Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series.

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%. Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations. This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades. The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene. A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder. Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder. All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome. All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy. In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS.

Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome.

BACKGROUND: Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively. PARTICIPANTS AND METHODS: Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm2; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI). RESULTS: Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm2 in gastric antrum, duodenum, and colon, respectively. CONCLUSIONS: The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS.

Exploring the role of the endogenous opiate system in the pathogenesis of anemia in an opiate receptor knock-out model of Restless Legs Syndrome.

Restless Legs Syndrome (RLS) is characterized by bothersome leg discomfort accompanied by an urge to move to obtain relief and symptoms are worse at night and on lying down. There is at least partial and temporary relief with activity. It is also an opioid responsive disorder, often accompanied by iron deficiency with or without anemia, and inflammation may be a precipitating factor in some cases. We created two in-vivo opiate receptor knock out mouse models of RLS - a triple opiate receptor knock-out mouse and a mu opiate receptor knock-out mouse. Both sets of animals were restless during the sleep period as is also true of RLS. Both of our knockout models showed statistically significantly decreased Hemoglobin and Hematocrit indicating anemia and both models showed statistically significant decreases in serum iron suggestive of either iron deficiency anemia or inflammatory anemia. The rest of the hematologic studies were not consistent enough to determine which of these two types of anemia was present in either model. An additional experiment in normal wild type mice showed a statistically significant decrease in serum iron when an opiate receptor blocker was used. To our knowledge this is the first demonstration that deficiency of endogenous opioids might play a role in the production of anemia. Our hypothesis is that an intact endogenous opiate system is necessary for red cell homeostasis. The presence of opioid receptors both on red blood cells and on various immunologically based white blood cells suggest mechanisms by which deficiency in the endogenous opiate system could cause anemia of either the iron deficiency or inflammatory types. The administration of opioid agonists or antagonists to iron deficient cultures of red blood cell precursors is a next step in determining the role of the endogenous opiate system in the maintenance of red cell homeostasis and in the possible prevention of iron deficiency or inflammatory anemia where iron dysregulation is key.

Efficacy and toxicity of hydroxyurea in mast cell activation syndrome patients refractory to standard medical therapy: retrospective case series.

Determine efficacy and adverse events (AEs) of hydroxyurea (HU) in mast cell activation syndrome (MCAS) patients who were refractory to standard medical therapy. An electronic chart review was performed to find MCAS patients who received HU in a MCAS medical practice. Diagnosis of MCAS was established on the basis of mast cell (MC) activation symptoms in ≥ 5 systems plus ≥ 1 abnormal MC mediators and/or ≥ 20 MC/high power field on duodenal biopsies. Medicines not providing significant clinical improvement prior to HU were tabulated. The following symptoms were evaluated by patients on a 0-10 scale prior to and at the study conclusion: bone pain, abdominal pain, diarrhea, bloating, and nausea. Safety labs were obtained on a regular basis. Twenty out of three hundred ten (8.4%) MCAS patients received HU. Patients included 22 females, average age 42.4 years. Dysautonomia was present in 60%. An average of 10.6 (SD 1.7, range 8-13) medications were used prior to adding HU to various concomitant medications. Average dose of HU was 634 mg. In 20 patients who continued therapy for ≥ 2 months, there was statistically significant reduction of bone pain, abdominal pain, diarrhea, bloating, and nausea. Fourteen patients noted prolonged success with therapy. Six patients stopped HU within 6 weeks owing to AEs. Four patients treated ≥ 2 months had AEs and 2 led to HU cessation. All AEs were reversible. Refractory MCAS patients showed clear significant improvement in bone pain and gastrointestinal symptoms on HU. Systematic monitoring was effective in preventing the occurrence of severe HU-induced adverse events.

Restless legs syndrome is associated with long-COVID in women.

STUDY OBJECTIVES: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre-coronavirus disease 2019 (pre-COVID-19) time points. METHODS: Adults on LC-focused Facebook pages were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥ 18 years of age who never had overt symptoms of COVID-19. Pregnancy was an exclusion criterion for both groups. RESULTS: There were 136 participants with LC (89.7% females, age 46.9 ± 12.9 years) and 136 controls (65.4% females, age 49.2 ± 15.5). RLS prevalence in females with LC was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (P < .01) vs 6.7% in control females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among females with LC failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity, or use of antihistamines and antidepressants. CONCLUSIONS: The baseline prevalence of RLS in females with LC was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Postinfectious immunological mechanisms may be at play in the production for RLS symptoms. CITATION: Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Restless legs syndrome is associated with long-COVID in women. J Clin Sleep Med. 2022;18(5):1413-1418.

Molds, Mycotoxins, the Brain, the Gut and Misconceptions.

Molds are present in homes and other indoor places that are water damaged and they produce mycotoxins. One mold species can produce several different mycotoxins and one mycotoxin can come from several different molds. Even small amounts of mold growth in an air conditioner or in ducts will result in the occupants being chronically exposed, constantly breathing mold spores and mycotoxins, causing illness.

Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease?

For nearly a decade, case reports and series have emerged regarding dysautonomias-particularly postural orthostatic tachycardia syndrome (POTS)-presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently recognized, MCAS is being increasingly appreciated as a prevalent and chronic multisystem disorder, often emerging early in life and presenting with inflammatory ± allergic phenomena following from known mast cell (MC) mediator effects. There is rising recognition, too, of associations of MCAS with central and peripheral neuropathic disorders, including autonomic disorders such as POTS. Given the recognized potential for many antigens to trigger a major and permanent escalation of baseline MC misbehavior in a given MCAS patient, we hypothesize that in our patients described herein, vaccination with Gardasil may have caused pre-existing (but not yet clinically recognized) MCAS to worsen to a clinically significantly degree, with the emergence of POTS and other issues. The recognition and management of MCAS prior to vaccinations in general may be a strategy worth investigating for reducing adverse events following HPV vaccinations and perhaps even other types of vaccinations.

Mast cell activation symptoms are prevalent in Long-COVID.

OBJECTIVES: Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC. METHODS: Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms. RESULTS: There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. CONCLUSIONS: MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.

Restless Legs Syndrome Shows Increased Silent Postmortem Cerebral Microvascular Disease With Gliosis.

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease (P=0.015) and gliosis (P=0.003). T cells were increased in RLS compared with controls (P=0.009) and tended to colocalize with microvascular disease (P=0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T-cell invasion may be a secondary phenomenon.

Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Mast Cell Activation Syndrome: A Primer for the Gastroenterologist.

Mast cell activation syndrome is thought to be a common, yet under-recognized, chronic multi-system disorder caused by inappropriate mast cell activation. Gastrointestinal symptoms are frequently reported by these patients and are often mistaken by physicians as functional gastrointestinal disorders. This syndrome can be diagnosed by the medical history and measurable biomarkers. Gastroenterologists manage diseases associated with active inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils. The mast cell has only recently been recognized as a major player in our specialty. Gastrointestinal disorders from mast cell mediators often present with apparent irritable bowel syndrome, dyspepsia, chronic or cyclical nausea, and heartburn. Individuals with mast cell activation syndrome experience significant delays in diagnosis. The gastrointestinal symptoms are often refractory to symptom-targeted prescription medications. Beyond avoiding triggers, the best therapy is directed at modulating mast cell activation and the effects of the mediators. Many of these therapies are simple over-the-counter medications. In this article, we review mast cell function and dysfunction and the gastrointestinal symptoms, comorbid conditions, diagnosis, and management of mast cell activation syndrome. Gastroenterologists who become aware of this syndrome can dramatically improve the quality of life for their patients who previously have been labeled with a functional gastrointestinal disorder.

Restless legs syndrome is increased in postural orthostatic tachycardia syndrome.

STUDY OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) and restless legs syndrome (RLS) are both characterized by sleep disturbance along with autoimmune/inflammatory features and autonomic dysfunction. However, to our knowledge, there has been no direct study looking at the prevalence of RLS in patients with POTS patients compared with healthy participants (controls). METHODS: Ninety-six physician-diagnosed patients with POTS (89 female and 7 male) and 130 controls (99 female and 31 male) were administered the Cambridge Hopkins questionnaire. Participants who were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire were then contacted to determine the severity of RLS with the International Restless Legs Scale. RESULTS: More patients with POTS (15 of 96; 15.6%) than controls (6 of 130; 4.6%) were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire (P = .0048). A sensitivity analysis with only female respondents yielded similar results. RLS severity was in the moderate range (12.23 ± 9.22). CONCLUSIONS: There is a higher prevalence of RLS in patients with POTS patients compared with controls. This association may have to do with shared increased inflammatory/autoimmune load and autonomic dysfunction.

Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome.

OBJECTIVES: One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. METHODS: Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS. RESULTS: The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19's hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors' treated MCAS patients with Covid-19 suffered severe infection, let alone mortality. CONCLUSIONS: Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.

Low-dose Naltrexone Therapy for Psoriasis.

Safe, inexpensive, and convenient psoriasis therapy is desirable. Two recent case reports suggested that low-dose naltrexone is effective. Cases from our practice are presented in order to further the evidence of efficacy and safety of low-dose naltrexone in the treatment of psoriasis. Patients included 13 females, 2 males; mean age 57 years; mean psoriasis duration 16 years. Of the patients, 8 had psoriatic arthritis. In the past, 5 had completely failed and 10 had partially responded to =1 topical therapies. Patients used a self-assessed Likert scale on the effect of low-dose naltrexone on their psoriasis: 1 - worse; 2 - unchanged; 3 - slightly improved; 4 - somewhat improved; 5 - marked improvement. The response to 4.5 mg of oral naltrexone was as follows: 8/15 marked improvement; 2/15 somewhat improved; and 5/15 unchanged. Three adverse events included insomnia, diarrhea, and self-limited headache. Marked improvement was seen by 53% of the 15 patients. Low-dose naltrexone regulates lymphocyte responses, reduces cytokine production, and likely reduces mast cell activity. Low-dose naltrexone is safe, inexpensive, and appears be effective in this open-label study.

Restless legs syndrome is associated with mast cell activation syndrome.

STUDY OBJECTIVES: Mast cell activation syndrome (MCAS) is an inflammatory and allergic disorder. We determined the prevalence of restless legs syndrome (RLS) in MCAS because each common syndrome may be inflammatory in nature and associated with dysautonomia. METHODS: Individuals with MCAS were evaluated for RLS by two standard questionnaires. Prevalence comparisons included spouse control patients and two prevalence publications. MCAS diagnosis required mast cell (MC) symptoms in ≥ 2 organs plus ≥ 1 elevated MC mediators, improvement with MC therapy, and/or increased intestinal MC density. Clinical variables were studied. RESULTS: There were 174 patients with MCAS (146 female, 28 male, mean age 44.8 years) and 85 spouse control patients (12 female, 73 male, mean age 50.9 years). Patients with MCAS as a whole had a higher prevalence of RLS (40.8%) than spouse control (12.9%) (P < .0001) Male patients with MCAS had a higher prevalence of RLS (32.1%) than male controls (12.3%, odds ratio [OR] 3.4, confidence interval [CI] 1.2-9.7, P = .025), American men (8.4%, OR 5.2, CI 2.2-12.0, P < .001), and French men (5.8%, OR 7.7, CI 3.4-17.1, P < .001). Female patients with MCAS also had a higher prevalence of RLS (42.5%) than female controls (16.7%) but this did not reach statistical significance perhaps because of the sample size of the female controls. However, female patients with MCAS had a statistically higher prevalence of RLS than American women (10.0%, OR 6.7, CI 4.5-9.7, P < .0001) and French women (10.8%, OR 6.1, CI 4.4-8.6, P < .0001). CONCLUSIONS: RLS appears to be associated with MCAS. Effects of mast cell mediators, inflammation, immune mechanisms, dysautonomia, or hypoxia may theoretically activate RLS in MCAS.

Mast cell deposition and activation may be a new explanation for epiploic appendagitis.

Epiploic appendagitis is as an acute painful condition of the fat on the outside of the intestine. Thus far, there have been no publications to our knowledge that appendagitis can be caused by mast cells or can be associated with chronic pain. A patient with multisystemic disorders suffered with both chronic and acute attacks of abdominal pain for a year. The worst attack led to surgical resection of an enlarged sigmoid colon epiploic appendage. Careful review of her complex medical history and mast cell stains of gastrointestinal biopsies led to the diagnosis of mast cell activation syndrome. Re-examination of the resected appendage using an immunohistochemical stain demonstrated a high mast cell density which is a new histopathological finding. Treatment of mast cell activation syndrome and other related syndromes led to marked improvement in her health, including all types of chronic abdominal pain.

Decreasing recurrent bowel obstructions, improving quality of life with physiotherapy: Controlled study.

AIM: To compare (1) quality of life and (2) rate of recurrent small bowel obstructions (SBO) for patients treated with novel manual physiotherapy vs no treatment. METHODS: One hundred and three subjects (age 19-89) with a history of recurrent adhesive SBO were treated with a manual physiotherapy called the Clear Passage Approach (CPA) which focused on decreasing adhesive crosslinking in abdominopelvic viscera. Pre- and post-therapy data measured recurring obstructions and quality of life, using a validated test sent 90 d after therapy. Results were compared to 136 untreated control subjects who underwent the same measurements for subjects who did not receive any therapy, which is the normal course for patients with recurring SBO. Comparison of the groups allowed us to assess changes when the physiotherapy was added as an adjunct treatment for patients with recurring SBO. RESULTS: Despite histories of more prior hospitalizations, obstructions, surgeries, and years impacted by bowel issues, the 103 CPA-treated subjects reported a significantly lower rate of repeat SBO than 136 untreated controls (total obstructions P = 0.0003; partial obstructions P = 0.0076). Subjects treated with the therapy demonstrated significant improvements in five of six total domains in the validated Small Bowel Obstruction Questionnaire (SBO-Q). Domains of diet, pain, gastrointestinal symptoms, quality of life (QOL) and pain severity when compared to post CPA treatment were significantly improved (P < 0.0001). The medication domain was not changed in the CPA treated group (P = 0.176). CONCLUSION: CPA physical therapy was effective for patients with adhesive SBO with significantly lower recurrence rate, improvement in reported symptoms and overall quality of life of subjects.

Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment.

A patient with severe postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS) received immunotherapy with low-dose naltrexone (LDN) and intravenous immunoglobulin (IVIg) and antibiotic therapy for small intestinal bacterial overgrowth (SIBO). A dramatic and sustained response was documented. The utility of IVIg in autoimmune neuromuscular diseases has been published, but clinical experience with POTS is relatively unknown and has not been reported in MCAS. As a short-acting mu-opioid antagonist, LDN paradoxically increases endorphins which then bind to regulatory T cells which regulate T-lymphocyte and B-lymphocyte production and this reduces cytokine and antibody production. IVIg is emerging as a promising therapy for POTS. Diagnosis and treatment of SIBO in POTS is a new concept and appears to play an important role.