Monday, November 12, 2012

FPWR Conference - Dr. Jennifer Miller

In the PWS world, Dr. Miller needs no introduction. :) Here are my notes from her presentation on Saturday:


Dr. Jennifer Miller
Therapies in PWS

Growth Hormone
Compared with controls, children with isolated GH deficiency had lower full-scale IQ and other cognitive measures

-verbal comprehension index scores correlated significantly with IGF-1 and IGFBP-3 scores
-children with isolated GH deficiency had smaller splenium of the corpus callosum (connects two sides), left globus pallidum, etc.

GH deficiency that is untreated in childhood may results in abnormalities in brain structure and cognition

Dosing
Standard recommended starting dose is 1 mg/m2/day

On standard starting dose of 1 mg/m2/day, fat mass declines initially, but then increases after 2 yrs of treatment. Whereas on a higher dose of 1.5 mg/m2/day, the fat mass continues to decline over time, indicating that higher doses may be more beneficial for infants over time.
à these results validated by studies in the Netherlands and Sweden
à take-away: treat children like individuals and not just with standards that others hand down

those on GH show improved mental and motor development compared to controls

those with lowest motor dev’t show the most profound improvement on GH

GH decreases ghrelin (hunger hormone) which is high even in infants with PWS, so may alter the natural course of the appetite progression in PWS

Data in PWS mice shows hypoglycemia and deficits in insulin secretion in infancy – GH increases insulin and glucose levels, which may be why it is beneficial for infants in terms of cognitive development. à hypoglycemia not good for the developing brain

GH treatment shortens the initial failure-to-thrive phase of PWS

Kids treated before age 1 had decreased fat mass, lower BMI, and higher resting energy expenditure à early treatment may ameliorate later effects in nutritional stage 3

In general population, GH significantly improves abstract reasoning and visuospacial skills in children. With no treatment there is a decline in certain cognitive skills in adolescence with PWS, but GH treatment prevents that decline of IQ in adolescence.

GH in adults improves muscle mass and decreases body fat
-Most common side effect of adult treatment was edema
-Insulin and glucose levels increased during treatment, but no increased incidence of diabetes
-Few patients had headache and myalgia
-Contraindications: morbid obesity, severe untreated obstructive sleep apnea
-Adult cognition à improvement in mental speed and flexibility and motor performance; when GH stopped, documented impairment in physical and social status as well as overall functioning; parents reported improvement in self-control and both parents and patients reported increased vitality on GH. Patients reported improvement in overall quality of life
-Monitoring IGF-1 levels à surrogate marker for GH; increases significantly over years of treatment and is above normal range in the great majority of individuals with PWS after 2 years of treatment; reducing GH dose causes increases in body fat and decreases in muscle mass, so it is suggested to reduce the dose only if the IGF-1 levels are more than 2 standard deviations above the mean; we recommend monitoring IGF-1 levels every 3-6 months in infants and children and every 6-12 months in adults
            -insulin resistance around 2 years old causes higher IGF-1 à lower carbs, you lower the insulin resistance and you drop your IGF-1 levels so they’re not too high
-GH causes growth of lymphoid tissue, but does not worsen obstructive sleep apnea
-no difference in the causes of death between those who are treated with GH vs. those who are not
-Causes of mortality: respiratory insufficiency or infection, cardiac arrest, sudden unexplained death, infections, choking, ruptured/necrotic stomach
-premature mortality peaks in newborn/early infancy and adulthood, increased in males à obesity is a factor

Provigil (Modafinil)
-most typical stimulants cause adverse effects in individual with PWS (skin-picking, tics)
-works in the hypothalamus instead of in the frontal brain à this is why no bad side effects
-Provigil works well and thus far, has been safe and effective in this population
-has shown significant benefit when given prior to therapies and also helping with cognition in school
-can robustly activate front-cortical areas involved in higher cognitive functions and a network of pro-arousing areas (inc. hypothalamus)
-risk of severe allergic reaction/rash in young children (Steven-Johnsons Syndrome)  (black-box warning for kids under 16 yo)

Modafinil (generic of Provigil)
-double-blind placebo controlled studies indicate that modafinil improves visuospacial memory accuracy and problem solving ability
-improves mood and improves responsiveness to SSRIs for patients with depression
-improves planning and decision making
-improves enjoyment of task performance
-may help impulse control
-the memory-enhancing properties might be the result of the glutaminergic/dopaminergic increased neuronal activation in the hippocampus and in the prefrontal cortex
-other neurotransmitters are also activated by modafinil in various limbic brain areas, suggesting that the drug acts on these brain regions to influence emotional responses
-needs research to determine if these effects exist in PWS and if they may be amplified or attenuated in children with PWS

N-acetylcysteine
-through its role as a modulator of the glutamatergic system, cysteine influences the reward-reinforcement pathway
-maybe exert a therapeutic effect on psychiatric disorders allegedly related to oxidative stress (schizophrenia, bipolar disorder), OCD, etc.
-reduces inflammatory cytokines à increase BDNF?  à might even be good for people who don’t have compulsive behaviors
-more research needs to be done to determine if it will increase BDNF in PWS
-NAC can be oxidized easily, so if it smells bad it means it has been oxidized and is not as effective
-Pharma-NAC comes in individually sealed packets, so won’t be oxidized prior to use à dose is 900 mg per tablet, and that seems to work
à this brand seems to work for some people when other brands don’t
à there is some reason to believe that PharmaNAC helps with immune system and respiratory issues

Hyperphagia Conference
-need to define hyperphagia, because if you can’t define it, you can’t get figure out if medications are helping or not
-mouse models are good to use to start with for treatments, but not always representative of what will happen in humans
-metformin à doesn’t cure hyperphagia, but helps it in girls; in boys, seems to worsen behavior; other effects: decreases Alzheimer’s risk in obese mice with leptin resistance; reduces risk of some cancers; prevents ghrelin signaling pathway in hypothalamus
-diazoxide à usually used to raise blood sugar
            -the molecular endpoint of the leptin signaling pathway in hypothalamic neurons seems to be the K+-ATP channel; loss of Magel-2 gene appears to disrupt the leptin signaling pathway, which leads the body to believe that it’s in a constant state of starvation and contributes to hyperphagia, increased rate of adipose tissue deposition, decreased metabolic rate, GH deficiency,
            -may bypass the signaling defect in the K+-ATP
            -not yet tried in humans


Hypoglycemia
-appears to play a role in appetite and weight issues in PWS
-recent study indicates that 12% of infants had severe hypoglycemia (blood glucose less than 40 mg/dl)
-those who had hypoglycemia seem to have more difficult time with weight control and possibly behaviors as they get older
-diazoxide increases blood glucose levels
-might be bad for brain development

Other medications
-some lower ghrelin, which may work in conjunction with GH (which lowers ghrelin) to decrease hyperphagia in PWS
-others may work more on body weight and have a secondary effect of decreasing hyperphagia by increasing signals of satiety to the brain
-some medications may be able to be used in certain circumstances (like going to a party with an open buffet) to reduce appetite but may have undesirable side effects if used long-term

Oxytocin
-preliminary studies in adults suggest that OT may decrease appetite, as well as decreasing depressive symptoms and tantrums while increasing trust
-in infants, OT may help decrease high ghrelin levels which may be beneficial in preventing hyperphagia later in life
-dosing regimen still uncertain – some doses appear to be ineffective
-studies of 5-10 year olds starting soon through RDCRN (rare disease network)
-working since April on getting a trial done à hoping to start March-June
-oxytocin could potentially cause low sodium levels (seizures). Also, medications from compounding pharmacies could be contaminated and dangerous à DO NOT TRY THIS ON YOUR OWN
-through the nose, so it’s going right to the brain

Carbetocin
-safer than oxytocin in terms of potential side effects
-Ferring Pharmaceuticals is interested in trial in PWS
-Will need to start with adults in nutritional phase 3
-working on FDA approval for trial in PWS

Current Projects at UF
-natural history study on effects of GH (infants-adults)
-oxytocin (ages 5-10)
-hypoglycemia and diabetes (infants-adults)
-metabolomics in PWS vs. siblings (infants-adults)
-ketogenic diet (ages 5-30)
-orexin (infants-adults)



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