1. Neonatal Lupus: 
- Ro/SSA and La/SSB are IgGs and can cross placenta and cause neonatal lupus - can manifest as cutaneous rash or as complete heart block
2. Lupus Prognosis: 
- Early deaths (<5 years - disease more active at onset) tend to be due to disease or complications of surgery.
- Late deaths (>8 years) due to premature cardiovascular disease or thrombotic events - Patients age 35-44 have 50x increased risk for CAD
- Survival at 5 years - 93%
3. Lupus antibodies: 
- ANA - 95% positive
- Anti-Smith: 20-40%, higher in african american women. Specific.
- Anti dsDNA - 60%. Specific.
- Depleted C3 and C4 - 50% ; not as specific, reflects only immune deposition disease.
 4. Lupus genetics: 
- 30-50% concordance among monozygotic twins
- 5% risk in first degree relatives (50x higher than population)
5. Lupus pathophys: 
- Immune complexes against nuclear antigens (RNP and DNA)
- Immune complexes (IC) deposit in small vessels, stimulate dendritic cells to create pro-inflammatory state
- IC cause platelet activation -> microthrombi, complement activation
- IC attract immune cells that then attack the vessels and cause small vessel vasculitis.
6. Lupus etiology:
- Increased basal IFN-a, increased apoptotic debris (decreased clearance)
- Exposed to dendritic cells, activate toll like receptors (innate immune) particularly TLR7 and TLR9, which increases IFN-a and cytokines, activates adaptive immune system (T and B cells), make antibodies against the apoptotic debris
7. Lupus treatments: 
- Hydroxychloroquine: inhibits toll-like receptor signaling via effects of endosomal pH. Bread and butter of treatment. Very good for skin lupus.
- Steroids: suppress lymphocytes, complement, reduces cytokines; effective but morbid (osteoporosis, DM, obesity, HTN)
- Steroid-sparing immunosuppressants: azothiaprine
- Cytotoxic agents for severe disease.
8. Targeted lupus treatments: 
- B-cell targets: rituximab, belimumbab (anti-BLyS, a b-cell growth factor), epratuzumab
- T-cell targets: abatacept
- Anti-cytokines blocking IFN-a and IL-6
9. Drugs/Toxins that worsen gout:
- diuretics, aspirin, high fructose corn syrup, cyclosporine, pyrazinamide, ethambutol, lead
10. Modifiable risk factors for gout:
- HTN, hyperlipidemia

CYP2D6
- metabolizes about 20% of all drugs: codeine - 2D6 metabolizes to morphine, antidepressants like most SSRIs, TCAs, buproprion, tamoxifen, antipsychotics - haldol, risperidone, chlorpromazine, beta blocker, opiates
- can ask "Does codeine/tylenol 3 work for you" - if no, then they are likely CYP 2D6 mutants.
- problematic because there are lots of polymorphisms, duplicate copies, pseudogenes
- CYP2D6 can be mutated to the point where people are "ultrarapid metabolizers" - common in middle east
- "Generally, for European Caucasians and their descendants, the functional group of alleles are predominant, with a frequency of 71%. Non-functional alleles represent 26% of the variability, mainly CYP2D6*4. In Asians and their close descendants, functional alleles represent only ~ 50% of the frequency of CYP2D6 alleles. Asians and Pacific Islanders have a high frequency (median = 41%) of a reduced function allele, CYP2D6*10, contributing to the population shift to the right of metabolic rates indicating slower metabolism. Information concerning Amerindians from North (Canada), Central and South America indicate comparatively low frequencies of CYP2D6*10, perhaps a ”founders“effect. The frequency of functional alleles in Africans and African Americans is also about 50%. Both Africans and African Americans have reduced function alleles representing 35% of allele variation, mainly CYP2D6*17. African Americans, however, have more than twice the median frequency of nonfunctional alleles compared with Africans (14.5% vs. 6.3%)."{pharmacogenomics}

CYP3A4 
- metabolize about 25-50% of all drugs.
- notable drugs metabolized by CYP3A4 that lead to toxicities when combined with cyp inhibitors:
Steroids (budesonide, dexamethasone, fluticasone) - cushing's syndrome
PDE5 inhibitors (sildenafil, tadalfil) - hypotension, syncope
Vinblastine - bone marrow suppression
Vincristine - peripheral neuropathy, ileus
Pimozide - torsades
simvastatin - rhabdo
Benzos - excessive CNS depression
Carbamazepine - HA, vomiting, dizziness
Antiarrhythmics (disopyrimide, quinidine) - arrhythmias
Ergots - ergotism (peripheral ischemia, cyanosis, hypertension)

Infectious Brain Pathology - Clinical 

Fever + Petechiae
- Can't miss: neisseria + RMSF. Neisseria will progress to purpura fulminans
- Could also be other things: itp, ttp, etc

Blanching rash - common in west nile encephalitis

Meningococcemia
- Conjunctivial hemorrhage - thrombosis and gangene of extremities - purpura fulminans
- Sepsis +/- meningitis
- imparied consciousness and petechae may appear only later in the course
- non blanching purpuric rash
- Don't always see petechiae
- severe muscle pain of lower extremities is an early clinical sign.

DDx purpura fulminans
- meningiococcemia
- s.pneumo in people without spleen
- capnocyophaga canimorsus afer dog bite in asplenic patient
- vibrio vulnificans after raw oysters in cirrhotic patients

Severe bacterial meningitis - occurrence of symptoms 
HA, fever > 90%
menigismus > 85%
kernigs/bruzinsky > 50%
vom/sz > 30%
focal neruo deficit 10-20
papiledema <1%

If you suspect bacterial meningitis you have to tap - exam is not sensitive except in severe disease - meningismus/kernigs/brudzinski's - often absent in less severe cases

Aseptic meningitis ( = neg culture)
- usually due to viruses which is pretty benign
- other infectious etiologies - syphillis, TB, fungal (crypto, cocci, histo), ricketssia, leptosirosis, lyme dz
- non infectious - drug induced (ie drug allergy to IVIg, NSAIDs, bactrim), malignancy, lupus (ie lupus cerebritis - subacute presentation), paraneoplastic (antibody mediated autoimmune)

Viral menginitis
- Enteroviruses common, esp in summer and fall
- West nile common
- Mumps in non vaccinated kids
- HSV2 - causes recurrent aseptic meningitis -  Bad for neoates but in immunocompetent adults usually causes a benign viral meningitis - (vs HSV1 causes more encephalitis and is worse )
- VZV, EBV
- CMV if immunocompromised
- Arboviruses - west nile, La Crosse, st louis
- Acute HIV
- Lymphocytic chroiomeningits virus - mice and hamster pets
- Resp viruses: measles, influenza, adenovirus, paraflu
- Don't test for everything - test for can't miss/must treat (HSV2, HIV) and for common things (enteroviruses, west nile)

Management: 
- Steroids, blood cx, start abx, LP.
- Blood cx before abx but don't delay your abx if waiting for scan or tap.

CI to LP
- absolute: infected skin, trauma
- relative: coagulopathy/thrombocytopenia, increased intracranial pressure/mass effect
- When you should def get CT before LP: age > 60, immunocomp, papilleedema, altered consciousnss, focal deficit, new onset sz, known cancer, known cns lesions, suspect brain abscess (ivdu, endocarditis, local parameningial infeciton- dental/sinusitis/otitis
- If the CT shows supratentorial and infratentorial pressure differential - loss of cisterns, posterior fossa mass

LP complications
- HA ( low pressure HA - improves with lying down) - if it doesn't resolve, may have CSF leak - blood patch
- back pain
- infection
- bleeding - coag abnl, spinal subdurla/epidural hematomas
- hernation

CSF tests: 
- cell count, glucose total protein, gram stain
- vdrl, lyme, crypto ag
- pcr for entero, hsv, vzv, ebv, cmv
- csf ab for west nile
- keep 1 tube of csf in case you need add'l testing (tb, aids, jcv, ebv, cmv, toxo)

Bact meningitis by age
- 0-4 wks : GBS, e.coli, listeira, kleb, enterococcus, salmonella
- 5-12 wks: GBS, ecoli, list, hib, spnemoneisseira
- 3 mos- 18 yrs: h flu (rare these days s/p HiB vaccine), neisseria, s.pneumo
- 18 - 50 yrs: s penumo, neisseira
- >50 yrs: s.pneumo, neisseria, listeria, gram negs

Empiric tx bacteria menigntis - acute onset of fever and HA
- HIGH DOSE Vanc and ceftriaxone
- + Amp for babies and old people - Gram stain often neg in listeria
- Steroids EARLY - s.pneumo, H flu, TB most benefit with steroids

Subacute/chronic meningitis
- immunocompetent: neurosyphilis, crypto. TB, coccidio, histo

Encephalitis
- immunocomptent: arboviruses (west nile, EEE), vzv, lymphochoriomeningiis

Recurrent neisseria meningitis: 
- terminal complement deficiency
- more benign course of meningoccemia meningitis

Recurrent meningits with Upper resp colonizers s.pneumo, think of csf leak

Infectious Brain Pathology 

Acute bacterial meningitis
- Affects meninges
- Hematogenous to CSF or brain vs direct inculation
- Usually immunocompetent host
- Edema of brain parenchyma
- S pneumo invades subarachnoid space but spares brain parenchyma - inflammation of vessels in subarachoid space can cause thrombosis/vasculopathic changes - mottled edematous cortex (ischemia from artery supply, venous congestion from venous compromise, bacterial toxins and chemokines - edema. Edema can cause seizures - arachnoid granulation damage - hydrocephalus.

Chronic bacterial meningitis
- Most common - TB
- Hematogenous spread
- chronic course
- gross anatomy - lesions more fibrotic, rather than pururlent
- path: necrotizing granulomas, vasculopathic changes (dmg to vessels - ischemia)
- can present at skull base - "basal meningitis"
- May present with individual cranial nerve deficits (CN run in subarachnoid space)

Bacterial Abscess
- hematogenous - presumed septic microemboli
- granulation tissue like response - leaky vessels - edema
- may be ring enhancing
- surrounding edema - from angiogenesis nearby to bring increased inflammation - new vessels have compromised BBB
- may have fibrotic capsule
- intraparenchymal, usually hemtogenous spread

HSV encephalitis
- hemorrhagic necrosis of temporal lobes and inferior frontal lobes. - can cause focal neuro exam (sz, complex temporal seizures, memory loss, hallucinations, frontal or brainstem sx )
- path: immune cells around blood vessels
- nuclear inclusions - cowdry A
- chronically, can cause atrophy/encephalomalacia of temporal lobes
- affects parenchyma
- typically accute course
- typically immunocompetent hosts
- no seasonal variation, no vector
- tx: high dose acyclovir for 14 - 21 days
- dx with hsv1 pcr

Seasonal viral encephalitis
- west nile can mimic polio
- parenchymal distribution
- immunocompetent host
- typically has a vector (bird, mosquito)
- eastern equine encephalitis, western equaline encephalitis, etc
- "microglial nodules" on path - hypercellular areas, with spindle nuclei (?) representing microglia

PML
- JC viruls - affects oligodendroglial cells (ie spares grey matter)
- hematogenous spread
- typically activation of latent infetion - no effect in immunocompetnet hosts
- infects and transforms astrocytes to make them look darker and atypical - can mimic astrocytoma
- immunocompromised host
- path: foamy macrophages (ie mphage repsonding to tissue injury) - plum colored inclusions in oligodedroglial cells

HIV/AIDS
- can lead to CNS lymphoma
- Toxo, cryptococus, PML, CMV
- HIV encephalitis/dementia - AIDS defining illness, atrophy with microgila nodules, patchy demyelination, low grade inflammation, multinucleated cells

Fungal infections
- immunocompromised
- hematongeous - usu pulm, systemic disease
- intraparenchymal disease
- favor vessels
- aspergillus : vasculocentric growth, hemorrhagic necrosis - hyphae forms on path with 45 degree branching - grow next/into to blood vessels - can cause hemorrhage or ischemia from occlusion of vascular supply
- mucor - also causes necrosis and hemorrhage. grow as ribbony hyphae with 90 degree branches, can be result of local extension of fungal sinusitis. immunocomp or diabetic
- cryptococcus - subacute/crhonic (vs mucor/aspergillus which are more acute). "slime capsule" - sclear space around organisms on some stains - small narrow budding eyast - test c crypto Ag (99%sensitivie in csf, 95% in blood) immunocomproimsmised (not nly aids but lupus, maglinancy, steroids). can affect mengines or parenchymal "soap bubble" lesions - grow as yeast; tx IV amphotericin b and PO fluctyosine for 2 weeks, then high dose oral fluconaozole
- Histoplasma - yeast form - grow inside cytoplasm of histiocyte - look like foamy macrophages. small budding yesat - thickened leptiomingines - granulomatous - may mimic TB

Toxo
- sporozoan- unicellular parasite
- cat feces/undercooked meat
- can get congenital infection
- immunocompromised (reactivation of latent infection)
- necrotizing hemorrhagic parenchymal infection (tachyzoites - extracellular), bradyzoites - encysted - IHC can be helpful.
- path: cysts that look almost like nuclei (bradyzoites) - cells proliferating inside shielded from immune system - rupture and release organisms - attract inflammatory cells

Amoebas
- primary amebic encephalitis - acute, rapidly fatal, immunocompetent, direct invasion, usually nagleria
- granulomatous amebic encephalitis - chronic/subachute, immunocompromised, debliited, malnourished, probably hematogenous from skin/respiratory tracts - acanthameoba Balmuthia
- rarely entamameboa

Cysticercosis
- Taneia solium
- adult worm infect humans - eggs shed in feces - pig (intermediate host) consumes eggs - larval cysts in pig
- human becomes intermediate host from eating eggs
- larvae form single or multiple cysts

Herbal Medicines

Echinacea 
- wounds and infection, used for cold and flu
- stimulates phagocytosis?
- murky evidence of efficacy

Methods: 

- Three preparations of echinacea, with distinct phytochemical profiles, were produced by extraction from E. angustifolia roots 

- 437 volunteers were randomly assigned to receive either prophylaxis (beginning seven days before the virus challenge) or treatment (beginning at the time of the challenge) either with one of these preparations or with placebo. 

- The results for 399 volunteers who were challenged with rhinovirus type 39 and observed in a sequestered setting for five days were included in the data analysis.

Results: 

- There were no statistically significant effects of the three echinacea extracts on rates of infection or severity of symptoms. Similarly, there were no significant effects of treatment on the volume of nasal secretions, on polymorphonuclear leukocyte or interleukin-8 concentrations in nasal-lavage specimens, or on quantitative-virus titer.

Ephedra 
- Ephedrine - sympathomimetic
- Used for respiratory symptoms in chinese medicine
- Abuse: performance enhancer, stimulant, weight loss
- Linked to increased risk of MI and stroke - potentially even hypersensitivity myocarditis

Garlic 
- Platelet inhibition - should be discontinued 1 week before surgery
- Has been associated with reduced size of plaque in placebo controlled trial (athersclerosis 1999)

Ginko 
- Terpenoids and flavonoids
- Vasoregulation? Effect on platelets?
- Should be discontinued 1week before surgery

Ginseng 
- Terpenoids and flavenoids and ginsenosides
- Antioxidant? Effects on blood glucose?

Kava
- Anxiolytic, sedatives, anti-epileptic
- Kavalactones
- Sedation via GABA
- Rare instances of severe hepatotoxicity

J Clin Psychopharmacol. 2013 Oct;33(5):643-8. doi: 10.1097/JCP.0b013e318291be67.

Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study.

Sarris J1, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I.

Abstract

Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders-diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to kava.

Medicinal Mushroom
- Ganoderma lucidum
- Ling zhi/reishi
- Terpenoids

Milk thistle 
- silymarin - biologically active flavenoids
- supposedly protects hepatic cells and promotes regeneration

St John's Wort
- Inhibits Ser/Norepi/DA reuptake
- 2002 NIH study: both this drug (and zoloft) ineffective against
- P450 inducer - but not immediate. Can take several weeks of use before the cyp induction becomes obvious
- can cause serotonin syndrome in combination with other drugs that affect serotonins.

Valerian 
- Sedative, sleep aid
- Valepotriates
- Works via GABA
- Can potentiate sedative, can cause benzo-like withdrawal.

Fish Oil (omega 3) 
- EPA and DHA

Methods: double blind, placebo control, randomized.  n=12,536, subjects with diabetes/impaired glucose tolerance at high risk for cardiovascular events. Outcome: death from cardiovascular events.

Results: 

- Median follow up of 6.2 years

- Incidence of the primary outcome not significantly different between two groups

- No significant effect on the rates of major vascular events, death from any cause, or death from arrhythmia 

- Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n–3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. 

- Adverse effects were similar in the two groups.

Glucosamine/Chondroitin 
- Sea cucumber - 15% mucopolysaccharides
- "reduces pain"
- No definitive evidence that it is superior to placebo for either pain reduction or slowing loss of cartilage