Acta Neuropathol (1992) 84:433 - 436
Acta Heuropathologica (~) Springer-Verlag1992
Occurrence of active demyelinating lesions in children with hereditary motor and sensory neuropathy (HMSN) type I A. Vital 1, C. VitaP, J. Julien 2, and D. Fontan 3 Departments of 1Neuropathology, 2Neurology and 3Pediatry, Bordeaux II University, France Received February 11, 1992/Revised, accepted April 21, 1992
Summary. In three children with dominant hereditary m o t o r and sensory n e u r o p a t h y type I, peripheral nerve biopsy showed the classical lesions of segmental demyelination with remyelination and onion bulb formations. In two cases, ultrastructural examination also d e m o n strated n u m e r o u s characteristic features of active demyelination. The presence of active demyelinating lesions suggests an a u t o i m m u n e attack superimposed on the course of a chronic genetic disease.
were, respectively, 3, 5 and 8 years old. In each case, a minimal peroneal nerve biopsy was performed from the antero-external aspect of the leg. The specimen was fixed immediately in buffered glutaraldehyde and prepared in the usual way for electron microscopy. On account of the patients' ages, no additional specimen was taken for paraffin or frozen sections. The density of myelinated fibres per mm2 of endoneurial area was determined directly with a semiautomatic analyser from transverse semithin sections of Epon-embedded nerve stained with paraphenylenediamine. Transverse thin sections were cut and contrasted with uranyl acetate and lead citrate.
Key words: Active demyelination - H e r e d i t a r y m o t o r and sensory n e u r o p a t h y type I - Childhood
Differential diagnosis between chronic i n f l a m m a t o r y demyelinating p o l y n e u r o p a t h y (CIDP) and CharcotMarie-Tooth ( C M T ) disease in the type I or III hereditary m o t o r and sensory n e u r o p a t h y (HMSN) variants is often difficult to assess in children, especially in the absence of a familial history of C M T disease. A peripheral nerve biopsy m a y be p e r f o r m e d to support the diagnosis. F r o m a classical and morphological point of view, peripheral nerve lesions in C M T disease consist mainly of segmental demyelination with remyelination and onion bulb formations. In this study, ultrastructural examination of peripheral nerve biopsies showed features of active demyclination in two out of three children with dominantly inherited C M T disease in the type I H M S N variant. These morphological findings are comp a r e d with o t h e r observations in the literature.
Material and methods On the basis of clinical and electrophysiological data, HMSN type I was diagnosed in three children. A family history of CMTdisease with dominant inheritance was obvious in the three cases. They Correspondence to: A. Vital, Laboratoire d'Anatomie Pathologique, H6pital Pellegrin, Place Am61ie-Raba-L4on, F-33076 Bordeaux Cedex, France
Results Morphological findings concerning the three children are summarized inTable 1.Two (cases 1 and 2) presented a m a r k e d loss of myelinated fibres. Clusters of regenerating fibres were n u m e r o u s only in case 3. In the three patients, n u m e r o u s onion bulb formations c o m p o s e d of concentric Schwann cell processes were surrounding demyelinated or remyelinated fibres, often with abnormally thin myelin sheaths (Fig. la). Totally demyelin a t e d fibres were frequently observed in the three cases, and macrophagic histiocytes overloaded with myelin debris were sometimes present in the vicinity of these modified fibres (Fig. lb). Moreover, lesions of "active demyelination" were found in two children (cases 1 and 2).These were characterised by the presence of activated m a c r o p h a g e processes stripping away the myelin lamelTable 1. Summary of morphological findings Cases
Sex
Age
MF/mm 2 CI
OB
DF
AD
1 2 3
F M F
3 5 8
5,822 4,076 10,050
+++ ++ ++
+++ ++ ++
++ ++ 0
0 + ++
ME myelinated fibres; C1, clusters of regenerating fibres; OB, onion bulb formations; DE demyelinated fibres; AD, active demyelination Lesions of nerve fibres are graded from + + + (large number of typical aspects) to 0 (absence of typical aspects)
434
Fig. 1. a Two myelinated fibres are surrounded by concentric Schwann cell processes. One has an abnormally thin myelin sheath, b Two macrophagic histiocytes overloaded with myelin debris are present in the vicinity of this demyelinated fibre, a, b Case 2; a • 6,000; b x 8,000
Fig. 2. a Case 1: A macrophagic process (arrow) is stripping away the myelin lamellae; the axon (ax) is not damaged, h Case 2: A macrophage with nucleus and thin elongated process (arrow) has invaded this myelinated fibre; the axon (ax) is intact, a x 8,400; h • 8,000
435
Fig. 3. Case 1: A macrophageoverloadedwith myelindebris has invaded this fibre. Three mononuclearceils with scantycytoplasm are present in the vicinity, x 4,420
lae, while the axon remained intact (Fig. 2a, b). In these two patients (cases 1 and 2), a few cells with scanty cytoplasm were observed in the endoneurium and considered as scattered lymphocytes (Fig. 3).
Discussion We excluded from this study cases of HMSN without a familial history of CMT disease to avoid inclusion of children with CIDR Dominant inheritance was obvious in the three selected children with HMSN type I, and their peripheral nerve biopsy presented demyelinating and remyelinating lesions consistent with this diagnosis. Two also exhibited signs of "active demyelination". These active demyelinating lesions are characteristic when thin elongated macrophagic processes are seen peeling away the myelin lamellae, and when the axon remains intact. Mononuclear cells invading the Schwann cell cytoplasm and peeling of some myelin lamellae along the interperiod line were demonstrated in the first reports on experimental allergic neuritis [11, 20], and in other experimental demyelinating situations such as proximal to axotomy [18]. In human pathology, "active demyelination" is a prominent histological finding in Guillain-Barrd syndrome [4, 16]. It was also reported in CIDP [2, 17]. Gabreels-Festen [9] emphasized the early morphological features in HMSN type I. We agree with
these authors that "florid demyelination" and totally demyelinated fibres are more frequently observed on peripheral nerve biopsies taken in the first years of life, but they did not report characteristic "active demyelination". Active demyelination in CMTdisease was noticed initially by Madrid et al. [13], but not described in detail and without any clinicopathological correlation. Recently, occasional active demyelinating lesions have been reported in children with CMT disease [5, 19]. These morphological findings are interesting because two points of view may be considered. It may be thought that "active demyelination" is similar to "florid demyelination", and that the peripheral nerve biopsy is no use for differential diagnosis between HMSN type I and CIDR Indeed, mononuclear cell infiltrates are often mild in CIDP [6], and not a good criterion per se. In nine autopsied cases of Guillain-Barr6 syndrome, Honavar et al. [10] evidenced that the extent and severity of cell infiltration was variable, usually being less prominent than in previous reports, and sometimes sparing nerves in which myelin destruction was severe. The second and our personal point of view is that "florid demyelination" and "active demyelination" are different lesions, and that the latter strongly suggests an autoimmune process superimposed on the course of a chronic genetic disease. Moreover, this could explain the possible corticosteroid responsiveness of clinical attacks in CMT disease [12]. Gabreels-Festen et al. [8] presented two siblings with CIDP and discussed the diagnostic problems in distinguishing the progressive form of this disease in childhood from HMSN types I and III. Cases of ClDP associated with a history of familial polyneuropathy have been reported in the literature [1, 7, 14, 15]. Dyck et al. [7] considered that the two disorders are linked by some common mechanisms; indeed, there may be a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds. Bird and Sladky [31 recently reported three children with corticosteroidresponsive inflammatory demyelinating polyneuropathy from families with dominantly inherited neuropathy, and the authors also suggested a genetic susceptibility in some patients to an inflammatory demyelinating disorder.
Acknowledgements.The authors are verygratefulto I. Coadouand G. Herfaut for expert technical assistance, to M. Castaniera for preparation of the final photographs and to R. Cookefor linguistic help.
References 1. Antoine JC, Michel D, Kopp N, Gonnaud PM, Laurent B (1989) Neuropathies pdriphdriques chroniques d'allure hdrddod6gdndrativecorticosensibles:deux cas. Rev Neurol (Paris) 145:469-473 2. AsburyAK,JohnsonPC (1978) Pathologyof peripheral nerve. Saunders, Philadelphia, pp 120-135 3. BirdSJ, SladkyJT (1991) Corticosteroid-responsivedominantly inherited neuropathy in childhood. Neurology 41:437-439 4. Brechenmacher C, Vital C, Demini6re C, Laurentjoye L, CastaingY, Gbikpi-BenissanG, CardinaudJP, Favarel-Garri-
436
5.
6.
7. 8.
9.
10.
11.
gues JP (1987) Guillain-Barr6 syndrome: an ultrastructural study of peripheral nerve in 65 patients. Clin Neuropathol 6:19-24 Crawford TO, Griffin JW (1991) Morphometrical and ultrastructural evaluation of the sural nerve in children with Charcot-Marie-Tooth: implications for pathogenesis and treatment. Ann Neurol 30:500 Dyck PJ, Arnason B (1984) Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds) Peripheral neuropathy, vol 2, 2nd edn. Saunders, Philadelphia, pp 2101-2114 Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH (1982) Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 57:239-246 Gabre~ls-Festen AAWM, Hageman ATM, Gabre~ls FJM, Josten EMG, Renier WO,Weemaes CMR,Ter Laak HJ (1986) Chronic inflammatory demyelinating polyneuropathy in two siblings. J Neurol Neurosurg Psychiatry 49:152-156 Gabre~ls-Festen AAWM, Joosten EMG, Gabre~ls FJM, Jennekens FGI, Janssen-van Kempen TW (1992) Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). J Neurol Sci 107:145-154 Honavar M, Tharakan JKJ, Hughes RAC, Leibowitz S, Winer JB (1991) A clinicopathological study of the Guillain-Barr6 syndrome. Nine cases and literature review. Brain 114:1245-1269 Lampert PW (1969) Mechanism of demyelination in experimental allergic neuritis. Lab Invest 20:127-138
12. Lyon G, Evrard P (1987) Neurop6diatrie. Masson, Paris, pp 295-309 13. Madrid R, Bradley WG, Davis CJF (1977) The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological and nerve biopsy studies. 2. Observations on pathological changes in sural nerve biopsies. J Neurol Sci 32:91-122 14. Mitchell GW, Bosch EE Hart MN (1987) Response to immunosuppressive therapy in patients with hereditary motor and sensory neuropathy and associated dysimmune neuromuscular disorders. Eur Neurol 27:188-196 15. Pasternak JF, Fulling K, Nelson J, Prensky AL (1982) An infant with chronic, relapsing polyneuropathy responsive to steroids. Dev Med Child Neurol 24:504-524 16. Prineas JW (1972) Acute idiopathic polyneuritis. An electron microscope study. Lab Invest 26:133-147 17. Prineas JW, McLeod JG (1976) Chronic relapsing polyneuritis. J Neurol Sci 27:427-458 18. Spencer PS, Thomas PK (1970) The examination of isolated nerve fibres by light and electron microscopy, with observations on demyelination proximal to neuromas. Acta Neuropathol (Berl) 16:177-186 19. Vital A, Vital C, Brechenmacher C, Fontan D, Castaing Y (1990) Chronic inflammatory demyelinating polyneuropathy in childhood: ultrastructural features of peripheral nerve biopsies in four case. Eur J Pediatr 149:654-658 20. Wisniewski H, Prineas J, Raine CS (1969) An ultrastructural study of experimental demyelination and remyelination: acute experimental allergic encephalomyelitis in the peripheral nervous system. Lab Invest 21:105-118
Acta Heuropathologica (~) Springer-Verlag1992
Occurrence of active demyelinating lesions in children with hereditary motor and sensory neuropathy (HMSN) type I A. Vital 1, C. VitaP, J. Julien 2, and D. Fontan 3 Departments of 1Neuropathology, 2Neurology and 3Pediatry, Bordeaux II University, France Received February 11, 1992/Revised, accepted April 21, 1992
Summary. In three children with dominant hereditary m o t o r and sensory n e u r o p a t h y type I, peripheral nerve biopsy showed the classical lesions of segmental demyelination with remyelination and onion bulb formations. In two cases, ultrastructural examination also d e m o n strated n u m e r o u s characteristic features of active demyelination. The presence of active demyelinating lesions suggests an a u t o i m m u n e attack superimposed on the course of a chronic genetic disease.
were, respectively, 3, 5 and 8 years old. In each case, a minimal peroneal nerve biopsy was performed from the antero-external aspect of the leg. The specimen was fixed immediately in buffered glutaraldehyde and prepared in the usual way for electron microscopy. On account of the patients' ages, no additional specimen was taken for paraffin or frozen sections. The density of myelinated fibres per mm2 of endoneurial area was determined directly with a semiautomatic analyser from transverse semithin sections of Epon-embedded nerve stained with paraphenylenediamine. Transverse thin sections were cut and contrasted with uranyl acetate and lead citrate.
Key words: Active demyelination - H e r e d i t a r y m o t o r and sensory n e u r o p a t h y type I - Childhood
Differential diagnosis between chronic i n f l a m m a t o r y demyelinating p o l y n e u r o p a t h y (CIDP) and CharcotMarie-Tooth ( C M T ) disease in the type I or III hereditary m o t o r and sensory n e u r o p a t h y (HMSN) variants is often difficult to assess in children, especially in the absence of a familial history of C M T disease. A peripheral nerve biopsy m a y be p e r f o r m e d to support the diagnosis. F r o m a classical and morphological point of view, peripheral nerve lesions in C M T disease consist mainly of segmental demyelination with remyelination and onion bulb formations. In this study, ultrastructural examination of peripheral nerve biopsies showed features of active demyclination in two out of three children with dominantly inherited C M T disease in the type I H M S N variant. These morphological findings are comp a r e d with o t h e r observations in the literature.
Material and methods On the basis of clinical and electrophysiological data, HMSN type I was diagnosed in three children. A family history of CMTdisease with dominant inheritance was obvious in the three cases. They Correspondence to: A. Vital, Laboratoire d'Anatomie Pathologique, H6pital Pellegrin, Place Am61ie-Raba-L4on, F-33076 Bordeaux Cedex, France
Results Morphological findings concerning the three children are summarized inTable 1.Two (cases 1 and 2) presented a m a r k e d loss of myelinated fibres. Clusters of regenerating fibres were n u m e r o u s only in case 3. In the three patients, n u m e r o u s onion bulb formations c o m p o s e d of concentric Schwann cell processes were surrounding demyelinated or remyelinated fibres, often with abnormally thin myelin sheaths (Fig. la). Totally demyelin a t e d fibres were frequently observed in the three cases, and macrophagic histiocytes overloaded with myelin debris were sometimes present in the vicinity of these modified fibres (Fig. lb). Moreover, lesions of "active demyelination" were found in two children (cases 1 and 2).These were characterised by the presence of activated m a c r o p h a g e processes stripping away the myelin lamelTable 1. Summary of morphological findings Cases
Sex
Age
MF/mm 2 CI
OB
DF
AD
1 2 3
F M F
3 5 8
5,822 4,076 10,050
+++ ++ ++
+++ ++ ++
++ ++ 0
0 + ++
ME myelinated fibres; C1, clusters of regenerating fibres; OB, onion bulb formations; DE demyelinated fibres; AD, active demyelination Lesions of nerve fibres are graded from + + + (large number of typical aspects) to 0 (absence of typical aspects)
434
Fig. 1. a Two myelinated fibres are surrounded by concentric Schwann cell processes. One has an abnormally thin myelin sheath, b Two macrophagic histiocytes overloaded with myelin debris are present in the vicinity of this demyelinated fibre, a, b Case 2; a • 6,000; b x 8,000
Fig. 2. a Case 1: A macrophagic process (arrow) is stripping away the myelin lamellae; the axon (ax) is not damaged, h Case 2: A macrophage with nucleus and thin elongated process (arrow) has invaded this myelinated fibre; the axon (ax) is intact, a x 8,400; h • 8,000
435
Fig. 3. Case 1: A macrophageoverloadedwith myelindebris has invaded this fibre. Three mononuclearceils with scantycytoplasm are present in the vicinity, x 4,420
lae, while the axon remained intact (Fig. 2a, b). In these two patients (cases 1 and 2), a few cells with scanty cytoplasm were observed in the endoneurium and considered as scattered lymphocytes (Fig. 3).
Discussion We excluded from this study cases of HMSN without a familial history of CMT disease to avoid inclusion of children with CIDR Dominant inheritance was obvious in the three selected children with HMSN type I, and their peripheral nerve biopsy presented demyelinating and remyelinating lesions consistent with this diagnosis. Two also exhibited signs of "active demyelination". These active demyelinating lesions are characteristic when thin elongated macrophagic processes are seen peeling away the myelin lamellae, and when the axon remains intact. Mononuclear cells invading the Schwann cell cytoplasm and peeling of some myelin lamellae along the interperiod line were demonstrated in the first reports on experimental allergic neuritis [11, 20], and in other experimental demyelinating situations such as proximal to axotomy [18]. In human pathology, "active demyelination" is a prominent histological finding in Guillain-Barrd syndrome [4, 16]. It was also reported in CIDP [2, 17]. Gabreels-Festen [9] emphasized the early morphological features in HMSN type I. We agree with
these authors that "florid demyelination" and totally demyelinated fibres are more frequently observed on peripheral nerve biopsies taken in the first years of life, but they did not report characteristic "active demyelination". Active demyelination in CMTdisease was noticed initially by Madrid et al. [13], but not described in detail and without any clinicopathological correlation. Recently, occasional active demyelinating lesions have been reported in children with CMT disease [5, 19]. These morphological findings are interesting because two points of view may be considered. It may be thought that "active demyelination" is similar to "florid demyelination", and that the peripheral nerve biopsy is no use for differential diagnosis between HMSN type I and CIDR Indeed, mononuclear cell infiltrates are often mild in CIDP [6], and not a good criterion per se. In nine autopsied cases of Guillain-Barr6 syndrome, Honavar et al. [10] evidenced that the extent and severity of cell infiltration was variable, usually being less prominent than in previous reports, and sometimes sparing nerves in which myelin destruction was severe. The second and our personal point of view is that "florid demyelination" and "active demyelination" are different lesions, and that the latter strongly suggests an autoimmune process superimposed on the course of a chronic genetic disease. Moreover, this could explain the possible corticosteroid responsiveness of clinical attacks in CMT disease [12]. Gabreels-Festen et al. [8] presented two siblings with CIDP and discussed the diagnostic problems in distinguishing the progressive form of this disease in childhood from HMSN types I and III. Cases of ClDP associated with a history of familial polyneuropathy have been reported in the literature [1, 7, 14, 15]. Dyck et al. [7] considered that the two disorders are linked by some common mechanisms; indeed, there may be a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds. Bird and Sladky [31 recently reported three children with corticosteroidresponsive inflammatory demyelinating polyneuropathy from families with dominantly inherited neuropathy, and the authors also suggested a genetic susceptibility in some patients to an inflammatory demyelinating disorder.
Acknowledgements.The authors are verygratefulto I. Coadouand G. Herfaut for expert technical assistance, to M. Castaniera for preparation of the final photographs and to R. Cookefor linguistic help.
References 1. Antoine JC, Michel D, Kopp N, Gonnaud PM, Laurent B (1989) Neuropathies pdriphdriques chroniques d'allure hdrddod6gdndrativecorticosensibles:deux cas. Rev Neurol (Paris) 145:469-473 2. AsburyAK,JohnsonPC (1978) Pathologyof peripheral nerve. Saunders, Philadelphia, pp 120-135 3. BirdSJ, SladkyJT (1991) Corticosteroid-responsivedominantly inherited neuropathy in childhood. Neurology 41:437-439 4. Brechenmacher C, Vital C, Demini6re C, Laurentjoye L, CastaingY, Gbikpi-BenissanG, CardinaudJP, Favarel-Garri-
436
5.
6.
7. 8.
9.
10.
11.
gues JP (1987) Guillain-Barr6 syndrome: an ultrastructural study of peripheral nerve in 65 patients. Clin Neuropathol 6:19-24 Crawford TO, Griffin JW (1991) Morphometrical and ultrastructural evaluation of the sural nerve in children with Charcot-Marie-Tooth: implications for pathogenesis and treatment. Ann Neurol 30:500 Dyck PJ, Arnason B (1984) Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds) Peripheral neuropathy, vol 2, 2nd edn. Saunders, Philadelphia, pp 2101-2114 Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH (1982) Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 57:239-246 Gabre~ls-Festen AAWM, Hageman ATM, Gabre~ls FJM, Josten EMG, Renier WO,Weemaes CMR,Ter Laak HJ (1986) Chronic inflammatory demyelinating polyneuropathy in two siblings. J Neurol Neurosurg Psychiatry 49:152-156 Gabre~ls-Festen AAWM, Joosten EMG, Gabre~ls FJM, Jennekens FGI, Janssen-van Kempen TW (1992) Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). J Neurol Sci 107:145-154 Honavar M, Tharakan JKJ, Hughes RAC, Leibowitz S, Winer JB (1991) A clinicopathological study of the Guillain-Barr6 syndrome. Nine cases and literature review. Brain 114:1245-1269 Lampert PW (1969) Mechanism of demyelination in experimental allergic neuritis. Lab Invest 20:127-138
12. Lyon G, Evrard P (1987) Neurop6diatrie. Masson, Paris, pp 295-309 13. Madrid R, Bradley WG, Davis CJF (1977) The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological and nerve biopsy studies. 2. Observations on pathological changes in sural nerve biopsies. J Neurol Sci 32:91-122 14. Mitchell GW, Bosch EE Hart MN (1987) Response to immunosuppressive therapy in patients with hereditary motor and sensory neuropathy and associated dysimmune neuromuscular disorders. Eur Neurol 27:188-196 15. Pasternak JF, Fulling K, Nelson J, Prensky AL (1982) An infant with chronic, relapsing polyneuropathy responsive to steroids. Dev Med Child Neurol 24:504-524 16. Prineas JW (1972) Acute idiopathic polyneuritis. An electron microscope study. Lab Invest 26:133-147 17. Prineas JW, McLeod JG (1976) Chronic relapsing polyneuritis. J Neurol Sci 27:427-458 18. Spencer PS, Thomas PK (1970) The examination of isolated nerve fibres by light and electron microscopy, with observations on demyelination proximal to neuromas. Acta Neuropathol (Berl) 16:177-186 19. Vital A, Vital C, Brechenmacher C, Fontan D, Castaing Y (1990) Chronic inflammatory demyelinating polyneuropathy in childhood: ultrastructural features of peripheral nerve biopsies in four case. Eur J Pediatr 149:654-658 20. Wisniewski H, Prineas J, Raine CS (1969) An ultrastructural study of experimental demyelination and remyelination: acute experimental allergic encephalomyelitis in the peripheral nervous system. Lab Invest 21:105-118
