Anemia Hypothyroidism Thyrotoxicosis Adrenal insufficiency (rare) Lyme disease

1. Dextroamphetamine sulfate provides marked improvement for patients suffering from chronic fatigue even when the etiology is unexplainedDiane Check, B.S., Brittney Katsoff, M.D.Jerome H. Check, M.D., Ph.D., Rachael Cohen, D.O. Deanna Greco Cooper Medical School of Rowan University, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology & Infertility, Camden, NJ

2. Palliative.org:  Palliative care is specialized medical care for people with serious illness. This type of care is focused on providing relief from the symptoms and stress of a serious illness. The goal is to improve quality of life for both the patient and the family. • Wikipedia: A multidisciplinary approach to specialized medical care for people with life-limiting illnesses. It focuses on providing people with relief from the symptoms, pain, physical stress, and mental stress of the terminal diagnosis. The goal of such therapy is to improve quality of life • Webster:  Medical and related care provided to a patient with a serious, life-threatening, or terminal illness that is not intended to provide curative treatment but rather to manage symptoms, relieve pain and discomfort, improve quality of life, and meet the  social, and emotional spiritual needs of the patient.

3. WHO: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.  • MedLine: Palliative care is treatment of the discomfort, symptoms, and stress of serious illness. It provides relief from distressing symptoms including: • Pain • Shortness of breath • Fatigue • Constipation • Nausea • Loss of appetite • Problems with sleep

4. People suffering from fatigue may have a known etiology which when corrected can improve the fatigue • Anemia • Hypothyroidism • Thyrotoxicosis • Adrenal insufficiency (rare) • Lyme disease

5. Chronic fatigue may be associated with certain disorders and significantly contribute to the morbidity from the disorder but not be correctable by standard treatments • Cancer • Autoimmune disorders • Chronic renal disease • Chronic liver disease

6. Chronic fatigue can sometimes be transient, related to certain infectious diseases, e.g., infectious mononucleosis. • However, if the fatigue persists longer, even after the disease is gone, one needs to consider that the fatigue was not caused by the infection. Thus, the fatigue is considered now unexplained.

7. Chronic fatigue syndrome of unexplained etiology is the most common presentation in patients not known to have associated severe co-morbidities.

8. We present a hypothesis suggesting that relative sympathetic nervous system hypofunction is the etiologic factor in a wide variety of chronic disorders, especially, but not limited to women. Check JH, Katsoff D, Kaplan H, Liss J, Boimel P: A disorder of sympathomimetic amines leading to increased vascular permeability may be the etiologic factor in various treatment refractory health problems in women. Med Hypothesis 2008;70(3):671-677.

9. Hypothesis continues that: • These chronic disorders are related to increased cellular permeability. • Increased cellular permeability allows infusion of unwanted chemicals into tissues. • Infusion of unwanted chemicals into tissues may lead to inflammation and pain. • Infusion of unwanted chemicals into mitochondria may lead to functional impairment of muscle function.

10. Hypothesis continues that: • One of the functions of the biogenic amine dopamine is to decrease cellular permeability. • Dopamine is secreted by the sympathetic nervous system. • Dextroamphetamine sulfate releases more dopamine from sympathetic nerve fibers. • Thus, theoretically treatment with dextroamphetamine sulfate may help to alleviate chronic pain symptoms, chronic muscle dysfunction, and other disorders that may be related to increased cellular permeability.

11. Theoretically the increased cellular permeability may be: • Genetic inheritance of tissue weakness • Acquired, e.g., from infection or trauma • Inheritance of diminished sympathetic tone.

12. Indeed evidence has accrued that treatment with dextroamphetamine sulfate may help alleviate suffering from a variety of these chronic, treatment-refractory, pathological disorders. Check JH, Cohen R, Katsoff B, Check D: Hypofunction of the sympathetic nervous system is an etiologic factor for a wide variety of chronic treatment-refractory pathologic disorders which all respond to therapy with sympathomimetic amines. Med Hypoth 2011;77:717-725. Check JH: Sympathomimetic amines are a safe, highly effective therapy for several female chronic disorders that do not respond well to conventional therapy. Clin Exp Obst Gyn 2015;42:267-278.

13. We have published case reports showing dramatic improvement following treatment with dextroamphetamine sulfate that support the concept that its beneficial effect on fatigue is related to improving mitochondrial function possibly by correcting excessive permeability.

14. A very interesting case of extreme fatigue was published by our own group entitled “Improvement in symptoms of the syndrome of mitochondrial encephalopathy, lactic-acidosis, and stroke-like symptoms (MELAS) following treatment with sympathomimetic amines – possible implications for improving fecundity in women of advanced reproductive age”. Potestio CP, Check JH, Mitchell-Williams J: Clin Exp Obstet Gynecol 2014;41:343-345.

15. Case of MELAS syndrome • Shortly after delivery of second child at age 27 a woman complained of troubling headaches. • Slurred speech • Drooping eyelids • Muscle pain • Then developed stroke-like episodes • Legs became paralyzed for days then would return to full strength • Developed seizures • Narcolepsy

16. MELAS case (con’t) • The diagnosis was established by muscle biopsy. • Diffuse mitochondrial proliferation consistent with MELAS. • Skeletal muscle oxidative phosphorylation enzymology showed low levels in the complex I assay (CoQ1 (only 31 nmol/minute/mg mitochondrial protein with normal values 93-375.

17. MELAS • Extreme fatigue progressed to the point of being wheelchair ridden for 20 years. • The woman seeked our help at age 52. • She was started on 15mg dextroamphetamine sulfate extended release capsules. • After 1 month of treatment she noticed: • Marked decrease in muscle pain • Marked improvement in the fatigue leading to her walking for the first time in over 20 years.

18. MELAS • The dosage was increased to 30mg extended release capsules • It has been 7 years and she reports that she is perfectly normal. • Normal energy • Walking fine • Very little pain • Marked improvement in edema

19. Autoimmune Hepatitis • We published another very interesting case of severe chronic fatigue responding to amphetamines. • A 34 year old woman, who for several years had moderate liver enzyme elevation, but with normal bilirubin, developed progressive weakness to the point that she was too weak even for a wheelchair and was bed ridden. The weakness was assumed to be related to an autoimmune process related to probable autoimmune hepatitis. Her husband was advised that she probably had no more than 6 months to live. Weidner J, Check JH: Marked improvement of the autoimmune syndrome associated with autoimmune hepatitis by treatment with sympathomimetic amines. Clin Exp Obst Gyn 2014;41:460-461.

20. Autoimmune hepatitis (con’t) • She was started on 15mg dextroamphetamine sulfate extended release capsules. • After 1 month she resumed her work as a nurse working 3 days, 12 hour shifts and worked 1 day at home. • She is still fine 7 years later.

21. Interesting case of a 19 year old young lady. • She had seen a multitude of specialists and was diagnosed with 26 different conditions. She failed to improve her symptoms, especially fatigue, despite a variety of empirical therapies. • She responded quickly and very well to sympathomimetic amine therapy. • Recent muscle biopsy consistent with MELAS syndrome. Check JH, Roopnarine AJ, DiAntonio G: Increased cellular permeability syndrome causing multi-organ system abnormalities and response to treatment with sympathomimetic amines. Presented at the 2017 American Association for Clinical Endocrinologists.

22. A 45 year old man whose brother was a paraplegic secondary to hereditary spastic paraplegia. • He developed muscle weakness of his legs, associated with spasticity, and developed a right foot drop, which progressed over a 1 year period. Check JH, Dougherty M, Check D: Complete reversal of clinical symptoms and signs of the hereditary spastic paraplegia syndrome following a short course of sympathomimetic amine. Endo Prac 2015;21 (Suppl 2, May 2015), abstract no. 834, pg. 164.

23. Following treatment with dextroamphetamine sulfate, he noticed marked improvement in his weakness and spasticity, and no longer had foot drop. • He is performing normal strenuous activity for the last 3 years while remaining on sympathomimetic amine therapy.

24. Another condition showing marked improvement with treatment with dextroamphetamine sulfate is hypokalemic periodic paralysis. Check JH, Aly J, Check D, Cohen R, Kaplan H: Idiopathic hypokalemic paralysis successfully treated with sympathomimetic amines. 25th Annual Meeting of the American Association for Clinical Endocrinologists, Orlando, Florida, May 25 – 29, 2016. Endo Pract 2016;22:281-282. Abst. #1161.

25. Smooth muscle disorders of the gastroenterology system have also responded dramatically well to treatment with dextroamphetamine sulfate including gastroparesis and pseudointestinal obstruction Boimel P, Check JH, Katsoff B: Sympathomimetic amine therapy may improve refractory gastroparesis similar to its effect on chronic pelvic pain – case report. Clin Exp Obstet Gynecol 2007;34:185-187. Check JH, Cohen R: Successful treatment of a female with chronic pseudo-intestinal obstruction with sympathomimetic amines and thyroid hormone replacement. Clin Exp Obst Gyn 2010;37:115-116.

26. Though these cases were unexplained chronic fatigue, sometimes dextroamphetamine therapy should be considered even when a known cause of the fatigue is suspected.

27. A woman with chronic fatigue syndrome, whose serology was positive for Lyme disease, failed to show any improvement despite 3 protracted courses of antibiotics. • Treating this patient with dextroamphetamine sulfate prevented her from a fourth course of antibiotics (this time intravenous) with all of the potential risks of prolonged antibiotic therapy. Check JH, Cohen R: Sympathetic neural hyperalgesia edema syndrome, a frequent cause of pelvic pain in women, mistaken for Lyme disease with chronic fatigue. Clin Exp Obst Gyn 2011;38:412-413.

28. A 43 year old woman presented with classic symptoms of hypothyroidism (fatigue, cold intolerance, constipation, dry skin) but normal serum thyroxin and thyroid stimulating hormone levels. • We were the second opinion. The first endocrinologist diagnosed the patient with thyroid hormone resistance syndrome and would have potentially caused muscle, heart, or bone damage from excessive thyroid hormone dosage. • She became normal after treatment with dextroamphetamine sulfate. Check JH, Cohen R, Check D: Sympathetic nervous system hypofunction as the etiologic factor in what appeared to be a thyroid hormone resistance condition. 23rd Annual American Association for Clinical Endocrinologists, Las Vegas, NV, May 14-18, 2014.

29. Dextroamphetamine sulfate in both cases of chronic fatigue from Lyme and thyroid hormone resistance was a safer option than the proposed IV antibiotics or treat with L-thyroxin to make the thyroid levels higher than normal. • It was also the option most likely to relieve the symptoms of debilitating fatigue.

30. A prospective observational study was performed on women whose chief complaint was chronic fatigue of unknown etiology.

31. Fifty women were enlisted who had unexplained chronic fatigue syndrome. • Patients with a known history of cancer and multiple sclerosis were excluded, as were women diagnosed with autoimmune disorders, confirmed by laboratory testing. • Patients were excluded with anemia, hypothyroidism, uncorrected thyrotoxicosis, or adrenal insufficiency, by appropriate laboratory testing. • Patients were not excluded if only a positive antinuclear antibody test was found, without confirmation by further testing for autoimmune disorders, e.g., lupus erythematosis, rheumatoid arthritis, scleroderma, or Sjogren’s syndrome.

32. Amphetamine salts 15mg extended release capsules, containing about 9.4mg dextroamphetamine sulfate, was the initial therapy. • They were evaluated on a monthly basis where the dosage could be 1) reduced, 2) increased, or remained stable based on response vs. side effects. • The maximum dosage allowed was 60mg extended release capsules in 2 divided dosages.

33. After 6 months after initial of therapy, the patients filled out a questionnaire as follows: • The chronic fatigue syndrome was (please check one): • 1) worse • 2) stable but no better • 3) slightly better • 4) moderately better • 5) markedly better

34. Markedly better – 48/50 (96%) • Moderately better – 2/50 (4%)

35. The palliative care specialist should consider dextroamphetamine sulfate for severe fatigue even in patients suffering from: • Cancer • Multiple sclerosis • “Autoimmune” disorders

36. “80% of cancer patients and in up to 99% of patients following radio or chemotherapy complains of severe fatigue.” • “Fatigue also plays a major role in palliative care from non-cancer patients with HIV, multiple sclerosis, chronic obstructive pulmonary disease or heart failure” Lolas Radbrusch et al: Fatigue in palliative care patients – an EAPL approach. Palliative Medicine 2008;22:13-22.

37. In a 2017 palliative case update Overview of fatigue mechanisms and asthenia. Edvarto Bruara, M.D. and Sriram Yennurajalingan, M.D. stated: • Bed rest/relaxation was the most common treatment recommendation – 37% • 40% of patients were not offered any recommendations.

38. Dextroamphetamine sulfate is • Well tolerated • No long-term risks • Non-addicting with dosage used

39. Based on the observational study of 50 patients with unexplained chronic fatigue, in a group not typically seen by palliative care specialists, but with the dramatic benefits found in this study, our hope is that our results can stimulate a prospective observational study determining the efficacy of amphetamine treatment for fatigue in cancer patients or patients with other debilitating chronic illnesses.