Cases from Scripps Mercy Hospital San Diego

Leukemia cutis, cerebral venous sinus thrombosis, and more.


Case 1: Leukemia cutis

By Marie Bernardo, MD, and Arsh Chopra, MD

The patient

Figure 1 Gross image of the legs with diffuse nontender nonblanching violaceous macules and patches
Figure 1. Gross image of the legs, with diffuse, nontender, nonblanching, violaceous macules and patches.

A 71-year-old man with a history of acute myeloid leukemia (AML) diagnosed two weeks prior presented with a new rash that started on his ankles and progressed up to his thighs. The rash was initially pruritic, but the pruritus resolved after one day. However, the lesions over his bilateral lower extremities had persisted for over a week at the time of presentation. He reported no history of a similar rash. Examination of the skin revealed diffuse, nontender, nonblanching, violaceous macules and patches (Figure 1).

Figure 2 Pathology image with evidence of perivascular infiltrate of pleomorphic atypical cells in the dermis
Figure 2. Pathology image, with evidence of perivascular infiltrate of pleomorphic, atypical cells in the dermis.

Punch biopsy of this patient's skin lesions showed perivascular infiltrate of pleomorphic, atypical cells in the dermis (Figure 2). The cutaneous involvement by myeloblasts stained positive for CD34, CD117, and CD33; this pattern was noted to be similar to the immunohistochemical staining of circulating blasts from patient's peripheral blood smear and bone marrow biopsy when he was originally diagnosed with AML. By week two of decitabine treatment for his AML, the visible lesions had resolved.

The diagnosis

The patient was diagnosed with leukemia cutis, an infiltrative disorder of the skin by leukemic cells. Leukemia cutis has been described in multiple subtypes of lymphocytic and myeloid acute and chronic leukemias but is most commonly associated with acute myeloid leukemia (estimated to occur in 10% to 15% of cases). Skin lesions can be single or multiple, papules or plaques, and most commonly have a violaceous or red-brown color. The legs are most commonly involved. Leukemia cutis is associated with more aggressive disease, with a one-year survival rate of less than 20%.

An important alternative cause of nonblanching violaceous rash in patients with leukemia is vasculitis, which can result from malignancy, chemotherapy, or antibiotics and other medications. Skin biopsy is essential for making a definitive diagnosis of leukemia cutis, with combined histopathologic and immunophenotypic findings. Leukemia cutis usually occurs after a diagnosis of leukemia has been established, but skin involvement can be the initial presentation of the leukemia.

Pearls

  • Leukemia cutis can be seen in multiple subtypes of acute and chronic leukemias, but it is most commonly associated with acute myeloid leukemia.
  • Skin biopsy is indicated in a patient with new-onset rash and history of leukemia to differentiate leukemic infiltration from other causes such as vasculitis.

Case 2: Cerebral venous sinus thrombosis

By Michelle Miles, DO, MS, ACP Resident/Fellow Member, and Jonathan Harrison, MD, ACP Resident/Fellow Member

The patient

A 24-year-old African-American woman without known medical comorbidity and recently confirmed to be in early pregnancy presented to the hospital after being found unconscious by her significant other. Collateral history revealed that she had a one-week history of intermittent headache and that she had gone to bed early the previous night in an attempt to relieve the pain. The patient had a family history of sickle-cell trait.

Figure 3 MRI of the brain showing hyperintense lesions involving bilateral parietal lobes arrows consistent with ischemic infarct
Figure 3. MRI of the brain showing hyperintense lesions involving bilateral parietal lobes (arrows) consistent with ischemic infarct.
Figure 4 Left Magnetic resonance angiography showing absence of flow in the superior sagittal sinus posteriorly top arrow and left internal jugular vein and evidence of diminished flow in the left
Figure 4. Left: Magnetic resonance angiography showing absence of flow in the superior sagittal sinus posteriorly (top arrow) and left internal jugular vein and evidence of diminished flow in the left transverse and sigmoid veins (bottom arrow); Right: MR angiography six days later showing partial restoration of flow after heparin treatment.

On initial evaluation, the patient was only partially able to participate in the interview and physical exam. Left-sided weakness was noted, but sensory, cerebellar, and cranial nerve abnormalities were not. An MRI of the brain found bilateral parietal lobe infarctions (Figure 3). Magnetic resonance venography showed extensive venous thrombosis involving the superior sagittal vein and the left transverse and sigmoid veins, along with absence of flow in the left internal jugular vein at the level of the skull base (Figure 4, left).

Hypercoagulability testing was negative. Hemoglobin electrophoresis showed sickle-cell trait. The patient was started on a heparin drip, and due to seizure activity, levetiracetam was initiated. Repeat head CT showed an increase in infarct size and associated subarachnoid hemorrhage.

Despite the hemorrhage, anticoagulation with enoxaparin was continued. Repeat magnetic resonance angiography showed increased venous flow throughout the superior sagittal vein and left transverse veins (Figure 4, right). The patient was eventually discharged to a rehabilitation facility with improved headaches, normal mental status, and mild left upper-extremity weakness. Continued enoxaparin treatment was planned until 12 weeks postpartum, as was levetiracetam for 9 to 12 months with close outpatient follow-up. The patient underwent vaginal delivery at term without complication.

The diagnosis

The patient was diagnosed with cerebral venous sinus thrombosis (CVST), a rare cause of ischemic stroke, representing fewer than 1% of cerebrovascular accidents. CVST presents with a wide variety of symptoms, including headache, seizures, and focal neurologic deficits. CVST causes symptoms from two pathological mechanisms: obstruction of blood drainage from the brain and decreased drainage of cerebrospinal fluid. Obstruction of blood drainage causes increased venous and capillary pressure in the brain, which can lead to rupture and hemorrhage. The decreased cerebral spinal fluid drainage causes an increase in intracranial hemorrhage, resulting in headaches and seizures. Factors that predispose patients to CVST include pregnancy, use of oral contraceptive pills, and inherited thrombophilias. Sickle-cell trait has been linked to an increased risk of cerebral venous thrombosis. Magnetic resonance angiography/venography has the highest sensitivity for diagnosing CVST.

Treatment of CVST is systemic anticoagulation. Unfractionated or low-molecular-weight heparin is often used in the acute setting; patients are usually transitioned to warfarin, but in this case heparin was continued due to pregnancy. Guidelines for CVST treatment from the American Academy of Chest Physicians recommend anticoagulation even in patients with intracranial hemorrhage. Case series in patients with CVST on anticoagulation have demonstrated less than 5% risk of new hemorrhage on anticoagulation, supporting the presumption that reducing overall clot burden normalizes venous and capillary pressures, decreasing the likelihood of new hemorrhage.

Pearls

  • CVST presents in patients with risk factors for hypercoagulability with headaches, focal neurological deficits, encephalopathy, and/or seizures.
  • Long-term anticoagulation is recommended even in cases where intracerebral or subarachnoid hemorrhage is present on imaging.

Case 3: Hemophagocytic lymphohistiocytosis in mononucleosis

By Jonathan Harrison, MD; Eric Dahms, MD, FACP; and Omar Khayyat, MD, ACP Resident/Fellow Member

The patient

A 30-year-old man was admitted to the hospital with abdominal pain, jaundice, and subjective fevers. Approximately one week prior to admission, he had been diagnosed with Epstein-Barr virus (EBV)-infectious mononucleosis. On admission, he was febrile to 39.5 °C, with a blood pressure of 81/51 mm Hg and a pulse of 106 beats/min. Physical examination showed jaundice, a palpable liver edge 6 cm below the costal margin, and both inguinal and axillary lymphadenopathy.

Figure 5 CT scan of the abdomen and pelvis showing hepatosplenomegaly and inguinal lymphadenopathy arrows
Figure 5. CT scan of the abdomen and pelvis, showing hepatosplenomegaly and inguinal lymphadenopathy (arrows).

Laboratory testing was significant for pancytopenia with a white cell count of 27,000 cells/µL, a hemoglobin level of 10.2 g/dL, and a platelet count of 63,000 cells/µL. A chemistry panel was notable for a total bilirubin level of 17.6 mg/dL, an alkaline phosphatase level of 923 U/L (reference range, 38 to 126 U/L), an aspartate aminotransferase level of 188 U/L, and an alanine aminotransferase level of 219 U/L. Ferritin level was 2,091 ng/mL (reference range, 26 to 388 ng/mL), triglyceride level was 423 mg/dL (reference range, <150 mg/dL), fibrinogen level was less than 50 mg/dL (reference range, 170 to 330 mg/dL), and CD25 (interleukin-2) level was 1,270 pg/mL (reference range, ≤1,033 pg/mL). CT scan of the abdomen and pelvis was notable for hepatosplenomegaly and inguinal lymphadenopathy (Figure 5).

The patient was initially treated with fluids and broad-spectrum antibiotics. Infectious workup revealed 1 million copies of EBV DNA/mL (reference range, <5 copies/mL). A bone marrow biopsy and subsequent liver biopsy revealed hemophagocytosis. The patient was started on etoposide, dexamethasone, and rituximab. The patient's laboratory values and clinical condition did not improve significantly, and he was referred for evaluation for bone marrow transplant.

The diagnosis

The patient was diagnosed with hemophagocytic lymphohistiocytosis (HLH), which is a rare complication of EBV infection. HLH is a life-threatening syndrome of pathologic immune activation and is diagnosed by clinical and laboratory criteria. Non-congenital HLH is diagnosed by meeting at least five of the following eight criteria: fever of 38.5°C or greater; splenomegaly; peripheral blood cytopenia (at least two of the following: hemoglobin level <9 g/dL, platelet count <100,000 cells/µL, or absolute neutrophil count <1,000/µL); hypertriglyceridemia (fasting triglyceride level >265 mg/dL) and/or hypofibrinogenemia (fibrinogen level <150 mg/dL); hemophagocytosis in bone marrow, spleen, lymph node, or liver; ferritin level above 500 ng/mL; low or absent natural killer (NK) cell activity; and soluble CD25 (soluble IL-2 receptor alpha) elevated two standard deviations above age-adjusted laboratory-specific norms.

HLH can manifest as a primary familial disorder with known genetic mutations and in sporadic cases without known genetic abnormalities. In adults, sporadic cases are more common than congenital and are often triggered by events that disrupt the immune system, such as a viral syndrome (e.g., EBV, HIV, parvovirus B19, human herpesvirus 6, and cytomegalovirus), malignancies (especially lymphoma or leukemia), or autoimmune conditions (e.g., systemic lupus erythematosus and Still's disease). EBV infection is the most commonly associated secondary condition and is seen in approximately one-third of cases of HLH. The mortality rate in adults is above 40% but can be improved with early recognition and treatment. Diagnosis is often delayed because HLH is uncommon and many of the laboratory abnormalities are nonspecific and can be associated with the triggering event. Treatment is targeted toward the underlying disorder; in this patient, rituximab was used to treat the underlying EBV infection. For acutely ill or deteriorating patients, HLH-specific chemotherapy should be promptly instituted. Bone marrow transplant is considered in patients for whom initial therapy fails.

Pearls

  • HLH is an uncommon, life-threatening disorder of immune activation and can be triggered in adults by infections such as EBV.
  • Early recognition and initiation of treatment are crucial in improving survival; treatment for acutely ill patients consists of chemotherapy as well as treating the underlying trigger for the disease.

Case 4: Adult-onset Still's disease

By Ni Mo, DO, ACP Resident/Fellow Member

The patient

A 42-year-old man was initially admitted to the hospital with a three-week history of fevers, arthralgias, body aches, and sore throat. During hospitalization, the patient exhibited twice-daily fevers up to 39.5 °C. Laboratory testing was significant for leukocytosis of 26,000 cells/µL with 89% neutrophils, a C-reactive protein level of 229 mg/L (normal range, <10 mg/L), an erythrocyte sedimentation rate of 85 mm/h (normal range, <15 mm/h), and a ferritin level of 8,076 ng/mL (normal range, 26 to 388 ng/mL). A CT of the chest, abdomen, and pelvis showed mild mediastinal and right hilar lymphadenopathy. The patient was treated with empiric antibiotics and supportive therapies. He was eventually discharged after remaining afebrile for 72 hours and with improvement of his leukocytosis.

One week later, the patient was readmitted for persistent fevers up to 39.7 °C, headaches, myalgia, sore throat, and arthralgias. Examination at this time was notable for pharyngeal erythema without exudates and mild tenderness of bilateral metacarpophalangeal joints. Laboratory testing again showed leukocytosis with neutrophilic predominance, hyperferritinemia, and elevated acute-phase reactants. His lactate dehydrogenase (LDH) level was elevated at 975 units/L (normal range, 313 to 618 units/L). Antinuclear antibody and rheumatoid factor testing were negative. An extensive infectious workup, including testing for HIV, EBV, hepatitis, and parvovirus, was negative. The patient was started on twice-daily naproxen. Subsequently, he had defervescence and significant improvement of pharyngitis and headaches.

The diagnosis

The patient was diagnosed with adult-onset Still's disease (AOSD) based on the Yamaguchi classification. AOSD is an uncommon inflammatory disorder with features including quotidian fevers, arthritis, and classic evanescent rash. AOSD is diagnosed after exclusion of other causes, such as infection, malignancy, or autoimmune disease. Multiple sets of diagnostic criteria have been proposed for AOSD, with the Yamaguchi criteria having the highest sensitivity and being the most widely used. Diagnosis requires five features, including at least two of the following major criteria: fever ≥39 °C for at least 1 week, arthralgia for >2 weeks, evanescent salmon-colored maculopapular rash on trunk or extremities, or leukocytosis >10,000/µL and ≥80% granulocytes. Minor criteria include sore throat, lymphadenopathy, hepatomegaly or splenomegaly, abnormal liver function tests, or negative anti-neutrophil antibody (ANA) and rheumatoid factor (RF).

Treatment of AOSD depends on severity of disease. Mild disease may manifest with fevers, rash, and arthralgias and may be controlled with NSAIDs alone. Patients with moderate disease may have evidence of non-life-threatening cardiac, pulmonary, or hepatic involvement. These patients generally require glucocorticoids for symptomatic control and usually achieve response within hours to days. Patients with severe disease may have life-threatening complications such as acute respiratory distress, cardiac tamponade, or fulminant liver failure. These patients typically require high-dose IV glucocorticoids with a biologic agent such as an interleukin (IL)-1 or IL-6 inhibitor.

Pearls

  • AOSD is an uncommon but potentially life-threatening disorder that is characterized by quotidian fevers, arthralgias, and an evanescent rash.
  • Diagnosis of AOSD is based on a combination of clinical and laboratory findings after exclusion of infectious, malignant, or other autoimmune conditions; the Yamaguchi criteria have the highest sensitivity and are the most widely used.

Case 5: Malaria in a returning traveler

By Patricia K. Riggs, DO, ACP Resident/Fellow Member, and Marie Bernardo, MD

The patient

A 32-year-old healthy woman presented with four days of intermittent headaches, fevers, and chills. She also had associated symptoms of nausea, vomiting, mild diarrhea, sore throat, generalized weakness, night sweats, and dark urine. She worked as a photographer and had returned from a trip to Kenya nine days prior to presentation. She did not receive any vaccinations or prophylactic medications for her trip. She slept with mosquito netting at night but was outdoors most of the day. She reported no sick contacts, and none of her fellow travelers were ill.

Figure 6 Peripheral thin blood smear demonstrating a ringed form of less-thanigreater-thanP falciparumless-thanslashigreater-than within a red blood cell arrow
Figure 6. Peripheral thin blood smear, demonstrating a ringed form of P. falciparum within a red blood cell (arrow).

On initial evaluation, the patient was afebrile, tachycardic (heart rate, 118 beats/min), and hypotensive (blood pressure, 92/61 mm Hg). Examination revealed scleral icterus and no palpable hepatosplenomegaly. Significant laboratories include thrombocytopenia with platelet count 36,000 cells/µL (normal range, 150,000 to 450,000 cells/µL) without leukocytosis or anemia. She had an international normalized ratio of 1.5, transaminitis five to 10 times the upper limit of normal, and a bilirubin level of 7.9 mg/dL (normal range, 0.2 to 1.3 mg/dL). Thick and thin blood smears confirmed ringed forms of Plasmodium falciparum (Figure 6) with initial parasite density of 0.5%. She was treated with IV quinidine and oral doxycycline and was switched to atovaquone/proguanil after clinical stabilization due to QT prolongation. Parasitemia resolved on day three.

The diagnosis

The diagnosis is malaria due to Plasmodium falciparum infection. Malaria is a consideration in all febrile patients with a history of recent travel to endemic regions. Of all the Plasmodium species, P. falciparum is most common and most likely to cause severe malaria and higher parasite densities. Both thick and thin blood smears are needed for malaria diagnosis and should be performed daily until parasitemia resolves in order to monitor treatment response. Thick smears are best for screening for presence of parasites, while thin smears allow for species identification and measurement of parasite density.

Treatment of malaria depends on whether the case is uncomplicated or severe and whether the infection occurred in a region with known chloroquine resistance. Severe malaria is diagnosed if the patient has any of the following: jaundice with a bilirubin level greater than 3 mg/dL, altered mental status, seizures, acidosis, hypoglycemia, severe anemia, disseminated intravascular coagulation, renal impairment, pulmonary edema, shock, or parasitemia greater than 10%. For severe malaria (as in this case), irrespective of chloroquine resistance, first-line treatment in the United States is IV quinidine and oral doxycycline. IV quinidine requires hourly QTc monitoring.

Pearls

  • Of all the Plasmodium species, P. falciparum is most common and most likely to cause severe malaria and higher parasite densities.
  • Management of malaria depends on whether the infection is severe, as well as on chloroquine resistance patterns; first-line treatment for severe malaria in the United States is IV quinidine and oral doxycycline.

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