Cases from the Medical College of Wisconsin

Ocular syphilis, cefepime neurotoxicity, primary empty sella, and more.


Case 1: Ocular syphilis

By Jeremiah Stromich, MD, ACP Resident/Fellow Member; Jamal Saleh, MD; and Pinky Jha, MD, MPH, FACP

The patient

less-thanbgreater-thanFigure 1less-thanslashbgreater-than Funduscopic examination of the right eye demonstrating hazy media due to vitreitis obscuring detailed view of the fundus Blurred optic disc margins are also noted arrow suggestiv
Figure 1. Funduscopic examination of the right eye, demonstrating hazy media due to vitreitis obscuring detailed view of the fundus. Blurred optic disc margins are also noted (arrow), suggestive of optic disc edema. All photos courtesy of the case authors.
less-thanbgreater-thanFigure 2less-thanslashbgreater-than Fluorescein angiography of the left eye with leakage around the optic disc thin arrow and diffuse leakage of the retinal veins examples shown by short arrows suggestive of phlebitis
Figure 2. Fluorescein angiography of the left eye, with leakage around the optic disc (thin arrow) and diffuse leakage of the retinal veins (examples shown by short arrows), suggestive of phlebitis.

A 27-year-old man presented with a three-week history of blurriness in his right eye. Further history revealed sexual encounters with both male and female partners. A dilated funduscopic examination revealed severe vitreitis, panuveitis, and retinal vasculitis in the right eye, and mild vitreitis in the left (Figure 1, Figure 2). Snellen vision of 20/300 on the right and 20/30 on the left was noted. Vital signs on admission were unremarkable.

less-thanbgreater-thanFigure 3less-thanslashbgreater-than Tan macules and patches are seen along the plantar surfaces of the feet bilaterally
Figure 3. Tan macules and patches are seen along the plantar surfaces of the feet bilaterally.

Physical examination further demonstrated multiple genital chancres along the base of his glans penis. Skin examination revealed tan-brown macules and patches along the right palm and the plantar surfaces of his feet bilaterally (Figure 3). Neurological exam was without further deficits other than those noted in his visual fields.

Laboratory testing revealed a positive serum treponemal antibody test (FTA-Abs) and rapid plasma reagin (RPR). Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, leukocytosis, and elevated protein levels. CSF-Venereal Disease Research Laboratory (VDRL) testing was negative. HIV testing was positive with a CD4 count of 255 cells/µL (reference range, 410 to 1,540 cells/µL).

The patient was admitted for treatment with intravenous penicillin-G, which he received for a total of 14 days. With treatment, the patient reported gradual improvement in right-eye vision, and improvement in vitreous haze was seen on ophthalmic exam.

The diagnosis

This patient has secondary syphilis, complicated by neurosyphilis and ocular syphilis. Rates of primary and secondary syphilis have doubled in the United States since the turn of the century. Ocular syphilis is an insidious but potentially sight-threatening illness. Classic findings of syphilis in the eye include posterior uveitis or panuveitis, but additional manifestations may include anterior uveitis, optic neuropathy, retinal vasculitis, and interstitial keratitis. With treatment, a substantial percentage (89%) of patients will have improvement in their vision. The recommended treatment of choice for neurosyphilis and ocular syphilis in patients with and without HIV infection remains intravenous penicillin-G for 14 days.

The CDC has recently issued a clinical advisory regarding the increasing incidence of ocular syphilis, especially in men who have sex with men. As such, all cases of ocular syphilis should be reported to the local health department. Ocular syphilis has many infectious, autoimmune, and rheumatic mimickers. Of note, CSF-VDRL results may be falsely negative in up to 70%. In HIV-infected patients, non-treponemal test results (RPR/VDRL) may be falsely positive in up to 4%. In addition, seroreactivity may be delayed or absent in patients with HIV infection, and serum nontreponemal reagin levels may decline more slowly after treatment. A high index of suspicion for this entity is required for patients presenting with suggestive ocular findings and risk factors.

Pearls

  • Neurosyphilis and ocular syphilis are separate entities with substantial overlap and can occur at any syphilis stage.
  • Ocular syphilis should be considered in patients with visual symptoms, risk factors, and an ophthalmic exam revealing posterior uveitis or panuveitis.

Case 2: Cefepime neurotoxicity

By Sushma Bangalore-Raju, MD, ACP Member; Allison Bock, MD; Pinky Jha, MD, MPH, FACP; and Meenu Singh, MD

The patient

A 65-year-old man with a history of diabetes complicated by prior stroke, chronic foot ulcers, and end-stage renal disease on hemodialysis presented with fever and increased drainage from a right foot ulcer. A CT scan of the foot demonstrated cortical destruction and sclerosis consistent with osteomyelitis. The patient underwent a toe amputation and was prescribed a six-week course of intravenous cefepime and vancomycin.

Three days after starting cefepime, the patient became confused during hemodialysis and had difficulty grasping objects with his right hand. A CT scan of the head was negative for acute intracranial pathology. Laboratory testing was unremarkable. A brain MRI, lumbar puncture, and electroencephalogram (EEG) did not reveal the cause of his encephalopathy. All sedating and psychotropic medications were suspended, but his mental status did not improve.

Careful review of the medical record revealed that for two days following his amputation, he received cefepime at a dose that was not adjusted for his impaired renal function. Cefepime was withdrawn, and the patient's mental status improved. Two days later, the patient was back to his baseline mental status without neurological sequelae. He was switched to ertapenem and vancomycin to complete treatment for osteomyelitis. No further encephalopathy was observed during hospitalization.

The diagnosis

This patient's diagnosis is cefepime neurotoxicity. Cefepime is a parenteral fourth-generation antibiotic used to treat a wide range of infections. Cefepime is primarily (85%) excreted by the kidney, and therefore drug accumulation can occur in patients with impaired renal function. Cefepime neurotoxicity has been reported to cause encephalopathy, myoclonus, seizures, nonconvulsive status epilepticus, and death, and risk is increased in the presence of impaired renal function.

The incidence of cefepime neurotoxicity is unknown, as it may not always be reported or recognized. Most affected patients have some degree of renal impairment or incorrect dosing, but cases have also been reported in patients with normal renal function. When cefepime is prescribed to patients with renal disease, the maintenance dose should be reduced and the patient should be monitored for neurotoxicity. Symptoms usually present between one and 10 days after administration of the medication and resolve within two to seven days after discontinuation of treatment. Cefepime neurotoxicity should be suspected when a patient taking the drug has an acute neurologic change, after exclusion of other possible causes. If not recognized, cefepime-induced encephalopathy can have severe, sometimes fatal outcomes.

Pearls

  • While the incidence of cefepime neurotoxicity is unknown, it has been reported to cause encephalopathy, myoclonus, seizures, nonconvulsive status epilepticus, and death.
  • Cefepime neurotoxicity most commonly occurs in patients with renal impairment, and the dose should be adjusted to prevent neurotoxicity in such patients.

Case 3: Primary empty sella

By Pinky Jha, MD, MPH, FACP, and Geoffrey Lamb, MD, FACP

The patient

A 33-year-old woman with a history of Crohn's disease and hypothyroidism presented with recurrent episodes of weakness, dizziness, and nausea. Over the past 18 months, she reported five episodes of hypoglycemia that occurred after skipping a meal. On arrival, her fingerstick blood glucose reading was 41 mg/dL, which was corrected with intravenous dextrose. Physical exam was unremarkable.

Laboratory findings included anemia, an elevated thyroid-stimulating hormone level of 9.38 IU/mL (reference range, 0.350 to 5.500 IU/mL), a low free T4 level of 0.54 ng/dL (reference range, 0.89 to 1.76 ng/dL), a normal HbA1c level, a normal C-peptide level, and a normal pro-insulin level. Cosyntropin stimulation demonstrated low cortisol levels of 0.1 μg/dL, 0.2 μg/dL, and 0.3 μg/dL at 0, 30, and 60 minutes, respectively (reference range, >18 to 20 μg/dL). An adrenocorticotropic hormone level drawn four hours after the cosyntropin test was less than 1.0 pg/mL, indicating secondary adrenal insufficiency.

less-thanbgreater-thanFigure 4less-thanslashbgreater-than Sagittal image of brain MRI demonstrating a partially empty sella arrow with a thin sliver of pituitary tissue at the floor of the sella turcica
Figure 4. Sagittal image of brain MRI demonstrating a partially empty sella (arrow) with a thin sliver of pituitary tissue at the floor of the sella turcica.

An MRI showed a partially empty sella with a thin sliver of pituitary tissue at the floor of the sella turcica (Figure 4). Additional laboratory testing showed normal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), along with a slightly elevated prolactin level of 24 ng/mL (reference range, 2.80 to 23.30 ng/mL) and a low somatomedin C level of 52 ng/mL (reference range, 57 to 195 ng/mL). The patient was started on hydrocortisone for her adrenal insufficiency and levothyroxine for her hypothyroidism, and her hypoglycemic episodes resolved.

The diagnosis

This patient has evidence of hormone deficiencies in the setting of primary empty sella. Empty sella is defined as herniation of the subarachnoid space into the sella turcica, which is associated with stretching of the pituitary stalk and flattening of the pituitary gland against the sellar floor. The result is a condition in which the sella turcica, which normally houses the pituitary gland, appears “empty” on imaging.

Empty sella has been reported in 6% to 20% of individuals, most commonly in multiparous women with obesity and hypertension. It has both primary and secondary etiologies. Secondary empty sella can result from pituitary adenoma, infection, vasculitis, trauma, or surgery. Primary empty sella is due to a congenitally incomplete formation of the sellar diaphragm, or increased intracranial pressure.

Empty sella is often an asymptomatic incidental finding, although some patients may have associated endocrine dysfunction. The most commonly associated endocrine abnormality is hyperprolactinemia, and the most common hormone deficiency is isolated growth hormone deficiency (as measured by somatomedin C). Other isolated pituitary deficiencies occur in a smaller percentage of cases (hypogonadism in 6% and hypothyroidism or hypoadrenalism in 1%). In the setting of hypoadrenalism, the renin-aldosterone system remains intact, hence mineralocorticoid treatment is not necessary.

Treatment of empty sella is replacement of the deficient hormones. Patients with newly diagnosed empty sella should undergo endocrine, neurological, and ophthalmological evaluations. Timely evaluation is important because adequate treatment of pituitary dysfunction can prevent long-term complications.

Pearls

  • Empty sella refers to the appearance on brain imaging of the herniation of the subarachnoid space into the sella turcica, with stretching of the pituitary stalk and flattening of the pituitary gland against the sellar floor.
  • Empty sella can be found in up to 20% of individuals and can be associated with a variety of symptoms relative to specific hormone deficiencies.

Case 4: Lyme meningitis

By Pinky Jha, MD, MPH, FACP; Sudhi Tyagi, MD; and Kurt Pfeifer, MD, FACP

The patient

A 21-year-old man with no significant medical history presented with left-sided facial weakness, severe headache, and neck stiffness for one day. Symptoms of fever, headache, and neck pain started two months prior while he was working at a summer camp in the Upper Peninsula of Michigan. Laboratory testing obtained during an ED visit at that time, including lumbar puncture with cerebrospinal fluid (CSF) culture and West Nile viral titers, were normal. His symptoms resolved within two to three days with supportive care and did not recur until 10 days before this current admission with return of headache, neck stiffness, and malaise. He was unable to drink water without having it spill out of his mouth, could not smile, and noticed slurring while talking and a changed sensation of taste.

On presentation, his vital signs were within normal limits. Physical examination revealed nuchal rigidity and left-sided facial weakness, decreased left-sided nasolabial crease, and inability to close his left eye or puff out his cheeks. Results of extensive laboratory evaluations, including complete blood count, culture, monospot test, HIV test, rapid plasma reagin (RPR), herpes simplex virus (HSV), and West Nile titers, were normal. An electrocardiogram showed normal sinus rhythm. A CT of the head was negative for acute process.

A Lyme enzyme immunoassay (EIA) was positive. CSF studies showed a white blood cell count of 83/µL (reference range, 0 to 10/µL), a differential with 84% lymphocytes and 2% neutrophils, a protein level of 67 mg/dL (reference range, 15 to 45 mg/dL), a glucose level of 49 mg/dL (reference range, 40 to 70 mg/dL), and negative culture. Lyme western blot testing was positive, with elevated Lyme IgG and IgM. The patient was treated with a two-week course of intravenous ceftriaxone. At a clinic follow-up visit one month later, the patient's neurological symptoms had completely resolved.

The diagnosis

This patient has early neurologic Lyme disease, manifested by facial nerve palsy and lymphocytic meningitis. Lyme disease is caused by infection with the spirochete Borrelia burgdorferi, transmitted by the bite of the nymph and adult female Ixodes scapularis tick. The most commonly affected organs include the skin, joints, heart, and nervous system. The classic hallmark of Lyme infection, erythema migrans, is present in 70% to 80% of patients and typically occurs one to two weeks after exposure. Early neurologic Lyme disease occurs in approximately 10% to 15% of cases and develops within one to two months of the tick bite. Neurologic syndromes include facial nerve palsy, lymphocytic meningitis, or radiculopathy. The diagnosis of Lyme meningitis involves CSF studies consistent with aseptic meningitis, a history with possibility of tick exposure, a physical examination with focal neurological deficits or signs of meningitis, and positive Lyme testing.

The standard of care for Lyme disease testing is two-tiered serology that includes EIA followed by western blot testing for antibodies (IgG and IgM) against more specific Borrelia surface proteins. Western blot testing alone is recommended when symptoms have been present for longer than four weeks. Serology is considered positive if both tiers are positive (e.g., the EIA is positive or equivocal followed by positive IgM or IgG bands). Serologic testing is more sensitive for patients with neurologic or cardiac manifestations at presentation (80%). However, serology is not useful to monitor response to treatment. Central nervous system involvement can be suggested by testing CSF for intrathecal borrelial antibody production, borrelial DNA, or both, but these tests have variable or poor sensitivity and therefore are not recommended for diagnosis. While most cases of Lyme meningitis are treated with intravenous ceftriaxone, there are data to suggest that ambulatory patients can be effectively treated with oral doxycycline. In either case, a 14-day course of therapy is recommended.

Pearls

  • Early neurologic Lyme disease develops in 10% to 15% of patients with Lyme disease and can manifest as facial nerve palsy, lymphocytic meningitis, or radiculopathy.
  • The diagnosis of Lyme meningitis involves CSF studies consistent with aseptic meningitis, a history with possibility of tick exposure, a physical examination with focal neurological deficits or signs of meningitis, and positive Lyme testing.

Case 5: Daptomycin-induced eosinophilic pneumonia

By Pinky Jha, MD, MPH, FACP; Alexander Katz, MD; and Janak Wagle, MD, ACP Member

The patient

A 58-year-old woman who was recently hospitalized for culture-negative osteodiscitis of the cervical spine presented with worsening shortness of breath for two days. She had been started on a six-week course of ertapenem and daptomycin two weeks prior. Upon admission, she was afebrile, tachypneic (respiratory rate of 24 breaths/min), hypertensive (blood pressure 172/80 mm Hg), and hypoxic (oxygen saturation of 87% on room air). Oxygen saturation improved to 92% with 4 liters of oxygen. Physical examination was notable for marked respiratory distress and diffuse crackles.

less-thanbgreater-thanFigure 5less-thanslashbgreater-than Anteroposterior chest radiograph demonstrating bilateral patchy opacification and vascular congestion
Figure 5. Anteroposterior chest radiograph, demonstrating bilateral patchy opacification and vascular congestion.

Laboratory results were significant for an elevated creatine kinase level of 1,865 U/L (reference range, 24 to 189 U/L) and a white blood cell count of 13,100 cells/µL (reference range, 4,000 to 11,000 cells/µL) with 10% eosinophils (reference range, 0% to 6%). New bilateral patchy opacities were seen on chest X-ray (Figure 5), and CT showed moderate adenopathy and multifocal consolidation in both lungs surrounded by ground-glass opacities, along with new bilateral pleural effusions.

Daptomycin was suspected to be responsible for her clinical syndrome, and she was switched to linezolid for ongoing treatment of her osteodiscitis. Vasculitis and infection were ruled out after extensive workup. Bronchoscopy with bronchoalveolar lavage (BAL) was significant for eosinophil count of 29% (reference range, <5%). After discontinuation of daptomycin treatment, the patient's respiratory symptoms resolved, a repeat chest X-ray one week later showed complete clearing of the bilateral interstitial thickening, and repeat labs demonstrated normalization of peripheral eosinophil count (5%) and creatine kinase level (170 U/L).

The diagnosis

This patient's diagnosis is daptomycin-induced eosinophilic pneumonia. Eosinophilic pneumonia in general has a broad differential, including medications, namely antibiotics and NSAIDs; hypersensitivity syndromes, such as allergic pulmonary aspergillosis; vasculitis, including Churg-Strauss syndrome; and infection. Eosinophilic pneumonia usually presents with fever, hypoxia, new lung infiltrates and either peripheral eosinophilia or pulmonary eosinophilia via BAL or biopsy. Diagnosis is based on greater than 25% eosinophils in lung tissue or BAL fluid in the setting of pulmonary infiltrates. Daptomycin is a cyclic lipopeptide commonly prescribed for gram-positive infections, and daptomycin-induced eosinophilic pneumonia is rare. A recent FDA review identified a total of 58 cases of daptomycin-induced acute eosinophilic pneumonia.

The following can be used diagnose drug-induced acute eosinophilic pneumonia (AEP): 1) presence of AEP, as defined by the above-mentioned criteria; 2) presence of a causative drug with appropriate temporal relationship; 3) no other cause of AEP such as a fungal or parasitic infection; 4) clinical improvement after withdrawal of the drug; and 5) recurrence of AEP with rechallenge of the drug. Medication rechallenge is not recommended in clinical practice. When the diagnosis remains unclear, bronchoscopy with or without lung biopsy should be considered.

The exact pathophysiology of this disease is unclear, but it is hypothesized that the process starts with daptomycin binding to pulmonary surfactant, rendering it inactive but sequestering it in the lung. This complex acts as an antigen for alveolar macrophages to present to TH-2 helper T cells that release interleukin-5, leading to eosinophilic release into the lung parenchyma, which yields inflammation and damage. Treatment includes withdrawal of the offending agent, and steroids can be considered to further augment recovery.

Pearls

  • Early recognition of drug-induced eosinophilic pneumonia and withdrawal of the offending agent are critical to management.
  • Daptomycin is one of many causes of drug-induced eosinophilic pneumonia; diagnosis is based on history of daptomycin use, hypoxia, diffuse pulmonary infiltrates, and eosinophilia.

Case 6: Scedosporiosis of the sphenoid sinus

By Geetanjali Dang, MD; Pinky Jha, MD, MPH, FACP; Kory Koerner, MD, FACP; and Mona Lalehzari, MD

The patient

A 76-year-old man presented with a 10-day history of headache and acute-onset, bilateral vision loss. His family reported that they had been vacationing in Mexico for the past three months, during which time the patient began reporting headaches and intermittent jaw pain. Vital signs on presentation were temperature, 98.4 °F; blood pressure, 186/80 mm Hg; heart rate, 64 beats/min; respiratory rate, 16 breaths/min; and oxygen saturation of 98% on room air. Physical examination confirmed complete bilateral loss of vision, and pupils demonstrated sluggish reaction to light bilaterally. The remainder of the physical examination was unremarkable.

Initial lab tests, including complete blood count and comprehensive metabolic panel, were significant for a sodium level of 119 mEq/L, a leukocyte count of 10,500 cells/µL, a C-reactive protein level of 5.2 mg/dL (reference range, 0 to 0.50 mg/dL), and an erythrocyte sedimentation rate of 32 mm/h (reference range, 0 to 19 mm/h). Blood cultures drawn at admission showed no growth after five days of incubation.

less-thanbgreater-thanFigure 6less-thanslashbgreater-than MRI of the brain showing findings compatible with a left sphenoid sinus mucocele arrow with expansion of the left sphenoid sinus and associated thinning of the sphenoid sinus walls
Figure 6. MRI of the brain showing findings compatible with a left sphenoid sinus mucocele (arrow), with expansion of the left sphenoid sinus and associated thinning of the sphenoid sinus walls and anterior clivus.

A CT of the head, carotid ultrasound, and brain MRI were unremarkable. An MRI of the orbits showed abnormal enhancement within the anterior cranial fossa and bilateral orbital apices concerning for pachymeningitis with a left sphenoid sinus mucocele (Figure 6). Empiric antibacterial (ceftriaxone) and antifungal (amphotericin B) coverage was initiated, and operative mucocele drainage was performed. Lumbar puncture was performed with an opening pressure of 15 cm H2O. Cerebrospinal fluid (CSF) analysis showed total white blood cell count of 14/µL (63% neutrophils, 21% lymphocytes), two red blood cells, a protein level of 67 mg/dL, and a glucose level of 88 mg/dL. Cryptococcal antigen, aerobic, anaerobic, and fungal cultures from CSF remained negative.

Despite aggressive treatment, the patient continued to deteriorate with respiratory distress, worsening headaches, and no return of his vision. Tissue cultures identified aseptate hyphae and grew Scedosporium apiospermum. Antimicrobial coverage was changed to voriconazole, micafungin, and terbinafine to cover the full spectrum of Scedosporium. The patient's hospital course was further complicated by a cerebrovascular accident secondary to cavernous sinus thrombosis and septic emboli from fungal sinusitis. Ultimately, the decision was made to pursue comfort care measures. He was discharged home with oral antifungal medications and eventually died of his illness.

The diagnosis

This patient has invasive sphenoid sinus scedosporiosis. Scedosporium, a mold that resembles Aspergillus, is a growing cause of invasive infections in the immunocompromised population, although localized infections have also been described in immunocompetent patients. Two members of this genus, Scedosporium apiospermum and Scedosporium prolificans, are considered major human pathogens. Human infection often results from inhalation of spores from the environment into the lungs or paranasal sinuses or through direct inoculation via skin puncture. Clinical manifestations of such infections are dependent on localization and include respiratory distress, keratitis, neurologic symptoms, skin lesions, and, very rarely, changes in visual acuity.

One study estimates 12-week mortality rates of 70% and 100% for S. apiospermum and S. prolificans infections, respectively. Diagnosis requires both a histopathologic specimen revealing tissue invasion and a culture result positive for mold. Given the high mortality rate, early diagnosis and treatment with antifungals of appropriate spectrum are necessary, as Scedosporium species are resistant to most commonly utilized empiric antifungal agents. For the empiric treatment of S. apiospermum infections, voriconazole monotherapy is suggested. Because S. prolificans is resistant to most of the antifungal agents available, voriconazole plus terbinafine, with or without an echinocandin, is suggested empiric therapy. Surgical debridement should be performed when feasible (e.g., when the infection is localized), as it has been associated with improved outcomes.

Pearls

  • Scedosporiosis is an emerging cause of invasive fungal infections in immunocompromised and immunocompetent hosts.
  • Antifungal therapy should be initiated as soon as possible for Scedosporium infections and should be tailored according to in vitro susceptibility results.