patient with amyotrophic lateral sclerosis. American academy of Neurology. 2009; 73:1218–1226.

Symptoms to be treated PBA (Pseudobulbar Affect) Thick mucus Sialorrhea Muscle spasticity Cramps Insomnia Fatigue

PBA (Pseudobulbar Affect) Definition: Emotional lability in the form of laughter, crying, or yawning at inappropriate times Very common in ALS patients (around 50%) Medications Combination quinidine and dextromethorphan (Nuedexta®) 20 mg DM/10 mg quinidine once daily for 7 days then increase to BID Amitriptyline 25 mg once daily (can go up to 100mg/day as tolerated) Fluvoxamine 50 mg once daily Citalopram not to exceed 40 mg/day. Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Thick mucus Can complicate breathing by getting stuck in respiratory tract Medications N-acetylcysteine 200-400 mg by mouth TID Any combination of the following: Beta antagonist and nebulizer w/ saline (carvedilol, propranolol etc…) Anticholinergic bronchodilator (tiotropium etc…) Furosemide Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Sialorrhea (excessive drooling) Medications Amitriptyline 10 mg tablet by mouth TID Atropine 0.5-1% sublingual drops, one drop 3-4 times daily Scopolamine 1.5 mg transdermal patch every 3 days Careful with anticholinergics in older patients Botulinum toxin injection Should be reserved for refractory sialorrhea Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Muscle Spasms Physical therapy is the most important aspect of treatment Medications Antispastic medications such as baclofen or tizanidine No clinical trials with ALS patients but has been used Intrathecal baclofen In cases of severe/refractory spasticity Gabapentin, memantine, dantrolene, tetrazepam, diazepam. Have been used but no testing in ALS patients has been conducted. Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Cramps Can be debilitating in patients with ALS, especially at night. Medications Levetiracetam Quinine sulfate Physical therapy can help tremendously with this issue. Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Insomnia Patients can have trouble, especially as symptoms progress to leg cramps and more associated pain. Medications Amitriptyline Mirtazapine Zolpidem Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Fatigue Most common side effect of riluzole Discussion about discontinuing medication if fatigue is too devastating QOL vs. prolonging life Two trials showed that modafinil was effective in increasing patients energy Long term effects on ALS patients has yet to studied. Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375.

Stem cells Stem cell research is being conducted with the goal of protecting the affected motor neurons The theory is that these stem cells will produce growth factors or other molecules to protect motor neurons in the spinal cord. Stem cell treatment is still in the early phases of clinical trials but stem cells from ALS patients are being used for research purposes. Stem Cells [Internet]. Washington DC: The ALS Association; 2016 [cited 2016 Dec 1] Available from: http://www.alsa.org/research/focus-areas/stem-cells/

Revisiting JD Patient was suspected to have a UTI due to WBC’s and blood in urine Was treated with a 4 day course of Zosyn, clinically improved and altered mental status returned to baseline

Revisiting JD’s Medications Baclofen Docusate Mirtazapine Morphine Nystatin Omeprazole Riluzole Senna Simvastatin Sucralfate Venlafaxine

References What is ALS? [Internet]. Washington DC: The ALS Association; 2016 [cited 2016 Dec 1] Available from: http://www.alsa.org/about-als/what-is-als.html Lexicomp. Rilizole. [online] 1 December 2016 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group [abstract]. N. Engl. J. Med. 1994 March; 330(9): 585-91. Miller R.G., Jackson C.E., Kasarskis E.J., et al. The care of the patient with amyotrophic lateral sclerosis. American academy of Neurology. 2009; 73:1218–1226. Anderson P, Abrahams S, Borasio G, et al. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis. European Journal of Neurology. 2012; 19: 360–375. Stem Cells [Internet]. Washington DC: The ALS Association; 2016 [cited 2016 Dec 1] Available from: http://www.alsa.org/research/focus-areas/stem-cells/