Mental nerve paresthesia secondary to sickle-cell crisis Lyle E. Kit-son, D.D.S., CLEVELAND
and A. J. Tomaro,
METROPOLITAN
GENERAL
D.D.S.,
* Cleveland,
Ohio
HOSPITAL
Two individual cases in which mental nerve paresthesia developed concurrently with sickle-cell crisis are described. A brief review of the hemoglobinopathies follows, with genetic considerations and clinical manifestations discussed.
I
n the United States, approximately one out of ten Negros carries the genetic trait of sickle-cell anemia. Of these, more than one out of forty are sickle-cell homozygous. 1 Many more have mixed hemoglobinopathies which manifest themselves in varying degrees of severity. It was not until the 1850’s that Hoppe-Seyler first described the hemoglobin molecule, and not until nearly 100 years after that, were variants of the hemoglobin molecule shown to be related to disease.* Not until 1949 did Pauling and associates3 first demonstrate that the electrophoretic mobility of sickle-cell hemoglobin differed from that of normal adult hemoglobin. In 1957 Ingram4 demonstrated the chemical difference between normal adult hemoglobin and sickle-cell hemoglobin and showed the difference to be but a single amino acid substitution in a protein molecule of 574 amino acids. The genetic make-up of the hemoglobinopathies are now well documented, and the clinical consequences are quite well known. We will describe an interesting complication of the sickle-cell crisis which occurred in two cases seen at our clinic and review the disease. CASE 1
An l&year-old black male patient was admitted to Cleveland Metropolitan General Hospital in May, 1977. This was his seventh admission to the hospital since June, 1969, and, as on all previous admissions, the primary diagnosis at this time was sickle-cell disease with pain crisis. The patient had experienced his first pain crisis at the age of 3 years, and a diagnosis of sickle-cell disease was made at that time. Subsequently, hemoglobin electrophoresis showed the patient to be suffering from sickle SC disease. Upon admission, the physical examination showed a cooperative and alert, thin, 1%year-old black male. Lungs were clear to percussion and auscultation, and cardiovascular *Director and Professor, Division of Oral and Maxillofacial 003C-4220/79/120509+04$00.40/0
0
Surgery.
1979 The C. V. Mosby Co.
examination findings were within normal limits with a normal SllS2 and no murmur or gallop. A right posterior cervical node, 0.5 cm. in diameter, and a 1 cm. left axillary node were palpable. The liver measured 10 cm. by percussion, and the spleen was palpable in the left lateral position. Genitourinary examination showed a stool that was trace heme positive. Extremities were without joint swelling, effusions, or heat. However, there was pain to palpation over the right tibia and thigh. Neurologic examination findings were normal, and cranial nerves showed no deficit. Laboratory examinations revealed a hematocrit of 38.6 percent, hemoglobin of 12.6, and a white count of 10,800. SMA, was within normal limits and SMA,, showed elevated liver function which was attributed to red cell sludging in the liver. Urinalysis was negative. An electrocardiogram revealed sinus arrhythmia, an x-ray film of the chest showed a small calcified granuloma in the lingula but was otherwise normal. Two days following admission, the oral surgery service was consulted when the patient developed increasing pain behind his left ear and over the left zygoma, ramus, and subcondylar region. He was unable to open his mouth wide or to bring his teeth tightly together because of the discomfort. Concurrently, an area of paresthesia developed throughout the distribution of the left mental nerve. Oral examination revealed soft tissues to be within normal limits, as were all major salivary glands. Occlusion was acceptable, with slight anterior open-bite and tongue-thrust. Oral hygiene was fair, and several small carious lesions were noted. A panogram revealed a questionable radiolucency in the superior portion of the left ramus, extending into the subcondylar region. No swelling or masses were noted. Pain in the mandible decreased over the next few days, and as the sickle crisis had resolved the patient was discharged from the hospital. He was readmitted the following month for biopsy, under general anesthesia, of the radiolucent lesion of the left mandible. The paresthesia of the lower left lip persisted at this time. Biopsy of the lesion revealed no tumor, and the patient was discharged. Follow-up of the case revealed total resolution of the men509
510
Kit-son and Tomaro
tal nerve neuropathy approximately 9 months after the initial problem. The patient has not experienced any similar symptoms since that time, although he has had subsequentsickle crises. CASE 2
In December, 1977, a 29-year-old black man was admitted to our hospital with sickle-thalassemiadiseaseand pain crisis. This was his eighteenthadmissionto this hospital. The patient was first noted to have sickle-B-thalassemiadiseaseat the age of 5. and subsequenthemoglobin electrophoresisrevealed 94 percent hemoglobin S and 6 percent hemoglobin F. Physical examination was notable for scleral icterus, systolic ejection murmur of grade II/VI, a palpable liver 5 cm. below the right costal margin, and a palpable spleen tip. Neurologic examination revealed a sensorydeficit in the distribution of the right mental nerve. Laboratory examination showed a hematocrit of 37.8 percent, hemoglobin of 12.1, and a white blood cell count of 19.000.SMAti was normal and SMA,? revealedelevatedliver function. Urinalysis was normal, and an x-ray film of the chest showed slight cardiomegaly with clear lung fields. Oral examination by our service revealed normal soft tissues and salivary glands. There was a full range of mandibular motion, and occlusion was acceptable. Oral hygiene was good, with no caries evident. The patient stated that he had
experiencedpain of the right mandible and subsequentparesthesia of the right lower lip and chin with the onset of the present generalized pain crisis. A panogram revealed no radiographic abnormalities. The patient was followed closely, and over the next few days he reported resolution of the mandibular pain. Follow-up revealed total resolution of the paresthesia within 1 month. DISCUSSION
The hemoglobinopathies represent a hereditary group of diseases in which there is a qualitative abnormality in the globin, or protein, portion of the hemoglobin molecule. Thalassemia, while not demonstrating a qualitatively abnormal hemoglobin, is also regarded as a hemoglobinopathy. In this hereditary disease, there exists a subnormal rate of synthesis of one of the substructures of the protein portion of the hemoglobin molecule.5 The clinical significance of the hemoglobinopathies is highly variable; many hemoglobinopathies manifest few, if any, clinical effects, while others are responsible for severe clinical sequelae. The majority of the normal adult’s hemoglobin, approximately 97 percent, is termed hemoglobin A (HbA). The globin portion of HbA is comprised of two pairs of polypeptide chains; two (Ychains, each formed of 141 amino acids, and two /3 chains, each containing 146 amino acids (HbA = (Y&J. The remaining 3 percent of the normal adult hemoglobin is mostly hemoglobin AZ (HbA2). In HbAz the two LYchains are identical with that of HbA; however, the /3 chains are replaced by different polypeptide chains which are desig-
Oral Surg. December, I979
nated 6 chains (HbA2 = (Ye6,). At birth there is very little, if any, adult hemoglobin present. Instead, the predominant hemoglobin is fetal type, HbF, and is comprised of two 01chains, identical to those of HbA, and two y chains, which have the identical number of amino acids as do the p chains of HbA but differ in the amino acid sequence (HbF = 6, y2). Over the first 6 months of life, the concentration of HbF slowly decreases and is replaced by the adult hemoglobins. It is at this stage that the adverse effects from abnormal adult hemoglobin begin to manifest themselves. With the exception of Hb (Harlem), a single amino acid substitution in one of the polypeptide chains is responsible for the hemoglobinopathy. This substitution is transmitted as a hereditary trait. When a single chain is affected, the heterozygous state, the condition is termed a trait and is usually harmless under normal conditions. When both chains of a pair are affected in an identical manner, the homozygous state, the condition is termed a disease and may have severe and deleterious effects. Complicating the situation are various combinations of abnormal polypeptide chains which, when paired, form mixed hemoglobinopathies with varying degrees of clinical significance. The amino acid substitution for sickle hemoglobin (HbS) occurs in the sixth position of the /3 chain, where valine is found in place of the normal glutamic acid. With decrease in oxygen tension, cy and the abnormal p chains react in such a way that the red blood cells assume the rigid, sickle shapes. If concentrations of HbS are not sufficiently high, as in the heterozygous state, sickling will not occur. In the first case report, the patient suffered from sickle SC disease in which the p6 va’ine chain is inherited from one parent and the @” IYsinechain (hemoglobin C disease) is inherited from the second parent. Sickle SC disease usually manifests less severe clinical symptoms than does homozygous sickle-cell disease, and hence the life expectancy of these patients is much greater. However, they do suffer from a mild to moderate hemolytic anemia and are also prone to vascular occlusive episodes which are the underlying cause of most of the damaging effects of sickle-cell disease. In sickle-B-thalassemia, the disease present in the second case report, a sickle gene is inherited from one parent (p6 “aiinr) and the thalassemia gene from the other parent (fl-thalassemia). Sickle-B-thalassemia is extremely variable in its clinical severity. If no normal /3 chains are produced by the thalassemia gene, the resulting disease is very similar to homozygous sicklecell anemia. If some normal p chains are produced, the severity is not as great, since the p” ra’i”c’ chain concentration is somewhat diluted. Interestingly, with decreased p chain production, there is sometimes “com-
Volume 48 Number 6
Mental nerve paresthesia secondary to sickle-cell crisis
pensatory ” synthesis of y chains which can combine with free a chains to form stable HbF.G The majority of the clinical problems associated with sickle-cell disease are related to the vascular occlusive processes that occur. As sickling of the red blood cells develops, the cells are unable to pass freely through the microcirculation. As the blood flow stagnates, waste products are poorly cleared, resulting in an acidosis and increased sickling. Oxygen and waste product clearance suffers in an ever-increasing area. Upon reoxygenation, sickled cells are able to regain their original shape; however, repeated cycles take their toll. The normal life expectancy of a sickle cell is 15 to 20 days, as compared to 120 days for a normal cell. Painful crises appear at irregular intervals and normally manifest themselves in the abdomen, chest, and joints. Patients may go several months without problems and then incur several pain crises in quick succession. Precipitating factors include infection, dehydration, overexercise, cold in some patients, and heat in others.7 Often no precipitating factor is evident. Sickle patients appear to be more prone to infection, which is probably directly attributable to the spleen’s impaired ability to clear circulating bacteria. There also appears to be a deficiency of heat-labile opsonin, preventing effective coating of bacteria.‘j Bacterial pneumonia, osteomyelitis, meningitis, and urinary tract infections are among the more common infectious problems plaguing the sickle patient, and bacterial infection is the single most common cause of death in sickle-cell anemia. * Chronic organ damage frequently involves the lungs, kidneys, skeleton, skin, liver, and spleen.6, g The etiology is again the recurrent vaso-occlusive episodes. Lung damage can result in such problems as intrapulmonary A-V shunting and decreased pulmonary function, while kidney involvement can lead to decreasing renal function and, rarely, total renal failure. Bone involvement, such as avascular necrosis of the femoral heads93lo, l1 and susceptibility to osteomyelitis ,s, 9 has frequently been described, and compromised circulation to the skin often results in numerous and painful ulcerations. Hepatobiliary complications involve deteriorations of liver functions, increased tendency toward gallstone formation, and icterus. The latter is secondary to the hemolytic nature of the anemia. The spleen is initially enlarged in the earlier years of life, but progressively undergoes infarction and fibrosis and decreases in size to a small mass of fibrous tissue. Central nervous system involvement may lead to seizure, stroke, and/or coma.12 Quite frequently, these episodes reverse themselves, but this is not always the case. As patients age, congestive heart failure frequently develops and systolic ejection murmurs be-
511
come evident. The latter is primarily due to the anemia and hyperdynamic circulation. Radiographic changes of the mandible and maxilla have been widely reported in the literature. The most common observations involve loss of the normal trabecular pattern, a generalized increase in the radiolucency of the bones, and the development of a coarse trabecular pattern. 13, lg This is attributed to a compensatory hyperplasia of the bone marrow secondary to the chronic state of anemia. Other radiographic observations have included thinning of the inferior borders of the mandible’“* 20, *l and areas of increased radiopacity secondary to healing infarcts.‘” However, not all reports have supported or included such findings.15-17 Thinning of the lamina dura, development of small paranasal sinuses, and thickening of portions of the calvarium have also been reported. 13*I65l8 Infarction of nerves is not an unusual occurrence in sickle-cell crisis, and we are suggesting that the etiologic factor in the mental nerve paresthesia is secondary to a vaso-occlusive episode involving the inferior alveolar nerve at or near the mental foramen. This propensity for involvement of the mental nerve may be due to the unusual bending course the nerve travels just prior to exiting from the mandible. Konotey-Ahulu” reported five similar cases over a 2-year period, All of these patients experienced mandibular bone pain prior to the onset of the neuropathy, and recovery time ranged up to 18 months. In the two cases we have presented here, the neuropathies were also preceded by mandibular pain and recovery time was somewhat shorter. In cases such as these, of course, it is essential to rule out the possibility of other ongoing processes. Such factors as infection, trauma, benign and malignant tumors or cysts, and certain systemic diseases involving nerves must all be considered. Thorough examination, including radiographic studies, should be employed to assure that two separate entities are not progressing simultaneously. However, the sequence of generalized sickle-cell crisis with mandibular pain, followed closely by sensation loss of the mental nerve on the same side as the mandibular pain, point strongly to sickle-cell disease as the underlying cause. REFERENCES 1. Robbins, S.: Pathology, ed. 3, Philadelphia, 1968, W. B. Saunders Company, pp. 626627. 2. Necheles, T., Allen, D., and Finkel, H.: Clinical Disorders of Hemoglobin Structure and Synthesis, New York, 1969, Meredith Corp., pp. I-3. 3. Pauling, L., Itano, H. A., Singer, S. J., and Wells, I. C.: Sickle Cell Anemia, a Molecular Disease, Science 110: 543-548, 1949. 4. Ingram, V. M.: Gene Mutations in Human Hemoglobin: The Chemical Difference Between Normal and Sickle Hemoglobin, Nature (London) 180: 326, 1957.
512
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Oral Surg. December, 1979
5. Hutchison, H. E.: An Introduction to the Haemoglobinopathies. London, 1967, Edward Arnold & Co., Ltd., p. 27. 6. Cooper, R. A., and Bunn, H. F.: Harrison’s Principles of Internal Medicine, ed. 8, New York, 1977, McGraw-Hill Book Company, Inc., pp. 1688- 1697. 7. McFarlane. J.: Sickle Cell Disorders, Am. J. Nurs. 77: 194% 1954, 1977. 8. Barrett-Connor, E.: Bacterial Infection and Sickle Cell Anemia, Medicine 50: 97- 111, 1971. 9. Tuttle, A., and Koch, B.: Clinical and Hematological Manifestations of Hemoglobin CS Disease in Children, J. Pediatr. 56: 331-342, 1960. 10. Keeling, M. M., Lockwood, W. B., and Harris, E. A.: Avascular Necrosis and Erythrocytosis in Sickle-Cell Trait, N. Engl. J. Med. 290: 442-444, 1974. Il. Herndon, J. H., and Aufranc, 0. E.: Avascular Necrosis of the Femoral Head in the Adult, Clin. Orthop. 86: 49-61, 1972. 12. Portnoy, B. A., and Herion, J. C.: Neurological Manifestations in Sickle Cell Disease, Ann. Int. Med. 76: 643-652, 1972. 13. Halstead, C. L.: Oral Manifestations of Hemoglobinopathies, ORAL SURG. 30: 615-623, 1970. 14. Prowler, J. R., and Smith, E. W.: Dental Bone Changes Occurring in Sickle-Cell Diseases and Abnormal Hemoglobin Traits, Radiology, 65: 762-769, 1955. 15. Mourshed, F., and Tuckson, C. R.: A Study of the Radiographic Features of the Jaws in Sickle-Cell Anemia, ORAL SURG. 37: 812-819, 1974.
INFORMATION
16. Poyton, H. G., and Davey, K. W.: Thalassemia, Changes Visible in Radiographs Used in Dentistry, ORAL SURG. 25: 564. 1968. 17. Robinson, I. B., and Sarnat, B. G.: Roentgen Studies of the Maxillae and Mandible in Sickle-Cell Anemia, Radiology 58: 517, 1952. 18. Caffey, J.: Cooley’s Anemia: A Review of the Roentgen@ graphic Findings in the Skeleton, Am. J. Roentgenol. 78: 381, 1957. 19. Morris, A. L.. and Stahl, S. S.: Intraoral Radiographic Changes in Sickle-Cell Anemia, ORAL SURG. 7: 787, 1954. 20. Reynolds, J.: An Evaluation of Some Roentgenographic Signs in Sickle-Cell Anemia and Its Variants, South Med. J. 55: 11231128, 1962. 21. Reynolds. J.: The Roentgenological Features of Sickle-Cell Disease and Related Hemoglobinopathies, Springfield, Ill., Charles C Thomas, Publisher, pp. 87-93. 22. Konotey-Ahulu, F. I.: Mental-Nerve Neuropathy: A Complication of Sickle-Cell Crisis, Lancet 2 (773): 388, 1977. Reprint
requests
to:
Dr. A. J. Tomaro Cleveland Metropolitan General Hospital 3395 Scranton Rd.
Cleveland, Ohio 44109
FOR AUTHORS
Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: “The undersigned
author transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors.” Authors will be consulted, when possible, regarding republication of their material.
and A. J. Tomaro,
METROPOLITAN
GENERAL
D.D.S.,
* Cleveland,
Ohio
HOSPITAL
Two individual cases in which mental nerve paresthesia developed concurrently with sickle-cell crisis are described. A brief review of the hemoglobinopathies follows, with genetic considerations and clinical manifestations discussed.
I
n the United States, approximately one out of ten Negros carries the genetic trait of sickle-cell anemia. Of these, more than one out of forty are sickle-cell homozygous. 1 Many more have mixed hemoglobinopathies which manifest themselves in varying degrees of severity. It was not until the 1850’s that Hoppe-Seyler first described the hemoglobin molecule, and not until nearly 100 years after that, were variants of the hemoglobin molecule shown to be related to disease.* Not until 1949 did Pauling and associates3 first demonstrate that the electrophoretic mobility of sickle-cell hemoglobin differed from that of normal adult hemoglobin. In 1957 Ingram4 demonstrated the chemical difference between normal adult hemoglobin and sickle-cell hemoglobin and showed the difference to be but a single amino acid substitution in a protein molecule of 574 amino acids. The genetic make-up of the hemoglobinopathies are now well documented, and the clinical consequences are quite well known. We will describe an interesting complication of the sickle-cell crisis which occurred in two cases seen at our clinic and review the disease. CASE 1
An l&year-old black male patient was admitted to Cleveland Metropolitan General Hospital in May, 1977. This was his seventh admission to the hospital since June, 1969, and, as on all previous admissions, the primary diagnosis at this time was sickle-cell disease with pain crisis. The patient had experienced his first pain crisis at the age of 3 years, and a diagnosis of sickle-cell disease was made at that time. Subsequently, hemoglobin electrophoresis showed the patient to be suffering from sickle SC disease. Upon admission, the physical examination showed a cooperative and alert, thin, 1%year-old black male. Lungs were clear to percussion and auscultation, and cardiovascular *Director and Professor, Division of Oral and Maxillofacial 003C-4220/79/120509+04$00.40/0
0
Surgery.
1979 The C. V. Mosby Co.
examination findings were within normal limits with a normal SllS2 and no murmur or gallop. A right posterior cervical node, 0.5 cm. in diameter, and a 1 cm. left axillary node were palpable. The liver measured 10 cm. by percussion, and the spleen was palpable in the left lateral position. Genitourinary examination showed a stool that was trace heme positive. Extremities were without joint swelling, effusions, or heat. However, there was pain to palpation over the right tibia and thigh. Neurologic examination findings were normal, and cranial nerves showed no deficit. Laboratory examinations revealed a hematocrit of 38.6 percent, hemoglobin of 12.6, and a white count of 10,800. SMA, was within normal limits and SMA,, showed elevated liver function which was attributed to red cell sludging in the liver. Urinalysis was negative. An electrocardiogram revealed sinus arrhythmia, an x-ray film of the chest showed a small calcified granuloma in the lingula but was otherwise normal. Two days following admission, the oral surgery service was consulted when the patient developed increasing pain behind his left ear and over the left zygoma, ramus, and subcondylar region. He was unable to open his mouth wide or to bring his teeth tightly together because of the discomfort. Concurrently, an area of paresthesia developed throughout the distribution of the left mental nerve. Oral examination revealed soft tissues to be within normal limits, as were all major salivary glands. Occlusion was acceptable, with slight anterior open-bite and tongue-thrust. Oral hygiene was fair, and several small carious lesions were noted. A panogram revealed a questionable radiolucency in the superior portion of the left ramus, extending into the subcondylar region. No swelling or masses were noted. Pain in the mandible decreased over the next few days, and as the sickle crisis had resolved the patient was discharged from the hospital. He was readmitted the following month for biopsy, under general anesthesia, of the radiolucent lesion of the left mandible. The paresthesia of the lower left lip persisted at this time. Biopsy of the lesion revealed no tumor, and the patient was discharged. Follow-up of the case revealed total resolution of the men509
510
Kit-son and Tomaro
tal nerve neuropathy approximately 9 months after the initial problem. The patient has not experienced any similar symptoms since that time, although he has had subsequentsickle crises. CASE 2
In December, 1977, a 29-year-old black man was admitted to our hospital with sickle-thalassemiadiseaseand pain crisis. This was his eighteenthadmissionto this hospital. The patient was first noted to have sickle-B-thalassemiadiseaseat the age of 5. and subsequenthemoglobin electrophoresisrevealed 94 percent hemoglobin S and 6 percent hemoglobin F. Physical examination was notable for scleral icterus, systolic ejection murmur of grade II/VI, a palpable liver 5 cm. below the right costal margin, and a palpable spleen tip. Neurologic examination revealed a sensorydeficit in the distribution of the right mental nerve. Laboratory examination showed a hematocrit of 37.8 percent, hemoglobin of 12.1, and a white blood cell count of 19.000.SMAti was normal and SMA,? revealedelevatedliver function. Urinalysis was normal, and an x-ray film of the chest showed slight cardiomegaly with clear lung fields. Oral examination by our service revealed normal soft tissues and salivary glands. There was a full range of mandibular motion, and occlusion was acceptable. Oral hygiene was good, with no caries evident. The patient stated that he had
experiencedpain of the right mandible and subsequentparesthesia of the right lower lip and chin with the onset of the present generalized pain crisis. A panogram revealed no radiographic abnormalities. The patient was followed closely, and over the next few days he reported resolution of the mandibular pain. Follow-up revealed total resolution of the paresthesia within 1 month. DISCUSSION
The hemoglobinopathies represent a hereditary group of diseases in which there is a qualitative abnormality in the globin, or protein, portion of the hemoglobin molecule. Thalassemia, while not demonstrating a qualitatively abnormal hemoglobin, is also regarded as a hemoglobinopathy. In this hereditary disease, there exists a subnormal rate of synthesis of one of the substructures of the protein portion of the hemoglobin molecule.5 The clinical significance of the hemoglobinopathies is highly variable; many hemoglobinopathies manifest few, if any, clinical effects, while others are responsible for severe clinical sequelae. The majority of the normal adult’s hemoglobin, approximately 97 percent, is termed hemoglobin A (HbA). The globin portion of HbA is comprised of two pairs of polypeptide chains; two (Ychains, each formed of 141 amino acids, and two /3 chains, each containing 146 amino acids (HbA = (Y&J. The remaining 3 percent of the normal adult hemoglobin is mostly hemoglobin AZ (HbA2). In HbAz the two LYchains are identical with that of HbA; however, the /3 chains are replaced by different polypeptide chains which are desig-
Oral Surg. December, I979
nated 6 chains (HbA2 = (Ye6,). At birth there is very little, if any, adult hemoglobin present. Instead, the predominant hemoglobin is fetal type, HbF, and is comprised of two 01chains, identical to those of HbA, and two y chains, which have the identical number of amino acids as do the p chains of HbA but differ in the amino acid sequence (HbF = 6, y2). Over the first 6 months of life, the concentration of HbF slowly decreases and is replaced by the adult hemoglobins. It is at this stage that the adverse effects from abnormal adult hemoglobin begin to manifest themselves. With the exception of Hb (Harlem), a single amino acid substitution in one of the polypeptide chains is responsible for the hemoglobinopathy. This substitution is transmitted as a hereditary trait. When a single chain is affected, the heterozygous state, the condition is termed a trait and is usually harmless under normal conditions. When both chains of a pair are affected in an identical manner, the homozygous state, the condition is termed a disease and may have severe and deleterious effects. Complicating the situation are various combinations of abnormal polypeptide chains which, when paired, form mixed hemoglobinopathies with varying degrees of clinical significance. The amino acid substitution for sickle hemoglobin (HbS) occurs in the sixth position of the /3 chain, where valine is found in place of the normal glutamic acid. With decrease in oxygen tension, cy and the abnormal p chains react in such a way that the red blood cells assume the rigid, sickle shapes. If concentrations of HbS are not sufficiently high, as in the heterozygous state, sickling will not occur. In the first case report, the patient suffered from sickle SC disease in which the p6 va’ine chain is inherited from one parent and the @” IYsinechain (hemoglobin C disease) is inherited from the second parent. Sickle SC disease usually manifests less severe clinical symptoms than does homozygous sickle-cell disease, and hence the life expectancy of these patients is much greater. However, they do suffer from a mild to moderate hemolytic anemia and are also prone to vascular occlusive episodes which are the underlying cause of most of the damaging effects of sickle-cell disease. In sickle-B-thalassemia, the disease present in the second case report, a sickle gene is inherited from one parent (p6 “aiinr) and the thalassemia gene from the other parent (fl-thalassemia). Sickle-B-thalassemia is extremely variable in its clinical severity. If no normal /3 chains are produced by the thalassemia gene, the resulting disease is very similar to homozygous sicklecell anemia. If some normal p chains are produced, the severity is not as great, since the p” ra’i”c’ chain concentration is somewhat diluted. Interestingly, with decreased p chain production, there is sometimes “com-
Volume 48 Number 6
Mental nerve paresthesia secondary to sickle-cell crisis
pensatory ” synthesis of y chains which can combine with free a chains to form stable HbF.G The majority of the clinical problems associated with sickle-cell disease are related to the vascular occlusive processes that occur. As sickling of the red blood cells develops, the cells are unable to pass freely through the microcirculation. As the blood flow stagnates, waste products are poorly cleared, resulting in an acidosis and increased sickling. Oxygen and waste product clearance suffers in an ever-increasing area. Upon reoxygenation, sickled cells are able to regain their original shape; however, repeated cycles take their toll. The normal life expectancy of a sickle cell is 15 to 20 days, as compared to 120 days for a normal cell. Painful crises appear at irregular intervals and normally manifest themselves in the abdomen, chest, and joints. Patients may go several months without problems and then incur several pain crises in quick succession. Precipitating factors include infection, dehydration, overexercise, cold in some patients, and heat in others.7 Often no precipitating factor is evident. Sickle patients appear to be more prone to infection, which is probably directly attributable to the spleen’s impaired ability to clear circulating bacteria. There also appears to be a deficiency of heat-labile opsonin, preventing effective coating of bacteria.‘j Bacterial pneumonia, osteomyelitis, meningitis, and urinary tract infections are among the more common infectious problems plaguing the sickle patient, and bacterial infection is the single most common cause of death in sickle-cell anemia. * Chronic organ damage frequently involves the lungs, kidneys, skeleton, skin, liver, and spleen.6, g The etiology is again the recurrent vaso-occlusive episodes. Lung damage can result in such problems as intrapulmonary A-V shunting and decreased pulmonary function, while kidney involvement can lead to decreasing renal function and, rarely, total renal failure. Bone involvement, such as avascular necrosis of the femoral heads93lo, l1 and susceptibility to osteomyelitis ,s, 9 has frequently been described, and compromised circulation to the skin often results in numerous and painful ulcerations. Hepatobiliary complications involve deteriorations of liver functions, increased tendency toward gallstone formation, and icterus. The latter is secondary to the hemolytic nature of the anemia. The spleen is initially enlarged in the earlier years of life, but progressively undergoes infarction and fibrosis and decreases in size to a small mass of fibrous tissue. Central nervous system involvement may lead to seizure, stroke, and/or coma.12 Quite frequently, these episodes reverse themselves, but this is not always the case. As patients age, congestive heart failure frequently develops and systolic ejection murmurs be-
511
come evident. The latter is primarily due to the anemia and hyperdynamic circulation. Radiographic changes of the mandible and maxilla have been widely reported in the literature. The most common observations involve loss of the normal trabecular pattern, a generalized increase in the radiolucency of the bones, and the development of a coarse trabecular pattern. 13, lg This is attributed to a compensatory hyperplasia of the bone marrow secondary to the chronic state of anemia. Other radiographic observations have included thinning of the inferior borders of the mandible’“* 20, *l and areas of increased radiopacity secondary to healing infarcts.‘” However, not all reports have supported or included such findings.15-17 Thinning of the lamina dura, development of small paranasal sinuses, and thickening of portions of the calvarium have also been reported. 13*I65l8 Infarction of nerves is not an unusual occurrence in sickle-cell crisis, and we are suggesting that the etiologic factor in the mental nerve paresthesia is secondary to a vaso-occlusive episode involving the inferior alveolar nerve at or near the mental foramen. This propensity for involvement of the mental nerve may be due to the unusual bending course the nerve travels just prior to exiting from the mandible. Konotey-Ahulu” reported five similar cases over a 2-year period, All of these patients experienced mandibular bone pain prior to the onset of the neuropathy, and recovery time ranged up to 18 months. In the two cases we have presented here, the neuropathies were also preceded by mandibular pain and recovery time was somewhat shorter. In cases such as these, of course, it is essential to rule out the possibility of other ongoing processes. Such factors as infection, trauma, benign and malignant tumors or cysts, and certain systemic diseases involving nerves must all be considered. Thorough examination, including radiographic studies, should be employed to assure that two separate entities are not progressing simultaneously. However, the sequence of generalized sickle-cell crisis with mandibular pain, followed closely by sensation loss of the mental nerve on the same side as the mandibular pain, point strongly to sickle-cell disease as the underlying cause. REFERENCES 1. Robbins, S.: Pathology, ed. 3, Philadelphia, 1968, W. B. Saunders Company, pp. 626627. 2. Necheles, T., Allen, D., and Finkel, H.: Clinical Disorders of Hemoglobin Structure and Synthesis, New York, 1969, Meredith Corp., pp. I-3. 3. Pauling, L., Itano, H. A., Singer, S. J., and Wells, I. C.: Sickle Cell Anemia, a Molecular Disease, Science 110: 543-548, 1949. 4. Ingram, V. M.: Gene Mutations in Human Hemoglobin: The Chemical Difference Between Normal and Sickle Hemoglobin, Nature (London) 180: 326, 1957.
512
Kit-son and Tomaro
Oral Surg. December, 1979
5. Hutchison, H. E.: An Introduction to the Haemoglobinopathies. London, 1967, Edward Arnold & Co., Ltd., p. 27. 6. Cooper, R. A., and Bunn, H. F.: Harrison’s Principles of Internal Medicine, ed. 8, New York, 1977, McGraw-Hill Book Company, Inc., pp. 1688- 1697. 7. McFarlane. J.: Sickle Cell Disorders, Am. J. Nurs. 77: 194% 1954, 1977. 8. Barrett-Connor, E.: Bacterial Infection and Sickle Cell Anemia, Medicine 50: 97- 111, 1971. 9. Tuttle, A., and Koch, B.: Clinical and Hematological Manifestations of Hemoglobin CS Disease in Children, J. Pediatr. 56: 331-342, 1960. 10. Keeling, M. M., Lockwood, W. B., and Harris, E. A.: Avascular Necrosis and Erythrocytosis in Sickle-Cell Trait, N. Engl. J. Med. 290: 442-444, 1974. Il. Herndon, J. H., and Aufranc, 0. E.: Avascular Necrosis of the Femoral Head in the Adult, Clin. Orthop. 86: 49-61, 1972. 12. Portnoy, B. A., and Herion, J. C.: Neurological Manifestations in Sickle Cell Disease, Ann. Int. Med. 76: 643-652, 1972. 13. Halstead, C. L.: Oral Manifestations of Hemoglobinopathies, ORAL SURG. 30: 615-623, 1970. 14. Prowler, J. R., and Smith, E. W.: Dental Bone Changes Occurring in Sickle-Cell Diseases and Abnormal Hemoglobin Traits, Radiology, 65: 762-769, 1955. 15. Mourshed, F., and Tuckson, C. R.: A Study of the Radiographic Features of the Jaws in Sickle-Cell Anemia, ORAL SURG. 37: 812-819, 1974.
INFORMATION
16. Poyton, H. G., and Davey, K. W.: Thalassemia, Changes Visible in Radiographs Used in Dentistry, ORAL SURG. 25: 564. 1968. 17. Robinson, I. B., and Sarnat, B. G.: Roentgen Studies of the Maxillae and Mandible in Sickle-Cell Anemia, Radiology 58: 517, 1952. 18. Caffey, J.: Cooley’s Anemia: A Review of the Roentgen@ graphic Findings in the Skeleton, Am. J. Roentgenol. 78: 381, 1957. 19. Morris, A. L.. and Stahl, S. S.: Intraoral Radiographic Changes in Sickle-Cell Anemia, ORAL SURG. 7: 787, 1954. 20. Reynolds, J.: An Evaluation of Some Roentgenographic Signs in Sickle-Cell Anemia and Its Variants, South Med. J. 55: 11231128, 1962. 21. Reynolds. J.: The Roentgenological Features of Sickle-Cell Disease and Related Hemoglobinopathies, Springfield, Ill., Charles C Thomas, Publisher, pp. 87-93. 22. Konotey-Ahulu, F. I.: Mental-Nerve Neuropathy: A Complication of Sickle-Cell Crisis, Lancet 2 (773): 388, 1977. Reprint
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