Case 1: Wernicke's encephalopathy
By Keniesha Thompson, MD, ACP Member, and Ritesh Rampure, MD, ACP Member
A 55-year-old man with a history of alcohol use disorder was admitted for evaluation of gait imbalance. The patient reported unsteadiness on his feet that had become progressively worse in the month prior to presentation, with frequent falls. Symptoms were persistent even during periods of sobriety. On physical examination, he was oriented to time, place, and person. He revealed no oculomotor abnormality, and motor strength was normal in all extremities. The sensory examination was significant for loss of pain and temperature sensation in his extremities in a stocking-glove distribution. His joint position and vibration sensation were preserved, and Romberg test was negative. Dysmetria was noted on bilateral heel-to-knee and finger-to-nose test. The patient's stance was unsteady, and his gait was observed to be severely ataxic, requiring a two-person assist. Labs demonstrated macrocytic anemia with a hemoglobin level of 12.0 g/dL (reference range, 12.4 to 17.5 g/dL) and mean corpuscular volume of 98.9 fL (reference range, 81 to 97 fL). Vitamin B12 level was 160 pg/mL (reference range, 213 to 816 pg/mL). MRI and angiography of the head and neck were normal.
Because of the patient's history of alcohol use disorder, oral thiamine supplementation at a dose of 100 mg daily was initiated on admission, along with parenteral vitamin B12 repletion based on his megaloblastic anemia and low B12 level. After five days without clinical improvement, a therapeutic trial of high-dose IV thiamine (1,500 mg IV daily) was initiated. The following day, the patient's gait was demonstrably improved; three days later he was able to ambulate independently. The patient was discharged home and was subsequently lost to follow-up.
The patient's diagnosis is Wernicke's encephalopathy, a neuropsychiatric condition due to acute thiamine deficiency. Wernicke's encephalopathy is among a spectrum of thiamine deficiency disorders that includes such subacute and chronic thiamine deficiencies as wet beriberi (affecting the cardiovascular system) and dry beriberi (affecting the peripheral nervous system). Wernicke's encephalopathy is classically heralded by the triad of confusion, ataxia, and oculomotor dysfunction. It is important to note that 60% of patients with alcohol use disorder and Wernicke's encephalopathy do not manifest this triad, and 25% of patients do not have encephalopathy. Ataxia in Wernicke's encephalopathy is believed due to a combination of polyneuropathy, cerebellar, and vestibular dysfunction. Although laboratory studies and neuroimaging studies can be helpful, Wernicke's encephalopathy is primarily a clinical diagnosis. In addition, a normal blood thiamine level does not rule out Wernicke's encephalopathy, and MRI brain findings of symmetric diencephalic and periventricular lesions lack diagnostic sensitivity.
Although this patient also had biochemical evidence of vitamin B12 deficiency, the lack of proprioceptive loss on physical exam made this a less likely cause of his ataxia. Symptoms persisted on oral thiamine but responded dramatically to IV thiamine, presumably due to erratic gastrointestinal absorption of thiamine, which is often impaired in patients with alcohol use disorder and in malnourished patients. A therapeutic trial of IV thiamine is the most effective way to confirm Wernicke's encephalopathy. Response to treatment with high-dose IV thiamine (500 mg every eight hours) is typically seen within days. Lack of clinical improvement within three days of treatment should prompt reconsideration of the diagnosis of Wernicke's encephalopathy.
- Most patients with Wernicke's encephalopathy and alcohol use disorder present without the classic triad of confusion, ataxia, and oculomotor dysfunction.
- Parenteral, high-dose thiamine is the appropriate treatment for Wernicke's encephalopathy, and response to treatment often confirms the diagnosis.
Case 2: Idiopathic splenic infarction
By Daniele Valentini, MD, ACP Resident/Fellow Member; Arfaa Ali, MD, ACP Member; and Sarah Chan, ACP Medical Student Member
A 28-year-old woman with a history of discoid lupus presented with a one-day history of left flank pain radiating to the back, abdominal “tightness,” and emesis. She reported no abdominal trauma or recent illness. Physical examination revealed unremarkable vital signs but was notable for tenderness to palpation in the left upper quadrant without organomegaly. Labs, including a complete metabolic profile, complete blood count, and coagulation testing, were unremarkable. CT imaging of the abdomen and pelvis revealed a segmental hypo-enhancement in the inferior pole of the spleen measuring 2.7 cm. Hypercoagulability evaluation, including lupus anticoagulant testing, was negative. She was treated with supportive care and discharged after three days. Five days later, she returned with worsening left flank and left lower quadrant abdominal pain associated with nausea, vomiting, and diarrhea. A repeat CT of the abdomen and pelvis with contrast revealed an enlarging splenic infarction of 3.2 cm in diameter (Figure 1). CT angiogram was negative for vasculitis or ischemia, and transesophageal echocardiogram was unremarkable. Testing for viral hepatitis, HIV, mononucleosis, and hemoglobin electrophoresis for sickle cell disease was negative. Her pain improved with supportive care, and she was discharged with plans for frequent surveillance imaging.
The patient's diagnosis is idiopathic splenic infarction. Splenic infarction occurs when the splenic artery or its branches become occluded by an embolus or thrombus. Although it is rare, it most commonly has a cardiogenic cause (over 60% in case series), including atrial fibrillation, infective endocarditis, cardiac procedures, and valvular disease. Rarer causes include autoimmune diseases such as antiphospholipid syndrome, malignancies (including pancreatic cancer), hematologic disease such as myeloproliferative disorder, and viral infections such as infectious mononucleosis and HIV.
Idiopathic infarction is a diagnosis of exclusion. Presenting symptoms include left flank or left upper quadrant tenderness, fever, leukocytosis, nausea, vomiting, and splenomegaly. If splenic infarction is suspected, patients should undergo early imaging; there are no practice guidelines for workup of the underlying cause, but many patients undergo echocardiography and evaluation for thrombophilia.
Initial management for splenic infarction includes hydration, analgesia, and frequent monitoring. Symptoms should resolve in seven to 14 days. Further treatment depends on whether an underlying cause is found; idiopathic splenic infarction is managed conservatively. The role of systemic anticoagulation in idiopathic splenic infarction has not been formally addressed, and therefore it is not a routine treatment. Splenectomy is rarely performed (<5% of cases) and can be considered on a case-by-case basis in patients with infected necrosis or rupture. There are no guidelines for follow-up of idiopathic splenic infarction, and sequential imaging can be recommended based on infarct size and other patient considerations.
- Splenic infarction can be difficult to diagnose given that it is uncommon and has nonspecific presenting symptoms; a CT of the abdomen with contrast is the diagnostic modality of choice.
- No evidence-driven guidelines exist for the diagnosis, treatment, or surveillance of splenic infarction; empiric anticoagulation for idiopathic cases is not recommended.
Case 3: Acyclovir-induced nephrotoxicity
By Ashley Chapel, MD, MPH, ACP Resident/Fellow Member, and Hiral Choksi, MD, FACP
A 70-year-old man was transferred from an outside hospital with ongoing fevers and altered mental status. He had initially presented eight days prior with two days of fever and altered mental status. He was empirically treated for bacterial meningitis and herpes simplex virus (HSV) encephalitis with parenteral antimicrobials (including acyclovir) for eight days and was transferred to our facility due to lack of improvement. Upon arrival, he was afebrile, with a blood pressure of 154/84 mm Hg, a pulse of 96 beats/min, and a normal respiratory rate and oxygen saturation. The physical examination was most significant for an alteration in mental status, notably confusion to time and place but oriented to person. There was no nuchal rigidity or focal neurologic deficit. Labs on arrival were notable for a normal serum creatinine level (0.5 mg/dL). Lumbar puncture at our facility demonstrated pleocytosis, an elevated protein level, and positive testing for HSV.
The patient was started on acyclovir, 10 mg/kg every eight hours, for HSV encephalitis. After 48 hours of treatment, his serum creatinine level rapidly increased to a peak of 4.7 mg/dL. The patient became increasingly somnolent, arousable only to sternal rub. Urinalysis was positive for blood, protein, and granular casts. Acyclovir was discontinued, and IV hydration with intermittent doses of furosemide was given to maintain adequate urine output. Serum creatinine level trended down to 3.0 mg/dL approximately 24 hours after acyclovir cessation, and improvement in mental status was noted. No additional antivirals were given, as the patient was determined to have completed an adequate course of therapy. After one week, his creatinine level had returned to baseline (0.7 mg/dL).
This case demonstrates acyclovir-induced nephrotoxicity in a patient being treated for HSV encephalitis. The mechanism of renal toxicity is a crystal-induced tubular injury. More than half of acyclovir is excreted unchanged in the kidneys and is incompletely soluble in urine. When nephrotoxicity occurs, acyclovir precipitates into intratubular crystals, especially in the distal convoluted tubules, and leads to obstruction and tubular damage. This can be exacerbated in low-flow states such as those encountered with volume depletion and chronic kidney disease. In patients receiving high-dose IV acyclovir, the occurrence of nephrotoxicity is estimated at 12% to 48%. High doses of IV acyclovir (greater than 1,500 mg/m2) are associated with increased luminal concentrations. To mitigate the risk of acyclovir-induced tubular injury, IV hydration is recommended when starting IV acyclovir, and the rate of acyclovir infusions can be slowed over one to two hours to prevent rapid tubular accumulation.
Acyclovir-induced renal toxicity is indicated by rapidly rising serum creatinine levels or abnormal urine sediment (hematuria, proteinuria, and birefringent needle-shaped crystals) within 24 to 48 hours of treatment initiation. In patients with suspected nephrotoxicity, acyclovir should be immediately discontinued. Treatment of the crystal-induced nephrotoxicity is aimed at preventing crystal precipitation and further renal impairment. This is best achieved by maintaining a goal urine output of 100 to 150 cc/h. Often, a loop diuretic is given with IV fluids to maintain high urinary flow through the kidneys if the goal urine output is not met. However, caution must be taken to avoid over-diuresis, which can lead to hypovolemia and further renal damage.
No guidelines address the optimal time to discontinue IV acyclovir due to nephrotoxicity or to restart treatment after acute kidney injury. One strategy is to resume acyclovir when creatinine levels begin to improve, but with an initial dose limited to less than 250 mg/m2. If this initial dose is tolerated, the dose can then be cautiously increased as necessary. There is little evidence to support changing to another antiviral medication, and such decisions should be made based on individual risks and benefits.
- Acyclovir can cause a crystal-induced nephrotoxicity that results in a rapid and marked rise in creatinine levels following treatment initiation.
- Treatment of acyclovir-induced nephrotoxicity is supportive and focuses on acyclovir cessation and maintenance of high urine output (100 to 150 cc/h) to further prevent crystal precipitation.
Case 4: Disseminated nocardiosis in an immunocompetent patient
By Ritesh Rampure, MD, ACP Member; Swapna Kolli, MD, ACP Member; and Rory Deol, MD
A 61-year-old man with a history of an alcohol use disorder presented with a three-month history of weakness, headache, gait difficulties, episodes of confusion, and “blacking out.” The patient did not report fever, chills, chest pain, or cough. Vital signs were unremarkable. Physical examination revealed mild weakness of the right upper and lower extremities, left inferior quadrantanopia, and a hemiplegic gait. He was oriented to place, person, and time. Labs were remarkable for mild hyponatremia (sodium level, 130 mEq/L; reference range, 135 to 145 mEq/L) and thrombocytosis (platelet count, 455,000 cells/µL; reference range, 150,000-400,000 cells/µL). An MRI of the brain showed two 3-cm masses, one in the right parietal and the other in the occipital lobe, both associated with vasogenic edema and midline shift (Figure 2). Thoracic CT imaging revealed a large, spiculated right infra-hilar necrotic lung mass that was concerning for primary lung cancer. He was started on dexamethasone and levetiracetam.
Endobronchial ultrasound with biopsy of the lung lesion demonstrated no evidence of malignancy but did show acid-fast filamentous organisms (Figure 3). Cultures grew Nocardia wallacei. Bronchial cultures were negative for mycobacterium. HIV testing was negative. The patient underwent right occipital craniotomy for biopsy of the brain lesion, which was also consistent with Nocardia (Figure 4). Brain fungal cultures were negative. Empiric treatment with IV trimethoprim/sulfamethoxazole (TMP-SMX) and imipenem was initiated and narrowed to IV ceftriaxone and oral TMP-SMX when the sensitivities were available. The plan was to continue therapy for one year.
The patient was monitored with surveillance imaging studies. At three months, chest CT showed a decrease in the pulmonary consolidation but brain CT demonstrated an increase in his cerebral lesions. He subsequently underwent right craniotomy and resection of the cerebral abscess. The patient was discharged in stable condition but died a few weeks later.
The diagnosis in this case is disseminated pulmonary nocardiosis, occurring in an immunocompetent patient. Nocardiosis is an uncommon gram-positive bacterial infection caused by aerobic actinomycetes of the genus Nocardia, which are ubiquitous soil organisms. Inhalation is the most common mode of infection, although ingestion of contaminated food and cutaneous infection via trauma or surgery are also possible. Nocardia can disseminate from a pulmonary or cutaneous infection to any organ. The spread is hematogenous, but Nocardia rarely grows in blood cultures. Clinical presentation is nonspecific and dependent on organ involvement. Two-thirds of infections occur in immunocompromised patients, including those with malignancy, long-term steroid use, solid organ transplantation, and HIV infection. Only a small number of cases of disseminated disease have been identified in immunocompetent patients. Conditions such as chronic lung disease, diabetes mellitus, and alcoholism increase the risk of Nocardia infection in immunocompetent populations.
The diagnosis is suspected based on identification of filamentous, branching, acid-fast gram-positive rods in a clinical specimen, either in the form of pus or tissue biopsy. It is confirmed with cultures that take one to three weeks. Due to the rarity and diverse clinical presentation of this infection, diagnosis is often delayed. Studies have estimated an average of six weeks to a year from onset of symptoms to diagnosis.
Treatment is not evidence-based and depends on the extent of disease and immune state. Localized disease in an immunocompetent patient, excluding the central nervous system, can be treated with monotherapy for six months. The remainder of cases require at least two-drug therapy for a minimum of one year. TMP-SMX is the mainstay of any treatment regimen, but choice of a second agent is based on susceptibility to sulfonamides, third-generation cephalosporins, aminoglycosides, macrolides, and carbapenems. Typically, response to appropriate therapy is clinically identifiable at two weeks. Inadequate response could be due to drug resistance, inadequate dosing, poor tissue penetration, or presence of an abscess requiring surgical drainage. Monitoring is recommended, with surveillance imaging of the involved organ at one, three, six, and 12 months. Patients also need to be monitored for drug toxicity. Secondary prophylaxis with once-daily double-strength TMP-SMX is recommended in those who successfully complete treatment but continue to be immunosuppressed. Mortality rates range widely (7% to 44%, with immunosuppressed patients in the higher end of the range) and are higher (about 50%) in those with brain abscess.
- Nocardia typically originate in lungs or skin and can disseminate to any organ, particularly the brain, often mimicking metastatic cancer and making diagnosis difficult.
- Nocardiosis can progress despite appropriate therapy and has been associated with high mortality rates, even in immunocompetent patients.