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Scapuloperoneal neuropathy: A distinct clinicopathologic entity
Journal of the Neurological Sciences, 1988, 87:91-102 Elsevier
91
JNS 03049
Scapuloperoneal neuropathy" a distinct clinicopathologic entity Craig L. Hyser, John T. Kissel, John R. Warmolts and Jerry R. Mendell Department of Neurology, Ohio State University Hospital, Columbus, OH 43210 (U.S.A.) (Received 1 March, 1988) (Revised, received 31 May, 1988) (Accepted 31 May, 1988)
SUMMARY
Peripheral neuropathy as a cause for the scapuloperoneal syndrome continues to be controversial. This report provides further evidence in support of a scapuloperoneal neuropathy as a separate nosologic entity. Three men had a slowly progressive disorder of 5-17 years duration with prominent weakness and atrophy of scapular stabilizer, shoulder girdle and distal lower extremity muscles accompanied by a distal panmodality sensory loss. Electrodiagnostic studies and sural nerve biopsies indicated a primary axonal neuropathy with secondary demyelination and remyelination.
Keywords: Peripheralneuropathy; Scapuloperonealneuropathy; Clinicopathological entity
INTRODUCTION
Brossard was the first to describe a syndrome of weakness affecting the shoulder girdle and distal lower extremity muscles (Brossard 1886). Since then numerous case studies and literature reviews have attempted to clarify this heterogeneous group of disorders (Kaeser 1975; Bethlem 1979; Carroll 1979; Serratrice et al. 1979; Harding 1984). Despite a lack of sufficient detail in some reports, there appears to be enough information to support the point of view that scapuloperoneal syndromes can result Correspondence to: Dr. J.R. Mendell, Department of Neurology, Ohio State University Hospital, 1655 Upham Drive, Columbus, OH 43210, U.S.A.
92 from disorders of skeletal muscle (Oransky 1927; Ricker and Mertens 1968; Feigenbaum and Munsat 1970; Kazakov et al. 1975; Thomas et al. 1975), spinal motor neurons (Kaeser 1965; Emery et al. 1968; Meadows and Marsden 1969; Tsukagoshi et al. 1969; Mercelis et al. 1980) and peripheral nerve (Davidenkow 1939; Schwartz and Swash 1975; Nakahara et al. 1986; Ronen et al. 1986). The specific objective of this report is to expand on only the scapuloperoneal syndrome caused by a peripheral neuropathy, a condition sometimes referred to as Davidenkow's syndrome (Schwartz and Swash 1975; Ronen et al. 1986). In 1939, Davidenkow (1939) published his experience in 4 families and 1 sporadic case and collated the existing literature in order to describe an entity with overlapping but also distinctive features from the "amyotrophy of Charcot and Marie" and the "myopathy of Landouzy and Dejerine". The salient characteristics of the condition were autosomal dominant inheritance, onset usually at age 17-20 (but sometimes as late as 45), atrophy of the shoulder girdle, pectoral, trapezius, rhomboids, and serratus anterior muscles, distal lower extremity muscle involvement, a tendency toward pes cavus and a distal sensory loss. While this summary seems clear enough, confusion continues to arise over the existence of a separate form of scapuloperoneal syndrome caused by a peripheral neuropathy. Experience in 3 sporadic cases rekindled our interest in this rarely reported entity. We believe that the criteria outlined by Davidenkow (1939) were accurate in describing a form of scapuloperoneal syndrome caused by a peripheral neuropathy, and propose the term scapuloperonealneuropathybe used in preference to Davidenkow's syndrome when referring to this condition.
CASE REPORTS Case I
This 66-year-old white male dated the onset of his symptoms to 1965 when, at age 49, he noticed numbness of his feet and distal lower extremity weakness. These symptoms progressed over the next 17 years and he developed bilateral foot drop. Family history revealed his father and a paternal aunt (both deceased) had developed difficulty with ambulation in the sixth decade. Examination revealed normal cranial nerves. There was marked weakness and atrophy (Fig. 1) of the scapular stabilizer muscles as well as pelvic girdle and anterior compartment leg muscles. Sensory examination revealed distal impairment to pin, touch and temperature to the knees. Vibration sensation was reduced to the ankle and position sense was decreased in the toes. All tendon reflexes were absent and there was mild pes cavus. Case 2
This white male had a history of muscle cramps since his twenties. At the age of 67, 4 years prior to evaluation, he noted difficulty walking because of lower extremity weakness. One year later he noted numbness and tingling distally in the lower extremities. Within 2 years he developed the same sensory disturbance in his hands. Over the year prior to evaluation the lower extremity strength worsened and he began having difficulty using his arms. Sensory loss progressed to the knees and elbows bilaterally. Although there was a remote history of alcoholism, the patient had stopped drinkin8 at age 47. There was no other significant medical history and the family history was negative. Examination at age 71 revealed normal cranial nerves. There was weakness and wasting of the shoulder girdle muscles, particularly the scapular stabilizers. In the lower extremities there was prominent weakness of the anterior compartment muscles below the knee as well as the pelvic girdle. Pin, cold and touch sensations were impaired to the level of the elbows and knees. Vibration was impaired to the wrists
93
Fig. 1. Photograph of case 1 showing atrophy of scapular stabilizer muscles with resulting scapular winging. and knees and position sense was decreased in the toes. The tendon reflexes were hypoactive in the upper extremities, normal at the knees, and absent at the ankles. The patient had a mild thoracic levoscoliosis. Case 3
This 57-year-old white male presented with a 5-year history of progressive weakness involving the lower more than the upper extremities and numbness which first involved the distal fight lower extremity but later involved both legs to the knees and both arms to the elbows. The past medical history was unremarkable and there was no family history of neuromuscular problems. Examination revealed normal cranial nerve function. There was weakness and atrophy of the proximal upper extremity muscles most prominent in the trapezius, infraspinatus and rhomboids. In the lower extremities, there was weakness of the pelvic girdle and anterior compartment leg muscles. There was distal impairment to pin, touch and cold sensation to the level of the wrists and knees. Position sense was impaired in the fingers and toes. Vibration was reduced in the toes. The tendon reflexes were absent.
LABORATORY FINDINGS T h e following l a b o r a t o r y findings were n o r m a l in each case: c o m p l e t e b l o o d c o u n t , s e r u m electrolytes, s e r u m glucose, creatine kinase, b l o o d u r e a nitrogen, creatinine, liver f u n c t i o n studies, t h y r o i d f u n c t i o n studies, s e r u m B12, s e r u m folate, s e r u m p r o t e i n electrophoresis, erythrocyte s e d i m e n t a t i o n rate, r h e u m a t o i d factor, antin u c l e a r a n t i b o d y , s e r u m c o m p l e m e n t s , s e r u m a n d u r i n e i m m u n o e l e c t r o p h o r e s i s , urine screen for h e a v y m e t a l s a n d p o r p h y r i n s .
94 MATERIALS AND METHODS
Sural nerve biopsies were performed 18-20 cm above the base of the heel. A 3.5-cm segment of nerve was removed and placed in 3~o glutaraldehyde in 0.1 M phosphate buffer and processed for resin sections, electron microscopy and nerve fiber teasing as previously described (Ramirez et al. 1986). Random blocks of nerve cut in cross-section were selected for morphometric analysis. One #m thick sections were stained with toluidine blue and projected at a magnification of x 1500 to perform a size-frequency histogram. The area of the nerve was determined using a Zeiss Videoplan Morphometry Unit. Morphometric measurements were also performed on electron micrographs of thin transverse sections stained with uranyl acetate and lead citrate. Measurements were made of 50 different sequentially encountered myelinated nerve fibers for each case, The perimeters of the inner and outermost major dense lines of myelin were determined and the axon area measured with the Zeiss Videoplan Morphometry Unit. The number of major dense lines of myelin was counted through a binocular dissecting microscope. Myelin membrane length (MML) for each fiber was determined using the formula
where Po and Pi are the perimeters of the outer and inner major dense lines, respectively, and n is the total number of myelin turns. Regression lines relating the natural logarithms of the axon area to M M L were constructed and analyzed over various intervals of MML according to the method of Nukada et al. (1983). The assessment of randomness of occurrence of segmental demyelination and remyelination was determined on 150 teased nerve fibers (50 per case) as previously described (O'Brien 1976; Dyck et al. 1977). The presence or absence of segmental demyelination and remyelination was plotted and counted according to the sequence encountered. Only internodes with a myelin thickness less than 50~o of the adjacent internodal myelin were included. In addition, only one score was given for each territory of an "old" intemode irrespective of partial or total demyelination or both demyelination and remyelination. Statistical analysis of randomness versus clustering of demyelinated and remyelinated internodes was determined by conceptually placing individual teased nerve fibers end-to-end (O'Brien 1976; Dyck etal. 1977). The sample standard deviation was chosen to measure departure from random distribution (Dyck et al. 1977, 1981). Fifty nerve fibers from each case were teased and classified according to a modification of the Dyck classification (Dyck et al. 1984; Ramirez et al. 1986): A = normal; B = myelin wrinkling and redundant loops of myelin; C = demyelination (paranodal and segmental); D = remyelination in which myelin thickness is less than 50% of the adjacent internodal myelin; E = demydination and remyelination; F = wallerian degeneration.
95 Control sural nerve biopsies were available from 2 normal men, ages 25 and 42, giving informed consent under the guidelines of the Institutional Human Studies Committee. Sensory nerve conduction velocities were calculated by dividing the distance (digit to wrist, or calf to malleolus) between cathode and active surface electrode by the latency to the first positive peak of the electronically averaged sensory nerve action potential. Distal limb temperature was maintained at 33-35 °C by an external heat source. Motor nerve conduction velocities (elbow-wrist and fibular head-ankle) were determined in the conventional manner using surface stimulating and recording electrodes, with latencies measured by an electronic cursor placed on a trace on a storage oscilloscope. Needle electromyography was conducted with monopolar recording electrodes.
RESULTS Electrodiagnostic studies In each case, the major finding on electromyographic examination was a reduction in motor unit recruitment relative to effort. This was apparent in both proximal and distal muscles of the upper and lower extremities particularly in the scapuloperoneal distribution. Fibrillation potentials, positive sharp waves, and pathologically enlarged motor unit potentials were infrequently encountered but when present were found in both proximal and distal muscles. Motor and sensory nerve conduction velocities were either normal or mildly slowed when a response could be evoked, as summarized in Table 1. Sural nerve biopsies Nerve changes were consistent between patients although there was variability in severity which correlated with the duration of disease. In each case there was a loss of myelinated nerve fibers, particularly the larger sizes (Fig. 2). In 1-/~m thick resin sections prominent changes included the presence of thinly myelinated axons and clusters of regenerating axons surrounded by multiple Schwann cell processes (Fig. 3). Myelin ovoids typical of wallerian degeneration were occasionally seen. Teased nerve fibers included a spectrum of abnormalities. Myelin wrinkling (condition B, case 1 = 18~ ; case2=26~; c a s e 3 = 13~o) and remyelinating segments (condition D, case 1 = 1 4 ~ ; case 2 = 10~o; case 3 -- 12~) were the most common changes. Demyelination was most prominent in case 3 (condition C, case 1 = 3 ~o ; case 2 = 1 ~ ; case3 = 10~; condition E, case 1 = 1~o; case2 = 1 ~ ; case3 = 10~o). Wallerian degeneration was rare (condition F, 1 ~o for cases 1 and 2). A plot of the regression lines of axonal area in relation to M M L showed a diminution of axonal area for the larger myelinated fibers (Fig. 4). This is consistent with axonal shrinkage for the large myelinated fiber population. The occurrence of demyelinated and remyelinated segments on 50 single teased nerve fibers for each case (totalling 1091 internodes), handled as if placed end to end,
57.5 + 4.8
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Sensory NCV (m/sec)
Motor NCV (m/sec)
Case
SNAP = sensory nerve action potential; NCV = nerve conduction velocity; N R = no response.
NERVE C O N D U C T I O N VELOCITY D A T A
TABLE 1
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Fig. 2. Fiber size-frequency distribution histograms for the sural nerve biopsies from cases I(A), 2(B), and 3(C) compared to a normal control (D) demonstrating a loss of myvlinated fibers in all cases, particularly affecting the intermediate and larger size fibers.
Fig. 3. One #m resin-embedded sections from cases 1 (A) and 3 (B) showing myelinated nerve fiber loss and Schwann cell proliferation in relation to thinly myelinated axons and clusters of regenerating axons (toluidine blue stain, x 1500).
99 4.0• CASE 3
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Myelin Membrone Length (In juml Fig. 4. Regression lines relating axon area to myelin membrane length (MML) for 2 control nerves and nerves from the 3 scapuloperonealeases (dashed line). For a given MML, there is a significant diminution of axonal area compared to controls for the larger myelinatedfiber populations. The P values are given for each case compared to the controls over the intervals shown (NS = not significant). strongly favored a clustered or non-random distribution (O'Brien 1976; Dyck et al. 1977) at P < 0.001. The statistical significance was unchanged if the cases were analyzed separately or collectively.
DISCUSSION The 3 patients reported here all had a peripheral neuropathy as a cause for their scapuloperoneal syndrome. Electrodiagnostic studies showed decreased motor unit recruitment, pathologically enlarged motor units, and normal or mildly slowed conduction velocities. The sural nerve biopsies, studied in far greater detail than in prior reports were consistent with an axonopathy with secondary demyelination related to axonal atrophy. Morphometric studies confmned the presence of a non-random distribution of segmental demyelination and remyelination associated with a reduction of axonal area for a given M M L . The data for M M L from our 3 patients was indicative of axonal atrophy if plotted against our limited number of controls or the more extensive data of Nukada et al. (1982) using 41 controls ages 20-51. The clinical picture of the patients presented here is similar to the narrative description of s o m e but not all of the cases presented in Davidenkow's (1939) report. In addition, although subsequent reports of this entity are relatively few, there have been some case studies of patients identical to ours. This is best illustrated by the sporadic
100 TABLE 2 SCAPULOPERONEALNEUROPATHIES Type I
Type II
Age of onset Inheritance Distribution of weakness
Before 20 years AD/sporadic Scapuloperoneal
Sensory loss Pes cavus Nerve pathology
Distal Greater tendency Prominent demyelination with onion bulbs
After 30 years AD/sporadic Scapuloperoneal and pelvic girdle involvement Distal Lesser tendency Axonal atrophy with secondarydemyelination
case of Schwartz and Swash (1975) and the 9 cases, 4 with autosomal dominant inheritance, reported by Nakahara et al. (1986). We believe these cases most likely represent a specific subgroup of scapuloperoneal neuropathy. Clinical features include sporadic occurrence or dominant inheritance, relatively late onset (usually over 30 years), distal sensory loss and muscle weakness in a scapuloperoneal distribution. In addition an important finding in these patients is weakness of pelvic girdle muscles. Nerve conduction studies are normal or mildly reduced and morphometric analysis of sural nerves is indicative of an axonopathy with secondary demyelination. The features of the subgroup of scapuloperoneal neuropathy described in this report, however, do not appear to encompass the entire clinical spectrum of patients with this entity. Review of the literature suggests that at least one other subgroup of scapuloperoneal neuropathy can be distinguished (Table 2) exemplified by the patients of Ronen et al. (1986), Serratrice et al. (1979) and some of Davidenkow's cases (1939). Description of these cases reveals a younger onset, usually before 20 years. Autosomal dominant or sporadic occurrence is the same in both subgroups as is the sensory loss and muscle weakness, with one notable exception. The pelvic girdle weakness demonstrated in our patients has not been reported in the subgroup of neuropathy occurring in the younger patients. The earlier onset eases also have a greater tendency toward pes cavus, slower nerve conduction velocities and pathologic changes in the nerve more indicative of a demyelinating neuropathy, although issues of primary versus secondary demyelination still need to be addressed. Any discussion of the scapuloperoneal neuropathies will again raise the issue as to whether such cases are in fact an overlapping phenotypic manifestation of the more common types of hereditary motor and sensory neuropathies. Harding and Thomas (1980a) presented one family with such overlapping features in an otherwise typical hereditary motor and sensory neuropathy type I. While such phenotypic heterogeneity may occur in some families, it should be noted that the case illustrated by Harding and Thomas was not characteristic of the scapuloperoneal neuropathy since the predominant upper extremity weakness in their case affected deltoid and spinati and not the scapular stabilizer muscles. Furthermore, it seems unlikely that phenotypic hetero-
101
geneity in hereditary motor sensory neuropathies could account for the majority of reported cases of scapuloperoneal neuropathy especially since large series of patients reported by Ricker and Mertens (1968), Dyck and Lambert (1968a, b) and Harding and Thomas (1980b) failed to show any overlap. On the basis of these observations, we join others (Schwartz and Swash 1975; Nakahara et al. 1986) supporting the view that a peripheral neuropathy can cause the scapuloperoneal syndrome. To avoid confusion we propose that the term "scapuloperoneal neuropathy" be used when referring to these patients. This term is more descriptive and more accurate in reflecting the site of pathology and differentiates the condition from the muscle and anterior horn cell varieties of scapuloperoneal syndrome. We also tentatively suggest that at least two varieties of scapuloperoneal neuropathy exist (Table 2). In this regard it is attractive to consider analogies between the two forms of scapuloperoneal neuropathy distinguished here (one with slowed NCV and the other with normal or mildly reduced NCV) and the hereditary motor and sensory neuropathies, type I (peripheral nerve form of Charcot-Marie-Tooth disease) and type II (neuronal form of Charcot-Marie-Tooth disease). More detailed case examples will need to be reported before such a classification can be justified. The purpose of this report is to provide a framework for comparison in the reporting of subsequent cases of scapuloperoneal neuropathies.
REFERENCES Bethlem, J. (1979) The scapuloperoneal syndrome. In: Serratrice, G. and H. Roux (Eds.), PeronealAtrophies and Related Disorders. Masson Publishing Inc., New York, pp. 225-23 I. Brossard, J. (1886) ~tude clinique sur une forme h ~ l i t a i r e d'atrophie musculaire progressive d~butant par les membres inf~rieurs (type f~maoralavec gritfe des orteils). Steinheil, Paris. Carroll, J. E. (1979) Facioscapulohumeral and scapuloperoneal syndromes. In: P.J. Vinken and G. W. Bruyn (Eds.), Handbook ofClinicalNeurology, VoL 40, North Holland PublishingCo., Amsterdam, New York, Oxford, pp. 415-431. Davidenkow, S. (1939) Scapuloperoneal amyotrophy. Arch. Neurol. Psychiat. (Chic.), 41: 694-701. Dyck, P.J. and E.H. Lambert (1968a) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathy. Arch. NeuroL (Chic.), 18: 603-618. Dyck, P.J. and E.H. Lambert (1968b) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic and electrophysiologic findings in various neuronal degenerations. Arch. Neurol. (Chic.), 18: 619-625. Dyck, P.J., P.C. O'Brien and A. Ohnishi (1977) Lead neuropathy. 2. Random distribution of segmental demyelination among "old internodes" of myelinated fibers. J. Neuropatbol. Exp. Neurol., 36: 570-575. Dyck, P.J., A.C. Lais, J.L. Karnes etal. (1981) Permanent axotomy, a model of axonal atrophy and secondary segmental demyelination and remyelination. Ann. Neurol., 9: 575-583. Dyck, P.J., J. Karnes, A. Lais et al. (1984) Pathologic alterations of the peripheral nervous system of humans. In: Dyck, P.J., P. K. Thomas, E.H. Lambert and R. Bunge (Eds.), PeripheralNeuropathy, 2nd edn., W.B. Saunders Co., Philadelphia, PA, pp. 760-870. Emery, E.S., G.M. Fenichei and G. Eng (1968) A spinal muscular atrophy with scapuloperoneal distribution. Arch. Neurol. (Chic.), 18: 129-133. Feigenbaum, J.A. and T.L. Munsat (1970) A neuromuscular syndrome of scapuloperoneal distribution. Bull. Los Angeles Neurol. Soc., 35: 47-57. Harding, A.E. 0984) Neuronal atrophy and degeneration of lower motor neurons. In: Dyck, P.J., P.K. Thomas, E.H. Lambert and R. Bunge (Eds.), Peripheral Neuropathy, 2nd edn. W.B. Sannders Co., Philadelphia, PA, pp. 1537-1556.
102 Harding, A.E. and P.K. Thomas (1980a) Distal and scapuioperoneal distributions of muscle involvement occurring within a family with type I hereditary motor and sensory neuropathy. J. Neurol., 224:17-23. Harding, A. E. and P. K. Thomas (1980b) The clinical features of hereditary motor and sensory neuropathy (types I and II). Brain, 103: 259-280. Kaeser, H.E. (1965) Scapuloperoneal muscular atrophy. Brain, 88: 407-418. Kaeser, H.E. (1975) Scapulo-peroneal syndrome. In: P.J. Vinken and G.W. Bruyn (Ed.), Handbook of Clinical Neurology, Vol. 22. North-Holland Publishing Co., Amsterdam, New York, Oxford, pp. 57-65. Kazakov, V.M., D.K. Bogorodinski and A. Skorometz (1975) Myogenic scapuloperoneal syndromemuscular dystrophy in the K kindred. Eur. Neurol., 13: 350-359. Meadows, J.C. and C.D. Marsden (1969) Scapuloperoneal amytrophy Arch. Neurol. (Chic.), 20: 9-12. Mercelis, R., J. Demeester and J.J. Martin (1980) Neurogenic scapuloperoneal syndrome in childhood. J. Neurol. Neurosurg. Psychiat., 43: 888-896. Nakahara, K., S. Higa, T. Nishihira, T. Toyonaga, M. Kawahira, M. Suehara, H. Yosidome, K. Arimura, S. Izumo and M. Osame (1986) A new type of hereditary motor sensory neuropathy on Okinawa Island. Clinical and Pathological study. Muscle Nerve, 9:126 (abstract). Nukada, H., P.J. Dyck and J.L. Karnes (1983) Thin axons relative to myelin spiral length in hereditary motor and sensory neuropathy, type 1. Ann. Neurol., 14: 648-655. O'Brien, P.C. (1976) A test for randomness. Biometrics, 32: 391-401. Oransky, W. (1927) [3ber einen hereditttren Typus progressiver Muskeldystrophie. Dtsch. Z. Nervenheilk., 99: 147-155. Ramirez, J.A., J.R. Mendell, J.R. Warmolts and R.C. Griggs (1986) Phenytoin neuropathy: structural changes in the sural nerve. Ann. Neurol., 19: 162-167. Ricker, K. and H-G. Mertens (1968)The differential diagnosis of the myogenic-(facio)-scapulo-peroneal syndrome. Eur. Neurol., 1: 275-307. Ricker, K., H.G. Mertens and K. Schimrigk (1968) The neuroganic scapulo-peroneal syndrome. Eur. Neurol.. 1: 257-274. Ronen, G. M., N. Lowry, J. H. Wedge, H. B. Sarnat and A. Hill (1986) Hereditary motor sensory neuropathy type I presenting as scapuloperoneal atrophy (Davidenkow syndrome) electrophysiological and pathological studies. Can. J. Neurol. Sci., 13: 264-266. Schwartz, M. S. and M. Swash (1975) Scapuloperoneal atrophy with sensory involvement: Davidenkow's syndrome. J. Neurol. Neurosurg. Psychiat., 38: 1063-1067. Serratrice, G., J.F. Pellissier, G. Cremieux et at. (1979) Scapuloperoneal myopathies, myelopathies, and neuropathies. In: Serratrice, G. and H. Roux (Eds.), PeronealAtrophies and Related Disorders, Masson Publishing Inc., New York, pp. 233-252. Thomas, P.K., G.D. Schott and J.A. Morgan-Hughes (1975) Adult onset scapuloperoneal myopathy. J. NeuroL Neurosurg. Psychiat., 38: 1008-1015. Tsukagoshi, H., T. Takasu, M. Yoshida et al. (1969) A family with scapuloperoneal muscular atrophy. Clin, Neurol. (Tokyo), 9: 511-517. Wohlfart, S. (1926) Progressive amyotrophia of Charcot-Marie type. Acta Med. Scand., 63: 195-219.
91
JNS 03049
Scapuloperoneal neuropathy" a distinct clinicopathologic entity Craig L. Hyser, John T. Kissel, John R. Warmolts and Jerry R. Mendell Department of Neurology, Ohio State University Hospital, Columbus, OH 43210 (U.S.A.) (Received 1 March, 1988) (Revised, received 31 May, 1988) (Accepted 31 May, 1988)
SUMMARY
Peripheral neuropathy as a cause for the scapuloperoneal syndrome continues to be controversial. This report provides further evidence in support of a scapuloperoneal neuropathy as a separate nosologic entity. Three men had a slowly progressive disorder of 5-17 years duration with prominent weakness and atrophy of scapular stabilizer, shoulder girdle and distal lower extremity muscles accompanied by a distal panmodality sensory loss. Electrodiagnostic studies and sural nerve biopsies indicated a primary axonal neuropathy with secondary demyelination and remyelination.
Keywords: Peripheralneuropathy; Scapuloperonealneuropathy; Clinicopathological entity
INTRODUCTION
Brossard was the first to describe a syndrome of weakness affecting the shoulder girdle and distal lower extremity muscles (Brossard 1886). Since then numerous case studies and literature reviews have attempted to clarify this heterogeneous group of disorders (Kaeser 1975; Bethlem 1979; Carroll 1979; Serratrice et al. 1979; Harding 1984). Despite a lack of sufficient detail in some reports, there appears to be enough information to support the point of view that scapuloperoneal syndromes can result Correspondence to: Dr. J.R. Mendell, Department of Neurology, Ohio State University Hospital, 1655 Upham Drive, Columbus, OH 43210, U.S.A.
92 from disorders of skeletal muscle (Oransky 1927; Ricker and Mertens 1968; Feigenbaum and Munsat 1970; Kazakov et al. 1975; Thomas et al. 1975), spinal motor neurons (Kaeser 1965; Emery et al. 1968; Meadows and Marsden 1969; Tsukagoshi et al. 1969; Mercelis et al. 1980) and peripheral nerve (Davidenkow 1939; Schwartz and Swash 1975; Nakahara et al. 1986; Ronen et al. 1986). The specific objective of this report is to expand on only the scapuloperoneal syndrome caused by a peripheral neuropathy, a condition sometimes referred to as Davidenkow's syndrome (Schwartz and Swash 1975; Ronen et al. 1986). In 1939, Davidenkow (1939) published his experience in 4 families and 1 sporadic case and collated the existing literature in order to describe an entity with overlapping but also distinctive features from the "amyotrophy of Charcot and Marie" and the "myopathy of Landouzy and Dejerine". The salient characteristics of the condition were autosomal dominant inheritance, onset usually at age 17-20 (but sometimes as late as 45), atrophy of the shoulder girdle, pectoral, trapezius, rhomboids, and serratus anterior muscles, distal lower extremity muscle involvement, a tendency toward pes cavus and a distal sensory loss. While this summary seems clear enough, confusion continues to arise over the existence of a separate form of scapuloperoneal syndrome caused by a peripheral neuropathy. Experience in 3 sporadic cases rekindled our interest in this rarely reported entity. We believe that the criteria outlined by Davidenkow (1939) were accurate in describing a form of scapuloperoneal syndrome caused by a peripheral neuropathy, and propose the term scapuloperonealneuropathybe used in preference to Davidenkow's syndrome when referring to this condition.
CASE REPORTS Case I
This 66-year-old white male dated the onset of his symptoms to 1965 when, at age 49, he noticed numbness of his feet and distal lower extremity weakness. These symptoms progressed over the next 17 years and he developed bilateral foot drop. Family history revealed his father and a paternal aunt (both deceased) had developed difficulty with ambulation in the sixth decade. Examination revealed normal cranial nerves. There was marked weakness and atrophy (Fig. 1) of the scapular stabilizer muscles as well as pelvic girdle and anterior compartment leg muscles. Sensory examination revealed distal impairment to pin, touch and temperature to the knees. Vibration sensation was reduced to the ankle and position sense was decreased in the toes. All tendon reflexes were absent and there was mild pes cavus. Case 2
This white male had a history of muscle cramps since his twenties. At the age of 67, 4 years prior to evaluation, he noted difficulty walking because of lower extremity weakness. One year later he noted numbness and tingling distally in the lower extremities. Within 2 years he developed the same sensory disturbance in his hands. Over the year prior to evaluation the lower extremity strength worsened and he began having difficulty using his arms. Sensory loss progressed to the knees and elbows bilaterally. Although there was a remote history of alcoholism, the patient had stopped drinkin8 at age 47. There was no other significant medical history and the family history was negative. Examination at age 71 revealed normal cranial nerves. There was weakness and wasting of the shoulder girdle muscles, particularly the scapular stabilizers. In the lower extremities there was prominent weakness of the anterior compartment muscles below the knee as well as the pelvic girdle. Pin, cold and touch sensations were impaired to the level of the elbows and knees. Vibration was impaired to the wrists
93
Fig. 1. Photograph of case 1 showing atrophy of scapular stabilizer muscles with resulting scapular winging. and knees and position sense was decreased in the toes. The tendon reflexes were hypoactive in the upper extremities, normal at the knees, and absent at the ankles. The patient had a mild thoracic levoscoliosis. Case 3
This 57-year-old white male presented with a 5-year history of progressive weakness involving the lower more than the upper extremities and numbness which first involved the distal fight lower extremity but later involved both legs to the knees and both arms to the elbows. The past medical history was unremarkable and there was no family history of neuromuscular problems. Examination revealed normal cranial nerve function. There was weakness and atrophy of the proximal upper extremity muscles most prominent in the trapezius, infraspinatus and rhomboids. In the lower extremities, there was weakness of the pelvic girdle and anterior compartment leg muscles. There was distal impairment to pin, touch and cold sensation to the level of the wrists and knees. Position sense was impaired in the fingers and toes. Vibration was reduced in the toes. The tendon reflexes were absent.
LABORATORY FINDINGS T h e following l a b o r a t o r y findings were n o r m a l in each case: c o m p l e t e b l o o d c o u n t , s e r u m electrolytes, s e r u m glucose, creatine kinase, b l o o d u r e a nitrogen, creatinine, liver f u n c t i o n studies, t h y r o i d f u n c t i o n studies, s e r u m B12, s e r u m folate, s e r u m p r o t e i n electrophoresis, erythrocyte s e d i m e n t a t i o n rate, r h e u m a t o i d factor, antin u c l e a r a n t i b o d y , s e r u m c o m p l e m e n t s , s e r u m a n d u r i n e i m m u n o e l e c t r o p h o r e s i s , urine screen for h e a v y m e t a l s a n d p o r p h y r i n s .
94 MATERIALS AND METHODS
Sural nerve biopsies were performed 18-20 cm above the base of the heel. A 3.5-cm segment of nerve was removed and placed in 3~o glutaraldehyde in 0.1 M phosphate buffer and processed for resin sections, electron microscopy and nerve fiber teasing as previously described (Ramirez et al. 1986). Random blocks of nerve cut in cross-section were selected for morphometric analysis. One #m thick sections were stained with toluidine blue and projected at a magnification of x 1500 to perform a size-frequency histogram. The area of the nerve was determined using a Zeiss Videoplan Morphometry Unit. Morphometric measurements were also performed on electron micrographs of thin transverse sections stained with uranyl acetate and lead citrate. Measurements were made of 50 different sequentially encountered myelinated nerve fibers for each case, The perimeters of the inner and outermost major dense lines of myelin were determined and the axon area measured with the Zeiss Videoplan Morphometry Unit. The number of major dense lines of myelin was counted through a binocular dissecting microscope. Myelin membrane length (MML) for each fiber was determined using the formula
where Po and Pi are the perimeters of the outer and inner major dense lines, respectively, and n is the total number of myelin turns. Regression lines relating the natural logarithms of the axon area to M M L were constructed and analyzed over various intervals of MML according to the method of Nukada et al. (1983). The assessment of randomness of occurrence of segmental demyelination and remyelination was determined on 150 teased nerve fibers (50 per case) as previously described (O'Brien 1976; Dyck et al. 1977). The presence or absence of segmental demyelination and remyelination was plotted and counted according to the sequence encountered. Only internodes with a myelin thickness less than 50~o of the adjacent internodal myelin were included. In addition, only one score was given for each territory of an "old" intemode irrespective of partial or total demyelination or both demyelination and remyelination. Statistical analysis of randomness versus clustering of demyelinated and remyelinated internodes was determined by conceptually placing individual teased nerve fibers end-to-end (O'Brien 1976; Dyck etal. 1977). The sample standard deviation was chosen to measure departure from random distribution (Dyck et al. 1977, 1981). Fifty nerve fibers from each case were teased and classified according to a modification of the Dyck classification (Dyck et al. 1984; Ramirez et al. 1986): A = normal; B = myelin wrinkling and redundant loops of myelin; C = demyelination (paranodal and segmental); D = remyelination in which myelin thickness is less than 50% of the adjacent internodal myelin; E = demydination and remyelination; F = wallerian degeneration.
95 Control sural nerve biopsies were available from 2 normal men, ages 25 and 42, giving informed consent under the guidelines of the Institutional Human Studies Committee. Sensory nerve conduction velocities were calculated by dividing the distance (digit to wrist, or calf to malleolus) between cathode and active surface electrode by the latency to the first positive peak of the electronically averaged sensory nerve action potential. Distal limb temperature was maintained at 33-35 °C by an external heat source. Motor nerve conduction velocities (elbow-wrist and fibular head-ankle) were determined in the conventional manner using surface stimulating and recording electrodes, with latencies measured by an electronic cursor placed on a trace on a storage oscilloscope. Needle electromyography was conducted with monopolar recording electrodes.
RESULTS Electrodiagnostic studies In each case, the major finding on electromyographic examination was a reduction in motor unit recruitment relative to effort. This was apparent in both proximal and distal muscles of the upper and lower extremities particularly in the scapuloperoneal distribution. Fibrillation potentials, positive sharp waves, and pathologically enlarged motor unit potentials were infrequently encountered but when present were found in both proximal and distal muscles. Motor and sensory nerve conduction velocities were either normal or mildly slowed when a response could be evoked, as summarized in Table 1. Sural nerve biopsies Nerve changes were consistent between patients although there was variability in severity which correlated with the duration of disease. In each case there was a loss of myelinated nerve fibers, particularly the larger sizes (Fig. 2). In 1-/~m thick resin sections prominent changes included the presence of thinly myelinated axons and clusters of regenerating axons surrounded by multiple Schwann cell processes (Fig. 3). Myelin ovoids typical of wallerian degeneration were occasionally seen. Teased nerve fibers included a spectrum of abnormalities. Myelin wrinkling (condition B, case 1 = 18~ ; case2=26~; c a s e 3 = 13~o) and remyelinating segments (condition D, case 1 = 1 4 ~ ; case 2 = 10~o; case 3 -- 12~) were the most common changes. Demyelination was most prominent in case 3 (condition C, case 1 = 3 ~o ; case 2 = 1 ~ ; case3 = 10~; condition E, case 1 = 1~o; case2 = 1 ~ ; case3 = 10~o). Wallerian degeneration was rare (condition F, 1 ~o for cases 1 and 2). A plot of the regression lines of axonal area in relation to M M L showed a diminution of axonal area for the larger myelinated fibers (Fig. 4). This is consistent with axonal shrinkage for the large myelinated fiber population. The occurrence of demyelinated and remyelinated segments on 50 single teased nerve fibers for each case (totalling 1091 internodes), handled as if placed end to end,
57.5 + 4.8
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Sensory NCV (m/sec)
Motor NCV (m/sec)
Case
SNAP = sensory nerve action potential; NCV = nerve conduction velocity; N R = no response.
NERVE C O N D U C T I O N VELOCITY D A T A
TABLE 1
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Fig. 2. Fiber size-frequency distribution histograms for the sural nerve biopsies from cases I(A), 2(B), and 3(C) compared to a normal control (D) demonstrating a loss of myvlinated fibers in all cases, particularly affecting the intermediate and larger size fibers.
Fig. 3. One #m resin-embedded sections from cases 1 (A) and 3 (B) showing myelinated nerve fiber loss and Schwann cell proliferation in relation to thinly myelinated axons and clusters of regenerating axons (toluidine blue stain, x 1500).
99 4.0• CASE 3
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Myelin Membrone Length (In juml Fig. 4. Regression lines relating axon area to myelin membrane length (MML) for 2 control nerves and nerves from the 3 scapuloperonealeases (dashed line). For a given MML, there is a significant diminution of axonal area compared to controls for the larger myelinatedfiber populations. The P values are given for each case compared to the controls over the intervals shown (NS = not significant). strongly favored a clustered or non-random distribution (O'Brien 1976; Dyck et al. 1977) at P < 0.001. The statistical significance was unchanged if the cases were analyzed separately or collectively.
DISCUSSION The 3 patients reported here all had a peripheral neuropathy as a cause for their scapuloperoneal syndrome. Electrodiagnostic studies showed decreased motor unit recruitment, pathologically enlarged motor units, and normal or mildly slowed conduction velocities. The sural nerve biopsies, studied in far greater detail than in prior reports were consistent with an axonopathy with secondary demyelination related to axonal atrophy. Morphometric studies confmned the presence of a non-random distribution of segmental demyelination and remyelination associated with a reduction of axonal area for a given M M L . The data for M M L from our 3 patients was indicative of axonal atrophy if plotted against our limited number of controls or the more extensive data of Nukada et al. (1982) using 41 controls ages 20-51. The clinical picture of the patients presented here is similar to the narrative description of s o m e but not all of the cases presented in Davidenkow's (1939) report. In addition, although subsequent reports of this entity are relatively few, there have been some case studies of patients identical to ours. This is best illustrated by the sporadic
100 TABLE 2 SCAPULOPERONEALNEUROPATHIES Type I
Type II
Age of onset Inheritance Distribution of weakness
Before 20 years AD/sporadic Scapuloperoneal
Sensory loss Pes cavus Nerve pathology
Distal Greater tendency Prominent demyelination with onion bulbs
After 30 years AD/sporadic Scapuloperoneal and pelvic girdle involvement Distal Lesser tendency Axonal atrophy with secondarydemyelination
case of Schwartz and Swash (1975) and the 9 cases, 4 with autosomal dominant inheritance, reported by Nakahara et al. (1986). We believe these cases most likely represent a specific subgroup of scapuloperoneal neuropathy. Clinical features include sporadic occurrence or dominant inheritance, relatively late onset (usually over 30 years), distal sensory loss and muscle weakness in a scapuloperoneal distribution. In addition an important finding in these patients is weakness of pelvic girdle muscles. Nerve conduction studies are normal or mildly reduced and morphometric analysis of sural nerves is indicative of an axonopathy with secondary demyelination. The features of the subgroup of scapuloperoneal neuropathy described in this report, however, do not appear to encompass the entire clinical spectrum of patients with this entity. Review of the literature suggests that at least one other subgroup of scapuloperoneal neuropathy can be distinguished (Table 2) exemplified by the patients of Ronen et al. (1986), Serratrice et al. (1979) and some of Davidenkow's cases (1939). Description of these cases reveals a younger onset, usually before 20 years. Autosomal dominant or sporadic occurrence is the same in both subgroups as is the sensory loss and muscle weakness, with one notable exception. The pelvic girdle weakness demonstrated in our patients has not been reported in the subgroup of neuropathy occurring in the younger patients. The earlier onset eases also have a greater tendency toward pes cavus, slower nerve conduction velocities and pathologic changes in the nerve more indicative of a demyelinating neuropathy, although issues of primary versus secondary demyelination still need to be addressed. Any discussion of the scapuloperoneal neuropathies will again raise the issue as to whether such cases are in fact an overlapping phenotypic manifestation of the more common types of hereditary motor and sensory neuropathies. Harding and Thomas (1980a) presented one family with such overlapping features in an otherwise typical hereditary motor and sensory neuropathy type I. While such phenotypic heterogeneity may occur in some families, it should be noted that the case illustrated by Harding and Thomas was not characteristic of the scapuloperoneal neuropathy since the predominant upper extremity weakness in their case affected deltoid and spinati and not the scapular stabilizer muscles. Furthermore, it seems unlikely that phenotypic hetero-
101
geneity in hereditary motor sensory neuropathies could account for the majority of reported cases of scapuloperoneal neuropathy especially since large series of patients reported by Ricker and Mertens (1968), Dyck and Lambert (1968a, b) and Harding and Thomas (1980b) failed to show any overlap. On the basis of these observations, we join others (Schwartz and Swash 1975; Nakahara et al. 1986) supporting the view that a peripheral neuropathy can cause the scapuloperoneal syndrome. To avoid confusion we propose that the term "scapuloperoneal neuropathy" be used when referring to these patients. This term is more descriptive and more accurate in reflecting the site of pathology and differentiates the condition from the muscle and anterior horn cell varieties of scapuloperoneal syndrome. We also tentatively suggest that at least two varieties of scapuloperoneal neuropathy exist (Table 2). In this regard it is attractive to consider analogies between the two forms of scapuloperoneal neuropathy distinguished here (one with slowed NCV and the other with normal or mildly reduced NCV) and the hereditary motor and sensory neuropathies, type I (peripheral nerve form of Charcot-Marie-Tooth disease) and type II (neuronal form of Charcot-Marie-Tooth disease). More detailed case examples will need to be reported before such a classification can be justified. The purpose of this report is to provide a framework for comparison in the reporting of subsequent cases of scapuloperoneal neuropathies.
REFERENCES Bethlem, J. (1979) The scapuloperoneal syndrome. In: Serratrice, G. and H. Roux (Eds.), PeronealAtrophies and Related Disorders. Masson Publishing Inc., New York, pp. 225-23 I. Brossard, J. (1886) ~tude clinique sur une forme h ~ l i t a i r e d'atrophie musculaire progressive d~butant par les membres inf~rieurs (type f~maoralavec gritfe des orteils). Steinheil, Paris. Carroll, J. E. (1979) Facioscapulohumeral and scapuloperoneal syndromes. In: P.J. Vinken and G. W. Bruyn (Eds.), Handbook ofClinicalNeurology, VoL 40, North Holland PublishingCo., Amsterdam, New York, Oxford, pp. 415-431. Davidenkow, S. (1939) Scapuloperoneal amyotrophy. Arch. Neurol. Psychiat. (Chic.), 41: 694-701. Dyck, P.J. and E.H. Lambert (1968a) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathy. Arch. NeuroL (Chic.), 18: 603-618. Dyck, P.J. and E.H. Lambert (1968b) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic and electrophysiologic findings in various neuronal degenerations. Arch. Neurol. (Chic.), 18: 619-625. Dyck, P.J., P.C. O'Brien and A. Ohnishi (1977) Lead neuropathy. 2. Random distribution of segmental demyelination among "old internodes" of myelinated fibers. J. Neuropatbol. Exp. Neurol., 36: 570-575. Dyck, P.J., A.C. Lais, J.L. Karnes etal. (1981) Permanent axotomy, a model of axonal atrophy and secondary segmental demyelination and remyelination. Ann. Neurol., 9: 575-583. Dyck, P.J., J. Karnes, A. Lais et al. (1984) Pathologic alterations of the peripheral nervous system of humans. In: Dyck, P.J., P. K. Thomas, E.H. Lambert and R. Bunge (Eds.), PeripheralNeuropathy, 2nd edn., W.B. Saunders Co., Philadelphia, PA, pp. 760-870. Emery, E.S., G.M. Fenichei and G. Eng (1968) A spinal muscular atrophy with scapuloperoneal distribution. Arch. Neurol. (Chic.), 18: 129-133. Feigenbaum, J.A. and T.L. Munsat (1970) A neuromuscular syndrome of scapuloperoneal distribution. Bull. Los Angeles Neurol. Soc., 35: 47-57. Harding, A.E. 0984) Neuronal atrophy and degeneration of lower motor neurons. In: Dyck, P.J., P.K. Thomas, E.H. Lambert and R. Bunge (Eds.), Peripheral Neuropathy, 2nd edn. W.B. Sannders Co., Philadelphia, PA, pp. 1537-1556.
102 Harding, A.E. and P.K. Thomas (1980a) Distal and scapuioperoneal distributions of muscle involvement occurring within a family with type I hereditary motor and sensory neuropathy. J. Neurol., 224:17-23. Harding, A. E. and P. K. Thomas (1980b) The clinical features of hereditary motor and sensory neuropathy (types I and II). Brain, 103: 259-280. Kaeser, H.E. (1965) Scapuloperoneal muscular atrophy. Brain, 88: 407-418. Kaeser, H.E. (1975) Scapulo-peroneal syndrome. In: P.J. Vinken and G.W. Bruyn (Ed.), Handbook of Clinical Neurology, Vol. 22. North-Holland Publishing Co., Amsterdam, New York, Oxford, pp. 57-65. Kazakov, V.M., D.K. Bogorodinski and A. Skorometz (1975) Myogenic scapuloperoneal syndromemuscular dystrophy in the K kindred. Eur. Neurol., 13: 350-359. Meadows, J.C. and C.D. Marsden (1969) Scapuloperoneal amytrophy Arch. Neurol. (Chic.), 20: 9-12. Mercelis, R., J. Demeester and J.J. Martin (1980) Neurogenic scapuloperoneal syndrome in childhood. J. Neurol. Neurosurg. Psychiat., 43: 888-896. Nakahara, K., S. Higa, T. Nishihira, T. Toyonaga, M. Kawahira, M. Suehara, H. Yosidome, K. Arimura, S. Izumo and M. Osame (1986) A new type of hereditary motor sensory neuropathy on Okinawa Island. Clinical and Pathological study. Muscle Nerve, 9:126 (abstract). Nukada, H., P.J. Dyck and J.L. Karnes (1983) Thin axons relative to myelin spiral length in hereditary motor and sensory neuropathy, type 1. Ann. Neurol., 14: 648-655. O'Brien, P.C. (1976) A test for randomness. Biometrics, 32: 391-401. Oransky, W. (1927) [3ber einen hereditttren Typus progressiver Muskeldystrophie. Dtsch. Z. Nervenheilk., 99: 147-155. Ramirez, J.A., J.R. Mendell, J.R. Warmolts and R.C. Griggs (1986) Phenytoin neuropathy: structural changes in the sural nerve. Ann. Neurol., 19: 162-167. Ricker, K. and H-G. Mertens (1968)The differential diagnosis of the myogenic-(facio)-scapulo-peroneal syndrome. Eur. Neurol., 1: 275-307. Ricker, K., H.G. Mertens and K. Schimrigk (1968) The neuroganic scapulo-peroneal syndrome. Eur. Neurol.. 1: 257-274. Ronen, G. M., N. Lowry, J. H. Wedge, H. B. Sarnat and A. Hill (1986) Hereditary motor sensory neuropathy type I presenting as scapuloperoneal atrophy (Davidenkow syndrome) electrophysiological and pathological studies. Can. J. Neurol. Sci., 13: 264-266. Schwartz, M. S. and M. Swash (1975) Scapuloperoneal atrophy with sensory involvement: Davidenkow's syndrome. J. Neurol. Neurosurg. Psychiat., 38: 1063-1067. Serratrice, G., J.F. Pellissier, G. Cremieux et at. (1979) Scapuloperoneal myopathies, myelopathies, and neuropathies. In: Serratrice, G. and H. Roux (Eds.), PeronealAtrophies and Related Disorders, Masson Publishing Inc., New York, pp. 233-252. Thomas, P.K., G.D. Schott and J.A. Morgan-Hughes (1975) Adult onset scapuloperoneal myopathy. J. NeuroL Neurosurg. Psychiat., 38: 1008-1015. Tsukagoshi, H., T. Takasu, M. Yoshida et al. (1969) A family with scapuloperoneal muscular atrophy. Clin, Neurol. (Tokyo), 9: 511-517. Wohlfart, S. (1926) Progressive amyotrophia of Charcot-Marie type. Acta Med. Scand., 63: 195-219.