125) New Hope for HO- mast cell activation and antihistamines

We, the parents of kids with rare diseases, become default experts of their medical conditions in order to find answers where the medical profession falls short.  We read the research literature, network with other parents/patients in similar situations, network with experts, and act as sleuths to solve problems that doctors cannot solve; we do it out of love and out of desperation. One such mother is CM (who prefers to remain anonymous for now).  CM has been a relentless medical sleuth for her son's idiosyncratic and idiopathic conditions since his birth and I am very excited to share an interview of her on her recent discoveries that provide even more hope for HO and more!

1.  Please give a brief description of your son’s medical history

Since birth my son has experienced unusual difficulty regulating stress. But aside from situational stress regulation, he has had no other social, intellectual or emotional issues. It’s been a baffling and frustrating experience for him. Difficulties escalated at age 12, likely with the onset of puberty. Serious and sudden depression began at this age along with strong Cushings-like features. He reported constant hunger and began intense food-seeking. Depression was treatment-resistant to several trials of psych meds from ages 12-16. Professionals often remarked that he was not a typical case. 

At age 19, lab work revealed endocrine issues and much of his puzzle began making sense. At age 20, a week-long visit at the National Institute of Health confirmed that the issues were hypothalamic in nature. Doctor’s believed that my son had something resembling Froelich syndrome, but they did not know the cause and assumed that it might be genetic. Whole exome genetic testing was ordered for my entire family, but nothing was identified.

[Note that my personal hypothesis is that my son’s endocrine issues relate to his time in utero. I have an auto-immune condition called antiphospholipid syndrome that causes my blood to clot too well and can cause issues during pregnancy. My son was not growing well because of my blood clotting and was considered to be growth-restricted (IUGR). I was given three full courses of betamethasone to increase lung growth before his premature birth at 34 weeks. This dosing would be considered excessive today.]  

2.         What treatments have you tried in the past to help your son?

Unfortunately, we did not know the origins of our son’s condition for many years. His HO behavior began at age 12.5 along with very serious, suicidal depression and sleep issues. We began traditional antidepressants and other psych drugs. These consistently made problems worse and also caused adverse side effects. After four years of trying different medication combinations, we had him tested for genetic markers that relate to psychiatric medicines and learned that he was lacking liver enzymes to process many psych drugs. We turned to Neurofeedback (NF). Although NF didn’t bring fast relief, over time it helped him normalize his sleeping hours and resolved his depression. We could see by his EEG that his brain waves were functioning much better. He felt much better too, but issues remained. His daily life was still impaired by the constant hunger, serious fatigue (even with better sleep patterns), and an inability to complete basic work tasks. Additionally, he was dealing with severe Seasonal Affective Disorder (SAD), making the winter months very tough. 

When we did finally learn of his hormone deficiencies, he was 19. I quit my job and began my research, looking for connections. So much now made sense, but there were still questions.  Treating the hormones helped greatly with the fatigue, but problems still remained. The HO and SAD did not resolve with the hormone treatments, and his ability to complete basic tasks remained a curious problem that didn’t fit the endocrine pathology. In fact, it was this inability to do the things he wanted to do that bothered him most and confused me greatly. 

His local endocrinologist was fantastic and assisted me as we explored novel treatments based on the research I was doing. Overtime, we tried several approaches including oxytocin, metformin, Victoza, ADHD medication, and micro-dosing of dexamethasone. None of these treatments helped much and we discontinued the trials. But I continued to amass research as I tried to understand the biology and think through new options. 

3.         For which vexing symptoms have you found successful treatment?

Demand Avoidance

The most vexing symptom to our son was his inability to complete things that should be easy. This problem bothered him most and made very little sense to anyone who observed him. Tasks that were demanded daily, like brushing his teeth or doing homework, were the hardest. Doctors at the NIH called this an “atypical psych symptom.”

The only other population who seemed to experience this unusual problem was the autistic population. But our son was not autistic in any other way. He has had full psych evaluations, had seen many therapists, and had years of schooling where no professional thought he was the least bit autistic.

As I researched further, I learned about a sub-classification of autism used only in the UK called Pathological Demand Avoidance (PDA). Proposed criteria as listed on Wikipedia include:

1.     Passive early history in the first year, avoiding ordinary demands and missing milestones

2.     Continuing to avoid demands, panic attacks if demands are escalated

3.     Surface sociability, but apparent lack of sense of social identity

4.     Lability of mood and impulsive

5.     Comfortable in role play and pretending

6.     Language delay, seemingly the result of passivity, often caught up quickly

7.     Obsessive behavior

8.     Neurological signs (awkwardness, similar to autism spectrum disorders)

Wikipedia contributors. (2019, June 21). Pathological demand avoidance. In Wikipedia, The Free Encyclopedia. Retrieved 21:27, July 5, 2019, from https://en.wikipedia.org/w/index.php?title=Pathological_demand_avoidance&oldid=902800995

My son ONLY fits the second of these criteria. But I kept this connection to autism in mind as I researched. 

Last fall I was introduced to the work of Dr T.C. Theoharides , he believes that mast cell activation in the hypothalamus is the cause of autism for a subset of the autistic population. This was fascinating to me as I knew that my son had hypothalamic disease of unknown origin and he had one unusual trait that was shared with the autistic population.

I learned that inflammation in the hypothalamus can be exasperated when mast cells (immune cells) react to cortisol releasing hormone (CRH). CRH is released when our body experiences stress. Dr Theoharides believes that these mast cells degranulate, which is sort of like a mini explosion, and affect nearby neurons that influence behavior. He treats with an antihistamine that can cross the blood-brain barrier and a flavonoid supplement that acts as a mast cell stabilizer. 

I began this treatment with my son on March 15th and by April 4th he was noticing changes. I was expecting to be treating the one autistic trait that he hated, his inability to handle demands. 

Turns out we got a big bonus!

Hypothalamic Obesity 

Not only did the demand problem show improvement, the HO with hyperphagia has shockingly resolved! His constant hunger subsided. Of course his hypothalamic obesity has been a seriously vexing problem too and it was contributing to horrible weight gain and the related problems that accompany metabolic syndrome and morbid obesity.

Because of the appetite decrease, he began to employ intermittent fasting in an attempt to lose weight. This would have been impossible prior to treatment. My son is 5'10"  (177.8 cm) and on March 28, he weighed 337 pounds (153 kg). He’s been actively trying to lose weight this way with for the last three months and is now 293 pounds (133 kg), down 44 pounds (20 kg). Now that his hunger is controlled, losing weight is far less work now compared to before when he was trying not to binge every night. 

Iron, WBC & Insulin Normalize

But there was more! Labs run seven weeks after starting the treatment had some great surprises. Iron which had been chronically low when my son wasn’t supplementing was fully normalized even though my son hadn’t taken iron in seven months. Additionally his chronically high white blood count and insulin level both normalized too. 

4.       What medicines and at what doses is your son using?

For Growth Hormone Deficiency (diagnosed April 2017)

• Omnitrope 0.6 mg -injected daily 

For Hypogonadotropic Hypogonadism (dx April 2017)

• Testosterone cypionate 200mg/ml - 0.25ml (44mg) IM/SQ TIW -injected
• HCG 250iu SQ TIW -injected
• Anastrozole 0.30mg po EOD -oral

For Hypothyroidism (dx April 2017)

• Liothyronine 50mg ( 25mg 2x/day) -oral

For Seasonal Affective Disorder (treating since late summer 2018)

• Bupropion XL 300mg (added mid-Aug 2018, started 150 and went up after 3 weeks) -oral
• Desvenlafax Succ ER 12.5mg  (added 9/13/2018) -oral (only a small dose is tolerated)

For Inflammation (began 3/15/2019): these are the featured medicines of this interview

• Hydroxyzine HCL 25mg-  2x/day -oral
• Neuroprotek (flavonoid supplement containing Luteolin, Quercetin, Rutin) 4-6 per day, although he started with 2/day for the first four weeks -oral

Other Supplements:

• Vit C (500mg) -oral
• Vit D3 (42,000iu/ week) -oral
• Multivitamin (no iron) -oral
• ProbioMax Lean DF probiotic (began 4/25/19)

5.          How did you discover the treatment? 

An internet friend who knew of my son’s diagnosis forwarded me a video by Dr T.C. Theoharides entitled  Brain Allergy and ASD.  There was no mention of hormone deficiencies or hypothalamic obesity but I watched intently wondering if my son’s hypothalamic dysfunction could be tied to inflammation.

My previous research had been focused on the endocrine effects of over-exposure to steroids in utero. I had learned from this work that there are immune system effects as well as endocrine effects, but I didn’t understand the immune component.  

I then gleaned more specific information about the actual treatments that Dr. Theoharides was using by listening to podcast interviews and taking notes. I shared the findings with his endocrinologist who was very positive about doing a trail of treatments:

1.     All Things Mast Cell with Dr. Theoharides

2.     Interview with Scott Forsgren: Mast Cell Master

Some articles of interest: 

1.     Is a subtype of autism an allergy of the brain? 

2.     Mast cell activation and autism 

3.     Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis

4.     Thyroid Hormone, Thyroid Hormone Metabolites and Mast Cells: A Less Explored Issue

5.     Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin

6.     Flavonoids: A Promising Therapy for Obesity due to the High-Fat Diet

7.     Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity.***

8.     The Histamine H3 Receptor and Eating Behavior ***

***Note that these articles suggest that an H1 antihistamine like hydroxyzine would be contraindicated for obesity. Yet, the opposite is occurring in my son’s case and he reports that his hunger is significantly decreased when he takes Hydroxyzine. More research is needed to understand this paradox. But clearly there exists a relationship between histamine receptors and feeding behavior.

6.         What is the theory of how treatment is working?

The hypothesis goes like this: 

Brain inflammation, particularly inflammation in the hypothalamus, was an unidentified problem for my son. This inflammation was made worse by any and all stress he experienced in life. Stress would cause his hypothalamus to produce higher amounts of cortisol-releasing hormone (CRH) and the CRH would trigger a reaction, like an allergy, that would in turn trigger neurons in his hypothalamus that adversely affect behavior and increase hunger. 

Treating with anti-inflammatory agents that can cross the blood-brain barrier would theoretically bring down the inflammation and stop the allergic-type reaction. In my son’s case behavior and hunger are improved, hunger drastically so! 

Specifically hydroxyzine and flavonoids (Luteolin, Quercetin and Rutin as found in Neuroprotek) were trialled with success. 

7.             How might these treatments may be helpful to persons with similar conditions?

The treatments we are using were developed for a subset of the autistic population thought to be suffering from brain and hypothalamic mast cell (immune cell) issues.

My son’s condition was marked by one autistic-like symptom, along with hormone deficiencies, hypothalamic obesity and premature gray hair. 

It’s interesting to note that individuals with Prader-Willi syndrome also exhibit autistic-like symptoms, hormone deficiencies, and hypothalamic obesity. Informal surveys on in the craniopharyngioma Facebook groups also indicate that the cranio population exhibits some autistic-like characteristics as well as the more commonly experienced hormonal deficiencies and HO.

I currently know of one craniopharyngioma teen* who is trying an antihistamine based on my son’s success. This young man is also reporting notable weight loss and positive behavioral changes based on six-weeks of treatment. 

Could others benefit too? We surely hope so!

* ADDENDUM (by Eugenie)
I have been in contact with the mother of this cranio teen boy with HO and she has also reported some remarkable findings with her son's use of an antihistamine.  Interestingly, she noticed that he seemed to lose weight without reason or intention in the month of August; about 1 pound per week. He would strangely regain the weight in September. After learning about CM's discovery, she realized that it was probably because her son always took an antihistamine medication to help with his seasonal allergies only in the month of August. Since learning of CM's success, she has re-administered the antihistamine (citrazine, 10 mg, a super inexpensive OTC Costco-brand drug, lol!) to her son (not for allergies this time) and has noticed weight loss, loss of hunger, less inhibition (acting more like a carefree, playful teenager), less inflammation (less "puffy"), more motivation, and better heat tolerance. In the last six weeks since starting citrazine, her son has lost almost 9 pounds (4 kg) in only 6 weeks without really trying.

As both of these cases are only in the first several weeks of their results, I will post an update in a few months on the progress of these young men.  

If, after reading this post and investigating the links, you have questions for these moms, please post them under comments on the blog.  This will help economize their time and help all readers (from various FB groups) be able to see the answers.  Thank you.