Neuro Clinical notes - neuropathies, dementias, pain

The differential diagnosis for multiple infarcts in multiple vascular distributions
#1 embolism
#2 coagulopathy
#3 vasculitis
#4 all the rest

Primary CNS vasculitis is also called granulomatous angiitis


Respiratory patterns and critical illness
Cheynes Stokes -diffuse forebrain pathology
central neurogenic hyperventilation- midbrain and upper pons
apneustic - tegmentum
cluster breathing - tegmentum and lower pons
ataxic -reticular activating and dorsomedial medulla

Differential diagnosis of a large fiber neuropathy that spares the small fibers
Sjogren's
B12 deficiency
CIDP
multifocal motor neuropathy with delayed conduction


Small fiber distal symmetric neuropathy differential diagnosis
diabetes
heavy-metal poisoning
amyloid -classic for small fiber neuropathy
paraneoplastic
hematologic
inherited
idiopathic


Patient has a positive finding on a monoclonal study, you need to consider fat aspirate and refer to hematology

Diagnostic tests for small fiber neuropathies can normally be made clinically if all you have is tingling and burning. However consider a qSART, thermoregulatory sweat test. Key points to ask in history are autonomic symptoms bowel bladder dysfunction sexual dysfunction and orthostatic hypotension. Parkinson's and multiple systems atrophy can often present with complete hypohidrosis.

Indications for a sural nerve biopsy:
suspected sarcoidosis without any other good biopsy site
leprosy
vasculitis
amyloid
unexplained neuropathy


Approach to the patient with dementia. Key questions to sort out in the history.
Is this a dementia?
Is this reversible?
In the history TIA history of stroke?
Sleep history
who is doing the finances, has the patient ever gotten lost, as the patient lost the ability to drive, does the patient have obstructive sleep apnea, has the patient's sense of smell changed?

Keep in mind many causes of dementia are overlapping for example Lewy body dementia and vasculitis or Alzheimer's disease and vasculitis

early short-term memory loss is a clue for Alzheimer's. First to changes are in the entorhinal cortex and then progress to the hippocampus to the medial temporal lobe and then to the frontal lobe.

Lewy body dementia
presenting with a dementia then the synucleinopathy is in the cortex
presenting with parkinsonism than the synucleinopathy is in the substantia nigra
REM sleep disorders come from lesions in the peduncular pontine nuclei

REM sleep disorder, new data show a 50% chance of progression to dementia and 15 years from the onset of their REM sleep disorder, 82% at 25 years
anti MA–1 anti-voltage gated potassium channel anti-bodies are also associated with REM sleep behavior disorder



Quick notes on chronic pain meds
alpha lipoic acid has been used successfully in painful diabetic neuropathy
acetyl l-carnitine has also been used for painful diabetic neuropathy
for any given agent patient has to be on it for a few weeks to make a clinical judgment as to whether it works.

The big mistake with tricyclic antidepressants and painful neuropathy is that the dose is too low. Increased doses are usually done with extreme caution because of the anticholinergic side effects. This usually prevents finding an adequate dose.

Duloxetine – 60 mg daily for paying 60 mg twice daily to double cover psychiatric disease.
  Side effects while described hyperhidrosis withdrawal and increases bleeding risk with patients on warfarin

Gabapentin big side effect is swelling dizziness and sedation. You can increase the dose but be aware that the G.I. transporters saturate at around 2000 mg daily. This is not seen with pregabalin because it's effective at a much lower dose.

Topiramate -for chronic pain should be working at doses between 200 to 400 mg daily. Lower doses are usually seen with migraine prophylaxis. Major side effects include renal stones and paresthesias and cognitive cloudiness.\

Lamotrigine- normally avoided because of risk of Stevens-Johnson syndrome. Active doses around 200 400 mg per day six-week titration to minimize the risk of Stevens-Johnson syndrome.


When treating pain start with level I which is to treat the cause topical agents gabapentin pregabalin TCAs and duloxetine

 level II – anti-epileptics specifically the sodium channel blockers and the SNR eyes such as venlafaxine

  Level III opioids and other interventions such as tens units intrathecal pumps

Miscellaneous clinical pain & neuroanatomy

Miscellaneous clinical notes space-chronic pain

*Allodynia to cold is an indicator of central sensitization

*Patient's especially sensitive to cold are more likely to be sympathetically maintained

*Cord injury,

CRPS space-four criteria for diagnosis

#1. In inciting event

#2. Pain out of proportion

#3. Vasomotor autonomic phenomenon

#4. Lack of an alternative explanation for the pain

*This is a controversial topic because of disability implications of this diagnosis

Three drugs with NMDA receptor antagonism

Amantadine

Dextromethorphan

Methadone

Treating migraine in a pregnant patient

Thorazine or magnesium

Treatment of chronic pain

#1  cool water, compounded cream consisting of ketamine and amitriptyline

#2 anti-inflammatory agents, antidepressants and antiepileptic agents

-Antidepressants good for neuropathic pain, and epileptic prescription for neuralgic patients

#3 dorsal cord stimulators peripheral nerve stimulator is

#4 intrathecal pump

#5 motor cortex and deep brain stimulator implantation

#6 destructive procedures although not currently recommended and is only recommended for terminal patients because of major complication anesthesia dolorosa which has no known treatment

Localization in clinical neurology of Paul Brazis textbook notes

Weber syndrome - third nerve palsy with contralateral hemiparesis lesion at the crus cerebri

The descending corticospinal tract has ~1million fibers on a side, only 3% originate from Betz cells (layer V in the primary motor cortex)

*Cortical spinal neurons also arise from postcentral gyrus and a somatosensory cortex, lateral prefrontal supplemental motor and cingulate gyrus as well

eponym for the pyramidal decussation -Mistichelli crossing - anywhere between 75-90%.

Cortical spinal fibers that descend ipsilaterally do so in Turcks bundle otherwise known as the anterior

corticospinal tract - although most of these will eventually decussate as well only 2% at the end remained

ipsilateral innervating axial musculature

Corticobulbar pathway- descends in the genu of the internal capsule

The ventral aspect of the facial nucleus innervating the lower two thirds has a crossed supranuclear input

Emotional facial movements do not descend via the internal capsule, the right cerebral hemisphere is dominant for facial expression or motion

Three direct pathways of cortical input to the basal ganglia

#1 internal capsule

#2 external capsule

#3 subcallosal fasciculus

Indirect pathways for cortical input to the basal ganglia

cortical thalamic striate pathway

Cortical olivary pathway

Cortical pontine pathway

Cortical association areas projected predominantly to the caudate nucleus

Sensorimotor cortical areas projected predominantly to the basal ganglia

The cortex also directly inputs the substantia nigra subthalamic nucleus and claustrum

Cortical thalamic pathway-descending feedback mechanism for ascending thalamco cortical fibers -also known as the thalamic radiations, also known as corticofugal pathway. descending mainly in the anterior limb of the internal capsule

Thalamic nuclei involved in cortical thalamic pathway feedback

anterior nucleus -> posterior cingulate gyrus

ventral lateral -> primary motor cortex

anterior ventral -> supplementary motor cortex

posterior -> sensory cortex

LGN -> primary visual cortex

MGN -> primary auditory cortex

Dorsomedial -> prefrontal cortex

Cortical hypothalamic tract

Multiple inputs to the hypothalamus (prefrontal cingulate amygdala olfactory hippocampus septal)

Alzheimer's disease quick numbers and facts to have on hand

Alzheimer's seminar notes

dementia has several features

impairment in daily life that is clinically significant

dyspraxia - inability to do rehearsed motor function

ideomotor - small well rehearsed motor tasks

ideation - dressing/writing

agnosia - 50% of cases unaware of their own dementia

decreased executive function

Alzheimer's path comes in two stages

insidious amyloid beta aggregation (can begin ~10.5 years prior to symptoms presentation)
  Keep in mind of 30% of the population has amyloid burden without any clinical indicators of dementia

Tau hyperphosphorylation w/tangles

Course of the disease includes pathological tissue aggregations well before clinical impairment is seen

1. Medial temporal/entorhinal cortex first to be affected

2. Cingulate

3. Neocortex

i.e. - memory, then limbic, then higher cognitive function

Alzheimer prevalence

5 million Americans, 26 million worldwide

Age 65-74 - 3-5%

Age 75-84 - 15%

Age 85+ - 45%

Risk factors

1. age most robust risk factor

2. female - (could be result of survival bias, women outlive men)

3. genetics (minor), APP, presenilin 1-2, APO-e4

Diabetes and smoking? Odd's ratio of getting Alzheimer's increased to 18-20!!

Anaplastic astrocytoma neuropath notes

Anaplastic, WHOIII, infiltrating aggressive, normally in cerebral hemispheres
-nuclear atypia, mitoses, high proliferation,
-mean age 45-50,
-Genetics (high tp53 mutation)
-mean time to transition to gbm ~2yrs, EGFr mutations have worse prognosis

Glioblastoma
-most frequent, most malignant brain tumor, WHO IV, can arise de novo or as malignant transformation, very invasive and cannot be fully resected, peak incidence 45-75.
-tumor most likely to be in cerebral hemispheres. however basal ganglia, thalamus, brainstem not uncommon, but see more in children.
-tumor very commonly spreads through corpus callosum, butterfly appearance on imaging
-imaging: ring enhancing, significant edema,
-GBM does not usually go to subarachnoid and so does not show up in CSF, hematogenous spread does not happen (very rare).
- multifocal GBM -true incidence unknown, estimated to be 2.4% of GBM to be multifocal

medicine clincial notes from 3rd year medical school recently discovered

low complement in renal disease suggests immune complex mediated pathology

when assessing complement levels, it helps to have two time points to establish a trend

Henoch Schonlein Purpura - 1/2 of all cases preceded by URI, especially strep, or vaccination or insect bites. Renal biopsy stain IgA, C3, Fibrin

Palpable Purpura (100%)

Arthritis (43-75%)

Abdominal Pain (20-30%)

Renal (21-54%)

 

women w/MI present very atypically

stigmata of chronic infection- temporal wasting, thenar wasting, interossei wasting, adenopathy

pulmonary manifestations of RA -

pulmonary effusion, greatly decreased glucose

pulmonary nodules

airway manifestations

interstitial lung disease associated with RA (NSIP)

decreased glucose? infection or RA

studding of diaphragm on cxr? interstitial disease

honeycombing is an end stage process of interstitial lung disease

never order ACE for sarcoid, its not an informative test

differential for miliary pattern on cxr

tb

sarcoid

pcp

varicella

metastasis

Clinical consult notes

neuro consults clinical notes

A call to the emergency department to see a patient with intractable facial pain. The patient was a 60 something-year-old woman with a history of trigeminal neuralgia who has had multiple at least 10 neurosurgical procedures in the past 20 years for facial pain. Two years ago she had a motor cortex stimulator implanted and has been using an unknown setting to help control facial pain. She is also taking carbamazepine which has been partially therapeutic. Recently in the last two weeks she has noticed that the stimulator is not helping her pain and she has been having breakthrough episodes of recurrent lancinating sharp-like episodic paroxysmal facial pain. These last anywhere between 30 seconds to two minutes and come in intervals which have been more or less constant for the previous week she has had very little sleep or food as a result. Aside from the carbamazepine she takes oxycodone with limited therapeutic effect. In the last few days she was seen in clinic and multiple setting changes were made both increasing and decreasing the voltage as well as changing the signal firing pattern. We are now been consulted by the emergency department for recommendations for this intractable facial pain. On exam she was otherwise stable but she was teary and the right face was flushed full a little swollen. Every now and again she would wretch forward with outbursts of moaning in pain. There were no focal neurological deficits

The most important first step is to control the patient's pain for which there are a couple of options. First we could increase the dose of the opioid medication in hopes that this could somehow treat the pain. Emergency Department personnel had already tried this, but it was not working after a few hours. Their method was to use oxycodone oral, approximately 30% stronger than oral morphine. We recommended intravenous opioids particularly hydromorphone as far stronger than oxycodone. The patient also kept a log of which stimulator settings worked best to control her pain. The current setting was not the most optimal setting that she previously had found. We recommended altering the setting to a prior pattern which she did with limited therapeutic effect.  These combined interventions were responsive for the patient in this instance and she was able to discharge with a prescription for oral opioids converted to the strength of the intravenous dose for the next day until she had follow up with her specialist. Had this not worked I have seen case reports of fosphenytoin loading for acute pain. And had that not worked unfortunately the last resort is general anesthesia and admission for intractable pain. Luckily for this patient she experienced symptomatic relief with stronger dose opioids for breakthrough pain and was able to leave the emergency department and make her clinic visit the day after.

Complications of donor and patient apheresis

 

Complication rates of donors:
Overall rate ranges between 0.81 to 2%
complication rate requiring hospitalization 1/200,000
this is in comparison to between 10 to 20% in whole blood donors.

Common reactions: hematoma, pain, citrate toxicity, vasovagal, vasovagal with syncope

 

Complication rate of therapeutic apheresis (for patients)
reported to be approximately 4.75%
reactions include: allergic febrile transfusion reactions, citrate toxicity, hypotension, vasovagal
mortality rate in therapeutic apheresis estimated to be 3 per 10,000 procedures

Citrate toxicity: a calcium chelator that inhibits coagulation. Normally citrate is distributed throughout the entire extracellular fluid it is rapidly metabolized and any calcium deficit is mobilized from albumin. Secondarily parathyroid mobilizes bone stores and renal handling of calcium increases urinary calcium resorption. Despite these companies employ mechanisms it is still possible to to see clinically significant hypocalcemia. Factors that have been associated with citrate toxicity are hypoventilation, hypoalbuminemia, total amount of citrate and the rate of infusion (high rate intermittent).

**Citrate toxicity cannot cause bleeding from inhibiting coagulation factors. This is because in order to prevent coagulation calcium levels must be reduced to 0.2 mmol per liter. This level of hypocalcemia is incompatible with life and occurs only in the machine and not in the patient.

Remember that between 40 to 55% of total calcium is albumin bound. Transfusing albumin is normally stripped of calcium and can cause a significant decrease in calcium store. It is recommended to add calcium gluconate to albumin prior to administration. You can also give intravenous calcium gluconate or slow the rate of infusion.

Keep in mind citrate also chelates magnesium. Clinical signs of hypomagnesiumemia include muscle spasm weakness decreased vascular tone and cardiac contractility abnormality. Important to remember that hypomagnesemia inhibits parathyroid hormone action and can be a secondary cause of hypocalcemia in addition to citrate toxicity.

Citrate is metabolized into bicarbonate. In settings where the patient cannot excrete bicarbonate significant metabolic alkalosis with resultant hypokalemia has been observed. Therefore remember to check your potassium before initiating therapy and replete as necessary.

 

ALLERGIC and ANAPHYLACTOID
urticaria and other allergic reactions that are seen in blood donors typically are an allergy to ethylene oxide. Ethylene oxide is used to sterilize the disposables. The combined plasma proteins and initiate an immune response. This is seen in donors of multiple donations.

Anaphylactic reactions may be triggered by ethylene oxide, hydroxyethyl starch, immunoglobulin A, albumin.

Immunoglobulin A deficiency is seen in one in 700 Caucasian. Must use IgA deficient blood products.

Anaphylaxis isnormally triggered by complement fragments C3a C5a as well as anti-bodies to immunoglobulin G & E.

ACE inhibitors:
electrostatic materials in the apheresis columns as well as enzymatic activity in donor albumin convert bradykininogen to bradykinin. Furthermore ace inhibitors in addition to blocking angiotensin-converting enzyme also block kninases (degradation enzymes of bradykinin). This leads to unopposed bradykinin activity which clinically presents flushing hypotension bradycardia dyspnea. That's why you want to stop all ace inhibitor therapy between one and two days prior to the procedure. If that didn't happen and you are suspecting this, immediately discontinue the procedure.

THROMBOCYTOPENIA OF PLASMA EXCHANGE
therapeutic plasma exchange expect to see a reduction in platelets anywhere between 0 to 71%. In the hematopoetic stem cell collections anywhere between 24 and 54% has been reported.
Plasma exchange also reduces coagulation factors, so monitor go as as well as fibrinogen. This is especially important in hemostatic challenged patients.

Reversing heparin induced bleeding - protamine sulfate dose of 1 mg for every 100 units of heparin.

Transfusion medicine – clinical notes

Patient has an anaphylactic reaction to albumin? It is likely sodium caprylate which is an additive in the mixture.

Sequence of clinical presentation of symptomatic hypocalcemia:

#1 paresthesias

#2 shivering lightheadedness 

#3 twitching and tremors

#4 nausea and vomiting

#5 hypotension carpalpedal spasm tetany and seizure

hold Ace inhibitors 24 to 48 hours prior to apheresis especially with LDL apheresis

Human immunoglobulin M - half life 10 days in the serum is highly efficient at fixing complement and agglutination.

Human immunoglobulin A- serum half-life is 5-8 interesting is a monomer in the serum but it is a dimer in secretions

there are two subclasses of immunoglobulin A IgA1 and IgA2, if you're suspecting an anaphylactic reaction to a blood transfusion in somebody who is IgA deficient is best to check in anti-IGA level and not the absolute IGA level because you can be deficient in one particular subclass and therefore the anaphylactic reaction is directed against a particular subclass which is deficient. Bottom line is draw the anti-IgA.

anti human globulin -this is a probably specific anti-immunoglobulin G and an anti-complement used for ABO blood typing

P antigen is the receptor for parvovirus can give you a paroxysmal cold hemoglobinuria that fixes complement upon rewarming than causing hemolysis

But blood cell antigen Kidd fixes complement and can cause intravascular hemolysis, exposure to this antigen in previous transfusions creates anti-bodies that are known to fade from circulation over time.

Clinically significant red blood cell antigens are of course the ABO groups, but also include Rh Kell Duffy Kidd and Ss.

Buffy is the receptor for plasmodium vivax

Donated platelets come in two particular flavors those that are acquired by apheresis and those that are whole blood derived.

This is important clinically because when you are transfusing platelets that are derived from apheresis you must match crossmatch the plasma because they are red blood cell depleted. However if you are transfusing platelets that are whole blood derived you must match ABO blood group because you have red blood cells present in the mixture. Even having small amounts of red blood cells present in the mixture is a risk because that creates allo sensitization to other clinically significant red blood cell antigens and thus increasing the risk of harmful reactions in future transfusions.

On the coagulopathy of trauma

massive injury rapidly consumes platelets. Fun facts: the surface area of capillaries in your lungs can cover a football field, you have enough platelets to cover 82 ft.² large amounts of tissue injury creates endothelial micro tears which expose collagen tissue factor and other platelet aggregating substances. This is seen clinically because in trauma 5% present with with platelet counts less than 100,000.

In the setting of major trauma coagulopathy is exacerbated by the presence of hypothermia and metabolic acidosis. These clinical factors create a feedforward cycle that worsens coagulopathy and thus inevitably results with high mortality. This is the coagulopathy of trauma

ACIDOSIS

For example the activity of Xa is reduced by 55% when the pH goes from 7.4 to 7.0 furthermore the activity of the prothrombinase complex has been found to be reduced by 70% at a pH of 7.0 compared to normal physiological pH. 

Mechanisms of action of platelet dysfunction in the setting of acidosis

the presence of H+ adversely affects Na/H exchange transport across the platelet membrane. The increased proton gradient inhibits the alkalinaztion of the platelet cytosol. An alkaline cytosol is necessary for platelet degranulation. If the platelet cytosol pH remains less than 7.0 then it cannot degranulate.

Thus one platelets and turn acidotic microcirculation they are very much impaired

An interesting pathophysiological idea is that acidosis inferred from systemic pH is falsely high in comparison to the microenvironment of low flow regions in trauma patients. The point being that you can correct serum pH but low flow tissue beds have a systemic acidosis that process as a result of low flow.

HYPOTHERMIA

Every 10°C decrease reduces enzymatic activities broadly by 50%. This includes coagulation reactions. An interesting idea is that prothrombin and activated partial thromboplastin time assays should be performed at the core temperature of the patient to get a true indicator of the degree of coagulopathy. Core temperature is below 33°C are significantly impaired.

DILUTIONAL COAGULOPATHY FROM LARGE VOLUME RESUSCITATION IN SEPSIS

current guidelines for volume resuscitation in sepsis do not adequately address clotting factor replacement during significant hemorrhage. 

Current protocol from Gonzales et al Journal of trauma in 2007 - if continued bleeding following six units of RBC transfusion than two units of FFP for every additional five units of RBC. No formal criteria on platelets or cryoprecipitate.

Borgman et al in Journal trauma 2007- found improved survival with a higher FFP to RBC ratio.

Additional miscellaneous gastrointestinal notes

clinical management of shortcut syndrome

#1 control the diarrhea – dihpenoxylate, opioids, anticholinergics

#2 controlled diet small frequent meals low in sugar (osmolarity)

#3 nutrient replacement specifically magnesium calcium and micronutrients #number four total parenteral nutrition

Alpha-1 anti-trypsin clearance - clinical marker for protein malabsorption

Painless outlet bleeding

#1 diverticulosis approximately 30%

#2 hemorrhoids 15 to 20%

#3 malignancy 15 and 20%

#4 colitis

Thiamine deficiency seen after bariatric surgery so-called bariatric beriberi

1 quart of caffeine can deplete your entire same in stores

hyperemesis gravidarum check thiamine, they can be deficient

Clinical history hopping differentiate radiation enteritis versus radiation proctitis

  -enteritis is bloody outlet bleeding, proctitis is hematochezia and pain

Chromium is a micronutrient cofactor necessary for the action of insulin. Therefore in patients with hyperglycemia consider that chromium may be deficient. This is especially true in the setting of total parenteral nutrition because many formulations are lacking this micronutrient.

Manganese access the setting of total parenteral nutrition can present as paper dense deposits in the basal ganglia

Post polypectomy bleeding window of presentation is normally between 5– 7 days

electrocautery causes delayed bleeding

Subtle clinical clues for picking up zinc deficiency -abnormal taste, acrodermatitis enteropathica

Copper deficiency can present in the setting up gastrectomy or chelator therapy

Mantle cell lymphoma often presents in a colon polyp

Solid tissue biopsy report says "granulocytic sarcoma" - that is an acute myeloid leukemia in the tissue

Diagnosing systemic lupus erythematosus

4/11 criteria
Serositis
oral ulcers oral ulcers
arthritis
photosensitivity
cytopenias autoimmune hemolytic anemia
renal failure, glomerulonephritis RBC casts
antiglare antibiotic titers double-stranded DNA titers, anti-Smith titers
immunologic phenomenon
neurologic phenomenon psychosis seizure
malar rash
discoid rash



Overheard in rounds "bursas don't do well when you put needles in them" meaning don't ever drain and inflamed bursa if you do they can be complicated by chronic nonhealing and drainage

Autoimmune polyglandular endocrine disorders specifically adrenal and thyroid- be very careful if you treat a thyroid disorder first you may cause cardiovascular collapse from adrenal insufficiency.


Anti-emetics

Compazine promethazine Thorazine - dopaminergic antagonism cholinergic antagonism is to monarchic antagonism, good to use in the setting of a small bowel obstruction because they are not pro-motility agents

Haloperidol – powerful dopaminergic antagonism with very little anticholinergic activity. Special mention because this is a medication that is great for renal failure because it is not clear by the kidney.

Metoclopramide - dopaminergic antagonism and at high doses serotonergic antagonism, this agent has promotility so avoided the setting of small bowel obstruction. Good to double cover in people with gastroparesis.

Antihistamines great antinausea if you're trying to double cover motion sickness or a vestibular component.

Anticholinergics – scopolamine, atropine. Okay to use in the setting of small bowel obstruction because they do not increase gastrointestinal motility

Cannabinoids -have been used for chemotherapy induced nausea and also helps with appetite stimulation, dysphoria in the elderly has been observed clinically

Ondansetron granisetron, alosetron -best pick for chemotherapy induced nausea

Corticosteroids -useful for nausea and also covering appetite stimulation as well as increased intracranial pressure, major con are the long-term side effects

Headache in the emergency department - clinical guidelines

the patient presents with headache of unknown etiology to the emergency department. After evaluating for red flag symptoms on the clinical history and deciding on any or all appropriate laboratory investigations and imaging the following is a general treatment guideline.

Gentle intravenous hydration and ketorolac 30 mg IV, intramuscular will last longer but some people prefer not to have a shot. It's also recommended to choose an anti emetic. Typically Compazine between 2.5 to 10 mg, metoclopramide between 5 to 10 mg or droperidol, up to 2.5 mg (it's a QT Prolonger see may want to get EKG).

Did it get better? If so safe to go home, consider dexamethasone 10 mg intravenous out the door, with outpatient follow-up

Not getting better? Consider whether the patient has any contraindications to ergot alkaloids (cardiovascular disease serotonergic agents or other vasoconstrictors onboard, history of myocardial infarction, pregnancy, hypertensive, hypersensitivity, history of basilar migraine etc.)

If no contraindications go ahead with 0.5 mg IV as a test dose.

  If the patient tolerates the ergot alkaloids go ahead and give another 0.5 mg IV up to an hour later

If there are no contraindications 1 g intravenous valproate over an hour.

If resolved safe to go home with follow up, consider given dexamethasone 10 mg intravenous out the door.

However is not getting better consider opioid. If there opioid naïve and they get better out the door with outpatient follow-up. If they are not opioid naïve or they are not getting better on an opioid consider a neurology consult.

Keep in mind:

valproate should be avoided in the setting of liver disease, hypersensitivity that's been documented or in the rare instance of urea cycle disorder.

Random pulmonology notes

Miscellaneous pulmonology notes:

Pleural pearls:

Normal pH of pleural fluid is 7.6 secondary to bicarbonate rich pleural fluid -so if you get a pH of 7.4 that’s actually abnormal

pH and glucose move the same direction- glucose can be falsely elevated or falsely low, rely on the pH
Diagnosis: Urinothorax- if pleural creatinine is greater than two times the serum creatinine
Pleural fluid adenosine deaminase?-high sensitivity for tuberculosis

Cytology will have low sensitivity when you tap midlung field because most of thelymphatics of vasculature are near the diaphragm and so that is why you end up missing it.
Sensitivity of cytology is around 60% but that increases about 10-15% on the second tap
Sensitivity of cytology for a thoracentesis for mesothelioma is around 20%
*Neurovascular bundle in the intercostal is unpredictable within 10 cm of the spine

chylous effusion- lymphoma obstructing the thoracic duct

75% of all pleural effusions?
CHF then pneumonia then malignancy (lung > breast >lymphoma)
CHF the pleural effusion is always transudative

“Never let the sun set on a pleural effusion” as true today as when it was said whenever that was.
CT scan for further evaluating pleural lining.
The parietal pleura secretes most of the effusion.


Miscellaneous neurology notes:

Clinical clue: Classic presentation of neuro invasive West Nile virus
Flaccid paralysis with parkinsonism typically, in the late summer
Post infection fatigue and less up to one year
*yellow fever vaccine can also cause false positive West Nile
**West Nile IgM to be positive in the serum and CSF up to one year


Potent pimpables: Neurological manifestation of Whipple's disease oculomasticatory myodysrhythmia

Transfusion medicine random notes

: Coombs test: elution of cold autoantibody uses anti-complement. elution of warm autoantibodies as antiIgG


Half-life of immunoglobulin G 21 days
Immunoglobulin a monomer in serum but it dimers in secretions

Most likely bacterial contaminant In packed red blood cells Gram-negative rods particularly your Sennea because They like the cold I like iron

Transfusion reaction summary
Hepatitis B 1:220K
Hepatitis C 1:1.8 million
H I V one and 2.3 million


Red blood cell
Intravascular hemolysis: 1:250,000 to 1 in 1 million Mortality is 3.5% Clinical management: Stop transfusion intervenous hydration Maintain renal perfusion Allergic three and 1000 -Only transfusion Reaction where you can restart after pre medication Anaphylaxis one and 17,000 -Most likely etiology anti-immunoglobulin a antibiotic- Don't bother getting an IGA level just get anti-IGA because isotype variation Febrile nonhemolytic: Secondary to anti-granulocyte antibiotics. Stop the transfusion. Dear antipyretics and meperidine for severe rigors


TRALI -transfusion related acute lung injury- One in 5000 presents between three and six hours normally with ARDS picture Most likely etiology of agranulocyte antibodies from the donor-Donor must deferred Platelet Donors are mostly male now because lower risk of leukocyte allo-sensitization

Transfusion associated circulatory overload TACO One 700 presents as dyspnea cough cyanosis chf exacerbation Management is diuresis and supportive

Transfusion related sepsis one and 500,000 for red blood cells 1:12,000 for platelets Red blood cell associated sepsis higher mortality rate

Delayed hemolytic - One in 7000- anamnestic immune response to RBC antigen - Patient will require antigen negative RBC

Graft versus host:- 1:400,000
etiology Lymphocyte contamination Cellular Products the setting of immune compromised host
Presentation is normally between four and 10 days posttransfusion 90% mortality rate
Prevention is with irradiated blood products



Post transfusion Purpura: 1:200k'
Presentation is DIC picture between one and 24 days after transfusion Etiology is antiplatelet antibody Lysis of transfused and autologous platelets Treatment is intravenous immunoglobulin and plasma exchange Patient will require antigen negative platelets or washed products going forward


Iron overload: At least greater than 50 RBC transfusion

GI miscellaneous notes summary

Caudate lobe hypertrophy finding think hepatic vein thrombosis


Ulcerative colitis clinical notes:

Ulcerative colitis flare the max benefit with steroids 40 mg prednisone equivalent not better in 7-10 days?  Not going to get better
Consider steroid enema
   FYI mesalamine makes the diarrhea worse and hold and see what happens
Ulcerative colitis flare did not need to be n.p.o. unless toxic megacolon


Three mechanisms of protein-losing enteropathy

#1.   Malabsorption
#2.   Right-sided cardiac failure

#3.   Lymphedema and poor lymphatic return



Carcinoid
Diarrhea secondary to carcinoid does not happen until metastasis to the liver.
We will therefore go looking in the liver with an ultrasound prior to the fancy expensive serotonin/histamine metabolite urinalysis.


When calculating stool osmolality gap he did not actually need the stool unless you or ruling out factitious diarrhea, in the words of Arora "the sole function of the GI tract is to maintain stool osmolality that of plasma"


"The likelihood of ERCP complication is inverseley proportional to the to the indication of needing it"

Strong indications for ERCP: Common bile duct stone or ascending  cholangitis  or bilirubin greater than four
Melanosis coli finding on colonoscopy indicative of laxative abuse however can also be seen with chronic senna use
Alanine aminotransferase  is not elevated and alcoholic liver disease because  this enzyme is  dependent upon  vitamin B6  which is usually deficient in alcoholics.



Extrahepatic manifestations of hepatitis
1. are normally immune complex regulated and result in deposition to the glomerular basement membrane
2. As well, these circulating immune complexes  are termed mixed cryoglobulinemia and deposit in the vessels and joints.



Councilman bodies- acidophilic degeneration at the bedside secondary viral disease an immune response



Worldwide hepatitis B surface antigen carriers number greater than 350 million
In the words are, "Hep B surface antigen positivity is either acute or chronic"

Incubation period for hepatitis
  hepatitis A-15-45 days
  Hepatitis B and D-3 -180 days
  Hepatitis C  15-160 days mean seven weeks

 



Trivia: What is the eponym for Hepatitis B presentation in children?
  Giannotti-Crosti syndrome -  lymphadenopathy & papular acrodermatitis







What is the differential diagnosis of terminal ileitis?
Inflammatory bowel disorder
   Infection 
       tuberculosis Yersinia actinomyces histoplasmosis CMV
    malignancy lymphoma T-cell, carcinoid
Infiltrative diseases such as amyloid and sarcoid
Vasculitides such as ? and Behçet's disease
Vasoconstrictive medications such as amphetamine cocaine



Clinical triad chronic mesentery ischemia
#1 postprandial pain
#2 sitophobia - abnormal aversion to food
#3 weight loss


**acute mesenteric ischemia CT abdomen is completely normal early on
You need to get selective mesenteric angiography with papaverine

Clinical clue: constipation and renal failure watch for hyperkalemia

Mechanisms of action of lactulose
#1 ammonia ion trapping
#2 catharsis
#3  changing the colonic microFlora to increase nitrogen fixation


infiltrative disorders of the liver commonly present with isolated elevated alkaline phosphatase



Eosinophilic esophagitis
Six food elimination diet -Eggs dairy soy seafood tree nuts wheat
*Dairy and wheat comprised 60% of the clinical response and six food elimination diet
Treatment of eosinophilic esophagitis -proton pump inhibitor - a second line is intranasal budesonide


Gastrografin can cause pneumonitis but less likely mediastinitis  so if suspecting esophageal perforation use this contrast however unfortunately it has low sensitivity
Barium in the mediastinum is bad news so do not use it if you are suspecting esophageal perforation
CT of the chest as the highest specificity and sensitivity for assessing for esophageal perforation



Clinical clue: Drug-induced cholestasis most likely offenders of antibiotics are clavulanic acid and trimethoprim sulfamethoxazole


Clinical clue: differentiating hyperkeratinemia from jaundice - not likely to find scleral icterus in patients that have hypervitaminosis A.


Landmark study - new England  journal of medicine medicine 1999-
Spontaneous bacterial peritonitis trial arms were antibiotics versus antibiotics plus albumin mortality 30% decreased to 15% in the antibiotics/albumin arm
pathophysiological mechanism: albumin decreased acute kidney injuries #1 driver and mortality benefit
The one year relapse rate of spontaneous bacterial peritonitis roughly 70%.
-> with antibacterial prophylaxis this is less than 10% annually
*drawbacks include increased microbial resistance

Why are we using ceftriaxone as a treatment for spontaneous bacterial peritonitis?
because cultures are showing increased enterococcus so you want gram positive coverage.

Recurrent ascites?
#1 salt restriction- this works less than 10% secondary to nonadherence
#2 furosemide : spironolactone ratio 1:2.5 spironolactone has the mortality benefit furosemide is incorporated to maintain potassium homeostasis
#3 large-volume paracentesis versus TIPS
#4 transplant
TIPS are good for variceals bad for ascites meld score greater than 18
bad prognosis for TIPS




Clinical clue: Wilson’s - picking up the diagnosis
Young female acute liver failure hemolyzing
Decreased alkaline phosphatase? secondary to zinc depletion because of copper overload
increases in AST? - RBC membrane rich in AST
The treatment is liver transplant can be lifesaving.





Little known treatment for obscure GI bleed:
Thalidomide 100 mg daily for four months side effects: edema fatigue constipation


Ascorbic acid in high doses can cause a calcium oxalate crystals because vitamin C tablets often contain oxalic acid



Causes of hepatic encephalopathy...
Hypovolemia
Gastrointestinal bleeding
Hypokalemia secondary to ammonia production
Portal vein thrombosis shunting
Hypoxia
Infection SBP
Hepatocellular carcinoma although rare
Sedatives

Clinical clue: reversal sleep wake pattern is seen in hepatic encephalopathy







Ammonia (serum)
Venous or arterial? arterial is better but must be kept on ice the longer and since the higher will go up
only 20-30% of people with hepatic encephalopathy will have abnormal ammonia level making its negative predictive value weak



CELIAC DISEASE
Fun fact: Celiac disease is named such because pathologic bowel is found to be perfused by this arterial branch
lymphoma associated with celiac disorder is enteropathy associated T-cell lymphoma



Diagnostic criteria for celiac disease he need all three if you do not have all three reconsider your diagnosis
#1 positive serology
#2 small bowel biopsy
#3 positive response to gluten-free diet



What is the differential diagnosis of intrahepatic cholestasis?
Hepatitis
drug-induced
PBC
postop
pregnancy
graft-versus-host
sepsis


Differential diagnosis of benign extrahepatic cholestasis?
Postop cholestasis
PSC
IgG4
AIDS
cholangiopathy
Mirizzi syndrome



Malignant etiologies of extrahepatic cholestasis?
cholangiocarcinoma
adenopathy secondary to a systemic disorder (lymphoma)
pancreatic cancer



Contraindications for corticosteroids with people who have high discriminate function?
Renal failure
infection
GI bleed

Silver stool? Thoman’s sign- happens with the combination of acholic stools and gastrointestinal bleeding, will turn silver-colored.

celiac and familial adenomatous polyposis have a 5% overlap

Daptomycin:  Monitor creatinine kinase weekly or you will be sued, another complication his pulmonary infiltrates with eosinophilia AKA PIE, and finally its deactivated by surfactant so don’t use it for pneumonia

Risk for hepatocellular carcinoma with hepatitis B can happen prior to developing cirrhosis
The risk for hepatocellular carcinoma with hepatitis C happens after progression to cirrhosis


In familial adenomatous polyposis after resection of the colon the next most common presentation is ampullary tumor in the duodenum

Bililrubins greater than 20 are always intrahepatic cholestatic.

reflection upon exiting medical school

As I graduate medical school and begin my training I would like to reflect on some observations about the economics and practice of medicine I made while a student.

Physicians’ sensitivity to financial incentive is greater than I thought-

When I first came to medical school, I was more idealistic about the role of physicians in society. I had chosen this profession because I believed it was a path to living a just life. I had very little understanding regarding the economics of medicine. As I listened to conversations between my superiors on the wards, both residents and attending physicians, I was surprised by the preoccupation with money. This critique is more directed at the procedural specialties but can apply to us all. American physician reimbursement is the highest in the world, and it is creating a serious financial incentive to enter medicine, even in today’s more highly regulated healthcare setting. It is also creating an even more powerful incentive to specialize. This drive to use medicine for personal enrichment is supported by the preferences of competitive medical student applicants to enter highly reimbursed specialties. This financial incentive attracts those who prioritize financial reward; this adversely impacts the humanity and compassion of the profession as a whole. Those who choose lucrative specialties with minimal patient interaction offer much rationalization. Still, in doing so they stray from the classical definition of physician as a healer. Under the guise of a physician concerned with the sick and unhealthy, these specialists operate as highly skilled technical specialists. It is masquerade. The rational conclusion is that far too many doctors, and those entering the field are motivated by money.

The advent of hospitalists and salaried shift physicians will herald the loss of physician autonomy unless physicians become more organized politically.

As physicians continue to specialize, their interests have diverged greatly and solidarity has suffered both philosophically and politically. Desires for reductions in workload and relinquishing responsibilities of practice management have resulted in the creation of shift working physicians. Autonomy and controlling interest has been traded for better work hours and less administrative work, such that physicians are now managers without ownership. This phenomenon is compounded by narrowly focused specialist physicians, now more closely resembling technicians, blinded to both larger economic trends in healthcare delivery and the interests of their colleagues. Whereas allied health providers are strongly organized and unionized; organizing physicians has been likened to “herding cats”. Role confusion of specialist and shift physicians will adversely impact us all. Physician autonomy will now compete with newly established firmly adhered practice guidelines (to which practicing physicians may not have created). Finally, the much sought after salaried shift work no-call hospital physician position will face increased price pressure as the owners attempt to constrain costs of these generous salaries. Physicians now neither owners nor effectively organized will face these pressures divided and unleveraged.

The entitlement of subspecialty physicians in a fee for service model of inappropriately priced healthcare procedures-

Fee for service medicine creates financial incentive to increase procedural volume. Those sensitive to this incentive are subject to a conflict of interest in the administration of their service. They naturally pursue their rational interest to maximize profit. In the setting of increasing medical specialization, new medical technology (imaging, procedures, pharmaceuticals) is increasingly expensive and offers ostensibly better medical care yet possesses marginal utility in health outcomes. Though these procedures, improperly vetted by an underpowered governmental reimbursement body are still provided by third party payers. These payers in turn ultimately disperse the cost of these procedures onto that population whom comprise their risk pool. In combination with this, subspecialty physicians now with ever-narrowing scopes of practice proliferate and still require same broad physician privileges (in terms of patient contact, leadership, and management) afforded generalists in previous eras. Thus several “teams of doctors” may be involved in any single case many times voicing conflicting medical opinions. This is both confusing and exhausting as the parade of consulting physicians each have their 5 minutes with the patient, seldom altogether.

An ounce of prevention is worth a pound of cure, which is why if you want to make money it makes sense to sell cures by the pound.

Preventive medicine is inappropriately valued because prevention is too often not profitable for physicians and unpopular for patients. As well, these solutions many times reduce economic consumption and thus do not propagate a deficit-sustained society. They are of no interest to policy makers because their economic impact has not been believably quantified. Until real cost savings can be demonstrated, preventive medicine (especially where prevention means “doing nothing”) will not have a role in modern western medicine.

How healthcare expenditure is required for increased GDP and the necessity of increasing healthcare spending in maintaining American sovereignty.

Calls to reduce medical expenditure must account for the fact that healthcare spending is greater than 17% of GDP and increases every year. Therefore, significant reductions in spending would adversely affect GDP and increase federal budget deficits. Every dollar of health care spending eventually goes to someone, in some form. Reduction in federal health expenditure thus reduces "federally subsidized" economic output. Increased budget deficits (already scheduled for $1.2 trillion in 2012) decrease US borrowing capacity, which undermines US economic stability and sovereignty. Thus, much talked about reductions in healthcare spending and subsequent GDP reductions must be accounted for either by increased economic activity or further reductions in non-GDP contributing government spending.

The individual mandate is constitutional only in the setting of health insurance being purchased from a governmental body unconcerned with profit.

If healthcare is a public trust, then an individual mandate is a civil duty. However, the purchase of health insurance from private for profit corporations without allegiance to the citizenry violates the definition of a public trust. Thus, the only tenable means by which the individual mandate can be upheld is through compulsory purchase of government insurance or tax because it is the government who must by law serve its citizens and it will be the government who ultimately bears the cost burden of the uninsured.

prohibition and cirrhosis

a comment was made in today's pharmacology lecture-

"US alcohol prohibition reduced rates of liver cirrhosis, and therefore was good for public health in this particular instance."

i think because none of use had ever looked into this question combined with the fact that it seemed so intuitive, we all took it as fact. however i was interested in seeing whether any data exist to support this claim.

national board of economic research published a paper, Alcohol Prohibition and Cirrhosis, by Dills and Miron, in 2003. The paper examined death rates in the context of state and federal prohibitions. All the cirrhosis death rates declined during the prohibition period by 10-20%, they caution concluding this solely to prohibition for the following reasons:

-there have been substantial fluctuations in cirrhosis death rates comparable to the ones seen during prohibition, outside of periods of prohibition

-cirrhosis did not increase to pre-prohibition levels upon repeal

-cirrhosis levels had declined by the time prohibition began, allow little time for this effect

you decide!

random pharmacology notes

clinical pharmacology notes

takes 3 half lives of elimination to achieve steady state, so drugs w/long half lives o elimination (amiodarone - 40 days) can fool one into changing them before they've reached steady state. don't make any changes to meds unless they have been in patient for greater than 3 half lives.

aminoglycosides and fluoroquinolones are concentration dependent for bacterial infections

penicillins are time dependent

thus don't underdose fluoroquinolones, don't short course penicillins

quinidine is the most potent inhibitor of CYP2D6 in man

clinical clue: nail through the tennis shoe- think s. aureus or p. aeruginosa because these bacteria grow great in sneakers.

fluoroquinolone with Ca2+ (as in milk or iron fortified OJ) going to form Ca fluoroquinolone precipitates in the gut and less antibiotic will be available. this is bad because fluoroquinolones are concentration dependent anti-bacterial agents

interesting findings surrounding acetaminophen and EtOH. Chronic EtOH induces CYP2E1 for which acetaminophen is a substrate. the acetaminophen is metabolized to a hepatotoxic byproduct associated w/liver failure, thus the total recommended daily dosage for acetaminophen for someone who has at least 2 drinks a day is 2gms! interestingly, in binge drinking college kids - EtOH acutely inhibits CYP2E1, thus they are not bound by the same restriction of 2gm/day of acetaminophen-

clinical pain management notes/ renal notes

random clinical notes from pain management and renal service

Epidural steroid injection

methylprednisolone or triamcinolone - less post injection flare

dilute w/local anesthetic for less atrohpy/rupture

3 causes of lumbar stenosis

1. ligamentum flavum hypertrophy

2. disc bulge

3. facet hypertrohpy/osteophyte

chief complaint: i have back pain.

clinical question: should you image?

in light of data indicating false positive findings on normals, one should image only in cases of:

history of trauma

unexplained weight loss

fever

immunosuppression

h/o neoplasm

steroid use

age >70

intravenous drug use

definite change in neurological status

chronic pain -76.2 million people in US

20% of outpatient office visits

12% of prescriptions

untreated pain estimated economic impact ~$100 billion/year

pain categories by etiology

nociceptive (somatic, visceral) - this pain is adaptive (keep you out of trouble)

musculoskeletal/inflammatory/mechanical

neuropathic - (this pain no longer helpful, lingers, remains past point of being informative)

sympathetically mediated

peripheral (post herpetic neuralgia, neuromas)

central (post stroke, phantom limb)

nociceptive afferents come in two categories

peptidergic - calcitonin gene related peptide (CGRP), somatostatin, trkA, trpV1

non-petidergic -purinergic ligand gated ion (Ca++) channels, scn9A (sodium channel)

ascending signals are subject to descending modulation from the following neuroanatomical structures

somatosensory cortex, hypothalamus, peri-aqueductal grey, pons, prefrontal, anterior cingulate, - these descend by DLF (dorsal longitudinal fasciculus)

COMPLEX REGIONAL PAIN SYNDROME

type 1 - RSD - reflex sympathetic dystrophy, no evidence of actual tissue damage

type 2 -causalgia - has an identifiable etiology

treatment - sympathetic block and PT/OT.

a sympathetic block is determined to be successful in the the ipsilateral the skin temperature increases >1 degree C in the distrubution of the nerve. the temperature increases presumably because sympathetics are responsible for sweat, which cool the body by transfer of heat to H2O. side effect - horners syndrome

cervical blocks be aware - 0.5cc of of local into the vertebral artery is all that it takes to cause a seizure

don't do b/l cervical blocks because you can knock out the phrenic nerve

3 things to do to decrease ICP

1. hyperventilate

2. mannitol

3. steroids

acute increased in ICP only 1/3-1/2 will get papilledema

old tenet in medicine, "the real problem is greater than the potential problem"

i don't know if i agree with this all the time!

RENAL STUFF

PTH - catabolic for cortical bone, anabolic for trabecular

osteocalcin - blast marker

c-telopeptide - breakdown product of collagen, an osteoclast marker

alk phos - blast product (marker of mineralization) not metabolized by kidney

SIADH

A - erratic, greatly increased levels of ADH

B- constant ADH leak

C - osmostat reset

D -genetic increase in V2 aquaporin

etiologies of SIADH

cns - stroke, hemorrhage, infection, trauma, psychosis

malignancy - ectopic ADH secretion (usually in small cell lung ca) - a neuroendocrine tumor

drugs - carbamazepine, cyclyophosphamide, SSRI, valproate, ecstasy, interferons

surgery - 2/2 pain, can see triphasic presentation 1. polyuria, 2. siadh, 3. diabetes insipidus

pulmonary - pneumonia (viral bacteria tb)

hormone def - adrenal insufficiency and hypothyroid!!

hiv

treatment

free water restrict

salt tabs and furosemide (to wash out intramedullary gradient and prevent the ability to concentrate urine)

hypertonic saline (only in emergency hyponatremia)

classic blunder: giving IVF to siadh patient, anything fluid given is hypotonic to the patient's urine will only exacerbate free water retention

tolvaptan - V2 receptor antagonist

potent pimpable!

what is the differential diagnosis for increased BUN in the setting of normal GFR?

prerenal

catabolic process

high protein diet

GI bleed or other hemorrhage - (tissue destruction)

glucocorticoids (increases tissue destruction)

tetracycline therapy (decreasing tissue anabolism)

cystatin - a ubiquitous cysteine protease inhibitor looking to challenge creatinine as clinical measure of GFR

patient all of the sudden gone into A-FIB? don't forget about PE on your differential.

40 & 5, 40% O2 and 5cm PEEP - lowest vent settings (either coming off or going on)

drug discovery review

preclinical drug discovery methods

screening by target

phenotype screening

natural substance modification

biologics

259 agents approved by FDA between '99-08

75 w/new molecular mechanisms of action

50 small molecules

25 biologics

28 were developed using phenotype screening

17 were developed using target based

drug discovery main focus since 1990's has been on targets - clone the receptor or protein and modify it, the rational basis

tools that aid the discovery of compounds - high throughput, x-ray crystallography, computational modelling/screening

prior to molecular era of the 90's was phenotypic screening - less emphasis on mechanism of action

pros/cons of target vs phenotypic screening

target based discovery

pro

hypothesis driven based on molecular/chemical knowledge, all biologics are discovered this way

con

the hypothesis is not useful because it is not involved in pathophysiology

phenotype screening

pro

do not need to know mechanism of action

cons

without mechanism, designing is difficult because don't know which properties to modify, also - screening can be less efficient (low throughput)

the following is a list of CNS drugs approved for these years (taken from their table), most do not have an identifiable target, and 3/7 do not have a known MMOA

Target MMOA

Levetiracetam unknown unknown

Memantine receptor receptor kinetics

rufinamide unknown unknown

varenicline ion channel partial agonist

zonisamide unknown unknown

ramelteon receptor equilibrium binding

discoveries by modification of natural substance

acamprosate ion channel modulator

term

biochemical efficiency - binding affinity/functional response (Ki/EC50)

28 of the first in class small molecules were identified with phenotypic screening -

25 were intentionally targeted, 3 incidentally discovered

MOA were reversed engineered after observing physiological phenomena

18/50 first in class molecules came from natural substances

ramelteon - a melatonin receptor agonist approved for insomnia was discovered with a target specific strategy.

biologics - large peptide molecules - all created using target based approach

enzyme replacement

novel functioning

inhibition of normal function

augmentation of normal function

phenotypic approach worked best for CNS and ID, target based approach worked well for cancer, ID, and metabolic disease