What follows are my notes from this weekend's lecture to Mass CFIDS by Dr. Hugh Calkins, one of the original Johns Hopkins researchers to publish on the link between CFS and Neurally Mediated Hypotension (NMH). Dr. Calkins said it was the same lecture he usually gives to physicians and cardiologists, and he went awfully fast. But I believe I got the major points. I hope people find my notes useful. Feel free to share these with others who may find them useful (but let them know they are the unofficial notes of a PWC with fast but not infallable typing fingers!)
Dr. Hugh Calkins' lecture to Mass. CFIDS
Saturday, June 6, 1998
General Mass. CFIDS Notes
AACFS (American Assoc for Chronic Fatigue Syndrome) conference in October in Cambridge (MA, USA) -- first two days research presentations (open to patients); third day is for patients who can't attend the whole 3 day conference. Discount for Mass CFIDS members. Dr. Komaroff is chairing the meeting.
Oprah Winfrey show next month will cover CFS!! (Thanks to efforts by Patti Schmidt) Title of show will be: "Serious Illness which took forever to be diagnosed" (illnesses covered: thyroid, lyme, MS, leukemia, and CFS). *Wednesday, July 29th on ABC*. Oprah has a web site on AOL for people to give feedback, encouragement, and thanks.
NEURALLY MEDIATED HYPOTENSION (NMH) AND THE CHRONIC FATIGUE SYNDROME (CFS)
Dr. Hugh Calkins, Cardiologist and Electrophysiologist
Researcher Johns Hopkins University
Co-author of original March 1995 article linking CFS and NMH
Reviewed research they've been doing linking NMH and CFS. In cardiology community CFS (and NMH link) getting more legitimacy.
NMH (also called Vasodepressor syncope, and other things) -- is a fainting disorder. Many people with the condition learn to sit down before they faint. The initial study showed that patient did not need to faint to have the condition.
Very important how the Tilt Table Test (TTT) is done. Temp of room must be kept constant, no talking, no fidgeting, etc.
At the moment, CFS is an "emerging" reason for TTT -- so insurance probably won't reimburse. If your doctor sends it in as a test for lightheadedness or pre-syncope, then it will probably be covered. It's an _accepted test_ for those symptoms.
Back in the 1930s there was a link in the medical literature between salt, heat and lightheadedness, fatigue, and many symptoms similar to CFS.
First Johns Hopkins (JHU) study: "Is Neurally Mediated Hypotension an Unrecognized Cause of Chronic Fatigue?" Rowe PC, Bou-Holaigah I, Kan JS, Calkins H.
The hypothesis they were trying to prove: a proportion of patients with CFS actually have treatable NMH.
Hopkins Protocol for TTT
Stage 1: 70 degree tilt, for 45 min
Stage 2: 70 degree tilt, gave 1-2 mcg/min isoproterenol(adrenaline), then tilted for 15 min
Stage 3: 70 degree tilt, 3-4 mcg/min isoproterenol, then tilted 10 mins
Positive TTT result:
1) syncope or pre-syncope (don't need to faint to have positive test)
2) >25mm HG drop in SBP
3) no associated increase of heart rate
Virtually every patient of that small study improved on treatment. Memory, well-being, and activity level improvements -- 47% had complete resolution of symptoms, 37% partial improvement, 26% didn't respond.
When they tried to get that initial study published, it was refused by the New England Journal of Medicine, because they believed CFS was mental and their results must be placebo.
Submitted proposal to NIH and get rejected. Then they got hooked up with the CFS part of the NIH (Stephen Strauss willing to fund it with his own group's money and fought other part of NIH to get funding). Got funding. Expecting study to be done in 6 months (will finish sooner if they get more subjects).
Found: 340 patients with CFS
Postural Tachycardia Syndrome (POTS) -- this is different than NMH, and can be diagnosed by any doctor checking. Doctors should be checking blood pressure laying down and then standing up (several times at an interval whilst standing).
62 % had NMH
5 % POTS
11 % Both
77% either NMH or POTs
More severe symptoms are more likely to have POTS; less severe symptoms more likely to have NMH.
Fibromyalgia -- studied that because it was so similar. Well over 90% had positive TTT. All Fibro patients had their symptoms exacerbated by TTT (10 min median onset of symptoms). Have not yet pursued a study of these fibromyalgia patients (due to lack of staff/funding). One of the JHU physicians beginning to study Lupus patients who test positive in TTT. Getting there, but slow process.
JHU has TT tested several thousand patients. For other researchers who are getting different results, they would question their TTT protocols. The protocol (listed above) is very important.
1/3 get a lot better; 1/3 get some better; 1/3 don't respond.
CFS is closely associated with NMH Fibromyalgia may also be associated. These preliminary clinical observations may be valuable, providing a framework to understand the clinical features of this disease, and help redirect research efforts.
Dr. Calkins was struck by the cognitive symptoms of CFS -- this is a problem linked to lack of blood flow to brain. Abdominal symptoms: when there are blood pressure problems, irritable bowel, pain, etc., lack of blood flow to stomach (body trying to redirect blood flow to brain); Pain: blood flow to skin level problems.
Frequent CFS symptoms include problems standing on lines in stores, etc., and these kinds of symptoms are consistent with NMH.
JHU/NIH studying randomized double-blinded test of Florinef (fludrocortisone).
***Looking for volunteers of this study:
***Johns Hopkins, call: 1-800-624-4562 or
***call NIH: 1-800-772-5464 ext 659
***(difference -- NIH pays for travel if you have positive TTT)
Current Approach to Evaluation and treatment of patients with CFS
1) if TTT positive -- increase salt intake (>3gms/day) increased fluid
2) Florinef: 0.05 mg/day, increase to .2mg/day as needed & Kdur 20 mg/day
3) if incomplete response: beta blocker (they've stopped using disopyramide), also consider SRI (e.g. Serzone 100 mg bid, then 150 mg bid)
4) Theodur, Ritalin, Midodrine (potent alpha-receptor agonist) -- initial dose 2.5 mg tid, (mean dose 14+/-8mg), (Range 5 to 32.5 mg/day) -- typical dosage is 10mg
If patients failed on Florinef, they are now doing study on Midodrine (more commonly known as Proamotine (not sure of spelling). Midodrine was very expensive but seems to have come down in price. If you failed florinef, call JHU to see if you qualify for Midodrine study (see 800 number above).
1. Unanswered questions they are looking into:
Optimal evaluation and management?
Existence of subgroups exist?
Relationship with POTS?
Is TTT necessary?
2. How they look at the link between CFS and NMH -- viral infection or "insult" event causes problem in blood vessels in hands and feet and increased pooling in legs.
Salt has gotten a really bad wrap in the public press. PWCs are often on low-salt diets. Salt restriction really very ineffective way of controlling high blood pressure. A typical example of a case is that the father got hypertension, salt was removed from the family table, and the child has CFS and NMH symptoms.
Related study: "Low Urinary Sodium is Associated with Greater Risk of Myocardial Infarction Among Treated Hypertensive Men" (Alderman et al. Hypertension 1995)
Questions and Answers
1) Has anyone done PET and SPECT scans before, during and after TTT? --
Money issue. They are pursuing it; study defined, but lacking funding (tests are expensive). Hoping to do it.
2) Many PWCs seem to have initial positive response to Florinef and then it seems to wear off.--
We don't think we are 'curing' CFS, just treating symptoms. Florinef may help, then some other 'insult' (e.g. virus, diarrhea, sweating more), and need to adjust salt intake and florinef. They don't have resources to follow the 2000+ TTT patients and how they've responded longer term. All funding is currently going to the Florinef study.
3) Dosages of Florinef? --
Florinef can cause acne. Patients that have problems with Florinef, go to Midodrine usually. Other medical specialties use Florinef (for other conditions) go up to 0.4mg. Dr. Calkins doesn't usually go above 0.2mg.
4) Do you often put PWCs on Florinef and Midodrine together?
No. Florinef usually helps. If they don't tolerate Florinef (e.g. edema, acne, depression), then go off and try something else. If they tolerate Florinef, but get no good effect, then stay on it and then add other drugs. So Midodrine patients are often on Florinef, but Florinef patients not always on Midodrine.
5) How to educate physicians on this?
*** Physician information packet and Patient Information Packet available from JHU. Call 800-624-4562. ***
6) If someone has a negative tilt elsewhere, do you think they should be retilted if the JHU TTT protocol was not followed? Probably -- JHU is the only published protocol documented to work. If they are doing things (e.g. talking to patient, poking, saline before test, etc.) that neutralise test, then should have redone somewhere that uses same JHU protocol.
7) If you have Hypertension can you have NMH?
Yes. Many NMH patients have borderline low normal blood pressure. However, you can be hypertensive and have NMH. A hypERtensive patient can take florinef and have their blood pressure go down. Hypertension does NOT rule out using Florinef.
If you have severe hypertension, treatments can make NMH symptoms worse. Beta blocker and ACE-inhibits best hypertension treatments that can help NMH.
8) Beta blocker - side effect of beta blocker can be fatigue... how can you use a drug that may cause fatigue to cure fatigue?
The trigger is first blood pooling (for which useful things are: salt, water, support hose, putting up head of bed), then once less blood is getting back to heart, then sensors increase adrenaline. Beta blocker blocks increase in adrenaline to block strong heart contraction that drops blood pressure (bp). In most patients you don't need both Florinef and beta blocker.
9) Question about Dr. Bell and Dr. David Steitchen's work on blood volume and circulating red blood cells problems and how this relates to NMH? Dr. Calkins thinks they are all heading in the same direction. Bell, etc., are studying underlying reasons of these abnormalities.
10) Impact, if any, of asthma drugs on the heart and NMH.
There is a tremendous overlap with allergic disease and CFS. Until allergies are under control, can't treat the NMH effectively. Theodur/Theophylline should help NMH. No objective evidence that asthma treatments can make NMH reflex worse (even though they are often adrenaline-like).
11) What are your thoughts of treating with licorice root for people sensitive to Florinef?
If patients can't tolerate Florinef, licorice root is useful to try. Hard to get dosage right. (*see below for a PWC's reference for good source of licorice)
12) Are you tracking whether people are running fevers? Magnesium and potassium can cause problems for PWCs; are you tracking who is getting mag and potassium?
Yes, they test the electrolytes and everyone gets mag and potassium. They think immune system activation is secondary. Details of study are very thorough (Dr. Stephen Strauss has been a big help because he's a skeptic, so study is designed to overcome his skeptism.) and tracks this. They find these secondary immune activation symptoms (e.g. fevers, swollen glands) get better when NMH is able to be successfully treated.
13) NIH is getting much more generous and encouraging grants for studies that explain what JHU found with CFS and NMH. The good thing is that people are getting involved who are not long-standing CFS supporters. New thinking and new support.
14) Someone expressed suspicion that immune activation is _secondary_ to NMH problem. E.g. fevers, swollen lymph nodes, etc.
Dr. Calkins said that all these symptoms got better when a patient was successfully treated for NMH.
15) Question about unknown weight loss and NMH.
Dr. Calkins said they must exclude cancer, severe depression, and other illnesses that can cause unknown weight loss. In general, weight loss will exacerbate NMH! Prefers people NOT go on diet to try to lose weight while trying to do the JHU NMH protocol.
16) Florinef can cause depression (as can beta blockers) - Midodrine and Ritalin don't have this side effect.
*17) Where to get Licorice extract -- patient suggested Clark Pharmacy (licorice root compound) 1-800-480-3432 US$31 for 8oz (PWC mentioned she takes 1/4 tsp in morning)
18) Ritalin dosage Dr. Calkins uses: 5mg 3 times a day (up to 15 mg 3 times a day)
19) If patient has POTS, then avoid beta blocker, which would make POTS worse.
20) Sleep disorders ?
When NMH gets better, sleep disorders improved.
21) What kind of doctor would you send someone to to follow up on this?
A good open-minded doctor who is willing to be educated An internist is fine -- the internist can follow up and call cardiologist and ask for TTT, etc. as long as they are willing to be educated about NMH.
22) Have you been finding abnormal levels of cortisol in PWCs?
Each researcher follows their own theories. They are not seeing any data (about cortisol) to make them think so.
23) Do patients have subjected feelings of coldness?
The part of the brain that controls heat/cold intolerance is right next to part of brain that controls bp. (Reynaud's is separate illness which causes circulation problems in the hands and feet).
24) re: Midodrine
Need this study to be published, so that Midodrine will be a known treatment (for CFS) or insurance won't pay for it. Midodrine study starts in a month -- call same 800 number (listed above) for information and eligibility criteria.
25) Would you put someone on Florinef if they don't have a positive TTT?
Difficulty lies in, if Florinef doesn't work, then it's Midodrine (and other stronger drugs). Florinef without a firm diagnosis of NMH would be ok, but stronger medicines shouldn't be prescribed without TTT diagnosis.
26) They think a large proportion (majority) of CFS patients have NMH -- not all. Of the people with NMH, 1/3 won't respond to this treatment.
27) ALL DOCTORS SHOULD TEST BP LAYING DOWN AND STANDING UP!!
Orthostatic hypotension and POTS (different from NMH) are well known and treatable -- Midodrine is approved for that. How long should you be standing for? Take it laying and then take it standing and take it ever minute for 5 minutes whilst standing.
28) Do you check AHD levels?
No. That's interesting research being done in CA.
29) Precursor symptoms as important as the fainting. Some cardiologists are ill-informed about NMH and importance of pre-syncope (pre-fainting) symptoms.
30) If you are intolerant to caffeine should you not take Midodrine?
31) Is POTS same as Orthostatic Tachycardia -- yes. it has many names.