Case Reports

Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidality. Due to the risk of severe neutropenia, clozapine is available only through a restricted Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program, which requires provider certification, patient enrollment and adherence with absolute neutrophil count (ANC) testing and monitoring, and dispensing pharmacy certification.¹ In addition, clozapine (Clozaril) prescribing information contains a boxed warning for potentially fatal cardiomyopathy. One recently published study from Australia demonstrated a 4.65% incidence of cardiomyopathy in patients started on clozapine, which is much higher than the incidence provided by national drug surveillance programs.^2-4 An increased awareness is needed among health care professionals, including physicians, pharmacists, and nurses, about this serious fatal condition.

Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.^5-7

Case Presentation

A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.

More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation.

This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).

Discussion

In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.

This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.

It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.

There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.⁸ The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).⁸

It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.

As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.

Conclusion

Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.

Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.

In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.

Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidality. Due to the risk of severe neutropenia, clozapine is available only through a restricted Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program, which requires provider certification, patient enrollment and adherence with absolute neutrophil count (ANC) testing and monitoring, and dispensing pharmacy certification.¹ In addition, clozapine (Clozaril) prescribing information contains a boxed warning for potentially fatal cardiomyopathy. One recently published study from Australia demonstrated a 4.65% incidence of cardiomyopathy in patients started on clozapine, which is much higher than the incidence provided by national drug surveillance programs.^2-4 An increased awareness is needed among health care professionals, including physicians, pharmacists, and nurses, about this serious fatal condition.

Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.^5-7

Case Presentation

A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.

More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation.

This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).

Discussion

In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.

This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.

It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.

There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.⁸ The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).⁸

It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.

As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.

Conclusion

Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.

Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.

In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.

Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidality. Due to the risk of severe neutropenia, clozapine is available only through a restricted Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program, which requires provider certification, patient enrollment and adherence with absolute neutrophil count (ANC) testing and monitoring, and dispensing pharmacy certification.¹ In addition, clozapine (Clozaril) prescribing information contains a boxed warning for potentially fatal cardiomyopathy. One recently published study from Australia demonstrated a 4.65% incidence of cardiomyopathy in patients started on clozapine, which is much higher than the incidence provided by national drug surveillance programs.^2-4 An increased awareness is needed among health care professionals, including physicians, pharmacists, and nurses, about this serious fatal condition.

Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.^5-7

Case Presentation

A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.

More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation.

This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).

Discussion

In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.

This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.

It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.

There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.⁸ The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).⁸

It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.

As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.

Conclusion

Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.

Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.

In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Cardiovascular diseases are some of the most common conditions found in the geriatric population. Ocular manifestations of systemic cardiovascular conditions often are the initial presentation of the systemic disease. Identifying these findings help reveal the underlying disease and prevent more serious visual and systemic complications or even death.

Hypoperfusion retinopathy can occur as an early manifestation of carotid occlusive disease. It results from poor arterial perfusion pressure secondary to significant or complete carotid artery blockage resulting in retinal changes. Atherosclerotic disease is generally the main culprit. Early manifestations can be seen as midperipheral retinal hemorrhages, dilated often nontortuous veins, and retinal neovascularization. Untreated or advanced cases of carotid occlusive disease can lead to a more serious ocular ischemic syndrome, which encompasses a panocular ischemia and can result in severe vision loss and neovascular glaucoma. Restoration of arterial perfusion pressure is the main goal for managing this condition.

Case Report

A 71-year-old white male was referred by his primary care physician (PCP) to the eye clinic for a routine comprehensive eye exam. The patient reported that his current progressive lenses, prescribed 2 years prior, were not strong enough at both distance and near, and that his eyes often felt dry. The symptoms were gradual in onset since his prior exam with no reported flashes, floaters, loss of vision, headaches, or ocular irritations.

The patient’s medical history was significant for morbid obesity, hypertension, borderline diabetes mellitus, and obstructive sleep apnea. His ocular history included recurrent conjunctivitis. At the time of the visit, the patient’s medications included 81 mg aspirin, 10 mg benazepril, 1,000 mg fish oil, 80 mg simvastatin, and use of a continuous positive airway pressure machine.

Best-corrected Snellen visual acuity was stable to his last eye exam at 20/25⁺² right eye and 20/25^-1 left eye with a manifest refraction of +2.25-0.75 × 077, and +2.75-1.25 × 096 in the right and left eye, respectively. Pupils were equally round and reactive to light with no afferent pupillary defect. Extraocular motility and finger counting fields were unremarkable. Anterior segment evaluation revealed lax bilateral upper lid apposition and mild cataracts in both eyes but were otherwise unremarkable (Figure 1). Dilated fundus examination revealed extensive hemorrhaging in the midperipheral retina of the right eye only (Figure 2). The left eye retina showed no abnormalities.

At this point the patient declined any additional symptoms, including eye pain, headache, transient vision loss, jaw claudication, and stroke signs. A complete blood count and hemoglobin A_1c (HbA_1c) was ordered, and all findings were unremarkable with no evidence of blood dyscrasia and with a HbA_1c of 6.0. A carotid ultrasound (CUS) was also performed and revealed severe narrowing of the proximal section of the right internal carotid artery (ICA) with a trickle flow (Figure 3). The peak systolic velocity (PSV) at this level was 508 cm/s. There also was severe narrowing and turbulent flow in both the mid and distal portions of the right ICA. The patient was sent for a vascular evaluation 2 days following the CUS.

Based on the ocular findings and CUS results, the diagnosis of hypoperfusion retinopathy secondary to carotid occlusive disease was made. Because the patient was asymptomatic with no additional ocular sequelae, he was scheduled for an eye clinic follow-up in 2 months. The electrocardiogram, chest X-ray, and exercise stress test results were negative for acute cardiopulmonary disease, ischemia, or arrhythmias. A computed tomography angiography was performed and confirmed a high-grade lesion of the right ICA of > 95%. The vascular surgeon reported an 11% risk of stroke within 5 years and a 1% risk of stroke with surgery. Based on these results the patient underwent a right carotid endarterectomy (CEA) 2 weeks later. A follow-up CUS was performed 1 month post-CEA and revealed no abnormal fluid or significant plaque with a PSV of 92 cm/s (prior to surgery PSV was 508 cm/s) (Figure 3).

The patient returned to the eye clinic 1 month after the CEA. Gonioscopy revealed no neovascularization of the iris or angle and the dilated eye exam showed resolution of the midperipheral blot hemorrhages in his right eye with no evidence of retinal neovascularization.

Discussion

Hypoperfusion retinopathy is characterized by posterior retinal changes secondary to chronic ocular ischemia from decreased arterial perfusion related to significant or complete carotid artery stenosis.^1-5 Early literature referred to this condition as venous stasis retinopathy; however, this term is misleading as the condition results from a reduction in arterial perfusion pressure and the term describes venous outflow obstruction.⁶ The terms carotid ischemic retinopathy, ischemic oculopathy, and hypotensive retinopathy also have been used interchangeably when describing hypoperfusion retinopathy.⁶

Incidence of hypoperfusion retinopathy is twice as high in males as it is in females due to a higher prevalence of cardiovascular disease.⁷ Hypoperfusion retinopathy rarely presents before the age of 50 years, with the average age of onset around 65 years.⁷ The exact rate of occurrence is unknown as this condition often is underdiagnosed because it mimics other vascular conditions, such as venous occlusive disease and diabetic retinopathy.^1,7 Patients can present asymptomatically where findings are incidental on a dilated eye exam, or they may present with vision loss that can be gradual, sudden, or transient in nature.^5,6,8

Gradual vision loss can follow a period of weeks to months and can occur secondary to posterior ischemia, macular edema, or choroidal hypoperfusion.^1,3,8,9 Sudden vision loss can occur from severe hypoperfusion, creating an acute inner layer retinal ischemia. This type of vision loss often is accompanied by a cherry red spot in the macula and can be caused by an embolic plaque.^1,8 Transient vision loss (TVL) also can be secondary to a plaque emboli or light induced. Patients with light-induced TVL report poor to blurry vision or prolonged after image when exposed to bright lights. In theory when the retina is exposed to light, there is an increase in metabolic demand that is unmet in those with choroidal vascular insufficiency from significant carotid stenosis.^3,8,10

The clinical presentation most often is unilateral. Early stages of the disease generally affect the midperipheral retina but can be found in the posterior pole with chronicity. Early findings include microaneurysms, nerve fiber layer and inner retinal layer hemorrhages, and dilated, but generally not tortuous, veins.⁵ Chronic stage findings include arteriolar narrowing, extreme venous dilation, occasionally macular edema, and neovascularization of the disc and or retina.⁵ Disc edema or collaterals usually are not present.⁵

The mechanism behind hypoperfusion retinopathy results from an overall ischemic cascade and starts with comorbid cardiovascular conditions, such as hypertension, hypercholesterolemia, diabetes, heart disease, and history of smoking.^1,2,5 These conditions play a role in creating atherosclerotic buildup in the arterial lumen leading to chronic narrowing and a decrease in arterial perfusion pressure. Over time, a low-grade hypoxic situation is formed, generating vascular endothelial cell damage and pericytes cell loss, thus causing leakage of fluid.^1,2,5 With these chronic hypoxic states, angiogenic factor release eventually leads to posterior neovascularization.^1,2,5 Further chronicity of carotid occlusive disease can create a panocular ischemia that also involves anterior structures, including iris, conjunctiva, episclera, or cornea. At this point, hypoperfusion retinopathy progresses to a more severe condition called ocular ischemic syndrome (OIS).^2,5

Ocular ischemic syndrome can be associated with a 40% mortality rate within 5 years of onset as it is generally found in those with overall poor health.⁵ Along with posterior neovascularization, anterior structures also are involved. Sixty-seven percent of cases have iris or angle neovascularization of which 35% go on to develop neovascular glaucoma and its complications.^1,8 With OIS, 90% of cases have some type of vision loss, and 40% report ipsilateral ocular pain.^1,8 Visual loss can be gradual, sudden, or transient. The pain can occur from ocular ischemia, ruptured corneal epithelial microcysts secondary to acute glaucoma, elevated intraocular pressure (IOP) with neovascular glaucoma, or from ipsilateral dural ischemia.^1,5,6,8 Fluorescein angiography is commonly used to diagnose and manage OIS, because it allows for the visualization of retinal and choroidal circulation and the detection of neovascular proliferation and ischemic areas.

Diagnostic Imaging

Several diagnostic testing strategies are available to evaluate for carotid occlusive disease. Carotid ultrasonography is a noninvasive, safe, and inexpensive screening tool to evaluate for high-grade stenosis. However, it can sometimes overestimate the degree of stenosis and is not reliable with severe calcifications.⁸ Computed tomography angiography and magnetic resonance angiography are minimally invasive tools that can be used to screen or confirm the degree of stenosis.⁸ These can be used in addition or instead of ultrasonography, especially in instances where patients have a short neck or high carotid bifurcation that may affect reliability. Both are contraindicated in those with renal failure as both modalities require the use of a contrast dye. Magnetic resonance angiography is far more expensive, time consuming, and not readily available.⁸ Carotid angiography is considered the gold standard for imaging the entire carotid artery system because it allows for the evaluation of plaque morphology, atherosclerotic disease, and collateral circulations.⁸ The disadvantages to this invasive and high-cost procedure include a risk of mortality that can occur secondary to an embolic stroke, myocardial infarction (MI), carotid artery dissection, or arterial thrombosis.⁸

Treatment

Treatment and management for carotid artery stenosis is focused on combined effort with the patient’s PCP and other specialists, including cardiologist, neurologist, and vascular surgeons.¹¹ Treatment of comorbid conditions, education on healthy lifestyle, and smoking cessation are all imperative to the patient’s well-being. Managing ocular sequelae is based on specific findings and can include intravitreal antivascular edothelial growth factor or steroidal injections, pan retinal photocoagulation, or hypotensive drops.^6,7

Restoration of arterial perfusion pressure is the main goal of treatment, and this can be done through CEA or carotid artery stents. Surgical intervention by CEA is determined based on each patient and his or her overall health. A full cardiac workup is required due to surgical risks. The North American Symptomatic Carotid Endarterectomy Trial evaluated symptomatic stenosis and the effectiveness of surgical intervention on stroke prevention. The trial reported that CEA was beneficial in symptomatic patients with 55% to 99% stenosis and especially in those with higher grade stenosis (> 70% up to 95%).^5,7,8,12 With regard to asymptomatic patients with high-grade stenosis, CEA has been found to reduce the risk of stroke if there is at least 60% stenosis.^5,7,8

Carotid artery stents can be used as an alternative when CEA is not effective or contraindicated due to a history of previous CEA, neck radiation, unstable angina, congestive heart failure, or recent MI.^5,7,8 Neither CEA nor stenting is considered effective in complete occlusions due to the high risk of thromboembolism formation.^5,7,8

Conclusion

Hypoperfusion retinopathy describes posterior retinal findings that occur secondary to poor arterial perfusion caused by carotid occlusive disease. Early intervention and restoration of this pressure can prevent the risk of developing a more serious condition characterized by a panocular ischemia called OIS. Unlike hypoperfusion retinopathy, OIS also includes anterior segment findings such as iris neovascularization, which may lead to neovascular glaucoma, whereas hypoperfusion retinopathy is localized to the posterior pole. Patients that develop OIS are at a 40% risk of mortality within 5 years due to poor overall health. Understanding the patient’s signs and symptoms can aid in the diagnosis of both conditions. Collaborative management with the patient’s PCP and specialists in treating comorbid conditions is vital to the patients’ well-being.

Cardiovascular diseases are some of the most common conditions found in the geriatric population. Ocular manifestations of systemic cardiovascular conditions often are the initial presentation of the systemic disease. Identifying these findings help reveal the underlying disease and prevent more serious visual and systemic complications or even death.

Hypoperfusion retinopathy can occur as an early manifestation of carotid occlusive disease. It results from poor arterial perfusion pressure secondary to significant or complete carotid artery blockage resulting in retinal changes. Atherosclerotic disease is generally the main culprit. Early manifestations can be seen as midperipheral retinal hemorrhages, dilated often nontortuous veins, and retinal neovascularization. Untreated or advanced cases of carotid occlusive disease can lead to a more serious ocular ischemic syndrome, which encompasses a panocular ischemia and can result in severe vision loss and neovascular glaucoma. Restoration of arterial perfusion pressure is the main goal for managing this condition.

Case Report

A 71-year-old white male was referred by his primary care physician (PCP) to the eye clinic for a routine comprehensive eye exam. The patient reported that his current progressive lenses, prescribed 2 years prior, were not strong enough at both distance and near, and that his eyes often felt dry. The symptoms were gradual in onset since his prior exam with no reported flashes, floaters, loss of vision, headaches, or ocular irritations.

The patient’s medical history was significant for morbid obesity, hypertension, borderline diabetes mellitus, and obstructive sleep apnea. His ocular history included recurrent conjunctivitis. At the time of the visit, the patient’s medications included 81 mg aspirin, 10 mg benazepril, 1,000 mg fish oil, 80 mg simvastatin, and use of a continuous positive airway pressure machine.

Best-corrected Snellen visual acuity was stable to his last eye exam at 20/25⁺² right eye and 20/25^-1 left eye with a manifest refraction of +2.25-0.75 × 077, and +2.75-1.25 × 096 in the right and left eye, respectively. Pupils were equally round and reactive to light with no afferent pupillary defect. Extraocular motility and finger counting fields were unremarkable. Anterior segment evaluation revealed lax bilateral upper lid apposition and mild cataracts in both eyes but were otherwise unremarkable (Figure 1). Dilated fundus examination revealed extensive hemorrhaging in the midperipheral retina of the right eye only (Figure 2). The left eye retina showed no abnormalities.

At this point the patient declined any additional symptoms, including eye pain, headache, transient vision loss, jaw claudication, and stroke signs. A complete blood count and hemoglobin A_1c (HbA_1c) was ordered, and all findings were unremarkable with no evidence of blood dyscrasia and with a HbA_1c of 6.0. A carotid ultrasound (CUS) was also performed and revealed severe narrowing of the proximal section of the right internal carotid artery (ICA) with a trickle flow (Figure 3). The peak systolic velocity (PSV) at this level was 508 cm/s. There also was severe narrowing and turbulent flow in both the mid and distal portions of the right ICA. The patient was sent for a vascular evaluation 2 days following the CUS.

Based on the ocular findings and CUS results, the diagnosis of hypoperfusion retinopathy secondary to carotid occlusive disease was made. Because the patient was asymptomatic with no additional ocular sequelae, he was scheduled for an eye clinic follow-up in 2 months. The electrocardiogram, chest X-ray, and exercise stress test results were negative for acute cardiopulmonary disease, ischemia, or arrhythmias. A computed tomography angiography was performed and confirmed a high-grade lesion of the right ICA of > 95%. The vascular surgeon reported an 11% risk of stroke within 5 years and a 1% risk of stroke with surgery. Based on these results the patient underwent a right carotid endarterectomy (CEA) 2 weeks later. A follow-up CUS was performed 1 month post-CEA and revealed no abnormal fluid or significant plaque with a PSV of 92 cm/s (prior to surgery PSV was 508 cm/s) (Figure 3).

The patient returned to the eye clinic 1 month after the CEA. Gonioscopy revealed no neovascularization of the iris or angle and the dilated eye exam showed resolution of the midperipheral blot hemorrhages in his right eye with no evidence of retinal neovascularization.

Discussion

Hypoperfusion retinopathy is characterized by posterior retinal changes secondary to chronic ocular ischemia from decreased arterial perfusion related to significant or complete carotid artery stenosis.^1-5 Early literature referred to this condition as venous stasis retinopathy; however, this term is misleading as the condition results from a reduction in arterial perfusion pressure and the term describes venous outflow obstruction.⁶ The terms carotid ischemic retinopathy, ischemic oculopathy, and hypotensive retinopathy also have been used interchangeably when describing hypoperfusion retinopathy.⁶

Incidence of hypoperfusion retinopathy is twice as high in males as it is in females due to a higher prevalence of cardiovascular disease.⁷ Hypoperfusion retinopathy rarely presents before the age of 50 years, with the average age of onset around 65 years.⁷ The exact rate of occurrence is unknown as this condition often is underdiagnosed because it mimics other vascular conditions, such as venous occlusive disease and diabetic retinopathy.^1,7 Patients can present asymptomatically where findings are incidental on a dilated eye exam, or they may present with vision loss that can be gradual, sudden, or transient in nature.^5,6,8

Gradual vision loss can follow a period of weeks to months and can occur secondary to posterior ischemia, macular edema, or choroidal hypoperfusion.^1,3,8,9 Sudden vision loss can occur from severe hypoperfusion, creating an acute inner layer retinal ischemia. This type of vision loss often is accompanied by a cherry red spot in the macula and can be caused by an embolic plaque.^1,8 Transient vision loss (TVL) also can be secondary to a plaque emboli or light induced. Patients with light-induced TVL report poor to blurry vision or prolonged after image when exposed to bright lights. In theory when the retina is exposed to light, there is an increase in metabolic demand that is unmet in those with choroidal vascular insufficiency from significant carotid stenosis.^3,8,10

The clinical presentation most often is unilateral. Early stages of the disease generally affect the midperipheral retina but can be found in the posterior pole with chronicity. Early findings include microaneurysms, nerve fiber layer and inner retinal layer hemorrhages, and dilated, but generally not tortuous, veins.⁵ Chronic stage findings include arteriolar narrowing, extreme venous dilation, occasionally macular edema, and neovascularization of the disc and or retina.⁵ Disc edema or collaterals usually are not present.⁵

The mechanism behind hypoperfusion retinopathy results from an overall ischemic cascade and starts with comorbid cardiovascular conditions, such as hypertension, hypercholesterolemia, diabetes, heart disease, and history of smoking.^1,2,5 These conditions play a role in creating atherosclerotic buildup in the arterial lumen leading to chronic narrowing and a decrease in arterial perfusion pressure. Over time, a low-grade hypoxic situation is formed, generating vascular endothelial cell damage and pericytes cell loss, thus causing leakage of fluid.^1,2,5 With these chronic hypoxic states, angiogenic factor release eventually leads to posterior neovascularization.^1,2,5 Further chronicity of carotid occlusive disease can create a panocular ischemia that also involves anterior structures, including iris, conjunctiva, episclera, or cornea. At this point, hypoperfusion retinopathy progresses to a more severe condition called ocular ischemic syndrome (OIS).^2,5

Ocular ischemic syndrome can be associated with a 40% mortality rate within 5 years of onset as it is generally found in those with overall poor health.⁵ Along with posterior neovascularization, anterior structures also are involved. Sixty-seven percent of cases have iris or angle neovascularization of which 35% go on to develop neovascular glaucoma and its complications.^1,8 With OIS, 90% of cases have some type of vision loss, and 40% report ipsilateral ocular pain.^1,8 Visual loss can be gradual, sudden, or transient. The pain can occur from ocular ischemia, ruptured corneal epithelial microcysts secondary to acute glaucoma, elevated intraocular pressure (IOP) with neovascular glaucoma, or from ipsilateral dural ischemia.^1,5,6,8 Fluorescein angiography is commonly used to diagnose and manage OIS, because it allows for the visualization of retinal and choroidal circulation and the detection of neovascular proliferation and ischemic areas.

Diagnostic Imaging

Several diagnostic testing strategies are available to evaluate for carotid occlusive disease. Carotid ultrasonography is a noninvasive, safe, and inexpensive screening tool to evaluate for high-grade stenosis. However, it can sometimes overestimate the degree of stenosis and is not reliable with severe calcifications.⁸ Computed tomography angiography and magnetic resonance angiography are minimally invasive tools that can be used to screen or confirm the degree of stenosis.⁸ These can be used in addition or instead of ultrasonography, especially in instances where patients have a short neck or high carotid bifurcation that may affect reliability. Both are contraindicated in those with renal failure as both modalities require the use of a contrast dye. Magnetic resonance angiography is far more expensive, time consuming, and not readily available.⁸ Carotid angiography is considered the gold standard for imaging the entire carotid artery system because it allows for the evaluation of plaque morphology, atherosclerotic disease, and collateral circulations.⁸ The disadvantages to this invasive and high-cost procedure include a risk of mortality that can occur secondary to an embolic stroke, myocardial infarction (MI), carotid artery dissection, or arterial thrombosis.⁸

Treatment

Treatment and management for carotid artery stenosis is focused on combined effort with the patient’s PCP and other specialists, including cardiologist, neurologist, and vascular surgeons.¹¹ Treatment of comorbid conditions, education on healthy lifestyle, and smoking cessation are all imperative to the patient’s well-being. Managing ocular sequelae is based on specific findings and can include intravitreal antivascular edothelial growth factor or steroidal injections, pan retinal photocoagulation, or hypotensive drops.^6,7

Restoration of arterial perfusion pressure is the main goal of treatment, and this can be done through CEA or carotid artery stents. Surgical intervention by CEA is determined based on each patient and his or her overall health. A full cardiac workup is required due to surgical risks. The North American Symptomatic Carotid Endarterectomy Trial evaluated symptomatic stenosis and the effectiveness of surgical intervention on stroke prevention. The trial reported that CEA was beneficial in symptomatic patients with 55% to 99% stenosis and especially in those with higher grade stenosis (> 70% up to 95%).^5,7,8,12 With regard to asymptomatic patients with high-grade stenosis, CEA has been found to reduce the risk of stroke if there is at least 60% stenosis.^5,7,8

Carotid artery stents can be used as an alternative when CEA is not effective or contraindicated due to a history of previous CEA, neck radiation, unstable angina, congestive heart failure, or recent MI.^5,7,8 Neither CEA nor stenting is considered effective in complete occlusions due to the high risk of thromboembolism formation.^5,7,8

Conclusion

Hypoperfusion retinopathy describes posterior retinal findings that occur secondary to poor arterial perfusion caused by carotid occlusive disease. Early intervention and restoration of this pressure can prevent the risk of developing a more serious condition characterized by a panocular ischemia called OIS. Unlike hypoperfusion retinopathy, OIS also includes anterior segment findings such as iris neovascularization, which may lead to neovascular glaucoma, whereas hypoperfusion retinopathy is localized to the posterior pole. Patients that develop OIS are at a 40% risk of mortality within 5 years due to poor overall health. Understanding the patient’s signs and symptoms can aid in the diagnosis of both conditions. Collaborative management with the patient’s PCP and specialists in treating comorbid conditions is vital to the patients’ well-being.

Cardiovascular diseases are some of the most common conditions found in the geriatric population. Ocular manifestations of systemic cardiovascular conditions often are the initial presentation of the systemic disease. Identifying these findings help reveal the underlying disease and prevent more serious visual and systemic complications or even death.

Hypoperfusion retinopathy can occur as an early manifestation of carotid occlusive disease. It results from poor arterial perfusion pressure secondary to significant or complete carotid artery blockage resulting in retinal changes. Atherosclerotic disease is generally the main culprit. Early manifestations can be seen as midperipheral retinal hemorrhages, dilated often nontortuous veins, and retinal neovascularization. Untreated or advanced cases of carotid occlusive disease can lead to a more serious ocular ischemic syndrome, which encompasses a panocular ischemia and can result in severe vision loss and neovascular glaucoma. Restoration of arterial perfusion pressure is the main goal for managing this condition.

Case Report

A 71-year-old white male was referred by his primary care physician (PCP) to the eye clinic for a routine comprehensive eye exam. The patient reported that his current progressive lenses, prescribed 2 years prior, were not strong enough at both distance and near, and that his eyes often felt dry. The symptoms were gradual in onset since his prior exam with no reported flashes, floaters, loss of vision, headaches, or ocular irritations.

The patient’s medical history was significant for morbid obesity, hypertension, borderline diabetes mellitus, and obstructive sleep apnea. His ocular history included recurrent conjunctivitis. At the time of the visit, the patient’s medications included 81 mg aspirin, 10 mg benazepril, 1,000 mg fish oil, 80 mg simvastatin, and use of a continuous positive airway pressure machine.

Best-corrected Snellen visual acuity was stable to his last eye exam at 20/25⁺² right eye and 20/25^-1 left eye with a manifest refraction of +2.25-0.75 × 077, and +2.75-1.25 × 096 in the right and left eye, respectively. Pupils were equally round and reactive to light with no afferent pupillary defect. Extraocular motility and finger counting fields were unremarkable. Anterior segment evaluation revealed lax bilateral upper lid apposition and mild cataracts in both eyes but were otherwise unremarkable (Figure 1). Dilated fundus examination revealed extensive hemorrhaging in the midperipheral retina of the right eye only (Figure 2). The left eye retina showed no abnormalities.

At this point the patient declined any additional symptoms, including eye pain, headache, transient vision loss, jaw claudication, and stroke signs. A complete blood count and hemoglobin A_1c (HbA_1c) was ordered, and all findings were unremarkable with no evidence of blood dyscrasia and with a HbA_1c of 6.0. A carotid ultrasound (CUS) was also performed and revealed severe narrowing of the proximal section of the right internal carotid artery (ICA) with a trickle flow (Figure 3). The peak systolic velocity (PSV) at this level was 508 cm/s. There also was severe narrowing and turbulent flow in both the mid and distal portions of the right ICA. The patient was sent for a vascular evaluation 2 days following the CUS.

Based on the ocular findings and CUS results, the diagnosis of hypoperfusion retinopathy secondary to carotid occlusive disease was made. Because the patient was asymptomatic with no additional ocular sequelae, he was scheduled for an eye clinic follow-up in 2 months. The electrocardiogram, chest X-ray, and exercise stress test results were negative for acute cardiopulmonary disease, ischemia, or arrhythmias. A computed tomography angiography was performed and confirmed a high-grade lesion of the right ICA of > 95%. The vascular surgeon reported an 11% risk of stroke within 5 years and a 1% risk of stroke with surgery. Based on these results the patient underwent a right carotid endarterectomy (CEA) 2 weeks later. A follow-up CUS was performed 1 month post-CEA and revealed no abnormal fluid or significant plaque with a PSV of 92 cm/s (prior to surgery PSV was 508 cm/s) (Figure 3).

The patient returned to the eye clinic 1 month after the CEA. Gonioscopy revealed no neovascularization of the iris or angle and the dilated eye exam showed resolution of the midperipheral blot hemorrhages in his right eye with no evidence of retinal neovascularization.

Discussion

Hypoperfusion retinopathy is characterized by posterior retinal changes secondary to chronic ocular ischemia from decreased arterial perfusion related to significant or complete carotid artery stenosis.^1-5 Early literature referred to this condition as venous stasis retinopathy; however, this term is misleading as the condition results from a reduction in arterial perfusion pressure and the term describes venous outflow obstruction.⁶ The terms carotid ischemic retinopathy, ischemic oculopathy, and hypotensive retinopathy also have been used interchangeably when describing hypoperfusion retinopathy.⁶

Incidence of hypoperfusion retinopathy is twice as high in males as it is in females due to a higher prevalence of cardiovascular disease.⁷ Hypoperfusion retinopathy rarely presents before the age of 50 years, with the average age of onset around 65 years.⁷ The exact rate of occurrence is unknown as this condition often is underdiagnosed because it mimics other vascular conditions, such as venous occlusive disease and diabetic retinopathy.^1,7 Patients can present asymptomatically where findings are incidental on a dilated eye exam, or they may present with vision loss that can be gradual, sudden, or transient in nature.^5,6,8

Gradual vision loss can follow a period of weeks to months and can occur secondary to posterior ischemia, macular edema, or choroidal hypoperfusion.^1,3,8,9 Sudden vision loss can occur from severe hypoperfusion, creating an acute inner layer retinal ischemia. This type of vision loss often is accompanied by a cherry red spot in the macula and can be caused by an embolic plaque.^1,8 Transient vision loss (TVL) also can be secondary to a plaque emboli or light induced. Patients with light-induced TVL report poor to blurry vision or prolonged after image when exposed to bright lights. In theory when the retina is exposed to light, there is an increase in metabolic demand that is unmet in those with choroidal vascular insufficiency from significant carotid stenosis.^3,8,10

The clinical presentation most often is unilateral. Early stages of the disease generally affect the midperipheral retina but can be found in the posterior pole with chronicity. Early findings include microaneurysms, nerve fiber layer and inner retinal layer hemorrhages, and dilated, but generally not tortuous, veins.⁵ Chronic stage findings include arteriolar narrowing, extreme venous dilation, occasionally macular edema, and neovascularization of the disc and or retina.⁵ Disc edema or collaterals usually are not present.⁵

The mechanism behind hypoperfusion retinopathy results from an overall ischemic cascade and starts with comorbid cardiovascular conditions, such as hypertension, hypercholesterolemia, diabetes, heart disease, and history of smoking.^1,2,5 These conditions play a role in creating atherosclerotic buildup in the arterial lumen leading to chronic narrowing and a decrease in arterial perfusion pressure. Over time, a low-grade hypoxic situation is formed, generating vascular endothelial cell damage and pericytes cell loss, thus causing leakage of fluid.^1,2,5 With these chronic hypoxic states, angiogenic factor release eventually leads to posterior neovascularization.^1,2,5 Further chronicity of carotid occlusive disease can create a panocular ischemia that also involves anterior structures, including iris, conjunctiva, episclera, or cornea. At this point, hypoperfusion retinopathy progresses to a more severe condition called ocular ischemic syndrome (OIS).^2,5

Ocular ischemic syndrome can be associated with a 40% mortality rate within 5 years of onset as it is generally found in those with overall poor health.⁵ Along with posterior neovascularization, anterior structures also are involved. Sixty-seven percent of cases have iris or angle neovascularization of which 35% go on to develop neovascular glaucoma and its complications.^1,8 With OIS, 90% of cases have some type of vision loss, and 40% report ipsilateral ocular pain.^1,8 Visual loss can be gradual, sudden, or transient. The pain can occur from ocular ischemia, ruptured corneal epithelial microcysts secondary to acute glaucoma, elevated intraocular pressure (IOP) with neovascular glaucoma, or from ipsilateral dural ischemia.^1,5,6,8 Fluorescein angiography is commonly used to diagnose and manage OIS, because it allows for the visualization of retinal and choroidal circulation and the detection of neovascular proliferation and ischemic areas.

Diagnostic Imaging

Several diagnostic testing strategies are available to evaluate for carotid occlusive disease. Carotid ultrasonography is a noninvasive, safe, and inexpensive screening tool to evaluate for high-grade stenosis. However, it can sometimes overestimate the degree of stenosis and is not reliable with severe calcifications.⁸ Computed tomography angiography and magnetic resonance angiography are minimally invasive tools that can be used to screen or confirm the degree of stenosis.⁸ These can be used in addition or instead of ultrasonography, especially in instances where patients have a short neck or high carotid bifurcation that may affect reliability. Both are contraindicated in those with renal failure as both modalities require the use of a contrast dye. Magnetic resonance angiography is far more expensive, time consuming, and not readily available.⁸ Carotid angiography is considered the gold standard for imaging the entire carotid artery system because it allows for the evaluation of plaque morphology, atherosclerotic disease, and collateral circulations.⁸ The disadvantages to this invasive and high-cost procedure include a risk of mortality that can occur secondary to an embolic stroke, myocardial infarction (MI), carotid artery dissection, or arterial thrombosis.⁸

Treatment

Treatment and management for carotid artery stenosis is focused on combined effort with the patient’s PCP and other specialists, including cardiologist, neurologist, and vascular surgeons.¹¹ Treatment of comorbid conditions, education on healthy lifestyle, and smoking cessation are all imperative to the patient’s well-being. Managing ocular sequelae is based on specific findings and can include intravitreal antivascular edothelial growth factor or steroidal injections, pan retinal photocoagulation, or hypotensive drops.^6,7

Restoration of arterial perfusion pressure is the main goal of treatment, and this can be done through CEA or carotid artery stents. Surgical intervention by CEA is determined based on each patient and his or her overall health. A full cardiac workup is required due to surgical risks. The North American Symptomatic Carotid Endarterectomy Trial evaluated symptomatic stenosis and the effectiveness of surgical intervention on stroke prevention. The trial reported that CEA was beneficial in symptomatic patients with 55% to 99% stenosis and especially in those with higher grade stenosis (> 70% up to 95%).^5,7,8,12 With regard to asymptomatic patients with high-grade stenosis, CEA has been found to reduce the risk of stroke if there is at least 60% stenosis.^5,7,8

Carotid artery stents can be used as an alternative when CEA is not effective or contraindicated due to a history of previous CEA, neck radiation, unstable angina, congestive heart failure, or recent MI.^5,7,8 Neither CEA nor stenting is considered effective in complete occlusions due to the high risk of thromboembolism formation.^5,7,8

Conclusion

Hypoperfusion retinopathy describes posterior retinal findings that occur secondary to poor arterial perfusion caused by carotid occlusive disease. Early intervention and restoration of this pressure can prevent the risk of developing a more serious condition characterized by a panocular ischemia called OIS. Unlike hypoperfusion retinopathy, OIS also includes anterior segment findings such as iris neovascularization, which may lead to neovascular glaucoma, whereas hypoperfusion retinopathy is localized to the posterior pole. Patients that develop OIS are at a 40% risk of mortality within 5 years due to poor overall health. Understanding the patient’s signs and symptoms can aid in the diagnosis of both conditions. Collaborative management with the patient’s PCP and specialists in treating comorbid conditions is vital to the patients’ well-being.

Take-Home Points

• Importance of on-field management.
• Preseason drilling of spinal injury management.
• Early and rapid intervention.
• Possible benefit of moderate systemic hypothermia as treatment for acute cervical injury.

In 2010, we reported the case of a professional American football player who sustained a complete cervical spinal cord injury (SCI) while tackling an opposing player.¹ He received prompt medical and surgical care based on then-current recommendations, but was also treated with systemic hypothermia soon after his injury. Although systemic hypothermia had been used in the management of other neurologic injuries at that time, it had not been used in humans with acute SCI, except as described in 2 case reports.^2,3 However, Dietrich⁴ described early emerging animal data on the efficacy of systemic hypothermia for acute SCI. We now provide a clinical update on our patient, who provided written informed consent for print and electronic publication of this case report.

Case Report

During a National Football League game, the player sustained a C3–C4 fracture-dislocation after a helmet-to-helmet hit on an opposing player. He fell face down on the ground and did not move. The team’s physician and trainer rushed to the player’s side, immediately assessed him, and initiated the emergency spinal resuscitation protocol.

As per protocol, the assigned team leader took charge of managing the player’s head to maintain in-line traction with the helmet in place until the head was secured in place on a backboard designed to accommodate the helmet.

Conclusion

At the time this player was injured, use of systemic hypothermia with standard therapy for acute SCI was unique and controversial. Since then, smaller randomized human studies have described the tolerable safety profile, efficacy, and potential benefits of this intervention in acute SCI in humans.^8-10 Now, modest systemic hypothermia can be one of many tools considered in the treatment of acute SCI. Before it can become the standard of care, however, additional larger prospective randomized studies need to be completed.

Am J Orthop. 2017;46(2):E79-E82. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Importance of on-field management.
• Preseason drilling of spinal injury management.
• Early and rapid intervention.
• Possible benefit of moderate systemic hypothermia as treatment for acute cervical injury.

In 2010, we reported the case of a professional American football player who sustained a complete cervical spinal cord injury (SCI) while tackling an opposing player.¹ He received prompt medical and surgical care based on then-current recommendations, but was also treated with systemic hypothermia soon after his injury. Although systemic hypothermia had been used in the management of other neurologic injuries at that time, it had not been used in humans with acute SCI, except as described in 2 case reports.^2,3 However, Dietrich⁴ described early emerging animal data on the efficacy of systemic hypothermia for acute SCI. We now provide a clinical update on our patient, who provided written informed consent for print and electronic publication of this case report.

Case Report

During a National Football League game, the player sustained a C3–C4 fracture-dislocation after a helmet-to-helmet hit on an opposing player. He fell face down on the ground and did not move. The team’s physician and trainer rushed to the player’s side, immediately assessed him, and initiated the emergency spinal resuscitation protocol.

As per protocol, the assigned team leader took charge of managing the player’s head to maintain in-line traction with the helmet in place until the head was secured in place on a backboard designed to accommodate the helmet.

Conclusion

At the time this player was injured, use of systemic hypothermia with standard therapy for acute SCI was unique and controversial. Since then, smaller randomized human studies have described the tolerable safety profile, efficacy, and potential benefits of this intervention in acute SCI in humans.^8-10 Now, modest systemic hypothermia can be one of many tools considered in the treatment of acute SCI. Before it can become the standard of care, however, additional larger prospective randomized studies need to be completed.

Am J Orthop. 2017;46(2):E79-E82. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Importance of on-field management.
• Preseason drilling of spinal injury management.
• Early and rapid intervention.
• Possible benefit of moderate systemic hypothermia as treatment for acute cervical injury.

In 2010, we reported the case of a professional American football player who sustained a complete cervical spinal cord injury (SCI) while tackling an opposing player.¹ He received prompt medical and surgical care based on then-current recommendations, but was also treated with systemic hypothermia soon after his injury. Although systemic hypothermia had been used in the management of other neurologic injuries at that time, it had not been used in humans with acute SCI, except as described in 2 case reports.^2,3 However, Dietrich⁴ described early emerging animal data on the efficacy of systemic hypothermia for acute SCI. We now provide a clinical update on our patient, who provided written informed consent for print and electronic publication of this case report.

Case Report

During a National Football League game, the player sustained a C3–C4 fracture-dislocation after a helmet-to-helmet hit on an opposing player. He fell face down on the ground and did not move. The team’s physician and trainer rushed to the player’s side, immediately assessed him, and initiated the emergency spinal resuscitation protocol.

As per protocol, the assigned team leader took charge of managing the player’s head to maintain in-line traction with the helmet in place until the head was secured in place on a backboard designed to accommodate the helmet.

Conclusion

At the time this player was injured, use of systemic hypothermia with standard therapy for acute SCI was unique and controversial. Since then, smaller randomized human studies have described the tolerable safety profile, efficacy, and potential benefits of this intervention in acute SCI in humans.^8-10 Now, modest systemic hypothermia can be one of many tools considered in the treatment of acute SCI. Before it can become the standard of care, however, additional larger prospective randomized studies need to be completed.

Am J Orthop. 2017;46(2):E79-E82. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Case Report

A 50-year-old man with a history of antisynthetase syndrome (positive for anti–Jo-1 polymyositis with interstitial lung disease) and sarcoidosis presented for evaluation of numerous new moles. The lesions had developed on the trunk, arms, legs, hands, and feet approximately 3 weeks after starting azathioprine 100 mg once daily for pulmonary and muscular involvement of antisynthetase syndrome. He denied any preceding cutaneous inflammation or sunburns. He had no personal or family history of skin cancer, and no family members had multiple nevi. Physical examination revealed 30 to 40 benign-appearing, 2- to 5-mm, hyperpigmented macules scattered on the medial aspect of the right foot (Figure 1A), left palm (Figure 1B), back, abdomen, chest, arms, and legs. A larger, somewhat asymmetric, irregularly bordered, and irregularly pigmented macule was noted on the left side of the upper back. A punch biopsy of the lesion revealed a benign, mildly atypical lentiginous compound nevus (Figure 2). Pathology confirmed that the lesions represented eruptive melanocytic nevi (EMN). The patient continued azathioprine therapy and was followed with regular full-body skin examinations. Mycophenolate mofetil was suggested as an alternative therapy, if clinically appropriate, though this change has not been made by the patient’s rheumatologists.

Comment

A PubMed search of articles indexed for MEDLINE using the search terms eruptive melanocytic nevi and azathioprine revealed 14 cases of EMN in the setting of azathioprine therapy, either during azathioprine monotherapy or in combination with other immunosuppressants, including systemic corticosteroids, biologics, and cyclosporine (Table).^1-5 The majority of these cases occurred in renal transplant patients,¹ with 3 additional cases reported in the setting of Crohn disease,^2,3,5 and another in a patient with myasthenia gravis.⁴ Patients ranged in age from 8 to 42 years (mean age, 22 years), with lesions developing a few months to up to 7 years after starting therapy. When specified, the reported lesions typically were small, ranging from 1 to 3 mm in size, and developed rapidly over a couple of months with a predilection for the palms, soles, and trunk. Although dysplastic nevi were described in only 2 patients, melanomas were not detected.

Various hypotheses have sought to explain the largely unknown etiology of EMN. Bovenschen et al³ suggested that immunocompromised patients have diminished immune surveillance in the skin, which allows for unchecked proliferation of melanocytes. Specifically, immune suppression may induce melanocyte-stimulating hormone or melanoma growth stimulatory activity, with composition-specific growth in skin at the palms and soles.^3,4 The preferential growth on the palms and soles suggests that those regions may have special sensitivity to melanocyte-stimulating hormone.⁴ Woodhouse and Maytin⁶ postulated that the increased density of eccrine sweat glands in the palms and soles as well as the absence of pilosebaceous units and apocrine glands and plentiful Pacinian and Meissner corpuscles may allow for a unique response to circulating melanocytic growth factors. Another hypothesis suggests the presence of genetic factors that allow subclinical nests of nevus cells to form, which become clinical eruptions following chemotherapy or immunosuppressive therapy.³ Azathioprine also has been suggested to induce various transcription factors that play a critical role in differentiation and proliferation of melanocytic stem cells, which leads to the formation of nevi.⁴ Our case and others similar to it implore that further studies be done to determine the molecular mechanism driving this phenomenon and whether a specific genetic predisposition exists that lowers the threshold for rapid proliferation of melanocytes given an immunosuppressed status.²

The risk for melanoma development in cases of EMN is unknown. Although our review of the literature did not reveal any melanomas reported in cases attributed to azathioprine, a theoretical risk exists given the established associations between melanoma and immunosuppression as well as increased numbers of nevi.⁶ Accordingly, these patients should be followed with regular skin examinations and biopsies of atypical-appearing lesions as indicated.^2,3,5 Braun et al⁴ also suggested the discontinuance of azathioprine and switch to mycophenolic acid, which has not been noted to cause such eruptions; this drug was recommended in our case.

Case Report

A 50-year-old man with a history of antisynthetase syndrome (positive for anti–Jo-1 polymyositis with interstitial lung disease) and sarcoidosis presented for evaluation of numerous new moles. The lesions had developed on the trunk, arms, legs, hands, and feet approximately 3 weeks after starting azathioprine 100 mg once daily for pulmonary and muscular involvement of antisynthetase syndrome. He denied any preceding cutaneous inflammation or sunburns. He had no personal or family history of skin cancer, and no family members had multiple nevi. Physical examination revealed 30 to 40 benign-appearing, 2- to 5-mm, hyperpigmented macules scattered on the medial aspect of the right foot (Figure 1A), left palm (Figure 1B), back, abdomen, chest, arms, and legs. A larger, somewhat asymmetric, irregularly bordered, and irregularly pigmented macule was noted on the left side of the upper back. A punch biopsy of the lesion revealed a benign, mildly atypical lentiginous compound nevus (Figure 2). Pathology confirmed that the lesions represented eruptive melanocytic nevi (EMN). The patient continued azathioprine therapy and was followed with regular full-body skin examinations. Mycophenolate mofetil was suggested as an alternative therapy, if clinically appropriate, though this change has not been made by the patient’s rheumatologists.

Comment

A PubMed search of articles indexed for MEDLINE using the search terms eruptive melanocytic nevi and azathioprine revealed 14 cases of EMN in the setting of azathioprine therapy, either during azathioprine monotherapy or in combination with other immunosuppressants, including systemic corticosteroids, biologics, and cyclosporine (Table).^1-5 The majority of these cases occurred in renal transplant patients,¹ with 3 additional cases reported in the setting of Crohn disease,^2,3,5 and another in a patient with myasthenia gravis.⁴ Patients ranged in age from 8 to 42 years (mean age, 22 years), with lesions developing a few months to up to 7 years after starting therapy. When specified, the reported lesions typically were small, ranging from 1 to 3 mm in size, and developed rapidly over a couple of months with a predilection for the palms, soles, and trunk. Although dysplastic nevi were described in only 2 patients, melanomas were not detected.

Various hypotheses have sought to explain the largely unknown etiology of EMN. Bovenschen et al³ suggested that immunocompromised patients have diminished immune surveillance in the skin, which allows for unchecked proliferation of melanocytes. Specifically, immune suppression may induce melanocyte-stimulating hormone or melanoma growth stimulatory activity, with composition-specific growth in skin at the palms and soles.^3,4 The preferential growth on the palms and soles suggests that those regions may have special sensitivity to melanocyte-stimulating hormone.⁴ Woodhouse and Maytin⁶ postulated that the increased density of eccrine sweat glands in the palms and soles as well as the absence of pilosebaceous units and apocrine glands and plentiful Pacinian and Meissner corpuscles may allow for a unique response to circulating melanocytic growth factors. Another hypothesis suggests the presence of genetic factors that allow subclinical nests of nevus cells to form, which become clinical eruptions following chemotherapy or immunosuppressive therapy.³ Azathioprine also has been suggested to induce various transcription factors that play a critical role in differentiation and proliferation of melanocytic stem cells, which leads to the formation of nevi.⁴ Our case and others similar to it implore that further studies be done to determine the molecular mechanism driving this phenomenon and whether a specific genetic predisposition exists that lowers the threshold for rapid proliferation of melanocytes given an immunosuppressed status.²

The risk for melanoma development in cases of EMN is unknown. Although our review of the literature did not reveal any melanomas reported in cases attributed to azathioprine, a theoretical risk exists given the established associations between melanoma and immunosuppression as well as increased numbers of nevi.⁶ Accordingly, these patients should be followed with regular skin examinations and biopsies of atypical-appearing lesions as indicated.^2,3,5 Braun et al⁴ also suggested the discontinuance of azathioprine and switch to mycophenolic acid, which has not been noted to cause such eruptions; this drug was recommended in our case.

Case Report

A 50-year-old man with a history of antisynthetase syndrome (positive for anti–Jo-1 polymyositis with interstitial lung disease) and sarcoidosis presented for evaluation of numerous new moles. The lesions had developed on the trunk, arms, legs, hands, and feet approximately 3 weeks after starting azathioprine 100 mg once daily for pulmonary and muscular involvement of antisynthetase syndrome. He denied any preceding cutaneous inflammation or sunburns. He had no personal or family history of skin cancer, and no family members had multiple nevi. Physical examination revealed 30 to 40 benign-appearing, 2- to 5-mm, hyperpigmented macules scattered on the medial aspect of the right foot (Figure 1A), left palm (Figure 1B), back, abdomen, chest, arms, and legs. A larger, somewhat asymmetric, irregularly bordered, and irregularly pigmented macule was noted on the left side of the upper back. A punch biopsy of the lesion revealed a benign, mildly atypical lentiginous compound nevus (Figure 2). Pathology confirmed that the lesions represented eruptive melanocytic nevi (EMN). The patient continued azathioprine therapy and was followed with regular full-body skin examinations. Mycophenolate mofetil was suggested as an alternative therapy, if clinically appropriate, though this change has not been made by the patient’s rheumatologists.

Comment

A PubMed search of articles indexed for MEDLINE using the search terms eruptive melanocytic nevi and azathioprine revealed 14 cases of EMN in the setting of azathioprine therapy, either during azathioprine monotherapy or in combination with other immunosuppressants, including systemic corticosteroids, biologics, and cyclosporine (Table).^1-5 The majority of these cases occurred in renal transplant patients,¹ with 3 additional cases reported in the setting of Crohn disease,^2,3,5 and another in a patient with myasthenia gravis.⁴ Patients ranged in age from 8 to 42 years (mean age, 22 years), with lesions developing a few months to up to 7 years after starting therapy. When specified, the reported lesions typically were small, ranging from 1 to 3 mm in size, and developed rapidly over a couple of months with a predilection for the palms, soles, and trunk. Although dysplastic nevi were described in only 2 patients, melanomas were not detected.

Various hypotheses have sought to explain the largely unknown etiology of EMN. Bovenschen et al³ suggested that immunocompromised patients have diminished immune surveillance in the skin, which allows for unchecked proliferation of melanocytes. Specifically, immune suppression may induce melanocyte-stimulating hormone or melanoma growth stimulatory activity, with composition-specific growth in skin at the palms and soles.^3,4 The preferential growth on the palms and soles suggests that those regions may have special sensitivity to melanocyte-stimulating hormone.⁴ Woodhouse and Maytin⁶ postulated that the increased density of eccrine sweat glands in the palms and soles as well as the absence of pilosebaceous units and apocrine glands and plentiful Pacinian and Meissner corpuscles may allow for a unique response to circulating melanocytic growth factors. Another hypothesis suggests the presence of genetic factors that allow subclinical nests of nevus cells to form, which become clinical eruptions following chemotherapy or immunosuppressive therapy.³ Azathioprine also has been suggested to induce various transcription factors that play a critical role in differentiation and proliferation of melanocytic stem cells, which leads to the formation of nevi.⁴ Our case and others similar to it implore that further studies be done to determine the molecular mechanism driving this phenomenon and whether a specific genetic predisposition exists that lowers the threshold for rapid proliferation of melanocytes given an immunosuppressed status.²

The risk for melanoma development in cases of EMN is unknown. Although our review of the literature did not reveal any melanomas reported in cases attributed to azathioprine, a theoretical risk exists given the established associations between melanoma and immunosuppression as well as increased numbers of nevi.⁶ Accordingly, these patients should be followed with regular skin examinations and biopsies of atypical-appearing lesions as indicated.^2,3,5 Braun et al⁴ also suggested the discontinuance of azathioprine and switch to mycophenolic acid, which has not been noted to cause such eruptions; this drug was recommended in our case.

THE CASE

A 31-year-old right-handed college baseball coach presented to his family physician (FP) with concerns about the “yips” in his right arm. His ability to throw a baseball had been gradually deteriorating. Involuntary upper right arm muscle contractions and spasms, which began intermittently when he was a teenager, were now a real problem for him as an adult. (See the video below.) The patient was having difficulty rolling a baseball underhand to players as part of infield practice and he was experiencing muscle spasms when lifting his right arm over his head. “Twitches” in the patient’s upper arm were making drinking difficult, but he had no problems feeding himself, writing, or performing other basic activities of daily living.

The patient experienced the same symptoms whether it was baseball season or not. He hadn’t noticed a change in symptoms with caffeine and denied use of any other stimulants in the last 4 years. His symptoms didn’t improve or worsen with greater or lesser quantity or quality of sleep or when he concentrated on stifling the involuntary movements. He had attempted to learn to throw left-handed to overcome the impairment, but was concerned that the same problem would occur in his left arm.

The patient had previously worked with a sports psychologist and hypnotherapist to overcome any potential subconscious performance anxiety, but this hadn’t helped. Stretching and strengthening with a physical therapist and numerous sessions with an acupuncturist hadn’t helped either. Despite this, he believed the problem to be primarily psychological.

The patient’s history included mild attention deficit disorder and exercise-induced asthma; his family history was negative for any movement or psychiatric disorders. He had 2 dislocation repairs on his left, non-throwing shoulder in his early twenties. His medications included fluticasone-salmeterol twice daily and albuterol, as needed.

The patient denied myalgia or arthralgia, decreased passive range of motion, shoulder or arm weakness, swelling, or muscle atrophy. He also didn’t have paresthesias in his right arm or hand, a resting tremor, difficulty moving (other than drinking from a cup), difficulty moving other extremities, dizziness, imbalance, or seizures.

The patient’s vital signs were normal. He had full range of motion and 5 out of 5 strength without pain during right shoulder abduction, external and internal rotation, an empty can test, a lower back lift off (Gerber’s) test, and a test of bicep and tricep strength, along with negative Neer and Hawkins tests.

There was no evidence of muscle wasting or asymmetry in the bilateral upper extremities. The patient’s deep tendon reflex grade was 2+ out of 4 in both of his arms. He didn’t have a sensory deficit to light touch in areas of C5 to T1 and he had normal cranial nerves II to XII. He had normal rapid alternating movements, heel-to-shin testing, and finger-to-nose testing, as well as a normal gait and Romberg test.

The patient provided a video showing the abnormal involuntary flexion of his shoulder when attempting to throw a baseball.

THE DIAGNOSIS

The patient’s FP was aware of the “yips,” a condition that is commonly viewed as psychological or related to performance anxiety. (The “yips” are colloquially known as “Steve Blass Disease”—named after a Pittsburgh Pirates pitcher who suddenly lost the ability to control his pitches.¹) But based on the patient’s clinical presentation and history of seeing a number of mental health care providers—in addition to his worsening symptoms—the FP ordered magnetic resonance imaging (MRI) of the brain. The MRI turned out to be unremarkable, so the patient was referred to Neurology.

In the general neurology clinic, a diagnosis of Wilson’s disease (a condition that leads to excess copper deposition in mul­tiple organ systems, including the nervous system) was considered, as it can cause symptoms similar to those our patient was experiencing. However, a complete blood count, complete metabolic panel, antinuclear antibody test, ceruloplasmin test, and copper level were all normal, effectively ruling it out. An MRI of the cervical spine showed mild to moderate right foraminal stenosis at C3-4 and C5-6, but this did not explain the patient’s symptoms.

A diagnosis of paroxysmal exercise-induced dystonia was also considered at the time of the initial work-up, as our patient’s symptoms were most pronounced during physical activity. But this condition usually responds to antiepileptics, and carbamazepine and phenytoin were each tried for multiple months early in his evaluation without benefit.

3 factors led to a diagnosis of focal limb dystonia: Only our patient’s right arm was affected, his laboratory and imaging work-ups were negative, and he didn’t respond to antiepileptic treatment. Characterization of a movement disorder is based upon phenomenology. In this case, the patient had sustained abnormal posturing at the shoulder during right upper limb activation, which was only triggered with specific voluntary actions. This was consistent with dystonia, a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures—often initiated or worsened by voluntary action.²

DISCUSSION

The “yips,” or intermittent, transient tremors, jerks, or spasms³ that are seen in athletes, are well-documented in the lay press, but haven’t been significantly addressed in the medical literature.⁴ Stigma surrounding the condition among athletes likely leads to under-reporting. Athletes typically experience yips with fine motor movements, such as short putts in golf and pitching in baseball. In fact, while the majority of the medical literature on yips revolves around golfers, many talented baseball players have had their careers altered by the condition. The yips may also affect movements in sports like darts, cricket, table tennis, and billiards.

Athletes typically experience the "yips" with fine motor movements, such as short putts in golf or pitching in baseball.

In 1984, dystonia was defined as a disorder of sensorimotor integration that results in co-contraction of agonist/antagonist muscles, and may be characterized by state dependence (exacerbation with specific activities) or sensory tricks (amelioration with specific types of sensory input).⁵ In 2013, the definition was revised to remove “co-contraction” from the definition because phenomenology alone is sufficient to make the diagnosis.¹

Many athletes and sports fans believe the yips are caused by performance anxiety or related phobias, but evidence suggests that many athletes with the movement disorder may actually have focal limb dystonia.^6,7 The yips can, however, lead to performance anxiety,³ but there has been no difference noted between the anxiety level of golfers with or without the yips.⁷ Psychological treatment approaches are commonly employed, but surface electromyograms have shown abnormal co-contraction of wrist flexor and extensor muscles in 5 out of 10 golfers with the yips (but 0 of those without) while putting—which is consistent with focal limb dystonia.⁸

Botulinum toxin injections are Tx of choice, but can cause weakness

Muscle relaxers, such as baclofen and benzodiazepines, as well as dopamine antagonists, can ameliorate dystonia.⁹ Focal limb dystonia may also respond to the antispasmodic trihexyphenidyl, but the dose must often be limited due to adverse effects such as nausea, dizziness, and anxiety.¹⁰

There are few reports of the use of botulinum toxin injections in athletes, where the adverse effect of weakness could affect performance.

Botulinum toxin injections have proven effective for focal limb dystonia¹¹ and are considered the treatment of choice. However, there are few reports on their use in athletes, where the adverse effect of weakness could affect performance. One case report also showed improvement of yips with acupuncture, although this has not been extensively studied.¹²

Our patient didn’t respond to low-dose (2 mg twice a day) trihexyphenidyl. Tetrabenazine, a dopamine depletor frequently used for hyperkinetic disorders, was not effective at 25 mg taken prior to coaching sessions. Higher doses of an anticholinergic could have been effective, but the patient declined our recommendation to pursue this (or botulinum toxin injections). He decided instead to train himself to use his left arm while coaching.

THE TAKEAWAY

Athletes who play sports that require precision movements commonly develop the yips. While the prevailing theory among athletes is that this is a psychological phenomenon, evidence shows that this may in fact be a neurologic focal dystonia caused by repetitive use. Greater awareness of yips as a possible organic, treatable neurologic condition is needed in order to stimulate more research on this topic.

THE CASE

A 31-year-old right-handed college baseball coach presented to his family physician (FP) with concerns about the “yips” in his right arm. His ability to throw a baseball had been gradually deteriorating. Involuntary upper right arm muscle contractions and spasms, which began intermittently when he was a teenager, were now a real problem for him as an adult. (See the video below.) The patient was having difficulty rolling a baseball underhand to players as part of infield practice and he was experiencing muscle spasms when lifting his right arm over his head. “Twitches” in the patient’s upper arm were making drinking difficult, but he had no problems feeding himself, writing, or performing other basic activities of daily living.

The patient experienced the same symptoms whether it was baseball season or not. He hadn’t noticed a change in symptoms with caffeine and denied use of any other stimulants in the last 4 years. His symptoms didn’t improve or worsen with greater or lesser quantity or quality of sleep or when he concentrated on stifling the involuntary movements. He had attempted to learn to throw left-handed to overcome the impairment, but was concerned that the same problem would occur in his left arm.

The patient had previously worked with a sports psychologist and hypnotherapist to overcome any potential subconscious performance anxiety, but this hadn’t helped. Stretching and strengthening with a physical therapist and numerous sessions with an acupuncturist hadn’t helped either. Despite this, he believed the problem to be primarily psychological.

The patient’s history included mild attention deficit disorder and exercise-induced asthma; his family history was negative for any movement or psychiatric disorders. He had 2 dislocation repairs on his left, non-throwing shoulder in his early twenties. His medications included fluticasone-salmeterol twice daily and albuterol, as needed.

The patient denied myalgia or arthralgia, decreased passive range of motion, shoulder or arm weakness, swelling, or muscle atrophy. He also didn’t have paresthesias in his right arm or hand, a resting tremor, difficulty moving (other than drinking from a cup), difficulty moving other extremities, dizziness, imbalance, or seizures.

The patient’s vital signs were normal. He had full range of motion and 5 out of 5 strength without pain during right shoulder abduction, external and internal rotation, an empty can test, a lower back lift off (Gerber’s) test, and a test of bicep and tricep strength, along with negative Neer and Hawkins tests.

There was no evidence of muscle wasting or asymmetry in the bilateral upper extremities. The patient’s deep tendon reflex grade was 2+ out of 4 in both of his arms. He didn’t have a sensory deficit to light touch in areas of C5 to T1 and he had normal cranial nerves II to XII. He had normal rapid alternating movements, heel-to-shin testing, and finger-to-nose testing, as well as a normal gait and Romberg test.

The patient provided a video showing the abnormal involuntary flexion of his shoulder when attempting to throw a baseball.

THE DIAGNOSIS

The patient’s FP was aware of the “yips,” a condition that is commonly viewed as psychological or related to performance anxiety. (The “yips” are colloquially known as “Steve Blass Disease”—named after a Pittsburgh Pirates pitcher who suddenly lost the ability to control his pitches.¹) But based on the patient’s clinical presentation and history of seeing a number of mental health care providers—in addition to his worsening symptoms—the FP ordered magnetic resonance imaging (MRI) of the brain. The MRI turned out to be unremarkable, so the patient was referred to Neurology.

In the general neurology clinic, a diagnosis of Wilson’s disease (a condition that leads to excess copper deposition in mul­tiple organ systems, including the nervous system) was considered, as it can cause symptoms similar to those our patient was experiencing. However, a complete blood count, complete metabolic panel, antinuclear antibody test, ceruloplasmin test, and copper level were all normal, effectively ruling it out. An MRI of the cervical spine showed mild to moderate right foraminal stenosis at C3-4 and C5-6, but this did not explain the patient’s symptoms.

A diagnosis of paroxysmal exercise-induced dystonia was also considered at the time of the initial work-up, as our patient’s symptoms were most pronounced during physical activity. But this condition usually responds to antiepileptics, and carbamazepine and phenytoin were each tried for multiple months early in his evaluation without benefit.

3 factors led to a diagnosis of focal limb dystonia: Only our patient’s right arm was affected, his laboratory and imaging work-ups were negative, and he didn’t respond to antiepileptic treatment. Characterization of a movement disorder is based upon phenomenology. In this case, the patient had sustained abnormal posturing at the shoulder during right upper limb activation, which was only triggered with specific voluntary actions. This was consistent with dystonia, a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures—often initiated or worsened by voluntary action.²

DISCUSSION

The “yips,” or intermittent, transient tremors, jerks, or spasms³ that are seen in athletes, are well-documented in the lay press, but haven’t been significantly addressed in the medical literature.⁴ Stigma surrounding the condition among athletes likely leads to under-reporting. Athletes typically experience yips with fine motor movements, such as short putts in golf and pitching in baseball. In fact, while the majority of the medical literature on yips revolves around golfers, many talented baseball players have had their careers altered by the condition. The yips may also affect movements in sports like darts, cricket, table tennis, and billiards.

Athletes typically experience the "yips" with fine motor movements, such as short putts in golf or pitching in baseball.

In 1984, dystonia was defined as a disorder of sensorimotor integration that results in co-contraction of agonist/antagonist muscles, and may be characterized by state dependence (exacerbation with specific activities) or sensory tricks (amelioration with specific types of sensory input).⁵ In 2013, the definition was revised to remove “co-contraction” from the definition because phenomenology alone is sufficient to make the diagnosis.¹

Many athletes and sports fans believe the yips are caused by performance anxiety or related phobias, but evidence suggests that many athletes with the movement disorder may actually have focal limb dystonia.^6,7 The yips can, however, lead to performance anxiety,³ but there has been no difference noted between the anxiety level of golfers with or without the yips.⁷ Psychological treatment approaches are commonly employed, but surface electromyograms have shown abnormal co-contraction of wrist flexor and extensor muscles in 5 out of 10 golfers with the yips (but 0 of those without) while putting—which is consistent with focal limb dystonia.⁸

Botulinum toxin injections are Tx of choice, but can cause weakness

Muscle relaxers, such as baclofen and benzodiazepines, as well as dopamine antagonists, can ameliorate dystonia.⁹ Focal limb dystonia may also respond to the antispasmodic trihexyphenidyl, but the dose must often be limited due to adverse effects such as nausea, dizziness, and anxiety.¹⁰

There are few reports of the use of botulinum toxin injections in athletes, where the adverse effect of weakness could affect performance.

Botulinum toxin injections have proven effective for focal limb dystonia¹¹ and are considered the treatment of choice. However, there are few reports on their use in athletes, where the adverse effect of weakness could affect performance. One case report also showed improvement of yips with acupuncture, although this has not been extensively studied.¹²

Our patient didn’t respond to low-dose (2 mg twice a day) trihexyphenidyl. Tetrabenazine, a dopamine depletor frequently used for hyperkinetic disorders, was not effective at 25 mg taken prior to coaching sessions. Higher doses of an anticholinergic could have been effective, but the patient declined our recommendation to pursue this (or botulinum toxin injections). He decided instead to train himself to use his left arm while coaching.

THE TAKEAWAY

Athletes who play sports that require precision movements commonly develop the yips. While the prevailing theory among athletes is that this is a psychological phenomenon, evidence shows that this may in fact be a neurologic focal dystonia caused by repetitive use. Greater awareness of yips as a possible organic, treatable neurologic condition is needed in order to stimulate more research on this topic.

THE CASE

A 31-year-old right-handed college baseball coach presented to his family physician (FP) with concerns about the “yips” in his right arm. His ability to throw a baseball had been gradually deteriorating. Involuntary upper right arm muscle contractions and spasms, which began intermittently when he was a teenager, were now a real problem for him as an adult. (See the video below.) The patient was having difficulty rolling a baseball underhand to players as part of infield practice and he was experiencing muscle spasms when lifting his right arm over his head. “Twitches” in the patient’s upper arm were making drinking difficult, but he had no problems feeding himself, writing, or performing other basic activities of daily living.

The patient experienced the same symptoms whether it was baseball season or not. He hadn’t noticed a change in symptoms with caffeine and denied use of any other stimulants in the last 4 years. His symptoms didn’t improve or worsen with greater or lesser quantity or quality of sleep or when he concentrated on stifling the involuntary movements. He had attempted to learn to throw left-handed to overcome the impairment, but was concerned that the same problem would occur in his left arm.

The patient had previously worked with a sports psychologist and hypnotherapist to overcome any potential subconscious performance anxiety, but this hadn’t helped. Stretching and strengthening with a physical therapist and numerous sessions with an acupuncturist hadn’t helped either. Despite this, he believed the problem to be primarily psychological.

The patient’s history included mild attention deficit disorder and exercise-induced asthma; his family history was negative for any movement or psychiatric disorders. He had 2 dislocation repairs on his left, non-throwing shoulder in his early twenties. His medications included fluticasone-salmeterol twice daily and albuterol, as needed.

The patient denied myalgia or arthralgia, decreased passive range of motion, shoulder or arm weakness, swelling, or muscle atrophy. He also didn’t have paresthesias in his right arm or hand, a resting tremor, difficulty moving (other than drinking from a cup), difficulty moving other extremities, dizziness, imbalance, or seizures.

The patient’s vital signs were normal. He had full range of motion and 5 out of 5 strength without pain during right shoulder abduction, external and internal rotation, an empty can test, a lower back lift off (Gerber’s) test, and a test of bicep and tricep strength, along with negative Neer and Hawkins tests.

There was no evidence of muscle wasting or asymmetry in the bilateral upper extremities. The patient’s deep tendon reflex grade was 2+ out of 4 in both of his arms. He didn’t have a sensory deficit to light touch in areas of C5 to T1 and he had normal cranial nerves II to XII. He had normal rapid alternating movements, heel-to-shin testing, and finger-to-nose testing, as well as a normal gait and Romberg test.

The patient provided a video showing the abnormal involuntary flexion of his shoulder when attempting to throw a baseball.

THE DIAGNOSIS

The patient’s FP was aware of the “yips,” a condition that is commonly viewed as psychological or related to performance anxiety. (The “yips” are colloquially known as “Steve Blass Disease”—named after a Pittsburgh Pirates pitcher who suddenly lost the ability to control his pitches.¹) But based on the patient’s clinical presentation and history of seeing a number of mental health care providers—in addition to his worsening symptoms—the FP ordered magnetic resonance imaging (MRI) of the brain. The MRI turned out to be unremarkable, so the patient was referred to Neurology.

In the general neurology clinic, a diagnosis of Wilson’s disease (a condition that leads to excess copper deposition in mul­tiple organ systems, including the nervous system) was considered, as it can cause symptoms similar to those our patient was experiencing. However, a complete blood count, complete metabolic panel, antinuclear antibody test, ceruloplasmin test, and copper level were all normal, effectively ruling it out. An MRI of the cervical spine showed mild to moderate right foraminal stenosis at C3-4 and C5-6, but this did not explain the patient’s symptoms.

A diagnosis of paroxysmal exercise-induced dystonia was also considered at the time of the initial work-up, as our patient’s symptoms were most pronounced during physical activity. But this condition usually responds to antiepileptics, and carbamazepine and phenytoin were each tried for multiple months early in his evaluation without benefit.

3 factors led to a diagnosis of focal limb dystonia: Only our patient’s right arm was affected, his laboratory and imaging work-ups were negative, and he didn’t respond to antiepileptic treatment. Characterization of a movement disorder is based upon phenomenology. In this case, the patient had sustained abnormal posturing at the shoulder during right upper limb activation, which was only triggered with specific voluntary actions. This was consistent with dystonia, a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures—often initiated or worsened by voluntary action.²

DISCUSSION

The “yips,” or intermittent, transient tremors, jerks, or spasms³ that are seen in athletes, are well-documented in the lay press, but haven’t been significantly addressed in the medical literature.⁴ Stigma surrounding the condition among athletes likely leads to under-reporting. Athletes typically experience yips with fine motor movements, such as short putts in golf and pitching in baseball. In fact, while the majority of the medical literature on yips revolves around golfers, many talented baseball players have had their careers altered by the condition. The yips may also affect movements in sports like darts, cricket, table tennis, and billiards.

Athletes typically experience the "yips" with fine motor movements, such as short putts in golf or pitching in baseball.

In 1984, dystonia was defined as a disorder of sensorimotor integration that results in co-contraction of agonist/antagonist muscles, and may be characterized by state dependence (exacerbation with specific activities) or sensory tricks (amelioration with specific types of sensory input).⁵ In 2013, the definition was revised to remove “co-contraction” from the definition because phenomenology alone is sufficient to make the diagnosis.¹

Many athletes and sports fans believe the yips are caused by performance anxiety or related phobias, but evidence suggests that many athletes with the movement disorder may actually have focal limb dystonia.^6,7 The yips can, however, lead to performance anxiety,³ but there has been no difference noted between the anxiety level of golfers with or without the yips.⁷ Psychological treatment approaches are commonly employed, but surface electromyograms have shown abnormal co-contraction of wrist flexor and extensor muscles in 5 out of 10 golfers with the yips (but 0 of those without) while putting—which is consistent with focal limb dystonia.⁸

Botulinum toxin injections are Tx of choice, but can cause weakness

Muscle relaxers, such as baclofen and benzodiazepines, as well as dopamine antagonists, can ameliorate dystonia.⁹ Focal limb dystonia may also respond to the antispasmodic trihexyphenidyl, but the dose must often be limited due to adverse effects such as nausea, dizziness, and anxiety.¹⁰

There are few reports of the use of botulinum toxin injections in athletes, where the adverse effect of weakness could affect performance.

Botulinum toxin injections have proven effective for focal limb dystonia¹¹ and are considered the treatment of choice. However, there are few reports on their use in athletes, where the adverse effect of weakness could affect performance. One case report also showed improvement of yips with acupuncture, although this has not been extensively studied.¹²

Our patient didn’t respond to low-dose (2 mg twice a day) trihexyphenidyl. Tetrabenazine, a dopamine depletor frequently used for hyperkinetic disorders, was not effective at 25 mg taken prior to coaching sessions. Higher doses of an anticholinergic could have been effective, but the patient declined our recommendation to pursue this (or botulinum toxin injections). He decided instead to train himself to use his left arm while coaching.

THE TAKEAWAY

Athletes who play sports that require precision movements commonly develop the yips. While the prevailing theory among athletes is that this is a psychological phenomenon, evidence shows that this may in fact be a neurologic focal dystonia caused by repetitive use. Greater awareness of yips as a possible organic, treatable neurologic condition is needed in order to stimulate more research on this topic.

Headaches—pain or discomfort in the head, scalp, or neck—are a very common reason for ED visits.¹ In 2011, the World Health Organization estimated that 46.5% of the population in North and South America aged 18 to 65 years old experienced at least one headache within the previous year.¹

Migraine is a recurrent headache disorder that afflicts 18% of US women and 9% of US men,² resulting in at least 1.2 million visits to US EDs annually.¹ The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity.³ Management and treatment for migraine headache in the ED commonly include intravenous (IV) or intramuscular (IM) medications, fluids, or oxygen. While ultimately effective, these methods require nursing care and additional time for posttreatment monitoring, both of which adversely affect patient flow.

In 2006, Mellick et al⁴ described the safety and effectiveness of paraspinous cervical nerve block (PCNB) to abort migraine headaches. Despite its demonstrated efficacy and safety, a decade later, PCNB is still rarely used. Friedman et al⁵ ranked peripheral nerve blocks as the fourth step in management suggestions for primary headache.

Case Reports of Headache Patients

We report on seven headache patients we treated in our ED with PCNB who had good-to-complete resolution of pain, suggesting that PCNB is efficacious and can potentially shorten the ED length of stay. This series of seven patients (six female, one male) was a convenience sample of primary headache patients who presented over a 10-month period and were safely and rapidly treated with PCNB (Table).

In each case, the PCNB procedure was explained to the patient and consent was obtained. Each patient was treated with a total of 3 cc of 0.5% bupivacaine with epinephrine injected into the posterior neck according to the method described by Mellick et al.⁴ Our seven patients achieved an average 5-point reduction in pain on a 10-point pain scale, with 0 = no pain and 10 = worse possible pain.

Other than the provision of medications, no nursing assistance was required. Only one of the patients required further treatment after the PCNB, and none had an adverse reaction. All of the patients reported that their headaches were similar in nature to past headaches. Based on their history and physical examination, none were diagnosed to be experiencing a secondary, more serious cause of headache, and none subsequently returned to our institution with a secondary type of headache.

The Paraspinal Cervical Nerve Block

Paraspinous cervical nerve block requires less time to administer and recovery is shorter than that from IM or IV opioids, sedatives, or neuroleptics. It is an easy technique to teach since it requires bilateral injections.

Technique

Prior to the procedure, cleanse the bilateral paravertebral zones surrounding C6 and C7 with chlorhexidine. Next, fill a 3 cc syringe using 0.5% bupivacaine with epinephrine.

Once the injection is complete, withdraw the needle completely, and compress and massage the injection site to facilitate anesthetic diffusion to surrounding tissues.

Indications

Paraspinous cervical nerve block is an appropriate treatment only for patients who are having a typical episode of chronic, recurring headaches, whose history and physical examination do not suggest the need for any further diagnostic work-up, and who, in the judgment of the treating clinician, require only pain relief.

Contraindications

A patient should not be considered for PCNB if he or she has a new-onset headache, fever, altered mental status, focal neurological deficits, meningismus, findings suggestive of meningitis, papilledema, increased intracranial pressure from a space-occupying lesion, recent head trauma with concern for intracranial hemorrhage, or suspicion of an alternate diagnosis.

Efficacy and Patient Response

Paraspinous cervical nerve block has been shown to decrease pain in patients who had failed standard migraine therapy and patients reported no complications. Of the seven patients in this case report, only one patient received opioids in the ED and none received prescriptions for opioids upon discharge for outpatient use.

Mellick and Mellick⁶ have postulated that pain may be modified due to the PCNB effect on the convergence of the trigeminal nerve with sensory fibers from the upper cervical roots. Since cervical innervation provides feeling to the head and upper neck, blocking this input can ameliorate pain.⁶

Summary

This series of seven patients provides further evidence of the effectiveness of PCNB in relieving headache symptoms for patients with recurrent, primary headaches when a secondary, more serious cause has been clinically excluded. Each of the seven patients had marked improvement of their pain and required only minimal nursing attention; moreover, all stated they would willingly undergo the procedure for future painful episodes.

Although there were no reported complications, this series is too small to demonstrate complete safety of the procedure. While this report is limited by a small sample size, it demonstrates that this is a quick, effective, and easily learned method of addressing a common ED complaint that obviates the need for parenteral medications and offers a potentially decreased patient length of stay.

Paraspinous cervical nerve block is a promising modality of treatment of ED patients who present with headache and migraine symptoms who do not respond to their outpatient “rescue” therapy. This procedure should be considered as an early treatment for migraine and other primary headaches unless contraindicated.

Headaches—pain or discomfort in the head, scalp, or neck—are a very common reason for ED visits.¹ In 2011, the World Health Organization estimated that 46.5% of the population in North and South America aged 18 to 65 years old experienced at least one headache within the previous year.¹

Migraine is a recurrent headache disorder that afflicts 18% of US women and 9% of US men,² resulting in at least 1.2 million visits to US EDs annually.¹ The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity.³ Management and treatment for migraine headache in the ED commonly include intravenous (IV) or intramuscular (IM) medications, fluids, or oxygen. While ultimately effective, these methods require nursing care and additional time for posttreatment monitoring, both of which adversely affect patient flow.

In 2006, Mellick et al⁴ described the safety and effectiveness of paraspinous cervical nerve block (PCNB) to abort migraine headaches. Despite its demonstrated efficacy and safety, a decade later, PCNB is still rarely used. Friedman et al⁵ ranked peripheral nerve blocks as the fourth step in management suggestions for primary headache.

Case Reports of Headache Patients

We report on seven headache patients we treated in our ED with PCNB who had good-to-complete resolution of pain, suggesting that PCNB is efficacious and can potentially shorten the ED length of stay. This series of seven patients (six female, one male) was a convenience sample of primary headache patients who presented over a 10-month period and were safely and rapidly treated with PCNB (Table).

In each case, the PCNB procedure was explained to the patient and consent was obtained. Each patient was treated with a total of 3 cc of 0.5% bupivacaine with epinephrine injected into the posterior neck according to the method described by Mellick et al.⁴ Our seven patients achieved an average 5-point reduction in pain on a 10-point pain scale, with 0 = no pain and 10 = worse possible pain.

Other than the provision of medications, no nursing assistance was required. Only one of the patients required further treatment after the PCNB, and none had an adverse reaction. All of the patients reported that their headaches were similar in nature to past headaches. Based on their history and physical examination, none were diagnosed to be experiencing a secondary, more serious cause of headache, and none subsequently returned to our institution with a secondary type of headache.

The Paraspinal Cervical Nerve Block

Paraspinous cervical nerve block requires less time to administer and recovery is shorter than that from IM or IV opioids, sedatives, or neuroleptics. It is an easy technique to teach since it requires bilateral injections.

Technique

Prior to the procedure, cleanse the bilateral paravertebral zones surrounding C6 and C7 with chlorhexidine. Next, fill a 3 cc syringe using 0.5% bupivacaine with epinephrine.

Once the injection is complete, withdraw the needle completely, and compress and massage the injection site to facilitate anesthetic diffusion to surrounding tissues.

Indications

Paraspinous cervical nerve block is an appropriate treatment only for patients who are having a typical episode of chronic, recurring headaches, whose history and physical examination do not suggest the need for any further diagnostic work-up, and who, in the judgment of the treating clinician, require only pain relief.

Contraindications

A patient should not be considered for PCNB if he or she has a new-onset headache, fever, altered mental status, focal neurological deficits, meningismus, findings suggestive of meningitis, papilledema, increased intracranial pressure from a space-occupying lesion, recent head trauma with concern for intracranial hemorrhage, or suspicion of an alternate diagnosis.

Efficacy and Patient Response

Paraspinous cervical nerve block has been shown to decrease pain in patients who had failed standard migraine therapy and patients reported no complications. Of the seven patients in this case report, only one patient received opioids in the ED and none received prescriptions for opioids upon discharge for outpatient use.

Mellick and Mellick⁶ have postulated that pain may be modified due to the PCNB effect on the convergence of the trigeminal nerve with sensory fibers from the upper cervical roots. Since cervical innervation provides feeling to the head and upper neck, blocking this input can ameliorate pain.⁶

Summary

This series of seven patients provides further evidence of the effectiveness of PCNB in relieving headache symptoms for patients with recurrent, primary headaches when a secondary, more serious cause has been clinically excluded. Each of the seven patients had marked improvement of their pain and required only minimal nursing attention; moreover, all stated they would willingly undergo the procedure for future painful episodes.

Although there were no reported complications, this series is too small to demonstrate complete safety of the procedure. While this report is limited by a small sample size, it demonstrates that this is a quick, effective, and easily learned method of addressing a common ED complaint that obviates the need for parenteral medications and offers a potentially decreased patient length of stay.

Paraspinous cervical nerve block is a promising modality of treatment of ED patients who present with headache and migraine symptoms who do not respond to their outpatient “rescue” therapy. This procedure should be considered as an early treatment for migraine and other primary headaches unless contraindicated.

Headaches—pain or discomfort in the head, scalp, or neck—are a very common reason for ED visits.¹ In 2011, the World Health Organization estimated that 46.5% of the population in North and South America aged 18 to 65 years old experienced at least one headache within the previous year.¹

Migraine is a recurrent headache disorder that afflicts 18% of US women and 9% of US men,² resulting in at least 1.2 million visits to US EDs annually.¹ The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity.³ Management and treatment for migraine headache in the ED commonly include intravenous (IV) or intramuscular (IM) medications, fluids, or oxygen. While ultimately effective, these methods require nursing care and additional time for posttreatment monitoring, both of which adversely affect patient flow.

In 2006, Mellick et al⁴ described the safety and effectiveness of paraspinous cervical nerve block (PCNB) to abort migraine headaches. Despite its demonstrated efficacy and safety, a decade later, PCNB is still rarely used. Friedman et al⁵ ranked peripheral nerve blocks as the fourth step in management suggestions for primary headache.

Case Reports of Headache Patients

We report on seven headache patients we treated in our ED with PCNB who had good-to-complete resolution of pain, suggesting that PCNB is efficacious and can potentially shorten the ED length of stay. This series of seven patients (six female, one male) was a convenience sample of primary headache patients who presented over a 10-month period and were safely and rapidly treated with PCNB (Table).

In each case, the PCNB procedure was explained to the patient and consent was obtained. Each patient was treated with a total of 3 cc of 0.5% bupivacaine with epinephrine injected into the posterior neck according to the method described by Mellick et al.⁴ Our seven patients achieved an average 5-point reduction in pain on a 10-point pain scale, with 0 = no pain and 10 = worse possible pain.

Other than the provision of medications, no nursing assistance was required. Only one of the patients required further treatment after the PCNB, and none had an adverse reaction. All of the patients reported that their headaches were similar in nature to past headaches. Based on their history and physical examination, none were diagnosed to be experiencing a secondary, more serious cause of headache, and none subsequently returned to our institution with a secondary type of headache.

The Paraspinal Cervical Nerve Block

Paraspinous cervical nerve block requires less time to administer and recovery is shorter than that from IM or IV opioids, sedatives, or neuroleptics. It is an easy technique to teach since it requires bilateral injections.

Technique

Prior to the procedure, cleanse the bilateral paravertebral zones surrounding C6 and C7 with chlorhexidine. Next, fill a 3 cc syringe using 0.5% bupivacaine with epinephrine.

Once the injection is complete, withdraw the needle completely, and compress and massage the injection site to facilitate anesthetic diffusion to surrounding tissues.

Indications

Paraspinous cervical nerve block is an appropriate treatment only for patients who are having a typical episode of chronic, recurring headaches, whose history and physical examination do not suggest the need for any further diagnostic work-up, and who, in the judgment of the treating clinician, require only pain relief.

Contraindications

A patient should not be considered for PCNB if he or she has a new-onset headache, fever, altered mental status, focal neurological deficits, meningismus, findings suggestive of meningitis, papilledema, increased intracranial pressure from a space-occupying lesion, recent head trauma with concern for intracranial hemorrhage, or suspicion of an alternate diagnosis.

Efficacy and Patient Response

Paraspinous cervical nerve block has been shown to decrease pain in patients who had failed standard migraine therapy and patients reported no complications. Of the seven patients in this case report, only one patient received opioids in the ED and none received prescriptions for opioids upon discharge for outpatient use.

Mellick and Mellick⁶ have postulated that pain may be modified due to the PCNB effect on the convergence of the trigeminal nerve with sensory fibers from the upper cervical roots. Since cervical innervation provides feeling to the head and upper neck, blocking this input can ameliorate pain.⁶

Summary

This series of seven patients provides further evidence of the effectiveness of PCNB in relieving headache symptoms for patients with recurrent, primary headaches when a secondary, more serious cause has been clinically excluded. Each of the seven patients had marked improvement of their pain and required only minimal nursing attention; moreover, all stated they would willingly undergo the procedure for future painful episodes.

Although there were no reported complications, this series is too small to demonstrate complete safety of the procedure. While this report is limited by a small sample size, it demonstrates that this is a quick, effective, and easily learned method of addressing a common ED complaint that obviates the need for parenteral medications and offers a potentially decreased patient length of stay.

Paraspinous cervical nerve block is a promising modality of treatment of ED patients who present with headache and migraine symptoms who do not respond to their outpatient “rescue” therapy. This procedure should be considered as an early treatment for migraine and other primary headaches unless contraindicated.