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Showing posts with label Autism. Show all posts
Showing posts with label Autism. Show all posts

Monday, 10 June 2019

The Safe Use of Bumetanide in Children with Autism



Today's post is Agnieszka's new guide to the safe use of bumetanide as an autism therapy in children.

Since most people actually read this blog on their smart phone, the document is repeated below and it will be much easier to read on a smartphone in the blog format, rather than the PDF document, because your phone should adjust the formatting. 

It is clear that most people treating autism are using Facebook and a smartphone. I am doing it with a big computer monitor and twenty windows open, each with a different scientific paper.  In the end all that matters is the result.


Practical Tips for Parents and Professionals

Agnieszka Wroczyńska MD, PhD 1, Peter Lloyd-Thomas MEng, MBA2  

1. Medical University of Gdańsk, Poland
wroczynska@gumed.edu.pl

Updated: 06.06.2019

Bumetanide is a prescription diuretic drug usually used to treat heart diseases or hypertension in adults. It also affects neuronal chloride regulation and was found to improve the quality of life of autistic children targeting core autism symptoms in clinical trials in Europe. Bumetanide has been used off-label in children and adults across the autism spectrum for several years, mostly in France. It is a safe drug with a long history of use in medicine and well-known precautions ensure side effects are avoided.
Details of bumetanide’s mechanism of action and its beneficial effects in autism were discussed elsewhere – see the references below. According to the most recent review of bumetanide clinical trials in autism:
"Current evidence suggests bumetanide, with close monitoring, may be useful in patients with moderate to severe ASD when traditional behavioral therapies are not available or an irritability-modifying pharmacological agent is not required” [James et al. 2019].

#1 Myth: Bumetanide is an experimental drug.
No. Bumetanide has been used in medicine for years. It’s safety profile and recommended precautions are well known and understood. Bumetanide has been studied in both adults and children and found to be well tolerated.
Bumetanide treatment should be supervised by a physician. Multinational phase 3 trial of bumetanide for children with autism aged 2-17 years of age started in Europe in 2018. If you live elsewhere and consider bumetanide, this article can be used as a practical companion to ensure safe treatment. It is written for parents and physicians who are not experienced with diuretic use in children or bumetanide itself. While bumetanide’s safety precautions can be summarized in short as “drinking more water, eating bananas and if required, use potassium supplementation”, this document aims to explain those in detail and provide practical tips for a variety of clinical scenarios.
Who can use bumetanide? What should you do before starting bumetanide?
If you are considering using bumetanide, make sure to check with your doctor if there are any contraindications in your child. Bumetanide is a sulfonamide drug. Children with allergy to sulfonamides should not take bumetanide. Another sulfonamide drug commonly used in children is an antibiotic called trimethoprim/ sulfamethoxazole (TMP/SMX), also known as co-trimoxazole. In many European countries co-trimoxazole’s brand name is Bactrim. If your child is allergic to co-trimoxazole (Bactrim) or any other sulfonamide drug, then bumetanide should not be used.
It is important to make a distinction between sulfonamide drugs and other sulfur-containing medications and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group. Allergic reactions associated with sulfonamides are not associated with sulfur, sulfates or sulfites intolerance.
The full list of bumetanide interactions with other drugs is long, but most of the drugs included are not usually used in children.
Children with liver or kidney diseases as well as those with abnormal ECG (electrocardiogram) findings were excluded from the French bumetanide trials. If your child suffers from one of these conditions you need to discuss bumetanide safety with the relevant specialist. Epilepsy does not preclude bumetanide use. In fact, preliminary research showed bumetanide has a positive impact on seizures in temporal lobe epilepsy in adults.
What laboratory tests are needed before and during bumetanide treatment in children
Bumetanide is a safe drug, provided basic precautions related to its diuretic mechanism of action are taken. One of the most important safety considerations associated with bumetanide use is electrolyte balance. Bumetanide can affect electrolyte blood level and increase potassium loss. Extremely low potassium levels are dangerous, but this is preventable with simple measures in a person using bumetanide.


#2 Myth: Bumetanide use in children with autism is associated with significant risk of dangerous adverse effects.
No. Clinical trials and off-label prescribing experience proved that bumetanide adverse effects can be easily prevented in children. No dangerous symptoms were related to bumetanide in studies on its use in children with autism.
No serious symptoms associated with low potassium levels or electrolyte imbalance were seen in children included into bumetanide trials and case reports so far. However, they might affect a child’s well-being and possibly reduce bumetanide’s positive behavioral or sensory effect. You may not see the expected results of bumetanide treatment if an adequate potassium level and hydration are not ensured in your child.
That is why it is necessary to test electrolytes levels (potassium, sodium, chloride, magnesium and calcium) before bumetanide introduction and repeat them, especially potassium blood concentration, after the treatment is started.
In the French bumetanide trials several other blood tests were offered to children i.e.  g-glutamyltransferase, transaminases, alkaline phosphatases, glucose, uric acid and creatinine. While it is not required to order all of them in a similar way as in the research clinical studies, they are basic and cheap tests, available in most laboratories and it is prudent to check these parameters at least once during early phase of the bumetanide treatment. In clinical trials children were examined by a physician on a regular basis and had their heart rate, blood pressure and weight checked. Such approach also improves safety of bumetanide use. In turn, all these simple steps increase the chance of experiencing positive effects of bumetanide treatment. Bumetanide proved to be a safe treatment in the trials. Blood pressure and results of the routine tests did not differ between the bumetanide and placebo groups. Kidney ultrasound did not reveal any abnormalities during treatment. Children in the trials had also ECG (electrocardiogram) done as a precaution. It is prudent to offer a child such test as they are non-invasive and can be done in a stress-free manner.
As bumetanide is a diuretic drug, it is highly recommended to explain its effects prior to treatment and with the use of the communication means used by that child. Social stories, visuals and AAC tools can be helpful for some children. This approach can reduce psychological stress potentially related to the diuretic treatment in children prone to anxiety in new situations.

Fig. 1. Visuals can help a child anticipate and accept bumetanide diuretic effect prior to start of treatment.
The diuretic effect of bumetanide is strongest within the first 2 hours of taking the drug. Bumetanide given early in the morning (straight after waking up) lets the child avoid unnecessary toilet visits at school or kindergarten. Giving bumetanide once a day may be much more convenient depending on the person’s particular circumstances.
Starting bumetanide - what dose should be used and what to expect?

In the first randomized clinical trial in France the dose of 0.5 mg bumetanide was given twice daily to children 3-11 years old and was found effective in many of them. However, for some people this dose may not be sufficient as actually only about 1% of bumetanide can cross the blood brain barrier and act on neurons.  In the 2017 bumetanide study doses up to 2 mg twice daily were trialed. While using higher doses may increase the amount of bumetanide that would reach the brain and so enhance the positive effects of the treatment, it also was found that drug-related adverse event risk is dose dependent and 0.5 mg b.i.d (twice daily) dose was found to be the best tolerated. It is a matter of a careful, individual trial to find an optimal dose for each person.
The benefits of bumetanide treatment can sometimes be seen as early as after 2 weeks, but it is not uncommon to have to wait longer. It is recommended to continue up to 3 months to assess the full impact of bumetanide use. Minor effects may indicate that the child is indeed a bumetanide responder, but the dose needs to be increased.
The beneficial effects seen in a child taking bumetanide are highly variable and individual. In general, this drug targets core autism symptoms and improvements in communication, social skills, including eye contact, speech and sensory issues were reported on bumetanide, as well as stereotyped behaviors decrease, better mood or increased cognition. Many parents can notice more awareness in their children and describe it as if “the fog has lifted”. Behavioral improvements were also reported on bumetanide e.g. reduction in aggressive behaviors.
The only known indicator of which people with autism respond to bumetanide, is a previous unexpected negative reaction to Valium (diazepam), or other benzodiazepine drug.  These drugs should be calming, but in some people with the GABA neurotransmitter dysfunction targeted by bumetanide, the effect can be agitation and aggression.
How to control hydration in children using bumetanide?
Bumetanide belongs to the “loop diuretics” class of drugs which can lower blood potassium level and increase the body fluid loss. You need to monitor hydration in a child treated with bumetanide. If fluid consumption is increased to compensate for the diuresis, there will be no significant blood pressure lowering effect from bumetanide, nor will there be dehydration. The daily amount of fluid required varies, but it usually needs to be significantly higher than the volume drank by a child before bumetanide treatment.
Some children drink up to 3 liters (3 US quarts) per day while on bumetanide, others need less. It is safer to err on the side of too much fluid intake rather than too little. Drinking 3 liters of fluids a day in a teenager on bumetanide is not unusual.
In children who still wear diapers/nappies the amount of diuresis may cause a problem with leakage.


Monitoring hydration and potassium control are two key safety precautions in bumetanide use in children with autism.
No severe adverse clinical symptoms related to dehydration were found during the bumetanide pediatric trials. However, a child who develops dehydration issues on bumetanide may feel unwell, so it is highly recommended to prevent it.

An easy way to check hydration status in a child is an assessment of mouth mucosa. You can ask your child to present her or his tongue and compare the tongue look with another member of the family. It can be made a good fun for younger children. If the tongue mucosa looks drier in a child on bumetanide, then you need to help the child drink more. Most children automatically drink more fluids, but some refuse to cooperate and drink more.  Finding out beverages attractive for your child (e.g. drinking water from a dispenser, juice with ice-cubes etc.) may be useful in such a situation.

Fig. 2. Monitoring hydration may be done in a funny way to make the treatment stress-free.

Monitoring hydration with weight checks or measuring urine volume, while used in other situations, are impractical in a person on bumetanide. 
You can read more on child dehydration symptoms here. It is useful to learn about those symptoms as a parent even if you do not plan to use bumetanide.
How to ensure enough potassium intake in a child on bumetanide?
Simple dietary modifications can provide necessary additional potassium and are recommended for every child on bumetanide. Use potassium salt and increase other dietary potassium in your kitchen. Bananas, kiwis, dried fruit, tomatoes are all examples of foods rich in potassium. The daily recommended intake of potassium is 3 to 4 g depending on age. A medium sized banana contains about 0.5g. Most people do not achieve the RDA for potassium but exceed the maximum limit for sodium, which is about 2g. More on potassium food content can be found here.

#3 Myth: Potassium supplements can cause serious heart rhythm issues in children on bumetanide.
No. Recommended potassium daily intake is well above the supplement doses usually used with bumetanide. Provided normal kidney function, there is no significant risk of dietary/oral supplement potassium overdose when typically recommended doses are considered.
Apart from dietary modifications, low dose potassium supplementation can be used in addition to bumetanide from the beginning of the treatment. In the first weeks of bumetanide use it is also necessary to test potassium blood level. In the French trial blood potassium levels were checked before bumetanide introduction and then at 7, 30, 60 and 90 days after the treatment started. You may consider potassium blood level test sooner than after 30 days: it can be scheduled 2-3 weeks after bumetanide introduction to detect low potassium level early. The normal blood level range of potassium is 3,5 - 5,0 mmol/l.  In case of abnormally low blood potassium level (which is called “hypokalemia”) you need to consult your doctor and add or adjust the dose of potassium supplement for your child. The target is to keep the potassium level well within the normal range. In the first bumetanide randomized clinical trial 22% of children taking bumetanide 0.5 mg b.i.d. (twice daily) experienced benign hypokalemia (low potassium), which was resolved by giving potassium gluconate syrup. In the next French trial the potassium level fell below normal range in 30% of children on that dose, but no serious potassium-related adverse event was seen. A potassium supplement was given to all these children to correct the low blood level.
 The potassium dose should be adjusted individually according to blood level and repeat tests may be helpful. As some autistic children seem not to tolerate even minor drops in potassium level, you and your doctor may consider increasing potassium supplementation to keep its level in the upper normal range in those cases.

Side effects of bumetanide and how to manage them:
- “Accidents” caused by diuresis: need to plan ahead. Don’t give bumetanide before starting a long car journey or before sleep.
- Dehydration has many effects that you may not notice. Make sure your child carries a water bottle and so has easy access to fluids.
- Low potassium has many effects and so add potassium to diet as a precaution. Most people are nowhere near the recommended intake of potassium, so add potassium-rich food to diet.
The optimal dose of potassium varies and is highly individual: few children need dietary modifications only, some use as low as 100 mg potassium daily, while some require 500 mg t.i.d. (three times a day) to maintain normal potassium level on bumetanide. Potassium supplements come in different forms e.g. syrup, effervescent tablets, slow-release capsules. Liquid supplements, including effervescent drinks, seem free from the risk of GI distress associated with tablets, which may be especially important in a child who is not able to communicate the pain. It is very hard to do harm by eating too much dietary potassium, because it is absorbed very slowly. Many potassium supplements are absorbed quickly and so giving more than 500mg at once is unwise.  Note that in America most potassium supplement tablets do not contain more than 100mg.
It is necessary to actively prevent dehydration and potassium loss while on bumetanide treatment. The good news is that it is easy to achieve with simple steps described above. These precautions become even more important in children who struggle to report thirst and distress due to communication difficulties as well as in situations which make a child prone to dehydration regardless of diuretic use e.g. diarrhea, vomiting, fever or very hot summer temperatures, especially during physical exercise. If such issues occur, you need to be vigilant, consider a doctor’s appointment and potassium blood level check with additional supplementation as needed.
In case of persistent low blood potassium concentration it is recommended to check blood levels of magnesium as well. Magnesium deficiency may contribute to hypokalemia (low potassium). If this is the case, supplementing magnesium along with potassium is a solution. Low potassium levels can also be made worse by high sodium levels.
Is long term bumetanide use safe and practical?

#4 Myth: While on bumetanide every child is required to have often blood draws to check potassium.
No. Repeated blood draws are required at the beginning of bumetanide treatment to assess individual supplemental potassium needs. Later there is no need to test potassium on regular basis.
Over time, on a proper diet and potassium supplementation, a child treated with bumetanide usually achieves a stable electrolyte balance, so control blood tests are rarely required on long term bumetanide treatment. In fact long term bumetanide use is very practical, and the simple safety precautions required are nothing compared to coping with untreated symptoms common in severe autism e.g. sensory suffering, which may significantly improve on bumetanide.
If a blood draw is an issue in a child with anxiety or sensory disorders, this is what might help:
-          Visuals to reduce anxiety in a child e.g. picture social stories explaining blood draw procedure
-          AAC used for communication in a non-verbal or minimally verbal children
-          Video modeling or blood draw play at home before the procedure
-          Skilled nurse and friendly environment, which can be arranged in advance
-          At home blood draw service.


Fig. 3. Visuals can help with reducing the blood draw related anxiety.

It needs to be stressed that in general, presumed behavioral difficulties should not be a barrier to necessary medical examinations or procedures needed for health in autistic children, as avoiding them can result in increasing the medical risks in a population already prone to co-morbidities and poor health outcomes. It is the responsibility of the health provider and the parent to find the most convenient and effective way to perform the examinations needed. It is not unusual that all medical procedures get easier over the time in a child who uses bumetanide and develops communications skills and improves their cognitive function and awareness.
How to deal with the “bumetanide has stopped working” problem?
After some months or even years some parents may feel that “bumetanide has stopped working”, this may well not be their imagination and it can be very disconcerting. A little science is required to explain what may be happening. It appears that bumetanide responders have too many NKCC1 transporters in their neurons and too few KCC2. Only about 1% of bumetanide can cross the blood brain barrier where it blocks the NKCC1 transporter. An inflammatory response elsewhere in the body sends inflammatory signals throughout the body and some reach the brain where this causes an increase in NKCC1 and a reduction in KCC2 expression.  This effect can wipe out the beneficial effect of that tiny 1% of bumetanide that is present.  You can increase the dose of bumetanide and try and reduce the source of inflammation, which might be as simple as an allergy, or the cause might be harder to identify.  There will be many other biological reasons why a shift in NKCC1/KCC2 might occur, so some detective work will be needed.  The beneficial effect of bumetanide will then be restored. 
Conclusions
Almost all parents whose children were included into the first bumetanide randomized clinical trial in France asked for treatment continuation after the study finished. Safe use of bumetanide for up to 2 years later were reported in this group. According to personal communication, bumetanide has been successfully subsequently used off label for at least 8 years in children and youth with autism, and no long-term issues emerged on long-term treatment. While this treatment does not offer an “autism cure”, it could significantly increase the quality of life of autistic persons thanks its potential to bring about improvements in sensory processing and hypersensitivity, cognition and acquiring communication skills (see published studies, linked below, for details on potential positive effects of bumetanide).

Acknowledgements: Thanks to  Natasa Blagojevic-Stokic for language editing and comments.
Conflict of interest:  none
References:

1.       Lemonnier et al.: A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2012 2:e202.  https://www.ncbi.nlm.nih.gov/pubmed/23233021

2.       Lemonnier et al.: Treating Fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 2013, 102(6):e288-90 http://www.ncbi.nlm.nih.gov/pubmed/23647528

3.       Grandgeorge et al.: The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep 2014 pii: bcr2013202092. http://www.ncbi.nlm.nih.gov/pubmed/24488662

4.       Bruining et al.: Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders? Pediatrics 2015 136(2): e539-43 http://www.ncbi.nlm.nih.gov/pubmed/26216321

5.       Lemonnier et al.: Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry 2017, 7(3):e1056 https://www.ncbi.nlm.nih.gov/pubmed/28291262

6.       James et al.: Bumetanide for Autism Spectrum Disorder in Children: A Review of Randomized Controlled Trials. Ann Pharmacother. 2019, 53(5):537-544 https://www.ncbi.nlm.nih.gov/pubmed/30501497

7.       Gharaylou et al.: A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy. CNS Drugs. 2019, 33(3):283-291 https://www.ncbi.nlm.nih.gov/pubmed/30784026


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Tuesday, 4 June 2019

Meningeal Lymphatics in Autism - at least two possibly relevant dysfunctions




  
I am always surprised how popular some posts with complicated titles are on this blog. Meningeal lymphatics in Bart Simpson speak would be “brain plumbing”.  Today we discover that:-

·        Immune cells can enter the brain by climbing up the brain’s plumbing pipes, entering originally via lymph nodes outside the brain

·        Those same plumbing pipes get blocked and waste is not free flowing out of the brain. The blockage may be at a brain-draining lymph node.

Today’s post follows up some research that I think Tyler highlighted a long time ago, about the recent discovery that the brain has its own lymphatic system.





                       
Human Lymphatic System before 2015              Human Lymphatic System after 2015




In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.

Structural and functional features of central nervous system lymphatic vessels


Editorial Summary

A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system. Jonathan Kipnis and colleagues now show that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders. 

  

Knowledge has moved on a bit further since 2015 and hence today’s post, but the research is focused on MS and Alzheimer’s rather than autism.

The lymphatic system carries a clear fluid call lymph.

The lymphatic system has multiple interrelated functions

·         It is responsible for the removal of interstitial fluid from tissues
·         It absorbs and transports fatty acids and fats as chyle from the digestive system
·         It transports white blood cells to and from the lymph nodes into the bones
·         The lymph transports antigen-presenting cells, such as dendritic cells, to the lymph nodes where an immune response is stimulated.

The discovery in 2015 - A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system.

Jonathan Kipnis discovered that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders.






When a tissue is infected by a pathogen, like a virus, bacteria, or parasite, bits and pieces of the offending pathogen end up in the lymph. These pieces, along with immune cells from the infected tissue, reach the lymph node, and the cells in the lymph node then react to coordinate a specific immune response to the pathogen. Thus, the system not only allows for recirculation of bodily fluid, but it also provides a means for the immune system to sift through material from around the body in order to scan for infection. Without lymphatics, fluid would build up in body tissues, and there would be no way to alert the adaptive immune system to invading pathogens.


Alzheimer's, Autism, MS and Beyond

The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist

It is now suggested that several organs may be sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS.

What that means is an immune dysfunction far away from the brain and its blood brain barrier defences can send its messengers up the brain’s drain pipes and directly into the brain.

By closing the drain pipes you can prevent serious brain inflammation like that found in Multiple Sclerosis.

 Kipnis’ idea is to target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels.  In other words, you block the inflammatory signals from entering the brain.

The research has now shown that this is indeed achievable in the mouse model of multiple sclerosis.

The problem with blocking the flow through the pipes is that you need them to be free flowing to avoid dementia and cognitive decline.  The Alzheimer’s research suggests that opening up the pipes wide to clear away accumulated junk in the brain might well stave off the disease.

The solution might involve some complex plumbing adjustment.

For old people it might be key to modify the lymphatic system inside the brain, so as to open those blocked pipes.  It may be that in some autism a variant of this problem also exists.  There is a section on this later in the post, with some case histories.
For people with MS and inflammatory-type autism it might be the case of closing the pipes at a clever location in the lymphatic system outside the brain to stop inflammatory messengers entering the lymph system and heading up into the brain. 

While autism research is rarely class-leading, MS research and Alzheimer’s research attracts plenty of smart scientists and research dollars.  This means that you may want to keep an eye on research in those two diseases.

Now we look at the research:

  • Multiple Sclerosis
  • Alzheimer’s
  • Autism


Multiple Sclerosis

Great strides are being made in MS research and some of the off-label therapies like Ibudilast, referred to in this autism blog, are showing promise in clinical trials.

Brain-draining lymph nodes exist outside the brain and you can actually measure how much CSF is flowing out of the brain.  In older brains the flow rate is much less, as if the drains have got clogged up. 

Brain-draining lymph nodes also allow inflammatory messengers to enter the central nervous system (CNS) that was supposed to be kept safe behind the blood brain barrier.

Brain's lymphatic vessels as new avenue to treat multiple sclerosis

Vessels carry mysterious message from brain that causes MS, research suggests

                          
Lymphatic vessels that clean the brain of harmful material play a crucial role in the development and progression of multiple sclerosis, new research from the University of Virginia School of Medicine suggests. The vessels appear to carry previously unknown messages from the brain to the immune system that ultimately trigger the disease symptoms. Blocking those messages may offer doctors a new way to treat a potentially devastating condition that affects more than 2 million people.
The discovery comes from the lab of UVA researchers who identified the lymphatic vessels surrounding the brain, vessels that textbooks long insisted did not exist. In an exciting follow-up, the researchers have determined that the vessels play an important role in not only multiple sclerosis but, most likely, many other neuroinflammatory diseases and in dangerous brain infections.
"Our data suggests that there is a signal coming from the brain to the lymph nodes that tells immune cells to get back into the brain, causing the [multiple sclerosis] pathology," said researcher Antoine Louveau, PhD, of UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG). "This is an important proof of principle that exploring the role of these vessels in different neurological disorders, including multiple sclerosis, is worth it."
Stopping Multiple Sclerosis
The researchers at UVA, led by Jonathan Kipnis, PhD, were able to impede the development of multiple sclerosis in mice by targeting the lymphatic vessels surrounding the brain. They used multiple strategies to block the lymphatics or destroy them with a precision laser. All led to the same outcome: a decrease in the number of destructive immune cells capable of causing paralysis.
"The idea was to prevent more widespread damage to the nervous system," said researcher Jasmin Herz. "If communication of brain inflammation through lymphatic vessels is the root cause of multiple sclerosis, therapies targeting these vessels could be clinically important."
The message from the brain that appears to drive multiple sclerosis remains poorly understood. The researchers can tell the message is being sent, and they can tell what it is instructing the immune system to do, but they don't yet know what mechanism the brain is using to send it. "I think the next step in this specific research is to identify what that signal is. Is it a cellular signal, is it a molecular signal?" Louveau said. "And then to try to target that signal specifically."
The researchers noted that removing the vessels did not stop multiple sclerosis entirely. That suggests there are likely other factors at play -- and much more for scientists to explore.

An Important Proof of Principle
UVA's new research offers important insight into the function and role of the lymphatic vessels that connect the brain to the immune system. In most aspects, they work exactly as scientists would expect -- just like other lymphatic vessels in the body.
"Meningeal lymphatic vessels are quite small compared to other lymphatics in the body, and we and others wondered if this might limit the amount and size of cargo they can pass through," Herz said. "During inflammation, they did not change in size or complexity much, but what was really exciting to discover [was that] they allowed whole immune cells to traffic through them, and we found the molecular cues for that."
the lab's recent research also highlights the complexity doctors face when trying to But manipulate the vessels to benefit human health. For example, blocking the vessels had a benefit in the multiple sclerosis model, but the lab has also shown that the vessels' healthy function is vital to staving off Alzheimer's disease and preventing the cognitive decline that comes with age.
That means that it's unlikely that stopping MS could be as simple as blocking the flow inside the vessels. It also suggests that there is probably no one treatment approach that will work for every neurological disorder. But the emerging importance of the vessels offers doctors an exciting new avenue for tackling neurological diseases.
"These findings on the role of brain-draining lymphatic vessels in MS, together with our recent work on their role in Alzheimer's disease, demonstrate that the brain and the immune system are closely interacting. When these interactions go out of control, pathologies emerge," said Kipnis, chairman of UVA's Department of Neuroscience and director of the BIG Center. "The idea that we could target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels, is beyond exciting. Through our collaboration with PureTech Health, we hope to bring these laboratory findings to improve patients' lives one day."
Kipnis recently signed a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.


CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature


Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfil two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

Discussion

Here we show that meningeal lymphatic vessels sample macromolecules and immune cells from the CSF and serve as an important conduit for CNS drainage. We also describe structural features of spinal cord meningeal lymphatics. We expand on our understanding of immune-cell trafficking via the meningeal lymphatic vessels to the draining lymph nodes, which is primarily dependent on CCR7. Using a pharmacological method that we adopted to specifically ablate meningeal (or nasal) lymphatic vessels, we demonstrated that the nasal route drains directly into the sCLNs, while the meningeal lymphatic route drains into both the dCLNs and sCLNs. RNAseq analysis of LECs from mouse meninges, diaphragm, and skin revealed that the meningeal lymphatic vessels exhibited a unique transcriptional profile, which, under local inflammatory conditions, might underlie the distinct behavior of meningeal lymphatics. Attenuation of EAE was obtained after surgical and pharmacological blockade of lymphatic function, suggesting that drainage contributed to the activation of encephalitogenic T cells in the lymph nodes. Supporting this notion, reduction of meningeal lymphatic drainage reduced interactions of 2D2 T cells with local antigen-presenting cells. RNA-seq of activated 2D2 T cells isolated from dCLNs showed that T cells from mice lacking lymphatic drainage acquired a different phenotype from that of controls. These findings warrant further research to identify the cellular (and/or molecular) mediators draining from the CNS and driving T cell encephalitogenicity. Meningeal lymphatic vessels are embedded within the dura. This raises an obvious question: how can macromolecules and immune cells drain from the CSF into meningeal lymphatic vessels, given that the arachnoid mater is supposedly impermeable to CSF45? We noticed, however, that certain spots along the meningeal lymphatics could be seen to take up the tracer from the CSF almost immediately after its injection, whereas tracer uptake along remaining parts of the vessels was slower. Subsequent experiments revealed certain spots along the meningeal lymphatics where the vessel structure was more complex and ramified and where extensions were exposed to the CSF. The structure of these lymphatic sprouts is reminiscent of peripheral-tissue lymphatic buttons, which serve as entry gates into the lymphatic vasculature. Further experiments using electron microscopy technique will be necessary to demonstrate that the meningeal lymphatic vessels are physically crossing the arachnoid mater. Previous reports have implicated the cribriform plate as a major player in the passage of immune cells from the CNS to its draining lymph nodes. Furthermore, a recent study has challenged the potential contribution of the meningeal lymphatics in the drainage of CSF into the CLNs6 . Here using live-imaging, our data (supported by others46) clearly demonstrates the uptake by meningeal lymphatics of tracers injected into the CSF. Our observations, however, do not exclude alternative routes as previously suggested. In the present study, we injected exogenous cells into the cisterna magna and also observed cells in the nasal mucosa and associated lymphatics. However, we could not detect any T cells on the nasal side of the cribriform plate under physiological conditions. Moreover, we labeled endogenous meningeal T cells using laser photoconversion but could not detect any labeled cells in the nasal mucosa. It is possible that if photoconversion of meningeal T cells was complete, some crossing of the cribriform plate by meningeal T cells could have been observed. Furthermore, the speed of injection (and, hence, change in intracranial pressure) appears to be a major factor in facilitating crossing of the cribriform plate by CNS immune cells. Our results thus suggest that the cribriform plate in all probability does not represent a major physiological immunerelevant exit route. This structure has been shown, however, to play an important role in the regulation of CSF homeostasis, since its surgical blockade results in an immediate and constant increase in CSF pressure47. Our results also show that chronic neuroinflammation is accompanied by expansion of the lymphatic vasculature localized around the cribriform plate (as opposed to brain and spinal cord meningeal lymphatics), suggesting that the nasal region might have a more important function at later stages of disease development. Several organs (such as lungs48, for example) have been suggested as sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS. Our data suggest that dCLNs could be another site for T cell licensing or reactivation. Dendritic cells migrating from different tissues have been shown to uniquely influence T cell activation and migration49, and MOG-loaded dendritic cells reportedly activate T cells in the CLNs before their migration into the CNS50. In the context of EAE (both induced and spontaneous), excision of the brain-draining lymph nodes has been shown to delay or attenuate disease development38–40. In spontaneous models, limitation of the drainage of MOG into the dCLNs, thereby preventing activation of MOG-specific T cells, is a likely mechanism. A similar scenario might apply when meningeal lymphatics are ablated. It is important to note that meningeal lymphatic ablation only attenuates and ameliorates EAE but does not completely stop it, suggesting that other routes are involved. Although no side effects were found when using the Visudyne approach, future development of targeted techniques will allow researchers to discern the role of anatomically distinct lymphatics in EAE. Overall, the work described here provides the first characterization, to our knowledge, of the meningeal lymphatic system in the context of brain immunity and neuroinflammation and opens the way to a better understanding of brain immune surveillance and the generation of CNS-directed immune responses. These results might help to uncover the etiology of the immune imbalance typical of neuroinflammatory disorders, with promising implications for therapy

  
                           

Dementia including Alzheimer’s

Brain discovery could block aging's terrible toll on the mind

Faulty brain plumbing to blame in Alzheimer's, age-related memory loss -- and can be fixed


Aging vessels connecting the brain and the immune system play critical roles in both Alzheimer's disease and the decline in cognitive ability that comes with time, new research reveals. By improving the function of the lymphatic vessels, scientists have dramatically enhanced aged mice's ability to learn and improved their memories. The work may provide doctors an entirely new path to treat or prevent Alzheimer's disease, age-related memory loss and other diseases. 
Kipnis and his colleagues were able to use a compound to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice. The vessels became larger and drained better, and that had a direct effect on the mice's ability to learn and remember. "Here is the first time that we can actually enhance cognitive ability in an old mouse by targeting this lymphatic vasculature around the brain," Kipnis said. "By itself, it's super, super exciting, but then we said, 'Wait a second, if that's the case, what's happening in Alzheimer's?'"
The researchers determined that obstructing the vessels in mice worsens the accumulation of harmful amyloid plaques in the brain that are associated with Alzheimer's. This may help explain the buildup of such plaques in people, the cause of which is not well understood. "In human Alzheimer's disease, 98 percent of cases are not familial, so it's really a matter of what is affected by aging that gives rise to this disease," said researcher Sandro Da Mesquita, PhD. "As we did in mice, it will be interesting to try and figure out what specific changes are happening in the old [brain] lymphatics in humans so we can develop specific approaches to treat age-related sickness."
Kipnis noted that impairing the vessels in mice had a fascinating consequence: "What was really interesting is that with the worsening pathology, it actually looks very similar to what we see in human samples in terms of all this aggregation of amyloid protein in the brain and meninges," he said. "By impairing lymphatic function, we made the mouse model more similar to human pathology."

Treating -- or Preventing -- Alzheimer's
The researchers now will work to develop a drug to improve the performance of the lymphatic vessels in people. (Kipnis just inked a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.) Da Mesquita also noted that it would be important to develop a method to determine how well the meningeal lymphatic vasculature is working in people.
The researchers believe that the best way to treat Alzheimer's might be to combine vasculature repair with other approaches. Improving the flow through the meningeal lymphatic vessels might even overcome some of the obstacles that have doomed previously promising treatments, moving them from the trash heap to the clinic, they said.
It may be, though, that the new discovery offers a way to stave off the onset of Alzheimer's to the point that treatments are unnecessary -- to delay it beyond the length of the current human lifespan.
"It may be very difficult to reverse Alzheimer's, but maybe we would be able to maintain a very high functionality of this lymphatic vasculature to delay its onset to a very old age," Kipnis said. "I honestly believe, down the road, we can see real results."


Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice


Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions 


Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease




Autism

While Kipnis is busy developing a drug to improve the lymphatic drainage from the aging brain, some people believe they can achieve something similar via massage.

I have no idea if this really is possible, but this is the idea being practised on children with autism in Italy.

So, because this is after all an autism blog, let’s see what the Italian have been up to.





In this study we report the results of a protocol for improving brain lymphatic flow in autism through lymphatic drainage massage, a technique successfully used in a variety of conditions where intracranial lymphatic circulation is hampered by obstacles at the level of deep cervical nodes. At the end of May 2018, the Biomedical Centre for Autism Research and Treatment started implementing a protocol of manual lymphatic drainage of the deep cervical nodes on autistic subjects. By October 2018, several scores of patients had been treated with this protocol. In this report, we describe the cases of three autistic patients for whom manual lymphatic massage was remarkably effective. To our knowledge, this is the first report of lymphatic drainage massage at the level of the deep cervical nodes in autism. Symptomatic improvement was robust and we attribute these results to the effects of the massage on the intracranial lymph or sometimes referred to as the glymphatic circulation with improvement of brain lymphatic drainage believed leading to a decrease of neuroinflammation. In addition to stimulating lymphatic drainage, we postulate that the protocol may serve also as vagus nerve stimulation. The protocol also targets the larynx in a manner similar as described for laryngeal manual therapy for the treatment of dysphonia, and this factor may be contributing to the overall improvement of symptoms, with particular reference to speech. Based on the cases described in this report and on our ongoing research, we are convinced that this type of inexpensive, harmless and easy-to-implement approach of manual lymphatic drainage can be beneficial to autistic patients and represents a new and promising treatment. We expect that the described protocol will play a central role in future treatments for autism, both alone and in combination with other therapies such as behavioral therapies or nutritional interventions.

Case Reports

Patient 1:

Male, 2 years and 9 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 20 months of age when he lost the few words he had learned, lost eye contact, stopped responding when called, and began bizarre behaviors - motor stereotypies - that included flapping. Subsequently, this patient developed crises of anger and violent tantrums, in particular when contradicted. The patient did not show significant bio-humoral alterations with the exception of slightly elevated platelet count and IgE. The patient had frequent bowel movements with very soft and hypocholic feces. Three days after implementation of the manual lymphatic drainage protocol, the patient spontaneously begun speaking a few words and eating without the need of assistance, properly using the tableware. Bowel movement were reduced to two movements per day with well-formed feces. The patient begun showing curiosity toward new foods and flapping progressively disappeared. In the following two months, he significantly increased the complexity of his vocabulary and the ability to appropriately follow complex instructions. Stereotypies disappeared and ability of learning during behavioral therapies significantly improved.

Patient 2:

Female, 9 years old at the time of implementing the manual lymphatic drainage protocol, with confirmed diagnosis of early-onset autism and recurrent allergic asthma requiring desloratadine treatment. The most prominent autism symptoms were motor stereotypies, speech limited to very simple sentences, and significant delay in learning. Immediately after implementation of the manual lymphatic drainage, a slight, temporary, enlargement of latero-cervical nodes lasting for a few days was noted, possibly due to mobilization of lymph. Evident improvement of autistic symptoms consisted in spontaneous, faster and easier learning at school with increased alertness and focus. Ability in performing coordinated fine movements significantly increased and the patient began to write; this in turn resulted in increased self-esteem. Motor stereotypies significantly decreased and personal autonomy significantly increased.

Patient 3:

Male, 6 years and 6 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 15 months of age when he stopped developing speech, lost eye contact, stopped responding when called and refrained from social interactions. A diagnosis of atypical autism with hyperactivity and attention deficit was proposed at the age of 5. The child had chronic allergic rhinitis and sinusitis with persistent nasal congestion that caused open mouth breathing. The patient was very selective in his eating habits and only ate a few types of fried foods. Following implementation of the manual lymphatic drainage protocol, chronic nasal congestion was rapidly resolved, and nose breathing was reestablished. Eating habits were significantly improved and the patient began eating a variety of healthier foods. The patient also showed improvement in socialization; began to look at other children, trying to imitate their actions. Also, significant improvements in speech were observed with the patient speaking more complex sentences with better pronunciation.



Conclusion

I think it is very likely that something in today’s post is indeed very relevant to much autism.

Now we know not to blame only the vagus nerve for transmitting inflammatory signals from the body to the brain.

Hopefully the researchers will eventually pursue their original idea from 2015 that the study of meningeal lymphatics might lead to autism therapies.

We are of course at liberty to learn from the Alzheimer’s and MS research and develop our own therapies.