Dr. Lapp’s presentation in Japan, November 4, 2012
I have come to talk to you today about Persons with CFS.
The worldwide prevalence of CFS/ME is about 400 cases per 100,000 (but up to 300 cases per 100,000 in
Japan). This means that up to 400,000 Japanese people may suffer with this illness. This incidence
makes CFS much more prevalent than Rheumatoid Arthritis, Multiple Sclerosis, or even breast cancer.
CFS/ME is reported worldwide, and recognized as “real” by the WHO and many eminent medical
associations; however, CFS/ME is still regarded by some a (1) a wastebasket term or (2) just depression.
Based on Japanese studies, from 300,000 to 400,000 Japanese people awaken every day with symptoms
of influenza, aching, foggy thinking, and exhaustion after minimal activities such as bathing, dressing,or fixing a meal. They do not sleep soundly and they do not awaken feeling refreshed. They may have
daily sore throats, swollen lymph glands, and headache. Many experience excessive sensitivity to light,
sound, temperature, odors, and medications. They may be overly vigilant due to an overactive
sympathetic nervous system. As a result they are nervous and anxious like an animal that has beenfrightened, and frightened, and frightened over and over.
It is no surprise that such individuals would present with 20 or more symptoms. They are complex andvery challenging. But they are like a person who is drowning, and it is the job of the physician to throw
them a life preserver. Such individuals also impose a tremendous economic burden on the Japanesenation. Based on data from the United States, this illness could account for $180 million (14 billion Yen)in total healthcare expenditures in Japan, and $0.5 billion (37 billion Yen) of lost productivity (Lin J,
Cost Eff Resour Alloc. 2011).
I am going to focus today on 5 areas: (1) the signs and symptoms of CFS; (2) the evidence that CFS is areal illness; (3)the evidence that CFS is not due to depression; (4)the American approach to
management; and (5)Pediatric CFS. My approach to managing CFS may differ significantly from theapproach taken in Japan, but it is my humble hope that the treatments we have found effective in the
United States will be of great benefit to you in Japan. And I hope that my presentation will not only
provide a framework for CFS sufferers to follow, but that Japanese physicians will also benefit from thisapproach.
2. Brain Abnormalities
MRI Scans show high intensity white spots in 80% of cases. SPECT Scans show decreased blood flow in
specific areas of the brain, especially the midbrain and temporal lobes. Neuro-psychiatric testing
confirms problems with attention, memory, and processing speed.
3. Autonomic Nervous System
Abnormalities of the sympathetic and parasympathetic nervous system are common, including
tachycardia (or fast heart rate), orthostatic intolerance (fainting) in up to 100% of subjects, and low
plasma volume and red blood cell mass. Patients tend to have rapid heart rate, low blood pressure, andsyncope (fainting).
4. Sleep Disruption
Sleep is markedly disturbed in up to 62.5% of patients. Evaluation in the sleep laboratory frequently
reveals sleep apnea, sleep walking, narcolepsy or upper airway resistance.
5. HPA Axis
Abnormalities of the mid-brain cause suppression of the hypothalamus. This in turn suppresses thepituitary. Suppression of the pituitary leads to diminished function in the endocrine glands, including
the thyroid, adrenal gland, and gonads (sexual glands). Thus, many patients have low cortisol and
DHEA, low thyroid, and sexual dysfunction such as early menopause and loss of libido.
6. Immune System
The immune system is affected in CFS. This is manifested by “cytotoxic” T cells, poorly functioning
natural killer cells, upregulation of the anti-viral enzyme RNaseL, increased inflammatory cytokines,
and reduced levels of antibodies. As a result we can see reactivation of old viral infections,
auto-antibodies, inability to fend off viral and fungal infections, recurrent Staphylococcal andStreptococcal infections, influenza symptoms, and fevers.
7. Genetics
Twin studies and the study of family histories has demonstrated that these Human Leukocyte Antigens
are inherited, and that the risk of a descendant developing CFS ranges from 2.7 times normal forchildren, 2 times normal for more distant relatives. Several gene variants that are present in persons
with CFS control neurotransmitters (brain chemicals) that control tryptophan (TPH2), serotonin(COMT), and glucocorticoids (NR3C1). These genes control mood, sleep, motivation, pain, bodydevelopment, and metabolism, which explains many of the symptoms that we see in persons with CFS.
8. Oxidative Stress / Energy Metabolism
Oxidative stress is increased in persons with CFS as measured by an increase in low density lipoprotein(LDL) and the most reliable marker of free radical accumulation, F2 isoprostanes. Cellular energy – asmeasured by ATP – is reduced in persons with CFS. This may explain why persons with CFS have very
low energy levels, poor stamina, and malaise after minimal exertion.
9. Gene Expression of mRNA
These graphs demonstrate that moderate exercise increases mRNA expression for sensory, adrenergic,
and immune genes in CFS patients but not in normal subjects. Dr. Light at the University of Utahmeasured the production of mRNA by genes in controls and patients. Each color represents a different
mRNA and each cluster represents a period of time after modest exercise on a stationary bicycle. You
can see clusters of data for 30 minutes, then 8, 24, and 48 hours after exercise. It is clear that persons
with CFS (in the lower graph) produce more mRNA in response to exercise than the controls in theupper graph. Using these gene expression studies it is possible to distinguish normal individuals frompersons with CFS; discriminate CFS from FM; determine the severity of the CFS; and even predict who
will have orthostatic intolerance. This technology shows real promise as a marker for persons with
ME/CFS or FM.
11. Gene expression tracks the severity of CFS
12. Post-Infectious CFS
75-85% of cases occur abruptly following a viral or flu-like illness. Two studies validate that common
infections can trigger CFS. In 2006 and Australian study followed individuals who contractedmononucleosis (EBV), Q-Fever, and Ross River Fever. While most recovered from these illnesses, at one
year 11% of patients met criteria for CFS. CFS did not develop more frequently in persons with ahistory of psychiatric illness, which suggests again that depression occurs as a result of CFS, and does
not cause CFS. A more recent study followed over 300 adolescents who contracted mononucleosis. At 12
months 7% of patients met criteria for CFS – which is consistent with the Dubbo Study -- and at 24
months 4% of children still met CFS criteria.
13. Myth
Next I would like to dispel the myth that CFS/ME is caused by depression. Epidemiology, symptoms,

course of illness, and medical fact all support that CFS/ME is not caused by or due to depression.
14. Depression versus CFS/ME : Onset
First, depression usually develops insidiously, while 75-85% of CFS cases occur abruptly.
15. Depression versus CFS/ME : Epidemiology
CFS occasionally occurs in clusters or populations of patients. Small epidemics have been reported inEngland, the United States, Iceland, New Zealand, and many areas throughout the world. Depression
occurs in individuals.
16. Depression versus CFS/ME : Medical Therapy
Antidepressants can significantly improve depression, but are seldom helpful in CFS.
17. Depression versus CFS/ME : Exercise
Likewise, exercise improves depression, but it worsens CFS. We will talk more about this later.
18. Depression versus CFS/ME : Symptoms
Many symptoms of CFS overlap with those of depression – particularly sleepiness, fatigue, anddiscomfort or pain. These symptoms are much more severe in CFS, however. And some symptoms, suchas fever, headache, and post-exertional malaise are common in CFS but are not typical of depression.
19. Depression versus CFS/ME : Outlook
Perhaps the most obvious distinction between depression and CFS is that depressed persons arehopeless, helpless and withdrawn. On the other hand, persons with CFS tend to be very proactive, theyseek medical treatment, and they tend to be politically active – like all of YOU!
20. Biological Evidence Against Depression
Biological evidence against depression as a cause for CFS can be found in the HPA Axis. The
hypothalamus controls the pituitary, and the pituitary controls the endocrine glands. When adrenal
function is studied, cortisol is elevated in persons with depression due to elevated CRH from thepituitary. CFS is just the opposite: serum cortisol production is reduced due to a deficiency of pituitary
CRH.
21. Four Cardinal Symptoms of CFS
Let us turn now to the symptoms and management of CFS. There are no tests that diagnose CFS, so wemust rely upon symptoms (or a clinical case definition). The four core (or cardinal) symptoms of CFS are
pain, trouble with thinking, fatigue, and non-restorative sleep. By non-restorative sleep I mean thatsleep is very shallow and no matter how much sleep a patient gets, she will still awaken feeling very
tired, stiff, and foggy.
22. Overlaps Syndromes
In addition to the four core symptoms, persons with CFS are 7 to 9 times more likely to havecomorbidities or overlap syndromes. The most common overlap syndromes are irritable bowel, irritable
bladder, migraine, dry eyes and mouth (Sjögren ‘s syndrome), sacro-iliac (low back) pain, etc.
Epidemiology
From an epidemiological standpoint there is no known cause for CFS, but triggers have been identified.
In about 85% of cases the trigger is a viral or flu-like infection. Long term studies in the United Statesshow that a majority of persons with CFS improve over time, usually months to years. However,
23. CFS/ME Triangle

To help understand CFS, I frequently refer to the CFS Triangle: Sleep – Pain – Fatigue. These three
symptoms are all interrelated. For example, if you have pain it is difficult to sleep and pain is
exhausting or fatiguing. There are few treatments for fatigue, but pain and sleep are eminently
treatable. Fatigue (and cognition) tend to improve when sleep and pain are addressed.
24. Managing Sleep Problems
To manage sleep, it is first important to have good sleep habits. For example:
Use the bed only for sleeping
Go to bed when sleepy; never try to make yourself sleep
Hide the clock from view (so that the time of night does not cause anxiety)
Don’t be afraid of insomnia; quiet rest is almost as good as sleep
Keep a regular schedule. Set an alarm and get up at the same time every morning.
When good sleep habits alone are not sufficient, then simple sleep aids might be helpful, such as
melatonin or an antihistamine. The next step would be to add a patented sleep medication such as
eszopiclone, zaleplon, ramelteon, or zolpidem. If sleep is not improved with these simple therapies, it isimportant to consult a sleep specialist because severe sleep disorders occur in up to 62.5% of persons
with CFS (compared to 7% in the general population).
25. Managing Pain
Pain can be managed with medications or non-pharmacological therapies. Non-pharmacologicaltherapies include rest, cold, heat, mineral baths, liniments, massage and physical therapies.
Pharmacological therapy begins with over-the-counter medications such as acetaminophen, aspirin,
and ibuprofen. In the United States, three medications have been approved for the neuropathic pain of
CFS. These are pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella). These reduce
pain modestly, but may have side effects such as nausea, sleepiness, and dizziness. Acute pain or severe
pain may need to be addressed with narcotic medications (such as tramadol, hydrocodone, oxycodone, ormorphine), although we try to avoid such medications because of possible addiction and side effects
such as drowsiness, hearing loss, and infertility.
26. 4 CFS Characteristics
In addition to the Four Core Symptoms CFS is accompanied by four typical characteristics:
First, CFS is an exertional illness. If you exert too much you get ill; on the other hand, if you rest too
much you will get stiff, sore, and deconditioned. So the lesson here is that it is important to “stay active
but not too active.”
Second, CFS is positional. That is, the illness gets worse with standing, but is relieved by lying down.
The lesson here is that lying down frequently is very important.
Third, persons with CFS have unique sensitivities. They become sensitive to light, sound, the chemicals,
odors and fumes; and the temperature must be just right! If you get too cold you will suffer severe
shivering; if you get too hot you will feel weak and maybe even faint.
Last, persons with CFS do not tolerate any stress. “Stress” may include deadline or appointments,
confrontation with family or friends, even difficulty with paperwork or dealing with government
regulations. It is important to know that mental stress (like reading, concentrating, or using thecomputer) is exhausting also, so it is important to take frequent breaks from such activities. I
recommend a rest period after 30-45 minutes of such activities.
27. Pacing
This is perhaps the most important concept that I can report to you: it is important to rest frequently
and set limits on activity. Please consider taking at least 2-3 rest periods each day. Usually 10-30
minutes is sufficient, but because the positional sensitivity you must recline; and due to stressintolerance you must clear your mind. In other words, do not read, make plans, watch television, talk on
the telephone while attempting to rest.

You might hear from some sources -- including your own doctor – that it is important to exercise
aggressively. Actually scientific evidence has shown that too much exertion will actually make yoursymptoms worse. Most persons with CFS tend to “push and crash.” That is, they exert too much thenare exhausted for hours to days afterward. Persons who “push and crash” regularly will not get better
because the body never has an opportunity to recover. The key to improvement is “energy conservation.”
That is, find out what are the limits of your energy and then stay within those limits. Once again, it isimportant to “stay active but not too active.” In order to accomplish this you may need help fromfamily and friends; or you may need to delegate work such as housekeeping or cooking; and you may
have to lower your expectations for keeping house, working, or exercising.
28. The Fallacy of Pushing and CrashingThis slide illustrates the fallacy of pushing and crashing. Let us suppose that you have ten blocks ofenergy to use over 4 days. Here is one block. If you exert too much for a day or two, then there is little
energy left for the next two days. So you may be very active for two days but then must recuperate fortwo days. This type of activity is common, but prevents improvement from CFS. On the other hand, if
you moderate activity for the first two days, then you still have energy for the next two days. You canaccomplish more with this approach!
29. Activity
Resting all the time is just as bad as pushing and crashing. No one ever gets better from lying around
all the time. Once again, despite what you may hear from other sources even the sickest patient can dosome activity, and it is important to attempt some activity if you expect to improve. Studies have shownthat even CFS patients in wheelchairs can exercise as long as they do not over-exert. That leads to thequestion, how much exertion is too much. Exercise studies in our laboratory and elsewhere havedemonstrated at least three ways to set objective limits on your exertion: interval activity, limiting yourheart rate, and limiting the number of steps taken per day.
30. Anaerobic Interval Activity
Using a technology called Cardiopulmonary Exercise Testing we are able to better understand why
persons with CFS have low energy, reduced stamina, and malaise after exertion. One of the first lessons
we learned was that persons with CFS cannot tolerate anaerobic activity. “Anaerobic” means that notenough oxygen gets to muscles. The muscles then must use glucose instead of oxygen as a source ofenergy, and glucose metabolism produces toxic products such as lactic acid. Most persons with CFS can
only exert 3-5 minutes before reaching this Anaerobic Threshold ; then they must rest for 5 minutes inorder to recover. Therefore it is possible to reduce flares and relapses by exerting for only 3-5 minutes at
a time, followed by 5 minutes of rest. We call this Interval Activity. The problem with Interval Activity
is that most people prefer NOT to vacuum, mow, or exercise in short intervals. They like to keep going…
31. Heart Rate Limits
The second lesson that we learned was that the Anaerobic Threshold always occurs at the same heartrate. Applying this principle, we can prevent relapses by limiting exertion so that the heart rate neverexceeds this level. Cardiopulmonary Exercise Testing helps us determine the heart rate at theAnaerobic Threshold. We can estimate this maximum heart rate, however, by using the formula
shown here. A person’s maximum predicted heart rate is equal to 230 minus the age in years. For a 50
year old individual, then, the Maximum Predicted Heart Rate is 230 minus 50, or 180 beats per minute.
The heart rate at the Anaerobic Threshold is 60% of the Maximum Predicted Heart Rate. So 180
multiplied by 0.6 equals 108 beats per minute. With this number in mind, you can purchase an
inexpensive heart monitor to insure that you do not exceed this limit.
32. Pedometer (Steps Per Day)

One last way to limit exertion is by monitoring steps per day. Just obtain an inexpensive pedometer andwear it all day. We know from experience that 1000 steps per day is too little activity and will lead tostiffness, soreness, and deconditioning. 5000 steps per day is too much for most, and could trigger aflare or relapse.
33. Severely Affected Patients
Please keep in mind: so far I have been making recommendations for persons with moderate symptomsof CFS. I understand, however, that many Japanese patients are severely affected. They are mostly
house bound, sometimes chair or bed bound. They experience considerable difficulty with all aspects ofpersonal care and may need help with even meal planning and preparation. Many are incapable ofliving independently. In addition, they are more likely to suffer food and chemical sensitivities, and may
be extremely sensitive to light, sound, and temperature. Some have severe neurological symptoms suchas atypical seizures, swallowing or speech difficulties, muscular jerking, or profound weakness.We do
not know why some patients are more severely affected than others. Many can be rehabilitated but ittakes special effort such as: Home visits from the doctor or specialist (or telephone consultations) Occupational therapy to improve the home environment (e.g., assistive devices, walkers, special
computer stands, ergonomic beds)
 Home physical therapy (range of motion or resistance against gravity, supine)
It is important for these individuals to stay active also, although the limitations are
greater Home Health Aid or caregiver (for cooking, laundry, housekeeping, shopping)
Patients should be provided with balanced nutrition and healthy organic or whole foods
 Insure pleasant activities (such as writing, embroidery or knitting, watching nature, music,
books on CD)
 Insure socialization (such as brief visits from friends or family, Facebook or other social media)
34. Severely Ill Patients
 Due to sensitivities, minimize medications and supplements to those absolutely necessary
 Prescribe medications in very low doses and titrate slowly
 Stress management and grief/loss counseling can be extremely helpful
 Encouragement. Try to achieve something every day; and do not accept your current restrictions.
(Aim to improve 1% each week!)
 Have lowered expectations for themselves and from others Above all the severely ill need “peace of mind and a feeling that they and their family weretaken care of, so that they could use all their energy on getting better.”
35. Pediatric CFS/ME : Epidemiology
Another topic that is infrequently discussed is CFS/ME in children and adolescents. While CFS/ME iscommon in adults, it is much less prevalent in chidlren and adolescents. One very large survey in
Chicago (USA) identified NO children with CFS/ME under the age of 12. On the other hand, theprevalence is adolescents (age 13-17 years) was 181 per 100,000. Overall , the prevalence of pediatric
CFS/ME in the United States is estimated at 100 to 300 cases per 100,000 persons. Takako Johdoi
reported in 2009 that the Japanese prevalence was “about the same” as in the United States. As in
adults, a predominance of females are involved, with ratios of two to five females for each male with thedisorder.
36. Comparison of Symptoms in Adolescents and Adults
Adolescents and adults have similar core CFS/ME symptoms, such as pain, fatigue, cognitivedifficulties, and non-restorative sleep. However, adolescents are much more likely to complain of
abdominal pain, sore throat, photophobia (or eye pain), swollen glands, and rashes.

37. Differences Between Adolescent and Adult Definitions• De-emphasizes fatigue and highlights symptoms(dizziness, decreased endurance, pain, &flu-like)• Symptoms endured for only three months• Abdominal symptoms have been added to list
• Autonomic symptoms added(orthostatic intolerance, palpitations, dizziness, shortness of breath)• Symptoms rated according to severity
1 = not present
4 = moderate
7 = severe• Symptoms must be either moderate to severe to meet criteria
38. Pediatric CFS/ME Management
The management of pediatric CFS/ME is similar to that of adults: sleep and pain are addressed first,
then comorbidities such as orthostatic intolerance and abdominal issues. Additionally, in children it isnecessary to assure that education is continued (sometimes by means of home instruction, tutoring, or ashortened school curriculum. Because children may not be able to attend school and make friends,
outside activities and social development needs to be addressed also. Lastly, a Japanese study showedthat 36% of school phobia cases were attributed to CFS/ME, confirming that CFS/ME takes a
psychological toll on adolescents.
39. Prognosis in Adolescents(15 Year Follow-Up )A longitudinal 15 year study by my associate, Dr. David Bell, demonstrated that the prognosis foradolescent CFS/ME is much better than adults, with almost 80% of subjects having recovered or
improved significantly. 20% remained ill or very ill. Similar studies in the US and UK have shown
similar improvement rates.
40. Summary of Pediatric CFS/ME
Another topic that is infrequently discussed is CFS/ME in children and adolescents. While the incidenceof CFS/ME is high in adults, it is almost unheard of in children under the age of 10, and estimates ofprevalence range from 100 per 100,000 to 300 per 100,000 in adolescents aged 10-17. The core
symptoms of CFS/ME are similar in adolescents and adults, but children tend to have more abdominal
pain, orthostatic intolerance (such as Neurally Mediated Hypotension and Postural Tachycardia), sorethroat, photophobia, and rashes. The diagnosis of Pediatric CFS is made clinically using a “casedefinition” that was published in 2008. Dr. Terahusa Miike and I were authors on that paper.
Management is mostly symptomatic, addressing pain and sleep problems first, then orthostatic andgastrointestinal issues. Children frequently have difficulty maintaining their school work, and so thephysician must also assure that education continues, that the child has social opportunities andmatures naturally. School phobia is a common problem that needs to be considered in adolescents.
Lastly, the prognosis is more favorable in adolescents than adults, with up to 80% reported significant
improvement or recovery, and about 20% remaining ill after 15 years.
41. Supplements
Many patients ask me what supplements I recommend in the management of CFS. First let me say that
supplements only optimize health, but they DO NOT treat CFS Left panel: I consider this group to be“essential supplements” Right upper panel: these are worthy considerations. Right lower panel: these
supplements are frequently recommended for mitochondrial support and are strictly optional. Pleaseminimize supplements. Not all supplements are safe, and many interfere with necessary medications.
42. Advanced Therapies

Some patients may benefit from more specific therapies. Orthostatic intolerance occurs in up to 50% of
adults and most adolescents with CFS. It is usually characterized by low blood pressure, rapid heart
rates, and possible syncope (fainting). Treatment involves drinking lots of water and ingesting
supplemental salt, but medications may be required. Many persons with CFS report diet sensitivities.
Most common are sensitivities to gluten (wheat, barley, and rye) and dairy products. Many patientsneed to avoid aspartame and monosodium glutamate also. Antiviral medications may be indicated whenlaboratory studies demonstrate reactivation of viruses or there are immunological symptoms such as
fever, sore throat, and swollen glands. Because the HPA Axis is suppressed, a subset of patients may
benefit from supplementation of cortisol or growth hormone. Lastly, two experimental treatments for
CFS that show great promise are Ampligen and rituximab. Both are immune modulators.
43. Summary
 Biological evidence for CFS is abundant CFS is not due to depression
 Begin management by addressing pain and sleep disorders first It is important to stay physically active, but not too active to trigger a flare
44. Summary (continued)
 Use interval activity, heart rate monitoring, or steps-per-day to prevent over-exertion The severely ill require additional care and resources, but can be rehabilitated Advanced therapy may benefit specific subsets of patients

Don’t ever give up!
45. HUNTER-HOPKINS CENTER
This is our office in Charlotte, North Carolina. We occupy the top floor.