Shistocytes indicate intravascular hemolysis

Disseminated Intravascular Coagulation (DIC):
Characteristics:
– Activation of coagulation
– Generation of thrombin
– Consumption of clotting factors
– Destruction of platelets

Lab findings:
-Elevated PT (due to consumption of factor VII ~ shortest half life)
– +/- Elevated PTT
– Low fibrinogen
– Elevated D-Dimer
– Low platelets
– MAHA (~50% of patients)
* Coagulation studies will be NORMAL in TTP – one way to differentiate from DIC.

Thrombotic Thrombocytopenia Purpura (TTP):
Due to a deficiency with ADAMTS13

Pentad (remember FAT RN) of TTP:
1) Fever
2) Anemia (microangiopathic hemolytic)
3) Thrombocytopenia
4) Renal disease
5) CNS disease (encephalopathy)

Other causes of MAHA (not a complete list):
– DIC
– HELLP
– Antiphospholipid syndrome
– Malignant hypertension
– Vasculitis
– Scleroderma renal crisis
– Many more…

Hereditary Hemochromatosis:

Triad:
Diabetes
Cirrhosis
Skin bronzing

Associated conditions:
– CPPD
– Arthropathy
– Hypogonadism
– Heart disease
– Destructive arthritis

Treatment:
Phlebotomy

*Caution patients about eating raw seafood or undercooked pork – increased incidence of Vibro vulnificus and Yersinia entercolitica in iron overload

von Willebrand Disease (vWD):
– MOST COMMON inherited bleeding disorder
– Symptoms similar to platelet disorders: nosebleeds, easy bruising, bleeding gums, and post-surgical bleeding; GYN bleeding is especially common.

Underlying problem:
– vWF protects factor VIII from degradation

Lab abnormalities:
– prolonged aPTT (see below) – due to degradated factor VIII

Treatment:
– DDAVP (desmopressin) – causes preformed stores of vWF and factor VIII to be released from endothelial cells

Hereditary Spherocytosis:
– Due to mutations causing deficiencies/dysfunction in erythrocyte membrane proteins – reducing surface-to-volume ratio
– Patient’s are at an increased risk of pigmented (bilirubin) gallstones

Lab abnormalities:
– Spherocytes on blood smear
– Varying degrees of anemia/reticulocytosis/bilirubin elevation
– ↑ MCHC reflecting membrane loss – CHARACTERISTIC

– see spherocytes on peripheral smear
– Osmotic fragility test can aid in the diagnosis when it is not clear (i.e. no family history)

Treatment options:
– Folate supplementation
– Splenomegaly (reduces hemolysis) ~ reserved for severe form; ensure vaccination against encapsulated organisms S. pneumoniae, H. influenza, N. meningitidis

Polycythemia vera (PV):
– PV is a disorder of myeloid/erythroid stem cell that causes erythropoietin-independent proliferation of erythrocytes
– Activating mutation of JAK2 (JAK2 V617F) is present in ~95% of PV

First step in making the diagnosis of PV:
– Exclude secondary causes of elevated Hct/red cell mass: chronic hypoxia and excess erythropoietin

Clues to the diagnosis of PV:
– Itching after a shower (aquagenic pruritus)
– Painful/red palms/soles (erythromelagia)
– Splenomegaly

Treatment:
– Phlebotomy (goal Hct <45%)
– +/- Myelosuppression (hydroxyurea)
– Aspirin

*Look out for a question that introduces acute leukemia in a patient with a history of PV

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD):
– X-linked – therefore men are primarily affected
– G6PD is important for cells to counterbalance oxidative stress

Known triggers (not a full list):
– Medications: Sulfonamides, Nitrofurantonin, Anti-malarials, Rasburicase
– Naphthalene in mothballs
– Fava beans
– Infection

Peripheral smear:
Bite cells: membrane defect that appears as a semicircular “bite” has been taken out of an erythrocytes – caused by removal of denatured hemoglobin by macrophages in the spleen

Heinz bodies: denatured oxidized hemoglobin visualized as intranuclear inclusions

Antiphospholipid Antibody Syndrome (APLS):
– Need ONE LAB criteria (confirmed 12 weeks apart) and ONE CLINICAL criteria

Lab Criteria:
– B2 Glycoprotein
– Anti-Cardiolipin antibody
– Lupus anticoagulant (measured as DRVVT that does not correct with mixing study)
*Positivity of all three lab tests is associated with the highest risk of thrombosis and pregnancy loss.

Clinical Criteria:
– Any thrombosis (venous or arterial)
– Fetal loss/miscarriage

Clinical Features of APLS:
– Prolonged PTT (50%)
– Livedo reticularis (20%)
– Cardiac valvular disease ~ MR
– DVT (32%)
– Stroke (13%)
– Hemolytic anemia (7%)

Paroxysmal Nocturnal Hemoglobinuria (PNH):
– PNH is an acquired disease – results in cells (RBCs, WBCs, platelets) lacking normally attached surface proteins
– CD55/CD59 are responsible for inactivating complement on RBC surface; lacking this protein, therefore, results in more complement-mediated lysis

Why does it occur at night?
– Complement-mediated lysis occurs more readily at lower pH levels and PCO2 levels rise at night – so patients report AM hematuria

Other associated conditions (besides hemolysis)
– Developing thrombosis (at unusual sites) – not fully explained; consider PNH in patients with both venous/arterial clots – Budd-Chiari syndrome may be a clue!

Treatment:
– Eculizumab – anti-CD5 monoclonal antibody that ceases hemolysis by inhibiting complement

Hairy Cell Leukemia (HCL):
Two clues to help make the diagnosis:
– Photo showing thread-like projections emanating from the cell surface (i.e. “hairy” appearing cells)

– Bone marrow biopsy resulting in a “dry tap” – occurs when marrow is difficult to extract due to firbrosis (seen in some cases of HCL)

Waldenström Macroglobulinemia:
– Key is to know that Waldenström’s overproduces the IgM paraprotein, but myeloma rarely does – it usually overproduces the IgG

Diagnosis:
– Clinical
– IgM monoclonal gammopathy
– Marrow biospy showing >10% lymphoplasmacytic cells
– Flow cytometry

Treatment:
– Plasmapheresis for hyper-viscosity
– Rituximab

 

Remember the breakdown and differentiation between AML, ALL, CML, CLL.  It starts with understanding the cell line formation:

Nice overview provided by Khan Academy: https://www.khanacademy.org/science/health-and-medicine/hematologic-system-diseases-2/leukemia/v/leukemia-classifications

Condition	Epidemiology	Clinical Signs/Symptoms	CBC	Morphology	Translocations
Acute Lymphoblastic Leukemia (ALL)	Childen (2-5 yo), male > female, association with Downs syndrome	↓ RBCs, ↓ PMNs, ↓ platelets, +HSM, bone pain, CNS manifestions, tumor lysis syndrome, mediastinal mass	Anemia, thrombocytopenia, variable WBC (>25% lymphobasts)	Condensed chromatin, scant cytoplasm, B cell – CD10+, Tdt+	t (12;21) kids – good prognosis; t(9;22) – poor prognosis
Chronic Lymphoblastic Leukemia (CLL)	Adults Male >>> Female	Asymptomatic or nonspecific, autoimmune hemolytic anemia	Lymphocytosis >5000, low platelets, ↓ antibodies (hypogammaglobulinemia)	Smudge cells, condensed chromatin, scant cytoplasm
Acute Myeloid Leukemia (AML)	Adults > 60 yo (mean 67)	Spontnaeous bleeding, petechiae, ecchymosis, DIC	Anemia, thombocytopenia, >30% myeloblasts	Auer rods, myeloblasts, monoblasts	t (15;17) – APML – treat with ATRA
Chronic Myeloid Leukemia (CML)	Ages 20-50; Rare in children	Insidious onset, mild symptoms, splenomegaly	Symptomatic WBC > 200k	Hypercellular marrow	t (9;22) – BCR-ABL – treat with TKI

 Smudge Cells (CLL)

 Auer Rods (AML)

How do you recognize a Posterior STEMI?

-FIRST, you need to suspect it!
-Only 10 % occur as isolated Posterior STEMI, most occur WITH inferior or lateral STEMI

What do you look for on an EKG?

-Remember that the EKG leads look at the anterior heart so the mirror image must be true for a Posterior STEMI in leads V1-v3

-Instead of ST elevations, you see ST Depressions
-Instead of Q waves, you see tall R waves
-Instead of flipped T waves, you see upright T waves

Example

How can you look at the posterior leads on an EKG?

–Place 3 leads (V7,V8,V9) below the right scapula (see picture) and look for ST elevations, Q waves and T wave inversions!

What coronary vessel is often implicated?

Posterior Descending Artery of the Right Coronary Artery (right dominant circulation)

How do you recognize a right ventricular infarction on an EKG?

-Often see ST elevations in V1, and in Lead III>Lead II
–ST elevations in the right sided leads (especially V4R)-see picture below
–Get that Right sided EKG if you suspect RV infarct!

Why is it important to recognize?

-Up to 40% of inferior STEMI can be associated with a RV infarction
-These patients are PRELOAD sensitive, so their blood pressures will tank if you give them nitrates or other preload reducers-they need FLUID RESUSCITATION

References

LITFL (Life in the Fast Lane)- an excellent resource for ECGs amongst others

 

Main etiologies of Aortic Stenosis

-Calcific/atherosclerotic: usually in patients >70, RF include HTN, Elevated TG, ESRD
–Congenital: etiology in 50 % of patients <70, usually bicuspid AV
–Rheumatic heart disease-usually associated with MV disease as well

TRIAD of Aortic Stenosis (not commonly seen)

-Heart Failure
-Syncope (usually with exertion when systemic vasodilation in the presence of a fixed SV causes BP to drop)
-Angina

The most common presenting symptom is DOE followed by decreased exercise tolerance, and pre-syncope.

What to look for on echocardiography if you suspect AS

-Maximum instantaneous velocity across valve (Peak Velocity)
-Mean aortic valve gradient
–Aortic Valve Area (AVA)

When is it considered SEVERE aortic stenosis?

-Mean gradient >40, Max Jet Velocity >4 m/s
–AVA <1 cm2, or < 0.5 cm2/m2 BSA

When should you replace the valve (surgical replacement vs. TAVR)

-Anyone with SYMPTOMS (usually only in severe AS and can be subtle like decreased exercise tolerance)
–Asymptomatic patients with severe AS with decrease in EF (EF<50 %)
-Asymptomatic patients with severe AS who are undergoing other cardiac surgery (eg: CABG)

Note that asymptomatic patients with severe AS do NOT need routinely need surgery.

What if AVA<1 but mean gradient is <40 and peak velocity <4?

This could be due to LOW FLOW-LOW GRADIENT Aortic Stenosis.

Diagnose it with a Dobutamine Echo

If TRUE Aortic Stenosis-Measured AVA will not change but the mean pressure gradient and transvalvular gradient will increase-these patients will benefit from replacement of the valve
If PSEUDO-severe stenosis, low cardiac output is due to myocardial dysfunction, and AVA will increase with dobutamine with minimal change in the gradient-likely will NOT benefit from replacement of the valve.

Medical treatment

-There is NO good medical treatment for severe Aortic Valve stenosis!
-Patients with severe AS can be considered to have a fixed afterload and pre-load dependent, so caution with use of diuretics, afterload reducers, and negative inotropes (CCB/BB) or you can cause them to syncopize!

 

Infection	CD4 Count	Prophylaxis
PCP pneumonia	< 200	TMP-SMX
Toxoplasmosis	< 100	TMP-SMX
MAC	< 50	Azithromycin

Toxoplasmosis:

Presumptive Diagnosis: *usually made to avoid brain biopsy

1. CD4 < 100
2. Lack of effective prophylaxis
3. Clinical syndrome (headache, neuro symptoms, fever, etc.)
4. + T. gondii IgG antibody
5. Imaging consistent with disease (multiple ring-enhancing lesions)

* If present >90% probably of TE.

Definitive Diagnosis:

1. Clinical syndrome (headache, neuro symptoms, fever, etc.)
2. Identification of ≥ 1 mass lesion by brain imaging
3. Detection of organism in biopsy specimen

Treatment:

1. Sulfadiazine
2. Pyrimethamine
3. Leucovorin – to prevent pyrimethamine induced hematologic toxicity

• Measure response to treatment with daily neurological exams and repeat neuroimaging after 2-3 weeks
• 75-80% of patients with TE will show radiographic and/or neurologic improvement
• Treat for 6 weeks followed by maintenance therapy

ART:

• 3 drugs from 2 different classes
• Usually 2 nucleoside RTIs “backbone” and 3rd agent – either  a protease inhibitor or an integrase inhibitor

Post-Exposure Prophylaxis:

• Started immediately after exposure => continued for 4 weeks
• Test immediately, 6 weeks, 12 weeks, and 6 months
• 3 Drug Regimen: Tenofovir-Emtricitabine + Raltegravir

Pre-Exposure Prophylaxis:

• Recommended for certain high-risk populations: heterosexual partners of infected patients, MSM, IVDU
• 2 Drug Regimen: Tenofovir-Emtricitabine

 

GBS Variants:

-AIDP (Acute inflammatory demyelinating polyneuropathy)- 85-95 % of GBS
-Miller Fisher Variant (5 % US but up to 25 % in Japan)
-AMAN (Acute motor axonal neuropathy)
-AMSAN (Acute sensorimotor axonal neuropathy)

Timing:

Acute (<4 weeks)

Pathophysiology:

Due to molecular mimicry from immune response to preceding infection that cross reacts with components of the peripheral nerve.

Diagnostic Criteria:

1. Progressive weakness of ≥ 2 limbs due to neuropathy
2. Areflexia
3. Disease course < 4 weeks
4. Exclusion of other causes

Supportive criteria:

1. Symmetric weakness
2. Mild sensory involvement
3. Absence of fever
4. Typical CSF profile
5. EMG evidence of demylination

Most common infectious triggers:
-Campylobacter Jejuni (most common), CMV, EBV, HIV, VZV, Mycoplasma, and even Zika virus

Most sensitive physical exam findings in GBS

-Absent/Depressed DTR (90 %)
-Ascending extremity weakness (90 %)
-Paresthesias (80 %)
-Dysautonomia (70 %)
-Facial weakness or bulbar signs (55 %)
-Back/extremity pain, respiratory failure, oculomotor weakness

What do you see on LP?

Albumino-cytologic dissociation (normal WBC with high protein)

Miller Fisher variant TRIAD:

-Ophthalmoplegia
-Ataxia
-Areflexia
Antibodies against GQ1b (anti-ganglioside) present in 85-90 % of patients

Treatment

-Supportive treatment
-IVIG
-Plasma Exchange

Remember that steroids are not effective!

Surreptitious Insulin Use:
– Exogenous insulin intake is associated with increased insulin and low C-peptide levels

Whipple’s Triad:
1.Symptoms consistent with hypoglycemia
2.Documented low plasma glucose when symptoms are present
3.Relief of symptoms following resolution of hypoglycemia

– Consider a psychiatric evaluation in patient’s suspected of intentional exogenous insulin use

– Endogenous insulin is formed as two insulin chains (A&B) linked by C-peptide.  Measurement of C-peptide can help distinguish from endogenous versus exogenous insulin

Insulinoma:
Diagnosis:
– Clinical + measurement of insulin (normal or elevated), proinsulin (normal or elevated), and C-peptide (normal or elevated)
– Localization of tumor with imaging; start with CT of the abdomen

	Glucose	Insulin	Proinsulin	C-peptide	BHB
Exogenous Insulin	↓	↑	↓	↓	↓
Insulinoma, NIPHS, PGHS	↓	↑/NL	↑/NL	↑/NL	↓
Sulfonylurea Ingestion	↓	↑	↑	↑	↓

– Use a urine sulfonylurea toxicity screen to distinguish insulinoma from sulfonylurea ingestion

Pheochromocytoma:

– always think about pheo when the clinical case includes episodes of hypertension and headache

– Pheochromocytomas are tumors composed of chromaffin cells of the adrenal gland

– Pheochromocytomas almost always realease catecholamines

Classic Triad:

– Diaphoresis

– Headache

– Tachycardia

Genetic disorder associated with pheochromocytoma:

– MEN 2A and 2B

– Neurofibromatosis type 1

– Von Hippel-Lindau syndrome

Diagnosis: – Plasma / Urine catecholamines

– plasma high sensitivity (96-100%), but lower specificity (85-89%); 24 hour urine sensitivity/specificity (91-98%)

– Plasma will exclude a pheo when negative, but need to confirm if positive

– Following biochemical diagnosis – radiographic localization is needed

Preoperative management:

– Alpha-blocker – typically with phenoxybenzamine – is first-line therapy; followed by B-blockers (metoprolol, propranolol) to treat reflex tachycardia

MEN 1, 2A, and 2B disorders:

MEN 1: Pituitary adenoma, Parathyroid hyperplasia, Pancreatic tumors

MEN 2A: Medullary thyroid cancer, Parathyroid hyperplasia, Pheochromcytoma

MEN 2B: Medullary thyroid cancer, Marfanoid habitus/Mucosal neuroma, Pheochromocytoma

Cushing Syndrome:
– Bright purple abdominal striae always, always, always are associated with Cushing syndrome – striae larger than 1 cm in width are highly specific for hypercortisolism

Other classic stigmata:
– cervicodorsal fat pad aka “buffalo hump,” acne, hirsutism, moon facies, plethora, easy bruising, hypertension, insulin resistance, hypokalemic metabolic alkalosis, osteoporosis

Cause:
– Elevated cortisol
– Most common cause is exogenous glucocorticoid therapy for another cause

3 biochemical testing options for CS:
– 1 mg (low dose) dexamethasone suppression test – failure to suppress AM cortisol indicates true Cushing syndrome
– 24 hour urine free cortisol (UFC) – excludes CS when not elevated
– Late-night salivary cortisol
Never measure a random cortisol as part of the work up

After confirming CS biochemically, measure ACTH to establish etiology
– differentiate between ACTH-dependent/Cushing Disease (usually > 20 pg/mL) and ACTH-independent (usually < 5 pg/mL)

If ACTH-dependent CS: order pituitary MRI
If ACTH-independent CS: adrenal gland imaging (either CT or MRI)

ACTH-secreting pituitary adenoma is known as Cushing disease
Pearl: pituitary adenomas do not suppress with low-dose dex, but do suppress with high dose

Other possible ACTH-secreting tumors (but very rare):
– An ectopic ACTH-secreting tumor
– Usually these are primary lung cancers or a carcinoid tumor
– The clinical presentation of an ectopic lung tumor usually is less cushingoid (presenting with only HTN and metabolic abnormalities) due to the rapid growth of these tumors

Pneumocystis jiroveci pneumonia (PJP):
– opportunistic infections are the most common etiologies of infection in patients 1-6 months after solid organ transplant.
Common signs/symptoms of PJP:
– Progressive exertional dyspnea (95%)
– Fever (90%)
– Non-productive cough (90%)
Pearl: walk patients with suspected PCP to reveal hypoxemia!

Diagnosis:
– Direct fluorescent antibody stain (DFA stain)
– Gomori methenamine silver stain (GMS stain)
*Must visualize the cystic/trophic forms directly

Treatment: TMP/SMX for 21 days
– Add steroids for pO2 ≤ 70 or A-a gradient ≥ 35

Toxic Shock Syndrome:
– expect a TSS board question to present as overwhelming sepsis in the context of a menstruating female or a post-surgical wound infection
– toxins (called super antigens) stimulate cytokine production, resulting in systemic signs of shock

Triad of TSS:
– Shock
– Fever
– Rash – diffuse macular rash with subsequent desquamation, especially on the palms and soles
*Along with involvement of at least 3 organ systems

Organisms often involved:
– S. aureus
– S. pyogenes

Treatment:
S. pyogenes: penicillin plus clindamycin
MSSA: Nafcillin or oxcillin plus clindamycin
MRSA: Vancomycin plus clindamycin
* add clindamycin to suppress protein synthesis and, therefore, toxin production

Scarlet Fever:
Key features:
– “circumoral pallor” – pale area around mouth
– “Pastia lines” – petechial lines in the skin creases
– desquemation

Most common organism: Group A Streptococcus

5 “S'” of Scarlet Fever:
– Streptococci (causative organism)
– Sorethorat
– Swollen tonsils
– Strawberry tongue
– Sandpaper rash

Treatment: Oral penicillin V; amoxicillin, 1st generation cephalosporins, and IM PCN G are alternatives

Lyme Disease:
– Erythema migrans is the associated rash

– Borelia burgdorferi is the causitive organism and Ixodes tick is the vector
– > 95% of cases occur in regions where the Ixodes tick is abundant

Other infections spread by Ixodes tick:
– Babesiosis
– Anaplasmosis

Signs/Symptoms of different stages of Lyme disease:
Localized: erythema migrans (target lesion at site of tick attachment ~ 60-80%), fever/other systemic symptoms are rarely present
Early disseminated: erythema migrans at multiple sites, febrile illness with constitutional symptoms (myalgia, arthralgia, and headache)
Cardiac: asymptomatic PR prolongation → complete heart block
Neurologic: facial nerve palsy (most common) either unilateral or bilateral
Late disseminated: oligoarticular inflammatory arthritis involving large joints (i.e. knee)

Rocky Mountain Spotted Fever:
Look for a history of exposure to ticks in endemic areas (southeast / south central US) and features of:
– Pancytopenia (esp thrombocytopenia)
– Hyponatremia
– No evidence of DIC (normal PT/PTT)
– ↑ transaminases

Rash of RMSF:
– >85% of patients by 1 week
– May lag behind other symptoms (~50% by day 3)
– Typically starts at the distal extremities and progress centrally; involves the palms/soles in >30% and typicially spares the face

Treatment:
– Doxycycline; choloramphenicol is an alternative option in pregnancy

Ehrlichiosis:
Think of Ehrlichia as “Rocky Moutain spotless fever”
– presents similarly to Anaplasmosis
– endemic to the southcentral and southeastern US
– spread via the Lone Star tick

Symptoms in order of frequency:
Fever (~90%) > headache > myalgia > arthralgia > meningismus

– Blood smear can help with visualization of intracytoplasmic inclusions in WBCs; only present in ~30%

Treatment:
– Doxycycline

Coccidioides Infection (Valley Fever):
– Clues to be aware of: Arizona/New Mexico and erythema nodosum
– Endemic to SW US (Arizona, New Mexico, Texas, and central valley of California)
– Route of infection: inhalation of fungal particles found in the sand
– Arthralgia of multiple joints “desert rheumatism” is common.

Diagnosis confirmed on fungal stains
– Thick walled spherules (10-80 uM) with endospores are seen in tissue

No treatment for mild disease; use itraconazole or fluconazole for severe illness

Histoplasmosis:
Exposure history is key here; think of histo with any of the following exposures in the SE/SC US:
– Bats (or guano)
– “Spelunking” (cave exposure)
– Farm buildings / bird-roosting locations

Most infections are subclinical (~95%); can see mucocutaneous lesions
Antigen detection in urine great for disseminated infections (>85%)

Blastomycosis:
– Endemic to Ohio and Mississippi/ River valleys

– Primarily a pulmonary infection, may disseminate to the skin and bone
– Well demarcated skin lesion is most common manifestation of disseminated disease

– Appears as a broad based budding pattern at 37 C

Normal Pressure Hydrocephalus:
Crude mnemonic: Wet (incontinence), Wobbly (ataxia), and Wacky (dementia)
Abnormal gait typically develops first!
“Magnetic gait” – is the characteristic gait of NPH – the patient’s walk appears as if his/her feet are stuck to the floor.
The gait is wide based, with slow, small steps, and reduced foot-to-floor clearance

Visualize hydrocephalus on CT/MRI – specifically ventriculomegaly that is disproportionate to corticol atrophy

LP: Normal (or slighty elevated) opening pressure and cell count

Standard of care: Ventriculoperitoneal (VP) shut – can perform large volume (30-50 mL) LP prior to placement to verify benefit

Cluster Headache:
Presentation: Shorter duration (usually < 3 hours), ipsilateral congestion and lacrimation with headache, nocturnal attacks
Epidemiology: Young or middle aged, male sex, history of cigarette smoking
Common trigger: Alcohol

First-line therapy: Inhalation of 100% oxygen and/or SQ or intranasal sumatriptans
Prevention medication: Verapamil

Transverse Myelitis:
TM is thought to be due to an autoimmune inflammation
~50% of the time it is preceded by an infection

Diagnosis requires:
– Presence of clinical features
– Evidence of inflammation (either leukocytosis in CSF or contrast enhancement on MRI)
– Exclusion of other potential causes

Treatment: IV methylprednisolone; plasmapheresis or cyclophosphamide for refractory disease

Alzheimer Disease:
Presentation: >60 years old, decline is insidious and progressive, definite impairment in 2 or more domains of cognition that impacts daily living

Treatment options:
– Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine
– N-methyl-D-asapartate receptor antagonists: Memantine
*mild improvements in measured cognition and performance of some activities; no clinically significant outcome

Frontotemproal Dementia:
– 3rd most common type of neurodegenerative disorder (2nd in those < 65 years old); average age of onset is 50-60
– Social behavior / personality changes are variable
– Genetics of FTD are heterogenous ~40% of patients with FTD have at least one family member with a neurodegenerative disorder

Difference with Lewy Body Dementia – Lack of significant psychosis – especially visual hallucinations

Parkinson Disease:
4 main features:
– Tremor: “pill-rolling” and always gets better with action
– Bradykinesia
– Rigidity
– Gait/Postural impairment: “festinating gait” – meaning hurried small shuffles, often on tippy toes
* diagnostic criteria require the presence of bradykinesia with at least one other cardinal feature
* MRI is recommended to rule out vascular lesions and hydrocephalus when suspected

Treatment options:
– Non-pharmacologic: rigorous daily exercise
– Pharmacologic: Dopamine substrate (levodopa), Decarboxylase inhibitors (carbidopa), Dopamine agonists (Ropinirole, Bromocriptine, Pergolide), Catechol-O-methyltransferase inhibitors (Entacapone, Tolcapone), Monoamine oxidase type B inhibitors (Selegiline, Rasagiline), Glutamate antagonist (Amatadine), Anticholinergic agents (Benztropine)
– Surgical: Deep brain stimulation (DBS) – consider in patients who have sustained motor benefit from medication, but are limited by adverse effect of medications

Myasthenia Gravis:
Cause: autoimmune disease directed against post-synaptic NM junction
Labs:
– Anti-acetylchoine receptor antibodies (~90% sensitive)
– Anti-muscle-specific kinase (MuSK) antibodies
EMG: repetitive nerve stimulation shows decremental response
Imaging: CT or MRI of mediastinum to screen for thymoma (~15% present, 85% hyperplasia)

Treatment:
– Cholinesterase inhibitors: pyridostigmine
– Glucocorticoids
– Immunosuppressive agents: azathioprine, cyclosporine, etc.

Crisis Treatment:
– Plasmapheresis or IVIG

Lambert-Eaton Syndrome:
Cause: autoantibodies against voltage-gated calcium channels located at the presynaptic NM junction
Associations: small cell lung cancer – can occur before tumor has been discovered; found in as many as 60% of patients

Differentiate from MG:
– Repetitive contraction IMPROVES muscle strength
– Hyporeflexia and dysautonomia are also present

Treatment:
– Remove the malignancy
– IVIG +/- immunomodulators

Melioidosis (Whitmore’s disease)

-Caused by the Gram (-) organism Burkholderia pseudomallei

Epidemiology

–Predominantly in Southeast Asia, Northern Australia, and China (most commonly from Thailand, Malaysia, Singapore)

Transmission

–Percutaneous inoculation (soil/contaminated water)
-Inhalation (more common during severe weather events, eg:Tsunami/Hurricane)
-Aspiration
-Rarely Ingestion

Risk factors

–Occupational exposure (Eg: Rice farming)
–Immunocompromised
–DMII
–Alcohol use
–CKD
–Chronic lung disease
–Thalassemia

However, can occur in healthy individuals as well! 

Clinical Manifestations

1)Localized Infection-skin ulcers/abscesses
2)Pulmonary Infection->50 % of patients, with >25 % having cavitary pulmonary nodules 
3)Bloodstream infection-More than half of patients have bacteremia on presentation and septic shock develops in >20 % of patients 
4)Disseminated infection-Septic Arthritis, osteomyelitis, but can form parenchymal abscesses in ANY organ (eg: Spleen, Kidney, Prostate, Brain amongst others)

Can MIMIC Tb and Malignancy-Consider Melioidosis in any patient with cavitary nodules and skin findings! 

Treatment 

Remember that Burkholderia is inherently RESISTANT to penicillin, ampicillin, 1st/2nd gen cephalosporins amongst others-Treatment is very prolonged!

Intensive phase (10-14d): IV Ceftazidime, Meropenem, or Imipenem
Oral Eradication Therapy (3-6 months): TMP-SMX (preferred over doxycycline)

Source Control! Search and Treat internal-organ abscesses