April L McVey, M.D. - PowerPoint Presentation

April L McVey, M.D. Professor, Department of NeurologyUniversity of Kansas Medical Center END OF LIFE ISSUES IN ALS

ALS TIMELINE 1830 Bell reports a case of a progressive paralysis of limbs and tongue with preservation of sensation 1850 Aran names the condition of progressive muscular atrophy 1865 C harcot describes progressive lateral sclerosis (PLS) 1870 C harcot describes progressive bulbar palsy 1874 C harcot names ALS (de la sclérose laterále amyotrophique ) 1939 Lou Gehrig’s diagnosis and first clinical trial with vitamin E 1941 Lou Gehrig dies of ALS 1943 Vitamin E injections are shown not to be effective to treat ALS

ALS TIMELINE 1952 H irano describes the guam ALS/ Dementia / P arkinson Complex 1969 L ambert – Diagnostic criteria using EMG 1980 report of nerve growth factor published 1984 Use of percutaneous endoscopic gastrostomy (peg) reported in ALS. 1987 glutamate metabolism abnormality reported in ALS. 1993 SOD-1 gene identified. 1994 WFN El Escorial criteria for diagnosis of ALS published. 1995 first positive clinical trial for ALS. Riluzole has an effect on survival, prolonging life by 2-3 months.

Symptomatic Treatment

Pain Muscle cramps Spasticity Musculoskeletal pain Joint contractures/frozen shoulder Skin pressure pain due to immobility Non-ALS pain Decubitus ulcers Morphine Hydromorphone Fentanyl transdermal SL and SC

Fatigue Fatigue may be a symptom of depression poor sleep abnormal muscle activation immobility respiratory dysfunction Fatigue was a side effect of riluzole in 26% of patients vs 13% taking placebo ( p = 0.07; number needed to harm = 8) (Class III) . Asthenia occurred in 18% of patients taking riluzole vs 12% of patients taking placebo in a larger study . AAN practice parameter 2009

Fatigue Screen for nocturnal hypoventilation Energy conservation Modafinil Amantadine Pyridostigmine Methylphenidate

Sleep Disturbances Respiratory insufficiency with frequent awakenings due to n0cturnal hypoventilation Anxiety and depression Inability to change position during sleep due to weakness Fasciculations and muscle cramps Dysphagia and aspiration of saliva

Constipation Reduced mobility Fluid intake Meds (muscle relaxants, sedatives and anti- cholinergics ) Fluid intake Fiber Senna Bisacodyl suppository Magnesium citrate/Lactulose

Sialorrhea Glycopyrrolate Amitryptyline Transderm scopolamine patch Atropine 1% OP drops Trihexyphenidyl Clonidine Hyoscamine Myobloc Radiation

Randomized Double-Blind Study of Botulinum Toxin Type B for Sialorrhea in ALS Patients Muscle Nerve 39: 137–143, 2009 CARLAYNE E. JACKSON, MD,1 GARY GRONSETH, MD1, JEFFREY ROSENFELD, PhD, MD,3 RICHARD J. BAROHN, MD,3 RICHARD DUBINSKY, MD, MPH,2. C. BLAKE SIMPSON, MD,1, APRIL MCVEY, MD,2 PAMELA P. KITTRELL, MSN,1 RUTH KING, MHA,3, LAURA HERBELIN, BS,2 and the MUSCLE STUDY GROUP 1 University of Texas Health Science Center, 2 University of Kansas Medical Center, Kansas City, Kansas, USA 3 Carolinas Medical Center, Charlotte, North Carolina, USA

Protocol Parotid glands: 500U per site - 2 sites per gland (1000U total) Submandibular glands: 750U per site - 2 sites per gland (1500U total) 22 patients Improvement 2 weeks 12 weeks myobloc 82% 50% placebo 38% 14%

Other Symptoms Urinary urgency and frequency Lower extremity edema Jaw quivering or clenching Laryngosapsm GERD Nasal congestion Excessive yawning Early satiety Cramps/ fasciculations Urinary urgency and frequency

Cognition There is now clear clinicopathological overlap between ALS and frontotemporal dementia, and with rigorous neuropsychological testing it may be possible to demonstrate mild cognitive impairment in up to 50% of patients. Although frank dementia is rare (and often an early feature when present), mild frontal lobe dysfunction might in theory impair executive function and influence decision making. Thus there may be a need to consider some decisions earlier on in the disease process, to allow patients to be fully involved Estimates of cognitive impairment range from 10% (Class III) to 75% (Class III). Fifteen% of patients presenting with FTD later develop motor neuron degeneration (Class III).

Cognitive and behavioral impairment ALS-FTD FTD , as defined by Neary et al . has insidious onset, gradual progression, altered social conduct, emotional blunting, and loss of insight. These criteria are required for the diagnosis of FTD, which is supported by neuropsychological abnormalities, language dysfunction, and poor self care. F rontotemporal dysfunction with deficits in attention, cognitive flexibility, and word generation, with relative sparing of visuospatial function and memory. C hanges in social interactions unrelated to a psychiatric condition .

Cognitive and behavioral impairment The Mini-Mental State Examination is less sensitive to the cognitive impairment seen in ALS and does not examine for behavioral dysfunction. There is no consensus regarding the best screening tests for cognitive impairment in ALS. Two 1-minute word generation tests had 65% sensitivity, 90% specificity, and 88% positive predictive value in detecting possible, probable, or definite FTD by Neary criteria (Class II) . A 1-minute letter fluency measure (F words) had 73% sensitivity, 88% specificity, and 79% accuracy to detect ALS with cognitive impairment. MOCA

Early Signs of Respiratory Involvement Sleep related complaints Morning headaches Waking tired Daytime naps Snoring Vivid dreams/ nightmares Night sweats Frequent awakenings

AAN practice parameters FVC is the most commonly used respiratory measurement in ALS and is a significant predictor of survival. FVC may be insensitive since 13/20 patients with an FVC >70% had abnormal maximal inspiratory pressure (MIP) <−60 cm. Nocturnal desaturations <90% for 1 cumulative minute more sensitive indicator of nocturnal hypoventilation than FVC or MIP. FVC correlated poorly with symptoms of nocturnal hypoventilation and desaturation. Nocturnal oximetry correlated with survival (mean O 2 saturations <93 mm Hg were associated with mean survival of 7 months vs 18 months when mean O 2 saturation >93 mm Hg). Supine FVC, although more difficult to perform, may be a better predictor of diaphragm weakness than erect FVC.

Criteria for Implementing NPPV: HCFA FVC < 50% of predicted or MIP < -60 cm H2O or PCO2 > 45mm Hg or Nocturnal SpO2 < 88% for 5 continuous minutes

NPPV Trials in ALS Improved survival Aboussouan 2001 NPPV survival 20 months No NPPV 5 months Kleopa 1999 NPPV survival 14 months/no NPPV 4 Improves QOL Lyall 2001 Bourke 2003

Non Invasive Ventilation (NIV) Use nocturnally initially Traditional Bilevel machines Set inspiratory and expiratory pressure Back up rate Ventilators used non-invasively Can do pressure or volume assisted breaths “Smart” – target tidal volumes, adjusts pressure to reach it Can use in sip/puff mode Longer battery life CPAP not used Weakness of oropharyngeal muscles Increased burden breathing out against high pressure

Management of respiratory symptoms in ALS Orla Hardiman J Neurol (2011) 258:359–365 A significant minority of patients are unable to tolerate NIV. The mask may induce a sense of claustrophobia, and patients may have difficult acclimatizing to the sensation of increased inspiratory air pressure. Consider lorazepam at the initiation of NIV to help with relaxation. A variety of different types of masks are available. Factors that adversely affect the ability of patients to tolerate non-invasive positive pressure ventilators (NIPPV) include: presence of bulbar symptoms with increased secretions ability to manually adjust the mask presence of cognitive impairment

Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140–147. In a randomized controlled study, patients using NIV experienced a median survival benefit of 205 days (Class I) . NIV was initiated based on orthopnea with an MIP <−60 cm or symptomatic hypercapnia . No survival benefit was seen in patients with poor bulbar function . FVC declined more slowly after introducing NIV (pre −2.2%/month compared to post −1.1%/month) (Class I/III ) and the decline was slower in those who used NIV >4 hours/day (Class III) . A survival benefit of 20 months was observed in NIV-tolerant patients vs 5 months in NIV-intolerant patients (Class III) .

Invasive Ventilation Less than 10% of ALS patients in the US use IV Study found that of those ventilated, 70% did so under emergency conditions Does not slow progression of the disease High cost for home care on a vent and not covered by most insurances Many ALS patients who receive IV end up in an extended care facility Increased burden on caregiver

Interventions to clear secretions Mechanical insufflation/ exsufflation (MIE) increased the PCEF by 17% in healthy controls, 26% in bulbar patients, and 28% in nonbulbar patients. Manually assisted cough increased flow by 11% in bulbar and 13% in nonbulbar patients. High frequency chest wall oscillation (HFCWO) is an alternative approach to clearing airway secretions that was effective in patients with cystic fibrosis. HFCWO in 9 patients with ALS showed no benefit in rate of decline of FVC or survival. I n a controlled study of 46 patients, HFCWO users had less breathlessness and fatigue but coughed more at night.

Interventions to clear secretions Conclusions MIE is possibly effective for clearing upper airway secretions in patients with ALS who have reduced peak cough flow, although the clinically meaningful difference is unknown (4 Class III studies). HFCWO is unproven for adjunctive airway secretion management (2 Class III studies with conflicting results). Recommendations MIE may be considered to clear secretions in patients with ALS who have reduced peak cough flow, particularly during an acute chest infection (Level C). There are insufficient data to support or refute HFCWO for clearing airway secretions in patients with ALS (Level U). Clinical context. Medications with mucolytics like guaifenesin or N- acetylcysteine , a B-receptor antagonist (such as metoprolol or propanolol ), nebulized saline, or an anticholinergic bronchodilator such as ipratropium are widely used; however, no controlled studies exist in ALS.

PEG or RIG Timing Dysphagia Weight loss Breathing Time to eat meal Percutaneous or radiographic May improve QOL Patient and caregiver Unclear impact on survival Does stabilize weight/BMI

PEG

Neurology. 2014 May 13;82(19):1674-7. Venous thromboembolism in amyotrophic lateral sclerosis: a prospective study. Gladman M, Dehaan M, Pinto H, Geerts W, Zinman Subjects with leg-onset ALS or significant leg weakness had a 1-year VTE incidence rate of 35.8% and 35.5%, respectively. C linically important VTE is common in patients with ALS, particularly those with leg weakness and reduced mobility. Given these results, the potential benefits of routine VTE screening and primary prophylaxis in high-risk patients with ALS with leg weakness should be explored in future studies. In the meantime, physicians should have a low threshold for considering VTE in patients with ALS with leg weakness.

Survey of cannabis use in patients with amyotrophic lateral sclerosis Dagmar Amtmann, Patrick Weydt , Kurt L. Johnson, Mark P. Jensen and Gregory T. Carter AM J HOSP PALLIAT CARE 2004 21: 95 This study is the first, anonymous survey of persons with ALS regarding the use of cannabis with 131 respondents. The results indicate that cannabis may be moderately effective at reducing symptoms of appetite loss d epression pain Spasticity drooling Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction The loss of appetite, drooling, shortness of breath, spasticity, and pain were reported to be relieved on average for approximately one hour or less

Tracheostomy and invasive ventilation in Japanese ALS patients : decision -making and survival analysis: 1990-2010 J Neurol Sci . 2014 Sep 15;344(1-2):158-64. Survival time until death or tracheostomy obtained 160 patients. Fifty- two patients (33%) underwent tracheostomy / mechanical ventilation . Tracheostomy and invasive ventilation prolonged median survival time (74 months), as did non-invasive ventilation (48 months ) when compared to a non- ventilation - supported control group (32 months ; p<0.001 each ). NIV significantly prolonged survival until a primary outcome by more than 16 M, but the prolongation of survival with NIV was still significantly shorter than that with TIV. An age of ≤ 65 years is advantageous for long-term survival after a tracheostomy . Age, spouse and shorter duration were associated to the performance of tracheostomy . We showed longer survival in patients who resided at home after a tracheostomy.

Tracheostomy and invasive ventilation in Japanese ALS patients: Decision-making and survival analysis: 1990– 2010 First , the frequency of TIV appears to be higher not only in Japan but also in Asian countries (12.7–21 %). The rather widespread use of TIV could be attributed to religious, ethnic and cultural differences. In Western countries, TIV has seldom been applied for ALS, with rates of 0% in a British series of 50 patients and 3% in Germany [22], to reported frequencies of 1.4–14% in the United States [23], [24] and [25], 1.5% in Canada [26], 2–5% in France [27] and [28] and 7% for males and 3.8% for females in Norway [29]. The largest study in north Italy was performed on 1260 ALS patients and indicated that TIV was used in 10.6% of patients over the 10-year period of 1995–2004 [30]. Recent reports have described TIV as being performed in approximately 30% of the overall ALS population from Italy [31] and 22% from Denmark [32], and Spain has been reported to have an even higher rate of TIV, including emergent settings from respiratory care units [33]. Second , financial considerations are important. The ratios of the gross medical budget to the gross national product (GNP) were 5.9% in 1990 and 10.7% in 2010, which were not high compared to other countries; however, the Japanese government covers all costs for noninvasive/invasive mechanical ventilation at any age for both inpatients and outpatients. Third , regular follow-up examinations at the same institute may influence the rate of TIV due to the increased availability of continuous services and improved knowledge and education regarding ALS. Fourth , peer counseling by the Japanese ALS Association (JALSA) has contributed to the increased adoption of TIV. Fifth , the implementation of the long-term care insurance (LTCI) as a new and fundamentally reformed social insurance system at 2000 in Japan may have facilitated multidisciplinary team care and may be associated with the increase in the use of TIV.

Tracheostomy and invasive ventilation in Japanese ALS patients: Decision-making and survival analysis: 1990– 2010 In Japan, after the initiation of TIV, mechanical ventilation may not be legally discontinued. Guidelines for the withdrawal of mechanical have not yet been finalized in our institute. Professional caregiver support is given to patients through the LTCI system established in 2000 in Japan. Palliative care programs, such as hospices in institutes, provide emotional and physical support to patients and families throughout the course of the disease. We have no hospice care system and no palliative care consultation team available for ALS patients at our institute. As an issue of palliative care at the time of respiratory failure, the use of opioids for the relief of intolerable shortness of breath has not gained general acceptance in Japan.

Tracheostomy mechanical ventilation in patients with amyotrophic lateral sclerosis: Clinical features and survival analysis Rossella Spataro a, Valeria Bono a, Santino Marchese b, Vincenzo La Bella Journal of the Neurological Sciences 323 (2012) 66–70 It is known that tracheostomy significantly prolongs survival in ALS bringing patients well beyond the natural history of the disease. If compared with the patients who died without being tracheostomized , we found that those placed into an invasive me- chanical ventilation survived a median time of 12 months longer. However , less than 4% of our TMV ALS patients showed a survival longer than 4 years, and none was alive beyond 5 years. This is in line with another study where it was shown that, among patients under- going tracheostomy, those with ALS had the poorest long term survival , with only 5% alive at 5 years [16].

Withdrawal of Invasive Home Mechanical Ventilation in Patients with Advanced Amyotrophic Lateral Sclerosis: Ten Years of Danish Experience Pia Sander Dreyer, Michael Felding, Charlotte Sønderskov Klitnæs . Journal of Palliative Medicine. February 17, 2012, 15(2): 205-209. Deep sedation was achieved with high-dose morphine (median,100 mg; range, 60–400 mg) and diazepam (median, 100 mg; range, 20–120 mg) before the ventilator was disconnected. No suffering was observed in any of the patients after this procedure. Median time from discontinuation to apnea was 15 minutes (range, 0–18 hours) and to death 28 minutes (range, 5 minutes to 18 hours) . In all cases follow-up interviews with relatives were offered after 1 month and carried out in 10 of the 12 cases. The relatives stated in all cases that they had been apprehensive regarding the death scenario but they were also in agreement in describing how the dis- continuation of treatment passed off peacefully and in a dignified way in accordance with their relative’s wishes.

End of Life Discussion End of life conversations are difficult for patients, families and professionals. There may be multiple interactions, with conflicts between individuals, both within families and professional teams. There is no one right way that fits the wide range of human experience, emotion and behavior and may expose aspects of personality or past experience. Such conversations can be a source of intense discomfort to the patient, families and professionals, and as a result such discussions may be overlooked or avoided. The issue of advanced directives should be raised soon after diagnosis. The team must understand that patients can change their minds and the issue should be revisited every 6 months. failure to address the issue can precipitate a crisis in which a patient who did not want to artificially ventilated is intubated.

Neudert C, Oliver D, Wasner M, Borasio GD. The course of the terminal phase in patients with amyotrophic lateral sclerosis. J Neurol 2001;248:612–616. The fear of "choking to death" is on the mind of most patients suffering from ALS. We therefore performed a structured telephone interview with the relatives of 121 patients who died from ALS and were followed by the Motor Neuron Outpatient Clinic of the Department of Neurology, University of Munich, Germany. These data are compared with those obtained by a retrospective analysis of medical records of 50 ALS patients who were followed by the Wisdom Hospice, Rochester, UK. The data show that most ALS patients (Germany 88%, UK 98%) died peacefully, and no patient "choked to death". The symptoms most frequently reported for the last 24 hours were dyspnea , coughing, anxiety and restlessness. Around half (G 55%, UK 52%) of the patients died at home. The main palliative measures in place during the terminal phase were: home mechanical ventilation (G 21%, UK 0%), percutaneous endoscopic gastrostomy (G 27%, UK 14%), morphine (G 27%, UK 82%) and benzodiazepines (G 32%, UK 64%). The use of these palliative measures was judged to be beneficial by almost all relatives. These data support the hypothesis of a peaceful death process in ALS and should be communicated to patients and their relatives, at the latest after the onset of dyspnea , to relieve unwarranted fears.

Czaplinski , A. et al. Arch Neurol 2006;63:1139-1143 . Prognosis in ALS

Cause of death in 302 French patients with ALS Most patients (63%) died in a medical facility The most frequently reported cause of death was: respiratory failure (77%) Including terminal respiratory insufficiency (58%) pneumonia (14%) asphyxia due to a foreign body (3%) pulmonary embolism (2%) Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%) The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside) Gil J, Funalot B, Verschueren A et al. Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study. Eur J Neurol 2008;15:1245–51.

Causes of death in a post-mortem series of French ALS patients 100 ALS patients who died in the ALS clinic of Salpétrière had a complete macroscopic and microscopic post‐mortem analysis. The concordance between clinical and pathological conclusions was insufficient (20%) to consider clinical assessment as a reliable marker of causes of death. At autopsy, broncho ‐pneumonia and pneumonia were the main causes of death. Heart failure, representing 10% of deaths, was two times more frequent in bulbar than in spinal ALS. Pulmonary embolism representing 6% of death was exclusively found in spinal onset patients and is related to lower limb disability . Corcia P, Pradat P-F, Calachas F et al. Causes of death in a post-mortem series of ALS patients. ALS Other MND 2008;9:59–62.

Causes of death in a series of Italian ALS patients Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M ⁄ F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Respiratory failure (terminal respiratory insufficiency, pneumonia) was the most frequent cause of death (81.3%), which included six cases (3.3%) who requested a terminal sedation. Sudden death and death during sleep accounted for by 6.0% and 6.6% of all deaths, respectively. Heart -related causes of death were relatively infrequent in our cohort, accounting for by 7.1% of all deaths (i.e. sudden death: 6.0% and myocardial infarct: 1.1%). Patients (85.2%) died at home. The leading cause of death in ALS remains respiratory failure, followed by the sudden death and death during sleep. Spataro R, Lo Re M, Piccoli T, Piccoli F, La BellaV . Causes and place of death in Italian patients with amyotrophic lateral sclerosis. Acta Neurol Scand : 2010: 122: 217–223.

Reported Reasons Why Patients Request Physician-Assisted Suicide *JAMA. 2002;288(1):91-98 .

Attitudes Toward Assisted Suicide and Life- Prolonging Measures in Swiss ALS Patients and Their Caregivers . Front Psychol . 2012 Oct 25;3:443 . In the terminal phase respiratory distress, anxiety, and other distressing symptoms may occur. Given the suffering associated with the disease, some patients choose to decline life-prolonging measures such as Percutaneous Endoscopic Gastrostomy (PEG) and Non-Invasive Ventilation (NIV) and/or wish to hasten death. In the Netherlands, during the 2000–2005 period 16.8% of ALS patients decided for euthanasia or PAS ( Maessen et al., 2009), while in Sweden (where PAS is not legalized ), ALS patients have a sixfold increased risk of committing suicide (Fang et al., 2008). Factors such as depression, hopelessness, loss of meaning, and purpose in life have been discussed to be associated with the wish to hasten death, whereas the contrary applies to religious faith and spiritual beliefs

Hospice Care Morphine SL or SC Lorazepam 1-2 mg q 4 hours Haldol 0.5- 1 mg up to hourly Hydromorphone liquid Fentanyl patch Versed continuous infusion Subcutaneous 20-30 min peak effect IV 6-10 min peak effect Senna , Dulcolax supp

Responding to Requests for Physician-Assisted Suicide: JAMA. 2002;288(1):91-98.