Thoughts on treatment of Gulf War Syndrome patients:

provided to the Veterans Affairs Research Advisory Committee (RAC) on GWS, February 2003; updated November 2003

Meryl Nass, MD

The basic idea of this treatment model is to identify all the patient’s problems (since this is a multi-symptom and multi-organ syndrome) and address each one. Improving nutrition, healing the GI tract, identifying and treating chronic infections, and using vitamins and low dose thyroid hormone have been the most helpful interventions in my practice. Suggested reading includes the books From Fatigued to Fantastic by Jacob Teitelbaum, MD and Making Sense of Fibromyalgia by Daniel Wallace, MD.

At every visit I inquire about pain, sleep, gastrointestinal function, energy, mood and cognition, diet, and adjust treatments to achieve improvements in all these areas. I also ask about hypotensive symptoms, arrhythmias, allergies, chemical sensitivity symptoms and additional problems when relevant.

I plan to update these recommendations as new information appears.

If sleep disorder exists:

• Trouble falling or staying asleep? If trouble only falling asleep, a short duration drug will do
• Do you wake because of pain?
• “Hot flashes” may occur secondary to SSRI antidepressants, indicating a need to adjust dosing, generally giving the drug more frequently
• Are medications interfering? (for example, an evening dose of wellbutrin)
• Can other medications be changed to promote sleep? (for example, take lisinopril and cal-mag supplements before bedtime)
• Any significant history of apneic episodes, daily headaches, daytime somnolence, cognitive impairment, snoring or marked obesity?

--If so, consider nocturnal O2 saturation monitor (inexpensive) or sleep study

--Males with fibromyalgia are especially likely to have sleep apnea

Treatments:

• Benadryl 25-50 mg 1-2 hrs before bed (duration 6-10 hours; makes the occasional person feel “wired”)
• Melatonin 3-6 mg 1-2 hrs before bed (mild)
• Valerian (variable dosing) duration 3-4 hours (mild)
• 5 Hydroxy-tryptophan 50-200 mg before bed (serotonin precursor; may help depression; mild )
• Amitryptiline 5-50 mg 1-2 hrs before bed, or another tricyclic antidepressant
• Trazodone 25-200 mg (mild antidepressant, may cause priapism so I avoid in males)
• Neurontin 100-800mg (also helps with pain)
• Cyclobenzaprine 5-20 mg 1-2 hrs before bed (duration 6-10 hrs, muscle relaxant)
• Ambien 5-10 mg 15 minutes before bed (duration 4-10 hrs, too strong for some patients, may disorient them; acts suddenly)
• Remeron 15-30 mg (causes weight gain so reserve for those underweight, is an antidepressant)
• Benzodiazepines (for short-term use; helpful if anxiety a problem; use benzodiazepines with a short half-life in those who are weak or may fall)

If dizziness, low blood pressure, syncope or orthostatic symptoms are present:

• Check levels of aldosterone and ADH; replace low aldosterone level with Florinef or licorice root (glycerrhizinic acid is the active ingredient; do NOT use DGL [deglycerrized] licorice); replace ADH with DDAVP (nasal or oral) if ADH low
• Adjust other medications if indicated, ie avoid most antihypertensives; in particular, diuretics and beta blockers may also be fatiguing
• Increase salt and water intake
• Rarely use midodrine after volume loading, for severe cases with syncope
• I do not use tilt table test due to high number of false negatives and positives; I do take orthostatic vital signs and careful history
• Theoretically, compressive stockings should also help

For patients with chronic pain:

• Determine if the pain is fibromyalgia-like (tends to be generalized, or to move around the body, appears to have no cause or be way out of proportion to the cause, and often severe at tendon insertions)
• Stretches and exercise as tolerated, warm soaks and massage VERY helpful
• Medications and therapy:

• Magnesium malate (or magnesium glycinate if patient tends to have diarrhea) in gradually increasing doses
• Low dose thyroid hormone is remarkably helpful; start after checking levels (free T4, free T3, TSH) with, for example, .05 mg thyroxin per day. Some patients do better, for unknown reasons, with armour thyroid or T3 plus T4 supplementation. Treat even if in normal range, but avoid doses that bring TSH out of the normal range, unless it is inappropriately low to begin with
• Feldenkrais physical therapy, to learn to adjust body mechanics thereby decreasing minor traumas
• Other forms of physical therapy or Yoga may also be very helpful
• Neurontin, which has a wide range of dosages
• Tricyclic antidepressants, low dose
• NSAIDS or Cox-2 Inhibitors only if no GI symptoms, with warnings to notify MD if any problems, gastrointestinal or otherwise
• If narcotics are required in rare instances, I always use a contract with patients and cease prescribing if the contract is broken. Purdue Pharma has excellent sample contracts
• For muscle aches or spasm, many different drugs can be tried: skelaxin, flexeril, soma (can be addicting), lioresal
• For the very common ‘restless leg syndrome (RLE),’ check for iron deficiency; try neurontin, amantadine, other antiparkinsonian meds if necessary; RLE is another cause of sleeplessness
• Quinine worth a try for nocturnal leg cramps
• Guiafenesin seems to help some patients but the regimen is rigorous, as they must avoid all salicylates in foods, drugs and personal care products and it takes months to get results (see book and website of Paul St. Amand, MD)
• Topical Lidoderm patches and various “pain creams” are extremely helpful for some patients

If severe localized pain, it may be due to fibromyalgia in addition to injury or other pathology

• Fibromyalgia greatly magnifies other types of pain
• Evaluate fully for other pathology
• Consider lidoderm patches for local anesthetic effect, often quite good for temporary amelioration (max dose is 3 patches for 12 hours per day)
• For severe headaches, try the gamut of available meds, including ergotamine and

triptan drugs. Try volume loading and florinef or licorice root if blood pressure is on the low side and/or patient is dizzy, as headaches may be due to CNS traction in patients with low blood volume, which is extremely common and can be hard to diagnose. Consider osteopathic manipulation, physical therapy, craniosacral therapy

For gastrointestinal distress, a good history is essential, and it should be worked up in the usual manner, ie endoscopy with biopsies, stool cultures and stool antigen tests, look for blood (and white blood cells) in the stool if chronic or recurrent diarrhea, etc.

• For chronic constipation, magnesium malate will usually solve the problem, and doses can be adjusted for optimal stool frequency; ground flax seeds are also useful
• Consider screening for gluten enteropathy with transglutaminase and antigliadin antibodies (thought to occur in 1 in 200 people; false negatives occur in patients on low gluten diets; blunted villi on biopsy still the gold standard but neg if diet does not include moderate amount of gluten; untreated can go on to develop lymphoma)
• Consider empiric trial of 2 weeks of Nystatin 200,000-500,000 units 5 times daily for gastrointestinal yeast, a hidden cause of diarrhea and sometimes malabsorption (the labs never seem to diagnose this, but I have been amazed how often this empiric treatment works; patients may need retreatment months or years later if they have a tendency toward candidiasis: for example, chronic mucocutaneous candidiasis; use especially in women who complain of frequent vaginitis); occasionally you need Diflucan or Mycelex if yeast are resistant to Nystatin
• Food allergies are surprisingly common, especially in those patients who have developed chemical sensitivities; use standard elimination diets to identify food intolerances and for treatment; avoiding problem foods also sometimes diminishes or entirely eliminates other (non-gastrointestinal) symptoms. I provide sample elimination diet handouts and spend a long time teaching patients how to use them.
• Other supplements that can be extremely beneficial include the “good bacteria:” lactobacillus/bifidobacteria replacement with a high quality product, and the use of digestive enzymes capsules with meals. Digestive enzymes can be obtained by prescription or at a fraction of the cost as a supplement. I used “Digestzymes” purchased inexpensively at emersonecologics.com. Suggest one month treatment trials of these substances.
• Supplements worth trying for upper GI distress (reflux, gastritis, non-Helicobacter ulcers) include DGL, aloe, mastica gum, digestive enzymes
• Glutamine is said to improve small bowel function in patients with short gut or with other forms of malabsorption (500mg bid)

Problems with fatigue and cognition are difficult to treat directly, but may respond to vitamin or other nutrient or hormonal supplementation:

· Screening labs on all patients included CBC, chemistries and LFTs, Magnesium, ESR (usually very low in CFS patients), B12, Free T3 and T4, TSH, DHEA.

· In selected patients additional tests include Lyme ELISA and/or PCR, tests for the presence of immune complexes, other tests for autoimmune disorders, blood gases and carboxyhemoglobin level, additional hormone levels (testosterone was frequently low in males, growth hormone treatment has been recommended for fibromyalgia patients with low levels)

· Additional tests for chronic infections such as Lyme, mycoplasma fermentans, if the sed rates or white counts tend to be high, or patients have lived in Lyme-endemic areas; patients frequently benefit from long-term (months to years) treatment with doxycycline 100 mg bid with meals or other antibiotics—note that many tests will miss these infections (false negative results are common) yet it is possible that in some patients their cure is necessary before you see good results from the other treatments you are providing. The implication is that empiric treatments are reasonable in this setting.

· Rule out chronic sinusitis with H and P and sometimes CT scan

· Tests of metabolic activity, such as the urine organic acid test (performed and developed by Metametrix lab in Atlanta) can direct your supplement recommendations; they provide a comprehensive explanation of the test and results, and will also do free consultations regarding results and treatment recommendations

· If the patient has fibro symptoms and is in the lower half of the normal range wrt thyroid tests, I supplement judiciously

· I check MMA (methyl malonic acid) levels in patients with B12 below 400 and supplement if abnormal, usually with sublingual B12 from Amni (emersonecologics.com); some patients only needed to use this 1-2 times weekly, others daily to get their B12 levels in the high normal range. One can also teach patients to inject B12, and B12 solutions with high concentrations (for example 30,000 mcg/ml) can be obtained from compounding pharmacies for occasional patients who need these high doses (for example, to detoxify cyanide or in patients with Leber’s hereditary optic neuropathy). Some patients seem to feel better with very high doses.

· I recommended that all patients take a high quality megavitamin with minerals, which frequently improved cognition and/or energy (Vital Nutrients has a good one that is inexpensive: http://www.vitalnutrients.net/vn.asp --you need a doctor’s [MD, DO, ND or chiropractor] order to buy from them, but they have excellent products.)

· Helping patients obtain high quality sleep helps a lot

· Omega 3 fatty acids may be missing: try 1 tsp to 2 tbl of flax or fish oil daily

· Improve the patient’s environment, ie avoid pesticides, petrochemical exhausts and other poisons

· N-acetyl cysteine may improve glutathione levels and also help detoxify acetaminophen and other drugs, in patients who require a lot of pain medications.

· The supplements NADH (Enada, 10-20 mg q am), Coenzyme Q10 (30-200 mg/day) and possibly SAMe may also help some patients with energy; also there are at least four different types of ginseng that are helpful for some

· Supplement DHEA in both sexes if low (usually 10 mg/day in females, 25 mg/day in males but blood levels can be repeated on replacement to assure proper dosage)

· WellbutrinSR may increase energy in depressed patients; 75-150 mg q am or bid, second dose should be taken by 2 pm to avoid insomnia. The new XL form is taken once daily in the am.

· I think GWS worsens latent psychopathology (ie OCD/depression/anxiety) that was well-compensated before chronic illness intervened, so consider psychotherapy.

· I use antidepressants but find their benefit limited. Sometimes a combination works better than one drug.

· Provigil may help with focus and cognition, plus wakefulness. It is indicated for idiopathic hypersomnolence

· Other supplements may sometimes improve cognition: acetyl L carnitine, phosphatidyl serine, ginkgo biloba

· Some patients are unable to hold on to electrolytes (the electrolyte pumps in cells require very large amounts of ATP which patients may not be able to produce) so supplying them (potassium, magnesium, calcium and sometimes sodium) as tablets or in powder form is very helpful in some patients, particularly those who develop arrhythmias. They should be buffered; “TriSalts” is a good brand.

If patient has chemical sensitivity by history, elicit all known noxious exposures and symptoms associated with them. Sometimes by simply removing the patient from exposures, many symptoms will resolve

· Give patients a questionnaire to use at home to help them check for possible noxious dermal, inhalant and food exposures, so they know what to avoid

· Mold may be a significant problem

· So are solvent and other petrochemical exposures (vehicle exhaust, pesticides, etc.)

· For acute exposure symptoms, patients may benefit from consuming the combination of buffered Vitamin C (or Emergen-C) and either Trisalts (buffered electrolytes) or Alka Seltzer Gold.

· Some patients report these buffered electrolyte solutions (Na, K, Ca and Mg bicarbonates) give them energy or improved sense of well-being

· Going to the ocean beach is very helpful for patients with chemical sensitivity; I do not know why

· Episodic severe cognitive impairment (for instance, getting lost while driving a familiar route) is often due to a noxious exposure in patients with chemical sensitivities, such as to vehicle exhaust.

· Educating these patients about chemical sensitivity is critical

For patients with a history of persisting symptoms related to vaccinations, I recommend they be certain additional vaccinations of any kind are essential before they receive them, as any vaccination frequently causes a relapse of symptoms

For patients with neurological findings, a complete workup is essential. They may have potentially serious illnesses, such as multiple sclerosis, ALS or polyarteritis nodosa. They can present with very unusual findings that do not fit standard diagnostic criteria. They may have Lyme Disease or another occult infection. They may have neurologic illnesses in addition to more common symptoms of GWS, fibromyalgia etc.

For women with severe premenstrual syndrome, I found 50% benefited from progesterone. Follow PAPs and all gynecologic issues closely in female GW veterans, who appear to have a high rate of abnormalities.

GWS patients often report that spouses and sometimes other family members have similar symptoms. We need a new approach to seeking transmissible agents routinely in these patients.

Dr. Ritchie Shoemaker (Pocomoke, Md)’s ideas deserve a clinical trial. Questran (a cholesterol binding resin) helped one of my patients considerably.

Other treatments suggested for CFS/FMS may be helpful though I have no personal experience with them for GWS:

· Oxygen therapy (via nasal cannula at 5 liters/min or hyperbaric, should be tried in patients with chronic dyspnea)

· Evaluate for excess tendency for thrombosis and treat appropriately

· Saunas for detoxification, especially for the chemically sensitive

Three homeopathic remedies have been recommended for GWS; although I know of no data to support these treatments, they have no side effects at all and are inexpensive. However, there are certain caveats to the use of homeopathic remedies, which must be followed to get any benefit, so patients will need to consult a homeopath or read about homeopathy. The remedies are: sulfur, thuja occidentalis and anthracinum.

Daniel Clauw, professor of rheumatology at U. Michigan and an expert on GWS, suggests that acupuncture and myofascial release therapy are helpful, according to at least one clinical trial in FM patients.