Case 1: Pernicious anemia
By Eric A. Meyerowitz, MD, ACP Resident/Fellow Member
A 54-year-old woman presented with progressive dyspnea. She had been in her usual state of health until two weeks earlier, when she began to notice fatigue that progressed to profound dyspnea on exertion. By the day of admission, even the act of standing up left her feeling extremely short of breath. She also reported a 15-pound weight loss over the preceding two months that she attributed to poor appetite. Her review of systems was otherwise negative, and her medical history included hypertension, depression, and low back pain. She had a remote 10 pack-year smoking history. She reported no history of illicit drug use and occasional alcohol use, with last consumption more than a month earlier.
On presentation, she was afebrile and tachycardic. Orthostatic changes in vital signs were present. Physical examination was otherwise normal, including a normal cardiopulmonary examination. Initial laboratory investigation showed macrocytic anemia with a hematocrit of 30% (reference range, 34.9% to 44.5% in women) and a mean corpuscular volume (MCV) of 135.9 fL/red cell (reference range, 80 to 96 fL/red cell). Coagulation parameters were normal. Liver function tests were remarkable for a mildly elevated total bilirubin level and a markedly elevated lactate dehydrogenase (LDH) level at 2,253 U/L (reference range, 0 to 249 U/L). Haptoglobin level was low at 16 mg/dL (reference range, 30 to 275 mg/dL). Peripheral blood smear reviewed on admission showed evidence of megaloblastic anemia, including hypersegmented neutrophils along with red-cell teardrop poikilocytes and macro-ovalocytes (Figure 1). Vitamin B12 level was found to be profoundly low at 42 pg/mL (normal range >300 pg/mL). The antiparietal-cell antibody and intrinsic factor blocking antibody levels were markedly elevated. Helicobacter pylori stool antigen and serologic tests were negative.
The patient was started on cyanocobalamin (B12) with one intramuscular dose and was subsequently transitioned to oral daily supplementation. Her symptoms of dyspnea on exertion improved over the next three days. Her hemolytic anemia also improved rapidly, with normalization of her LDH within one week of B12 administration.
This patient's diagnosis is pernicious anemia, with associated hemolytic anemia. Severe B12 deficiency has been associated with a number of hematologic abnormalities, including pancytopenia and a hemolytic anemia, presumed related to intramedullary hemolysis from ineffective erythropoiesis or as a direct effect of elevated homocysteine levels. Hypersegmented neutrophils are seen because of impaired division of neutrophil precursors. A detailed review of 201 patients with vitamin B12 deficiency found that hemolysis was present in 1.5%.
Aggressive repletion is the mainstay of therapy. B12 repletion leads to complete correction of hematologic abnormalities in at least two-thirds of patients. Oral B12 replacement at 1,000 μg/d has been demonstrated to be as effective as intramuscular dosing, due to passive diffusion of B12 that is independent of intrinsic factor-mediated absorption. In addition to administration of B12, patients with pernicious anemia may require folate supplementation, even with normal folate levels, due to increased folate usage as cell lines recover with restored hematopoiesis.
Patients with pernicious anemia require evaluation for Helicobacter pylori infection, since there is a strong association between the two conditions. In fact, studies suggest that half to two-thirds of cases of pernicious anemia arise in patients with longstanding H. pylori infection, possibly from cross reactivity of antigens. Pernicious anemia is also associated with a number of autoimmune conditions, including vitiligo, type 1 diabetes, Hashimoto's thyroiditis, and Addison's disease.
- Severe vitamin B12 deficiency can present with a variety of hematologic abnormalities, including intramedullary hemolysis, that improve with B12 supplementation.
- Oral B12 replacement is as effective as intramuscular dosing, due to passive diffusion of B12 that is independent of intrinsic factor-mediated absorption.
Dr. Meyerowitz is affiliated with the University of Washington in Seattle.
Case 2: Acute disseminated encephalomyelitis
By Rami Eltaraboulsi, MD, ACP Resident/Fellow Member, and Eric Stern, MD
A 17-year-old man with no significant medical history presented with progressive headache, double vision, and decreased oral intake for one week. On admission, he was afebrile and his vital signs were normal. His physical examination was significant for right-sided dysmetria, but he had an otherwise normal neurologic exam. His initial laboratory studies were unremarkable, including a normal white blood cell count, electrolyte panel, and inflammatory markers. A head CT and brain MRI on admission were without significant pathology.
As the hospitalization progressed, the patient became more somnolent and eventually unresponsive. A lumbar puncture showed mild lymphocytic pleocytosis. Empiric acyclovir treatment, started for presumed herpes simplex virus encephalitis, was discontinued after a negative polymerase chain reaction test result. A repeat brain MRI, performed 10 days from the initial study, showed diffuse subcortical white matter changes.
Due to high suspicion of acute disseminated encephalomyelitis (ADEM), the patient was treated with high-dose steroids, IV immunoglobulins (IVIGs), and plasmapheresis. His mental status normalized within 72 hours. His only neurologic sequela at the time of discharge was weakness with right shoulder abduction.
ADEM is an immune-mediated disease that usually occurs after an infection or vaccination. It is more common in children but can occur in adults. The illness usually starts with nonspecific constitutional signs such as nausea, vomiting, fever, and headache but progresses to neurologic deficits like motor weakness, sensory loss, ataxia, and extrapyramidal symptoms. In ADEM, mental status can rapidly deteriorate and result in somnolence or coma. Typical findings on MRI include demyelinating changes in the subcortical or deep white matter. Prompt recognition is critical because ADEM can be fatal if untreated and infectious causes and other neurologic disorders must be ruled out.
ADEM should be treated promptly with high-dose steroids based on empirical evidence. IVIG and plasmapheresis are additional treatment options; their use is subject to local availability and input from consulting neurologists. One study showed full recovery in 46% of treated patients, minor neurologic deficits in 35%, and major neurologic deficits in 12%. The mortality rate has been cited as 8% to 12%.
Distinguishing ADEM from multiple sclerosis (MS) is a diagnostic challenge, especially during the first clinical episode. Approximately one-third of patients initially diagnosed with ADEM will subsequently be diagnosed with MS. ADEM is more likely to be associated with more global neurological deficits, whereas MS tends to be monosymptomatic (e.g., optic neuritis) and follow a relapsing-remitting course. ADEM is often noted to have poorly defined lesions on MRI that appear to be of uniform acuity. MS is associated with more defined demyelinating lesions that more frequently appear to be of differing duration. In both ADEM and MS, cerebral spinal fluid studies are usually normal or show a mildly elevated white blood cell count with lymphocytic predominance. Oligoclonal bands can also be seen in both disorders.
- ADEM should be considered in a patient with acute, multifocal neurologic symptoms and should be promptly treated to reduce the risk of significant morbidity and mortality.
- ADEM can be difficult to distinguish from MS, particularly during the first episode; elements suggestive of ADEM include the development of symptoms after a viral illness, presence of global neurological deficits on exam, and poorly defined, diffuse demyelinating changes on brain MRI.
Dr. Eltaraboulsi is a resident and Dr. Stern is an attending physician, both at MedStar Georgetown University Hospital in Washington, D.C.
Case 3: Entamoeba histolytica liver abscess
By Pooja Mehra, MD, ACP Resident/Fellow Member; Alexander Millard, MD; and Andrew Parsons, MD, MPH, ACP Member
A 29-year-old woman with chronic urticaria presented with one week of sharp epigastric pain, nausea without emesis or diarrhea, and two weeks of intermittent fevers and chills. Symptoms began four days after she returned from a week-long trip to Mexico. She reported no illnesses during her travel and no known sick contacts. She recalled a previous three- to four-day diarrheal illness after a one-week trip to Nicaragua 10 months earlier while taking maintenance omalizumab for her chronic urticaria. She was not on omalizumab at the time of presentation.
Physical examination on initial presentation found no jaundice but revealed severe right upper quadrant tenderness to palpation with a negative Murphy's sign. She was afebrile but tachycardic. Labs showed leukocytosis with a left shift, thrombocytosis, and normal liver function tests. CT of the abdomen with contrast disclosed a 6-cm × 5-cm hypoenhancing lesion with surrounding edema in the right hepatic lobe, favored to represent either amoebic or pyogenic abscess and not echinococcal cyst (Figure 2). Empiric antibiotics were started, and a drainage catheter was placed under ultrasound guidance with immediate aspiration of 80 mL of purulent fluid. Gram stain and culture of the abscess were negative. Entamoeba histolytica was detected via stool polymerase chain reaction testing, and serum Entamoeba histolytica antibody was positive. The patient was discharged from the hospital on a 10-day course of metronidazole. The drain was removed after repeated ultrasound one week later revealed no residual abscess. She was then prescribed a seven-day course of paromomycin.
Entamoeba histolytica causes amoebic dysentery and liver abscess. This anaerobic parasite affects 50 million people worldwide, with the highest prevalence in India, sub-Saharan Africa, Mexico, and parts of Central and South America. Travelers spending a month or more in endemic areas are at highest risk, but cases have been reported with less than one week of exposure. In amoebic liver abscess, fever and right upper quadrant pain typically develop approximately three months after consumption of contaminated food or water, but patients can present years later. While it is impossible to state with certainty, the patient's previous trip to Nicaragua was thought to be the most likely time of acquisition.
Patients may report dysentery at the time of or within a few weeks of exposure. Aspiration classically yields “anchovy paste” consisting of necrotic trophozoites. Pyogenic liver abscess presents similarly and should be cultured to guide therapy. Superinfection of the amoebic abscess is also possible. Echinococcus, an important diagnostic alternative, can be excluded based on serology and imaging, which typically shows a well-defined cyst with calcifications and daughter cysts for Echinococcus. The radiographic appearance of Entamoeba histolytica is a single cyst with surrounding edema.
Entamoeba histolytica can be detected in stool or by serum antibody, both of which are suggestive of prior exposure. Both serologic and stool testing are recommended at presentation due to the high sensitivity and low specificity of the serologic antibody test and the low sensitivity and high specificity of the stool antigen test, as colitis is often not present at presentation. Treatment with metronidazole is required to kill the trophozoites that cause liver abscesses and parenchymal disease in other organs. Paromomycin or diloxanide furoate is subsequently prescribed to eradicate luminal oocysts and prevent re-infection. Omalizumab is a monoclonal antibody directed against IgE and has been associated with an increased risk of parasitic infections.
- Entamoeba histolytica is an important and common cause of liver abscess in a returning traveler.
- Stepwise treatment of hepatic abscess is necessary, with initial therapy directed at killing trophozoites and subsequent treatment aimed at eradicating the luminal oocysts that may cause re-infection.
Drs. Mehra, Millard, and Parsons are affiliated with the University of Virginia in Charlottesville.
Case 4: Squamous cell carcinoma of the oral cavity
By William Johnson, DO, ACP Resident/Fellow Member; Ryan C. Miller, DO; and Zonera Ali, MD
A 75-year-old woman presented with two months of progressive facial pain that had been only partially relieved by over-the-counter NSAIDs. She reported no significant medical history or prior tobacco or heavy alcohol use. A complete oral examination revealed an erythe matous and irregularly exophytic mass protruding from the right maxillary alveolar ridge and extending onto the hard palate (Figure 3). There was no palpable adenopathy. Laboratory examination revealed only a mild anemia.
CT of the head and neck revealed a heterogeneously enhancing soft tissue mass, centered along the posterior right maxillary alveolar ridge with osseous destruction and invasion into the right maxillary sinus and hard palate (Figure 4). Biopsy confirmed the diagnosis of squamous cell carcinoma (SCC). Human papillomavirus subtype testing was negative. A complete bronchoscopy and esophagogastroduodenoscopy revealed no additional lesions. Positron emission tomography (PET)/CT exhibited F-18 fluorodeoxyglucose (FDG)-avid uptake of the right maxillary lesion, as well as multiple FDG-avid, enlarged right cervical and submandibular lymph nodes. There were no distant metastatic sites. She was staged at T4aN2bM0 (stage IVa) and referred to medical oncology for further treatment.
This patient has a squamous cell carcinoma (SCC) of the head and neck. More than 600,000 new diagnoses of head and neck cancer are made worldwide each year. In the United States, the incidence of head and neck cancer is approximately 50,000 cases per year and there are 11,000 deaths each year from head and neck cancer. Over 90% of head and neck cancers are SCC. Alcohol and tobacco use are risk factors for head and neck cancer, contributory in up to 75% of cases, and synergistic when combined. The incidence of human papillomavirus–related oropharyngeal cancer is increasing, but this subtype is associated with a younger age at onset and an improved overall survival.
Historically, the five-year overall survival rate for localized SCC of the oral cavity is 70%, compared to 20% in metastatic disease. Staging evaluation includes a complete head and neck examination. Bronchoscopy, upper endoscopy, and colonoscopy are encouraged for more aggressive disease and in cases associated with tobacco or alcohol. Chest imaging is required, while complete PET/CT imaging is recommended only in advanced disease (stages III-IV). Treatment should incorporate a multidisciplinary approach. Early disease can be treated surgically or by radiotherapy with curative intent. In advanced, unresectable, or high-risk disease, concurrent chemoradiation therapy remains an option.
- SCC is the most common type of head and neck cancer, with tobacco and alcohol use as significant and synergistic risk factors.
- Treatment of early-stage SCC involves radiation or surgery with intent for cure, while concurrent chemoradiation is reserved for unresectable, advanced, or high-risk disease.
Dr. Johnson is an internal medicine resident, Dr. Miller is a radiology resident, and Dr. Ali is a hematologist/oncologist, all at Lankenau Hospital in Wynnewood, Pa.
Case 5: Crowned dens syndrome
By Elizabeth Heisler and Kosuke Yasukawa, MD, ACP Member
A 60-year-old woman with a history of chronic obstructive pulmonary disease and osteoarthritis presented with severe neck pain. She reported chronic neck and back pain since involvement in a motor vehicle accident six months prior to presentation. She awoke the morning before admission with acute, excruciating posterior neck pain and inability to rotate her head, feeling as though she were “paralyzed.” She reported no headache or photophobia.
Upon admission, the patient was afebrile with normal vital signs and no alteration in mental status. Physical examination demonstrated decreased and painful range of motion of the cervical spine, right wrist, and left ankle, as well as a warm and erythematous right wrist, left ankle, and left first metatarsal joint. Neurological examination demonstrated grossly intact cranial nerves and normal strength and sensation. There was no hyperreflexia or Babinski reflex. Laboratory studies were notable for markedly elevated inflammatory markers, specifically C-reactive protein (CRP) of 310.8 mg/L (reference range, 0 to 10 mg/L) and erythrocyte sedimentation rate (ESR) of 130 mm/h (reference range, 0 to 30 mm/h).
An MRI of the cervical spine showed no evidence of spinal infection and confirmed degenerative changes, most notably at C6-C7. Bilateral wrist radiographs demonstrated mild degenerative changes and chondrocalcinosis. Arthrocentesis of the right wrist was unsuccessful. Subsequent CT of the cervical spine revealed calcification surrounding the odontoid process of the axis (Figure 5). The patient had significant improvement of her symptoms after starting prednisone, 20 mg/d. She was discharged on prednisone and scheduled for outpatient rheumatology follow-up.
The patient was diagnosed with crowned dens syndrome (CDS). In 1985, Bouvet and colleagues reported that frontal-view cervical X-rays in such cases showed a “crown-like” density, hence the subsequent appellation. CDS is characterized by acute neck pain, often associated with fever and elevated inflammatory markers (ESR and CRP). Neck rigidity, shoulder pain, and occipital or temporal headaches may also be seen. CDS can thus be misdiagnosed as meningitis, polymyalgia rheumatica, or giant-cell arteritis, which results in unnecessary diagnostic testing.
CDS typically presents in elderly patients, with a mean age of approximately 70 years. The mechanism of disease in CDS is presumed to be the deposition of calcium around the C2 vertebra, which causes the mechanical injury and a local inflammatory response. CT of the cervical spine, focusing on C1-C2 and demonstrating calcium deposition surrounding the odontoid process, is the gold standard for the diagnosis of CDS and is more sensitive than cervical MRI.
Oral NSAIDs, colchicine, or corticosteroids are conventionally used in the treatment of CDS, typically improving symptoms within days. Complications of CDS, including fracture of the atlas and myelopathy, have been reported.
- CDS should be considered in patients presenting with neck pain and elevated inflammatory markers.
- CT scan is more sensitive than MRI in diagnosing CDS, which is suggested by calcium deposition around the odontoid process.
Ms. Heisler is a physician assistant student and Dr. Yasukawa is a hospitalist, both at Rhode Island Hospital in Providence, R.I.