Case Reports

Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

THE CASE

A 58-year-old married Asian woman with no apparent psychiatric history presented to the emergency department (ED) in an acute state with ideas of reference, paranoid delusions, and multiple, vague somatic symptoms.

Based on information in the patient’s medical record, there had been suspicion of an underlying psychiatric disorder 6 years earlier. At that time, the patient had presented to her primary care provider (PCP) with vague somatic complaints, including diffuse body pain, dry cough, chills, weakness, facial numbness, and concerns about infections. A physical examination and work-up did not reveal the source of her complaints. Unfortunately, the patient’s complaints increased in number and severity over time.

Her medical records also indicated that she had been assessed for depression severity using the Patient Health Questionnaire-9 (PHQ-9), with scores of 0 (4 years earlier) and 3 (3 years earlier). The scores suggested that she was not suffering from depression.

During this time, the patient also saw a psychiatrist; however, it was unclear whether her symptoms met the criteria for delusional disorder or schizophrenia because she did not exhibit negative symptoms or sensory hallucinations. In addition, the patient was extremely high-functioning in the community—she participated in dance classes and other social events—and had the equivalent of a medical degree from another country. Based on chart review, when she went to the psychiatrist 3 years prior to her current presentation, there were no antipsychotics prescribed.

In the weeks leading up to her current presentation, the patient reported that she was struggling with sleep, sometimes spending days in bed and other times needing unspecified medication obtained overseas to help her sleep. Her husband reported that she had become increasingly withdrawn and stopped attending her dance classes and social events.

The patient believed the government was trying to poison her via radiation and that unknown people were trying to harm her via an online messaging application. Immediately prior to her arrival in the ED, the police were called to pull her away from oncoming traffic because she ran into the road to find the assassins that were stalking her.

During this recent visit to the ED, the patient presented with labile affect, rapid speech, and anxious and angry mood. She complained about darkened spots on her arm (inflicted through radiation by the media), vaginal bleeding, paralysis below the waist (although she was pacing around), and unspecific pain around her belly. Physical examination revealed no obvious signs of head trauma, intact extraocular movements, no coughing or wheezing, regular heart rate and rhythm, a nontender abdomen to palpation, and normal bowel sounds. No focal neurological deficits were appreciated. She had no rashes, bruises, or skin abrasions on her abdomen or upper extremities.

Continue to: The patient tried to...

The patient tried to leave the ED, saying that her third eye could see the radiation. She required medication and 4-point restraints.

Her initial laboratory work-up for heavy metals, Lyme disease, human immunodeficiency virus (HIV), syphilis, delirium, and drug use were all negative. She also underwent head imaging studies that were also found to be negative. Her mental status exam was notable for a tangential thought process, preservation of delusions with loose associations, labile mood, and dysphoric affect. The patient demonstrated limited insight and judgment, although she was fully oriented to person, place, and time, which suggested against delirium at the time of evaluation.

THE DIAGNOSIS

Based on the patient’s current presentation and in light of her medical history, the health care team arrived at a working diagnosis of late-onset schizophrenia (LOS). The treatment team was able to identify that the current presentation in the ED was the patient’s first episode of psychosis for LOS. The prior 5 to 10 years illustrated a slow progression of odd, yet feasible, chief complaints to multiple clinicians. Reaching the LOS diagnosis sooner had been complicated by the fact that the patient was extremely high functioning in the community.

DISCUSSION

Schizophrenia is a severe, lifelong mental disorder characterized by at least 2 symptoms of delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms for at least 6 months, with significant social, occupational, and functional deterioration. Current models attribute the neurodevelopmental deregulation of the brain in patients with schizophrenia to dopaminergic hyperactivity and hypofunction of the glutamatergic neurotransmitter system, explaining why its onset is usually in adolescence or young adulthood.^1,2 However, 23% of patients present with symptoms after age 40, with 7% of patients being diagnosed between the ages of 51 and 60.³

Late-onset vs early-onset schizophrenia. LOS is often a missed diagnosis because the clinical presentation is different from early-onset schizophrenia (EOS). Although the prodromal symptoms of EOS and LOS are similar and include marked isolation that subsequently progresses to suspiciousness and ideas of reference,⁴ patients with EOS often also have prodromal negative symptoms. These prodromal negative symptoms associated with EOS may include loss of motivation, social passivity, and disorganized behavior. These symptoms are hypothesized to be caused by dopaminergic dysregulation in the anterior cingulate cortex. EOS is characterized by the patient experiencing more negative symptoms than LOS, which is characterized by the patient experiencing more positive symptoms.

Continue to: Patients with late-onset schizophrenia...

Patients with late-onset schizophrenia often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.

Patients with LOS typically do not exhibit negative symptoms because remodeling and myelination of neuronal circuitry matures by late adulthood, and thus becomes more resistant to impairment of motivational processes in the anterior cingulate gyrus.^4,5,6

LOS is characterized by paranoid personality with predominantly positive symptoms, likely due to disruptions in cortico-striato-pallido-thalamic circuitry that manifest in increased frequency and severity of acoustic, tactile, or olfactory hallucinations and persecutory delusions.^1,6,7 Patients with LOS often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.⁸ The prevalence of delusions positively correlates with increased age at diagnosis.⁹ Patients with LOS also often develop comorbid schizoid or schizotypal personalities.⁸ In contrast, patients with EOS primarily present with disorganized behavior and speech; hallucinations; and delusions.

Other features of LOS include a high female:male ratio and symptomatic improvement with antipsychotics.^7,10 Studies show that the LOS ratio of women:men can range from 2.2:1 to 22.5:1, which could be explained by the effect of dopaminergic-modulating estrogen from different sex-specific aging brain patterns.^8,11,12 Finally, patients with LOS are less likely to seek care for sensory deficits than their age-equivalent counterparts.^8,10 Fortunately, many of the characteristics of LOS predict good prognosis: Patients are usually female, display positive symptoms, have acute onset of symptoms, and are married with social support.¹⁰

Diagnosing LOS

LOS can be challenging to diagnose because of its atypical presentation compared with EOS, relative rarity in the population, and its propensity to be confused with progressive Alzheimer disease/dementia, delusional disorder, and major depressive disorder with psychotic features.^3,6 Patients with no prior psychiatric history often do not have ready access to psychiatrists and depend on PCPs and other clinicians to identify mental health issues. A careful history, including familial involvement, utilization of the Montreal Cognitive Assessment (MoCA) test, and evaluation of environmental factors, are crucial to arriving at the proper diagnosis.

Continue to: Differential diagnosis

Differential diagnosis. When psychosis appears later in life, it is important to consider a broad differential (TABLE^13-18), which includes the following:

Alzheimer disease. LOS can be easily differentiated from psychosis associated with Alzheimer disease or dementia through findings from neuropsychologic assessments and brain imaging. The initial first-line assessment for Alzheimer disease includes determining time course of daily living impairment and memory with follow-up brain imaging. Magnetic resonance imaging of patients with Alzheimer disease shows clear atrophy of the medial temporal lobes and general brain atrophy.¹⁹ Other than hypoperfusion in the frontal and temporal area, brain imaging of patients with LOS will not reveal any pathology.¹

Delusional disorder and LOS are often more challenging to differentiate because symptoms can overlap, and many of the negative symptoms that would otherwise help clinicians diagnose schizophrenia in a younger population are absent in LOS. The milder symptoms of LOS may also lead clinicians to favor a diagnosis of delusional disorder. However, the following differences can help physicians differentiate between LOS and delusional disorder. Delusional disorder^20-22:

• often will include paranoid beliefs, but these beliefs will not be bizarre, and the patient’s daily functioning will not be impaired, whereas patients with schizophrenia would have an increase in isolation and impairment in functioning that tends to be distinct from baseline.
• is more rare than schizophrenia. Delusional disorder has a prevalence of 0.05% to 0.1% compared to 1% for schizophrenia.

Major depressive disorder (MDD) with psychotic features. Major depressive disorder with psychotic features is an important differential to consider in this setting because the treatment intervention can be considerably different. Among patients who have MDD with psychotic features, a significant mood component is present, and treatment typically focuses on optimizing a selective serotonin reuptake inhibitor (SSRI); depending on severity, electroconvulsive therapy (ECT) also may be warranted.¹⁹

Continue to: For patients with LOS...

Delusional disorder and late-onset schizophrenia are often more challenging to differentiate because symptoms can overlap.

For patients with LOS, optimizing an antipsychotic medication is the typical course of treatment, and ECT would likely have less of an impact than it does with MDD with psychotic features. Furthermore, in the case of our patient, her medical records showed that she was evaluated with the PHQ-9 in the outpatient setting prior to hospitalization. The patient’s PHQ-9 scores ranged from 0 to 3, suggesting against any significant depressive symptoms.

Other. Finally, in an acute setting, other differential diagnoses for mental status changes (depending on clinical findings) might include:

• drug/medication use
• delirium
• nutrient deficiencies
• acute head trauma
• chronic subdural hematoma
• syphilis
• Lyme disease
• HIV encephalitis
• heavy metal toxicity.

Treatment involves antipsychotics—especially certain ones

Antipsychotic medications are utilized for the treatment of patients with LOS. A Cochrane review concluded that there are no trial-based evidence guidelines for the treatment of patients with LOS, and that physicians should continue with their current practice and use clinical judgment and prescribing patterns to guide their selection of antipsychotic medications.^22,23 Pearlson et al²⁴ found that 76% of patients with schizophrenia achieved at least partial remission and 48% achieved full remission with antipsychotic treatment.

The preferred treatment for patients with schizophrenia is low doses of newer antipsychotics (atypical or second-generation antipsychotics [SGAs]) because they are less likely to cause extrapyramidal symptoms/adverse effects than first-generation antipsychotics. Examples of SGAs include aripiprazole, risperidone, olanzapine, quetiapine, and ziprasidone.

Effective treatment for LOS includes antipsychotics at a quarter to one-half of the usual therapeutic doses. In patients with very late-onset schizophrenia, doses should be started at a tenth of therapeutic dose.^1,23 Physicians should titrate up carefully, as needed.

Continue to: As with any significant mental illness...

As with any significant mental illness, to improve clinical outcomes, family support may help patients’ medication adherence and ensure they attend scheduled medical appointments.

As with any significant mental illness, family support may help with a patient’s medication adherence

Our patient was eventually stabilized on long-acting injectable risperidone, 25 mg, with improvement in symptoms. Unfortunately, she was not convinced that her symptoms were psychiatric in nature and did not continue with her medications as an outpatient.

The patient’s nonadherence to her medication regimen led to 2 more hospitalizations with similar presentations over the following 2 years. On her most recent discharge, she was stabilized on oral olanzapine, 10 mg every night at bedtime, with close outpatient follow-up and family education.

THE TAKEAWAY

The prodromal phase of patients with LOS is similar to patients with EOS and includes withdrawal and isolation from others, making it difficult for physicians to evaluate and treat patients. Patients with LOS predominantly experience positive symptoms that may include delusions and hallucinations. Brain imaging studies can help rule out progressive dementia diseases. A neuropsychological evaluation can assess the patient’s functional level and types of delusions, which helps to differentiate LOS from other late-age psychoses. Treatment with SGAs make for a good prognosis; however, this requires patients to be adherent to treatment.

CORRESPONDENCE
Sandy Chan, MD, Department of Internal Medicine, UMass Memorial Medical Center, 55N Lake Avenue, Worcester, MA 01605; [email protected]

THE CASE

A 58-year-old married Asian woman with no apparent psychiatric history presented to the emergency department (ED) in an acute state with ideas of reference, paranoid delusions, and multiple, vague somatic symptoms.

Based on information in the patient’s medical record, there had been suspicion of an underlying psychiatric disorder 6 years earlier. At that time, the patient had presented to her primary care provider (PCP) with vague somatic complaints, including diffuse body pain, dry cough, chills, weakness, facial numbness, and concerns about infections. A physical examination and work-up did not reveal the source of her complaints. Unfortunately, the patient’s complaints increased in number and severity over time.

Her medical records also indicated that she had been assessed for depression severity using the Patient Health Questionnaire-9 (PHQ-9), with scores of 0 (4 years earlier) and 3 (3 years earlier). The scores suggested that she was not suffering from depression.

During this time, the patient also saw a psychiatrist; however, it was unclear whether her symptoms met the criteria for delusional disorder or schizophrenia because she did not exhibit negative symptoms or sensory hallucinations. In addition, the patient was extremely high-functioning in the community—she participated in dance classes and other social events—and had the equivalent of a medical degree from another country. Based on chart review, when she went to the psychiatrist 3 years prior to her current presentation, there were no antipsychotics prescribed.

In the weeks leading up to her current presentation, the patient reported that she was struggling with sleep, sometimes spending days in bed and other times needing unspecified medication obtained overseas to help her sleep. Her husband reported that she had become increasingly withdrawn and stopped attending her dance classes and social events.

The patient believed the government was trying to poison her via radiation and that unknown people were trying to harm her via an online messaging application. Immediately prior to her arrival in the ED, the police were called to pull her away from oncoming traffic because she ran into the road to find the assassins that were stalking her.

During this recent visit to the ED, the patient presented with labile affect, rapid speech, and anxious and angry mood. She complained about darkened spots on her arm (inflicted through radiation by the media), vaginal bleeding, paralysis below the waist (although she was pacing around), and unspecific pain around her belly. Physical examination revealed no obvious signs of head trauma, intact extraocular movements, no coughing or wheezing, regular heart rate and rhythm, a nontender abdomen to palpation, and normal bowel sounds. No focal neurological deficits were appreciated. She had no rashes, bruises, or skin abrasions on her abdomen or upper extremities.

Continue to: The patient tried to...

The patient tried to leave the ED, saying that her third eye could see the radiation. She required medication and 4-point restraints.

Her initial laboratory work-up for heavy metals, Lyme disease, human immunodeficiency virus (HIV), syphilis, delirium, and drug use were all negative. She also underwent head imaging studies that were also found to be negative. Her mental status exam was notable for a tangential thought process, preservation of delusions with loose associations, labile mood, and dysphoric affect. The patient demonstrated limited insight and judgment, although she was fully oriented to person, place, and time, which suggested against delirium at the time of evaluation.

THE DIAGNOSIS

Based on the patient’s current presentation and in light of her medical history, the health care team arrived at a working diagnosis of late-onset schizophrenia (LOS). The treatment team was able to identify that the current presentation in the ED was the patient’s first episode of psychosis for LOS. The prior 5 to 10 years illustrated a slow progression of odd, yet feasible, chief complaints to multiple clinicians. Reaching the LOS diagnosis sooner had been complicated by the fact that the patient was extremely high functioning in the community.

DISCUSSION

Schizophrenia is a severe, lifelong mental disorder characterized by at least 2 symptoms of delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms for at least 6 months, with significant social, occupational, and functional deterioration. Current models attribute the neurodevelopmental deregulation of the brain in patients with schizophrenia to dopaminergic hyperactivity and hypofunction of the glutamatergic neurotransmitter system, explaining why its onset is usually in adolescence or young adulthood.^1,2 However, 23% of patients present with symptoms after age 40, with 7% of patients being diagnosed between the ages of 51 and 60.³

Late-onset vs early-onset schizophrenia. LOS is often a missed diagnosis because the clinical presentation is different from early-onset schizophrenia (EOS). Although the prodromal symptoms of EOS and LOS are similar and include marked isolation that subsequently progresses to suspiciousness and ideas of reference,⁴ patients with EOS often also have prodromal negative symptoms. These prodromal negative symptoms associated with EOS may include loss of motivation, social passivity, and disorganized behavior. These symptoms are hypothesized to be caused by dopaminergic dysregulation in the anterior cingulate cortex. EOS is characterized by the patient experiencing more negative symptoms than LOS, which is characterized by the patient experiencing more positive symptoms.

Continue to: Patients with late-onset schizophrenia...

Patients with late-onset schizophrenia often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.

Patients with LOS typically do not exhibit negative symptoms because remodeling and myelination of neuronal circuitry matures by late adulthood, and thus becomes more resistant to impairment of motivational processes in the anterior cingulate gyrus.^4,5,6

LOS is characterized by paranoid personality with predominantly positive symptoms, likely due to disruptions in cortico-striato-pallido-thalamic circuitry that manifest in increased frequency and severity of acoustic, tactile, or olfactory hallucinations and persecutory delusions.^1,6,7 Patients with LOS often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.⁸ The prevalence of delusions positively correlates with increased age at diagnosis.⁹ Patients with LOS also often develop comorbid schizoid or schizotypal personalities.⁸ In contrast, patients with EOS primarily present with disorganized behavior and speech; hallucinations; and delusions.

Other features of LOS include a high female:male ratio and symptomatic improvement with antipsychotics.^7,10 Studies show that the LOS ratio of women:men can range from 2.2:1 to 22.5:1, which could be explained by the effect of dopaminergic-modulating estrogen from different sex-specific aging brain patterns.^8,11,12 Finally, patients with LOS are less likely to seek care for sensory deficits than their age-equivalent counterparts.^8,10 Fortunately, many of the characteristics of LOS predict good prognosis: Patients are usually female, display positive symptoms, have acute onset of symptoms, and are married with social support.¹⁰

Diagnosing LOS

LOS can be challenging to diagnose because of its atypical presentation compared with EOS, relative rarity in the population, and its propensity to be confused with progressive Alzheimer disease/dementia, delusional disorder, and major depressive disorder with psychotic features.^3,6 Patients with no prior psychiatric history often do not have ready access to psychiatrists and depend on PCPs and other clinicians to identify mental health issues. A careful history, including familial involvement, utilization of the Montreal Cognitive Assessment (MoCA) test, and evaluation of environmental factors, are crucial to arriving at the proper diagnosis.

Continue to: Differential diagnosis

Differential diagnosis. When psychosis appears later in life, it is important to consider a broad differential (TABLE^13-18), which includes the following:

Alzheimer disease. LOS can be easily differentiated from psychosis associated with Alzheimer disease or dementia through findings from neuropsychologic assessments and brain imaging. The initial first-line assessment for Alzheimer disease includes determining time course of daily living impairment and memory with follow-up brain imaging. Magnetic resonance imaging of patients with Alzheimer disease shows clear atrophy of the medial temporal lobes and general brain atrophy.¹⁹ Other than hypoperfusion in the frontal and temporal area, brain imaging of patients with LOS will not reveal any pathology.¹

Delusional disorder and LOS are often more challenging to differentiate because symptoms can overlap, and many of the negative symptoms that would otherwise help clinicians diagnose schizophrenia in a younger population are absent in LOS. The milder symptoms of LOS may also lead clinicians to favor a diagnosis of delusional disorder. However, the following differences can help physicians differentiate between LOS and delusional disorder. Delusional disorder^20-22:

• often will include paranoid beliefs, but these beliefs will not be bizarre, and the patient’s daily functioning will not be impaired, whereas patients with schizophrenia would have an increase in isolation and impairment in functioning that tends to be distinct from baseline.
• is more rare than schizophrenia. Delusional disorder has a prevalence of 0.05% to 0.1% compared to 1% for schizophrenia.

Major depressive disorder (MDD) with psychotic features. Major depressive disorder with psychotic features is an important differential to consider in this setting because the treatment intervention can be considerably different. Among patients who have MDD with psychotic features, a significant mood component is present, and treatment typically focuses on optimizing a selective serotonin reuptake inhibitor (SSRI); depending on severity, electroconvulsive therapy (ECT) also may be warranted.¹⁹

Continue to: For patients with LOS...

Delusional disorder and late-onset schizophrenia are often more challenging to differentiate because symptoms can overlap.

For patients with LOS, optimizing an antipsychotic medication is the typical course of treatment, and ECT would likely have less of an impact than it does with MDD with psychotic features. Furthermore, in the case of our patient, her medical records showed that she was evaluated with the PHQ-9 in the outpatient setting prior to hospitalization. The patient’s PHQ-9 scores ranged from 0 to 3, suggesting against any significant depressive symptoms.

Other. Finally, in an acute setting, other differential diagnoses for mental status changes (depending on clinical findings) might include:

• drug/medication use
• delirium
• nutrient deficiencies
• acute head trauma
• chronic subdural hematoma
• syphilis
• Lyme disease
• HIV encephalitis
• heavy metal toxicity.

Treatment involves antipsychotics—especially certain ones

Antipsychotic medications are utilized for the treatment of patients with LOS. A Cochrane review concluded that there are no trial-based evidence guidelines for the treatment of patients with LOS, and that physicians should continue with their current practice and use clinical judgment and prescribing patterns to guide their selection of antipsychotic medications.^22,23 Pearlson et al²⁴ found that 76% of patients with schizophrenia achieved at least partial remission and 48% achieved full remission with antipsychotic treatment.

The preferred treatment for patients with schizophrenia is low doses of newer antipsychotics (atypical or second-generation antipsychotics [SGAs]) because they are less likely to cause extrapyramidal symptoms/adverse effects than first-generation antipsychotics. Examples of SGAs include aripiprazole, risperidone, olanzapine, quetiapine, and ziprasidone.

Effective treatment for LOS includes antipsychotics at a quarter to one-half of the usual therapeutic doses. In patients with very late-onset schizophrenia, doses should be started at a tenth of therapeutic dose.^1,23 Physicians should titrate up carefully, as needed.

Continue to: As with any significant mental illness...

As with any significant mental illness, to improve clinical outcomes, family support may help patients’ medication adherence and ensure they attend scheduled medical appointments.

As with any significant mental illness, family support may help with a patient’s medication adherence

Our patient was eventually stabilized on long-acting injectable risperidone, 25 mg, with improvement in symptoms. Unfortunately, she was not convinced that her symptoms were psychiatric in nature and did not continue with her medications as an outpatient.

The patient’s nonadherence to her medication regimen led to 2 more hospitalizations with similar presentations over the following 2 years. On her most recent discharge, she was stabilized on oral olanzapine, 10 mg every night at bedtime, with close outpatient follow-up and family education.

THE TAKEAWAY

The prodromal phase of patients with LOS is similar to patients with EOS and includes withdrawal and isolation from others, making it difficult for physicians to evaluate and treat patients. Patients with LOS predominantly experience positive symptoms that may include delusions and hallucinations. Brain imaging studies can help rule out progressive dementia diseases. A neuropsychological evaluation can assess the patient’s functional level and types of delusions, which helps to differentiate LOS from other late-age psychoses. Treatment with SGAs make for a good prognosis; however, this requires patients to be adherent to treatment.

CORRESPONDENCE
Sandy Chan, MD, Department of Internal Medicine, UMass Memorial Medical Center, 55N Lake Avenue, Worcester, MA 01605; [email protected]

THE CASE

A 58-year-old married Asian woman with no apparent psychiatric history presented to the emergency department (ED) in an acute state with ideas of reference, paranoid delusions, and multiple, vague somatic symptoms.

Based on information in the patient’s medical record, there had been suspicion of an underlying psychiatric disorder 6 years earlier. At that time, the patient had presented to her primary care provider (PCP) with vague somatic complaints, including diffuse body pain, dry cough, chills, weakness, facial numbness, and concerns about infections. A physical examination and work-up did not reveal the source of her complaints. Unfortunately, the patient’s complaints increased in number and severity over time.

Her medical records also indicated that she had been assessed for depression severity using the Patient Health Questionnaire-9 (PHQ-9), with scores of 0 (4 years earlier) and 3 (3 years earlier). The scores suggested that she was not suffering from depression.

During this time, the patient also saw a psychiatrist; however, it was unclear whether her symptoms met the criteria for delusional disorder or schizophrenia because she did not exhibit negative symptoms or sensory hallucinations. In addition, the patient was extremely high-functioning in the community—she participated in dance classes and other social events—and had the equivalent of a medical degree from another country. Based on chart review, when she went to the psychiatrist 3 years prior to her current presentation, there were no antipsychotics prescribed.

In the weeks leading up to her current presentation, the patient reported that she was struggling with sleep, sometimes spending days in bed and other times needing unspecified medication obtained overseas to help her sleep. Her husband reported that she had become increasingly withdrawn and stopped attending her dance classes and social events.

The patient believed the government was trying to poison her via radiation and that unknown people were trying to harm her via an online messaging application. Immediately prior to her arrival in the ED, the police were called to pull her away from oncoming traffic because she ran into the road to find the assassins that were stalking her.

During this recent visit to the ED, the patient presented with labile affect, rapid speech, and anxious and angry mood. She complained about darkened spots on her arm (inflicted through radiation by the media), vaginal bleeding, paralysis below the waist (although she was pacing around), and unspecific pain around her belly. Physical examination revealed no obvious signs of head trauma, intact extraocular movements, no coughing or wheezing, regular heart rate and rhythm, a nontender abdomen to palpation, and normal bowel sounds. No focal neurological deficits were appreciated. She had no rashes, bruises, or skin abrasions on her abdomen or upper extremities.

Continue to: The patient tried to...

The patient tried to leave the ED, saying that her third eye could see the radiation. She required medication and 4-point restraints.

Her initial laboratory work-up for heavy metals, Lyme disease, human immunodeficiency virus (HIV), syphilis, delirium, and drug use were all negative. She also underwent head imaging studies that were also found to be negative. Her mental status exam was notable for a tangential thought process, preservation of delusions with loose associations, labile mood, and dysphoric affect. The patient demonstrated limited insight and judgment, although she was fully oriented to person, place, and time, which suggested against delirium at the time of evaluation.

THE DIAGNOSIS

Based on the patient’s current presentation and in light of her medical history, the health care team arrived at a working diagnosis of late-onset schizophrenia (LOS). The treatment team was able to identify that the current presentation in the ED was the patient’s first episode of psychosis for LOS. The prior 5 to 10 years illustrated a slow progression of odd, yet feasible, chief complaints to multiple clinicians. Reaching the LOS diagnosis sooner had been complicated by the fact that the patient was extremely high functioning in the community.

DISCUSSION

Schizophrenia is a severe, lifelong mental disorder characterized by at least 2 symptoms of delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms for at least 6 months, with significant social, occupational, and functional deterioration. Current models attribute the neurodevelopmental deregulation of the brain in patients with schizophrenia to dopaminergic hyperactivity and hypofunction of the glutamatergic neurotransmitter system, explaining why its onset is usually in adolescence or young adulthood.^1,2 However, 23% of patients present with symptoms after age 40, with 7% of patients being diagnosed between the ages of 51 and 60.³

Late-onset vs early-onset schizophrenia. LOS is often a missed diagnosis because the clinical presentation is different from early-onset schizophrenia (EOS). Although the prodromal symptoms of EOS and LOS are similar and include marked isolation that subsequently progresses to suspiciousness and ideas of reference,⁴ patients with EOS often also have prodromal negative symptoms. These prodromal negative symptoms associated with EOS may include loss of motivation, social passivity, and disorganized behavior. These symptoms are hypothesized to be caused by dopaminergic dysregulation in the anterior cingulate cortex. EOS is characterized by the patient experiencing more negative symptoms than LOS, which is characterized by the patient experiencing more positive symptoms.

Continue to: Patients with late-onset schizophrenia...

Patients with late-onset schizophrenia often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.

Patients with LOS typically do not exhibit negative symptoms because remodeling and myelination of neuronal circuitry matures by late adulthood, and thus becomes more resistant to impairment of motivational processes in the anterior cingulate gyrus.^4,5,6

LOS is characterized by paranoid personality with predominantly positive symptoms, likely due to disruptions in cortico-striato-pallido-thalamic circuitry that manifest in increased frequency and severity of acoustic, tactile, or olfactory hallucinations and persecutory delusions.^1,6,7 Patients with LOS often have paranoid or partition delusions and believe people or objects can permeate through barriers and access their home with malignant intent.⁸ The prevalence of delusions positively correlates with increased age at diagnosis.⁹ Patients with LOS also often develop comorbid schizoid or schizotypal personalities.⁸ In contrast, patients with EOS primarily present with disorganized behavior and speech; hallucinations; and delusions.

Other features of LOS include a high female:male ratio and symptomatic improvement with antipsychotics.^7,10 Studies show that the LOS ratio of women:men can range from 2.2:1 to 22.5:1, which could be explained by the effect of dopaminergic-modulating estrogen from different sex-specific aging brain patterns.^8,11,12 Finally, patients with LOS are less likely to seek care for sensory deficits than their age-equivalent counterparts.^8,10 Fortunately, many of the characteristics of LOS predict good prognosis: Patients are usually female, display positive symptoms, have acute onset of symptoms, and are married with social support.¹⁰

Diagnosing LOS

LOS can be challenging to diagnose because of its atypical presentation compared with EOS, relative rarity in the population, and its propensity to be confused with progressive Alzheimer disease/dementia, delusional disorder, and major depressive disorder with psychotic features.^3,6 Patients with no prior psychiatric history often do not have ready access to psychiatrists and depend on PCPs and other clinicians to identify mental health issues. A careful history, including familial involvement, utilization of the Montreal Cognitive Assessment (MoCA) test, and evaluation of environmental factors, are crucial to arriving at the proper diagnosis.

Continue to: Differential diagnosis

Differential diagnosis. When psychosis appears later in life, it is important to consider a broad differential (TABLE^13-18), which includes the following:

Alzheimer disease. LOS can be easily differentiated from psychosis associated with Alzheimer disease or dementia through findings from neuropsychologic assessments and brain imaging. The initial first-line assessment for Alzheimer disease includes determining time course of daily living impairment and memory with follow-up brain imaging. Magnetic resonance imaging of patients with Alzheimer disease shows clear atrophy of the medial temporal lobes and general brain atrophy.¹⁹ Other than hypoperfusion in the frontal and temporal area, brain imaging of patients with LOS will not reveal any pathology.¹

Delusional disorder and LOS are often more challenging to differentiate because symptoms can overlap, and many of the negative symptoms that would otherwise help clinicians diagnose schizophrenia in a younger population are absent in LOS. The milder symptoms of LOS may also lead clinicians to favor a diagnosis of delusional disorder. However, the following differences can help physicians differentiate between LOS and delusional disorder. Delusional disorder^20-22:

• often will include paranoid beliefs, but these beliefs will not be bizarre, and the patient’s daily functioning will not be impaired, whereas patients with schizophrenia would have an increase in isolation and impairment in functioning that tends to be distinct from baseline.
• is more rare than schizophrenia. Delusional disorder has a prevalence of 0.05% to 0.1% compared to 1% for schizophrenia.

Major depressive disorder (MDD) with psychotic features. Major depressive disorder with psychotic features is an important differential to consider in this setting because the treatment intervention can be considerably different. Among patients who have MDD with psychotic features, a significant mood component is present, and treatment typically focuses on optimizing a selective serotonin reuptake inhibitor (SSRI); depending on severity, electroconvulsive therapy (ECT) also may be warranted.¹⁹

Continue to: For patients with LOS...

Delusional disorder and late-onset schizophrenia are often more challenging to differentiate because symptoms can overlap.

For patients with LOS, optimizing an antipsychotic medication is the typical course of treatment, and ECT would likely have less of an impact than it does with MDD with psychotic features. Furthermore, in the case of our patient, her medical records showed that she was evaluated with the PHQ-9 in the outpatient setting prior to hospitalization. The patient’s PHQ-9 scores ranged from 0 to 3, suggesting against any significant depressive symptoms.

Other. Finally, in an acute setting, other differential diagnoses for mental status changes (depending on clinical findings) might include:

• drug/medication use
• delirium
• nutrient deficiencies
• acute head trauma
• chronic subdural hematoma
• syphilis
• Lyme disease
• HIV encephalitis
• heavy metal toxicity.

Treatment involves antipsychotics—especially certain ones

Antipsychotic medications are utilized for the treatment of patients with LOS. A Cochrane review concluded that there are no trial-based evidence guidelines for the treatment of patients with LOS, and that physicians should continue with their current practice and use clinical judgment and prescribing patterns to guide their selection of antipsychotic medications.^22,23 Pearlson et al²⁴ found that 76% of patients with schizophrenia achieved at least partial remission and 48% achieved full remission with antipsychotic treatment.

The preferred treatment for patients with schizophrenia is low doses of newer antipsychotics (atypical or second-generation antipsychotics [SGAs]) because they are less likely to cause extrapyramidal symptoms/adverse effects than first-generation antipsychotics. Examples of SGAs include aripiprazole, risperidone, olanzapine, quetiapine, and ziprasidone.

Effective treatment for LOS includes antipsychotics at a quarter to one-half of the usual therapeutic doses. In patients with very late-onset schizophrenia, doses should be started at a tenth of therapeutic dose.^1,23 Physicians should titrate up carefully, as needed.

Continue to: As with any significant mental illness...

As with any significant mental illness, to improve clinical outcomes, family support may help patients’ medication adherence and ensure they attend scheduled medical appointments.

As with any significant mental illness, family support may help with a patient’s medication adherence

Our patient was eventually stabilized on long-acting injectable risperidone, 25 mg, with improvement in symptoms. Unfortunately, she was not convinced that her symptoms were psychiatric in nature and did not continue with her medications as an outpatient.

The patient’s nonadherence to her medication regimen led to 2 more hospitalizations with similar presentations over the following 2 years. On her most recent discharge, she was stabilized on oral olanzapine, 10 mg every night at bedtime, with close outpatient follow-up and family education.

THE TAKEAWAY

The prodromal phase of patients with LOS is similar to patients with EOS and includes withdrawal and isolation from others, making it difficult for physicians to evaluate and treat patients. Patients with LOS predominantly experience positive symptoms that may include delusions and hallucinations. Brain imaging studies can help rule out progressive dementia diseases. A neuropsychological evaluation can assess the patient’s functional level and types of delusions, which helps to differentiate LOS from other late-age psychoses. Treatment with SGAs make for a good prognosis; however, this requires patients to be adherent to treatment.

CORRESPONDENCE
Sandy Chan, MD, Department of Internal Medicine, UMass Memorial Medical Center, 55N Lake Avenue, Worcester, MA 01605; [email protected]

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

Bronchogenic cyst is a rare foregut malformation that typically presents during the second decade of life that arises due to aberrant development from the tracheobronchial tree.¹ Mediastinal bronchogenic cyst is the most common primary cystic lesion of the mediastinum, and bronchogenic cysts of the mediastinum represent 18% of all primary mediastinal malformations.² Patients with mediastinal bronchogenic cysts may present with symptoms of cough, dyspnea, or wheezing if there is encroachment on surrounding structures.

Rarely, bronchogenic cysts can become infected. Definitive treatment of bronchogenic cysts is surgical excision; however, endobronchial ultrasound (EBUS)-guided drainage also can be employed. EBUS-guided drainage may be used when the cyst cannot be distinguished from solid mass on computed tomography (CT) images, to relieve symptomatic compression of surrounding structures, or to provide a histologic or microbial diagnosis in cases where surgical excision is not immediately available. We present the first-ever described case of bronchogenic cyst infected with Actinomyces, diagnosed by EBUS-guided drainage as well as a review of the literature regarding infected bronchogenic cysts and management of cysts affecting mediastinal structures.

Case Presentation

A 57-year-old African American male presented with a 4-day history of continuous, sharp, substernal chest pain accompanied by dyspnea. Additionally, the patient reported progressive dysphagia to solids. The posteroanterior view of a chest X-ray showed a widened mediastinum with splaying of the carina. A contrast-enhanced CT of the chest showed a large, middle mediastinal mass of heterogenous density measuring 7.3. × 7.0 × 6.0 cm with compression of the right pulmonary artery, left atria, superior vena cava and esophagus (Figure 1).

The mass demonstrated neither clear fluid-fluid level nor rounded structure with a distinct wall and uniform attenuation consistent with pure cystic structure and, in fact, was concerning for malignant process, such as lymphoma. Due to the malignancy concern and the findings of significant compression of surrounding mediastinal structures, the decision was made to proceed with bronchoscopy and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to assist in diagnosis and potentially provide symptomatic relief.

Under general anesthesia a P160 Olympus bronchoscope was advanced into the tracheobronchial tree; bronchoscopy with airway inspection revealed splayed carina with obtuse angle but was otherwise unremarkable. Next, an EBUS P160 fiber optic Olympus bronchoscope was advanced; ultrasound demonstrated a cystic structure. The EBUS-TBNA of cystic structure yielded 20 mL of brown, purulent fluid with decompression bringing pulmonary artery in ultrasound field (Figure 2). Rapid on-site cytology was performed with no preliminary findings of malignancy. The fluid was then sent for cytology and microbiologic evaluation.

The patient was placed on amoxicillin/clavulanate 875 mg to 125 mg twice daily for 4 weeks based on antibiotic susceptibility testing to prevent progression to mediastinitis related to Actinomyces infection. The duration of therapy was extrapolated from treatment regimens described in case series of cervicofacial and abdominal Actinomyces infections.³ Thoracic surgery evaluation for definitive excision of cyst was recommended after the patient completed his course of antibiotics.

The patient underwent dental evaluation to identify the source of Actinomyces infection but there appeared to be no odontogenic source. The patient also had extensive skin survey with no findings of overt source of Actinomyces and CT abdomen/pelvis also identified no abscess that could be a potential source. He subsequently underwent thoracoscopic resection with pathology demonstrating a fibrous cyst wall lined with ciliated columnar epithelium consistent with diagnosis of bronchogenic cyst (Figure 5).

Discussion

Bronchogenic cysts can present at birth or later in life; patients may be asymptomatic for decades prior to discovery.⁴ Cysts located in the mediastinum can cause compression of the trachea and esophagus and cause cough, dyspnea, chest pain, and dysphagia.⁵ More life-threatening complications include infection, tracheal compression, malignant transformation, superior vena cava syndrome, or spontaneous rupture into the airway.^6,7

Infection can occasionally occur, and various bacterial etiologies have been described. Hernandez-Solis and colleagues describe 12 cases of superinfected bronchogenic cysts with Staphylococcus aureus and Pseudomonas aeroginosa, the most commonly described organisms.⁸ Casal and colleagues describe a case of α-hemolytic Streptococci treated with amoxicillin.⁹ Liman and colleagues describe 2 cases of bronchogenic cyst infected with Mycobacterium and cite an additional case report by Lin and colleagues similarly infected by Mycobacterium.^10,11 Only 1 case was identified to have direct bronchial communication as a potential source of introduction of infection into bronchogenic cyst. In other cases, potential sources of infection were not identified, though it was postulated that direct ventilation could be a potential source of inoculation.

Surgical resection of mediastinal bronchogenic cysts has traditionally been considered the definitive treatment of choice.^12,13 However, bronchogenic cysts may sometimes be difficult to differentiate from soft tissue tumors by chest CT, especially in cases of cysts with nonserous fluid. In particular, cysts that are infected are likely to have increased density and high attenuation on imaging; therefore, surgical excision may be delayed until diagnosis is made.¹⁴ Due to low complication rates, EBUS is increasingly used in the diagnosis and therapeutic management of bronchogenic cysts as an alternative to surgery, particularly for those who are symptomatic.^15,16 Ultrasound guidance can allow for complete aspiration of the cyst, causing complete collapse of the cystic space and can facilitate adhesion between the mucosal surfaces lining the cavity and reduce recurrence.¹⁷ Nonetheless, bronchogenic cysts that are found to be infected, recur, or have a malignant component should be resected for definitive treatment.¹⁸

The mass discovered on our patient’s imaging appeared to have heterogenous attenuation consistent with malignancy rather than homogenous attenuation surrounded by a clearly demarcated wall consistent with a cystic structure; therefore, EBUS-TBNA was initially pursued and yielded an expedited diagnosis of the first-ever described bronchogenic cyst with Actinomyces superinfection as well as dramatic symptomatic relief of compression of surrounding mediastinal structures, particularly of the right pulmonary artery. As this is a congenital malformation, the patient was likely asymptomatic until the cyst became infected, after which he likely experience cyst growth with subsequent encroachment of surrounding mediastinal structures. Additionally, identification of pathogen by TBNA allowed for treatment before surgical excision, possibly avoiding accidental spread of pathogen intraoperatively.

Conclusions

Our case adds to the literature on the use of EBUS-TBNA as a diagnostic and therapeutic modality for bronchogenic cyst. While cases of mediastinitis and pleural effusion following EBUS-guided aspiration of bronchogenic cysts have been reported, complications are extremely rare.¹⁹ EBUS is increasingly favored as a means of immediate diagnosis and treatment in cases where CT imaging may not overtly suggest cystic structure and in patients experiencing compression of critical mediastinal structures.

Studies have recommended dog walking as an activity designed to improve the overall health of older adults.^1,2 Benefits purportedly associated with dog walking include lower body mass index, fewer chronic diseases, reduction in the number of physician visits, and decreased limitations of activities of daily living.² The Arthritis Foundation even recommends dog walking to relieve arthritis symptoms.³ Of course, dogs also provide comfort in companionship, and dog walking can be an enjoyable way for a pet and owner to spend time together.

However, this seemingly benign activity poses a notable and perhaps grossly underrecognized risk for injury in older adults. The annual number of patients 65 years and older who presented to US emergency departments (EDs) for fractures directly associated with walking leashed dogs more than doubled from 2004 to 2017.⁴ Interestingly, this dramatic increase parallels a nationwide trend in dog ownership demographics. Between 2006 and 2016, the median age of dog owners in the United States rose from 46 to 49 years.⁵

These trends raise concern for more than just the health of older Americans’ bones. Intuitively, a dog- walking accident that results in a bone fracture will likely also lead to some degree of skin trauma. Older adults have thin fragile skin due to flattening of the dermoepidermal junction and disintegration or degeneration of dermal collagen and elastin.⁶ This loss of connective tissue as well as subcutaneous tissue in some body areas facilitates shearing injury; concurrently, weakened perivascular support increases the risk for vascular injury and bruising.⁷ Therefore, when an older person falls while walking a dog, trauma can easily damage delicate aged skin.

Older adults are particularly susceptible to falls, the leading cause of fatal and nonfatal injuries in this age group.⁸ There are multiple risk factors for falls, including polypharmacy, impaired balance and gait, visual impairments, and cognitive decline, among others.⁹

Also, many older adults with atrial fibrillation or venous thromboembolism take an anticoagulant drug to prevent stroke. The use of anticoagulants is associated with an increased risk for bleeding, ranging from minor cutaneous bleeding to fatal intracranial hemorrhage.¹⁰

A predisposition to falling and bleeding can be hazardous for a dog owner whose excited pet suddenly jumps, runs, or scratches. The use of a leash, mandatory in many urban jurisdictions, tethers the human to the dog, which expedites a fall associated with any sudden, forceful forward or lateral movement by the dog. The following case reports describe a variety of cutaneous injuries experienced by older adults while dog walking.

Case Reports

Patient 1
A 79-year-old woman was quietly walking her dog when the dog spotted a squirrel climbing a tree. The dog became excited, turned to the owner, and jumped on her, which caused the dog’s claws to dig into the owner’s fragile forearm skin, creating several superficial but painful abrasions and lacerations (Figure 1). These injuries healed well with conservative therapy including application of an occlusive ointment.

Patient 2
A 68-year-old woman was walking her dog when the dog saw a cat running across the street. The dog suddenly leaped toward the cat, causing the owner to fall forward as the animal’s momentum was transferred through the leash. The owner fell awkwardly on her side, leading to an extensive abrasion and contusion of the shoulder (Figure 2). The lesion healed well with conservative management, albeit with moderate postinflammatory hypochromia.

Comment

These 5 cases illustrate the notable skin (and neurologic) trauma that can occur due to a dog-walking accident (Table).^11-15

Regrettably, obtaining an accurate national estimate of the annual incidence of cutaneous dog-walking injuries is difficult. Researchers who have described the rise in dog walking–associated bone fractures queried the US Consumer Product Safety Commission’s National Electronic Injury Surveillance System database for its numbers.⁴ This public database generates incidence estimates of activity- or product-related injuries based on data from a nationally representative sample of approximately 100 hospital EDs.¹⁶

We queried the same database for the diagnoses avulsion, abrasion or contusion, and laceration.¹⁷ These terms were searched in association with pet supplies, including leashes, and patients 65 years and older. This search yielded fewer than 800 total cases from 2008 to 2017, resulting in unreliable estimates for each year.

The National Electronic Injury Surveillance System database no doubt underestimates the true incidence of dog walking–related skin trauma; the great majority of patients with cutaneous injury, as illustrated here, likely never present to the ED, unlike patients with bone fracture. Moreover, data do not capture cases handled by providers outside the ED and self-treated injuries.

In the absence of accurate estimates of cutaneous morbidity related to dog-walking injury, the case reports here are clearly a cautionary tale. Physicians and older adults need to be cognizant of the hazards of this activity. Providers should discuss with older patients the potential risks of dog walking before recommending or condoning this exercise.

The presence of other comorbidities that could hamper a person’s ability to control a leashed dog warrants special consideration. Older prospective dog owners might consider adopting a small, easily manageable breed. These measures can help protect older adults’ fragile skin (and bones) from avoidable minor to potentially life-threatening trauma.

Studies have recommended dog walking as an activity designed to improve the overall health of older adults.^1,2 Benefits purportedly associated with dog walking include lower body mass index, fewer chronic diseases, reduction in the number of physician visits, and decreased limitations of activities of daily living.² The Arthritis Foundation even recommends dog walking to relieve arthritis symptoms.³ Of course, dogs also provide comfort in companionship, and dog walking can be an enjoyable way for a pet and owner to spend time together.

However, this seemingly benign activity poses a notable and perhaps grossly underrecognized risk for injury in older adults. The annual number of patients 65 years and older who presented to US emergency departments (EDs) for fractures directly associated with walking leashed dogs more than doubled from 2004 to 2017.⁴ Interestingly, this dramatic increase parallels a nationwide trend in dog ownership demographics. Between 2006 and 2016, the median age of dog owners in the United States rose from 46 to 49 years.⁵

These trends raise concern for more than just the health of older Americans’ bones. Intuitively, a dog- walking accident that results in a bone fracture will likely also lead to some degree of skin trauma. Older adults have thin fragile skin due to flattening of the dermoepidermal junction and disintegration or degeneration of dermal collagen and elastin.⁶ This loss of connective tissue as well as subcutaneous tissue in some body areas facilitates shearing injury; concurrently, weakened perivascular support increases the risk for vascular injury and bruising.⁷ Therefore, when an older person falls while walking a dog, trauma can easily damage delicate aged skin.

Older adults are particularly susceptible to falls, the leading cause of fatal and nonfatal injuries in this age group.⁸ There are multiple risk factors for falls, including polypharmacy, impaired balance and gait, visual impairments, and cognitive decline, among others.⁹

Also, many older adults with atrial fibrillation or venous thromboembolism take an anticoagulant drug to prevent stroke. The use of anticoagulants is associated with an increased risk for bleeding, ranging from minor cutaneous bleeding to fatal intracranial hemorrhage.¹⁰

A predisposition to falling and bleeding can be hazardous for a dog owner whose excited pet suddenly jumps, runs, or scratches. The use of a leash, mandatory in many urban jurisdictions, tethers the human to the dog, which expedites a fall associated with any sudden, forceful forward or lateral movement by the dog. The following case reports describe a variety of cutaneous injuries experienced by older adults while dog walking.

Case Reports

Patient 1
A 79-year-old woman was quietly walking her dog when the dog spotted a squirrel climbing a tree. The dog became excited, turned to the owner, and jumped on her, which caused the dog’s claws to dig into the owner’s fragile forearm skin, creating several superficial but painful abrasions and lacerations (Figure 1). These injuries healed well with conservative therapy including application of an occlusive ointment.

Patient 2
A 68-year-old woman was walking her dog when the dog saw a cat running across the street. The dog suddenly leaped toward the cat, causing the owner to fall forward as the animal’s momentum was transferred through the leash. The owner fell awkwardly on her side, leading to an extensive abrasion and contusion of the shoulder (Figure 2). The lesion healed well with conservative management, albeit with moderate postinflammatory hypochromia.

Comment

These 5 cases illustrate the notable skin (and neurologic) trauma that can occur due to a dog-walking accident (Table).^11-15

Regrettably, obtaining an accurate national estimate of the annual incidence of cutaneous dog-walking injuries is difficult. Researchers who have described the rise in dog walking–associated bone fractures queried the US Consumer Product Safety Commission’s National Electronic Injury Surveillance System database for its numbers.⁴ This public database generates incidence estimates of activity- or product-related injuries based on data from a nationally representative sample of approximately 100 hospital EDs.¹⁶

We queried the same database for the diagnoses avulsion, abrasion or contusion, and laceration.¹⁷ These terms were searched in association with pet supplies, including leashes, and patients 65 years and older. This search yielded fewer than 800 total cases from 2008 to 2017, resulting in unreliable estimates for each year.

The National Electronic Injury Surveillance System database no doubt underestimates the true incidence of dog walking–related skin trauma; the great majority of patients with cutaneous injury, as illustrated here, likely never present to the ED, unlike patients with bone fracture. Moreover, data do not capture cases handled by providers outside the ED and self-treated injuries.

In the absence of accurate estimates of cutaneous morbidity related to dog-walking injury, the case reports here are clearly a cautionary tale. Physicians and older adults need to be cognizant of the hazards of this activity. Providers should discuss with older patients the potential risks of dog walking before recommending or condoning this exercise.

The presence of other comorbidities that could hamper a person’s ability to control a leashed dog warrants special consideration. Older prospective dog owners might consider adopting a small, easily manageable breed. These measures can help protect older adults’ fragile skin (and bones) from avoidable minor to potentially life-threatening trauma.

Studies have recommended dog walking as an activity designed to improve the overall health of older adults.^1,2 Benefits purportedly associated with dog walking include lower body mass index, fewer chronic diseases, reduction in the number of physician visits, and decreased limitations of activities of daily living.² The Arthritis Foundation even recommends dog walking to relieve arthritis symptoms.³ Of course, dogs also provide comfort in companionship, and dog walking can be an enjoyable way for a pet and owner to spend time together.

However, this seemingly benign activity poses a notable and perhaps grossly underrecognized risk for injury in older adults. The annual number of patients 65 years and older who presented to US emergency departments (EDs) for fractures directly associated with walking leashed dogs more than doubled from 2004 to 2017.⁴ Interestingly, this dramatic increase parallels a nationwide trend in dog ownership demographics. Between 2006 and 2016, the median age of dog owners in the United States rose from 46 to 49 years.⁵

These trends raise concern for more than just the health of older Americans’ bones. Intuitively, a dog- walking accident that results in a bone fracture will likely also lead to some degree of skin trauma. Older adults have thin fragile skin due to flattening of the dermoepidermal junction and disintegration or degeneration of dermal collagen and elastin.⁶ This loss of connective tissue as well as subcutaneous tissue in some body areas facilitates shearing injury; concurrently, weakened perivascular support increases the risk for vascular injury and bruising.⁷ Therefore, when an older person falls while walking a dog, trauma can easily damage delicate aged skin.

Older adults are particularly susceptible to falls, the leading cause of fatal and nonfatal injuries in this age group.⁸ There are multiple risk factors for falls, including polypharmacy, impaired balance and gait, visual impairments, and cognitive decline, among others.⁹

Also, many older adults with atrial fibrillation or venous thromboembolism take an anticoagulant drug to prevent stroke. The use of anticoagulants is associated with an increased risk for bleeding, ranging from minor cutaneous bleeding to fatal intracranial hemorrhage.¹⁰

A predisposition to falling and bleeding can be hazardous for a dog owner whose excited pet suddenly jumps, runs, or scratches. The use of a leash, mandatory in many urban jurisdictions, tethers the human to the dog, which expedites a fall associated with any sudden, forceful forward or lateral movement by the dog. The following case reports describe a variety of cutaneous injuries experienced by older adults while dog walking.

Case Reports

Patient 1
A 79-year-old woman was quietly walking her dog when the dog spotted a squirrel climbing a tree. The dog became excited, turned to the owner, and jumped on her, which caused the dog’s claws to dig into the owner’s fragile forearm skin, creating several superficial but painful abrasions and lacerations (Figure 1). These injuries healed well with conservative therapy including application of an occlusive ointment.

Patient 2
A 68-year-old woman was walking her dog when the dog saw a cat running across the street. The dog suddenly leaped toward the cat, causing the owner to fall forward as the animal’s momentum was transferred through the leash. The owner fell awkwardly on her side, leading to an extensive abrasion and contusion of the shoulder (Figure 2). The lesion healed well with conservative management, albeit with moderate postinflammatory hypochromia.

Comment

These 5 cases illustrate the notable skin (and neurologic) trauma that can occur due to a dog-walking accident (Table).^11-15

Regrettably, obtaining an accurate national estimate of the annual incidence of cutaneous dog-walking injuries is difficult. Researchers who have described the rise in dog walking–associated bone fractures queried the US Consumer Product Safety Commission’s National Electronic Injury Surveillance System database for its numbers.⁴ This public database generates incidence estimates of activity- or product-related injuries based on data from a nationally representative sample of approximately 100 hospital EDs.¹⁶

We queried the same database for the diagnoses avulsion, abrasion or contusion, and laceration.¹⁷ These terms were searched in association with pet supplies, including leashes, and patients 65 years and older. This search yielded fewer than 800 total cases from 2008 to 2017, resulting in unreliable estimates for each year.

The National Electronic Injury Surveillance System database no doubt underestimates the true incidence of dog walking–related skin trauma; the great majority of patients with cutaneous injury, as illustrated here, likely never present to the ED, unlike patients with bone fracture. Moreover, data do not capture cases handled by providers outside the ED and self-treated injuries.

In the absence of accurate estimates of cutaneous morbidity related to dog-walking injury, the case reports here are clearly a cautionary tale. Physicians and older adults need to be cognizant of the hazards of this activity. Providers should discuss with older patients the potential risks of dog walking before recommending or condoning this exercise.

The presence of other comorbidities that could hamper a person’s ability to control a leashed dog warrants special consideration. Older prospective dog owners might consider adopting a small, easily manageable breed. These measures can help protect older adults’ fragile skin (and bones) from avoidable minor to potentially life-threatening trauma.

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.