Mute and Unresponsive… 8/29/2018

Today Elise presented a case of a middle age woman, with a history of schizoaffective disorder and recent psych med changes, who came in unresponsive and mute. She was hypertensive and catatonic on exam but afebrile. Labs revealed moderately elevated CK. She responded well to IV Ativan. The final diagnosis was drug-induced catatonia!

Catatonia

  • Features:
    • Hypokinesis or akinesis
    • Excessive purposeless movements
    • Mutism
    • Decreased alertness/response to stimuli
    • Negativism (resistant to all instructions, commands)
    • Posturing
    • Fixed stare
    • Echolalia (repetition of another person’s words) or echopraxia (repetition of another’s actions)
    • Subtypes
      • Retarded Catatonia:
        • Mainly negativism, hypokinesis, mutism, staring.
        • +/- anorexia, incontinence, stupor
      • Excited catatonia:
        • Hyperkinesis, restlessness, impulsivity, aggression
      • Malignant catatonia
        • Life threatening: Fever, autonomic instability (labile BP, tachycardia, tachypnea, diaphoresis), delirium, rigidity.
        • Labs: Leukocytosis, elevated CK
        • Thought to be a spectrum of NMS
      • Management:
        • Withdrawal of offending medication if suspecting drug-related
        • Initial treatment: Benzos, if pt improves with the “benzo challenge,” then this supports the dx of catatonia.
        • Electro-convulsive therapy is an option.

NMS

  • Tetrad:
    • Encephalopathy
    • Muscular rigidity (lead pipe)
    • Hyperthermia
    • Autonomic instability
  • Associated with antipsychotics exposure, even some anti-emetics.
  • Can present days to weeks after exposure.
  • Management: DC offending agent, benzos, bromocriptine, supportive measures

NMS vs Catatonia

NMS can be a spectrum:

Woodbury

NMS can be confused with Serotonin Syndrome! Key to get a detailed medication history since SS is due to Serotonin, and NMS is due to Dopamine pathways! There are certain clues on the exam and presentation that can distinguish the two:

NMS SS

 

Thyroid storm! Or is it?… 8/28/18

Thanks Hong for presenting the case of a middle-aged woman with recent diagnosis of Grave’s disease off methimazole who presented with A fib with RVR and congestive heart failure, raising a debate on thyroid storm!


Clinical Pearls:

  • Thyroid storm is an extremely rare (1 in 500,000) but life-threatening diagnosis (up to 30% mortality) that should not be missed.
  • Degree of thyroid hormone elevation or TSH suppression is not a criteria for diagnosing thyroid storm! In fact, levels are typically similar to those of patients with uncomplicated thyrotoxicosis.
  • Common clinical feature is cardiovascular symptoms (heart failure, arrhythmia, tachycardia) but more specific finding is AMS.
  • Scoring criteria to screen for thyroid storm include Burch/Wartofsky and the Akamizu criteria, but they have not been validated.
  • Consult endocrine early if you suspect thyroid storm!

Thyroid storm: 

Risk factors:

  • Longstanding untreated hyperthyroidism
  • Precipitants:
    • Thyroid/non-thyroidal surgery
    • Trauma
    • Infection
    • Acute iodine load
    • Parturition
    • Irregular use or discontinuation of antithyroid treatment

Etiology: not clearly understood, but possibly related to the following

  • Rapid rate of increase in thyroid hormone levels?
  • Increased responsiveness to catecholamines?
  • Enhanced cellular responses to thyroid hormone?
  • The degree of thyroid hormone elevation or TSH suppression is not typically more profound than uncomplicated thyrotoxicosis

Clinical features:

  • CV (>60% of cases)
    • Tachycardia
    • CHF
    • Arrhythmias
  • Hyperpyrexia
  • AMS (considered by many to be essential to diagnosis)
    • Agitation, anxiety, delirium, psychosis, stupor, coma
  • Features associated with worse outcomes?
    • AMS
    • Older age >60
    • Mechanical ventilation
    • Not using antithyroid drugs or beta blockers

Diagnosis: 

  • Clinical! No universally accepted criteria or validated clinical tools.  Degree of hyperthyroidism is not a criterion for diagnosis.  Some to know of that might be helpful:
    • Burch and Wartofsky (sensitive, not specific)
      • > 45: highly suggestive of thyroid storm
      • 25 – 44: impending storm
      • <25: thyroid storm unlikely
    • Akamizu (Japanese) system developed in 2012 (less sensitive but more specific)

Treatment

  • ICU admission!
  • Regimen
    • Beta blockers ⇒ control symptoms from increased adrenergic tone
    • Thionamide ⇒ block new hormone synthesis. PTU is preferred because it blocks peripheral conversion of T4 to T3.
    • Iodine solution ⇒ block release of thyroid hormone (saturated solution of potassium iodide)
    • Iodinated radiocontrast agent (not available anymore in most places) ⇒  inhibit peripheral conversion of T4 to T3
    • Glucocorticoids ⇒ reduce T4 to T3 conversion, promote vasomotor stability, and treat any associated relative adrenal insufficiency
    • Bile acid sequestrants ⇒ decrease enterohepatic recycling of thyroid hormones (only in very severe cases)
  • Principles
    • Start with beta blockers + PTU, and stress dose steroids
    • 1 hour later: start SSKI q6h (after hormone synthesis has been halted with PTU, otherwise SSKI can make thyroid storm worse)

Suspiciously High Protein Gap… MM? 8/23/18

An elderly lady presented to the ED with what seems like orthostatic hypotension… Found to be anemic but otherwise no complaints. Her lab work incidentally revealed anemia, low anion gap, and grossly elevated protein gap (11.3), but otherwise nothing else! What’s going on?


Low Anion Gap:

  • Definition: Less than 3
  • Most common cause: Lab error!
  • Other causes: hypoalbuminemia, severe hyperchloremic metabolic acidosis, lithium intoxication, hyperklameia, hypercalcemia, hypermagnesemia…
  • Could also be a hint of presence of weird proteins!

Elevated Protein Gap:

  • Recall: Protein gap = Serum Protein – Serum Albumin, greater than 4 = elevated
  • Non-specific finding but can be caused by any processes that leads to an increase in non-albumin serum proteins, again could be a hint of presence of weird proteins??

Her peripheral blood smear revealed presence of Rouleaux, which is another hint of elevated levels of serum protein (but we already know that!). Hematology was consulted and the top differential at this point is some sort of gammopathy, with Waldenstrom’s Macroglobulinemia and Multiple Myeloma highest on the possibilities:

  MM Waldenstrom macroglobulinemia
Presentation Fatigue, anemia, Bsx, bone pain, rarely has hyperviscosity Fatigue, anemia, Bsx, neurologic sx (hyperviscosity, more common)
M-protein IgG, IgM is very very rare IgM
Bone-marrow >10% clonal plasma cells, CD56 positive Lymphoplasmacytic infiltration, CD 19, CD 20 positive. CD56 negative.

SPEP revealed monoclonal IgG spike, and bone marrow revealed > 60% plasmacytosis, hence pt has multiple myeloma!

Do not be tricked! If SPEP revealed polyclonal protein elevation, it could be due to a systemic inflammatory process or infection (Hep C, HIV for instance!)

MM Spectrum


Multiple Myeloma

  • Diagnosis
    • SPEP/UPEP for immune proteins
    • Smar: > 50% Rouleaux formation, seen with elevated serum proteins
    • BM Bx: Looks at % of plasma cells in the marrow, also can do cytogenetics
    • Xrays: Lytic lesions (Bone Survey, not a bone scan)
    • Other: Cr, calcium, albumin, beta 2 microglobulin (levels help determine staging with prognostic differences)
    • > 60% plasma cells on BM has poor prognosis
    • UA picks up albumin, NOT light chains
    • Light chain: Normal kappa/Lambda FLC ratio is 0.26 – 1.65, MM would have one that’s grossly elevated
  • MM Presentation
    • Almost all pts will have M-protein spike
    • 73% with anemia, 66% with lytic bone lesions, 29% with renal insufficiency.
    • Fatigue and normocytic anemia are common findings, blood smear might reveal rouleaux.
    • Might cause pancytopenia
  • MM Types: based on the kind of abnrl protein
    • IgG: 55% of the time, followed by IgA (25%), least common is IgM (0.5%). 20% are light chains only, lacking expression of the immunoglobulin heavy chain.
    • Cytogenetics determine high risk vs standard risk myeloma
      • High risk = Del 17P, t(14; 16), t(14;20) on FISH
  • Management:
    • Smouldering: Watch
    • Active: treat
      • Chemo: 3 drug regimen preferred
        • VRd: Bortezomib, lenalidomide, dexamethasone
        • VCd/CyBorD: Bortezomib, cyclophosphamide, dexamethasone
        • VTd: Bortezomib, thalidomide, dex
      • Hematopoietic cell transplantation (HCT): High dose chemo followed by autologous HCT is standard of care if eligible.
      • US: case by case, but if pt meets one of the following, they are not eligible for transplant:
        • Age > 77
        • Cirrhosis
        • Poor performance status
        • NYHA 3-4

Encephalitis and CJD! – 8/22/18

Thanks to Joe for presenting the case of an elderly man presenting with subacute onset of AMS, vision changes, and ataxia, found to have creutzfeldt jakob disease (CJD).


Clinical Pearls

  • Rapidly progressive encephalitis should trigger prion disease, paraneoplastic encephalitis, or Whipple’s!
  • Most common malignancies associated with paraneoplastic encephalitis are SCLC, testicular tumors, thymomas, breast cancer, and hodgkin lymphoma
  • >90% of cases of CJD are sporadic
  • Definitive diagnosis of CJD is made by brain biopsy.  CSF testing of 14-3-3 protein marker and the RT-QuIC protein assay combined have sensitivity and specificity >90%.
  • If prion diseases are on your differential, be sure to let infection control know before doing an LP because strict precautions are required to prevent spread of infection!

Encephalitis:

Defined as AMS > 24 hours plus 2 of the following:

  1. Fever
  2. Focal neurologic deficit
  3. Seizure
  4. CSF pleocytosis
  5. Abnormal findings on EEG or neuroimaging

Differential

Capture

Prion diseases:

  • AKA transmissible spongiform encephalopathies
  • Rare, closely related, fatal, neurodegenerative conditions
  • Occur in humans and mammals
  • Result of accumulation of aggregated forms of the prion protein in the CNS
  • >90% are sporadic, the rest are infectious (kuru, variant CJD, and iatrogenic CJD)
    • Iatrogenic mostly resulting from receipt of growth hormone prepared from cadaveric pituitaries and contaminated cadaveric dura mater allografts
    • Sporadic is not transmissible by blood
  • Kuru was the first one recognized to be transmissible and linked to cannibalism among tribes in New Guinea

CJD: 

  • Most prominent clinical feature is disordered cognition
  • Typically, patients also have motor signs, such as ataxia or spasticity, vague sensory problems, or changes in visual perception
  • Myoclonus is common
  • Progressive neurologic decline resulting in death within 6-12 months
  • One in a million
  • Mean age of onset 57 – 62
  • More common in white people (may be ascertainment bias)

Diagnosis:

  • Elevated CSF levels of 14-3-3 are not very sensitive or specific.  Adding RT-QuIC protein assay to the test increases both sensitivity and specificity to >90%.
  • CDC requires the following criteria for diagnosis:
    • Progressive dementia AND
    • 2 of the following: myoclonus, visual or cerebellar disturbance, pyramidal/extrapyramidal dysfunction, akinetic mutism AND
    • Atypical EEG and/or positive 14-3-3 CSF assay  with clinical duration to death <2 years and or typical MRI abnormalities (see nice example here)

Prognosis:

  • Poor, majority die within 1 year
  • No treatment available

Renal Cell Carcinoma 8/21/2018

Narges presented an unfortunate case of a young woman in her 20s who presented with worsening abdominal pain, nausea, and vomiting 8 days after a lap-chole for biliary cholic, found to have metastatic renal cell carcinoma in the absence of any risk factors.

Renal Cell Carcinoma

  • Epidemiology:
    • Most common primary malignant renal tumors (90-95%)
    • M > F (3:2)
    • Median age of onset: 50-70
  • Risk Factors
    • Obesity
    • Smoking (doubles risk)
    • Von-Hippel Lindau (Up to 2/3 of patients with VHL! Clear cell RCC)
    • Acquired cystic kidney disease (long term dialysis), 30x increase
    • Exposure: Asbestos, cadmium, leather tanning or petroleum industrial  products
  • Presentation
    • Usually asx until late stage
    • B Sx
    • Most common finding = gross or microscopic hematuria
    • Men: Left sided varicocele, anatomic obstruction of testicular vein
    • Flank pain, FUO, mass, hypertension, edema, liver dysfunction (Stauffer syndrome)
    • Paraneoplastic: 20% of cases
      • Erythrocytosis (inc erythropoietin)
      • Anemia (weird right?)
      • Hypercalcemia
      • Secondary (AA) amyloidosis
    • Diagnosis
      • CT w/ con or MRI
      • Renal mass that is enhanced by contrast strongly suggests RCC
      • Smaller lesions: biopsy, larger lesions: partial nephrectomy
    • Management
      • 5 year survival, once metastatic, is around 8%
      • Early: Partial or radical nephrectomy can be curative
        • If localized within renal vein involvement: resection is curative, no role for adjuvant therapy.
      • Advanced: Depends! If metastatic to only adrenal gland, radical nephrectomy still potentially. Otherwise tx is palliative. Traditional cytotoxic chemo has not been found to be helpful. Systemic immunotherapy and tumor debulking (as much as possible). A study published in NEJM in 2001 found that nephrectomy prior to chemo improves survival (11.1 vs 8.1 months), study drug was inferferon alfa though.
        • Radiation: No role in management
        • “Conventional” cytotoxic chemo: Not shown to be helpful
        • Anti VEGF
          • Sunitinib (tyrosine kinase inhibitor)
          • Bevacizumab (anti-VEGF MAB)
          • Used for advanced metastatic disease but no role in adjuvant therapy
        • PD1: Phase III trial in 2017, combination of Nivolumab + Ipilimumab is superior vs Sunitinib
          • 18 month survival: 75% vs 60%
        • mTOR inhibitors
          • Temsirolimus
          • Everolimus
      • Commonly asked complications:
        • Higher incidence of spontaneous intracranial hemorrhage with metastatic RCC to the brain, be careful with anticoagulation but this is not an absolute contraindication. Individualized decision!
        • Paper published in 2015 in Blood, retrospective cohort study, 293 pts with brain mets. Sub-group analyses showed 4x inc in intracranial hemorrhage of metastatic melanoma and RCC, but not influenced by administration of therapeutic dose of Lovenox.

GI Kaposi Sarcoma – 8/20/18

Thanks to Wendy for presenting a case of an elderly man with h/o remote renal transplant presenting with chronic progressive DOE, lower extremity edema, and upper and lower GI bleed, found to have AIDS-related GI kaposi sarcoma and associated protein-losing enteropathy!


Clinical Pearls:

  • Keep a broad differential for patients on immunosuppression
  • Incidence of KS is higher with CD4 counts <200 but it can be seen in CD4>500 as well.
  • Prognosis is generally good with treatment.  Poorer prognosis is associated with visceral involvement (as opposed to cutaneous), multiple opportunistic infections, and CD4<200
  • Mainstay of therapy is anti-retrovirals.  Chemotherapy can be used for ARV unresponsive disease, significant edema, extensive organ involvement, or IRIS.  Studies on chemo + ARV vs ARV alone showed no survival benefit with the former.
  • Thanks to Dr. Szumowski for the clinical pearl on use of sirolimus in renal transplant recipients with KS (article here).

Differential for odynophagia:

  • Infectious
    • HSV
    • CMV
    • Fungal
      • Candida ⇒ risk factors include dentures, immunosuppression (AIDS, chemo), radiation to head and neck, recent antibiotics
      • Others: crypto, histo, blasto, aspergillus
    • Mycobacteria
  • Medication-induced
  • Less common
    • Reflux esophagitis
    • Crohn’s

Kaposi Sarcoma:

  • Vascular tumor associated with HHV-8
  • Four different epidemiologic forms:
    1. AIDS-related: most common type in US
      • Higher incidence with CD4 <200 but can be seen with CD4 >500 as well.
    2. Endemic/African
    3. Organ transplant-associated (higher incidence after solid organ transplant)
    4. Classic (indolent cutaneous proliferative disease in older men of Mediterranean or Jewish descent)

KS in the GI tract:

  • Can occur in the absence of cutaneous disease
  • Symptoms range from asymptomatic to weight loss, abdominal pain, n/v, UGIB/LGIB, malabsorption, diarrhea
  • Inflammatory cytokine syndrome:
    • Systemic inflammation in AIDS-related KS
    • Symptoms:
      • Fever
      • Edema
      • Neuropathy
      • GI/respiratory symptoms
      • Hypoalbuminemia (can occur in the absence of the who syndrome)
        • Secondary to protein losing enteropathy (check stool clearance of alpha-1 antitrypsin)
      • Thrombocytopenia
      • Splenomegaly
Staging of KS: 
  • Extent of tumor (T): limited to skin with minimal oral cavity involvement is good.  Visceral involvement has poor prognosis.
  • Immune status (I): Degree of immunosuppression from HIV. CD4 <200 has worse prognosis
  • Severity of systemic illness (S): poor prognosis a/w h/o OI, thrush, B symptoms, etc.
  • Endoscopy and bronchoscopy are only done if initial stool test and CXR are abnormal
Treatment:
  • Goal: palliation, prevention of disease progression, and shrinkage of tumor to alleviate edema, organ compromise, and psychological distress
  • Systemic
    • Treatment with potent ART
      • IRIS can occur within 3-6 weeks of initiation
    • Chemo: for patients with advanced KS and rapid progression
      • Indications
        • >25 lesions
        • Unresponsive to local treatment or ART alone
        • Extensive edema
        • Symptomatic visceral involvement
        • IRIS
      • Agents:
        • Pegylated liposomal doxorubicin or daunorubicin
        • Paclitaxel, bleo, vinblastine, vincristine, etoposide
    • Chemo + ART or ART alone? While response rates are higher with the former, no survival benefit
  • Local symptomatic therapy
    • Intralesional chemo (vinblastine)
    • Radiation therapy
    • Topical alitretinoin

 

CML, leukocytosis, and leukostasis – 8/14/18

Yours truly presented a case of a middle aged man admitted for traumatic rib fracture overnight and found to have a WBC of 368k with cytogenetics consistent with CML!


Clinical Pearls

  • WBC > 100k is most consistent with leukemia.
  • WBC up to 75k can be seen with C diff infection.
  • Leukostasis is most commonly associated with AML > ALL > CML > CLL and defined as hyperleukocytosis with evidence of end-organ damage (CNS, renal, pulm)
    • Hematologic emergency!
    • Treatment is three-fold:
      • cytoreduction: leukapharesis, hydroxyurea, TKI (especially for CML), induction chemo (with other malignancies)
      • FLUIDS
      • prevention of tumor lysis syndrome (another heme emergency): allopurinol, FLUIDS

Differential for leukocytosis:

Blood Cell Lineage

  • Neutrophilia (most common, >7000/mm^3)
    • Infections
    • Stress/trauma
    • Chronic inflammation
    • Meds
    • Leukemias
  • Lymphocytosis (>4500/mm^3)
    • Pertussis
    • Syphilis
    • Viral infections
    • Hypersensitivity reactions
    • Leukemias/lymphomas
  • Monocytosis (>880/mm^3)
      • EBV
      • TB
      • Fungal disease
      • Autoimmune disease
      • Splenectomy
      • Protozoan/rickettsial infections
      • Leukemias

     

  • Eosinophilia (>500/mm^3):
    • Neoplasm
    • Adrenal insufficiency
    • Asthma/atopy
    • Collagen vascular disease
    • Parasites

CML:

  • Refer to this and this prior posts on the blog for all the details!
  • Some details to highlight
    • Smear tends to show lots of immature myeloid cells from many different stages of maturation (some blasts, metamyelocytes, myelocytes, bands, and mature neutrophils)
    • If >20% blasts, then think AML

Leukostasis:

  • Defined as symptomatic hyperleukocytosis and is a hematologic emergency!
  • Mortality rate is can be as high as 40% within the first week of presentation.
  • Clinical manifestations of ischemia primarily in CNS, lungs, and kidneys.  Can also see limb ischemia and priapism.
  • Malignancies at highest risk of leukostasis in order of prevalence:
    • AML (WBC >50k)
    • ALL (WBC >100k, though tends to present with TLS and DIC much more commonly than leukostasis)
    • CML (WBC >100k)
    • CLL (WBC >400k)
  • Treatment:
    • FLUIDS, lots and lots of fluids
    • Cytoreduction: lowers the WBC
      • Leukapharesis: not readily available as it requires a dialysis line and trained nursing staff
      • Hydroxyurea: to lower the WBC
      • Tyrosine kinase inhibitors (especially for CML related leukostasis)
      • Induction chemo (for non-CML related leukostasis)
    • Prevent tumor lysis syndrome:
      • FLUIDS
      • Allopurinol
    • In hemodynamically stable patients AVOID TRANSFUSION – it’s like adding fuel to the fire and can worsen ischemia.