Orbit, 2014; 33(6): 459–461 ! Informa Healthcare USA, Inc. ISSN: 0167-6830 print / 1744-5108 online DOI: 10.3109/01676830.2014.950289
C ASE REPORT
Blepharoptosis and HAART Related Mitochondrial Myopathy Kristin Ow Chapman and Gary Lelli
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
Weill Cornell Medical Center, New York, USA
ABSTRACT Purpose: To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy. Methods: A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years. Results: Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions. Conclusions: This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders. Keywords: Blepharoptosis, HAART, HIV, mycopathy
Blepharoptosis in patients with human immunodeficiency virus (HIV) is often multifactorial and can be from the HIV virus, medication or common causes found in the general population. HAART therapy has changed the disease projection for patients with HIV, and though the therapy has increased life expectancy and quality of life, it is important to carefully consider the side effect profiles of these potent and effective drugs. Antiretroviral therapy-induced lipodystrophy can occur in 40% of patient’s within one year of use.1,2 A case series found that HIV related ptosis on HAART occurred after an average of 14 years of known HIV infection and 9 years on HAART.2 Histopathologic series of muscle fibers in HIV patients on HAART status post blepharoplasty demonstrated myopathy with levator fibers demonstrating atrophy, fibrosis and regeneration.3 In this case, we discuss a case of bilateral ptosis consistent with acquired myopathy secondary to
mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders.
CASE REPORT A 51-year-old man with hepatitis C and HIV treated with HAART for 19 years presented with blepharoptosis. His medication regimen had included a nucleoside analog reverse transcriptase inhibitor (NRTI), abacavir (Ziagen, GlaxoSmithKline, New York, NY, USA), a non-nucleoside reverse transcriptase inhibitor, efavirenz (Sustiva, BristolMyers Squibb Company, Princeton, NJ), and a reverse transcriptase inhibitor didanosine (Videx, BristolMyers Squibb Company, Princeton, NJ). On examination, his best corrected visual acuity was 20/20 in both eyes. His MRD 1 was 0.5 mm in both eyes with levator excursion of 13 mm in both
Received 15 January 2014; Revised 3 April 2014; Accepted 28 July 2014; Published online 11 September 2014 Correspondence: Dr. Gary Lelli Jr., Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA, Tel.: (646) 962-2020, Fax: (646) 962-0603, E-mail: [email protected]
459
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
460 K. O. Chapman and G. Lelli eyes. There was 2 mm of inferior scleral show in both eyes and the palpebral fissure of the right and left eye was 8 mm and 6 mm respectively. The patient demonstrated increased frontalis involvement and head tilting with chin-up positioning. Testing for Cogan eyelid twitch was negative. Humphrey visual field testing revealed superior visual field defects that resolved with taping in both eyes. External levator aponeurosis reinsertion was performed on the bilateral upper eyelids. The patient tolerated the procedure well. Post operative results demonstrated and increase in MRD1 and overall aesthetic and functional improvement. Pathology specimens of levator muscle stained with hematoxylin and eosin stain (H&E stain) demonstrated normal striated muscle in both eyelid samples (Figure 1). Analysis of DNA isolated from levator muscle demonstrated multiple deletions in mitochondrial DNA by Southern blot testing. Southern blot remains the ‘‘gold standard’’ of detection of mitochondrial DNA deletions.4 DNA was digested with Pvull restriction enzymes, electrophoresed on agarose gels and hybridized to a probe detecting mitochondrial DNA. The pattern of multiple deletions was reported to be consistent to those in patients with ptosis and ophthalmoplegia (Figure 2).
Our patient’s history of hepatitis C could have increase the rate of mitochondrial toxicity.2 A case series of two patients with HIV on HAART with ptosis and mitochondrial deletions suggests that the patients may have had underlying mitochondrial disorders that were ‘‘unmasked’’ with HAART therapy.5 These patients also exhibited ophthalmoplegia. Our patient’s extraocular movements were full and orthostatic, and there was very low suspicion for chronic progressive ophthalmoplegia or Kearns-Sayre syndrome in this case. A review of the literature helped to further guide the medical management of this patient. In some case series, ptosis has improved when NRTI’s are held and it has been proposed that antivirals play an important role in delaying HIV related myopathy by lowering viral load.2,6 Efforts have been made to limit the side effects of the NRTI’s by giving coenzymes, antioxidants and vitamin supplementation.5 In light of the known association between mitochondrial disorders and conduction abnormalities, an electrocardiogram may be warranted in patients who exhibit signs of
Comment Multiple factors determine if a patient on HAART will be at risk to develop ptosis. Different NRTI’s have a greater level of mitochondrial blockage with didanosine known to cause higher levels of toxicity compared to others including abacavir.5 Our patient used both didanosine and abacavir. The incidence of mitochondrial toxicity can also be increased by underlying organ dysfunction, disease process and synergistic drug administration.2,6
FIGURE 1. H&E staining demonstrated normal striated muscle in levator muscle.
FIGURE 2. Southern blot results from the patient’s levator muscle with the patient’s (P) smeared bands under the normal bands compared with controls (C1 and C2), which demonstrate his multiple deletions of mitochondrial DNA. Orbit
Ptosis and HAART Related Mitochondrial Myopathy ophthalmoplegia or other neurologic dysfunctions in order to evaluate for conduction abnormalities. Surgical treatment of ptosis in HIV patients on HAART should help to correct symptoms if a trial of medication cession fails or is not possible if the risks of holding a particularly effective medication outweigh the potential benefits. Knowing and understanding the connection between HIV, NRTI HAART therapy, and ptosis is essential in understanding how to treat patients and anticipate changes.
DECLARATION OF INTEREST
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
The authors report no financial relationships and no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
!
2014 Informa Healthcare USA, Inc.
461
REFERENCES 1. Pfeffer G, Cote HCF, Montaner JS, et al. Ophthalmoplegia and ptosis: mitochondrial toxicity in patients receiving HIV therapy. Neurology 2009;73:71–72. 2. Stack RR, Thompson AM, Weatherhead RG. The levator aponeurosis exposed. Ophthalmic Plast Rec 2008; 24(5):426–428. 3. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000;356:1423–1340. 4. Taylor RW, Schaefer AM, Barron MJ, et al. The diagnosis of mitochondrial muscle disease. Neuromuscular Disord 2004; 14(4):237–245. 5. Blanco JR, Perez-Martinez L, Perez-Matute P, Oteo JA. Palpebral ptosis related to antiretroviral therapy: report of two new cases and review of the literature. HIV AIDS Rev 2010;9(4):109–111. 6. Moscato EE, Bloomer MM, Garcia-Kennedy R, Seiff SR. Human immunodeficiency virus-associated blepharoptosis. Ophthalmic Plast Rec 2011;27(5):360–363.
C ASE REPORT
Blepharoptosis and HAART Related Mitochondrial Myopathy Kristin Ow Chapman and Gary Lelli
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
Weill Cornell Medical Center, New York, USA
ABSTRACT Purpose: To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy. Methods: A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years. Results: Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions. Conclusions: This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders. Keywords: Blepharoptosis, HAART, HIV, mycopathy
Blepharoptosis in patients with human immunodeficiency virus (HIV) is often multifactorial and can be from the HIV virus, medication or common causes found in the general population. HAART therapy has changed the disease projection for patients with HIV, and though the therapy has increased life expectancy and quality of life, it is important to carefully consider the side effect profiles of these potent and effective drugs. Antiretroviral therapy-induced lipodystrophy can occur in 40% of patient’s within one year of use.1,2 A case series found that HIV related ptosis on HAART occurred after an average of 14 years of known HIV infection and 9 years on HAART.2 Histopathologic series of muscle fibers in HIV patients on HAART status post blepharoplasty demonstrated myopathy with levator fibers demonstrating atrophy, fibrosis and regeneration.3 In this case, we discuss a case of bilateral ptosis consistent with acquired myopathy secondary to
mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders.
CASE REPORT A 51-year-old man with hepatitis C and HIV treated with HAART for 19 years presented with blepharoptosis. His medication regimen had included a nucleoside analog reverse transcriptase inhibitor (NRTI), abacavir (Ziagen, GlaxoSmithKline, New York, NY, USA), a non-nucleoside reverse transcriptase inhibitor, efavirenz (Sustiva, BristolMyers Squibb Company, Princeton, NJ), and a reverse transcriptase inhibitor didanosine (Videx, BristolMyers Squibb Company, Princeton, NJ). On examination, his best corrected visual acuity was 20/20 in both eyes. His MRD 1 was 0.5 mm in both eyes with levator excursion of 13 mm in both
Received 15 January 2014; Revised 3 April 2014; Accepted 28 July 2014; Published online 11 September 2014 Correspondence: Dr. Gary Lelli Jr., Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA, Tel.: (646) 962-2020, Fax: (646) 962-0603, E-mail: [email protected]
459
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
460 K. O. Chapman and G. Lelli eyes. There was 2 mm of inferior scleral show in both eyes and the palpebral fissure of the right and left eye was 8 mm and 6 mm respectively. The patient demonstrated increased frontalis involvement and head tilting with chin-up positioning. Testing for Cogan eyelid twitch was negative. Humphrey visual field testing revealed superior visual field defects that resolved with taping in both eyes. External levator aponeurosis reinsertion was performed on the bilateral upper eyelids. The patient tolerated the procedure well. Post operative results demonstrated and increase in MRD1 and overall aesthetic and functional improvement. Pathology specimens of levator muscle stained with hematoxylin and eosin stain (H&E stain) demonstrated normal striated muscle in both eyelid samples (Figure 1). Analysis of DNA isolated from levator muscle demonstrated multiple deletions in mitochondrial DNA by Southern blot testing. Southern blot remains the ‘‘gold standard’’ of detection of mitochondrial DNA deletions.4 DNA was digested with Pvull restriction enzymes, electrophoresed on agarose gels and hybridized to a probe detecting mitochondrial DNA. The pattern of multiple deletions was reported to be consistent to those in patients with ptosis and ophthalmoplegia (Figure 2).
Our patient’s history of hepatitis C could have increase the rate of mitochondrial toxicity.2 A case series of two patients with HIV on HAART with ptosis and mitochondrial deletions suggests that the patients may have had underlying mitochondrial disorders that were ‘‘unmasked’’ with HAART therapy.5 These patients also exhibited ophthalmoplegia. Our patient’s extraocular movements were full and orthostatic, and there was very low suspicion for chronic progressive ophthalmoplegia or Kearns-Sayre syndrome in this case. A review of the literature helped to further guide the medical management of this patient. In some case series, ptosis has improved when NRTI’s are held and it has been proposed that antivirals play an important role in delaying HIV related myopathy by lowering viral load.2,6 Efforts have been made to limit the side effects of the NRTI’s by giving coenzymes, antioxidants and vitamin supplementation.5 In light of the known association between mitochondrial disorders and conduction abnormalities, an electrocardiogram may be warranted in patients who exhibit signs of
Comment Multiple factors determine if a patient on HAART will be at risk to develop ptosis. Different NRTI’s have a greater level of mitochondrial blockage with didanosine known to cause higher levels of toxicity compared to others including abacavir.5 Our patient used both didanosine and abacavir. The incidence of mitochondrial toxicity can also be increased by underlying organ dysfunction, disease process and synergistic drug administration.2,6
FIGURE 1. H&E staining demonstrated normal striated muscle in levator muscle.
FIGURE 2. Southern blot results from the patient’s levator muscle with the patient’s (P) smeared bands under the normal bands compared with controls (C1 and C2), which demonstrate his multiple deletions of mitochondrial DNA. Orbit
Ptosis and HAART Related Mitochondrial Myopathy ophthalmoplegia or other neurologic dysfunctions in order to evaluate for conduction abnormalities. Surgical treatment of ptosis in HIV patients on HAART should help to correct symptoms if a trial of medication cession fails or is not possible if the risks of holding a particularly effective medication outweigh the potential benefits. Knowing and understanding the connection between HIV, NRTI HAART therapy, and ptosis is essential in understanding how to treat patients and anticipate changes.
DECLARATION OF INTEREST
Orbit Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15 For personal use only.
The authors report no financial relationships and no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
!
2014 Informa Healthcare USA, Inc.
461
REFERENCES 1. Pfeffer G, Cote HCF, Montaner JS, et al. Ophthalmoplegia and ptosis: mitochondrial toxicity in patients receiving HIV therapy. Neurology 2009;73:71–72. 2. Stack RR, Thompson AM, Weatherhead RG. The levator aponeurosis exposed. Ophthalmic Plast Rec 2008; 24(5):426–428. 3. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000;356:1423–1340. 4. Taylor RW, Schaefer AM, Barron MJ, et al. The diagnosis of mitochondrial muscle disease. Neuromuscular Disord 2004; 14(4):237–245. 5. Blanco JR, Perez-Martinez L, Perez-Matute P, Oteo JA. Palpebral ptosis related to antiretroviral therapy: report of two new cases and review of the literature. HIV AIDS Rev 2010;9(4):109–111. 6. Moscato EE, Bloomer MM, Garcia-Kennedy R, Seiff SR. Human immunodeficiency virus-associated blepharoptosis. Ophthalmic Plast Rec 2011;27(5):360–363.
