neuro case for incoming 3rd years

neuro onc notes & pilocytic and diffuse astrocytoma

TP53 mutations are hallmark of low grade astros, EGFr mutations are hallmark of primary GBM/high grade. if high grade has tp53 mutation, likely transformed from a low grade.

Pilocytic astrocytoma WHO grade I
-slow growing, cystic, children young adults, associated w/NF-1
-rosenthal fibers (intermediate filament of astros)
-site: optic nerve, thalamus, basal ganglia, cerebellum
Presentation
-seizures not usual presentation because not cortical
-headache common presentation, visual loss
Imaging
-well circumscribed, contrast enhancing
-cysts
Histopath - rare mitosis, hyperchromatic nuclei, glomeruloid vascular prolif, rosenthal fibers
eosin granular bodies - located in astro foot processes (PAS positive)
Proliferation - low
Prognostic factors - long survival
NF-1 associated tumors -less aggressive
Higher mitotic activity

Pilomyxoid astrocytoma (WHOII)- has mucoid matrix, typical w/o Rosenthal fibers or Eosin gran bodies
location: hypothalamic/chiasm most common
Prognosis - more aggressive than pilocytic

Pleomorphic xanthoastrocytoma (WHOII)- favorable prognosis, lipidized cells, GFAP, S-100 EGB +
develops in children/young adults, 2/3<18yrs, superficial location (cerebrum)
90% supratentorial,
Presentation: seizure! b/c cortical/superficial preference
Imaging - edema not pronounced b/c slow growth
Histo - intracellular lipid, granular bodies, GFAP+, reticulin fibers,
Prognosis -80%@5 & 70%@10 yrs

Diffuse Astrocytoma - WHOII
-peak incidence 30-40 yrs,
location - supratentorium, presents w/seizures, speech difficulty,
imaging -T1 hypointense, T2 hyperintense, enhancement is very uncommon, but tends to happen with transition to anaplastic astro (WHOIII)
histo- well differentiated, fibrillary, absent mitoses,
differential diagnosis
-fibrillary- nuc atypia w/o mitoses, microvasc prolif
-gemistocytic at >35% gemistocytes (stressed astrocytes),
-protoplasmic -rare, large eosinophilic cytoplasm, displaced nuclei, perivascular lymphocyte infiltrate, low mitotic index,

prognosis of diffuse astros ~6-8yrs w/surgery, high variation.
young age at diagnosis is favorable, gross total resection increases survival, patients who present with only seizures do better than focal neuro deficit.

Neurologic manifestations of scleroderma

Neuromuscular manifestations of systemic sclerosis - comes mainly from case reports/case series

frequency 0-66%

Cranial, entrapment, peripheral cutaneous, autonomic NEUROPATHIES

Myopathy

CNS/headache/seizure/stroke/vascular disease/radiculopathy/myelopathy

Increased risk w/antiScl-70 (anti topoisomerase) & anti U1RNP (normally in diffuse)

Pathophys

Cranial/peripheral - vascular (deterioration of vasa nervorum)

Compression 2/2 edema/fibrosis

Autoimmune -antimyelin antibodies do not correlate w/neuropathy

Cranial Neuropathy

most common is trigeminal (less so 2-9, rarely 8)

CNIII - inflammatory/restrictive ophthalmopathy

Trigeminal V2V3 - numbness, pain (burn), paresthesia - 24months to max deficit

MOTOR NOT AFFECTED

tx - steroids mixed efficacy - antidepressants/anticonvulsants

Entrapments

Median nerve at the carpal tunnel 5-25% 2/2 fibrosis/calcific deposition

ulnar, posterior tib, ilioinguinal, meralgia (lat fem cutaneous)

Peripheral polyneuropathies - common in diffuse

pathology - ^^collagen, loss of myelinated fibers, intimal thickening/hyalinosis of endo/perineurial blood vessels

Sensory - distal/symmetric

Mixed sensorimotor

Mononeuritis multiplex -2/2 inflammation of vasa nervorum, rarely infarct,

Brachial plexopathy

Cutaneous

Autonomic - GI motility, impotence, sympathetic skin response

Radiculoapthy -2/2 nerve compression by vertebral destruction/epidural calcinosis

NMJ - SSc and myasthenia can co-occur

Myopathy & Myositis

myopathy - proximal - mild increase in CK, EMG - decreased duration of motor unit potential & increased frequency of polyphasic motor units

TX - indolent usually nonprogressive

myositis - severe weakness, CK 2x nml - Dx w/muscle biopsy - TX glucocorticoids +/- cytotoxic

CNS - headache/stroke/seizure/myelopathy - sever CNS abnormalities are RARE

Headache - tx similar but do not give ergots bc vasoconstricting

Seizure - normally 2/2 compmlications (uremia/htn)

Stroke - causal relationship not yet demonstrated, stroke 2/2 athero/htn

CNS vasculitis - RARE - tx -glucocorticoids, cyclophos, cyclosporine

Myelopathy - 2/2 calcinosis

custom tailoring cognitive performance enhancements for goal specific tasks

augmenting NREM cortical consolidation

ocular dominance plasticity has been shown to be weakened by administering NMDA antagonists during sleep. if this idea can be translated to other cortical areas, and potentially work in reverse, the question is: has anyone attempted NMDA agonist action right before sleep after a hard days learning? more for visuospatial and motor tasks as opposed to explicit memory consolidation, but it would be interesting to know if learning is augmented.

recent idea is synaptic homeostasis hypothesis

the idea that wakefullness increases en bloc all NT potentiation, and that during sleep this potentiation is brought back down (or balanced) and possibly certain memory traces are pruned and retained during this diurnal event.

...

Synaptol ingredients

I have seen a new supplement advertised on the internet. It is called Synaptol. Maybe you've seen it. Here it is:

It is marketed to treat symptoms of ADD/ADHD. I wanted to know the mechanism of this product as it is not FDA regulated. So after some search I came across its ingredients. They are many and listed below:

Synaptol

Synaptol Ingredients: Official US Homeopathic Pharmacopoeia Aconitum Ferox, Adrenalinum, Apis Mellifica, Argentum Nitricum, Avena Sativa, Baptisia Tinctoria, Cochlearia Armoracia, Medorrhinum, Phosphorus, Scutellaria Laterifolia, Sumbulus Moschatus, Viola Odorata

It seems to be marketed as a Homeopathic remedy. Interested as I am in plant based pharmaceuticals, I have put together a quick review of the ingredients taken from referenced sources Wiki, Pubmed, and various chemical databases.

So here we go...

Aconitum Ferox (aka wolfsbane) - perennial that is indigenous to India (West Bengal). Very poisonous!

Well known in Ayurvedic medicine - poison bikh, or bish, contains a alkaloid in the roots called pseudaconitine or nepaline pictured here:

Mechanism of action: cholinesterase inhibitor - keep in mind this is the same mechanism of action of approved Alzheimer's treatments donepezil and galantamine

Adrenalinum

Somewhat alarming, but it appears as though this ingredient adrenalinum is what I thought, epinephrine. For sale online by several different homeopathic remedy listings, this ingredient is treatment for "muscle pains" and marketed as "extract of suprarenal bodies". It does not mention whose suprarenal bodies.

Apis mellifica

apis (latin for bee), melli- (latin for "sweet", think diabetes mellitus), gound up honeybee. Used as therapy for bee stings, rashes, even carpal tunnel. The active ingredient in this preparation has not been isolated. Bee venom (which is sometimes removed from these preparations), out of curiosity (and off topic), is also called apitoxin, and is a combination of:

Apamin (pictured left)- blocks CNS and smooth muscle Ca++ activated K+ channels, so called SK channels. These channels control afterpolarizations, inhibiting them makes the neuron more excitable because presumably you reduce the neurons post-firing hyperpolarization. What is interesting about this compound is its potential therapeutic uses, including ataxia, epilepsy, memory disorders. SK channels are found in the hippocampus too!

Adolapin (not pictured) - an 11kD (103 AA residue) polypeptide found to be a potent anti-inflammatory (inhbits cat spleen cyclo-oxygenase) and analgesic. Isolated in 1982 by Shkenderov and Koburova. PMID7080045

Phopholipases

Hyauronidases - dilates and chews through capillary glycocalyx so toxins can spread.

Histamine!

Dopamine/norepinephrine

Non-specific protease inhibitors

Argentum Nitricum (silver nitrate)

Uses: antiseptic/antibiotic (think newborn baby drops!), however this compound is an oxidant and therefore corrosive/toxic and can lead to silver deposition and staining.

Avena Sativa - the common cereal oat. Its extract has medicinal uses that are many however mechanisms are not worked out. a short list includes, food ingredient, brewery, soluble fiber, improvement of cholesterol profile, increased libido. Its benefits are marketed without pharmacologic mechanisms.

Baptisia tinctoria

perennial wildflower, aka yellow wild indigo. used commercially as a dye, however extracts are also marketed for health purposes; stimulating healing and digestion, also reported to have antiviral properties. Active ingredients listed in marketing materials are:

cytisine - an alkaloid, a nictonic acetylcholine agonist

anagyrine - another alkaloid, a nicotinic acetylcholine agonist (found to have teratogenic effects in cattle, PMID 20116429),

genistein - an isoflavone (i.e. anti-oxidant), found in plants, getting a lot of attention as anti-tumor agent (has topoisomerase inhibitory action, as well as estrogen receptor agonism - see pubmed review PMID 21844907

Cochlearia Armoracia

well known as the horseradish plant, i tried to find any compounds within this plant that would have nervous system activity, but I have found that it is mainly its oils which can be broken into thiocyanates which become irritants and possess antibiotic activity. it can be used for sinusitis, and is also listed as a diuretic to treat UTI, although I need to dig more to find a mechansim, many of the primary literature is in German, and sadly mein Übersetzer verfolgt nur eine Richtung auf einmal. Very hardy, famous plant.

Medorrhinum

In homeopathy, where this ingredient originates, there exists the concept of nosodes. Nosodes, much like vaccines, are very small portions of diseased material introduced to the body by practitioner's of homeopathy in order to provoke a response to the larger threat, the quote, "like cures like". According the Materia Medica of the Nosodes by Henry Clay Allen MD, medorrhinum are "potencies made from the gonorrheal virus". Gonorrhea is in fact a bacterium. I really cannot find any reliable source (albeit a cursory search), on the composition of this ingredient. Do you want to surf a strange wave on the internet? Google medorrhinum.

Scutellaria Laterifolia - an herb, aka Blue/Virginian/Mad-dog Skullcap

this plant has been receiving a lot of attention, wikipedia provides a concise referenced summary, but in short- almost 300 pharmacologically active compounds have been identified in this plant. Many of them flavonoids (plant pigments), terpenes (a type of basic hydrocarbon C5H8- upon which more complex lipids are synthesized), and phenols. Among the functions listed of these are anti-tumor, anti-inflammatory, anxiolytic (via benzodiazepine receptor binding site). Interesting, chrysin, pictured below, is a flavone (plant pigment) extract of this plant that was described to be an aromatase inhbitor in Science PMID: 6474163

Sumbulus Moschatus

seems to be homeopathic remedy, derived from a Eurasian plant Muskroot, another nosode, it is listed for many specific complaints which sound like neuropathy/nerve compression ("shooting tingling down arms") to possibly a-fib ("palpitations"), and according to Encyclopedia Britannica, believed to be similar to asafoetida, a dried root resin from the Ferula plant, an herb native to Iran and India. Either one of these plants are not well characterized. Sumbulus (muskroot) is definitely not well characterized.

and finally...

Viola Odorata

- well known as Sweet/English/Common/Garden Violet. Used in Ayurvedic medicine for sore throat/tonsilliits. Used primarily in perfumes and food colorings. The medicinal component of this plant may relate to anthocyanins (cyan- blue) a type of flavonoid which has been shown to have, anti tumor, anti inflammatory, anti oxidant acitivities. There are many papers published on the effects of anthocyanins, a complete review is not possible in this space. But to bring it back to Synaptol, this article PMID 20041802, out of Regenburg Germany, shows anthocyanins with affinity to cannabinoid receptors, moderate as the Ki for there top two anthocyanins (cyanidin and delphinidin) was between 16-23 uM (moderate) for the CB1.

Well, it seems that synaptol contains many active ingredients that in the right doses could amount to polypharmacy. There are known Ach esterase inhbitors, nAchR agonists, homogenized adrenals not otherwise specified, delayed Ca activated K+ channel inhibitors, "nosodes" (new term for me) of "the gonorrhea virus", possibly an aromatase inhibitor, GABA receptor agonists, potientially CB1 receptor agonists, possibly antibiotic compounds, and many many more still completely unknown, altogether in doses unknown. There is only one way to find out if this stuff works. I will sprinkle some into my friends morning coffee and observe him present on rounds. Just kidding, I am piqued enough to try some myself. I will report an anecdotal unbiased cognitive and physiological (vital signs) review of the effects Synaptol at some future point.

The problem with these products is that they have too many ingredients, it is impossible to sort out all of these different compounds and there many effects on all the body's systems. We'll see.

more wisdom mcnuggets

fulfillment consists in activity. it is a running steam, not a stagnant pool.

-Oliver Wendell Holmes

A stout heart breaks bad luck

-Cervantes

Science without religion is lame, religion without science is blind.

-Einstein

The gem cannot be polished without friction, nor man without trials.

-Confucius

What you do not want done to yourself, do not do to others.

-Confucius

The young man knows the rules, the old man knows the exceptions.

-Holmes

If a man empties his purse into his head, no one can take it from him.

-Ben Franklin

He's the best physician that knows the worthlessness of most medicines.

-Ben Franklin

Imagination is more important than knowledge.

-Einstein

Three marks of superior man: Being virtuous, free from anxiety. Being wise, free from perplexity. Being brave, free from fear.

-Confucius

Every man takes the limits of his own field of vision for the limits of the world.

-Schopenhauer

Weakness on both sides is the motto of all quarrels.

-Voltaire

It is better to be deceived by one's friends than to deceive them.

-Goethe

I'm a little wounded, but I am not slain; I will lay down to bleed awhile. Then I'll rise and fight again.

-John Dryden

An excuse is worse than a lie, for an excuse is a lie guarded.

-Pope

An explanation of cause is not justification by reason.

-CS Lewis

The safest road to hell is the gradual one; gentle slope, soft underfoot, without sudden turning, without milestones or signpost.

-CS Lewis

What the mother sings to the cradle goes all the way down to the coffin.

-Henry Ward Beecher

A proverb is no proverb to you till life has illustrated it.

-Keats

It is easier to build strong children than to repair broken men.

-Frederick Douglass

The man who will use his skill and imagination to see how much he can give for a dollar instead of how little he can give for a dollar is bound to succeed.

-Ford

The bookful blockhead, ignorantly read, with loads of learned lumber in his head.

-Pope

As long as you can start, you are all right. The juice will come.

-Hemmingway

Looking at small advantages prevents great affairs from being accomplished.

-Confucius

Defining intelligence in order to improve it.

Nootropic (nous - mind, tropos -twist) drugs are meant to increase/enhance cognitive function, intelligence, creativity, motivation, attention etc... ie make you a better version of yourself. The most recent popular exposition of this classic Faustian bargain (pictured left) this very interesting and relevant topic was the film adaptation of Alan Glynn's novel the Dark Fields, Limitless. The bottom line is; if the risk/reward profile of such a drug were acceptable to your values, would you take it?

I would answer yes because, I already do in the form of caffeine, which has been shown to increase alertness and concentration, especially in sleep deprived states. However its unclear if caffeine ever gave me a comparative advantage, I would argue yes, but I couldn't prove it. Developing "smart pills" is more difficult than other medications because standardized methods for assessing its effects are not as predictive. Take for example blood pressure meds. The final common pathway for antihypertensive medications is measured by a blood pressure cuff. This is a workable metric, easy to monitor, and reasonably predictive (taking nothing away from the very interesting complex, and challenging concepts of cardiovascular physiology). On the other hand, there is no reliable way to measure "smartness", which confounds efforts to develop agents to improve this capacity. Therefore, I think its necessary to define what I'm after in a smart pill. Increased intelligence. What is that? Intelligence is a very hard concept to define, and there is no agreed upon definition to date. Also, I don't think there ever will be consensus. And I think that if ever a drug were developed that increased intelligence in radical meaningful ways, it would not have come about by focusing on more accurate definitions or "measurements" of intelligence. What tests that exist now are enough to capture what effect I'm after, and even if they were incapable of doing so, if the effect were bona fide, then it would not matter. Therefore, I have arranged a working definition of intelligence that is suitable for me, and so now I can start tackling specific topics related to it.

Intelligence - an emergence from a series of interacting collection of abilities used together to create awareness to and solutions for drives (whatever the origin- socio-, biological, spiritual, or cosmically otherwise)

the functions that matter-

abstract thought (abstract - ab meaning "from" , -stract -from latin trahere "to draw off") abstracting - separating or dissociating an idea, relationship, or presumably a truth from the object it inhabits.

for example use abstract reasoning to find one similarity between a gardener's hoe and a bow and arrow...

reasoning - the ability to order or arrange connections between what is thought or observed, (can be anything -concrete or abstract) into new or pre-existing abstract arrangements

learning - the ability to acquire abstractions, concepts, sensory/perceptual phenomena

memory - very closely related to learning, memory is the capacity to retain and recall learned information

explicit memory - fact recall, working memory, semantic memory, episodic memory, your mind's eye

implicit memory - motor tasks that are not conscious, procedural

emotional intelligence - identify, control, and apply the emotional states of self and others for a desired outcome

no actual agreed upon definition of intelligence. even more difficult to "measure" it, but certain agreed upon approaches are the best options available right now.

IQ (intelligence quotient) tests:

Stanford-Binet

Raven's Progressive Matrix

Wechsler Adult Intelligence Scale

Kaufman Assessment

...many many many more

Gardner's theory - multiple different intelligences. He subdivides intelligence into

logical - the mathematician

spatial - engineering/design

interpersonal - politician, clergy, teacher

linguistic - writer of course

musical - the list goes on...

kinesthetic - athletes, dancers, craftsmen

Triarchic theory

analytic intelligence

creative intelligence

practical intelligence

Then came the unifying theory.

The g factor-

Defined by Spearmen (psychologist) who analyzed the results of children's test scores and found unrelated areas of positive correlation in certain individuals. He dubbed this ability the "g factor" or general intelligence factor, it is the Holy Grail of intelligence. It is widely accepted.

Cattell-Horn-Carroll then subdivided g into 10 abilities -

fluid g - reasoning, concept formation, problem solving

crystal g - acquired knowledge and the ability to access it

quantitative g - comprehension and manipulation of numerical symbols

read/writing - the ability to read and write

short term memory- holding concepts in awareness

long term memory- efficient storage and retrieval of retained information

visual g - applying visual memory to aid in thinking

auditory g - applying auditory memory to aid in thinking

processing speed - maintaining attention in tasks under time pressure

reaction time- speed at which one reacts to stimuli

Not included among this, and something I think central to all intelligence is creativity - I would add creative g to this list, but figuring out how to measure this would take a lot more creative g! I think creative is what comes through in real life anyhow, thus testing doesn't matter if one possesses ample amounts of this. Already it is clear that there are several domains of function. But I find the central concept of g (general intelligence) appealing if for no other reason than its singularity. I wonder what it is and how to increase it, if it is increasable.