Case Reports

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).¹ Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.

Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.

Case Presentation

A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.

The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.

The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O₂ saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.

Treatment

In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.

In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.

The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.

Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2). 

The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for difenacoum and brodifacoum. Given the long half-lives of these 2 substances, the patient required ongoing high-dose vitamin K therapy.
The patientwas seen 2 days and 9 days after hospital discharge by his primary care physician. He had no recurrence of bleeding. His INR had a slight upward trend from 1.50 to 1.70, so his vitamin K dose was increased to twice daily 60 mg vitamin K. A subsequent visit documented a follow-up INR of 1.28 on this higher dose. Six weeks after hospital discharge a repeat echocardiogram showed a recovered ejection fraction of 50% to 55%. A cardiology consult suggested that cardiomyopathy was largely tachycardia-induced and that with control of the ventricular rate, the cardiac function had recovered.

The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.

Discussion

Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.² These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.³ Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.⁴ More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.⁴

It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.^5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.^5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.^5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.^6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.⁷ In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.⁷

The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.⁸ As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.⁹

As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.^9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.^13,14 Animal models show difenacoum has a tissue half-life of about 62 days.¹⁵ Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.^16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.

The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.¹⁹ IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).

The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.²⁰ The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.

Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.²¹ For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.

Conclusion

In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.

Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.

Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).¹ Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.

Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.

Case Presentation

A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.

The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.

The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O₂ saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.

Treatment

In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.

In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.

The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.

Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2). 

The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for difenacoum and brodifacoum. Given the long half-lives of these 2 substances, the patient required ongoing high-dose vitamin K therapy.
The patientwas seen 2 days and 9 days after hospital discharge by his primary care physician. He had no recurrence of bleeding. His INR had a slight upward trend from 1.50 to 1.70, so his vitamin K dose was increased to twice daily 60 mg vitamin K. A subsequent visit documented a follow-up INR of 1.28 on this higher dose. Six weeks after hospital discharge a repeat echocardiogram showed a recovered ejection fraction of 50% to 55%. A cardiology consult suggested that cardiomyopathy was largely tachycardia-induced and that with control of the ventricular rate, the cardiac function had recovered.

The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.

Discussion

Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.² These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.³ Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.⁴ More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.⁴

It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.^5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.^5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.^5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.^6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.⁷ In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.⁷

The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.⁸ As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.⁹

As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.^9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.^13,14 Animal models show difenacoum has a tissue half-life of about 62 days.¹⁵ Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.^16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.

The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.¹⁹ IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).

The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.²⁰ The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.

Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.²¹ For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.

Conclusion

In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.

Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.

Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).¹ Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.

Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.

Case Presentation

A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.

The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.

The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O₂ saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.

Treatment

In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.

In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.

The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.

Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2). 

The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for difenacoum and brodifacoum. Given the long half-lives of these 2 substances, the patient required ongoing high-dose vitamin K therapy.
The patientwas seen 2 days and 9 days after hospital discharge by his primary care physician. He had no recurrence of bleeding. His INR had a slight upward trend from 1.50 to 1.70, so his vitamin K dose was increased to twice daily 60 mg vitamin K. A subsequent visit documented a follow-up INR of 1.28 on this higher dose. Six weeks after hospital discharge a repeat echocardiogram showed a recovered ejection fraction of 50% to 55%. A cardiology consult suggested that cardiomyopathy was largely tachycardia-induced and that with control of the ventricular rate, the cardiac function had recovered.

The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.

Discussion

Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.² These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.³ Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.⁴ More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.⁴

It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.^5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.^5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.^5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.^6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.⁷ In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.⁷

The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.⁸ As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.⁹

As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.^9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.^13,14 Animal models show difenacoum has a tissue half-life of about 62 days.¹⁵ Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.^16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.

The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.¹⁹ IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).

The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.²⁰ The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.

Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.²¹ For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.

Conclusion

In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.

Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer in the United States. It develops most often on sun-exposed skin, including the face and neck. Although BCCs are slow-growing tumors that rarely metastasize, they can cause notable local destruction with disfigurement if neglected or inadequately treated. Basal cell carcinoma arising on the legs is relatively uncommon.^1,2 We present an interesting case of delayed diagnosis of BCC on the left knee due to earlier misdiagnoses of a dermoid cyst and bursitis.

Case Report

A 67-year-old man with no history of skin cancer presented with a painful growing tumor on the left knee of approximately 2 years’ duration. The patient’s primary care physician as well as a general surgeon initially diagnosed it as a dermoid cyst and bursitis. The nodule failed to respond to conservative therapy with nonsteroidal anti-inflammatory drugs and continued to grow until it began to ulcerate. Concerned about the possibility of septic arthritis, the patient’s primary care physician referred him to the emergency department. He was subsequently sent to the dermatology clinic.

On examination by dermatology, a 6.3×4.4-cm, tender, mobile, ulcerated nodule was noted on the left knee (Figure 1A). No popliteal or inguinal lymph nodes were palpable. Basal cell carcinoma, squamous cell carcinoma, or atypical infection (eg, Leishmania, deep fungal, mycobacterial) was suspected clinically. The patient underwent a diagnostic skin biopsy; hematoxylin and eosin–stained sections revealed lobular proliferation of basaloid cells with peripheral palisading and central tumoral necrosis, consistent with primary BCC (Figure 2).

Comment

Exposure to UV radiation is the primary causative agent of most BCCs, accounting for the preferential distribution of these tumors on sun-exposed areas of the body. Approximately 80% of BCCs are located on the head and neck, 10% occur on the trunk, and only 8% are found on the lower extremities.¹

Giant BCC, the finding in this case, is defined by the American Joint Committee on Cancer as a tumor larger than 5 cm in diameter. Fewer than 1% of all BCCs achieve this size; they appear more commonly on the back where they can go unnoticed.² Neglect and inadequate treatment of the primary tumor are the most important contributing factors to the size of giant BCCs. Giant BCCs also have more aggressive biologic behavior, with an increased risk for local invasion and metastasis.³ In this case, the lesion was larger than 5 cm in diameter and occurred on the lower extremity rather than on the trunk.

This case is unusual because delayed diagnosis of BCC was the result of misdiagnoses of a dermoid cyst and bursitis, with a diagnostic skin biopsy demonstrating BCC almost 2 years later. It should be emphasized that early diagnosis and treatment could prevent tumor expansion. Physicians should have a high degree of suspicion for BCC, especially when a dermoid cyst and knee bursitis fail to respond to conservative management.

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer in the United States. It develops most often on sun-exposed skin, including the face and neck. Although BCCs are slow-growing tumors that rarely metastasize, they can cause notable local destruction with disfigurement if neglected or inadequately treated. Basal cell carcinoma arising on the legs is relatively uncommon.^1,2 We present an interesting case of delayed diagnosis of BCC on the left knee due to earlier misdiagnoses of a dermoid cyst and bursitis.

Case Report

A 67-year-old man with no history of skin cancer presented with a painful growing tumor on the left knee of approximately 2 years’ duration. The patient’s primary care physician as well as a general surgeon initially diagnosed it as a dermoid cyst and bursitis. The nodule failed to respond to conservative therapy with nonsteroidal anti-inflammatory drugs and continued to grow until it began to ulcerate. Concerned about the possibility of septic arthritis, the patient’s primary care physician referred him to the emergency department. He was subsequently sent to the dermatology clinic.

On examination by dermatology, a 6.3×4.4-cm, tender, mobile, ulcerated nodule was noted on the left knee (Figure 1A). No popliteal or inguinal lymph nodes were palpable. Basal cell carcinoma, squamous cell carcinoma, or atypical infection (eg, Leishmania, deep fungal, mycobacterial) was suspected clinically. The patient underwent a diagnostic skin biopsy; hematoxylin and eosin–stained sections revealed lobular proliferation of basaloid cells with peripheral palisading and central tumoral necrosis, consistent with primary BCC (Figure 2).

Comment

Exposure to UV radiation is the primary causative agent of most BCCs, accounting for the preferential distribution of these tumors on sun-exposed areas of the body. Approximately 80% of BCCs are located on the head and neck, 10% occur on the trunk, and only 8% are found on the lower extremities.¹

Giant BCC, the finding in this case, is defined by the American Joint Committee on Cancer as a tumor larger than 5 cm in diameter. Fewer than 1% of all BCCs achieve this size; they appear more commonly on the back where they can go unnoticed.² Neglect and inadequate treatment of the primary tumor are the most important contributing factors to the size of giant BCCs. Giant BCCs also have more aggressive biologic behavior, with an increased risk for local invasion and metastasis.³ In this case, the lesion was larger than 5 cm in diameter and occurred on the lower extremity rather than on the trunk.

This case is unusual because delayed diagnosis of BCC was the result of misdiagnoses of a dermoid cyst and bursitis, with a diagnostic skin biopsy demonstrating BCC almost 2 years later. It should be emphasized that early diagnosis and treatment could prevent tumor expansion. Physicians should have a high degree of suspicion for BCC, especially when a dermoid cyst and knee bursitis fail to respond to conservative management.

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer in the United States. It develops most often on sun-exposed skin, including the face and neck. Although BCCs are slow-growing tumors that rarely metastasize, they can cause notable local destruction with disfigurement if neglected or inadequately treated. Basal cell carcinoma arising on the legs is relatively uncommon.^1,2 We present an interesting case of delayed diagnosis of BCC on the left knee due to earlier misdiagnoses of a dermoid cyst and bursitis.

Case Report

A 67-year-old man with no history of skin cancer presented with a painful growing tumor on the left knee of approximately 2 years’ duration. The patient’s primary care physician as well as a general surgeon initially diagnosed it as a dermoid cyst and bursitis. The nodule failed to respond to conservative therapy with nonsteroidal anti-inflammatory drugs and continued to grow until it began to ulcerate. Concerned about the possibility of septic arthritis, the patient’s primary care physician referred him to the emergency department. He was subsequently sent to the dermatology clinic.

On examination by dermatology, a 6.3×4.4-cm, tender, mobile, ulcerated nodule was noted on the left knee (Figure 1A). No popliteal or inguinal lymph nodes were palpable. Basal cell carcinoma, squamous cell carcinoma, or atypical infection (eg, Leishmania, deep fungal, mycobacterial) was suspected clinically. The patient underwent a diagnostic skin biopsy; hematoxylin and eosin–stained sections revealed lobular proliferation of basaloid cells with peripheral palisading and central tumoral necrosis, consistent with primary BCC (Figure 2).

Comment

Exposure to UV radiation is the primary causative agent of most BCCs, accounting for the preferential distribution of these tumors on sun-exposed areas of the body. Approximately 80% of BCCs are located on the head and neck, 10% occur on the trunk, and only 8% are found on the lower extremities.¹

Giant BCC, the finding in this case, is defined by the American Joint Committee on Cancer as a tumor larger than 5 cm in diameter. Fewer than 1% of all BCCs achieve this size; they appear more commonly on the back where they can go unnoticed.² Neglect and inadequate treatment of the primary tumor are the most important contributing factors to the size of giant BCCs. Giant BCCs also have more aggressive biologic behavior, with an increased risk for local invasion and metastasis.³ In this case, the lesion was larger than 5 cm in diameter and occurred on the lower extremity rather than on the trunk.

This case is unusual because delayed diagnosis of BCC was the result of misdiagnoses of a dermoid cyst and bursitis, with a diagnostic skin biopsy demonstrating BCC almost 2 years later. It should be emphasized that early diagnosis and treatment could prevent tumor expansion. Physicians should have a high degree of suspicion for BCC, especially when a dermoid cyst and knee bursitis fail to respond to conservative management.

First reported in 1895, nevus sebaceus (NS) is a con genital papillomatous hamartoma most commonly found on the scalp and face. ¹ Lesions typically are yellow-orange plaques and often are hairless. Nevus sebaceus is most prominent in the few first months after birth and again at puberty during development of the sebaceous glands. Development of epithelial hyperplasia, cysts, verrucas, and benign or malignant tumors has been reported. ¹ The most common benign tumors are syringocystadenoma papilliferum and trichoblastoma. Cases of malignancy are rare, and basal cell carcinoma is the predominant form (approximately 2% of cases). Squamous cell carcinoma (SCC) and adnexal carcinoma are reported at even lower rates. ¹ Malignant transformation occurring during childhood is extremely uncommon. According to a PubMed search of articles indexed for MEDLINE using the terms nevus sebaceous, malignancy, and squamous cell carcinoma and narrowing the results to children, there have been only 4 prior reports of SCC developing within an NS in a child. ^2-5 We report a case of SCC arising in an NS in a 13-year-old adolescent girl with perineural invasion.

Case Report

A 13-year-old fair-skinned adolescent girl presented with a hairless 2×2.5-cm yellow plaque at the hairline on the anterior central scalp. The plaque had been present since birth and had progressively developed a superiorly located 3×5-mm erythematous verrucous nodule (Figure 1) with an approximate height of 6 mm over the last year. The nodule was subjected to regular trauma and bled with minimal insult. The patient appeared otherwise healthy, with no history of skin cancer or other chronic medical conditions. There was no evidence of lymphadenopathy on examination, and no other skin abnormalities were noted. There was no reported family history of skin cancer or chronic skin conditions suggestive of increased risk for cancer or other pathologic dermatoses. Differential diagnoses for the plaque and nodule complex included verruca, Spitz nevus, or secondary neoplasm within NS.

Excision was conducted under local anesthesia without complication. An elliptical section of skin measuring 0.8×2.5 cm was excised to a depth of 3 mm. The resulting wound was closed using a complex linear repair. The section was placed in formalin specimen transport medium and sent to Walter Reed National Military Medical Center (Bethesda, Maryland). Microscopic examination of the specimen revealed features typical for NS, including mild verrucous epidermal hyperplasia, sebaceous gland hyperplasia, presence of apocrine glands, and hamartomatous follicular proliferations (Figure 2). An even more papillomatous epidermal proliferation that was comprised of atypical squamous cells was present within the lesion. Similar atypical squamous cells infiltrated the superficial dermis in nests, cords, and single cells (Figure 3A). One focus showed perineural invasion with a small superficial nerve fiber surrounded by SCC (Figure 3B). The tumor was completely excised, with negative surgical margins extending approximately 2 mm. Adjuvant radiation therapy and further specialized Mohs micrographic excision were not performed because of the clear histologic appearance of the carcinoma and strong evidence of complete excision.

At 2-week follow-up, the surgical scar on the anterior central forehead was well healed without evidence of SCC recurrence. On physical examination there was neither lymphadenopathy nor signs of neurologic deficit, except for superficial cutaneous hypoesthesia in the immediate area surrounding the healed site. Following discussion with the patient and her parents, it was decided that the patient would obtain baseline laboratory tests, chest radiography, and abdominal ultrasonography, and she would undergo serial follow-up examinations every 3 months for the next 2 years. Annual follow-up was recommended after 2 years, with the caveat to return sooner if recurrence or symptoms were to arise.

Comment

Historically, there has been variability in the histopathologic interpretation of SCC in NS in the literature. Retrospective analysis of the histologic evidence of SCC in the 2 earliest possible cases of pediatric SCC in NS have been questioned due to the lack of clinical data presented and the possibility that the diagnosis of SCC was inaccurate.⁶ Our case was histopathologically interpreted as superficially invasive, well-differentiated SCC arising within an NS; therefore, we classified this case as SCC and took every precaution to ensure the lesion was completely excised, given the potentially invasive nature of SCC.

Our case is unique because it represents SCC in NS with histologic evidence of perineural involvement. Perineural invasion is a major route of tumor spread in SCC and may result in increased occurrence of regional lymph node spread and distant metastases, with path of least resistance or neural cell adhesion as possible spreading methods.^7-9 However, there is a notable amount of prognostic variability based on tumor type, the nerve involved, and degree of involvement.⁹ It is common for cutaneous SCC to occur with invasion of small intradermal nerves, but a poor outcome is less likely in asymptomatic patients who have perineural involvement that was incidentally discovered on histologic examination.¹⁰

In our patient, the entire tumor was completely removed with local excision. Recurrence of the SCC or future symptoms of deep neural invasion were not anticipated given the postoperative evidence of clear margins in the excised skin and subdermal structures as well as the lack of preoperative and postoperative symptoms. Close clinical follow-up was warranted to monitor for early signs of recurrence or neural involvement. We have confidence that the planned follow-up regimen in our patient will reveal any early signs of new occurrence or recurrence.

In the case of recurrence, Mohs micrographic surgery would likely be indicated. We elected not to treat with adjuvant radiotherapy because its benefit in cutaneous SCC with perineural invasion is debatable based on the lack of randomized controlled clinical evidence.^10,11 The patient obtained postoperative baseline complete blood cell count with differential, posterior/anterior and lateral chest radiographs, as well as abdominal ultrasonography. Each returned negative findings of hematologic or distant organ metastases, with subsequent follow-up visits also negative for any new concerning findings.

First reported in 1895, nevus sebaceus (NS) is a con genital papillomatous hamartoma most commonly found on the scalp and face. ¹ Lesions typically are yellow-orange plaques and often are hairless. Nevus sebaceus is most prominent in the few first months after birth and again at puberty during development of the sebaceous glands. Development of epithelial hyperplasia, cysts, verrucas, and benign or malignant tumors has been reported. ¹ The most common benign tumors are syringocystadenoma papilliferum and trichoblastoma. Cases of malignancy are rare, and basal cell carcinoma is the predominant form (approximately 2% of cases). Squamous cell carcinoma (SCC) and adnexal carcinoma are reported at even lower rates. ¹ Malignant transformation occurring during childhood is extremely uncommon. According to a PubMed search of articles indexed for MEDLINE using the terms nevus sebaceous, malignancy, and squamous cell carcinoma and narrowing the results to children, there have been only 4 prior reports of SCC developing within an NS in a child. ^2-5 We report a case of SCC arising in an NS in a 13-year-old adolescent girl with perineural invasion.

Case Report

A 13-year-old fair-skinned adolescent girl presented with a hairless 2×2.5-cm yellow plaque at the hairline on the anterior central scalp. The plaque had been present since birth and had progressively developed a superiorly located 3×5-mm erythematous verrucous nodule (Figure 1) with an approximate height of 6 mm over the last year. The nodule was subjected to regular trauma and bled with minimal insult. The patient appeared otherwise healthy, with no history of skin cancer or other chronic medical conditions. There was no evidence of lymphadenopathy on examination, and no other skin abnormalities were noted. There was no reported family history of skin cancer or chronic skin conditions suggestive of increased risk for cancer or other pathologic dermatoses. Differential diagnoses for the plaque and nodule complex included verruca, Spitz nevus, or secondary neoplasm within NS.

Excision was conducted under local anesthesia without complication. An elliptical section of skin measuring 0.8×2.5 cm was excised to a depth of 3 mm. The resulting wound was closed using a complex linear repair. The section was placed in formalin specimen transport medium and sent to Walter Reed National Military Medical Center (Bethesda, Maryland). Microscopic examination of the specimen revealed features typical for NS, including mild verrucous epidermal hyperplasia, sebaceous gland hyperplasia, presence of apocrine glands, and hamartomatous follicular proliferations (Figure 2). An even more papillomatous epidermal proliferation that was comprised of atypical squamous cells was present within the lesion. Similar atypical squamous cells infiltrated the superficial dermis in nests, cords, and single cells (Figure 3A). One focus showed perineural invasion with a small superficial nerve fiber surrounded by SCC (Figure 3B). The tumor was completely excised, with negative surgical margins extending approximately 2 mm. Adjuvant radiation therapy and further specialized Mohs micrographic excision were not performed because of the clear histologic appearance of the carcinoma and strong evidence of complete excision.

At 2-week follow-up, the surgical scar on the anterior central forehead was well healed without evidence of SCC recurrence. On physical examination there was neither lymphadenopathy nor signs of neurologic deficit, except for superficial cutaneous hypoesthesia in the immediate area surrounding the healed site. Following discussion with the patient and her parents, it was decided that the patient would obtain baseline laboratory tests, chest radiography, and abdominal ultrasonography, and she would undergo serial follow-up examinations every 3 months for the next 2 years. Annual follow-up was recommended after 2 years, with the caveat to return sooner if recurrence or symptoms were to arise.

Comment

Historically, there has been variability in the histopathologic interpretation of SCC in NS in the literature. Retrospective analysis of the histologic evidence of SCC in the 2 earliest possible cases of pediatric SCC in NS have been questioned due to the lack of clinical data presented and the possibility that the diagnosis of SCC was inaccurate.⁶ Our case was histopathologically interpreted as superficially invasive, well-differentiated SCC arising within an NS; therefore, we classified this case as SCC and took every precaution to ensure the lesion was completely excised, given the potentially invasive nature of SCC.

Our case is unique because it represents SCC in NS with histologic evidence of perineural involvement. Perineural invasion is a major route of tumor spread in SCC and may result in increased occurrence of regional lymph node spread and distant metastases, with path of least resistance or neural cell adhesion as possible spreading methods.^7-9 However, there is a notable amount of prognostic variability based on tumor type, the nerve involved, and degree of involvement.⁹ It is common for cutaneous SCC to occur with invasion of small intradermal nerves, but a poor outcome is less likely in asymptomatic patients who have perineural involvement that was incidentally discovered on histologic examination.¹⁰

In our patient, the entire tumor was completely removed with local excision. Recurrence of the SCC or future symptoms of deep neural invasion were not anticipated given the postoperative evidence of clear margins in the excised skin and subdermal structures as well as the lack of preoperative and postoperative symptoms. Close clinical follow-up was warranted to monitor for early signs of recurrence or neural involvement. We have confidence that the planned follow-up regimen in our patient will reveal any early signs of new occurrence or recurrence.

In the case of recurrence, Mohs micrographic surgery would likely be indicated. We elected not to treat with adjuvant radiotherapy because its benefit in cutaneous SCC with perineural invasion is debatable based on the lack of randomized controlled clinical evidence.^10,11 The patient obtained postoperative baseline complete blood cell count with differential, posterior/anterior and lateral chest radiographs, as well as abdominal ultrasonography. Each returned negative findings of hematologic or distant organ metastases, with subsequent follow-up visits also negative for any new concerning findings.

First reported in 1895, nevus sebaceus (NS) is a con genital papillomatous hamartoma most commonly found on the scalp and face. ¹ Lesions typically are yellow-orange plaques and often are hairless. Nevus sebaceus is most prominent in the few first months after birth and again at puberty during development of the sebaceous glands. Development of epithelial hyperplasia, cysts, verrucas, and benign or malignant tumors has been reported. ¹ The most common benign tumors are syringocystadenoma papilliferum and trichoblastoma. Cases of malignancy are rare, and basal cell carcinoma is the predominant form (approximately 2% of cases). Squamous cell carcinoma (SCC) and adnexal carcinoma are reported at even lower rates. ¹ Malignant transformation occurring during childhood is extremely uncommon. According to a PubMed search of articles indexed for MEDLINE using the terms nevus sebaceous, malignancy, and squamous cell carcinoma and narrowing the results to children, there have been only 4 prior reports of SCC developing within an NS in a child. ^2-5 We report a case of SCC arising in an NS in a 13-year-old adolescent girl with perineural invasion.

Case Report

A 13-year-old fair-skinned adolescent girl presented with a hairless 2×2.5-cm yellow plaque at the hairline on the anterior central scalp. The plaque had been present since birth and had progressively developed a superiorly located 3×5-mm erythematous verrucous nodule (Figure 1) with an approximate height of 6 mm over the last year. The nodule was subjected to regular trauma and bled with minimal insult. The patient appeared otherwise healthy, with no history of skin cancer or other chronic medical conditions. There was no evidence of lymphadenopathy on examination, and no other skin abnormalities were noted. There was no reported family history of skin cancer or chronic skin conditions suggestive of increased risk for cancer or other pathologic dermatoses. Differential diagnoses for the plaque and nodule complex included verruca, Spitz nevus, or secondary neoplasm within NS.

Excision was conducted under local anesthesia without complication. An elliptical section of skin measuring 0.8×2.5 cm was excised to a depth of 3 mm. The resulting wound was closed using a complex linear repair. The section was placed in formalin specimen transport medium and sent to Walter Reed National Military Medical Center (Bethesda, Maryland). Microscopic examination of the specimen revealed features typical for NS, including mild verrucous epidermal hyperplasia, sebaceous gland hyperplasia, presence of apocrine glands, and hamartomatous follicular proliferations (Figure 2). An even more papillomatous epidermal proliferation that was comprised of atypical squamous cells was present within the lesion. Similar atypical squamous cells infiltrated the superficial dermis in nests, cords, and single cells (Figure 3A). One focus showed perineural invasion with a small superficial nerve fiber surrounded by SCC (Figure 3B). The tumor was completely excised, with negative surgical margins extending approximately 2 mm. Adjuvant radiation therapy and further specialized Mohs micrographic excision were not performed because of the clear histologic appearance of the carcinoma and strong evidence of complete excision.

At 2-week follow-up, the surgical scar on the anterior central forehead was well healed without evidence of SCC recurrence. On physical examination there was neither lymphadenopathy nor signs of neurologic deficit, except for superficial cutaneous hypoesthesia in the immediate area surrounding the healed site. Following discussion with the patient and her parents, it was decided that the patient would obtain baseline laboratory tests, chest radiography, and abdominal ultrasonography, and she would undergo serial follow-up examinations every 3 months for the next 2 years. Annual follow-up was recommended after 2 years, with the caveat to return sooner if recurrence or symptoms were to arise.

Comment

Historically, there has been variability in the histopathologic interpretation of SCC in NS in the literature. Retrospective analysis of the histologic evidence of SCC in the 2 earliest possible cases of pediatric SCC in NS have been questioned due to the lack of clinical data presented and the possibility that the diagnosis of SCC was inaccurate.⁶ Our case was histopathologically interpreted as superficially invasive, well-differentiated SCC arising within an NS; therefore, we classified this case as SCC and took every precaution to ensure the lesion was completely excised, given the potentially invasive nature of SCC.

Our case is unique because it represents SCC in NS with histologic evidence of perineural involvement. Perineural invasion is a major route of tumor spread in SCC and may result in increased occurrence of regional lymph node spread and distant metastases, with path of least resistance or neural cell adhesion as possible spreading methods.^7-9 However, there is a notable amount of prognostic variability based on tumor type, the nerve involved, and degree of involvement.⁹ It is common for cutaneous SCC to occur with invasion of small intradermal nerves, but a poor outcome is less likely in asymptomatic patients who have perineural involvement that was incidentally discovered on histologic examination.¹⁰

In our patient, the entire tumor was completely removed with local excision. Recurrence of the SCC or future symptoms of deep neural invasion were not anticipated given the postoperative evidence of clear margins in the excised skin and subdermal structures as well as the lack of preoperative and postoperative symptoms. Close clinical follow-up was warranted to monitor for early signs of recurrence or neural involvement. We have confidence that the planned follow-up regimen in our patient will reveal any early signs of new occurrence or recurrence.

In the case of recurrence, Mohs micrographic surgery would likely be indicated. We elected not to treat with adjuvant radiotherapy because its benefit in cutaneous SCC with perineural invasion is debatable based on the lack of randomized controlled clinical evidence.^10,11 The patient obtained postoperative baseline complete blood cell count with differential, posterior/anterior and lateral chest radiographs, as well as abdominal ultrasonography. Each returned negative findings of hematologic or distant organ metastases, with subsequent follow-up visits also negative for any new concerning findings.

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]