A recording of this presentation is available HERE.
This week's Grand Rounds, by Dr. Alison Ohringer, was so phenomenal that I have literally been thinking about it nonstop since she finished. The topic-- Ehlers-Danlos Syndrome, Dysautonomia, and MCAS-- doesn't exactly sound titillating, but after years in primary care taking care of patients with chronic symptoms that I don't always know what to do with -- I had a serious physician "AHA moment".
Dr. Ohringer started with a silly meme that has now become an earworm for me: "If you cannot connect the issues, think connective tissues."
I have long thought of rheumatology and/or autoimmunity as a linking factor for non-specific symptoms in patients, particularly in women with fatigue, dizziness, and other systemic malfunctions. I also have long dreamed of studying how our enteric nervous system interacts with the central nervous system (leading to diarrhea, constipation, and anxiety), but I cannot say I had specifically tied in connective tissues to the issues-- until yesterday.
If you are a primary care provider, I definitely recommend watching this one! If you just want my notes, here goes. . .
Hypermobility= the ability of a joint to move beyond the normal range (can be isolated and/or benign (e.g. gymnasts) or generalized and/or symptomatic, impacting multiple joints and leading to pain, fatigue and can be associated with other symptoms)
Spectrum of severity of hypermobility:
Ehlers-Danlos Syndrome (EDS): a group of conditions characterized by one or more
of several common features: skin hyperextensibility, joint hypermobility, and tissue fragility, with
subtypes distinguished by family history, clinical criteria, and oftentimes genetic testing.
Hypermobile Ehlers-Danlos Syndrome (hEDS), previously referred to as EDS type III, the most common subtype, is
diagnosed by hx and clinical criteria. There is no genetic test. Many experience
symptoms of Mast Cell Activation Syndrome (MCAS), Postural Orthostatic Tachycardia
Syndrome (POTS) and related dysautonomia, small fiber neuropathy, and migraine
Hypermobility Spectrum Disorder (HSD) is diagnosed by history and clinical criteria, on a
spectrum ranging from asymptomatic to chronic pain. Some may have some of the hEDS
comorbidities, though they may be less severe
Prevalence:
- EDS 1/20-40,000 (vascular EDS 1/100K)
- hEDS 1/3000-5000
- HSD: ~1/500
Remember that there are connective tissues in skin, tendons/ligaments, cartilage, joint
capsules, blood vessels, bones, and organs including the GI tract. Also recall that mast cells reside in connective tissues This schematic below depicts Dr. Ohringer's explanation for the relationships between the issues. Note that MCAD=Mast cell activation disorders.
In this schematic, "Triggers" (including inhaled allergens, skin exposures, foods ingested) set off a sympathetic nervous system (fight/flight) mode that then triggers histamine>> leading to an activation of H1 receptors (allergic reactions, rash, hives), H2 receptors (GI, stomach, acid reflux, diarrhea), H3 receptors (mood and neurotransmitters: anxiety, OCD) and H4 receptors (small fiber pain and itch).
Symptoms of mast cell activation include a variety of organ systems, including not only allergy, but also cardiologic (hypotension, tachycardia), GI (diarrhea, cramping), and constitutional (fatigue and even memory/concentration problems).
MCAS (mast cell activation syndrome) = MCAD + abnormal labs
Dysautonomia and POTS:
Dysautonomia: all disorders of the autonomic nervous system resulting from
imbalanced sympathetic/parasympathetic activation
- can be a clinical diagnosis, can be diagnosed with certain tests
POTS: a form of dysautonomia meeting 2 specific diagnostic criteria:
- History of orthostatic intolerance with or without systemic symptoms
- Correlation of symptoms with a sustained increase in upright HR by at least
30 bpm (40 bpm if pt <20yo) within 10 minutes of standing or head-up tilt,
without orthostatic hypotension
Common symptoms in patients with MCAD and POTS/dysautonomia
General: fatigue, night sweats, anaphylaxis, weight changes
HEENT: itchy/watery eyes, nasal congestion, itchy throat
Cardiac: light headedness, pre-syncope, palpitations, tachycardia, labile BP
Pulm: shortness of breath, wheeze, cough
GI: refractory acid reflux, intermittent abdominal pain, nausea, vomiting, diarrhea
GU: bladder irritability and frequent voiding, uterine cramps, heavy menstrual bleeding
Derm: hives, itch, flushing, rash MSK: long bone pain
Neuro: LH/dizziness, brain fog, neuropathy
Diagnosis and Evaluation:
- Assess for hypermobility using the Beighton Score (score results dependent on puberty and age)
- Assess for EDS "red flags" (screening for vascular EDS and risk for ruptures, see image below)
- Eval for hEDS then
possibly for HSD once the red flags for the high-risk, genetic EDS subtypes have been ruled out
- Eval for comorbid dysautonomia and/or MCAD
- Rule out mimics (e.g. iron-deficiency, vit D deficiency, allergy, GERD, etc)
Management
This was my favorite part of the presentation-- for a cohort of patients that almost feel untreatable, Dr. Ohlinger gave us SO many ways to consider treating these patients. The general idea is outlined again on her schematic in green (details below). Trigger avoidance, mast cell stabilizers, Autonomic Nervous System regulation, and H1/H2 blockers.
Low-Histamine Diet
AVOID • Aged cheeses/Cured meats
• Fermented foods (sauerkraut, kimchi, yogurt)
• Alcohol (especially red wine)
• Vinegar-containing foods (pickles, soy sauce)
• Certain fish (tuna, mackerel, sardines)
• Leftover meats and fish
• High histamine fruits: strawberries, citrus fruits,
bananas, pineapples, papayas, plums, etc.
• High histamine vegetables: spinach, eggplant,
avocado, tomatoes, pumpkin, etc.
INCLUDE: Foods that are generally safe include:
• Fresh meat and freshly caught fish
• Fresh fruits (excluding those listed above)
• Fresh vegetables (excluding those listed above)
• Dairy substitutes (rice milk, coconut milk)
GOOD Eating Habits
• Eat fresh, home-cooked meals.
• Freeze leftovers immediately to prevent
histamine formation.
• Limit processed and packaged foods
Mast Cell Stabilizers:
Autonomic Nervous System Regulation - Systemic symptoms:
Glycemic control [1st line], Duloxetine or venlafaxine [1st line]
- Compression:
Compression socks (ideally to thigh) [1st line]
Abdominal binder IF no pelvic floor dysfunction [2nd line]
- Electrolyte repletion:
Daily oral rehydration solution [1st line]
• Normalyte powder, or LMNT powder, or DIY with ¾ tsp table salt, 2 tsp powdered sugar, ¼ tsp cream of
tartar, squeeze of lemon for taste, all in 750 mL water 1-2x/day
- Autonomic nervous system retraining:
Vagal tone exercises [1st line] see image below
- Symptomatic orthostatic tachycardia from POTS:
Cardio-selective beta blocker (or propranolol if no asthma/resp sx) [1st line]
Ivabradine (Corlanor) 5mg bid [2nd line]
Fludrocortisone [3rd line]
Midodrine [4th line]
H1/H2 Blockade
H1: allegra, loratadine, etc
H2: high dose famotidine
Pro Tips:
1) IF you cannot get a patient in with a genetic counselor, primary care CAN order an Invitae Genetic Panel
2) Low hanging fruit for everyone:
• Iron repletion for goal ferritin >50 (or >100 if baseline inflammation)
• Ferrous sulfate or iron bisglycinate M/W/F (Pure Encapsulations OptiFerin-C) if GI sx from other iron
• Vitamin D repletion for goal vitamin D >30
• Magnesium glycinate before bed is good for everyone who doesn't have diarrhea
I particularly appreciated how Dr. Ohlinger finished off her talk: with primary care strategies for managing what is a patient population that has often been dismissed, stigmatized, mislabeled, and struggled with a undeniably fragmented system. . .
Validate lived experiences: “Your symptoms are real and recognized.”
- Lean in to the "I don't know" with a commitment to find solutions together.
- Use structured frameworks (Beighton, consensus criteria) when possible to guide workup.
- Document functional impact clearly to support referrals and accommodations
The ANCHOR Trial, published in NEJM 2022 was a multi-site RCT that showed that, YES, screening at risk populations does work to prevent anal cancer. Primary outcome: anal cancer. Test subjects: Men with HIV age >35. Study found 9 anal cancers in the treatment group (those screened>> HRA>> treatment) vs. 21 cancers in the observation group. This equates to a 60% decrease in anal cancer.
