Case Reports

THE CASE

A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.

Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.

A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.

Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.

THE DIAGNOSIS

Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.

We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.

DISCUSSION

Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.

Continue to: There are many reports in the literature...

There are many reports in the literature of adverse reactions to excipients.^1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin² and a rash that developed from a coloring agent in oral iron.³ Other reports have noted dyes in foods and even toothpaste as triggers.^4,5

Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.⁶ Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.⁶

Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.⁷ Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.⁷

We prescribed the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects.

Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.⁷ Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.⁷

Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.^8,9

Continue to: Yellow dye was to blame

Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.^1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.

Our patient

The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.

THE TAKEAWAY

It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.

CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]

THE CASE

A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.

Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.

A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.

Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.

THE DIAGNOSIS

Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.

We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.

DISCUSSION

Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.

Continue to: There are many reports in the literature...

There are many reports in the literature of adverse reactions to excipients.^1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin² and a rash that developed from a coloring agent in oral iron.³ Other reports have noted dyes in foods and even toothpaste as triggers.^4,5

Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.⁶ Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.⁶

Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.⁷ Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.⁷

We prescribed the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects.

Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.⁷ Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.⁷

Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.^8,9

Continue to: Yellow dye was to blame

Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.^1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.

Our patient

The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.

THE TAKEAWAY

It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.

CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]

THE CASE

A 24-year-old man with no past medical history was referred to a nephrologist for a 5-month history of leg swelling and weight gain. His only medication was furosemide 40 mg/d, prescribed by his primary care physician. His physical examination was unremarkable except for lower extremity and scrotal edema.

Laboratory values included a creatinine of 0.8 mg/dL (reference range, 0.6 to 1.2 mg/dL); hemoglobin concentration, 14.4 g/dL (reference range, 14 to 18 g/dL); albumin, 1.9 g/dL (reference range, 3.5 to 5.5 g/dL); and glucose, 80 mg/dL (reference range, 74 to 106 mg/dL). Electrolyte levels were normal. Urinalysis revealed 3+ blood and 4+ protein on dipstick, as well as the presence of granular and lipid casts on microscopic exam. A 24-hour urine collection contained 10.5 g of protein. Antinuclear antibody titers, complement levels, hepatitis serologies, and antineutrophil cytoplasmic antibody titers were all normal.

A renal biopsy revealed idiopathic focal segmental glomerulosclerosis. The patient was started on oral prednisone 40 mg twice daily.

Two days later, he developed a diffuse pruritic maculopapular rash. He stopped taking the prednisone, and the rash resolved over the next 3 to 5 days. He was then instructed to restart the prednisone for his nephrotic syndrome. When he developed a new but similar rash, the prednisone was discontinued. The rash again resolved.

THE DIAGNOSIS

Since the patient had already been taking furosemide for 6 weeks without an adverse reaction, it was presumed that the prednisone tablet was causing his rash. It would be unusual for prednisone itself to cause a drug eruption, so an additive or coloring agent in the tablet was thought to be responsible for the reaction.

We noted that the patient had been taking a 20-mg orange tablet of prednisone. So we opted to “tweak” the prescription and prescribe the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects and completed a full 9 months of prednisone therapy without any recurrence of skin lesions. His glomerular disease went into remission.

DISCUSSION

Excipients are inert substances that are added to a food or drug to provide the desired consistency, appearance, or form. They are also used as a preservative for substance stabilization.

Continue to: There are many reports in the literature...

There are many reports in the literature of adverse reactions to excipients.^1-3 These include skin rashes induced by the coloring agent in the capsule shell of rifampicin² and a rash that developed from a coloring agent in oral iron.³ Other reports have noted dyes in foods and even toothpaste as triggers.^4,5

Hypersensitivity. Although a specific reaction to prednisone was considered unlikely in this case, type IV delayed hypersensitivity reactions to corticosteroids have been reported. The most common type of corticosteroid-related allergy is contact dermatitis associated with topical corticosteroid use.⁶ Many cases of delayed maculopapular reactions are thought to be T-cell–mediated type IV reactions.⁶

Type I immediate hypersensitivity reactions to corticosteroids are also well documented. In a literature review of 120 immediate hypersensitivity reactions to corticosteroids, anaphylactic symptoms were more commonly reported than urticaria or angioedema.⁷ Intravenous exposure was most frequently associated with reactions, followed by the intra-articular and oral routes of administration.⁷

We prescribed the same daily dose but in the form of 10-mg white tablets. The patient tolerated this new regimen without any adverse effects.

Causative agents. The same literature review identified methylprednisolone as the most common steroid to cause a reaction; dexamethasone and prednisone were the least frequently associated with reactions.⁷ Pharmacologically inactive ingredients were implicated in 28% of the corticosteroid hypersensitivity reactions.⁷

Additives suspected to be triggers include succinate and phosphate esters, carboxymethylcellulose, polyethylene glycol, and lactose. Interestingly, there have been reports of acute allergic reactions to methylprednisolone sodium succinate 40 mg/mL intravenous preparation in children with milk allergy, due to lactose contaminated with milk protein.^8,9

Continue to: Yellow dye was to blame

Yellow dye was to blame. In our case, the 20-mg tablet that the patient had been taking contained the coloring agent FD&C yellow #6, an azo dye also known as sunset yellow or E-110 in Europe. Several reports have described adverse reactions to this coloring agent.^1,3 There were other additives in the 20-mg tablet, but a comparison revealed that the 10-mg tablet contained identical substances—but no dye. Thus, it was most likely that the coloring agent was the cause of the patient’s probable type IV exanthematous drug reaction.

Our patient

The patient was instructed to avoid all medications and food containing FD&C yellow #6. No formal allergy testing or re-challenge was performed, since the patient did well under the care of his nephrologist.

THE TAKEAWAY

It’s important to recognize that adverse drug reactions can occur from any medication—not only from the drug itself, but also from excipients contained within. This case reminds us that when a patient complains of an adverse effect to a medication, dyes and inactive ingredients need to be considered as possible inciting agents.

CORRESPONDENCE
Neil E. Soifer, MD, Lakeside Nephrology, 2277 West Howard, Chicago, IL 60645; [email protected]

Hemiballismus is an acquired hyperkinetic movement disorder characterized by unilateral, involuntary, often large-amplitude limb movements. Ballistic movements are now considered to be on the choreiform spectrum.1 Movements usually involve both the arm and leg, and in half of cases, facial movements such as tongue clucking and grimacing are seen.^2,3 Presentations of hemiballismus vary in severity from intermittent to nearly continuous movements, which, in some cases, may lead to exhaustion, injury, or disability. Some patients are unable to ambulate or feed themselves with the affected limb.

Background

The 2 most common causes of hemichorea-hemiballismus are stroke and hyperglycemia, with an incidence of 4% and unknown incidence, respectively.^1,3,4 Other causes include HIV, traumatic brain injury, encephalitis, vasculitis, mass effect, multiple sclerosis, and adverse drug reactions. ^4-7 Acute or subacute hemiballismus is classically attributed to a lesion in subthalamic nucleus (STN), but this is true only in a minority of cases. Hemiballismus can be caused by any abnormality in various subnuclei of the basal ganglia, including the classic location in the STN, striatum, and globus pallidus.⁴ Evidence shows the lesions typically involve a functional network connected to the posterolateral putamen.⁸

Although not commonly recognized, hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is the second most common cause of hemichoreahemiballismus. ³ Over the past 90 years, numerous case reports have described patients with DM with acute and subacute onset of hemiballistic and hemichoreiform movements while in a hyperglycemic state or after its resolution. Reported cases have been limited to small numbers of patients with only a few larger-scale reviews of more than 20 patients.^7,9 Most reported cases involve geriatric patients and more commonly, females of Eastern Asian descent with an average age of onset of 71 years.^4,10 Patients typically present with glucose levels from 500 to 1,000 mg/dL and hemoglobin A1c (HbA1c) levels almost double the normal values. Interestingly, neuroimaging findings in these patients have consistently shown hyperintense signal in the contralateral basal ganglia on T1-weighted magnetic resonance images (MRIs). Noncontrast computed tomography (CT) shows well-defined unilateral increased density in the contralateral basal ganglia without mass effect.^1,9,11

This report aims to illustrate and enhance the understanding of hemiballismus associated with hyperglycemia. One patient presented to the US Department of Veterans Affairs (VA) Bay Pines VA Healthcare System (BPVAHCS) in Florida, which motivated us to search for other similar cases. We reviewed the charts of 2 other patients who presented to BPVAHCS over the past 10 years. The first case presented with severe hyperglycemia and abnormal movements that were not clearly diagnosed as hemiballismus. MRI findings were characteristic and assisted in making the diagnosis. The second case was misdiagnosed as hemiballismus secondary to ischemic stroke. The third case was initially diagnosed as conversion disorder until movements worsened and the correct diagnosis of hyperglycemia-induced hemichorea hemiballismus was confirmed by the pathognomonic neuroimaging findings.

Case Presentations

Case 1

A 65-year-old male with a history of uncontrolled T2DM presented with repetitive twitching and kicking movements that involved his left upper and lower extremities for 3 weeks. The patient reported that he did not take his medications or follow the recommended diabetes diet. His HbA1c on admission was 12.2% with a serum glucose of 254 mg/dL. The MRI showed a hyperintense T1 signal within the right basal ganglia including the right caudate with sparing of the internal capsule (Figure 1). There was no associated mass effect or restricted diffusion. It was compatible with a diagnosis of hyperglycemia- induced hemichorea-hemiballismus. The patient was advised to resume taking glipizide 10 mg daily, metformin 1,000 mg by mouth twice daily, and to begin 10 units of 70/30 insulin aspart 15 minutes before meals twice daily, and to follow a low carbohydrate diet, with reduce dietary intake of sugar. At his 1-month follow-up visit, the patient reported an improvement in his involuntary movements. At the 5-month follow-up, the patient’s HbA1c level was 10.4% and his hyperkinetic movements had completely resolved.

Case 2

of T2DM, hypertension, and hyperlipidemia was admitted due to increased jerky movements in the left upper extremity. On admission, his vital signs were within normal limits and his physical examination demonstrated choreoathetoid movements with ballistic components of his left upper extremity. His laboratory results showed a glucose level of 528 mg/dL with a HbA1c of 16.3%. An initial CT obtained in the emergency department (ED) demonstrated a well-defined hyperdensity in the striatal (caudate and lentiform nucleus) region (Figure 2). There was no associated edema/mass effect that would be typical for an intracranial hemorrhage.

An MRI obtained 1 week later showed hyperintense TI signal corresponding to the basal ganglia (Figure 3). In addition, there was a questionable lacunar infarct in the right internal capsule. Due to lack of awareness regarding hyperglycemic associated basal ganglia changes, the patient’s movement disorder was presumed to be ischemic in etiology. The patient was prescribed oral amantadine 100 mg 3 times daily for the hemiballismus in conjunction with treatment of his T2DM. The only follow-up occurred 5 weeks later, which showed no improvement of uncontrollable movements. Imaging at that time (not available) indicated the persistence of the abnormal signal in the right basal ganglia. This patient died later that year without further follow-up.

Case 3

A 78-year-old white male with a history of syncope, transient ischemic attacks (TIAs), and poorly controlled T2DM presented with a 1-month history of progressively worsening involuntary, left-sided movements that began in his left shoulder and advanced to involve his arm, hand, and leg, and the left side of his face with grimacing and clucking of his tongue. Three weeks earlier, the patient had been discharged from the ED with a diagnosis of conversion disorder particularly because he experienced decreased movements when given a dose of Vitamin D. It was overlooked that administration of haloperidol had occurred a few hours before, and because the sounds made by his tongue were not felt to be consistent with a known movement disorder. A MRI of the brain was read as normal.

The patient returned 3 weeks later (the original presentation) due to his inability to perform activities of daily living because of his worsening involuntary movements. On admission, his HbA1c was 11.1% and his glucose was 167 mg/dL. On chart review, it was revealed that the patient’s HbA1c had been > 9% for the past 3 years with an increase from 10.1% to 11.1% in the 3 months preceding the onset of his symptoms.

On admission a MRI showed a unilateral right-sided T1 hyperintensity in the basal ganglia, no acute ischemia (Figure 4). In retrospect, subtle increased T1 signal can be seen on the earlier MRI (Figure 5). In view of the patient’s left-sided symptoms, DM, and MRI findings, a diagnosis of hyperglycemia-induced hemichorea- hemiballismus was made as the etiology of the patient’s symptoms.

The patient was prescribed numerous medications to control his hyperkinesia including (and in combination): benztropine, gabapentin, baclofen, diphenhydramine, benzodiazepines, risperidone, olanzapine, and valproic acid, which did not control his movements. Ultimately, his hyperglycemic hemiballismus improved with tight glycemic control and oral tetrabenazine 12.5 mg twice daily. This patient underwent a protracted course of treatment with 17 days of inpatient medical admission, 3 weeks inpatient rehabilitation, and subsequent transfer to an assisted living facility.

Discussion

The 3 cases presented in this report contribute to the evidence that severe persistent hyperglycemia can result in movement disorders that mimic those seen after basal ganglia strokes. As with Case 2, past literature describes many cases of acute hyperglycemic episodes with glucose ranging from 500 to 1,000 mg/mL presenting with hemiballismus.^1,3 However, there are many cases that describe hemiballismus occurring after glycemic correction, persisting despite glycemic correction, and presenting without an acute hyperglycemic episode, but in the setting of elevated HbA_1c, as in Case 3.^12,13 Notably, all 3 cases in this series had marked elevation in their HbA_1c levels, which suggests that a more chronic hyperglycemic state or multiple shorter periods of hyperglycemia may be necessary to produce the described hyperkinetic movements.

Case reports describe the pathognomonic T1 hyperintensity of the basal ganglia that is identified in all 3 cases presented here. While the exact etiology remains unclear, the to metabolic derangements caused by hyperviscosity of the blood in the small end arteries feeding the basal ganglia.^3,11 These abnormalities in turn interrupt the signaling cascade with abnormal firing rates or firing patterns, leading to reduced inhibition of the motor thalamus and ultimately present as hemiballismus.^1,3,7 While most cases presented with unilateral hyperkinesis and associated contralateral basal ganglia abnormalities, there are reports of both unilateral and bilateral movements associated with bilateral basal ganglia hyperintensities on imaging. ⁹ The predilection for unilateral brain lesions may be explained by the varying degree of small vessel disease in different areas of the brain leading to perfusion deficits worsened by hyper viscosity. Further research into this is required to elucidate the exact pathophysiologic mechanism.

The course of disease for patients ranges from resolution within hours of tight glycemic control to persistent movements for > 3 months with a gradual improvement in severity.^12,13 Treatments center on the importance of tight glycemic control to protect against the protracted course described in Case 3. Swift recognition of this rare condition is critical because improved glycemic control decreases the severity and duration of this disease. The significant disability associated with Case 3 highlights the need for prompt recognition and early, aggressive glycemic management to prevent the progression of hemiballismus. In addition to glycemic control, various CNS medications such as typical and atypical antipsychotics and tetrabenazine are firstline therapy with chemodenervation and surgical lesioning in cases unresponsive to medication therapy.

When unrecognized, hyperglycemic hemiballismus is associated with significant morbidity and mortality. The patients presented in this report were subject to either delayed diagnosis or misdiagnosis as stroke or psychiatric disorder. The rarity of the disorder, lack of evidence delineating pathogenesis and causality, low level of awareness, and varying presentations of patients all contribute to the challenge of recognizing, diagnosing, and treating hemiballismus due to hyperglycemia. This challenge can subsequently result in deteriorating symptoms, prolonged hospital stays, and unnecessary health care costs.

Conclusion

While hemiballismus due to severe persistent hyperglycemia is rare, the goal of this report is to highlight its occurrence in patients with T2DM. Further research can help develop a standardized, effective treatment strategy for these patients. Currently, lowering and maintaining appropriate glucose and HbA_1c levels is the most effective treatment approach. Potential areas of research include alternative medical and surgical treatment interventions for patients while glycemic control is being achieved or for those who fail to benefit from glycemic control alone. Some success has been demonstrated with the use of antidopaminergic medications such as atypical antipsychotics and tetrabenazine and these medications should be considered when tight, sustained glycemic control alone is not successful in treating this disorder in the acute stages. Hopefully, with increasing awareness and recognition of hemiballismus related to hyperglycemia, more large-scale clinical trials can be conducted that will result in an effective treatment strategy for this devastating disorder.

Hemiballismus is an acquired hyperkinetic movement disorder characterized by unilateral, involuntary, often large-amplitude limb movements. Ballistic movements are now considered to be on the choreiform spectrum.1 Movements usually involve both the arm and leg, and in half of cases, facial movements such as tongue clucking and grimacing are seen.^2,3 Presentations of hemiballismus vary in severity from intermittent to nearly continuous movements, which, in some cases, may lead to exhaustion, injury, or disability. Some patients are unable to ambulate or feed themselves with the affected limb.

Background

The 2 most common causes of hemichorea-hemiballismus are stroke and hyperglycemia, with an incidence of 4% and unknown incidence, respectively.^1,3,4 Other causes include HIV, traumatic brain injury, encephalitis, vasculitis, mass effect, multiple sclerosis, and adverse drug reactions. ^4-7 Acute or subacute hemiballismus is classically attributed to a lesion in subthalamic nucleus (STN), but this is true only in a minority of cases. Hemiballismus can be caused by any abnormality in various subnuclei of the basal ganglia, including the classic location in the STN, striatum, and globus pallidus.⁴ Evidence shows the lesions typically involve a functional network connected to the posterolateral putamen.⁸

Although not commonly recognized, hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is the second most common cause of hemichoreahemiballismus. ³ Over the past 90 years, numerous case reports have described patients with DM with acute and subacute onset of hemiballistic and hemichoreiform movements while in a hyperglycemic state or after its resolution. Reported cases have been limited to small numbers of patients with only a few larger-scale reviews of more than 20 patients.^7,9 Most reported cases involve geriatric patients and more commonly, females of Eastern Asian descent with an average age of onset of 71 years.^4,10 Patients typically present with glucose levels from 500 to 1,000 mg/dL and hemoglobin A1c (HbA1c) levels almost double the normal values. Interestingly, neuroimaging findings in these patients have consistently shown hyperintense signal in the contralateral basal ganglia on T1-weighted magnetic resonance images (MRIs). Noncontrast computed tomography (CT) shows well-defined unilateral increased density in the contralateral basal ganglia without mass effect.^1,9,11

This report aims to illustrate and enhance the understanding of hemiballismus associated with hyperglycemia. One patient presented to the US Department of Veterans Affairs (VA) Bay Pines VA Healthcare System (BPVAHCS) in Florida, which motivated us to search for other similar cases. We reviewed the charts of 2 other patients who presented to BPVAHCS over the past 10 years. The first case presented with severe hyperglycemia and abnormal movements that were not clearly diagnosed as hemiballismus. MRI findings were characteristic and assisted in making the diagnosis. The second case was misdiagnosed as hemiballismus secondary to ischemic stroke. The third case was initially diagnosed as conversion disorder until movements worsened and the correct diagnosis of hyperglycemia-induced hemichorea hemiballismus was confirmed by the pathognomonic neuroimaging findings.

Case Presentations

Case 1

A 65-year-old male with a history of uncontrolled T2DM presented with repetitive twitching and kicking movements that involved his left upper and lower extremities for 3 weeks. The patient reported that he did not take his medications or follow the recommended diabetes diet. His HbA1c on admission was 12.2% with a serum glucose of 254 mg/dL. The MRI showed a hyperintense T1 signal within the right basal ganglia including the right caudate with sparing of the internal capsule (Figure 1). There was no associated mass effect or restricted diffusion. It was compatible with a diagnosis of hyperglycemia- induced hemichorea-hemiballismus. The patient was advised to resume taking glipizide 10 mg daily, metformin 1,000 mg by mouth twice daily, and to begin 10 units of 70/30 insulin aspart 15 minutes before meals twice daily, and to follow a low carbohydrate diet, with reduce dietary intake of sugar. At his 1-month follow-up visit, the patient reported an improvement in his involuntary movements. At the 5-month follow-up, the patient’s HbA1c level was 10.4% and his hyperkinetic movements had completely resolved.

Case 2

of T2DM, hypertension, and hyperlipidemia was admitted due to increased jerky movements in the left upper extremity. On admission, his vital signs were within normal limits and his physical examination demonstrated choreoathetoid movements with ballistic components of his left upper extremity. His laboratory results showed a glucose level of 528 mg/dL with a HbA1c of 16.3%. An initial CT obtained in the emergency department (ED) demonstrated a well-defined hyperdensity in the striatal (caudate and lentiform nucleus) region (Figure 2). There was no associated edema/mass effect that would be typical for an intracranial hemorrhage.

An MRI obtained 1 week later showed hyperintense TI signal corresponding to the basal ganglia (Figure 3). In addition, there was a questionable lacunar infarct in the right internal capsule. Due to lack of awareness regarding hyperglycemic associated basal ganglia changes, the patient’s movement disorder was presumed to be ischemic in etiology. The patient was prescribed oral amantadine 100 mg 3 times daily for the hemiballismus in conjunction with treatment of his T2DM. The only follow-up occurred 5 weeks later, which showed no improvement of uncontrollable movements. Imaging at that time (not available) indicated the persistence of the abnormal signal in the right basal ganglia. This patient died later that year without further follow-up.

Case 3

A 78-year-old white male with a history of syncope, transient ischemic attacks (TIAs), and poorly controlled T2DM presented with a 1-month history of progressively worsening involuntary, left-sided movements that began in his left shoulder and advanced to involve his arm, hand, and leg, and the left side of his face with grimacing and clucking of his tongue. Three weeks earlier, the patient had been discharged from the ED with a diagnosis of conversion disorder particularly because he experienced decreased movements when given a dose of Vitamin D. It was overlooked that administration of haloperidol had occurred a few hours before, and because the sounds made by his tongue were not felt to be consistent with a known movement disorder. A MRI of the brain was read as normal.

The patient returned 3 weeks later (the original presentation) due to his inability to perform activities of daily living because of his worsening involuntary movements. On admission, his HbA1c was 11.1% and his glucose was 167 mg/dL. On chart review, it was revealed that the patient’s HbA1c had been > 9% for the past 3 years with an increase from 10.1% to 11.1% in the 3 months preceding the onset of his symptoms.

On admission a MRI showed a unilateral right-sided T1 hyperintensity in the basal ganglia, no acute ischemia (Figure 4). In retrospect, subtle increased T1 signal can be seen on the earlier MRI (Figure 5). In view of the patient’s left-sided symptoms, DM, and MRI findings, a diagnosis of hyperglycemia-induced hemichorea- hemiballismus was made as the etiology of the patient’s symptoms.

The patient was prescribed numerous medications to control his hyperkinesia including (and in combination): benztropine, gabapentin, baclofen, diphenhydramine, benzodiazepines, risperidone, olanzapine, and valproic acid, which did not control his movements. Ultimately, his hyperglycemic hemiballismus improved with tight glycemic control and oral tetrabenazine 12.5 mg twice daily. This patient underwent a protracted course of treatment with 17 days of inpatient medical admission, 3 weeks inpatient rehabilitation, and subsequent transfer to an assisted living facility.

Discussion

The 3 cases presented in this report contribute to the evidence that severe persistent hyperglycemia can result in movement disorders that mimic those seen after basal ganglia strokes. As with Case 2, past literature describes many cases of acute hyperglycemic episodes with glucose ranging from 500 to 1,000 mg/mL presenting with hemiballismus.^1,3 However, there are many cases that describe hemiballismus occurring after glycemic correction, persisting despite glycemic correction, and presenting without an acute hyperglycemic episode, but in the setting of elevated HbA_1c, as in Case 3.^12,13 Notably, all 3 cases in this series had marked elevation in their HbA_1c levels, which suggests that a more chronic hyperglycemic state or multiple shorter periods of hyperglycemia may be necessary to produce the described hyperkinetic movements.

Case reports describe the pathognomonic T1 hyperintensity of the basal ganglia that is identified in all 3 cases presented here. While the exact etiology remains unclear, the to metabolic derangements caused by hyperviscosity of the blood in the small end arteries feeding the basal ganglia.^3,11 These abnormalities in turn interrupt the signaling cascade with abnormal firing rates or firing patterns, leading to reduced inhibition of the motor thalamus and ultimately present as hemiballismus.^1,3,7 While most cases presented with unilateral hyperkinesis and associated contralateral basal ganglia abnormalities, there are reports of both unilateral and bilateral movements associated with bilateral basal ganglia hyperintensities on imaging. ⁹ The predilection for unilateral brain lesions may be explained by the varying degree of small vessel disease in different areas of the brain leading to perfusion deficits worsened by hyper viscosity. Further research into this is required to elucidate the exact pathophysiologic mechanism.

The course of disease for patients ranges from resolution within hours of tight glycemic control to persistent movements for > 3 months with a gradual improvement in severity.^12,13 Treatments center on the importance of tight glycemic control to protect against the protracted course described in Case 3. Swift recognition of this rare condition is critical because improved glycemic control decreases the severity and duration of this disease. The significant disability associated with Case 3 highlights the need for prompt recognition and early, aggressive glycemic management to prevent the progression of hemiballismus. In addition to glycemic control, various CNS medications such as typical and atypical antipsychotics and tetrabenazine are firstline therapy with chemodenervation and surgical lesioning in cases unresponsive to medication therapy.

When unrecognized, hyperglycemic hemiballismus is associated with significant morbidity and mortality. The patients presented in this report were subject to either delayed diagnosis or misdiagnosis as stroke or psychiatric disorder. The rarity of the disorder, lack of evidence delineating pathogenesis and causality, low level of awareness, and varying presentations of patients all contribute to the challenge of recognizing, diagnosing, and treating hemiballismus due to hyperglycemia. This challenge can subsequently result in deteriorating symptoms, prolonged hospital stays, and unnecessary health care costs.

Conclusion

While hemiballismus due to severe persistent hyperglycemia is rare, the goal of this report is to highlight its occurrence in patients with T2DM. Further research can help develop a standardized, effective treatment strategy for these patients. Currently, lowering and maintaining appropriate glucose and HbA_1c levels is the most effective treatment approach. Potential areas of research include alternative medical and surgical treatment interventions for patients while glycemic control is being achieved or for those who fail to benefit from glycemic control alone. Some success has been demonstrated with the use of antidopaminergic medications such as atypical antipsychotics and tetrabenazine and these medications should be considered when tight, sustained glycemic control alone is not successful in treating this disorder in the acute stages. Hopefully, with increasing awareness and recognition of hemiballismus related to hyperglycemia, more large-scale clinical trials can be conducted that will result in an effective treatment strategy for this devastating disorder.

Hemiballismus is an acquired hyperkinetic movement disorder characterized by unilateral, involuntary, often large-amplitude limb movements. Ballistic movements are now considered to be on the choreiform spectrum.1 Movements usually involve both the arm and leg, and in half of cases, facial movements such as tongue clucking and grimacing are seen.^2,3 Presentations of hemiballismus vary in severity from intermittent to nearly continuous movements, which, in some cases, may lead to exhaustion, injury, or disability. Some patients are unable to ambulate or feed themselves with the affected limb.

Background

The 2 most common causes of hemichorea-hemiballismus are stroke and hyperglycemia, with an incidence of 4% and unknown incidence, respectively.^1,3,4 Other causes include HIV, traumatic brain injury, encephalitis, vasculitis, mass effect, multiple sclerosis, and adverse drug reactions. ^4-7 Acute or subacute hemiballismus is classically attributed to a lesion in subthalamic nucleus (STN), but this is true only in a minority of cases. Hemiballismus can be caused by any abnormality in various subnuclei of the basal ganglia, including the classic location in the STN, striatum, and globus pallidus.⁴ Evidence shows the lesions typically involve a functional network connected to the posterolateral putamen.⁸

Although not commonly recognized, hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is the second most common cause of hemichoreahemiballismus. ³ Over the past 90 years, numerous case reports have described patients with DM with acute and subacute onset of hemiballistic and hemichoreiform movements while in a hyperglycemic state or after its resolution. Reported cases have been limited to small numbers of patients with only a few larger-scale reviews of more than 20 patients.^7,9 Most reported cases involve geriatric patients and more commonly, females of Eastern Asian descent with an average age of onset of 71 years.^4,10 Patients typically present with glucose levels from 500 to 1,000 mg/dL and hemoglobin A1c (HbA1c) levels almost double the normal values. Interestingly, neuroimaging findings in these patients have consistently shown hyperintense signal in the contralateral basal ganglia on T1-weighted magnetic resonance images (MRIs). Noncontrast computed tomography (CT) shows well-defined unilateral increased density in the contralateral basal ganglia without mass effect.^1,9,11

This report aims to illustrate and enhance the understanding of hemiballismus associated with hyperglycemia. One patient presented to the US Department of Veterans Affairs (VA) Bay Pines VA Healthcare System (BPVAHCS) in Florida, which motivated us to search for other similar cases. We reviewed the charts of 2 other patients who presented to BPVAHCS over the past 10 years. The first case presented with severe hyperglycemia and abnormal movements that were not clearly diagnosed as hemiballismus. MRI findings were characteristic and assisted in making the diagnosis. The second case was misdiagnosed as hemiballismus secondary to ischemic stroke. The third case was initially diagnosed as conversion disorder until movements worsened and the correct diagnosis of hyperglycemia-induced hemichorea hemiballismus was confirmed by the pathognomonic neuroimaging findings.

Case Presentations

Case 1

A 65-year-old male with a history of uncontrolled T2DM presented with repetitive twitching and kicking movements that involved his left upper and lower extremities for 3 weeks. The patient reported that he did not take his medications or follow the recommended diabetes diet. His HbA1c on admission was 12.2% with a serum glucose of 254 mg/dL. The MRI showed a hyperintense T1 signal within the right basal ganglia including the right caudate with sparing of the internal capsule (Figure 1). There was no associated mass effect or restricted diffusion. It was compatible with a diagnosis of hyperglycemia- induced hemichorea-hemiballismus. The patient was advised to resume taking glipizide 10 mg daily, metformin 1,000 mg by mouth twice daily, and to begin 10 units of 70/30 insulin aspart 15 minutes before meals twice daily, and to follow a low carbohydrate diet, with reduce dietary intake of sugar. At his 1-month follow-up visit, the patient reported an improvement in his involuntary movements. At the 5-month follow-up, the patient’s HbA1c level was 10.4% and his hyperkinetic movements had completely resolved.

Case 2

of T2DM, hypertension, and hyperlipidemia was admitted due to increased jerky movements in the left upper extremity. On admission, his vital signs were within normal limits and his physical examination demonstrated choreoathetoid movements with ballistic components of his left upper extremity. His laboratory results showed a glucose level of 528 mg/dL with a HbA1c of 16.3%. An initial CT obtained in the emergency department (ED) demonstrated a well-defined hyperdensity in the striatal (caudate and lentiform nucleus) region (Figure 2). There was no associated edema/mass effect that would be typical for an intracranial hemorrhage.

An MRI obtained 1 week later showed hyperintense TI signal corresponding to the basal ganglia (Figure 3). In addition, there was a questionable lacunar infarct in the right internal capsule. Due to lack of awareness regarding hyperglycemic associated basal ganglia changes, the patient’s movement disorder was presumed to be ischemic in etiology. The patient was prescribed oral amantadine 100 mg 3 times daily for the hemiballismus in conjunction with treatment of his T2DM. The only follow-up occurred 5 weeks later, which showed no improvement of uncontrollable movements. Imaging at that time (not available) indicated the persistence of the abnormal signal in the right basal ganglia. This patient died later that year without further follow-up.

Case 3

A 78-year-old white male with a history of syncope, transient ischemic attacks (TIAs), and poorly controlled T2DM presented with a 1-month history of progressively worsening involuntary, left-sided movements that began in his left shoulder and advanced to involve his arm, hand, and leg, and the left side of his face with grimacing and clucking of his tongue. Three weeks earlier, the patient had been discharged from the ED with a diagnosis of conversion disorder particularly because he experienced decreased movements when given a dose of Vitamin D. It was overlooked that administration of haloperidol had occurred a few hours before, and because the sounds made by his tongue were not felt to be consistent with a known movement disorder. A MRI of the brain was read as normal.

The patient returned 3 weeks later (the original presentation) due to his inability to perform activities of daily living because of his worsening involuntary movements. On admission, his HbA1c was 11.1% and his glucose was 167 mg/dL. On chart review, it was revealed that the patient’s HbA1c had been > 9% for the past 3 years with an increase from 10.1% to 11.1% in the 3 months preceding the onset of his symptoms.

On admission a MRI showed a unilateral right-sided T1 hyperintensity in the basal ganglia, no acute ischemia (Figure 4). In retrospect, subtle increased T1 signal can be seen on the earlier MRI (Figure 5). In view of the patient’s left-sided symptoms, DM, and MRI findings, a diagnosis of hyperglycemia-induced hemichorea- hemiballismus was made as the etiology of the patient’s symptoms.

The patient was prescribed numerous medications to control his hyperkinesia including (and in combination): benztropine, gabapentin, baclofen, diphenhydramine, benzodiazepines, risperidone, olanzapine, and valproic acid, which did not control his movements. Ultimately, his hyperglycemic hemiballismus improved with tight glycemic control and oral tetrabenazine 12.5 mg twice daily. This patient underwent a protracted course of treatment with 17 days of inpatient medical admission, 3 weeks inpatient rehabilitation, and subsequent transfer to an assisted living facility.

Discussion

The 3 cases presented in this report contribute to the evidence that severe persistent hyperglycemia can result in movement disorders that mimic those seen after basal ganglia strokes. As with Case 2, past literature describes many cases of acute hyperglycemic episodes with glucose ranging from 500 to 1,000 mg/mL presenting with hemiballismus.^1,3 However, there are many cases that describe hemiballismus occurring after glycemic correction, persisting despite glycemic correction, and presenting without an acute hyperglycemic episode, but in the setting of elevated HbA_1c, as in Case 3.^12,13 Notably, all 3 cases in this series had marked elevation in their HbA_1c levels, which suggests that a more chronic hyperglycemic state or multiple shorter periods of hyperglycemia may be necessary to produce the described hyperkinetic movements.

Case reports describe the pathognomonic T1 hyperintensity of the basal ganglia that is identified in all 3 cases presented here. While the exact etiology remains unclear, the to metabolic derangements caused by hyperviscosity of the blood in the small end arteries feeding the basal ganglia.^3,11 These abnormalities in turn interrupt the signaling cascade with abnormal firing rates or firing patterns, leading to reduced inhibition of the motor thalamus and ultimately present as hemiballismus.^1,3,7 While most cases presented with unilateral hyperkinesis and associated contralateral basal ganglia abnormalities, there are reports of both unilateral and bilateral movements associated with bilateral basal ganglia hyperintensities on imaging. ⁹ The predilection for unilateral brain lesions may be explained by the varying degree of small vessel disease in different areas of the brain leading to perfusion deficits worsened by hyper viscosity. Further research into this is required to elucidate the exact pathophysiologic mechanism.

The course of disease for patients ranges from resolution within hours of tight glycemic control to persistent movements for > 3 months with a gradual improvement in severity.^12,13 Treatments center on the importance of tight glycemic control to protect against the protracted course described in Case 3. Swift recognition of this rare condition is critical because improved glycemic control decreases the severity and duration of this disease. The significant disability associated with Case 3 highlights the need for prompt recognition and early, aggressive glycemic management to prevent the progression of hemiballismus. In addition to glycemic control, various CNS medications such as typical and atypical antipsychotics and tetrabenazine are firstline therapy with chemodenervation and surgical lesioning in cases unresponsive to medication therapy.

When unrecognized, hyperglycemic hemiballismus is associated with significant morbidity and mortality. The patients presented in this report were subject to either delayed diagnosis or misdiagnosis as stroke or psychiatric disorder. The rarity of the disorder, lack of evidence delineating pathogenesis and causality, low level of awareness, and varying presentations of patients all contribute to the challenge of recognizing, diagnosing, and treating hemiballismus due to hyperglycemia. This challenge can subsequently result in deteriorating symptoms, prolonged hospital stays, and unnecessary health care costs.

Conclusion

While hemiballismus due to severe persistent hyperglycemia is rare, the goal of this report is to highlight its occurrence in patients with T2DM. Further research can help develop a standardized, effective treatment strategy for these patients. Currently, lowering and maintaining appropriate glucose and HbA_1c levels is the most effective treatment approach. Potential areas of research include alternative medical and surgical treatment interventions for patients while glycemic control is being achieved or for those who fail to benefit from glycemic control alone. Some success has been demonstrated with the use of antidopaminergic medications such as atypical antipsychotics and tetrabenazine and these medications should be considered when tight, sustained glycemic control alone is not successful in treating this disorder in the acute stages. Hopefully, with increasing awareness and recognition of hemiballismus related to hyperglycemia, more large-scale clinical trials can be conducted that will result in an effective treatment strategy for this devastating disorder.

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; [email protected].

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; [email protected].

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; [email protected].

Case Report

A 92-year-old Eastern European woman presented to our nail clinic with a history of onychodystrophy and arthralgia of the digits of several months’ duration. Her dermatologic history was notable for irritant hand dermatitis. A prior nail plate clipping with histopathologic examination was negative for fungal elements. Physical examination revealed onychorrhexis of all fingernails as well as onycholysis and subungual hyperkeratosis of the right fourth fingernail. Blue-green staining was incidentally noted on the right second and third fingernails and nail folds (Figure 1). Contact dermoscopy using ultrasound gel revealed translucent areas with sparse pigment, though denser areas had a fine branching pattern (Figure 2). When questioned, the patient reported use of “zelyonka,” a brilliant green solution, to self-treat the nails. Histopathology on repeat nail clippings showed parakeratosis and serum, which was most consistent with her known history of irritant hand dermatitis. Radiographs of the hands revealed osteoarthritis that was most prominent at the distal interphalangeal joints.

Comment

Brilliant green is a triphenylmethane dye commonly used in Eastern Europe and other regions for the treatment of superficial skin infections and onychomycosis.¹ Its use as an antiseptic and wound healing agent has been investigated in the scientific literature since at least the early 20th century.² Brilliant green typically is applied in a 0.1% to 2% ethanol solution.¹ The dye has bactericidal activity against gram-positive organisms, particularly staphylococci and streptococci.^2,3 It has been used for the treatment of fungal skin and nail infections since at least the early 20th century, with anecdotal success.⁴ Although there have been no studies investigating use of brilliant green alone for the treatment of onychomycosis, it is sometimes used in combination with conventional oral agents for this purpose.⁵ Because of its availability, safety, ease of use, and low cost, brilliant green has been promoted as an antiseptic in resource-poor settings.³ The revival of brilliant green and other antiseptic dyes in these settings has been suggested as an alternative to oral antibiotic agents, to which resistance is rising, and as a potential cancer therapy.^6,7 Although brilliant green’s mechanism of action in treating skin infections is unclear, it has been shown to form covalent adducts with thioredoxin reductase 2, a protein conserved from bacteria to humans with an essential function for cellular activity.⁷

Early case studies suggested that brilliant green was beneficial in treating wounds²; however, this indication is controversial. In a guinea pig study, brilliant green was shown to inhibit wound healing and the formation of granulation tissue.⁸ It also should be noted that when used topically, brilliant green may cause skin sensitization, necrotic skin reactions, and permanent staining of clothing. It has no known anti-inflammatory properties and also may cause skin irritation.⁸ Brilliant green may cause blindness if it comes in contact with the eyes.¹

Brilliant green has other potential dermatologic indications. For example, a combination of brilliant green and gentian violet, a related dye, has demonstrated efficacy in the treatment of cutaneous hemangiomas in mouse models by blocking expression of angiopoietin-2.⁷

Dermatologists should be familiar with brilliant green and its common uses as well as adverse effects. Brilliant green is commercially available for a low cost ($5 to $20) in specialty pharmacies or online (eg, Amazon). It is sold alone or in combination with gentian violet and proflavine hemisulfate, and a prescription is not required. Due to its low cost and accessibility, patients may use brilliant green to self-treat dermatologic conditions. Green nails due to staining with brilliant green dye must be distinguished from other etiologies causing green nail discoloration, such as infection with Pseudomonas aeruginosa or Aspergillus, bullous disorders, jaundice, “old” hematomas, nail polish, and other exogenous pigments.

Case Report

A 92-year-old Eastern European woman presented to our nail clinic with a history of onychodystrophy and arthralgia of the digits of several months’ duration. Her dermatologic history was notable for irritant hand dermatitis. A prior nail plate clipping with histopathologic examination was negative for fungal elements. Physical examination revealed onychorrhexis of all fingernails as well as onycholysis and subungual hyperkeratosis of the right fourth fingernail. Blue-green staining was incidentally noted on the right second and third fingernails and nail folds (Figure 1). Contact dermoscopy using ultrasound gel revealed translucent areas with sparse pigment, though denser areas had a fine branching pattern (Figure 2). When questioned, the patient reported use of “zelyonka,” a brilliant green solution, to self-treat the nails. Histopathology on repeat nail clippings showed parakeratosis and serum, which was most consistent with her known history of irritant hand dermatitis. Radiographs of the hands revealed osteoarthritis that was most prominent at the distal interphalangeal joints.

Comment

Brilliant green is a triphenylmethane dye commonly used in Eastern Europe and other regions for the treatment of superficial skin infections and onychomycosis.¹ Its use as an antiseptic and wound healing agent has been investigated in the scientific literature since at least the early 20th century.² Brilliant green typically is applied in a 0.1% to 2% ethanol solution.¹ The dye has bactericidal activity against gram-positive organisms, particularly staphylococci and streptococci.^2,3 It has been used for the treatment of fungal skin and nail infections since at least the early 20th century, with anecdotal success.⁴ Although there have been no studies investigating use of brilliant green alone for the treatment of onychomycosis, it is sometimes used in combination with conventional oral agents for this purpose.⁵ Because of its availability, safety, ease of use, and low cost, brilliant green has been promoted as an antiseptic in resource-poor settings.³ The revival of brilliant green and other antiseptic dyes in these settings has been suggested as an alternative to oral antibiotic agents, to which resistance is rising, and as a potential cancer therapy.^6,7 Although brilliant green’s mechanism of action in treating skin infections is unclear, it has been shown to form covalent adducts with thioredoxin reductase 2, a protein conserved from bacteria to humans with an essential function for cellular activity.⁷

Early case studies suggested that brilliant green was beneficial in treating wounds²; however, this indication is controversial. In a guinea pig study, brilliant green was shown to inhibit wound healing and the formation of granulation tissue.⁸ It also should be noted that when used topically, brilliant green may cause skin sensitization, necrotic skin reactions, and permanent staining of clothing. It has no known anti-inflammatory properties and also may cause skin irritation.⁸ Brilliant green may cause blindness if it comes in contact with the eyes.¹

Brilliant green has other potential dermatologic indications. For example, a combination of brilliant green and gentian violet, a related dye, has demonstrated efficacy in the treatment of cutaneous hemangiomas in mouse models by blocking expression of angiopoietin-2.⁷

Dermatologists should be familiar with brilliant green and its common uses as well as adverse effects. Brilliant green is commercially available for a low cost ($5 to $20) in specialty pharmacies or online (eg, Amazon). It is sold alone or in combination with gentian violet and proflavine hemisulfate, and a prescription is not required. Due to its low cost and accessibility, patients may use brilliant green to self-treat dermatologic conditions. Green nails due to staining with brilliant green dye must be distinguished from other etiologies causing green nail discoloration, such as infection with Pseudomonas aeruginosa or Aspergillus, bullous disorders, jaundice, “old” hematomas, nail polish, and other exogenous pigments.

Case Report

A 92-year-old Eastern European woman presented to our nail clinic with a history of onychodystrophy and arthralgia of the digits of several months’ duration. Her dermatologic history was notable for irritant hand dermatitis. A prior nail plate clipping with histopathologic examination was negative for fungal elements. Physical examination revealed onychorrhexis of all fingernails as well as onycholysis and subungual hyperkeratosis of the right fourth fingernail. Blue-green staining was incidentally noted on the right second and third fingernails and nail folds (Figure 1). Contact dermoscopy using ultrasound gel revealed translucent areas with sparse pigment, though denser areas had a fine branching pattern (Figure 2). When questioned, the patient reported use of “zelyonka,” a brilliant green solution, to self-treat the nails. Histopathology on repeat nail clippings showed parakeratosis and serum, which was most consistent with her known history of irritant hand dermatitis. Radiographs of the hands revealed osteoarthritis that was most prominent at the distal interphalangeal joints.

Comment

Brilliant green is a triphenylmethane dye commonly used in Eastern Europe and other regions for the treatment of superficial skin infections and onychomycosis.¹ Its use as an antiseptic and wound healing agent has been investigated in the scientific literature since at least the early 20th century.² Brilliant green typically is applied in a 0.1% to 2% ethanol solution.¹ The dye has bactericidal activity against gram-positive organisms, particularly staphylococci and streptococci.^2,3 It has been used for the treatment of fungal skin and nail infections since at least the early 20th century, with anecdotal success.⁴ Although there have been no studies investigating use of brilliant green alone for the treatment of onychomycosis, it is sometimes used in combination with conventional oral agents for this purpose.⁵ Because of its availability, safety, ease of use, and low cost, brilliant green has been promoted as an antiseptic in resource-poor settings.³ The revival of brilliant green and other antiseptic dyes in these settings has been suggested as an alternative to oral antibiotic agents, to which resistance is rising, and as a potential cancer therapy.^6,7 Although brilliant green’s mechanism of action in treating skin infections is unclear, it has been shown to form covalent adducts with thioredoxin reductase 2, a protein conserved from bacteria to humans with an essential function for cellular activity.⁷

Early case studies suggested that brilliant green was beneficial in treating wounds²; however, this indication is controversial. In a guinea pig study, brilliant green was shown to inhibit wound healing and the formation of granulation tissue.⁸ It also should be noted that when used topically, brilliant green may cause skin sensitization, necrotic skin reactions, and permanent staining of clothing. It has no known anti-inflammatory properties and also may cause skin irritation.⁸ Brilliant green may cause blindness if it comes in contact with the eyes.¹

Brilliant green has other potential dermatologic indications. For example, a combination of brilliant green and gentian violet, a related dye, has demonstrated efficacy in the treatment of cutaneous hemangiomas in mouse models by blocking expression of angiopoietin-2.⁷

Dermatologists should be familiar with brilliant green and its common uses as well as adverse effects. Brilliant green is commercially available for a low cost ($5 to $20) in specialty pharmacies or online (eg, Amazon). It is sold alone or in combination with gentian violet and proflavine hemisulfate, and a prescription is not required. Due to its low cost and accessibility, patients may use brilliant green to self-treat dermatologic conditions. Green nails due to staining with brilliant green dye must be distinguished from other etiologies causing green nail discoloration, such as infection with Pseudomonas aeruginosa or Aspergillus, bullous disorders, jaundice, “old” hematomas, nail polish, and other exogenous pigments.

Case Report

A 37-year-old woman presented to the dermatology clinic with an itchy rash involving the right hand. The rash had been present for 10 days but had become increasingly pruritic and vesicular over the last 5 days. She denied new exposures or other household members with similar symptoms. The patient reported that she had purchased a 4-toed, white-bellied African pygmy hedgehog (Atelerix albiventris) approximately 4 months prior. Upon questioning, she stated that she handled the hedgehog a couple of times a week and always washed her hands with soap and water immediately after. The patient’s medical and personal history were otherwise unremarkable.

Review of systems, including fevers, chills, and night sweats, was negative. Clinical examination revealed erythema with overlying vesicles and pustules on the right radial palm, radial dorsal hand, and interdigital web space of the first and second digit (Figure 1). The eruption was actively discharging serous exudate. No other lesions were present.

Comment

Tinea manuum is a dermatophytic epidermal infection of the hand. The most common causative organisms are Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. Infection can be acquired from contact with an infected person or animal, fomites, soil, or autoinoculation. Tinea manuum often is associated with tinea pedis. The hand that is used to excoriate the pruritic feet becomes infected, resulting in the classic two feet–one hand syndrome, which this patient did not have.¹

Dermatophytes colonize keratin-containing tissues—skin, hair, and nails—utilizing the keratin for nutrients, and they do not invade living tissue in immunocompetent hosts. Dermatophytes cause clinical disease from an allergic host response to fungal antigens or their metabolic products.¹ Tinea incognito results from the use of corticosteroids to treat a cutaneous fungal infection. The immunomodulatory effects of corticosteroids alter the appearance of the lesion. Hallmark signs and symptoms of a tinea infection, including scale, prominent border, erythema, and pruritus, can be reduced with corticosteroid use, giving the false impression that the lesion is resolving.^2,3 

The diagnosis of tinea manuum can be made clinically and often is supported with the findings of a KOH preparation. Scraping from an active scaling border generally provides the best results for obtaining fungal elements. For vesiculobullous lesions, the roof of a vesicle can provide an adequate specimen. Fungal culture and specific dermatophyte testing mediums can be used as confirmatory tests or allow for speciation, which help establish the diagnosis.¹

Trichophyton mentagrophytes is a species complex—a group of closely related organisms that share morphologic appearance to the point that boundaries between them often are unclear. It can be identified by gross and microscopic morphology; however, variants of T mentagrophytes (eg, Trichophyton interdigitale, Trichophyton erinacei) require a confirmatory test or molecular analysis to be correctly identified.^4-6 The laboratory used at our facility does not routinely attempt to identify the variant due to of lack of clinical significance.^7,8

Anthropophilic fungi such as T rubrum, E floccosum, and T interdigitale generally do not cause a robust immunologic reaction. Infection usually is chronic in nature, though cases of pustular and vesicular tinea have been described.^9,10Trichophyton erinacei and T mentagrophytes are zoophilic dermatophytes that cause an acute host response and are more likely to present with vesiculobullous lesions. Trichophyton erinacei is the most common fungal pathogen associated with A albiventris and has been isolated from its epidermal mites and quills,^11,12 which likely facilitates interspecies transmission and compromises the cutaneous barrier of human hosts when the hedgehog is handled.

Atelerix albiventris is the most common domesticated hedgehog in the United States. These mild-mannered, nocturnal insectivores are unique, low-maintenance pets that have recently gained popularity. They are notable for their propensity to curl into a ball when frightened (Figure 5). The spines are not barbed and do not detach, as those of a porcupine do, but are still capable of piercing the skin. Atelerix albiventris is known to cause zoonotic dermatosis in humans and should be handled with gloves.¹³ Performing a KOH preparation early in the diagnostic workup can help initiate antifungal therapy, as results of fungal culture can take several weeks.

Conclusion

This case illustrates the importance of close follow-up of skin lesions that only partially respond to initial treatment and maintaining a high index of suspicion as exotic pets become popular.

Case Report

A 37-year-old woman presented to the dermatology clinic with an itchy rash involving the right hand. The rash had been present for 10 days but had become increasingly pruritic and vesicular over the last 5 days. She denied new exposures or other household members with similar symptoms. The patient reported that she had purchased a 4-toed, white-bellied African pygmy hedgehog (Atelerix albiventris) approximately 4 months prior. Upon questioning, she stated that she handled the hedgehog a couple of times a week and always washed her hands with soap and water immediately after. The patient’s medical and personal history were otherwise unremarkable.

Review of systems, including fevers, chills, and night sweats, was negative. Clinical examination revealed erythema with overlying vesicles and pustules on the right radial palm, radial dorsal hand, and interdigital web space of the first and second digit (Figure 1). The eruption was actively discharging serous exudate. No other lesions were present.

Comment

Tinea manuum is a dermatophytic epidermal infection of the hand. The most common causative organisms are Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. Infection can be acquired from contact with an infected person or animal, fomites, soil, or autoinoculation. Tinea manuum often is associated with tinea pedis. The hand that is used to excoriate the pruritic feet becomes infected, resulting in the classic two feet–one hand syndrome, which this patient did not have.¹

Dermatophytes colonize keratin-containing tissues—skin, hair, and nails—utilizing the keratin for nutrients, and they do not invade living tissue in immunocompetent hosts. Dermatophytes cause clinical disease from an allergic host response to fungal antigens or their metabolic products.¹ Tinea incognito results from the use of corticosteroids to treat a cutaneous fungal infection. The immunomodulatory effects of corticosteroids alter the appearance of the lesion. Hallmark signs and symptoms of a tinea infection, including scale, prominent border, erythema, and pruritus, can be reduced with corticosteroid use, giving the false impression that the lesion is resolving.^2,3 

The diagnosis of tinea manuum can be made clinically and often is supported with the findings of a KOH preparation. Scraping from an active scaling border generally provides the best results for obtaining fungal elements. For vesiculobullous lesions, the roof of a vesicle can provide an adequate specimen. Fungal culture and specific dermatophyte testing mediums can be used as confirmatory tests or allow for speciation, which help establish the diagnosis.¹

Trichophyton mentagrophytes is a species complex—a group of closely related organisms that share morphologic appearance to the point that boundaries between them often are unclear. It can be identified by gross and microscopic morphology; however, variants of T mentagrophytes (eg, Trichophyton interdigitale, Trichophyton erinacei) require a confirmatory test or molecular analysis to be correctly identified.^4-6 The laboratory used at our facility does not routinely attempt to identify the variant due to of lack of clinical significance.^7,8

Anthropophilic fungi such as T rubrum, E floccosum, and T interdigitale generally do not cause a robust immunologic reaction. Infection usually is chronic in nature, though cases of pustular and vesicular tinea have been described.^9,10Trichophyton erinacei and T mentagrophytes are zoophilic dermatophytes that cause an acute host response and are more likely to present with vesiculobullous lesions. Trichophyton erinacei is the most common fungal pathogen associated with A albiventris and has been isolated from its epidermal mites and quills,^11,12 which likely facilitates interspecies transmission and compromises the cutaneous barrier of human hosts when the hedgehog is handled.

Atelerix albiventris is the most common domesticated hedgehog in the United States. These mild-mannered, nocturnal insectivores are unique, low-maintenance pets that have recently gained popularity. They are notable for their propensity to curl into a ball when frightened (Figure 5). The spines are not barbed and do not detach, as those of a porcupine do, but are still capable of piercing the skin. Atelerix albiventris is known to cause zoonotic dermatosis in humans and should be handled with gloves.¹³ Performing a KOH preparation early in the diagnostic workup can help initiate antifungal therapy, as results of fungal culture can take several weeks.

Conclusion

This case illustrates the importance of close follow-up of skin lesions that only partially respond to initial treatment and maintaining a high index of suspicion as exotic pets become popular.

Case Report

A 37-year-old woman presented to the dermatology clinic with an itchy rash involving the right hand. The rash had been present for 10 days but had become increasingly pruritic and vesicular over the last 5 days. She denied new exposures or other household members with similar symptoms. The patient reported that she had purchased a 4-toed, white-bellied African pygmy hedgehog (Atelerix albiventris) approximately 4 months prior. Upon questioning, she stated that she handled the hedgehog a couple of times a week and always washed her hands with soap and water immediately after. The patient’s medical and personal history were otherwise unremarkable.

Review of systems, including fevers, chills, and night sweats, was negative. Clinical examination revealed erythema with overlying vesicles and pustules on the right radial palm, radial dorsal hand, and interdigital web space of the first and second digit (Figure 1). The eruption was actively discharging serous exudate. No other lesions were present.

Comment

Tinea manuum is a dermatophytic epidermal infection of the hand. The most common causative organisms are Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. Infection can be acquired from contact with an infected person or animal, fomites, soil, or autoinoculation. Tinea manuum often is associated with tinea pedis. The hand that is used to excoriate the pruritic feet becomes infected, resulting in the classic two feet–one hand syndrome, which this patient did not have.¹

Dermatophytes colonize keratin-containing tissues—skin, hair, and nails—utilizing the keratin for nutrients, and they do not invade living tissue in immunocompetent hosts. Dermatophytes cause clinical disease from an allergic host response to fungal antigens or their metabolic products.¹ Tinea incognito results from the use of corticosteroids to treat a cutaneous fungal infection. The immunomodulatory effects of corticosteroids alter the appearance of the lesion. Hallmark signs and symptoms of a tinea infection, including scale, prominent border, erythema, and pruritus, can be reduced with corticosteroid use, giving the false impression that the lesion is resolving.^2,3 

The diagnosis of tinea manuum can be made clinically and often is supported with the findings of a KOH preparation. Scraping from an active scaling border generally provides the best results for obtaining fungal elements. For vesiculobullous lesions, the roof of a vesicle can provide an adequate specimen. Fungal culture and specific dermatophyte testing mediums can be used as confirmatory tests or allow for speciation, which help establish the diagnosis.¹

Trichophyton mentagrophytes is a species complex—a group of closely related organisms that share morphologic appearance to the point that boundaries between them often are unclear. It can be identified by gross and microscopic morphology; however, variants of T mentagrophytes (eg, Trichophyton interdigitale, Trichophyton erinacei) require a confirmatory test or molecular analysis to be correctly identified.^4-6 The laboratory used at our facility does not routinely attempt to identify the variant due to of lack of clinical significance.^7,8

Anthropophilic fungi such as T rubrum, E floccosum, and T interdigitale generally do not cause a robust immunologic reaction. Infection usually is chronic in nature, though cases of pustular and vesicular tinea have been described.^9,10Trichophyton erinacei and T mentagrophytes are zoophilic dermatophytes that cause an acute host response and are more likely to present with vesiculobullous lesions. Trichophyton erinacei is the most common fungal pathogen associated with A albiventris and has been isolated from its epidermal mites and quills,^11,12 which likely facilitates interspecies transmission and compromises the cutaneous barrier of human hosts when the hedgehog is handled.

Atelerix albiventris is the most common domesticated hedgehog in the United States. These mild-mannered, nocturnal insectivores are unique, low-maintenance pets that have recently gained popularity. They are notable for their propensity to curl into a ball when frightened (Figure 5). The spines are not barbed and do not detach, as those of a porcupine do, but are still capable of piercing the skin. Atelerix albiventris is known to cause zoonotic dermatosis in humans and should be handled with gloves.¹³ Performing a KOH preparation early in the diagnostic workup can help initiate antifungal therapy, as results of fungal culture can take several weeks.

Conclusion

This case illustrates the importance of close follow-up of skin lesions that only partially respond to initial treatment and maintaining a high index of suspicion as exotic pets become popular.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that affects > 700,000 people in the US.¹ The hallmarks of MS pathology are axonal or neuronal loss, demyelination, and astrocytic gliosis. Of these, axonal or neuronal loss is the main underlying mechanism of permanent clinical disability.

MS also has been associated with an increased prevalence of psychiatric illnesses, with mood disorders affecting up to 40% to 60% of the population, and psychosis being reported in 2% to 4% of patients.² The link between MS and mood disorders, including bipolar disorder and depression, was documented as early as 1926,with mood disorders hypothesized to be manifestations of central nervous system (CNS) inflammation.³ More recently, inflammation-driven microglia have been hypothesized to impair hippocampal connectivity and activate glucocorticoid-insensitive inflammatory cells that then overstimulate the hypothalamic-pituitary-adrenal axis.^4,5

Although the prevalence of psychosis in patients with MS is significantly rarer, averaging between 2% and 4%.⁶ A Canadian study by Patten and colleagues reviewed data from 2.45 million residents of Alberta and found that those who identified as having MS had a 2% to 3% prevalence of psychosis compared with 0.5% to 1% in the general population.⁷ The connection between psychosis and MS, similar to that between mood disorders and MS, has been described as a common regional demyelination process. Supporting this, MS manifesting as psychosis has been found to present with distinct magnetic resonance imaging (MRI) findings, such as diffuse periventricular lesions.⁸ Still, no conclusive criteria have been developed to distinguish MS presenting as psychosis from a primary psychiatric illness, such as schizophrenia.

In patients with combat history, it is possible that both neurodegenerative and psychotic symptoms can be explained by autoantibody formation in response to toxin exposure. When soldiers were deployed to Iraq and Afghanistan, they may have been exposed to multiple toxicities, including depleted uranium, dust and fumes, and numerous infectious diseases.⁹ Gulf War illness (GWI) or chronic multisymptom illness (CMI) encompass a cluster of symptoms, such as chronic pain, chronic fatigue, irritable bowel syndrome, dermatitis, and seizures, as well as mental health issues such as depression and anxiety experienced following exposure to these combat environments.^10,11

In light of this diagnostic uncertainty, the authors detail a case of a patient with significant combat history previously diagnosed with MS and unspecified schizophrenia spectrum and other psychotic disorder (USS & OPD) presenting with acute psychosis.

Case Presentation

A 35-year-old male veteran, with a history of MS, USS & OPD, posttraumatic stress disorder, and traumatic brain injuries (TBIs) was admitted to the psychiatric unit after being found by the police lying in the middle of a busy intersection, internally preoccupied. On admission, he reported a week of auditory hallucinations from birds with whom he had been communicating telepathically, and a recurrent visual hallucination of a tall man in white and purple robes. He had discontinued his antipsychotic medication, aripiprazole 10 mg, a few weeks prior for unknown reasons. He was brought to the hospital by ambulance, where he presented with disorganized thinking, tangential thought process, and active auditory and visual hallucinations. The differential diagnoses included USS & OPD, schizophrenia, schizoaffective disorder and ruled out substance-induced psychotic disorder, and psychosis as a manifestation of MS.

The patient had 2 psychotic episodes prior to this presentation. He was hospitalized for his first psychotic break in 2015 at age 32, when he had tailed another car “to come back to reality” and ended up in a motor vehicle accident. During that admission, he reported weeks of thought broadcasting, conspiratorial delusions, and racing thoughts. Two years later, he was admitted to a psychiatric intensive care unit for his second episode of severe psychosis. After several trials of different antipsychotic medications, his most recent pharmacologic regimen was aripiprazole 10 mg once daily.

His medical history was complicated by 2 TBIs, in November 2014 and January 2015, with normal computed tomography (CT) scans. He was diagnosed with MS in December 2017, when he presented with intractable emesis, left facial numbness, right upper extremity ataxia, nystagmus, and imbalance. An MRI scan revealed multifocal bilateral hypodensities in his periventricular, subcortical, and brain stem white matter. Multiple areas of hyperintensity were visualized, including in the right periatrial region and left brachium pontis. More than 5 oligoclonal bands on lumbar puncture confirmed the diagnosis.

He was treated with IV methylprednisolone followed by a 2-week prednisone taper. Within 1 week, he returned to the psychiatric unit with worsening symptoms and received a second dose of IV steroids and plasma exchange treatment. In the following months, he completed a course of rituximab infusions and physical therapy for his dysarthria, gait abnormality, and vision impairment.

His social history was notable for multiple first-degree relatives with schizophrenia. He reported a history of sexual and verbal abuse and attempted suicide once at age 13 years by hanging himself with a bathrobe. He left home at age 18 years to serve in the Marine Corps (2001-2006). His service included deployment to Afghanistan, where he received a purple heart. Upon his return, he received BA and MS degrees. He married and had 2 daughters but became estranged from his wife. By his most recent admission, he was unemployed and living with his half-sister.

On the first day of this most recent psychiatric hospitalization, he was restarted on aripiprazole 10 mg daily, and a medicine consult was sought to evaluate the progression of his MS. No new onset neurologic symptoms were noted, but he had possible residual lower extremity hyperreflexia and tandem gait incoordination. The episodes of psychotic and neurologic symptoms appeared independent, given that his psychiatric history preceded the onset of his MS.

The patient reported no visual hallucinations starting day 2, and he no longer endorsed auditory hallucinations by day 3. However, he continued to appear internally preoccupied and was noticed to be pacing around the unit. On day 4 he presented with newly pressured speech and flights of ideas, while his affect remained euthymic and his sleep stayed consistent. In combination with his ongoing pacing, his newfound symptoms were hypothesized to be possibly akathisia, an adverse effect (AE) of aripiprazole. As such, on day 5 his dose was lowered to 5 mg daily. He continued to report no hallucinations and demonstrated progressively increased emotional range. A MRI scan was done on day 6 in case a new lesion could be identified, suggesting a primary MS flare-up; however, the scan identified no enhancing lesions, indicating no ongoing demyelination. After a neurology consult corroborated this conclusion, he was discharged in stable condition on day 7.

As is the case with the majority of patients with MS-induced psychosis, he continued to have relapsing psychiatric disease even after MS treatment had been started. Unfortunately, because this patient had stopped taking his atypical antipsychotic medication several weeks prior to his hospitalization, we cannot clarify whether his psychosis stems from a primary psychiatric vs MS process.

Discussion

Presently, treatment preferences for MS-related psychosis are divided between atypical antipsychotics and glucocorticoids. Some suggest that the treatment remains similar between MS-related psychosis and primary psychotic disorders in that atypical antipsychotics are the standard of care.¹² A variety of atypical antipsychotics have been used successfully in case reports, including zipradisone, risperidone, olanzapine, quetiapine, and aripiprazole.^13,14 First-generation antipsychotics and other psychotropic drugs that can precipitate extra-pyramidal AEs are not recommended given their potential additive effect to motor deficits associated with MS.¹² Alternatively, several case reports have found that MS-related psychotic symptoms respond to glucocorticoids more effectively, while cautioning that glucocorticoids can precipitate psychosis and depression.^15,16 One review article found that 90% of patients who received corticosteroids saw an improvement in their psychotic symptoms.²

Finally, it is possible that our patient’s neuropsychiatric symptoms can be explained by autoantibody formation in response to toxin exposure during his time in Afghanistan. In a pilot study of veterans with GWI, Abou-Donia and colleagues found 2-to-9 fold increase in autoantibody reactivity levels of the following neuronal and glial-specific proteins relative to healthy controls: neurofilament triplet proteins, tubulin, microtubule-associated tau proteins, microtubule-associated protein-2, myelin basic protein, myelin-associated glycoprotein, glial fibrillary acidic protein, and calcium-calmodulin kinase II.^17,18 Many of these autoantibodies are longstanding explicit markers for neurodegenerative disorders, given that they target proteins and antigens that support axonal transport and myelination. Still Gulf War veteran status has yet to be explicitly linked to an increased risk of MS,¹⁹ making this hypothesis less likely for our patient. Future research should address the clinical and therapeutic implications of different autoantibody levels in combat veterans with psychosis.

Conclusion

For patients with MS, mood disorder and psychotic symptoms should warrant a MRI given the possibility of a psychiatric manifestation of MS relapse. Ultimately, our patient’s presentation was inconsistent with the expected clinical presentations of both a primary psychotic disorder and psychosis as a manifestation of MS. His late age at his first psychotic break is atypical for primary psychotic disease, and the lack of MRI imaging done at his initial psychotic episodes cannot exclude a primary MS diagnosis. Still, his lack of MRI findings at his most recent hospitalization, negative symptomatology, and strong history of schizophrenia make a primary psychotic disorder likely.

Following his future clinical course will be necessary to determine the etiology of his psychotic episodes. Future episodes of psychosis with neurologic symptoms would suggest a primary MS diagnosis and potential benefit of immunosuppressant treatment, whereas repeated psychotic breaks with minimal temporal lobe involvement or demyelination as seen on MRI would be suspicious for separate MS and psychotic disease processes. Further research on treatment regimens for patients experiencing psychosis as a manifestation of MS is still necessary.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that affects > 700,000 people in the US.¹ The hallmarks of MS pathology are axonal or neuronal loss, demyelination, and astrocytic gliosis. Of these, axonal or neuronal loss is the main underlying mechanism of permanent clinical disability.

MS also has been associated with an increased prevalence of psychiatric illnesses, with mood disorders affecting up to 40% to 60% of the population, and psychosis being reported in 2% to 4% of patients.² The link between MS and mood disorders, including bipolar disorder and depression, was documented as early as 1926,with mood disorders hypothesized to be manifestations of central nervous system (CNS) inflammation.³ More recently, inflammation-driven microglia have been hypothesized to impair hippocampal connectivity and activate glucocorticoid-insensitive inflammatory cells that then overstimulate the hypothalamic-pituitary-adrenal axis.^4,5

Although the prevalence of psychosis in patients with MS is significantly rarer, averaging between 2% and 4%.⁶ A Canadian study by Patten and colleagues reviewed data from 2.45 million residents of Alberta and found that those who identified as having MS had a 2% to 3% prevalence of psychosis compared with 0.5% to 1% in the general population.⁷ The connection between psychosis and MS, similar to that between mood disorders and MS, has been described as a common regional demyelination process. Supporting this, MS manifesting as psychosis has been found to present with distinct magnetic resonance imaging (MRI) findings, such as diffuse periventricular lesions.⁸ Still, no conclusive criteria have been developed to distinguish MS presenting as psychosis from a primary psychiatric illness, such as schizophrenia.

In patients with combat history, it is possible that both neurodegenerative and psychotic symptoms can be explained by autoantibody formation in response to toxin exposure. When soldiers were deployed to Iraq and Afghanistan, they may have been exposed to multiple toxicities, including depleted uranium, dust and fumes, and numerous infectious diseases.⁹ Gulf War illness (GWI) or chronic multisymptom illness (CMI) encompass a cluster of symptoms, such as chronic pain, chronic fatigue, irritable bowel syndrome, dermatitis, and seizures, as well as mental health issues such as depression and anxiety experienced following exposure to these combat environments.^10,11

In light of this diagnostic uncertainty, the authors detail a case of a patient with significant combat history previously diagnosed with MS and unspecified schizophrenia spectrum and other psychotic disorder (USS & OPD) presenting with acute psychosis.

Case Presentation

A 35-year-old male veteran, with a history of MS, USS & OPD, posttraumatic stress disorder, and traumatic brain injuries (TBIs) was admitted to the psychiatric unit after being found by the police lying in the middle of a busy intersection, internally preoccupied. On admission, he reported a week of auditory hallucinations from birds with whom he had been communicating telepathically, and a recurrent visual hallucination of a tall man in white and purple robes. He had discontinued his antipsychotic medication, aripiprazole 10 mg, a few weeks prior for unknown reasons. He was brought to the hospital by ambulance, where he presented with disorganized thinking, tangential thought process, and active auditory and visual hallucinations. The differential diagnoses included USS & OPD, schizophrenia, schizoaffective disorder and ruled out substance-induced psychotic disorder, and psychosis as a manifestation of MS.

The patient had 2 psychotic episodes prior to this presentation. He was hospitalized for his first psychotic break in 2015 at age 32, when he had tailed another car “to come back to reality” and ended up in a motor vehicle accident. During that admission, he reported weeks of thought broadcasting, conspiratorial delusions, and racing thoughts. Two years later, he was admitted to a psychiatric intensive care unit for his second episode of severe psychosis. After several trials of different antipsychotic medications, his most recent pharmacologic regimen was aripiprazole 10 mg once daily.

His medical history was complicated by 2 TBIs, in November 2014 and January 2015, with normal computed tomography (CT) scans. He was diagnosed with MS in December 2017, when he presented with intractable emesis, left facial numbness, right upper extremity ataxia, nystagmus, and imbalance. An MRI scan revealed multifocal bilateral hypodensities in his periventricular, subcortical, and brain stem white matter. Multiple areas of hyperintensity were visualized, including in the right periatrial region and left brachium pontis. More than 5 oligoclonal bands on lumbar puncture confirmed the diagnosis.

He was treated with IV methylprednisolone followed by a 2-week prednisone taper. Within 1 week, he returned to the psychiatric unit with worsening symptoms and received a second dose of IV steroids and plasma exchange treatment. In the following months, he completed a course of rituximab infusions and physical therapy for his dysarthria, gait abnormality, and vision impairment.

His social history was notable for multiple first-degree relatives with schizophrenia. He reported a history of sexual and verbal abuse and attempted suicide once at age 13 years by hanging himself with a bathrobe. He left home at age 18 years to serve in the Marine Corps (2001-2006). His service included deployment to Afghanistan, where he received a purple heart. Upon his return, he received BA and MS degrees. He married and had 2 daughters but became estranged from his wife. By his most recent admission, he was unemployed and living with his half-sister.

On the first day of this most recent psychiatric hospitalization, he was restarted on aripiprazole 10 mg daily, and a medicine consult was sought to evaluate the progression of his MS. No new onset neurologic symptoms were noted, but he had possible residual lower extremity hyperreflexia and tandem gait incoordination. The episodes of psychotic and neurologic symptoms appeared independent, given that his psychiatric history preceded the onset of his MS.

The patient reported no visual hallucinations starting day 2, and he no longer endorsed auditory hallucinations by day 3. However, he continued to appear internally preoccupied and was noticed to be pacing around the unit. On day 4 he presented with newly pressured speech and flights of ideas, while his affect remained euthymic and his sleep stayed consistent. In combination with his ongoing pacing, his newfound symptoms were hypothesized to be possibly akathisia, an adverse effect (AE) of aripiprazole. As such, on day 5 his dose was lowered to 5 mg daily. He continued to report no hallucinations and demonstrated progressively increased emotional range. A MRI scan was done on day 6 in case a new lesion could be identified, suggesting a primary MS flare-up; however, the scan identified no enhancing lesions, indicating no ongoing demyelination. After a neurology consult corroborated this conclusion, he was discharged in stable condition on day 7.

As is the case with the majority of patients with MS-induced psychosis, he continued to have relapsing psychiatric disease even after MS treatment had been started. Unfortunately, because this patient had stopped taking his atypical antipsychotic medication several weeks prior to his hospitalization, we cannot clarify whether his psychosis stems from a primary psychiatric vs MS process.

Discussion

Presently, treatment preferences for MS-related psychosis are divided between atypical antipsychotics and glucocorticoids. Some suggest that the treatment remains similar between MS-related psychosis and primary psychotic disorders in that atypical antipsychotics are the standard of care.¹² A variety of atypical antipsychotics have been used successfully in case reports, including zipradisone, risperidone, olanzapine, quetiapine, and aripiprazole.^13,14 First-generation antipsychotics and other psychotropic drugs that can precipitate extra-pyramidal AEs are not recommended given their potential additive effect to motor deficits associated with MS.¹² Alternatively, several case reports have found that MS-related psychotic symptoms respond to glucocorticoids more effectively, while cautioning that glucocorticoids can precipitate psychosis and depression.^15,16 One review article found that 90% of patients who received corticosteroids saw an improvement in their psychotic symptoms.²

Finally, it is possible that our patient’s neuropsychiatric symptoms can be explained by autoantibody formation in response to toxin exposure during his time in Afghanistan. In a pilot study of veterans with GWI, Abou-Donia and colleagues found 2-to-9 fold increase in autoantibody reactivity levels of the following neuronal and glial-specific proteins relative to healthy controls: neurofilament triplet proteins, tubulin, microtubule-associated tau proteins, microtubule-associated protein-2, myelin basic protein, myelin-associated glycoprotein, glial fibrillary acidic protein, and calcium-calmodulin kinase II.^17,18 Many of these autoantibodies are longstanding explicit markers for neurodegenerative disorders, given that they target proteins and antigens that support axonal transport and myelination. Still Gulf War veteran status has yet to be explicitly linked to an increased risk of MS,¹⁹ making this hypothesis less likely for our patient. Future research should address the clinical and therapeutic implications of different autoantibody levels in combat veterans with psychosis.

Conclusion

For patients with MS, mood disorder and psychotic symptoms should warrant a MRI given the possibility of a psychiatric manifestation of MS relapse. Ultimately, our patient’s presentation was inconsistent with the expected clinical presentations of both a primary psychotic disorder and psychosis as a manifestation of MS. His late age at his first psychotic break is atypical for primary psychotic disease, and the lack of MRI imaging done at his initial psychotic episodes cannot exclude a primary MS diagnosis. Still, his lack of MRI findings at his most recent hospitalization, negative symptomatology, and strong history of schizophrenia make a primary psychotic disorder likely.

Following his future clinical course will be necessary to determine the etiology of his psychotic episodes. Future episodes of psychosis with neurologic symptoms would suggest a primary MS diagnosis and potential benefit of immunosuppressant treatment, whereas repeated psychotic breaks with minimal temporal lobe involvement or demyelination as seen on MRI would be suspicious for separate MS and psychotic disease processes. Further research on treatment regimens for patients experiencing psychosis as a manifestation of MS is still necessary.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that affects > 700,000 people in the US.¹ The hallmarks of MS pathology are axonal or neuronal loss, demyelination, and astrocytic gliosis. Of these, axonal or neuronal loss is the main underlying mechanism of permanent clinical disability.

MS also has been associated with an increased prevalence of psychiatric illnesses, with mood disorders affecting up to 40% to 60% of the population, and psychosis being reported in 2% to 4% of patients.² The link between MS and mood disorders, including bipolar disorder and depression, was documented as early as 1926,with mood disorders hypothesized to be manifestations of central nervous system (CNS) inflammation.³ More recently, inflammation-driven microglia have been hypothesized to impair hippocampal connectivity and activate glucocorticoid-insensitive inflammatory cells that then overstimulate the hypothalamic-pituitary-adrenal axis.^4,5

Although the prevalence of psychosis in patients with MS is significantly rarer, averaging between 2% and 4%.⁶ A Canadian study by Patten and colleagues reviewed data from 2.45 million residents of Alberta and found that those who identified as having MS had a 2% to 3% prevalence of psychosis compared with 0.5% to 1% in the general population.⁷ The connection between psychosis and MS, similar to that between mood disorders and MS, has been described as a common regional demyelination process. Supporting this, MS manifesting as psychosis has been found to present with distinct magnetic resonance imaging (MRI) findings, such as diffuse periventricular lesions.⁸ Still, no conclusive criteria have been developed to distinguish MS presenting as psychosis from a primary psychiatric illness, such as schizophrenia.

In patients with combat history, it is possible that both neurodegenerative and psychotic symptoms can be explained by autoantibody formation in response to toxin exposure. When soldiers were deployed to Iraq and Afghanistan, they may have been exposed to multiple toxicities, including depleted uranium, dust and fumes, and numerous infectious diseases.⁹ Gulf War illness (GWI) or chronic multisymptom illness (CMI) encompass a cluster of symptoms, such as chronic pain, chronic fatigue, irritable bowel syndrome, dermatitis, and seizures, as well as mental health issues such as depression and anxiety experienced following exposure to these combat environments.^10,11

In light of this diagnostic uncertainty, the authors detail a case of a patient with significant combat history previously diagnosed with MS and unspecified schizophrenia spectrum and other psychotic disorder (USS & OPD) presenting with acute psychosis.

Case Presentation

A 35-year-old male veteran, with a history of MS, USS & OPD, posttraumatic stress disorder, and traumatic brain injuries (TBIs) was admitted to the psychiatric unit after being found by the police lying in the middle of a busy intersection, internally preoccupied. On admission, he reported a week of auditory hallucinations from birds with whom he had been communicating telepathically, and a recurrent visual hallucination of a tall man in white and purple robes. He had discontinued his antipsychotic medication, aripiprazole 10 mg, a few weeks prior for unknown reasons. He was brought to the hospital by ambulance, where he presented with disorganized thinking, tangential thought process, and active auditory and visual hallucinations. The differential diagnoses included USS & OPD, schizophrenia, schizoaffective disorder and ruled out substance-induced psychotic disorder, and psychosis as a manifestation of MS.

The patient had 2 psychotic episodes prior to this presentation. He was hospitalized for his first psychotic break in 2015 at age 32, when he had tailed another car “to come back to reality” and ended up in a motor vehicle accident. During that admission, he reported weeks of thought broadcasting, conspiratorial delusions, and racing thoughts. Two years later, he was admitted to a psychiatric intensive care unit for his second episode of severe psychosis. After several trials of different antipsychotic medications, his most recent pharmacologic regimen was aripiprazole 10 mg once daily.

His medical history was complicated by 2 TBIs, in November 2014 and January 2015, with normal computed tomography (CT) scans. He was diagnosed with MS in December 2017, when he presented with intractable emesis, left facial numbness, right upper extremity ataxia, nystagmus, and imbalance. An MRI scan revealed multifocal bilateral hypodensities in his periventricular, subcortical, and brain stem white matter. Multiple areas of hyperintensity were visualized, including in the right periatrial region and left brachium pontis. More than 5 oligoclonal bands on lumbar puncture confirmed the diagnosis.

He was treated with IV methylprednisolone followed by a 2-week prednisone taper. Within 1 week, he returned to the psychiatric unit with worsening symptoms and received a second dose of IV steroids and plasma exchange treatment. In the following months, he completed a course of rituximab infusions and physical therapy for his dysarthria, gait abnormality, and vision impairment.

His social history was notable for multiple first-degree relatives with schizophrenia. He reported a history of sexual and verbal abuse and attempted suicide once at age 13 years by hanging himself with a bathrobe. He left home at age 18 years to serve in the Marine Corps (2001-2006). His service included deployment to Afghanistan, where he received a purple heart. Upon his return, he received BA and MS degrees. He married and had 2 daughters but became estranged from his wife. By his most recent admission, he was unemployed and living with his half-sister.

On the first day of this most recent psychiatric hospitalization, he was restarted on aripiprazole 10 mg daily, and a medicine consult was sought to evaluate the progression of his MS. No new onset neurologic symptoms were noted, but he had possible residual lower extremity hyperreflexia and tandem gait incoordination. The episodes of psychotic and neurologic symptoms appeared independent, given that his psychiatric history preceded the onset of his MS.

The patient reported no visual hallucinations starting day 2, and he no longer endorsed auditory hallucinations by day 3. However, he continued to appear internally preoccupied and was noticed to be pacing around the unit. On day 4 he presented with newly pressured speech and flights of ideas, while his affect remained euthymic and his sleep stayed consistent. In combination with his ongoing pacing, his newfound symptoms were hypothesized to be possibly akathisia, an adverse effect (AE) of aripiprazole. As such, on day 5 his dose was lowered to 5 mg daily. He continued to report no hallucinations and demonstrated progressively increased emotional range. A MRI scan was done on day 6 in case a new lesion could be identified, suggesting a primary MS flare-up; however, the scan identified no enhancing lesions, indicating no ongoing demyelination. After a neurology consult corroborated this conclusion, he was discharged in stable condition on day 7.

As is the case with the majority of patients with MS-induced psychosis, he continued to have relapsing psychiatric disease even after MS treatment had been started. Unfortunately, because this patient had stopped taking his atypical antipsychotic medication several weeks prior to his hospitalization, we cannot clarify whether his psychosis stems from a primary psychiatric vs MS process.

Discussion

Presently, treatment preferences for MS-related psychosis are divided between atypical antipsychotics and glucocorticoids. Some suggest that the treatment remains similar between MS-related psychosis and primary psychotic disorders in that atypical antipsychotics are the standard of care.¹² A variety of atypical antipsychotics have been used successfully in case reports, including zipradisone, risperidone, olanzapine, quetiapine, and aripiprazole.^13,14 First-generation antipsychotics and other psychotropic drugs that can precipitate extra-pyramidal AEs are not recommended given their potential additive effect to motor deficits associated with MS.¹² Alternatively, several case reports have found that MS-related psychotic symptoms respond to glucocorticoids more effectively, while cautioning that glucocorticoids can precipitate psychosis and depression.^15,16 One review article found that 90% of patients who received corticosteroids saw an improvement in their psychotic symptoms.²

Finally, it is possible that our patient’s neuropsychiatric symptoms can be explained by autoantibody formation in response to toxin exposure during his time in Afghanistan. In a pilot study of veterans with GWI, Abou-Donia and colleagues found 2-to-9 fold increase in autoantibody reactivity levels of the following neuronal and glial-specific proteins relative to healthy controls: neurofilament triplet proteins, tubulin, microtubule-associated tau proteins, microtubule-associated protein-2, myelin basic protein, myelin-associated glycoprotein, glial fibrillary acidic protein, and calcium-calmodulin kinase II.^17,18 Many of these autoantibodies are longstanding explicit markers for neurodegenerative disorders, given that they target proteins and antigens that support axonal transport and myelination. Still Gulf War veteran status has yet to be explicitly linked to an increased risk of MS,¹⁹ making this hypothesis less likely for our patient. Future research should address the clinical and therapeutic implications of different autoantibody levels in combat veterans with psychosis.

Conclusion

For patients with MS, mood disorder and psychotic symptoms should warrant a MRI given the possibility of a psychiatric manifestation of MS relapse. Ultimately, our patient’s presentation was inconsistent with the expected clinical presentations of both a primary psychotic disorder and psychosis as a manifestation of MS. His late age at his first psychotic break is atypical for primary psychotic disease, and the lack of MRI imaging done at his initial psychotic episodes cannot exclude a primary MS diagnosis. Still, his lack of MRI findings at his most recent hospitalization, negative symptomatology, and strong history of schizophrenia make a primary psychotic disorder likely.

Following his future clinical course will be necessary to determine the etiology of his psychotic episodes. Future episodes of psychosis with neurologic symptoms would suggest a primary MS diagnosis and potential benefit of immunosuppressant treatment, whereas repeated psychotic breaks with minimal temporal lobe involvement or demyelination as seen on MRI would be suspicious for separate MS and psychotic disease processes. Further research on treatment regimens for patients experiencing psychosis as a manifestation of MS is still necessary.

Hemolytic uremic syndrome (HUS) is a rare illness that can be acquired through the consumption of food products contaminated with strains of Shiga toxin-producing Escherichia coli (E coli; STEC).¹ Between 6% and 15% of individuals infected with STEC develop HUS, with children affected more frequently than adults.^2,3 This strain of E coli releases Shiga toxin into the systemic circulation, which causes a thrombotic microangiopathy resulting in the characteristic HUS triad of symptoms: acute renal insufficiency, thrombocytopenia, and hemolytic anemia.^4-6

Although neurologic features are common in HUS, they have not been extensively studied, particularly in adults. We report a case of STEC 0157:H7 subtype HUS in an adult with severe neurologic complications. This case highlights the neurological sequelae in an adult with typical STEC-HUS. The use of treatment modalities, such as plasmapheresis and eculizumab, and their use in adult typical STEC-HUS also is explored.

Case

A 53-year-old white woman with no pertinent past medical history presented to the Bay Pines Veterans Affairs Healthcare System Emergency Department with a 2-day history of abdominal pain, vomiting, nausea, diarrhea, and bright bloody stools. She returned from a cruise to the Bahamas 3 days prior, where she ate local foods, including salads. She reported no fever, shortness of breath, chest pain, headache, and cognitive difficulties. She presented with a normal mental status and neurologic exam. Apart from leukocytosis and elevated glucose level, her laboratory results at initial presentation were normal, (Table). A stool sample showed occult blood with white blood cell counts (WBCs) but was negative for Clostridium difficile. She was started on ciprofloxacin 400 mg and metronidazole 500 mg on the day of admission.

Hematuria was found on hospital day 2. On hospital day 4, the patient exhibited word finding difficulties. Blood studies revealed anemia, thrombocytopenia, leukocytosis, and increasing blood urea nitrogen (BUN) and creatinine. A computed tomography scan of the head was normal. Laboratory analysis showed schistocytes in the peripheral blood smear.

The patient’s cognitive functioning deteriorated on hospital day 5. She was not oriented to time or place. Her laboratory results showed complement level C3 at 70 mg/dL (ref: 83-193 mg/dL) complement C4 at 12 mg/dL (ref: 15-57mg/dL). The patient exhibited oliguria and hyponatremia, as well as both metabolic and respiratory acidosis; dialysis was then initiated. Results from the stool sample that was collected on hospital day 1 were received and tested positive for Shiga toxin.

At this point, the patient’s presentation of hemolytic anemia and thrombocytopenia in the setting of acute bloody diarrheal illness with known Shiga toxin, schistocytes on blood smear, and lack of pertinent medical history for other causes of this presentation made STEC-HUS the leading differential diagnosis. Plasmapheresis was ordered and performed on hospital day 6 and 7. Shiga toxin was no longer detected in the stool and antibiotics were stopped on hospital day 7.

The patient’s progressive deterioration in mental status continued on hospital day 8. She was not oriented to time or place, unable to perform simple calculations, and could not spell the word “hand” backwards. Physicians observed repetitive jerking motions of the upper extremities that were worse on the left side. An electroencephalogram (EEG) revealed right hemispheric sharp waves that were thought to be epileptiform (Figure 1). The patient began taking levetiracetam 1500 mg IV with 750 mg bid maintenance for seizure control. Plasmapheresis was discontinued due to her continued neurologic deterioration on this therapy. Consequently, eculizumab 900 mg IV was given along with the Neisseria meningitidis (N meningitidis) vaccine and a 19-day course of azithromycin 250 mg po as prophylaxis for encapsulated bacteria.

The patient continued to seize on hospital days 10 through 13. Oculocephalic maneuvers showed a tendency to keep her eyes deviated to the right. Her pupils continued to react to light. A repeat EEG showed diffuse slowing (5-6 Hz) with no epileptic activity seen (Figure 2). A second dose of eculizumab 900 mg IV was administered on hospital day 15. The patient experienced cardiac arrest on hospital day 16 and was successfully resuscitated. On hospital day 25 (10 days after receiving her second dose of eculizumab), the patient was able to speak and follow simple commands but exhibited difficulty concentrating and poor impulse control.

The patient was alert and oriented to person, place, time, and situation on hospital day 28 (6 days after the third and final dose of eculizumab). A neurologic exam was significant only for a slight intention tremor. She was continued on levetiracetam with a plan to be maintained on the medication for the next 6 months for seizure control. She was discharged on hospital day 30.

Twenty-eight days postdischarge (57 days postadmission), the patient showed marked recovery. She had returned to her previous employment as a business administrator on a part-time basis and exhibited no deficiencies in executive functioning or handling activities of daily living. Although she had been very active prior to this illness, she now experienced decreased physical and mental endurance; however, this gradually improved with physical therapy. She planned on returning to work on a full-time basis when she had regained her stamina. She also noticed difficulties in retaining short term memory since her discharge but believed that these symptoms were remitting. On examination her mental status and neurologic exam was significant for inability to continue serial 7s, left sided 4/5 muscle strength in quadriceps and thumb to 5th metacarpal adduction, bilateral 1+ reflexes in muscle groups tested (triceps, biceps, brachioradialis, patellar, and Achilles), loss of dull pinprick sensation bilaterally at web of hands, deficit in tandem gait while looking away, and slight intention tremor on finger to nose testing bilaterally (with left hand tremor more pronounced than right). Her complete blood count was normal. Her recovery continues to be monitored in an outpatient setting.

Discussion

HUS is characterized by 3 core clinical features: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.⁴ Schistocytes are seen on peripheral blood smear and occur due to the passage of red blood cells over the microvascular thrombi induced by the disease. HUS can be classified as typical, atypical, or occurring with a coexisting disease. Typical HUS is associated with STEC 0157:H7 subtype, a bacterium known to be acquired through contaminated food and via human-to-human transmission.^6-8 In the case of typical STEC 0157:H7, the bacterium releases a verotoxin that damages the vascular endothelium, thereby leading to activation of the coagulation cascade and eventually the formation of thrombi.⁴ It has been hypothesized that the Shiga toxin also activates the alternative complement pathway directly, which could contribute to thrombosis.⁹ This would explain the findings of low complement levels in our patient. Atypical HUS is primarily attributable to mutations in the alternative complement pathway. Causes for the third type of HUS can include Streptococcus pneumoniae, HIV, drug toxicity, and alterations in the metabolism of cobalamin C.

Epidemiologically, 15.3% of children aged < 5 years develop typical HUS after exposure to STEC compared with 1.2% of adults aged 18 to 59 years. The median age of patients who developed HUS from STEC exposure was 4 years compared with 16 years for those who did not develop HUS.²

Neurologic manifestations increase mortality for HUS patients.¹⁰ These have been described in the pediatric population as alteration in consciousness (85%), seizures (71%), pyramidal syndrome (52%), and extrapyramidal syndrome with hypertonia (42%).¹¹ Brain imaging in children has demonstrated hemorrhagic lesions involving the pons, basal ganglia, and occipital cortex.¹¹ Blood flow to areas such as the cerebellum, brainstem, and orbitofrontal area can be compromised.¹⁰ Adult patients with HUS can present without lesions on cranial magnetic resonance imaging (MRI), but instead with transient symmetric vasogenic edema of the central brain stem.¹² Unfortunately in this case, MRI was not performed because it was thought to provide limited aid in diagnosis and to avoid unnecessary testing for the acutely ill patient.

The underlying pathophysiology of neurologic manifestations in patients may be due to a metabolic disturbance, toxin-mediated damage of the vascular endothelium, or toxin-induced cytokine release resulting in death of neural cells and subsequent neuroinflammation. However, the most likely mechanism is parenchymal ischemic changes related to microangiopathy.^11,13 Pediatric patients often experience seizures and altered mental status, and their EEGs display delta waves.¹³ This patient’s diffuse slowing on her second EEG and altered mental status suggests that the neuropathologic mechanisms for typical HUS in adults may be similar to those in children.

HUS Treatment

The treatment and management of adults with typical STEC-HUS is evolving. The patient was first suspected to have an infectious colitis and empiric antibiotics were initiated. Some studies suggest that antibiotic administration may worsen the course of HUS in children as it may lead to release and subsequent absorption of Shiga toxin in the intestine.^9,14 However, there is little evidence to suggest harm or efficacy of administration in adults. It is unclear what role antibiotic administration played in the recovery time of HUS given the co-administration of other treatments such as eculizumab and plasmapheresis, but it does appear to have helped with the initial E coli infection.

Plasmapheresis was subsequently administered, due to its documented benefit in the treatment of HUS.¹⁵ However, it should be noted that even though plasmapheresis is currently used in patients with CNS involvement, it remains unproven with conflicting information on its efficacy.^3,16 The mechanism of action is unclear, but it has been hypothesized that plasmapheresis prevents microangiopathy caused by microthrombi.^3,16 For this reason, eculizumab is becoming the mainstay for treatment of STEC-HUS with neurologic complications given the lack of well researched alternative treatments. In this case study, the use of plasmapheresis did not result in clinical improvement, and was abandoned after 2 days of treatment.

Eculizumab is a humanized, recombinant monoclonal IgG antibody that is a terminal complement inhibitor of the alternative complement system at the final step to cleave C5.¹⁷ The Shiga toxin may directly activate the complement system via the alternative pathway, which can result in uncontrolled platelet and white blood cell activation and depletion, endothelial cell damage, and hemolysis. The galvanized complement system leads to a series of cascading events that contribute to organ damage and death.⁹ Eculizumab is FDA approved for use in atypical HUS.¹⁸ It also can be used off-label to treat typical-HUS in adults with neurologic complications.

Eculizumab interferes with the immune response against encapsulated bacteria because it inhibits the alternative complement pathway. Thus, vaccination against N meningitides is recommended 2 weeks prior to the administration of eculizumab. However, in situations where the risks of delaying eculizumab for 2 weeks are greater than the risk of developing an N meningitides infection, eculizumab may be given without delay.¹⁸ Given the rapid deterioration of our patient’s condition, the vaccine and eculizumab were given together with prophylactic azithromycin. Although penicillin is the standard for prophylaxis in this situation, the patient’s penicillin allergy led to the use of azithromycin 250 mg po once a day. Literature also suggests azithromycin reduces the carriage duration of E coli-induced colitis.¹⁹ As such, it is possible that some improvement in the patient’s condition could be attributed to the elimination of the pathogen and toxin.

Conclusion

Three doses of eculizumab were administered at weekly intervals, with the first dose on hospital day 8 and the final dose on hospital day 22. Prior to the first dose, the patient displayed significant decline in mental status with EEG findings of right hemisphere epileptogenic discharges. After her third dose, she was found to have a drastically improved mental status exam and a normal EEG. One week later, she was discharged home. At the time of her 1-month follow-up, she was independent in all activities of daily living and had returned to part-time work. Apart from subtle cognitive changes, the remainder of her neurologic exam was normal.

There is evidence that supports the efficacy of eculizumab in children with HUS with neurologic symptoms on dialysis.²⁰ However, its use in adults is not well established.²¹ This patient required dialysis and had neurologic symptoms similar to pediatric patients described in the literature, and responded similarly to the eculizumab. The rationale for the use of eculizumab in STEC-HUS also is evidenced by in vitro demonstrations of complement activation in STEC-HUS.^22-25 This case report adds to the literature supporting the use of eculizumab in adult patients with typical HUS with neurological complications. Further research is necessary to develop guidelines in the treatment of adult STEC-HUS with regards to neurologic complications.

Acknowledgments

The authors would like to thank Pete DiStaso, REEGT for his work on obtaining the electroencephalograms and Anthony Rinaldi, PsyD; Julie Cessnapalas, PsyD; and Syed Faizan Sagheer for proof-reading the article.

Hemolytic uremic syndrome (HUS) is a rare illness that can be acquired through the consumption of food products contaminated with strains of Shiga toxin-producing Escherichia coli (E coli; STEC).¹ Between 6% and 15% of individuals infected with STEC develop HUS, with children affected more frequently than adults.^2,3 This strain of E coli releases Shiga toxin into the systemic circulation, which causes a thrombotic microangiopathy resulting in the characteristic HUS triad of symptoms: acute renal insufficiency, thrombocytopenia, and hemolytic anemia.^4-6

Although neurologic features are common in HUS, they have not been extensively studied, particularly in adults. We report a case of STEC 0157:H7 subtype HUS in an adult with severe neurologic complications. This case highlights the neurological sequelae in an adult with typical STEC-HUS. The use of treatment modalities, such as plasmapheresis and eculizumab, and their use in adult typical STEC-HUS also is explored.

Case

A 53-year-old white woman with no pertinent past medical history presented to the Bay Pines Veterans Affairs Healthcare System Emergency Department with a 2-day history of abdominal pain, vomiting, nausea, diarrhea, and bright bloody stools. She returned from a cruise to the Bahamas 3 days prior, where she ate local foods, including salads. She reported no fever, shortness of breath, chest pain, headache, and cognitive difficulties. She presented with a normal mental status and neurologic exam. Apart from leukocytosis and elevated glucose level, her laboratory results at initial presentation were normal, (Table). A stool sample showed occult blood with white blood cell counts (WBCs) but was negative for Clostridium difficile. She was started on ciprofloxacin 400 mg and metronidazole 500 mg on the day of admission.

Hematuria was found on hospital day 2. On hospital day 4, the patient exhibited word finding difficulties. Blood studies revealed anemia, thrombocytopenia, leukocytosis, and increasing blood urea nitrogen (BUN) and creatinine. A computed tomography scan of the head was normal. Laboratory analysis showed schistocytes in the peripheral blood smear.

The patient’s cognitive functioning deteriorated on hospital day 5. She was not oriented to time or place. Her laboratory results showed complement level C3 at 70 mg/dL (ref: 83-193 mg/dL) complement C4 at 12 mg/dL (ref: 15-57mg/dL). The patient exhibited oliguria and hyponatremia, as well as both metabolic and respiratory acidosis; dialysis was then initiated. Results from the stool sample that was collected on hospital day 1 were received and tested positive for Shiga toxin.

At this point, the patient’s presentation of hemolytic anemia and thrombocytopenia in the setting of acute bloody diarrheal illness with known Shiga toxin, schistocytes on blood smear, and lack of pertinent medical history for other causes of this presentation made STEC-HUS the leading differential diagnosis. Plasmapheresis was ordered and performed on hospital day 6 and 7. Shiga toxin was no longer detected in the stool and antibiotics were stopped on hospital day 7.

The patient’s progressive deterioration in mental status continued on hospital day 8. She was not oriented to time or place, unable to perform simple calculations, and could not spell the word “hand” backwards. Physicians observed repetitive jerking motions of the upper extremities that were worse on the left side. An electroencephalogram (EEG) revealed right hemispheric sharp waves that were thought to be epileptiform (Figure 1). The patient began taking levetiracetam 1500 mg IV with 750 mg bid maintenance for seizure control. Plasmapheresis was discontinued due to her continued neurologic deterioration on this therapy. Consequently, eculizumab 900 mg IV was given along with the Neisseria meningitidis (N meningitidis) vaccine and a 19-day course of azithromycin 250 mg po as prophylaxis for encapsulated bacteria.

The patient continued to seize on hospital days 10 through 13. Oculocephalic maneuvers showed a tendency to keep her eyes deviated to the right. Her pupils continued to react to light. A repeat EEG showed diffuse slowing (5-6 Hz) with no epileptic activity seen (Figure 2). A second dose of eculizumab 900 mg IV was administered on hospital day 15. The patient experienced cardiac arrest on hospital day 16 and was successfully resuscitated. On hospital day 25 (10 days after receiving her second dose of eculizumab), the patient was able to speak and follow simple commands but exhibited difficulty concentrating and poor impulse control.

The patient was alert and oriented to person, place, time, and situation on hospital day 28 (6 days after the third and final dose of eculizumab). A neurologic exam was significant only for a slight intention tremor. She was continued on levetiracetam with a plan to be maintained on the medication for the next 6 months for seizure control. She was discharged on hospital day 30.

Twenty-eight days postdischarge (57 days postadmission), the patient showed marked recovery. She had returned to her previous employment as a business administrator on a part-time basis and exhibited no deficiencies in executive functioning or handling activities of daily living. Although she had been very active prior to this illness, she now experienced decreased physical and mental endurance; however, this gradually improved with physical therapy. She planned on returning to work on a full-time basis when she had regained her stamina. She also noticed difficulties in retaining short term memory since her discharge but believed that these symptoms were remitting. On examination her mental status and neurologic exam was significant for inability to continue serial 7s, left sided 4/5 muscle strength in quadriceps and thumb to 5th metacarpal adduction, bilateral 1+ reflexes in muscle groups tested (triceps, biceps, brachioradialis, patellar, and Achilles), loss of dull pinprick sensation bilaterally at web of hands, deficit in tandem gait while looking away, and slight intention tremor on finger to nose testing bilaterally (with left hand tremor more pronounced than right). Her complete blood count was normal. Her recovery continues to be monitored in an outpatient setting.

Discussion

HUS is characterized by 3 core clinical features: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.⁴ Schistocytes are seen on peripheral blood smear and occur due to the passage of red blood cells over the microvascular thrombi induced by the disease. HUS can be classified as typical, atypical, or occurring with a coexisting disease. Typical HUS is associated with STEC 0157:H7 subtype, a bacterium known to be acquired through contaminated food and via human-to-human transmission.^6-8 In the case of typical STEC 0157:H7, the bacterium releases a verotoxin that damages the vascular endothelium, thereby leading to activation of the coagulation cascade and eventually the formation of thrombi.⁴ It has been hypothesized that the Shiga toxin also activates the alternative complement pathway directly, which could contribute to thrombosis.⁹ This would explain the findings of low complement levels in our patient. Atypical HUS is primarily attributable to mutations in the alternative complement pathway. Causes for the third type of HUS can include Streptococcus pneumoniae, HIV, drug toxicity, and alterations in the metabolism of cobalamin C.

Epidemiologically, 15.3% of children aged < 5 years develop typical HUS after exposure to STEC compared with 1.2% of adults aged 18 to 59 years. The median age of patients who developed HUS from STEC exposure was 4 years compared with 16 years for those who did not develop HUS.²

Neurologic manifestations increase mortality for HUS patients.¹⁰ These have been described in the pediatric population as alteration in consciousness (85%), seizures (71%), pyramidal syndrome (52%), and extrapyramidal syndrome with hypertonia (42%).¹¹ Brain imaging in children has demonstrated hemorrhagic lesions involving the pons, basal ganglia, and occipital cortex.¹¹ Blood flow to areas such as the cerebellum, brainstem, and orbitofrontal area can be compromised.¹⁰ Adult patients with HUS can present without lesions on cranial magnetic resonance imaging (MRI), but instead with transient symmetric vasogenic edema of the central brain stem.¹² Unfortunately in this case, MRI was not performed because it was thought to provide limited aid in diagnosis and to avoid unnecessary testing for the acutely ill patient.

The underlying pathophysiology of neurologic manifestations in patients may be due to a metabolic disturbance, toxin-mediated damage of the vascular endothelium, or toxin-induced cytokine release resulting in death of neural cells and subsequent neuroinflammation. However, the most likely mechanism is parenchymal ischemic changes related to microangiopathy.^11,13 Pediatric patients often experience seizures and altered mental status, and their EEGs display delta waves.¹³ This patient’s diffuse slowing on her second EEG and altered mental status suggests that the neuropathologic mechanisms for typical HUS in adults may be similar to those in children.

HUS Treatment

The treatment and management of adults with typical STEC-HUS is evolving. The patient was first suspected to have an infectious colitis and empiric antibiotics were initiated. Some studies suggest that antibiotic administration may worsen the course of HUS in children as it may lead to release and subsequent absorption of Shiga toxin in the intestine.^9,14 However, there is little evidence to suggest harm or efficacy of administration in adults. It is unclear what role antibiotic administration played in the recovery time of HUS given the co-administration of other treatments such as eculizumab and plasmapheresis, but it does appear to have helped with the initial E coli infection.

Plasmapheresis was subsequently administered, due to its documented benefit in the treatment of HUS.¹⁵ However, it should be noted that even though plasmapheresis is currently used in patients with CNS involvement, it remains unproven with conflicting information on its efficacy.^3,16 The mechanism of action is unclear, but it has been hypothesized that plasmapheresis prevents microangiopathy caused by microthrombi.^3,16 For this reason, eculizumab is becoming the mainstay for treatment of STEC-HUS with neurologic complications given the lack of well researched alternative treatments. In this case study, the use of plasmapheresis did not result in clinical improvement, and was abandoned after 2 days of treatment.

Eculizumab is a humanized, recombinant monoclonal IgG antibody that is a terminal complement inhibitor of the alternative complement system at the final step to cleave C5.¹⁷ The Shiga toxin may directly activate the complement system via the alternative pathway, which can result in uncontrolled platelet and white blood cell activation and depletion, endothelial cell damage, and hemolysis. The galvanized complement system leads to a series of cascading events that contribute to organ damage and death.⁹ Eculizumab is FDA approved for use in atypical HUS.¹⁸ It also can be used off-label to treat typical-HUS in adults with neurologic complications.

Eculizumab interferes with the immune response against encapsulated bacteria because it inhibits the alternative complement pathway. Thus, vaccination against N meningitides is recommended 2 weeks prior to the administration of eculizumab. However, in situations where the risks of delaying eculizumab for 2 weeks are greater than the risk of developing an N meningitides infection, eculizumab may be given without delay.¹⁸ Given the rapid deterioration of our patient’s condition, the vaccine and eculizumab were given together with prophylactic azithromycin. Although penicillin is the standard for prophylaxis in this situation, the patient’s penicillin allergy led to the use of azithromycin 250 mg po once a day. Literature also suggests azithromycin reduces the carriage duration of E coli-induced colitis.¹⁹ As such, it is possible that some improvement in the patient’s condition could be attributed to the elimination of the pathogen and toxin.

Conclusion

Three doses of eculizumab were administered at weekly intervals, with the first dose on hospital day 8 and the final dose on hospital day 22. Prior to the first dose, the patient displayed significant decline in mental status with EEG findings of right hemisphere epileptogenic discharges. After her third dose, she was found to have a drastically improved mental status exam and a normal EEG. One week later, she was discharged home. At the time of her 1-month follow-up, she was independent in all activities of daily living and had returned to part-time work. Apart from subtle cognitive changes, the remainder of her neurologic exam was normal.

There is evidence that supports the efficacy of eculizumab in children with HUS with neurologic symptoms on dialysis.²⁰ However, its use in adults is not well established.²¹ This patient required dialysis and had neurologic symptoms similar to pediatric patients described in the literature, and responded similarly to the eculizumab. The rationale for the use of eculizumab in STEC-HUS also is evidenced by in vitro demonstrations of complement activation in STEC-HUS.^22-25 This case report adds to the literature supporting the use of eculizumab in adult patients with typical HUS with neurological complications. Further research is necessary to develop guidelines in the treatment of adult STEC-HUS with regards to neurologic complications.

Acknowledgments

The authors would like to thank Pete DiStaso, REEGT for his work on obtaining the electroencephalograms and Anthony Rinaldi, PsyD; Julie Cessnapalas, PsyD; and Syed Faizan Sagheer for proof-reading the article.

Hemolytic uremic syndrome (HUS) is a rare illness that can be acquired through the consumption of food products contaminated with strains of Shiga toxin-producing Escherichia coli (E coli; STEC).¹ Between 6% and 15% of individuals infected with STEC develop HUS, with children affected more frequently than adults.^2,3 This strain of E coli releases Shiga toxin into the systemic circulation, which causes a thrombotic microangiopathy resulting in the characteristic HUS triad of symptoms: acute renal insufficiency, thrombocytopenia, and hemolytic anemia.^4-6

Although neurologic features are common in HUS, they have not been extensively studied, particularly in adults. We report a case of STEC 0157:H7 subtype HUS in an adult with severe neurologic complications. This case highlights the neurological sequelae in an adult with typical STEC-HUS. The use of treatment modalities, such as plasmapheresis and eculizumab, and their use in adult typical STEC-HUS also is explored.

Case

A 53-year-old white woman with no pertinent past medical history presented to the Bay Pines Veterans Affairs Healthcare System Emergency Department with a 2-day history of abdominal pain, vomiting, nausea, diarrhea, and bright bloody stools. She returned from a cruise to the Bahamas 3 days prior, where she ate local foods, including salads. She reported no fever, shortness of breath, chest pain, headache, and cognitive difficulties. She presented with a normal mental status and neurologic exam. Apart from leukocytosis and elevated glucose level, her laboratory results at initial presentation were normal, (Table). A stool sample showed occult blood with white blood cell counts (WBCs) but was negative for Clostridium difficile. She was started on ciprofloxacin 400 mg and metronidazole 500 mg on the day of admission.

Hematuria was found on hospital day 2. On hospital day 4, the patient exhibited word finding difficulties. Blood studies revealed anemia, thrombocytopenia, leukocytosis, and increasing blood urea nitrogen (BUN) and creatinine. A computed tomography scan of the head was normal. Laboratory analysis showed schistocytes in the peripheral blood smear.

The patient’s cognitive functioning deteriorated on hospital day 5. She was not oriented to time or place. Her laboratory results showed complement level C3 at 70 mg/dL (ref: 83-193 mg/dL) complement C4 at 12 mg/dL (ref: 15-57mg/dL). The patient exhibited oliguria and hyponatremia, as well as both metabolic and respiratory acidosis; dialysis was then initiated. Results from the stool sample that was collected on hospital day 1 were received and tested positive for Shiga toxin.

At this point, the patient’s presentation of hemolytic anemia and thrombocytopenia in the setting of acute bloody diarrheal illness with known Shiga toxin, schistocytes on blood smear, and lack of pertinent medical history for other causes of this presentation made STEC-HUS the leading differential diagnosis. Plasmapheresis was ordered and performed on hospital day 6 and 7. Shiga toxin was no longer detected in the stool and antibiotics were stopped on hospital day 7.

The patient’s progressive deterioration in mental status continued on hospital day 8. She was not oriented to time or place, unable to perform simple calculations, and could not spell the word “hand” backwards. Physicians observed repetitive jerking motions of the upper extremities that were worse on the left side. An electroencephalogram (EEG) revealed right hemispheric sharp waves that were thought to be epileptiform (Figure 1). The patient began taking levetiracetam 1500 mg IV with 750 mg bid maintenance for seizure control. Plasmapheresis was discontinued due to her continued neurologic deterioration on this therapy. Consequently, eculizumab 900 mg IV was given along with the Neisseria meningitidis (N meningitidis) vaccine and a 19-day course of azithromycin 250 mg po as prophylaxis for encapsulated bacteria.

The patient continued to seize on hospital days 10 through 13. Oculocephalic maneuvers showed a tendency to keep her eyes deviated to the right. Her pupils continued to react to light. A repeat EEG showed diffuse slowing (5-6 Hz) with no epileptic activity seen (Figure 2). A second dose of eculizumab 900 mg IV was administered on hospital day 15. The patient experienced cardiac arrest on hospital day 16 and was successfully resuscitated. On hospital day 25 (10 days after receiving her second dose of eculizumab), the patient was able to speak and follow simple commands but exhibited difficulty concentrating and poor impulse control.

The patient was alert and oriented to person, place, time, and situation on hospital day 28 (6 days after the third and final dose of eculizumab). A neurologic exam was significant only for a slight intention tremor. She was continued on levetiracetam with a plan to be maintained on the medication for the next 6 months for seizure control. She was discharged on hospital day 30.

Twenty-eight days postdischarge (57 days postadmission), the patient showed marked recovery. She had returned to her previous employment as a business administrator on a part-time basis and exhibited no deficiencies in executive functioning or handling activities of daily living. Although she had been very active prior to this illness, she now experienced decreased physical and mental endurance; however, this gradually improved with physical therapy. She planned on returning to work on a full-time basis when she had regained her stamina. She also noticed difficulties in retaining short term memory since her discharge but believed that these symptoms were remitting. On examination her mental status and neurologic exam was significant for inability to continue serial 7s, left sided 4/5 muscle strength in quadriceps and thumb to 5th metacarpal adduction, bilateral 1+ reflexes in muscle groups tested (triceps, biceps, brachioradialis, patellar, and Achilles), loss of dull pinprick sensation bilaterally at web of hands, deficit in tandem gait while looking away, and slight intention tremor on finger to nose testing bilaterally (with left hand tremor more pronounced than right). Her complete blood count was normal. Her recovery continues to be monitored in an outpatient setting.

Discussion

HUS is characterized by 3 core clinical features: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.⁴ Schistocytes are seen on peripheral blood smear and occur due to the passage of red blood cells over the microvascular thrombi induced by the disease. HUS can be classified as typical, atypical, or occurring with a coexisting disease. Typical HUS is associated with STEC 0157:H7 subtype, a bacterium known to be acquired through contaminated food and via human-to-human transmission.^6-8 In the case of typical STEC 0157:H7, the bacterium releases a verotoxin that damages the vascular endothelium, thereby leading to activation of the coagulation cascade and eventually the formation of thrombi.⁴ It has been hypothesized that the Shiga toxin also activates the alternative complement pathway directly, which could contribute to thrombosis.⁹ This would explain the findings of low complement levels in our patient. Atypical HUS is primarily attributable to mutations in the alternative complement pathway. Causes for the third type of HUS can include Streptococcus pneumoniae, HIV, drug toxicity, and alterations in the metabolism of cobalamin C.

Epidemiologically, 15.3% of children aged < 5 years develop typical HUS after exposure to STEC compared with 1.2% of adults aged 18 to 59 years. The median age of patients who developed HUS from STEC exposure was 4 years compared with 16 years for those who did not develop HUS.²

Neurologic manifestations increase mortality for HUS patients.¹⁰ These have been described in the pediatric population as alteration in consciousness (85%), seizures (71%), pyramidal syndrome (52%), and extrapyramidal syndrome with hypertonia (42%).¹¹ Brain imaging in children has demonstrated hemorrhagic lesions involving the pons, basal ganglia, and occipital cortex.¹¹ Blood flow to areas such as the cerebellum, brainstem, and orbitofrontal area can be compromised.¹⁰ Adult patients with HUS can present without lesions on cranial magnetic resonance imaging (MRI), but instead with transient symmetric vasogenic edema of the central brain stem.¹² Unfortunately in this case, MRI was not performed because it was thought to provide limited aid in diagnosis and to avoid unnecessary testing for the acutely ill patient.

The underlying pathophysiology of neurologic manifestations in patients may be due to a metabolic disturbance, toxin-mediated damage of the vascular endothelium, or toxin-induced cytokine release resulting in death of neural cells and subsequent neuroinflammation. However, the most likely mechanism is parenchymal ischemic changes related to microangiopathy.^11,13 Pediatric patients often experience seizures and altered mental status, and their EEGs display delta waves.¹³ This patient’s diffuse slowing on her second EEG and altered mental status suggests that the neuropathologic mechanisms for typical HUS in adults may be similar to those in children.

HUS Treatment

The treatment and management of adults with typical STEC-HUS is evolving. The patient was first suspected to have an infectious colitis and empiric antibiotics were initiated. Some studies suggest that antibiotic administration may worsen the course of HUS in children as it may lead to release and subsequent absorption of Shiga toxin in the intestine.^9,14 However, there is little evidence to suggest harm or efficacy of administration in adults. It is unclear what role antibiotic administration played in the recovery time of HUS given the co-administration of other treatments such as eculizumab and plasmapheresis, but it does appear to have helped with the initial E coli infection.

Plasmapheresis was subsequently administered, due to its documented benefit in the treatment of HUS.¹⁵ However, it should be noted that even though plasmapheresis is currently used in patients with CNS involvement, it remains unproven with conflicting information on its efficacy.^3,16 The mechanism of action is unclear, but it has been hypothesized that plasmapheresis prevents microangiopathy caused by microthrombi.^3,16 For this reason, eculizumab is becoming the mainstay for treatment of STEC-HUS with neurologic complications given the lack of well researched alternative treatments. In this case study, the use of plasmapheresis did not result in clinical improvement, and was abandoned after 2 days of treatment.

Eculizumab is a humanized, recombinant monoclonal IgG antibody that is a terminal complement inhibitor of the alternative complement system at the final step to cleave C5.¹⁷ The Shiga toxin may directly activate the complement system via the alternative pathway, which can result in uncontrolled platelet and white blood cell activation and depletion, endothelial cell damage, and hemolysis. The galvanized complement system leads to a series of cascading events that contribute to organ damage and death.⁹ Eculizumab is FDA approved for use in atypical HUS.¹⁸ It also can be used off-label to treat typical-HUS in adults with neurologic complications.

Eculizumab interferes with the immune response against encapsulated bacteria because it inhibits the alternative complement pathway. Thus, vaccination against N meningitides is recommended 2 weeks prior to the administration of eculizumab. However, in situations where the risks of delaying eculizumab for 2 weeks are greater than the risk of developing an N meningitides infection, eculizumab may be given without delay.¹⁸ Given the rapid deterioration of our patient’s condition, the vaccine and eculizumab were given together with prophylactic azithromycin. Although penicillin is the standard for prophylaxis in this situation, the patient’s penicillin allergy led to the use of azithromycin 250 mg po once a day. Literature also suggests azithromycin reduces the carriage duration of E coli-induced colitis.¹⁹ As such, it is possible that some improvement in the patient’s condition could be attributed to the elimination of the pathogen and toxin.

Conclusion

Three doses of eculizumab were administered at weekly intervals, with the first dose on hospital day 8 and the final dose on hospital day 22. Prior to the first dose, the patient displayed significant decline in mental status with EEG findings of right hemisphere epileptogenic discharges. After her third dose, she was found to have a drastically improved mental status exam and a normal EEG. One week later, she was discharged home. At the time of her 1-month follow-up, she was independent in all activities of daily living and had returned to part-time work. Apart from subtle cognitive changes, the remainder of her neurologic exam was normal.

There is evidence that supports the efficacy of eculizumab in children with HUS with neurologic symptoms on dialysis.²⁰ However, its use in adults is not well established.²¹ This patient required dialysis and had neurologic symptoms similar to pediatric patients described in the literature, and responded similarly to the eculizumab. The rationale for the use of eculizumab in STEC-HUS also is evidenced by in vitro demonstrations of complement activation in STEC-HUS.^22-25 This case report adds to the literature supporting the use of eculizumab in adult patients with typical HUS with neurological complications. Further research is necessary to develop guidelines in the treatment of adult STEC-HUS with regards to neurologic complications.

Acknowledgments

The authors would like to thank Pete DiStaso, REEGT for his work on obtaining the electroencephalograms and Anthony Rinaldi, PsyD; Julie Cessnapalas, PsyD; and Syed Faizan Sagheer for proof-reading the article.

Acute pyogenic vertebral osteomyelitis is often due to hematogenous spread of aerobic bacteria.^1-4 Conversely, only 0.5% of anaerobic bacteremias lead to osteomyelitis.⁵ Anaerobic osteomyelitis typically results from the contiguous spread of polymicrobial infections through breaks in the gut mucosal barrier and involves the vertebral bodies in only 2% to 5% of cases.^5,6 Although Bacteroides fragilis (B fragilis) is the most common anaerobic pathogen cultivated from blood, accounting for about half of all anaerobic blood isolates, it seldom leads to osteomyelitis.^1,2,7-11 We report an uncommon case of B fragilis bacteremia and vertebral osteomyelitis confounded by uncertainties in anaerobic identification and susceptibilities.

Case Presentation

A healthy-appearing male aged 55 years presented to the Naval Medical Center Portsmouth (NMCP) with subacute low back pain and fevers of 103 °F for > 3 weeks. While traveling 4 weeks prior, he completed a course of oseltamivir for influenza B infection; afterward, he was diagnosed with community-acquired pneumonia and treated with a dose of ceftriaxone and a 7-day course of doxycycline. The patient presented to the same facility a week later for low back pain and nonresolving respiratory symptoms, and his therapy was changed to azithromycin, cefuroxime, prednisone, and inhalers. Additionally, after being treated for influenza, he developed constipation and hematochezia for which he did not seek care. The hematochezia was similar to a previous episode from an anal fissure 1 year prior that resolved with stool softeners. When he was finally seen at NMCP after 3 weeks of worsening back pain and fevers, lumbosacral magnetic resonance imaging (MRI) demonstrated vertebral osteomyelitis and discitis at L4-L5 and admitted to the hospital (Figure 1).

After a fluoroscopy-guided biopsy of the L4 vertebral body on hospital day 1, the patient was started on cefepime and vancomycin. The biopsy sample was inoculated onto solid media (blood agar, chocolate agar, and MacConkey agar) and incubated at 36 °C for 24 hours in a 5% CO₂ atmosphere, as well as onto Shaedler agar with vitamin K and chopped meat glucose broth and incubated at 36 °C for 48 hours under anaerobic conditions. Metronidazole was added and vancomycin discontinued after 2 anaerobic blood culture vials obtained on hospital day 1, incubated in a Becton Dickinson BACTEC FX automated system, which demonstrated Gram-negative bacilli after 48 hours. The blood culture isolates demonstrated a > 99% probability of being identified as ß-lactamase positive Prevotella loescheii using Thermo Fischer Scientific RapID ANA II biochemical testing. Nitrocefinase discs were used to detect ß-lactamase activity.

The biopsy demonstrated nongranulomatous focal areas of necrotic bone and neutrophilia in a hematopoietic background consistent with acute osteomyelitis (Figure 2); on hospital day 4, ß-lactamase positive B fragilis grew from the bone culture. Additionally, 1 anaerobic vial from a surveillance blood culture set that was obtained on hospital day 3 grew ß-lactamasepositive B fragilis using the same identification methods. With these results he was thought to have a polymicrobial infection (B fragilis and Prevotella loescheii [P loescheii]) from a suspected bowel source based on his hematochezia and history of anal fissure. No aerobic, Gram-negative enterobacteriaceae were isolated, but he had previously been on cefuroxime, which has potential activity against these organisms, for ≥ 2 weeks prior to hospitalization and cultures. He was discharged on moxifloxacin and metronidazole pending final culture results, including requested anaerobic susceptibility testing.

At 1-week follow-up, both aerobic and anaerobic vials from surveillance blood cultures remained negative for any microbes, so antibiotics were deescalated to moxifloxacin monotherapy. However, after 3 days the patient was readmitted for increasing C-reactive protein (CRP) levels and intractable back pain with worsening bilateral radiculopathy. A repeat MRI demonstrated interval disease progression with near obliteration of the L4-L5 disc space and hyperenhancement of the prevertebral soft tissues and adjacent psoas musculature without focal rim-enhancing fluid collection (Figure 3). After repeat L4 biopsy, metronidazole was restarted and ertapenem added for enterobacteriaceae coverage, given the known B fragilis and potential suppression from previous cephalosporin therapy; moxifloxacin was discontinued. L4 biopsy cultures showed no growth, and CRP levels trended down from 154.2 mg/L (start of first admission) to 42.4 mg/L (start of second admission) to 14.9 mg/L (day of discharge) (reference range, 5-9.9 mg/L). He was discharged on ertapenem and metronidazole. He completed a 6-week course without further complication.

Discussion

In the era of growing antibiotic resistance patterns, antimicrobial stewardship programs recommend interventions to improve antimicrobial use through targeted narrow- spectrum antibiotics.¹² The Clinical and Laboratory Standards Institute (CLSI) maintains guidelines on the major indications for anaerobic antimicrobial susceptibility testing (AST) to help direct narrow-targeted antimicrobial therapy. However, in a 2008 practice survey Goldstein and colleagues reported that less than half of US hospitals performed anaerobic AST, and only 21% of these facilities did it in-house, while the remainder sent out their isolates for testing.^11-14 The CLSI major indications for AST include situations in which the selection of agents is important because of the (1) known resistance of a particular species; (2) confirmation of appropriate therapy for severe infections or for those that may require long-term therapy; (3) persistence of infection despite adequate treatment with an appropriate therapeutic regimen; and (4) difficulty in making empirical decisions based on precedent.¹⁴ Additionally, isolates from brain abscess, endocarditis, osteomyelitis, joint infection, infection of prosthetic devices or vascular grafts, bacteremia, and normally sterile body sites (unless contamination suspected) should be tested.¹⁴

Because of the lack of anaerobic AST, health care providers must base empiric treatment on reported sensitivities from the medical literature. Empiric selection of antimicrobials for anaerobic infections is made even more challenging by the increased rates of resistance reported in the literature, leading to recommendations to increase susceptibility testing to guide therapy.^13,15,16 Empiric therapy of deep-seated anaerobic infections may lead to use of inactive agents or overly broad-spectrum antibiotics. Current antimicrobial stewardship initiatives recognize the importance of narrow-spectrum antibiotics to minimize risk of adverse events and selective pressure for antimicrobial resistance.

Although we attempted to confirm the identification of the anaerobic isolates via commercially available methods, it was not until we performed genetic testing that we were able verify the isolates as B fragilis. Furthermore, earlier susceptibility testing would have allowed for more narrow-targeted antimicrobial therapy and could have potentially prevented our patient’s readmission and use of ertapenem, despite its > 98% susceptibility rates against B fragilis.^13,17

All of the B fragilis isolates carried the cepA gene, which is a cephalosporinase that encodes for resistance to cephalosporins and aminopenicillins but not to ß-lactam ß-lactamase inhibitor combinations.¹³ Although not a substitution for susceptibility analysis, genetic testing showed that all of the isolates carried a nonsynonymous mutation from serine to a phenylalanine at amino acid position 82 (S82F) in the gyrA gene. The S82F mutation has been implicated in fluoroquinolone resistance, via inhibition of substrate–target recognition and binding between fluoroquinolones and the target topoisomerase protein,¹⁸ and may potentially explain why our patient clinically worsened while on moxifloxacin monotherapy. Although moxifloxacin susceptibility was not performed, susceptibility rates remain highly variable, ranging from 50% to 70% for B fragilis.^13,15,16

It is important to note that the metronidazole the patient received during his first hospital admission could have sterilized the vertebral body without completely eradicating the microbe; thus could explain his clinical worsening while on moxifloxacin monotherapy despite no growth from the repeat biopsy culture. Our rationale for initially continuing moxifloxacin was based on its excellent bioavailability and bone penetration properties. Additionally, of the fluoroquinolones it has the most reliable anaerobic activity and is the only one recommended as monotherapy for complicated intraabdominal infections.¹⁹ However, guidelines recommend avoiding its use in patients who have received a fluoroquinolone in the past 90 days or at institutions with high rates of resistance. At our institution Escherichia coli has a > 90% susceptibility rate to fluoroquinolones. Given this rate and our concern that the patient had a polymicrobial infection, we felt that moxifloxacin would provide appropriate anaerobic and aerobic coverage, especially since he had no previous fluoroquinolone exposure.

Conclusions

We report a case of B fragilis bacteremia and vertebral osteomyelitis complicated by challenges in anaerobic identification and sensitivities that led to brief use of a possibly inactive antimicrobial and the subsequent use of carbapenem therapy, which may have been avoided if susceptibility testing were more readily available. This case led to changes in our hospital’s processing of anaerobic isolates to include susceptibility testing on request.

Acknowledgments

We thank Keith Thompson, MD (staff pathologist, Naval Medical Center Portsmouth Virginia), for providing the pathology images from the initial vertebral biopsy, and Dr. Kate Hinkle (director, Multidrug-Resistant Organism Repository and Surveillance Network, Silver Spring, Maryland ) for providing the whole genome sequencing results from the B fragilis isolates.

Acute pyogenic vertebral osteomyelitis is often due to hematogenous spread of aerobic bacteria.^1-4 Conversely, only 0.5% of anaerobic bacteremias lead to osteomyelitis.⁵ Anaerobic osteomyelitis typically results from the contiguous spread of polymicrobial infections through breaks in the gut mucosal barrier and involves the vertebral bodies in only 2% to 5% of cases.^5,6 Although Bacteroides fragilis (B fragilis) is the most common anaerobic pathogen cultivated from blood, accounting for about half of all anaerobic blood isolates, it seldom leads to osteomyelitis.^1,2,7-11 We report an uncommon case of B fragilis bacteremia and vertebral osteomyelitis confounded by uncertainties in anaerobic identification and susceptibilities.

Case Presentation

A healthy-appearing male aged 55 years presented to the Naval Medical Center Portsmouth (NMCP) with subacute low back pain and fevers of 103 °F for > 3 weeks. While traveling 4 weeks prior, he completed a course of oseltamivir for influenza B infection; afterward, he was diagnosed with community-acquired pneumonia and treated with a dose of ceftriaxone and a 7-day course of doxycycline. The patient presented to the same facility a week later for low back pain and nonresolving respiratory symptoms, and his therapy was changed to azithromycin, cefuroxime, prednisone, and inhalers. Additionally, after being treated for influenza, he developed constipation and hematochezia for which he did not seek care. The hematochezia was similar to a previous episode from an anal fissure 1 year prior that resolved with stool softeners. When he was finally seen at NMCP after 3 weeks of worsening back pain and fevers, lumbosacral magnetic resonance imaging (MRI) demonstrated vertebral osteomyelitis and discitis at L4-L5 and admitted to the hospital (Figure 1).

After a fluoroscopy-guided biopsy of the L4 vertebral body on hospital day 1, the patient was started on cefepime and vancomycin. The biopsy sample was inoculated onto solid media (blood agar, chocolate agar, and MacConkey agar) and incubated at 36 °C for 24 hours in a 5% CO₂ atmosphere, as well as onto Shaedler agar with vitamin K and chopped meat glucose broth and incubated at 36 °C for 48 hours under anaerobic conditions. Metronidazole was added and vancomycin discontinued after 2 anaerobic blood culture vials obtained on hospital day 1, incubated in a Becton Dickinson BACTEC FX automated system, which demonstrated Gram-negative bacilli after 48 hours. The blood culture isolates demonstrated a > 99% probability of being identified as ß-lactamase positive Prevotella loescheii using Thermo Fischer Scientific RapID ANA II biochemical testing. Nitrocefinase discs were used to detect ß-lactamase activity.

The biopsy demonstrated nongranulomatous focal areas of necrotic bone and neutrophilia in a hematopoietic background consistent with acute osteomyelitis (Figure 2); on hospital day 4, ß-lactamase positive B fragilis grew from the bone culture. Additionally, 1 anaerobic vial from a surveillance blood culture set that was obtained on hospital day 3 grew ß-lactamasepositive B fragilis using the same identification methods. With these results he was thought to have a polymicrobial infection (B fragilis and Prevotella loescheii [P loescheii]) from a suspected bowel source based on his hematochezia and history of anal fissure. No aerobic, Gram-negative enterobacteriaceae were isolated, but he had previously been on cefuroxime, which has potential activity against these organisms, for ≥ 2 weeks prior to hospitalization and cultures. He was discharged on moxifloxacin and metronidazole pending final culture results, including requested anaerobic susceptibility testing.

At 1-week follow-up, both aerobic and anaerobic vials from surveillance blood cultures remained negative for any microbes, so antibiotics were deescalated to moxifloxacin monotherapy. However, after 3 days the patient was readmitted for increasing C-reactive protein (CRP) levels and intractable back pain with worsening bilateral radiculopathy. A repeat MRI demonstrated interval disease progression with near obliteration of the L4-L5 disc space and hyperenhancement of the prevertebral soft tissues and adjacent psoas musculature without focal rim-enhancing fluid collection (Figure 3). After repeat L4 biopsy, metronidazole was restarted and ertapenem added for enterobacteriaceae coverage, given the known B fragilis and potential suppression from previous cephalosporin therapy; moxifloxacin was discontinued. L4 biopsy cultures showed no growth, and CRP levels trended down from 154.2 mg/L (start of first admission) to 42.4 mg/L (start of second admission) to 14.9 mg/L (day of discharge) (reference range, 5-9.9 mg/L). He was discharged on ertapenem and metronidazole. He completed a 6-week course without further complication.

Discussion

In the era of growing antibiotic resistance patterns, antimicrobial stewardship programs recommend interventions to improve antimicrobial use through targeted narrow- spectrum antibiotics.¹² The Clinical and Laboratory Standards Institute (CLSI) maintains guidelines on the major indications for anaerobic antimicrobial susceptibility testing (AST) to help direct narrow-targeted antimicrobial therapy. However, in a 2008 practice survey Goldstein and colleagues reported that less than half of US hospitals performed anaerobic AST, and only 21% of these facilities did it in-house, while the remainder sent out their isolates for testing.^11-14 The CLSI major indications for AST include situations in which the selection of agents is important because of the (1) known resistance of a particular species; (2) confirmation of appropriate therapy for severe infections or for those that may require long-term therapy; (3) persistence of infection despite adequate treatment with an appropriate therapeutic regimen; and (4) difficulty in making empirical decisions based on precedent.¹⁴ Additionally, isolates from brain abscess, endocarditis, osteomyelitis, joint infection, infection of prosthetic devices or vascular grafts, bacteremia, and normally sterile body sites (unless contamination suspected) should be tested.¹⁴

Because of the lack of anaerobic AST, health care providers must base empiric treatment on reported sensitivities from the medical literature. Empiric selection of antimicrobials for anaerobic infections is made even more challenging by the increased rates of resistance reported in the literature, leading to recommendations to increase susceptibility testing to guide therapy.^13,15,16 Empiric therapy of deep-seated anaerobic infections may lead to use of inactive agents or overly broad-spectrum antibiotics. Current antimicrobial stewardship initiatives recognize the importance of narrow-spectrum antibiotics to minimize risk of adverse events and selective pressure for antimicrobial resistance.

Although we attempted to confirm the identification of the anaerobic isolates via commercially available methods, it was not until we performed genetic testing that we were able verify the isolates as B fragilis. Furthermore, earlier susceptibility testing would have allowed for more narrow-targeted antimicrobial therapy and could have potentially prevented our patient’s readmission and use of ertapenem, despite its > 98% susceptibility rates against B fragilis.^13,17

All of the B fragilis isolates carried the cepA gene, which is a cephalosporinase that encodes for resistance to cephalosporins and aminopenicillins but not to ß-lactam ß-lactamase inhibitor combinations.¹³ Although not a substitution for susceptibility analysis, genetic testing showed that all of the isolates carried a nonsynonymous mutation from serine to a phenylalanine at amino acid position 82 (S82F) in the gyrA gene. The S82F mutation has been implicated in fluoroquinolone resistance, via inhibition of substrate–target recognition and binding between fluoroquinolones and the target topoisomerase protein,¹⁸ and may potentially explain why our patient clinically worsened while on moxifloxacin monotherapy. Although moxifloxacin susceptibility was not performed, susceptibility rates remain highly variable, ranging from 50% to 70% for B fragilis.^13,15,16

It is important to note that the metronidazole the patient received during his first hospital admission could have sterilized the vertebral body without completely eradicating the microbe; thus could explain his clinical worsening while on moxifloxacin monotherapy despite no growth from the repeat biopsy culture. Our rationale for initially continuing moxifloxacin was based on its excellent bioavailability and bone penetration properties. Additionally, of the fluoroquinolones it has the most reliable anaerobic activity and is the only one recommended as monotherapy for complicated intraabdominal infections.¹⁹ However, guidelines recommend avoiding its use in patients who have received a fluoroquinolone in the past 90 days or at institutions with high rates of resistance. At our institution Escherichia coli has a > 90% susceptibility rate to fluoroquinolones. Given this rate and our concern that the patient had a polymicrobial infection, we felt that moxifloxacin would provide appropriate anaerobic and aerobic coverage, especially since he had no previous fluoroquinolone exposure.

Conclusions

We report a case of B fragilis bacteremia and vertebral osteomyelitis complicated by challenges in anaerobic identification and sensitivities that led to brief use of a possibly inactive antimicrobial and the subsequent use of carbapenem therapy, which may have been avoided if susceptibility testing were more readily available. This case led to changes in our hospital’s processing of anaerobic isolates to include susceptibility testing on request.

Acknowledgments

We thank Keith Thompson, MD (staff pathologist, Naval Medical Center Portsmouth Virginia), for providing the pathology images from the initial vertebral biopsy, and Dr. Kate Hinkle (director, Multidrug-Resistant Organism Repository and Surveillance Network, Silver Spring, Maryland ) for providing the whole genome sequencing results from the B fragilis isolates.

Acute pyogenic vertebral osteomyelitis is often due to hematogenous spread of aerobic bacteria.^1-4 Conversely, only 0.5% of anaerobic bacteremias lead to osteomyelitis.⁵ Anaerobic osteomyelitis typically results from the contiguous spread of polymicrobial infections through breaks in the gut mucosal barrier and involves the vertebral bodies in only 2% to 5% of cases.^5,6 Although Bacteroides fragilis (B fragilis) is the most common anaerobic pathogen cultivated from blood, accounting for about half of all anaerobic blood isolates, it seldom leads to osteomyelitis.^1,2,7-11 We report an uncommon case of B fragilis bacteremia and vertebral osteomyelitis confounded by uncertainties in anaerobic identification and susceptibilities.

Case Presentation

A healthy-appearing male aged 55 years presented to the Naval Medical Center Portsmouth (NMCP) with subacute low back pain and fevers of 103 °F for > 3 weeks. While traveling 4 weeks prior, he completed a course of oseltamivir for influenza B infection; afterward, he was diagnosed with community-acquired pneumonia and treated with a dose of ceftriaxone and a 7-day course of doxycycline. The patient presented to the same facility a week later for low back pain and nonresolving respiratory symptoms, and his therapy was changed to azithromycin, cefuroxime, prednisone, and inhalers. Additionally, after being treated for influenza, he developed constipation and hematochezia for which he did not seek care. The hematochezia was similar to a previous episode from an anal fissure 1 year prior that resolved with stool softeners. When he was finally seen at NMCP after 3 weeks of worsening back pain and fevers, lumbosacral magnetic resonance imaging (MRI) demonstrated vertebral osteomyelitis and discitis at L4-L5 and admitted to the hospital (Figure 1).

After a fluoroscopy-guided biopsy of the L4 vertebral body on hospital day 1, the patient was started on cefepime and vancomycin. The biopsy sample was inoculated onto solid media (blood agar, chocolate agar, and MacConkey agar) and incubated at 36 °C for 24 hours in a 5% CO₂ atmosphere, as well as onto Shaedler agar with vitamin K and chopped meat glucose broth and incubated at 36 °C for 48 hours under anaerobic conditions. Metronidazole was added and vancomycin discontinued after 2 anaerobic blood culture vials obtained on hospital day 1, incubated in a Becton Dickinson BACTEC FX automated system, which demonstrated Gram-negative bacilli after 48 hours. The blood culture isolates demonstrated a > 99% probability of being identified as ß-lactamase positive Prevotella loescheii using Thermo Fischer Scientific RapID ANA II biochemical testing. Nitrocefinase discs were used to detect ß-lactamase activity.

The biopsy demonstrated nongranulomatous focal areas of necrotic bone and neutrophilia in a hematopoietic background consistent with acute osteomyelitis (Figure 2); on hospital day 4, ß-lactamase positive B fragilis grew from the bone culture. Additionally, 1 anaerobic vial from a surveillance blood culture set that was obtained on hospital day 3 grew ß-lactamasepositive B fragilis using the same identification methods. With these results he was thought to have a polymicrobial infection (B fragilis and Prevotella loescheii [P loescheii]) from a suspected bowel source based on his hematochezia and history of anal fissure. No aerobic, Gram-negative enterobacteriaceae were isolated, but he had previously been on cefuroxime, which has potential activity against these organisms, for ≥ 2 weeks prior to hospitalization and cultures. He was discharged on moxifloxacin and metronidazole pending final culture results, including requested anaerobic susceptibility testing.

At 1-week follow-up, both aerobic and anaerobic vials from surveillance blood cultures remained negative for any microbes, so antibiotics were deescalated to moxifloxacin monotherapy. However, after 3 days the patient was readmitted for increasing C-reactive protein (CRP) levels and intractable back pain with worsening bilateral radiculopathy. A repeat MRI demonstrated interval disease progression with near obliteration of the L4-L5 disc space and hyperenhancement of the prevertebral soft tissues and adjacent psoas musculature without focal rim-enhancing fluid collection (Figure 3). After repeat L4 biopsy, metronidazole was restarted and ertapenem added for enterobacteriaceae coverage, given the known B fragilis and potential suppression from previous cephalosporin therapy; moxifloxacin was discontinued. L4 biopsy cultures showed no growth, and CRP levels trended down from 154.2 mg/L (start of first admission) to 42.4 mg/L (start of second admission) to 14.9 mg/L (day of discharge) (reference range, 5-9.9 mg/L). He was discharged on ertapenem and metronidazole. He completed a 6-week course without further complication.

Discussion

In the era of growing antibiotic resistance patterns, antimicrobial stewardship programs recommend interventions to improve antimicrobial use through targeted narrow- spectrum antibiotics.¹² The Clinical and Laboratory Standards Institute (CLSI) maintains guidelines on the major indications for anaerobic antimicrobial susceptibility testing (AST) to help direct narrow-targeted antimicrobial therapy. However, in a 2008 practice survey Goldstein and colleagues reported that less than half of US hospitals performed anaerobic AST, and only 21% of these facilities did it in-house, while the remainder sent out their isolates for testing.^11-14 The CLSI major indications for AST include situations in which the selection of agents is important because of the (1) known resistance of a particular species; (2) confirmation of appropriate therapy for severe infections or for those that may require long-term therapy; (3) persistence of infection despite adequate treatment with an appropriate therapeutic regimen; and (4) difficulty in making empirical decisions based on precedent.¹⁴ Additionally, isolates from brain abscess, endocarditis, osteomyelitis, joint infection, infection of prosthetic devices or vascular grafts, bacteremia, and normally sterile body sites (unless contamination suspected) should be tested.¹⁴

Because of the lack of anaerobic AST, health care providers must base empiric treatment on reported sensitivities from the medical literature. Empiric selection of antimicrobials for anaerobic infections is made even more challenging by the increased rates of resistance reported in the literature, leading to recommendations to increase susceptibility testing to guide therapy.^13,15,16 Empiric therapy of deep-seated anaerobic infections may lead to use of inactive agents or overly broad-spectrum antibiotics. Current antimicrobial stewardship initiatives recognize the importance of narrow-spectrum antibiotics to minimize risk of adverse events and selective pressure for antimicrobial resistance.

Although we attempted to confirm the identification of the anaerobic isolates via commercially available methods, it was not until we performed genetic testing that we were able verify the isolates as B fragilis. Furthermore, earlier susceptibility testing would have allowed for more narrow-targeted antimicrobial therapy and could have potentially prevented our patient’s readmission and use of ertapenem, despite its > 98% susceptibility rates against B fragilis.^13,17

All of the B fragilis isolates carried the cepA gene, which is a cephalosporinase that encodes for resistance to cephalosporins and aminopenicillins but not to ß-lactam ß-lactamase inhibitor combinations.¹³ Although not a substitution for susceptibility analysis, genetic testing showed that all of the isolates carried a nonsynonymous mutation from serine to a phenylalanine at amino acid position 82 (S82F) in the gyrA gene. The S82F mutation has been implicated in fluoroquinolone resistance, via inhibition of substrate–target recognition and binding between fluoroquinolones and the target topoisomerase protein,¹⁸ and may potentially explain why our patient clinically worsened while on moxifloxacin monotherapy. Although moxifloxacin susceptibility was not performed, susceptibility rates remain highly variable, ranging from 50% to 70% for B fragilis.^13,15,16

It is important to note that the metronidazole the patient received during his first hospital admission could have sterilized the vertebral body without completely eradicating the microbe; thus could explain his clinical worsening while on moxifloxacin monotherapy despite no growth from the repeat biopsy culture. Our rationale for initially continuing moxifloxacin was based on its excellent bioavailability and bone penetration properties. Additionally, of the fluoroquinolones it has the most reliable anaerobic activity and is the only one recommended as monotherapy for complicated intraabdominal infections.¹⁹ However, guidelines recommend avoiding its use in patients who have received a fluoroquinolone in the past 90 days or at institutions with high rates of resistance. At our institution Escherichia coli has a > 90% susceptibility rate to fluoroquinolones. Given this rate and our concern that the patient had a polymicrobial infection, we felt that moxifloxacin would provide appropriate anaerobic and aerobic coverage, especially since he had no previous fluoroquinolone exposure.

Conclusions

We report a case of B fragilis bacteremia and vertebral osteomyelitis complicated by challenges in anaerobic identification and sensitivities that led to brief use of a possibly inactive antimicrobial and the subsequent use of carbapenem therapy, which may have been avoided if susceptibility testing were more readily available. This case led to changes in our hospital’s processing of anaerobic isolates to include susceptibility testing on request.

Acknowledgments

We thank Keith Thompson, MD (staff pathologist, Naval Medical Center Portsmouth Virginia), for providing the pathology images from the initial vertebral biopsy, and Dr. Kate Hinkle (director, Multidrug-Resistant Organism Repository and Surveillance Network, Silver Spring, Maryland ) for providing the whole genome sequencing results from the B fragilis isolates.

THE CASE

A 28-year-old G1P1 initially presented to the family medicine clinic 4 weeks postpartum to discuss possibilities for contraception. She had received her prenatal care through a midwife and had had a successful home delivery. She was exclusively breastfeeding her infant daughter but wanted to ensure adequate spacing between her pregnancies.

During the discussion of possible options, the patient revealed that she had previously had an intrauterine device (IUD) placed and expressed interest in using this method again. A levonorgestrel-releasing IUD (Mirena) was placed at 6 weeks postpartum, after a negative pregnancy test was obtained.

The patient returned to the clinic about 6 months later with complaints of increased difficulty maintaining her milk supply.

THE DIAGNOSIS

The patient had taken a home pregnancy test, which was positive—a finding confirmed in clinic via a urine pregnancy test.

Gestational age. Since the patient had an IUD in place and had been exclusively breastfeeding, gestational age was difficult to determine. A quantitative human chorionic gonadotropin (hCG) test showed an hCG level of 12,469 U/L, consistent with a 4-to-8-week pregnancy. An ultrasound performed the next day showed a single intrauterine pregnancy at 21 weeks.

IUD location. There was also the question of the location of the IUD and whether it would interfere with the patient’s ability to maintain the pregnancy. On ultrasound, the IUD was noted within the cervix and myometrium. After discussion of the risks, the patient chose to leave it in place.

DISCUSSION

IUDs are among the most effective forms of contraception; levonorgestrel-releasing IUDs are more effective than copper IUDs.¹ The rates of failure in the first year of use are 0.8% and 0.2% for copper and levonorgestrel-releasing IUDs, respectively.¹

Continue to: The Lactational Amenorrhea Method

The Lactational Amenorrhea Method (LAM), which is defined as providing infant nutrition exclusively through breastmilk during the first 6 months postpartum, also provides protection against pregnancy. LAM has a failure rate of 0% to 1.5%.²

It is not surprising that this patient thought she was adequately protected against pregnancy. That said, no contraceptive method is foolproof (as this case demonstrates).

Risks to the pregnancy. When pregnancy does occur with an IUD in place, the patient should be informed of the possible risks to the pregnancy. These include complications such as spontaneous abortion, chorioamnionitis, and preterm delivery.³ Risk is further increased if the IUD is malpositioned (as this one was), meaning that any part of the IUD is located in the lower uterine segment, myometrium, or endocervical canal.^4,5

Removal of the IUD is generally recommended if the device and its strings can be located, although removal does not completely mitigate risk. In a study done in Egypt, 46 of 52 IUDs were removed successfully, with 2 spontaneous abortions as a result.⁶ Of note, the IUDs extracted in this study were Lippes loop and copper models, not levonorgestrel-releasing IUDs such as our patient had. There is a single case report⁷ of a patient who had a Mirena inserted very early in a pregnancy; the IUD had to be left in place due to the risk for miscarriage, but she was able to carry the infant to term and did not experience any adverse effects.

It is not surprising that this patient thought she was adequately protected against pregnancy.

Our patient

The patient delivered a male infant vaginally at term without issue. However, the IUD was not expelled during this process. Ultrasound showed that it was embedded in the posterior myometrium with a hypoechoic tract. The patient was referred to Gynecology, and the IUD was successfully removed.

Continue to: THE TAKEAWAY

Even the most reliable method of contraception can fail—so pregnancy should always be in the differential diagnosis for a sexually active woman. Location of IUD placement is important; it must be in the right place to be effective. The tenets of LAM must be followed precisely in order for breastfeeding to provide protection against pregnancy. Patients can successfully carry a pregnancy to term with an IUD, as this patient did, but it places them at higher risk for ectopic pregnancy, premature rupture of membranes, and infection.

ACKNOWLEDGEMENT
The author thanks Jenny Walters, lactation consultant, for her assistance in the preparation of the manuscript.

CORRESPONDENCE
Hannah Maxfield, MD, 3901 Rainbow Boulevard, MS 4010, Kansas City, KS 66160; [email protected]

THE CASE

A 28-year-old G1P1 initially presented to the family medicine clinic 4 weeks postpartum to discuss possibilities for contraception. She had received her prenatal care through a midwife and had had a successful home delivery. She was exclusively breastfeeding her infant daughter but wanted to ensure adequate spacing between her pregnancies.

During the discussion of possible options, the patient revealed that she had previously had an intrauterine device (IUD) placed and expressed interest in using this method again. A levonorgestrel-releasing IUD (Mirena) was placed at 6 weeks postpartum, after a negative pregnancy test was obtained.

The patient returned to the clinic about 6 months later with complaints of increased difficulty maintaining her milk supply.

THE DIAGNOSIS

The patient had taken a home pregnancy test, which was positive—a finding confirmed in clinic via a urine pregnancy test.

Gestational age. Since the patient had an IUD in place and had been exclusively breastfeeding, gestational age was difficult to determine. A quantitative human chorionic gonadotropin (hCG) test showed an hCG level of 12,469 U/L, consistent with a 4-to-8-week pregnancy. An ultrasound performed the next day showed a single intrauterine pregnancy at 21 weeks.

IUD location. There was also the question of the location of the IUD and whether it would interfere with the patient’s ability to maintain the pregnancy. On ultrasound, the IUD was noted within the cervix and myometrium. After discussion of the risks, the patient chose to leave it in place.

DISCUSSION

IUDs are among the most effective forms of contraception; levonorgestrel-releasing IUDs are more effective than copper IUDs.¹ The rates of failure in the first year of use are 0.8% and 0.2% for copper and levonorgestrel-releasing IUDs, respectively.¹

Continue to: The Lactational Amenorrhea Method

The Lactational Amenorrhea Method (LAM), which is defined as providing infant nutrition exclusively through breastmilk during the first 6 months postpartum, also provides protection against pregnancy. LAM has a failure rate of 0% to 1.5%.²

It is not surprising that this patient thought she was adequately protected against pregnancy. That said, no contraceptive method is foolproof (as this case demonstrates).

Risks to the pregnancy. When pregnancy does occur with an IUD in place, the patient should be informed of the possible risks to the pregnancy. These include complications such as spontaneous abortion, chorioamnionitis, and preterm delivery.³ Risk is further increased if the IUD is malpositioned (as this one was), meaning that any part of the IUD is located in the lower uterine segment, myometrium, or endocervical canal.^4,5

Removal of the IUD is generally recommended if the device and its strings can be located, although removal does not completely mitigate risk. In a study done in Egypt, 46 of 52 IUDs were removed successfully, with 2 spontaneous abortions as a result.⁶ Of note, the IUDs extracted in this study were Lippes loop and copper models, not levonorgestrel-releasing IUDs such as our patient had. There is a single case report⁷ of a patient who had a Mirena inserted very early in a pregnancy; the IUD had to be left in place due to the risk for miscarriage, but she was able to carry the infant to term and did not experience any adverse effects.

It is not surprising that this patient thought she was adequately protected against pregnancy.

Our patient

The patient delivered a male infant vaginally at term without issue. However, the IUD was not expelled during this process. Ultrasound showed that it was embedded in the posterior myometrium with a hypoechoic tract. The patient was referred to Gynecology, and the IUD was successfully removed.

Continue to: THE TAKEAWAY

Even the most reliable method of contraception can fail—so pregnancy should always be in the differential diagnosis for a sexually active woman. Location of IUD placement is important; it must be in the right place to be effective. The tenets of LAM must be followed precisely in order for breastfeeding to provide protection against pregnancy. Patients can successfully carry a pregnancy to term with an IUD, as this patient did, but it places them at higher risk for ectopic pregnancy, premature rupture of membranes, and infection.

ACKNOWLEDGEMENT
The author thanks Jenny Walters, lactation consultant, for her assistance in the preparation of the manuscript.

CORRESPONDENCE
Hannah Maxfield, MD, 3901 Rainbow Boulevard, MS 4010, Kansas City, KS 66160; [email protected]

THE CASE

A 28-year-old G1P1 initially presented to the family medicine clinic 4 weeks postpartum to discuss possibilities for contraception. She had received her prenatal care through a midwife and had had a successful home delivery. She was exclusively breastfeeding her infant daughter but wanted to ensure adequate spacing between her pregnancies.

During the discussion of possible options, the patient revealed that she had previously had an intrauterine device (IUD) placed and expressed interest in using this method again. A levonorgestrel-releasing IUD (Mirena) was placed at 6 weeks postpartum, after a negative pregnancy test was obtained.

The patient returned to the clinic about 6 months later with complaints of increased difficulty maintaining her milk supply.

THE DIAGNOSIS

The patient had taken a home pregnancy test, which was positive—a finding confirmed in clinic via a urine pregnancy test.

Gestational age. Since the patient had an IUD in place and had been exclusively breastfeeding, gestational age was difficult to determine. A quantitative human chorionic gonadotropin (hCG) test showed an hCG level of 12,469 U/L, consistent with a 4-to-8-week pregnancy. An ultrasound performed the next day showed a single intrauterine pregnancy at 21 weeks.

IUD location. There was also the question of the location of the IUD and whether it would interfere with the patient’s ability to maintain the pregnancy. On ultrasound, the IUD was noted within the cervix and myometrium. After discussion of the risks, the patient chose to leave it in place.

DISCUSSION

IUDs are among the most effective forms of contraception; levonorgestrel-releasing IUDs are more effective than copper IUDs.¹ The rates of failure in the first year of use are 0.8% and 0.2% for copper and levonorgestrel-releasing IUDs, respectively.¹

Continue to: The Lactational Amenorrhea Method

The Lactational Amenorrhea Method (LAM), which is defined as providing infant nutrition exclusively through breastmilk during the first 6 months postpartum, also provides protection against pregnancy. LAM has a failure rate of 0% to 1.5%.²

It is not surprising that this patient thought she was adequately protected against pregnancy. That said, no contraceptive method is foolproof (as this case demonstrates).

Risks to the pregnancy. When pregnancy does occur with an IUD in place, the patient should be informed of the possible risks to the pregnancy. These include complications such as spontaneous abortion, chorioamnionitis, and preterm delivery.³ Risk is further increased if the IUD is malpositioned (as this one was), meaning that any part of the IUD is located in the lower uterine segment, myometrium, or endocervical canal.^4,5

Removal of the IUD is generally recommended if the device and its strings can be located, although removal does not completely mitigate risk. In a study done in Egypt, 46 of 52 IUDs were removed successfully, with 2 spontaneous abortions as a result.⁶ Of note, the IUDs extracted in this study were Lippes loop and copper models, not levonorgestrel-releasing IUDs such as our patient had. There is a single case report⁷ of a patient who had a Mirena inserted very early in a pregnancy; the IUD had to be left in place due to the risk for miscarriage, but she was able to carry the infant to term and did not experience any adverse effects.

It is not surprising that this patient thought she was adequately protected against pregnancy.

Our patient

The patient delivered a male infant vaginally at term without issue. However, the IUD was not expelled during this process. Ultrasound showed that it was embedded in the posterior myometrium with a hypoechoic tract. The patient was referred to Gynecology, and the IUD was successfully removed.

Continue to: THE TAKEAWAY

Even the most reliable method of contraception can fail—so pregnancy should always be in the differential diagnosis for a sexually active woman. Location of IUD placement is important; it must be in the right place to be effective. The tenets of LAM must be followed precisely in order for breastfeeding to provide protection against pregnancy. Patients can successfully carry a pregnancy to term with an IUD, as this patient did, but it places them at higher risk for ectopic pregnancy, premature rupture of membranes, and infection.

ACKNOWLEDGEMENT
The author thanks Jenny Walters, lactation consultant, for her assistance in the preparation of the manuscript.

CORRESPONDENCE
Hannah Maxfield, MD, 3901 Rainbow Boulevard, MS 4010, Kansas City, KS 66160; [email protected]