Hearing loss and auditory function in sickle cell disease

Journal of Communication Disorders 38 (2005) 321–329

Hearing loss and auditory function in sickle cell disease G. Pamela Burch-Sims *, Valeria R. Matlock Department of Speech Pathology and Audiology, College of Health Sciences, Tennessee State University, 330 Tenth Avenue North, Nashville, TN 37203, USA Received 1 December 2004; received in revised form 11 February 2005; accepted 11 February 2005

Abstract Sickle cell disease was first reported in 1910 by J. Herrick, and since then, various associated conditions and complications have been described. Sickle cell disease is a hereditary disorder characterized by abnormality of the hemoglobin in the red blood cell. During periods of decreased oxygen tension in the red blood cell’s environment, the abnormal hemoglobin within the red blood cell polymerizes and causes it to assume its sickled shaped. This morphological change and its associated physiological changes drastically reduce the ability of red blood cells to navigate and deliver oxygen throughout the body. Sickle cell disease is a significant health problem affecting 1 in 400 African-Americans in the United States. One in 10 African-Americans in the United States has sickle cell trait. A variety of hemoglobinapathies are classified as sickle cell disease. Variants that simultaneously occur with hemoglobin S in high frequency are hemoglobins C and b Thalassemia, and less frequently hemoglobin E. Sickle cell disease is characterized by chronic hemolytic anemia, end-organ damage, a heightened susceptibility to infections, and intermittent episodes of vascular occlusion causing both acute and chronic pain. Neurological symptoms are frequent in patients diagnosed with sickle cell disease. Considering the vaso-occlusive nature of sickle cell disease, the potential for auditory damage is not unexpected. However, the incidence of subjective hearing impairment among sickle cell anemia subjects is very low; therefore, the interest in hearing loss associated with the disease is not in its symptomatology, but in its pathogenesis. The relationship between sickle cell anemia and hearing loss is documented, but little is known about the relationship. Numerous investigations have assessed peripheral auditory sensitivity with a wide disparity of results.

* Corresponding author. Tel.: +1 625 963 7059; fax: +1 625 963 7119. E-mail address: [email protected] (G.P. Burch-Sims). 0021-9924/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jcomdis.2005.02.007

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G.P. Burch-Sims, V.R. Matlock / Journal of Communication Disorders 38 (2005) 321–329

In the article, we will discuss: The genetic characteristics and the pathophysiology of sickle cell disease; The prevalence and predominate site of hearing loss and/or auditory dysfunction during sickle cell crisis and with the disease under control (non-crisis); A model for appropriate audiological assessment and treatment of sickle cell disease patients, including published results of investigations utilizing this model. In view of the diversity of results and speculative etiology presented here and in the literature, the relationship between sickle cell anemia, auditory sensitivity, and auditory function warrants additional investigation. Learning outcomes: As a result of this activity, the participant will read descriptions of the genetic and pathophysiological characteristics of sickle cell disease. The participant will examine evidence of the prevalence of hearing loss and auditory dysfunction in the sickle cell population, as well as the overall hearing health risk for sickle cell patients in comparison to the risk for the normal hemoglobin population. The participant will examine a model for appropriate audiological assessment of treatment of patients with sickle cell disease. # 2005 Elsevier Inc. All rights reserved.

1. The genetic characteristics and the pathophysiology of sickle cell disease Sickle cell disease is a hereditary disorder characterized by an abnormality of hemoglobin (a protein) in the red blood cell (erythrocyte). Since first reported by Herrick (1910), a variety of conditions and complications associated with sickle cell have been described. The molecular basis of the process of vaso-occlusion that underlies the painful crisis and chronic organ damage associated with sickle cell disease has been well documented. Considering the vaso-occlusive nature of sickle cell disease, the potential for auditory damage is not unexpected. However, the incidence of subjective hearing impairment among sickle cell patients is very low; therefore, our interest in hearing loss and auditory function associate with the disease is not in its symptomatology, but in its pathogenesis (Burch-Sims & Matlock, 2004). Normal erythrocytes are soft, disc-shaped cells that flow easily through the smallest blood vessels and live about 120 days. In stark contrast, the sickle-shaped cells are hard, often get stuck in small blood vessels, and live for only 20 or fewer days. The sickle cells interrupt blood flow by blocking small blood vessels. This morphological change, and its associated physiological change, drastically reduces the ability of red blood cell to navigate and deliver oxygen throughout the body. Sickle cells are stickier—even when they are not sickle-shaped. During periods of decreased oxygen in the red blood cells environment, the abnormal hemoglobin within the cell polymerizes and causes the red blood cell shape to become sickled. This vaso-occlusive process results in blockage of blood flow to tissue. Significant tissue damage is the physiologic event underlying painful sickle cell crisis. Sickle cell disease is a worldwide health problem, as it is found in Africa, the Mediterranean, the Middle East, Southeast Asia and parts of India (Mgbor & Emodi, 2004). A variety of hemoglobinapathies are classified as sickle cell disease (CORN, 1999). Hemoglobin type varies with region. Hemoglobin SS is found in equatorial African, Hemoglobin SC on the western coast of Africa, Hemoglobin D in India, Beta Thalassemia in


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the Mediterranean, and Hemoglobin E is associated with Southeast Asia. Sickle cell disease is a significant health problem in the United States, affecting 1 in 400 African-Americans in the United States (Pass et al., 2000; U.S. DHHS, 2002). One in 10 African-Americans in the United States has a sickle cell trait, making it is the most common genetic disease in this country. In many states, all newborn babies are tested at birth for sickle cell disease so that prevention can be started immediately. A simple blood test is conducted on the infant, as well. Each variant of sickle cell disease is associated with medical complications such as splenic sequestion, hemolytic anemia, acute and chronic pain episodes, stroke or brain damage, kidney failure, pneumonia or chest syndrome (Clinical Practice Guideline, 1993). Sickle cells become trapped and destroyed in the spleen. Treatment may include spleen removal, or splenectomy. Anemia or a low red blood cell count is a lifelong condition with sickle cell disease, usually beginning within the first year of life. The average sickle cell life, reduced from a normal of 120 days down to 20 or fewer days, produces anemia, a high reticulocyte count, and a bone marrow factory that is producing three to four times more red cells than normal. Another problem related to the anemia is jaundice (elevated indirect bilirubin), which later in childhood and early adult life can result in gallstones (U.S. DHHS, 2002). Prolonged and constant pain due to bone tissue damage results in bone infarction, sickle arthritis, and aseptic necrosis of the long bones of the arm and legs, often requiring hip and/ or joint replacement. Stroke is a devastating and potentially fatal complication to sickle cell disease. The median age at which patients with sickle cell disease suffer their first stroke is 5-year-old (Cohen, Martin, & Silber, 1992; Ohene-Frempong et al., 1998). Pneumonias or infections in the lung and acute chest syndrome, caused by sickling red cells blocking blood vessels in the lung, are the most common complications. Infections are treated with antibiotics, and acute chest syndromes are treated with blood transfusions. Both treatments are used, as it is difficult to differentiate the two. Kidney damage starts very early and progresses throughout life, causing complications in many individuals with sickle syndromes. The kidneys may not filter normally, passing protein and/or excessive amounts of water. Sickle dactylitis (hand–foot syndrome) is one of the first complications in sickle cell disease, with the highest incidence between ages 6 months and 2 years (Sickle Cell Disease Guideline Panel, 1993). The sickle red cells cause painful swelling of the hands and feet. Sickle cells tend to cluster and stick together in the blood vessels, making it difficult or impossible for the blood to circulate. This sickling and sludging drastically reduces circulation and causes oxygen shortages—especially in hands, feet and bones. Sickle cells can cause damage to the blood vessels in the eye, especially in sickle cell disease. Sickle cell crisis can last for hours or weeks and may occur several times per year. The cardinal symptoms of sickle cell crisis are severe pain, fever, edema and inflammation (Sickle Cell Disease Guideline Panel, 1993).

2. The prevalence and predominate site of hearing loss and/or auditory dysfunction associated with sickle cell disease Considering the vaso-occlusive nature of sickle cell disease, the potential for auditory damage is not unexpected. Numerous investigations have assessed peripheral auditory

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Table 1 Review of the literature: summary of group studies Investigator(s)

Year

N

Procedurea

Hearing loss

Todd, Serjeant and Larson Sharp and Orchik Friedman et al. Forman-Franco et al. Odetoyinbo and Adekile Elwany and Kamel Wiliams et al. Crawford et al. Gould et al. Ajulo, Osiname and Myatt Murugan and Hammad MacDonald et al. Chiodo et al. Gentry, Davis and Dancer MacDonald, Bauer and McMahon Piltcher et al., Brazil Downs, Stuart and Holbert Koussi et al. Onakoya et al. Mgbor and Emodi Burch-Sims and Matlock

1973 1978 1980 1982 1987 1988 1988 1991 1991 1993 1996 1999 1997 1997 1999 2000 2000 2001 2002 2004 2004

83 09 43 54 56 10 22 75 34 52 100 84 75 100 84 28 20 24 167 50 113

PT HE HE HE HE HE, ABR CAP HE HE, ABR PT HE, ABR PT PT PT screening PT PT, Tym DPOAE HE, ABR PT PT HE, ABR

22% 1/9 12% 11% 21% Abnormal 0% 41% 13/34, 6/25 13.5% 19% 21.4% 57% 12% failed 22 abnormal 21.4% Amplitudes significantly larger 4.6% 66% 13.4% 21%

a Pure tone thresholds (PT); hearing evaluation (HE); auditory brainstem response (ABR); central auditory processing (CAP); distortion product otoacoustic emissions (DPOAE).

sensitivity, with a wide disparity of results. Table 1 summarizes the group studies reported over the past 30 years. The prevalence of hearing impairment reported range from 0 to 66%. Different patterns and degrees of hearing loss are reported, ranging from profound bilateral losses with partial recovery over time, to mild to moderate unilateral losses— predominately in the high frequencies (Casano, Morrison, & Melvin, 1990; Crawford et al., 1991; Diggs, 1956; Elwany & Kamel, 1988; Friedman, Herer, Luban, & Williams, 1980; Gould et al., 1991; MacDonald, Bauer, Cox, & McMahon, 1999; Morganstein & Manace, 1969; Odetoyinbo & Adekile, 1987; Onakoya, Nwaorgu, & Shokunbi, 2002; Orchick & Dunn, 1977; Todd, Serjeant, & Larson, 1973; Urban, 1973; Wilimas, McHaney, Presbury, Dahl, & Wang, 1988). Limited electrophysiological assessment of sickle cell patients has appeared in the literature (Burch-Sims & Matlock, 2004; Downs, Stuart, & Holbert, 2000; Elway & Kamel, 1988; Gould et al., 1991; Koussi et al., 2001). Various investigators speculate that auditory impairment associated with sickle cell disease is a consequence of sickling and slugging of the blood in the cochlea (Diggs, 1956; Morganstein & Manace, 1969; Odetoyinbo & Adekile, 1987; Todd et al., 1973). Ischemia of the stria vascularis, with secondary organ of Corti hypoxia as a direct result of sickle cell crisis, poses significant risk to the auditory system. Increased blood viscosity by crystallization of red blood cells, with subsequent slugging, development of stasis, ischemia or hypoxia appears to be the outstanding pathophysiological phenomenon during crisis (Diggs, 1956). The enormously extensive and elaborated vascular system of the inner ear reflects the abundant blood supply to the cochlea. Given its size, this tiny organ receives a


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disproportionate percentage of the body’s blood (Miller & Dengerink, 1988). The extensive cochlear vascular anatomy, the high metabolic activity required to maintain both ionic and electrical characteristics of endolymph, and the highly dependent nature of evoked responses from the inner ear on brief episodes of anoxia suggest that a secure and extensive cochlea blood flow is critical (Brown, Nuttall, Masta, & Lawrence, 1983; Russell & Cowley, 1983). 2.1. An investigation We investigated the relationship between sickle cell disease and hearing in 183 sickle cell subjects. Each received routine audiological and electrophysiological assessments. There were 86 males and 97 female African-American subjects with hemoglobin electrophoresis diagnosis of SS, SC, Sb-thalassemia, or EF enrolled at the Comprehensive Sickle Cell Center (CSCC) of Meharry Medical College in Nashville, Tennessee. Subjects recruited from the Comprehensive Sickle Cell Center were tested at the center or in the Audiology Testing and Research Clinic at Tennessee State University. Each subject received comprehensive audiological evaluations and auditory electrophysiological assessments in a non-crisis or steady state (per Institutional Review Board approved protocol). The crisis versus non-crisis data has been previously reported (Burch-Sims & Matlock, 2004). Strict confidentiality was maintained for all subjects. The patient consent from clearly described the test procedures and ensured subject rights to consent or refuse participation without affecting their standard of treatment or medical care. Hemoglobin type by hearing status (Table 2) showed that 80% of the hearing-impaired sickle cell subjects had hemoglobin SS, as did 59% of the normal hearing sickle cell subjects. The remaining hearing-impaired sickle cell subjects were hemoglobin SC (7%), Sb-thalassemia (7%) and EF (6%). Of the remaining normal hearing sickle cell subjects, 25% were hemoglobin SC, 12% Sb-thalassemia, and 5% AS. Since most normal and hearing impaired sickle cell subjects had hemoglobin SS, the most severe form of the disease, potential severity of disease did not predict hearing status. High frequency sensorineural impairment was dominant (78%). Characteristic ABR changes in the wave I (AP) in the sickle cell population, such as reduced amplitude and/or decreased latency, may reflect the modulation of the cochlear blood flow. The delayed or unidentifiable Wave I in the crisis condition suggests transient auditory dysfunction at the cochlea or proximal VIII auditory nerve (Burch-Sims & Matlock, 2004). Table 2 Hemoglobin type by hearing status Hemoglobin type

Normal hearing (%)

Hearing impaired (%)

SS Sb SC AS EF

59 12 24 5 0

80 7 7 na 6

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Distortion product otoacoustic emissions (DPOAEs) were obtained from 255 ears in sickle cell subjects. Responses were signal averaged and analyzed according to standard conventions. The criterion for the presence of a DPOAE was an amplitude of 3 dB or more above the noise floor, with an absolute amplitude of at least 4 dB SPL. The two tones (F1 and F2) were presented simultaneously at an intensity level of 70 dB SPL and a frequency ratio of 1:2. Two complete frequency sweeps (F2: 700–8000) were made at 8 points per octave. The pure tone thresholds determined at five frequencies (500, 1000, 2000, 4000 and 8000 Hz) were compared to DPOAEs obtained at the same ear. All subjects also had standard immittance testing to eliminate ears with evidence of middle ear pathology. 2.2. Results The results indicated a significant relationship between high frequency sensorineural hearing loss and DPOAEs. DPOAEs were consistently present in frequency regions exhibiting normal pure tone hearing sensitivity. DPOAE amplitudes were reduced as pure tone thresholds increased, and they were absent at frequencies where thresholds were greater than 50 dB for 251 of the 255 ears tested. For four ears, the DPOAEs and pure tone audiograms were not correlated. Further investigation revealed these DPOAEs were from two patients scheduled for chelation therapy due to iron overload. Reevaluation prior to chelation therapy showed normal pure tone audiogram with significantly reduced amplitudes or absent DPOAES in the presence of normal middle ear function Since otoacoustic emissions provide an objective measure of hair-cell function independent of retrocochlear activity, the clinical application of the procedure is an ideal method to confirm the cochlear origin of the hearing loss associated with sickle cell disease There was a significant difference in the amplitude of the DPOAEs when comparing pre- and postchelation measures. Koussi et al. (2001), investigators in the Thalassemia Unit at Aristotle University of Thessaloniki, Greece, found a low incidence of sensorineural hearing loss in Greek sickle cell disease patients—probably due to different hematological and clinical profile of Sb-thalassemia. We also found a lower incidence of sensorineural hearing loss in Sb-thalassemia (Table 2). The results suggest that, although sickle cell subjects are a heterogeneous population, they are at significant risk for auditory damage, and the auditory deficit associated with sickle cell appears to be cochlear in nature.

3. A model for appropriate audiological assessment of treatment of patients with sickle cell disease Each subject received a comprehensive audiological evaluation, electrophysiological assessment and otologic examination. The audiological evaluation consisted of pure tone thresholds from 250 to 8000 Hz, including half octaves above 2000 Hz. Investigators also conducted speech reception testing, word recognition testing, and immittance audiometery, including tympanometry and acoustic reflex testing. The auditory electrophysiologic assessment included auditory brainstem response (ABR) and Otoacoustic Emissions (transient and distortion product emissions). Each patient received a comprehensive


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otologic/medical examination to rule out hearing loss due to etiologies other than sickle cell disease. The overall ramifications of sickle cell disease on hearing and auditory function are currently being established. As the mortality and morbidity associated with sickle cell anemia decrease, management of associated health risks such as hearing impairment will greatly benefit the comprehensive treatment and care of the patient. In view of the diversity of results and speculative etiology presented here and in the literature, the relationship among sickle cell anemia, auditory sensitivity and function warrants much additional investigation.

Acknowledgements NIH Grant P 60-HL38737 provided Grant Support, Ernest A. Turner, M.D. Principal Investigator. Meharry Medical College, Comprehensive Sickle Cell Center, 1989–1999. Dr. Ernest Turner and Dr. James W. Hall, III served as consultants to this research project. The following audiologist assisted with data collection: Martia Good, M.S., CCC-A; Kiara Ebinger, M.S., CCC-A; Kimberly Harville, M.S., CCC-A; and Valeria Matlock, Ed.D., CCC-A.

Appendix A. Continuing education 1. What is sickle cell disease? a. It is a birth defect occurring randomly in the population b. It is a hereditary disorder characterized by an abnormality of the hemoglobin in the red blood cell c. It is a communicable disease associated with the transmission of malaria by mosquitoes d. None of the above 2. Sickle cell disease is significant health problem affection, one in African Americans in the U.S. a. 200 b. 1,000 c. 400 d. 10,000 3. Sickle cell disease is associated with medical complications such as a. Increase risk of infection b. Anemia c. Chronic pain d. All of the above 4. The potential for auditory damage in sickle cell disease occurs due to a. Vaso-occlusion resulting in blockage of blood flow b. Acute and chronic pain episodes c. Anemia or low red blood cell count

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5. Researchers speculate that the predominate site of auditory damage associated with sickle cell disease is a. the cochlea b. VIII cranial nerve c. the middle ear d. superior olivary complex

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