Case Report 1:

1. Male, 5 yoa
   
   
2. Epilepsy
   
   
3. Autism (Autism Spectrum Disorder)
   
   

Doctor's impression: ND presents with a unique and eclectic mixture of symptoms. ND shows symptoms of mitochondrial dysfunction, excessive oxidation, impaired methylation (confirmed via genetic testing) and possible glutamate dysregulation (as per genetic testing). Initially ND was non-verbal, unresponsive to most stimuli and experiencing unrelenting seizures (partially intractable). Numerous medications were attempted with poor results, a ketogenic diet (no carbohydrates) was partially successful but unsustainable. After correcting impaired methylation and enhancing neuroprotection ND began to improve in overall amount and magnitude of seizures. It was also at this time (within 1-2 weeks) that his awareness and language made significant leaps. Mitochondrial support was added 1 month after with further improvements in both ASD symptoms and Epilepsy (significant seizure reduction with mitochondrial/energetics treatment). Currently he is on a varied diet (off ketogenic), no pharmaceuticals and a daily supplement regimen specifically tailored to his needs and unique issues.


Parental Report




In a few sentences could you describe in your words ND's health previous to starting with Dr. Gulliver. List Diagnoses where applicable.

• Epilepsy diagnosed April 11, 2013
  
  
• Autism diagnosed June, 2013
  
  
• ND at the age of one seemed to be developing above that of his peers (walking, talking, and using two hands). At the age of 17 months ND started to have focal seizures which occurred maybe once or twice a week. It is at this time ND had regression in language and development.
  
  
• Just prior to consulting Dr. Gulliver ND was having 30+ clusters of seizures a day, lasting from five minutes to 22 minutes each. After each cluster ND would sleep anywhere from one hour to two and a half hours. He would wake, eat, have a seizure and sleep. That was his routine, sleeping 16-18 out of 24 hours a day. When he was awake he was not interested or aware of anything around him. He was unable to walk with any confidence because he was so off balance.
  
  
• Overall, I would say that ND's health prior to consulting Dr. Gulliver was very weak.
  
  
• Abnormal EEG, significant seizure activity.
  
  

List of trialed medications, diets or otherwise trialed before seeing Dr. Gulliver




Clobazam 2.5 mg, April 14, 2013 – June 22, 2013

Valproic Acid 50mg/ml, May 24, 2013 – August 19, 2013

Phenobarbital 60mg, June 7, 2013 – June 8, 2013

Ethosuximide 50mg/ml August 8, 2013 – May 1, 2014

Depakote Sprinkles 125mg per cap, August 20, 2013 – December 3, 2014

Kepprea 100mg/ml, November 2, 2013 – December 26, 2013

Topiramate Sprinkles 15mg per cap, January 15, 2014 – March 8, 2015

Clonazepam 0.25mg, June 4, 2014 – July 2, 2014

Melatonin 3mg, June 11, 2014 – June 13, 2014




Ketogenic Diet September 9, 2013 – March 21, 2014


Overall impression of his developmental stage, language, awareness, interaction with the environment.(1-10, for scale of development, 10 being no interaction or progression) Prior to Dr. Gulliver.

• Developmental stage – Chronological age of 3 with developmental age of 1.5 years (2 for scale of development)
  
  
• Language – Non-verbal. Was verbal but had regression at age 22 months. (2 for scale of development)
  
  
• Awareness – None aware of surroundings. He was in and out of seizures so frequently that he slept almost 16 out of 24 hours a day. (2 for scale of development)
  
  
• Interaction with environment – Zero to little interaction with his environment as he was unable to walk with balance and when not in a seizure or sleeping was in a “zombie” like state. (2 for scale of development).
  
  

Amount of seizures, magnitude etc before seeing Dr. Gulliver, abnormal EEG's are relevant. (1-10 rating as well, 10 being very severe).

• Nicholas’ seizures, type and frequency of, changed almost with every medication change. At the beginning the seizures were focal in nature and very faint, unnoticeable to most. Than they changed to myoclonic jerk seizures. In this stage, and at that time, he was at his worst having 30+ clusters a day with 200+ head jerks. It was during this time that the magnitude of the seizures were at their worst. He would drop in mid stride and the force behind the head jerk was very very powerful. Rating of 10 (very severe) for seizure activity prior to seeing Dr. Gulliver. If he was not having a seizure he was sleeping. Rating of 8 for magnitude of seizures.
  
  

After treatment with Dr. Gulliver.

Overall health (1-10) scale. 10 being exceptional health.

• Overall health rating of 8. ND has developed many skills and is expressing himself verbal more and more every day. First noticeable one month after consulting Dr. Gulliver. (ND said “Mom”). 
• Improvements in awareness, stereotypical behaviour, language generation and understanding/reception. Improvements in sensory needs and imagination (via play) have been evident.
  
  

Development and progression. (1-10), 10 indicating rapid progression (this is relative to before).

• Development and progression 7. ND went from not being able to walk up or down the stairs without assistance to jumping from the second step down within three months. Attributed to the development in his balance and awareness of environment.
  
  
• Rating of 9 in development with the addition of the last Compound. Hugh development in verbal attempts and interest in environment within two weeks after starting supplement.
  
  

NOTE: Each supplement addition and/or change brought with it changes in development and progression.




3. Seizure activity, magnitude, overall impression (1-10)(10 being good)

• Seizure activity 9. From 30+ clusters to 4-5 seizures daily
  
  
  
  

Overall impression 8. For health, development, progression, language development. ND is now aware and able to interact with his environment because the seizure activity is less frequent.

EEG showed significant reductions in activity, and focal epileptiform discharges.ND has continued to do well on his current regimen, however,  he still faces significant challenges, his joyful nature and his parents tireless efforts will ensure continued progression.


NAC for OCD

A systematic review has recently been conducted on NAC and it's utility in Obsessive Compulsive disorder.

Clin Psychopharmacol Neurosci. 2015 Apr 30;13(1):12-24. doi: 10.9758/cpn.2015.13.1.12.
N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review.Oliver G1,
Abstract:
Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area.

METHODS:PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NACstudies were contacted for any unpublished data.

RESULTS:Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day ofNAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation.

CONCLUSIONS:Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.


NAC also has research indicating that it may be useful for other OCD spectrum disorders, such as grooming disorders, addiction/substance abuse, skin picking and nail biting!

Traditionally ADHD is treated with stimulants or non-stimulant medication that increases dopamine and/or norepinephrine. Throughout the literature it is clear that those with ADHD (and subtypes) have improper dopamine/adrenaline release which is the basis for the symptomatology (inattention, impulsivity, hyperactivity etc). Are there any lifestyle or dietary measures that can reduce these symptoms? if so, how?

Exercise is one of the best treatment modalities for improving ADHD symptoms. Anecdotally, patients find exercise extremely helpful for hyperkinetic symptoms (hyperactivity) and for impulsivity specifically.  

Exercise improves Dopamine function! 

• This is a complicated issue that isn't quite as simple as increasing dopamine. Some receptors, such as the D2 (second dopamine receptor), decreases neuron excitability, or said in plain english, it reduces the activity of dopamine. Reducing D2 receptor expression, while not directly increasing dopamine, has downstream effects that improve symptoms and overall dopamine transmission (communication between cells)
• Exercise (aerobic) has been shown to reduce the D2 receptor in a murine model and alleviate hyperactivity and impulsivity (PMID: 25671205).

Exercise improves symptoms and some of the physiological aberrations

• A 12 week pilot study looking at table tennis exercise found improvements in both motor skills and executive function. The improvements in executive function are extremely important as this is the seat of dysfunction in ADHD.(PMID: 25646023)
• In another study in a murine model, levels of tyrosine hydroxylase(TH) were measured before and after treadmill exercise.  TH is the rate-limiting step in dopamine production, low levels are found in ADHD. exercise using a treadmill was able to increase TH levels significantly and reduced induced ADHD symptoms.

Imaging studies further support aerobic exercise

• Studies examining EEG  (measures brain electrical activity) before and after exercise have been conducted. When post exercise EEG measures are taken, those with ADHD show increased levels of theta brain waves, which indicates deep relaxation.  It also appears to reduce alpha waves which are associated with stress.

Exercise, improves electrical activity in the brain, increases dopamine function, reduces adrenaline and can help correct some of the underlying issues plaguing those with ADHD.  Thirty minutes of cardiovascular exercise such as jogging, swimming or playing sports daily can have a significant impact on symptoms. 


MINDFULNESS:

• Meditation has significant effects on ADHD symptoms.
• An 8 week pilot study looking at mindfulness meditation found significant improvements in core symptoms (hyperactivity etc) and emotional dysregulation. (PMID: 24305060)

• The combination of exercise (in the form of play) and meditation had significant effects on in class behaviours. The benefits were seen at six weeks and continued throughout the 12 month period.

• Meditation has been shown to increase cortical thickness in areas related to attention. Meditation activated these areas which are generally under active, improving hypo-functioning of these brain regions.(PMID: 23046904 )

Exercise and meditation have significant impact on both core and peripheral symptoms of ADHD. These therapies may help correct some of the underlying brain abnormalities and can be done with or without medication.  Thirty minutes of daily exercise and ten minutes of mindfulness meditation can go a long way!

The role of inflammation in depression (and all conditions ostensibly) is a central issue in biomedical research. Every day more research hints at the link between local (neuro/brain) and systemic inflammation.

increased levels of particular markers that indicate neuro (brain/CNS) inflammation have been found and replicated. This indicates that there is a degree of inflammation in the brain during Major Depressive Disorder/Episode(MDD/MDE). Does it precede depressive symptoms or is it simply a consequence of the illness? it appears to be both, inflammation is worsened during depression (immune suppression/dysfunction) and high levels of inflammation can induce depression by deranging multiple neurotransmitter systems creating a positive feedback loop.
Inflammation

1. "This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE": 25629589.   In this study a marker for neuroinflammation, Translocator protein density, was used and found to be elevated.
2. "The cascade of antioxidative and inflammatory events is orchestrated by several transcription factors, with Nrf2 and NF-κB having particular relevance to MDD"- PMID: 25580634.  levels of oxidation (requiring high levels of anti-oxidants) is created by activation of genes that regulate inflammation. High levels of oxidation in turn  stimulate the action of these molecules creating a cycle of chronic inflammation.
3. "The study concluded that in the absence of known oxidative injury causative agents, the lowered levels of antioxidants and higher levels of MDA implicate the high degree of oxidative stress in unipolar depression":PMID 25653939. - This study was consistent with the others in indicating that multiple avenues of inflammation are activated in depression and that unchecked inflammation can lead to depression.
   

Elevated levels of homo-cysteine (Hcy)

1. "the findings suggested that the increased Hcy concentration in the plasma might be the result of stress-induced depression" PMID: 25286230 - This is most likely a perpetuating issue, not causal.
   
2. "In this large population-based study, elevated tHcy concentrations are associated with lifetime MDD and particularly with remitted MDD among men". PMID 23707477 - Interestingly, woman tended towards the inverse correlation, that is, high levels of Hcy had no correlation with MDD and in fact, trended in the opposite direction of the men in the study. 
3. "Homocysteine also appears to enhance neurotoxicity and damage via glutamate"PMID: 24266734

Agents that reduce inflammation have shown potential in depression:

1. "Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects: PMID 25322082.- Celecoxib is used for pain and inflammation as it is an NSAID.
   
2. "Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action:PMID 25523883"- Curcumin is a potent anti-inflammatory
   
3. "These results suggest that ibuprofen may have an antidepressant effect through inhibition of PGE2 and NO production, especially in depression secondary to chronic inflammation.: PMID 25101545 . 

Taken together, evidence is mounting that inflammation is a significant component of depressive disorders. A sub population of those with chronic recurrent depression may benefit from targeted anti-inflammatory therapy. More specifically, agents that reduce brain inflammation should be trailed.

I have had a lot of inquiries into methylation and Autism, the why, how , when and what of it all. It certainly is a complex topic but let me do my best to examine the research and make it useful for everyone. Warning, this is a large topic and I never did well in language arts as a kid. The field of research in ASD is thick and cumbersome like a double big mac, so let's break into quater pounders if you will.

The best place to start with this topic is at the level of oxidation and anti-oxidants. Everyone has heard of anti-oxidants and their benefits but why are they beneficial. Well, oxidation is a normal process in the body things like peroxides (1) are created in order to destroy bacteria and other problematic organisms amongst other things. The problem is, once this oxidant (reactive oxygen species ) is done with it's job it needs to be cleaned up per se, that's were anti-oxidants come into play. If you don't have enough anti-oxidants or the right type you risk oxidation damaging your cells and ultimately causing ill health. Almost all diseases have components of oxidative stress but just any old anti-oxidant won't do.


So what is methylation and how do we best categorize it? It is aptly named the methylation cycle for a reason, it is a continuous circle or cycle in the body that actively re-cycles molecules into usable forms. Think of it like a nascar track, it has no end and the cars are the molecules that need to be serviced just like our body. That is the cars move along this track just like methyl donors (b12,tmg etc) revolve around this cycle. Every good racetrack has pit stops, in this case the methylation cycle has three main ones, methionine, homocysteine and SAM. At each pitstop something different is added or removed from the car, it may be the brakes or a refill of gas, whatever it is each stop is important to ensure the cars move along the track smoothly.


 If one pit stop is ensured with the job of changing the tires and doesn't complete it's task the next pit stop will have more work and likely do a poor job. This is exactly the issue we see in Autism(ASD), do to lack of workers/tools at the pit stop (methyl donors) or poorly skilled workers (enzyme defects) the cars (our bodies) don't function correctly. 


But what exactly does not functioning properly mean? Well a multitude of research studies have indicated that methylation is indeed impaired in ASD (1,2,3,4,5,6). Properly working methylation is required for cognition, behaviour, anti-oxidant defenses, Protein activation etc. Methylation helps keep the stuff under the hood (the brain/body) working smoothly. The cycle also produces a substance called Glutathione, the bodies master anti-oxidant, It is the gas of the car if you will, other anti-oxidants are regular, but glutathione is premium unleaded gas, the stuff no one buys.


In ASD low levels of glutathione have been found (2,3,4), High levels of homocysteine, one of the pitstops that supplies the gas (glutathione) and high levels of oxidative stress (wear and tear). How can this be corrected? supplying the pitstops with the proper tools (methyl donors) seems to resolve this problem. Improvements in all biomarkers related to poor methylation improved when proper dosages of these nutrients were supplied,that is the pit stops worked properly when the right tools and workers were supplied.


Improvements in language, behaviour (aggression, tantrums) socialization have been noted with therapies aimed at  correcting this cycle and combating oxidation. Improving methylation increases glutathione, reduces oxidative stress, improves neurotransmitter function and keeps our genes working correctly(2,6,7,8,9).


Why is this happening in ASD? no one is sure it's likely a host of things combining to cause this issue. Enzyme deficiencies and defects have been noted, reduced intake of raw materials (methyl donors) is also a factor and the genetics of autism perhaps holds some further clues.


some insights from the researchers:


"An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism. " (2). 


"Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement" (7).


my goal is to take the guesswork out of the data for my patients and help develop workable, science based strategies for treatment.


I would love any comments or questions, debate sparks innovation. 





References:


1.Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem. 2009 Jul;42(10-11):1032-40. 

2. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7. 

3.Pastural E, et al. Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Essent Fatty Acids. 2009 Oct;81(4):253-64. 

4.Blaylock, R. Interactions of cytokines, excitotoxins, and reactive nitrogen and oxygen species in autism spectrum disorders. J Amer Nutr Assoc 2003: 6: 21-35. 

5.James SJ, et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009 Jan;89(1):425-30. 

6.Krajcovicova-Kudlackova M, Valachovicova M, Mislanova C, Hudecova Z, Sustrova M, Ostatnikova D. Plasma concentrations of selected antioxidants in autistic children and adolescents. Bratisl Lek Listy. 2009;110(4):247-50. 


7.Mol Psychiatry. 2012 Jan 10. doi: 10.1038/mp.2011.175. [Epub ahead of print]Cerebral folate receptor autoantibodies in autism spectrum disorder.Frye et al.



8.Neurology. 2005 Mar 22;64(6):1088-90.
Cerebral folate deficiency with developmental delay, autism, and response tofolinic acid.Moretti P, et al.
Source


9.J Altern Complement Med. 2011 Mar;17(3):271-4.

Effectiveness of nutritional supplements for reducing symptoms in autism-spectrum disorder: a case report.XIa, RR.


10.Magnes Res. 2006 Mar;19(1):53-62.Improvement of neurobehavioral disorders in children supplemented withmagnesium-vitamin B6. II. Pervasive developmental disorder-autism.Mousain-Bosc M et al