Acta Neuropathol (1992) 84: 574- 576
Ada HeuropathologJca (~) Springer-Verlag 1992
Myelination of two axons by a single Schwann cell H. Kusaka, T. Imai, S. Matsumoto, H. Ito, and M. Yamasaki Department of Neurology, Kitano Hospital and Neurological Center, 13-3, Kamiyama-cho, Kita-ku, Osaka 530, Japan Received April 7, 1992/Revised, accepted May 18, 1992
Summary. A S c h w a n n cell c a n f o r m o n l y o n e i n t e r n o d e of myelin around an axon. However, we observed the f o r m a t i o n b y a single S c h w a n n cell o f m y e l i n a r o u n d t w o a x o n s o f d i f f e r e n t d i a m e t e r s in t h e sural n e r v e o f a 45-year-old man with mononeuritis multiplex. Schwann cell p r o c e s s e s s p i r a l e d in t h e s a m e d i r e c t i o n a r o u n d e a c h a x o n , f o r m i n g m e s a x o n s . T h e f i n d i n g s in this case a p p e a r to be an undescribed type of aberrant myelination. Key words: A b e r r a n t m y e l i n a t i o n - A x o n - M y e l i n a t i o n - S c h w a n n cell
and subperineurial edema. Severity of nerve fiber loss in the fascicles varied (myelinated fiber density: 706 - 3,877/mm3), as did that within a single fascicle. Inflammatory cells were absent, and no signs of vasculitis were found. The following laboratory test results were all negative: complete blood count, erythrocyte sedimentation rate, creatine kinase, thyroid function, serum immunoglobulins, cryoglobulin, antinuclear antibody, anti-neutrophil cytoplasmic autoantibodies, HIV and hepatitis serology, T and B lymphocyte subpopulation, and CSF (protein 31 mg/100 ml). Subsequent long-term trial of corticosteroid under the provisional diagnosis of nonsystemic vasculitic neuropathy resulted in almost complete recovery of muscle strength without improvement of sensory dysfunction in 6 months.
Ultrastructure I n t h e c e n t r a l n e r v o u s s y s t e m , a single o l i g o d e n d r o g l i a can f o r m as m a n y as 18 t o 60 s e g m e n t s o f m y e l i n [8]. C o n v e r s e l y , in t h e p e r i p h e r a l n e r v o u s s y s t e m , a single S c h w a n n cell c a n f o r m o n l y o n e i n t e r n o d e o f m y e l i n a r o u n d an a x o n [4, 9 - 1 1 ] . W e r e p o r t h e r e i n t h e n o v e l f i n d i n g o f f o r m a t i o n b y a single S c h w a n n cell o f m y e l i n sheaths around two different axons.
Case report A 45-year-old male construction worker with no relevant past medical or family history, noted paresthesia distal to the right ankle upon awakening on November 1, 1990. Nine days later, lancinating pain and paresthesia developed in the right fourth and fifth fingers as well as on the lateral side of the left foot. He was admitted t'o a hospital, where he was diagnosed as having mononeuritis multiplex and treated with corticosteroids for 2 weeks without effect. He was referred to Kitano Hospital for further evaluation on April 10, 1991. Neurological examination revealed motor and sensory impairment in the territories of the right ulnar, right common peroneal, right tibial and left sural nerves. Electrophysiological studies demonstrated denervation in the muscles innervated by these nerves, with small amplitudes of evoked potentials. Biopsy of the right sural nerve revealed severe-to-moderate nerve fiber loss and axonal degeneration with myelin ovoids, scattered macrophages Correspondence to: H. Kusaka (address see above)
A portion of the biopsied right sural nerve was processed for electron microscopy by conventional methods. Electron microscopic examination confirmed axonal degeneration, which consisted of presence of myelin ovoids, dissolution of axoplasm, accumulation of organelles and filaments within the axon. In addition, several fibers presented thin myelin suggestive of remyelination. One unexpected finding was that one cell process contained two myelinated axons (Fig. 1). The cytoplasm of the process was completely surrounded by redundant and duplicated basal laminae, containing intermediate filaments, proliferating smooth endoplasmic reticulum and many glycogen granules. Two outer mesaxons were identified, and clockwise spiraling of myelin lamellae were observed around each axon (Fig. 1). The diameters of the two axons were different with corresponding thickness of the myelin lamellae. Similar configurations were found in two other Schwann cells.
Discussion T h e u l t r a s t r u c t u r e o f t h e cell p r o c e s s f o r m i n g m y e l i n a r o u n d t h e two a x o n s o b s e r v e d in t h e p r e s e n t s t u d y c o n f o r m e d to t h e c h a r a c t e r i s t i c s o f S c h w a n n cells. T h e redundancy of basal lamina would represent remodeling o f t h e d e g e n e r a t e d n e r v e fibers. A s s e s s m e n t o f t h e course of the mesaxons suggested that two separate p r o c e s s e s p r o c e e d e d a n d w r a p p e d a r o u n d t h e a x o n s in the same direction, and the myelin lamellae formed were
575
Fig. 1. Five cell processes are surrounded by a common basal lamina. One contains a nucleus (upper right). Basal laminae are redundant and duplicated in several places. One process encases two myelinated axons (lower left), displaying two outer mesaxons
(arrows). Numerous cisterns of smooth endoplasmic reticulum and glycogen granules are observed in the process as well as in the axons with different diameters. • 17,400
of a p p r o p r i a t e thickness for each axon. If one axon h a d b e n t sharply, t h e n two m y e l i n a t e d axons could have b e e n seen in the S c h w a n n cell cytoplasm. H o w e v e r , if this were so, the spiraling direction o f myelin lamellae w o u l d have b e e n opposite. A l t h o u g h t h e y are rarer in the peripheral t h a n in the central n e r v o u s s y s t e m [11], several instances of aberrant m y e l i n a t i o n have b e e n e n c o u n t e r e d u n d e r develop-
m e n t a l or o t h e r conditions; a single myelin s h e a t h has b e e n o b s e r v e d to s u r r o u n d multiple axons [1, 2, 12], and two myelin sheaths to encircle o n e a x o n [3, 6]. Findings similar to t h o s e in o u r case were f o u n d in a peripheral nerve of a h a m s t e r with hind leg paralysis (see Fig. 10 in [5]), but were p r e s u m e d to represent the tangential section t h r o u g h the p s e u d o n o d e s , with o n e myelin sheath containing the true axon and the o t h e r s u r r o u n d -
576 ing a p r o t r u d i n g p o r t i o n of the s a m e a x o n (see Fig. 12 in [5]). T h e s e e x a m p l e s o f a b e r r a n t m y e l i n a t i o n differ f r o m t h a t in the p r e s e n t case. I n d e v e l o p m e n t a l stages o f the n e r v o u s system, the acquisition o f a length o f o n e a x o n by a single S c h w a n n cell is d e e m e d to be a necessary condition b e f o r e m y e l i n a t i o n can o c c u r [9, 11]. E v e n in r e m y e l i n a t i o n by S c h w a n n cells in the central n e r v o u s system, o n e S c h w a n n cell a p p a r e n t l y f o r m s only o n e i n t e r n o d e a r o u n d an a x o n [7]. A s far as we know, t h e r e has b e e n no r e p o r t o f m y e l i n a t i o n of two axons by a single S c h w a n n cell, a finding contradicting the established d o g m a that o n e S c h w a n n cell can f o r m only o n e i n t e r n o d e o f the peripheral n e r v e fiber [4, 9-11]. This p r o b a b l y represents an u n u s u a l t y p e of a b e r r a n t myelination.
Acknowledgements.We wish to thank Dr.T. Osugi for referring the patient and Prof. A. Hirano, Division of Neuropathology, Montefiore Medical Center, Bronx, New York, for his helpful comments and discussion.We also thank Mr. S. Fukui and Mrs. A. Asada for their skillful technical assistance.
References 1. Beuche W, Friede RL (1984) Naked axon bundles enclosed by single segments in the nerves of non-dystrophic C57BL-ob/ +mice. Neuropathol Appl Neurobiol 10:369-377
2. Brown M J, Radich SJ (1979) Polyaxonal myelination in developing dystrophic and normal mouse nerves. Muscle Nerve 2:217-222 3. Heath JW (1982) Double myelination of axons in the sympathetic nervous system. J Neurocytol 11:249-262 4. Hirano A (1981) A guide to neuropathology. Igaku-shoin, Tokyo, pp 225-264 5. Hirano A (1984) Nodes of Ranvier in pathological conditions. In: Zagoren JC, Fedoroff S (eds) The node of Ranvier. Academic press, Orland, pp 213-243 6. Kidd GJ, Heath JW (1988) Double myelination of axons in the sympathetic nervous system of the mouse. I. ultrastructural features and distribution. J Neurocytol 17:245-261 7. Ludwin SK (1985) Remyelination in the central nervous system of the mouse. In: Adachi M, Hirano A, Aronson SM (eds) The pathology of the myelinated axon. Igaku-shoin, New York, pp 49-79 8. Matthews MA, Duncan D (1971) A quantitative study of the morphological changes accompanying the initiation and progress of myelin production in the dorsal funiculus of the rat spinal cord. J Comp Neurol 142:1-22 9. Raine CS (1984) Morphology of myelin and myelination. In: Morrel P (ed) Myelin, 2nd edn. Plenum publishing, NewYork, pp 1-50 10. Raine CS (1991) Oligodendrocytes and central nervous system myelin. In: Davis RL, Robertson DM (eds) Textbook of neuropathology, 2nd edn. Williams & Wilkins, Baltimore, pp 115-140 11. Peters A, Palay SL,Webster H-deF (1991) The fine structure of the nervous system. Neurons and their supporting cells, 3rd edn. Oxford University Press, New York, pp 212-272 12. Webster H-deF (1964) Some ultrastructural features of segmental demyelination and myelin regeneration in peripheral nerve. Prog Brain Res 13:151-174
Ada HeuropathologJca (~) Springer-Verlag 1992
Myelination of two axons by a single Schwann cell H. Kusaka, T. Imai, S. Matsumoto, H. Ito, and M. Yamasaki Department of Neurology, Kitano Hospital and Neurological Center, 13-3, Kamiyama-cho, Kita-ku, Osaka 530, Japan Received April 7, 1992/Revised, accepted May 18, 1992
Summary. A S c h w a n n cell c a n f o r m o n l y o n e i n t e r n o d e of myelin around an axon. However, we observed the f o r m a t i o n b y a single S c h w a n n cell o f m y e l i n a r o u n d t w o a x o n s o f d i f f e r e n t d i a m e t e r s in t h e sural n e r v e o f a 45-year-old man with mononeuritis multiplex. Schwann cell p r o c e s s e s s p i r a l e d in t h e s a m e d i r e c t i o n a r o u n d e a c h a x o n , f o r m i n g m e s a x o n s . T h e f i n d i n g s in this case a p p e a r to be an undescribed type of aberrant myelination. Key words: A b e r r a n t m y e l i n a t i o n - A x o n - M y e l i n a t i o n - S c h w a n n cell
and subperineurial edema. Severity of nerve fiber loss in the fascicles varied (myelinated fiber density: 706 - 3,877/mm3), as did that within a single fascicle. Inflammatory cells were absent, and no signs of vasculitis were found. The following laboratory test results were all negative: complete blood count, erythrocyte sedimentation rate, creatine kinase, thyroid function, serum immunoglobulins, cryoglobulin, antinuclear antibody, anti-neutrophil cytoplasmic autoantibodies, HIV and hepatitis serology, T and B lymphocyte subpopulation, and CSF (protein 31 mg/100 ml). Subsequent long-term trial of corticosteroid under the provisional diagnosis of nonsystemic vasculitic neuropathy resulted in almost complete recovery of muscle strength without improvement of sensory dysfunction in 6 months.
Ultrastructure I n t h e c e n t r a l n e r v o u s s y s t e m , a single o l i g o d e n d r o g l i a can f o r m as m a n y as 18 t o 60 s e g m e n t s o f m y e l i n [8]. C o n v e r s e l y , in t h e p e r i p h e r a l n e r v o u s s y s t e m , a single S c h w a n n cell c a n f o r m o n l y o n e i n t e r n o d e o f m y e l i n a r o u n d an a x o n [4, 9 - 1 1 ] . W e r e p o r t h e r e i n t h e n o v e l f i n d i n g o f f o r m a t i o n b y a single S c h w a n n cell o f m y e l i n sheaths around two different axons.
Case report A 45-year-old male construction worker with no relevant past medical or family history, noted paresthesia distal to the right ankle upon awakening on November 1, 1990. Nine days later, lancinating pain and paresthesia developed in the right fourth and fifth fingers as well as on the lateral side of the left foot. He was admitted t'o a hospital, where he was diagnosed as having mononeuritis multiplex and treated with corticosteroids for 2 weeks without effect. He was referred to Kitano Hospital for further evaluation on April 10, 1991. Neurological examination revealed motor and sensory impairment in the territories of the right ulnar, right common peroneal, right tibial and left sural nerves. Electrophysiological studies demonstrated denervation in the muscles innervated by these nerves, with small amplitudes of evoked potentials. Biopsy of the right sural nerve revealed severe-to-moderate nerve fiber loss and axonal degeneration with myelin ovoids, scattered macrophages Correspondence to: H. Kusaka (address see above)
A portion of the biopsied right sural nerve was processed for electron microscopy by conventional methods. Electron microscopic examination confirmed axonal degeneration, which consisted of presence of myelin ovoids, dissolution of axoplasm, accumulation of organelles and filaments within the axon. In addition, several fibers presented thin myelin suggestive of remyelination. One unexpected finding was that one cell process contained two myelinated axons (Fig. 1). The cytoplasm of the process was completely surrounded by redundant and duplicated basal laminae, containing intermediate filaments, proliferating smooth endoplasmic reticulum and many glycogen granules. Two outer mesaxons were identified, and clockwise spiraling of myelin lamellae were observed around each axon (Fig. 1). The diameters of the two axons were different with corresponding thickness of the myelin lamellae. Similar configurations were found in two other Schwann cells.
Discussion T h e u l t r a s t r u c t u r e o f t h e cell p r o c e s s f o r m i n g m y e l i n a r o u n d t h e two a x o n s o b s e r v e d in t h e p r e s e n t s t u d y c o n f o r m e d to t h e c h a r a c t e r i s t i c s o f S c h w a n n cells. T h e redundancy of basal lamina would represent remodeling o f t h e d e g e n e r a t e d n e r v e fibers. A s s e s s m e n t o f t h e course of the mesaxons suggested that two separate p r o c e s s e s p r o c e e d e d a n d w r a p p e d a r o u n d t h e a x o n s in the same direction, and the myelin lamellae formed were
575
Fig. 1. Five cell processes are surrounded by a common basal lamina. One contains a nucleus (upper right). Basal laminae are redundant and duplicated in several places. One process encases two myelinated axons (lower left), displaying two outer mesaxons
(arrows). Numerous cisterns of smooth endoplasmic reticulum and glycogen granules are observed in the process as well as in the axons with different diameters. • 17,400
of a p p r o p r i a t e thickness for each axon. If one axon h a d b e n t sharply, t h e n two m y e l i n a t e d axons could have b e e n seen in the S c h w a n n cell cytoplasm. H o w e v e r , if this were so, the spiraling direction o f myelin lamellae w o u l d have b e e n opposite. A l t h o u g h t h e y are rarer in the peripheral t h a n in the central n e r v o u s s y s t e m [11], several instances of aberrant m y e l i n a t i o n have b e e n e n c o u n t e r e d u n d e r develop-
m e n t a l or o t h e r conditions; a single myelin s h e a t h has b e e n o b s e r v e d to s u r r o u n d multiple axons [1, 2, 12], and two myelin sheaths to encircle o n e a x o n [3, 6]. Findings similar to t h o s e in o u r case were f o u n d in a peripheral nerve of a h a m s t e r with hind leg paralysis (see Fig. 10 in [5]), but were p r e s u m e d to represent the tangential section t h r o u g h the p s e u d o n o d e s , with o n e myelin sheath containing the true axon and the o t h e r s u r r o u n d -
576 ing a p r o t r u d i n g p o r t i o n of the s a m e a x o n (see Fig. 12 in [5]). T h e s e e x a m p l e s o f a b e r r a n t m y e l i n a t i o n differ f r o m t h a t in the p r e s e n t case. I n d e v e l o p m e n t a l stages o f the n e r v o u s system, the acquisition o f a length o f o n e a x o n by a single S c h w a n n cell is d e e m e d to be a necessary condition b e f o r e m y e l i n a t i o n can o c c u r [9, 11]. E v e n in r e m y e l i n a t i o n by S c h w a n n cells in the central n e r v o u s system, o n e S c h w a n n cell a p p a r e n t l y f o r m s only o n e i n t e r n o d e a r o u n d an a x o n [7]. A s far as we know, t h e r e has b e e n no r e p o r t o f m y e l i n a t i o n of two axons by a single S c h w a n n cell, a finding contradicting the established d o g m a that o n e S c h w a n n cell can f o r m only o n e i n t e r n o d e o f the peripheral n e r v e fiber [4, 9-11]. This p r o b a b l y represents an u n u s u a l t y p e of a b e r r a n t myelination.
Acknowledgements.We wish to thank Dr.T. Osugi for referring the patient and Prof. A. Hirano, Division of Neuropathology, Montefiore Medical Center, Bronx, New York, for his helpful comments and discussion.We also thank Mr. S. Fukui and Mrs. A. Asada for their skillful technical assistance.
References 1. Beuche W, Friede RL (1984) Naked axon bundles enclosed by single segments in the nerves of non-dystrophic C57BL-ob/ +mice. Neuropathol Appl Neurobiol 10:369-377
2. Brown M J, Radich SJ (1979) Polyaxonal myelination in developing dystrophic and normal mouse nerves. Muscle Nerve 2:217-222 3. Heath JW (1982) Double myelination of axons in the sympathetic nervous system. J Neurocytol 11:249-262 4. Hirano A (1981) A guide to neuropathology. Igaku-shoin, Tokyo, pp 225-264 5. Hirano A (1984) Nodes of Ranvier in pathological conditions. In: Zagoren JC, Fedoroff S (eds) The node of Ranvier. Academic press, Orland, pp 213-243 6. Kidd GJ, Heath JW (1988) Double myelination of axons in the sympathetic nervous system of the mouse. I. ultrastructural features and distribution. J Neurocytol 17:245-261 7. Ludwin SK (1985) Remyelination in the central nervous system of the mouse. In: Adachi M, Hirano A, Aronson SM (eds) The pathology of the myelinated axon. Igaku-shoin, New York, pp 49-79 8. Matthews MA, Duncan D (1971) A quantitative study of the morphological changes accompanying the initiation and progress of myelin production in the dorsal funiculus of the rat spinal cord. J Comp Neurol 142:1-22 9. Raine CS (1984) Morphology of myelin and myelination. In: Morrel P (ed) Myelin, 2nd edn. Plenum publishing, NewYork, pp 1-50 10. Raine CS (1991) Oligodendrocytes and central nervous system myelin. In: Davis RL, Robertson DM (eds) Textbook of neuropathology, 2nd edn. Williams & Wilkins, Baltimore, pp 115-140 11. Peters A, Palay SL,Webster H-deF (1991) The fine structure of the nervous system. Neurons and their supporting cells, 3rd edn. Oxford University Press, New York, pp 212-272 12. Webster H-deF (1964) Some ultrastructural features of segmental demyelination and myelin regeneration in peripheral nerve. Prog Brain Res 13:151-174
