5. Mork SJ, Lindegaard K-F, Halvorsen TB, et al. Olgodendroglioma: incidence and biological behavior in a defined population. J Neurosurg 1985;63:881-889 6. Wilkinson I, Anderson JR, Holmes AE. Olgodendroglioma: an analysis of 42 cases. J Neurol Neurosurg Psychiatry 1987;50 304-312 7. Burger PC, Rawlings CE, Cox EB, et al. Clinicopathologiccorrelations in the oligodendroglioma. Cancer 1987;59:1345-1352
Contrast-enhanced CT scans before (left)and afer (right) two courses of PCV-3 demonstrating disappearance of residual left frontal anaplastic oligodendroglioma.
oligodendroglioma may not predict its clinical behavior {3}. Others found that high cell density, nuclear pleomorphism, frequent mitoses, endothelial proliferation, or necrosis are associated with a poorer prognosis 1471. Given uncertainty as to the predictive value of histology, and recognizing that treatment may be toxic, which patients do we select for aggressive treatment at diagnosis? We have found that most clinically and radiologically aggressive oligodendrogliomas are anaplastic and that anaplastic oligodendrogliomas behave aggressively, as do some nonanaplastic tumors; both are symptomatic, enlarging, enhancing tumors on CT scan. We give chemotherapy after initial surgery to patients with residual tumor measurable by CT scan (either anaplastic oligodendroglioma or symptomatic, enlarging, enhancing, nonanaplastic tumor). We do not give chemotherapy to patients with nonenlarging, nonenhancing, histologically “typical” oligodendroglioma. Supported in part by grant SRC-5-P50-NS20023 from the National Institutes of Health. The authors thank V. DeVita, Jr for helpful discussions and P. Gray for preparing the manuscript.
References 1. Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 1988;23: 360-364 2. Levin VA, Edwards MS, Wright DC, et al. Modified procarbazine, CCNU and vincristine (PCV-3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep 1980;64:237-241 3. Rubinstein LJ. Tumors of the central nervous system. Washington DC: Armed Forces Institute of Pathology (Fascicle 6), 1972 4. Smith MT, Ludwig CL, Godfrey AD, Armbrustmacher VM. Grading of oligodendrogliornas. Cancer 1983;52:2 107-2 114
574
Dominantly Transmitted Congenital-Indifference to Piin P. Landrieu, MD,* G. Said, MD,? and C . Allaire, MDS
Two patients from a family with dominantly inherited indifference to pain were investigated. Perception of the other sensory modalities was normal as was the remainder of the neurological examination. Electrophysiological studies and morphometric evaluation of myelinated and unmyelinated fibers of nerve biopsy specimenswere normal. This is the first morphometric study of peripheral nerve in dominantly inherited indifference to pain. Landrieu P, Said G, Allaire C. Dominantly transmitted congenital indifference to pain. Ann Neurol 1990;27:574-578
The terms congenital insensitivity to pain and congenital indifference to pain are often used interchangeably in describing the lack of reaction to painful stimuli. There is, however, a major difference between the two syndromes, since “indifference” implies a lack of concern to a stimulus well received whereas “insensitivity” describes an absence of sensation or failure to receive a perception 111. In indifference to pain, the sensory pathways are considered normal, whereas in insensitivity to pain, the absence of painful sensation results from a detectable defect of sensory pathways. It may be difficult, however, to differentiate these two entities, especially in young children. Some children with a diagnosis of congenital indifference to pain had abnormal nerve biopsies, casting doubt on the reality of the syndrome 12-51. From the *Service de Neurologie PCdiatrique, Centre Hospitalier Universitaire de BicCtre, the ?Service de Neurologie, CHU de BicCtre, Secteur Pierre-Marie, Le Kremlin BicCtre, and the $Service de Neurologie, C H U de Rennes, France. Received Feb 28, 1989, and in revised form Aug 8 and Oct 19. Accepted for publication Nov 6, 1989. Address correspondence to Dr Landrieu, Service de Neurologie Pediatrique, Centre Hospitalier Universitaire de BicCtre, 94275 Le Kremlin BicCtre, France.
Copyright 0 1990 by the American Neurological Association
We report on a woman and her daughter who fulfill the criteria for congenital indifference to pain. We performed a number of investigations including a light and electron microscopic study of myelinated and of unmyelinated fibers of nerve biopsy specimens. Our findings demonstrate that congenital indifference to pain is not a variety of hereditary sensory neuropathy. Patients Patient 1 This 5-year-old girl, whose father was unknown, had been suspected of having congenital indifference to pain since her first year of life because she manifested no adverse reactions to sour foods or to casual injuries. These abnormalities had been noticed by her mother who was affected by the same disorder. By her second year, scratching lesions around her nose led to persistent erosions. From 11/2 to 5 years of age, she had several painless fractures of the lower extremities. Examination showed normal size and psychomotor development. Behavior was unremarkable, including the usual tearful reactions to medical procedures. The left ankle was swollen, and radiograms showed advanced destruction of the calcaneum and astragalus. Proliferating scars were present around her nostrils, and she had painless paronychia. Sensory examination, including light touch, pinprick, heat and cold, joint position, vibration, and pressure on tendons and muscles, was normal, as were myotatic reflexes. Withdrawal reflexes, grimacing, and vocal reactions were present to pinprick of normal intensity and to application of hot water (43"C), but the child was indifferent to prolongation or repetition of the stimuli anywhere on the body. There were no autonomic disturbances, and the following tests were normal: Schirmer's test, pupillary responses to topically applied drugs, sweating in response to heat and to injection of pilocarpine, and local vasoconstriction, regional piloerection, and blood pressure elevation in response to immersion of one arm in cold water (4°C for 3 minutes). Temperature, sleep, respiration, and intestinal and sphincter motility were normal. Subcutaneous injections of 0.5% histamine induced a 3-mm painless flare. Serum immunoglobulins, urine vanillylmandelic and 5 hydroxyindoleacetic acids, amino acids, and organic acids were normal. Plasma cortisol, 11-desoxycortisol, adrenocorticotropic hormone, lipouophin, and beta endorphin responded normally to metapyrone. In the cerebrospinal fluid, endorphin was 40 p g h l and metenkephalin 37.9 pg/ml (both normal).
Patient 2 The mother of the first patient is the second child of healthy parents (see Figure 1 for genealogy). Her maternal grandfather and her younger sister were said to be remarkably resistant to pain but had no known
I
Fig 1 . Genealogy of the family: f = Patient 1 , ? = members reportedly unusually resistant to painful stimuli.
complications resulting from lack of pain perception. The patient had tolerated minor traumas without discomfort since infancy, although she had experienced some pain once at the dentist's. The diagnosis of indifference to pain was considered at adolescence after she experienced a number of painless orthopedic injuries including necrosis of the left femoral head at age 12. At age 16, the patient developed painless bilateral sciatic paralysis as the result of a severe lumbar disc herniation and spondylolisthesis, which led to lumbar laminectomy and intersomatic vertebral grafting. On examination, she was a 35-year-old, wheelchairbound, intelligent woman with well-adapted behavior. Her higher cortical functions were normal. She was unable to walk without aid because of a bilateral foot drop with complete paralysis of the muscles supplied by the L-5 spinal root. This was the result of the painless lumbar disc herniation she had at age 16. Myotatic reflexes were normal except at the Achilles tendons. Sensory examination showed normal discrimination of all modalities including light touch, two-point discrimination, heat and cold, vibratory sense, and position sense. Pinprick was recognized over the whole body, but the patient did not feel discomfort. Noxious stimuli could be repeated without complaint. Withdrawal reaction occurred without pain after stimulation with water at 45°C. Subcutaneous injections of histamine gave normal results. Responses of POMCrelated peptides to metapyrone were normal.
Newophysiological Investigations Total motor denervation was found in the territory of the peroneal nerves in Patient 2. No signs of denervation were found by elecuomyography in Patient 1. Motor nerve conduction velocities were normal in both patients, except in the peroneal nerves of Patient 2, which remained unexcitable. Sensory conduction was 56 mas-' in the sural nerve of Patient 1 (amplitude: 10.5 pV). In Patient 2, the amplitudes of the sensory action potential were respectively 26 and 10 pV and the conduction velocity 50 and 43.5 m-s-' in the ulnar and median nerves. The threshold of the
Brief Communication: Landrieu et al: Hereditary Indifference to Pain 575
knee flexor muscle nociceptive reflex [6} was 10 to 11 mA in Patient 1 and 13 to 14 mA in Patient 2 (normal values, 10 5 2 mA). Cortical sensory evoked potentials had normal patterns and latencies after stimulation in the upper and in the lower limbs in Patient 1.
Morphological Studies A skin biopsy of the dorsal aspect of the second toe was performed in Patient 1 and was normal by light and electron microscopy; the dermal unmyelinated fibers looked normal. A specimen of the lateral peroneal muscle, taken during the nerve biopsy procedure, was histologically normal. The superficial branch of the peroneal nerve and the radial cutaneous nerve were sampled respectively in Patients 1 and 2. The nerve specimens were fixed in isotonic buffered 3.6% glutaraldehyde at p H 7.4. After fixation, they were divided into three parts. One fragment was embedded in paraffin, serially sectioned at 5 pm, and examined after hematoxylin and eosin staining. The second fragment was embedded in Epon. One-micron-thick transverse sections were stained with 1% thionine and used for morphometric studies. Ultrathin sections were prepared with an LKB Ultratome I11 and a diamond knife, stained with uranyl acetate and lead citrate, and examined in an electron microscope (Siemens Elmiskope CT 150). The third fragment (15 mm long) was osmicated after fixation and macerated in 66% glycerin for 48 hours before dissection in pure glycerin. One hundred consecutive fibers were isolated and classified according to their morphology. NERVE BIOPSY.
::
Fig 2. Electron micrograph of a nerve specimen from Patient 1. Both the myelinated and the unmyelinated fibers look normal. Stain: uranyl acetate and lead citrate. Bar: 1 pm.
Myelinared flbers
Densty/mm’
rotal density
46 Fkbers ( 8p
3000
Zoo0
The density of the myelinated fibers per square millimeter of endoneurial area was evaluated on semithin sections by use of a semiautomatic method [ 7 } . The density and size distribution of unmyelinated fibers were assessed on photographs by measuring at least one-third of the endoneurial areas and more than 250 fibers at a final magnification of 9,000 X . MORPHOMETRIC EVALUATION.
10000
Comments The patients reported here fulfill the criteria for the diagnosis of congenital indifference to pain. These in-
576 Annals of Neurology Vol 27 No 5
May 1990
n
h
2
01 (2vears old1
T D z 11 160/mm2
%F( 8 ~ ~ 6 4 %
2ooot.
RESULTS. All fibers looked normal by light and electron microscopy (Fig 2). There were no abnormal deposits. Teased fiber preparations were also normal. Morphometry of myelinated fibers (Fig 3) showed a normal biphasic size distribution with a substantial number of small myelinated fibers. In both patients, the histograms of unmyelinated fibers were similar to those of controls (Fig 4 ) .
= 18950/mm2 = 77%
%F(8p=62%
n
-
1600 1200 800
400 0
2
4
6
8HJ1214
Mother
0
2
4
Control
6
8
10 12 14 16
(adult1
Fig 3. Size density distribution of the myelinatedfibers:Top, Histogram of myelinatedfibers of the superficialbranch of the peroneal nerve in Patient 1 and in controlfrom the same age group. Bottom, Histogram of the myelinatedfibers ofthe cutaneous branch of the radial nerve in Patient 2 and age-matched control. T D = total density.
Unmvellnated fibers
J ~50680/mm~
j.) 135 Zyears 185 195 old1
TD=18 510/mm2
TD =15870/mm2
1000
015 0.5
0 75 105 135 165 195 2 2 5
Mother
015 0 4 5 075 105 135 165 195 2 2 5
Control
(
adult I
Fig 4 . Size density distribution of the unmyelinatedjibers in Patient 1 and in age-matched control (top) and Patient 2 and age-matched control (bottom).In both patients the density and distribution of the unmyelinatedjibers were normal.
clude absence from birth of recognition of pain, lack of reaction to painful stimuli over the entire body, normal sensitivity to other sensory modalities, and normal myotatic reflexes. It is well known that indifference to pain may vary in degree and that slight discomfort or occasional pain may be experienced in this condition, as observed in Patient 2. In both patients the peripheral nerves, especially the C fibers, which convey polymodal nociceptive modalities, were morphologically normal. It is also remarkable that no other neurological abnormality was found in the mother of Patient 1 with the exception of the bilateral L-5 root palsy, which was obviously the consequence of a disc herniation and abnormalities of the lumbar spine. Special to this family was the autosomal dominant mode of inheritance, probably with incomplete expression in the sister and grandfather of Patient 2. The syndrome of congenital indifference to pain [1, 8-13] has also been called asymbolia for pain 1141, congenital pure analgesia 1151, or congenital universal insensitivity to pain 116-191. In these classic reports,
the patients did not experience pain from needle prick or injury anywhere on the body. Although they could identify the prick from the head of a pin, they had no physiological responses to noxious stimuli and no evidence of peripheral nerve abnormality. In our patients, the most striking clinical sign was a normal primary withdrawal response to noxious stimuli, in contrast to a total indifference when the stimuli were maintained and reinforced. This phenomenon was in agreement with the normal threshold of the knee flexor nociceptive reflex and could be a contributing sign in differentiating indifference to pain from sensory neuropathies. Previous biopsy and postmortem studies have not disclosed structural abnormalities of nerves, spinal cord, or the brain 118-221, but the nerves were not studied by methods now available. It has therefore been suggested that abnormahties of unmyelinated fibers and of small myelinated fibers mght not have been detected 12, 51 and that patients with congenital indifference to pain could actually suffer from hereditary sensory neuropathy. This necessitated further morphometric studies of nerve fibers, especially of those conveying pain sensations, both at the light and at the electron microscopic levels. Our study, however, does not exclude the possibility of an abnormal mechanical nociceptor, the morphology of which has not yet been determined, or of a defect in a neurotransmitter, but normal morphometric findings exclude the possibility of a selective loss of unmyelinated nociceptive fibers, because these constitute the large majority of the unmyelinated fibers in human cutaneous nerve (for review see 1231). The morphological study was also required in the present patients because of the autosomal dominant mode of inheritance of congenital indifference to pain, which usually presents as a sporadic disorder. Occasional cases after consanguineous marriages, or among several siblings with normal parents 112, 24, 251 have suggested an autosomal recessive inheritance. Dominantly transmitted lack of reaction to noxious stimuli is more often due to sensory neuropathy 126-281, also called hereditary sensory and autonomic neuropathy type I 131, than to congenital indifference to pain, a much rarer condition. In our 2 patients, this possibility was ruled out by normal findings on morphological examination of nerve samples. In conclusion, our study demonstrates that true indifference to pain does exist and is not a variety of hereditary sensory neuropathy. We thank D. Schoevaert (nerve morphometry),J. C. Willer and A. Ropert (electrophysiological studies),J. Girard and F. Cesselin (pep tides determinations), and A. Durand (nerve sample processing) for their collaboration.
Brief Communication: Landrieu et al: Hereditary Indifference to Pain 577
References 1. Jewesburry ECO. Congenital indifference to pain. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, vol 8. Amsterdam: Elsevier, 1979:187-204 2. Dyck PJ, Mellinger JF, Reagan JR, et al. Not indifference to pain, but varieties of hereditary sensory and automatic neuropathy. Brain 1983;106:373-390 3. Dyck PJ, Ohta M. Neuronal atrophy degeneration predominantly affecting peripheral sensory neurons. In: Dyck PJ, Thomas PK, Lambert EH, eds. Peripheral neuropathy, vol 2. Philadelphia: WB Saunders, 1975:791-824 4. Low PA, Burke WJ, McLeod JG. Congenital insensitivity to pain with selective loss of small myelinated fibers. Ann Neurol 1978;3:177-182 5. Donaghy M, Hakin RM, Bamford JM, et al. Hereditary sensory neuropathy with neurotrophic keratis. Brain 1987;110:563583 6. Willer JC. Nociceptive flexion reflexes as a tool for pain research in man. In: Desmedt JE, ed. Motor control mechanisms in health and disease. New York: Raven Press, 1983:209-227 7. Selva J, Schoevart-Brossault D, Said G. Automated morphometric analysis of cross sections of normal and pathological surd nerve biopsy specimens. Biol Cell 1981;42:57-74 8. Arbuse DI, Cantor MB, Barenberg PA. Congenital indifference to pain. J Pediatr 1949;35:221-226 9. Boyd DA, Nie LW. Congenital indifference to pain. Arch Neurol 1949;61:402-4 12 10. Westlake EK. Congenital indifference to pain. Brit Med J 1952;1:144 11. Critchley M. Congenital indifference to pain. Ann Intern Med 1956;45:737-747 12. Fanconi G , Ferrazzini F. Kongenitale Analgie (Kongenitale generalisierte Schmerzindifferenz). Helv Paediatr Acta 1957; 12:79-115 13. Silverman FN, Gilden JJ. Congenital insensitivity to pain: a neurologic syndrome with bizarre skeletal lesions. Radiology 1959;72:176- 170 14. Schilder P, Stengel E. Asymbolia for pain. Arch Neurol Psychiat (Chic) 1931;25:598-600 15. Dearborn GVN. A case of congenital general pure analgesia. J New Ment Dis 1932;75:612-615 16. Ford FR, Wilkins L. Congenital universal insensitiveness to pain: a clinical report of three cases in children, with discussion of the literature. Bull Johns Hopkins Hospital 1938;62:448-466 17. McMurray GA. Experimental study of a case of insensitivity to pain. Arch Neurol Psychiat (Chic) 1950;64:650-667 18. Feindel W. Note on the nerve endings in a subject with arthropathy and congenital absence of pain. J Bone Joint Surg 1753 ;35B:402-407 19. Baxter DW, Olszewski J. Congenital universal insensitivity to pain. Brain 1960;83:381-393 20. Moffie D. Congenital universal indifference to pain and temperature. Confinia Neurologica 1951;11:219-226 21. Ogden TE, Robert F, Carmichael EA. Some sensory syndromes in children: indifference to pain and sensory neuropathy. J Neurol Neurosurg Psychiatry 1959;22:267-276 22. Magee KR. Congenital indifference to pain. An anatomic0 pathological study. Arch Neurol 1963;9:635-640 23. Light AR, Per1 ER. Peripheral sensory systems. In: Dyck PJ, Thomas PK, Lambert EH, eds. Peripheral neuropathy, vol 1. Philadelphia: WB Saunders, 1984:210-230 24. Durand P, Belotti BM. Un caso di indifferenza congenita al dolore (algoatarassia).Primo contriburo della letteratura italiana. Helv Paediatr Acta 1957;12:116-126 25. Thrush DC. Congenital insensitivity to pain. Brain 1973;96: 369-386
26. Hicks EP. Hereditary perforating ulcer of the foot. Lancet 1922;1:3 19-32 1 27. Denny-Brown D. Hereditary sensory radicular neuropathies. J Neurol Neurosurg Psychiatry (Chicago) 1951;14:237-252 28. Thevenard A. L‘acropathie ulckro-mutilante familiale. Rev Neurol 1942;72:193-212
An Unusual Variant of Becker Muscular Dystrophy Marianne de Visser, MD,* Egbert Bakker, PhDJ Joep C. Defesche, MSc,t Piet A. Bolhuis, PhD,’? and Gert Jan van Ommen, PhD3 We report on 5 brothers with slowly progressive limbgirdle weakness. Calf hypertrophy was absent. The levels of creatine kinase, electromyography, and findings from a muscle biopsy specimen were compatible with muscular dystrophy. The propositus’s biopsy specimen also showed numerous rimmed vacuoles. DNA analysis revealed a deletion in the dystrophin gene, establishing a diagnosis of Becker muscular dystrophy. Both the absence of calf hypertrophy and the presence of rimmed vacuoles are unusual features in this disorder. de Visser M, Bakker E, Defesche JC, Bolhuis PA, van Ommen GJ. An unusual variant of Becker muscular dystrophy. Ann Neurol 1990;27: 5 78-58 1
Becker muscular dystrophy (BMD) is an X-linked recessive muscular dystrophy. The genes for BMD and Duchenne muscular dystrophy (DMD) are allelic, the so-called dystrophin gene, and assigned to band p21 on the short arm of the X chromosome 11, 2). The clinical criteria for the diagnosis of BMD are: X-linked recessive inheritance; slow progressive muscle weakness, greater proximally than distally; ambulation maintained at least until the age of 16 years; and hypertrophy of the calf. Laboratory features include significantly elevated activities of serum creatine kinase (CK), and electromyographical (EMG) and histopathological changes indicating mostly acute and/or chronic From the Departments of *Neurology and ?Experimental Medicine, University of Amsterdam, Amsterdam, and the Department of $Human Genetics, State University Leiden, Leiden, The Netherlands. Received Aug 9, 1989, and in revised form Oct 13. Accepted for publication Nov 6, 1989. Address correspondence to D r de Visser, Department of Neurology, Academic Medical Center, Meibergdreef 9, 1105 A 2 Amsterdam, The Netherlands.
578 Copyright 0 1990 by the American Neurological Association
Contrast-enhanced CT scans before (left)and afer (right) two courses of PCV-3 demonstrating disappearance of residual left frontal anaplastic oligodendroglioma.
oligodendroglioma may not predict its clinical behavior {3}. Others found that high cell density, nuclear pleomorphism, frequent mitoses, endothelial proliferation, or necrosis are associated with a poorer prognosis 1471. Given uncertainty as to the predictive value of histology, and recognizing that treatment may be toxic, which patients do we select for aggressive treatment at diagnosis? We have found that most clinically and radiologically aggressive oligodendrogliomas are anaplastic and that anaplastic oligodendrogliomas behave aggressively, as do some nonanaplastic tumors; both are symptomatic, enlarging, enhancing tumors on CT scan. We give chemotherapy after initial surgery to patients with residual tumor measurable by CT scan (either anaplastic oligodendroglioma or symptomatic, enlarging, enhancing, nonanaplastic tumor). We do not give chemotherapy to patients with nonenlarging, nonenhancing, histologically “typical” oligodendroglioma. Supported in part by grant SRC-5-P50-NS20023 from the National Institutes of Health. The authors thank V. DeVita, Jr for helpful discussions and P. Gray for preparing the manuscript.
References 1. Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 1988;23: 360-364 2. Levin VA, Edwards MS, Wright DC, et al. Modified procarbazine, CCNU and vincristine (PCV-3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep 1980;64:237-241 3. Rubinstein LJ. Tumors of the central nervous system. Washington DC: Armed Forces Institute of Pathology (Fascicle 6), 1972 4. Smith MT, Ludwig CL, Godfrey AD, Armbrustmacher VM. Grading of oligodendrogliornas. Cancer 1983;52:2 107-2 114
574
Dominantly Transmitted Congenital-Indifference to Piin P. Landrieu, MD,* G. Said, MD,? and C . Allaire, MDS
Two patients from a family with dominantly inherited indifference to pain were investigated. Perception of the other sensory modalities was normal as was the remainder of the neurological examination. Electrophysiological studies and morphometric evaluation of myelinated and unmyelinated fibers of nerve biopsy specimenswere normal. This is the first morphometric study of peripheral nerve in dominantly inherited indifference to pain. Landrieu P, Said G, Allaire C. Dominantly transmitted congenital indifference to pain. Ann Neurol 1990;27:574-578
The terms congenital insensitivity to pain and congenital indifference to pain are often used interchangeably in describing the lack of reaction to painful stimuli. There is, however, a major difference between the two syndromes, since “indifference” implies a lack of concern to a stimulus well received whereas “insensitivity” describes an absence of sensation or failure to receive a perception 111. In indifference to pain, the sensory pathways are considered normal, whereas in insensitivity to pain, the absence of painful sensation results from a detectable defect of sensory pathways. It may be difficult, however, to differentiate these two entities, especially in young children. Some children with a diagnosis of congenital indifference to pain had abnormal nerve biopsies, casting doubt on the reality of the syndrome 12-51. From the *Service de Neurologie PCdiatrique, Centre Hospitalier Universitaire de BicCtre, the ?Service de Neurologie, CHU de BicCtre, Secteur Pierre-Marie, Le Kremlin BicCtre, and the $Service de Neurologie, C H U de Rennes, France. Received Feb 28, 1989, and in revised form Aug 8 and Oct 19. Accepted for publication Nov 6, 1989. Address correspondence to Dr Landrieu, Service de Neurologie Pediatrique, Centre Hospitalier Universitaire de BicCtre, 94275 Le Kremlin BicCtre, France.
Copyright 0 1990 by the American Neurological Association
We report on a woman and her daughter who fulfill the criteria for congenital indifference to pain. We performed a number of investigations including a light and electron microscopic study of myelinated and of unmyelinated fibers of nerve biopsy specimens. Our findings demonstrate that congenital indifference to pain is not a variety of hereditary sensory neuropathy. Patients Patient 1 This 5-year-old girl, whose father was unknown, had been suspected of having congenital indifference to pain since her first year of life because she manifested no adverse reactions to sour foods or to casual injuries. These abnormalities had been noticed by her mother who was affected by the same disorder. By her second year, scratching lesions around her nose led to persistent erosions. From 11/2 to 5 years of age, she had several painless fractures of the lower extremities. Examination showed normal size and psychomotor development. Behavior was unremarkable, including the usual tearful reactions to medical procedures. The left ankle was swollen, and radiograms showed advanced destruction of the calcaneum and astragalus. Proliferating scars were present around her nostrils, and she had painless paronychia. Sensory examination, including light touch, pinprick, heat and cold, joint position, vibration, and pressure on tendons and muscles, was normal, as were myotatic reflexes. Withdrawal reflexes, grimacing, and vocal reactions were present to pinprick of normal intensity and to application of hot water (43"C), but the child was indifferent to prolongation or repetition of the stimuli anywhere on the body. There were no autonomic disturbances, and the following tests were normal: Schirmer's test, pupillary responses to topically applied drugs, sweating in response to heat and to injection of pilocarpine, and local vasoconstriction, regional piloerection, and blood pressure elevation in response to immersion of one arm in cold water (4°C for 3 minutes). Temperature, sleep, respiration, and intestinal and sphincter motility were normal. Subcutaneous injections of 0.5% histamine induced a 3-mm painless flare. Serum immunoglobulins, urine vanillylmandelic and 5 hydroxyindoleacetic acids, amino acids, and organic acids were normal. Plasma cortisol, 11-desoxycortisol, adrenocorticotropic hormone, lipouophin, and beta endorphin responded normally to metapyrone. In the cerebrospinal fluid, endorphin was 40 p g h l and metenkephalin 37.9 pg/ml (both normal).
Patient 2 The mother of the first patient is the second child of healthy parents (see Figure 1 for genealogy). Her maternal grandfather and her younger sister were said to be remarkably resistant to pain but had no known
I
Fig 1 . Genealogy of the family: f = Patient 1 , ? = members reportedly unusually resistant to painful stimuli.
complications resulting from lack of pain perception. The patient had tolerated minor traumas without discomfort since infancy, although she had experienced some pain once at the dentist's. The diagnosis of indifference to pain was considered at adolescence after she experienced a number of painless orthopedic injuries including necrosis of the left femoral head at age 12. At age 16, the patient developed painless bilateral sciatic paralysis as the result of a severe lumbar disc herniation and spondylolisthesis, which led to lumbar laminectomy and intersomatic vertebral grafting. On examination, she was a 35-year-old, wheelchairbound, intelligent woman with well-adapted behavior. Her higher cortical functions were normal. She was unable to walk without aid because of a bilateral foot drop with complete paralysis of the muscles supplied by the L-5 spinal root. This was the result of the painless lumbar disc herniation she had at age 16. Myotatic reflexes were normal except at the Achilles tendons. Sensory examination showed normal discrimination of all modalities including light touch, two-point discrimination, heat and cold, vibratory sense, and position sense. Pinprick was recognized over the whole body, but the patient did not feel discomfort. Noxious stimuli could be repeated without complaint. Withdrawal reaction occurred without pain after stimulation with water at 45°C. Subcutaneous injections of histamine gave normal results. Responses of POMCrelated peptides to metapyrone were normal.
Newophysiological Investigations Total motor denervation was found in the territory of the peroneal nerves in Patient 2. No signs of denervation were found by elecuomyography in Patient 1. Motor nerve conduction velocities were normal in both patients, except in the peroneal nerves of Patient 2, which remained unexcitable. Sensory conduction was 56 mas-' in the sural nerve of Patient 1 (amplitude: 10.5 pV). In Patient 2, the amplitudes of the sensory action potential were respectively 26 and 10 pV and the conduction velocity 50 and 43.5 m-s-' in the ulnar and median nerves. The threshold of the
Brief Communication: Landrieu et al: Hereditary Indifference to Pain 575
knee flexor muscle nociceptive reflex [6} was 10 to 11 mA in Patient 1 and 13 to 14 mA in Patient 2 (normal values, 10 5 2 mA). Cortical sensory evoked potentials had normal patterns and latencies after stimulation in the upper and in the lower limbs in Patient 1.
Morphological Studies A skin biopsy of the dorsal aspect of the second toe was performed in Patient 1 and was normal by light and electron microscopy; the dermal unmyelinated fibers looked normal. A specimen of the lateral peroneal muscle, taken during the nerve biopsy procedure, was histologically normal. The superficial branch of the peroneal nerve and the radial cutaneous nerve were sampled respectively in Patients 1 and 2. The nerve specimens were fixed in isotonic buffered 3.6% glutaraldehyde at p H 7.4. After fixation, they were divided into three parts. One fragment was embedded in paraffin, serially sectioned at 5 pm, and examined after hematoxylin and eosin staining. The second fragment was embedded in Epon. One-micron-thick transverse sections were stained with 1% thionine and used for morphometric studies. Ultrathin sections were prepared with an LKB Ultratome I11 and a diamond knife, stained with uranyl acetate and lead citrate, and examined in an electron microscope (Siemens Elmiskope CT 150). The third fragment (15 mm long) was osmicated after fixation and macerated in 66% glycerin for 48 hours before dissection in pure glycerin. One hundred consecutive fibers were isolated and classified according to their morphology. NERVE BIOPSY.
::
Fig 2. Electron micrograph of a nerve specimen from Patient 1. Both the myelinated and the unmyelinated fibers look normal. Stain: uranyl acetate and lead citrate. Bar: 1 pm.
Myelinared flbers
Densty/mm’
rotal density
46 Fkbers ( 8p
3000
Zoo0
The density of the myelinated fibers per square millimeter of endoneurial area was evaluated on semithin sections by use of a semiautomatic method [ 7 } . The density and size distribution of unmyelinated fibers were assessed on photographs by measuring at least one-third of the endoneurial areas and more than 250 fibers at a final magnification of 9,000 X . MORPHOMETRIC EVALUATION.
10000
Comments The patients reported here fulfill the criteria for the diagnosis of congenital indifference to pain. These in-
576 Annals of Neurology Vol 27 No 5
May 1990
n
h
2
01 (2vears old1
T D z 11 160/mm2
%F( 8 ~ ~ 6 4 %
2ooot.
RESULTS. All fibers looked normal by light and electron microscopy (Fig 2). There were no abnormal deposits. Teased fiber preparations were also normal. Morphometry of myelinated fibers (Fig 3) showed a normal biphasic size distribution with a substantial number of small myelinated fibers. In both patients, the histograms of unmyelinated fibers were similar to those of controls (Fig 4 ) .
= 18950/mm2 = 77%
%F(8p=62%
n
-
1600 1200 800
400 0
2
4
6
8HJ1214
Mother
0
2
4
Control
6
8
10 12 14 16
(adult1
Fig 3. Size density distribution of the myelinatedfibers:Top, Histogram of myelinatedfibers of the superficialbranch of the peroneal nerve in Patient 1 and in controlfrom the same age group. Bottom, Histogram of the myelinatedfibers ofthe cutaneous branch of the radial nerve in Patient 2 and age-matched control. T D = total density.
Unmvellnated fibers
J ~50680/mm~
j.) 135 Zyears 185 195 old1
TD=18 510/mm2
TD =15870/mm2
1000
015 0.5
0 75 105 135 165 195 2 2 5
Mother
015 0 4 5 075 105 135 165 195 2 2 5
Control
(
adult I
Fig 4 . Size density distribution of the unmyelinatedjibers in Patient 1 and in age-matched control (top) and Patient 2 and age-matched control (bottom).In both patients the density and distribution of the unmyelinatedjibers were normal.
clude absence from birth of recognition of pain, lack of reaction to painful stimuli over the entire body, normal sensitivity to other sensory modalities, and normal myotatic reflexes. It is well known that indifference to pain may vary in degree and that slight discomfort or occasional pain may be experienced in this condition, as observed in Patient 2. In both patients the peripheral nerves, especially the C fibers, which convey polymodal nociceptive modalities, were morphologically normal. It is also remarkable that no other neurological abnormality was found in the mother of Patient 1 with the exception of the bilateral L-5 root palsy, which was obviously the consequence of a disc herniation and abnormalities of the lumbar spine. Special to this family was the autosomal dominant mode of inheritance, probably with incomplete expression in the sister and grandfather of Patient 2. The syndrome of congenital indifference to pain [1, 8-13] has also been called asymbolia for pain 1141, congenital pure analgesia 1151, or congenital universal insensitivity to pain 116-191. In these classic reports,
the patients did not experience pain from needle prick or injury anywhere on the body. Although they could identify the prick from the head of a pin, they had no physiological responses to noxious stimuli and no evidence of peripheral nerve abnormality. In our patients, the most striking clinical sign was a normal primary withdrawal response to noxious stimuli, in contrast to a total indifference when the stimuli were maintained and reinforced. This phenomenon was in agreement with the normal threshold of the knee flexor nociceptive reflex and could be a contributing sign in differentiating indifference to pain from sensory neuropathies. Previous biopsy and postmortem studies have not disclosed structural abnormalities of nerves, spinal cord, or the brain 118-221, but the nerves were not studied by methods now available. It has therefore been suggested that abnormahties of unmyelinated fibers and of small myelinated fibers mght not have been detected 12, 51 and that patients with congenital indifference to pain could actually suffer from hereditary sensory neuropathy. This necessitated further morphometric studies of nerve fibers, especially of those conveying pain sensations, both at the light and at the electron microscopic levels. Our study, however, does not exclude the possibility of an abnormal mechanical nociceptor, the morphology of which has not yet been determined, or of a defect in a neurotransmitter, but normal morphometric findings exclude the possibility of a selective loss of unmyelinated nociceptive fibers, because these constitute the large majority of the unmyelinated fibers in human cutaneous nerve (for review see 1231). The morphological study was also required in the present patients because of the autosomal dominant mode of inheritance of congenital indifference to pain, which usually presents as a sporadic disorder. Occasional cases after consanguineous marriages, or among several siblings with normal parents 112, 24, 251 have suggested an autosomal recessive inheritance. Dominantly transmitted lack of reaction to noxious stimuli is more often due to sensory neuropathy 126-281, also called hereditary sensory and autonomic neuropathy type I 131, than to congenital indifference to pain, a much rarer condition. In our 2 patients, this possibility was ruled out by normal findings on morphological examination of nerve samples. In conclusion, our study demonstrates that true indifference to pain does exist and is not a variety of hereditary sensory neuropathy. We thank D. Schoevaert (nerve morphometry),J. C. Willer and A. Ropert (electrophysiological studies),J. Girard and F. Cesselin (pep tides determinations), and A. Durand (nerve sample processing) for their collaboration.
Brief Communication: Landrieu et al: Hereditary Indifference to Pain 577
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An Unusual Variant of Becker Muscular Dystrophy Marianne de Visser, MD,* Egbert Bakker, PhDJ Joep C. Defesche, MSc,t Piet A. Bolhuis, PhD,’? and Gert Jan van Ommen, PhD3 We report on 5 brothers with slowly progressive limbgirdle weakness. Calf hypertrophy was absent. The levels of creatine kinase, electromyography, and findings from a muscle biopsy specimen were compatible with muscular dystrophy. The propositus’s biopsy specimen also showed numerous rimmed vacuoles. DNA analysis revealed a deletion in the dystrophin gene, establishing a diagnosis of Becker muscular dystrophy. Both the absence of calf hypertrophy and the presence of rimmed vacuoles are unusual features in this disorder. de Visser M, Bakker E, Defesche JC, Bolhuis PA, van Ommen GJ. An unusual variant of Becker muscular dystrophy. Ann Neurol 1990;27: 5 78-58 1
Becker muscular dystrophy (BMD) is an X-linked recessive muscular dystrophy. The genes for BMD and Duchenne muscular dystrophy (DMD) are allelic, the so-called dystrophin gene, and assigned to band p21 on the short arm of the X chromosome 11, 2). The clinical criteria for the diagnosis of BMD are: X-linked recessive inheritance; slow progressive muscle weakness, greater proximally than distally; ambulation maintained at least until the age of 16 years; and hypertrophy of the calf. Laboratory features include significantly elevated activities of serum creatine kinase (CK), and electromyographical (EMG) and histopathological changes indicating mostly acute and/or chronic From the Departments of *Neurology and ?Experimental Medicine, University of Amsterdam, Amsterdam, and the Department of $Human Genetics, State University Leiden, Leiden, The Netherlands. Received Aug 9, 1989, and in revised form Oct 13. Accepted for publication Nov 6, 1989. Address correspondence to D r de Visser, Department of Neurology, Academic Medical Center, Meibergdreef 9, 1105 A 2 Amsterdam, The Netherlands.
578 Copyright 0 1990 by the American Neurological Association
