Clonidine and Guanfacine for ADHD, mast cell activation, sleep disorders, tics and some self-injurious behavior (SIB)

 

Both clonidine and guanfacine were raised recently to me, they have been covered in various earlier posts and in my book. Here is a round-up of the information.

These two drugs are α2A-adrenergic receptor agonists originally used to treat high blood pressure. Subsequently many additional uses of these drugs have been discovered.

I was asked about its use to treat mast cell activation syndrome (MCAS) and the mechanism by which it achieves this effect is interesting.

Calming mast cells – the ones that release histamine during an allergic reaction

Clonidine/guanfacine, as alpha-2 adrenergic agonists, inhibit mast cells primarily by interacting with the central and peripheral nervous systems, leading to a decrease in the release of inflammatory mediators. Its mechanism involves stimulating alpha-2 adrenergic receptors, which in turn suppresses the release of norepinephrine and other neurotransmitters.

In terms of mast cell stabilization, clonidine/guanfacine is thought to reduce intracellular calcium levels and inhibit the degranulation process that releases histamine and other pro-inflammatory substances. Lower intracellular calcium prevents the activation of key signaling pathways that normally trigger mast cell activation and degranulation.

This stabilizing effect helps prevent excessive allergic and inflammatory responses, making clonidine/guanfacine beneficial in conditions where such inhibition is useful.

Clonidine/guanfacine have some calcium channel-blocking properties, though they are not classified as a traditional calcium channel blocker. By indirectly lowering intracellular calcium levels, clonidine/guanfacine inhibit the signaling pathways that lead to mast cell degranulation and the release of inflammatory mediators. The end result is a reduction in cellular excitability and a dampening of the inflammatory response, including mast cell stabilization.

Clearly, you could just go directly to a calcium channel blocker like verapamil.

Clonidine/guanfacine and indeed verapamil are not seen as first line treatments for MCAS but may well be beneficial.

Conventional First-Line Treatments for MCAS

Antihistamines

H1 blockers (e.g., cetirizine, loratadine) to manage allergic-type symptoms like itching, hives, and flushing.

H2 blockers (e.g., famotidine, ranitidine) to control gastrointestinal symptoms and histamine release in the stomach.

Mast Cell Stabilizers

Cromolyn sodium is often considered one of the most effective mast cell stabilizers for MCAS, especially for gastrointestinal symptoms.

Ketotifen, another mast cell stabilizer with antihistamine properties, can also be helpful.

Rupatadine and azelastine are also potentially beneficial as mast cell stabilizers.

Leukotriene Inhibitors

Medications like montelukast can help manage symptoms related to leukotrienes, which are other mediators released by mast cells.

Aspirin

Aspirin can play a role in managing MCAS, particularly in controlling specific symptoms like flushing, hives, and inflammation. Its primary action in MCAS involves inhibiting prostaglandin D2 (PGD2), which is one of the inflammatory mediators released by mast cells and contributes to the vascular symptoms seen in MCAS.

Sleep disorders

Some people with autism do not sleep well.

Clonidine/guanfacine can help some individuals fall asleep faster and stay asleep longer by promoting relaxation and calming overactivity in the brain.

It is sometimes used in pediatric populations, such as children with autism or ADHD, to help with sleep initiation and minimize frequent nighttime awakenings.

Clonidine/guanfacine, being alpha-2 adrenergic agonists, lower the activity of the sympathetic nervous system (the fight-or-flight response).

Clonidine/guanfacine is typically prescribed at a low dose for sleep, as higher doses can lead to daytime drowsiness. Taking clonidine at night, about 30-60 minutes before bed, is common practice.

Guanfacine has a longer half-life than clonidine, which means it provides a more sustained effect throughout the night and may lead to fewer night-time awakenings. This can be particularly useful for individuals who need consistent support for sleep through the night.

Tics

Clonidine/guanfacine have long been used off-label to treat Tourette’s syndrome, which is a tic disorder.

Clonidine/guanfacine can help manage some stereotypical behaviors (repetitive, non-functional behaviors) in individuals with autism, when these behaviors are driven by hyperactivity, impulsivity, or anxiety.

Clonidine/guanfacine helps manage tics by calming the nervous system, modulating norepinephrine release, reducing stress, and helping with impulse control.

This effect has been noted by our reader AW.

Self-injurious behavior (SIB)

Self-injurious behavior (SIB) is usually considered the worst feature of autism. It becomes a learned behavior which can be very hard to extinguish.

Clonidine/guanfacine is on the long list of sometimes effective therapies. Take a note of this!

 

Clonidine as a Treatment of Behavioural Disturbances in Autism Spectrum Disorder: A Systematic Literature Review

Clonidine has a limited evidence base for use in the management of behavioural problems in patients with ASD. Most evidence originates from case reports. Given the paucity of pharmacological options for addressing challenging behaviours in ASD patients, a clonidine trial may be an appropriate and cost-effective pharmaceutical option for this population.

Beneficial Effects of Clonidine on Severe Self-Injurious Behavior in a 9-Year-Old Girl with Pervasive Developmental Disorder

ADHD

ADHD is very commonly diagnosed these days.

The genes involved in ADHD, autism, bipolar and schizophrenia are overlapping, so it is not surprising that many people are now being diagnosed with both ADHD and autism.

What I find very odd is that people with ADHD line up for medical treatment, but most people with comorbid autism think there cannot be a medical treatment for their autism because it is just how their brain is “wired-up differently.” It is hard to reconcile these views - both conditions are clearly treatable.

Most ADHD treatments are stimulants. Medications like methylphenidate (Ritalin, Concerta) and amphetamine-based drugs (Adderall, Vyvanse) are typically considered first-line treatments for ADHD. They work by increasing levels of dopamine and norepinephrine in the brain, which help improve focus, attention, and impulse control in people with ADHD.

Not all individuals with ADHD can tolerate stimulants, and in some cases, they may experience unwanted side effects like anxiety, sleep disturbances, or increased irritability.

The most common non-stimulant options are Clonidine and Guanfacine. They does not directly increase dopamine or norepinephrine but instead reduces norepinephrine release, promoting a calming effect.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (NRI), which increases norepinephrine in the brain by blocking its reuptake.

After years of off-label use in by 2010 both clonidine and guanfacine were FDA approved for use in ADHD.

 

Conclusion

As I mentioned to one reader, we should take note that both clonidine and guanfacine are approved for use in children (with ADHD) and so there is plenty of safety information and dosage guidance.

The effective dose for MCAS, sleep disorders, tics and SIB may well vary from person to person but the safe boundaries are well established from ADHD.

In general, guanfacine tends to be better tolerated than clonidine.

AW might note that guanfacine can cause sleep problems, including insomnia or vivid dreams.

Here is a useful list I found:

Common Side Effects:

Sedation/Drowsiness: Like clonidine, guanfacine can cause drowsiness, especially during the initial stages of treatment or when the dose is increased.

Fatigue: Many people report feeling fatigued or tired when starting guanfacine, which can affect daytime functioning.

Low Blood Pressure (Hypotension): Guanfacine also lowers blood pressure, potentially leading to dizziness or light-headedness, particularly when standing up quickly.

Dry Mouth: This is another common side effect, similar to clonidine, and may cause discomfort.

Headache: Some people experience headaches, especially when starting treatment.

Stomach Problems (e.g., abdominal pain, constipation): Gastrointestinal side effects can occur in some individuals, such as constipation or stomach discomfort.

Irritability and Mood Swings: In some cases, guanfacine may cause irritability or emotional instability.

Less Common but Serious Side Effects:

Bradycardia (slow heart rate): As with clonidine, guanfacine can cause a slow heart rate, which could be concerning for individuals with underlying heart issues.

Rebound Hypertension: Discontinuing guanfacine too abruptly can cause rebound hypertension (a sudden increase in blood pressure), so it should be tapered gradually under a healthcare provider’s guidance.

Sleep disturbances: In some cases, though less common than with clonidine, guanfacine can cause sleep problems, including insomnia or vivid dreams.

The role of the microbiome in aggression. Gut microbe imbalances that predict autism and ADHD. Biogaia trial for Autism.

 

By December 2020 7.3% of the Swedish cohort born in 1997-9 had been diagnosed with a Neurodevelopmental Disorder (ND). This can be predicted by samples previously collected.

Today’s post is all about the microbiome and covers three different areas covered recently in the research. Eight years after I wrote a post about our informal trial of Biogaia probiotics for autism, we now have a published paper.

Aggression and self injurious behavior (SIB) affects at least half of those diagnosed with level 3 autism at some point in their lives. SIB can become the overriding concern for care givers.

Our first paper looks at the role of the microbiome in aggression.

Gut-brain axis appears to play a critical role in aggression

A series of experiments on mice has found that they become more aggressive when their gut microbiome is depleted. Additionally, transplanting gut microbiota from human infants exposed to antibiotics led to heightened aggression in mice compared to those receiving microbiome transplants from non-exposed infants. The research was published in Brain, Behavior, and Immunity.

In the past decade, scientists have discovered a complex communication pathway linking gut microbiota—the trillions of microorganisms living in the human gut—with the brain. This pathway is called the microbiota-gut-brain axis. It regulates various physiological functions, including digestion and immunity, but also affects mood and behavior. The gut microbiota produces neurotransmitters and other metabolites that can influence brain function through neural, immune, and endocrine pathways.

Recent studies have demonstrated that symptoms of various disorders, once considered primarily psychological or neurological, can be transferred to rodents by transplanting gut microbiota from humans with these disorders. For example, researchers have shown that transplanting gut microorganisms from people with Alzheimer’s disease into mice (whose gut microbiota had been depleted to enhance transplant effectiveness) resulted in cognitive impairments in the mice. Similarly, symptoms of anxiety have been induced in mice by transplanting gut microbiota from humans with social anxiety.

For the humanized mice, the researchers obtained fecal samples from infants who had been exposed to antibiotics shortly after birth, as well as from unexposed infants. These samples were transplanted into five-week-old germ-free mice. The researchers then waited for four weeks before testing the mice for aggression.

To measure aggression, the researchers employed the resident-intruder test, a well-established behavioral assay in which a male mouse (the “resident”) is introduced to another unfamiliar male mouse (the “intruder”) in its home cage. Aggression was quantified based on the latency to the first attack (how quickly the resident mouse attacked the intruder) and the total number of attacks during a 10-minute period.

The results showed that mice raised without gut bacteria (germ-free) and those treated with antibiotics exhibited higher levels of aggression compared to the control group. These mice attacked more frequently and were quicker to initiate aggressive behavior in the resident-intruder test.

The researchers found that humanized mice receiving fecal microbiota from antibiotic-exposed infants were significantly more aggressive than those receiving transplants from non-exposed infants. Even though the infants’ microbiomes had a month to recover after antibiotic exposure, the aggressive behavior was still evident in the recipient mice.

Biochemical analyses revealed that aggressive mice (both germ-free and antibiotic-treated) had distinct metabolite profiles compared to control mice. Specifically, levels of tryptophan—a precursor to serotonin, a neurotransmitter associated with mood and behavior—were elevated in these mice. Additionally, the levels of certain metabolites associated with microbial activity, such as indole-3-lactic acid, were reduced in the aggressive mice, suggesting that the absence of a healthy microbiome might alter key biochemical pathways involved in aggression.

Here is the link to the original paper:

A gut reaction? The role of the microbiome in aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. Here, we compared behavior profiles of control, germ-free (GF), and antibiotic-treated mice, as well as re-colonized GF mice to understand the impact of the gut microbiome on aggression using the resident-intruder paradigm. Our findings revealed a link between gut microbiome depletion and higher aggression, accompanied by notable changes in urine metabolite profiles and brain gene expression. This study extends beyond classical murine models to humanized mice to reveal the clinical relevance of early-life antibiotic use on aggression. Fecal microbiome transplant from infants exposed to antibiotics in early life (and sampled one month later) into mice led to increased aggression compared to mice receiving transplants from unexposed infants. This study sheds light on the role of the gut microbiome in modulating aggression and highlights its potential avenues of action, offering insights for development of therapeutic strategies for aggression-related disorders

Note the ABX means antibiotics

We include a study of humanized mice using unique fecal samples of 1-month-old infants, collected nearly a month after early-life ABX administration. In previous work (Uzan-Yulzari et al. 2021, Nat Comm), we have demonstrated that ABX in this critical period of life can have lasting effects of childhood growth. Here, we extend these findings using samples from the same cohort. Using fecal samples collected weeks after ABX administration also reduces the direct chemical effects of ABX on the host, highlighting the causative role of the dysbiotic host microbiome and associated metabolome in driving aggressive behavior. We demonstrate that infant microbiota, perturbed within the first 48 h of life, has a lasting signature through 1 month of age that, when transplanted into GF mice, results in increased aggression (3–5 weeks after transplant) when compared to effects of stools of infants not exposed to any early-life antibiotics. The findings are revolutionary as they show how ABX-altered microbiota during a critical development window can lead to persisting behavioral deficits.

 

Gut microbe imbalances could predict a child’s risk for autism, ADHD and speech disorders years before symptoms appear.

Study Identifies Gut Microbe Imbalances That Predict Autism And ADHD

We are researchers who study the role the microbiome plays in a variety of conditions, such as mental illness, autoimmunity, obesity, preterm birth and others. In our recently published research on Swedish children, we found that microbes and the metabolites they produce in the guts of infants – both found in poop and cord blood – could help screen for a child’s risk of neurodevelopmental conditions such as autism. And these differences can be detected as early as birth or within the first year of life. These markers were evident, on average, over a decade before the children were diagnosed. 

The imbalance in microbial composition – what microbiologists call dysbiosis – we observed suggests that incomplete recovery from repeated antibiotic use may greatly affect children during this vulnerable period. Similarly, we saw that repeated ear infections were linked to a twofold increased likelihood of developing autism.

Children who both repeatedly used antibiotics and had microbial imbalances were significantly more likely to develop autism. More specifically, children with an absence of Coprococcus comes, a bacterium linked to mental health and quality of life, and increased prevalence of Citrobacter, a bacterium known for antimicrobial resistance, along with repeated antibiotic use were two to four times more likely to develop a neurodevelopmental disorder.

Antibiotics are necessary for treating certain bacterial infections in children, and we emphasize that our findings do not suggest avoiding their use altogether. Parents should use antibiotics if they are prescribed and deemed necessary by their pediatrician. Rather, our study suggests that repeated antibiotic use during early childhood may signal underlying immune dysfunction or disrupted brain development, which can be influenced by the gut microbiome. In any case, it is important to consider whether children could benefit from treatments to restore their gut microbes after taking antibiotics, an area we are actively studying.

Another microbial imbalance in children who later were diagnosed with neurodevelopmental disorders was a decrease in Akkermansia muciniphila, a bacterium that reinforces the lining of the gut and is linked to neurotransmitters important to neurological health.

Even after we accounted for factors that could influence gut microbe composition, such as how the baby was delivered and breastfeeding, the relationship between imbalanced bacteria and future diagnosis persisted. And these imbalances preceded diagnosis of autism, ADHD or intellectual disability by 13 to 14 years on average, refuting the assumption that gut microbe imbalances arise from diet.

We found that lipids and bile acids were depleted in the cord blood of newborns with future autism. These compounds provide nutrients for beneficial bacteria, help maintain immune balance and influence neurotransmitter systems and signaling pathways in the brain.

The full paper is here: 

Infant microbes and metabolites point to childhood neurodevelopmental disorders 

Highlights

• Infant microbes and metabolites differentiate controls and future NDs

• Early-life otitis lowers Coprococcus and increases Citrobacter in future NDs

• Preterm birth, infection, stress, parental smoking, and HLA DR4-DQ8 increase ND risk

• Linolenic acid is lower and PFDA toxins higher in the cord serum of future ASD

Summary

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immune-dysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.

ABIS = All Babies in Southeast Sweden cohort

NDs = Neurodevelopmental disorders

Young children later diagnosed with ASD or exhibiting significant autistic traits tend to experience more ear and upper respiratory symptoms. In ABIS, infants who had otitis in their first year were found to be more prone to acquiring NDs if they lacked detectable levels of Coprococcus or harbored Citrobacter. The absence of Coprococcus, despite comparable levels in controls irrespective of otitis, raises questions about microbial community recovery. This potential failure of the microbiome to recover following such events may serve as a mechanism connecting otitis media to ND risk. Moreover, antibiotic-resistant Citrobacter was more prevalent in these infants. The presence of strains related  to Salmonella and Citrobacter, labeled in this investigation as SREB, was significantly higher in infants who later developed comorbid ASD/ADHD (21%), compared to controls (3%). This disruption may have consequences on neurodevelopment during a critical period. Salmonella and Citrobacter have shown the ability to upregulate the Wingless (Wnt) signaling. The Wnt pathway is vital for immune dysregulation and brain development, and its disruption has been implicated in ASD pathogenesis. 

Two fatty acid differences were notable in the stool of future ASD versus controls: omega-7 monounsaturated palmitoleic acid, (9Z)-hexadec-9-enoic acid (below the level of detection in 87.0% of future ASD but present in 43.5% of controls), and palmitic acid (elevated in future ASD). Palmitoleic acid has been associated with a decreased risk of islet and primary insulin autoimmunity. Conversely, palmitic acid, a saturated fatty acid, has been linked to neuronal homeostasis interference. Its effects are partially protected by oleic acid, which although approaching significance, was lower in the cord serum of future ASD.

Few metabolites were higher in stool of infants with future ASD, but there are a few notable examples: α-d-glucose, pyruvate, and 3-isopropylmalate. Coprococcus inversely correlated with 3-isopropylmalate, suggesting gut-brain connections and a possible imbalance in branched-chain amino acid (BCAA) pathways given the role of 3-isopropylmalate dehydrogenase in leucine and isoleucine biosynthesis. An increase in dehydroascorbate suggests potential disruptions in vitamin C metabolism, crucial for neurotransmitter synthesis and antioxidant defense, while elevated pyruvate suggests disturbance of neurotransmitter synthesis or energy production early in life. Pimelic acid elevation, found in disorders of fatty acid oxidation, suggests disruption of mitochondrial pathways for fatty acid oxidation.

Akkermansia and Coprococcus, absent or reduced in infants with future NDs, positively correlated with signals in stool representing neurotransmitter precursors and essential vitamins in stool. Specifically, Akkermansia correlated with tyrosine and tryptophan (i.e., catecholamine and serotonin precursors, respectively) and Coprococcus with riboflavin. Disruption of BCAA metabolism in ASD has been documented, involving coding variants in large amino acid transporters (LATs) and reduced utilization of trypotphan and large aromatic amino acids along with increased glutamate and decreases in tyrosine, isoleucine, phenylalanine, and tryptophan in children with ASD. Oxidative stress, a diminished capacity for efficient energy transport, and deficiencies in vitamins (like vitamin B2) essential for neurotransmitter synthesis and nerve cell maintenance have been implicated. Riboflavin as an antioxidant reduces oxidative stress and inflammation, demonstrating neuroprotective benefits in neurological disorders, possibly through maintenance of vitamin B6, which is necessary for glutamate conversion to glutamine and 5-hydroxytryptophan to serotonin.

Together, these findings support a hypothesis of early-life origins of NDs, mediated by gut microbiota. This provides a foundation for research and for developing early interventions for NDs.

 

Today’s final paper was highlighted recently in a comment on a post I wrote eight years ago, when we were trialing Biogaia probiotics. This original interest was prompted by a reader sharing her successful experiences of treating her son with severe autism. Perhaps she left the recent comment?

The two bacteria involved are both types of L. reuteri.

L. reuteri 6475 is sold as Biogaia Osfortis

L. reuteri 17938 is sold Biogaia Protectis

The combination of L. reuteri 17938 and L. reuteri 6475 is sold as Biogaia Gastrus.

My old post from 2016:-

Epiphany: Biogaia Trial for Inflammatory Autism Subtypes

The recently published trial:

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial -

Highlights

• L. reuteri (6475 + 17938) improves social functioning in children with autism

• L. reuteri does not improve overall autism severity or repetitive behaviors

• L. reuteri does not significantly alter microbiome composition or immune profile

•  Only the 6475 strain reverses the social deficits in a mouse model for autism

we performed a double-blind, randomized, placebo-controlled, parallel-design pilot trial in children with ASD. Importantly, we found that L. reuteri, compared with placebo, significantly improved social functioning, both in terms of reducing social deficits, as measured by the social responsiveness scale (SRS^31,32), and increasing adaptive social functioning, as measured by the social adaptive composite score of the Adaptive Behavior Assessment System, Second Edition (ABAS-2³³). L. reuteri did not improve overall autism severity, restricted and repetitive behaviors, and co-occurring psychiatric and behavioral problems, nor did it significantly modulate the microbiome or immune response. Thus, this safe microbial manipulation has the potential for improving social deficits associated with ASD in children.

I had to amend my old post with a warning long ago.

UPDATE: A significant minority of parents report negative reaction to Bio Gaia, this seems to relate to histamine; but more than 50% report very positive effects without any side effects; so best to try a very small dose initially to see if it is not well tolerated. 

Histamine Reaction to BioGaia gastrus

Conclusion

The gut microbiota does indeed play a key role in how your brain functions, but the gut-brain axis works in both directions. What goes on in your brain can affect your gut and not just the other way around. It is called bidirectional signaling.

Antibiotics taken during pregnancy, or during early childhood, will have unintended consequences. Often there is no choice, like for those readers whose baby experienced sepsis at birth (bacterial blood stream infection); you have to give antibiotics to avoid death.

In today’s second paper we see that the researchers are thinking about therapeutical implications. Perhaps the newborn’s gut flora should be repopulated during the weeks after the antibiotic treatment?

I receive many questions about how to treat self injurious behavior that does not respond to anything the doctor has prescribed. Rifaximin, an antibiotic used to treat irritable bowel syndrome with diarrhea, is one therapy that does help some types of SIB (and SIBO, small intestinal bacterial overgrowth, of course). This probably would not surprise the authors of today’s first paper.

Biogaia Gastrus (L. reuteri 6475 + 17938) from today’s third paper worked wonders for the SIB of one reader’s child.

Not surprisingly fecal microbiota transplantation (FMT) can improve SIB in some people.

The Swedish data shows interesting insights such as that lipids and bile acids were depleted in the cord blood of newborns with future autism. The researchers think they can predict the diagnosis of autism or ADHD. The question is and then what? Even when there is a diagnosis of autism, not much changes for most children.

Educating children with level 3 Autism

 

Some people do not like South Park, but it is a good example of genuine inclusion

The number of children with autism and intellectual disability continues to rise and this is putting a strain on government resources in many parts of the world. Increasing budgets can never match the increased perception of needs.

In spite of the vast amounts of money being spent very little attention is given to evaluating what gives the best results.

In the US it has long been put forward that the earlier the intervention starts the better the results will be and often it is stated that 40 hours a week of one-to-one therapy is needed.  This view is generally limited to the US.    

ABA therapy became a big business in the US and many providers are now owned by private equity investors.

I did point out that in the book the Politics of Autism, the author recounts her discussions with the founding father of ABA, Ivar Lovaas, that revealed he had rigged his clinical studies by excluding those children who did not respond to his 40 hours a week therapy from the final results. He just dropped them before the end of the trial. This would totally invalidate his conclusions.

There is a recent study on this very subject.

Rethinking the Gold Standard for Autism Treatment

Research shows some autistic children may get more treatment hours than needed.

The JAMA Pediatrics study looked at the relationship between the amount of intervention provided (hours per day, duration, and cumulative intensity) and the outcomes for young autistic children. Researchers analyzed data from 144 studies involving more than 9,000 children, making it one of the most comprehensive analyses of its kind.

Contrary to what many have long believed, the study found no significant association between the amount of intervention and improved developmental outcomes. As the authors write, “health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.”

Determining Associations Between Intervention Amount and Outcomes for Young Autistic Children A Meta-Analysis

A total of 144 studies including 9038 children (mean [SD] age, 49.3 [17.2] months; mean [SD] percent males, 82.6% [12.7%]) were included in this analysis. None of the meta-regression models evidenced a significant, positive association between any index of intervention amount and intervention effect size when considered within intervention type.

Conclusions and Relevance  Findings of this meta-analysis do not support the assertion that intervention effects increase with increasing amounts of intervention. Health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.

Some parents in the US get to the bizarre situation where their child can receive 40 hours of ABA for free, but if they say they want only 20 hours because they have other activities for the rest of the week, this is refused.  It is the full 40 hours or none.   

School segregation

Segregation is a word with negative connotations, but it is used when it comes to the merits of inclusive education versus special schools.

There are many ways in which schools are segregated, including

By sex

It is still very common to have separate boys' schools and girls' schools in many countries

By religion

Religious schools are common in both public and private sectors

By ethnicity

This was widely practiced in the United States and South Africa. The legacy of these policies is still evident today.

By ability

Selecting pupils by academic level is very common.

By disability

Segregation of those with learning disabilities into special schools or special classes within a mainstream school is widespread.

By socioeconomic status

Segregation by the ability to pay is common all over the world. In parts of the world there is no schooling for those whose family cannot afford it.

Homeschooling

In parts of the world homeschooling is legal and thriving. The US has by far the largest contingent, with 6% of children home-schooled.  In Germany it is illegal.

What is the best type of school for level 3 autism?

There is no “best” choice.

From the parents' perspective, some are desperate for their child to attend a special(ist) school and some are desperate not to attend such a school.

Some parents choose to home school.

Some parents look for some kind of hybrid solution.

Most parents just take what is given to them.

Inclusion vs segregation

The key issue here is whether the child is “includable”. It is fashionable in Western countries to be anti-segregation and pro inclusion.

Some children are not includable and some school environments are hostile rather than welcoming.  Even some children with level 1 autism struggle to cope in mainstream school.

Monty was lucky and completed all his schooling in a mainstream school with very small class sizes, about 12 pupils. He had his own teaching assistant throughout. Two of his former assistants later became class teachers at his school. We paid for the school and the assistants.

Had Monty attended a school with 30 children in the class with 3 other special needs kids, each with their own teaching assistant, the result would not have been so good.

As you can see it is a question of “inclusion in what” versus “segregation in what”.

What is the purpose of “school”

If you talk to parents of older children you will discover that over the years their view of schooling changes. It is an illusion, one grandfather told me. For many schooling is just daycare for the pupil and respite care for the parents.

Some parents do not want their child to be just taught daily living skills, they want the academic curriculum.

Some schools teach non-verbal children an alternative method of communication, whereas other do not bother.

It is not surprising that the result is often nobody is satisfied.

Peter’s idea about schooling for level 3 autism

I would require all children with level 3 autism to be taught at primary/elementary school a means of communication. Remarkably this is not done.

Proactive parents have been doing this for decades at home, but what if your parents are not proactive?

I read the other day that a mother commented that her non-verbal 7 year old daughter would greatly benefit from an augmentative communication device, but that the council/municipality did not want to provide one. In previous decades these were expensive devices, but nowadays these are just apps that you install on an iPad, or android device. Some of these apps are even free !!

Clearly, I would ensure all pupils with level 3 autism were screened and treated for any type of treatable intellectual disability, the most common one being elevated chloride inside neurons, which was the case for Monty.

I recently was contacted by a parent who, after trying to help his son for 7 years, has finally had success by increasing his dose of leucovorin (calcium folinate). Now his son responds to verbal instructions like "wash your hands".

Some of these children, once under medical treatment, will be able to follow much of the core academic curriculum and be genuinely included in mainstream classes. That was the outcome for Monty, now aged 21.

Children who remain with a lower IQ should not be in classes that teach academic concepts far above their level of understanding. This is pointless and will just lead to frustration.

One non-verbal child I know, who cannot read or write is “taught” a second language at school. How about teaching him a first language?

Children should be taught in groups of similar ability/functioning level, rather than grouping them by age. I thought this would be just common sense, but not in the world of education.

If the material has not been mastered there is no point moving forward, just repeat it. After 15 years at school there should have been measurable progress.

Beware of prompt-dependence and assistant-dependence. Skills learned at school need to be such that the child can apply them independently and can generalize them to new situations. Some wealthy schools provide very high levels of support and this risks that the child will become an adult dependent on a similar level of support. This is an example of “too much of a good thing”.

 

The services “cliff-edge”

Some people with autism, and their families, receive very considerable support for two decades and become dependent on it. At some point in early adulthood these supports may get abruptly withdrawn.

In other parts of the world, there was only ever very minimal support and the family became more self-reliant and so do not experience such a cliff-edge. The family and the young adult learnt to cope.

Level 1 autism / Asperger’s

This post is about level 3 autism, but I am always surprised how many people with level 1 autism write to me so here are some thoughts on them.

You would think that all people with level 1 autism should be able to thrive in mainstream education these days. There is so much in the media, or social media, about accommodating differences and promoting the “able disabled” who are featured everywhere, so how come kids at school are still bullying/tormenting their classmates who are 1% different. Times have not really changed as much as we might have thought.

Most kids with level 3 autism love going to school.  Monty adored it.

Many kids with level 1 autism clearly hate it.

During my time helping to run my children’s school one of the things teachers told me was that kids are actually very supportive of those who are clearly disabled but will delight in picking on kids who are a tiny bit different.

The net result is that many children with level 1 autism thoroughly enjoyed their on-line education during the pandemic away from all that awkwardness at school.

Many parents whose child goes to a special school for autism or Down syndrome are completely unaware that there are also some special schools for level 1 autism. It greatly surprised me.

 

Conclusion

The idea of trying to educate children with level 3 autism is relatively new. In the recent past they were just put aside in institutions and forgotten about.  Today much is possible, but a lot comes down to who the parents are and where they happen to live.

The Education for All Handicapped Children Act (EAHCA) of 1975 (later renamed the Individuals with Disabilities Education Act, or IDEA, in 1990) was the major turning point in the US. This ultimately opened the door to a flood of ABA, paid for by private health insurance, but only in the US.

My doctor mother once commented to me that we had shown that such children can be taught and can genuinely learn. This was a combination of personalized medicine and personalized learning.

Good things don’t just happen, you have to make them happen.

The outcome in level 3 autism is hugely variable and that is rather sad.

Is it safe to treat autism in very young children? Plus, the impact of impaired autophagy on cognition and treating SIB

This blog is full of clinical trials that use existing drugs that are repurposed to treat autism. One constant issue is whether the trial drug is free from side effects. Generally speaking side effects tend not to be a problem, but there always can be exceptions.

I was recently contacted by the parents of a two year old with a single gene (monogenic) type of autism and they want to treat their child to improve his outcome.  This is the youngest case I have encountered.

With monogenic autisms you often have clear indications from a very early age that something unusual is present. Once you have a diagnosis you quickly discover what issues the child is going to face. You therefore have a good idea of what will happen if you do nothing. Some other two year olds have delayed speech and other signs of autism, but within a couple of years develop normally – it was a case of delayed maturation.

I noted long ago that American autism doctors tend to want to treat younger patients with supplements rather than drugs.

The reality is that the sooner you start to correct a severe biological dysfunction the better the outcome will be. We even see that some treatments are only effective if given to toddlers. This makes perfect sense although it may be uncomfortable to accept.

I was looking for supporting evidence for very early intervention. I found a glowing report of the treatment of a 2 year old with Fragile X syndrome using Metformin. I am amazed Fragile X still remains untreated in most cases.

On examination at age 2 years, typical physical features of FXS were observed, and baseline laboratory findings were normal (see Table Table1).1). He was started on metformin at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was gradually increased to 200 mg twice a day (bid) over 1 year (see Table Table1).1). After initiation of metformin, his sleep disturbance resolved, only occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4 blocks to stacking a tower of 11 or more blocks; within a few more weeks, he began building more complex structures comprised of different size blocks. He showed marked improvement in self‐help and motor activities, including toilet training, clearing the table and loading the dishwasher, brushing his own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were unaware of metformin treatment, told his mother that “it's like something just clicked or he just woke up. He's a whole different kid.”

Source: Metformin treatment in young children with fragile X syndrome

Some drugs including bumetanide are already safely given to babies.

Nonetheless, it is a brave step to start treatment in a two year old. I did connect the parents to a reader of this blog whose child has the same syndrome but is a few years older.

Today’s post was prompted by the news that the child is already showing improvements from the first therapy, which is a small dose of clemastine. In this syndrome there is a mutation in TCF4 and there is impaired myelination and very likely activated microglia (the brain’s immune cells). The near immediate beneficial effect cannot be on myelination, but it could be resetting microglia to the resting state.

Other genes very recently raised have been TRIT1 and PSMB9; neither of these are classed as autism genes, but evidently can cause it. Mutations in TRIT1 cause a problem in the mitochondria and PSMB9 mutations cause the immune system to misbehave.  It looks like both can lead to an autism diagnosis.

A common issue parents encounter is that often the interest shown by researchers and clinicians stops at the point of diagnosis. What really matters is what to do next. Only very rarely will such “experts” suggest what to do next. 

It looks like there nearly always are therapeutic avenues to pursue after such a diagnosis. It should be noted that even in single gene (monogenic) autisms there are varying levels of response to the same therapy. We saw this a while back with the new FDA approved therapy for Rett syndrome – it works for some, but not for others.

 

Treating self injurious behavior (SIB) in idiopathic autism

I recently received feedback from several parents who have had success in treating SIB based on ideas in this blog.

Verapamil came up again as successful.

Pioglitazone, at a low dose of 7.5mg, was the game changer for one child.

Ibuprofen worked in another case, but this cannot be used long term. Celecoxib should be better tolerated and in theory should be as effective. Time will tell.

More people are trying the add-on therapy of a small dose of taurine.

 

Macroautophagy as a cause of impaired cognition

Impaired autophagy came up recently in two people’s genetic testing results. There is a lot in this blog about autophagy and dementia/mild cognitive impairment.

Today we have a paper that links impaired autophagy with impaired cognition.

Twenty years ago severe autism generally also meant impaired cognition. Nowadays it does not; you can have severe autism with normal cognition.

There are various different types of autophagy but in general it is all about collecting bits of cellular garbage that might clog things up. As we get older this intracellular garbage collection process works less well and then diseases like Alzheimer’s follow decades later.

Impaired autophagy may contribute to impaired cognition at any age. Most research concerns dementia treatment, or other conditions affecting older people like Huntington’s disease.

There is little focus on younger populations, even though we know that children with Down syndrome are prone to get early onset Alzheimer’s. Treating young people with Down syndrome to improve autophagy might bring both short and long term benefits. 

Here is the recent paper on this subject. 

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lymphoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

 

There are different types of autophagy and there are some overlaps. 

·      mTOR dependent (Fasting or Rapamycin)

·      AMPK dependent (Spermidine)

·      P53 dependent (no simple therapies)

·      Calcium signalling dependent (Verapamil)

The OTC way to increase autophagy is to use Spermidine, which is made from wheat germ or rice germ. Studies in humans are rather mixed and I think the dose is likely far too low. Supplements tend to contain about 1mg; I suspect you need much more to have an impact. You can indeed grow your own wheat sprouts which are highly nutritious and a rich source of spermidine. You can eat them raw or even in smoothies. 100 g of sprouts contains 10-15mg of spermidine.

The most researched calcium channel drug to induce autophagy is Verapamil, from my son’s original autism Polypill.

My takeaway continues to be to look for convergent mechanisms, like impaired autophagy, myelination, microglial activation etc that commonly occur in severe autism, of any origin. You then try and treat these likely dysfunctions rather than getting overly focused on individual genes.

 

Taurine – a cheap Autism intervention worth a trial

 

I did recently write a post all about Taurine and the many effects it has on the body, some of which really should affect autism. 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

Having read the literature, it looked to me that anyone over 50 years old is likely to benefit from a little extra Taurine, but it certainly was not clear whether it would make my 21 year old’s autism better or worse. I went ahead and ordered some to investigate.

In theory one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter that takes chloride out of neurons the “wrong” way. The other effects include on calcium homeostasis, which we know is disturbed in most autism.

 

N = 2 Trial

Subject #1 (Peter)

I took 2g a day for a month and noticed no effect at all, other than some mild GI irritation.

In adults the long-term effects are numerous and varied throughout the body. Even the cells that remodel your bones (osteoblasts and osteoclasts) have special taurine transporters, whose sole role is to let taurine inside – taurine makes the osteoblasts work harder, while encouraging osteoclasts to take a break. The net effect should be stronger bones.  As you get older your natural levels of taurine fall substantially. There are taurine-rich foods you can eat and if you engage in strenuous exercise your liver starts making more taurine.

 

Subject #2 (Monty)

There is a clear contradiction when it comes to Taurine and sleep. Many energy drinks contain Taurine to keep you alert, but in theory Taurine should be calming and many people take it add bedtime to improve sleep.

Monty, aged 21 with ASD, likes getting up early and going to bed early.

Adding 2g a day of Taurine at breakfast shifted his circadian rhythms, so that he now goes to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours. 

The most beneficial change has been on his spring and summertime aggression. This has been controlled for years using an L-type calcium channel blocker. This does not resolve the allergy at all, but it “switches off” the consequential anxiety/aggression. With the addition of allergy therapies and the immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors are controlled.

It appears that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect on calcium channels and broader calcium homeostasis is the reason why. Anyway, it works – simple, cheap, OTC and effective.  It has no effect on allergy, in case you are wondering.

  

Conclusion

Taurine can be bought as a bulk powder for very little money. It is not like those numerous expensive supplements that would cost you several hundred dollars/euros/pounds a year.

If you have your own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol, type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few pennies more and add a scoop of taurine.

The people who write to me and tell me how Verapamil has transformed life at home, by banishing aggression and self-injurious behaviors, should seriously consider a trial of Taurine.

 

Can you safely take Bumetanide or Acetazolamide (Diamox) if you have a Sulfonamide allergy?

I was contacted by a reader in Italy whose child with autism may respond to bumetanide, but has a sulfonamide allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.

Other readers have pointed out how they dare not try bumetanide because they know their child has a sulfonamide allergy. I think our longtime reader Tanya is one example.

 

Key Point to Note

Most people discover their sulfonamide after being giving an antibiotic in early childhood.

It is now well established that many (but not all) people with an allergy to sulfonamide antibiotics can safely take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented in case studies later in this post.

 

Sulfonamide Drugs

Many common drugs are “sulfonamides”. Their chemical structure includes a sulfonyl (–SO2) group attached to an amine group (–NH2). They include common antibiotics, like erythromycin, many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).

 

Sulfonamide Allergy

Many parents discover early in their child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated to a “sulfa allergy.”

The symptoms of a sulfonamide allergy can vary but may include:

• Skin reactions (rash, hives, or itching)
• Fever
• Swelling
• Respiratory issues (shortness of breath)
• Anaphylaxis (in severe cases)

Usually the symptoms are minor, but once diagnosed the parents usually take note never to give their child any sulfonamide drug.

 

If you have the allergy must you avoid all sulfonamide drugs?

The standard assumption has been that if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide (Diamox).

Upon further investigation in the research, this may not always be true.

 

What happens when there is no alternative drug?

When treating ion channel/transporter dysfunctions there may not be a non-sulfonamide alternative.

Acetazolamide (Diamox) is documented in the literature as a case in point. Bumetanide has not yet made it to the literature.

Furosemide fortunately has been researched and a safe desensitization protocol exists. Furosemide is a very similar drug to bumetanide.

 

Desensitization strategies

I did recently write about enzyme potentiated desensitization, which is an old, mostly overlooked, technique to overcome allergic reactions. I was interested in pollen allergy.

The best-known kinds of desensitization are allergy shots and more recently overcoming nut allergies, which gets media attention. 

Oral immunotherapy for peanut allergy in young children

The study also found that the youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission. 

“The landmark results of the trial suggest a window of opportunity in early childhood to induce remission of peanut allergy through oral immunotherapy,” says NIAID Director Dr. Anthony Fauci. “It is our hope that these study findings will inform the development of treatment modalities that reduce the burden of peanut allergy in children.”

 

I did wonder that if it works for nuts then why not bumetanide.

It turns out that I am not the first to consider desensitization to a drug allergy. The best known method is rapid drug desensitization (RDD), usually intravenous, which opens a window to be able to start taking a drug you are allergic to. Once you stop taking the drug, you then again become allergic to it.

The other approach is more like dealing with nut allergies, it is called slow drug desensitization (SDD) and involves taking a tiny initial dose and then slowly increasing it over weeks and months.

Drug desensitization is normally done in hospital as part of some therapy when you absolutely must have a drug that you are allergic to.

The paper below contains information on a very large number of common drugs where drug desensitization has been successfully carried out.

 

Desensitization for the prevention of drug hypersensitivity reactions

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca²⁺ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Two categories of desensitization protocols are currently available: RDD and slow drug desensitization (SDD). RDD is recommended for immediate reactions, both allergic and nonallergic. The most widely used RDD protocol is doubling the dosage every 15 minutes until the therapeutic dose is achieved. SDD is recommended for type IV delayed hypersensitivity reactions with T cell involvement, and can be performed both orally and intravenously. There is as yet no consensus on SDD protocols, including the initial dose, dose increments between steps, and dosing interval. Further clinical experience and research are required to establish the role and efficacy of desensitization for delayed reactions.

H1 blockers, H2 blockers, and glucocorticoids can be used as premedication. Aspirin and montelukast block the end products of the arachidonic acid cascade and decrease the incidence and severity of BTRs. NSAIDs can help to control the symptoms of cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent the initial degranulation of mast cells. 

The desensitization process is known to be antigen-specific, as the level of drug-specific immunoglobulin E (IgE) decreases but the levels of other allergen-specific IgE remain consistent throughout the treatment period. However, the cellular and molecular mechanisms underlying drug desensitization are not yet fully understood.

Aspirin/NSAID desensitization is considered for patients with cardiovascular or musculoskeletal diseases who require aspirin or NSAID administration for prolonged periods.

The temporary tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization. Therefore, hypersensitivity reactions can recur 2 to 5 days after discontinuation if the therapeutic dose is not continued.

 

DHR to β-lactams, such as penicillin or cephalosporin, is more common than that to non-β-lactams. Desensitization can be performed for both immediate and delayed hypersensitivity reactions. The protocol should be selected based on patient characteristics, hospital capacity, and physician preferences. It is generally started with 1/1,000 of the therapeutic dose and then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration is preferred due to its ease, safety, and effectiveness. Desensitization to penicillin and cephalosporins has been well established. Successful desensitization has also been reported for other β-lactams, such as carbapenem and monobactam, and non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides, aminoglycosides, tetracycline, and ciprofloxacin.

Successful desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B, fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals, such as acyclovir, valganciclovir, ribavirin, and nevirapine.

 

Furosemide desensitization

There is no literature specific to bumetanide but there is on the very similar drug furosemide.

 

RAPID ORAL DESENSITIZATION TO FUROSEMIDE

Furosemide is a commonly used loop diuretic that contains a sulfonamide group. Although there are rare reports of hypersensitivity to furosemide, severe reactions, including anaphylaxis, have been reported. Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no longer available in oral formulation, thus posing a dilemma in the outpatient treatment of patients with furosemide allergy.

Published protocols for furosemide desensitization include rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5 The oral protocols were performed in patients with non–type I hypersensitivity reactions. We present a rapid, oral protocol for desensitization in a patient with presumed type 1 furosemide allergy manifesting as urticaria.

 

Desensitization to sulfonamide-containing antibiotics has been extensively used, but desensitization to furosemide is uncommon. The oral protocols previously described took 3 to 10 days and were performed in patients with non–type I hypersensitivity reactions, one with pancytopenia and the other with pancreatitis. The patient with a type I hypersensitivity reaction underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has not been previously described. The potential advantages of oral desensitization are that it is probably safer than intravenous desensitization, it may be more cost-effective in terms of monitoring and staff requirements, and it may be possible to perform in an outpatient setting. We propose our protocol as a novel approach to furosemide desensitization therapy for patients with non–life threatening reactions to furosemide. Further progress in the diagnosis and treatment of hypersensitivity to sulfonamide drugs will require identification of the major antigenic determinant and standardization of skin testing and specific IgE testing.

I think we should say good work to Dr Naureen Alim, then at Baylor College of Medicine Houston, Texas.

If anyone wants to desensitize to a bumetanide allergy I think she is the one to contact for advice. She is easy to find via Google. 

Here is another case example. 

Desensitization therapy in a patient with furosemide allergy

Allergy to furosemide is a rare phenomenon. Desensitization to this sulfa-containing drug has not been frequently performed. We describe a patient with severe congestive heart failure and type I allergy to furosemide. Because of the severity of her condition, we decided to use a rapid intravenous desensitization protocol. Following the desensitization, the patient was treated with intravenous and oral furosemide with a dramatic improvement in her clinical state. We suggest that rapid desensitization may be a safe and effective way of introducing furosemide to allergic patients for whom loop diuretics are urgently indicated.

 

In the case of Acetazolamide, here is one published desensitization method:

  

Desensitization to acetazolamide in a patient with previous antimicrobial sulfonamide allergy

Acetazolamide is a carbonic anhydrase inhibitor that is frequently used in the management of idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent; specifically, it is a non sulfonylarylamine, which lacks the amine moiety found at the N4 position that is seen in sulfa antibiotics. 

Sulfonamide antibiotics contain a substituted ring at the N1 position that is thought to be the driving factor in immediate hypersensitivity reactions.  

Although sulfa allergies are commonly reported, there is no evidence to suggest cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. However, patients can report a history of allergy to both categories of drugs. We present a rapid desensitization protocol to acetazolamide in a patient with history of immediate hypersensitivity reactions to both a sulfonamide antibiotic and acetazolamide. 

We formulated a 12-step intravenous protocol that was performed in the intensive care unit setting (Table 1). Informed consent was provided by the patient, and she tolerated the procedure well without any adverse reactions. The desensitization procedure took 395 minutes or approximately 6.5 hours. She was monitored overnight in the hospital and was observed the following morning after taking 500 mg of acetazolamide orally to ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide without any issues to date.

 

Allergy to a sulfonamide antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide drugs.

  

Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies

The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.

Conclusions

These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.

 

Acetazolamide has been used for the treatment of episodic ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide is also effective in the periodic paralyses. Carbonic anhydrase inhibitors have been used to prevent altitude sickness, to lower intraocular pressure in open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial epilepsy as part of multidrug regimens. Acetazolamide has recently been used for hemiplegic migraine and idiopathic intracranial hypertension. 

The lack of available clinical or pharmacological evidence to support cross-reactivity between sulfonamide antibiotics and acetazolamide lends supports to the use of acetazolamide to treat patients with episodic ataxia and periodic paralysis. Of our 3 sulfonamide-allergic patients, 2 improved in symptoms after treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide allergy should not be a contraindication to treatment with acetazolamide in patients with neurologic channelopathies. 

 

Acetazolamide and sulfonamide allergy: a not so simple story

 Allergies and adverse reactions to sulfonamide medications are quite common. Two distinct categories of drugs are classified as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their chemical structure, use, and the rate at which adverse reactions occur. Cross-reactivity between the two groups has been implied in the past, but is suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the prevention and treatment of high altitude issues and may not need to be avoided in individuals with a history of sulfonamide allergy. This review addresses the differences between the groups and the propensity for intergroup and intragroup adverse reactions based on the available literature. We also examine the different clinical presentations of allergy and adverse reactions, from simple cutaneous reactions with no sequelae through Stevens-Johnson syndrome and anaphylaxis, with risk for significant morbidity and mortality. We offer a systematic approach to determine whether acetazolamide is a safe option for those with a history of allergy to sulfonamides.

Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions, after the b-lactams (penicillins and cephalosporins). In one large study, the incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides is not well established; it is clearly less than with antibiotics.

 

There are several approaches to the use of sulfonamide drugs (specifically acetazolamide) in patients with past reactions to this class of medications. The choice of strategy depends on the type and severity of the previous reaction, as well as the class of drug (antibiotic versus non antibiotic) and the risk–benefit profile for the patient. However, regardless of the approach, the risks of subsequent reactions cannot be completely eliminated, and a thorough discussion between the medical provider and the patient should include this point so that an informed decision regarding the use of acetazolamide can be made. The safest approach for the patient with any prior reaction to a sulfa drug, multiple drug allergies, or penicillin allergy would be to avoid all drugs in the sulfonamide group, including acetazolamide.

 

Avoidance of the entire sulfonamide drug group is warranted for individuals whose previous reaction included a serious and/or life-threatening condition such as anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or a sulfonamide in the same group is strictly contraindicated. Published evidence has shown that SJS/TEN can recur with even minor reexposures and may be more severe in the second episode. Even though SJS/TEN reactions are so far not associated with nonantibiotic sulfonamides, because of the severity and life-threatening nature of these reactions, a safe practice is to avoid all sulfonamides in patients with past SJS or TEN from sulfonamide containing medications.

 

This paper was published in a journal on high altitude medicine. That is why the suggested alternatives are staged ascents of the mountain and oxygen.

  

Conclusion

The first key point is that you can have an allergy to sulfonamide antibiotics and have absolutely no negative reaction to sulfonamide drugs like bumetanide and acetazolamide (Diamox).

If you do have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies that are proven to work in many people.

It looks like rapid oral desensitization to bumetanide and acetazolamide is likely possible, based on what has been shown possible with furosemide and a wide variety of other drugs.

Clearly the level of sensitivity and hence the nature of the allergic reaction can vary massively from person to person, this is why rapid desensitization usually takes place in hospital.

If you opt for the slower process, much less is known, because it is not generally used. If you did it in hospital it would require a very long stay and so would be hugely expensive.

It is suggested that slow drug desensitization (SDD) should be much more long lasting and hopefully might become permanent – as is the hope for nut allergy treatment.

When posed the initial question by our reader wanting to use bumetanide, I was thinking along the lines of slow drug desensitization (SDD), because this is how you would treat a pollen allergy. If rapid oral desensitization will work for taking bumetanide once a day that would be great. To maintain the protection from allergy it might be safer to take a small second daily dose.

 

Here is a quick overview of desensitization options for sulfonamide allergy:

• Rapid Desensitization (RDD):
• Faster process (hours)
• Temporary tolerance achieved
• May be repeated if needed
• Slow Desensitization (SDD):
• Slower process (days, weeks, or months)
• Might offer a greater chance of longer-lasting
• Still requires close monitoring

Important Considerations:

• Always consult your doctor: They can assess your allergy severity, treatment options, and the suitability of desensitization if necessary.
• Desensitization is not without risks: It requires careful monitoring.

 

I for one found this an interesting investigation and with promise for parents of those with severe autism who have been unable to trial Bumetanide due to a sulfonamide allergy. 

Hopefully our reader Dr Antonucci will follow up on this and make a bumetanide desensitization protocol for those people with autism and a sulfonamide allergy. Maybe he has already done it. It looks very achievable.