B12 deficiency induced hemolytic anemia – 6/27/18

Ernest presented an interesting case of a middle aged man with h/o CVA presenting with symptomatic megaloblastic anemia, found to have vitamin B12 deficiency induced thrombotic microangiopathy!

Clinical Pearls:

  • A “pseudo” TMA can develop in patients with severe vitamin B12 deficiency via red cell destruction in the bone marrow, leading to high LDH but modest rise in total bilirubin.
  • B12 related hemolysis is similar to TTP so the latter must be ruled out!
  • Treatment involves aggressive vitamin B12 replacement and is not responsive to plasmapharesis.

Differential for megaloblastic (MCV >120) anemia:

  • Vitamin B12 deficiency (elevation of both MMA and homocysteine)
  • Folate deficiency (elevation of homocysteine alone)
  • Drug induced (methotrexate, hydroxyurea, zidovudine, azathioprine, 5-FU, acyclovir, capecitabine)
  • Copper deficiency

When schistocytes are on the smear –> non-immune hemolysis.

Primary TMA syndromes:

  • TTP
    • Low levels of ADAMTS13
    • Renal failure, neurologic changes, fever, schistocytes, thrombocytopenia
      • Classic pentad only seen in 1/3 of patients
      • Triad of elevated LDH, schistos, and thrombocytopenia? –> check ADAMTS13
  • Shiga toxin mediated HUS
    • Shigella and certain serotypes of E Coli such as O157:H7 and O104:H4.
    • Classically with renal dysfunction and HTN as predominant findings
    • Bloody diarrhea
    • More common in children
  • Complement mediated
    • Hereditary deficiency of regulatory proteins in the alternative complement pathway
  • Drug mediated
    • Quinine, quetiapine, immunosuppressants, chemotherapy, calcineurin inhibitors
  • Metabolism mediated
    • Cobalamin C deficiency (inborn error of metabolism)
      • Mutations in the MMACHC gene (methylmalonic aciduria and homocystinuria type C)
  • Coagulation mediated
    • Hereditary deficiency of proteins in the coag pathway

Systemic disorder associated with MAHA and thrombocytopenia:

  • Pregnancy complications (HELLP)
  • Severe HTN
  • Systemic infections (bacterial endocarditis, HIV, CMV, RMSF)
  • Malignancies (with or without DIC)
  • Autoimmune diseases: SLE, systemic scleroderma, APLS.
  • DIC
  • Severe vitamin B12 deficiency

Final note on pernicious anemia:

  • Most common in Nothern Europeans
  • Check in people with vitamin B12 deficiency and no other identifiable cause
  • Intrinsic factor antibodies are the test of choice
    • Low sensitivity but high specificity
    • High sensitivity but low specificity (seen in other autoimmune disease as well as healthy individuals without autoimmune disease)
  • What about Schilling test?
    • Not available anymore!


Acharya et al. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J Hematol Oncol. 2008.

TB Pericarditis! 6/25/18

Today, we learned about a young man with no significant medical history who presented with fever of unknown origin, noted to have R sided lymphadenopathy and a pericardial friction rub.  Work up revealed a moderate sized pericardial effusion, a thickened pericardium, and a necrotic LN showing caseating granulomas on biopsy consistent with TB pericarditis!

Clinical Pearls:

  • Most common cause of pericarditis in the west is idiopathic.
  • Indications for pericardiocentesis
    • Tamponade
    • Suspicion for purulent/tuberculous/neoplastic pericarditis
    • Moderate to large pericardial effusions not responding to anti-inflammatory therapy
  • Purulent pericarditis occurs in 1% of infectious cases with staph aureus being the most common underlying pathogen.
  • TB pericarditis:
    • Leading cause of pericarditis in high HIV prevalent and resource limited settings around the world
    • Treatment requires anti-TB medications.  Steroids are not routinely recommended but may benefit high risk populations
    • Leading complication is constrictive pericarditis, early therapy does not decrease likelihood of development.


Diagnosis: (Requires 2 out of the following 4)

  1. Typical chest pain
  2. Pericardial friction rub
  3. EKG with diffuse ST elevations
  4. TTE with an effusion


  • Idiopathic
    • Primary cause of pericarditis in the west
  • Infectious
    • Viral
      • Coxsackie, EBV, adeno, HIV
    • Bacterial
      • Staph aureus (most common cause), TB, strep pneumo, neisseria, legionella, nocardia
    • Other
      • Toxoplasma
      • Echiconoccus
  • Non-infectious:
    • Neoplastic
      • hematologic malignancies, lung CA, breast CA, melanoma, mesothelioma
    • Metabolic disorders
      • Uremia, hypothyroidism
    • Autoimmune diseases
      • SLE, RA, scleroderma, MCD, sjogren’s, vasculitides
    • Cardiac injury
      • Trauma, MI, post-PCI, post cardiothoracic surgery
    • Drugs
      • INH, doxorubicin

Indications for pericardiocentesis:

  • Tamponade
  • Suspicion for purulent/tuberculous/neoplastic process
  • Moderate to large effusions of unknown etiology that are not improving with conservative management

 TB pericarditis 

  • Diagnosis is often delayed or missed leading to constrictive pericarditis and increased mortality
  • Occurs in 1-2% of patients with pulmonary TB.
  • Symptoms:
    • Cough, dyspnea, CP, fever, night sweats, orthopnea, weight loss
  • Exam
    • Fever
    • Tachycardia
    • Elevated JVP
    • Hepatomegaly
    • Ascites
    • Peripheral edema
    • Friction rub
    • Distant heart sounds
    • Kussmaul’s sign (lack of inspiratory decline in JVP), prominent Y descent, pericardial knock
  • Evaluation
    • TTE
    • Sputum AFB and culture
    • PTB noted on CXR 32-72% of the time
    • Pericardiocentesis indicated for diagnosis but does not reduce likelihood of developing complications or death
      • Send fluid studies for cell count, protein concentration, LDH, AFB smear/culture, GS and bacterial culture, ADA, and cytology
      • Fluid has high protein content and lymphocytic/monocytic leukocytosis
  • Complications
    • Constrictive pericarditis (30-60% of patients) even with prompt therapy, more common in HIV uninfected individuals
    • Effusive constrictive pericarditis
    • Myopericarditis
    • Cardiac tamponade
  • Treatment:
    • Anti-TB therapy
    • Steroids?
      • Not routinely recommended and do not consistently prevent complications
      • Could consider in high risk groups with early signs of constriction
    • Pericardiectomy for those with persistent constriction


All about seizures! – 6.5.2018

Today, Hugo presented a case of a middle aged man with schizophrenia and recently diagnosed seizure disorder who presented with worsening seizures, found to have toxic levels of clozapine!

  • Etiologies of seizures:
    • Idiopathic
      • >75% of seizure disorders
    • Primary neurological condition
      • Structural brain lesion
        • Stroke
        • Hemorrhage
        • Tumor
        • Head trauma
        • Abscess
        • Neurocystercircosis
        • AVM
      • Meningitis/encephalitis
      • HIV encephalopathy
      • Global cerebral ischemia (post cardiac arrest)
    • Systemic disorder
      • Metabolic
        • Hypo/hyperglycemia
        • Hypo/hypernatremia
        • Hypo/hypercalcemia
        • Hypomagnesemia
        • Uremia
        • Vitamin B6 deficiency
      • Drug
        • Intoxication
          • Cocaine
          • Phencyclidine
          • Methamphetamines
        • Withdrawal
          • ETOH
          • Benzos
          • Barbiturates
          • Baclofen
        • Med-induced lowered seizure threshold
          • Bupropion
          • Abx: cefepime, Cipro, imipenem, INH
          • Clozapine
          • Cyclosporine
          • Tacrolimus
          • Theophylline
          • TCAs
          • Tramadol
        • Eclampsia
        • Hyperthermia
        • Hypertensive encephalopathy
        • Hepatic encephalopathy
        • Porphyria
      • Etiology by age
        • 10-40 years
          • Idiopathic, trauma, drugs/withdrawal, metabolic
        • 40-60 years
          • Tumor, trauma, drugs/withdrawal
        • >60 years
          • Vascular, tumor, subdural, infection

DDx for seizure:

  • Syncope
  • Movement disorder
  • Tremor
  • Psychogenic nonepileptic seizure
    • Forced eye closure
    • Long duration
    • Hypermotor activity that starts and stops
    • Pelvic thrusting
    • Dx?
      • Inpatient video EEG
      • Strong association with PTSD
    • Narcolepsy


Clozaril toxicity:

  • Metabolic syndrome
  • Sedation
  • Anticholinergic side effects
    • Especially urinary retention
  • Orthostatic hypotension
  • QTc prolongation
  • Prolactin elevation (+)
  • EPS/TD (+)
  • Seizures (lower threshold, 3% incidence per year, highest of any other secong gen antipsychotic, dose dependent)
  • Agranulocytosis (1%)
  • Myocarditis and cardiomyopathy (fatal, within few weeks or months of treatment)
  • Gastrohypomotility (usually bowel)



  • Defined as two or more unprovoked seizures


Seizure Classifications:

Seizure Type Characteristics
Simple partial Normal consciousness/awareness

Single neurologic modality involving single region of body

Complex partial Conscious but not aware

May have an aura

Automatism (lip smacking, swallowing, or manipulating objects)

Postictal confusion

Primary generalized LOC

No prodromal or localizing symptoms

Whole-body stiffening (tonic) and/or jerking (clonic) seizures



  • When is continuous EEG needed?
    • If patient is not returning toward baseline in 15 mins after a seizure, goal is to rule out nonconvulsive seizures
  • How to define status?
    • > 5 mins



  • Start AED after > 2 unprovoked seizures
  • Start AED after first unprovoked seizure if
    • Age > 65
    • h/o significant head trauma
    • h/o partial seizure
    • h/o post-ictal weakness or paralysis
    • focal findings on neuroimaging
    • focal findings on EEG
  • If therapy is unsuccessful:
    • D/c first drug and start second drug as single agent


Which AED to initiate:

Drug Seizure type Side effects Notes
Lamotrigine Both SJS, SI  
Keppra Both Few DDIs, well tolerated


Safe in pregnancy
Topamax Both Kidney stones


Depakote Both Weight gain, HLD, PCOS, teratogenic


Superior to other AEDs for generalized seizures
Zonisamide Both Kidney stoNes


Carbamazepine Partial Interacts with other hepatically metabolized drugs, osteoporosis, HLD, hyponatremia




Refractory disease?

  • Temporal lobectomy:
    • Mesial temporal lobe sclerotic lesion resection
  • PNES?
    • Refer to psych


Symptom free in 2-5 years?

  • Withdraw AEDs