Cases from Yale-New Haven Hospital: Trainee Edition

Leukocytoclastic vasculitis associated with cocaine abuse, the Sister Mary Joseph nodule as presentation of advanced malignant peritoneal mesothelioma, and other cases are discussed.


Case 1: Leukocytoclastic vasculitis associated with cocaine abuse

The patient

A 38-year-old woman with active polysubstance abuse presented with a chief symptom of diffuse joint pain of four days' duration in the setting of a recent cocaine binge. She developed a rash over her elbows and on her lower back. She reported a temperature at home of 102.9°F, chills, rigors, nausea, and vomiting. She reported no family history of autoimmune or rheumatologic disease. Admission physical examination was most notable for 18 to 20 pink papules on her lower back ranging in size from 5 to 9 mm, some with pinpoint hemorrhagic crust. Similar papules were present over the bilateral extensor surfaces of her elbows. Examination of her extremities revealed tenosynovitis over elbows, hands, and wrists bilaterally. Laboratory studies were remarkable for an elevated C-reactive protein level of 225 mg/L (reference range, 0.1 to 3.0 mg/L). Urine toxicology was positive for cocaine, opiates, benzodiazepines, oxycodone, and methadone. Serologic testing was negative for cryoglobulins, and rheumatoid factor was less than 20. Antinuclear antibody (ANA) screen was positive with a titer of 1:80 and homogenous pattern, but clinically the patient was assigned a low likelihood of having a connective tissue disease. Multiple tests for various infections were negative, including gonorrhea, hepatitis B and C, HIV, Epstein-Barr virus, and enterovirus. Skin biopsies from her left elbow and left thigh demonstrated leukocytoclastic vasculitis.

The diagnosis

This patient's diagnosis is a leukocytoclastic vasculitis associated with cocaine that was potentially contaminated with levamisole. The medical complications related to cocaine use are widely described, and those associated with contaminants such as levamisole are being increasingly documented. Levamisole is a veterinary anthelmintic agent with known immunomodulatory properties that was first reported as a contaminant in cocaine in 2001, with a steady increase in use over time. Recent estimates indicate that rates of levamisole contamination of cocaine consumed in the U.S. are nearly 70%. Levamisole prevalence is likely a result of the agent's amphetamine-like and hallucinogenic effects, which are thought to increase the effects of cocaine. Cases of agranulocytosis and cutaneous vasculitis, among other toxicities, have been reported in association with levamisole. The papular exanthema in this case represents a presentation distinct from the purpuric retiform pattern with necrosis that has been classically associated with levamisole. However, given the patient's presentation, her recent history of a cocaine binge, an unrevealing infectious evaluation, and biopsy findings of leukocytoclastic vasculitis, we felt that her presentation was due to small-vessel vasculitis secondary to levamisole-contaminated cocaine. Unfortunately, testing to confirm the presence of levamisole in the urine is not available at our institution.

Pearls

  • Levamisole is a common contaminant of cocaine in the U.S., with various potential health consequences.
  • Levamisole-contaminated cocaine should be considered in the differential diagnosis of a leukocytoclastic vasculitis in patients who have a fitting history and presentation.

Case 2: The Sister Mary Joseph nodule as presentation of advanced malignant peritoneal mesothelioma

The patient

A 63-year-old man with a history of benign prostatic hyperplasia, hypertension, and chronic kidney disease presented with sudden onset of difficulty urinating and high blood pressure. On the day of presentation, the patient noticed difficulty urinating associated with penile swelling and discomfort. His left leg was chronically swollen but was noted to have increased in size in the three days prior to admission. Upon admission, the patient was afebrile and hypertensive. On examination, he was noted to have an “irreducible umbilical hernia,” firm and nodular, measuring approximately 4 cm. Labs were most notable for a creatinine concentration of 5.9 mg/dL, far above his baseline. Retroperitoneal ultrasound demonstrated severe bilateral hydronephrosis. Abdominal computed tomography revealed a 10-cm mass posterior to the bladder and satellite masses in the inguinal canal, in the retroperitoneum, and adjacent to the right hepatic lobe. Biopsy of the umbilical nodule was consistent with malignant peritoneal mesothelioma (MPM). Chemotherapy was initiated, but the patient ultimately elected to pursue further treatments near his family in a different state and was discharged from our care.

The diagnosis

The umbilical lesion with which the patient presented is a so-called Sister Mary Joseph (SMJ) nodule, indicative of underlying abdominal malignancy. Named for Sister Mary Joseph, the first assistant for Dr. William Mayo at the Mayo Clinic in the early 1900s, these umbilical nodules were often noted to be associated with advanced abdominal malignancies. Primary malignant nodules in the umbilical area are extremely rare. SMJ nodules are generally metastatic and are seen in 1% to 3% of all intra-abdominal and pelvic malignancies; however, they are the first and only sign of an underlying neoplasm in up to 30% of cases. The site of origin of malignancy remains unknown in more than 30% of cases as well. SMJ nodules are mainly adenocarcinomas, with half of the cases stemming from gastrointestinal cancers such as those of the stomach, colon, or pancreas.

Approximately 10% of mesotheliomas are found in the abdomen. In the U.S., only about 400 cases are diagnosed annually. An umbilical nodule from metastatic mesothelioma is exceedingly rare, and to our knowledge there are only two case reports of a primary localized malignant mesothelioma in the umbilical area. We were not able to determine whether the umbilical nodule in our patient was the primary source, as further biopsies of his other abdominal tumors were deferred.

Pearls

  • The Sister Mary Joseph nodule is important to recognize as heralding a previously undiagnosed and likely advanced abdominal malignancy.
  • Abdominal mesotheliomas are uncommon tumors, and an umbilical nodule from metastatic mesothelioma is exceedingly rare.

Case 3: Selective serotonin reuptake inhibitors for treatment of vasovagal syncope

The patient

A 48-year-old morbidly obese woman with a history of hypertension, hyperlipidemia and anxiety presented to the emergency department after having four syncopal episodes over the course of one week. Each episode occurred in the setting of anxiety, including on an overcrowded airplane, in a busy restaurant, and during a thunderstorm. The episodes were preceded by hyperventilation and ringing in her ears. The patient also reported urinary incontinence while unconscious, but she reported no visual changes or vertigo. On review of systems, she reported having palpitations for the past 20 years, for which she takes atenolol. She also reported sleeping upright and occasionally waking up suddenly with shortness of breath. She had recently become increasingly stressed about her finances after losing her job.

On admission, her heart rate was 86 beats per minute (bpm) but occasionally fell to 30 to 35 bpm during her hospital stay. Telemetry demonstrated asystolic pauses of two to six seconds during sleep, which were thought to be associated with obstructive sleep apnea. Her electrocardiogram revealed no evidence of atrioventricular nodal or infra-nodal disease. Carotid massage was performed and demonstrated a fall in her heart rate noted on telemetry to 40 bpm, consistent with carotid hypersensitivity-induced bradycardia. She was diagnosed with anxiety-induced vasovagal syncope in the setting of carotid sinus hypersensitivity and was discharged with a prescription for paroxetine and scheduled for outpatient follow-up with cardiology.

The diagnosis

Vasovagal syncope is a common condition with a wide variety of treatment options, all with the goal of reducing syncopal episodes and avoiding physical trauma. Studies have shown that selective serotonin reuptake inhibitors (SSRIs) may reduce recurrence of vasovagal syncope by decreasing central sympathetic nervous system activity. One such study demonstrated that treatment with paroxetine significantly improved vasovagal syncope in patients whose symptoms were refractory to beta-blockers, vagolytics, negative inotropic agents, and mineralocorticoids. In this study, with 25-month follow-up, spontaneous syncope occurred in only 17.6% of patients treated with paroxetine and 52.9% of patients receiving placebo. Another investigation has proposed that SSRIs reduce vasovagal episodes by down-regulating postsynaptic serotonin receptors in the brain stem such that the effect of rapid fluctuations in serotonin levels is dampened, thus reducing the effects of serotonin on heart rate and blood pressure.

Pearls

  • In patients with vasovagal syncope, SSRIs such as paroxetine effectively reduce recurrent syncopal episodes.
  • SSRIs may be especially useful in patients with syncope refractory to traditional medical therapy.

Case 4: Alzheimer's dementia and normal-pressure hydrocephalus

The patient

A 79-year-old man was brought to the emergency department by his family for two falls and mental decline below baseline over a two-week period. Further questioning revealed that he was experiencing gait unsteadiness and had been intermittently incontinent of urine during the past few weeks, with episodes of “wetting himself.” His medical history was otherwise notable for advanced Alzheimer's dementia (AD). On admission, his vital signs were stable, and examination revealed intact motor strength and reflexes, with the exception of mild proximal muscle weakness in the lower extremities. Upper-extremity cerebellar examination was normal, and the patient was able to stand with assistance, but he could not ambulate due to weakness. He was disoriented to time and location, exhibited poor memory recall, and was unable to perform cognitive tasks such as a serial digit subtraction. Laboratory evaluation was unremarkable. Head computed tomography imaging demonstrated ventriculomegaly disproportional to sulcal size, highly suspicious for normal-pressure hydrocephalus (NPH). Lumbar puncture was performed with elevated opening pressure of 38 cm H2O (normal range, 7 to 18 cm H2O), and the patient exhibited equivocal gait improvement following therapeutic fluid removal. No further interventions were pursued.

The diagnosis

NPH is classically described as a clinical triad of dementia, urinary incontinence, and gait abnormalities worsening over an acute to subacute period. It is thought to emanate from impaired absorption of cerebral spinal fluid (CSF) by inflamed or fibrotic arachnoid granulations, of which the precise cause may vary from case to case. Accumulation of CSF is manifested as impaired coordination of muscle activation and deterioration of cortico-subcortical connections. Treatment consists of shunting to remove excess CSF, either by lumbar puncture or more definitively by drainage from the lateral ventricles into the abdomen via permanent catheter placement. NPH is a disease of the aging population; recent retrospective studies have documented that surgically managed NPH patients have an average age in the late 70s at the time of surgery. In a recent histopathological study of nine specimens from NPH patients, eight showed evidence of AD and the ninth showed progressive supranuclear palsy. Two recent studies of NPH treatment outcomes have demonstrated that worse baseline cognitive performance predicted worse postoperative improvement of NPH symptoms. AD patients failed to improve following permanent catheter placement.

Pearls

  • NPH is an uncommon entity that can clinically resemble other forms of cognitive impairment such as Alzheimer's dementia (AD).
  • The diagnosis of NPH in patients with AD may be less significant, as these patients are less likely to benefit from invasive management.

Case 5: Constrictive pericarditis as an occult cause of heart failure

The patient

A 51-year-old man with an unremarkable medical history presented with one week of dyspnea on exertion and two months of progressive lower-body edema extending to the abdomen. Also noted were orthopnea, decreased exercise tolerance, and significant weight gain. Review of systems was notable for flu-like symptoms three weeks prior to the development of edema. Physical examination at admission was significant for obesity, decreased breath sounds at the lung bases bilaterally, no cardiac murmur, and 4+ pitting edema from the feet to the umbilicus with associated scrotal edema. Laboratory results were significant for a brain natriuretic peptide level of 555 pg/mL (reference range, <300 pg/mL), normal thyroid-stimulating hormone level and liver function tests, and absent proteinuria. An echocardiogram demonstrated mildly decreased left ventricular systolic function, plethoric inferior vena cava with respiratory variation, and normal diastolic function. Nuclear stress testing incidentally noted pericardial thickening. Cardiac magnetic resonance imaging (MRI) confirmed a thickened pericardium with delayed gadolinium enhancement, consistent with constrictive pericarditis. Right- and left-heart catheterization confirmed constrictive physiology, demonstrating elevated right- and left-sided filling pressures with equalization of the diastolic pressures without restrictive physiology. Clinical euvolemia was achieved after one week of inpatient diuresis, and the patient underwent successful pericardiectomy one month after hospital discharge.

The diagnosis

Constrictive pericarditis (CP) is a rare precipitant of heart failure but an important etiology to consider because treatment is markedly different than for other causes. The differential diagnosis for heart failure includes myocardial dysfunction, structural heart diseases (including the pericardium), and arrhythmia. CP is generally idiopathic or viral in etiology in close to 50% of cases but can also develop after surgery or can be caused by radiation or connective tissue disease. History in these individuals is generally nonspecific and has much in common with other etiologies of heart failure. Physical examination clues to CP include elevation of jugular venous pulsation with Kussmaul's sign, a positive “pulsus paradoxus,” a pericardial friction rub, and a pericardial knock.

The evaluation of a patient suspected to have constrictive pericarditis includes an electrocardiogram, which may demonstrate low voltage, and chest radiography, which may show pericardial calcifications. Echocardiography may reveal findings including increased pericardial thickness in close to 40% of cases, as well as Doppler findings consistent with CP. Cardiac MRI is best able to assess the extent of pericardial thickness, delineate effusion from pericardial thickening, and determine the presence of myocardial involvement. Before treatment options are considered, cardiac catheterization is indicated to determine if restrictive physiology is present in addition to the constrictive physiology.

Treatment of CP is dependent on duration of symptoms and severity of congestive heart failure (CHF) symptoms. More chronic cases of CP and those associated with more severe symptoms are more likely to require surgical intervention with pericardiectomy. Milder CP cases with less severe CHF symptoms of shorter duration can possibly be managed more conservatively with nonsteroidal anti-inflammatory drugs (NSAIDs) and close follow-up.

Pearls

  • Constrictive pericarditis is a rare cause of congestive heart failure (CHF) but is important to consider because the treatment is markedly different from treatment for more common CHF precipitants.
  • Treatment of constrictive pericarditis depends on the duration and severity of HF symptoms.

Case 6: Acquired factor VIII deficiency: a rare but overlooked bleeding diathesis

The patient

An 81-year-old woman presented with a five-day history of worsening left upper-extremity edema in the absence of trauma. Upon admission, vital signs were stable and physical examination was remarkable for ecchymosis and non-pitting edema of the left mid-forearm extending proximally past the elbow. Upper-extremity venous Doppler ultrasound was notable for a hematoma with no evidence of thrombosis. A bleeding diathesis was suggested by an elevated activated partial thromboplastin time (aPTT) of 58 seconds. Subsequent hematologic testing demonstrated no correction of aPTT with mixing and a factor VIII inhibitor level of 105 Bethesda units, the highest level ever recorded in our hospital. Collectively, these results suggested a diagnosis of acquired factor VIII deficiency. Over the next several days, the left arm edema progressed, with subsequent involvement of the right upper extremity, neck, and back. The patient was aggressively treated with activated factor VII, prednisone, and rituximab. No compartment syndrome developed in the upper extremities, and she remained hemodynamically stable. After treatment, her inhibitor titer decreased to 38 Bethesda units. Further investigation did not reveal a malignancy or autoimmune precipitant. She was ultimately discharged home with arrangements for outpatient hematology follow-up.

The diagnosis

This case describes a bleeding diathesis attributed to an acquired factor VIII inhibitor in an elderly patient. Acquired factor VIII deficiency is a rare bleeding disorder (one to four cases per million per year) caused by antibodies against factor VIII clotting factor. While uncommon, it is associated with significant morbidity and mortality due to severe bleeding and requires immediate hospitalization. The typical age distribution of the disorder is biphasic, with a minor peak at ages 20 to 30 and a major peak at ages 68 to 80, as in the case of our patient. Bleeding usually occurs in the skin, muscles, soft tissues, and mucous membranes; this is in contrast to hereditary factor VIII deficiency, which usually presents with hemarthrosis. Diagnosis of factor VIII inhibitor in a patient with a suspected bleeding diathesis is suggested by a prolonged aPTT and a negative mixing study. Subsequently, factor VIII and factor VIII inhibitor levels can be established and used to guide therapy. Acquired factor VIII inhibitor is usually associated with other medical conditions, including malignancies and autoimmune disorders, and should be investigated at the time of diagnosis. In 50% of cases, no associated medical condition is found.

Pearls

  • Acquired factor VIII inhibitor should be considered in the differential diagnosis of a bleeding diathesis, especially in the elderly population.
  • This disorder can cause significant morbidity and mortality, requires immediate hematology evaluation, and can easily be screened with an initial aPTT.