Age: 16.0
Sex: F
Vaccine: HPV4, HPV9
Symptoms: Encephalopathy, Endoscopy gastrointestinal normal, Enema administration, Eructation, Fatigue
Clinical narrative: Mast Cell Activation Syndrome; Postural orthostatic tachycardia syndrome; This literature marketed information has been received from the authors in a published article title as stated below and refers to a 22-year-old female patient. The patient had already had virtually a lifetime of multisystem polymorbidity. At age 3 she began showing behavioral rigidity and anxiety. She had three episodes of streptococcal pharyngitis as a child, treated with antibiotics. Around age 8, she developed severe obsessive-compulsive disorder (OCD, involving symmetry and needing certain objects arranged in certain positions); this lasted six months and then spontaneously resolved. At 10 years old, she was diagnosed with growth hormone deficiency and central precocious puberty. She had a histrelin acetate subcutaneous implant inserted and was treated with growth hormone injections for three years. When she had 12 years old, she developed bulimia, which was coincident with not only resumption of puberty but also suffering bullying at school. At 14 she became anorexic. Four months later, she started psychotherapy and consulted a nutritionist. Food intake soon normalized, but four months later she relapsed, requiring hospitalization for six weeks at age 15. Inpatient refeeding seemed to worsen her anxiety. She was tried on many anxiolytics, which did not help. Seven months after discharge, she relapsed and lost about 20 pounds of weight to 88 pounds, again requiring brief hospitalization followed by intensive outpatient follow-up. Her family history was remarkable for a mother with a history of infertility, premature menopause at age 43, and hypoglycemia. A younger sister had anxiety, depression, precocious puberty, growth hormone deficiency, and history of an eating disorder. Her maternal grandmother had thyroid nodules. Her paternal grandmother had osteoporosis.  On an unspecified date, about three months later (at 16-yearsold), she was series vaccination with unidentified Merck hpv vaccine administered, also reported as Gardasil (lot number not provided)(expiration date, dose, route of administration and anatomical location of vaccine were not reported) for prophylaxis, each on schedule.   On an unspecified date, two months following the third injection, she developed migraine headaches, soon followed by irritable bowel syndrome with gastroparesis, abdominal pain, and constipation, which she never experienced previously. She began having difficulty tolerating food. Bidirectional gastro-intestinal (GI) tract endoscopy and colonoscopy was unremarkable. She was diagnosed with lactose intolerance and gluten intolerance, but despite changing her diet in accordance, her symptoms persisted. Digestive enzyme supplements were unhelpful. Testing for small intestinal bacterial overgrowth (SIBO) was negative. She soon developed severe depression. At 17-years-old, she was treated by an integrative psychiatrist for mood instability (especially in the pre-menstrual period) with a variety of pharmacologic and herbal anti-depressants without significant improvement. When she was 18 years old, she went away to college, but three weeks later she developed severe dizziness and light-headedness, fatigue, and cognitive dysfunction ("brain fog"). Her abdominal pain and constipation relapsed, too. The symptoms were so severe she had to leave school. She consulted with several physicians (including a neurologist, an otolaryngologist, and cardiologist (particularly for episodes of extreme tachycardia, with no specific findings on evaluation)) and was diagnosed, about three months after onset of these symptoms, with Lyme disease and briefly received treatment with oral antibiotics from the diagnosing physician before soon consulting at a large functional medicine center, where she was further treated with IV ceftriaxone for six months, seeing resolution of joint and muscle pain and fatigue. During this interval, she also was diagnosed by a dysautonomia specialist with Postural orthostatic tachycardia syndrome (POTS). A trial of fludrocortisone immediately proved intolerable. Propranolol was then tried but provided only minimal relief. Coincident with her POTS diagnosis, she also developed diffuse joint pain and weakness. Testing found positive fluorescent in-situ hybridization (FISH) for Bartonella species and a positive IgM Western Blot for relapsing fever Borrelia, so she was diagnosed with concurrent bartonellosis and borreliosis. (She had a history of multiple tick bites as a child but no history of the rashes classic for any tick-borne infectious diseases). Initial treatment consisted of a rotating schedule of oral cefuroxime 500 mg twice daily, doxycycline 100mg twice daily, and azithromycin 500 mg once daily, but after three months, she had not shown any improvement. A percutaneously inserted central catheter (PICC) was placed, and she then was treated for another six months with intravenous ceftriaxone 2 grams daily together with oral atovaquone 250 mg twice daily and proguanil 100 mg twice daily. With this regimen, her joint and muscle pains significantly improved, but her gastrointestinal symptoms, fatigue, dizziness, lightheadedness, and brain fog did not. She received psychiatric care for depression and anxiety.  Genetic testing to investigate potentially relevant pharmacogenomic polymorphisms prior to treatment found heterozygous MTHFR-C677T, homozygous COMT-V168M, and an unspecified heterozygous CACNA1C mutation as well. She was started on bupropion but did not tolerate it. She then was treated with nortriptyline 30 mg once daily, whose only benefit seemed to be slight improvement in her constipation. At initial evaluation at 19, she reported persistent fatigue, brain fog, dizziness, light-headedness, oligomenorrhea, and extreme mood swings. A two-week trial of an oral contraceptive worsened all her symptoms. She also complained of urge incontinence, dry mouth, heat intolerance, headaches, sensitivity to loud noises, irritability, depression and anxiety, lightheadedness, poor appetite, many food intolerances, burping, constipation, abdominal pain, and easy bruising. She was living at home with her parents and was not able to go to school or work at that time.  Physical exam was notable for dark circles under her eyes (consistent with "allergic shiners") and lentigo reticularis about her legs. Dermatographism was seen on skin exam. Orthostatic vital sign measurements revealed a symptomatic 20-point increase in heart rate from sitting to standing.  Initial laboratory evaluation was significant for repeatedly elevated plasma histamine and chromogranin A levels (histamine: 10 ng/ml, 12 ng/ml, 10 ng/ml, and 12 ng/ml checked over several months (normal 0-8); chromogranin A: 25 ng/ml and 26 ng/ml (normal minor or equal to 15, and without any evident confounding factors including cardiac, renal, or hepatic failure, proximate proton pump inhibitor use, neuroendocrine malignancy, or chronic atrophic gastritis)). Serum tryptase levels were repeatedly stable in the low-normal range. She additionally was found to be positive for HLA-DQ2 but was never diagnosed with celiac disease. Repeated hemograms were notable only for persistent mild leukopenia (3200-3500/mm3). Erythrocyte sedimentation rate was repeatedly mildly elevated (28-42 mm/hr, normal = 20). A "panel" of testing for dysautonomia-associated autoantibodies found borderline to slight elevations in anti-CaMKinase, anti-dopamine receptor D1, and anti-tubulin titer.   Mast cell activation syndrome (MCAS), long pre-existing but likely exacerbated/escalated by Gardasil vaccination, was diagnosed. Initial efforts to find helpful histamine H1 and H2 receptor antagonists appeared unsuccessful. She could not tolerate loratadine, diphenhydramine, fexofenadine, famotidine, ranitidine, cetirizine, and levocetirizine, suffering worsening brain fog and "brain burning" with all formulations tried. Oral cromoglicic acyd (CROMOLYN) was then tried and found well tolerated and slightly helpful for GI symptoms for two years but then had to be discontinued, as her OCD was worsening (in spite of no change in oral cromolyn formulation) and thought to be possibly attributable to cromolyn. Ketotifen was added, and she was able to tolerate up to 2 mg once daily with some improvement in food reactivity but then had to go down to 1.5 mg due to worsening OCD. Low dose naltrexone (LDN) was tried next (up to 3 mg once daily) but again worsened her OCD and require discontinuation. A generic formulation of imatinib was tried next at a low dose (100 mg once daily) but quickly worsened her brain fog and was soon stopped. Hydroxyzine and montelukast also caused severe brain fog and could not be tolerated.  She then re-tried low dose imatinib (GLEEVEC) formulation but again saw quick worsening of brain fog as well as depression and had to stop it. Prucalopride was tried for her constipation, with only minimal improvement. BPC-157 injections were started and provided some relief for her constipation. She presently requires ongoing daily coffee enemas to evacuate. Meanwhile, around the time of her diagnosis of MCAS, neurologic consultation also led to a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). She was treated with IVIG 2 g/kg over two days per month. This treatment appeared to markedly improve her CIDP and initially improved her "brain burning" and "brain fog". However, over time she became more reactive to the treatment (with this reactivity appearing to be more lot specific than brand-specific), and three months after the relapse of her OCD (not experienced since childhood), after about two years of IVIG treatment in total, this treatment was stopped.  Three months later, a repeat panel showed elevations in all markers except for the anti-dopamine receptor D2L titer. The anti-dopamine receptor D1 titer was 1:8000 (previously 1:2000, normal 1:500-1:2000), anti-tubulin 1:4000 (previously 1:2000, normal 1:250-1:1000), and anti-GM1 titer 1:320 (normal 1:80-1:320). CaM kinase II activity was one of the highest levels ever seen by the laboratory at 215% (normal 53-130%). These results were felt by the laboratory to be consistent with encephalopathy of possibly infectious or autoimmune etiology. Celecoxib 100 mg once daily, soon escalating to twice daily, was tried and was tolerated well but had no effect on her brain fog or OCD and was stopped. The only intervention which had an appreciable effect on her OCD was oral progesterone 100 mg once daily. This treatment immediately improved her OCD, but this improvement was lost after six weeks and was not regained even after increasing the dose to 200 mg once daily. Several courses of oral antibiotics were given after repeat testing for tick-borne infections showed elevated Babesia duncanii IgG antibodies and elevated Bartonella henselae IgG antibodies, but the patient had no response to any of the regimens, including various combinations of rifampin, hydroxychloroquine, azithromycin, clarithromycin, sulfamethoxazole-trimethoprim, minocycline, and doxycycline.  As of March 2020 (age 22), her chief persistent symptoms include severe OCD, oligomenorrhea, and persistent constipation. The OCD has not responded to numerous psychopharmacological interventions, including vilazodone, lamotrigine, and lurasidone. Alprazolam has been only mildly helpful for her anxiety. She is completely disabled from OCD. She was being evaluated for ketamine infusions.  Literature report:   Upon internal review the of Mast Cell Activation Syndrome (MCAs) was considered as medically significant.   This is one of several report from the same literature article.   A copy of the published article is attached as further documentation of the patient's experience.